CA2146548A1 - Antineoplastic heteronaphthoquinones - Google Patents
Antineoplastic heteronaphthoquinonesInfo
- Publication number
- CA2146548A1 CA2146548A1 CA002146548A CA2146548A CA2146548A1 CA 2146548 A1 CA2146548 A1 CA 2146548A1 CA 002146548 A CA002146548 A CA 002146548A CA 2146548 A CA2146548 A CA 2146548A CA 2146548 A1 CA2146548 A1 CA 2146548A1
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- Prior art keywords
- bch
- dioxo
- pyran
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- hydrogen
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Tricyclic heteronaphthoquinone derivatives, that have antineoplastic activity, are disclosed, together with processes for their synthesis. Some of these anti-neoplastics compounds have a saccharide moiety. Some members of this structurally distinct group exhibit activity against multiple drug resistant cancer cells.
Description
~A~ 4~5~
ANTINEOPLASTIC HETERONAPHTHOQUINONES
This invention relates to heterocyclic naphthoquinone derivatives, to processes and to intermediates for preparing these derivatives, to pharmaceutical compositions containing them and to the use of these derivatives as antitumor agents in mammals.
BACKGROUND OF THE INVENTION
Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B., Sarosy, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxorubicin, Academic Press, New York, 1980).
o ox o (1) daunorubicin R = H
~' ~ ~ (2) doxorubicin R=OH
~, c~
~ ' The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S.K., Anthracyclines; Current Status and New Developments, Academic Press, N.Y. 1980) and cardiotoxicity (Olson, R.D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E.G. et al, Cancer Research, 49, 8-15, 1989); McGrath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
Several thousand anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known naturalanthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, N.Y. 1980; Thomson, R.H., Naturally Occurring Quinones lll: Recent Advances, Chapman and Hall, New York 1987; Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J.R. and Iman, S.H., Recent Studies on Doxorubicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J.R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med.
Chem ., 15, 125-164, 1978) . The majority of known anthracyclines show two typesof structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides at~ached at C-7 or C-10 (doxorubicin numbering). Some examples of the structural diversity of anthracycline antibiotics are:
O O~ C1 0~ o CO~ M~
~OX ~
11, Co o 0~! 0 OB O 1~0 r ~ ~ vJ~ C~
211~, UY-R, C~
O ~
~ ~ ~ n O o~
o o~ o ~
~ co~cx, .`- ~ ~I ~ c~
01~ o o~ n ~
~oic~
o 03~
cc~ a Fl~. t Tricyclic variants (;~) of daunorubicin have been reported to possess antitumor activity (EPA 91202015.3) 1~' c~N~
R is COCH3 or C_CH or C_C-Si(CH3)3 R3 is H or COCF3 Pyranonaphthoquinones such as nanaomycin A (4) and kalafungin (O occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein) .
~ ~o Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.C., Soong, P.1 and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently thiopyranoanthraquinone (7) and pyranoanthraquinone (8) were found to possess antitumor activity (PCT, CA9100208). In contrast antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycies 26 (4), 879-82, 1 987).
- o o 7 H~ 8 J ~sr` ~0 9 R, = H;R2 = H,CH3 ~æ
10 R1 = Sugar,R2 = H,CH3 1 1 DESCRIPTION OF THE INVENTION
The present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
More specifically, the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused to a hydroxyl group or alternatively to a sugar moiety. This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity. Some of the compounds are active against certain doxorubicin-resistant tumor cells, and are more potent in some cases than the corresponding tetracyclic heteroanthracycline compound.
In one aspect of the invention, there is provided a compound of the formula (1 2):
~~z (~A2146548 R X~ ~ ~X3 3 . ~
X2 I:i~ or X2 Rti wherein X1 and X2 are independently selected from: O or S;
X3 is O or S;
X4 iS selected from the group consisting of C-Q, nitrogen, and NO:
R" R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1 16 alkyl, C~ 16 alkoxy, halogen, nitro, cyano, and amino which may be unsubstituted or substituted with C1 8 alkyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1 16 hydroxime, C28 alkenyl, C28 alkynyl, amino, cyano, dimethylphosphonato, and C1 8 acetyl, a group of the formula -C(R)=R* wherein R* is O and R is selected from the groupconsisting of: hydrogen, C1 16 alkyl, C1 8 thioalkyl, C3 8 cycloalkyl, C6 18 aryl, C7 18 aralkyl, fluoromethyl, C2 16 alkene, C2 ,6 alkyne, C6 18 thioaryl, C2 8 alkoxyalkyl, C1 8 alkoxy, hydroxy, acetoxymethyl, bromomethyl, and amino which may be unsubstituted or substituted with C1 8 alkyl, and C1 8 acyl, a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1 8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, and C1 8 alkyl, a group of the formula -(CH2)nZ* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1 8 acyl, C6 18 aryl, C7 18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1 8 acyl, C1 4 alkyl and C6 12 aryl, said heterocycle being optionally substituted with one or more halogen, hydroxy, C6 18 aryl sulfone, nitro, and amino, a group of the formula -C(OR)=O, where R is selected from the group consisting of hydrogen, C1 16 alkyl, C6 18 aryl, and C7 18 aralkyl, a group of the formula -(CH2)n C(R) =0, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C, ,6 alkyl, C6 18 aryl, C7 ~8 aralkyl, amino which may be unsubstituted, mono- or di-substituted by C1 8 alkyl, acyl, a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, S0, S02, P, P0, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C14 alkyl, and aryl;
R7 is selected from the group consisting of: hydrogen, C1 16 alkyl, halogen, amino, hydroxy, C1 16 alkoxy, and an acyl of the formula -C(R) =0 wherein R is selected from the group consisting of: hydrogen, C1 16 alkyl, C, ,~ alkoxy, C3 8 cycloalkyl;
R8 is selected from the group consisting of: hydrogen, halogen, C1 16 alkyl; andR5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C~ 16 alkoxyl, C1 16 alkyl, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selec~ed from the group consisting of: 0, S, N, S0, S02, P, P0 and NR
wherein R is selected from the group consisting of: hydrogen, hydroxyl, C1 8 acyl, and C14 alkyl, said heterocycle being optionally substituted with one or more halogen, hydroxy, cyano, C, ,6 alkoxy, C, 16 alkyl, nitro, amino which may be unsubstituted or mono-or di-substituted by C1 8 alkyl, C1 8 acyl, trifluoroacyl, C2 8 alkenyl, C2 8 alkynyl, and hydroxy.
R5 can also be a naturally occurring amino acid or a synthetic amino acid, mono or oligosaccharides of the formula:
wherein Y is oxygen;
Rg and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1 16 alkoxy, C1-16 alkyl, C3 8 ~ CA2 cycloalkyl, thiol, amino, trifluoroacetamiso, chloroethylnitrosoureido, and chloroethylureido;
R11 is selected from the group consisting of hydrogen, acylated amino, hydroxy, halogen, acetoxy, C, 16 alkoxy, and amino which may be unsubstituted or mono or di-substituted by C, 8 alkyl, C2 8 acyl, t-butylacyl, C1 8 alkoxy, and trifluoroacyl,;
R.2 is selected from the group consisting of: hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, C1 8 alkoxy, amino,mono- or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, C1 16 alkoxy, C2 8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2CI wherein n is O to 4.
Preferred compounds of formula (12) are those wherein X1 and X2 are both 0;
X3 is selected from the group consisting of: O, or S;
X4 iS CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C14 alkoxyl, fluorine, chlorine, and amino;
Z is one of C-R6, or C-R7;
R6 is selected from the group consisting of: hydrogen, C14 alkyl, an acyl of theformula -C(R) =0, wherein R is selected from the group consisting of:
hydrogen, C1 8 alkyl, C2 8 alkoxyalkyl, C2 ,2 acyloxyalkyl, and amino which may be unsubstituted or mono-or di-substituted with C, 8 alkyl, C3 8 cycloalkyl, C, 8 acyl, C, 8 trifluroacyl, C7 ,2 aralkyl or C6 ,2 aryl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, and C1 8 alkyl, a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of: hydrogen, straight or branched C1 8 alkyl, and amino which may be unsubstituted or mono- or di-substituted with C, 8 alkyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, NO, and NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1.8 alkoxy, C, 8 alkyl, amino which may be unsubstituted or mono- or disubstituted by C14 alkyl, trifluoroacyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, C~ 4 alkyl, and C14 alkoxy;
R8 is selected from the group consisting of: hydrogen, halogen, hydroxy, C, 8 alkoxy;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxyl, C, 8 alkoxy, amino, mono or dimethylated amino, C, 8 alkoxy, and benzoate, and a mono or oligosaccharide selected from the group consisting of from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, and trifluoroacetyldaunosamine, and a saccharide of formula wherein Rg and R~o are independently selected from the group consisting of: hydrogen, fluorine, chlorine, and hydroxyl;
R" is selected from the group consisting of: hydroxyl, C, 8 alkoxy, and amino which may be unsubstituted or mono-or di-substituted with C1 8 acetoxy, or trifluoroacyl;
and R-2 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, halogen, amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkylnitrosourea, acetoxy, and trifluoroacetoxy.
More preferred compounds of formula (12) are those wherein X, and X2 are both 0;
X3 is selected 0;
X4 iS CQ;
R" R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxy, methoxy, amino, and fluorine;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1 4 alkyl, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, acyloxymethyl, and amino;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, methyl, and ethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O,S, N, NO, and NH said heterocycle being optionally substituted with one or more halogen, hydroxy, C14 alkoxy, C1 4 alkyl, amino which may be unsubstituted or mono- or disubstituted by methyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R) =0, wherein R is selected from the group consisting of: hydrogen, C1 5 alkyl, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of:
hydrogen, C15 alkyl;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, methoxy, cyano, acetate, acetyl, and a saccharide of formula ~0 whereln Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxyl, acetoxy, amino, trifluoroacetamido;
R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine.
A still further preferred compound of formula (12) are those wherein X1 and X2 are both oxygen; ~ A 2 1 4 6 5 4 8 X3 is 0;
X4 iS CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: methyl, ethyl, an acyl of the formula -C(R) =0, wherein R is selected from the group consisting of:
methyl, fluoromethyl, and difluoromethyl, 1 0 and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, NH, said heterocycle being optionally substituted with one or more hydroxy, methyl, and amino;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, and cyano;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, hydroxy, bromine, chlorine, cyano, acetate, acetyl, and a saccharide of the formula:
o ~,~
wherein Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: amino, hydroxy, and acetoxy;
and R12 is hydroxy, or iodine.
Still further preferred compounds of formula (12) are those wherein X1 and X2 are both oxygen.
X3 is 0, or S;
X4 iS CQ;
CA~ 4~48 R2 and R3 are both hydrogen;
R, and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, an acyl of the formula -C(R) =0, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is hydrogen;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, and hydroxy.
Still, preferred compounds of the invention are compounds of formula 12 wherein:X1 and X2 are both oxygen;
X3 is 0;
X4 iS CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, and an acyl of the formula -C(R)=0, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is selected from the group consisting of: hydrogen, methyl, or fluorine;
R8 is hydrogen, hydroxyl, acetate, and acetyl;
R5 is a saccharide of the formula:
i f~R~`
RR; R~o wherein Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R" is selected from the group consisting of: hydroxy, acetoxy, amino, and trifluoroacetamido;
~ ¢~ 46~
R.2 is selected from the group consisting of: acetoxy, hydroxyl, hydrogen, and iodine.
The invention also seeks to provide a process for the preparation of a compound of formula 1 2, R1 Xl <R~
R~X4~X, X2 Rs -and pharmaceutically acceptable acid addition salts thereof wherein R6 is methyl ketone or is as defined above; and R1, R2, R3, R5, R7, R8, X" X2, X3, X4 and Z are as defined above, selected from the group of processes consisting of 1 ) selecting a precursor isochroman compound of formula C8, 0 R t ~;~
~' Cl~, R, wherein R5, R6, R7 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula t --I~R
O R,
ANTINEOPLASTIC HETERONAPHTHOQUINONES
This invention relates to heterocyclic naphthoquinone derivatives, to processes and to intermediates for preparing these derivatives, to pharmaceutical compositions containing them and to the use of these derivatives as antitumor agents in mammals.
BACKGROUND OF THE INVENTION
Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B., Sarosy, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxorubicin, Academic Press, New York, 1980).
o ox o (1) daunorubicin R = H
~' ~ ~ (2) doxorubicin R=OH
~, c~
~ ' The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S.K., Anthracyclines; Current Status and New Developments, Academic Press, N.Y. 1980) and cardiotoxicity (Olson, R.D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E.G. et al, Cancer Research, 49, 8-15, 1989); McGrath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
Several thousand anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known naturalanthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, N.Y. 1980; Thomson, R.H., Naturally Occurring Quinones lll: Recent Advances, Chapman and Hall, New York 1987; Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J.R. and Iman, S.H., Recent Studies on Doxorubicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J.R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med.
Chem ., 15, 125-164, 1978) . The majority of known anthracyclines show two typesof structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides at~ached at C-7 or C-10 (doxorubicin numbering). Some examples of the structural diversity of anthracycline antibiotics are:
O O~ C1 0~ o CO~ M~
~OX ~
11, Co o 0~! 0 OB O 1~0 r ~ ~ vJ~ C~
211~, UY-R, C~
O ~
~ ~ ~ n O o~
o o~ o ~
~ co~cx, .`- ~ ~I ~ c~
01~ o o~ n ~
~oic~
o 03~
cc~ a Fl~. t Tricyclic variants (;~) of daunorubicin have been reported to possess antitumor activity (EPA 91202015.3) 1~' c~N~
R is COCH3 or C_CH or C_C-Si(CH3)3 R3 is H or COCF3 Pyranonaphthoquinones such as nanaomycin A (4) and kalafungin (O occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein) .
~ ~o Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.C., Soong, P.1 and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently thiopyranoanthraquinone (7) and pyranoanthraquinone (8) were found to possess antitumor activity (PCT, CA9100208). In contrast antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycies 26 (4), 879-82, 1 987).
- o o 7 H~ 8 J ~sr` ~0 9 R, = H;R2 = H,CH3 ~æ
10 R1 = Sugar,R2 = H,CH3 1 1 DESCRIPTION OF THE INVENTION
The present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
More specifically, the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused to a hydroxyl group or alternatively to a sugar moiety. This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity. Some of the compounds are active against certain doxorubicin-resistant tumor cells, and are more potent in some cases than the corresponding tetracyclic heteroanthracycline compound.
In one aspect of the invention, there is provided a compound of the formula (1 2):
~~z (~A2146548 R X~ ~ ~X3 3 . ~
X2 I:i~ or X2 Rti wherein X1 and X2 are independently selected from: O or S;
X3 is O or S;
X4 iS selected from the group consisting of C-Q, nitrogen, and NO:
R" R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1 16 alkyl, C~ 16 alkoxy, halogen, nitro, cyano, and amino which may be unsubstituted or substituted with C1 8 alkyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1 16 hydroxime, C28 alkenyl, C28 alkynyl, amino, cyano, dimethylphosphonato, and C1 8 acetyl, a group of the formula -C(R)=R* wherein R* is O and R is selected from the groupconsisting of: hydrogen, C1 16 alkyl, C1 8 thioalkyl, C3 8 cycloalkyl, C6 18 aryl, C7 18 aralkyl, fluoromethyl, C2 16 alkene, C2 ,6 alkyne, C6 18 thioaryl, C2 8 alkoxyalkyl, C1 8 alkoxy, hydroxy, acetoxymethyl, bromomethyl, and amino which may be unsubstituted or substituted with C1 8 alkyl, and C1 8 acyl, a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1 8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, and C1 8 alkyl, a group of the formula -(CH2)nZ* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1 8 acyl, C6 18 aryl, C7 18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1 8 acyl, C1 4 alkyl and C6 12 aryl, said heterocycle being optionally substituted with one or more halogen, hydroxy, C6 18 aryl sulfone, nitro, and amino, a group of the formula -C(OR)=O, where R is selected from the group consisting of hydrogen, C1 16 alkyl, C6 18 aryl, and C7 18 aralkyl, a group of the formula -(CH2)n C(R) =0, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C, ,6 alkyl, C6 18 aryl, C7 ~8 aralkyl, amino which may be unsubstituted, mono- or di-substituted by C1 8 alkyl, acyl, a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, S0, S02, P, P0, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C14 alkyl, and aryl;
R7 is selected from the group consisting of: hydrogen, C1 16 alkyl, halogen, amino, hydroxy, C1 16 alkoxy, and an acyl of the formula -C(R) =0 wherein R is selected from the group consisting of: hydrogen, C1 16 alkyl, C, ,~ alkoxy, C3 8 cycloalkyl;
R8 is selected from the group consisting of: hydrogen, halogen, C1 16 alkyl; andR5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C~ 16 alkoxyl, C1 16 alkyl, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selec~ed from the group consisting of: 0, S, N, S0, S02, P, P0 and NR
wherein R is selected from the group consisting of: hydrogen, hydroxyl, C1 8 acyl, and C14 alkyl, said heterocycle being optionally substituted with one or more halogen, hydroxy, cyano, C, ,6 alkoxy, C, 16 alkyl, nitro, amino which may be unsubstituted or mono-or di-substituted by C1 8 alkyl, C1 8 acyl, trifluoroacyl, C2 8 alkenyl, C2 8 alkynyl, and hydroxy.
R5 can also be a naturally occurring amino acid or a synthetic amino acid, mono or oligosaccharides of the formula:
wherein Y is oxygen;
Rg and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1 16 alkoxy, C1-16 alkyl, C3 8 ~ CA2 cycloalkyl, thiol, amino, trifluoroacetamiso, chloroethylnitrosoureido, and chloroethylureido;
R11 is selected from the group consisting of hydrogen, acylated amino, hydroxy, halogen, acetoxy, C, 16 alkoxy, and amino which may be unsubstituted or mono or di-substituted by C, 8 alkyl, C2 8 acyl, t-butylacyl, C1 8 alkoxy, and trifluoroacyl,;
R.2 is selected from the group consisting of: hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, C1 8 alkoxy, amino,mono- or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, C1 16 alkoxy, C2 8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2CI wherein n is O to 4.
Preferred compounds of formula (12) are those wherein X1 and X2 are both 0;
X3 is selected from the group consisting of: O, or S;
X4 iS CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C14 alkoxyl, fluorine, chlorine, and amino;
Z is one of C-R6, or C-R7;
R6 is selected from the group consisting of: hydrogen, C14 alkyl, an acyl of theformula -C(R) =0, wherein R is selected from the group consisting of:
hydrogen, C1 8 alkyl, C2 8 alkoxyalkyl, C2 ,2 acyloxyalkyl, and amino which may be unsubstituted or mono-or di-substituted with C, 8 alkyl, C3 8 cycloalkyl, C, 8 acyl, C, 8 trifluroacyl, C7 ,2 aralkyl or C6 ,2 aryl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, and C1 8 alkyl, a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of: hydrogen, straight or branched C1 8 alkyl, and amino which may be unsubstituted or mono- or di-substituted with C, 8 alkyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, NO, and NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1.8 alkoxy, C, 8 alkyl, amino which may be unsubstituted or mono- or disubstituted by C14 alkyl, trifluoroacyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, C~ 4 alkyl, and C14 alkoxy;
R8 is selected from the group consisting of: hydrogen, halogen, hydroxy, C, 8 alkoxy;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxyl, C, 8 alkoxy, amino, mono or dimethylated amino, C, 8 alkoxy, and benzoate, and a mono or oligosaccharide selected from the group consisting of from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, and trifluoroacetyldaunosamine, and a saccharide of formula wherein Rg and R~o are independently selected from the group consisting of: hydrogen, fluorine, chlorine, and hydroxyl;
R" is selected from the group consisting of: hydroxyl, C, 8 alkoxy, and amino which may be unsubstituted or mono-or di-substituted with C1 8 acetoxy, or trifluoroacyl;
and R-2 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, halogen, amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkylnitrosourea, acetoxy, and trifluoroacetoxy.
More preferred compounds of formula (12) are those wherein X, and X2 are both 0;
X3 is selected 0;
X4 iS CQ;
R" R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxy, methoxy, amino, and fluorine;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1 4 alkyl, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, acyloxymethyl, and amino;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, methyl, and ethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O,S, N, NO, and NH said heterocycle being optionally substituted with one or more halogen, hydroxy, C14 alkoxy, C1 4 alkyl, amino which may be unsubstituted or mono- or disubstituted by methyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R) =0, wherein R is selected from the group consisting of: hydrogen, C1 5 alkyl, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of:
hydrogen, C15 alkyl;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, methoxy, cyano, acetate, acetyl, and a saccharide of formula ~0 whereln Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxyl, acetoxy, amino, trifluoroacetamido;
R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine.
A still further preferred compound of formula (12) are those wherein X1 and X2 are both oxygen; ~ A 2 1 4 6 5 4 8 X3 is 0;
X4 iS CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: methyl, ethyl, an acyl of the formula -C(R) =0, wherein R is selected from the group consisting of:
methyl, fluoromethyl, and difluoromethyl, 1 0 and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of 0, S, N, NH, said heterocycle being optionally substituted with one or more hydroxy, methyl, and amino;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, and cyano;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, hydroxy, bromine, chlorine, cyano, acetate, acetyl, and a saccharide of the formula:
o ~,~
wherein Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: amino, hydroxy, and acetoxy;
and R12 is hydroxy, or iodine.
Still further preferred compounds of formula (12) are those wherein X1 and X2 are both oxygen.
X3 is 0, or S;
X4 iS CQ;
CA~ 4~48 R2 and R3 are both hydrogen;
R, and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, an acyl of the formula -C(R) =0, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is hydrogen;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, and hydroxy.
Still, preferred compounds of the invention are compounds of formula 12 wherein:X1 and X2 are both oxygen;
X3 is 0;
X4 iS CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, and an acyl of the formula -C(R)=0, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is selected from the group consisting of: hydrogen, methyl, or fluorine;
R8 is hydrogen, hydroxyl, acetate, and acetyl;
R5 is a saccharide of the formula:
i f~R~`
RR; R~o wherein Rg and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R" is selected from the group consisting of: hydroxy, acetoxy, amino, and trifluoroacetamido;
~ ¢~ 46~
R.2 is selected from the group consisting of: acetoxy, hydroxyl, hydrogen, and iodine.
The invention also seeks to provide a process for the preparation of a compound of formula 1 2, R1 Xl <R~
R~X4~X, X2 Rs -and pharmaceutically acceptable acid addition salts thereof wherein R6 is methyl ketone or is as defined above; and R1, R2, R3, R5, R7, R8, X" X2, X3, X4 and Z are as defined above, selected from the group of processes consisting of 1 ) selecting a precursor isochroman compound of formula C8, 0 R t ~;~
~' Cl~, R, wherein R5, R6, R7 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula t --I~R
O R,
2) and cyclo-adding said quinone with a diene of formula I~ A~ 5 ~:8 R
R ,~X ~
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR cr -5R, wherein R is selected from the group consisting of hydrogen, C, ,6 alkyl, C1 l6 acyl, C, l6 aryl, C3 l6 alkylsilane, C8 l6 alkylaryl silane and dimethylamino, wherein Rl, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula i~ ~7~, and
R ,~X ~
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR cr -5R, wherein R is selected from the group consisting of hydrogen, C, ,6 alkyl, C1 l6 acyl, C, l6 aryl, C3 l6 alkylsilane, C8 l6 alkylaryl silane and dimethylamino, wherein Rl, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula i~ ~7~, and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is -OH, to a saccharide of formula }~c~ r~
18a 18b wherein Rg, Rlo/ Rll and Rl2 are defined above and L is a leaving group;
to yield a tricyclic saccharide of formula ~. o RD - ~ A ~ 5 ~ 8 .~
o H3 C~,,~
~2 Il. a) coupling the isochroman (14) of reaction (1)(1), above, wherein R5 is H, with a saccharide of formula OH
}~,, C~?,3 1 0 ~ R~ o wherein Rg, R10, R1~ and R12 are as defined in claim 1 to yield a bicyclic saccharide of formulaCH~O
~7 `W~3 C.~O O
~I,C~
R~, 7- R- O
b) oxidatively demethylating the methoxy group from formula (21) to yield a bicyclic quinone saccharide of formula .~
o o H, C~, o c) and cycloadding said chemical (19) with said diene ~16) of reaction (1)(2) to yield the tricyclic saccharide ~
o c R ~ :R. C
lll. 1) coupling the quinone of formula 15, ~' ~ s of step (I) (1) wherein R5 is -OH, with a saccharide of the formula ,~ c~ ~
18a 18b of step (I) (2), to yield a bicyclic quinone sacharide of the formula .~
H, c~R, l C
2) and cycloadding said quinone saccharide with the said diene of formula C~21 46~48 Rl`x or R~
wherein A is NR wherein R is selected from the group consisting of H, C1 ,6 alkyl, C7 16 acyl; and L is defined as above;
to yield a tricyclic saccharide of formula o o H3 C~
Rl~ R
IV. a) selecting a precursor benzoate compound of formula ~"F~a and condensing it with a dihalomethyl dimethoxybenzene wherein said halogens are independently selected from the group consisting of Cl, Br and 1, and X3 iS selected from the group consisting of 0, S, and N;
CH, O ?, C~ o ~
to yield a dimethoxyisochroman of formula, ~A~ ~ 4~5~
C a~7 C~ o P,~
b) oxidatively dimethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman;
the resulting dioxoisochroman is cyclically coupled with the diene of formula R, 0 R,~, R~ X.
wherein A is NR wherein R is selected from the group consisting of H, C1 16 alkyl, C7 1ff aryl, and L is a leaving group as defined in (1)(2): to yield an anthracenedione of formula ~, o R~
the resultant compound may optionally be converted to the hydroxyl form of formula .~ ;
The quinones at position Xl and X2 may be converted to other moities such as, for example, OH, S, NR, where R is hydrocarbon, and others. Such conversions are carried out using known methodology by chemists skilled in the art.
For example, these conversions are taught in "The chemistry of the quinonoid compounds" V 1 and 2. John Wiiey and Sons, 1988, which is incorporated by reference .
The compound may further be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula ~, o 1 0 ~cx, ~' c~, o may be optionally coupled with a saccharide of formula OH
}:.,C~
1 ) to yield a dimethoxybicyclic saccharide of formula ~:~-, ~ -'X3 0 0 ~;C~R9 R~ 2- ~
2) oxidatively demethylating the methoxy groups to yield a dioxobicyclic isochroman of formula ~1 o o ~, R .~
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29 0 R, CH3 H~
to yield a thiotricyclic saccharide of formula ~CH3 ~C~R;
R Pi' :R S~
~A21 46548 Compounds of formula:
Rl X, Ra ~Z
X2 Rs are obtained by treating a compound of formula:
1 0 ~X
X~ ~
with a base in the presence of air at an appropriate synthetic stage.
The term "alkyl" as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, Cl, Br, I or CF3, one or more alkoxy sustituent, one or hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
The term "cycloalkyl" as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and cyclooctyl.
The term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphtyl, substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C14 alkyl, halogen, C~ 4 alkoxy, hydroxy or nitro.
The term "halogen" as used herein means chlorine, bromine, fluorine or iodine.
The term "aralkyl" as used herein refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.
The term "aroyl" as used herein refers to a group of the formula - COAr wherein Ar denotes an "aryl" group as defined above.
The term "alkoxy" or "aralkoxy" as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
The term "alkoxyalkyl" as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
The term "aryloxyalkyl" as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
The term "araloxyalkyl" as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl .
The term "acyloxyalkyl" as used herein means a C, 8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
The term "hdyroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl.It will be appreciated by those skilled in the art that when R* = R4 =
hydroxyl and X,=X2=O that compounds of formula (42) exist in equilibrium with tautomers of formula (9~). Therefore, compounds of formula (43) are included within the scope of the invention.
~ O R~ C~ R~
(X1 = X2 = 0,R, = OH,X4 = C-OH) This invention also includes all the possible isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at C1, C2 and C3 as well as in all the other chiral centers.
This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes ofpreparing compounds of formulas (42) and (43).
Heteronaphthoquinones of general formula (12) are prepared by using Scheme 1. With reference to Scheme 1, new or known isochromans of formula 14, where R5 is not a saccharide (PCT CA 9100208), are oxydatively demethylated withan oxidant such as ceric ammonium nitrate or silver oxide in an adequate solventmixture such as acetonitrile-water, to give key isochromandiones of formula 15.
Cycloaddition of this latter quinone with dienes of general formula 16 in a solvent such as toluene can give the tricyclic heteronaphthoquionone of formula 17. In the case when R5 is a saccharide, two independent synthetic routes (A2 or B) may be employed .
With respect to route A2, glycosides of formula 12 (R5 = Saccharide, X1 =
X2 =) are obtained by reacting appropriate aglycones of general structure 17, in which R5 is an hydroxy, with known sugar derivatives of formula 18 in which Rg to R*2 are as defined herein and L is a displaceable atom or group.
Suitable leaving groups, L, include halogen, for example iodine, bromine or chlorine, an unsubstituted or substituted benzoyl group such as p-nitrobenzoyl, and -OR or -SR, where R is an unsubstituted or substituted alkyl group, for example a C116 alkyl group such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as C116 acyl group such as acetyl, or R is an unsubstituted or substituted aryl group or R is a C3 to Cl0 trialkyl silyl such as trimethylsilyl or dimethyl-t-butylsilyl.
Such sugars are obtained by derivatizing known saccharides of the family of anthracycline antibiotics which are available from commercial or natural sources, (see for example, Konneret, C., Martini, A., Pais, M., Carbohydrate Research, 166, 59-70, 1987 and references therein; Acton, E.M., Tong, G.L., Mosher, C.W., and Wolgemuth, R.L., J. Med. Chem. 27, 638-645, 1984 and references therein;
Arcamone F., Cancer Research, 45, 5995-5999, 1985 and references therein).
The aglycone of formula 17, is typically reacted with the appropriate sugar derivative of formula 18 in a compatible solvent such as methylene chloride using a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-sulfonate. Alternatively, as it is known in the art of anthracycline chemistry, when the leaving group of the sugar moiety is a halogen, the Koenigs-Knorr glycosidation or its modification may be used.
Alternatively glycosidation of 17 can be effected with known sugar derivates of formula 1 8b under protic catalysis to yield 12 (R5 = Saccharide, X1 = X2 = )-In the event that the glycosidation of aglycone 17 is impractical then route Bor B2 can be used to prepare glycosides of formula 12 (R5 = saccharide, X1 = X2 =
O). With reference to route B" an isochromandione of formula 15, in which R5 = OH, is glycosidated as described above for 17. Cycloaddition of intermediate 19 withdienes of formula 16 in a compatible solvent such as toluene or tetrahydrofuran yield the desired pyranonaphthoquinone glycosides of formula 1 2 (R5 = saccharide, X1 =
X2 = 0). Alternatively, glycosidated isochromandiones Scheme 1 t'~ 15 17 a2 ~6 b Bl ~.2 2a o ~, , 1~ ISD-~ r~,~
1~ R" ~ :~, .
Zl 12~ Sbcc~idc,XI~ 03 2 1 4 6 S ~ 8 2 ~
l;)CH, R, ~CR, ;~ g _R 7 ~3 ~R, H"Co OCH~
~ ~ .
qCH~ ~, T
OC~, L
L ~C --F~c ~C ~Rf H r o 9CH, 7, ~R~
1CH, R-of formula 19 can be obtained via route B2 by reacting isochromans of formula 14 with a saccharide of formula 20 in the presence of DDQ in a compatible solvent such as dichloromethane, and subsequent treatment of the glycosidated isochroman 21 with ceric ammonium nitrate using standard procedures.
It will also be appreciated that the following reactions may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl or aryl (e.g. 2,4-dinitrophenyl), subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in 'Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981, 1991). Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions.
Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups.
In the above processes, the compounds of formula (42) and (43) are generally obtained as a mixture of diastereoisomers. These isomers may be separated by conventional chromatography or fractional crystallization techniques.
Where the compound of formula (42) or (43) is desired as a single isomer, it maybe obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate .
Resolution of the final product, or an intermediate or starting material therefor, may be effected by any suitable method known in the art: see for example, "Stereochemistry of Carbon Compounds", by E.L. Eliel (McGraw Hill, 1962) and "Tables of Resolving Agents", by S.H. Wilen.
The compounds of the formula (12) and 13) possess anti-cancer and anti-tumor activity. While it is possible to administer one or more of the compounds of theinvention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
In another aspect, the invention therefore provides pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents, comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in association with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients. All the pharmaceutically acceptable salts for example the HCI and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
It will be appreciated by those familiar with the art of clinical oncology that the compound(s) of this invention can be used in combination with other therapeutic agents, including chemotherapeutic agents (Cancer: Principles and Practices of Oncology, 3rd Edition, V.T. DeVito Jr., S. Hellman and S.A. Rosenberg; Antineoplastic Agents edited by W.A. Remers, John Wiley and Sons, N.Y., 1984). Thus, it will beunderstood that the compounds or pharmaceutical compositions of the invention may be formulated with the therapeutic agent to form a composition and administered to the patient or the compounds or compositions and the therapeutic agent may be administered separately, as appropriate for the medical condition being treated.Therefore, for therapeutic purposes, a compound or composition of this inventioncan be used in association with one or more of the therapeutic agents belonging to any of the following groups:
1 ) Alkylating agent such as:
2-haloalkylamines (e.g. melphalan and chlorambucil):
2-haloalkylsulfides;
N-alkyl-N-nitrosoureas (e.g. carmustine, lornustine or semustine);
aryltriazines (e.g. decarbazine);
mitomycins (e.g. mitomycin C);
methylhydrazines (e.g. procarbazine);
bifunctional alkylating agents (e.g. mechlorethamine);
carbinolamines (e.g. sibiromycin);
streptozotocins and chlorozotocins;
phosphoramide mustards (e.g. cyclophosphamide);
urethane and hydantoin mustards 2) Antimetabolites such as:
mercaptopurines (e.g. 6-thioguanine and 6-(methylthiolpurine);
azapyrimidines and pyrimidines;
hydroxyureas;
5-fluorouracil;
folic acid antagonists (e.g. amethopterin);
cytarabines;
prednisones;
diglycoaldehydes;
methotrexate;
3) Intercalators such as:
bleomycins and related glycoproteins;
anthracylines (e.g. doxorubicin, daunorubicin, epirubicin, esorubicin, idarubicin, aclacinomycin A);
acridines (e.g. m-AMSA);
hycanthones;
ellipticines (e.g. 9-hydroxyellipticine);
actinomycins (e.g. actinccin);
anthraquinones (e.g. 1,4-bis[(aminoalklyl)-amino]-9,10-anthracenediones);
anthracene derivatives (e.g. pseudourea and bisanthrene);
phleomycine;
aureolic acids (e.g. mithramycin and olivomycin);
Camptothecins (e.g. topotecan);
18a 18b wherein Rg, Rlo/ Rll and Rl2 are defined above and L is a leaving group;
to yield a tricyclic saccharide of formula ~. o RD - ~ A ~ 5 ~ 8 .~
o H3 C~,,~
~2 Il. a) coupling the isochroman (14) of reaction (1)(1), above, wherein R5 is H, with a saccharide of formula OH
}~,, C~?,3 1 0 ~ R~ o wherein Rg, R10, R1~ and R12 are as defined in claim 1 to yield a bicyclic saccharide of formulaCH~O
~7 `W~3 C.~O O
~I,C~
R~, 7- R- O
b) oxidatively demethylating the methoxy group from formula (21) to yield a bicyclic quinone saccharide of formula .~
o o H, C~, o c) and cycloadding said chemical (19) with said diene ~16) of reaction (1)(2) to yield the tricyclic saccharide ~
o c R ~ :R. C
lll. 1) coupling the quinone of formula 15, ~' ~ s of step (I) (1) wherein R5 is -OH, with a saccharide of the formula ,~ c~ ~
18a 18b of step (I) (2), to yield a bicyclic quinone sacharide of the formula .~
H, c~R, l C
2) and cycloadding said quinone saccharide with the said diene of formula C~21 46~48 Rl`x or R~
wherein A is NR wherein R is selected from the group consisting of H, C1 ,6 alkyl, C7 16 acyl; and L is defined as above;
to yield a tricyclic saccharide of formula o o H3 C~
Rl~ R
IV. a) selecting a precursor benzoate compound of formula ~"F~a and condensing it with a dihalomethyl dimethoxybenzene wherein said halogens are independently selected from the group consisting of Cl, Br and 1, and X3 iS selected from the group consisting of 0, S, and N;
CH, O ?, C~ o ~
to yield a dimethoxyisochroman of formula, ~A~ ~ 4~5~
C a~7 C~ o P,~
b) oxidatively dimethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman;
the resulting dioxoisochroman is cyclically coupled with the diene of formula R, 0 R,~, R~ X.
wherein A is NR wherein R is selected from the group consisting of H, C1 16 alkyl, C7 1ff aryl, and L is a leaving group as defined in (1)(2): to yield an anthracenedione of formula ~, o R~
the resultant compound may optionally be converted to the hydroxyl form of formula .~ ;
The quinones at position Xl and X2 may be converted to other moities such as, for example, OH, S, NR, where R is hydrocarbon, and others. Such conversions are carried out using known methodology by chemists skilled in the art.
For example, these conversions are taught in "The chemistry of the quinonoid compounds" V 1 and 2. John Wiiey and Sons, 1988, which is incorporated by reference .
The compound may further be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula ~, o 1 0 ~cx, ~' c~, o may be optionally coupled with a saccharide of formula OH
}:.,C~
1 ) to yield a dimethoxybicyclic saccharide of formula ~:~-, ~ -'X3 0 0 ~;C~R9 R~ 2- ~
2) oxidatively demethylating the methoxy groups to yield a dioxobicyclic isochroman of formula ~1 o o ~, R .~
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29 0 R, CH3 H~
to yield a thiotricyclic saccharide of formula ~CH3 ~C~R;
R Pi' :R S~
~A21 46548 Compounds of formula:
Rl X, Ra ~Z
X2 Rs are obtained by treating a compound of formula:
1 0 ~X
X~ ~
with a base in the presence of air at an appropriate synthetic stage.
The term "alkyl" as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, Cl, Br, I or CF3, one or more alkoxy sustituent, one or hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
The term "cycloalkyl" as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and cyclooctyl.
The term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphtyl, substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C14 alkyl, halogen, C~ 4 alkoxy, hydroxy or nitro.
The term "halogen" as used herein means chlorine, bromine, fluorine or iodine.
The term "aralkyl" as used herein refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.
The term "aroyl" as used herein refers to a group of the formula - COAr wherein Ar denotes an "aryl" group as defined above.
The term "alkoxy" or "aralkoxy" as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
The term "alkoxyalkyl" as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
The term "aryloxyalkyl" as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
The term "araloxyalkyl" as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl .
The term "acyloxyalkyl" as used herein means a C, 8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
The term "hdyroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl.It will be appreciated by those skilled in the art that when R* = R4 =
hydroxyl and X,=X2=O that compounds of formula (42) exist in equilibrium with tautomers of formula (9~). Therefore, compounds of formula (43) are included within the scope of the invention.
~ O R~ C~ R~
(X1 = X2 = 0,R, = OH,X4 = C-OH) This invention also includes all the possible isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at C1, C2 and C3 as well as in all the other chiral centers.
This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes ofpreparing compounds of formulas (42) and (43).
Heteronaphthoquinones of general formula (12) are prepared by using Scheme 1. With reference to Scheme 1, new or known isochromans of formula 14, where R5 is not a saccharide (PCT CA 9100208), are oxydatively demethylated withan oxidant such as ceric ammonium nitrate or silver oxide in an adequate solventmixture such as acetonitrile-water, to give key isochromandiones of formula 15.
Cycloaddition of this latter quinone with dienes of general formula 16 in a solvent such as toluene can give the tricyclic heteronaphthoquionone of formula 17. In the case when R5 is a saccharide, two independent synthetic routes (A2 or B) may be employed .
With respect to route A2, glycosides of formula 12 (R5 = Saccharide, X1 =
X2 =) are obtained by reacting appropriate aglycones of general structure 17, in which R5 is an hydroxy, with known sugar derivatives of formula 18 in which Rg to R*2 are as defined herein and L is a displaceable atom or group.
Suitable leaving groups, L, include halogen, for example iodine, bromine or chlorine, an unsubstituted or substituted benzoyl group such as p-nitrobenzoyl, and -OR or -SR, where R is an unsubstituted or substituted alkyl group, for example a C116 alkyl group such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as C116 acyl group such as acetyl, or R is an unsubstituted or substituted aryl group or R is a C3 to Cl0 trialkyl silyl such as trimethylsilyl or dimethyl-t-butylsilyl.
Such sugars are obtained by derivatizing known saccharides of the family of anthracycline antibiotics which are available from commercial or natural sources, (see for example, Konneret, C., Martini, A., Pais, M., Carbohydrate Research, 166, 59-70, 1987 and references therein; Acton, E.M., Tong, G.L., Mosher, C.W., and Wolgemuth, R.L., J. Med. Chem. 27, 638-645, 1984 and references therein;
Arcamone F., Cancer Research, 45, 5995-5999, 1985 and references therein).
The aglycone of formula 17, is typically reacted with the appropriate sugar derivative of formula 18 in a compatible solvent such as methylene chloride using a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-sulfonate. Alternatively, as it is known in the art of anthracycline chemistry, when the leaving group of the sugar moiety is a halogen, the Koenigs-Knorr glycosidation or its modification may be used.
Alternatively glycosidation of 17 can be effected with known sugar derivates of formula 1 8b under protic catalysis to yield 12 (R5 = Saccharide, X1 = X2 = )-In the event that the glycosidation of aglycone 17 is impractical then route Bor B2 can be used to prepare glycosides of formula 12 (R5 = saccharide, X1 = X2 =
O). With reference to route B" an isochromandione of formula 15, in which R5 = OH, is glycosidated as described above for 17. Cycloaddition of intermediate 19 withdienes of formula 16 in a compatible solvent such as toluene or tetrahydrofuran yield the desired pyranonaphthoquinone glycosides of formula 1 2 (R5 = saccharide, X1 =
X2 = 0). Alternatively, glycosidated isochromandiones Scheme 1 t'~ 15 17 a2 ~6 b Bl ~.2 2a o ~, , 1~ ISD-~ r~,~
1~ R" ~ :~, .
Zl 12~ Sbcc~idc,XI~ 03 2 1 4 6 S ~ 8 2 ~
l;)CH, R, ~CR, ;~ g _R 7 ~3 ~R, H"Co OCH~
~ ~ .
qCH~ ~, T
OC~, L
L ~C --F~c ~C ~Rf H r o 9CH, 7, ~R~
1CH, R-of formula 19 can be obtained via route B2 by reacting isochromans of formula 14 with a saccharide of formula 20 in the presence of DDQ in a compatible solvent such as dichloromethane, and subsequent treatment of the glycosidated isochroman 21 with ceric ammonium nitrate using standard procedures.
It will also be appreciated that the following reactions may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl or aryl (e.g. 2,4-dinitrophenyl), subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in 'Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981, 1991). Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions.
Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups.
In the above processes, the compounds of formula (42) and (43) are generally obtained as a mixture of diastereoisomers. These isomers may be separated by conventional chromatography or fractional crystallization techniques.
Where the compound of formula (42) or (43) is desired as a single isomer, it maybe obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate .
Resolution of the final product, or an intermediate or starting material therefor, may be effected by any suitable method known in the art: see for example, "Stereochemistry of Carbon Compounds", by E.L. Eliel (McGraw Hill, 1962) and "Tables of Resolving Agents", by S.H. Wilen.
The compounds of the formula (12) and 13) possess anti-cancer and anti-tumor activity. While it is possible to administer one or more of the compounds of theinvention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
In another aspect, the invention therefore provides pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents, comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in association with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients. All the pharmaceutically acceptable salts for example the HCI and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
It will be appreciated by those familiar with the art of clinical oncology that the compound(s) of this invention can be used in combination with other therapeutic agents, including chemotherapeutic agents (Cancer: Principles and Practices of Oncology, 3rd Edition, V.T. DeVito Jr., S. Hellman and S.A. Rosenberg; Antineoplastic Agents edited by W.A. Remers, John Wiley and Sons, N.Y., 1984). Thus, it will beunderstood that the compounds or pharmaceutical compositions of the invention may be formulated with the therapeutic agent to form a composition and administered to the patient or the compounds or compositions and the therapeutic agent may be administered separately, as appropriate for the medical condition being treated.Therefore, for therapeutic purposes, a compound or composition of this inventioncan be used in association with one or more of the therapeutic agents belonging to any of the following groups:
1 ) Alkylating agent such as:
2-haloalkylamines (e.g. melphalan and chlorambucil):
2-haloalkylsulfides;
N-alkyl-N-nitrosoureas (e.g. carmustine, lornustine or semustine);
aryltriazines (e.g. decarbazine);
mitomycins (e.g. mitomycin C);
methylhydrazines (e.g. procarbazine);
bifunctional alkylating agents (e.g. mechlorethamine);
carbinolamines (e.g. sibiromycin);
streptozotocins and chlorozotocins;
phosphoramide mustards (e.g. cyclophosphamide);
urethane and hydantoin mustards 2) Antimetabolites such as:
mercaptopurines (e.g. 6-thioguanine and 6-(methylthiolpurine);
azapyrimidines and pyrimidines;
hydroxyureas;
5-fluorouracil;
folic acid antagonists (e.g. amethopterin);
cytarabines;
prednisones;
diglycoaldehydes;
methotrexate;
3) Intercalators such as:
bleomycins and related glycoproteins;
anthracylines (e.g. doxorubicin, daunorubicin, epirubicin, esorubicin, idarubicin, aclacinomycin A);
acridines (e.g. m-AMSA);
hycanthones;
ellipticines (e.g. 9-hydroxyellipticine);
actinomycins (e.g. actinccin);
anthraquinones (e.g. 1,4-bis[(aminoalklyl)-amino]-9,10-anthracenediones);
anthracene derivatives (e.g. pseudourea and bisanthrene);
phleomycine;
aureolic acids (e.g. mithramycin and olivomycin);
Camptothecins (e.g. topotecan);
4) Mitotic inhibitors such as:
~ C~2 1 ~
dimeric catharanthus alkaloids (e.g. vincristine, vinblastine and vindesine);
colchicine derivatives (e.g. trimethylcolchioinic acid) epipodophyllotoxins and podophylotoxins (e.g. etoposide and teniposide);
maytansinoids (e.g. maytansine and colubrinol);
terpenes (e.g. helenalin, tripdiolide and taxol);
steroids (e.g. 4,B-hyroxywithanolide E);
quassiniods (e.g. bruceantin);
1 0 pipobroman;
methylglyoxals (e.g. methylglyoxalbis-(thiosemicarbazone);
~ C~2 1 ~
dimeric catharanthus alkaloids (e.g. vincristine, vinblastine and vindesine);
colchicine derivatives (e.g. trimethylcolchioinic acid) epipodophyllotoxins and podophylotoxins (e.g. etoposide and teniposide);
maytansinoids (e.g. maytansine and colubrinol);
terpenes (e.g. helenalin, tripdiolide and taxol);
steroids (e.g. 4,B-hyroxywithanolide E);
quassiniods (e.g. bruceantin);
1 0 pipobroman;
methylglyoxals (e.g. methylglyoxalbis-(thiosemicarbazone);
5) Hormones (e.g. estrogens, androgens, tamoxifen, nafoxidine, progesterone, glucocorticoids, micotane, prolactin);
6) Immunostimulants (e.g. human interferons, levamisole and tilorane);
7) Monoclonal and polyclonal antibodies;
8) Radiosensitizing and radioprotecting compounds (e.g. metronidazole and misonidazole);
9) Other miscellaneous cytotoxic agents such as:
camptothecins;
quinolinequinones (e.g. streptonigrin and isopropylidene azastreptonigrin);
cisplatin, cisrhodium and related platinum series complexes;
tricothecenes (e.g. trichodermol or vermicarin A); cephalotoxines (e.g. harringtonine);
camptothecins;
quinolinequinones (e.g. streptonigrin and isopropylidene azastreptonigrin);
cisplatin, cisrhodium and related platinum series complexes;
tricothecenes (e.g. trichodermol or vermicarin A); cephalotoxines (e.g. harringtonine);
10)Cardioprotecting compounds, such as (+)-1,2-bis(3,5-dioxopiperazin-1-yl) propane, commonly known as ICRP-187, and ICRF-198;
1 1 ) Drug-resistance reversal compounds such as P-glycoprotein inhibitors, for example Varapamil, cyclosporin-c, fujimycin;
12) Cytotoxic cells such as lumphokine activated killer -cells or T-cells, 13) Other Immunostimulants such as interleukin factors or antigens.
14) Polynucleotides of sence or antisensing nature.
15) Polynucleotides capable of forming triple helices with DNA or RNA.
1 6) Polyethers 17) Distamycin and analogs.
18) Taxanes such as taxol and taxotere.
The above list of possible therapeutic agents is not intended to limit this invention in any way.
The pharmaceutical compositions of the invention can be in forms suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intraarterial, intraperitoneal, intramuscular, subcutaneous and intravenous administration), by inhalation or by insufflation. Where appropriate, the formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
For injectable use, the pharmaceutical composition forms include sterile aqueoussolutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol for example, chremophor-EL, tween 80', glycerol, dimethyl sulfoxide (DMS0), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable denotes trademark ~A~ ] 465~
compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique. These methods yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical formulations suitable for oral administration may conveniently bepresented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution;
as a suspension; or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in theart. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
As used herein, the expression "pharmaceutically acceptable carrier includes anyand all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the present composition is contemplated. Supplementary active ingredients can be incorporated into the inventive compositions.
CA2 ~ 46548 It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
The dosage of the principal active ingredient for the treatment of the indicatedconditions depends upon the age, weight and condition of the subject being treated;
the particular condition and its severity; the particular form of the active ingredient, the potency of the active ingredient, and the route of administration. A daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient. The preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier. In the case of compositions containing supplementary ~ ~. Z ~ $
active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Antitumor treatment comprises the administration of any of the compounds of this invention in an acceptable pharmaceutical formulation at the effective therapeutic dosage. It is understood that chemotherapy can require the use of any of the compounds of this invention bound to an agent which facilitates targeting the compound to the tumor cells. The agent may be chosen from, for example, monoclonal or polyclonal antibodies, proteins and liposomes. The compounds of this invention could also be administered as monomeric, dimeric, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
The compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian cancer, and melanoma. This list of conditions is however not exclusive, and it is believed that the compounds of the invention will exhibit activity against other tumors and cancers, such as for example pancreatic cancer, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxorubicin against P-170 mediated multidrug resistant cancers.
Methyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-A mixture of methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.485 mmol) and acetoxybutadiene (75,ul, 0.630 mmol) in dry benzene (5 mL) was heated for 12 hours at 60C under argon atmosphere. The solvent was thenremoved in vacuo and the resulting adduct dried under reduced pressure. The adduct was dissolved in 10 mL of ethanol and to this solution was added 1 mL of 1 % K2C03 aqueous solution. After stirring for 2 hours at R.T., the reaction mixture was neutralized (pH=6) and extracted with CH2CI2 (2x50 mL). The organic layer was then washed with water (3x50 mL) and dried over MgS04. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 69 mg (55% yield) of pure titled compound. (MP: 135-136C).
PMR (CDCI3,250MHz): 2.31 (s,3H,CH3), 2.54 (dddd,1H,J=18.0, 10.3, 3.6 and 1.8Hz,HCHa-CH), 2.97 (dm,1 H,J = 19 and 3.0Hz,HCHe-CH = ), 4.05 (dd, 1 H,J = 10.3 and 3.9Hz, CH2-CH), 4.58 (dt,1H,J=18.7 and 3.6Hz,HCHa-0). 4.92 (dd,1H,J=18.7 and 1.8Hz,HCHe-0), 7.72 (m,2H,Ar-H), 8.04 (m,2H,Ar-H). CMR-(CDCI3,75.44 MHz~:
24.42 (CH2-CH), 26,57 (COCH3), 63.97(CH2-O-), 78.63 (CH2-CH), 126.70, 127.08, 132.36 and 134.52 (CH aromatic); 132.20, 134.42, 141.30, and 142.41 (c quaternary), ~ 2 1 ~
183.51 nd 183.63 (C=0 quinone), 207.2S ~0-CH3).
EX~MPLE 1 OAc O O O O
O O
EX~M~E 2 Metihyl (7 b,.' ., 5,10-dioxo-3,4,5,10 1 ~ . p! ' ~ 12.3-C] pyr~n 3-yl) Icetone BCH-1129 A m~cturc of 1~ 3 ~' ~ylo~y L - (776 mg, 4.51 mmol) and methyl (5,8-dio~o-3,4,5,8; ~ l~ 12,3 Cl pyr n-3-yl) 15etone (309 mg, 1.50 mmol) in 6mL of dry toluene w s. stirred for 90 minutes t room ~ , ~ under rgon u - . ' e. Tho solvcnt wu~ then rcmoved 15 i~ v~cuo ~d thc dricd ro6iduc w~s J' ~v~xl ill 1O mL of THF. To thi~ oolution w 8 ~dded 2 mL of a 4% ~q. HCI solution. Thc ' ' org nic l-ycrs werc thcn w shed with w br u~d dried over MgS04.
Fl~sh ~ (tolucne: ethyl cet-b; 95%:5%) of the rof.idue gave 180 mg (65% yield) of the titlod 5 . ' (~IP: 169-170C).
PMR (DMSOd6, 250 MHz): 2.24 (s,3H,CH3), 2.45 (m,lH,HC_a-CH=), 2.77 (dd,lH,J--19 ~nd 3.0Hz,HC~e-CH),4.20 (dd,lH,J .9.8 ~nd 3.9Hz,CH2~D, 4.55 (d ~.. ' .~-d, lH, J--22 Hz,HC~a-0-), 4.78 (d o.. ~r ~ lH, J= 18.0Hz,HCHc-0), 7.15 (dd,lH,J=8.5 and 2.4Hz,Ar-H), 7.30 (2d, lH, J=2.5Hz,Ar-H), 7.88 (2d,1H,J=9.lHz,Ar-H), 10.96 (s,lH,Ar-OH).
E.Y~MPL15 2 O O O O
)TMS
O O
EX~M~LE 3 SU~S ~ T~ LrT
W O 94/11382 PC~r/CA93/00463 ~ 21~63'~ ~
Me~hyl (1 4.' . ~-5,10-dioxo-3,4,S,10 1 ~d . p~ ' - t2,3-Cl pyrs~n-3-yl) ketone BCR-1148 A mi~cture of methyl (l-metho~y-5,8 dio~c-t~ hyt ul~o t2,3-C~ pynn-3-yl) Icetone (100 mg, 0.450 mmol) uld ceto~y ' ' - (80 ~g, 0.675 mmol) in dry b~nzene (S mL) w 8 he~d for 3 hour~ ~t 60C
- under Yrgon . ' e. Tho solvent w~s then removed in ~cuo nd the .~ C ~dduct was ~
in 10 mL of toluene nd then 9 . ' on sili gel by fl~sh ~ (tolucne: cthyl ~te;
90%:10% followed by 70%:30%). E~ of the ~olvcnts g vc 37 mg (31% yield) of pure titled , PMR (Acetone d6, 250 MHz): 2.26 (s,3H,COCH3), 2,50 (dd,lH,J=11.6, l9.5Hz,HC_~-CH), 2.89 (dd,lH,J=4.2,19.5Hz,HCHe-CH), 4.71 (dd,lH, J=4.2,11.6 Hz,C_-CH2); 6.12 (bro~d s,lH,C_OH);
7.87 (m,2H,ArH); 8.07 (m,2H, ArH).
EX~LE 3 O O , O O
C
o OH o OH
EX~MPLE4 - r' '' . ' ~1 (5,10-diox~3,4,5,10 1 b~d . lU' ' I 12,3-C] py~n-3-yl~ Icetone 2 0 Step l: M ' ~momethyl (S,8-dimethoxy-3,4 t-' ~ L 12 p~-3-yl) I~e~one To a stilTed ~olution of methyl (5,8 :' ' y-3,4~ vl~ [2,3-c] pyran-3-yl) l~etone (1.905g, 8.04 mmol) nd I ' ~ lyl chlonde (1,530 ~1, 12.0 mmol) in t~ ~, r (48ml) under l~.L.o at -78C, wa8 dowly added lithium d-- r u~ nude (~" , u~l amine 10.71 mmol, n-butyl lithium 4.26 ml of a 2.5M solution in I ~d ~ r , Jmd 6.0 ml of l~ ~,- r ). After stiITing for 10 - minutes the h~ _ wa8 rused to 0C, nd stirring wa8 c ' for 10 re minutes. Solvent was ~emoved and the crude product wa8 ~ ~ in 48 ml of t ~, r 1> ~1- b~ ~ (1,716 - mg, 9.66 mmol) w 8 dded slowly to the solution. After 10 minutes, the re~lction system was worlced up 30 with d aqueous sodium I ~ w shed with brine. The titled . A - ~ was obtained fullu.. ~ f~h :' ; ,, . ' j (} - ' .~1 cetate, 9:1) of the cmde product. lH NMR (l - d6~
250 MHz) : 2.68 (dd, lH,HCHa), 3.16 (dd,lH,HC~e), 3.28 (s,3H,OCH3), 3.32 (s,3H,OCH3), 3.73 SUE~ 3~-3EET
(dd,lH,J=4.0,11.5Hz,CH), 3.81 (dd,2H,CH2Br), 4.51 (d,lH, J=15.8Hz, HCE~O), 5.05 (d,lH,J=15.8Hz,HCHeO), 6.335 (dd,2H,~rH), 4: Monofluoromethyl (S,10 s 3,4,5,10 ~ p~ .~Cl pyran-3-yl) ketone.
~1~3 1 ~Br 2 ~CH,~F _ OCH3 OCH3 OCE~
O O O O
~5F 4 ~F
O O
Step2: r~ (C~8~ -3,4t~3~ t2,3-Cl-p~n-3-yl)ketone To ~ solution of 1 ~ ' (3.75 rnM, 1.18 g) of ~ etone ' . from step 1 and 3 c~ (11.25 r~M, 2.160 g) of pTSA in 20 mL of dry THF wui ddod dowly, ~t R.T., 6 equi.
(22.5 mM, 22.5 rnL) of ~ lM solutio~ in 1~- of N~(Bu)4F-. After 6tirring one rlight t R.T., 15 mL
of H20 were ~tdet ~nt the mi~cture w~s _ ' with 3~c20 rnL of ethyl cotste. Aher drying with NaSO4 and solvent e. . - ~ the re6idue w s flssh ' ~ ' (Toluone: Ethyl c~to; 9.5:0.5) to give ~ S0~i yield of pure titlod r lH NMR (250 MHz, CDC13): 2.61 (dd,lH,HCHa), 3.11 (dd,lH,HC~e), 4.27 (dd,lH,CH), 4.63 (d,lH,HC_aO), 4.9g (d,lH,HCHeO), 5.33 (d, 2H, CH2F), 6.67 (dd,2H,ArH).
Step 3. r ' ~ , ' yl (~8 :' 3,~ ,P ' ~ ~ ~a~
12,3-Cl pyr~n-3-yl) Icetone To 1 ~, ~ '- (0.220 mM, 56 mg) of the fl ~ ' ~I}~nc ~ from step 2 ~ d in 3 mLof - '- at 0C w~ dded 3 ~ . ~ ' of ceric mmon um nit~te (0.66 mM). After 10 minutes, the r~ction mL~ro wa~ brought to R.T., stirred for 20 rninutes, and then . ' with dichloromethlme/THF (1/1). The organic layer w~ls dried over MgSO4. The titled quinone was obtained 2 5 (67 mg) following ~,. . - - ~ of solvent.
H NMR (250 MHz, CDC13): lH NMR (250 MHz, CDC13) : 2.46 SUBSTl ï l JTE SHEET
~0 94~11382 214 ~ ~ ~ 8 PCTJCA93/00463 (dddd,lH,J=3.0,4.0,10.4,18.9Hz,HC~a), 2.91 (dt, lH, J=3.5, 18.9Hz, HCHe), 4.2~(dd,J=3.8,10.4Hz,CH), 4.445 (dt,J=3.S,18.4Hz,HC~O), 4.77 (dd,J=2.2,18.5Hz,HCHeO), 5.25 (d,2H,CH2F), 6.75 (d~l 7~,~C=CH).
- step 4. r~ 1 (5,10 ~- 3,4,5,10 1 _b~
[2,3-Cl p~n-3-yl) Ice~one -To 1 r~ ~, ' (0.220 mM, 50 mg) of the I , - from step 3 ~ d in 5 mL of d~y toluene w~s sdded 1.3 ., ._' (0.286 mM, 32.0 m~, 35 ILI) of ~ y I ' ~nd sti~d u.. _' The raction mLstur6 w~ p~sed diroctly on silic gel colwnn. 20 mg of pure titled . , ~ w 8 isol ted ~fter two fl~sh ~ ' . " phy (2% EtOAc in toluene).
PMR (Acetone-d6, 250 MHz): 2.62 (dddd,lH,HC_ ), 2.94 (dt,lH,HC~e), 4.46 (dd,lH,CH), 4.62 (dt,lH,HCH~), 4.84 (dd,lH,HC~e), 5.43 (d, 2H, CH2F), 7.83 (m,2H,ArH), 8.03 ~m,2H,ArH).
EX~,MPI,E 5 S~ep 1.
(l'S,lR,3S) ~nd (l~s~ Me~hgl (~,.X L- 1-(2',3', 6'- trideoxg-3'-2 0 t ~ . ~ ~ ~ q' O F 'yl L I~) 3,4,5,8-' ., d ~ ' 12,3-C] pg~n-3-gl) Icetone To ~ gti~ed solution of 1,4-di~ F ol~v~d ~71 " or ~1 ~ - (1.584 g, 2.93 mmol) in 160 mL of dry ~ L-_ '- - nd 40 mL of o ' ~ ether, - ' ~t -35C under srgon ,' ~i, w s ddod ~L., .. - 1.132 m~ (5.85 mmol) of i '~1 8ilyl triflate (I~SOTf). ~er ~tirring for 1.5 hourli st 0C, ~e i . ~ W 8 lowe~ed to -15C Jnd cooled (0C) solution of methyl (1 h, ~r~ 5,8-dio~o-3,4,5,8 1 1 ~d ~,L~ [2,3-Cl pyr~n-3-yl) Icotone in dry ~' ' ' -(40 mL) w 8 Jdded. ~er li hourOs of ~tirring, the ~ction mi~cture W~6 put into ~ ~olution of 150 mL of ethyl rcot~te ~nd 50 mL of ~ ~ ~ N HCO3 Oolution. The org~nic l-yer w 8 w~shed with w ter nd 3 0 dried (~;7 2S04). Flu~ O , ' ~ of the re6idue g ve 917 mg (69 % yidd) of the mLlcture of titled SUBSTITUTE SHEET
WO 94/11382 21~ 5 .1 4 ~ PCI`/CA93/00463 Ex~mpb 5: r~j~ k' ~ d d~ V,8 of ~ rvrua~t~ wffl a metttyl ketone dde chah.
o o o o o o ~3 1 W~CH3 113C~ 3 ~
pNBoN~COCF3 P~Bo NHCOCF3 O O O O
l3 ~ C~3 O O o O
X3 ~ 8 ' ~13 C ~ 11 3 ~ Rl = OPNB R2 ~ NHCOCF3 ~ R~--O~NB R 2 = NHCOCF3 RI ~ OH (BCH-11831R2 ~ NHCOCF3 R~ - OH (BCH~ R2 ' NHCOCF3 ~o~ ~~"Q., ~3C~
1~12 R~ 2 9 ~ Rl ~ O~NB R 2 ' NHCOC~3 12~; Rl = OE~NB R 2 = NHCOCF3 Rl = OH R 2 ~ NHCOCF3 Rl = OH R 2 ~ NHCOCF3 A ~ocond fl~ thc ' ~, ' ' ' The l'S,lS,3R titled ~ H NMR (250 MHz, u:etone d6) _: 1.28 (d,3H,J--6.4Hz,CH3), 2.05 ~aidden m, lH,2'-CH2), 2.30 (s,lH, COCH3), 2.42-2.49 (m,2H,2'~H2 ~J.. ' ~ r e d wi~ HC~
2.84 (dd,l~,~C'~,) 4.S3-4.65 (bro~d m,lH,3'~, 4.635 (dd,2H,J=4.2, 11.6Hz,O~H~OCH3), 4.76 (bm~d q,lH,S'~, 5.50 (bro~d s,lH,4'-CH), S.69 (bro~d s,lH,I'~, 6.02 (~,lH,~C~-O), 6.90 (~.~ C= CH), 8.37 (m,4H,~rH), 8.68 (bro~d d,lH,N~.
SUBSTITUTE SHEET
94/11382 PCI`/CA93/00463 ~ 2 1 ~
The l'S,lR,3S titled ~' ~ had lH NMR (250 MHz, ~d6) _: 1.19 (d,3H,1=6.6Hz,CH3), 1.89 (dd,lH,J=4.6,13.1Hz,2'-CH2),2.32 (s, 3H,COCH3), 2.29-2.47 (m,2H,2'-CH2 o.~ '~r~d with HCHa), 2.89 (dd,lH, J=4.1Hz,HCHe), 4.60 (m,2H,3'-CH ~ '.red with S'~H), 4.71 (dd,lH, J=4.1,11.5Hz,O~H-COCH3), 5.48 (bro~d s, lH,4'~H), 5.64 (bro~t 6, lH,l'~H), 5.89 (s,lH,O-CH~), 6.87 (~ XC=CH), 8.37 (dd,4H, ArH), 8.69 (broad d, lH, NH).
St~p 2.
- (l'S,1P ~1 (5,10 . 1-(2',3',C' I ' ~-3'~ '` . ' ~'~p-' ,' yl L 1~ ' ~.,. ~) 3,4,5,10 ~ ~ . p~ 2,3-C] py~n-3-yl) ketone To a stilTed solution of l'S, lR, lS ~ om step 1 (r ,'- 5), (0.464 mmol) in dry bcnzene (10 mL) u~der argon wYs added 78~1 (696 mL) of 1 ~ ' ~ After stirring for 16 hours at room i e, thc re~ction mi%ture wss fl~sh .L~ ~ ,' -' (I ' ~~ ' ~1 scetate;
90%:10%)togive244mg(82% yidd)ofthepuretitletc~ , ' lH NMR (250 MHz, scoto~e~6): 1.22 (t,3H,J, i6.4Hz,CH3), 1.94 (tt,lH,J=4.7,13.1Hz,2'-CH2), 2.35 (s,3H,COCH3), 2.42 (m,lH,2'-CH2), 2.52 (tt,lH,J=11.6,19.8~7 ~I~.~9) 3.04 (dd,lH,J=3.9,19.6 Hz, HC~ç), 4.55-4.68 (o.. '.red m,2H,3'-CH ~d 5'-CH), 4.79 (dd,lH,J=4.0,11.5 Hz,O~j-COCH3), S.49 (bro~d s,lH,4'-CH), 5.75 (bro~d s,lH,l'-CH), 6.07 (s,lH,O-CH-O), 7.83-7.93 (m,2H,ArH), 8.06-8.14 (m,2H,ArH), 8.32-8.43 (m,4H,ArH), 8.67 (bro~d d,lH,NH).
S~ep 3.
(l'~,lP ~S) ''~' ~1 (S,10 :' 1-(2',3',6'-trideox~-3'-i '' .
~ -L 1~ * ,., ~ ~) 3,4,5, 10 1 ~~ ' ~ 12,3-C] p~n-3-~
Icetone BCH-1184 To a stirred solution of the ~1~ '- from step 2, (30 mg, 4.65~10-5 mmol) in 4 mL of dry -' 3 0 nd 1 mL Of r ~d¢~ THF t 0C nd under rgon, was sdded 11~L1 (4.66~10-5 mmol) of N OCH3 (4.37 M) solution in - -' After S minute6 of stirring, the r~ction wa6 ., ' -d with 1 mL of d NH4C1 solution nd . ' with CH2C12 . I;oll~.. g c., of solvent, flash . ., ph~ of the residue g ve 23 mg (100% yidd) of pure titled .
lH NMR (250 MHz, Acotono d6): 1.25 (d,3H,J=6.5Hz,CH3), 1.76 (dd,lH, J=4.5,12.9Hz,2'-CH2), 2.16 (m,lH,2' CH2), 2.32 (s,3H,COCH3), 2.48(dd, J~11.6,19.5Hz,HC_a), 2.99 (dd,lH,J--4.1,19.5 Hz,HC~), 3.68 (broad s,lH,4'~, 4.17-4.41 (o.. '~rei m,2H,3'-CH snd S'-CH), 4.69 (dd, lH,J=4.0,11.0Hz,~C_-COCH3), 5.53 (broad s,lH,l' CH), 5.97 (s,lH,~CH~), 7.82-7.90(m,2H,ArH), 8.01-8.05 (m,2H,~rH), 8.13 (broad d, lH,NH).
t~ 5~EI
WO 94~11382 PCI /CA93/00463 2 ~ 8 S~ep 4:
(l'S,1~;;"3R)-M~thyl (5,10 ~(2',3',C'~ 3'-h~r~ ' ~- q'~
~ yl L l~ o.) 3,4,5,10 1 ' ' ,.' . ~ 2,3-Cl py~-3-yl) Iceton~
~pj?!- b of tho p.. ~- _ ~ - d in step 2 of the p~se~t o~mplo on the l'S, lS, 3R quinone ~1). '- from step 1 g~vc thc titled: . ' which h t:
lH NMR (250 MHz, ~ G): 1.33 (t,3H,J~6.6Hz,CH3),1.94 to 2.08 (m,lH,2'-CH2), 2.33 (s,3H,COCH3), 2.49 (m,lH,2'-CH2), 2.58 (dd,lH, J=11.7,19.6Hz,HCH~), 3.01 (dd,lH,J--4.1,19.7Hz,HC~), 4.53-4.65 (m, lH,3'-CH), 4.71 (dd,lH,JC4.1,11.5 Hz,O-CE-COCH3), 4.90 (bro~d q,lH, S' CH), 5.S3 (bro~d s,lH,4'-CH), S.75 (bro~d ~,lH,l' CH), 6.21 (~, lH,O-CH~), 7.88-7.92 (m,2H,ArH), 8.08-8.16 (m,2H,ArH), 8.34-8.43 (m,4H,~rH), 8.69 (bro~d d,lH[,NH).
step S:
(l'S,1~ )-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-l."
hydro~y-L 1~ ) 3,4,5, 10 ~ p! ' ~ 12,3-Cl PY~~3~YI) I~etone BCH-1146 T~e~ment of thc 3~1~ ~ obt~inod from step 5 with liodium ' - '- ~ ~3< il~d in step 3 of this 2 0 c~mple yidded the titled ~ d, which h~d:
lH NMR (250 MHz, ~- ~ d6) 1.35 (d,3H,J=6.4Hz,CH3), 1.77(dd,1H, J- 4.5,12.9Hz,2'-CH2), 2.17 (dt,lH,J= 3.7,12.9Hz,2'-CH2), 2.30 (s,3H, COCH3), 2.56 (dd,lH,J=10.7,19.6Hz,HC~), 2.98 (dd,lH,J~4.2,19.8 Hz, HC~),3.70 (bro~d s,lH,4'-CH), 4.2-4.4 (m,lH,3'- CH), 4.60 (bro~d qu~t,lH,S'-CH), 4.66 (dd,lH,J ;4.2,11.5Hz,O~-COCH3), 5.52 (broad d,lH,l'-CH), 6.15 25 (s,lH,O CH-O), 7.86-7.92 (m,2H,~rH), 8.07-8.11 (m,2H,ArH), 8.15 (brosd d,lH,NH).
step 6:
(l'S,1P ~S)-Me~hyl (5,10 ' 1-(2',3',6'-hideoxy-3'-t~iflu . ~ '~ q'~
' ~ tlL l~ ) 7 ' J.' ~ ,~-3,4,S,10 ~ Ip~ 2,3-C
3 0 p~r~3-yl) lu~toDe The titled c , ' w~s ~d in 62% yield by ~ g the l'S, lR, 3S ~ ;de from ~tep 1 of this e~mple wit~ 1= ' y-3-1 ' ylb;lylc.A~ e s~ .~dm~; as d in ~ 2, in this ~ , w~s used.
35 lH NMR (250 MHz, Acetone-d6): 1.21 (d,3H,J=6.6Hz,CH3), 1-93 (m,lH, 2'-CH2], 2-34 (s,3H,COCH3), 2.49 (dd,lH,J=11.6,19.5Hz,HC~), 3.00 (dd,lH,J=4.1,19.5Hz,HC~), 4.574.69 (U., ~ ~r~d '`i~ 2H,3'-CH ~nd 5'~,4.76 (dd,lH,J=4.0,11.5Hz,0-CH-COCH3), 5.49 (b~d s, lH,4'~, 5.73 (b~d d,lH,l'-CH), 6.04 (s,lH,O{~H-O), 7.25 (dd, lH,J=2.5,8.5Hz,ArH), 7.46 (d,lH,J=2.5Hz,~rH), 7.98 (d,lH,Js 8.6Hz, ArH), 8.38 (m,4H,ArH), 8.58 (broad d,lH,NH) 10.23 SU~STi~lTE SI~IE~T
214654~
(b~d s,lH, ArOH).
Step 7:
(l'S,lR,3S) '~ 1 (S,10 d 1-(2',3',6'-~ideoxy-3'-L '` . '~ I~
1~ ' .JI - ~ 7 ~ u~-3,4,5, 10 1 bJ. ù 12,3-C] pyrsn-3-yl) Icetone ' ~ of the 1~.' Jl~.6 ~ clm.i ~' ' -d in step 3 of this e~mple to the l'S, lR, 3S tticyclic of 6tep 8 ~wlted in th~s removs~l of the p ~1 pl~ e g~up. The titled 1 0 h~d:
lH NMR (250 MHz, ~ dG): 1.63 (d,3H,J=6.4Hz,CH3), 2.14 (m,lH, 2'~CH2), 2.53 (m,lH,2'-CH2), 2.70 (s,3H,COCH3), 2.87 (dd,lH,J~11.7, 19.4Hz,HC~), 3.35 (dd,lH,J~4.1,19.4Hz,HC~), 4.07 (b~d 6,1H,4'-CH), 4.65 (o.. ' .red m,2H,3'-CH ~nd S'-CH), 5.07 (dd,lH,J=4.1,11.7 Hz,O-CH-COCH3), S.91 (bro~d d,lH,l'~CH), 6.35 (6,1H,~CH-O), 7.64 (dd,lH,J=2.S,8.5Hz,ArH), 7.84 (d,lH,J=2.5Hz,~rH), 8.35 (d,lH,J= 8.5 Hz,~rH), 8.48 (bro~d d,lH,NH), 10.23 (bro~d 6,1H,ArOH).
step 8:
(l'S,1~:,3~) '' ' /1 (S,10-dioxo-1-(2',3',C'-trideoxy-3'-L
nitrobenz~yl-L 1~ ' ~J-_ ~) 7~ -3,4,5,10-tet~h"L~ p' ' ~ 12,3-C
pyr~n-3-yl) I~
The titlod ~ . ' wu r--, d by ~ r~- ~ the ~me ~ 8 ~' ' -' In ~tep 8 on the l'S, lS, 3R, quiQone ~ - of stop 1 Of this ~ . '-lH NMR (250 MH~ d6): 1.32 (d,3H,J=6.4Hz,CH3),2.08 (m,lH, 2'~H2), 2.51 (m,lH,2'-CH2) 2.55 (dd,lH,J=ll.S,l9 ~i~7,~"~, 2.96 (dd,lH,J=4.2,19.6Hz,HC~ç), 4.51-4.62 (m,lH,3'-CH), 4.68 (dd,lH,J= 4.2,11.5Hz,O~-COCH3), 5.52 (bro~d 6,1H,4'~, 5.73 (brosd s,lH, l'-CH), 6.18 (6,1H,aC~I-O), 7.28 (dd,lH,J=2.6,8.5Hz,ArH), 7.47 (dd, lH,J=2.6,8.5Hz,ArH), 8.03 (d,lH,J--8.5H_,ArH), 8.38 (m,4H,ArH), 8.68 (bro~d d,lH,NH), 9.85 (bro~d s,lH,~rOH).
step 9:
(l'S,~ 1 (5,10 ~- 1-(2',3',6'-' ' ~-3' ;~ '' w ' L~
.. , ~ ) 7~ -3,4,S, 10 t~ 2,3-Cl pyr~n-3-yl) Icetone BCEl-1180 ~' of the h~ ' ol~ A~L ~il d in 6tep 3 of thi6 e~c mple to the l'S, lS, 3R tricyclic 3 5 ~ly~ ~ - of 6tep 11 ~sulted in the remov~l of the ~ vl~, l p.~ g group. The titled .
had:
lH NMR (250 MH~ ,) 1.73 (d,3H,J=6.6Hz,CH3), 2.17 (m,lH, 2'~H2), 2.58 (m,lH,2'-CH2), 2.68 (s,3H,COCH3), 2.90 (dd,lH,J=11.6, 19.7Hz,HC~), 3.33 (dd,lH,J~4.3,19.8Hz,HC~), 4.09 (b~d s,lH,4'~, 4.63 (m,lH,3'~H), 4.95-5.06 (~ ',, d m,2H,S'-CH, ~nd OCH-COCH3), SUBSTITUTE SHEET
21~6~
5.91 (bro~d d,lH,l' CH), 6.51 (~,lH,0~), 7.65 (dd,lH, J=2.6,8.5Hz,ArH), 7.85 (d,lH,J=2.6 Hz,ArH), 8.38 (d,H,J=8.5Hz, ~rH), 8.S2 (brwd d,lH,NH), 10.18 (bro~d ~,lH,~rOH).
EXAMPI,E 6 2-t4,~ 1',2'-dioxo-3' ~ hyl-(S,10 diox~3,4,5,10-b~ d . p' - - 12,3-C1 py~3-~1) Ice~e i~.,, `e 6: Tricyclic pyranylr aph~oquirones wiffl a squaric acid mde~y.
a~o o o o o o 1~ 1 ~ ¢~ 2 ~Br a~,o o o o a~
~0 o Step 1: B~ " 5,P: -b~ 2,3-C] pyr~n-3-yl) ~one To-solu~on_ eoneeS . ' of S,8 - ' ~-3l ~ (380mg,1.1mmol)in (18ml), ~t 0C under ~rgon, w~ ddod d~..- ~n quoous ~olution of ccric ~ -15 Ditrste (6.5g in 28ml H20). ~r stirring for 10 minutes, the mi~chue w~s ~ ~ d with 3 ~t 20ml of CH2C12. The ~- ' or~nic l-yer w~ driot ovcr MgSO4 Jnd then ~ to yield 263 mg of pure ~tled ~ , ~
lH NMR (2~50 MHz,CDC13): 2.43-2.69 ~m,lH,CH2), 2.82-3.07 (m,lH,CH2), 4.24 (dd,2H,CH2Br), 4.4-4.6 (m,2H,CH20 u~d C_COCH2Br), 4.52 (d,lH, CH20), 6.74 (~ ,~C=CH).
Step 2~ i (S,10 ~- S,10-dih~phtho ~,3-Cl p~ran-3-yl) Ketone To ~ ~olution ~ one . . -. ' of " (263mg, 0.92mmo1) from ~toD I (~ h 6) in 25ml of dry toluene w~ ~ddod tbroo ~ (2.7mmol) of ~ , Tho re~ction mi~ture 25 w~s stirred o.. _' under ~rgon ~t room I , nd t~en ~wo hours ~t 60C. APer remoY~l of l~cnt, the cn~de p~oduct w~s fl~h :- ~ , - ' (toluale/EtO~c,9: 1). T~e ~tlod or~ngc ~ .
ol~ted (192mg) in 62% yield.
H NMR (250 MHz,CDC13): 2.~2.6 (m,lH,CH2), 2.7-3.2 (m,lH,CH2), 4.3-4.4 (m,2H,CH2Br), 4.45 SUES ~ . ;¢ET
2146~8 (m,lH,C~-O), ~.64.7 (m,lH,CH20), 4.9-S.05 (m,lH,CH20), 7.6 (m,2H,ArH), 8.1 (m,2H,~rH).
Step3: 2~4'-Hydr~-1',2'-dio~c~3'~ meth~l(S,I~ diox~3,4,S,1 . [2,3 Cl p~3-~1) ICeto~#
Under u~on ~t room I , hvo .~ . ' (0.9mmol) of ~ric Jcid ~nd hvo 4~ ' of C6CO3 (0.9mmol) wo di-olvod in lOml of dry dimethyl f ' (DMP) (wn }
). To this olution v~s ~ddot ~e eql~iv lent (0.45mmol) of the 1~ - . ' ' ~ ~ from st~
3 (e~umple 6). The solution wY t~tod t 60-C for hvo hou~. AP~r coolin~, lOml of H20 W~6 ~od, 10 ~nd c w~ c rried out with 3 ~ lOml ETO~c. ~R t~ nd _ . - the re6idue w s purifiod hvice by ~ TLC. The titled con~ound w s o~ined m 30% yield.
lH NMR (2SO MHz,~ 2.S-2.6 (m,lH,CH2), 2.8-3.0 (m,lH, CH2), 4.4 (m,lH,CH{~), 4.6 (u.. ', ~ ~ d m,2H,COCH20), 4.8-5.0 (m,2H, CH20), 7.7 (m,2H,~rH), 8.1 (m,2H,ArH).
15 EXAMP~E 71 Tnqcl;.c ~ pbt~uiDo~ ntb ~ ~uanc uid ~de cbain Ex~mpk 7: Tlicydic pyr~ uinone ~ ric acic moiety.
o o o o o o _ 1 D ~ 2 ~
O ~ o n O O
~13 C-~ ~3 C~ 113 C~
~11110 J~ Pl~l~o ~ COCF3 Plllso ~ COCF3 + 1,3-diepimer + 1,3-diepimer + 1,3 Step l~ P ~ d (1'~ ,,3't)-B-. ~1 (5,10 ' 1-(2',3',C' ' ~ 1'~r-l 3'~1uo~ ~ ~ L 1~ ' ,J - ) (~,~"!i l~L
', ' . ~ tbo 12,3~ p~3-~1) Icetone At mom .ullder N2, to one _, . ' (0.482 mmol) of 1:1 mi~ture ~rting quinone- 2 5 ~ ' from d;~p6 3 nd 6 ~ . ' - 1) !" 1~.,d in 6 ml dry te~ hydro fu~n (~I~) v~ ddod 1.1 ~ . ' of~b~' 1 ' F_.l,.~ ' ~rhvohoun,to~e~olutionv~s dded7mlSX
N~HC03 lution nd ~ `1 d with 3 s 10 ml E~O~c. ~Rer d y~ ov N 2S04 ~nd ~,. . the ridue w~ing 95% tolueno -SX EtO~c olvenL Two, L ~jor fr~ction~ were isol~d Co~to the 2 io~ (yidd 40X of pure: , ' r tio # 1/1 isomer). PMRs of the 3 0 - . 3 i~oma~ re ~ ' 3 in ~tep 1 (c . ' 8) ~d ~bp 1 (r . ' 9).
~ U ~ T~ E ET
WO 94/11382 PCr/CA93/~463 214~
Step 2:
(l'S~ 3S) ~nd (l'S,1~;"3P)-2-14'~ -1',2'-dioxo-3' ~ ] methyl S (S~10 t- - 1-[2n,3n,6n-trideo~y-4n-0 ~ 1 3n ~
A~ - ~] 3~4~S~10 1 ~ ~d ~ p! ~ t2,3,c] py~-3-yl) Itetone The title c _~ ' wae obt~ined by zpplyi~g the p-. cc ' c~ d in ~p 4 (e~mple 6) to the tncyclic ~l~;d~ from ~tep 1 (e%~mple 7).
lH NMR (250 MHz, CD30D): 1.2 (d,3H,5~ CH3), 1.9 (dd,lH,2~H2), 2.42 (m,lH,2~-CH2), 4.6 (m,2H,CO-CH2-0), 4.8 (m,lH,OCH-CO), 5.5 (m, lH,4~, 5.8 (m,lH,l~-CH), 6.1 (m,lH,~ClH-O), 7.7-7.9 (m,2H, rom H), 8.05-8.1 (m,2H, uom H), 8.3-8.45 (m,4H, ~rom H), 8.7 (b~sd d, lH,NE~, 3.1 (m,lH,C4-H), 2.6 (m,lH,C4-H), 4.6-4.2 (u.. ' . r d m, 2H, 3~-CH ~nd 5~-CH).
15 EX~E 8 Step 1: (l'-S, l-R, 3~-1-(2'-3'-6'-brideo~ly 1' ~ 13~
1~ ~ 5.~ ) 3-(2 L . ~ v ~I)-S,10 :' ~ 3,4,S,10 ' J.' ~ lII z "' ' ~
(2,~ ~) t.
Ex~r4le 8 H3C~ H3C~ H3C~
f NHCOCF3 ~ IIHCOCF3 f~rHCOCF
liHAc NHAc NH2 ~-, ~ 5 O O O O ~ o O
H3C~ H3C~J BCH-1197 H3C~ BCH-1615 r NHCOCF3 r NHCOCF3 ~ NHCOCF3 Tl~i8 e~b ~ of r ~' group~; wherein ~ methyl Icetone; ~t R6 is c 'Iy ~ ~d to ~ ' d thi~zole ring.
SUBSTITUTE SHEET
Step 1 To a solution of (1'-S,1-R,3-S)-1-(2',3',6'-trideoxy-4'-p-nitro-benzoyl-3'-trifluoroacetamido-L-lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1 H-naphtho-(2,3-c)-pyran (87 mg, 0.135 mmole) in tetrahydrofuran (THF) (4.5 ml), stirred at room temperature, was added slowly a solution of pyridinium hydrobromide perbromide (43.1 mg, 0.136 mmole) in 3 ml of THF. The resulting yellow liquid was stirred for 2 hours at room temperature, then poured into water. Methylene chloride was used to extract the crude product from the aqueous layer. The combined methylene chloride extracts were washed with brine (10 ml) then dried over anhydrous sodium sulfate. The organic solvent was evaporated and the crude product was obtained as a orange oil (98 mg). Chromatographic purification (by volume, ethyl acetate:toluene ~ 1 :5) of the crude product gave a yellow sticky solid (40 mg) as a pure compound. A mixture (48 mg) containing the product (>34% mol) and unreacted starting material (<66% mol) was also obtained.
M.P. (Electrothermal IA-9100): 125-130C; decomposed at 175C.
'H NMR (250MHz, acetone-d6):1.25 (d,3H,J=6.5Hz,6'-CH3), 1.97 (dd, 1 H,J = 4.8Hz,13.7Hz,2'-HC_a), 2.48 (dt,1 H,J = 4.2Hz,13.7Hz,2'-HCHe), 2.64 (dd,1 H,J = 11.6Hz,25.6Hz,4-HCHa), 3.14 (dd,1 H,J = 5.7Hz,25.6Hz,4-HCHe), 4.66 (S,2H,COCH2Br), 4.71 (qua,lH,J=6.5Hz,5'-CH), 4.83 (overlapped m,1H,3'-CH), 5.08 (dd, 1 H, J = 5.7Hz,11.6Hz,3-CH), 5.52 (bs,1 H,4'-C H), 5.79 (bd,1 H ,J = 3. OHz,1 '-CH), 6.10 (S,lH,1-CH), 7.90 (m,2H,7,8-ArH), 8.08 (m,2H,6,9-ArH), 8.36 (d,2H,J = 7.4Hz,PNB-COC(CH2), 8.41 (d,2H,J = 7.4Hz,PNB-NO2C(CH)2), 8.75 (d.1 H,J = 7.7Hz,3'-NHCOCF3) .
IR(Nicolet 205 FT, film on Nacl tablet), cm~', 3625.9 (br,2), 3346.4 (str) 3079.5, 2955.5, 1732.6 (str), 1665.4 (str), 1596.0, 1530.9, 1274.5 (str), 1173.7, 1100.1, 974.04, 959.33 (m), 875.28, 721.29 (m).
Step 2: (1 'S,1 -R,3-S)-1 -(2',3',6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo,3,4,5,10-tetrahydro-1 H-naphtho-(2,3-c)pyran To a suspension of thiourea (2.2mg, 0.027 mmole) in ether (2 ml) was added a solution of bromomethyl ketone (20 mg, 0.026 mmole), from the previous step in methylene chloride (1 ml). The reaction mixture was stirred at room temperature for 20 minutes when a newly formed white suspension was observed. The reaction mixture was further stirred for 3 hours.
Solvents were removed under reduced pressure to give a white solid which was treated with saturated sodium bicarbonate aqueous solution and extracted with methylene chloride (4x3 ml). The organic layer was dried (over sodium sulfate) and evaporated to give a crude product which was chromatographed (by volume, chloroform:methanol 100:3, with one drop of pyridine) to yield the titled substance (3.5 mg) as a light colored solid.
M.P. (Electrothermal IA-9100): 142C (decomposed). 1H NMR (250 MHz, acetone-d6), ~: 1.13 (d,3H,J = 6.7Hz,6'-CH3), 1.92 (dd,1 H,J = 5.4Hz, 12.8Hz,2'-HCHa), 2.42 (dt,1H,J=3.4Hz,12.8Hz,2'-HC_e), 2.71 (dd,1H, J=12.2Hz,20.3Hz,4-HCHa), 3.12 (dd,1 H,J = 3.4Hz,20.3Hz,4-HCHe), 4.65 45a CA21 4654~
(m,1H,3'-CH), 4.67 (qua,1H,J=6.7Hz,5'-CH), 5.18 (dd,1H, J=3.4Hz, 12.2Hz,3-CH), 5.50 (bs,1 H,4'-CH), 5.68 (d,1 H,J = 2.7Hz,1 '-CH), 5.99 (s,1 H,1 -CH), 6.67 (S,1H,thiazole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.35 (d,2H,J=9.4Hz,PNB-COC(CH2), 8.42 (d,2H,J=9.4 Hz, PNB-NO2C(CH)2).
IR (Nicolet 205 FT, film on NaCL plate): cm~1, 3455.4 (w), 3346.8 (str), 3119.6 (w), 2923.8, 2850.3, 1731.5 (str), 1665.0 (str), 1532.2 (str), 1273.4 (str), 1217.5, 1182.5 (m), 1161.5 (m), 1101.8, 1005.5, 957.36 (m), 874.2, 721.18 (m).
Step 3: (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-p-nitrobenzoyl-L-Iyxohexopyranose)-3-(2-aza-3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro- 1 H-naphtho-[2,3-c]-pyran A solution of bromomethyl ketone (10mg, 8mmol), from step 1 (example 8), in methylene chloride (0.5 ml) was added to an ether solution (2 ml) of 1-methylthiourea (1.1mg, 1.0 mmol). The reaction mixture was stirred for 3 hours at room temperature then 3 hours at 40C. Solvent was evaporated and the crude product was analyzed by 1H NMR to see if the reaction was incomplete. The reaction mixture was redissolved in methylene chloride (0.5 ml) and ether (4 ml) and then stirred with newly added 1-acetylthiourea (1 mg, 1.0 mmol) and sodium iodide (0.06 mg, 0.05 mol.
eqv.) at 40C for 1 hour. Solvent was evaporated to give a crude product which was chromatographed (Eluent in volume ratio, chloroform:methanol 20:1, with 1 drop of pyridine) to yield the title substance as a light colored solid (6 mg).
M.P. (Electrothermal IA-9100): 145-150C, decomposed at 195C.
1H NMR (250 MHz, acetone-d6), ~: 1.09 (d,3H,J=7.4Hz,6'-CH3), 1.92 (dd,1H,J=4.7Hz,12;1Hz,2'-HCHa), 2.42 (dt,1H,J=2.3Hz,12.1Hz,2'-HC_e), 2.75 (dd,1H,J=11.7Hz,19.5Hz,4-HCHa), 3.14 (dd,1H,J=2.3Hz, 19.5Hz,4-HCHe), 4.62 (qua,1H,J=7.4Hz,5'-CH), 4.64 (m,1H,3'-CH), 5.31 (dd,1H,J=2.3Hz,11.7Hz,3-CH), 5.47 (bs,1H,4'-CH), 5.68 (bs,1H, 1'-CH), 6.00 (s,1H,1-CH), 7.20 (s,1H,thiazole-CH), 7.90(m,2H,7.8-ArH), 8.11 (m,2H,6.9-ArH), 8.34 (d,2H,J=7.8Hz,PNB:CO-C-(CH)2), 8.40 (d, 2H,J=7.8Hz,PNB:NO2-C-(CH)2), 8.72 (d,1 H,J = 7.4Hz, 3'-NHCOCF3), 11.08 (S,1 H,thiazole-NHAc) .
IR (Nicolet 205 FT, film on NaCI plate): 3539.7 (br,w), 3296.1 (str), 3083.7, 2919.4 (str), 1732.7 (str), 1667.5 (str), 1593.9 (w), 1547.7 (str), 1528.7 (str), 1127.1 (str), 1217.2, 1183.2, 1166.2, 1104.0, 1008.9, 975.46, 956.53, 718.14(m).
.
Step 4~ S,1-R,3-S)-1-(2'3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose) -3-(2-aza-3-acetamido thiazolyl)-5, 1 0-dioxo-3,4, 5,1 O-tetrahydro-1 H-naphtho-[2,3-c]-pyran To an ice-cold solution of PNB-derivative (3mg, 4.1 mmol), from the previous step, in a tri-solvent system containing water (98 ,ul), MeOH (422 ,ul) and methylene chloride (158,ul) was added an aqueous 46a WO 94/11382 PCI`/CA93/00463 21~6~
solution (20 ~LI) of ~otium ' : (0.51 mg, 6.11 mmol). The re~ction mu~ture w 8 then stirred at room , ~; for 1 hour. When the re ction W9C ~ , I ' d, (_8 judged by t~ t ,~
, , ' y), the reaction mL~ture W_8 poured into _ bi-l~yer system of ' ~ chloride and ~ u~ueous 9 chloride solution (5 ml/S ml). The well-shslcen mL~cture was then allowed to settled u~d the org_nic l_yer W9 ~ ~ ' d, dried over sodium sulfate, and 6.~ to give the titled - a8 a light colorod solid (1.4 mg).
M.P. (P' ~ ' ' LA-9100): 160-165C, ~ t 195C.
lH NMR (250 MHz, ~ ~ .~G), o: 1.12 (d,3H,J=7.9Hz,6'-CH3), 1.24 (dd,lH,J=6.7Hz,15.0Hz,2'-HC~I~), 2.14 (dt, lH,J--4.2Hz,15.0Hz,2'-HC~e), 2.25 (~,3H,COCH3), 2.64 (dd,lH,J=l~ ~H~ ~0 9Hz,4-HC~), 3.13 (dd,lH,J~4-~U7 ~n.9Hz,4-HC~e), 3.63 (bs,lH,4' CH), 4.21 (qua,lH, 1=7.9Hz, S'-CH), 4.30 (m,lH,3'~, 5.26 (dd,lH,J=4.2Hz,12.5Hz,3'-CH), 5.50 (d,lH,J=2.4HZ,1'~, 5.97 (s,lH,l-CH), 7.12 (8, lH, ;' If CH), 7.90 (m,2H,7.8,ArH), 8.10 ,~U,6 9,ArH)~ 11.07 (6, lH,thi_zole-NHAc).
IR (Nicolet 205 FT, film on N_CI plate): 3668.0-3119.7 (podced d 3268.3,br,str), 3073.7 (w), 2925.1, 1711.8 (str), 1669.4 (str), 1591.6 (w), 1549.1, 1375.8, 1290.9 (6tr), 1170.6, 1006.5 (w), 984.49(6tr), 716.33 (w).
Step S: (l'-S,l-R,3-S)-1-(2',3',C~ ~ ~-3' t '' . v ~ L l~ ' . ,. v ~) 3-(2~-3-~i~h~lyV-S, Woxo-3,4,5,10~ydro-lH-naphth)-lt,3-Cl pyr~n To a s mple of PNB ' . ~_ (2.5 ml~, 3.5 ~mol) from dep 2, ~ 1~ in t,; ~ '~,. sytatem e w ter (85.7,ul), ' ~1 (370~.1) nd methylene chloride (138/~1), at 0C, w~s sdded -solution of sodium ' ~~ ~ (0.66 mg, 7.0 ~mol, in 30~1 of wder). The re ction mi~cture w~s sti~ed a t room I ~ for 1.5h untill t~ tlotal t pt of the st~ng m~ial. It w~ pou~d into t~
d sodium b ~ solution (4ml) tnd e. . d with ' ~ - chloride (5~2ml). The organic layer was dried over odium t~ulf te nd then c., ' to givc a crude product which wa6 further purified by ,_.~ ' from - ~- - ' ' ~ " - to gi~te t n off-white solid (l.Smg).
M.P. (lik_h~ - ' IA-9100): 142-146C.
lH NMR (250 MHz, acot~d6), o: 1.14 (d,lH,J~5.9Hz,6'-CH3), 1.74 (dd,lH,J=12.5Hz,4.8Hz,2'-HCH-), 2.11 (m,lH,2'-HCHe), 2.62 (dd,lH, J=11.8Hz,18.4Hz,4'-HCHa), 3.12 (dd,lH,J=4.2Hz,18.4Hz,~HCHe), 3.65 (bs,lH,4'-CH), 4.24 (qu-,lH,J=S.9Hz,5'-CH), 4.33 (m,lH,3'{~, S.ll (dd,lH,J=4.2Hz,11.8Hz,3 CH), 5.48 (bd,lH,J=3.0Hz,l'{~, 5.92 (s, lH,l-CEI), 6.57 (8,1~,1' ' ~- CH), 7.87 (m,2H,7.8,ArH), 8.08 (m,2H, 6.9,ArH).
IR ~Nicolet 205FT, film on NaCI plt~lte): 3423.9 (str), 3341.1 (str), 2927.0, 2853.4 (w), 1718.5 (str), 1664.4 (str), 1597.5, 1524.7, 1335.0, 1300.1 (str), 1174.0, 100.4, 984.61 (str), 724.51, 707.71.
EXAM~E 9 SUBS I I~UT~ S~ET
Ex~71~ Y 2 1 ~
N HAC
O O
H ~Br ~ ~/S
~COJCF3 ~COJCF3 H3C~
PIIBO
NHAc O N~( ~ vs BCH-1198 H3C~
~ NHCOC i 3 OH
Step 1~ -S~ 3-R)-1-(2~.73~ 41 p ' ~ yl 31 L-'' G :~~ ' '~ L-) 3-(2 ~ I)-S,10 - 3,4,S,10 t ~. ~ lII "! q ~2~3 C] ~
To ~ 801utioll of (1'-S,l-S,3-R~1~2',3',6' t~ y~l' P .~ ~1 3~ 1 r ~~ ~ L-1~ ~ rJ ~ )-3~1-S,10-dio~o-3,4,S,10~ t2,3~ pys~ (50 ~g, 0.077 mmol) in W ~ r r (3 ml), 8tirrod ~t room i .i, W98 ~ olution of ~" ' -h~ 7 ~ ' pc.b._ '- (24.5 mg, 0.077 mmol) in THF. Thc re~ction mL~rc w~s sti~rod for 2 hour~
t room i thcn pourod into v~ter (10 ml) ~nd ~ d with ' ~- - chlonde (3~5 ml).
Tho . ' - ' org~ic e~~ v.~ere w sbod with brine (5 ml), nd dried ovor odium sulf te. The Holvent w~ ~ to ~pve ~ crude 7p~duct (68 mg) from which, vi~ " p' ~ (duent in volume r~tio, k ' ~ te~ 10:3), ~ pure 6unp1e of thc titled ' - e (27 mg) w~6 obtdnod 15 light yellow ~olid. U k d ~ting m teri-l (10 mg) w~ ~18O o~` - d.
lH NMR (250 ~7~J _' - d6), ~: 1.33 (d,3H,J--6~8~T~ 6'{~H3), 2.02 (dd, lH,J=4.9Hz,13.SH~,2'-HC~I), 2.48 (dt,lH,J=5.8Hz,13.5H_,2'-HC~e), 2.78 (dd~lH~J~l2.1~7~n~H7l4-Hc~ 3.12 (dd,lH, J 4.0Hz, J=20.3 Hz,4-HCHe), 4.29 (m,lH,3'{H), 4.52 (d,lH,J=1~.8~7.R~CHre), 4.67 (d,lH,J=13.~7 R~C_si), 4.88 (qlu,lH,J--6.8H_,5' CH), 5.04 (dd,lH, Js4.0H_,12.1H_,3 CH), 20 5.53 (bs,lH,4'~, 5.85 (bd,lH,J=3.4H_,I'-CH), 6.24 (6,1H,1~,7.90 (m,2H,7,8-ArH), 8.10 ,?~ 6 -~rH), 8.48 (qu~-lilce m,4H,PNB-ArH), 8.70 (bd,lH,J=7.4H_,3'-NHCOCF3).
Step2: (1'-S,l-S,3-R)-1-(2',3'C'-h ' ~1'~p-~iL~ 13'-triflu rr -~ido-I,-~ r--- ) 3--(2~--3 ~ ~) 5,10 ~ 3,4,S,10 1 ~. 1~--2 5 ~ phtho-[2,3-c]-p~all S U B S ~ 3 L ~ ë
WO 94/11382 PCI~/CA93/00463 214~
A -mple of 1 ~ ~ , 9.0 m~l) in o~or (2 ml) w s~d d room I , .~ while ~olution of h.~ etone (9 mg, 8mmol), from the previous step, in ' yl~c chloridc (0.5 ml) w98 ~dded. Thc ~6ulting mLlc~ w~s ~tirrcd for 3 hour~ ~t room I . e ~nd then for 4 hour~ ~t 5 40C. Solve~lt w .,., d to give cn~do product which w purifiod vi fl~h ~ L .~.~
(dualt in volume r~tio ~ r ~ 100:7, with 1 drop of pyridine ~ddod), to yield ~ product, which w furlher purified by ~ " - from CH2C12A~nc. The titlod ' w o~inod ~n off-whito ~olid (4mg).
lH NMR (250 MH_, ~d6), ~: 1.33 (d,3H,J~7.SHz,6'-CH3), 1.96 (dd,lH,J=5.8H_,15.2H_,2'-10 HCEO, 2.28 (s,3H,COCH3), 2.49 (dt,lH, J~ 3.8Hz,15.2H_2'-HC~c), 2.76 (dd,lH,J=12.S~ ~O.Q~7 ~H~), 3.15 (dd,lH,J--4 '~7 '~Qn~7 4-HC~c), 4.60 (m,lH,3'~,4.92 (qu~,lH, J~7.SHz,S'~, S.24 (dd,lH,J~4.2Hz,1~ ~7 ~{~, 5.55 (bs,lH,4'-CEI), 5.68 (bd,lH,J=3.0H_,1'~, 6.16 (s,lH,l{~, 7.18 (s,lH, 1' '- CH), 7.92 (m,2H,7,8-ArH), 8.14 ' ,~,6 9-ArH), 8.36 (t,2H, J~8.3Hz,PNB-OCOC(CH)2), 8.42 (d,2H,J=8.3H_,PNB-N02C(CH)2), 8.74 (bd, lH,J=7.9H_, 3'-~lCC~3), 11.07 (s,lH,thi zolo-NH~C).
Step 3: (1'-S,1-S,3-R)-1-(2',3',6'~ -3'-: ~ . ~etsmido ~1~ ' . ,,.~ose)-3-(2~-3-~mido-thi~zolyl)-S,10 ' ~ 3,4,S,10 ~ lH~phtho-12,3 c] ~, ~
20 A srmple of thc PNB d . -~o (4.0 mg, S.S mmol), ftom tho previou8 rbp, W t~cn into ~ solvont tcm c e b~' - cbloridc (212 /~1) ' -' (566 ~1) nd w~tor (131 ~LI), uld coolcd to 0C.
An squows lution of sodium ~- L (0.69 mg, 8.2 mmol in 20 ~1 of w~ter) w thcn rdded to the ~ction mLl~tu~e. Thc ~ction ~,.~ st 0C for 1 hour nd ~t mom ~ - for 20 minutcs. The re ction mLl~turC w~ pourod into ~ cturc of - J- - chlondc ~nd ~ 9 chlonde 25 ~uoous ~olution (Sml/Sml). Tho orlpnic l-ycr w~ t . d. driod o~r odium sulf te nd then _. . d to drg~4. Tho c~ p~ducl w ~ f~ ' ' - - " - to yield the titled ~ li,' t-e ' ~ olid.
M.P. (F~ ~-9lOO): n~,c . - ~ st 195C.
lH NMR (250 MHz, ~ ), o: 1.35 (d,3H,J--7.5Hz,6'-CH3), 1.76 (dd,lH,J=5.8Hz,14.2Hz,2'-30 HC~), 2.16 (dt,lH,J~4.2Hz,14.2Hz,2'-HC e), 2.75 (dd,lH,J~12.1~'~o.~ 4-HC~), 3.12 (dd,lH,J~.4.0Hz, 2n ~"1 II~_e), 3.72 (bs,lH,4'-CH), 4.28 (m,lH,3'-CH), 4.58 (qu~,lH, J--7.5Hz,S'~, S.18 (dd,lH,J--4.0Hz,12.1Hz,3~, 5.48 (bd,lH, J=2.9Hz,l'~, 6.10 (s,lH,1-CH), 7.16 (6,1~ - l~ CH), 7.90 (m,2H,7,8-ArH), 8.11 ( ,~,6,9-~rH), 8.17 (d,lH,~... - . p d,~'-NHCOCF3), 11.07 (8,1~,1- ' NH~c).
35 IR (Nicolet 205 FT, film ~n N~CI pl~te): 374~3048 (p~lcod Yt 3388.3, br,dr), 2923.2, 1712.9 (6tr), 1664.9 (6tr), 1591.9, lS50.1, 1535.5 (6tr), 1289.3 (6tr), 1243.4 (m), 1145.4 (w), 1124.5, 1080.7, lOOl.S, 971.57 (6tr), 936.11, 709.75 (w).
SU~S~I~UTE SHEET
WO 94/11382 pcr/cA93/oo463 214~'~a~ --EXL~M~E 10 r p~lo X~
NH2-N(CH3)2 c~ O
}~c~
~o~l o o o o X~ X~
o o o R~O~' E~O
O O O o X~
O O O O
~' ~
5 Sbp 1: r~ N,N
Under N2, Jt room ~ , .;, w~s mL~cd 3g (SOmM) of ~ in 60dium " ' - ' 801ution 7. lg (SOmM) in SO ml H20 ~nd 3.5g (SOmM) , ' The muchlre wus ~,;Oc,1~ sti~Ted for 10 minutes ~It 60C ~d then 30 mlllUte8 ~It room I , ~i. The 801ution wa8 e ' ' Wlth Et20 SUBSTITUTE SHEET
.
WO 94/1 1382 ~ r PCT/CA93/00463 2i46.~
(3~40 rnl), dried over MgSO4, nd c. . ~ ' rho rcsidue w~s fl~ L~ ' using CH2C12 ~s oluellt; 5. lg of colorless oil W~8 isol ted.
lH NMR (250 MHz, CDCl3)~i: 2.13 (s,3H,CH3), 3.04 (~,6H,N(CH3)2), 5.23 (bro~d 6,1H,C=CH2), 5.32 (bro~d s,lH,C~CH2), 7.25 (s,lH,C~CH).
-Step2: (l'S,l.C;,'R) snd (1'S,lR,3S) methyl (1-12',3',6'-trideoxy-3'-L '` .- '- q'~
' ~ Jl L 1~ ` r~-~ ] S~10 ;~- 3~4~5~10 I ~ 7 ~1 g -- o~phtho 12,3-cl pyr~n-3-yl Icelone 10 Under N2 ~t room i , ~, lo 235 mg (0.394 mM) of quinonc from step 1 (o~mple 5) ~ ,d in 20 ml of dry 1~, w~ ddcd 1.1 oq. (47 mg, 0.399 mol) of lb~.' ~ from stcp 1 (~ , '~ 10), nd 1.1 oq of F ~' - sulfonic cid (0.4 mM, 76 mg). After stirring 1 d~y ~t room t~ ~" the mi~cturc wss pourod into 20 rnl of H20, ~nd - ~ with EtOAc (3~c15 ml). After trying snd e., tho rosiduc w~s fb~h ' . O .' -d [EtOAc 1: toluene 31 to giYC 95.1 mg of titled 15 ~ . ' (40% yield).
lH NMR (250 MHz, CDC13)~: 1.22 (d,3H,5'-CH3), 1.75 (dd,lH,2'-CH2), 2.18 (m,lH,2'-CH2), 2.32 (s,3H,COCH3), 2.59 (s,3H,C7-CH3), 2.62 (u.. ' .r d m,lH,H-C4-H), 3.1-3.3 (m,lH,HC4H), 4.32 (m,lH,5'{H), 4.S3 (m,lH,CHCOCH3), 5.4 (m,lH,3'~I); 5.5 (m,lH,4'-CH), 5.7 (m,lH, 1'-CH), 6.2 (~,lH,C1-H); 6.4 (m, bro~d,lH,NH), 8.2 (~ d m, lH,C6~ ), 8.2-8.4 (m,4H,p-L ~1), 8.2(m,1H,Cg-Huom).
Step3: (1'.~,1.~,3'~) ~nd (l'~ S) methyl-1-(2',3',6'-trideoxy-3'-tril . ~ J~
L 1~, ' J. ) S,10 ~- 3~4~S~10 1 ~ 7 ~ Jl O _ l~ - - 12~3-c] p~n-3-~l lceto~e To 80 m~ (0.121 mM) of ~ , ~ f~m ~tep 2 (o~mple 10), ~ 3d in 13 rnl MoOH nd 3.2 ml H20, w~s ddod 10.4 mg (0.121 mM) of N HCO3. ~er stirring for 2 hours, the r~ction wss over, nd 15 ml of H2O w dded. The mLlcture wss o '11 with 3~15 ml EtOAc. After drying snd .., ~ ~ the rosidue w~s purifiod by p..i, ~_ TLC nd yidded 30.4 mg of puro titlod _ , 30 (50% yidd).
lH NMR (250 MHz, CDC13)~: 1.24 (d,3H,J=6.5Hz,CH3), 1.76 (dd,lH,2'-CH2), 2.16 (m,lH,2'-CH2), 2.30 (s,3H,COCH3), 2.58 (s,3H,C7~I3), 4.3 (m,lH;5'-CH), 4.52 (m,lH,CH-COCH3), 5.3 (dd,lH,3'-CH), 5.5 (dd,lH, 4'-CH), 5.6 (m,lH,l'-CH), 6.1 (s,lH,CI-H), 6.4 (m, bro~d, lH,NH), 8.2 (m,lH,C6-H ~rom), 8.9 (m,lH, Cg-H uom).
SI~E~ ET
WO 94/11382 214 6 ~ 4 ~ PCI`/CA93/00463 r - ,pr L~IF-, af . ,~ ~-CIpgTan ~ ~ of o o ~+ ~
o o o o ~+ ~
o o o i.
R~30~ p~o CP~8 o o o o ~+ ~"O"U~
o o o ~
R~o~8 R~30~8 Step 1: n~ foc~
To ~ stirrod solu~ion of ~ fuc~l (114 mg, 0.53 mmol) in -1 (2.5 ml) wuc ~ddod ~ solution of sodium '- in ' -' (25~1, 4.37 M, 0.1 mmol) ~fter 45 n~inute~ ' w~s c~, ' under vscuum. The crudc product w~ d- h~ in CH2C12 (2.5 ml) ~nd pyritine (1.5 ml) ~nd ~t 0C, p -~ ,I chlonde (2.1 mmol, 390 mg) w~ ~dded. After ~ few milute6 ~t 0C, the re~ction 10 mLlchlro w~ poured in CH2C12 (20 ml) nt w~shed with w~ter, N~HCO3 10%, Jnd theD bIine. The titled product w~ purifiod by fl~h -' . O , ' ~ tc (AcOct S: 1)) (MP: 130-132C)(210mg, 909G).
lH NMR (250 MHz, CD2C12)o: 1.40 (d,3H,-CH3), 4.40 (q,lH,H-S), 4.85 (m,lH,H-2), 5.65 (m,lH,H-4), 5.90 (m,lH,H-3), 6.6 (m,lH,H-l).
SUBSTITUTE SHEET
-2 ~ 8 Step 2:
(l'S~1~C,3'~)snd l'S,~3S) byl 1-(2',6' t- ' ~-3',4'-di-0 ~
1~ * ~ ) S,10 1 3,4,5,101 b,~d ~~ p~ - ~ 12,3~1 PY~3~Yl) IcetoDe To ~ musturc of mcthyl (1 hyL~.~r-5,8~io~ 5,8~ ~ 3-yl) Icetonc (698 mg, 3.1 mmol), 1,5; ' ~.' ~3,4 di~ ~ 1-2,6~ideo~cy-L 1~ ~'~ -l-autol (1.58g, 3.7 mmol), snd '- ' sicve6 4 A (3.8g) in CH2C12 (150 ml), ~t -60C, w~ ulded L;.,t~ (0.24 ml, 1.7 mmol), Jnd I ~ 1 b '' . '; '' (0.64 ml, 3.3 mmol), ' ,, 'ly. ~er stirring for 40 mil~utes, the ro ction W9S, ' - ' by sdding ~queous N HC03 (50 ml) Jt -60C ~d ,, ' ~, w~rmed up to room i . ~;. T ~ werc filterod off nd thc filtr~te w~ ~ ' into CH2C12.
The org~uc phs6e w~s w~hed with ~queous HCI (0. lN), lOOml, w~tcr nd brine, dried over MgS04 nd the solvcnt c~ to give 2.36 g of cn~de ~ ' - - gl~;dc. This W~8 used without ~ny furthcr r - - To ~ solution of the ~uinone (mL~ture of :' 0.16g, 0.25 mmol) in 2.5 ml of dry toluene, under Jrgon ~t room i . ~, wrs dded 1 ~ ' - (0.15 ml, 5 eq) snd the re~lction mLlcturc wss 6tirred for 18 hour6. Silic~ gel (1.0 g) wss then ~ d snd sir ww bubbled through the . ~fter 15 minute6, the mi~cture w~ ' . . .'-d (sili-~ gel, 3:1 ~'ell~ co~e) to give 0.13 K (74%) of . . ' 178-2401 (1:1 mi~cture of ~' . ) 20 yellow li' , 129-132. lH NMR (CDC13)li: 8.34-7.73 (m,12H), 6.23+6.06 (2s,1H), 5.82+5.72 (2d,1H,J=2.8), 5.62-S.S2 (m,2H), 4.88+4.43 (2q,lH,J=6.5), 4.62+4.58 (2dd,1H,J 4.1,11.5), 3.10+3.02 (2dd,1H,J 4.1,6.1), 2.62-2.10 (m,3H), 2.35+2.33 (2s,3H), 1.42+1.28 (2d,3H,J=6.5).
EX~ME~E 12 SUBSTITUTE SHEET
W O 94/11382 PCT/CA~93/00463 2 1 ~
O ~ O Me ~ 1, ~ ~
OMe O_~ OMc O
~3, O OH OMe OH
~ ~~
Mc ~ M~
~ OAc ADO QAc BC~ 7 Stqpl: 2~rrbilboor~4-h~dnD~butyl)-ben l~' b~d~ co~
To ~ ooolod(-lS-C) lu~on of2,5 ~xl~ (13.2 ~; 44.6 ~nol)in 300 5 n~ of ~ ~d ~ u ~dded l.hvl,.. . under ~rgon, n P ~ (32.2 n~ of J~ 2.5M
solu~on in 1 - ~ ~ m}nol). Thc n~i-Ab~rc w~s wu~od to -7C ~ timd ~ , for S hou~. Ibe 106ulting mL~tu~ w~s ooolod to -78-C, tre tod w~ e&c~tc (21.8 ml; 177 mmol), ~d 1,2 ~A~ - (10.2 ml; 119 m~nol). ~er ~g Jt -78-C for 60 minut~ thc ~ction mi-Atu~e w~ qua~ot with ~ ~ch~tot solution of 1 ~ Jnd then ~c' d wilh clher. Thc org~nic SU~5~iTUT~ S~-~EET
Iayers were combined, washed with water, and brine, and were dried over MgSO4.
Removal of the solvent gave a crude oil which was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford 2.39 g of pure starting material (18%) and 5.21 g (52% based on S.M. recovered) of 2,5-dimethoxy-6-(2 hydroxybutyl)benzaldehydedioxane acetal as an oil.
'H NMR (250 MHz, CDCI3)~: 0.95 (t,J=7.3 Hz,3H,-CH2CH3), 1.35 (1H, dm,J = 13.6Hz,-CH2-CH~q-CH2), 1.55 (2H,m,-CH2-CH3), 2.18 (1 H,m,-CH2-CH~x-CH2) 2.98 (1 H,dd,J = 2.7 and 13.7 Hz, = C-CH2-CH-O-), 3.36 (1 H,dd, J = 10.3 and 13.6 Hz=C-CH2-CH-O) 3.65 (3H,s,-OCH3), 3.66 (3H,s,-OCH3), 3.60 - 4.10 (4H,m,-CH~q-O-,-CH-O~.), 4.16 (2H,m,-CH~x-O-), 6.16 (1H,s,-O-CH-0-), 6.61 (1H,d,J=9.0 Hz,Ar-H), 6.70 (1H,d,J=9.0 Hz,Ar-H).
Step 2: 5,8-Dimethoxy-3-ethyl-1-hydroxy-isochroman To a stirred solution of 2,5 dimethoxy-6-(2-hydroxybutyl) benzaldehydedioxane acetal (5.2 g; 17.6 mmol) in 700 ml of THF at room temperature was added dropwise 25 mlof a 1 N solution of HCI. The resulting mixture was stirred for an hour at room temperature and then quenched with a saturated solution of sodium bicarbonate. It was then diluted with 1000 ml of dichloromethane and the aqueous layer, after separation, was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. Evaporation of the solvent gave pure 5,8-dimethoxy-3-ethyl-1-hydroxy-isochroman (4.1 g; 98%) which could be recrystallized in dichloromethane/hexane to give white crystals (M . P.: 108.9- 110.1 C) .
H NMR (250 MHz, C6D6)~: 1.02(3H,t,J=7.4Hz,CH2-CH3), 1.60 (1H,m,-CHH-CH3), 1.76 (1H,m,-CHH-CH3), 2.48 (1H,dd,J=11.6 and 17.3 Hz, Ar-CH-~x-), 2.88 (1H,dd,J=3.3 and 17.3 Hz, Ar-CH-~q), 2.98 (1H,d,J=3.9 Hz,-O~), 3.34 and 3.38 (6H,2S,-O-CH3), 4.28 (1H,m,-CH-CH2-CH3), 6.40 (2H,m,ArH and -O-CH-O-), 6.46 (1 H,d,J = 8.8 Hz,ArH).
Step 3: 3-Ethyl-1-hydroxy-isochroman-5,8-dione.
To a stirred solution of 5,8-dimethoxy-3-ethyl-1-hydroxy-isochroman (760 mg; 3.19 mmol) in 160 ml of acetonitrile at 0C was added dropwise a solution of ceric ammonium nitrate (CAN) (5.25 g; 9.57 mmol) and sodium bicarbonate (1.45 g; 17.2 mmol) in 40 ml of water. The resulting mixture was stirred for an hour at 0C and was quenched by adding a saturated bicarbonate solution. The aqueous layer was extracted 3 times with dichloromethane and the combined organic layer was washedwith water, brine, and dried over MgSO4. Evaporation of solvent gave a crude quinone which was suitably pure to undergo further reactions (600 mg; 90%).
1H NMR (CDCI3)~: 1.02 (3H,t,J=7.4 Hz,-CH2-CH3), 1.70 (2H,m,-CH2-CH3), 2.15 (1H,ddd,J=1.1,12.4 and 19.5 Hz,Ar-CH-~x-), 2.60 (1H,dd,J=3.2 and 19.5 Hz,Ar-CH~~oq~)~ 3.20 (1H,br s,-OH), 4.08 (1H,m,-CH-CH2-CH3), 5.91 (1H,s,-O-CH-O-), 6.76 (2H, 2 parts of an AB system, Ar-H).
55a CA2 1 46~48 Step 4: (1 ' S,1 S,3S) a nd (1 ' S,1 R,3R) -5,10-d ioxo-3-ethyl- 1 -(2',3' ,4',6 '-tetradeoxy -3',4'-diacetoxy-L-lyxohexo-pyranose)-3,4,5,10-tetrahydro-1 H-naphtho[2,3-C]pyran To a cooled solution (-60C) of 3-ethyl-1-hydroxy-isochroman-5,8-dione (150 mg;.72 mmol) in dichloromethane (40 ml) were added sequentially molecular sieves (4A,864 mg), 3,4-di-0-acetyl-L-fucal (246 mg; 1.15 mmol), triethylamine (56,ul) and trimethylsilyl trifluoromethanesulfonate (138,ul; .72 mmol). The resulting mixture was stirred at -60C for 3 hours and was quenched with an aqueous saturated bicarbonate solution. Extraction with dichloromethane was followed by washing of the combined organic layers with 1 N HCI, brine, and then drying over MgS04. Following evaporation, 407 mg of the resulting crude thick oil was dissolved in 20 ml of toluene.
To this solution was added 1-acetoxy-1,3-butadiene (521 mg; 4.82 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Solvent was thenpartially evaporated to about 4 ml volume and the residue was applied to a column of silica gel (eluent, toluene, ethyl acetate 90:10) affording 2 fractions. The first one (48 mg, 14% overall) contained a 2:1 mixture favoring the (1'S, 1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L-lyoxohexopyranose)-3,4,5,10-tetrahydro-1 H-naphtho] 2,3-C]pyran over its (1 'S,1 R,3R) isomer and a second fraction (157 mg; 46% overall) consisting in a 1.5:1 mixture of the same major diastereomer that was about 80% pure from 'H NMR analysis.
1H NMR (1'S,1S,3S isomer, CD2CI2)~: 1.00 (3H,t,J=7.3Hz,-CH2-CHJ, 1.23 (3H,d,J=6.4Hz,6'-CH3), 1.55-2.20 (4H,m,-CH2-CH3 and H-2'), 1.89 and 2.12 (6H,2s,0 = C-CH3), 2.27 (1 H,dd,J = 11.3 and 19.3Hz,Hax-4), 2.74 (1 H,dd,J = 3.3 and 19.5Hz,Heq-4), 3.95 (1H,m,H-3), 4.58 (1H,q,J=6.5 Hz,H-5'), 5.10 (2H,m,H-3' and H-4'), 5.46 (1H,d,J=3.5Hz,H-1'), 5.95 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H).
'H NMR (1'S,1R,3R isomer, CD2-CI2)~: 1.01 (3H,t,J=7.3Hz,-CH2-CH3), 1.11 (3H,d,J=6.5Hz,6'-CH3), 1.55-2.35 (5H,m,-CH2-CH3,H-2' and HaX-4), 1.89 and 2.12 (6H,2s,0=C-CH3), 2.74 (1H,dd,J=3.3 and 19.5Hz, H~q-4), 4.00 (1H,m,H-3), 4.22 (1 H,q,J = 6.5Hz,H-5'), 5.10 (2H,m,H-3' and H-4'), 5.54 (1 H,d,J = 3.0Hz,H-1 '), 5.79 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H). The (1'S,1S,3S) diastereoisomer was obtained pure by recrystallization.
WO 94/11382 2 14 ~ ~ 4 8 PCI/CA93/00~63 F. ,~r- 13 Fl . of ~ ~] r~ &~ly~lCS.
+~
,~ NaOCH3, CH~
2~ ~+
OCH3 OMe OCH3 OMe (2:1) 3, 5 O OMe O O~Ie O O O O
~+~
o OMe o OMe O O O O
~ + ~5 o OH o OH
step 1: 3 ~
SUBST~TlJ ~ E ~E~
WO 94/11382 2 1~ 6 ~ ~ 3 . PCI/CA93/00463 1-T~ ... 2-one (10.083g,51.97r~nole) was ~ ~ in MeOH (100ml), cooled to 0C, followed by the 61Ow ddition of NaOMe (4.37M,14.3ml,62.36mmol). The rwulting mi~ture was stirred at 0C for 3/4 hr. It wa6 then cooled to -78C followed by the dow ~ddition of 2,3~il..~ ' yl-1,4-~ (6.74g,20.79 rnmol) in CH2C12: MeOH (60:20ml). The re~ulting mLsture was 610wly5 w rmed to R.T. nd stirrod for 2 112 hrs. NH4C1 ~ ~ solution) w~s dded Jnd it w~
6 ~ - d with - ethyl ~cetste. The . ' ' org nic ph~6e6 were dried over MXS04, filtered uld r~ ' in v~cuum. Thc crude obtuned W~16 fl~h ~m ~ ' to give thc titled c . ' (2.08g,8.25mrnol) in 41 % yield.
lHNMR(250MHz, CD3COCD3)~;: 2.31 (s,3H,CH3),2.83(dd,1H,J=1.06, 8.55 Hz, HC~CH-S), 2.99 10 (dd,lH,J=2.44,6.17Hz, HC~eCH-S), 3.44 (m,lH, CH-S), 3.78 (2s,6H,OCH3), 3.85 (2H,CH2-S), 6.78 (dd,2H, J=8.95, 12.58Hz,ArH). IR (cm~l): 2900: CH, 1707: C~O.
Step 2: Tn~ 3-sceto-1,5,8-t. ' ~1' ' ~nd c~3-sceto 1,S,8-1~ ' ~;' ' The i ' . from step 1 (r , '- 13) ~100.0mg,0.40 mmmol) was ~ d in CH2C12 (12ml) und MeOH (4ml) Lll. ..~ by the addition of DDQ (109.0mg,0.~ -1,1.2eq [I~) ~t R.T. The resulting mLlcture was 6tirred ~t rvom I . ~7 v._.~hl. H20 w s ulded und it W~ with CH2C12.
The ~ ' - ' org Dic ph~es wcre w shed with w ter, dried over MgS04, filtered und c~ q ' in 2 0 vu uum. The crude obt ,ed w s fl sh ~ ' ' u6ing toluene: dh~-- ~ (95:5) to give the t~ titled ~ , ~ (65.0mg,0.~ ' -l) in 58% yield (MP: 84C).
lH NMR ('~n''~7CDCI3)~: 2.34 (s,3H,CH3CO), 2.91 (dd,lH, J~11.73,17.78H_,HC~aCHC-S), 3.27 (dd,lH,J 4.10,17.77~ ~C~ç~C-S), 3.54 (s,3H,OCH3), 3.78 (s,3H,OCH3), 3.82 (s,3H,OCH3), 4.16 (dd,lH, 4.13,11.79Hz,CH-S), 5.69 (s,lH,O-CH-S), 6.75 (dd,2H,J~8.96, 14.36 25 H_,ArH). IR (cm~1): 2925: CH, 1705.7: C=O. Cis-3~ceto 1,S,8: ' ~ ' ' (32.4mg,0.11mmol) w s obtuned in 30% yield (MP: 129C).
lH NMR (250MHz,CDC13)~i: 2.34 (s,3H,CH3), 3.25 (d,2H,J=6.S8Hz, ~.C~eCHC-S), 3.46(s,3H,OCH3), 3.59 (dd,lH,J~6.75,13.55H_,CH-S), 3.79 (2s,6H,OCH3), 5.73 (s,1H,O-CH-S), 6.76 (dd,2H,J=9-~0,~1.3QT~7 ArH).
Sbep3: Tr~ns-3-~ceto-1 ' ~-~,~ ~- ' ' ~
The ~ _ from 6tep 2 (e~ample 13) (178.2 mg, 0.63 rnmole) W~6 ~ ~ iD
- '- (10 ml) nd H20 (10 ml), followed by thc ddition of N~HCO3 (100.8 m~, 1.22 Dle).
35 The mi~ture wa6 cooled to 0C, followed by the slow uldition of CAN (1.04g, 1.89 mmole). After 20 ~ utes of ~tirring, H20 w~ dded nd themi~ture w~s - ' with CH2C12. The ~ ' -' organic p~ses were wuihed with H20, dried over MgSO4, filtered ~d ' in v cuum. Thc crude obt iDed was found to be pure titled compouDd by lNMR aDd was u~ed in the ÇU~ g step (>95%
yield).
S U ~ S ~ il E ~ k 214~4~
lH NMR (250 MH_, CDC13)o: 1.73 (~,3H,COCH3), 2.62 (dd,lH, J=11.32, 19.81Hz,HCHaCH-S), 2.87 (td,lH,J=4.28, 20 ~n~r ~C_eCH-S), 3.21 (s, 3H,OCH3), 3.61 (dd,lH,J=4.31, 11.42Hz,CHS), 5.97 (m,2H,HC=CH).
Step 4: Tr~-3-~ceto-1 ' / 1,~ ~,4 1 ~ d . (2-6ull~ ~ ' ~ S,10-dione ~nd cis-3-- sceto-l ' ~-1,2,3,4 1 ~ ,d ~ ' ~ S,lWione Tran6-3-aceto-l ~-5,8 ~ ~ (0.66 rnmole) w~s d' 1~ in dry toluene (14ml), followot by thc ddition of thc dicnc (120.0 mg, 1.07 m~nole). The ro6ulting mucturo was stirred at room 10 i , ., v_' Solvont w 8 ro noved and tho crudo obtunet w 8 flash :' I " . ' ' using pure toluono to dvo t~o titled ~ . ' in r~tio of bout 1:1, in 48% yield.
lH NMR (~CQ' '~17 CDC13)~: 2.37, 2.39 (2~,6H,CH3, cis ndlor tran6), 2.75 (dd,lH,J=6.42,19.81Hz,HCHaCH-S, Ci8 ortrns), 2.90(dd,lH, J=11.79, 20.08 H_,HC~a-CH-S, cis or tr n6), 3.27 (dd,lH,J~3.98, 2n~n~7 HCHeCH-S, cis or ~sns), 3.58 (6,3H,OCH3, ci6 or trans), 3.60 (s,3H,OCH3, cis or t~n~), 3.64 (m,2H,CH-S, Ci8 or tr ns), 4.11 (dd,lH,J--3.92,11.80Hz,CH-S, cis or tr n6), 5.30 (c,lH,OCH-S, cis or t~ns), S.49,(s,1H,OCH-S, Ci8 or tran6), 7.74 (m, 4H,ArH, ci6 nd tru~s), 8.10 (m,4H,ArH, cis ~t trJns). IR (cm~l): 2900:CH; 1709.4:C=O; 1668.1, 1631.9:C=O
quinono.
StepS: cis3~ -S,~
0 ' ~ . by u6iug thc ~ from 6tep 3 (e~ample 13), of ci6-3-sce~1,5,8-~;- ~' . gavethetitled lin98%yield.
Hl NMR (250 MHz, CDC13)~: 2.04 (s,3H,CH3), 2.23 (dt,lH,J=4.88, 19.49Hz, HCHaCH-S), 2.54 25 (d,lH,J=5.68Hz,HCHoCH-S), 3.56 (dt, lH, 1=2.10, 19.23Hz,HCHa,o-S), S.09 (s,lH,CH-S), 5.96 (dd,2H,J--10.30, 1~ ~n~7 ~rH).
~up 6: ~ .,4: ' jd ~ (2-6~r~ '' - S,10 dione snd tr~ns-3-,4 1 b,~ ' - 5,10-dione ~1'- - of ~e ~ d~ d for ~p 4 (e~le 13) to ~ns-3-~1 - y-5,8-d - - ~ g~ve pure titled lH NMR (250 MHz, CDC13)~;: 2.37 (s,3H,CH3), 2.75 (dd,lH,J=6.42, 19.81Hz,HCHaCH-S), 3.58 (6,3H,OCH3), 3.64 (m,2H,CH-S,HCHeCH-S), 5.49 (s,lH,~CH-S), 7.74 (m,2H~ArH), 8.1035 (m,2H,ArH). IR (cm l): 2900:CH; 1707.8:C=O; 1660.0, 1630.2, 1594.4:C=O quinone.
Step 7: trsns-3 - ~ 1 b~ ,4 b,.' . (2ffulfur) - ' _ - 5,10-dione and cis-3-9 ~ d ~ ,4 t b,~ ~ (2-sulfur) ' ~ 5,10-dione The mLlCture of - . obt~ined from step 6 (elc~le 13) (30.8 mg, 0.102 mmole) was ~L~vl~
SUBSTITUTE SHEET
WO 94/11382 ~ PCI-/CA93/00463 CH3COOH:H20 C2:0,4 ml) at 0C. The re~ulting m"cture W98 stirred at 0C for about 2 hour6.
NaHC03 (5 %) w~s d~ed ~nd it wss _ ' with CH2C12. The ' -d organic phnse~ were w~hed with H20, dried over MgS04, filtcred nd a~- ' in vscuum. T~e crude product obt~ned war, flsr,h ~ .' ' uung '~ ~1 acetste (7:3) to givc tlle titled ~_~ ' in 7% yield.
5 According to NMR one ixomer i~ m~or:
lH NMR (250 MHz, CDC13)o: 2.74 (r"3H,CH3), 3.00 (dd,lH, J=ll.99, 20.74Hz,HCHaCH-S), 3.26 (dd,lH,J~3.96, 20.61Hz,HC~eCH-S), 4.37 (dd, lH,J=3.99,12.0Hz,CH-S), 6.67 (s,lH,O CH-S), 7.73 (m,2H,ArH), 8.08 (m,2H,ArH).
SUBS~ TE ~ ET
WO 94/11382 . PCT/CA93/00463 ~l 46~4~
EXAME~LE 14 - Tl rJ- J ~r F. "r 1~ n of . ~C]thiopyr~
~/~ ~5+~
O~H3 ~H OCE~ ~ ~ O~H3 () A~O OA~ OA~
A~O A~O
St~p 2 O O O O
O O O ~
H~C~ H,C~
OAD OA~
AcO ADO
S~sp 3 O O O o .~ ~
O O o ~
C~
OA~ OA~
~0 A~O
Step 1:
(l'S,lP ~S) ~u~d (l'S,1.C ~) methyl (1;9J~ d- " ~-1-(2',3',4',6' ~ 3',4'-~ ~-L l~ ' I J- lC ) 3,4,: ' .,. . ' [2,3-cl i I J- 3-yl) l~eto~e A mLlcture of ' ' . from 8tep 1 (e~a~ e 13) (96.0 mg, 0.38 mmol), dicyano dichloro t ~ - (DDQ) (104.0 mg, 0.46 mmol) uld 3,4-di~cetyl-2,6-dideo~y-L-ly.
SUE~
WO 94~11382 PCT/CA93/00463 211165~
/B ~ 3; 106.4 mg, 0.46 mmol) in 5 ml of CH2C12 W95 stirrod Jlt room h~ under rgon for 2.5 hours. After D~ of S ml of NsHCO3 solution (59~) ~ nd 10 ml of H20, the products were e ~ 1 with CH2C12 (25 ml ~c 4). The e ' -' orgsnic ph~se wss w~hed with H20 (lS ml), dried over MgS04, filtered snd then c.. ' The ro~iduç W95 purified by flssh cL~ O ,' y (b ~~'CH2C12/ethyl ~cetste, 2=1=1) to provide ~ ture of titlod ~~, ' (2=1, 116.9 mg, 0.24 mmol) in 64% yiold ~long with ,~ ,d sugsr (48 mg, 0.21 ~nol).
lH NMR (CDC13), the msjor ~ 1.20 (d,3H,J=6.2Hz), 1.70-2.30 (m,2H), 1.94 (s,3H), 2.20 (s,3H), 2.29 (s,3H), 2.98 (dd,lH, J=16.5Hz,10.5Hz), 3.28 (dd,lH,J=16.5Hz,S.lHz), 3.80 ~s,6H), 4.14 (dd,lH,J=lO.SHz,S.lHz), 4.42 (q,lH,J=6.3Hz), J6.3Hz), 5.10-5.25 (m, 2H), 5.65 (d,lH,J=3.2Hz), 6.27 (s,lH), 6.72 (d,lH,J~9.8Hz), 6.81 (d,lH,J 9.5Hz); t~e mi~or isomer: 1.19 (s,3H), 1.70-2.30 (m,2H), l.9S (s,3H), 2.19 (~,3H), 2.34 (s,3H), 2.96 (dd,lH,J=16.5Hz, 10.5Hz), 3.30 (dd,lH,J~16.5Hz,S.lHz), 3.81 (s,6H), 4.22 (dd,lH, J=lO.SHz,S.lHz), 4.42 (q,lH,J=6.3Hz), 5.10-5.25 (m,2H), S.S0 (d,lH, J=3.2Hz), 6.03 (6,1II), 6.70 (d,lH,J=9.8Hz, 6.79 (d,lH,J=9.8Hz).
Step 2:
(l'S,lP~s) ~nd (1'~ "3P.) me~hyl (C~8 ~ 1-(2',3', 4',6' i ' de ~^3',4'-t- ~ ~-L 1~ . ) 3,.~ tP ~ 12,3-c] 1- ')rJ- 3-yl) ketone 2 0 To ~ stirred solution of the i' ' ~ ~;d~ from step 1 (e~umple 14) (106.0 mg, 0.22 mmol) in S ml of CH3CN W9~ ~dded ~ solution of NsHCO3 (35.0 mg, 0.42 mn ol) in 2 ml of w~ter. After cooling to 0C, ~ ~olution of c~ (362.0 mg, 0.66 mmol) in 2 ml of wster ws~ sddod Lv~ After being stimd t 0C for 20 minutes, t~e mi~ture wss e ' with CH2C12 (25 ml ~c 2). The orgsnic l~yer w~s w~shed wi~ H20, dried over MgS04, filtered nd then ~ Thc r~6idue (94.3 mg, 2 5 0.21 Dl) w~s found to be the title ~ . ' (2: 1) by lH NMR. The yidd w~s 9S % .
lH NMR (C~C13), the m~jor isomer: ~: 1.28 (d,3H,J=7.6Hz), 1.53-2.40 (m,2H), 1.99 (s,3H), 2.17 (s,3H), 2.33 (s,3H), 2.74 (dd,lH,J=18.8Hz,ll.OHz), 3.14 (dd,lH,J=18.8Hz,4.8Hz), 4.00 (dd,lH,J~ll.OHz,4.8Hz), 4.24 (q,lH,J=7.6Hz), 4.95-5.20 (m,2H), 5.56Hz (d,lH9J=3.2Hz), 6.00 (s,lH), 6.19 (d,lH,J=ll.OHz), 6.85 (d,lH,J=ll.OHz); the minor isomor: 1.18 (d,3H,J=7.5Hz), 1.53-30 2.40 (m,2H), 1.99 (s,3H), 2.17 (s,3H), 2.37 (s,3H), 2.70 (dd,lH,J=l9.OHz,lO.SHz) 3.15 (dd,lH,J=19.0Hz,4.8Hz), 4.07 (dd,lH,J=lO.SHz,4.8Hz), 4.33 (q,lH,J=7.5Hz), 4.95-5.20 (m,2H), 5.52 (d,lH,J=3.2Hz), 5.77 (s,lH), 6.70 (d,lH,J=ll.OHz), 6.78 (d,lH,J=ll.OHz).
Step 3:
(l'S,lP ~S) ~nd (1'~;,1.~;"3~) methyl (i~8 ~ (2',3', 4',6' . ~ -3',4'-~- ~-L 1~, ~' r~ 3,4,S,10 1 ~d~ p' - ~ 12,3-c1 ' r~- ~~ 3~YI) ketone The },.. ' G for the ~ r 8i of ~c titled . . ' is ~ d~ ikd ~ in ~tep 1 (e~ample 1).
SU~STE ~ U . ~- 5~ET
W O 94/11382 PC~r/CA93/00463 ~ 21~6~48 Thuc, the re~ction of the isoch.~ 1 -- (94.3 m8, 0.21 mmol), ob~ined from the previo~c tep with l-~ceto~y L ' - (0.10 ml, 94.5 mg, 0.84 mmol) g~ve the titled c , ~c 2:1 (74.2 mg, 0.15 mmol) in 70% yield ~fter fl~sh ~ O "h~,.
lH NMR (CDC13), the m~jor isomcr h~d ~: 1.32 (d,3H,J=6.5Hz), 1.70-2.40 (m,2H), 1.94 (s,3H), 2.17 (s,3H), 2.36 (s,3H), 2.91 (dd,lH, J=20.0Hz,11.9Hz), 3.30 (dd,lH,J=19.9Hz,4.2Hz), 4.06 (dd,lH, J=12.0Hz,4.1Hz), 4.38 (m,lH), S.05-5.22 (m,2H), 5.61 (d,lH, J=3.8Hz), 6.23 (s,lH), 7.70-7.80 (m,2H), 8.05-8.15 (m,2H); the minor isomer h~d ~: 1.19 (d,3H,J=6.SHz), 1.7~2.40 (m,2H), l.9S
(s,3H), 2.17 (s,3H), 2.39 (c,3H), 2.87 (dd,lH,J=20.0Hz,12.0Hz), 3.32 (dd,lH,Jc20.0Hz,4.1Hz), 4.15 (dd,lH,J=12.0Hz,4.1Hz), 4.38 (m, lH), 5.0S-5.22 (m,2H), 5.63 (d,lH,J=3.8Hz), 6.00 (s,lH), 7.70-7.80 (m,2H), 8.0S-8.15 (m,2H), IR (ne~t): 3866, 2987-2939, 1745(8), 1715, 1667, 1645, 1597, 1368, 1285, 1252, 1229, 1021, 988, 737 cm l.
EX~MPI,E lS - In Vitro Cy ty - ' . ' .; T~ ' ~sy The " t~ ' ~y w~s u~ed to tcst in vitro c~ ,. This ~y is ~ ~d in Plumb, J.A. ot ~1., 1989 Culcor P- _h 49, 4435 ~440, which i8 ~crein - r ' ~ by .~f~ -e The c.~ , of c . ' towuds tumor ceU6 is d in vitro using the ~y. This u~y method i8 b~cd upon the ~bility of livc, but not dead ceUs to rcducc the ycUow w~ter soluble dye 3~4,5-' ~Ith;~1-2-yl)-2,5~i,' ~' ' bromide (MTI~ to its w~ter I ' '- purple f 2 0 product.
The fuUu.. e rc~gents we~e lu;cd for:
li~ue Culture, (Irvine S- C~log) -MEM: ~ ~' ' (C~t~log * 9144) Fet~l Bovine S~um (C~log # 3000) ~' . ' mino cids (C t log # 9304) n ~ buffered Dline (C t log # 9240) Sodium pyruv te (C~log # 9334).
All other tissue culture nd gener l re~gents were from Sigm~ r . ~.
Human Tunor Cdl lines, used were:
3 0 SKOV3 (Ov ri n ~ ,.v . ;ded by Dr. V. Ling, Ont~io C ncer Institute.
SKVLB (Ov~n; ' ' ~ 1~ ~) - Dr. V. Ling, Ont rio CJncer T
T47D (Dwt~l -. . of b~st) - ATCC c t~log # HTB-133.
Lo~ ) - S~ ' P~ T
HT 29 (Colon ~1 - ) ATCC cst~log # HTB-38.
3 5 The cells were - ~ in e~r ' growth in culture in minima1 e6sentisl medis (MEM) with- . ' mino cids, nd r e 15% (v/v) fetd bovine ~erum, 5~M L-> 1 mM sodium ~".... ~L ~nd 0'1 U/ml in~ulin. AU ceU lines were grown at 37C in sn 9' , ' Ci of 5 % CO2 in Yir.
Stocl~ ' , used we~e the f~" ..- o, sues~ E~EET
WO 94/11382 PCr/CA93/00463 -`2 1 ~
MTT: 2 mg/ml in ~' . ' bufferod s line (6t~blc ~t 4C in d~ for 1 weelc).
Se '8 buffer: 0.1M glycinetN~OH, pH 10.5, ~ ~ 0.1M N~CI.
Te6t c . ' 20 mM in DMSO nd diluted to find ~ of 200 ~lM in culture rnedium before u6e.
The Ç~llv.. E i6 the generic ~ p~ of the ~y mAhod. It should be noted that dthough the 1--- A~ d wor~ well with the cell6 li6ted ~bove, the initid pl ting den6ity nd the MTT
c - - used 6hoult be verifiet for esch new cell line uset to to6t ~ .
For e ch u~y, du.~.,..' is i~cluded ~s n intcr~y ~rd. This ~llows U8 to molutor the of the us~y in generd, nd in ~ L.,ul~, to checlc th~t the SKVLB line h~s - ' its resist~nt,' 15 The pl~lte l-yout is done in the r ~ - e m~nner:
The u~ys re c~rried out in 96-weD (8 weD, ~c 12 well) , pl~tes. Serid dilutions of the re te~ted ~long the length of the pl~te. A 1:3 serid dilution of c . ' in culture medium covers c--~ r nge fiom 100 ~M to 1.7nM. E~ch ~ of c . ' i6 te6ted in ~, ~ . ,' t, llowing two ~ . ' to be te6ted per plate. Wells . e no ceDs (bl~nk) snd cells 2 0 w~th ~o test ~ . ' (control) re included on e ch ph~e.
Cells rc pl ted out in 100 ~1 of culture mediwn in the 3~ pl te6 t dbn6ity of ~round 1,500 -4,000 ceU8 per well. The pl tes are ~.. . - to llow the cells to bocome dherent after which the test ~ . ' is ~led (100 ~1 of ~. r dilution per well). The cells rc ' with te6t 2 5 e . ' t 37C for 48h fter which the - . ' i8 repl ced with fresh modium. After a further 48h at 37C, SO ~1 of MIT solution (2mg/ml) is dded to oach well. The plate~ re: ~ ' in the d~c for 4h at 37C fter which the mediwn is removed. The MIT r product is _ from the cell6 by the ddition of 200 /~1 DMSO followed by 50 ~1 of S~ '6 buffer. The plate6 are O-h~lcen briefly nd the ' ; -- ~ 570 is read using a M~' ' - Dwice6 W m~ plab reader.
3 0 Curves re fit to the MTI' ~6ay d h using ~ four I logi6tic r . nd the d~ta ~re - - ' to fit 0% to 100% surviv 1 scale.
RESULTS
3 5 Tables 1 snd 2 show the sntitumor sctivity of ~ome of synthetie trieyelie pyrulylnsphthoquinones of this .. ' ~n A r n~ e of poteney is ~ d. In this 6et of c . ' Seve~l tricyclic . ' - - .
re 1~ potent nd re effective in the ' ~ ro6ist 1nt cell line SKVLB. In bre~t cancer, MCF-7, BCH-1146 i6 les6 potent than ~ ' .~. but nearly ~18 effoetive in the sensitive ~nd ~
resi6tsnt cell line. Thesc re6ult~ wgge~t tb~t tricyclic d~ ,6 wch a5 BCH-1184 ~nd 1146 6hould be SUES~T~ 5~
WO 94/11382 PCI'/CA93/00463 21~16~8 useful in the L, of certain re6istant c~ncers. Most notably BCH-2051, a r ~ ~ ~ tricyclic - ,' '~. , ,~ intense in vitro potency while :c ~ avoiding multidrug e ss obsa red from the SKVLB cell line.
SU BS ~ t ~ S i~ E ET
WO 94/113~2 PCI`/CA93/00463 2 ~
EXAMPLE 1~
BIOLOGICAL RESULTS
IC50 ~M -COMPOu~n S~Q~3 SKVLB 1~1~ LQ~ 2 ~R/oV3 Adriamycin 0.012 1.49 0.07 0.034 0.090 121.5 BCH1125 ~100 92.90 36.40 52.80 >100 BCH1129 73.30 ~100 59.40 88.20 63.20 BCH1146 0.8910 6.97 5.87 3.82 0.9100 7.82 BCH1148 >100 >100 >100 >100 ~100 BCH1169 7.14 60.10 26.50 9.63 6.29 8.42 BCH1177 9.67 16.50 ,13.30 29.70 25.10 1.71 BCH1180 0.8510 8.68 7.61 3.33 0.4680 10.20 BCH1181 2.26 8.48 9.23 3.07 0.5360 3.75 BCH1184 0.0050 0.0536 - 0.2840 0.0186 0.0023 4.75 --0.0631 0.3000 - -0.2280 - 22.34 0.5300 0.0161 RC~1188 0.8590 2.41 0.6640 0.9470 2.49 2.81 BCH1189 6.50 26.60 12.50 14.30 16.60 4.09 BCH1192 28.60 31.60 29.90 37.60 BCH1607 7.26 19.80 14.70 8.97 21.60 2.73 BCH1608 3.31 15.10 9.55 5.22 14.30 4.56 BCH1620 0.0042 0.2160 0.1830 0.0227 0.0328 51.31 BCH1643 1.74 5.17 3.49 1.65 6.71 2.97 BCH1644 0.5050 1.52 1.27 0.6410 2.65 3.01 BCH1648 0.0519 0.3150 0.3600 0.1380 0.3090 6.07 BCH1649 0.1100 0.4590 0.3800 0.2170 0.3310 4.17 BCH1654 0.7100 3.73 1.59 1.19 3.58 5.25 BCH1658 0.2330 1.47 0.4940 0.3160 0.6610 6.31 BCH1665 25.40 28.90 11.50 60.40 1.14 BCH1666 0.2720 0.2050 0.1250 0.0783 0.75 BCH1667 0.0122 0.0893 0.0133 0.0016 7.32 BCH1688 0.6340 2.77 0.4020 1.35 4.37 BCH1689 2.78 16.50 1.72 3.66 5.94 BCH1690 1.78 13.70 1.62 3.01 7.70 SUBS ~ ~ ~ U ~ E 55~iEE~
WO 94/11382 21~ 8 PCT/CA93/00463 BCH1691 8.83 18.50 4.49 7.16 2.10 BCH1697 3.70 13.20 18.00 5.32 11.00 3.57 BCH1998 0.1250 1.66 0.1140 0.0631 0.0363 13.28 BCH2000 0.0950 6.64 0.3380 0.0905 0.0378 69.89 BCH2014 21.50 39.80 61.80 35.90 61.30 1.85 BCH2015 0.3670 1.17 0.9090 1.09 0.5570 3.19 _ BCH2017 0.2500 8.94 0.4970 0.2500 0.4300 35.76 BCH2018 3.11 17.70 8.56 2.38 14.20 5.69 BCH2019 0.0633 0.3280 0.0486 0.0627 0.0230 4.95 BCH2020 11.20 25.90 9.42 5.45 19.10 2.31 BCH2021 12.40 46.40 19.00 10.60 37.80 3.74 BCH2022 0.4420 1.87 0.9340 0.4840 0.5320 4.23 BCH2023 0.73 3.2 5.5 0.67 0.98 4.39 BCH2024 0.924 5.23 3.7 0.85 0.404 5.66 BCH2026 15 >100 31.40 2.12 22 >7 BCH2027 7.01 29 23.30 3.04 15.40 4.02 BCH2031 6.0 18 16 2.8 8.5 3 BCH2032 6.01 - 17.60 - 15.80 - 2.83 - 8.49 - 2 -12 28 23 5.1 9.3 2.93 BCH2035 0.28 6.23 1.5 0.75 2.31 22.33 BCH2037 0.59 - 3.8 - 2.2 - 0.54 - 1.1 - 0.93 -5.09 4.73 2.29 0.816 4.25 6.41 BCH2038 0.832 3.5 2.0 0.173 2.0 4.16 BCH2041 2.14 10 5.62 1.9 1.9 5 BCH2042 3.8 13.20 8.0 2.22 1.2 3.51 BCH2043 3.1 9.23 11 2.92 4.7 3 BCH2044 1.44 5.11 4.25 0.38 0.194 3.55 BCH2045 5.3 15 13 4.6 1.11 3 BCH2046 0.0075 0.22 0.0675 0.015 0.0071 31 BCH2047 0.017 0.523 0.151 0.021 0.0041 31 BCH2051 0.0073 0.0675 - 0.0419 0.0167 0.091 9.3 --0.029 0.403 - - 0.03 - 14.14 0.0685 0.134 BCH2052 5.4 - 20.50 - 9.54 - 3.04 - 10.60 3.78 -7.01 28.20 23.30 3.22 - 4.02 15.40 BCH2053 4.73 21.20 12.30 3.25 14 4.48 BCH2054 6.33 11.30 4.95 3.23 4.30 1.79 SUBSTITUTE SI~EET
BCH2060 1.14 2.5 0.562 1.95 0.26 2.19 BCH2061 0.0083 0.141 0.27 0.045 0.054 18 BCH2062 0.8100 0.8420 0.7760 0.3540 1.14 1.04 BCH206S 1.54 6.1 2.2 1.4 3.42 4 BCH2067 1.2 2.24 0.54 1.1 0.323 2 BCH2068 1.2 1.2 0.422 1.3 0.13 BCH2069 0.0494 0.083 - 1.11 0.0903 0.35 2 -0.483 9.78 BCH2070 0.0084 0.12 0.018 0.015 0.006 14.34 -_ 15 0.534 BCH2071 0.133 0.43 0.201 0.21 0.05 3.22 BCH2072 0.0641 0.315 - 0.0236 0.102 0.0539 2.79 -- 0.991 -0.35 -0.101 15.46 0.1130 BCH2075 16 31 ~13 8.8 31 2 BCH2076 1.43 12.40 6.53 1.8 2.6 9 BCH2077 1.94 21 7.7 1.91 3.4 11 BCH2078 0.4140 2.24 0.5070 0.2690 5.41 BCH2079 0.0163 0.124 0.032 0.066 0.005 8 BCH2081 1.3 19 7.4 2.7 3.8 15 BCH2082 1.8 5.6 4.0 1.6 2.6 3 BCH2087 0.069 0.472 0.18 0.064 0.028 7 BCH2090 11 36 10.40 3.29 BCH2091 13.40 32 16 3.3 11.30 3 BCH2092 1.1 3.0 0.98 0.30 2.42 3 BCH2095 0.19 1.6 0.37 0.14 0.0996 8.16 BCH2096 0.702 3.11 1.7 0.84 1.7 4.43 8CH2098 8.0 30 10 4.2 17 4 BCH2099 O.S99 - 0.462 - 0.728 - 0.128 - 0.303 0.77 -2.0 8.4 3.4 1.1 - 1.7 2 8CH2100 2.7 8.22 4.0 3.0 5.12 3.04 BCH2102 0.13 0.723 0.30 0.186 0.15 5.65 BCH2104 0.21 1.1 0.613 0.24 0.171 5.05 BCH2105 0.003 0.37 0.019 0.025 0.0069 123 BCH2109 0.79 3.2 1.04 1.1 0.12 4.02 BCH2112 0.104 1.7 0.27 0.21 0.065 15.96 -SUB5TITUTE SH~T
WO 94~11382 - . PCr/CA93/00463 - 21~6'Sq~
BCH2113 0~171 0~72 0~27 0~19 0~059 4~20 BCH2114 0~4720 2~04 0~6550 0~3730 0~2570 4~32 BCH2115 2~3 ~100 5~3 4~0 5~6 >50 BCH2117 0~0095 0~332 0~0374 0~073 0~03 35~13 BCH2118 0~12 0~79 0~244 0~203 6~68 BCH2119 >100 >100 >100 ~100 BCH2121 0~21 1~3 0~34 ~34 BCH2122 0~37 2~0 0~73 0~64 BCH2126 0~6770 1.68 0~7060 0~3730 3~95 2~48 BCH2127 0~35 4~1 2~0 2~7 BCH2128 1~7 5~8 1~4 1~6 BCH2129 0~3590 1~06 0~4520 0~2280 2~07 2~95 BCH2131 35~80 34~60 12~80 12~50 43~40 0~97 BCH2132 99~80 70~60 ~ 34~70 28~40 >100 0~71 BCH2135 0~66 1~3 1~1 0~31 0~88 BCH2138 >100 >100 90 >100 >100 BCH2140 2~2 13 1~5 0~45 3~2 BCH2141 8~12 9~96 3~79 1~82 6~44 1~23 BCH2142 92 46 45 18 >100 BCH2144 21.40 16.10 7~22 3~28 5~93 0~75 BCH2145 8~19 13~40 1~78 0~8300 2~48 1~64 BCH2147 12~50 10~10 3~92 1~88 10~00 ~081 BCH2148 12~60 9~93 2~36 1~55 7~50 0~79 BCH2149 32~70 29~80 11~40 10~00 28~20 Oa91 SUe~Tt ~ E ~
W O 94/11382 PCr/cA93/00463 .
TABL~ 2 ICS0 ~
C~MPQuND MCF-7MCF-7/An~ MAT-B MAT-B/A~R
Adri~myc~n 0.005 6.5 0.0046 2.50 1146 0.044 0.19 0.46 0.56 1177 >10.0 0.66 ~10.0 ~10.0 s u ~ EET
WO 94/11382 214 & ~ 4 8 PCr/CA93/0~463 F pl- 16: ~. of OMe O OMe O o o I, [~Ol~k 7, ~Or~k OMe U 0 - O O O O O O
~OMe O OMc O OMe O 0 O O O O
~o H I -- I~,o H I . HCI . ~0 O OMe O 0~
BCH~51 S Step 1: Methyl (l~S~lr '' ,~ ' . 3-yl) fonDde Methyl (5,8 ~ ~ 3-yl) formate (lS.00 g, 59.46 mmol) ~nd DDQ (16.20 g, 71.35 rmnol) woro ~' ih ~,d in dry ~' ' ' - ~ ' - (500 rnl), ~nd dry " -1 ( 7.2 ml, 178.3 î rnrnol) w~s sdded. Tho solution wss sti~d t unbient i . ~ o.. _' t, then reflmed for 8 hour~. M~
10 (1.0 ml, 24.69 mmol) nd DDQ (2.00 g, 8.81 m nol) W~8 ~dded nd further reflu~ted for 8 hours. The re~ction rni~ture W~8 cooled down, filtered, nd the filtr~te was poured onto ~ ' solution of sodium I ~ (200 rnl). The org~nic ph~se WS8 ~, d, ws~hed with ' sodium L b~ 601ution (100 ml), dried (MgSO4) nd ~ mdcr roduced prff sure. The re~iduc was - d from ' -' to give the titlc product (white cryst~ls, 14.34 g, 85.1 %).
lS lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.70 (lH, dd, J=11.8 ~nd 17.1 Hz, 4-H,,~), 3.08 (lH, dd, J=4.2 ~nd 17.1 Hz, ~Heq)~ 3.S7 (3H, s, l-MeO), 3.77 (3H, 8, Ar~k~), 3.80 (3H, s, Ar-52~s2), 3.83 (3H, s, COOMe), 4.79 (lH, dd, J~4.2 ~nd 11.8 Hz, 3-H~c), 5.70 (lH, s, l-H), 6.68 (lH, d, J=8 Hz, Ar-H), 6.74 (2H, d, J=8 Hz, Ar-H).
- 20 Step 2: Methyl (1 '' ' ~-S~P :' S~P ' ' Jd ~ ' ' . 3-yl) fonnate - The &olution of CAN (83.24 1~. 151.84 mmol) Jnd &odium ' ~ (8.50 g, 101.22 mmol~ in water (500 ml) wJs ~led to thc &olution of methyl (1,5,8 1 ~ 3-yl) formatc (14.34 g,50.61 mmol) in - - I~ (700 ml) t 0 - 5 C over 20 minutes. The resction mi~cture w~8 stirred at 0 25 C for 20 minutes, then ~: ~ d with d~ (4,~200 ml). The t ' - i organic phases were SU~S~E ~ il)T~ 6~EET
WO 94/11382 2 1 ~ 6 ~ A ~ PCT/CA93/00463 wsshed with brine (200 ml), dried (MgSO4) and c. . - - ~ under reduced pressure to give ~ light yellow solid (12.76 g,, ~ yidd) which W95 used for the ne~t step without further ~ ;~
lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.52 (lH, dd, J=11.4 ~And 19.4 Hz, 4-H~c), 2.83 (lH, dd, J=4.2 Ynd 19.4, 4-Hcq), 3.56 (lH, 8, l-MeO), 3.82 (lH, s, COOMe), 4.66 (IH, dd, J=4.2 and 11.4 S Hz, 3-H~c), 5.48 (lH, 8, l-H), 6.62 (lH, d, CHCO), 6.78 (lH, d, CHCO).
- Step3: Methyl (I ~ 5,10-diox~3,4,S,10 b.,.~. lII ~ [~ ~ cl~. 3-yl) fomute Methyl (1 ' ~-5,8 dio~o-5,8 .' ~ 3-yl) forrn~to (12.70 g, 50.35 mmol), 1-10 ~ (30.00 g, 267.55 r ol) nd dg tolue le (100 ml) wss lltirrod c,.. _' . t 50 C. The solvellt W98 rcmovod under reducod pre&sure, the ro~idue W98 .~ " ' from ' ' to give yellow cgstals (11.05 g). The product W..8 d ~vud in toluene (200 ml), silic~ gel (20 g) W~AS .,dded And stirred over 24 hours in sn open flsslc st sJnbient I . c. The silic~AA WPAS filtered, the f;ltrstc was c - I to dgne~. The residue W95 ~ nt~ll;~d in ~1 The mother liquor w9s ~
15 to dryness snd the silic~ gel t W98 repe~ted 98 ~bove. After "~~ " the mother liquor W98 c ~ ' to dryness snd the residue wss purified by flssh c~ _ . ' y on sili~. Eluent:
~Lyl ~co~te (4/1). All the cgstd6 ~nd the cle~n frsction from flssh ~ ~ were ' --' to give 9.07 g, (59.6 ~i) title product.
lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.68 (lH, dd, J= 11.1 nd 19.9 Hz, 4-H9"), 3.07 (lH, dd, J=4.4 nd 19.9 Hz, 4-Hoq)~ 3.62 (lH, 8, I-MeO), 3.83 (lH, s, COOMe), 4.72 (lH, dd, J 4.4 ~d
1 1 ) Drug-resistance reversal compounds such as P-glycoprotein inhibitors, for example Varapamil, cyclosporin-c, fujimycin;
12) Cytotoxic cells such as lumphokine activated killer -cells or T-cells, 13) Other Immunostimulants such as interleukin factors or antigens.
14) Polynucleotides of sence or antisensing nature.
15) Polynucleotides capable of forming triple helices with DNA or RNA.
1 6) Polyethers 17) Distamycin and analogs.
18) Taxanes such as taxol and taxotere.
The above list of possible therapeutic agents is not intended to limit this invention in any way.
The pharmaceutical compositions of the invention can be in forms suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intraarterial, intraperitoneal, intramuscular, subcutaneous and intravenous administration), by inhalation or by insufflation. Where appropriate, the formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
For injectable use, the pharmaceutical composition forms include sterile aqueoussolutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol for example, chremophor-EL, tween 80', glycerol, dimethyl sulfoxide (DMS0), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable denotes trademark ~A~ ] 465~
compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique. These methods yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical formulations suitable for oral administration may conveniently bepresented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution;
as a suspension; or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in theart. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
As used herein, the expression "pharmaceutically acceptable carrier includes anyand all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the present composition is contemplated. Supplementary active ingredients can be incorporated into the inventive compositions.
CA2 ~ 46548 It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
The dosage of the principal active ingredient for the treatment of the indicatedconditions depends upon the age, weight and condition of the subject being treated;
the particular condition and its severity; the particular form of the active ingredient, the potency of the active ingredient, and the route of administration. A daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient. The preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier. In the case of compositions containing supplementary ~ ~. Z ~ $
active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Antitumor treatment comprises the administration of any of the compounds of this invention in an acceptable pharmaceutical formulation at the effective therapeutic dosage. It is understood that chemotherapy can require the use of any of the compounds of this invention bound to an agent which facilitates targeting the compound to the tumor cells. The agent may be chosen from, for example, monoclonal or polyclonal antibodies, proteins and liposomes. The compounds of this invention could also be administered as monomeric, dimeric, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
The compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian cancer, and melanoma. This list of conditions is however not exclusive, and it is believed that the compounds of the invention will exhibit activity against other tumors and cancers, such as for example pancreatic cancer, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxorubicin against P-170 mediated multidrug resistant cancers.
Methyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-A mixture of methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.485 mmol) and acetoxybutadiene (75,ul, 0.630 mmol) in dry benzene (5 mL) was heated for 12 hours at 60C under argon atmosphere. The solvent was thenremoved in vacuo and the resulting adduct dried under reduced pressure. The adduct was dissolved in 10 mL of ethanol and to this solution was added 1 mL of 1 % K2C03 aqueous solution. After stirring for 2 hours at R.T., the reaction mixture was neutralized (pH=6) and extracted with CH2CI2 (2x50 mL). The organic layer was then washed with water (3x50 mL) and dried over MgS04. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 69 mg (55% yield) of pure titled compound. (MP: 135-136C).
PMR (CDCI3,250MHz): 2.31 (s,3H,CH3), 2.54 (dddd,1H,J=18.0, 10.3, 3.6 and 1.8Hz,HCHa-CH), 2.97 (dm,1 H,J = 19 and 3.0Hz,HCHe-CH = ), 4.05 (dd, 1 H,J = 10.3 and 3.9Hz, CH2-CH), 4.58 (dt,1H,J=18.7 and 3.6Hz,HCHa-0). 4.92 (dd,1H,J=18.7 and 1.8Hz,HCHe-0), 7.72 (m,2H,Ar-H), 8.04 (m,2H,Ar-H). CMR-(CDCI3,75.44 MHz~:
24.42 (CH2-CH), 26,57 (COCH3), 63.97(CH2-O-), 78.63 (CH2-CH), 126.70, 127.08, 132.36 and 134.52 (CH aromatic); 132.20, 134.42, 141.30, and 142.41 (c quaternary), ~ 2 1 ~
183.51 nd 183.63 (C=0 quinone), 207.2S ~0-CH3).
EX~MPLE 1 OAc O O O O
O O
EX~M~E 2 Metihyl (7 b,.' ., 5,10-dioxo-3,4,5,10 1 ~ . p! ' ~ 12.3-C] pyr~n 3-yl) Icetone BCH-1129 A m~cturc of 1~ 3 ~' ~ylo~y L - (776 mg, 4.51 mmol) and methyl (5,8-dio~o-3,4,5,8; ~ l~ 12,3 Cl pyr n-3-yl) 15etone (309 mg, 1.50 mmol) in 6mL of dry toluene w s. stirred for 90 minutes t room ~ , ~ under rgon u - . ' e. Tho solvcnt wu~ then rcmoved 15 i~ v~cuo ~d thc dricd ro6iduc w~s J' ~v~xl ill 1O mL of THF. To thi~ oolution w 8 ~dded 2 mL of a 4% ~q. HCI solution. Thc ' ' org nic l-ycrs werc thcn w shed with w br u~d dried over MgS04.
Fl~sh ~ (tolucne: ethyl cet-b; 95%:5%) of the rof.idue gave 180 mg (65% yield) of the titlod 5 . ' (~IP: 169-170C).
PMR (DMSOd6, 250 MHz): 2.24 (s,3H,CH3), 2.45 (m,lH,HC_a-CH=), 2.77 (dd,lH,J--19 ~nd 3.0Hz,HC~e-CH),4.20 (dd,lH,J .9.8 ~nd 3.9Hz,CH2~D, 4.55 (d ~.. ' .~-d, lH, J--22 Hz,HC~a-0-), 4.78 (d o.. ~r ~ lH, J= 18.0Hz,HCHc-0), 7.15 (dd,lH,J=8.5 and 2.4Hz,Ar-H), 7.30 (2d, lH, J=2.5Hz,Ar-H), 7.88 (2d,1H,J=9.lHz,Ar-H), 10.96 (s,lH,Ar-OH).
E.Y~MPL15 2 O O O O
)TMS
O O
EX~M~LE 3 SU~S ~ T~ LrT
W O 94/11382 PC~r/CA93/00463 ~ 21~63'~ ~
Me~hyl (1 4.' . ~-5,10-dioxo-3,4,S,10 1 ~d . p~ ' - t2,3-Cl pyrs~n-3-yl) ketone BCR-1148 A mi~cture of methyl (l-metho~y-5,8 dio~c-t~ hyt ul~o t2,3-C~ pynn-3-yl) Icetone (100 mg, 0.450 mmol) uld ceto~y ' ' - (80 ~g, 0.675 mmol) in dry b~nzene (S mL) w 8 he~d for 3 hour~ ~t 60C
- under Yrgon . ' e. Tho solvent w~s then removed in ~cuo nd the .~ C ~dduct was ~
in 10 mL of toluene nd then 9 . ' on sili gel by fl~sh ~ (tolucne: cthyl ~te;
90%:10% followed by 70%:30%). E~ of the ~olvcnts g vc 37 mg (31% yield) of pure titled , PMR (Acetone d6, 250 MHz): 2.26 (s,3H,COCH3), 2,50 (dd,lH,J=11.6, l9.5Hz,HC_~-CH), 2.89 (dd,lH,J=4.2,19.5Hz,HCHe-CH), 4.71 (dd,lH, J=4.2,11.6 Hz,C_-CH2); 6.12 (bro~d s,lH,C_OH);
7.87 (m,2H,ArH); 8.07 (m,2H, ArH).
EX~LE 3 O O , O O
C
o OH o OH
EX~MPLE4 - r' '' . ' ~1 (5,10-diox~3,4,5,10 1 b~d . lU' ' I 12,3-C] py~n-3-yl~ Icetone 2 0 Step l: M ' ~momethyl (S,8-dimethoxy-3,4 t-' ~ L 12 p~-3-yl) I~e~one To a stilTed ~olution of methyl (5,8 :' ' y-3,4~ vl~ [2,3-c] pyran-3-yl) l~etone (1.905g, 8.04 mmol) nd I ' ~ lyl chlonde (1,530 ~1, 12.0 mmol) in t~ ~, r (48ml) under l~.L.o at -78C, wa8 dowly added lithium d-- r u~ nude (~" , u~l amine 10.71 mmol, n-butyl lithium 4.26 ml of a 2.5M solution in I ~d ~ r , Jmd 6.0 ml of l~ ~,- r ). After stiITing for 10 - minutes the h~ _ wa8 rused to 0C, nd stirring wa8 c ' for 10 re minutes. Solvent was ~emoved and the crude product wa8 ~ ~ in 48 ml of t ~, r 1> ~1- b~ ~ (1,716 - mg, 9.66 mmol) w 8 dded slowly to the solution. After 10 minutes, the re~lction system was worlced up 30 with d aqueous sodium I ~ w shed with brine. The titled . A - ~ was obtained fullu.. ~ f~h :' ; ,, . ' j (} - ' .~1 cetate, 9:1) of the cmde product. lH NMR (l - d6~
250 MHz) : 2.68 (dd, lH,HCHa), 3.16 (dd,lH,HC~e), 3.28 (s,3H,OCH3), 3.32 (s,3H,OCH3), 3.73 SUE~ 3~-3EET
(dd,lH,J=4.0,11.5Hz,CH), 3.81 (dd,2H,CH2Br), 4.51 (d,lH, J=15.8Hz, HCE~O), 5.05 (d,lH,J=15.8Hz,HCHeO), 6.335 (dd,2H,~rH), 4: Monofluoromethyl (S,10 s 3,4,5,10 ~ p~ .~Cl pyran-3-yl) ketone.
~1~3 1 ~Br 2 ~CH,~F _ OCH3 OCH3 OCE~
O O O O
~5F 4 ~F
O O
Step2: r~ (C~8~ -3,4t~3~ t2,3-Cl-p~n-3-yl)ketone To ~ solution of 1 ~ ' (3.75 rnM, 1.18 g) of ~ etone ' . from step 1 and 3 c~ (11.25 r~M, 2.160 g) of pTSA in 20 mL of dry THF wui ddod dowly, ~t R.T., 6 equi.
(22.5 mM, 22.5 rnL) of ~ lM solutio~ in 1~- of N~(Bu)4F-. After 6tirring one rlight t R.T., 15 mL
of H20 were ~tdet ~nt the mi~cture w~s _ ' with 3~c20 rnL of ethyl cotste. Aher drying with NaSO4 and solvent e. . - ~ the re6idue w s flssh ' ~ ' (Toluone: Ethyl c~to; 9.5:0.5) to give ~ S0~i yield of pure titlod r lH NMR (250 MHz, CDC13): 2.61 (dd,lH,HCHa), 3.11 (dd,lH,HC~e), 4.27 (dd,lH,CH), 4.63 (d,lH,HC_aO), 4.9g (d,lH,HCHeO), 5.33 (d, 2H, CH2F), 6.67 (dd,2H,ArH).
Step 3. r ' ~ , ' yl (~8 :' 3,~ ,P ' ~ ~ ~a~
12,3-Cl pyr~n-3-yl) Icetone To 1 ~, ~ '- (0.220 mM, 56 mg) of the fl ~ ' ~I}~nc ~ from step 2 ~ d in 3 mLof - '- at 0C w~ dded 3 ~ . ~ ' of ceric mmon um nit~te (0.66 mM). After 10 minutes, the r~ction mL~ro wa~ brought to R.T., stirred for 20 rninutes, and then . ' with dichloromethlme/THF (1/1). The organic layer w~ls dried over MgSO4. The titled quinone was obtained 2 5 (67 mg) following ~,. . - - ~ of solvent.
H NMR (250 MHz, CDC13): lH NMR (250 MHz, CDC13) : 2.46 SUBSTl ï l JTE SHEET
~0 94~11382 214 ~ ~ ~ 8 PCTJCA93/00463 (dddd,lH,J=3.0,4.0,10.4,18.9Hz,HC~a), 2.91 (dt, lH, J=3.5, 18.9Hz, HCHe), 4.2~(dd,J=3.8,10.4Hz,CH), 4.445 (dt,J=3.S,18.4Hz,HC~O), 4.77 (dd,J=2.2,18.5Hz,HCHeO), 5.25 (d,2H,CH2F), 6.75 (d~l 7~,~C=CH).
- step 4. r~ 1 (5,10 ~- 3,4,5,10 1 _b~
[2,3-Cl p~n-3-yl) Ice~one -To 1 r~ ~, ' (0.220 mM, 50 mg) of the I , - from step 3 ~ d in 5 mL of d~y toluene w~s sdded 1.3 ., ._' (0.286 mM, 32.0 m~, 35 ILI) of ~ y I ' ~nd sti~d u.. _' The raction mLstur6 w~ p~sed diroctly on silic gel colwnn. 20 mg of pure titled . , ~ w 8 isol ted ~fter two fl~sh ~ ' . " phy (2% EtOAc in toluene).
PMR (Acetone-d6, 250 MHz): 2.62 (dddd,lH,HC_ ), 2.94 (dt,lH,HC~e), 4.46 (dd,lH,CH), 4.62 (dt,lH,HCH~), 4.84 (dd,lH,HC~e), 5.43 (d, 2H, CH2F), 7.83 (m,2H,ArH), 8.03 ~m,2H,ArH).
EX~,MPI,E 5 S~ep 1.
(l'S,lR,3S) ~nd (l~s~ Me~hgl (~,.X L- 1-(2',3', 6'- trideoxg-3'-2 0 t ~ . ~ ~ ~ q' O F 'yl L I~) 3,4,5,8-' ., d ~ ' 12,3-C] pg~n-3-gl) Icetone To ~ gti~ed solution of 1,4-di~ F ol~v~d ~71 " or ~1 ~ - (1.584 g, 2.93 mmol) in 160 mL of dry ~ L-_ '- - nd 40 mL of o ' ~ ether, - ' ~t -35C under srgon ,' ~i, w s ddod ~L., .. - 1.132 m~ (5.85 mmol) of i '~1 8ilyl triflate (I~SOTf). ~er ~tirring for 1.5 hourli st 0C, ~e i . ~ W 8 lowe~ed to -15C Jnd cooled (0C) solution of methyl (1 h, ~r~ 5,8-dio~o-3,4,5,8 1 1 ~d ~,L~ [2,3-Cl pyr~n-3-yl) Icotone in dry ~' ' ' -(40 mL) w 8 Jdded. ~er li hourOs of ~tirring, the ~ction mi~cture W~6 put into ~ ~olution of 150 mL of ethyl rcot~te ~nd 50 mL of ~ ~ ~ N HCO3 Oolution. The org~nic l-yer w 8 w~shed with w ter nd 3 0 dried (~;7 2S04). Flu~ O , ' ~ of the re6idue g ve 917 mg (69 % yidd) of the mLlcture of titled SUBSTITUTE SHEET
WO 94/11382 21~ 5 .1 4 ~ PCI`/CA93/00463 Ex~mpb 5: r~j~ k' ~ d d~ V,8 of ~ rvrua~t~ wffl a metttyl ketone dde chah.
o o o o o o ~3 1 W~CH3 113C~ 3 ~
pNBoN~COCF3 P~Bo NHCOCF3 O O O O
l3 ~ C~3 O O o O
X3 ~ 8 ' ~13 C ~ 11 3 ~ Rl = OPNB R2 ~ NHCOCF3 ~ R~--O~NB R 2 = NHCOCF3 RI ~ OH (BCH-11831R2 ~ NHCOCF3 R~ - OH (BCH~ R2 ' NHCOCF3 ~o~ ~~"Q., ~3C~
1~12 R~ 2 9 ~ Rl ~ O~NB R 2 ' NHCOC~3 12~; Rl = OE~NB R 2 = NHCOCF3 Rl = OH R 2 ~ NHCOCF3 Rl = OH R 2 ~ NHCOCF3 A ~ocond fl~ thc ' ~, ' ' ' The l'S,lS,3R titled ~ H NMR (250 MHz, u:etone d6) _: 1.28 (d,3H,J--6.4Hz,CH3), 2.05 ~aidden m, lH,2'-CH2), 2.30 (s,lH, COCH3), 2.42-2.49 (m,2H,2'~H2 ~J.. ' ~ r e d wi~ HC~
2.84 (dd,l~,~C'~,) 4.S3-4.65 (bro~d m,lH,3'~, 4.635 (dd,2H,J=4.2, 11.6Hz,O~H~OCH3), 4.76 (bm~d q,lH,S'~, 5.50 (bro~d s,lH,4'-CH), S.69 (bro~d s,lH,I'~, 6.02 (~,lH,~C~-O), 6.90 (~.~ C= CH), 8.37 (m,4H,~rH), 8.68 (bro~d d,lH,N~.
SUBSTITUTE SHEET
94/11382 PCI`/CA93/00463 ~ 2 1 ~
The l'S,lR,3S titled ~' ~ had lH NMR (250 MHz, ~d6) _: 1.19 (d,3H,1=6.6Hz,CH3), 1.89 (dd,lH,J=4.6,13.1Hz,2'-CH2),2.32 (s, 3H,COCH3), 2.29-2.47 (m,2H,2'-CH2 o.~ '~r~d with HCHa), 2.89 (dd,lH, J=4.1Hz,HCHe), 4.60 (m,2H,3'-CH ~ '.red with S'~H), 4.71 (dd,lH, J=4.1,11.5Hz,O~H-COCH3), 5.48 (bro~d s, lH,4'~H), 5.64 (bro~t 6, lH,l'~H), 5.89 (s,lH,O-CH~), 6.87 (~ XC=CH), 8.37 (dd,4H, ArH), 8.69 (broad d, lH, NH).
St~p 2.
- (l'S,1P ~1 (5,10 . 1-(2',3',C' I ' ~-3'~ '` . ' ~'~p-' ,' yl L 1~ ' ~.,. ~) 3,4,5,10 ~ ~ . p~ 2,3-C] py~n-3-yl) ketone To a stilTed solution of l'S, lR, lS ~ om step 1 (r ,'- 5), (0.464 mmol) in dry bcnzene (10 mL) u~der argon wYs added 78~1 (696 mL) of 1 ~ ' ~ After stirring for 16 hours at room i e, thc re~ction mi%ture wss fl~sh .L~ ~ ,' -' (I ' ~~ ' ~1 scetate;
90%:10%)togive244mg(82% yidd)ofthepuretitletc~ , ' lH NMR (250 MHz, scoto~e~6): 1.22 (t,3H,J, i6.4Hz,CH3), 1.94 (tt,lH,J=4.7,13.1Hz,2'-CH2), 2.35 (s,3H,COCH3), 2.42 (m,lH,2'-CH2), 2.52 (tt,lH,J=11.6,19.8~7 ~I~.~9) 3.04 (dd,lH,J=3.9,19.6 Hz, HC~ç), 4.55-4.68 (o.. '.red m,2H,3'-CH ~d 5'-CH), 4.79 (dd,lH,J=4.0,11.5 Hz,O~j-COCH3), S.49 (bro~d s,lH,4'-CH), 5.75 (bro~d s,lH,l'-CH), 6.07 (s,lH,O-CH-O), 7.83-7.93 (m,2H,ArH), 8.06-8.14 (m,2H,ArH), 8.32-8.43 (m,4H,ArH), 8.67 (bro~d d,lH,NH).
S~ep 3.
(l'~,lP ~S) ''~' ~1 (S,10 :' 1-(2',3',6'-trideox~-3'-i '' .
~ -L 1~ * ,., ~ ~) 3,4,5, 10 1 ~~ ' ~ 12,3-C] p~n-3-~
Icetone BCH-1184 To a stirred solution of the ~1~ '- from step 2, (30 mg, 4.65~10-5 mmol) in 4 mL of dry -' 3 0 nd 1 mL Of r ~d¢~ THF t 0C nd under rgon, was sdded 11~L1 (4.66~10-5 mmol) of N OCH3 (4.37 M) solution in - -' After S minute6 of stirring, the r~ction wa6 ., ' -d with 1 mL of d NH4C1 solution nd . ' with CH2C12 . I;oll~.. g c., of solvent, flash . ., ph~ of the residue g ve 23 mg (100% yidd) of pure titled .
lH NMR (250 MHz, Acotono d6): 1.25 (d,3H,J=6.5Hz,CH3), 1.76 (dd,lH, J=4.5,12.9Hz,2'-CH2), 2.16 (m,lH,2' CH2), 2.32 (s,3H,COCH3), 2.48(dd, J~11.6,19.5Hz,HC_a), 2.99 (dd,lH,J--4.1,19.5 Hz,HC~), 3.68 (broad s,lH,4'~, 4.17-4.41 (o.. '~rei m,2H,3'-CH snd S'-CH), 4.69 (dd, lH,J=4.0,11.0Hz,~C_-COCH3), 5.53 (broad s,lH,l' CH), 5.97 (s,lH,~CH~), 7.82-7.90(m,2H,ArH), 8.01-8.05 (m,2H,~rH), 8.13 (broad d, lH,NH).
t~ 5~EI
WO 94~11382 PCI /CA93/00463 2 ~ 8 S~ep 4:
(l'S,1~;;"3R)-M~thyl (5,10 ~(2',3',C'~ 3'-h~r~ ' ~- q'~
~ yl L l~ o.) 3,4,5,10 1 ' ' ,.' . ~ 2,3-Cl py~-3-yl) Iceton~
~pj?!- b of tho p.. ~- _ ~ - d in step 2 of the p~se~t o~mplo on the l'S, lS, 3R quinone ~1). '- from step 1 g~vc thc titled: . ' which h t:
lH NMR (250 MHz, ~ G): 1.33 (t,3H,J~6.6Hz,CH3),1.94 to 2.08 (m,lH,2'-CH2), 2.33 (s,3H,COCH3), 2.49 (m,lH,2'-CH2), 2.58 (dd,lH, J=11.7,19.6Hz,HCH~), 3.01 (dd,lH,J--4.1,19.7Hz,HC~), 4.53-4.65 (m, lH,3'-CH), 4.71 (dd,lH,JC4.1,11.5 Hz,O-CE-COCH3), 4.90 (bro~d q,lH, S' CH), 5.S3 (bro~d s,lH,4'-CH), S.75 (bro~d ~,lH,l' CH), 6.21 (~, lH,O-CH~), 7.88-7.92 (m,2H,ArH), 8.08-8.16 (m,2H,ArH), 8.34-8.43 (m,4H,~rH), 8.69 (bro~d d,lH[,NH).
step S:
(l'S,1~ )-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-l."
hydro~y-L 1~ ) 3,4,5, 10 ~ p! ' ~ 12,3-Cl PY~~3~YI) I~etone BCH-1146 T~e~ment of thc 3~1~ ~ obt~inod from step 5 with liodium ' - '- ~ ~3< il~d in step 3 of this 2 0 c~mple yidded the titled ~ d, which h~d:
lH NMR (250 MHz, ~- ~ d6) 1.35 (d,3H,J=6.4Hz,CH3), 1.77(dd,1H, J- 4.5,12.9Hz,2'-CH2), 2.17 (dt,lH,J= 3.7,12.9Hz,2'-CH2), 2.30 (s,3H, COCH3), 2.56 (dd,lH,J=10.7,19.6Hz,HC~), 2.98 (dd,lH,J~4.2,19.8 Hz, HC~),3.70 (bro~d s,lH,4'-CH), 4.2-4.4 (m,lH,3'- CH), 4.60 (bro~d qu~t,lH,S'-CH), 4.66 (dd,lH,J ;4.2,11.5Hz,O~-COCH3), 5.52 (broad d,lH,l'-CH), 6.15 25 (s,lH,O CH-O), 7.86-7.92 (m,2H,~rH), 8.07-8.11 (m,2H,ArH), 8.15 (brosd d,lH,NH).
step 6:
(l'S,1P ~S)-Me~hyl (5,10 ' 1-(2',3',6'-hideoxy-3'-t~iflu . ~ '~ q'~
' ~ tlL l~ ) 7 ' J.' ~ ,~-3,4,S,10 ~ Ip~ 2,3-C
3 0 p~r~3-yl) lu~toDe The titled c , ' w~s ~d in 62% yield by ~ g the l'S, lR, 3S ~ ;de from ~tep 1 of this e~mple wit~ 1= ' y-3-1 ' ylb;lylc.A~ e s~ .~dm~; as d in ~ 2, in this ~ , w~s used.
35 lH NMR (250 MHz, Acetone-d6): 1.21 (d,3H,J=6.6Hz,CH3), 1-93 (m,lH, 2'-CH2], 2-34 (s,3H,COCH3), 2.49 (dd,lH,J=11.6,19.5Hz,HC~), 3.00 (dd,lH,J=4.1,19.5Hz,HC~), 4.574.69 (U., ~ ~r~d '`i~ 2H,3'-CH ~nd 5'~,4.76 (dd,lH,J=4.0,11.5Hz,0-CH-COCH3), 5.49 (b~d s, lH,4'~, 5.73 (b~d d,lH,l'-CH), 6.04 (s,lH,O{~H-O), 7.25 (dd, lH,J=2.5,8.5Hz,ArH), 7.46 (d,lH,J=2.5Hz,~rH), 7.98 (d,lH,Js 8.6Hz, ArH), 8.38 (m,4H,ArH), 8.58 (broad d,lH,NH) 10.23 SU~STi~lTE SI~IE~T
214654~
(b~d s,lH, ArOH).
Step 7:
(l'S,lR,3S) '~ 1 (S,10 d 1-(2',3',6'-~ideoxy-3'-L '` . '~ I~
1~ ' .JI - ~ 7 ~ u~-3,4,5, 10 1 bJ. ù 12,3-C] pyrsn-3-yl) Icetone ' ~ of the 1~.' Jl~.6 ~ clm.i ~' ' -d in step 3 of this e~mple to the l'S, lR, 3S tticyclic of 6tep 8 ~wlted in th~s removs~l of the p ~1 pl~ e g~up. The titled 1 0 h~d:
lH NMR (250 MHz, ~ dG): 1.63 (d,3H,J=6.4Hz,CH3), 2.14 (m,lH, 2'~CH2), 2.53 (m,lH,2'-CH2), 2.70 (s,3H,COCH3), 2.87 (dd,lH,J~11.7, 19.4Hz,HC~), 3.35 (dd,lH,J~4.1,19.4Hz,HC~), 4.07 (b~d 6,1H,4'-CH), 4.65 (o.. ' .red m,2H,3'-CH ~nd S'-CH), 5.07 (dd,lH,J=4.1,11.7 Hz,O-CH-COCH3), S.91 (bro~d d,lH,l'~CH), 6.35 (6,1H,~CH-O), 7.64 (dd,lH,J=2.S,8.5Hz,ArH), 7.84 (d,lH,J=2.5Hz,~rH), 8.35 (d,lH,J= 8.5 Hz,~rH), 8.48 (bro~d d,lH,NH), 10.23 (bro~d 6,1H,ArOH).
step 8:
(l'S,1~:,3~) '' ' /1 (S,10-dioxo-1-(2',3',C'-trideoxy-3'-L
nitrobenz~yl-L 1~ ' ~J-_ ~) 7~ -3,4,5,10-tet~h"L~ p' ' ~ 12,3-C
pyr~n-3-yl) I~
The titlod ~ . ' wu r--, d by ~ r~- ~ the ~me ~ 8 ~' ' -' In ~tep 8 on the l'S, lS, 3R, quiQone ~ - of stop 1 Of this ~ . '-lH NMR (250 MH~ d6): 1.32 (d,3H,J=6.4Hz,CH3),2.08 (m,lH, 2'~H2), 2.51 (m,lH,2'-CH2) 2.55 (dd,lH,J=ll.S,l9 ~i~7,~"~, 2.96 (dd,lH,J=4.2,19.6Hz,HC~ç), 4.51-4.62 (m,lH,3'-CH), 4.68 (dd,lH,J= 4.2,11.5Hz,O~-COCH3), 5.52 (bro~d 6,1H,4'~, 5.73 (brosd s,lH, l'-CH), 6.18 (6,1H,aC~I-O), 7.28 (dd,lH,J=2.6,8.5Hz,ArH), 7.47 (dd, lH,J=2.6,8.5Hz,ArH), 8.03 (d,lH,J--8.5H_,ArH), 8.38 (m,4H,ArH), 8.68 (bro~d d,lH,NH), 9.85 (bro~d s,lH,~rOH).
step 9:
(l'S,~ 1 (5,10 ~- 1-(2',3',6'-' ' ~-3' ;~ '' w ' L~
.. , ~ ) 7~ -3,4,S, 10 t~ 2,3-Cl pyr~n-3-yl) Icetone BCEl-1180 ~' of the h~ ' ol~ A~L ~il d in 6tep 3 of thi6 e~c mple to the l'S, lS, 3R tricyclic 3 5 ~ly~ ~ - of 6tep 11 ~sulted in the remov~l of the ~ vl~, l p.~ g group. The titled .
had:
lH NMR (250 MH~ ,) 1.73 (d,3H,J=6.6Hz,CH3), 2.17 (m,lH, 2'~H2), 2.58 (m,lH,2'-CH2), 2.68 (s,3H,COCH3), 2.90 (dd,lH,J=11.6, 19.7Hz,HC~), 3.33 (dd,lH,J~4.3,19.8Hz,HC~), 4.09 (b~d s,lH,4'~, 4.63 (m,lH,3'~H), 4.95-5.06 (~ ',, d m,2H,S'-CH, ~nd OCH-COCH3), SUBSTITUTE SHEET
21~6~
5.91 (bro~d d,lH,l' CH), 6.51 (~,lH,0~), 7.65 (dd,lH, J=2.6,8.5Hz,ArH), 7.85 (d,lH,J=2.6 Hz,ArH), 8.38 (d,H,J=8.5Hz, ~rH), 8.S2 (brwd d,lH,NH), 10.18 (bro~d ~,lH,~rOH).
EXAMPI,E 6 2-t4,~ 1',2'-dioxo-3' ~ hyl-(S,10 diox~3,4,5,10-b~ d . p' - - 12,3-C1 py~3-~1) Ice~e i~.,, `e 6: Tricyclic pyranylr aph~oquirones wiffl a squaric acid mde~y.
a~o o o o o o 1~ 1 ~ ¢~ 2 ~Br a~,o o o o a~
~0 o Step 1: B~ " 5,P: -b~ 2,3-C] pyr~n-3-yl) ~one To-solu~on_ eoneeS . ' of S,8 - ' ~-3l ~ (380mg,1.1mmol)in (18ml), ~t 0C under ~rgon, w~ ddod d~..- ~n quoous ~olution of ccric ~ -15 Ditrste (6.5g in 28ml H20). ~r stirring for 10 minutes, the mi~chue w~s ~ ~ d with 3 ~t 20ml of CH2C12. The ~- ' or~nic l-yer w~ driot ovcr MgSO4 Jnd then ~ to yield 263 mg of pure ~tled ~ , ~
lH NMR (2~50 MHz,CDC13): 2.43-2.69 ~m,lH,CH2), 2.82-3.07 (m,lH,CH2), 4.24 (dd,2H,CH2Br), 4.4-4.6 (m,2H,CH20 u~d C_COCH2Br), 4.52 (d,lH, CH20), 6.74 (~ ,~C=CH).
Step 2~ i (S,10 ~- S,10-dih~phtho ~,3-Cl p~ran-3-yl) Ketone To ~ ~olution ~ one . . -. ' of " (263mg, 0.92mmo1) from ~toD I (~ h 6) in 25ml of dry toluene w~ ~ddod tbroo ~ (2.7mmol) of ~ , Tho re~ction mi~ture 25 w~s stirred o.. _' under ~rgon ~t room I , nd t~en ~wo hours ~t 60C. APer remoY~l of l~cnt, the cn~de p~oduct w~s fl~h :- ~ , - ' (toluale/EtO~c,9: 1). T~e ~tlod or~ngc ~ .
ol~ted (192mg) in 62% yield.
H NMR (250 MHz,CDC13): 2.~2.6 (m,lH,CH2), 2.7-3.2 (m,lH,CH2), 4.3-4.4 (m,2H,CH2Br), 4.45 SUES ~ . ;¢ET
2146~8 (m,lH,C~-O), ~.64.7 (m,lH,CH20), 4.9-S.05 (m,lH,CH20), 7.6 (m,2H,ArH), 8.1 (m,2H,~rH).
Step3: 2~4'-Hydr~-1',2'-dio~c~3'~ meth~l(S,I~ diox~3,4,S,1 . [2,3 Cl p~3-~1) ICeto~#
Under u~on ~t room I , hvo .~ . ' (0.9mmol) of ~ric Jcid ~nd hvo 4~ ' of C6CO3 (0.9mmol) wo di-olvod in lOml of dry dimethyl f ' (DMP) (wn }
). To this olution v~s ~ddot ~e eql~iv lent (0.45mmol) of the 1~ - . ' ' ~ ~ from st~
3 (e~umple 6). The solution wY t~tod t 60-C for hvo hou~. AP~r coolin~, lOml of H20 W~6 ~od, 10 ~nd c w~ c rried out with 3 ~ lOml ETO~c. ~R t~ nd _ . - the re6idue w s purifiod hvice by ~ TLC. The titled con~ound w s o~ined m 30% yield.
lH NMR (2SO MHz,~ 2.S-2.6 (m,lH,CH2), 2.8-3.0 (m,lH, CH2), 4.4 (m,lH,CH{~), 4.6 (u.. ', ~ ~ d m,2H,COCH20), 4.8-5.0 (m,2H, CH20), 7.7 (m,2H,~rH), 8.1 (m,2H,ArH).
15 EXAMP~E 71 Tnqcl;.c ~ pbt~uiDo~ ntb ~ ~uanc uid ~de cbain Ex~mpk 7: Tlicydic pyr~ uinone ~ ric acic moiety.
o o o o o o _ 1 D ~ 2 ~
O ~ o n O O
~13 C-~ ~3 C~ 113 C~
~11110 J~ Pl~l~o ~ COCF3 Plllso ~ COCF3 + 1,3-diepimer + 1,3-diepimer + 1,3 Step l~ P ~ d (1'~ ,,3't)-B-. ~1 (5,10 ' 1-(2',3',C' ' ~ 1'~r-l 3'~1uo~ ~ ~ L 1~ ' ,J - ) (~,~"!i l~L
', ' . ~ tbo 12,3~ p~3-~1) Icetone At mom .ullder N2, to one _, . ' (0.482 mmol) of 1:1 mi~ture ~rting quinone- 2 5 ~ ' from d;~p6 3 nd 6 ~ . ' - 1) !" 1~.,d in 6 ml dry te~ hydro fu~n (~I~) v~ ddod 1.1 ~ . ' of~b~' 1 ' F_.l,.~ ' ~rhvohoun,to~e~olutionv~s dded7mlSX
N~HC03 lution nd ~ `1 d with 3 s 10 ml E~O~c. ~Rer d y~ ov N 2S04 ~nd ~,. . the ridue w~ing 95% tolueno -SX EtO~c olvenL Two, L ~jor fr~ction~ were isol~d Co~to the 2 io~ (yidd 40X of pure: , ' r tio # 1/1 isomer). PMRs of the 3 0 - . 3 i~oma~ re ~ ' 3 in ~tep 1 (c . ' 8) ~d ~bp 1 (r . ' 9).
~ U ~ T~ E ET
WO 94/11382 PCr/CA93/~463 214~
Step 2:
(l'S~ 3S) ~nd (l'S,1~;"3P)-2-14'~ -1',2'-dioxo-3' ~ ] methyl S (S~10 t- - 1-[2n,3n,6n-trideo~y-4n-0 ~ 1 3n ~
A~ - ~] 3~4~S~10 1 ~ ~d ~ p! ~ t2,3,c] py~-3-yl) Itetone The title c _~ ' wae obt~ined by zpplyi~g the p-. cc ' c~ d in ~p 4 (e~mple 6) to the tncyclic ~l~;d~ from ~tep 1 (e%~mple 7).
lH NMR (250 MHz, CD30D): 1.2 (d,3H,5~ CH3), 1.9 (dd,lH,2~H2), 2.42 (m,lH,2~-CH2), 4.6 (m,2H,CO-CH2-0), 4.8 (m,lH,OCH-CO), 5.5 (m, lH,4~, 5.8 (m,lH,l~-CH), 6.1 (m,lH,~ClH-O), 7.7-7.9 (m,2H, rom H), 8.05-8.1 (m,2H, uom H), 8.3-8.45 (m,4H, ~rom H), 8.7 (b~sd d, lH,NE~, 3.1 (m,lH,C4-H), 2.6 (m,lH,C4-H), 4.6-4.2 (u.. ' . r d m, 2H, 3~-CH ~nd 5~-CH).
15 EX~E 8 Step 1: (l'-S, l-R, 3~-1-(2'-3'-6'-brideo~ly 1' ~ 13~
1~ ~ 5.~ ) 3-(2 L . ~ v ~I)-S,10 :' ~ 3,4,S,10 ' J.' ~ lII z "' ' ~
(2,~ ~) t.
Ex~r4le 8 H3C~ H3C~ H3C~
f NHCOCF3 ~ IIHCOCF3 f~rHCOCF
liHAc NHAc NH2 ~-, ~ 5 O O O O ~ o O
H3C~ H3C~J BCH-1197 H3C~ BCH-1615 r NHCOCF3 r NHCOCF3 ~ NHCOCF3 Tl~i8 e~b ~ of r ~' group~; wherein ~ methyl Icetone; ~t R6 is c 'Iy ~ ~d to ~ ' d thi~zole ring.
SUBSTITUTE SHEET
Step 1 To a solution of (1'-S,1-R,3-S)-1-(2',3',6'-trideoxy-4'-p-nitro-benzoyl-3'-trifluoroacetamido-L-lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1 H-naphtho-(2,3-c)-pyran (87 mg, 0.135 mmole) in tetrahydrofuran (THF) (4.5 ml), stirred at room temperature, was added slowly a solution of pyridinium hydrobromide perbromide (43.1 mg, 0.136 mmole) in 3 ml of THF. The resulting yellow liquid was stirred for 2 hours at room temperature, then poured into water. Methylene chloride was used to extract the crude product from the aqueous layer. The combined methylene chloride extracts were washed with brine (10 ml) then dried over anhydrous sodium sulfate. The organic solvent was evaporated and the crude product was obtained as a orange oil (98 mg). Chromatographic purification (by volume, ethyl acetate:toluene ~ 1 :5) of the crude product gave a yellow sticky solid (40 mg) as a pure compound. A mixture (48 mg) containing the product (>34% mol) and unreacted starting material (<66% mol) was also obtained.
M.P. (Electrothermal IA-9100): 125-130C; decomposed at 175C.
'H NMR (250MHz, acetone-d6):1.25 (d,3H,J=6.5Hz,6'-CH3), 1.97 (dd, 1 H,J = 4.8Hz,13.7Hz,2'-HC_a), 2.48 (dt,1 H,J = 4.2Hz,13.7Hz,2'-HCHe), 2.64 (dd,1 H,J = 11.6Hz,25.6Hz,4-HCHa), 3.14 (dd,1 H,J = 5.7Hz,25.6Hz,4-HCHe), 4.66 (S,2H,COCH2Br), 4.71 (qua,lH,J=6.5Hz,5'-CH), 4.83 (overlapped m,1H,3'-CH), 5.08 (dd, 1 H, J = 5.7Hz,11.6Hz,3-CH), 5.52 (bs,1 H,4'-C H), 5.79 (bd,1 H ,J = 3. OHz,1 '-CH), 6.10 (S,lH,1-CH), 7.90 (m,2H,7,8-ArH), 8.08 (m,2H,6,9-ArH), 8.36 (d,2H,J = 7.4Hz,PNB-COC(CH2), 8.41 (d,2H,J = 7.4Hz,PNB-NO2C(CH)2), 8.75 (d.1 H,J = 7.7Hz,3'-NHCOCF3) .
IR(Nicolet 205 FT, film on Nacl tablet), cm~', 3625.9 (br,2), 3346.4 (str) 3079.5, 2955.5, 1732.6 (str), 1665.4 (str), 1596.0, 1530.9, 1274.5 (str), 1173.7, 1100.1, 974.04, 959.33 (m), 875.28, 721.29 (m).
Step 2: (1 'S,1 -R,3-S)-1 -(2',3',6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo,3,4,5,10-tetrahydro-1 H-naphtho-(2,3-c)pyran To a suspension of thiourea (2.2mg, 0.027 mmole) in ether (2 ml) was added a solution of bromomethyl ketone (20 mg, 0.026 mmole), from the previous step in methylene chloride (1 ml). The reaction mixture was stirred at room temperature for 20 minutes when a newly formed white suspension was observed. The reaction mixture was further stirred for 3 hours.
Solvents were removed under reduced pressure to give a white solid which was treated with saturated sodium bicarbonate aqueous solution and extracted with methylene chloride (4x3 ml). The organic layer was dried (over sodium sulfate) and evaporated to give a crude product which was chromatographed (by volume, chloroform:methanol 100:3, with one drop of pyridine) to yield the titled substance (3.5 mg) as a light colored solid.
M.P. (Electrothermal IA-9100): 142C (decomposed). 1H NMR (250 MHz, acetone-d6), ~: 1.13 (d,3H,J = 6.7Hz,6'-CH3), 1.92 (dd,1 H,J = 5.4Hz, 12.8Hz,2'-HCHa), 2.42 (dt,1H,J=3.4Hz,12.8Hz,2'-HC_e), 2.71 (dd,1H, J=12.2Hz,20.3Hz,4-HCHa), 3.12 (dd,1 H,J = 3.4Hz,20.3Hz,4-HCHe), 4.65 45a CA21 4654~
(m,1H,3'-CH), 4.67 (qua,1H,J=6.7Hz,5'-CH), 5.18 (dd,1H, J=3.4Hz, 12.2Hz,3-CH), 5.50 (bs,1 H,4'-CH), 5.68 (d,1 H,J = 2.7Hz,1 '-CH), 5.99 (s,1 H,1 -CH), 6.67 (S,1H,thiazole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.35 (d,2H,J=9.4Hz,PNB-COC(CH2), 8.42 (d,2H,J=9.4 Hz, PNB-NO2C(CH)2).
IR (Nicolet 205 FT, film on NaCL plate): cm~1, 3455.4 (w), 3346.8 (str), 3119.6 (w), 2923.8, 2850.3, 1731.5 (str), 1665.0 (str), 1532.2 (str), 1273.4 (str), 1217.5, 1182.5 (m), 1161.5 (m), 1101.8, 1005.5, 957.36 (m), 874.2, 721.18 (m).
Step 3: (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-p-nitrobenzoyl-L-Iyxohexopyranose)-3-(2-aza-3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro- 1 H-naphtho-[2,3-c]-pyran A solution of bromomethyl ketone (10mg, 8mmol), from step 1 (example 8), in methylene chloride (0.5 ml) was added to an ether solution (2 ml) of 1-methylthiourea (1.1mg, 1.0 mmol). The reaction mixture was stirred for 3 hours at room temperature then 3 hours at 40C. Solvent was evaporated and the crude product was analyzed by 1H NMR to see if the reaction was incomplete. The reaction mixture was redissolved in methylene chloride (0.5 ml) and ether (4 ml) and then stirred with newly added 1-acetylthiourea (1 mg, 1.0 mmol) and sodium iodide (0.06 mg, 0.05 mol.
eqv.) at 40C for 1 hour. Solvent was evaporated to give a crude product which was chromatographed (Eluent in volume ratio, chloroform:methanol 20:1, with 1 drop of pyridine) to yield the title substance as a light colored solid (6 mg).
M.P. (Electrothermal IA-9100): 145-150C, decomposed at 195C.
1H NMR (250 MHz, acetone-d6), ~: 1.09 (d,3H,J=7.4Hz,6'-CH3), 1.92 (dd,1H,J=4.7Hz,12;1Hz,2'-HCHa), 2.42 (dt,1H,J=2.3Hz,12.1Hz,2'-HC_e), 2.75 (dd,1H,J=11.7Hz,19.5Hz,4-HCHa), 3.14 (dd,1H,J=2.3Hz, 19.5Hz,4-HCHe), 4.62 (qua,1H,J=7.4Hz,5'-CH), 4.64 (m,1H,3'-CH), 5.31 (dd,1H,J=2.3Hz,11.7Hz,3-CH), 5.47 (bs,1H,4'-CH), 5.68 (bs,1H, 1'-CH), 6.00 (s,1H,1-CH), 7.20 (s,1H,thiazole-CH), 7.90(m,2H,7.8-ArH), 8.11 (m,2H,6.9-ArH), 8.34 (d,2H,J=7.8Hz,PNB:CO-C-(CH)2), 8.40 (d, 2H,J=7.8Hz,PNB:NO2-C-(CH)2), 8.72 (d,1 H,J = 7.4Hz, 3'-NHCOCF3), 11.08 (S,1 H,thiazole-NHAc) .
IR (Nicolet 205 FT, film on NaCI plate): 3539.7 (br,w), 3296.1 (str), 3083.7, 2919.4 (str), 1732.7 (str), 1667.5 (str), 1593.9 (w), 1547.7 (str), 1528.7 (str), 1127.1 (str), 1217.2, 1183.2, 1166.2, 1104.0, 1008.9, 975.46, 956.53, 718.14(m).
.
Step 4~ S,1-R,3-S)-1-(2'3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose) -3-(2-aza-3-acetamido thiazolyl)-5, 1 0-dioxo-3,4, 5,1 O-tetrahydro-1 H-naphtho-[2,3-c]-pyran To an ice-cold solution of PNB-derivative (3mg, 4.1 mmol), from the previous step, in a tri-solvent system containing water (98 ,ul), MeOH (422 ,ul) and methylene chloride (158,ul) was added an aqueous 46a WO 94/11382 PCI`/CA93/00463 21~6~
solution (20 ~LI) of ~otium ' : (0.51 mg, 6.11 mmol). The re~ction mu~ture w 8 then stirred at room , ~; for 1 hour. When the re ction W9C ~ , I ' d, (_8 judged by t~ t ,~
, , ' y), the reaction mL~ture W_8 poured into _ bi-l~yer system of ' ~ chloride and ~ u~ueous 9 chloride solution (5 ml/S ml). The well-shslcen mL~cture was then allowed to settled u~d the org_nic l_yer W9 ~ ~ ' d, dried over sodium sulfate, and 6.~ to give the titled - a8 a light colorod solid (1.4 mg).
M.P. (P' ~ ' ' LA-9100): 160-165C, ~ t 195C.
lH NMR (250 MHz, ~ ~ .~G), o: 1.12 (d,3H,J=7.9Hz,6'-CH3), 1.24 (dd,lH,J=6.7Hz,15.0Hz,2'-HC~I~), 2.14 (dt, lH,J--4.2Hz,15.0Hz,2'-HC~e), 2.25 (~,3H,COCH3), 2.64 (dd,lH,J=l~ ~H~ ~0 9Hz,4-HC~), 3.13 (dd,lH,J~4-~U7 ~n.9Hz,4-HC~e), 3.63 (bs,lH,4' CH), 4.21 (qua,lH, 1=7.9Hz, S'-CH), 4.30 (m,lH,3'~, 5.26 (dd,lH,J=4.2Hz,12.5Hz,3'-CH), 5.50 (d,lH,J=2.4HZ,1'~, 5.97 (s,lH,l-CH), 7.12 (8, lH, ;' If CH), 7.90 (m,2H,7.8,ArH), 8.10 ,~U,6 9,ArH)~ 11.07 (6, lH,thi_zole-NHAc).
IR (Nicolet 205 FT, film on N_CI plate): 3668.0-3119.7 (podced d 3268.3,br,str), 3073.7 (w), 2925.1, 1711.8 (str), 1669.4 (str), 1591.6 (w), 1549.1, 1375.8, 1290.9 (6tr), 1170.6, 1006.5 (w), 984.49(6tr), 716.33 (w).
Step S: (l'-S,l-R,3-S)-1-(2',3',C~ ~ ~-3' t '' . v ~ L l~ ' . ,. v ~) 3-(2~-3-~i~h~lyV-S, Woxo-3,4,5,10~ydro-lH-naphth)-lt,3-Cl pyr~n To a s mple of PNB ' . ~_ (2.5 ml~, 3.5 ~mol) from dep 2, ~ 1~ in t,; ~ '~,. sytatem e w ter (85.7,ul), ' ~1 (370~.1) nd methylene chloride (138/~1), at 0C, w~s sdded -solution of sodium ' ~~ ~ (0.66 mg, 7.0 ~mol, in 30~1 of wder). The re ction mi~cture w~s sti~ed a t room I ~ for 1.5h untill t~ tlotal t pt of the st~ng m~ial. It w~ pou~d into t~
d sodium b ~ solution (4ml) tnd e. . d with ' ~ - chloride (5~2ml). The organic layer was dried over odium t~ulf te nd then c., ' to givc a crude product which wa6 further purified by ,_.~ ' from - ~- - ' ' ~ " - to gi~te t n off-white solid (l.Smg).
M.P. (lik_h~ - ' IA-9100): 142-146C.
lH NMR (250 MHz, acot~d6), o: 1.14 (d,lH,J~5.9Hz,6'-CH3), 1.74 (dd,lH,J=12.5Hz,4.8Hz,2'-HCH-), 2.11 (m,lH,2'-HCHe), 2.62 (dd,lH, J=11.8Hz,18.4Hz,4'-HCHa), 3.12 (dd,lH,J=4.2Hz,18.4Hz,~HCHe), 3.65 (bs,lH,4'-CH), 4.24 (qu-,lH,J=S.9Hz,5'-CH), 4.33 (m,lH,3'{~, S.ll (dd,lH,J=4.2Hz,11.8Hz,3 CH), 5.48 (bd,lH,J=3.0Hz,l'{~, 5.92 (s, lH,l-CEI), 6.57 (8,1~,1' ' ~- CH), 7.87 (m,2H,7.8,ArH), 8.08 (m,2H, 6.9,ArH).
IR ~Nicolet 205FT, film on NaCI plt~lte): 3423.9 (str), 3341.1 (str), 2927.0, 2853.4 (w), 1718.5 (str), 1664.4 (str), 1597.5, 1524.7, 1335.0, 1300.1 (str), 1174.0, 100.4, 984.61 (str), 724.51, 707.71.
EXAM~E 9 SUBS I I~UT~ S~ET
Ex~71~ Y 2 1 ~
N HAC
O O
H ~Br ~ ~/S
~COJCF3 ~COJCF3 H3C~
PIIBO
NHAc O N~( ~ vs BCH-1198 H3C~
~ NHCOC i 3 OH
Step 1~ -S~ 3-R)-1-(2~.73~ 41 p ' ~ yl 31 L-'' G :~~ ' '~ L-) 3-(2 ~ I)-S,10 - 3,4,S,10 t ~. ~ lII "! q ~2~3 C] ~
To ~ 801utioll of (1'-S,l-S,3-R~1~2',3',6' t~ y~l' P .~ ~1 3~ 1 r ~~ ~ L-1~ ~ rJ ~ )-3~1-S,10-dio~o-3,4,S,10~ t2,3~ pys~ (50 ~g, 0.077 mmol) in W ~ r r (3 ml), 8tirrod ~t room i .i, W98 ~ olution of ~" ' -h~ 7 ~ ' pc.b._ '- (24.5 mg, 0.077 mmol) in THF. Thc re~ction mL~rc w~s sti~rod for 2 hour~
t room i thcn pourod into v~ter (10 ml) ~nd ~ d with ' ~- - chlonde (3~5 ml).
Tho . ' - ' org~ic e~~ v.~ere w sbod with brine (5 ml), nd dried ovor odium sulf te. The Holvent w~ ~ to ~pve ~ crude 7p~duct (68 mg) from which, vi~ " p' ~ (duent in volume r~tio, k ' ~ te~ 10:3), ~ pure 6unp1e of thc titled ' - e (27 mg) w~6 obtdnod 15 light yellow ~olid. U k d ~ting m teri-l (10 mg) w~ ~18O o~` - d.
lH NMR (250 ~7~J _' - d6), ~: 1.33 (d,3H,J--6~8~T~ 6'{~H3), 2.02 (dd, lH,J=4.9Hz,13.SH~,2'-HC~I), 2.48 (dt,lH,J=5.8Hz,13.5H_,2'-HC~e), 2.78 (dd~lH~J~l2.1~7~n~H7l4-Hc~ 3.12 (dd,lH, J 4.0Hz, J=20.3 Hz,4-HCHe), 4.29 (m,lH,3'{H), 4.52 (d,lH,J=1~.8~7.R~CHre), 4.67 (d,lH,J=13.~7 R~C_si), 4.88 (qlu,lH,J--6.8H_,5' CH), 5.04 (dd,lH, Js4.0H_,12.1H_,3 CH), 20 5.53 (bs,lH,4'~, 5.85 (bd,lH,J=3.4H_,I'-CH), 6.24 (6,1H,1~,7.90 (m,2H,7,8-ArH), 8.10 ,?~ 6 -~rH), 8.48 (qu~-lilce m,4H,PNB-ArH), 8.70 (bd,lH,J=7.4H_,3'-NHCOCF3).
Step2: (1'-S,l-S,3-R)-1-(2',3'C'-h ' ~1'~p-~iL~ 13'-triflu rr -~ido-I,-~ r--- ) 3--(2~--3 ~ ~) 5,10 ~ 3,4,S,10 1 ~. 1~--2 5 ~ phtho-[2,3-c]-p~all S U B S ~ 3 L ~ ë
WO 94/11382 PCI~/CA93/00463 214~
A -mple of 1 ~ ~ , 9.0 m~l) in o~or (2 ml) w s~d d room I , .~ while ~olution of h.~ etone (9 mg, 8mmol), from the previous step, in ' yl~c chloridc (0.5 ml) w98 ~dded. Thc ~6ulting mLlc~ w~s ~tirrcd for 3 hour~ ~t room I . e ~nd then for 4 hour~ ~t 5 40C. Solve~lt w .,., d to give cn~do product which w purifiod vi fl~h ~ L .~.~
(dualt in volume r~tio ~ r ~ 100:7, with 1 drop of pyridine ~ddod), to yield ~ product, which w furlher purified by ~ " - from CH2C12A~nc. The titlod ' w o~inod ~n off-whito ~olid (4mg).
lH NMR (250 MH_, ~d6), ~: 1.33 (d,3H,J~7.SHz,6'-CH3), 1.96 (dd,lH,J=5.8H_,15.2H_,2'-10 HCEO, 2.28 (s,3H,COCH3), 2.49 (dt,lH, J~ 3.8Hz,15.2H_2'-HC~c), 2.76 (dd,lH,J=12.S~ ~O.Q~7 ~H~), 3.15 (dd,lH,J--4 '~7 '~Qn~7 4-HC~c), 4.60 (m,lH,3'~,4.92 (qu~,lH, J~7.SHz,S'~, S.24 (dd,lH,J~4.2Hz,1~ ~7 ~{~, 5.55 (bs,lH,4'-CEI), 5.68 (bd,lH,J=3.0H_,1'~, 6.16 (s,lH,l{~, 7.18 (s,lH, 1' '- CH), 7.92 (m,2H,7,8-ArH), 8.14 ' ,~,6 9-ArH), 8.36 (t,2H, J~8.3Hz,PNB-OCOC(CH)2), 8.42 (d,2H,J=8.3H_,PNB-N02C(CH)2), 8.74 (bd, lH,J=7.9H_, 3'-~lCC~3), 11.07 (s,lH,thi zolo-NH~C).
Step 3: (1'-S,1-S,3-R)-1-(2',3',6'~ -3'-: ~ . ~etsmido ~1~ ' . ,,.~ose)-3-(2~-3-~mido-thi~zolyl)-S,10 ' ~ 3,4,S,10 ~ lH~phtho-12,3 c] ~, ~
20 A srmple of thc PNB d . -~o (4.0 mg, S.S mmol), ftom tho previou8 rbp, W t~cn into ~ solvont tcm c e b~' - cbloridc (212 /~1) ' -' (566 ~1) nd w~tor (131 ~LI), uld coolcd to 0C.
An squows lution of sodium ~- L (0.69 mg, 8.2 mmol in 20 ~1 of w~ter) w thcn rdded to the ~ction mLl~tu~e. Thc ~ction ~,.~ st 0C for 1 hour nd ~t mom ~ - for 20 minutcs. The re ction mLl~turC w~ pourod into ~ cturc of - J- - chlondc ~nd ~ 9 chlonde 25 ~uoous ~olution (Sml/Sml). Tho orlpnic l-ycr w~ t . d. driod o~r odium sulf te nd then _. . d to drg~4. Tho c~ p~ducl w ~ f~ ' ' - - " - to yield the titled ~ li,' t-e ' ~ olid.
M.P. (F~ ~-9lOO): n~,c . - ~ st 195C.
lH NMR (250 MHz, ~ ), o: 1.35 (d,3H,J--7.5Hz,6'-CH3), 1.76 (dd,lH,J=5.8Hz,14.2Hz,2'-30 HC~), 2.16 (dt,lH,J~4.2Hz,14.2Hz,2'-HC e), 2.75 (dd,lH,J~12.1~'~o.~ 4-HC~), 3.12 (dd,lH,J~.4.0Hz, 2n ~"1 II~_e), 3.72 (bs,lH,4'-CH), 4.28 (m,lH,3'-CH), 4.58 (qu~,lH, J--7.5Hz,S'~, S.18 (dd,lH,J--4.0Hz,12.1Hz,3~, 5.48 (bd,lH, J=2.9Hz,l'~, 6.10 (s,lH,1-CH), 7.16 (6,1~ - l~ CH), 7.90 (m,2H,7,8-ArH), 8.11 ( ,~,6,9-~rH), 8.17 (d,lH,~... - . p d,~'-NHCOCF3), 11.07 (8,1~,1- ' NH~c).
35 IR (Nicolet 205 FT, film ~n N~CI pl~te): 374~3048 (p~lcod Yt 3388.3, br,dr), 2923.2, 1712.9 (6tr), 1664.9 (6tr), 1591.9, lS50.1, 1535.5 (6tr), 1289.3 (6tr), 1243.4 (m), 1145.4 (w), 1124.5, 1080.7, lOOl.S, 971.57 (6tr), 936.11, 709.75 (w).
SU~S~I~UTE SHEET
WO 94/11382 pcr/cA93/oo463 214~'~a~ --EXL~M~E 10 r p~lo X~
NH2-N(CH3)2 c~ O
}~c~
~o~l o o o o X~ X~
o o o R~O~' E~O
O O O o X~
O O O O
~' ~
5 Sbp 1: r~ N,N
Under N2, Jt room ~ , .;, w~s mL~cd 3g (SOmM) of ~ in 60dium " ' - ' 801ution 7. lg (SOmM) in SO ml H20 ~nd 3.5g (SOmM) , ' The muchlre wus ~,;Oc,1~ sti~Ted for 10 minutes ~It 60C ~d then 30 mlllUte8 ~It room I , ~i. The 801ution wa8 e ' ' Wlth Et20 SUBSTITUTE SHEET
.
WO 94/1 1382 ~ r PCT/CA93/00463 2i46.~
(3~40 rnl), dried over MgSO4, nd c. . ~ ' rho rcsidue w~s fl~ L~ ' using CH2C12 ~s oluellt; 5. lg of colorless oil W~8 isol ted.
lH NMR (250 MHz, CDCl3)~i: 2.13 (s,3H,CH3), 3.04 (~,6H,N(CH3)2), 5.23 (bro~d 6,1H,C=CH2), 5.32 (bro~d s,lH,C~CH2), 7.25 (s,lH,C~CH).
-Step2: (l'S,l.C;,'R) snd (1'S,lR,3S) methyl (1-12',3',6'-trideoxy-3'-L '` .- '- q'~
' ~ Jl L 1~ ` r~-~ ] S~10 ;~- 3~4~5~10 I ~ 7 ~1 g -- o~phtho 12,3-cl pyr~n-3-yl Icelone 10 Under N2 ~t room i , ~, lo 235 mg (0.394 mM) of quinonc from step 1 (o~mple 5) ~ ,d in 20 ml of dry 1~, w~ ddcd 1.1 oq. (47 mg, 0.399 mol) of lb~.' ~ from stcp 1 (~ , '~ 10), nd 1.1 oq of F ~' - sulfonic cid (0.4 mM, 76 mg). After stirring 1 d~y ~t room t~ ~" the mi~cturc wss pourod into 20 rnl of H20, ~nd - ~ with EtOAc (3~c15 ml). After trying snd e., tho rosiduc w~s fb~h ' . O .' -d [EtOAc 1: toluene 31 to giYC 95.1 mg of titled 15 ~ . ' (40% yield).
lH NMR (250 MHz, CDC13)~: 1.22 (d,3H,5'-CH3), 1.75 (dd,lH,2'-CH2), 2.18 (m,lH,2'-CH2), 2.32 (s,3H,COCH3), 2.59 (s,3H,C7-CH3), 2.62 (u.. ' .r d m,lH,H-C4-H), 3.1-3.3 (m,lH,HC4H), 4.32 (m,lH,5'{H), 4.S3 (m,lH,CHCOCH3), 5.4 (m,lH,3'~I); 5.5 (m,lH,4'-CH), 5.7 (m,lH, 1'-CH), 6.2 (~,lH,C1-H); 6.4 (m, bro~d,lH,NH), 8.2 (~ d m, lH,C6~ ), 8.2-8.4 (m,4H,p-L ~1), 8.2(m,1H,Cg-Huom).
Step3: (1'.~,1.~,3'~) ~nd (l'~ S) methyl-1-(2',3',6'-trideoxy-3'-tril . ~ J~
L 1~, ' J. ) S,10 ~- 3~4~S~10 1 ~ 7 ~ Jl O _ l~ - - 12~3-c] p~n-3-~l lceto~e To 80 m~ (0.121 mM) of ~ , ~ f~m ~tep 2 (o~mple 10), ~ 3d in 13 rnl MoOH nd 3.2 ml H20, w~s ddod 10.4 mg (0.121 mM) of N HCO3. ~er stirring for 2 hours, the r~ction wss over, nd 15 ml of H2O w dded. The mLlcture wss o '11 with 3~15 ml EtOAc. After drying snd .., ~ ~ the rosidue w~s purifiod by p..i, ~_ TLC nd yidded 30.4 mg of puro titlod _ , 30 (50% yidd).
lH NMR (250 MHz, CDC13)~: 1.24 (d,3H,J=6.5Hz,CH3), 1.76 (dd,lH,2'-CH2), 2.16 (m,lH,2'-CH2), 2.30 (s,3H,COCH3), 2.58 (s,3H,C7~I3), 4.3 (m,lH;5'-CH), 4.52 (m,lH,CH-COCH3), 5.3 (dd,lH,3'-CH), 5.5 (dd,lH, 4'-CH), 5.6 (m,lH,l'-CH), 6.1 (s,lH,CI-H), 6.4 (m, bro~d, lH,NH), 8.2 (m,lH,C6-H ~rom), 8.9 (m,lH, Cg-H uom).
SI~E~ ET
WO 94/11382 214 6 ~ 4 ~ PCI`/CA93/00463 r - ,pr L~IF-, af . ,~ ~-CIpgTan ~ ~ of o o ~+ ~
o o o o ~+ ~
o o o i.
R~30~ p~o CP~8 o o o o ~+ ~"O"U~
o o o ~
R~o~8 R~30~8 Step 1: n~ foc~
To ~ stirrod solu~ion of ~ fuc~l (114 mg, 0.53 mmol) in -1 (2.5 ml) wuc ~ddod ~ solution of sodium '- in ' -' (25~1, 4.37 M, 0.1 mmol) ~fter 45 n~inute~ ' w~s c~, ' under vscuum. The crudc product w~ d- h~ in CH2C12 (2.5 ml) ~nd pyritine (1.5 ml) ~nd ~t 0C, p -~ ,I chlonde (2.1 mmol, 390 mg) w~ ~dded. After ~ few milute6 ~t 0C, the re~ction 10 mLlchlro w~ poured in CH2C12 (20 ml) nt w~shed with w~ter, N~HCO3 10%, Jnd theD bIine. The titled product w~ purifiod by fl~h -' . O , ' ~ tc (AcOct S: 1)) (MP: 130-132C)(210mg, 909G).
lH NMR (250 MHz, CD2C12)o: 1.40 (d,3H,-CH3), 4.40 (q,lH,H-S), 4.85 (m,lH,H-2), 5.65 (m,lH,H-4), 5.90 (m,lH,H-3), 6.6 (m,lH,H-l).
SUBSTITUTE SHEET
-2 ~ 8 Step 2:
(l'S~1~C,3'~)snd l'S,~3S) byl 1-(2',6' t- ' ~-3',4'-di-0 ~
1~ * ~ ) S,10 1 3,4,5,101 b,~d ~~ p~ - ~ 12,3~1 PY~3~Yl) IcetoDe To ~ musturc of mcthyl (1 hyL~.~r-5,8~io~ 5,8~ ~ 3-yl) Icetonc (698 mg, 3.1 mmol), 1,5; ' ~.' ~3,4 di~ ~ 1-2,6~ideo~cy-L 1~ ~'~ -l-autol (1.58g, 3.7 mmol), snd '- ' sicve6 4 A (3.8g) in CH2C12 (150 ml), ~t -60C, w~ ulded L;.,t~ (0.24 ml, 1.7 mmol), Jnd I ~ 1 b '' . '; '' (0.64 ml, 3.3 mmol), ' ,, 'ly. ~er stirring for 40 mil~utes, the ro ction W9S, ' - ' by sdding ~queous N HC03 (50 ml) Jt -60C ~d ,, ' ~, w~rmed up to room i . ~;. T ~ werc filterod off nd thc filtr~te w~ ~ ' into CH2C12.
The org~uc phs6e w~s w~hed with ~queous HCI (0. lN), lOOml, w~tcr nd brine, dried over MgS04 nd the solvcnt c~ to give 2.36 g of cn~de ~ ' - - gl~;dc. This W~8 used without ~ny furthcr r - - To ~ solution of the ~uinone (mL~ture of :' 0.16g, 0.25 mmol) in 2.5 ml of dry toluene, under Jrgon ~t room i . ~, wrs dded 1 ~ ' - (0.15 ml, 5 eq) snd the re~lction mLlcturc wss 6tirred for 18 hour6. Silic~ gel (1.0 g) wss then ~ d snd sir ww bubbled through the . ~fter 15 minute6, the mi~cture w~ ' . . .'-d (sili-~ gel, 3:1 ~'ell~ co~e) to give 0.13 K (74%) of . . ' 178-2401 (1:1 mi~cture of ~' . ) 20 yellow li' , 129-132. lH NMR (CDC13)li: 8.34-7.73 (m,12H), 6.23+6.06 (2s,1H), 5.82+5.72 (2d,1H,J=2.8), 5.62-S.S2 (m,2H), 4.88+4.43 (2q,lH,J=6.5), 4.62+4.58 (2dd,1H,J 4.1,11.5), 3.10+3.02 (2dd,1H,J 4.1,6.1), 2.62-2.10 (m,3H), 2.35+2.33 (2s,3H), 1.42+1.28 (2d,3H,J=6.5).
EX~ME~E 12 SUBSTITUTE SHEET
W O 94/11382 PCT/CA~93/00463 2 1 ~
O ~ O Me ~ 1, ~ ~
OMe O_~ OMc O
~3, O OH OMe OH
~ ~~
Mc ~ M~
~ OAc ADO QAc BC~ 7 Stqpl: 2~rrbilboor~4-h~dnD~butyl)-ben l~' b~d~ co~
To ~ ooolod(-lS-C) lu~on of2,5 ~xl~ (13.2 ~; 44.6 ~nol)in 300 5 n~ of ~ ~d ~ u ~dded l.hvl,.. . under ~rgon, n P ~ (32.2 n~ of J~ 2.5M
solu~on in 1 - ~ ~ m}nol). Thc n~i-Ab~rc w~s wu~od to -7C ~ timd ~ , for S hou~. Ibe 106ulting mL~tu~ w~s ooolod to -78-C, tre tod w~ e&c~tc (21.8 ml; 177 mmol), ~d 1,2 ~A~ - (10.2 ml; 119 m~nol). ~er ~g Jt -78-C for 60 minut~ thc ~ction mi-Atu~e w~ qua~ot with ~ ~ch~tot solution of 1 ~ Jnd then ~c' d wilh clher. Thc org~nic SU~5~iTUT~ S~-~EET
Iayers were combined, washed with water, and brine, and were dried over MgSO4.
Removal of the solvent gave a crude oil which was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford 2.39 g of pure starting material (18%) and 5.21 g (52% based on S.M. recovered) of 2,5-dimethoxy-6-(2 hydroxybutyl)benzaldehydedioxane acetal as an oil.
'H NMR (250 MHz, CDCI3)~: 0.95 (t,J=7.3 Hz,3H,-CH2CH3), 1.35 (1H, dm,J = 13.6Hz,-CH2-CH~q-CH2), 1.55 (2H,m,-CH2-CH3), 2.18 (1 H,m,-CH2-CH~x-CH2) 2.98 (1 H,dd,J = 2.7 and 13.7 Hz, = C-CH2-CH-O-), 3.36 (1 H,dd, J = 10.3 and 13.6 Hz=C-CH2-CH-O) 3.65 (3H,s,-OCH3), 3.66 (3H,s,-OCH3), 3.60 - 4.10 (4H,m,-CH~q-O-,-CH-O~.), 4.16 (2H,m,-CH~x-O-), 6.16 (1H,s,-O-CH-0-), 6.61 (1H,d,J=9.0 Hz,Ar-H), 6.70 (1H,d,J=9.0 Hz,Ar-H).
Step 2: 5,8-Dimethoxy-3-ethyl-1-hydroxy-isochroman To a stirred solution of 2,5 dimethoxy-6-(2-hydroxybutyl) benzaldehydedioxane acetal (5.2 g; 17.6 mmol) in 700 ml of THF at room temperature was added dropwise 25 mlof a 1 N solution of HCI. The resulting mixture was stirred for an hour at room temperature and then quenched with a saturated solution of sodium bicarbonate. It was then diluted with 1000 ml of dichloromethane and the aqueous layer, after separation, was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. Evaporation of the solvent gave pure 5,8-dimethoxy-3-ethyl-1-hydroxy-isochroman (4.1 g; 98%) which could be recrystallized in dichloromethane/hexane to give white crystals (M . P.: 108.9- 110.1 C) .
H NMR (250 MHz, C6D6)~: 1.02(3H,t,J=7.4Hz,CH2-CH3), 1.60 (1H,m,-CHH-CH3), 1.76 (1H,m,-CHH-CH3), 2.48 (1H,dd,J=11.6 and 17.3 Hz, Ar-CH-~x-), 2.88 (1H,dd,J=3.3 and 17.3 Hz, Ar-CH-~q), 2.98 (1H,d,J=3.9 Hz,-O~), 3.34 and 3.38 (6H,2S,-O-CH3), 4.28 (1H,m,-CH-CH2-CH3), 6.40 (2H,m,ArH and -O-CH-O-), 6.46 (1 H,d,J = 8.8 Hz,ArH).
Step 3: 3-Ethyl-1-hydroxy-isochroman-5,8-dione.
To a stirred solution of 5,8-dimethoxy-3-ethyl-1-hydroxy-isochroman (760 mg; 3.19 mmol) in 160 ml of acetonitrile at 0C was added dropwise a solution of ceric ammonium nitrate (CAN) (5.25 g; 9.57 mmol) and sodium bicarbonate (1.45 g; 17.2 mmol) in 40 ml of water. The resulting mixture was stirred for an hour at 0C and was quenched by adding a saturated bicarbonate solution. The aqueous layer was extracted 3 times with dichloromethane and the combined organic layer was washedwith water, brine, and dried over MgSO4. Evaporation of solvent gave a crude quinone which was suitably pure to undergo further reactions (600 mg; 90%).
1H NMR (CDCI3)~: 1.02 (3H,t,J=7.4 Hz,-CH2-CH3), 1.70 (2H,m,-CH2-CH3), 2.15 (1H,ddd,J=1.1,12.4 and 19.5 Hz,Ar-CH-~x-), 2.60 (1H,dd,J=3.2 and 19.5 Hz,Ar-CH~~oq~)~ 3.20 (1H,br s,-OH), 4.08 (1H,m,-CH-CH2-CH3), 5.91 (1H,s,-O-CH-O-), 6.76 (2H, 2 parts of an AB system, Ar-H).
55a CA2 1 46~48 Step 4: (1 ' S,1 S,3S) a nd (1 ' S,1 R,3R) -5,10-d ioxo-3-ethyl- 1 -(2',3' ,4',6 '-tetradeoxy -3',4'-diacetoxy-L-lyxohexo-pyranose)-3,4,5,10-tetrahydro-1 H-naphtho[2,3-C]pyran To a cooled solution (-60C) of 3-ethyl-1-hydroxy-isochroman-5,8-dione (150 mg;.72 mmol) in dichloromethane (40 ml) were added sequentially molecular sieves (4A,864 mg), 3,4-di-0-acetyl-L-fucal (246 mg; 1.15 mmol), triethylamine (56,ul) and trimethylsilyl trifluoromethanesulfonate (138,ul; .72 mmol). The resulting mixture was stirred at -60C for 3 hours and was quenched with an aqueous saturated bicarbonate solution. Extraction with dichloromethane was followed by washing of the combined organic layers with 1 N HCI, brine, and then drying over MgS04. Following evaporation, 407 mg of the resulting crude thick oil was dissolved in 20 ml of toluene.
To this solution was added 1-acetoxy-1,3-butadiene (521 mg; 4.82 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Solvent was thenpartially evaporated to about 4 ml volume and the residue was applied to a column of silica gel (eluent, toluene, ethyl acetate 90:10) affording 2 fractions. The first one (48 mg, 14% overall) contained a 2:1 mixture favoring the (1'S, 1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L-lyoxohexopyranose)-3,4,5,10-tetrahydro-1 H-naphtho] 2,3-C]pyran over its (1 'S,1 R,3R) isomer and a second fraction (157 mg; 46% overall) consisting in a 1.5:1 mixture of the same major diastereomer that was about 80% pure from 'H NMR analysis.
1H NMR (1'S,1S,3S isomer, CD2CI2)~: 1.00 (3H,t,J=7.3Hz,-CH2-CHJ, 1.23 (3H,d,J=6.4Hz,6'-CH3), 1.55-2.20 (4H,m,-CH2-CH3 and H-2'), 1.89 and 2.12 (6H,2s,0 = C-CH3), 2.27 (1 H,dd,J = 11.3 and 19.3Hz,Hax-4), 2.74 (1 H,dd,J = 3.3 and 19.5Hz,Heq-4), 3.95 (1H,m,H-3), 4.58 (1H,q,J=6.5 Hz,H-5'), 5.10 (2H,m,H-3' and H-4'), 5.46 (1H,d,J=3.5Hz,H-1'), 5.95 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H).
'H NMR (1'S,1R,3R isomer, CD2-CI2)~: 1.01 (3H,t,J=7.3Hz,-CH2-CH3), 1.11 (3H,d,J=6.5Hz,6'-CH3), 1.55-2.35 (5H,m,-CH2-CH3,H-2' and HaX-4), 1.89 and 2.12 (6H,2s,0=C-CH3), 2.74 (1H,dd,J=3.3 and 19.5Hz, H~q-4), 4.00 (1H,m,H-3), 4.22 (1 H,q,J = 6.5Hz,H-5'), 5.10 (2H,m,H-3' and H-4'), 5.54 (1 H,d,J = 3.0Hz,H-1 '), 5.79 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H). The (1'S,1S,3S) diastereoisomer was obtained pure by recrystallization.
WO 94/11382 2 14 ~ ~ 4 8 PCI/CA93/00~63 F. ,~r- 13 Fl . of ~ ~] r~ &~ly~lCS.
+~
,~ NaOCH3, CH~
2~ ~+
OCH3 OMe OCH3 OMe (2:1) 3, 5 O OMe O O~Ie O O O O
~+~
o OMe o OMe O O O O
~ + ~5 o OH o OH
step 1: 3 ~
SUBST~TlJ ~ E ~E~
WO 94/11382 2 1~ 6 ~ ~ 3 . PCI/CA93/00463 1-T~ ... 2-one (10.083g,51.97r~nole) was ~ ~ in MeOH (100ml), cooled to 0C, followed by the 61Ow ddition of NaOMe (4.37M,14.3ml,62.36mmol). The rwulting mi~ture was stirred at 0C for 3/4 hr. It wa6 then cooled to -78C followed by the dow ~ddition of 2,3~il..~ ' yl-1,4-~ (6.74g,20.79 rnmol) in CH2C12: MeOH (60:20ml). The re~ulting mLsture was 610wly5 w rmed to R.T. nd stirrod for 2 112 hrs. NH4C1 ~ ~ solution) w~s dded Jnd it w~
6 ~ - d with - ethyl ~cetste. The . ' ' org nic ph~6e6 were dried over MXS04, filtered uld r~ ' in v~cuum. Thc crude obtuned W~16 fl~h ~m ~ ' to give thc titled c . ' (2.08g,8.25mrnol) in 41 % yield.
lHNMR(250MHz, CD3COCD3)~;: 2.31 (s,3H,CH3),2.83(dd,1H,J=1.06, 8.55 Hz, HC~CH-S), 2.99 10 (dd,lH,J=2.44,6.17Hz, HC~eCH-S), 3.44 (m,lH, CH-S), 3.78 (2s,6H,OCH3), 3.85 (2H,CH2-S), 6.78 (dd,2H, J=8.95, 12.58Hz,ArH). IR (cm~l): 2900: CH, 1707: C~O.
Step 2: Tn~ 3-sceto-1,5,8-t. ' ~1' ' ~nd c~3-sceto 1,S,8-1~ ' ~;' ' The i ' . from step 1 (r , '- 13) ~100.0mg,0.40 mmmol) was ~ d in CH2C12 (12ml) und MeOH (4ml) Lll. ..~ by the addition of DDQ (109.0mg,0.~ -1,1.2eq [I~) ~t R.T. The resulting mLlcture was 6tirred ~t rvom I . ~7 v._.~hl. H20 w s ulded und it W~ with CH2C12.
The ~ ' - ' org Dic ph~es wcre w shed with w ter, dried over MgS04, filtered und c~ q ' in 2 0 vu uum. The crude obt ,ed w s fl sh ~ ' ' u6ing toluene: dh~-- ~ (95:5) to give the t~ titled ~ , ~ (65.0mg,0.~ ' -l) in 58% yield (MP: 84C).
lH NMR ('~n''~7CDCI3)~: 2.34 (s,3H,CH3CO), 2.91 (dd,lH, J~11.73,17.78H_,HC~aCHC-S), 3.27 (dd,lH,J 4.10,17.77~ ~C~ç~C-S), 3.54 (s,3H,OCH3), 3.78 (s,3H,OCH3), 3.82 (s,3H,OCH3), 4.16 (dd,lH, 4.13,11.79Hz,CH-S), 5.69 (s,lH,O-CH-S), 6.75 (dd,2H,J~8.96, 14.36 25 H_,ArH). IR (cm~1): 2925: CH, 1705.7: C=O. Cis-3~ceto 1,S,8: ' ~ ' ' (32.4mg,0.11mmol) w s obtuned in 30% yield (MP: 129C).
lH NMR (250MHz,CDC13)~i: 2.34 (s,3H,CH3), 3.25 (d,2H,J=6.S8Hz, ~.C~eCHC-S), 3.46(s,3H,OCH3), 3.59 (dd,lH,J~6.75,13.55H_,CH-S), 3.79 (2s,6H,OCH3), 5.73 (s,1H,O-CH-S), 6.76 (dd,2H,J=9-~0,~1.3QT~7 ArH).
Sbep3: Tr~ns-3-~ceto-1 ' ~-~,~ ~- ' ' ~
The ~ _ from 6tep 2 (e~ample 13) (178.2 mg, 0.63 rnmole) W~6 ~ ~ iD
- '- (10 ml) nd H20 (10 ml), followed by thc ddition of N~HCO3 (100.8 m~, 1.22 Dle).
35 The mi~ture wa6 cooled to 0C, followed by the slow uldition of CAN (1.04g, 1.89 mmole). After 20 ~ utes of ~tirring, H20 w~ dded nd themi~ture w~s - ' with CH2C12. The ~ ' -' organic p~ses were wuihed with H20, dried over MgSO4, filtered ~d ' in v cuum. Thc crude obt iDed was found to be pure titled compouDd by lNMR aDd was u~ed in the ÇU~ g step (>95%
yield).
S U ~ S ~ il E ~ k 214~4~
lH NMR (250 MH_, CDC13)o: 1.73 (~,3H,COCH3), 2.62 (dd,lH, J=11.32, 19.81Hz,HCHaCH-S), 2.87 (td,lH,J=4.28, 20 ~n~r ~C_eCH-S), 3.21 (s, 3H,OCH3), 3.61 (dd,lH,J=4.31, 11.42Hz,CHS), 5.97 (m,2H,HC=CH).
Step 4: Tr~-3-~ceto-1 ' / 1,~ ~,4 1 ~ d . (2-6ull~ ~ ' ~ S,10-dione ~nd cis-3-- sceto-l ' ~-1,2,3,4 1 ~ ,d ~ ' ~ S,lWione Tran6-3-aceto-l ~-5,8 ~ ~ (0.66 rnmole) w~s d' 1~ in dry toluene (14ml), followot by thc ddition of thc dicnc (120.0 mg, 1.07 m~nole). The ro6ulting mucturo was stirred at room 10 i , ., v_' Solvont w 8 ro noved and tho crudo obtunet w 8 flash :' I " . ' ' using pure toluono to dvo t~o titled ~ . ' in r~tio of bout 1:1, in 48% yield.
lH NMR (~CQ' '~17 CDC13)~: 2.37, 2.39 (2~,6H,CH3, cis ndlor tran6), 2.75 (dd,lH,J=6.42,19.81Hz,HCHaCH-S, Ci8 ortrns), 2.90(dd,lH, J=11.79, 20.08 H_,HC~a-CH-S, cis or tr n6), 3.27 (dd,lH,J~3.98, 2n~n~7 HCHeCH-S, cis or ~sns), 3.58 (6,3H,OCH3, ci6 or trans), 3.60 (s,3H,OCH3, cis or t~n~), 3.64 (m,2H,CH-S, Ci8 or tr ns), 4.11 (dd,lH,J--3.92,11.80Hz,CH-S, cis or tr n6), 5.30 (c,lH,OCH-S, cis or t~ns), S.49,(s,1H,OCH-S, Ci8 or tran6), 7.74 (m, 4H,ArH, ci6 nd tru~s), 8.10 (m,4H,ArH, cis ~t trJns). IR (cm~l): 2900:CH; 1709.4:C=O; 1668.1, 1631.9:C=O
quinono.
StepS: cis3~ -S,~
0 ' ~ . by u6iug thc ~ from 6tep 3 (e~ample 13), of ci6-3-sce~1,5,8-~;- ~' . gavethetitled lin98%yield.
Hl NMR (250 MHz, CDC13)~: 2.04 (s,3H,CH3), 2.23 (dt,lH,J=4.88, 19.49Hz, HCHaCH-S), 2.54 25 (d,lH,J=5.68Hz,HCHoCH-S), 3.56 (dt, lH, 1=2.10, 19.23Hz,HCHa,o-S), S.09 (s,lH,CH-S), 5.96 (dd,2H,J--10.30, 1~ ~n~7 ~rH).
~up 6: ~ .,4: ' jd ~ (2-6~r~ '' - S,10 dione snd tr~ns-3-,4 1 b,~ ' - 5,10-dione ~1'- - of ~e ~ d~ d for ~p 4 (e~le 13) to ~ns-3-~1 - y-5,8-d - - ~ g~ve pure titled lH NMR (250 MHz, CDC13)~;: 2.37 (s,3H,CH3), 2.75 (dd,lH,J=6.42, 19.81Hz,HCHaCH-S), 3.58 (6,3H,OCH3), 3.64 (m,2H,CH-S,HCHeCH-S), 5.49 (s,lH,~CH-S), 7.74 (m,2H~ArH), 8.1035 (m,2H,ArH). IR (cm l): 2900:CH; 1707.8:C=O; 1660.0, 1630.2, 1594.4:C=O quinone.
Step 7: trsns-3 - ~ 1 b~ ,4 b,.' . (2ffulfur) - ' _ - 5,10-dione and cis-3-9 ~ d ~ ,4 t b,~ ~ (2-sulfur) ' ~ 5,10-dione The mLlCture of - . obt~ined from step 6 (elc~le 13) (30.8 mg, 0.102 mmole) was ~L~vl~
SUBSTITUTE SHEET
WO 94/11382 ~ PCI-/CA93/00463 CH3COOH:H20 C2:0,4 ml) at 0C. The re~ulting m"cture W98 stirred at 0C for about 2 hour6.
NaHC03 (5 %) w~s d~ed ~nd it wss _ ' with CH2C12. The ' -d organic phnse~ were w~hed with H20, dried over MgS04, filtcred nd a~- ' in vscuum. T~e crude product obt~ned war, flsr,h ~ .' ' uung '~ ~1 acetste (7:3) to givc tlle titled ~_~ ' in 7% yield.
5 According to NMR one ixomer i~ m~or:
lH NMR (250 MHz, CDC13)o: 2.74 (r"3H,CH3), 3.00 (dd,lH, J=ll.99, 20.74Hz,HCHaCH-S), 3.26 (dd,lH,J~3.96, 20.61Hz,HC~eCH-S), 4.37 (dd, lH,J=3.99,12.0Hz,CH-S), 6.67 (s,lH,O CH-S), 7.73 (m,2H,ArH), 8.08 (m,2H,ArH).
SUBS~ TE ~ ET
WO 94/11382 . PCT/CA93/00463 ~l 46~4~
EXAME~LE 14 - Tl rJ- J ~r F. "r 1~ n of . ~C]thiopyr~
~/~ ~5+~
O~H3 ~H OCE~ ~ ~ O~H3 () A~O OA~ OA~
A~O A~O
St~p 2 O O O O
O O O ~
H~C~ H,C~
OAD OA~
AcO ADO
S~sp 3 O O O o .~ ~
O O o ~
C~
OA~ OA~
~0 A~O
Step 1:
(l'S,lP ~S) ~u~d (l'S,1.C ~) methyl (1;9J~ d- " ~-1-(2',3',4',6' ~ 3',4'-~ ~-L l~ ' I J- lC ) 3,4,: ' .,. . ' [2,3-cl i I J- 3-yl) l~eto~e A mLlcture of ' ' . from 8tep 1 (e~a~ e 13) (96.0 mg, 0.38 mmol), dicyano dichloro t ~ - (DDQ) (104.0 mg, 0.46 mmol) uld 3,4-di~cetyl-2,6-dideo~y-L-ly.
SUE~
WO 94~11382 PCT/CA93/00463 211165~
/B ~ 3; 106.4 mg, 0.46 mmol) in 5 ml of CH2C12 W95 stirrod Jlt room h~ under rgon for 2.5 hours. After D~ of S ml of NsHCO3 solution (59~) ~ nd 10 ml of H20, the products were e ~ 1 with CH2C12 (25 ml ~c 4). The e ' -' orgsnic ph~se wss w~hed with H20 (lS ml), dried over MgS04, filtered snd then c.. ' The ro~iduç W95 purified by flssh cL~ O ,' y (b ~~'CH2C12/ethyl ~cetste, 2=1=1) to provide ~ ture of titlod ~~, ' (2=1, 116.9 mg, 0.24 mmol) in 64% yiold ~long with ,~ ,d sugsr (48 mg, 0.21 ~nol).
lH NMR (CDC13), the msjor ~ 1.20 (d,3H,J=6.2Hz), 1.70-2.30 (m,2H), 1.94 (s,3H), 2.20 (s,3H), 2.29 (s,3H), 2.98 (dd,lH, J=16.5Hz,10.5Hz), 3.28 (dd,lH,J=16.5Hz,S.lHz), 3.80 ~s,6H), 4.14 (dd,lH,J=lO.SHz,S.lHz), 4.42 (q,lH,J=6.3Hz), J6.3Hz), 5.10-5.25 (m, 2H), 5.65 (d,lH,J=3.2Hz), 6.27 (s,lH), 6.72 (d,lH,J~9.8Hz), 6.81 (d,lH,J 9.5Hz); t~e mi~or isomer: 1.19 (s,3H), 1.70-2.30 (m,2H), l.9S (s,3H), 2.19 (~,3H), 2.34 (s,3H), 2.96 (dd,lH,J=16.5Hz, 10.5Hz), 3.30 (dd,lH,J~16.5Hz,S.lHz), 3.81 (s,6H), 4.22 (dd,lH, J=lO.SHz,S.lHz), 4.42 (q,lH,J=6.3Hz), 5.10-5.25 (m,2H), S.S0 (d,lH, J=3.2Hz), 6.03 (6,1II), 6.70 (d,lH,J=9.8Hz, 6.79 (d,lH,J=9.8Hz).
Step 2:
(l'S,lP~s) ~nd (1'~ "3P.) me~hyl (C~8 ~ 1-(2',3', 4',6' i ' de ~^3',4'-t- ~ ~-L 1~ . ) 3,.~ tP ~ 12,3-c] 1- ')rJ- 3-yl) ketone 2 0 To ~ stirred solution of the i' ' ~ ~;d~ from step 1 (e~umple 14) (106.0 mg, 0.22 mmol) in S ml of CH3CN W9~ ~dded ~ solution of NsHCO3 (35.0 mg, 0.42 mn ol) in 2 ml of w~ter. After cooling to 0C, ~ ~olution of c~ (362.0 mg, 0.66 mmol) in 2 ml of wster ws~ sddod Lv~ After being stimd t 0C for 20 minutes, t~e mi~ture wss e ' with CH2C12 (25 ml ~c 2). The orgsnic l~yer w~s w~shed wi~ H20, dried over MgS04, filtered nd then ~ Thc r~6idue (94.3 mg, 2 5 0.21 Dl) w~s found to be the title ~ . ' (2: 1) by lH NMR. The yidd w~s 9S % .
lH NMR (C~C13), the m~jor isomer: ~: 1.28 (d,3H,J=7.6Hz), 1.53-2.40 (m,2H), 1.99 (s,3H), 2.17 (s,3H), 2.33 (s,3H), 2.74 (dd,lH,J=18.8Hz,ll.OHz), 3.14 (dd,lH,J=18.8Hz,4.8Hz), 4.00 (dd,lH,J~ll.OHz,4.8Hz), 4.24 (q,lH,J=7.6Hz), 4.95-5.20 (m,2H), 5.56Hz (d,lH9J=3.2Hz), 6.00 (s,lH), 6.19 (d,lH,J=ll.OHz), 6.85 (d,lH,J=ll.OHz); the minor isomor: 1.18 (d,3H,J=7.5Hz), 1.53-30 2.40 (m,2H), 1.99 (s,3H), 2.17 (s,3H), 2.37 (s,3H), 2.70 (dd,lH,J=l9.OHz,lO.SHz) 3.15 (dd,lH,J=19.0Hz,4.8Hz), 4.07 (dd,lH,J=lO.SHz,4.8Hz), 4.33 (q,lH,J=7.5Hz), 4.95-5.20 (m,2H), 5.52 (d,lH,J=3.2Hz), 5.77 (s,lH), 6.70 (d,lH,J=ll.OHz), 6.78 (d,lH,J=ll.OHz).
Step 3:
(l'S,lP ~S) ~nd (1'~;,1.~;"3~) methyl (i~8 ~ (2',3', 4',6' . ~ -3',4'-~- ~-L 1~, ~' r~ 3,4,S,10 1 ~d~ p' - ~ 12,3-c1 ' r~- ~~ 3~YI) ketone The },.. ' G for the ~ r 8i of ~c titled . . ' is ~ d~ ikd ~ in ~tep 1 (e~ample 1).
SU~STE ~ U . ~- 5~ET
W O 94/11382 PC~r/CA93/00463 ~ 21~6~48 Thuc, the re~ction of the isoch.~ 1 -- (94.3 m8, 0.21 mmol), ob~ined from the previo~c tep with l-~ceto~y L ' - (0.10 ml, 94.5 mg, 0.84 mmol) g~ve the titled c , ~c 2:1 (74.2 mg, 0.15 mmol) in 70% yield ~fter fl~sh ~ O "h~,.
lH NMR (CDC13), the m~jor isomcr h~d ~: 1.32 (d,3H,J=6.5Hz), 1.70-2.40 (m,2H), 1.94 (s,3H), 2.17 (s,3H), 2.36 (s,3H), 2.91 (dd,lH, J=20.0Hz,11.9Hz), 3.30 (dd,lH,J=19.9Hz,4.2Hz), 4.06 (dd,lH, J=12.0Hz,4.1Hz), 4.38 (m,lH), S.05-5.22 (m,2H), 5.61 (d,lH, J=3.8Hz), 6.23 (s,lH), 7.70-7.80 (m,2H), 8.05-8.15 (m,2H); the minor isomer h~d ~: 1.19 (d,3H,J=6.SHz), 1.7~2.40 (m,2H), l.9S
(s,3H), 2.17 (s,3H), 2.39 (c,3H), 2.87 (dd,lH,J=20.0Hz,12.0Hz), 3.32 (dd,lH,Jc20.0Hz,4.1Hz), 4.15 (dd,lH,J=12.0Hz,4.1Hz), 4.38 (m, lH), 5.0S-5.22 (m,2H), 5.63 (d,lH,J=3.8Hz), 6.00 (s,lH), 7.70-7.80 (m,2H), 8.0S-8.15 (m,2H), IR (ne~t): 3866, 2987-2939, 1745(8), 1715, 1667, 1645, 1597, 1368, 1285, 1252, 1229, 1021, 988, 737 cm l.
EX~MPI,E lS - In Vitro Cy ty - ' . ' .; T~ ' ~sy The " t~ ' ~y w~s u~ed to tcst in vitro c~ ,. This ~y is ~ ~d in Plumb, J.A. ot ~1., 1989 Culcor P- _h 49, 4435 ~440, which i8 ~crein - r ' ~ by .~f~ -e The c.~ , of c . ' towuds tumor ceU6 is d in vitro using the ~y. This u~y method i8 b~cd upon the ~bility of livc, but not dead ceUs to rcducc the ycUow w~ter soluble dye 3~4,5-' ~Ith;~1-2-yl)-2,5~i,' ~' ' bromide (MTI~ to its w~ter I ' '- purple f 2 0 product.
The fuUu.. e rc~gents we~e lu;cd for:
li~ue Culture, (Irvine S- C~log) -MEM: ~ ~' ' (C~t~log * 9144) Fet~l Bovine S~um (C~log # 3000) ~' . ' mino cids (C t log # 9304) n ~ buffered Dline (C t log # 9240) Sodium pyruv te (C~log # 9334).
All other tissue culture nd gener l re~gents were from Sigm~ r . ~.
Human Tunor Cdl lines, used were:
3 0 SKOV3 (Ov ri n ~ ,.v . ;ded by Dr. V. Ling, Ont~io C ncer Institute.
SKVLB (Ov~n; ' ' ~ 1~ ~) - Dr. V. Ling, Ont rio CJncer T
T47D (Dwt~l -. . of b~st) - ATCC c t~log # HTB-133.
Lo~ ) - S~ ' P~ T
HT 29 (Colon ~1 - ) ATCC cst~log # HTB-38.
3 5 The cells were - ~ in e~r ' growth in culture in minima1 e6sentisl medis (MEM) with- . ' mino cids, nd r e 15% (v/v) fetd bovine ~erum, 5~M L-> 1 mM sodium ~".... ~L ~nd 0'1 U/ml in~ulin. AU ceU lines were grown at 37C in sn 9' , ' Ci of 5 % CO2 in Yir.
Stocl~ ' , used we~e the f~" ..- o, sues~ E~EET
WO 94/11382 PCr/CA93/00463 -`2 1 ~
MTT: 2 mg/ml in ~' . ' bufferod s line (6t~blc ~t 4C in d~ for 1 weelc).
Se '8 buffer: 0.1M glycinetN~OH, pH 10.5, ~ ~ 0.1M N~CI.
Te6t c . ' 20 mM in DMSO nd diluted to find ~ of 200 ~lM in culture rnedium before u6e.
The Ç~llv.. E i6 the generic ~ p~ of the ~y mAhod. It should be noted that dthough the 1--- A~ d wor~ well with the cell6 li6ted ~bove, the initid pl ting den6ity nd the MTT
c - - used 6hoult be verifiet for esch new cell line uset to to6t ~ .
For e ch u~y, du.~.,..' is i~cluded ~s n intcr~y ~rd. This ~llows U8 to molutor the of the us~y in generd, nd in ~ L.,ul~, to checlc th~t the SKVLB line h~s - ' its resist~nt,' 15 The pl~lte l-yout is done in the r ~ - e m~nner:
The u~ys re c~rried out in 96-weD (8 weD, ~c 12 well) , pl~tes. Serid dilutions of the re te~ted ~long the length of the pl~te. A 1:3 serid dilution of c . ' in culture medium covers c--~ r nge fiom 100 ~M to 1.7nM. E~ch ~ of c . ' i6 te6ted in ~, ~ . ,' t, llowing two ~ . ' to be te6ted per plate. Wells . e no ceDs (bl~nk) snd cells 2 0 w~th ~o test ~ . ' (control) re included on e ch ph~e.
Cells rc pl ted out in 100 ~1 of culture mediwn in the 3~ pl te6 t dbn6ity of ~round 1,500 -4,000 ceU8 per well. The pl tes are ~.. . - to llow the cells to bocome dherent after which the test ~ . ' is ~led (100 ~1 of ~. r dilution per well). The cells rc ' with te6t 2 5 e . ' t 37C for 48h fter which the - . ' i8 repl ced with fresh modium. After a further 48h at 37C, SO ~1 of MIT solution (2mg/ml) is dded to oach well. The plate~ re: ~ ' in the d~c for 4h at 37C fter which the mediwn is removed. The MIT r product is _ from the cell6 by the ddition of 200 /~1 DMSO followed by 50 ~1 of S~ '6 buffer. The plate6 are O-h~lcen briefly nd the ' ; -- ~ 570 is read using a M~' ' - Dwice6 W m~ plab reader.
3 0 Curves re fit to the MTI' ~6ay d h using ~ four I logi6tic r . nd the d~ta ~re - - ' to fit 0% to 100% surviv 1 scale.
RESULTS
3 5 Tables 1 snd 2 show the sntitumor sctivity of ~ome of synthetie trieyelie pyrulylnsphthoquinones of this .. ' ~n A r n~ e of poteney is ~ d. In this 6et of c . ' Seve~l tricyclic . ' - - .
re 1~ potent nd re effective in the ' ~ ro6ist 1nt cell line SKVLB. In bre~t cancer, MCF-7, BCH-1146 i6 les6 potent than ~ ' .~. but nearly ~18 effoetive in the sensitive ~nd ~
resi6tsnt cell line. Thesc re6ult~ wgge~t tb~t tricyclic d~ ,6 wch a5 BCH-1184 ~nd 1146 6hould be SUES~T~ 5~
WO 94/11382 PCI'/CA93/00463 21~16~8 useful in the L, of certain re6istant c~ncers. Most notably BCH-2051, a r ~ ~ ~ tricyclic - ,' '~. , ,~ intense in vitro potency while :c ~ avoiding multidrug e ss obsa red from the SKVLB cell line.
SU BS ~ t ~ S i~ E ET
WO 94/113~2 PCI`/CA93/00463 2 ~
EXAMPLE 1~
BIOLOGICAL RESULTS
IC50 ~M -COMPOu~n S~Q~3 SKVLB 1~1~ LQ~ 2 ~R/oV3 Adriamycin 0.012 1.49 0.07 0.034 0.090 121.5 BCH1125 ~100 92.90 36.40 52.80 >100 BCH1129 73.30 ~100 59.40 88.20 63.20 BCH1146 0.8910 6.97 5.87 3.82 0.9100 7.82 BCH1148 >100 >100 >100 >100 ~100 BCH1169 7.14 60.10 26.50 9.63 6.29 8.42 BCH1177 9.67 16.50 ,13.30 29.70 25.10 1.71 BCH1180 0.8510 8.68 7.61 3.33 0.4680 10.20 BCH1181 2.26 8.48 9.23 3.07 0.5360 3.75 BCH1184 0.0050 0.0536 - 0.2840 0.0186 0.0023 4.75 --0.0631 0.3000 - -0.2280 - 22.34 0.5300 0.0161 RC~1188 0.8590 2.41 0.6640 0.9470 2.49 2.81 BCH1189 6.50 26.60 12.50 14.30 16.60 4.09 BCH1192 28.60 31.60 29.90 37.60 BCH1607 7.26 19.80 14.70 8.97 21.60 2.73 BCH1608 3.31 15.10 9.55 5.22 14.30 4.56 BCH1620 0.0042 0.2160 0.1830 0.0227 0.0328 51.31 BCH1643 1.74 5.17 3.49 1.65 6.71 2.97 BCH1644 0.5050 1.52 1.27 0.6410 2.65 3.01 BCH1648 0.0519 0.3150 0.3600 0.1380 0.3090 6.07 BCH1649 0.1100 0.4590 0.3800 0.2170 0.3310 4.17 BCH1654 0.7100 3.73 1.59 1.19 3.58 5.25 BCH1658 0.2330 1.47 0.4940 0.3160 0.6610 6.31 BCH1665 25.40 28.90 11.50 60.40 1.14 BCH1666 0.2720 0.2050 0.1250 0.0783 0.75 BCH1667 0.0122 0.0893 0.0133 0.0016 7.32 BCH1688 0.6340 2.77 0.4020 1.35 4.37 BCH1689 2.78 16.50 1.72 3.66 5.94 BCH1690 1.78 13.70 1.62 3.01 7.70 SUBS ~ ~ ~ U ~ E 55~iEE~
WO 94/11382 21~ 8 PCT/CA93/00463 BCH1691 8.83 18.50 4.49 7.16 2.10 BCH1697 3.70 13.20 18.00 5.32 11.00 3.57 BCH1998 0.1250 1.66 0.1140 0.0631 0.0363 13.28 BCH2000 0.0950 6.64 0.3380 0.0905 0.0378 69.89 BCH2014 21.50 39.80 61.80 35.90 61.30 1.85 BCH2015 0.3670 1.17 0.9090 1.09 0.5570 3.19 _ BCH2017 0.2500 8.94 0.4970 0.2500 0.4300 35.76 BCH2018 3.11 17.70 8.56 2.38 14.20 5.69 BCH2019 0.0633 0.3280 0.0486 0.0627 0.0230 4.95 BCH2020 11.20 25.90 9.42 5.45 19.10 2.31 BCH2021 12.40 46.40 19.00 10.60 37.80 3.74 BCH2022 0.4420 1.87 0.9340 0.4840 0.5320 4.23 BCH2023 0.73 3.2 5.5 0.67 0.98 4.39 BCH2024 0.924 5.23 3.7 0.85 0.404 5.66 BCH2026 15 >100 31.40 2.12 22 >7 BCH2027 7.01 29 23.30 3.04 15.40 4.02 BCH2031 6.0 18 16 2.8 8.5 3 BCH2032 6.01 - 17.60 - 15.80 - 2.83 - 8.49 - 2 -12 28 23 5.1 9.3 2.93 BCH2035 0.28 6.23 1.5 0.75 2.31 22.33 BCH2037 0.59 - 3.8 - 2.2 - 0.54 - 1.1 - 0.93 -5.09 4.73 2.29 0.816 4.25 6.41 BCH2038 0.832 3.5 2.0 0.173 2.0 4.16 BCH2041 2.14 10 5.62 1.9 1.9 5 BCH2042 3.8 13.20 8.0 2.22 1.2 3.51 BCH2043 3.1 9.23 11 2.92 4.7 3 BCH2044 1.44 5.11 4.25 0.38 0.194 3.55 BCH2045 5.3 15 13 4.6 1.11 3 BCH2046 0.0075 0.22 0.0675 0.015 0.0071 31 BCH2047 0.017 0.523 0.151 0.021 0.0041 31 BCH2051 0.0073 0.0675 - 0.0419 0.0167 0.091 9.3 --0.029 0.403 - - 0.03 - 14.14 0.0685 0.134 BCH2052 5.4 - 20.50 - 9.54 - 3.04 - 10.60 3.78 -7.01 28.20 23.30 3.22 - 4.02 15.40 BCH2053 4.73 21.20 12.30 3.25 14 4.48 BCH2054 6.33 11.30 4.95 3.23 4.30 1.79 SUBSTITUTE SI~EET
BCH2060 1.14 2.5 0.562 1.95 0.26 2.19 BCH2061 0.0083 0.141 0.27 0.045 0.054 18 BCH2062 0.8100 0.8420 0.7760 0.3540 1.14 1.04 BCH206S 1.54 6.1 2.2 1.4 3.42 4 BCH2067 1.2 2.24 0.54 1.1 0.323 2 BCH2068 1.2 1.2 0.422 1.3 0.13 BCH2069 0.0494 0.083 - 1.11 0.0903 0.35 2 -0.483 9.78 BCH2070 0.0084 0.12 0.018 0.015 0.006 14.34 -_ 15 0.534 BCH2071 0.133 0.43 0.201 0.21 0.05 3.22 BCH2072 0.0641 0.315 - 0.0236 0.102 0.0539 2.79 -- 0.991 -0.35 -0.101 15.46 0.1130 BCH2075 16 31 ~13 8.8 31 2 BCH2076 1.43 12.40 6.53 1.8 2.6 9 BCH2077 1.94 21 7.7 1.91 3.4 11 BCH2078 0.4140 2.24 0.5070 0.2690 5.41 BCH2079 0.0163 0.124 0.032 0.066 0.005 8 BCH2081 1.3 19 7.4 2.7 3.8 15 BCH2082 1.8 5.6 4.0 1.6 2.6 3 BCH2087 0.069 0.472 0.18 0.064 0.028 7 BCH2090 11 36 10.40 3.29 BCH2091 13.40 32 16 3.3 11.30 3 BCH2092 1.1 3.0 0.98 0.30 2.42 3 BCH2095 0.19 1.6 0.37 0.14 0.0996 8.16 BCH2096 0.702 3.11 1.7 0.84 1.7 4.43 8CH2098 8.0 30 10 4.2 17 4 BCH2099 O.S99 - 0.462 - 0.728 - 0.128 - 0.303 0.77 -2.0 8.4 3.4 1.1 - 1.7 2 8CH2100 2.7 8.22 4.0 3.0 5.12 3.04 BCH2102 0.13 0.723 0.30 0.186 0.15 5.65 BCH2104 0.21 1.1 0.613 0.24 0.171 5.05 BCH2105 0.003 0.37 0.019 0.025 0.0069 123 BCH2109 0.79 3.2 1.04 1.1 0.12 4.02 BCH2112 0.104 1.7 0.27 0.21 0.065 15.96 -SUB5TITUTE SH~T
WO 94~11382 - . PCr/CA93/00463 - 21~6'Sq~
BCH2113 0~171 0~72 0~27 0~19 0~059 4~20 BCH2114 0~4720 2~04 0~6550 0~3730 0~2570 4~32 BCH2115 2~3 ~100 5~3 4~0 5~6 >50 BCH2117 0~0095 0~332 0~0374 0~073 0~03 35~13 BCH2118 0~12 0~79 0~244 0~203 6~68 BCH2119 >100 >100 >100 ~100 BCH2121 0~21 1~3 0~34 ~34 BCH2122 0~37 2~0 0~73 0~64 BCH2126 0~6770 1.68 0~7060 0~3730 3~95 2~48 BCH2127 0~35 4~1 2~0 2~7 BCH2128 1~7 5~8 1~4 1~6 BCH2129 0~3590 1~06 0~4520 0~2280 2~07 2~95 BCH2131 35~80 34~60 12~80 12~50 43~40 0~97 BCH2132 99~80 70~60 ~ 34~70 28~40 >100 0~71 BCH2135 0~66 1~3 1~1 0~31 0~88 BCH2138 >100 >100 90 >100 >100 BCH2140 2~2 13 1~5 0~45 3~2 BCH2141 8~12 9~96 3~79 1~82 6~44 1~23 BCH2142 92 46 45 18 >100 BCH2144 21.40 16.10 7~22 3~28 5~93 0~75 BCH2145 8~19 13~40 1~78 0~8300 2~48 1~64 BCH2147 12~50 10~10 3~92 1~88 10~00 ~081 BCH2148 12~60 9~93 2~36 1~55 7~50 0~79 BCH2149 32~70 29~80 11~40 10~00 28~20 Oa91 SUe~Tt ~ E ~
W O 94/11382 PCr/cA93/00463 .
TABL~ 2 ICS0 ~
C~MPQuND MCF-7MCF-7/An~ MAT-B MAT-B/A~R
Adri~myc~n 0.005 6.5 0.0046 2.50 1146 0.044 0.19 0.46 0.56 1177 >10.0 0.66 ~10.0 ~10.0 s u ~ EET
WO 94/11382 214 & ~ 4 8 PCr/CA93/0~463 F pl- 16: ~. of OMe O OMe O o o I, [~Ol~k 7, ~Or~k OMe U 0 - O O O O O O
~OMe O OMc O OMe O 0 O O O O
~o H I -- I~,o H I . HCI . ~0 O OMe O 0~
BCH~51 S Step 1: Methyl (l~S~lr '' ,~ ' . 3-yl) fonDde Methyl (5,8 ~ ~ 3-yl) formate (lS.00 g, 59.46 mmol) ~nd DDQ (16.20 g, 71.35 rmnol) woro ~' ih ~,d in dry ~' ' ' - ~ ' - (500 rnl), ~nd dry " -1 ( 7.2 ml, 178.3 î rnrnol) w~s sdded. Tho solution wss sti~d t unbient i . ~ o.. _' t, then reflmed for 8 hour~. M~
10 (1.0 ml, 24.69 mmol) nd DDQ (2.00 g, 8.81 m nol) W~8 ~dded nd further reflu~ted for 8 hours. The re~ction rni~ture W~8 cooled down, filtered, nd the filtr~te was poured onto ~ ' solution of sodium I ~ (200 rnl). The org~nic ph~se WS8 ~, d, ws~hed with ' sodium L b~ 601ution (100 ml), dried (MgSO4) nd ~ mdcr roduced prff sure. The re~iduc was - d from ' -' to give the titlc product (white cryst~ls, 14.34 g, 85.1 %).
lS lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.70 (lH, dd, J=11.8 ~nd 17.1 Hz, 4-H,,~), 3.08 (lH, dd, J=4.2 ~nd 17.1 Hz, ~Heq)~ 3.S7 (3H, s, l-MeO), 3.77 (3H, 8, Ar~k~), 3.80 (3H, s, Ar-52~s2), 3.83 (3H, s, COOMe), 4.79 (lH, dd, J~4.2 ~nd 11.8 Hz, 3-H~c), 5.70 (lH, s, l-H), 6.68 (lH, d, J=8 Hz, Ar-H), 6.74 (2H, d, J=8 Hz, Ar-H).
- 20 Step 2: Methyl (1 '' ' ~-S~P :' S~P ' ' Jd ~ ' ' . 3-yl) fonnate - The &olution of CAN (83.24 1~. 151.84 mmol) Jnd &odium ' ~ (8.50 g, 101.22 mmol~ in water (500 ml) wJs ~led to thc &olution of methyl (1,5,8 1 ~ 3-yl) formatc (14.34 g,50.61 mmol) in - - I~ (700 ml) t 0 - 5 C over 20 minutes. The resction mi~cture w~8 stirred at 0 25 C for 20 minutes, then ~: ~ d with d~ (4,~200 ml). The t ' - i organic phases were SU~S~E ~ il)T~ 6~EET
WO 94/11382 2 1 ~ 6 ~ A ~ PCT/CA93/00463 wsshed with brine (200 ml), dried (MgSO4) and c. . - - ~ under reduced pressure to give ~ light yellow solid (12.76 g,, ~ yidd) which W95 used for the ne~t step without further ~ ;~
lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.52 (lH, dd, J=11.4 ~And 19.4 Hz, 4-H~c), 2.83 (lH, dd, J=4.2 Ynd 19.4, 4-Hcq), 3.56 (lH, 8, l-MeO), 3.82 (lH, s, COOMe), 4.66 (IH, dd, J=4.2 and 11.4 S Hz, 3-H~c), 5.48 (lH, 8, l-H), 6.62 (lH, d, CHCO), 6.78 (lH, d, CHCO).
- Step3: Methyl (I ~ 5,10-diox~3,4,S,10 b.,.~. lII ~ [~ ~ cl~. 3-yl) fomute Methyl (1 ' ~-5,8 dio~o-5,8 .' ~ 3-yl) forrn~to (12.70 g, 50.35 mmol), 1-10 ~ (30.00 g, 267.55 r ol) nd dg tolue le (100 ml) wss lltirrod c,.. _' . t 50 C. The solvellt W98 rcmovod under reducod pre&sure, the ro~idue W98 .~ " ' from ' ' to give yellow cgstals (11.05 g). The product W..8 d ~vud in toluene (200 ml), silic~ gel (20 g) W~AS .,dded And stirred over 24 hours in sn open flsslc st sJnbient I . c. The silic~AA WPAS filtered, the f;ltrstc was c - I to dgne~. The residue W95 ~ nt~ll;~d in ~1 The mother liquor w9s ~
15 to dryness snd the silic~ gel t W98 repe~ted 98 ~bove. After "~~ " the mother liquor W98 c ~ ' to dryness snd the residue wss purified by flssh c~ _ . ' y on sili~. Eluent:
~Lyl ~co~te (4/1). All the cgstd6 ~nd the cle~n frsction from flssh ~ ~ were ' --' to give 9.07 g, (59.6 ~i) title product.
lH-NMR (250 MHz, Bruclcer, CDC13), d: 2.68 (lH, dd, J= 11.1 nd 19.9 Hz, 4-H9"), 3.07 (lH, dd, J=4.4 nd 19.9 Hz, 4-Hoq)~ 3.62 (lH, 8, I-MeO), 3.83 (lH, s, COOMe), 4.72 (lH, dd, J 4.4 ~d
11.1 Hz, 3-HUC)~ 5.70 (lH, S, l-H), 7.75 (2H, m, Ar-H), 8.08 (2H, m Ar-H).
Step 4: Methyl ~ -S,10 d- S,lC ~ ' ,3 ~ lII p' - ~[~ ~ c]~" ~ 3-yl) folmate Methyl (1 - y-5,10-diO~cO-3,4,5,10 1 ' .~.' ~lI I . ' ' ~2,3-c]pyrn-3-yl) form~te (6.12 g, 20.25 mmol) w~ ~ d in . (120 ml), h ;~ (5 .64 rnl, 40.49 mmol ) w ~Added And stirrcd ~t ambient i _ over 1 hour. The ro~ction mi~ture W8 poured onto w~ter (100 rnl) Jnd dhyl ~cet~(400 ml), then ~ with acetic ,acid. The org~nic hyer w -, d, the w~ter layer w~ t I d wil~ e~Jyl ~ te (3~30 ml). The _ ' ' org~nic l-yers were driod (MgSO4) ~nd ~ todryness. To ther Oidue~' ' ~ - (60 ml) nd ' odium' L solution (20 ml) W.8 ~dded, then stir~cd for S minutes. After L, '- the orgnic layer w~ dried (MgSO4) nd ~ to 10 ml. Thi8 DolutioJ~ D filtered through ~ 6hort 6ilic. gel colu~m. Eluent:d ' ~ ' ~ nd S~i ethyl cetate in dichloro ' The cle. n f~ctions were ~ nd C J to drynes~ to give the title product (5.49g, 90.3 %).
lH-NMR (250 MHz, Bruclcer, CDCl3), d: 3.63 (3H, D~ 1-MeO), 3.92 (3H, 8, COOMe), 6.38 (lH, s, 1-H), 7.33 (1-H, 8, 4-H), 7.75 (2H, m, ~r-H), 8.13 (2H, m, Ar-H).
Step 5: Methyl (1 ~ ' ~-S,1C :' S,10 ~ L ' ' ~[~ J-- 3-yl) SUBSTITUTE SHEET
WO 94~ 11382 PCI JCA93/00463 2146~
Methyl (1 ~-5,8-dio~5,~ ' Jlv ~ 3-yl) for te (12.70 g, 50.35 mmol), 1-- (30.00 g, 267.55 mmol) and dry toluene (100 ml) w~s stirred overnight at 50 C. The solvent wa8 removed under reduced pres6ure, the residue w~s recrydallized from ' -' to give yellow cryst~ls (11.05 g). The product wa8 ~ d in ~' -' ~ ' - (200 ml), h;~yl&~ e (10.2 ml, S 73.11 mmol) w~6 sdded and stirred t unbiont i . - ~, ovcr 1 hour. The reaction mi~ture wa6 poured - onto w~ter (200 ml) nd dhyl cot~(800 ml), then - " ' with cetic cid. Thc organic l-yer was d, the w~r l-yer w~s ' with dhyl Jcot te (3~c30 ml). Thc ~ ' - ' organic layers were dried (MgSO4) an~d ~ ' to dryness. To the rosidue d ' '- (120 ml) nd ~ ~ sodium lolution (40 ml) w 8 ~led, stirred for 5 minutes. Ahor -, the organic l-yer W~8 10 dried (MgSO4) nd . to dryness to give tbe title product (8.98 g, 59.4 96).
lH-NMR (250 MHz, Bmclcer, CDCl3), d: 3.63 (3H, 8, 1-MeO), 3.92 (3H, S, COOMe), 6.38 (lH, 8, 1-H), 7.33 (l-H, 8, 4 H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 6~ -S,10 1 ~,10 ~ ', ' . lII p! ' ~[~ .,. 3 . I ~' - acid Methyl (1- ' ~-5,10-dio~co-5,10 ' ' ~rlI I . ' ' ~,2 ~-clpyr~n-3-yl) form~te (6.31 g, 21.01 mmol) was ! . ' - ' in; ' ~d~ r (126 ml) nd sodium h.~ Ai~ (0.92 g, 23.12 mmol) d lv~l in w ter (63 ml) was dded ~.. at 0 C over 30 minutes. The re~ction rnucture wa8 stirred at 0 C
over 1 hour, then it w 8 Jcidifiod to pH = 3 with S % h.~.l,~ ' ' - ~cid. Sodium chloride (2 g) was 20 dded. The w~ter l-ycr w~ v . ~ ~ and d with ethyl cehte (3A40 ml). The w ter layer was cidifiod to pH 2. The cryst 1~ formed were filtaod nd wa6hed with water. The filtr te w 8 e with ethyl cot~te (4A40 ml). All the organic fr~ctions - ~ the previous as well - were ' - ~, dried (MgSO4) nd ~ - ' to d~yne66. The rc6idue wa8 ~ ' - ' with the crystal6 filterod out of tbe w tcr phaso bofore, and stirred with ' ' (50 ml). for 15 minutes. The ydlow 25 cry6t~1s wore filterod, w~hod with ' -' to give the title product (5.21 g, 86.6 %).
lH-NMR (250 MHz, Bn~,er, DMSO-d6), d: 3.50 (3H, 8, l-MeO), 6.37 (lH, s, l-H), 7.02 (lH, s, 4-H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 7~ -S,10 :' 5,10 ' bJ.' . lII ~ J~ 3{N-(3-dimethylsm ~ ,. ~,/l)a~L ~]
1 ~ ' y-S,10-dioAo-S,10 '-' .~.~,lII .' ' ~2,3 cl~, 3 IA,A~I;C cid (4.6 g, 16.13 mmol) Wa6 ' ~ in h ' ' ~ (46 ml) ~nd DMF (0.1 ml) was dded. The ~ . wa6 cooled to 0 C
and oAalyl chloride (3.24 ml, 37.09 mrnol) was addod d.~ r ~.- over 10 minutes. The ro~ction miAh~re 35 wa8 stirrod t 0 C over 30 minutes, then ~ to drynes6 t reducod preosure. The ro6idue was d in t ~ Or (50 ml), cooled to 0 C and N,N~ - (2.23 ml, 17.74 mmol) w s ~d J,l,...... ...over 10 minute6. The oolution W9S stirred t 0 C over 15 minutes, then it was poured onto ~ ' solution of F c~l (20 ml). The organic layer was the w ter hyer w 8 ~ ' with ~' ' ~ ' - (3A10 ml). The o< ' ~ organic phases SUE~ E~T
WO 94/11382 PCI'/CA93/00463 21~6~
werc dried (MgSO4) ~nd ~ d to tryness. Thc residue w s ~ 1 in ' (50 ml) ~d stir~ed with charco~ t mbient I . e over 30 minutes. After filtr~ion the filtr~te w~
to dryness. The residuc was ~ ~ in ~ minim~l mount of ' -' snd ethcr (15 ml) w s added. The crystals were filtered, w~shed with cther to give thc ~itle pmduct (4.15 g, 69.6 %).
lH-NMR (250 MHz, Bmclcer, CDC13), d: 1.74 (2H, quint., CH2), 2.29 (6H, ~, NMe~?), 2.47 (2H, m, CH2), 3.35 - 3.65 (2H, m, CH2), 3.63 (3H, ~, l-MeO), 6.37 (lH, s, l-H), 7.33 (IH, s, 4-H), 7.75 (2H, m, Ar-H), 8.15 (2H, m, Ar-H), 8.70 (lH, b~d, NH).
Step 8~ -5,10 ~- 5,10 ~ lII p' ' ~ 3-{N-(3-1- by! ~ ] hydrocbloride~ BC~-2051 1 ~e ' ~-5,10-dio~co-5,10-dihydro-lII ,' ' ~,2,3-c]pynn-3-[N-(3~
propyl)~L ' ] (4.15 g, 11.23 mmol) wss d 1-~ in ~ ' ~b~ ~- ' ~ ' - (10 ml) and 1 M
Ly~ ' '- - cid solution in othcr (11.3 ml, 11.23 mmol) was sdded ~L~..-- at O C. At thc end more 15 cther (20 ml) was dded ~d thc . w 8 stirred t 0 C ova 30 minutes. Thc crystal6 were filtered under argon a~ , w shed with dr~ cther and ha~ane to give thc title product (4.32 g, 90.5 %)-lH-NMR (250 MHz, Bn~a, DMSO-d6), d: 1.90 (2H, m, 2'-CH2), 2.72 (6H, ~, NMe2), 3.00 (2H, m, 3'-CH2), 3.30 (2H, m, l'-CH2), 3.60 (3H, s,MeO), 6.35 (lH, 8, ~ ), 7.00 (lH, 8, 4 H), 7.90 (2H, 20 m, Ar-H), 8.05 (2H, m, ~r-H), 8.92 (lH, t, CONH), 10.53 (lH, broad, NH+).
3C-NMR (250 MHz, Bn~cr, DMSO-d6), d: 23.8, 36.1, 41.8, 54.0, S6.2, 94.9, 98.1, 124.5, 125.6, 126.1, 130.9, 131.5, 134.1, 134.5, 149.9, 159.6, 181.2, 181.4.
F pre 17: ri, . L ~ P
S U ~S~ S~ E ET
W O 94/11382 2 1~ ~ ~ 4 ~ PC~r/CA93/00463 NHeoc ~ ~ a + ~
~I
OMc 0 NH30C OMc 0 + ~ 2 OMe 0~ 0 -+1,3 '- . ' O O , U
C~ H 0 ~
C~N~ ~3N~N _ O ~ O ~
K:H 2000 +1,3 +1,3 -BC~2017 Stqp 1: N-BOC~ T~ - O Me S
To ~ 80hltiOn of T r ~ ~e c6ter.HCI (0.91 oq, 0.40 g) ~nd h;~ ' (1.2 oq, 0.3 ml) in dly e ' '~ ~ ' (24 rnl), undcr ~rgon, ~t room I . 1~, w~ dded N-Boc-Serine (O.S0 g, 2.43 mmols) Ynt then EEDQ (1.3 oq, 0.71 g). Thc solution w~ stil~et for 18 hours fter which the 601vent w~s _. . d The ro~idue w~s t lcen up in EtOAc snd w shod with 5% HCI (2~), s~t. ul. N~HC03 ~md 10 brine. The orguuc ph~lsc ws~ dried ovcr N~2S04, the solids filtered snd thc solv~nt c~ to give 0.71 g (87%) of N-Boc-Ser-Lou-OMe ~ ~ cle~lr oil th~t w~s usod without further I ' lH NMR (CDC13): 8 7.30 (bs, lH, NE~, 5.72 (bs, lH, NH), 4.51 (m, lH), 4.19 (m, lH), 3.90 (m, lEI), 3.68 (8, 3H), 3.62 (m, 2H), 1.55 (m, 3H), 1.34 (s, 9H), 0.79 (m, 6H).
Stqp 2: (lS,2'S,3R,5'S) ~nd (lR,2'S,3S,S'S)-l-tCl~N-BOC~in~T~ '~ ester]-3-~ceto-5)~ ~- 7 SU~ E~T
2i~6~g~
To a solution of 5,8~ 3 ~ (0.46g, 1.93 mmole), the peptide from step 1 (c~ mple 17) (0.71 g, 1.1 oq) ~nd . ' 4A -' - ' sieves (S00 mg) in dry CH2C12 (19 ml) was added DDQ (0.57 g, 1.3 eq). The solution Wl18 stirrod for 18 hours after which it w~s filtered through 5 celite. It v~s then poured in sat. aq. NJHCO3 ~d thc phasos werc , ' The aquoous phase was o ~ with CH2C12 (2~) nd thc ~ organic e~ctractl~ were dried over MgSO4. The solids were filtered nd the solvent was ~ ~ to give the titled mi~ture of ~- that were r ' ~ by cL. ~ (silica gel, 1: 1 he~e6tEtOAc).
The first running fraction: 0.395 g (36%). 'H NMR (CDC13): ~ 7.00 (bs, lH, NH), 6.74 (d, lH, J =
10 9.0, ArH), 6.68 (d, lH, J = 9.0, ArH), 5.81 (~, lH, H-l), 5.64 (bs, lH, NH), 4.52 (m, 2H), 4.29 (m, lH), 4.05 (m, lH), 3.88 (dd, lH, J = 7.4, 10.6), 3.81 (s, 3H, ArOMe), 3.73 (~, 3H, A OMe), 3.57 (8, 3H, CO~Me), 3.00 (dd, lH, J = 4.1, 17.6, H-4), 2.47 (dd, lH, J = 12.3, 17.6, H~), 2.29 (8, 3H, COMe), 1.57-1.46 (m, 3H, CH2-CH(Me)2), 1.41 (8, 9H, t-Bu), 0,84 (d, 3H, J = 3.3, ;~,n.~,l), 0.82 (d, 3H, J = 3.3, .~I,.v~
15 The ~ocond running f~ction: 0.420 g (389G), 'H NMR (CDC13): ~ 6.79 (m, 3H, 2ArH+NH), 6.10 (bs, lH, NH), 5.74 (s, lH, H-l), (4.62-4.33 (m, 3H), 3.91 (m, 2H), 3.77 (~, 6H, 2 ArOMe)~ 3.68 (s, 3H, CO2Me), 3.01 (dd, lH, J ~ 4.0, 17.6, H-4), 2.50 (dd, lH, J = 12.3, 17.6, H 4), 2.33 (~, 3H, COMe), 1.50 (~, 9H, t-Bu), 1.48-1.25 (m, 3H, CH2-CH(Me)2), 0.70 (d, 3H, J ~ 5.7, r VlJJI)~ 0.61 (d, 3H, J
~ 5-7, r v~Jl)-Step 3: (lS~2~S~3S~S~ .1l (l~-BOC~~ r~- ~sLer]-5,10 t-3,4,S,1~ ! - 12,3-c] pyll n-3-yl) ~etolw To ~ solution of the peptido ' from step 2 (e~mple 17) (0.40 g, 0.68 mmols) in CH3CN (9.7 ml), t 0C, w~ dded slowly ~ oolution of CAN (1.5 g, 4 eq) ~nd N HCO3 (0.4 y, 7 eq) in w~ter (7.8 ml). Thc oolution w~ stiITed ~t 0C for 30 minute6 ~ter which it w s powed in s~ q. N HCO3. The queous l~ycr v~6 then _ ' with CH2C12 (3~t) nd the ~ ' ' org~nic e~tr~cts were dried over MgSO4. T~e solid6 were filtered and the solvent c. . ~ The crude quinone w s then ~ ~ in dry toluene (7 ml) nd - ~L "- - w s sdded (0.4 ml, 5 eq). The ~olution w~s ~ined for 18 hours.
Silic~ gd v~ then dded (1 g) nd ~ir w~s bubbled through the oolution for 30 minutes. The silica gel w s filtc~d through Celite ~nd the solveDt w~s c. . ' The browll oil obt ined W~8 purified b~ fl-sh ~ O . ' J (silic~ gel, 1:1 he~ nes/EtOAc) to give 115 mg (29%) of the titled tricyclic lH NMR (CDC13): ~ 8.12-8.02 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 4.91 (bs, lH, ~, 5.92 (8, lH, H-l), 5.52 (bs, lH, NH), 4.62-4.47 (m, 3H, H-2' + H-5' + H-3), 4.17 (dd, lH, J--4.4, 10.9, H-1'), 3.83 (dd, lH, J ~ 8.6, 10.9, H-l'), 3.56 (s, 3H, CO2Mc), 3.02 (dd, lH, J = 4.0, 19.9, H-4), 2.51 (dd, lH, J--11.6, 19.9, H-4), 2.33 (s, 3H, COMe), 1.74-1.52 (m, 3H, CH2-CH(Me)2), 1.44 (s, 9H, t-Bu), 0.90 (d, 6H, J = 6.3, ~ v~,,l).
SU~ T ~ EET
~ Ç~8 step 4: (lS,2'S,3S,5'S) ~ J ~I-(l-O {Serine 1~ ~ e6ter]-5,10 dioxo-3,4,5,10-t~ ll~d-. l-II p~ ' - [2,3~ pg~n-3-yl) ke~one I ~.' . ' ' ;~:BCH-2000 A solution of the Boc ~,.ot ' tricyclic from step 3 (o~csmple 17) (54 mg, 0.092 mmol) in 96 % formic S scid (1 ml) wss stin~d st room t . ~i for 2 hours. The foImic cid w~ 6~_~ ~ d snd the ro~idue h~,d in 0.1 M HCI. The squoous ph~se w 8 w~shed with CH2C12 (2~c) nd the w ter W~IS
o- . ' The titled: ~ W98 obtsined 8 9 yellow oil w 8 dried under high vscuum for 18 hours sfter which it hsd c.~ '1i7~A- 40 mg (83 %).
lH NMR (DMSO-d6): ~ 8.98 (b8, lH, NH mide), 8.42 (b8, 3H, NH3CI), 8.06-7.98 (m, 2H, ArH), 10 7.93-7.87 (m, 2H, ArH), 5.82 (~, lH, H-l), 4.61 (dd, lH, J--3.9, 11.4), 4.34-4.23 (m, 2H), 4.13 (m, lH), 4.02 (td, lH, J ~ 5.7, 9.8), 3.61 (8, 3H, CO2Me), 2.88 (dd, lH, J 3.9, 19.6, H-4), 2.47 (m, lH, H-4 hidden under the DMSO peslc), 2.30 (8~ 3H, COMe), 1.62-1.49 (m, 3H, CH2-CH(Me)2), 0.88-0.82 (m, 6H, r ~1)-15 E~amplel8~ cidsubstitut~d p~'' ~ ~inone d ;.
-HO
0~ 0 o~ O
[~ + HO~ 2 0~4 Ol~b O~
BOCHN~CO2Mc +~3 - .-O O O O
~4 O O~ O O~
ClHlN~CO2Mc BOCHN~CO21.k BC}~165~ +1.3~diopuner Step 1: N-BOC~enne me~hgl e6ter 20 To solution of ~erinc methyl e6~r h~ ' . "c ' ~ (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, st mom ~;, under rgon, werc sd~ed ~ (10% solution, 0.16 ml) ~nd (BOC)2O
(0.19 g, 1.1 eq.) snd the solution W98 stimd for 60 minutes. It wss then poured in cold 2% HCI and the SU~ S~ E~ ~
WO 94/11382 PCI`/CA93/00463 21~65~ e Jquoous l~yer W~8 ~ J with CH2C12 (3~). The ~ org~nic e~ctr~cts were dried over MgSO4, the solids were filtered ~nd the solvent6 C-~r 1~ ~ to giYe 0.17 g (100%) of the titled ~ JIS a cle~r oil.
lH NMR (CDC13): ~ 5.56 (b6, lH, NH), 4.34 (m, lH, CH-C02Me), 3.88 (m, 2H, ~2-OH), 3.75 (s, 3H, C02Me), 2.96 (b6, lH, OH), 1.44 (~, 9H, BOC).
Step 2: (lS, 2'S, 3R) ~nd (lR, 2'S, 3S)-l-tOffine methyl ~ter3-3 ~ S~
.
10 The titlod . . were obt inod J8 per ~ ' ' d in ~tep 2, o~le 17. They werepurified vi~ fl-6h ' . O . ' y (silic~ gd, 2:1 he~n~/EtOAc). T~ cture of i8omerh i8 not r ''-by.- ~ .y lH NMR (CDC13): ~ 6.73 (m, 2H, ~rH), 6.07+5.78 (2d, lH, NH), 5.72+5.70 (2s, lH, H-l), 4.56-4.35 (m, 3H, H-l' u~d H-2'), 3.98 (m, lH, H-3), 3.90+3.81 +3.78+3.77+3.76+3.67 (6s, 18H
[6~3H], ~r-OMe ~d CO2Me), 3.04 (2dd, lH, H-4), 2.50 (2dd, lH, H-4), 2.32 (d, 3H, COCH3), 1.47+1.43 (28, 9H, BOC).
Step 3: (lS, 2'S, 3R) ~nd ~lR, 2'S, 3S) ~ 1 (l-tO-N-BOC~e methyl e~iterl-!i,10-dioxo-3,4,S,10 1 ~l~d ~ ! ~ [2,3-Cl p~3-91) ~o~
The s~me ~, ~ ' ' ~ in ~tep 3, oJ~mp1c 17, w~; u~ed for the titled ~ . d, which w~s punfied ~ fl~h ~ ilic~ gel, 2: 1 he~nes/EtOAc).
The mLlcturc of i~omers i8 not . ' ' by ~ ' ,, . ' ~.
lH NMR (CDC13): ~ 8.0S (m, 2H, ArH), 7.73 (m, 2H, ArH), 5.90+S.52 (2d, lH, NH), 5.73+5.72 (2s, lH, H-l), 4.60-4.05 (m, 4H, H-3, H-l' ~nd H-2'), 3.81 +3.70 (2s, 3H, CO2CH3), 3.01 (2m, lH, H-4), 2.48 (m, lH, H-4), 2.3S (2~, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 4: (lS, 2'S, 3R) ~nd (IR, 2'S, 3S) .11 (l-lO~ine meth!vl ~terl-S,10-dioxo-3,4,S,10 t ~ ~1~.' . . ' ' ~ 12,3-Cl p~3-~1) Icetone h~dl~ ' ' ' .
The titlod ~ . ' werc obt~ined ~6 per ~ d in step 4, eDmple 17.
lH NMR (DMSO): ~ 8.05-7.82 (m, 4H, ArH), 5.83+5.78 (2s, lH, H-l), 4.69 4.40 (m, 2H, H-l'), 4.27 (m, lH, H-3), 4.16 (m, lH, H-2'), 3.79+3.73 (2s, 3H, CO2Me), 2.91+2.87 (2m, lH, H-4), 2.S0 (m, lH, H-4), 2.31+2.29 (2s, 3H, COCH3).
3~
E~ple 19: ~mino 91cobo{ sub6tituted naphl' ~ ~ ~ deri ati~e Si~ ;r~ ,. s~-~EE7' 2 146 ~ ~ N
M~ BOC Ol~
0~ Olb 0~
~NBOC
+~ ' . ' o o o o o o~ o o~
+1,3-diqnmer ~NH2CI +1,3Jiq~ NBOC
Step 1: N-BOC r~.-' ~' 5 The titlod ~ , ' w~8 obt~inod ~s pe~ p,~: , Ac~ rd in stop 1, c~mplc 18.
lH NMR (CDC13): ~ 4.19 (bs, lH, OH), 3.95 (m, lH, H-2), 3.59 (m, 2H, CH2-OH), 3.42 (m, lH, H-5), 3.30 (m, lH, H-5), 2.01 (m, lH, H-3), 1.83 (m, 2H, H~), 1.60 (m, lH, H-3), 1.45 (s, 9H, BOC).
Step 2: (lS, 2'S, 3R) ~nd (lR, 2'S, 3S)-l-[O-N-BOC-1 ~r ~r]-3 - ~ S,8 ~
The titled ~ , ' were obt~inod ~s per p - ' , dr il .~ A i~ step 2, e~le 17. They were purifiedvi fl sh ' . ~ (6ilic gel, 7:3 he~unestEtOAc). ThemLlctureofisomers is ~IOt - ' '- by _ . ~Lo ~ Y-lH NMR (CDC13): o 6.72 (m, 2H, ArH), 5.82+5.77 (2s, lH, H-l), 4.54 (m, lH, H-3), 4.18-3.20 (m, 5H, H-l', H-2' uld H-5'), 3.82+3.79 (28, 6H, ArOMe), 3.05 (2m, lH, H-4), 2.53 (m, lH, H-4), 2.31 (s, 3H, COCH3), 2.07-1.75 (m, 4H, H-3' nd H~'), 1.46 (s, 9H, BOC).
Step 3: (lS, 2'S, 3R) ~nd (IR, 2'S, 3S) 1~ .~1 (l-[O-N-BOC-I ~P -q-S,10 :' 3,4,S,10-tdr~hydro-l Il p' t~ ~ [2,3-C] pyran-3-yl) ketone BCH-2067 SU BS~ S ~-r ~ ET
2146~
The titled: ~ , ' were obt~ined ~s per ~ il~ in step 3, e~mple 17. They were purified vi~ yer ' . O . ' ~ (silic~ gel, 7:3 he~ne~/othyl ~te).
IH NMR (CDC13): ~ 8.02 (m, 2H, ArH), 7.70 (m, 2H, ArH), 5.75+S.73 (28, lH, H-l), 4.47 (n, lH, 5 H-3), 4.15-3.18 (m, 5H, H-l', H-2' ~d H-5'), 2.97 (2m, lH, H 4), 2.5 (m, lH, H-4), 2.33~2.32 (28, 3H, COCH3), 2.05-1.72 (m, 4H, H-3' nd H-4'), 1.48 (s, 9H, BOC).
Step 4: (lS, 2'S, 3R) 9nd (lR, 2'S, 3S) ~~- yl (l-tO, ~ I]-3,4,~
Step 4: Methyl ~ -S,10 d- S,lC ~ ' ,3 ~ lII p' - ~[~ ~ c]~" ~ 3-yl) folmate Methyl (1 - y-5,10-diO~cO-3,4,5,10 1 ' .~.' ~lI I . ' ' ~2,3-c]pyrn-3-yl) form~te (6.12 g, 20.25 mmol) w~ ~ d in . (120 ml), h ;~ (5 .64 rnl, 40.49 mmol ) w ~Added And stirrcd ~t ambient i _ over 1 hour. The ro~ction mi~ture W8 poured onto w~ter (100 rnl) Jnd dhyl ~cet~(400 ml), then ~ with acetic ,acid. The org~nic hyer w -, d, the w~ter layer w~ t I d wil~ e~Jyl ~ te (3~30 ml). The _ ' ' org~nic l-yers were driod (MgSO4) ~nd ~ todryness. To ther Oidue~' ' ~ - (60 ml) nd ' odium' L solution (20 ml) W.8 ~dded, then stir~cd for S minutes. After L, '- the orgnic layer w~ dried (MgSO4) nd ~ to 10 ml. Thi8 DolutioJ~ D filtered through ~ 6hort 6ilic. gel colu~m. Eluent:d ' ~ ' ~ nd S~i ethyl cetate in dichloro ' The cle. n f~ctions were ~ nd C J to drynes~ to give the title product (5.49g, 90.3 %).
lH-NMR (250 MHz, Bruclcer, CDCl3), d: 3.63 (3H, D~ 1-MeO), 3.92 (3H, 8, COOMe), 6.38 (lH, s, 1-H), 7.33 (1-H, 8, 4-H), 7.75 (2H, m, ~r-H), 8.13 (2H, m, Ar-H).
Step 5: Methyl (1 ~ ' ~-S,1C :' S,10 ~ L ' ' ~[~ J-- 3-yl) SUBSTITUTE SHEET
WO 94~ 11382 PCI JCA93/00463 2146~
Methyl (1 ~-5,8-dio~5,~ ' Jlv ~ 3-yl) for te (12.70 g, 50.35 mmol), 1-- (30.00 g, 267.55 mmol) and dry toluene (100 ml) w~s stirred overnight at 50 C. The solvent wa8 removed under reduced pres6ure, the residue w~s recrydallized from ' -' to give yellow cryst~ls (11.05 g). The product wa8 ~ d in ~' -' ~ ' - (200 ml), h;~yl&~ e (10.2 ml, S 73.11 mmol) w~6 sdded and stirred t unbiont i . - ~, ovcr 1 hour. The reaction mi~ture wa6 poured - onto w~ter (200 ml) nd dhyl cot~(800 ml), then - " ' with cetic cid. Thc organic l-yer was d, the w~r l-yer w~s ' with dhyl Jcot te (3~c30 ml). Thc ~ ' - ' organic layers were dried (MgSO4) an~d ~ ' to dryness. To the rosidue d ' '- (120 ml) nd ~ ~ sodium lolution (40 ml) w 8 ~led, stirred for 5 minutes. Ahor -, the organic l-yer W~8 10 dried (MgSO4) nd . to dryness to give tbe title product (8.98 g, 59.4 96).
lH-NMR (250 MHz, Bmclcer, CDCl3), d: 3.63 (3H, 8, 1-MeO), 3.92 (3H, S, COOMe), 6.38 (lH, 8, 1-H), 7.33 (l-H, 8, 4 H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 6~ -S,10 1 ~,10 ~ ', ' . lII p! ' ~[~ .,. 3 . I ~' - acid Methyl (1- ' ~-5,10-dio~co-5,10 ' ' ~rlI I . ' ' ~,2 ~-clpyr~n-3-yl) form~te (6.31 g, 21.01 mmol) was ! . ' - ' in; ' ~d~ r (126 ml) nd sodium h.~ Ai~ (0.92 g, 23.12 mmol) d lv~l in w ter (63 ml) was dded ~.. at 0 C over 30 minutes. The re~ction rnucture wa8 stirred at 0 C
over 1 hour, then it w 8 Jcidifiod to pH = 3 with S % h.~.l,~ ' ' - ~cid. Sodium chloride (2 g) was 20 dded. The w~ter l-ycr w~ v . ~ ~ and d with ethyl cehte (3A40 ml). The w ter layer was cidifiod to pH 2. The cryst 1~ formed were filtaod nd wa6hed with water. The filtr te w 8 e with ethyl cot~te (4A40 ml). All the organic fr~ctions - ~ the previous as well - were ' - ~, dried (MgSO4) nd ~ - ' to d~yne66. The rc6idue wa8 ~ ' - ' with the crystal6 filterod out of tbe w tcr phaso bofore, and stirred with ' ' (50 ml). for 15 minutes. The ydlow 25 cry6t~1s wore filterod, w~hod with ' -' to give the title product (5.21 g, 86.6 %).
lH-NMR (250 MHz, Bn~,er, DMSO-d6), d: 3.50 (3H, 8, l-MeO), 6.37 (lH, s, l-H), 7.02 (lH, s, 4-H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 7~ -S,10 :' 5,10 ' bJ.' . lII ~ J~ 3{N-(3-dimethylsm ~ ,. ~,/l)a~L ~]
1 ~ ' y-S,10-dioAo-S,10 '-' .~.~,lII .' ' ~2,3 cl~, 3 IA,A~I;C cid (4.6 g, 16.13 mmol) Wa6 ' ~ in h ' ' ~ (46 ml) ~nd DMF (0.1 ml) was dded. The ~ . wa6 cooled to 0 C
and oAalyl chloride (3.24 ml, 37.09 mrnol) was addod d.~ r ~.- over 10 minutes. The ro~ction miAh~re 35 wa8 stirrod t 0 C over 30 minutes, then ~ to drynes6 t reducod preosure. The ro6idue was d in t ~ Or (50 ml), cooled to 0 C and N,N~ - (2.23 ml, 17.74 mmol) w s ~d J,l,...... ...over 10 minute6. The oolution W9S stirred t 0 C over 15 minutes, then it was poured onto ~ ' solution of F c~l (20 ml). The organic layer was the w ter hyer w 8 ~ ' with ~' ' ~ ' - (3A10 ml). The o< ' ~ organic phases SUE~ E~T
WO 94/11382 PCI'/CA93/00463 21~6~
werc dried (MgSO4) ~nd ~ d to tryness. Thc residue w s ~ 1 in ' (50 ml) ~d stir~ed with charco~ t mbient I . e over 30 minutes. After filtr~ion the filtr~te w~
to dryness. The residuc was ~ ~ in ~ minim~l mount of ' -' snd ethcr (15 ml) w s added. The crystals were filtered, w~shed with cther to give thc ~itle pmduct (4.15 g, 69.6 %).
lH-NMR (250 MHz, Bmclcer, CDC13), d: 1.74 (2H, quint., CH2), 2.29 (6H, ~, NMe~?), 2.47 (2H, m, CH2), 3.35 - 3.65 (2H, m, CH2), 3.63 (3H, ~, l-MeO), 6.37 (lH, s, l-H), 7.33 (IH, s, 4-H), 7.75 (2H, m, Ar-H), 8.15 (2H, m, Ar-H), 8.70 (lH, b~d, NH).
Step 8~ -5,10 ~- 5,10 ~ lII p' ' ~ 3-{N-(3-1- by! ~ ] hydrocbloride~ BC~-2051 1 ~e ' ~-5,10-dio~co-5,10-dihydro-lII ,' ' ~,2,3-c]pynn-3-[N-(3~
propyl)~L ' ] (4.15 g, 11.23 mmol) wss d 1-~ in ~ ' ~b~ ~- ' ~ ' - (10 ml) and 1 M
Ly~ ' '- - cid solution in othcr (11.3 ml, 11.23 mmol) was sdded ~L~..-- at O C. At thc end more 15 cther (20 ml) was dded ~d thc . w 8 stirred t 0 C ova 30 minutes. Thc crystal6 were filtered under argon a~ , w shed with dr~ cther and ha~ane to give thc title product (4.32 g, 90.5 %)-lH-NMR (250 MHz, Bn~a, DMSO-d6), d: 1.90 (2H, m, 2'-CH2), 2.72 (6H, ~, NMe2), 3.00 (2H, m, 3'-CH2), 3.30 (2H, m, l'-CH2), 3.60 (3H, s,MeO), 6.35 (lH, 8, ~ ), 7.00 (lH, 8, 4 H), 7.90 (2H, 20 m, Ar-H), 8.05 (2H, m, ~r-H), 8.92 (lH, t, CONH), 10.53 (lH, broad, NH+).
3C-NMR (250 MHz, Bn~cr, DMSO-d6), d: 23.8, 36.1, 41.8, 54.0, S6.2, 94.9, 98.1, 124.5, 125.6, 126.1, 130.9, 131.5, 134.1, 134.5, 149.9, 159.6, 181.2, 181.4.
F pre 17: ri, . L ~ P
S U ~S~ S~ E ET
W O 94/11382 2 1~ ~ ~ 4 ~ PC~r/CA93/00463 NHeoc ~ ~ a + ~
~I
OMc 0 NH30C OMc 0 + ~ 2 OMe 0~ 0 -+1,3 '- . ' O O , U
C~ H 0 ~
C~N~ ~3N~N _ O ~ O ~
K:H 2000 +1,3 +1,3 -BC~2017 Stqp 1: N-BOC~ T~ - O Me S
To ~ 80hltiOn of T r ~ ~e c6ter.HCI (0.91 oq, 0.40 g) ~nd h;~ ' (1.2 oq, 0.3 ml) in dly e ' '~ ~ ' (24 rnl), undcr ~rgon, ~t room I . 1~, w~ dded N-Boc-Serine (O.S0 g, 2.43 mmols) Ynt then EEDQ (1.3 oq, 0.71 g). Thc solution w~ stil~et for 18 hours fter which the 601vent w~s _. . d The ro~idue w~s t lcen up in EtOAc snd w shod with 5% HCI (2~), s~t. ul. N~HC03 ~md 10 brine. The orguuc ph~lsc ws~ dried ovcr N~2S04, the solids filtered snd thc solv~nt c~ to give 0.71 g (87%) of N-Boc-Ser-Lou-OMe ~ ~ cle~lr oil th~t w~s usod without further I ' lH NMR (CDC13): 8 7.30 (bs, lH, NE~, 5.72 (bs, lH, NH), 4.51 (m, lH), 4.19 (m, lH), 3.90 (m, lEI), 3.68 (8, 3H), 3.62 (m, 2H), 1.55 (m, 3H), 1.34 (s, 9H), 0.79 (m, 6H).
Stqp 2: (lS,2'S,3R,5'S) ~nd (lR,2'S,3S,S'S)-l-tCl~N-BOC~in~T~ '~ ester]-3-~ceto-5)~ ~- 7 SU~ E~T
2i~6~g~
To a solution of 5,8~ 3 ~ (0.46g, 1.93 mmole), the peptide from step 1 (c~ mple 17) (0.71 g, 1.1 oq) ~nd . ' 4A -' - ' sieves (S00 mg) in dry CH2C12 (19 ml) was added DDQ (0.57 g, 1.3 eq). The solution Wl18 stirrod for 18 hours after which it w~s filtered through 5 celite. It v~s then poured in sat. aq. NJHCO3 ~d thc phasos werc , ' The aquoous phase was o ~ with CH2C12 (2~) nd thc ~ organic e~ctractl~ were dried over MgSO4. The solids were filtered nd the solvent was ~ ~ to give the titled mi~ture of ~- that were r ' ~ by cL. ~ (silica gel, 1: 1 he~e6tEtOAc).
The first running fraction: 0.395 g (36%). 'H NMR (CDC13): ~ 7.00 (bs, lH, NH), 6.74 (d, lH, J =
10 9.0, ArH), 6.68 (d, lH, J = 9.0, ArH), 5.81 (~, lH, H-l), 5.64 (bs, lH, NH), 4.52 (m, 2H), 4.29 (m, lH), 4.05 (m, lH), 3.88 (dd, lH, J = 7.4, 10.6), 3.81 (s, 3H, ArOMe), 3.73 (~, 3H, A OMe), 3.57 (8, 3H, CO~Me), 3.00 (dd, lH, J = 4.1, 17.6, H-4), 2.47 (dd, lH, J = 12.3, 17.6, H~), 2.29 (8, 3H, COMe), 1.57-1.46 (m, 3H, CH2-CH(Me)2), 1.41 (8, 9H, t-Bu), 0,84 (d, 3H, J = 3.3, ;~,n.~,l), 0.82 (d, 3H, J = 3.3, .~I,.v~
15 The ~ocond running f~ction: 0.420 g (389G), 'H NMR (CDC13): ~ 6.79 (m, 3H, 2ArH+NH), 6.10 (bs, lH, NH), 5.74 (s, lH, H-l), (4.62-4.33 (m, 3H), 3.91 (m, 2H), 3.77 (~, 6H, 2 ArOMe)~ 3.68 (s, 3H, CO2Me), 3.01 (dd, lH, J ~ 4.0, 17.6, H-4), 2.50 (dd, lH, J = 12.3, 17.6, H 4), 2.33 (~, 3H, COMe), 1.50 (~, 9H, t-Bu), 1.48-1.25 (m, 3H, CH2-CH(Me)2), 0.70 (d, 3H, J ~ 5.7, r VlJJI)~ 0.61 (d, 3H, J
~ 5-7, r v~Jl)-Step 3: (lS~2~S~3S~S~ .1l (l~-BOC~~ r~- ~sLer]-5,10 t-3,4,S,1~ ! - 12,3-c] pyll n-3-yl) ~etolw To ~ solution of the peptido ' from step 2 (e~mple 17) (0.40 g, 0.68 mmols) in CH3CN (9.7 ml), t 0C, w~ dded slowly ~ oolution of CAN (1.5 g, 4 eq) ~nd N HCO3 (0.4 y, 7 eq) in w~ter (7.8 ml). Thc oolution w~ stiITed ~t 0C for 30 minute6 ~ter which it w s powed in s~ q. N HCO3. The queous l~ycr v~6 then _ ' with CH2C12 (3~t) nd the ~ ' ' org~nic e~tr~cts were dried over MgSO4. T~e solid6 were filtered and the solvent c. . ~ The crude quinone w s then ~ ~ in dry toluene (7 ml) nd - ~L "- - w s sdded (0.4 ml, 5 eq). The ~olution w~s ~ined for 18 hours.
Silic~ gd v~ then dded (1 g) nd ~ir w~s bubbled through the oolution for 30 minutes. The silica gel w s filtc~d through Celite ~nd the solveDt w~s c. . ' The browll oil obt ined W~8 purified b~ fl-sh ~ O . ' J (silic~ gel, 1:1 he~ nes/EtOAc) to give 115 mg (29%) of the titled tricyclic lH NMR (CDC13): ~ 8.12-8.02 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 4.91 (bs, lH, ~, 5.92 (8, lH, H-l), 5.52 (bs, lH, NH), 4.62-4.47 (m, 3H, H-2' + H-5' + H-3), 4.17 (dd, lH, J--4.4, 10.9, H-1'), 3.83 (dd, lH, J ~ 8.6, 10.9, H-l'), 3.56 (s, 3H, CO2Mc), 3.02 (dd, lH, J = 4.0, 19.9, H-4), 2.51 (dd, lH, J--11.6, 19.9, H-4), 2.33 (s, 3H, COMe), 1.74-1.52 (m, 3H, CH2-CH(Me)2), 1.44 (s, 9H, t-Bu), 0.90 (d, 6H, J = 6.3, ~ v~,,l).
SU~ T ~ EET
~ Ç~8 step 4: (lS,2'S,3S,5'S) ~ J ~I-(l-O {Serine 1~ ~ e6ter]-5,10 dioxo-3,4,5,10-t~ ll~d-. l-II p~ ' - [2,3~ pg~n-3-yl) ke~one I ~.' . ' ' ;~:BCH-2000 A solution of the Boc ~,.ot ' tricyclic from step 3 (o~csmple 17) (54 mg, 0.092 mmol) in 96 % formic S scid (1 ml) wss stin~d st room t . ~i for 2 hours. The foImic cid w~ 6~_~ ~ d snd the ro~idue h~,d in 0.1 M HCI. The squoous ph~se w 8 w~shed with CH2C12 (2~c) nd the w ter W~IS
o- . ' The titled: ~ W98 obtsined 8 9 yellow oil w 8 dried under high vscuum for 18 hours sfter which it hsd c.~ '1i7~A- 40 mg (83 %).
lH NMR (DMSO-d6): ~ 8.98 (b8, lH, NH mide), 8.42 (b8, 3H, NH3CI), 8.06-7.98 (m, 2H, ArH), 10 7.93-7.87 (m, 2H, ArH), 5.82 (~, lH, H-l), 4.61 (dd, lH, J--3.9, 11.4), 4.34-4.23 (m, 2H), 4.13 (m, lH), 4.02 (td, lH, J ~ 5.7, 9.8), 3.61 (8, 3H, CO2Me), 2.88 (dd, lH, J 3.9, 19.6, H-4), 2.47 (m, lH, H-4 hidden under the DMSO peslc), 2.30 (8~ 3H, COMe), 1.62-1.49 (m, 3H, CH2-CH(Me)2), 0.88-0.82 (m, 6H, r ~1)-15 E~amplel8~ cidsubstitut~d p~'' ~ ~inone d ;.
-HO
0~ 0 o~ O
[~ + HO~ 2 0~4 Ol~b O~
BOCHN~CO2Mc +~3 - .-O O O O
~4 O O~ O O~
ClHlN~CO2Mc BOCHN~CO21.k BC}~165~ +1.3~diopuner Step 1: N-BOC~enne me~hgl e6ter 20 To solution of ~erinc methyl e6~r h~ ' . "c ' ~ (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, st mom ~;, under rgon, werc sd~ed ~ (10% solution, 0.16 ml) ~nd (BOC)2O
(0.19 g, 1.1 eq.) snd the solution W98 stimd for 60 minutes. It wss then poured in cold 2% HCI and the SU~ S~ E~ ~
WO 94/11382 PCI`/CA93/00463 21~65~ e Jquoous l~yer W~8 ~ J with CH2C12 (3~). The ~ org~nic e~ctr~cts were dried over MgSO4, the solids were filtered ~nd the solvent6 C-~r 1~ ~ to giYe 0.17 g (100%) of the titled ~ JIS a cle~r oil.
lH NMR (CDC13): ~ 5.56 (b6, lH, NH), 4.34 (m, lH, CH-C02Me), 3.88 (m, 2H, ~2-OH), 3.75 (s, 3H, C02Me), 2.96 (b6, lH, OH), 1.44 (~, 9H, BOC).
Step 2: (lS, 2'S, 3R) ~nd (lR, 2'S, 3S)-l-tOffine methyl ~ter3-3 ~ S~
.
10 The titlod . . were obt inod J8 per ~ ' ' d in ~tep 2, o~le 17. They werepurified vi~ fl-6h ' . O . ' y (silic~ gd, 2:1 he~n~/EtOAc). T~ cture of i8omerh i8 not r ''-by.- ~ .y lH NMR (CDC13): ~ 6.73 (m, 2H, ~rH), 6.07+5.78 (2d, lH, NH), 5.72+5.70 (2s, lH, H-l), 4.56-4.35 (m, 3H, H-l' u~d H-2'), 3.98 (m, lH, H-3), 3.90+3.81 +3.78+3.77+3.76+3.67 (6s, 18H
[6~3H], ~r-OMe ~d CO2Me), 3.04 (2dd, lH, H-4), 2.50 (2dd, lH, H-4), 2.32 (d, 3H, COCH3), 1.47+1.43 (28, 9H, BOC).
Step 3: (lS, 2'S, 3R) ~nd ~lR, 2'S, 3S) ~ 1 (l-tO-N-BOC~e methyl e~iterl-!i,10-dioxo-3,4,S,10 1 ~l~d ~ ! ~ [2,3-Cl p~3-91) ~o~
The s~me ~, ~ ' ' ~ in ~tep 3, oJ~mp1c 17, w~; u~ed for the titled ~ . d, which w~s punfied ~ fl~h ~ ilic~ gel, 2: 1 he~nes/EtOAc).
The mLlcturc of i~omers i8 not . ' ' by ~ ' ,, . ' ~.
lH NMR (CDC13): ~ 8.0S (m, 2H, ArH), 7.73 (m, 2H, ArH), 5.90+S.52 (2d, lH, NH), 5.73+5.72 (2s, lH, H-l), 4.60-4.05 (m, 4H, H-3, H-l' ~nd H-2'), 3.81 +3.70 (2s, 3H, CO2CH3), 3.01 (2m, lH, H-4), 2.48 (m, lH, H-4), 2.3S (2~, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 4: (lS, 2'S, 3R) ~nd (IR, 2'S, 3S) .11 (l-lO~ine meth!vl ~terl-S,10-dioxo-3,4,S,10 t ~ ~1~.' . . ' ' ~ 12,3-Cl p~3-~1) Icetone h~dl~ ' ' ' .
The titlod ~ . ' werc obt~ined ~6 per ~ d in step 4, eDmple 17.
lH NMR (DMSO): ~ 8.05-7.82 (m, 4H, ArH), 5.83+5.78 (2s, lH, H-l), 4.69 4.40 (m, 2H, H-l'), 4.27 (m, lH, H-3), 4.16 (m, lH, H-2'), 3.79+3.73 (2s, 3H, CO2Me), 2.91+2.87 (2m, lH, H-4), 2.S0 (m, lH, H-4), 2.31+2.29 (2s, 3H, COCH3).
3~
E~ple 19: ~mino 91cobo{ sub6tituted naphl' ~ ~ ~ deri ati~e Si~ ;r~ ,. s~-~EE7' 2 146 ~ ~ N
M~ BOC Ol~
0~ Olb 0~
~NBOC
+~ ' . ' o o o o o o~ o o~
+1,3-diqnmer ~NH2CI +1,3Jiq~ NBOC
Step 1: N-BOC r~.-' ~' 5 The titlod ~ , ' w~8 obt~inod ~s pe~ p,~: , Ac~ rd in stop 1, c~mplc 18.
lH NMR (CDC13): ~ 4.19 (bs, lH, OH), 3.95 (m, lH, H-2), 3.59 (m, 2H, CH2-OH), 3.42 (m, lH, H-5), 3.30 (m, lH, H-5), 2.01 (m, lH, H-3), 1.83 (m, 2H, H~), 1.60 (m, lH, H-3), 1.45 (s, 9H, BOC).
Step 2: (lS, 2'S, 3R) ~nd (lR, 2'S, 3S)-l-[O-N-BOC-1 ~r ~r]-3 - ~ S,8 ~
The titled ~ , ' were obt~inod ~s per p - ' , dr il .~ A i~ step 2, e~le 17. They were purifiedvi fl sh ' . ~ (6ilic gel, 7:3 he~unestEtOAc). ThemLlctureofisomers is ~IOt - ' '- by _ . ~Lo ~ Y-lH NMR (CDC13): o 6.72 (m, 2H, ArH), 5.82+5.77 (2s, lH, H-l), 4.54 (m, lH, H-3), 4.18-3.20 (m, 5H, H-l', H-2' uld H-5'), 3.82+3.79 (28, 6H, ArOMe), 3.05 (2m, lH, H-4), 2.53 (m, lH, H-4), 2.31 (s, 3H, COCH3), 2.07-1.75 (m, 4H, H-3' nd H~'), 1.46 (s, 9H, BOC).
Step 3: (lS, 2'S, 3R) ~nd (IR, 2'S, 3S) 1~ .~1 (l-[O-N-BOC-I ~P -q-S,10 :' 3,4,S,10-tdr~hydro-l Il p' t~ ~ [2,3-C] pyran-3-yl) ketone BCH-2067 SU BS~ S ~-r ~ ET
2146~
The titled: ~ , ' were obt~ined ~s per ~ il~ in step 3, e~mple 17. They were purified vi~ yer ' . O . ' ~ (silic~ gel, 7:3 he~ne~/othyl ~te).
IH NMR (CDC13): ~ 8.02 (m, 2H, ArH), 7.70 (m, 2H, ArH), 5.75+S.73 (28, lH, H-l), 4.47 (n, lH, 5 H-3), 4.15-3.18 (m, 5H, H-l', H-2' ~d H-5'), 2.97 (2m, lH, H 4), 2.5 (m, lH, H-4), 2.33~2.32 (28, 3H, COCH3), 2.05-1.72 (m, 4H, H-3' nd H-4'), 1.48 (s, 9H, BOC).
Step 4: (lS, 2'S, 3R) 9nd (lR, 2'S, 3S) ~~- yl (l-tO, ~ I]-3,4,~
12,3-Cl pyrul-3-yl) Icetone ~.- ~ - ' ;~ ~slt.
The titled . ' were obt~inod ~ per 1,.. ~ ' ' in ~ 4, a~mple 17.
IH NMR (I)MSO): ~ 8.02 (m, 2H, ArH), 7.88 (m, 2H, ArH), 5.73 +5.71 (2s, lH, H-l), 4.68 (m, lH, H-3), 4.19-3.48 (m, 3H, H-2' ~nd H-l'), 3.10 (m, 2H, H-5'), 2.39 (dd, lH, H 4), 2.35 (m, lH, H-4), 2.32+2.31 (2s, 3H, COCH3), 2.10-1.55 (m, 4H, H-3' nd H-4').
15 r "~ of p~ [2,3-C1py~ g~osidecbain SUE5 ~ S~ET
WO 94~1 1382 21~ ~ 54 8 PCT/CA93/00463 ~ O o~ ~
W' I ¢¢,502Ph= ~,CN
0!~ Ob~ ~
O OMe ~N ~,CN
O OH OMII OH
\~, o ~N
O O
r.4~t PNBo NH~A
~CN
O O
H3~J
RO NHIFA
7 ~R-PN
B~16~
Step 1 5,8-dim~hox~-3 ~ ,~lsulphone L _ , S To ~ otirred ooluticn of 5,8 ~-3~ceto ' (12 8 g, S4 mmol) in ~' - chloride (350 ml) ~t room I - .; w o u~ded 3 ' - , L cid 80% (18 g, 83 mmol) in portion~ over 15 minutcs ~ftes 2 hou~, oulf te (6 8 g, 56 mmol) uld oulf~nic cid (10 g, 70 mmol) were dded ~r 2 hou~, ~ ~ d oolutioll of ~ - w~ sdded the l the re~lctios~ ~re wYo w~shed with w~ nd brine. Thc org~mic l~yer w~ dried over MgSO4 nd c., ' The titled -~ . ' wu~ purifiod by I in ether (11 g, 60%), m.p.: 118-119C.
lH N~ (250 MHz, C6D6), o: 7.99 (dd, J ~ 1.5 uld 8.0 Hz, 2H, Ar-H), 6.90 (m, 3H, Ar-H), 6.29 (2d, J ~ 8.9 Hz, 2H, Ar-H), S.08 (d, J ~ 15.5 Hz, lH, H-l), 4.53 (d, J = 15.5 Hz, lH, H-l), 4.40 (dd, J = 4.7 rnd 9.2 Hz, lH, H-3), 3.40 (dd, J ~ 4.7 uld 17.0 Hz, lH, H-4), 3.28 (s, 3H, ~CH3), 3.27 (dd, 9.2 Jnd 17.0 Hz, lH, H-4), 3.19 (6, 3H, ~CH3).
SUE~S I ~Tr S`i 3~ET
2146~48 ~
Step 2~ 3-cy~
To ~ stirred solution of ~IC13 (1.39 g, 10.4 rnmol) ~nd TMS-CN (1.4 rnl, 10.4 mmol) in CH2C12 (40 ml) at -78C under rgon W IB dded the ~ r ~ f~om step 1 (aumple 2) (1.16 g, 3.5 mmol) then 5 the j A o WI~B dowly r i~et to -20C. AP.er 4 hours, the rc~ction rnLs~ro w~s worlced up in - ~ - chloridc ~t w~ter. The orgu~ic l-y w 8 w~shed with brine nd dried over MgSO4. The sOIVerlt WIIB C. . ' ~ ult the rositue w a p~nfiot by fl~h ' ~ tAcOEt 3tl) to give ~hc titlod c . ~ (596 mg, 7896).
lH NMR (250 MHz, CDC13), o: 6.30 (2d, J ~ 8.2 Hz, 2H, Ar-H), 5.08 (d, J ~ 16.3 IIz, lH, H-l), 10 4.78 (d, J = 16.3 Hz, lH, H-l), 4.03 (t, J = 5.1 Hz, lH, H-3), 3.27 (B, 3H, -OCH3), 3.18 (s, 3H, -OCH3), 2.80 (td, J--5.1 nd 17.2 Hz, lH, H-4), 2.66 (td, J - 5.1 nd 17.2 Hz, lH, H-4).
step 3~ -3~
To stirred solution of 2,5 " ' ~-3-cy~ ' . (670 mg, 3.06 mmol) in CC14 (60 rnl) were 15 ~ddet N ~.~ ' (653 mg, 3.67 mmol) nd ~ c t lytic mount of AIBN. The mi~ue w~s he~ted to reflu~ d fbr 45 minutes, thc solvcnt w~ .,. . ' nd l ~ (40 ml) ~nd w~ter (40 ml) we~O ~ted. ~*er 1 hour, tho r~ction mLlcture W 8 worlced up in Other. The org~nic l~yer w~s w~shed with brine nd dried over MgS04. The solvent w~ c._. ' nd the re6idue purified by I ' " il~ ~ 8mdl mount of other to give the titled _ . . ' (453 mg, 63 %).
20 lH NMR (250 MHz, cotone D6): 6.90 (2d, J ~ 9.0 Hz, 2H, Ar-H), 6.06 (2d, J 8 5.2 Hz, 2H, H-l, -OH), 5.27 (dd, J ; 4.1 ~nd 12.1 Hz, lH, H-3), 3.81 (8, 3H, {~CH3), 3.78 (s, 3H, ~CH3), 3.09 (dd, J
= 4.1 nd 17.1 Hz, lH, H-4), 2.82 (dt, J = 12.1 Dd 17.1 Hz, lH, H-4).
St~p 4: 1 ~ -3 c/ ~ 5t~ ', d . ' 2~
The titled ~ . ' w~ obt ined in 77 % yield by ~pplying the ,~ d ~ d in 8tep 3, e~c~ple 12, to the ~ _ of step 3 of thi~i - . '-lH NMR (250 MHz, ~cetone D6) o: 6.86 (2d, J ~ 10.1 Hz, 2H, -CH--CH-), 6.61 (d, J ~ 5.7 Hz, lH, H-l), S.88 (d, J ~ 5.7 Hz, lH, -OH), 5.20 (dd, J ~ 3.8 nd 11.6 Hz, lH, H-3), 2.98 (dd, J = 3.8 nd 30 18.9 Hz, lH, H~), 2.73 (dd, J ~ 11.6 nd 18.9 Hz, lH, H 4).
Step 5 ~nd 6: (l'S, lS, 3R) uld (l'S, lR, 3S)-S,10-dioxo-3~wl-(2',3',6',-~rideox~-3'-1. '` ~ru '~ q'-O ~ ~L 11 1, 1~ ' , ,. ` 3,4,S,10-tet~ ' ' q ~2,3-c] pyrsn The titled s . ' wOre obhined in 27 % yield by fi~ . . g the ~ d i~ 4, e~mple 12, on the proalrsor of step 4 of ~is e~umple.
lH NMR (2S0 MHz, CD2C12) o: 8.30 (m, 4H, Ar-H), 8.10 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H), 6.55 (m, lH, -NH), 6.15 ~nd 5.95 (2~, lH, H-l), 5.70 (m, lH, H-4'), 5.60 nd S.SS (m, lH, H-l'), 5.10 (m, SUBSTi I ~ ~ L~ ~5~ET
WO 94/11382 PCI~/CA93/00463 21~6~.4~
lH, H-3), 4.704.20 (m, 2H, H-3', H-S'), 3.25-2.80 (m, 2H, H~), 2.40-2.00 (m, 2H, H-2'), 1.30 ~nd 1.20 (2d, J = 6.7 Hz, 3H, H-6').
Step 7: (l'-S, l-R, 3-S) u~d (l'-S, l-S, 3-R)-3~}1-[2',3',C'~rideox~r-3'-S I " . - ' '- ~' ',d . ~-L l~ ,. ~ ) S,10 d 3,4,S,l~
~ ~ P' ' - 12,3-C] p~n-3-yl BC~-1688 Thc titled ~ . ' were obt ined in 63 % yidd by f~llo.. e the ~ ' ' - ' in 8bp 3, e~le S, on the ~I. f~om 8tep 6 of thi8 ' j~-10 lH NMR (2S0 MHz, CD2C12) ~: 8.07 (m, 2H, Ar-H), 7.79 (m, 2H, Ar-H), 6.80 (m, lH, N-H), 6.09 snd 5.92 (2~, lH, H-l), S.52 nd S.42 (2d, lH, H-l'), S.Q4 (lm, lH, H-3), 4.40-4.05 (m, 2H, H-3', H-S'), 3.70 (m, lH, H-4'), 3.20-3.0~ (lm, lH, H~), 3.0~2.80 (lm, lH, H-4), 2.30-2.00 (m, 3H, ~H, H-2'), 1.38 ~nd 1.29 (2d, J--6.7 Hz, 3H, H-6').
SLIBS~T~TE ~ ET
2 ~
F ,)'-21: ~., ~ew~g~d OH ~OM~ O~ ~ OH
OH _ O~k _ OH
M~ Mc ~k Mc ~
-TBDMSO/~",~NHIFA 3 TBDMSO~"~NH'IF~.
~OH O
Me TBDI~ O~",~
r~
S Step 1 3,4 ' ~ fua~ nd 3 ' ~ fucal To a stimd solution of L-fucsl (400 ny~, 3 1 mmol) in ' ~'~ ' (7 5 ml) were dded mdhyl iodidc (0 85 ml, 3 6 mmol) uld ~ilv o~cide (1 16 g, 5 0 mmol) ~Per 1 5 hour, ~he re~ction mLl~ture w~s worlcod up in CH2C12 and w~ter The org~ic l-yer w~s w~hed with brine and driod over MgSO4 10 The fiolvent wul ~ , ' The p~duct~ werc , by fl sh c' ~ -/AcOEt 2/1) to give ' ' ~ fuc l (79 mg, 1696) lH NMR (250 MHz, CDC13) ~i 6 29 (dd, J = 1 3 and 6 2 Hz, lH, H-l), 4 72 (m, lH, H-2), 4 05 (m, 2H, H-5, H-4), 3 57 (~, 3H, -OCH3), 3 44 (m, lH, H-3), 3 39 (8, 3H, -OCH3), 1 31 (d, J ~ 6 6 Hz, 3H, H-6) 15 The 3 ' ~-L-fucal (20X yield) h~d lH NMR (250 MHz, CDC13) o 6 36 (dd, J = 1 2 nd 6 2 Hz, lH, H-l), 4 60 (m, lH, H-2), 4 05-3 80 (m, 3H, H-3, HJI, H-5), 3 40 (8, 3H, -OCH3), 2 37 (d, J = 3 9 Hz, lH, -OH), 1 36 (d, J = 6 6 Hz, 3H, H~) 20 Step 2 3 ' ~mesyl-I,~
Me~yl~tion of 3-metho~y-L-fi~l yielded (84%) of the titled ~ , SU~ 5~ E~T
~O 94/11382 ~ 9 PCT/CA93/00463 lH NMR (250 MHz, CDC13) o: 6.34 (dd, J = 2.1 ~nd 6.5 Hz, lH, H-l), 4.95 (m, lH, H-2), 4.73 ~m, lH, H~), 4.13 (m, 2H, H-3, H-5), 3.45 (s, 3H, -OCH3), 3.15 (s, 3H, -SO2CH3), 1.40 (d, J--6.6 Hz, 3H, H-6).
S Step 3~ Bubl d- ~ -3-L-~ ~ u ~ q ' 'f~ ,1 2,3,~hideoxy-Ll~ ' .,.
To ~ stirred solution of l-t-butyl ~ YIOAY~ 3: r ~, ~ ~ `1 ' ~ 2,3,6 t.id~A~ -L--r~ ~~ (504 mg, 1.41 mmol) in CH2C12 (7 rnl) ~t 0C wcre ddcd - r ,~1 chlonde 10 (218 111, 2.82 mmol) ~nd L.i~' - (590 ~11, 4.2 mmol). AP~r 2 1~ the ro~ction miAtutc was worlcod up with CH2C12 ~nd HCI 0.1 N. Tho org~nic l~ycr W~8 w shed with ~olution of N~HCO3 nd brinc then dried over MgSO4. The ~olvctlt w~ c . . ' to give l-t-butyl dimethyl silyloAy, 3-I r~ 2,3,6 tridcoAy 4 ~1 L--l~i~oh_Au~,~ (604 mg, 989~).
lH NMR (250 MHz, CDC13) ~: 7.28 (d, J = 7.7 Hz, lH, N-H), 4.83 (dd, J = 2.1 ~nd 9.1 Hz, lH, H-15 1), 4.71 (d, J = 2.2 Hz, lH, H-4), 4.25 (m, lH, H-3), 3.75 (q, J ~ 6.4 Hz, lH, H-5), 3.18 (s, 3H, -SO2-CH3), 2.0 (m, lH, H-2), 1.75 (m, lH, H-2~, 1.31 (d, J = 6.4 Hz, 3H, H-6), 0.89 (s, 9H, -C(CH3)3), 0.12 nd 0.11 (28, 6H, -Si(CH3)2).
Step 4~ Bubl diltlethylsilylo~y--3~ q O ~ 1--2,3,6--trideo~y--201~ ' >~, To ~ stirrod solution of 1 t-butyl d ~- IYIOAY-3 r~ 2,3,6 tl;de~,A~-L-(81 mg, 0.18 mmol) in CH2C12 (2 ml) t 0C were dded collidine (47 IJl, 0.36 mmol), uld ~.. - .~yI~.~ ' (24 ~1, 0.27 mmol). ~fter 1 hour, the ro~¢tion miAture ws~ worlced up 25 with CH2C12 nd w~ter. The org nic l~yor w~s w~hod with b~ine ~nd driod over MgS04. The solvent w 8 c. . - ' to give the titled _ . ' (76 mg, 745~).
lH NMR (W MHz, CDC13) ~: 6.47 (d, J ~ 8 Hz, lH, N-H), 5.03 (d, J = 3.0 Hz, lH, H-4), 4.84 (dd, J = 2.3 nd 9.0 Hz, lH, H-l), 4.35 (m, lH, H-3), 4.00 ~nd 3.80 (2d, J = 10.5 Hz, 2H, -CH2-Br), 3.75 (dq, J = 1 Hz, 6.5 Hz, lH, H-5), 2.05-1.70 (m, 2H, H-2), 1.20 (d, J ~ 6.5, 3H, -H6), 0.9 (s, 9H, 30C(CH3)3), 0.13 (28, 6H, -si(CH3)2) r p~( 22~ . of f~w p~ 2~3~1 p~n ~ ;. .
-SUB~Ti 3 ~ S;'~ ET
2 1 ~
M,~A o O
O
N,C~ H,~
O O
BCH-2105 ~,~
O O
H~J
O OMe BCE{-20n Step 1: (l'-S, l-S, 3-R) ~nd (l'-S, l-R, 3-S) b;~ 2',3',4',6' 1 ' ~-3'-q'-O ' ~ 1 L 1~ ' ~., ) S,10 d-3,4,S,10 i ~yd . p! ' ~ 12,3-c1 pyrsn-3-yl) ketoneBCH-20~S
Thc titlcd . , ' w~ obt-inod in 45~i yield by using thc ~,.. ' _ ;' ' d in step 2 of this acunple but with the sugllr obtsined f~om step 3, e~cunple 21. It W~6 purified by fhsh ~ ~ ~ . ' .y ~ ' ~ ~ 95/S).
lH NMR (250 MHz, CDC13) o: 8.10 (m, 2H, ~r-H), 7.80 (m, 2H, Ar-H), 7.1S (2d, J--8.0 Hz, lH, N-H), 6.16 And 6.00 (28, lH, H-l), 5.62 nd S.S0 (2d, J = l.S Hz, lH, H-l'), 4.89 uld 4.84 (2 brwd ~, lH, H-4'), 4.75 nd 4.25 (2q, J 5 6.6 Hz, H-S'), 4.50 (m, 2H, H-3, H-3'), 3.23 ~d 3.21 (2s, 3H, ~O2CH3), 3.10 (m, lH, H~), 2.55 (m, lH, H~), 2.33 snd 2.32 (2s, 3H, -CO-CH3), 2.00 (m, 2!H, H-15 2'), 1.45 ~nd 1.30 (2d, J = 6.6 EIz, H-6').
Step 2~ S, l-S, 3-R) 1~1 (1-12',3',4',6' tetradeoxy-3'-trifluoroacetsmido-4'~(2-~ ~ '~yl)--L--I~ r ~ - ~] 5, 10 d 3,4,5,10 ~ 2,3~]
pyrlm-3-yl) Ic~one BCH-2105 Sll~r~T~lT~ ~H~ET
~0 94/11382 PCT/CA93/00463 2 ~ 4~
To a stirrod solution of the aglycone from c~ample 3 (30 mg, 0.11 mmol), q ~ t~l-l-t-butyl ' yl~:lylo~cy 3 ~ .m ~ t~ (76 mg, 0.13 mmol) '- ' sievcs A
(62 mg) in CH2C12 (1.2 ml) at -50C under argon was dded; ' .~ lyl I '' ~ ' - '' (23 S 111, 0.12 mmol). Aftcr 2 hours at -30C, the rction mi~cture w~ worltod up with ~ solution of N~HCO3 10% nd CH2C12. Thc orgsIuc layer w~s washed with brinc and dried ovcr MgSO4, the rcsiduc w~s purified by flash ~ AcOEt 2:1) to give thc titlcd t . _ ' (8 mg, 1296).
lH NMR (250 MHz, CDCl3) ~: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, ~r-H), 6.33 (d, J z 8.1 Hz, lH, N-H), 6.00 (s, lH, H-l), 5.67 (8, lH, H-l'), 5.16 (s, lH, H-4'), 4.53 (dd, J = 3.9 and 11.6 Hz, lH, 10 H-3), 4.53 (m, lH, H-3'), 4.23 (q, J 6.7 Hz, lH, H-5'), 3.90 (2d, J ~ 10.9 Hz, 2H, -CH2-Br), 3.08 (dd, J 3.9 nd 19.8 Hz, lH, H-4), 2.S3 (dd, J = 11.6 uld 19.8 Hz, lH, H-4), 2.34 (8, 3H, -C~
CH3), 2.02 (m, 2H, H-2'), 1.19 (d, J ~ 6.7 Hz, 3H, H-6').
Step3: (l'-S, l-R,30 ' ~ 2',3',4',6' i ' .~-3' - ~-4'~
lS meth~ulfon~l-L 1~ ~' , / ~ ~) S,10 :' 3,4,S,10 tel~ D' " Q 12,3-cl p~n-3~ etone BCH-2070 The titled -.~ . ' wJIs obtsined in 22% yidd by pplying the ~ ' ill step 4, e~c mple 12, to the yl~ - from e~mple 3 nd the glycsl f~m step 2, e~mple 21. ~ ; WY8 csrried out 20 by fl~;h; ' ~ g5/5) M.P. 85-89C.
lH NMR (250 MHz, CDC13) ~: 8.11 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 5.98 (8, lH, H-l), 5.62 (d, J = 2.8 Hz, lH, H-l'), 4.85 (8, lH, H-4'), 4.46 (dd, J--4.0 ~nd 11.6 Hz, lH, H-3), 4.04 (q, J = 6.5 Hz, lH, H-5'), 3.62 (m, lH, H-3'), 3.39 (1~, 3H, -OCH3), 3.14 (s, 3H, ~2 CH3), 3.05 (dd, J ~ 4.0 ~nd 19.5 Hz, lH, H-4), 2.50 (dd, J ~ 11.6 nd 19.5 Hz, lH, H-4), 2.33 (8, 3H, -C~CH3), 2.00 (m, 25 2H, H-2'), 1.33 (t, J ~ 6.5 Hz, 3H, H-6').
Step 3 (Cont'd)~ S, 1'S, 3-R) ~ ' Jl (1-12',3',4',6' 1 ~ ~-3' ' ~-4'-O ' Ifonyl-L l~ ) S,10 ~-3,4,S,10 1 ~.' . ' ' ~ 12,3-c] py~n-3-yl) Icetone BCH-The titled . . ' w~ o1~t inod in 11 % yidd by u6iug the ~,.. _ t ' - ~ in xtep 3 of thiæ
mple but using the 1,3 ~ - M.P. 139-141C.
lH NMR (250 MHz, CDC13) ~: 8.12 (m, 2H, ~r-H), 7.77 (m, 2H, ~r-H), 6.15 (s, lH, H-l), 5.52 (d, 35 J = 1.5 Hz, lH, H-l'), 4.95 (d, J c 1.5 Hz, lH, H-4'), 4.59 (q, J c 6.5 Hz, lH, H-S'), 4.49 (dd, J =
4.1 ~nd 11.6 Hz, lH, H-3), 3.60 (m, lH, H-3'), 3.38 (s, 3H, -S02CH3), 3.15 (6, 3H, -OCH3), 3.07 (dd, J--4.1 ~nd 19.9 Hz, lH, H-4), 2.55 (dd, J = 11.6 uld 19.9 Hz, lH, H-4), 2.33 (6, 3H, -CO CH3), 1.95 (m, 2H, H-2'), 1.50 (d, J ~ 6.5 Hz, 3H, H-6').
SUES~ 5.~E~T
WO 94/11382 ~ 1 4 ~ 5 4 ~ PCI /CA93/00463 Step 4~ S, 3 R) nd (l-R, 3-S) b~ )-5,10-dioxo-3,4,S,10 i byd ~ ~p~ 2,3~1 p~rran.3-yl) ~etone BCH-2096 To ~tirred solution of the ~ . - from cDple 3 (7 mg, 0.026 mmol) in I ' ~ (1.6 ml) were ddedS,6 ;"' ,.' ~ 2H-py~n (29 ~1, .26 mmol) and~c t lytic lountofPISA. After 4 hou~i, the re~ction W~16 W011COd Up with CH2C12 Jnd NsHCO3 5 !~i . T~e orgsnic l~yer w~ w~hed with brine ~nd dried over MgSO4. The ~olvent W~8 _. . ~ ' to give the titlod . I (10 mg, 9696).
lH NMR (250 MHz, CDC13) 8: 8.10 (m, 2H, Ar-H), 7.70 (m, 2H, Ar-H), 6.34 (6, lH, H-l), 4.66 (dd, J--4.3 s~d 11.6 Hz, lH, H-3), 3.8~3.50 (m, 4H, -CH2~CH~), 3.40 (~, 3H, -OCH3), 3.06 (dd, J = 4.3 ~nd 19.7 Hz, lH, H-4), 2.S2 (dd, J = 11.6 nd 19.0 Hz, lH, H-4), 2.30 (~, 3H, -CO-CH3), 2.20-1.85 (m, 4H, CH2-C-CH2-).
SUB~TfTU~ SI~T
WO 94~11382 PCT/CA93/00463 21~
F. p' 23: ~. of , ~ 12,3.~] P~ ~ wlth ~ no methyl l~etone side ch~in OMc OMe CO2tBu 01 ¢~02Ph ~/ 2, ¢~
0~4 0~ OMC
~3 OMG
~, OM~ O
~ PNBO~
1~
o o ~b~
o o H,~
RO NH~A
R-PN
sc~.20s8 s Step l: S~8-n '' /-3-(t-bobl ~
To ~ ~od solutiolt of I~J r from s~ep 1, e~cJmple 20, (1.12 g, 3.35 mmol) in CH2C12 (40 ml) Dt -78C wore ddod ~ oolution of silyl enol ether of t-butyl 9- (10 mmol) in CH2C12 (10 ml) 10 Dnd AlC13 (1.33 g, 10 mmol). T: , .; w~s theD nusod to -30C for 2 hours. The re~ction mi~cture W~8 worlcod up with CH2C12 uld HCI 0.1 N. The org~mic W~8 w~&hod with brinc ~nd dried over MgSO4. The solvent w~s c., ' to give the titlc ~- - (519 mg, 43 %).
H NMR (250 MHz, CDC13), o: 6.63 (m, 2H, Ar-H), 4.91 uld 4.85 (2d, J--9.8 Hz, lH, H-l), 4.60 ~nd 4.53 (2d, J ~ 7.9 Hz, lH, H-l), 4.20 (m, lH, H-3), 3.76-3.74 (3s, 6H, OCH3), 3.62 (t, J = 9.5 SUBST~TLJT~ ~37E~T
Hz, lH), 2.90 (m, lH, H-4), 2.45 (m, lH, H-4), 2.32 uld 2.28 (2s, 3H, -C~CH3), 1.49 ~nd 1.47 (2s, 9H, -C(CH3)3) -step 2: 5,8-n t~ ~-3-(~... r --2 The product f~om step 1 of thio c~ple W~ J, in 91% yidd, with ~ ' ~qu~ous HBr in cetone.
lH NMR (250 MHz, CDC13) ~: 6.63 (2d, J = 9.0 Hz, 2H, Ar-H), 4.88 (d, J = lS.9 Hz, lH, H-4), 4.58 (d, J = lS.9 Hz, lH, H~), 4.06 (m, lH, H-3), 3.77 nd 3.75 (26, 6H, -OCH3), 2.85 (m, 2H, -10 CH2-C~), 2.63 (dd, J = 4.8 nd 16.5 Hz, lH, H-4), 2.40 (dd, J = 10.9 nd 16.5 Hz, lH, H-4), 2.24 (s, 3H, -CO CH3).
Step 3: S,8 1~ 3-( ., - 2 1 o~) 1-(2',3',6'-trideo~y-3'-L-~ . - ' 1'~
~ ~I L 1~ ~' ,.,. ) lS
Thc: ' ,from 2 hcrcin w~ ~ s pcr ~,~1~ A- ~ ih~d in step 3, c~mple 34. The title . ~ w~s obt ined in 97 % yield.
lH NMR (250 MHz, CDC13) o: 8.26 (d, J--2.0 Hz, 4H, ~r-H), 6.74 (m, 2H, Ar-H), 6.50 ~d 6.35 (2d, J ~ 7.0 Hz, lH, -NH), 6.02 nd 5.88 (2s, lH, H-l), 5.59 (8, lH, H-l'), 5.49 ~nd 5.46 (2s, lH, H-20 4'), 4.70 (m, 2H, H-3', H-3), 3.80 nd 3.78 (28, 6H, ~I3), 3.00 2.50 (m, 2H, H-4, {~H2~), 2.S0-2.00 (m, 2H, H-4, -CH2-C~), 2.24 nd 2.22 (2s, 3H, -CO CH3), 1.25 Jnd l.lS (2d, J = 6.5 Hz, 3H, H-6').
Step4: S,8-Dioxo-3-(1..~ ~ 2 ~) 1-(2',3',6'-trideoxy-3'~'~ ~ ' 1'~p-~ 1 Jl L 1~
The titl~d , ' w~s obt~ined ill 9496 yield vi~ ' of the I~L~ obt~ined from step 3 herein ~ per p t ~ d in step 4, e~mple 34.
lH NMR (250 MHz, Cl~C13), ~: 8.30 (d, J--5.7 Hz, 4H, ArH), 6.80 (m, 2H, ~r-H), 6.42 and 6.35 30 (2d, J = 7.0 Hz, lH, N-H), 5.81 nd 5.70 (2s, lH, H-l), S.S9 snd 5.54 (2s, lH, H-l'), 5.45 (2d, J =
1.5 Hz, lH, H-4'), 4.8~4.40 (m, 3H, H-3', H-S', H-3), 2.90 (m, lH, H-4), 2.70 (m, 2H, -CH2{~0), 2.40-1.90 (m, 3H, H-4, H-2'), 2.23 ~nd 2.21 (2s, 3H, -CO-CH3), 1.28 ~nd l. lS (2d, J = 6.5 Hz, 3H, H-6~).
3SSt~*5: S,10-Dioxo-3~ , 2 . o.` 1-(2',3',6' ' ~-3'~ '' w ~'~ ~'~
`~' .11 L 1~ t . ~ - -,) 3,4,S,10 1 ' bJ d ~ ~II p' '' ~ 12,3-c] pyran The titled . ' was obt~ ined vi~ c~ ' ' bdween 1 - ~: ' ~ and the quinone from s~ 4 herein by following the ~ d~ . iI fd in step S, e~ample 34.
S U ~ ET
WO 94/11382 2 ~ 8 PCT/CA93/OW63 lH NMR (250 MHz, CDC13), S: 8.31 (2d, 1 = 9.1 Hz, 4H, Ar-H), 8.11 (m, 2H, Ar-H), 7.78 (m, 2H, Ar-H), 6.45 ~nd 6.33 (2d, J = 7.3, lH, N-H), S.99 ~nd 5.88 (2s, lH, H-l), 5.71 ~nd 5.60 (2s, lH, H-1'), 5.48 (18, lH, H-4'), 4.80-4.40 (m, 3H, H-3, H-3', H-4'), 3.00-2.60 (m, 3H, H-4, -CH2-CO-), 2.50-2.00 (m, 3H, H-4, H-2'), 2.25 uld 2.23 (28, 3H, -CO-CH3), 1.33 ~nd 1.17 (2t, J = 6.5 Hz, 3H, S H-6').
.
Step 6: (l'-S, l-S, 3-R) ~nd (l'-S, l-R, 3~-1~6 ' ,. my-1-(2',3',C'-trideox~-3'-h ~ . r '~,4 ' Jd ~ ,~-L 1~ 10 3,4,5,10 ~. . lp! D [2,3-cl pyrsn-3-yl) 1 . . ~ 2 - r BCH-2098 The titlot ~ s obbinod fi~llo.. g d~.. l~l t of tho ~1~ ' from step 5 horein ~8 per step 6, e%~mplo 34.
lH NMR (250 MHz, CDC13) o: 8.10 (m, 2H, ~r-H), 7.75 (m, 2H, ~r-H), 6.73 (t, J = 7.5 Hz, lH, N-H), S.93 nd 5.81 (28, lH, H-l), 5.52 ~nd S.41 (2d, J = 2.7 Hz, lH, H-l'), 4.80-4.20 (m, 3H, H-3, 15 H-3', H-S'), 3.70 (m, lH, H-4'), 3.00-2.60 (m, 3H, H-4, {~H2-CO-), 2.40-1.70 (m, 4H, H-4, H-2', -OH), 2.23 uld 2.20 (28, 3H, ~CH3), 1.41 nd 1.20 (2d, J ~ 6.6 Hz, 3H, H-6').
mple24: .,~ !- of n "! - 12,3-c]py~nd ;. .. with~C-2'gl~
linl~ge S~BS~TUTE SHE~
WO 94/11382 ~ 8 PCI`/CA93/00463 ~ 1~ + ~
Oh~ OH Ol~ N~A Ob~,~,~ NH~.'-O~"OPNB O~"OPNB
Me ~
~ ~Q
~NHIFA O ~
O~ OPNB O~OPNB
o OO
0~40R O~OR
~ Mc CR~H ~ CR H
BC~21~ BC~2145 Step 1:(lR,3S) ~nd (1-S,3R)-1-(2',3',6' ~ -3'-~-~ . - ' ' 1'~p-~ .,lo~-l,~ L 1~ -5~8 ' ~o~y-3-S ~ ~ ~
2,5-r) ~-1 h~d~uA~-3 ~ ~ ws~ ctotwith l,~di~ ~ - k ............. ~ t d-u - - s pcr ~ firom sbqp 1, c~-mple S. Ihc ~od prDdw~ were , ~ by flbsh _ , ~ (C~H2C~2~cokDne 99tl).
IH NMR (250 ME~ CDC13) ~: 8.30 (m,3H, ~-H, N-H),8.09 (d, J - 8.7 Hz,2H, A~-H),6.71 (2d, J ~ 8.8 H~ 2H, A~-H),6.02 (8, lH, H-1'),5.84 ~d, J = 3.6 H~ lH, H-4'),5.62 (~, lH, H-1),5.30 (m, lH, H-3'),4.45 (m,2H, H-3, H-5'),3.81 (ls,3H, ~DCH3),3.76 (ls,3H, ~CH3),3.11 (dd, J ~
3.9 EIz ~nd 17.3 H~ lH, H-4),2.61 (dd, J = 12.1 snd 17.3 EIz, lH, H-4),1.95 (s,3H, -COCH3),1.28 (d, J 6.6 E~ 3H, H-6').
lS ~c ~ocond " hsd:
SU~5T; ~ S~E~T
WQ 94/11382 2 1~ PCIJCA93/00463 lH NMR (W MHz, CDC13) ~: 8.28 (2d, J = 9.0 Hz, 4H, ~r-H), 6.90 (d, J = 7.8 Hz, lH, N-H), 6.70 (2d, J ~ 9.0 Hz, 2H, ~-H), 6.18 (d, J = I.S Hz, lH, H-l'), 5.75 (d, J = 4.8 Hz, lH, H~'), 5.55 (s, lH, H-l), 5.30 (m, lH, H-3'), 4.30 (m, 2H, H-S', H-4), 3.80 (s, 3H, ~CH3), 3.60 (s, 3H, -OCH3), 3.02 (dd, J = 4.3 ~nd 17.6 Hz, lH, H-4), 2.57 (dd, J = 11.6 ~nd 17.6 Hz, lH, H~S), 2.29 (s, 5 3H, -CO CH3), 1.29 (d, J--6.6 Hz, 3H, H-6').
Step 2: (lR, 3S) 1--(2 ,3 ,~ 3 '~ JA~ 5 dih~dro-L 1~ - ~ ~ 2~ ,P ' :1 ~
10 The (lR, 3S) product from step 1 horein w~, ~ d u por ~ in step 3, c~mple 12.
lH NMR (250 MHz, CDC13) ~: 8.23 (d, J ~ 8.7 Hz, 2H, ~r-H), 8.03 (d, J ~ 8.7 Hz, 2H, Ar-H), 7.65 (d, J--6.6 Hz, lH, N-H), 6.75 (2d, J = 10.3 Hz, 2H, ~-H), 6.28 (d, J = 1.4 Hz, lH, H-l), 5.78 (d, J--3.8 Hz, lH, H-4'), 5.37 (s, lH, H-l'), 5.21 (m, lH, H-3'), 4.43 (q, J ~ 6.5 Hz, lH, H-lS S'), 4.24 (dd, J 3.8 ~d 11.2 Hz, lH, H-3), 2.90 (dd, J ~ 3.8 ~nd 19.5 Hz, lH, H-4), 2.40 (ddd, J
1.6, 11.2 ~d 19.S Hz, lH, H-4), 1.88 (s, 3H, -COCH3), 1.26 (d, J 6.5 Hz, 3H, H-6').
St43 (1R~3S)-1-12~3~6~ ;deO~3~ L ~ q~ 5-. L 1~ ' ~,. ~ 2 ,Ir1)-5,10 ~- 3,4,S,10 1 ' ~ ~ lEI-naphtho 12,3-c] p~
Thequiwnc*~m d~p2he~cinw~c~- '' d with 1 ~ ' from st~p 4, c~mplc12. T~c product h~d:
H NMR(250 MHz,CDC13)8: 8.30 (d, J ~ 8.7 Hz,2H,Ar-H), 8.10 (m, 4H,Ar-H), 7.80 (m, 2H, ~r-H),6.36 (d, J--1.9Hz,lH,H-1),5.86 (d, J~ 3.9Hz,lH, H-4'), 5.60 (8, lH, H-l'), 5.31(m, 2S lH, H-3'),4.49(q, J 6.6 Hz, lH, H-S'), 4.35 (dd, J = 3.9Hz,uld11.4Hz, lH, H-3),3.12 (dd, J
--3.9HzJnd 19.4 Hz, lH, H-4), 2.62 (ddd, J 1.9, 11.4 Hz, 19.4Hz, lH, H-4), 1.98 (6, 3H,-C~
CH3),1.31 (d, J ~ 6.6 Hz, 3H,H-6').
S~p4: (~3~-1-(2',3',C'~ -3'l~ ~ ' ' q'b~.'. ~-1,' ',.'~1, 30l~ ' .J. - 2~V-5,10~- 3,4,S,10~ L~ p~ 2,3~1p~n EK~H-2144 The tricyclic product from step 3hereinw 8 d r~ 8 per IJ ~ i from step 3,e~mpleS. The title product h~d:
3S lH NMR(250 MHz,CDC13)~: 8.20 (m, 2H,~r-H),7.75(m,3H,N-H,~r-H),6.25 (d, J--1.7Hz, lH,H-l),S.SS (8, lH,H-l'),S.ll (m, lH,H-3'),4.32 (dd, J = 4.0 Hzuld 11.1 Hz,lH,H-3),4.23 (q, J = 6.5 Hz,lH,H-5'),4.05 (d, J--3.7 Hz, lH,H~'),3.00 (dd, J--4.0 ~nd 19.8 Hz,lH,H 1), 2.59 (ddd, J = 1.7,ll.lJnd 19.8 Hz,lH, H-4), 2.28 (8, 3H,-CO-CH3), 1.70 (b~d ~, lH,-OH), 1.34 (d, J--6.5 Hz,3H,H-6').
SUBSlri ~ ~EE~
21~8~8 Step S: (lS, 3R)-1-(2',3',6' 3 ~-3' ~ 3 ~'-O p o~ h".~-1,5-L 1~ ~ " 2-~ ,P 1 chrom~n S The (lS, 3R) product ftom ~p 1 horein w~ . ' .~ d ~ per ~ In step 3, c~mplc 12.
lH NMR (250 MHz, C~DC13) ~: 8.32 (d, J ~ 9.0 Hz, 2H, Ar-H), 8.20 (d, J ~ 9.0 Hz, 2H, Ar-H), 7.58 (d, J ~ 8.3 Hz, lH, N-H), 6.80 (2d, J--10.1 Hz, 2H, ~r-H), 6.46 (d, J = 1.3 Hz, lH, H-l), 5.73 (d, J ~ 4.8 Hz, lH, H 1'), S.33 (d, J ~ 1.9 Hz, lH, H-l'), 5.25 (m, lH, H-3'), 4.35 (q, J - 6.6 10 Hz, lH, H-S'), 4.20 (dd, J--4.1 Hz uld lO.S Hz, lH, H-3), 2.88 (dd, J ~ 4.1 nd 19.9 Hz, lH, H4), 2.40 (ddd, J ~ 1.9, lO.S nd 19.9 Hz, lH, H-4), 2.27 (~, 3H, -COCH3), 1.32 (d, J ~ 6.6 Hz, 3H, H-6').
Step6: (lS,3R)-1-(2',3',6' 1 ~ ~-3' 1 ~ '- ,r ~ ~loxy-1,5-.'-', ' ~ L 1~ ' . ,. 2 .~ I)-S,10 :' 3,4,S,10-tah b,." lII p' ' ~
~2~c1 }~ ~
Thc quinone f~m ~top S ~ein w~ _,. ' W ~ ,~ c fiom step 4, oJumplc 12. Thc titlod product l~d:
lH NMR (250 MHz, CDC13) ~: 8.30 (d, J 8 8.9 HZ, 2H, ~r-H), 8.22 (d, J ; 8.9 Hz, 2H, ~r-H), 8.20 (m, lH, ~r-H), 8.00 (m, 2H, N-H, Ar-H), 7.86 (m, 2H, ~r-H), 6.53 (~, lH, H-l), 5.77 (d, J =
4.7 Hz, lH, H-4'), 5.50 (~, lH, H-l'), 5.30 (m, lH, H-3'), 4.37 (q, J 6.6 Hz, lH, H-5'), 4.27 (dd, J
--4.0 nd 10.7 Hz, lH, H-3), 3.08 (dd, J ~ 4.0 nd 19.8 Hz, lH, H-4), 2.55 (ddd, J = 1.0, 10.7 ~nd 19.8 Hz, lH, H-4), 2.31 (8, 3H, ~CH3), 1.31 (d, J = 6.6 Hz, 3H, H-6').
Step 7: (lS, 3Rt-1-(2',3',C' ~ ' ~-3' ~ ~ . ' ~' ', " ~-1,~ ~ ' ,d ~ L-I~ ~ .J_ - 2-~l)-S,10 ~- 3,4,S,10 1 ~ ' ' v 12,3-cl p BC~I-2145 Thc tricyclic product from dep 6 ha~in w~ d~,~ ' Som step 3, a~le 5. The titlod product h~d:
lH NMR (W MHz, CDC13) ~: 8.19 (d, J ~ 8.9 Hz, lH, N-H), 8.10 (d, J = 7.3 Hz, lH, Ar-H), 7.90 (d, J 8 7.3 Hz, lH, Ar-Hl), 7.70 (m, 2H, ~r-H), 6.26 (6, lH, H-l), 5.47 (s, lH, H-l'), S.10 (m, lH, H-3'), 4.20 (m, 2H, H-3, H-~'), 3.97 (d, J = 4.0 Hz, lH, H-4'), 3.00 (dd, J = 4.0 nd 20.0 Hz, lH, H-4), 2.55 (dd, J = 10.8 Hz, uld 20.0 Hz, lH, H-4), 2.32 (8, 3H, -CO~H3), 1.70 (bro~d 6, lH, -OEI), 35 1.36(t,J=6.4Hz,3H,H-6').
E~mple25: ~-~. ' of 3~ ' i ' ~. I ~I)-S,10-dioxo-3,4,S,10 ' ~d .
~" - 12,3 ~] ~.,. (BCH-1665) S-~ r~EET
2146~8 OCH, OCH, ¢~r 1~ ~
OCH, OCH3 O O
Ll CO2CH, ll CO2CH, ~CO2CH, 3 [Ç~CO2CH~
o o Step 1~ 3,3 bi~ L yl): ' To solution of 2,3 bis (~ 1)-1,4 ~ (1.30 g; 4.00 mmol) in 40 rnl of ~
mL~turc of l ~ r nt timethylfonn midc wcro ~ddod t yh-~-dimo~ylm~lon~te (1.06 g;4.19 mmol), ~ L (1.16 ~; 8.38 mmol) ~nt ce~ium -. L (1.37 g; 4.19 mmol). The - e mi~turo w~ 8ti rot 8t 80C (oil b th I . ) for 2.5 hou~s. It w~s then cooled to room ., nd filteret on p~d of ~ilic~ gel nt thc solvcnt~ were _. . ' using ~ vYcuum pump to yidd 2.3 g of cnJde ~'~' ' product which w~ ~ d in ' I (60 ml). To this solution w~
10 dded ~ Nolution of ~ in ' -' (4.57 ml; 4.37 M; S oq). Thc ' e mi~turc W9 s~rrod t room t_h~ for 2 hour Jnd w~s then e ~ to ~ volume of -10 ml. It w~
' - ' with 1 N HCI nd t 3 with :' ' ' . - The c ' - ' org~mic l~yer~ woro w~shed with brino nd dried over MgSO4. The crude product W~8 purifiod by colum~ Dgr phy on silic~
gd udng 10-2S % othyl cot te in ho~ne to ~fford the title c . ' (452 m~; 36 % o~ersll):
15 lH NMR (2S0 MHz; CDC13) o: 3.2S (2EI, ~, H-4), 3.72, 3.78, 3.79 (12H, 38, 4~t0CH3), 4.88 (2H, 8 H-1), 6.59 nd6.65 (2H, ~ ' ~r-H).
Step 2: S)~ :' 3,3 bis (metb ~. I yl)-S"~ :'-b., d ~
20 To ~ olution of S,8 ;- ~-3,3 bis ( ~ L ~1) ' . (70 mg; 0.23 mmol) in~~ ' - (5 ml) ~t room l . ~ w~ ~ r ~ ' aolution of ceric ~ ni~te (378 mg; 0.69 mmol) in w~ (1 ml). The e mLlcture W118 then dirred t room I . ~ for S
minute6 ndw~ ~ ' by dding ' ~diuml ~ solution. Thep~duct W~8 b with ~ '- . - nd the c - d orgsnic l~yers were w~hed with brine nd dried over MgSO4.
25 E~ ~ ~fforded the crude qui~e (60 mg; 95 %) which W~18 u6ed without further 1~
lH NMR (CDC13, 250 MHz) o: 3.03 (2H, t, J = 3Hz, H-4), 3.81 (6H, 8~ OCH3), 4.67 (2H, t, J =
3Hz, H-1), 6.70 ~nd 6.77 (2H, AB ~ Ar-H).
SIJ~T~ ~ ~JiTE S~;E~T
` 214~4~ --Step 3 3,3 bi~ ~ t~S,10 ' 3,4,S,10 b"~ ~ lII , ' 12 3~c]
P~
To OOlUtiO~I of S,8 dio~o-3,3 bu ( ' ~ ~ yl)-5,8 dib ~ ' . ' (S0 mg; 0 17 mmol) in tolu~ne (4 ml) t room w~ dded l~ooto~ty-1,3 1 - (113 ~11; 1 mmol) The ~tine mL~tur~ w~s ~od t room t , - for 24 holus ~ir w~s tb~ bub~lod tbrough for 30 minu~ ~nd the mL~ture W~8 - d to volume of ~ ppliod to oilic~ gd column Elutio l with 30%
ethyl cot te in ~e fforded pure title _ ~ ~20 mg; 34%) 8 ~ yellow ~olid; m p 210-222C
(d~) 10 lH N~R (250 MHz, CDC 13) ~ 3 22 (2H, t, J ~ 2 S Hz, H-4), 3 84 (6H, ~, C02CH3), 4 86 (2~I, t, J
~ 2 5 Hz, H-1), 7 75 (2H, m, ~H), 8 10 ~2H, m, ~H) IR (film) 2963, 1743, 1662, 1641, 1591, 1438, 1288, 1175, 1055, 791 ~d 692 cm~
SU~S~ T~ EET
2~46~8 F ~ 26~ of (l'S, lR, 3S) ~nd (l'S, lS, 3R)-S,10-dio~o-3-1 1-(2',3',6'-trideox~-3'~
) 3,4,S,10-tetr~hydro-lIl p - 12,3-c]-p~an (BCH-101) sDd BCH-lC93) S
OCH, O OC~ OCH, - OCH, OCH, OCH, O O
O o O
PNBO ~ PNBO ~
~ 14 O O
O o O O
PNBO ~ PNBO ~
1~ 16 O O
O o O O
HO NHIFA HO NN~A
~1691 B~1693 Step 1: 5,~ J-3 ' ,d . ~, ' yl - ' .
To ~ solution of S,8 ~ -3 - ~ ~ . (310 mg; 1.23 mmol) in 5 ml of t ~ r ~t 0C W 8 ddod lithium ' hydride (47 mg; 1.23 mmol). The mLlc~e w ls stinod st 0C for lS mi~utes uld w~s ~. ' ' with 1 N HCl. The product W~8 - ' with ether uld the c - ' org~uc layers we~e w~hed with brine nd dried over MgSO4 ~rr.,.. e crude title rlcohol (246 mg 90%) used s such for , 6teps:
S U E~ W ~ ET
WO 94/11382 PC~r/CA93/00463 lH ~D~R (250 MHz, CDC13) o: 2.42 (lH, m H~ ,2.55-2.75 (21I, rn, H-4 oq ~nd ~DH~,3.6C~3.90 (2H, m, C~12~H~,3.76 (3H, 8, ~DCH3),3.77 (3H, 8, ~CH3),4.62 (lH, br d, J = 16.0 Hz, H-l), 4.97 (lH, d, J ~ 16.0 Hz, H-1),6.61 nd 6.65 (2H, ~iB d ' ' '~ ~rH~.
S Step2: S,P ~ 3 - ' ,, - ~!- ' .
To a . - of ~x~um hydndo (70 mg of 60~ m o~; 1.78 n~nol) Ln l ' ~.' (3 n~) was ~dded ~ oolu~on of 5,8 ~ -3 h~ ' ~ ' yl (330 mg; 1.48 mmol) m 7 n~ of i ' ,1. ' The noR~ny n~u8 ~ o~rred ~ room ~ , - u~tl H2 ~-- ' o~ued ~-15 10 minuk~) ~nd i D~ ' - (500 ~1; 5 oq~ ~u ddod. Iho D~U~ ~n~ Lhon dinxd ~ room i for 30 munuk~. SDU~ tbc ro cion ~ DK* pr no~ur ~, . ' of ex~um hyt~dc ws~ ~d ~long witb 20 mg of ceuum o ' The mL~ s sti~ed for lS D~inuto~ nd W~8 3~, ' - ' with ' ~ chlodtc~olution~d d with ' ~ ' - The ~ ' ' orgsnic l~yers were wuhot with brin~ nd dried ovor MgSO4 The cmdo w~s purifiot by oolumn ~ on lS silic~ gd U8illg 259~ oShyl ~cot~ D1 ha~sne to fford the titlo ' (301 mg; 86 ~i) H NMR (250 MHz, CDC13) 8 2 45 (lH, br dd, J ~ 11 0 nt 1 î Hz, H 1 u~), 2 69 (lH, dm, J =
17 0 Hz, H-4 oq), 3 44 (3H, ~, C~2{)~3)~ 3 SS (2H, d, J ~ S S Hz, ~2~D), 3 7S (3H, 8, OCH3), 3 77 (3H, 8, OC'H3), 4 63 (lH, br d, J = 16 0 H[z, H-l), 4 97 (lH, d, J--16 0 Hz, H-l), 6 61 s~d 6 64 (2H, AB ~ ' ~r-H) 20 Step 3 (l'S, lR, 3S)-~,8 ' 3 ~' ~ b~l 1 (2',3',6'~ -3'-t ~ yl L 1~ ' ," ` S,8-' bJ~ ~ ~nd its (l'S, lS, 3R) ' To ~ olution of S,8 " ~-3 ' ~ ' (280 m~; 1 18 mmol) ill 16 ml of 25 ~ - ' - v~o~ ~t 2,3,6J '- ~-3 '' ~ ' 1 0 p ' ",1 -L-r ~ (555 mg; 1 42 mmol), 4A ~;ieve8 (500 mg) nt 2,3 d; ~,6-- (360 m~; 1 6 mmol) Tlho d~ groo~ ro ctia~ tu~o w~ stined t room , - for 14 ho~ It w~ 1, - ' wiSh - 3 N~HCO3 ~olution uld e ' with - The ~ ' ~ ot1pnic Isy~rs wer~ w~hod with - ~ d N~HCO3, brine ~d were 30 dried over N~2S04 -~n ~ fto~ 671 mg of ~ cn~dc dduct which w~u c' '~ in '- (20 ml) ~t 0C ~ lutio~ of conc 9 n itr~te (3 3 g; 6 mmol) in 10 rnl of wder w~s tro tod by po~tiom~ with ~olid ~odium ' ~ (886 mg) Thc re6ultiDg yoUo~,v ~olution w~s ~&ded d~ ~ to the ' Ilolution ~fbr tbe ~d the muhlre w~s sti Tod ~t 0C for 20 minutes, ' - ' witb d NiHCO3 rolution uld ~ ' witb ~' ' ' ' The ' - d orguuc 3S l~yers were w~bed with b~i~e uld dried o~er Na2S04 to fford uRcr c. . ~ cmde quinone which wu~ " ' from tichlorometb . yidding 225 mg of ~ s~reomeric quinone mi~
f~voring the title c ~ (2 1) lH NMR (250 MHz, CK~13) 1 20 (3H, t, J ~ 6 5 Hz, H-6'), 1 90 2 70 (4H, D~, H-2' ~nd H-4), 3 41 (3H, 6, -OCH3), 3 35-3 6S (3H, m, CH2-OCH3 ~nd H-3'), 4 154 70 (2H, m, H-3 ~nd H-S'), 5 44 (lH, S U ~S~ S ~ E -T
WO 94~11382 PCI~/CA93/00463 ~ 214~F~
br 8, H-l'), 5.60 (IH, br ~, H4'), 5.78 (lH, 8, H-l), 6.30 (lH, m, NH), 6.65~.90 (2H, m, Ar-H), 8.30 (4H, m, PNB): sign~l~ for minor (l'S, lS, 3R) i~omer re ~: 1.30 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.70 (4H, m, H-2' ~nd H4), 3.43 (3H, ~, ~I3), 3.35-3.65 (3H, m, CH2~CH3 nd H-3'), 4.15-4.70 (2H, m, H-3 ~d H-5'), 5.40 (lH, br 8, H-l'), S.59 (lH, br 8, H 4'), 5.91 (lH, 8, H-l), 6.40 5 (lH, m, N~, 6.65-6.90 (2H, m, Ar-H), 8.30 (2H, m, Ar-H).
Step 4: (l'S, lR, 3S)-S,1~o-3 " ~ l 1-(2',3',6'~ -3'-lII p' ' v [2,3 cl ~, To ~ olution of the quinooe mLlcture from ~top 3 of thi- - , ' o, (100 ~; 0.17 mmol) in 6 ml of tolue~e t mom I w~ ~dded 1- c~to~cy-1,3 ~ ' - (113 ~1; 1 mmol). The rest of the ' ~ is ite~tic l to step 2, e~ample 5, ~~ ' g thc title c . ~ (42 mg; 40%):
lH NMR (CD2C12, 250 MHz) o: 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.9~2.20 (2H, m, H-2'), 2.37 (lH, 15 dd, J 11.5 uld 19.5 Hz, H4 ~%), 2.70 (lH, dd, J 3.5 uld 19.5 Hz, H4 oq), 3.38 (3H, 8, O-CH3), 3.55 (2H, m, -CH2-OCH3), 4.254.70 (3H, mt H-3, H-3' rnd H-S'), 5.41 (lH, br 8, H-l '), 5.65 (lH, br 8, H-4'), 5.90 (lH, 8, H-l), 6.44 (lH, br d, J = 7 Hz, N-H), 7.7S (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.27 (4H, m, PNB).
Thc ~ocond ~' .
20 (1 S, lS, 3R)--5,10--dioAo--3 ~ 2 ,3 ,6 t~;d~A~--3 t . 4 {~--p--L Jl L 1~ ~ r~ ~ )-3,4,S,10 t ~.- ~lII ~ . - - - t2,3~l pyr n w~s obtdned ill 19%
yidd nd h d:
lH NMR (250 MHz, CD2C12) o: 1.30 (3H, d, J ~ 6.5 Hz, H-6'), 1.9~2.30 (2H, m, H-2'), 2.47 (lH, dd, J 11 nd l9.S Hz, H4 al~), 2.71 (lH, dd, J--4 rnd l9.S Hz, H4 oq), 3.89 (3H, ~, -OCH3), 25 3.57 (2H, d, J - S Hz, C_2-OCH3), 4.27 (lH, m, H-3), 4.52 (lH, m, H-3'), 4.75 (lH, q, J ~ 6.5 Hz, H-S'), 5.41 (lH br ~, H-l'), S.56 (lH, br ~, H4'), 6.03 (lH, 8, H-l), 6.46 (lH, br d, J 7.5 Hz, N~, 7.7S (2H, m, Ar-H), 8.07 (2H, m, Ar-H), 8.28 (4H, m, PNB).
S~ep S: (l'S, IR, 3S)-S,10 ' 3 ~ l 1-(2',3',~'-1 ' , 3'-t~ L 1~ ' , ,.~ ~~ ) 3,4,S~10-tdr~lhydro-lII l~' ' ~ t2,3-cl-p~ n (BCH-lC91) To ~ 801ution of (1 S, lR, 3S) S,10 dioAo--3 ~ 2 ,3 ,6 t~;~Ar 3 1 . I
4'~p ~. ~ ,I-L 1~ ' .. , )-3,4,S,10 t ' ~ ' ~lII- p! - 12,3 Clpyr~n(19mg; .029 35 mmol) in - -' (.4 ml) nd: ~d~ r (1.5 ml) t 0C w~s rddod .86 1l1 (.1 oq) of ~1 4.37 M
~olution of sodium - ~.- in - ~' Thc resulting mu~turc w stirrod ~t 0C for 20 minute6 ~nd wu~ 3 -' - ' with ~ ' NH4CI. r with ~ - followod by w~ing of the - ' o~uuc layer~ with brinc nd dryi~g with N~2SO4 r ~1~ cnule product which was punfiod by column ~ ' ,, p! ~ on ~ilic gel u~ing 5-10% ~nc in ba~ne ~ duent yieldillg the SUES~ , S~ T
WO 94/11382 PC~r/CA~93/O{k463 2146~4~
titlc c ' (14 mg; 96~) wbich w~8.~ '1i7^d from ~ to ~ive yd~ow crydb~s: M.P.: 140-159C; nR (ne~t): 3S00,3422,3320,2938, 1715, 1667, 1597,1295, 1178 snd 980 cm~l:
lH NMR (250 ~LE~ CD2C12) o: 1.21 (3H, d, J ~ 7.6 EL~ H-6'),1.S2 (lH, bs 8, O-H), 1.70-2.20 (2H, m, H-2'),2.35 (lH, dd, J ~ 11.7 ~nd 19.3 H~ H 4 ~),2.68 (lH, dd, J 3.4 nd 19.3 Elz, H-4 - oq~,3.56 (3H, b, OCH3),3.S2 (2H, d, J ~ 4.8 H~ CEI2~CKCH3),3.58 (lH, br ~, H4'),4.15-4.40 (3H, m, H-3, H-3', H-S'), S.46 (lH, br ~, H-l'), S.83 (lH, ~, H-1),6.73 (lH, br d, J - 7 E~ N-H),7.75 (2H, m, ~-H~,8.05 (21I, m, ~H).
Step 6: (l'S, lS,3R)-S,10 ~- 3rn~d/Yq~nncibyl-1-(2'~3',6' ' ~ ~-3'-t ~ . - '- L 1~ 3,~,10 ~ b~ lII p! ' 12~c]
p~n~n ~BC~I-lC93) l~hc ~r~ng p O~l ~ d ~cohol from ~p 4 of t`hi8 o~rnple (18 mg; 0.028 mmol) in .4 n~ nd 1.5 ml of t ~ trod~d ~nlh .83 ~1 of ~ 4.37 M solu~on of ~od~um ' ~- m -' r~ l~o p......... ~ from dkp 5 hcn~n to affori the title; . ' (12.5 I4g; 90~): m.p.: 92-102 C; IR (D~9~): 3485,3424,3323,2937, 1715, 1666,1595,1296, 1175, 1117,980 cm~l.
lH rlMR (CD2Ck,250 MHz) ~: 1.35 (3H, d, J - 6.5 E~ H-6'), 1.85 ~H, ~ H-2'), a~01 (lH, br d, J = 7 H~ C~E~,2.46 (lH, dd, J ll.S and 20 E~ H-4 r~),2.69 (lH, dd, J -ii 3.7 ~nd 20 E~ H-4 oq~,3.36 (3H, ~, CICH3),3.54 (2H, d, J ~ 4.7 E~ C~2-CKCH3),3.60 (lH, n~ H 1'),4.154.40 (2H, m, H-3' nd H-3),4.SS (lH, q, J 6.S H~ H-S'), S.39 (lH, br s, H-l'), S.98 (lH, , H-1),6.78 (lH, br d, J i 7 E~ -rDH~,7.7S (2H, m, ~-H~,8.05 (2H, n~ ~-H).
SUeST~ S}~EET
WO 94/11382 PCr/cA93/00463 2 ~ 4 ~
F "r- 27~ of (1'S,1P,~S) ~nd l'.S,~ S,10; - 3-eth91-1-(2',3',6'-trideox~-3'L ~ . ' I~;, -' ,.~r-- ) 3,4,5,10 ~ .~h,L~.
lH~phtbo~2,3 c] ~, (BCH-2026) 9nd BCiH-2020) ~nd (l'S,lS,3S)-S,10 :'- 3-etbyl-1-(2',3',6'~1 ~-3' _ - L 1~ ' ,. ) S 3,4,S,10-tetr~dro-lII "' - I?~ C] r~ 3 ~ (BCH-2021) OCH~ OCH~ OCH~
[~2 OCH~ OCH~ OCH~
CHJO CH~O
CH~O O + CH~O o NBO ~ ~ PNBO
1~ l7 O O
O o O O
NBoNHIF~ PNBoNHIF~
1~
O o O
~ ~0~ 0 ~0~
O O o O o pN80NHlFA pN80NHlFI~ PN80NH~CI
IC 198~1 O O
O o O O
HoNHlF~ HoNHlF~
~QZ~ 8CH-2020 Step 1: 1-(2,F . - -~P' .~'V 2-L ' ~!
- Under argon ~ , , 1,4 ~ L - 10.0 g (72.37 mmol) w~s .li~l~ in dry THF and this solution was cooled to 0C. n-BuIi (2.5 Mr s) 28.8 ml (72.37 mmol) w LS then ~d and the - r~action mL~ture wa8 warmed up to room , ; ant Istirring was left for 4 hours. ~fter 4 hourls, the reaction w~ coolod to -78C and 1,2 ~ ~ 5.2 ~ (72.37 mmol) w~ addod followed by 10.2 g (72.37 mmol) of boron trifluoro othaate. Stining wa8 then: -~' for a period of 1 hour. The rellction mfl~ture W~8 thon, - ' by pouring it into 125 ml of ~queous NH4CI. F ~ of the S U IE~ 5 ~, E rT
WO 94/11382 PCr/CA93/00463 21~65~ e ~queous l~yer were done ufiing CH2C12. The r ~ ' - ' orgsnic Isycrs werc driod over N 2S04, filtered Ynd the solvent wss rcmovet. Thc crute r~teri~l wss purifict by flssh .,~. O p' ~ with he~csnes-ethyl scet~te (9: 1) then (8:2) ~8 the eluent. The isol~tod titlct; , ' w fi ~ white fiolid (11.4 g, 75%).
S NMR lH (250 MHz) (CDC13; ppm): 6.75 (3H, m, ~ ~ 5) 3.79 (3H, 8, OCH3), 3.77 (lH, m, H2.), 3.76 (3H, s, OCH3), 2.85 (lH, tt, Jl c 3.8 Hz, J2 = 13-5 Hz, Hl.,), 2.65 (lH, dt, Jl--8.1 Hz, J2 = 13.5 Hz, Hlb), 2.16 (lH, t, J ~ 3.7 Hz, OH), 1.52 (2H, m, H3.) 0.99 (3H, dd, Jl = J2 =
7.4 Hz, -CH3)-10 Step 2: 5,~ b~
Under rgon ~ , ' .;, the 6tsrting rnderisl from step 1 of this ~ , 5.00 g (23.78 mmol) W9S
t in 100 rnl of try dher. D- ' ~ rneth nc 3.0 ml (33.90 mmol) snd boro~ trifluoro ether~Le 9.0 ml (71.35 mmol) were then ~tet nd stirring W98 left ~ ' The ro~ction w~ then ~
15 u~ng uluoous N~HC03. r were tone ufiing ether u~t the - ' org~nic c~tr~cts were dried over Ns2S04, filtered ~t the fiolvent wss ren~ovet. The isol~ted rosidue w~ then purificd by flssh ~- . ~ cetde (8:2) W~8 used ~8 the eluent. The desired titled ~ .
W~8 isol tcd ~ ~ white ~olid (4.9 g; 92 %).
NMR lH (250 MHz) (CDC13; ppm): 6.63 (2H, t, J ~ 3.4 Hz, ~ . ), 4.93 (lH, d, J = 15.9 Hz, 20 Hl,), 4.57 (lH, d, J = 15.9 Hz, Hlb), 3.78 (3H, 8, OCH3), 3.76 (3H, 8, OCH3), 3.47 (lH, m, H3), 2.74 (lH, d~d, H4~), 2.38 (lH, dd, H4b~, 1.68 (2H, m, CH2- side ch in) 1.03 (3H, dd, Jl = J2--7 4 Hz, -CH3)-Step 3: (l'S, ~R, 3R) 5)~ -3~ 1-1-(2',3',C'~ideo~-3'-l A
0 ~ ~* Jl L 1~ ' .J.
~,, ' of the fi~t prt of the ~ _c ~ ihrJ in 6top 3, e~ple 26, on the - from dep 2 haein ro~ultod with the titlod ~ ' s ~ yellow ~olid; 62%.
NMR lH (250 MHz) (C6D6; ppm): 7.72 (4H, m, ~ ), 6.48 (2H, d, J = 4.7 Hz, . - ), 30 6.17 (lH, 8, Hl), S.95 (lH, m, N~, S.67 (lH, d, H4.), 5.29 (lH, d, Hl.), 4.67 (lH, m, H3.), 4.26 (lH, q, Hs.), 4.20 (lH, m, H3), 3.49 (3H, 8, OCH3), 3.40 (3H, 6, OCH3), 3.01 (lH, dd, H4~), 2.52 (lH, dd, H4b), 1.90 (lH, m, -CH2 side c~in), 1.75 (lH, m, -CH2- side chsin), 1.61 (2H, m, -CH2-6ug~r), 1.06 (3H, d, -CH3 ~;ug~r), 1.03 (3H, m, CH3 6ide ch~in).
IR (film) (cm~l): 3316 (NH), 2933 (CH liphatic), 1733 (C=O), 1707 (C=O), 1603 (C=C), 1532 (C-35 N), 12S9 Jnd 1175 (C~).
SUe~T~T~ S~T
WO 94~11382 PCT/CA93/00463 St~p 4: (l'S, lR, 3R)-S,8~diox~3-ethyl-1-(2',3',6'-lrideoxy-3' ~
Arp~ of the ~cond p~rt of thc ~ i (CAN) d~ 1 in step 3, cDple 26, on the S ~, p from thc prcvious step resulted in n 87 % yield of thc titlet , NMR lH (250 MHz) (C6D6; ppm): 7.80 (4H, m, ~ . ), 6.92 (lH, 8b~d, NH), 6.08 (2H, m, - quinonc ring), S.72 (lH, ~, Hl), S.54 (lH, ~, H4.), 5.53 (lH, 8, Hl.), 4.74 (lH, m, H3.), 4.36 (lH, m, Hs~), 3.68 (lH, m, H3), 2.28 (lH, dd, Jl = 3.2 Hz, J2 ~ 19.3 Hz, H4~), 1.88 (2H, m, -CH2- sugar), 1.80 (lH, tt, H4b), 1.49 (2H, m, -CH2- ite ch in), 1.15 (3H, t, J = 6.5 Hz, CH3 sugYr), 0.89 (3H, dt, Jl = J2 = 7.4 Hz, -CH3 idc ch in).
StepS: (l'S, lR,3R)-S,10 ~- 3-ethyl-1-(2',3',6'-trideoxy-3' t~ '` ~~~ ~nido-4'-O-p-~ .JI L 1~ ~' ,.,.~ ~) 3,4,5,10 1 ~ ' ~ lII ~ ~p~ - ~ 12,3-c1 P~
lS
The titled ~ . ' w~s obt~ined via Diels-~lder ,~. ' ~ ' ' ~i betwe~n 1 ~ nd the quinonc from step 4 from thi~ umple using thc 1~ 1 in step 4 f om e~-mple 26.
NMR lH (250 MHz) (CD2C12; ppm): 8.28 (4H, d, J 5 4.3 Hz, 9 ~ 8.05 (2H, m, ~
7.73 (2H, m, 9 '- )~ 6.31 (lH, d, N~, 5.87 (lH, 8, Hl), 5.67 (lH, 8, H4.), 5.42 (lH, 8, Hl.), 20 4.58 (lH, m, H3~), 4.42 (lH, q, J ~ 6.3 Hz, Hs~), 4.05 (lH, m, H3), 2.78 (lH, dd, Jl = 3.4 Hz, J2 c l9.S Hz, H4~, 2.24 (lH, dd, Jl ~ 11.3 Hz, J2 = 19.0 Hz, H4b), 2.05 (2H, m, -CH2- I;ugar), 1.70 (2H, m, -CH2- s~de ch in), 1.18 (3H, d, J = 6.5 Hz, -CH3 wg~r), 1.05 (3H, dd, Jl 5 J2 = 7.4 Hz, -CH3 sidc duin).
IR (film) (cm~l): 3332 (N~, 2955 nt 2929 (CH ~liphatic), 1740 (C=O), 1669 (C=C), 1529 (C-N), 2S 1279 nd 1180 (C-O).
StepC: (l'S, lR,3R)-S,10 ~- 3-ethyl-1-(2',3',C'-trideoxy-3'-i '' ~ '- ~
1~ ' ,., ) 3,4S,10 1 ~d ~ ~ 12,3-c1 py~ ~BCH-202C) Thc titled ~ ' wa6 in 64% yidd from the gl~ ' of step 5 of this e~cunple ~ per ~vccd~c d~ i~d in dcp S of e~c mple 26.
NMR lH (2S0 MHz) (CD2C12; ppm): 8.03 (2H, m, r, - )~ 7.71 (2H, m, ~ . ), 6.77 (lH, d, N~, 5.81 (lH, 8, Hl), 5.50 (lH, d, J 5 2.8 Hz, Hl.), 4.26 (lH, m, H3~), 4.22 (lH, m, Hs.), 4.05 (lH, m, H3), 3.58 (lH, d, J = 2.2 Hz, H4.), 2.76 (lH, tt, Jl = 3-5 Hz, J2 5 19-5 Hz, H4a)~ 2.21 3S (lH, ddt, Jl--0.9 Hz, J2 5 11.0 Hz, J3 = l9.S Hz, H4b), 2.07 (lH, 8~d), OH), 1.83 (2H, m, -C~I2 ~ ), 1.67 (2H, m, -CH2- side ch~in), 1.23 (3H, d, J--6.6 Hz, ~H3 sugar ), 1.02 (3H, dt, Jl 2 = 7-5 Hz, -CH3 side ch in).
SU~ST~TI~ S~EET
Step 7: (l'S, lS, 3S)-5)~ :'3-ethyl-1-(2',3',6'-trideo~y-3'-1~ q'~p-l~it~benz~yl-L 1~. -o.~ S,8 ' ~. ' .
S To a ~olution of (l'S, lS, 3S)~,S ~ -3 othyl-1{2',3',6' t~ 3'; ^ r ~ ~p-~ b .,I-L-I~ J ) (372 mg; 0.60 mmol) in ~ - h (12 ml) W~lfi adlded a fiolution of C~N prop~d by ' ~ e cenc n tr t4 (2.0 g; 3.6 mmol) In 6 ml of water ~nd then ~lowly ~dding ~olit sodium ~i ~ (S3 1 mg). The ' e mLsture w~s sti~t at 0C for 20 rainutes ~nd w~s then q ' ' with ' ~- ~olution. Thc product was _ ' with 10 d- ' ~ ' - nnt the ~ ' ' org~nic l-yers were w~het with brine u d dried over N 2S04 to give ~fter~,. . thecn~ itle ;-(360 mg; 100%): lH NMR (250 MHz; CDC13) 8: 1.02 (3H, t, J--7.5 Hz, CH2~E3), 1.29 (3H, d, J
= 6.5 Hz, H-6'), 1.65 (2H, m, CH2-CH3), 1.80-2.30 (3H, m, H-2' uld H 1 ~c), 2.60 (lH, dd, J--3.5 ~nd 19.5 Hz, H-4 eq), 3.89 (lH, m, H-3), 4.50-4.80 (2H, m, H-3' ~nd H-5'), 5.41 (lH, br ~, H-l') lS 5.55 (lH, br 6~ H-4'), 5.87 (lH, 8~ H-l), 6.58 (lH, br d, J = 7.5 Hz, NH), 6.75 uld 6.81 (2H, AB
d ' '- ArH), 8.28 (4H, br s, PNB).
Step 8: (l'S, lS, 3S)-S,10 ~- 3-ethyl-1-(2',3',6' h~ 3' h-~
~ Jl L 1~ ' r~ ~~) 3,4,S,10 ~ lII p' '' ~ ~2,3 ~] ~, Using the ~. c ' ., ' ' d in s~ep 4, e~umple 26, the st rting quinone from ~p 7 herein (330 mg;
0.57 ml) W~8 t~ted with l~coto~y-1,3 ~ ' - (379 111; 3.4 mmol) in 20 ml of tolu~c to ~fford ' . _ .' ~ the title; . ~ (165 mg; 46%).
lH NMR (250 MHz, CD2C12) ~: 1.03 (3H, d, J = 7.5 Hz, CH2~3), 1.30 (3H, d, J = 6.5 Hz, H-25 6'), 1.68 (2H, qn, J = 7.5 Hz, C~2-CH3), 1.95 (lH, m, H-2 eq), 2.12 (lH, td, J ~ 13 ~nd 3.5 Hz, H-2' ~), 2.29 (lH, dd, J e 11~5 ~d 19.5 Hz, H~ a~c), 2.76 (lH, dd, J = 3.5 ~d 19.5 Hz, H 4 eq), 3.97 (lH, m, H-3), 4.55 (lH, m, H-3'), 4.78 (lH, q, J--6.5 Hz, H-5'), 5.41 (lH, br 8, H-l'), S.57 (lH, d, J ~ 6.5 Hz, H~'), 6.01 (lH, ~, H-l), 6.51 (lH, br d, J = 7.5 Hz, -NE~, 7.75 t2H, m, ArlE~, 8.07 (2H, m, Ar-H), 8.27 (4H, ~, PNB).
step g: (l'S, lS, 3S)-5,10 :' 3~yl-1-(2',3',6'~ -3'~
1~ ' . ,. ~ ) 3,4,5,10 t ' ~ 12,3 ~] I J (BClE~-2020) The ~rting ~ lcohol from ~ep 8 hereil~ (20 mg; .032 mmol) w~ ted with ~odium ~ A~.
3S ill ' -' (4.37 M, 1 ~1) in 1 ml of tetrshydro~ ~nd .3 ml of n~nol ~ ~ ' g to tho p.~l~.;
;~d iD 8tep 5, ~mplc 26, ~ e ~ - . ,, "! r (15 9~ ~cetonc in be~ne) the title compou~d (11.5 mg, 75%), M.P. 208-211C.
IR (nalt): 3540, 3292, 2978, 1705, 1666, 1556, 1295, 1187, 1165 ~nd 9gO cm~l.
SU~STI ~ UT~ ~hEET
WO 94/1 1382 t 2 1 ~ 6 ~ 4 B PCI`/CA93/00463 lH NMR (250 MHz, CD2C12): 1.00 (3H, t, 1 = 7.S Hz, CH2-CH3), 1.35 (3H, d, J = 6.5 Hz, H-6'), 1.66 (2H, qn, J z 7.5 Hz, C~2-CH3), 1.80-2.20 (3H, m, H-2' snd ~H), 2.27 (lH, dd, J = 11.0 ~nd l9.S Hz, H~ as), 2.75 (lH, dd, J--3.5 nd 19.5 Hz, H-4 eq), 3.61 (lH, br 8, H-4'), 3.96 (lH, m, H-3), 4.25 (lH, m, H-3'), 4.58 (lH, q, J--6.S Hz, H-5'), 5.40 (lH, t, 1 = 2.0 Hz, H-l'), 5.97 (lH, s, H-l), 6.77 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 10: (l'S, lS, 3S)-S,10 ~- 3-dhyl-1-(2',3',6'-trideo~y-3' ~
- 3~4~S~10 ~ ~.~. lII p1 " ~ [~ c] r~ (BCH-2021) 10 To ~ 601ution of the d rting ~ ' from otep 9 herein (43 mg; 0.07 mmol) in ~ ' - (6 ml) w~ ~ddot d ~, .. .1 N sodium ~ AI~ (3 ml). T~e mi%ture W98 s~od t 0C
for 30 minutos ~d ~ e%tr 1 ml of oodium h~d ~.~ oolution w ~dded nd the rooulting mi%b~ w s stimd for 1 hour t 0C. It w o then ~ ' ' with .1 N HCI nd ~ ' with ~" ' ~ ' - The w~tor l-yer w~s ' ' to pH -7 by ddition of dilute sodium h~L~o~. It w~ then ~ ' with ' ' ' ~ ' - To the org nic o%tr~ct wcre dded 1.5 mt of .1 N HCI, 5 ml of ' nd 2S ml of ether ~nd the mi%ture w_s ~ lly in o~der to induce ~ Since no cryotsll occured, the oolvont~ wero c.~ ~d the rooidue w 6 ~ d in ' -' (1 ml) nd 200 ,ul of .1 N HCI wero ddod followed by 2S ml of other. A p.~ -, formed which w 8 filtered ~nd washed with other yidding the clude title c ' (3.8 mg; 13 ~i).
lH NMR (2S0 MHz, DMSO-D6), ~: 0.97 (3H, t, J = 7.0 Hz, CH2~3), 1.23 (3H, d, J = 6.S Hz, H-6'), 1.50-1.80 (3H, m, CH2-CH3 nd H-2' oq), 1.97 (lH, m, H-2' ~), 2.23 (lH, dd, J ~ 11.0 ~nd 19.5 Hz, H-4 al~), 2.72 (lH, dd, J ~ 3.0 ~nd 19.5 Hz, H 1 eq), 3.63 (lH, m, H-4'), 3.87 (lH, m, H-3), 4.33 (lH, m, H-5'), S.29 (lH, br 8, H-l'), 5.53 (lH, m, H-3'), 5.82 (lH, 8, H-l), 7.85 (2H, m, ~r-H), 8.05 (5H, m, Ar-H Jnd N-H).
SU BST~ ET
WO 94/11382 214 6 ~ 4 8 PCT/C~93/0~463 F p'e 28~ , of tn~ S,10 dioxo-l-~ '- 3-ethyl-3,4,5,10 t~
lII "' ' - 12,3 c] r~- ~ (BCH-2027) ~nd 3 ~ l 5,10-diox~3,4,5,10-i ' ~,' ~ lII ~" ~ 12,3 cl r~- ~ (BCH-2154) OCH~ O
OCH, NHCOCH,
The titled . ' were obt~inod ~ per 1,.. ~ ' ' in ~ 4, a~mple 17.
IH NMR (I)MSO): ~ 8.02 (m, 2H, ArH), 7.88 (m, 2H, ArH), 5.73 +5.71 (2s, lH, H-l), 4.68 (m, lH, H-3), 4.19-3.48 (m, 3H, H-2' ~nd H-l'), 3.10 (m, 2H, H-5'), 2.39 (dd, lH, H 4), 2.35 (m, lH, H-4), 2.32+2.31 (2s, 3H, COCH3), 2.10-1.55 (m, 4H, H-3' nd H-4').
15 r "~ of p~ [2,3-C1py~ g~osidecbain SUE5 ~ S~ET
WO 94~1 1382 21~ ~ 54 8 PCT/CA93/00463 ~ O o~ ~
W' I ¢¢,502Ph= ~,CN
0!~ Ob~ ~
O OMe ~N ~,CN
O OH OMII OH
\~, o ~N
O O
r.4~t PNBo NH~A
~CN
O O
H3~J
RO NHIFA
7 ~R-PN
B~16~
Step 1 5,8-dim~hox~-3 ~ ,~lsulphone L _ , S To ~ otirred ooluticn of 5,8 ~-3~ceto ' (12 8 g, S4 mmol) in ~' - chloride (350 ml) ~t room I - .; w o u~ded 3 ' - , L cid 80% (18 g, 83 mmol) in portion~ over 15 minutcs ~ftes 2 hou~, oulf te (6 8 g, 56 mmol) uld oulf~nic cid (10 g, 70 mmol) were dded ~r 2 hou~, ~ ~ d oolutioll of ~ - w~ sdded the l the re~lctios~ ~re wYo w~shed with w~ nd brine. Thc org~mic l~yer w~ dried over MgSO4 nd c., ' The titled -~ . ' wu~ purifiod by I in ether (11 g, 60%), m.p.: 118-119C.
lH N~ (250 MHz, C6D6), o: 7.99 (dd, J ~ 1.5 uld 8.0 Hz, 2H, Ar-H), 6.90 (m, 3H, Ar-H), 6.29 (2d, J ~ 8.9 Hz, 2H, Ar-H), S.08 (d, J ~ 15.5 Hz, lH, H-l), 4.53 (d, J = 15.5 Hz, lH, H-l), 4.40 (dd, J = 4.7 rnd 9.2 Hz, lH, H-3), 3.40 (dd, J ~ 4.7 uld 17.0 Hz, lH, H-4), 3.28 (s, 3H, ~CH3), 3.27 (dd, 9.2 Jnd 17.0 Hz, lH, H-4), 3.19 (6, 3H, ~CH3).
SUE~S I ~Tr S`i 3~ET
2146~48 ~
Step 2~ 3-cy~
To ~ stirred solution of ~IC13 (1.39 g, 10.4 rnmol) ~nd TMS-CN (1.4 rnl, 10.4 mmol) in CH2C12 (40 ml) at -78C under rgon W IB dded the ~ r ~ f~om step 1 (aumple 2) (1.16 g, 3.5 mmol) then 5 the j A o WI~B dowly r i~et to -20C. AP.er 4 hours, the rc~ction rnLs~ro w~s worlced up in - ~ - chloridc ~t w~ter. The orgu~ic l-y w 8 w~shed with brine nd dried over MgSO4. The sOIVerlt WIIB C. . ' ~ ult the rositue w a p~nfiot by fl~h ' ~ tAcOEt 3tl) to give ~hc titlod c . ~ (596 mg, 7896).
lH NMR (250 MHz, CDC13), o: 6.30 (2d, J ~ 8.2 Hz, 2H, Ar-H), 5.08 (d, J ~ 16.3 IIz, lH, H-l), 10 4.78 (d, J = 16.3 Hz, lH, H-l), 4.03 (t, J = 5.1 Hz, lH, H-3), 3.27 (B, 3H, -OCH3), 3.18 (s, 3H, -OCH3), 2.80 (td, J--5.1 nd 17.2 Hz, lH, H-4), 2.66 (td, J - 5.1 nd 17.2 Hz, lH, H-4).
step 3~ -3~
To stirred solution of 2,5 " ' ~-3-cy~ ' . (670 mg, 3.06 mmol) in CC14 (60 rnl) were 15 ~ddet N ~.~ ' (653 mg, 3.67 mmol) nd ~ c t lytic mount of AIBN. The mi~ue w~s he~ted to reflu~ d fbr 45 minutes, thc solvcnt w~ .,. . ' nd l ~ (40 ml) ~nd w~ter (40 ml) we~O ~ted. ~*er 1 hour, tho r~ction mLlcture W 8 worlced up in Other. The org~nic l~yer w~s w~shed with brine nd dried over MgS04. The solvent w~ c._. ' nd the re6idue purified by I ' " il~ ~ 8mdl mount of other to give the titled _ . . ' (453 mg, 63 %).
20 lH NMR (250 MHz, cotone D6): 6.90 (2d, J ~ 9.0 Hz, 2H, Ar-H), 6.06 (2d, J 8 5.2 Hz, 2H, H-l, -OH), 5.27 (dd, J ; 4.1 ~nd 12.1 Hz, lH, H-3), 3.81 (8, 3H, {~CH3), 3.78 (s, 3H, ~CH3), 3.09 (dd, J
= 4.1 nd 17.1 Hz, lH, H-4), 2.82 (dt, J = 12.1 Dd 17.1 Hz, lH, H-4).
St~p 4: 1 ~ -3 c/ ~ 5t~ ', d . ' 2~
The titled ~ . ' w~ obt ined in 77 % yield by ~pplying the ,~ d ~ d in 8tep 3, e~c~ple 12, to the ~ _ of step 3 of thi~i - . '-lH NMR (250 MHz, ~cetone D6) o: 6.86 (2d, J ~ 10.1 Hz, 2H, -CH--CH-), 6.61 (d, J ~ 5.7 Hz, lH, H-l), S.88 (d, J ~ 5.7 Hz, lH, -OH), 5.20 (dd, J ~ 3.8 nd 11.6 Hz, lH, H-3), 2.98 (dd, J = 3.8 nd 30 18.9 Hz, lH, H~), 2.73 (dd, J ~ 11.6 nd 18.9 Hz, lH, H 4).
Step 5 ~nd 6: (l'S, lS, 3R) uld (l'S, lR, 3S)-S,10-dioxo-3~wl-(2',3',6',-~rideox~-3'-1. '` ~ru '~ q'-O ~ ~L 11 1, 1~ ' , ,. ` 3,4,S,10-tet~ ' ' q ~2,3-c] pyrsn The titled s . ' wOre obhined in 27 % yield by fi~ . . g the ~ d i~ 4, e~mple 12, on the proalrsor of step 4 of ~is e~umple.
lH NMR (2S0 MHz, CD2C12) o: 8.30 (m, 4H, Ar-H), 8.10 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H), 6.55 (m, lH, -NH), 6.15 ~nd 5.95 (2~, lH, H-l), 5.70 (m, lH, H-4'), 5.60 nd S.SS (m, lH, H-l'), 5.10 (m, SUBSTi I ~ ~ L~ ~5~ET
WO 94/11382 PCI~/CA93/00463 21~6~.4~
lH, H-3), 4.704.20 (m, 2H, H-3', H-S'), 3.25-2.80 (m, 2H, H~), 2.40-2.00 (m, 2H, H-2'), 1.30 ~nd 1.20 (2d, J = 6.7 Hz, 3H, H-6').
Step 7: (l'-S, l-R, 3-S) u~d (l'-S, l-S, 3-R)-3~}1-[2',3',C'~rideox~r-3'-S I " . - ' '- ~' ',d . ~-L l~ ,. ~ ) S,10 d 3,4,S,l~
~ ~ P' ' - 12,3-C] p~n-3-yl BC~-1688 Thc titled ~ . ' were obt ined in 63 % yidd by f~llo.. e the ~ ' ' - ' in 8bp 3, e~le S, on the ~I. f~om 8tep 6 of thi8 ' j~-10 lH NMR (2S0 MHz, CD2C12) ~: 8.07 (m, 2H, Ar-H), 7.79 (m, 2H, Ar-H), 6.80 (m, lH, N-H), 6.09 snd 5.92 (2~, lH, H-l), S.52 nd S.42 (2d, lH, H-l'), S.Q4 (lm, lH, H-3), 4.40-4.05 (m, 2H, H-3', H-S'), 3.70 (m, lH, H-4'), 3.20-3.0~ (lm, lH, H~), 3.0~2.80 (lm, lH, H-4), 2.30-2.00 (m, 3H, ~H, H-2'), 1.38 ~nd 1.29 (2d, J--6.7 Hz, 3H, H-6').
SLIBS~T~TE ~ ET
2 ~
F ,)'-21: ~., ~ew~g~d OH ~OM~ O~ ~ OH
OH _ O~k _ OH
M~ Mc ~k Mc ~
-TBDMSO/~",~NHIFA 3 TBDMSO~"~NH'IF~.
~OH O
Me TBDI~ O~",~
r~
S Step 1 3,4 ' ~ fua~ nd 3 ' ~ fucal To a stimd solution of L-fucsl (400 ny~, 3 1 mmol) in ' ~'~ ' (7 5 ml) were dded mdhyl iodidc (0 85 ml, 3 6 mmol) uld ~ilv o~cide (1 16 g, 5 0 mmol) ~Per 1 5 hour, ~he re~ction mLl~ture w~s worlcod up in CH2C12 and w~ter The org~ic l-yer w~s w~hed with brine and driod over MgSO4 10 The fiolvent wul ~ , ' The p~duct~ werc , by fl sh c' ~ -/AcOEt 2/1) to give ' ' ~ fuc l (79 mg, 1696) lH NMR (250 MHz, CDC13) ~i 6 29 (dd, J = 1 3 and 6 2 Hz, lH, H-l), 4 72 (m, lH, H-2), 4 05 (m, 2H, H-5, H-4), 3 57 (~, 3H, -OCH3), 3 44 (m, lH, H-3), 3 39 (8, 3H, -OCH3), 1 31 (d, J ~ 6 6 Hz, 3H, H-6) 15 The 3 ' ~-L-fucal (20X yield) h~d lH NMR (250 MHz, CDC13) o 6 36 (dd, J = 1 2 nd 6 2 Hz, lH, H-l), 4 60 (m, lH, H-2), 4 05-3 80 (m, 3H, H-3, HJI, H-5), 3 40 (8, 3H, -OCH3), 2 37 (d, J = 3 9 Hz, lH, -OH), 1 36 (d, J = 6 6 Hz, 3H, H~) 20 Step 2 3 ' ~mesyl-I,~
Me~yl~tion of 3-metho~y-L-fi~l yielded (84%) of the titled ~ , SU~ 5~ E~T
~O 94/11382 ~ 9 PCT/CA93/00463 lH NMR (250 MHz, CDC13) o: 6.34 (dd, J = 2.1 ~nd 6.5 Hz, lH, H-l), 4.95 (m, lH, H-2), 4.73 ~m, lH, H~), 4.13 (m, 2H, H-3, H-5), 3.45 (s, 3H, -OCH3), 3.15 (s, 3H, -SO2CH3), 1.40 (d, J--6.6 Hz, 3H, H-6).
S Step 3~ Bubl d- ~ -3-L-~ ~ u ~ q ' 'f~ ,1 2,3,~hideoxy-Ll~ ' .,.
To ~ stirred solution of l-t-butyl ~ YIOAY~ 3: r ~, ~ ~ `1 ' ~ 2,3,6 t.id~A~ -L--r~ ~~ (504 mg, 1.41 mmol) in CH2C12 (7 rnl) ~t 0C wcre ddcd - r ,~1 chlonde 10 (218 111, 2.82 mmol) ~nd L.i~' - (590 ~11, 4.2 mmol). AP~r 2 1~ the ro~ction miAtutc was worlcod up with CH2C12 ~nd HCI 0.1 N. Tho org~nic l~ycr W~8 w shed with ~olution of N~HCO3 nd brinc then dried over MgSO4. The ~olvctlt w~ c . . ' to give l-t-butyl dimethyl silyloAy, 3-I r~ 2,3,6 tridcoAy 4 ~1 L--l~i~oh_Au~,~ (604 mg, 989~).
lH NMR (250 MHz, CDC13) ~: 7.28 (d, J = 7.7 Hz, lH, N-H), 4.83 (dd, J = 2.1 ~nd 9.1 Hz, lH, H-15 1), 4.71 (d, J = 2.2 Hz, lH, H-4), 4.25 (m, lH, H-3), 3.75 (q, J ~ 6.4 Hz, lH, H-5), 3.18 (s, 3H, -SO2-CH3), 2.0 (m, lH, H-2), 1.75 (m, lH, H-2~, 1.31 (d, J = 6.4 Hz, 3H, H-6), 0.89 (s, 9H, -C(CH3)3), 0.12 nd 0.11 (28, 6H, -Si(CH3)2).
Step 4~ Bubl diltlethylsilylo~y--3~ q O ~ 1--2,3,6--trideo~y--201~ ' >~, To ~ stirrod solution of 1 t-butyl d ~- IYIOAY-3 r~ 2,3,6 tl;de~,A~-L-(81 mg, 0.18 mmol) in CH2C12 (2 ml) t 0C were dded collidine (47 IJl, 0.36 mmol), uld ~.. - .~yI~.~ ' (24 ~1, 0.27 mmol). ~fter 1 hour, the ro~¢tion miAture ws~ worlced up 25 with CH2C12 nd w~ter. The org nic l~yor w~s w~hod with b~ine ~nd driod over MgS04. The solvent w 8 c. . - ' to give the titled _ . ' (76 mg, 745~).
lH NMR (W MHz, CDC13) ~: 6.47 (d, J ~ 8 Hz, lH, N-H), 5.03 (d, J = 3.0 Hz, lH, H-4), 4.84 (dd, J = 2.3 nd 9.0 Hz, lH, H-l), 4.35 (m, lH, H-3), 4.00 ~nd 3.80 (2d, J = 10.5 Hz, 2H, -CH2-Br), 3.75 (dq, J = 1 Hz, 6.5 Hz, lH, H-5), 2.05-1.70 (m, 2H, H-2), 1.20 (d, J ~ 6.5, 3H, -H6), 0.9 (s, 9H, 30C(CH3)3), 0.13 (28, 6H, -si(CH3)2) r p~( 22~ . of f~w p~ 2~3~1 p~n ~ ;. .
-SUB~Ti 3 ~ S;'~ ET
2 1 ~
M,~A o O
O
N,C~ H,~
O O
BCH-2105 ~,~
O O
H~J
O OMe BCE{-20n Step 1: (l'-S, l-S, 3-R) ~nd (l'-S, l-R, 3-S) b;~ 2',3',4',6' 1 ' ~-3'-q'-O ' ~ 1 L 1~ ' ~., ) S,10 d-3,4,S,10 i ~yd . p! ' ~ 12,3-c1 pyrsn-3-yl) ketoneBCH-20~S
Thc titlcd . , ' w~ obt-inod in 45~i yield by using thc ~,.. ' _ ;' ' d in step 2 of this acunple but with the sugllr obtsined f~om step 3, e~cunple 21. It W~6 purified by fhsh ~ ~ ~ . ' .y ~ ' ~ ~ 95/S).
lH NMR (250 MHz, CDC13) o: 8.10 (m, 2H, ~r-H), 7.80 (m, 2H, Ar-H), 7.1S (2d, J--8.0 Hz, lH, N-H), 6.16 And 6.00 (28, lH, H-l), 5.62 nd S.S0 (2d, J = l.S Hz, lH, H-l'), 4.89 uld 4.84 (2 brwd ~, lH, H-4'), 4.75 nd 4.25 (2q, J 5 6.6 Hz, H-S'), 4.50 (m, 2H, H-3, H-3'), 3.23 ~d 3.21 (2s, 3H, ~O2CH3), 3.10 (m, lH, H~), 2.55 (m, lH, H~), 2.33 snd 2.32 (2s, 3H, -CO-CH3), 2.00 (m, 2!H, H-15 2'), 1.45 ~nd 1.30 (2d, J = 6.6 EIz, H-6').
Step 2~ S, l-S, 3-R) 1~1 (1-12',3',4',6' tetradeoxy-3'-trifluoroacetsmido-4'~(2-~ ~ '~yl)--L--I~ r ~ - ~] 5, 10 d 3,4,5,10 ~ 2,3~]
pyrlm-3-yl) Ic~one BCH-2105 Sll~r~T~lT~ ~H~ET
~0 94/11382 PCT/CA93/00463 2 ~ 4~
To a stirrod solution of the aglycone from c~ample 3 (30 mg, 0.11 mmol), q ~ t~l-l-t-butyl ' yl~:lylo~cy 3 ~ .m ~ t~ (76 mg, 0.13 mmol) '- ' sievcs A
(62 mg) in CH2C12 (1.2 ml) at -50C under argon was dded; ' .~ lyl I '' ~ ' - '' (23 S 111, 0.12 mmol). Aftcr 2 hours at -30C, the rction mi~cture w~ worltod up with ~ solution of N~HCO3 10% nd CH2C12. Thc orgsIuc layer w~s washed with brinc and dried ovcr MgSO4, the rcsiduc w~s purified by flash ~ AcOEt 2:1) to give thc titlcd t . _ ' (8 mg, 1296).
lH NMR (250 MHz, CDCl3) ~: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, ~r-H), 6.33 (d, J z 8.1 Hz, lH, N-H), 6.00 (s, lH, H-l), 5.67 (8, lH, H-l'), 5.16 (s, lH, H-4'), 4.53 (dd, J = 3.9 and 11.6 Hz, lH, 10 H-3), 4.53 (m, lH, H-3'), 4.23 (q, J 6.7 Hz, lH, H-5'), 3.90 (2d, J ~ 10.9 Hz, 2H, -CH2-Br), 3.08 (dd, J 3.9 nd 19.8 Hz, lH, H-4), 2.S3 (dd, J = 11.6 uld 19.8 Hz, lH, H-4), 2.34 (8, 3H, -C~
CH3), 2.02 (m, 2H, H-2'), 1.19 (d, J ~ 6.7 Hz, 3H, H-6').
Step3: (l'-S, l-R,30 ' ~ 2',3',4',6' i ' .~-3' - ~-4'~
lS meth~ulfon~l-L 1~ ~' , / ~ ~) S,10 :' 3,4,S,10 tel~ D' " Q 12,3-cl p~n-3~ etone BCH-2070 The titled -.~ . ' wJIs obtsined in 22% yidd by pplying the ~ ' ill step 4, e~c mple 12, to the yl~ - from e~mple 3 nd the glycsl f~m step 2, e~mple 21. ~ ; WY8 csrried out 20 by fl~;h; ' ~ g5/5) M.P. 85-89C.
lH NMR (250 MHz, CDC13) ~: 8.11 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 5.98 (8, lH, H-l), 5.62 (d, J = 2.8 Hz, lH, H-l'), 4.85 (8, lH, H-4'), 4.46 (dd, J--4.0 ~nd 11.6 Hz, lH, H-3), 4.04 (q, J = 6.5 Hz, lH, H-5'), 3.62 (m, lH, H-3'), 3.39 (1~, 3H, -OCH3), 3.14 (s, 3H, ~2 CH3), 3.05 (dd, J ~ 4.0 ~nd 19.5 Hz, lH, H-4), 2.50 (dd, J ~ 11.6 nd 19.5 Hz, lH, H-4), 2.33 (8, 3H, -C~CH3), 2.00 (m, 25 2H, H-2'), 1.33 (t, J ~ 6.5 Hz, 3H, H-6').
Step 3 (Cont'd)~ S, 1'S, 3-R) ~ ' Jl (1-12',3',4',6' 1 ~ ~-3' ' ~-4'-O ' Ifonyl-L l~ ) S,10 ~-3,4,S,10 1 ~.' . ' ' ~ 12,3-c] py~n-3-yl) Icetone BCH-The titled . . ' w~ o1~t inod in 11 % yidd by u6iug the ~,.. _ t ' - ~ in xtep 3 of thiæ
mple but using the 1,3 ~ - M.P. 139-141C.
lH NMR (250 MHz, CDC13) ~: 8.12 (m, 2H, ~r-H), 7.77 (m, 2H, ~r-H), 6.15 (s, lH, H-l), 5.52 (d, 35 J = 1.5 Hz, lH, H-l'), 4.95 (d, J c 1.5 Hz, lH, H-4'), 4.59 (q, J c 6.5 Hz, lH, H-S'), 4.49 (dd, J =
4.1 ~nd 11.6 Hz, lH, H-3), 3.60 (m, lH, H-3'), 3.38 (s, 3H, -S02CH3), 3.15 (6, 3H, -OCH3), 3.07 (dd, J--4.1 ~nd 19.9 Hz, lH, H-4), 2.55 (dd, J = 11.6 uld 19.9 Hz, lH, H-4), 2.33 (6, 3H, -CO CH3), 1.95 (m, 2H, H-2'), 1.50 (d, J ~ 6.5 Hz, 3H, H-6').
SUES~ 5.~E~T
WO 94/11382 ~ 1 4 ~ 5 4 ~ PCI /CA93/00463 Step 4~ S, 3 R) nd (l-R, 3-S) b~ )-5,10-dioxo-3,4,S,10 i byd ~ ~p~ 2,3~1 p~rran.3-yl) ~etone BCH-2096 To ~tirred solution of the ~ . - from cDple 3 (7 mg, 0.026 mmol) in I ' ~ (1.6 ml) were ddedS,6 ;"' ,.' ~ 2H-py~n (29 ~1, .26 mmol) and~c t lytic lountofPISA. After 4 hou~i, the re~ction W~16 W011COd Up with CH2C12 Jnd NsHCO3 5 !~i . T~e orgsnic l~yer w~ w~hed with brine ~nd dried over MgSO4. The ~olvent W~8 _. . ~ ' to give the titlod . I (10 mg, 9696).
lH NMR (250 MHz, CDC13) 8: 8.10 (m, 2H, Ar-H), 7.70 (m, 2H, Ar-H), 6.34 (6, lH, H-l), 4.66 (dd, J--4.3 s~d 11.6 Hz, lH, H-3), 3.8~3.50 (m, 4H, -CH2~CH~), 3.40 (~, 3H, -OCH3), 3.06 (dd, J = 4.3 ~nd 19.7 Hz, lH, H-4), 2.S2 (dd, J = 11.6 nd 19.0 Hz, lH, H-4), 2.30 (~, 3H, -CO-CH3), 2.20-1.85 (m, 4H, CH2-C-CH2-).
SUB~TfTU~ SI~T
WO 94~11382 PCT/CA93/00463 21~
F. p' 23: ~. of , ~ 12,3.~] P~ ~ wlth ~ no methyl l~etone side ch~in OMc OMe CO2tBu 01 ¢~02Ph ~/ 2, ¢~
0~4 0~ OMC
~3 OMG
~, OM~ O
~ PNBO~
1~
o o ~b~
o o H,~
RO NH~A
R-PN
sc~.20s8 s Step l: S~8-n '' /-3-(t-bobl ~
To ~ ~od solutiolt of I~J r from s~ep 1, e~cJmple 20, (1.12 g, 3.35 mmol) in CH2C12 (40 ml) Dt -78C wore ddod ~ oolution of silyl enol ether of t-butyl 9- (10 mmol) in CH2C12 (10 ml) 10 Dnd AlC13 (1.33 g, 10 mmol). T: , .; w~s theD nusod to -30C for 2 hours. The re~ction mi~cture W~8 worlcod up with CH2C12 uld HCI 0.1 N. The org~mic W~8 w~&hod with brinc ~nd dried over MgSO4. The solvent w~s c., ' to give the titlc ~- - (519 mg, 43 %).
H NMR (250 MHz, CDC13), o: 6.63 (m, 2H, Ar-H), 4.91 uld 4.85 (2d, J--9.8 Hz, lH, H-l), 4.60 ~nd 4.53 (2d, J ~ 7.9 Hz, lH, H-l), 4.20 (m, lH, H-3), 3.76-3.74 (3s, 6H, OCH3), 3.62 (t, J = 9.5 SUBST~TLJT~ ~37E~T
Hz, lH), 2.90 (m, lH, H-4), 2.45 (m, lH, H-4), 2.32 uld 2.28 (2s, 3H, -C~CH3), 1.49 ~nd 1.47 (2s, 9H, -C(CH3)3) -step 2: 5,8-n t~ ~-3-(~... r --2 The product f~om step 1 of thio c~ple W~ J, in 91% yidd, with ~ ' ~qu~ous HBr in cetone.
lH NMR (250 MHz, CDC13) ~: 6.63 (2d, J = 9.0 Hz, 2H, Ar-H), 4.88 (d, J = lS.9 Hz, lH, H-4), 4.58 (d, J = lS.9 Hz, lH, H~), 4.06 (m, lH, H-3), 3.77 nd 3.75 (26, 6H, -OCH3), 2.85 (m, 2H, -10 CH2-C~), 2.63 (dd, J = 4.8 nd 16.5 Hz, lH, H-4), 2.40 (dd, J = 10.9 nd 16.5 Hz, lH, H-4), 2.24 (s, 3H, -CO CH3).
Step 3: S,8 1~ 3-( ., - 2 1 o~) 1-(2',3',6'-trideo~y-3'-L-~ . - ' 1'~
~ ~I L 1~ ~' ,.,. ) lS
Thc: ' ,from 2 hcrcin w~ ~ s pcr ~,~1~ A- ~ ih~d in step 3, c~mple 34. The title . ~ w~s obt ined in 97 % yield.
lH NMR (250 MHz, CDC13) o: 8.26 (d, J--2.0 Hz, 4H, ~r-H), 6.74 (m, 2H, Ar-H), 6.50 ~d 6.35 (2d, J ~ 7.0 Hz, lH, -NH), 6.02 nd 5.88 (2s, lH, H-l), 5.59 (8, lH, H-l'), 5.49 ~nd 5.46 (2s, lH, H-20 4'), 4.70 (m, 2H, H-3', H-3), 3.80 nd 3.78 (28, 6H, ~I3), 3.00 2.50 (m, 2H, H-4, {~H2~), 2.S0-2.00 (m, 2H, H-4, -CH2-C~), 2.24 nd 2.22 (2s, 3H, -CO CH3), 1.25 Jnd l.lS (2d, J = 6.5 Hz, 3H, H-6').
Step4: S,8-Dioxo-3-(1..~ ~ 2 ~) 1-(2',3',6'-trideoxy-3'~'~ ~ ' 1'~p-~ 1 Jl L 1~
The titl~d , ' w~s obt~ined ill 9496 yield vi~ ' of the I~L~ obt~ined from step 3 herein ~ per p t ~ d in step 4, e~mple 34.
lH NMR (250 MHz, Cl~C13), ~: 8.30 (d, J--5.7 Hz, 4H, ArH), 6.80 (m, 2H, ~r-H), 6.42 and 6.35 30 (2d, J = 7.0 Hz, lH, N-H), 5.81 nd 5.70 (2s, lH, H-l), S.S9 snd 5.54 (2s, lH, H-l'), 5.45 (2d, J =
1.5 Hz, lH, H-4'), 4.8~4.40 (m, 3H, H-3', H-S', H-3), 2.90 (m, lH, H-4), 2.70 (m, 2H, -CH2{~0), 2.40-1.90 (m, 3H, H-4, H-2'), 2.23 ~nd 2.21 (2s, 3H, -CO-CH3), 1.28 ~nd l. lS (2d, J = 6.5 Hz, 3H, H-6~).
3SSt~*5: S,10-Dioxo-3~ , 2 . o.` 1-(2',3',6' ' ~-3'~ '' w ~'~ ~'~
`~' .11 L 1~ t . ~ - -,) 3,4,S,10 1 ' bJ d ~ ~II p' '' ~ 12,3-c] pyran The titled . ' was obt~ ined vi~ c~ ' ' bdween 1 - ~: ' ~ and the quinone from s~ 4 herein by following the ~ d~ . iI fd in step S, e~ample 34.
S U ~ ET
WO 94/11382 2 ~ 8 PCT/CA93/OW63 lH NMR (250 MHz, CDC13), S: 8.31 (2d, 1 = 9.1 Hz, 4H, Ar-H), 8.11 (m, 2H, Ar-H), 7.78 (m, 2H, Ar-H), 6.45 ~nd 6.33 (2d, J = 7.3, lH, N-H), S.99 ~nd 5.88 (2s, lH, H-l), 5.71 ~nd 5.60 (2s, lH, H-1'), 5.48 (18, lH, H-4'), 4.80-4.40 (m, 3H, H-3, H-3', H-4'), 3.00-2.60 (m, 3H, H-4, -CH2-CO-), 2.50-2.00 (m, 3H, H-4, H-2'), 2.25 uld 2.23 (28, 3H, -CO-CH3), 1.33 ~nd 1.17 (2t, J = 6.5 Hz, 3H, S H-6').
.
Step 6: (l'-S, l-S, 3-R) ~nd (l'-S, l-R, 3~-1~6 ' ,. my-1-(2',3',C'-trideox~-3'-h ~ . r '~,4 ' Jd ~ ,~-L 1~ 10 3,4,5,10 ~. . lp! D [2,3-cl pyrsn-3-yl) 1 . . ~ 2 - r BCH-2098 The titlot ~ s obbinod fi~llo.. g d~.. l~l t of tho ~1~ ' from step 5 horein ~8 per step 6, e%~mplo 34.
lH NMR (250 MHz, CDC13) o: 8.10 (m, 2H, ~r-H), 7.75 (m, 2H, ~r-H), 6.73 (t, J = 7.5 Hz, lH, N-H), S.93 nd 5.81 (28, lH, H-l), 5.52 ~nd S.41 (2d, J = 2.7 Hz, lH, H-l'), 4.80-4.20 (m, 3H, H-3, 15 H-3', H-S'), 3.70 (m, lH, H-4'), 3.00-2.60 (m, 3H, H-4, {~H2-CO-), 2.40-1.70 (m, 4H, H-4, H-2', -OH), 2.23 uld 2.20 (28, 3H, ~CH3), 1.41 nd 1.20 (2d, J ~ 6.6 Hz, 3H, H-6').
mple24: .,~ !- of n "! - 12,3-c]py~nd ;. .. with~C-2'gl~
linl~ge S~BS~TUTE SHE~
WO 94/11382 ~ 8 PCI`/CA93/00463 ~ 1~ + ~
Oh~ OH Ol~ N~A Ob~,~,~ NH~.'-O~"OPNB O~"OPNB
Me ~
~ ~Q
~NHIFA O ~
O~ OPNB O~OPNB
o OO
0~40R O~OR
~ Mc CR~H ~ CR H
BC~21~ BC~2145 Step 1:(lR,3S) ~nd (1-S,3R)-1-(2',3',6' ~ -3'-~-~ . - ' ' 1'~p-~ .,lo~-l,~ L 1~ -5~8 ' ~o~y-3-S ~ ~ ~
2,5-r) ~-1 h~d~uA~-3 ~ ~ ws~ ctotwith l,~di~ ~ - k ............. ~ t d-u - - s pcr ~ firom sbqp 1, c~-mple S. Ihc ~od prDdw~ were , ~ by flbsh _ , ~ (C~H2C~2~cokDne 99tl).
IH NMR (250 ME~ CDC13) ~: 8.30 (m,3H, ~-H, N-H),8.09 (d, J - 8.7 Hz,2H, A~-H),6.71 (2d, J ~ 8.8 H~ 2H, A~-H),6.02 (8, lH, H-1'),5.84 ~d, J = 3.6 H~ lH, H-4'),5.62 (~, lH, H-1),5.30 (m, lH, H-3'),4.45 (m,2H, H-3, H-5'),3.81 (ls,3H, ~DCH3),3.76 (ls,3H, ~CH3),3.11 (dd, J ~
3.9 EIz ~nd 17.3 H~ lH, H-4),2.61 (dd, J = 12.1 snd 17.3 EIz, lH, H-4),1.95 (s,3H, -COCH3),1.28 (d, J 6.6 E~ 3H, H-6').
lS ~c ~ocond " hsd:
SU~5T; ~ S~E~T
WQ 94/11382 2 1~ PCIJCA93/00463 lH NMR (W MHz, CDC13) ~: 8.28 (2d, J = 9.0 Hz, 4H, ~r-H), 6.90 (d, J = 7.8 Hz, lH, N-H), 6.70 (2d, J ~ 9.0 Hz, 2H, ~-H), 6.18 (d, J = I.S Hz, lH, H-l'), 5.75 (d, J = 4.8 Hz, lH, H~'), 5.55 (s, lH, H-l), 5.30 (m, lH, H-3'), 4.30 (m, 2H, H-S', H-4), 3.80 (s, 3H, ~CH3), 3.60 (s, 3H, -OCH3), 3.02 (dd, J = 4.3 ~nd 17.6 Hz, lH, H-4), 2.57 (dd, J = 11.6 ~nd 17.6 Hz, lH, H~S), 2.29 (s, 5 3H, -CO CH3), 1.29 (d, J--6.6 Hz, 3H, H-6').
Step 2: (lR, 3S) 1--(2 ,3 ,~ 3 '~ JA~ 5 dih~dro-L 1~ - ~ ~ 2~ ,P ' :1 ~
10 The (lR, 3S) product from step 1 horein w~, ~ d u por ~ in step 3, c~mple 12.
lH NMR (250 MHz, CDC13) ~: 8.23 (d, J ~ 8.7 Hz, 2H, ~r-H), 8.03 (d, J ~ 8.7 Hz, 2H, Ar-H), 7.65 (d, J--6.6 Hz, lH, N-H), 6.75 (2d, J = 10.3 Hz, 2H, ~-H), 6.28 (d, J = 1.4 Hz, lH, H-l), 5.78 (d, J--3.8 Hz, lH, H-4'), 5.37 (s, lH, H-l'), 5.21 (m, lH, H-3'), 4.43 (q, J ~ 6.5 Hz, lH, H-lS S'), 4.24 (dd, J 3.8 ~d 11.2 Hz, lH, H-3), 2.90 (dd, J ~ 3.8 ~nd 19.5 Hz, lH, H-4), 2.40 (ddd, J
1.6, 11.2 ~d 19.S Hz, lH, H-4), 1.88 (s, 3H, -COCH3), 1.26 (d, J 6.5 Hz, 3H, H-6').
St43 (1R~3S)-1-12~3~6~ ;deO~3~ L ~ q~ 5-. L 1~ ' ~,. ~ 2 ,Ir1)-5,10 ~- 3,4,S,10 1 ' ~ ~ lEI-naphtho 12,3-c] p~
Thequiwnc*~m d~p2he~cinw~c~- '' d with 1 ~ ' from st~p 4, c~mplc12. T~c product h~d:
H NMR(250 MHz,CDC13)8: 8.30 (d, J ~ 8.7 Hz,2H,Ar-H), 8.10 (m, 4H,Ar-H), 7.80 (m, 2H, ~r-H),6.36 (d, J--1.9Hz,lH,H-1),5.86 (d, J~ 3.9Hz,lH, H-4'), 5.60 (8, lH, H-l'), 5.31(m, 2S lH, H-3'),4.49(q, J 6.6 Hz, lH, H-S'), 4.35 (dd, J = 3.9Hz,uld11.4Hz, lH, H-3),3.12 (dd, J
--3.9HzJnd 19.4 Hz, lH, H-4), 2.62 (ddd, J 1.9, 11.4 Hz, 19.4Hz, lH, H-4), 1.98 (6, 3H,-C~
CH3),1.31 (d, J ~ 6.6 Hz, 3H,H-6').
S~p4: (~3~-1-(2',3',C'~ -3'l~ ~ ' ' q'b~.'. ~-1,' ',.'~1, 30l~ ' .J. - 2~V-5,10~- 3,4,S,10~ L~ p~ 2,3~1p~n EK~H-2144 The tricyclic product from step 3hereinw 8 d r~ 8 per IJ ~ i from step 3,e~mpleS. The title product h~d:
3S lH NMR(250 MHz,CDC13)~: 8.20 (m, 2H,~r-H),7.75(m,3H,N-H,~r-H),6.25 (d, J--1.7Hz, lH,H-l),S.SS (8, lH,H-l'),S.ll (m, lH,H-3'),4.32 (dd, J = 4.0 Hzuld 11.1 Hz,lH,H-3),4.23 (q, J = 6.5 Hz,lH,H-5'),4.05 (d, J--3.7 Hz, lH,H~'),3.00 (dd, J--4.0 ~nd 19.8 Hz,lH,H 1), 2.59 (ddd, J = 1.7,ll.lJnd 19.8 Hz,lH, H-4), 2.28 (8, 3H,-CO-CH3), 1.70 (b~d ~, lH,-OH), 1.34 (d, J--6.5 Hz,3H,H-6').
SUBSlri ~ ~EE~
21~8~8 Step S: (lS, 3R)-1-(2',3',6' 3 ~-3' ~ 3 ~'-O p o~ h".~-1,5-L 1~ ~ " 2-~ ,P 1 chrom~n S The (lS, 3R) product ftom ~p 1 horein w~ . ' .~ d ~ per ~ In step 3, c~mplc 12.
lH NMR (250 MHz, C~DC13) ~: 8.32 (d, J ~ 9.0 Hz, 2H, Ar-H), 8.20 (d, J ~ 9.0 Hz, 2H, Ar-H), 7.58 (d, J ~ 8.3 Hz, lH, N-H), 6.80 (2d, J--10.1 Hz, 2H, ~r-H), 6.46 (d, J = 1.3 Hz, lH, H-l), 5.73 (d, J ~ 4.8 Hz, lH, H 1'), S.33 (d, J ~ 1.9 Hz, lH, H-l'), 5.25 (m, lH, H-3'), 4.35 (q, J - 6.6 10 Hz, lH, H-S'), 4.20 (dd, J--4.1 Hz uld lO.S Hz, lH, H-3), 2.88 (dd, J ~ 4.1 nd 19.9 Hz, lH, H4), 2.40 (ddd, J ~ 1.9, lO.S nd 19.9 Hz, lH, H-4), 2.27 (~, 3H, -COCH3), 1.32 (d, J ~ 6.6 Hz, 3H, H-6').
Step6: (lS,3R)-1-(2',3',6' 1 ~ ~-3' 1 ~ '- ,r ~ ~loxy-1,5-.'-', ' ~ L 1~ ' . ,. 2 .~ I)-S,10 :' 3,4,S,10-tah b,." lII p' ' ~
~2~c1 }~ ~
Thc quinone f~m ~top S ~ein w~ _,. ' W ~ ,~ c fiom step 4, oJumplc 12. Thc titlod product l~d:
lH NMR (250 MHz, CDC13) ~: 8.30 (d, J 8 8.9 HZ, 2H, ~r-H), 8.22 (d, J ; 8.9 Hz, 2H, ~r-H), 8.20 (m, lH, ~r-H), 8.00 (m, 2H, N-H, Ar-H), 7.86 (m, 2H, ~r-H), 6.53 (~, lH, H-l), 5.77 (d, J =
4.7 Hz, lH, H-4'), 5.50 (~, lH, H-l'), 5.30 (m, lH, H-3'), 4.37 (q, J 6.6 Hz, lH, H-5'), 4.27 (dd, J
--4.0 nd 10.7 Hz, lH, H-3), 3.08 (dd, J ~ 4.0 nd 19.8 Hz, lH, H-4), 2.55 (ddd, J = 1.0, 10.7 ~nd 19.8 Hz, lH, H-4), 2.31 (8, 3H, ~CH3), 1.31 (d, J = 6.6 Hz, 3H, H-6').
Step 7: (lS, 3Rt-1-(2',3',C' ~ ' ~-3' ~ ~ . ' ~' ', " ~-1,~ ~ ' ,d ~ L-I~ ~ .J_ - 2-~l)-S,10 ~- 3,4,S,10 1 ~ ' ' v 12,3-cl p BC~I-2145 Thc tricyclic product from dep 6 ha~in w~ d~,~ ' Som step 3, a~le 5. The titlod product h~d:
lH NMR (W MHz, CDC13) ~: 8.19 (d, J ~ 8.9 Hz, lH, N-H), 8.10 (d, J = 7.3 Hz, lH, Ar-H), 7.90 (d, J 8 7.3 Hz, lH, Ar-Hl), 7.70 (m, 2H, ~r-H), 6.26 (6, lH, H-l), 5.47 (s, lH, H-l'), S.10 (m, lH, H-3'), 4.20 (m, 2H, H-3, H-~'), 3.97 (d, J = 4.0 Hz, lH, H-4'), 3.00 (dd, J = 4.0 nd 20.0 Hz, lH, H-4), 2.55 (dd, J = 10.8 Hz, uld 20.0 Hz, lH, H-4), 2.32 (8, 3H, -CO~H3), 1.70 (bro~d 6, lH, -OEI), 35 1.36(t,J=6.4Hz,3H,H-6').
E~mple25: ~-~. ' of 3~ ' i ' ~. I ~I)-S,10-dioxo-3,4,S,10 ' ~d .
~" - 12,3 ~] ~.,. (BCH-1665) S-~ r~EET
2146~8 OCH, OCH, ¢~r 1~ ~
OCH, OCH3 O O
Ll CO2CH, ll CO2CH, ~CO2CH, 3 [Ç~CO2CH~
o o Step 1~ 3,3 bi~ L yl): ' To solution of 2,3 bis (~ 1)-1,4 ~ (1.30 g; 4.00 mmol) in 40 rnl of ~
mL~turc of l ~ r nt timethylfonn midc wcro ~ddod t yh-~-dimo~ylm~lon~te (1.06 g;4.19 mmol), ~ L (1.16 ~; 8.38 mmol) ~nt ce~ium -. L (1.37 g; 4.19 mmol). The - e mi~turo w~ 8ti rot 8t 80C (oil b th I . ) for 2.5 hou~s. It w~s then cooled to room ., nd filteret on p~d of ~ilic~ gel nt thc solvcnt~ were _. . ' using ~ vYcuum pump to yidd 2.3 g of cnJde ~'~' ' product which w~ ~ d in ' I (60 ml). To this solution w~
10 dded ~ Nolution of ~ in ' -' (4.57 ml; 4.37 M; S oq). Thc ' e mi~turc W9 s~rrod t room t_h~ for 2 hour Jnd w~s then e ~ to ~ volume of -10 ml. It w~
' - ' with 1 N HCI nd t 3 with :' ' ' . - The c ' - ' org~mic l~yer~ woro w~shed with brino nd dried over MgSO4. The crude product W~8 purifiod by colum~ Dgr phy on silic~
gd udng 10-2S % othyl cot te in ho~ne to ~fford the title c . ' (452 m~; 36 % o~ersll):
15 lH NMR (2S0 MHz; CDC13) o: 3.2S (2EI, ~, H-4), 3.72, 3.78, 3.79 (12H, 38, 4~t0CH3), 4.88 (2H, 8 H-1), 6.59 nd6.65 (2H, ~ ' ~r-H).
Step 2: S)~ :' 3,3 bis (metb ~. I yl)-S"~ :'-b., d ~
20 To ~ olution of S,8 ;- ~-3,3 bis ( ~ L ~1) ' . (70 mg; 0.23 mmol) in~~ ' - (5 ml) ~t room l . ~ w~ ~ r ~ ' aolution of ceric ~ ni~te (378 mg; 0.69 mmol) in w~ (1 ml). The e mLlcture W118 then dirred t room I . ~ for S
minute6 ndw~ ~ ' by dding ' ~diuml ~ solution. Thep~duct W~8 b with ~ '- . - nd the c - d orgsnic l~yers were w~hed with brine nd dried over MgSO4.
25 E~ ~ ~fforded the crude qui~e (60 mg; 95 %) which W~18 u6ed without further 1~
lH NMR (CDC13, 250 MHz) o: 3.03 (2H, t, J = 3Hz, H-4), 3.81 (6H, 8~ OCH3), 4.67 (2H, t, J =
3Hz, H-1), 6.70 ~nd 6.77 (2H, AB ~ Ar-H).
SIJ~T~ ~ ~JiTE S~;E~T
` 214~4~ --Step 3 3,3 bi~ ~ t~S,10 ' 3,4,S,10 b"~ ~ lII , ' 12 3~c]
P~
To OOlUtiO~I of S,8 dio~o-3,3 bu ( ' ~ ~ yl)-5,8 dib ~ ' . ' (S0 mg; 0 17 mmol) in tolu~ne (4 ml) t room w~ dded l~ooto~ty-1,3 1 - (113 ~11; 1 mmol) The ~tine mL~tur~ w~s ~od t room t , - for 24 holus ~ir w~s tb~ bub~lod tbrough for 30 minu~ ~nd the mL~ture W~8 - d to volume of ~ ppliod to oilic~ gd column Elutio l with 30%
ethyl cot te in ~e fforded pure title _ ~ ~20 mg; 34%) 8 ~ yellow ~olid; m p 210-222C
(d~) 10 lH N~R (250 MHz, CDC 13) ~ 3 22 (2H, t, J ~ 2 S Hz, H-4), 3 84 (6H, ~, C02CH3), 4 86 (2~I, t, J
~ 2 5 Hz, H-1), 7 75 (2H, m, ~H), 8 10 ~2H, m, ~H) IR (film) 2963, 1743, 1662, 1641, 1591, 1438, 1288, 1175, 1055, 791 ~d 692 cm~
SU~S~ T~ EET
2~46~8 F ~ 26~ of (l'S, lR, 3S) ~nd (l'S, lS, 3R)-S,10-dio~o-3-1 1-(2',3',6'-trideox~-3'~
) 3,4,S,10-tetr~hydro-lIl p - 12,3-c]-p~an (BCH-101) sDd BCH-lC93) S
OCH, O OC~ OCH, - OCH, OCH, OCH, O O
O o O
PNBO ~ PNBO ~
~ 14 O O
O o O O
PNBO ~ PNBO ~
1~ 16 O O
O o O O
HO NHIFA HO NN~A
~1691 B~1693 Step 1: 5,~ J-3 ' ,d . ~, ' yl - ' .
To ~ solution of S,8 ~ -3 - ~ ~ . (310 mg; 1.23 mmol) in 5 ml of t ~ r ~t 0C W 8 ddod lithium ' hydride (47 mg; 1.23 mmol). The mLlc~e w ls stinod st 0C for lS mi~utes uld w~s ~. ' ' with 1 N HCl. The product W~8 - ' with ether uld the c - ' org~uc layers we~e w~hed with brine nd dried over MgSO4 ~rr.,.. e crude title rlcohol (246 mg 90%) used s such for , 6teps:
S U E~ W ~ ET
WO 94/11382 PC~r/CA93/00463 lH ~D~R (250 MHz, CDC13) o: 2.42 (lH, m H~ ,2.55-2.75 (21I, rn, H-4 oq ~nd ~DH~,3.6C~3.90 (2H, m, C~12~H~,3.76 (3H, 8, ~DCH3),3.77 (3H, 8, ~CH3),4.62 (lH, br d, J = 16.0 Hz, H-l), 4.97 (lH, d, J ~ 16.0 Hz, H-1),6.61 nd 6.65 (2H, ~iB d ' ' '~ ~rH~.
S Step2: S,P ~ 3 - ' ,, - ~!- ' .
To a . - of ~x~um hydndo (70 mg of 60~ m o~; 1.78 n~nol) Ln l ' ~.' (3 n~) was ~dded ~ oolu~on of 5,8 ~ -3 h~ ' ~ ' yl (330 mg; 1.48 mmol) m 7 n~ of i ' ,1. ' The noR~ny n~u8 ~ o~rred ~ room ~ , - u~tl H2 ~-- ' o~ued ~-15 10 minuk~) ~nd i D~ ' - (500 ~1; 5 oq~ ~u ddod. Iho D~U~ ~n~ Lhon dinxd ~ room i for 30 munuk~. SDU~ tbc ro cion ~ DK* pr no~ur ~, . ' of ex~um hyt~dc ws~ ~d ~long witb 20 mg of ceuum o ' The mL~ s sti~ed for lS D~inuto~ nd W~8 3~, ' - ' with ' ~ chlodtc~olution~d d with ' ~ ' - The ~ ' ' orgsnic l~yers were wuhot with brin~ nd dried ovor MgSO4 The cmdo w~s purifiot by oolumn ~ on lS silic~ gd U8illg 259~ oShyl ~cot~ D1 ha~sne to fford the titlo ' (301 mg; 86 ~i) H NMR (250 MHz, CDC13) 8 2 45 (lH, br dd, J ~ 11 0 nt 1 î Hz, H 1 u~), 2 69 (lH, dm, J =
17 0 Hz, H-4 oq), 3 44 (3H, ~, C~2{)~3)~ 3 SS (2H, d, J ~ S S Hz, ~2~D), 3 7S (3H, 8, OCH3), 3 77 (3H, 8, OC'H3), 4 63 (lH, br d, J = 16 0 H[z, H-l), 4 97 (lH, d, J--16 0 Hz, H-l), 6 61 s~d 6 64 (2H, AB ~ ' ~r-H) 20 Step 3 (l'S, lR, 3S)-~,8 ' 3 ~' ~ b~l 1 (2',3',6'~ -3'-t ~ yl L 1~ ' ," ` S,8-' bJ~ ~ ~nd its (l'S, lS, 3R) ' To ~ olution of S,8 " ~-3 ' ~ ' (280 m~; 1 18 mmol) ill 16 ml of 25 ~ - ' - v~o~ ~t 2,3,6J '- ~-3 '' ~ ' 1 0 p ' ",1 -L-r ~ (555 mg; 1 42 mmol), 4A ~;ieve8 (500 mg) nt 2,3 d; ~,6-- (360 m~; 1 6 mmol) Tlho d~ groo~ ro ctia~ tu~o w~ stined t room , - for 14 ho~ It w~ 1, - ' wiSh - 3 N~HCO3 ~olution uld e ' with - The ~ ' ~ ot1pnic Isy~rs wer~ w~hod with - ~ d N~HCO3, brine ~d were 30 dried over N~2S04 -~n ~ fto~ 671 mg of ~ cn~dc dduct which w~u c' '~ in '- (20 ml) ~t 0C ~ lutio~ of conc 9 n itr~te (3 3 g; 6 mmol) in 10 rnl of wder w~s tro tod by po~tiom~ with ~olid ~odium ' ~ (886 mg) Thc re6ultiDg yoUo~,v ~olution w~s ~&ded d~ ~ to the ' Ilolution ~fbr tbe ~d the muhlre w~s sti Tod ~t 0C for 20 minutes, ' - ' witb d NiHCO3 rolution uld ~ ' witb ~' ' ' ' The ' - d orguuc 3S l~yers were w~bed with b~i~e uld dried o~er Na2S04 to fford uRcr c. . ~ cmde quinone which wu~ " ' from tichlorometb . yidding 225 mg of ~ s~reomeric quinone mi~
f~voring the title c ~ (2 1) lH NMR (250 MHz, CK~13) 1 20 (3H, t, J ~ 6 5 Hz, H-6'), 1 90 2 70 (4H, D~, H-2' ~nd H-4), 3 41 (3H, 6, -OCH3), 3 35-3 6S (3H, m, CH2-OCH3 ~nd H-3'), 4 154 70 (2H, m, H-3 ~nd H-S'), 5 44 (lH, S U ~S~ S ~ E -T
WO 94~11382 PCI~/CA93/00463 ~ 214~F~
br 8, H-l'), 5.60 (IH, br ~, H4'), 5.78 (lH, 8, H-l), 6.30 (lH, m, NH), 6.65~.90 (2H, m, Ar-H), 8.30 (4H, m, PNB): sign~l~ for minor (l'S, lS, 3R) i~omer re ~: 1.30 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.70 (4H, m, H-2' ~nd H4), 3.43 (3H, ~, ~I3), 3.35-3.65 (3H, m, CH2~CH3 nd H-3'), 4.15-4.70 (2H, m, H-3 ~d H-5'), 5.40 (lH, br 8, H-l'), S.59 (lH, br 8, H 4'), 5.91 (lH, 8, H-l), 6.40 5 (lH, m, N~, 6.65-6.90 (2H, m, Ar-H), 8.30 (2H, m, Ar-H).
Step 4: (l'S, lR, 3S)-S,1~o-3 " ~ l 1-(2',3',6'~ -3'-lII p' ' v [2,3 cl ~, To ~ olution of the quinooe mLlcture from ~top 3 of thi- - , ' o, (100 ~; 0.17 mmol) in 6 ml of tolue~e t mom I w~ ~dded 1- c~to~cy-1,3 ~ ' - (113 ~1; 1 mmol). The rest of the ' ~ is ite~tic l to step 2, e~ample 5, ~~ ' g thc title c . ~ (42 mg; 40%):
lH NMR (CD2C12, 250 MHz) o: 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.9~2.20 (2H, m, H-2'), 2.37 (lH, 15 dd, J 11.5 uld 19.5 Hz, H4 ~%), 2.70 (lH, dd, J 3.5 uld 19.5 Hz, H4 oq), 3.38 (3H, 8, O-CH3), 3.55 (2H, m, -CH2-OCH3), 4.254.70 (3H, mt H-3, H-3' rnd H-S'), 5.41 (lH, br 8, H-l '), 5.65 (lH, br 8, H-4'), 5.90 (lH, 8, H-l), 6.44 (lH, br d, J = 7 Hz, N-H), 7.7S (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.27 (4H, m, PNB).
Thc ~ocond ~' .
20 (1 S, lS, 3R)--5,10--dioAo--3 ~ 2 ,3 ,6 t~;d~A~--3 t . 4 {~--p--L Jl L 1~ ~ r~ ~ )-3,4,S,10 t ~.- ~lII ~ . - - - t2,3~l pyr n w~s obtdned ill 19%
yidd nd h d:
lH NMR (250 MHz, CD2C12) o: 1.30 (3H, d, J ~ 6.5 Hz, H-6'), 1.9~2.30 (2H, m, H-2'), 2.47 (lH, dd, J 11 nd l9.S Hz, H4 al~), 2.71 (lH, dd, J--4 rnd l9.S Hz, H4 oq), 3.89 (3H, ~, -OCH3), 25 3.57 (2H, d, J - S Hz, C_2-OCH3), 4.27 (lH, m, H-3), 4.52 (lH, m, H-3'), 4.75 (lH, q, J ~ 6.5 Hz, H-S'), 5.41 (lH br ~, H-l'), S.56 (lH, br ~, H4'), 6.03 (lH, 8, H-l), 6.46 (lH, br d, J 7.5 Hz, N~, 7.7S (2H, m, Ar-H), 8.07 (2H, m, Ar-H), 8.28 (4H, m, PNB).
S~ep S: (l'S, IR, 3S)-S,10 ' 3 ~ l 1-(2',3',~'-1 ' , 3'-t~ L 1~ ' , ,.~ ~~ ) 3,4,S~10-tdr~lhydro-lII l~' ' ~ t2,3-cl-p~ n (BCH-lC91) To ~ 801ution of (1 S, lR, 3S) S,10 dioAo--3 ~ 2 ,3 ,6 t~;~Ar 3 1 . I
4'~p ~. ~ ,I-L 1~ ' .. , )-3,4,S,10 t ' ~ ' ~lII- p! - 12,3 Clpyr~n(19mg; .029 35 mmol) in - -' (.4 ml) nd: ~d~ r (1.5 ml) t 0C w~s rddod .86 1l1 (.1 oq) of ~1 4.37 M
~olution of sodium - ~.- in - ~' Thc resulting mu~turc w stirrod ~t 0C for 20 minute6 ~nd wu~ 3 -' - ' with ~ ' NH4CI. r with ~ - followod by w~ing of the - ' o~uuc layer~ with brinc nd dryi~g with N~2SO4 r ~1~ cnule product which was punfiod by column ~ ' ,, p! ~ on ~ilic gel u~ing 5-10% ~nc in ba~ne ~ duent yieldillg the SUES~ , S~ T
WO 94/11382 PC~r/CA~93/O{k463 2146~4~
titlc c ' (14 mg; 96~) wbich w~8.~ '1i7^d from ~ to ~ive yd~ow crydb~s: M.P.: 140-159C; nR (ne~t): 3S00,3422,3320,2938, 1715, 1667, 1597,1295, 1178 snd 980 cm~l:
lH NMR (250 ~LE~ CD2C12) o: 1.21 (3H, d, J ~ 7.6 EL~ H-6'),1.S2 (lH, bs 8, O-H), 1.70-2.20 (2H, m, H-2'),2.35 (lH, dd, J ~ 11.7 ~nd 19.3 H~ H 4 ~),2.68 (lH, dd, J 3.4 nd 19.3 Elz, H-4 - oq~,3.56 (3H, b, OCH3),3.S2 (2H, d, J ~ 4.8 H~ CEI2~CKCH3),3.58 (lH, br ~, H4'),4.15-4.40 (3H, m, H-3, H-3', H-S'), S.46 (lH, br ~, H-l'), S.83 (lH, ~, H-1),6.73 (lH, br d, J - 7 E~ N-H),7.75 (2H, m, ~-H~,8.05 (21I, m, ~H).
Step 6: (l'S, lS,3R)-S,10 ~- 3rn~d/Yq~nncibyl-1-(2'~3',6' ' ~ ~-3'-t ~ . - '- L 1~ 3,~,10 ~ b~ lII p! ' 12~c]
p~n~n ~BC~I-lC93) l~hc ~r~ng p O~l ~ d ~cohol from ~p 4 of t`hi8 o~rnple (18 mg; 0.028 mmol) in .4 n~ nd 1.5 ml of t ~ trod~d ~nlh .83 ~1 of ~ 4.37 M solu~on of ~od~um ' ~- m -' r~ l~o p......... ~ from dkp 5 hcn~n to affori the title; . ' (12.5 I4g; 90~): m.p.: 92-102 C; IR (D~9~): 3485,3424,3323,2937, 1715, 1666,1595,1296, 1175, 1117,980 cm~l.
lH rlMR (CD2Ck,250 MHz) ~: 1.35 (3H, d, J - 6.5 E~ H-6'), 1.85 ~H, ~ H-2'), a~01 (lH, br d, J = 7 H~ C~E~,2.46 (lH, dd, J ll.S and 20 E~ H-4 r~),2.69 (lH, dd, J -ii 3.7 ~nd 20 E~ H-4 oq~,3.36 (3H, ~, CICH3),3.54 (2H, d, J ~ 4.7 E~ C~2-CKCH3),3.60 (lH, n~ H 1'),4.154.40 (2H, m, H-3' nd H-3),4.SS (lH, q, J 6.S H~ H-S'), S.39 (lH, br s, H-l'), S.98 (lH, , H-1),6.78 (lH, br d, J i 7 E~ -rDH~,7.7S (2H, m, ~-H~,8.05 (2H, n~ ~-H).
SUeST~ S}~EET
WO 94/11382 PCr/cA93/00463 2 ~ 4 ~
F "r- 27~ of (1'S,1P,~S) ~nd l'.S,~ S,10; - 3-eth91-1-(2',3',6'-trideox~-3'L ~ . ' I~;, -' ,.~r-- ) 3,4,5,10 ~ .~h,L~.
lH~phtbo~2,3 c] ~, (BCH-2026) 9nd BCiH-2020) ~nd (l'S,lS,3S)-S,10 :'- 3-etbyl-1-(2',3',6'~1 ~-3' _ - L 1~ ' ,. ) S 3,4,S,10-tetr~dro-lII "' - I?~ C] r~ 3 ~ (BCH-2021) OCH~ OCH~ OCH~
[~2 OCH~ OCH~ OCH~
CHJO CH~O
CH~O O + CH~O o NBO ~ ~ PNBO
1~ l7 O O
O o O O
NBoNHIF~ PNBoNHIF~
1~
O o O
~ ~0~ 0 ~0~
O O o O o pN80NHlFA pN80NHlFI~ PN80NH~CI
IC 198~1 O O
O o O O
HoNHlF~ HoNHlF~
~QZ~ 8CH-2020 Step 1: 1-(2,F . - -~P' .~'V 2-L ' ~!
- Under argon ~ , , 1,4 ~ L - 10.0 g (72.37 mmol) w~s .li~l~ in dry THF and this solution was cooled to 0C. n-BuIi (2.5 Mr s) 28.8 ml (72.37 mmol) w LS then ~d and the - r~action mL~ture wa8 warmed up to room , ; ant Istirring was left for 4 hours. ~fter 4 hourls, the reaction w~ coolod to -78C and 1,2 ~ ~ 5.2 ~ (72.37 mmol) w~ addod followed by 10.2 g (72.37 mmol) of boron trifluoro othaate. Stining wa8 then: -~' for a period of 1 hour. The rellction mfl~ture W~8 thon, - ' by pouring it into 125 ml of ~queous NH4CI. F ~ of the S U IE~ 5 ~, E rT
WO 94/11382 PCr/CA93/00463 21~65~ e ~queous l~yer were done ufiing CH2C12. The r ~ ' - ' orgsnic Isycrs werc driod over N 2S04, filtered Ynd the solvent wss rcmovet. Thc crute r~teri~l wss purifict by flssh .,~. O p' ~ with he~csnes-ethyl scet~te (9: 1) then (8:2) ~8 the eluent. The isol~tod titlct; , ' w fi ~ white fiolid (11.4 g, 75%).
S NMR lH (250 MHz) (CDC13; ppm): 6.75 (3H, m, ~ ~ 5) 3.79 (3H, 8, OCH3), 3.77 (lH, m, H2.), 3.76 (3H, s, OCH3), 2.85 (lH, tt, Jl c 3.8 Hz, J2 = 13-5 Hz, Hl.,), 2.65 (lH, dt, Jl--8.1 Hz, J2 = 13.5 Hz, Hlb), 2.16 (lH, t, J ~ 3.7 Hz, OH), 1.52 (2H, m, H3.) 0.99 (3H, dd, Jl = J2 =
7.4 Hz, -CH3)-10 Step 2: 5,~ b~
Under rgon ~ , ' .;, the 6tsrting rnderisl from step 1 of this ~ , 5.00 g (23.78 mmol) W9S
t in 100 rnl of try dher. D- ' ~ rneth nc 3.0 ml (33.90 mmol) snd boro~ trifluoro ether~Le 9.0 ml (71.35 mmol) were then ~tet nd stirring W98 left ~ ' The ro~ction w~ then ~
15 u~ng uluoous N~HC03. r were tone ufiing ether u~t the - ' org~nic c~tr~cts were dried over Ns2S04, filtered ~t the fiolvent wss ren~ovet. The isol~ted rosidue w~ then purificd by flssh ~- . ~ cetde (8:2) W~8 used ~8 the eluent. The desired titled ~ .
W~8 isol tcd ~ ~ white ~olid (4.9 g; 92 %).
NMR lH (250 MHz) (CDC13; ppm): 6.63 (2H, t, J ~ 3.4 Hz, ~ . ), 4.93 (lH, d, J = 15.9 Hz, 20 Hl,), 4.57 (lH, d, J = 15.9 Hz, Hlb), 3.78 (3H, 8, OCH3), 3.76 (3H, 8, OCH3), 3.47 (lH, m, H3), 2.74 (lH, d~d, H4~), 2.38 (lH, dd, H4b~, 1.68 (2H, m, CH2- side ch in) 1.03 (3H, dd, Jl = J2--7 4 Hz, -CH3)-Step 3: (l'S, ~R, 3R) 5)~ -3~ 1-1-(2',3',C'~ideo~-3'-l A
0 ~ ~* Jl L 1~ ' .J.
~,, ' of the fi~t prt of the ~ _c ~ ihrJ in 6top 3, e~ple 26, on the - from dep 2 haein ro~ultod with the titlod ~ ' s ~ yellow ~olid; 62%.
NMR lH (250 MHz) (C6D6; ppm): 7.72 (4H, m, ~ ), 6.48 (2H, d, J = 4.7 Hz, . - ), 30 6.17 (lH, 8, Hl), S.95 (lH, m, N~, S.67 (lH, d, H4.), 5.29 (lH, d, Hl.), 4.67 (lH, m, H3.), 4.26 (lH, q, Hs.), 4.20 (lH, m, H3), 3.49 (3H, 8, OCH3), 3.40 (3H, 6, OCH3), 3.01 (lH, dd, H4~), 2.52 (lH, dd, H4b), 1.90 (lH, m, -CH2 side c~in), 1.75 (lH, m, -CH2- side chsin), 1.61 (2H, m, -CH2-6ug~r), 1.06 (3H, d, -CH3 ~;ug~r), 1.03 (3H, m, CH3 6ide ch~in).
IR (film) (cm~l): 3316 (NH), 2933 (CH liphatic), 1733 (C=O), 1707 (C=O), 1603 (C=C), 1532 (C-35 N), 12S9 Jnd 1175 (C~).
SUe~T~T~ S~T
WO 94~11382 PCT/CA93/00463 St~p 4: (l'S, lR, 3R)-S,8~diox~3-ethyl-1-(2',3',6'-lrideoxy-3' ~
Arp~ of the ~cond p~rt of thc ~ i (CAN) d~ 1 in step 3, cDple 26, on the S ~, p from thc prcvious step resulted in n 87 % yield of thc titlet , NMR lH (250 MHz) (C6D6; ppm): 7.80 (4H, m, ~ . ), 6.92 (lH, 8b~d, NH), 6.08 (2H, m, - quinonc ring), S.72 (lH, ~, Hl), S.54 (lH, ~, H4.), 5.53 (lH, 8, Hl.), 4.74 (lH, m, H3.), 4.36 (lH, m, Hs~), 3.68 (lH, m, H3), 2.28 (lH, dd, Jl = 3.2 Hz, J2 ~ 19.3 Hz, H4~), 1.88 (2H, m, -CH2- sugar), 1.80 (lH, tt, H4b), 1.49 (2H, m, -CH2- ite ch in), 1.15 (3H, t, J = 6.5 Hz, CH3 sugYr), 0.89 (3H, dt, Jl = J2 = 7.4 Hz, -CH3 idc ch in).
StepS: (l'S, lR,3R)-S,10 ~- 3-ethyl-1-(2',3',6'-trideoxy-3' t~ '` ~~~ ~nido-4'-O-p-~ .JI L 1~ ~' ,.,.~ ~) 3,4,5,10 1 ~ ' ~ lII ~ ~p~ - ~ 12,3-c1 P~
lS
The titled ~ . ' w~s obt~ined via Diels-~lder ,~. ' ~ ' ' ~i betwe~n 1 ~ nd the quinonc from step 4 from thi~ umple using thc 1~ 1 in step 4 f om e~-mple 26.
NMR lH (250 MHz) (CD2C12; ppm): 8.28 (4H, d, J 5 4.3 Hz, 9 ~ 8.05 (2H, m, ~
7.73 (2H, m, 9 '- )~ 6.31 (lH, d, N~, 5.87 (lH, 8, Hl), 5.67 (lH, 8, H4.), 5.42 (lH, 8, Hl.), 20 4.58 (lH, m, H3~), 4.42 (lH, q, J ~ 6.3 Hz, Hs~), 4.05 (lH, m, H3), 2.78 (lH, dd, Jl = 3.4 Hz, J2 c l9.S Hz, H4~, 2.24 (lH, dd, Jl ~ 11.3 Hz, J2 = 19.0 Hz, H4b), 2.05 (2H, m, -CH2- I;ugar), 1.70 (2H, m, -CH2- s~de ch in), 1.18 (3H, d, J = 6.5 Hz, -CH3 wg~r), 1.05 (3H, dd, Jl 5 J2 = 7.4 Hz, -CH3 sidc duin).
IR (film) (cm~l): 3332 (N~, 2955 nt 2929 (CH ~liphatic), 1740 (C=O), 1669 (C=C), 1529 (C-N), 2S 1279 nd 1180 (C-O).
StepC: (l'S, lR,3R)-S,10 ~- 3-ethyl-1-(2',3',C'-trideoxy-3'-i '' ~ '- ~
1~ ' ,., ) 3,4S,10 1 ~d ~ ~ 12,3-c1 py~ ~BCH-202C) Thc titled ~ ' wa6 in 64% yidd from the gl~ ' of step 5 of this e~cunple ~ per ~vccd~c d~ i~d in dcp S of e~c mple 26.
NMR lH (2S0 MHz) (CD2C12; ppm): 8.03 (2H, m, r, - )~ 7.71 (2H, m, ~ . ), 6.77 (lH, d, N~, 5.81 (lH, 8, Hl), 5.50 (lH, d, J 5 2.8 Hz, Hl.), 4.26 (lH, m, H3~), 4.22 (lH, m, Hs.), 4.05 (lH, m, H3), 3.58 (lH, d, J = 2.2 Hz, H4.), 2.76 (lH, tt, Jl = 3-5 Hz, J2 5 19-5 Hz, H4a)~ 2.21 3S (lH, ddt, Jl--0.9 Hz, J2 5 11.0 Hz, J3 = l9.S Hz, H4b), 2.07 (lH, 8~d), OH), 1.83 (2H, m, -C~I2 ~ ), 1.67 (2H, m, -CH2- side ch~in), 1.23 (3H, d, J--6.6 Hz, ~H3 sugar ), 1.02 (3H, dt, Jl 2 = 7-5 Hz, -CH3 side ch in).
SU~ST~TI~ S~EET
Step 7: (l'S, lS, 3S)-5)~ :'3-ethyl-1-(2',3',6'-trideo~y-3'-1~ q'~p-l~it~benz~yl-L 1~. -o.~ S,8 ' ~. ' .
S To a ~olution of (l'S, lS, 3S)~,S ~ -3 othyl-1{2',3',6' t~ 3'; ^ r ~ ~p-~ b .,I-L-I~ J ) (372 mg; 0.60 mmol) in ~ - h (12 ml) W~lfi adlded a fiolution of C~N prop~d by ' ~ e cenc n tr t4 (2.0 g; 3.6 mmol) In 6 ml of water ~nd then ~lowly ~dding ~olit sodium ~i ~ (S3 1 mg). The ' e mLsture w~s sti~t at 0C for 20 rainutes ~nd w~s then q ' ' with ' ~- ~olution. Thc product was _ ' with 10 d- ' ~ ' - nnt the ~ ' ' org~nic l-yers were w~het with brine u d dried over N 2S04 to give ~fter~,. . thecn~ itle ;-(360 mg; 100%): lH NMR (250 MHz; CDC13) 8: 1.02 (3H, t, J--7.5 Hz, CH2~E3), 1.29 (3H, d, J
= 6.5 Hz, H-6'), 1.65 (2H, m, CH2-CH3), 1.80-2.30 (3H, m, H-2' uld H 1 ~c), 2.60 (lH, dd, J--3.5 ~nd 19.5 Hz, H-4 eq), 3.89 (lH, m, H-3), 4.50-4.80 (2H, m, H-3' ~nd H-5'), 5.41 (lH, br ~, H-l') lS 5.55 (lH, br 6~ H-4'), 5.87 (lH, 8~ H-l), 6.58 (lH, br d, J = 7.5 Hz, NH), 6.75 uld 6.81 (2H, AB
d ' '- ArH), 8.28 (4H, br s, PNB).
Step 8: (l'S, lS, 3S)-S,10 ~- 3-ethyl-1-(2',3',6' h~ 3' h-~
~ Jl L 1~ ' r~ ~~) 3,4,S,10 ~ lII p' '' ~ ~2,3 ~] ~, Using the ~. c ' ., ' ' d in s~ep 4, e~umple 26, the st rting quinone from ~p 7 herein (330 mg;
0.57 ml) W~8 t~ted with l~coto~y-1,3 ~ ' - (379 111; 3.4 mmol) in 20 ml of tolu~c to ~fford ' . _ .' ~ the title; . ~ (165 mg; 46%).
lH NMR (250 MHz, CD2C12) ~: 1.03 (3H, d, J = 7.5 Hz, CH2~3), 1.30 (3H, d, J = 6.5 Hz, H-25 6'), 1.68 (2H, qn, J = 7.5 Hz, C~2-CH3), 1.95 (lH, m, H-2 eq), 2.12 (lH, td, J ~ 13 ~nd 3.5 Hz, H-2' ~), 2.29 (lH, dd, J e 11~5 ~d 19.5 Hz, H~ a~c), 2.76 (lH, dd, J = 3.5 ~d 19.5 Hz, H 4 eq), 3.97 (lH, m, H-3), 4.55 (lH, m, H-3'), 4.78 (lH, q, J--6.5 Hz, H-5'), 5.41 (lH, br 8, H-l'), S.57 (lH, d, J ~ 6.5 Hz, H~'), 6.01 (lH, ~, H-l), 6.51 (lH, br d, J = 7.5 Hz, -NE~, 7.75 t2H, m, ArlE~, 8.07 (2H, m, Ar-H), 8.27 (4H, ~, PNB).
step g: (l'S, lS, 3S)-5,10 :' 3~yl-1-(2',3',6'~ -3'~
1~ ' . ,. ~ ) 3,4,5,10 t ' ~ 12,3 ~] I J (BClE~-2020) The ~rting ~ lcohol from ~ep 8 hereil~ (20 mg; .032 mmol) w~ ted with ~odium ~ A~.
3S ill ' -' (4.37 M, 1 ~1) in 1 ml of tetrshydro~ ~nd .3 ml of n~nol ~ ~ ' g to tho p.~l~.;
;~d iD 8tep 5, ~mplc 26, ~ e ~ - . ,, "! r (15 9~ ~cetonc in be~ne) the title compou~d (11.5 mg, 75%), M.P. 208-211C.
IR (nalt): 3540, 3292, 2978, 1705, 1666, 1556, 1295, 1187, 1165 ~nd 9gO cm~l.
SU~STI ~ UT~ ~hEET
WO 94/1 1382 t 2 1 ~ 6 ~ 4 B PCI`/CA93/00463 lH NMR (250 MHz, CD2C12): 1.00 (3H, t, 1 = 7.S Hz, CH2-CH3), 1.35 (3H, d, J = 6.5 Hz, H-6'), 1.66 (2H, qn, J z 7.5 Hz, C~2-CH3), 1.80-2.20 (3H, m, H-2' snd ~H), 2.27 (lH, dd, J = 11.0 ~nd l9.S Hz, H~ as), 2.75 (lH, dd, J--3.5 nd 19.5 Hz, H-4 eq), 3.61 (lH, br 8, H-4'), 3.96 (lH, m, H-3), 4.25 (lH, m, H-3'), 4.58 (lH, q, J--6.S Hz, H-5'), 5.40 (lH, t, 1 = 2.0 Hz, H-l'), 5.97 (lH, s, H-l), 6.77 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 10: (l'S, lS, 3S)-S,10 ~- 3-dhyl-1-(2',3',6'-trideo~y-3' ~
- 3~4~S~10 ~ ~.~. lII p1 " ~ [~ c] r~ (BCH-2021) 10 To ~ 601ution of the d rting ~ ' from otep 9 herein (43 mg; 0.07 mmol) in ~ ' - (6 ml) w~ ~ddot d ~, .. .1 N sodium ~ AI~ (3 ml). T~e mi%ture W98 s~od t 0C
for 30 minutos ~d ~ e%tr 1 ml of oodium h~d ~.~ oolution w ~dded nd the rooulting mi%b~ w s stimd for 1 hour t 0C. It w o then ~ ' ' with .1 N HCI nd ~ ' with ~" ' ~ ' - The w~tor l-yer w~s ' ' to pH -7 by ddition of dilute sodium h~L~o~. It w~ then ~ ' with ' ' ' ~ ' - To the org nic o%tr~ct wcre dded 1.5 mt of .1 N HCI, 5 ml of ' nd 2S ml of ether ~nd the mi%ture w_s ~ lly in o~der to induce ~ Since no cryotsll occured, the oolvont~ wero c.~ ~d the rooidue w 6 ~ d in ' -' (1 ml) nd 200 ,ul of .1 N HCI wero ddod followed by 2S ml of other. A p.~ -, formed which w 8 filtered ~nd washed with other yidding the clude title c ' (3.8 mg; 13 ~i).
lH NMR (2S0 MHz, DMSO-D6), ~: 0.97 (3H, t, J = 7.0 Hz, CH2~3), 1.23 (3H, d, J = 6.S Hz, H-6'), 1.50-1.80 (3H, m, CH2-CH3 nd H-2' oq), 1.97 (lH, m, H-2' ~), 2.23 (lH, dd, J ~ 11.0 ~nd 19.5 Hz, H-4 al~), 2.72 (lH, dd, J ~ 3.0 ~nd 19.5 Hz, H 1 eq), 3.63 (lH, m, H-4'), 3.87 (lH, m, H-3), 4.33 (lH, m, H-5'), S.29 (lH, br 8, H-l'), 5.53 (lH, m, H-3'), 5.82 (lH, 8, H-l), 7.85 (2H, m, ~r-H), 8.05 (5H, m, Ar-H Jnd N-H).
SU BST~ ET
WO 94/11382 214 6 ~ 4 8 PCT/C~93/0~463 F p'e 28~ , of tn~ S,10 dioxo-l-~ '- 3-ethyl-3,4,5,10 t~
lII "' ' - 12,3 c] r~- ~ (BCH-2027) ~nd 3 ~ l 5,10-diox~3,4,5,10-i ' ~,' ~ lII ~" ~ 12,3 cl r~- ~ (BCH-2154) OCH~ O
OCH, NHCOCH,
13 12 o O NHCOCH~
1 4 1~CH-2027 o To ~ fiolutio~ of S,8 y-3 ~ 1 ' (1 0 g; 45 mmol) in :' ' ' - (30 ml) ~t 10 mom i , ~ were ~Ided ' -' (211 ~1; s.4 mmol), 4A -~ - sieves (2 g) Jnd 2,3-dichloro S,~ " ~ - h . - (1 21 g; S 4 mmol) The ~ulting d~ mi~ture w~ ~tinod for S hou~ nd W~8 then sl ' - ' with ' N~HCO3 olution It W_8 ' with ~' ' ' ' ~d the orgs~c l-yers were w~hod with ~ ine ~nt then driet a~er N 2S04 ~
1.0 g of crute ~,ttuct of which 300 mg (1.19 mmol 9 d) were plscod in pear-shspet fls~c JloDg with - - ' (70 mg; 1.19 mmol). Thc oolid mLstule wss thon he~tod to 130 C for 30 minutes. It w~ then coolot to room I . ~i snd ~' ' . ' wss adtct followot by pe~tane yielting ~ I , (160 mg) of which 120 mg (.43 mmol ~ssumet) wss ~ ,t in ~ - (15 ml) nt tro~ted with solution of CAN I . d by slowly ~ g sotium 1 ~ (384 mg) in w ter (S ml) ~ g cerium ~ nitrste (1.46 g; 2.5 mmol). The . " e mi~ re wss stirrot ~t room i , for 15 t utos ~nd wss ~ - ' with, d NsHC03 solution followed by o ~ with ~' ' ' . - - The _ ' ' osgsnic e~c~cts were wsshe~d wit~ brinc ~nd dnod ovor Ns2S04 to sfford the ti~dod ~ . ~ ~ yollow ~olid (125 mg; 42% ove~ll).
lH NMR (250 MHz, CDC13) o: 0.99 (3H, t, J = 7.5 Hz, C_3-CH2), 1.65 (2H, m, -CH2-CH3), 2.02 (3H, ~, -CH3), 2.20 (lH, m. H 4 alc ). 2.60 (lH, dd, J = 3.5 ~nd 19.5 Hz. H 1 oq), 3.70 (lH, m, H-3), 6.12 (2H, br 8, H-l snd N-H), 6.73 snd 6.78 (2H, AB ~y~Sem, Ar-H).
SUBST~ TÉ SE~ET
2i~6S~8 Step2: Tr~ S,10 dioxo-l = '- 3~thyl-3,4,5,10 ~ ' - [2,3-c]-py~
S To ~ solution of the sturting quinone from step 1 herein (56 mg; .22 mmol) in toluene (S0 ml) W~8 ~dded ceto~cy-1,3 b ' (30 111; 11 eq). The mLl~ture wss stimd o.. y' ~t room I . e nd w~s then ~ ' snd pplied to ~ column of silic gel using l-lS % ~tone in bellzene to dute the product which w s then ~ " ' from ~ ' " g the titlo ~ , ' ~6 -yellow solid (10 mg; 15%).
lH NMR (250 MHz, DMSO-D6), ~: 0.90 (3H, t, J ~ 7.S Hz, C~3-CH2), 1.58 (2H, m, CH2-CH3), 1.82 (3H, s, CH3-C=O), 2.20 (lH, m, H 4 ~), 2.64 (lH, br d, J ~ 16.0 Hz, H-4 eq), 3.71 (lH, m, H-3), 6.17 (lH, d, J = 8.0 Hz, H-l), 7.88 (2H, m, Ar-H), 8.01 (2H, m, Ar-H), 8.78 (lH, d, J = 8.0 Hz, N-H).
Step3: S,J~ ~- 3 ~ J~
To ~ solution of 3-cthyl-5,8~ - ' . (300 mg; 1.35 mmol) in '- (10 ml) t room .; W~8 ~dded ~.. - ~ olution of CAN (prep rod by ~ - e ceric ~ nitr~te (2.22 g; 4.0 mmol) in w~ter (S ml)). The rosulting mi~ture w~s !. ' - ' with ' ~ I
solution nd ~ ~ with 1'- ' ' - ~ ' - The . ' - ' or~ nic hycrs wcre wu hed with brine nd dried over N~2S04 ~'' " e tho cmdc titlc ~ . ' (251 mg; 97X) which w~ used ~8 a~h for ~ps.
lH NMR (250 MHz, CDC13) o: 0.97 (3H, t, J ~ 7.5 Hz, CH2-C_3), 1.60 (2H, m, ~_2-CH3), 2.10 (lH, m, H-4), 2.52 (lH, m, H-4), 3.35 (lH, m, H-3), 4.30 (lH, m, H-l), 4.62 (lH, br d, J = 16 Hz, H-l), 6.68 (2H, m, ~r-H).
Step 4: 3 2~b~1 S,10 ~- 3,4,S,10 1 ' ~ lII . ' ' ~ t2,3-c] p~n F~" .. e the p.. ~ ' ' d in ~tep 4, o~mple 26, the ~;brtiDg quinone from step 3 hereln (250 m~; 1.30 mmol) rnd l~coto~y-1,3 ~ ' - (876 ~1; 7.8 mmol) were re~ctod in toluene (10 ml) to yield 30 fter ~ ing 2X ethyl cet~te in toluene the title . ' (62 mg; 20X) ~long with mi~ed f~ctions c- E Iot of de~iired titled product (230 mg), M.P.: 98-101C.
IR (ne~lt): 2963, 2938, 2876, 1658, 1636, 1593, 1337, 1299, 1176 snd 698 cm~l.
lH NMR (250 MHz, CDC13) ~: 1.04 (3H, t, J ~ 7.5 Hz, CH3-), 1.70 (2H, m, C_2~I3), 2.30 (lH, m, H-4 uc), 2.75 (lH, br d, J = 19.0 Hz, H- eq), 3.45 (lH, m, H-3), 4.50 (lH, dt, J = 4.0 ~nd 18.5 3S Hz, H-l), 4.86 (lH, dd, J = 2.5 ~nd 18.5 Hz, H-l), 7.72 (2H, m, Ar-H), 8.18 (2H, m, Ar-H).
SUBST~ Si~ T
~l~6~a e r ' 2g~ . of (l'S,lR,3S) J~nd (l'S,l~ ,10-dioxo-3 .. ~1-1-(2',3',6'-trideoxy-3'-h ~ .'- L-l, ' ~,. ~) 3,4,5,10-~. ~ lII p! 12,3 cJ ~(BCH-2053) and (BCH-2052) OCH, OCH
[~--CHO I
OCH, OCH, ~ + ~"~
~' PNB~A
o 13 pNB~A PNB~A
ol~ 15 H~A HoNH~
S BCH-2053 B~H-2052 step 1: 3 ~ 59~
To a ~olu~ion of thc st~g ~ ~ (1.16 g; 6.44 mmol) ill; ' ~.~ ' (25 rnl) at 0C w~ added a 10 solutioll of ~ J~l magnesium chloride (2 M in THF; 6.4 r~l; 12.88 r~mol). The re6ultilllg mLl~ture was ~rod t 0C for 1 hour and t room , for 30 minutes. It w~ then ~ with ~ ~ chloridc solutioD nd ~ ' with ether. The . ' - ' orguuc l~ye~ were w shed with brinc nd dried over MgSO4 to yield a crude Icohol (1.29 g) wSicS was !~ l~ed in cther (40 ml). To thi~ oolution werc sdded ~ (777 111; 8.55 rnmol) nd boron I " ' 15 etherate (2.02 ml; 17.1 mrnol). The ro~wlting mi~tture wao stirr~d ~t room i . ., for 20 hou~ and wao then ~ ' - ' with - ~ oodium h- ' solution. It w 6 then ~ ' with ether and the ' - ' org~mic layers were w lihed with bmle nd dried over MgSO4. The cn~de product wa8 then SlJ~STOIl~T~ Si~EE~
WO 94/11382 PCI`/CA93J00463 ~146~4~
punfiod by colu~ on 8il~c~ gd using 20-30% ethyl ~ce~to in haune Y8 duent to give the title - . ' (607 mg; 409G over~ll).
lH NMR (CDC13) ~: 1.00 ~nd 1.05 (6H, 2d, J= 7 Hz, -CH~CH3)2), 1.84 (lH, ~ept., J = 7 Hz, CH-(CH3)2), 2.42 (lH, dd, J = 11 ~nd 17 Hz, H 4 ~s), 2.74 (lH, dm, J = 17 Hz, H~ oq), 3.22 (lH, m, S H-3), 3.76 (3H, ~, OCH3), 3.79 (3H, 8, OCH3), 4.56 (lH, dm, J = 16 Hz, H-l), 4.95 (lH, d, J = 16 Hz, H-l), 6.63 (2H, AB system, Ar-H).
- Step 2: (l'S, lR, 3S) and (l'S, lS, 3R)-~,JI ' 3 , .>~ /l 1-(2',3',6' ~ ~-3'-i~n (40:6~) Using the ~,. ' ~, ~' ' - ' i~ dep 3, o~u~ple 26, tho ~rting ' . from ~p 1 herein (300 mg; 1.27 mmol) ~fforded ~ cmde ' ~ ~ mLsture of gl~ ' ' ' . (515 mg) which w~ ctot with CAN ~ d in d~ 3, ac~mple 26, to ~fford ~ - title ~ ~
15 mLsture (450 mg; 59%) in ~ r~tio of (40:60) f voring the l'S, lS, 3R isomer which were used ~8 such for the ne~t -For minor isomer: lH NMR (250 MHz, CDCI3) o: 0.90-1.40 (9H, m, H-6' nd -CH(~3)2), 1.70-2.35 (4H, m, H-2', H-4 ~s nd C~-CH3), 2.62 (lH, m, H-4 oq), 3.80 (lH, m, H-3), 4.42 (lH, q, J =
6.5 Hz, H-S'), 4.S0-4.70 (lH, m, H-3'), 5.44 (lH, br 8, H-l'), 5.63 (lH, br ~, H-4'), 5.74 (lH, 8, H-20 1), 6.32 (lH, m, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
For m~jor isomer: 0.90-1.40 (9H, m, H-6' nd CH(-C~3)2), 1.70-2.3S (4H, m, H-2', H 4 a~c Jnt C~-CH3), 2.62 (lH, m, H 4 oq), 3.69 (lH, m, H-3), 4.50-4.75 (2H, m, H-3' nd H-S'), 5.42 (lH, br 8, H-1'), S.56 (lH, d, J ~ 3 Hz, H-4'), 5.88 (lH, 8, H-l), 6.43 (lH, br d, 1--7.5 Hz, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
Step3: (l'S, lS,3R)-S,10 :' 3 , ~,JI 1 (2',3',C' '~I ~-3' S -' . u ' d~
~ l L 1~ ~ ~., ) 3,4,S,10 1 ~.'r8 lII~! ' ~ 12,3-c]-p~r~n Using the ~ d- ' 1 in ~p 4, o~mple 26, tho duting quinone mLlcture f~m l~tep 2 herein (100 mg; .167 mmol) w~ tr~ted with l~ceto~y-1,3 b ~ (112 ~1; 1 mmol) in 5 ml of toluene to ~fford the title r . ' (34 mg pure + 9 mg of 1:1 mi~ture of d . ).
lH NMR (250 MHz, CD2C12) o: 1.01 nd 1.04 (6H, 2d, J = 6.5 Hz, ~H-(C~3)2), 1.31 (3H, d, J =
6.5 Hz, H-6'), 1.70-2.02 (2H, m, H-2' ~nd C~CH3)2), 2.13 (lH, t d, J ~ 3.5 nd 13 Hz, H-2'), 2.34 35 (lH, dd, J = 11.5 Ynd 19.5 Hz, H-4 ~), 2.78 (lH, dd, J = 3.5 Jnd l9.S Hz, H-4 oq), 3.76 (lH, m, H-3), 4.55 (lH, m, H-3'), 4.80 (lH, q, J = 6.5 Hz, H-S'), 5.42 (lH, d, J = 2.5 Hz, H-l'), 5.S8 (lH, d, J
--3 Hz, H-4'), 6.03 (lH, 8, H-l), 6.52 (lH, br d, J = 7.5 Hz, ~ , 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.28 (4H, s, PNB).
The socond ~
SU~ Y~ET
21~q8 ~-(l'S, lR, 3S)-5,10-dio~o- 3 . u~ 2'~3'~6' t.;~.~y-3'-t ~ '~ ~ ~UJI-L-~ )-3,4,5,10 1 ~.i.~lII p~ ' ~[2,3~1-pyr~n, obt~ined in 16% yield, h~d lH NMR
(250 MHz, CD2C12) ~: 0.90-1.10 (6H, m, CH~CH3)2), 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.40 (4H, m, H-2', (~CH3)2) ~nd H-4), 2.60 2.90 (lH, m, H-4), 3.87 (lH, m, H-3), 4.44 (lH, q, J = 6.S
S Hz, H-S'), 4.58 (lH, m, H-3'), S.42 (lH, br 8, H-l'), 5.69 (lH, br a, H-4'), S.89 (lH, o, H-l), 6.40 (lH, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.C6 (2H, m, Ar-H), 8.28 (4H, m, PNB).
step 4: (l'S, lR, 3S)-S,10 ' ~ l 1-(2',3',C' ~1 ~-3' ~' ~ . ~ ~ L-1~ ' ., ~ ) 3,4,S,lC I ' '~ lII p' - ~ 12,3 cl ~,. (BCI~-2053) Uoing the ~.. c e ~ dep 5, c~mple 26, the ~ting ~ Icohol from dep 3 herein (11 mg; .017 mmol) w~s t~tod wit~ N~OMe/MeOH (4.37 M; 1 1~1; .26 oq) to yield a~er column ' . O , ' ~ (79~ cetone in b~c) the title ~ , ' (5 mg; 59%), M.P.: 180-185C.
IR (ne~t): 3491, 3423, 3325, 2962, 2938, 1721, 1670, 1596, 1293, 1179, 982 cm~l.lH NMR (250 MHz, CD2C12): 1.00 uld 1.01 (6H, 2d, J ~ 6.5 Hz, -CH~C~3)2), 1.22 (3H, d, J ~
6.5 Hz, H-o'), 1.60-2.00 (4H, m, -C~CH3)2, H-2' uld OH), 2.27 (lH, br dd, J ~ 11.0 ~nd 19.5 Hz, H-4 ~s), 2.74 (lH, dd, J = 3.5 ~nd 19.5 Hz, H 4 oq), 3.58 (lH, d, J - 2.5 Hz, H-4'), 3.85 (lH, m, H-3), 4.25 (2H, m, H-3' ~nd H-S'), 5.52 (lH, d, J = 3.0 Hz, H-l'), 5.82 (lH, 8, H-l), 6.75 (lH, m, NH), 7.74 (2H, m, Ar-H), 8.03 (2H, m, Ar-H).
Step S (l~S~ lS~ 3R)-S,10~o~o-3 r ~ ~ JI 1-(2~3~6~ -31 ~ ~~ ~v I~-) 3~4~S~10 ~ lII p! ' - ~,3 c] 1 J - ~BClH-20S2) U~ing the ~ '- ' d i~ ~tep 5, e~mple 26, the st~rting r ~ ~ Jlcohol from d~p 3 hcrein (32 25 mg; .0495 mmol) ~ffordod ~fter fl~h v ph~ using 7 ~i cotone in ba zenc ~ dualt, ~ gummy product which W~8 ~- h ~1 in ~ nd ~,.. , ~ with pa~ne yielding the title product (16 mg; 6596), M.P.: 212-213C.
IR (ne~t): 3509, 3421, 3333, 2961, 2944, 1718, 1667, 1592, 1292, 1166 ~nd 979 cm~l.
lH NMR (250 MHz, CD2C12): 0.98 ~nd 1.00 (6H, 2d, J ~ 6.7 Hz, ~H(C~3)2), 1.36 (3H, d, J--6.5 30 Hz, H-6'), 1.7~2.00 (4H, m, ~_(CH3)2, H-2' ~d -OH), 2.32 (lH, dd, J--11.5 nd 19.5 Hz, H 1 u~), 2.76 (lH, dd, J 3.5 ~nd 19.5 Hz, H-4 oq), 3.61 (lH, br ~, H-4'), 3.74 (lH, ddd, J ~- 3.5, 6.5 ~nd 11.5 Hz, H-3), 4.24 (lH, m, H-3'), 4.59 (lH, q, J--6.5 Hz H-5'), 5.39 (lH, t, J z 2.0 Hz, H-l'), 5.97 (lH, s, H-l), 6.77 (lH, m, NH), 7.72 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
SU~ST~ EET
.
WO 94/11382 PCT/CA93/~0463 214l~5~3 F . 'r 30~ P tS) u~ S~ S~10 d- - 3 . ~ r .
(2',3',6'-trideo~-3'~ ~ . u ~o L l~ ' ,,. - ~.) 3,4,5,1~
lII p' - 12,3 cl ~, - (BC~-21S3) 9nd (BCH-21S2) 9Dd ~s-S,l~ 3 ~ 3,4,S,10 - 12,3 CJ rJ (B(~-2148) [~ I ~ 2 OCH3 OCH~ OCH~
CH~
CH~O O CH~O o PN80NHIFA PNPoN~FA
O O O O
PNBONHIF~ pNpoNHlFA
O o O O
HoNHlFA . HoNH~A
Sll!p 1: 5J~ ~- ~-3 To ~ solution of ~' ~ 1, ' , ' bromide (2.26 g; 6.4 mmol) in other (75 ml) at room (not totlllly soluble) wss added n-BuLi (2.5 M in he~unes; 2.03 ml; S. l mmol). The ~ulting mi~ture wss sti~rod at room ~ , ~i for 1 hour. A solution of S,8~' ' r-3-(1-acethyl)-' . (1.0 g; 4.2 mmol) w thcn dded to the yellow-or~ngc mL~ture and the ro~ulting solution5 w~ 6tirrod t room i , ~ for 3 hours. The mL~turo w~ then ~. ' d with NH4CI (s~t.) snd d with other. Tho c ' ' organic layer~ were ws~hed with brino and driod over Na2S04. The cn~do mi~cturo w~ then purifiod by column ' . ~ in 6ilica gel using 25% ethyl ~te in he~csno s eluent to afford the title , ' (541 mg; 55%)-SU~5~ L ~ 3~ T
WO 94/11382 PCr/CA93/00463 21 4~8 lH NMR (250 MHz, CDC13) ~: 1.86 (3H, 8, zC-CH3), 2.58 (lH, br dd, J = 11 ~d 17 Hz, H 4 a~), 2.85 (lH, ddd, J = l.S, 3.5 ~nd 17 Hz, H 4 oq), 3.77 nd 3.79 (6H, 2s, ~CH3), 4.00 (lH, dd, J =
3.5 ~nd 11 Hz, H-3), 4.66 (lH, br d, J = 16 Hz, H-l), 4.93 (lH, br 8, =CH2), 4.99 (lH, d, J = 16Hz, H-l), 5.09 (lH, br B, =CH2), 6.62 nd 6.67 (2H, 2d (AB), J -c 9 Hz, Ar-H).
S
Step2: ~ ` S,lQ ' 3 ~ 3,4,5,10 ~ 12,3-2148) U8ing thc ~ d in Btep 3, e~mple 26, t}# ~rting ' . (lS0 mg; .64 ~nol) nd ' -' (25 mg; .76 mmol) wore ~d with DDQ to ~fford ~ cmde ~duct (160 mg) which was then ~ted u ith CAN. ThiA re~ction yiddod n im~ro cmde quiwne (91 mg) which w~s ~d with 1-~ceto~y-1,3 h ~ 8 ~' ~' d in step 4, es~mplc 26, ~ g ~ ~
(0-2% ethyl ~to in toluene) the title ~ ' ~8 18 mg of sUghtly impure form nd S mg of purc product (13 % overdl) lS lH NMR (CDC13, 250 MHz) o 1 87 (3H, 8~ ~C~3), 2 49 (lH, dd, J ~ ll S nd 19 5Hz, H-4 uc), 2 84 (lH, dd, J = 3 5 ~nd 19 5 Hz, H-4 eq), 3 61 (3H, 6~ -OCH3), 4 50 (lH, dd, J = 3 5 ~nd ll S Hz, H-3), S 00 (lH, s, =CH), S lS (lH, 8~ ~CH), 5 63 (lH, 8, H-l), 7 7S (2H, m, ~r-H), 8 10 (2H, m, Ar-H).
20 step 3 (l'S, lS, 3R)-S,~ 3 , , Jl 1-(2',3',~'-trideo~-3'-FO11G.. g the p.. ~ ' ' 'x ~ in the f~;t p~rt of step 3, o~mplc 26, the st~ng ' from ~tep 1 horein (2S0 m~; 1 07 mmol) w s tro tet with ~-2,3,6 t~;~A~-3 t ~ .~ ~ ' 4.~ yl L 1~ ' r ~ ~ (461 mg; 1 17 mmol) nt DDQ (337 mg; 1 49 mmol) in ~ (20 ml) ~ g 4A ~ ieve~ (S00 mg) to yielt ~ ' r on silic~
gd using 2S % othyl Jcotdo in l~ne with 1 % ~ ' the title ~ 8 ~ tu~e with it6 (l'S, lR, 3S) ' - (1 1; 310 mg) Another t~CtiOII g vo pure titlet c ~ (131 mg; 199G) lH NMR (2S0 MHz, CD2C12) o 1 22 (3H, t, J - 6 S Hz, H-6'), 1 83 (3H, B, =C~3), 1 75-2 20 30 (2H, m, H-2'), 2 48 (lH, tt, J ~ 12 nt 17 S Hz, H~ ut), 2 89 (lH, td, J ~ 3 5 Ult 17 5 Hz, H-4 oq), 3 77 (3H, 8, OCH3), 3 78 (3H, ~, OCH3), 4 40-4 65 (2H, m, H-3 ~nd H-3'), 4 73 (lH, q, J--6 5 Hz, H-S'), 4 92 (lH, 8, ~CH), S.O9 (lH, ~,--CH), 5 42 (lH, br 8, H-l'), 5 S7 (lH, d, J--3 Hz, H-4'), 6 12 (lH, 8, H-l), 6 31 (lH, br t, J = 6 Hz, N-H), 6 73 ~nd 6 79 (2H, AB 1 ' ' Ar-H), 8 27 (4H, m, PNB) 3~ The (l'S, lR, 3S)-5,8 ' ' ~~3 r -r ~1 1-(2',3',6' L~IC~A~-3~-t ~ q~_o_p_ ,I-L 1~ t lH NMR (CD2C12, 250 MHz) ~ 1 10 (3H, d, J -6 5 Hz, H-6'), 1 83 (3H, 8, ~C~3), 1 90-2 2tl (2H, m, H-2'), 2 39 (lH, dd, J ~ 12 ~t 17 5 Hz, H-4 ~s), 2 89 (lH, dd, J--3 5 u~d 17 5 Hz, H 4 oq), 3 76 (3H, B, OCH3), 3 77 (3H, 8, OCH3), 4 35 (lH, q, J = 6 5 Hz, H-S'), 4 50-4 70 (2H, m, H-3 ~nd H-3'), 4 90 (lH, br 6, =CH), S 10 (lH, br 6, SUEST~ ~ ~7~ ET
WO 94/11382 2 1 g ~,~ 4 ~ PCI'/CA93il)04i63 =CH), 5.38 (lH, br 8, H-l'), S.54 (lH, br 8, H-4'), 5.94 (lH, 8, H-l), 6.31 (lH, m, N-H), 6.71 ~nd 6.77 (2H, AB sy~tem, Ar-H), 8.27 (4H, m, PNB).
Step 4: (1'S, lR, 3S)-S,10 :'- 3 ~ 1 1-(2',3',6'-1 ~I ~-3'~ " ~ ' ' 4'-0 ~ ' yl L l~ ' IJ - ` 3,4,S,10 1 ~.~. lII ~r " ~ 12,3-c]-p~ll Using th,c ~,mc ~ ~ ' ' - d in step 6 of thi~ _ , ' e, thc ~rting ' . from step 3 hercil~ (80 mg; .13 mmol) fford~ fte,r CAN ~ ,d Diels-Aldcr thc title produc,t (35 mg; 42%
10 ova~ll) cont~ tod by whd loolcs lilce ~gl~_ ~ systcms.
lH NM,R (250 MHz, CDC13) o: 1.17 (3H, d, J = 6.S Hz, H-6'), 1.87 (3H, 8, =C-CH3), 2.09 (2H, m, H-2'), 2.45 (lH, m, H4 u~), 2.90 (lH, m, H4 eq), 4.34 (lH, q, J--6.5 Hz, H-5'), 4.50-4.75 (2H, m, H-3 ~nd H-3'), 5.00 (lH, 8, =C-H), 5.17 (lH, 8, =C-H), 5.44 (lH, br 8, H-l'), 5.72 (lH, ~, H-4'), 5.99 (lH, 8, H-l), 6.40 (lH, br d, J = 7.5 Hz, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H), 8.28 15 (4H, m, PNB).
Step S: (l'S, lR, 3S)-!;,10-dioxo-3 ~ l 1-(2',3',6'~ -3'-L-~
L l~ ' .J. ~) 3,4,S,10 t ~d o llI ~ 12,3 ~] ~. (BCH-21S3) 20 Usmg the ~ , A~ d ill ~tep 3, c~c mple 32, thc d~rting p- ' ~Icohol from ~tep 6 herein (dightly impurc, 30 mg; .047 mmol) ~ffordod thc title ~ . ~ (11 mg; 48%), M.P.: 170C (dec).
IR (ne~t): 3417, 2936, 1716, 1664, 1596, 1293, 1167 ~nd 983 cm~l.
lH NMR (250 MHz, CDC13) o: 1.22 (3H, d, J--6.5 Hz, H-6'), 1.70-2.10 (3H, m, H-2' ~nd O-H), 1.85 (3H, 8, - C-GEI3), 2.41 (lH, dd, J = 11.5 nd 19.5 Hz, H4 as), 2.89 (lH, dd, J = 3.5 and l9.S
Hz, H4 oq), 3.59 (lH, m, H-4'), 4.16 (lH, q, J--6.5 Hz, H-5'), 4.35 (lH, m, H-3'), 4.52 (lH, dd, J
= 3.5 nd ll.S Hz, H-3), 4.96 (lH, 8, ;CEI), 5.13 (lH, 8,--CH), 5.54 (lH, d, J = 3.5 Hz, H-l'), 5.93 (lH, 8, H-l), 6.71 (lH, br d, J = 8.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, ArH).
Step 6: (1'S, lS,3R)-S,10 ;d- 3 ~ 1 1-(2',3',6' i '~ ~-3' ~
4'-O I ~ Jl L ~ .` 3,4,5,10 ~ ' ~d ~ lII p~ ' ~ 12,3-c1-P~
To a solution of the st rting . from stc~ 3 hercin (120 mg; 0.19 mmol) in ~ I~ (4 ml) at 0C was ddod a solution of CAN (p~c~ ~d by ~ e c~c r~it~te (630 mg; l.lS mmol) in water (2 ml) nd th~ adding slowly 60dium ' (169 mg)). After thc ~d " the mi~ture was stined for 10 minutes nd was thcn .. ' - ' with ! ' ' ~ sodium L L solution. The product v~s e d with ~" ' ' - - and the . ' - ' orgsnic e~ctr cts were w~ihed with brine nd dried over Na2SO4 to yield ~ crudc quinone (112 rng) which W~8 ~ d in toluene (5 rnl) and re~cted with l-acoto~cy-1,3 ~ ' - (113 ~1; 1 mmol) ~t room I , c for 15 hours. After this SUBSTITUTE SHEET
W O 94/11382 PCT/CA93/00463 2 1 ~
timo, silict gd w~ ldod nd ir W~8 bubblod through for 30 minutes The rosidue w~ y~plied to silic- gel column ~nd duted with 0-5 % ethyl ~te in toluene ~rru ~g slightly impure title (54 mg) ~long with pu~s product (17 mg; totd yield 575~).
lH Nn~R(250 MHz,CDC13)~: 1.36(3H,d,J = 6.5 Hz, H-6'),1.86(3H, s, =C~H3),1.99(lH,br 5 dd, J = S nd 12.5 Hz,H-2' e~, 2.13(lH, td, J - 3.5 nd 12.5 Hz,H-2'~),2.52 (lH, dd, J = 11.5 - nd 19 Hz, H4 ~), 2.91lH, dd, J = 3.5~nd 19 Hz, H4 o~, 4.48(lH, br d, J ~ ll S Hz,H-3),4.62 (lH, m, H-3'),4.84(lH,q, J ~ 6.S ~ H-S'),S.UO(lH, br s, !CH), S 14 (lH, ~ 8, =C-H),5.47 (lH, br 8, H-l'),S.62(lH, d, J = 2.S ~ H4'), 6.13(lH, B, H-1),6.47(lH, ~ d, J = 7 5 Hz,-NE~, 7.78(2H,m, ~r-H), 8.12(2H, m, ~-H),8.29(4H, m, PNB) Step 7 (l'S, lS, 3R)-S,10 ' 3 ),, , 11 1-t2',3',C' i ~I ~-3' 1 L 1~ ) 3,4,5,10 1 ',d ~ ~ p! ' ~ [2,3-cl-p~n (BCH-21-52) Uung ~c ~ ' - d in dbp 3~o~Iple32,~edhning p ~ ' dcohol fi~m d~p6ho~m(16 15 mg; .0248 mmol) ~ffordod tho titlo ~ ' (11 mg; 9096), M P 102-105C
IR(~t): 3418,2934, 1718, 1669, 1295, 1167,982 nd965cm~l.
lH NnMR(250 MHz,CDC13)o: 1.42(3H,d,J = 6.5 H~ H-6'), 1.84(3H,~, C-CH3), 1.86(2H,m, H-2'),l.99(lH,d,J - 8.0 Hz,~DH),2.51(lH,dd,J = ll.S~ndl9.5 Hz,H-4~),2.89(lH,dd,J =
3.5 ndl9.5 ~ H-4o~,3.65(1H,m,H-4'),4.35(1H,m,H-3'),4.46(1H,dd,J = 3.5 ndll.SH~, H-3),4.63(lH,q,J ~ 6.5 Hz,H-5'),4.98(lH,~, CH~,5.12(lH,~ ~C~,S.43(lH,~ ~,H-l'),6.07(lH, 8, H-1),6.72(1H,m,-Nn~,7.75(2H,m,A~-H),8.12(2H,m,A~-H).
r p! 31~ of(l'S,lP ~S)-S,10 t- 3 ~ L .11 l-t2',3',6'-~ideo~y-3'-~ A ~ L l~ ' .J ~ ~) 3,4,S,10 1 ~d ~ p! ' - ~2,3 cl r.~- ~ (BClI-2128) Sl J~S~ ET
2 14 ~ ~ ~ 8 OCH, ~H, ~,0 OC~, CH~H~ OCH
CH,O O + CH,O o PNBONHIFA PNBONHlFA
.~H~
O O O O
pN~oNslFA PNBoN~FA
o o ~ \4 pNBoNHlFA ~o o ~OCH, O O
HoNHlFA
Step 1: (l'S, lR, 3S) ~nd (l'S, lS, 3R)-S,8 dimetho~-3 ~ 1-(2',3',6'-S i~n.
U~g the r ~ d- - ~ d LG dbp 2, c~Jrople 32, thc o~u~n~ _ (S00 mg; 1.98 mmol) rf~orded ~hkr f~h . , ~ (S-20% codone in benzene . g ~ bRcc of I - ~ -) the mic~ue of ~c ~ . ' (490 mg; 40% (-1:1)).
lH ~n~R (2S0 ~LF~ CD2C~2) ~: (for l'S, lR,3S): l.lS (3H, d, J = 6.5 H~ H-6'),1.7oL2.2S (2H, m, H-2'), 2.65 (lH, m, H-4 ~),3.10 (lH, m, H 4 oq~,3.76-3.78 (9H, I , . d ~Dngle~, CKCH3), 4.38 (lH, q, J = 6.S H~ H-5'),4.4S-4.85 (2H, m, H-3 snd H-3'),5.41 (lH, m, H-1'),5.57 (lH, m, H-4'),5.97 (lH, 8, H-1),6.45 (lH, br d, J ~ 7.5 E~ -NlH~,6.65-6.8S (2H, m, Al-H), 8.26 (4H, m, P~DB); ~ (for l'S, lS,3R): 1.22 ~3H, d, J 6.5 H~ H-6'), 1.70-2.20 (2H, m, H-2'),2.66 (lH, m, H-4 ~),3.10 (lH, m, H ~ oq~,3.76-3.78 (9H, . . - ~ sLngle~, CPCH3),4.45-4.85 (3H, m, H-3, H-llS
SU~ST~lJT~ T
~146~4~ e 3' ~nd H-5'), 5.42 (IH, m, H-1'), 5.57 (lH, m, H-4'), 6.16 (lH, ~, H-l), 6.45 (lH, br d, J = 7.5 Hz, -N-H), 6.65-6.85 (2H, m, ~r-H), 8.26 (4H, m, PNB).
Step 2: (l'S, lR, 3S) ~nd (l'S, 1S, 3R)-S,8 dioxo-~ L yl 1-(2',3',6'-trideoxy-S 3~ O r ~ ~I L l~ ' r~ ) 5J8 ,~
To ~olutio~ of the ~g ' _ from ~p 1 haein (475 mg 0.74 mmol) in ~ D (15 ~1) ~t 0C w~s ~dded ~ solution of C~N (L . d by ~ e ~c nit~tc (2.42 ~) ill w ter (7 10 ml) ~nd th~ ~ with odium ' L (652 mg) ~d olowly). ~fter thc ~ ' " the mi~ture w~ stirred ~t 0C for 15 minute~ nd W98 thell i ' - ' with - ~ sotium b L ~olution l~nd ' w th ~' ' ' . ' - The: ' - ' org~nic layer~ werc w shed with brinc nt dried ovcr Na2S04 giving a cmde mL~re of tlle titlc !, ~ (422 mg; 939G) usod ~ uch for the lle~ct rc~ction.
lH NMR (2SO MHz, CD2C12) o: 1.15 (3H, d, J = 6.5 Hz, H-6'"~), 1.27 (3H, d, J = 6.5 Hz, H-6', 15 O, 1.70 -2.25 (2H, m, H-2', ~ Jnd 2H, m, H-2', O, 2.S5 (lH, m, H~ ~, A nd lH, m, H-4 ~, O, 2.85 (lH, m, H4 oq, A ~nd lH, m, H-4 oq, O, 3~76 (3H, 8, OCH3, O, 3.77 (3H, 8, OCH3, O, 4.34 (lH, q, J 6.5 Hz, H-5', ~), 4.4~4.70 (2H, m, H-3' nd H-3, ~ ~nd 3H, m, H-3', H-3 nd H-5', O, 5.39 (lH, m, H-l', ~ nd lH, m, H-l', O, S.54 (lH, d, J -3H, H~', O, 5.57 (lH, d, J = 3Hz, H-4', ~O, S-80 (lH, 8~ H-l, ~O. S.9S (lH, 8, H-l, O, 6.60 (lH, m, NH, A nd lH, m, NH, O, 6.80 (2H, m, 20 Ar-H, ~ nd 2H, m, ~.r-H, O, 8.26 (4H, m, PNB, ~ nd 4H, m, PNB, O.
~ A i8 (l'S, lR, 3S) d-- nd B i8 (l'S, lS, 3R) :' . .
step 3: (l'S, lR, 3S~-S,10 ~- 3 ' ~ l 1-(2',3',C' ' 11 ~-3'-~ q'- F ~ l L l~ ' ., ~ ` 3,4,S,10 . ~ b 2S III p! '' ~ r~ c] IJ
Using Ihc ~ d in ~p 4, c~lc 26, thc ~tsrting quinonc f~m 8t~p 2 hcrcin (400 mg;
.658 mmol of a 1:1 mi~c of 1'S, lR, 3S ~nd 1'S, lS, 3R) fforded purc titlc product (13 mg) dong wit}l a -1:1 mi~ct~rc of (l'S, lR, 3S) nd (l'S, lS, 3R) i80mer8 (275 mg).
30 lH NMR (2S0 MHz, C1~2C12) ~: 1.18 (3H, d, J ~ 6.5 Hz, H-6'), 1.9~2.20 (2H, m, H-2'), 2.68 (lH, dd, J = 11.5 nd 19 Hz, H4 ~), 3.08 (lH, did, J ~ 4 ~nd 19 Hz, H-4 oq), 3.80 (3H, ~, OCH3), 4.38 (lH, q, J 6.5 Hz, H-5'), 4.57 (lH, m, H-3'), 4.75 (lH, dd, J ~ 4 nd 11.5 Hz, H-3), S.42 (lH, br s, H-l'), S.69 (lH, br s, H-4'), S.99 (lH, s, H-l), 6.42 (lH, br d, J ~ 7 Hz, -N~, 7.7S (2H, m, Ar-H), 8.08 (2H, m, ~r-H), 8.28 (4H, m, PNB).5 Step 4: (l'S, lR, 3S)-5,10-dioxo-3 ' ~ L ~l 1-(2',3',6',trideoxy-3'-h-~ r '~ L l~ ' ~,. ~ ) 3,4,S,10~h~dro-lII ~ID! '- ~ 12,3~1-p~no (BC~I-2128) S~ T~ 3 ~F ~ T
W O 94/11382 21~ ~ A ~ PC~r/CA93~00463 Using the ~.. ' e ~ d ill step 5, e~mple 26, the st rti~g ~ Icohol from ste~ 3 herein (12 mg; 0.018 mmol) ffordot ~fkr column ch.. ~ (10% ~cetone in ~ ), the title . _ ' (5 mg; 54%) ~ ~ ydlow solid. M.P. 92-105C.
lH NMR (250 MHz, CD2C12) o: 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.55 (lH, br 8, OH), 1.70-2.00 (2H, S m, H-2'), 2.66 (lH, dd, J ~ 12.0 ~nd 19.0 Hz, H ~ ~), 3.06 (lH, dd, J ~ 4.0 uld 19.0 Hz, H-4 oq), 3.59 (lH, br 8, H-4'), 3.79 (3H, 8, -CO2CH3), 4.17 (lH, q, J ~ 6.5 Hz, H-S'), 4.28 (lH, m, H-3'), 4.73 (lH, dsl, J = 4.0 nd 11.5 Hz, H-3), 5.52 (lH, br ~, H-l'), 5.92 (lH, 8, H-l), 6.75 (lH, m, -NH), 7.75 (2H, m, ~r-H), 8.05 (2H, m, ~r-H).
S U ~ T
:
2146~
F "r.~ 32: ~ . ' of (l'S,lR,3S) , ~ l [5,10-dioxo-1-(2',3',C'-: ~-3'-L '1l . - '~:t '1 1,-1,~ ' r~ ) 3,4,5,10 1 ~L., l~I l"! " -2,3~] ~". .,1] ' (BCH-2112) + ~0 ~~ .
OCH, OCH, OCH, ~+ ~0"~
O o O O
PNBONHIF~ pNBoNHlFA
O O
HoNH~A
S ~
step 1: 1~ 3-yl)-lce~oDe To ~ olutioo of the ~ting o~ler (1.0 g; 3.97 mmol) ~n t ' ~ ' (30 ml) ~t 0C w~ ~led , , ,1 _ c~loritlc (2M, 4.17 mmol). Thc mLsture w 8 s~d t 0C for 20 minute~i ~d Jlt room i . for 1 hour. It wss then 1 ' ' with L ' ' d chloride solution ~nd e~ ' with ~ Thc ~ ' org~ic l yer~ wer~ w-shed with ~ e uld dried over MgSO4 to fford dter 6. . thc titlc ~ . I (240 mg; 239~ (40% b~ed on S.M. .~._~ d)).
lH NMR (250 MHz, CDC13) o: 1.13 (3H, d, J--6.5 Hz, CH3~, 1.16 (3H, t, J ~ 6.5 Hz, C~3-CH), 2.S9 (lH, br dd, J--11.5 ~d 17 Hz, H 4 ~I-A)~ 3.04 (lH, dm, J ~ 17 Hz, H-4 eq), 3.17 (lH, m, ~-CH3), 3.76 (3H, 8, OCH3), 3.78 (6H, 8, OCH3), 4.17 (lH, dd, J ~ 3.5 nd 11.5 Hz, H-3), 4.64 (lH, br d, J ~ 16 Hz, H-l), 5.03 (lH, d, J = 16 Hz, H-l), 6.65 (2H, ~B system, Ar-H).
5,8 ' ' ~-3 .~ JVA,~ w~sobt~inedu;-b, p..' ~ ' Efirom~ ' of the G- _ ' rcye~lt.
lH NMR (250 MHz, CDC13) ~: 1.29 (3H, d, J = 6Hz, CH3-CH), 1.30 (3H, d, J = 6 Hz, CH3 CH), 2.74 (lH, br dd, J 5 11 ~nd 17 Hz, H-4 ~c), 3.05 (lH, dm, J = 17 Hz, H 1 eq), 3.7S (3H, 8, OCH3), SUI~ST~ 3 ~E ~ E~
WO 94/11382 PCI/CA93~'00463 ~146~8 3.78 (3H, 8, OCH3), 4.19 (lH, dd, J ~ ~, ~d 11 Hz, H-3), 4.65 (lH, br d, J = 16 Hz, H-1), S.04 (lH, d, J = 16 Hz, H-1), 5.15 (lH, ~opt., J = 6 Hz, C~-CH3), 6.64 (2H, AB system, ~r-H).
step 2: (I'S, lR, 3S) . .. ,11 [1-(2',3',6'~ideQ~-3'-t '~ . e~mido~'~p-S ~L ,~1 L 1~ ' ,, ) S,10 ~- 3,4,S,10 1 ' ~ lII "r ' [2,3 cl ,,. ,~II-lcetone To ~solutionof~-2',3',6' 1 ' ~-3' ~ L yl L-ly~r' ., (408 mg; 1.04 mmol) nd st rting Icotonc f~m ~p 1 herein (230 mg; 0.87 mmol) in ~- ' ' ~ (IS
10 ml), werc dded 4A molocul-r uove~ (400 mg) ult 2,3: - ~' ~5,6~ (270 mg; 1.2 mmol). The mL~turo w ~ ctirred t room l . for 14 h~s uld w then q ' - ' with ' ~ solutionuld ' with ~" ' ' . ~ Thc c ' org nic l~yerswerewsshedwith brine nd dried over N~2S04 to ~fford ~ cmde dduct (S90 mg) which W91; ~ d i~ (20 ml) t 0C nd tre~ .. with ~ solution of ceric llitrs~e (3.15 g; 5.7 mmol) in w ter lS (10ml) c g~odiuml L (847mg). ARerthe-'' themi~turew sstin~ddOCfor lS minutes nd w~8 i ' - ' with ~ N HC, 03 nd a ~ with ~ ' ' ' ~ The c ' - ' orgsnic l~yer~ were w~hed with brine ~nd dried over Na2S04 to fford ~ csude quinone mi~cture (SS7 mg) of which 100 mg (.16 mmol) were d l~ _1 in tolueDe (6 ml) u~d t~d with 1-~ceto~cy-1,3 t - (113 ~1; 1 mmol) t rt~om I . .i for 14 hours. Silic ud ws~ dded to the 20 m~ture ~nd ~ir w~s bubbled throu~h for 1 hour while toluene p~ly ~ The residue wss spplied to ~ column of silic~ gd nd dutsd with 0-1096 othyl ~te in tolueno ~ g the title c~ . ' (20 mg) slightly ~ ' by ih (lS, 3R) ' ~ (-3:1).
lH NMR (250 MHz, CDC13) ~: 1.00-1.30 (9H, m, H~' nd CH~C~3)2), 1.60 2.40 ~2H, m, H-2'), 2.52 (lH, m, H-4 ~c), 3.00-3.35 (2H, m, H-4 oq snd C~CH3)2), 4.32 (lH, q, J = 6.5 Hz, H-S'), 25 4.50-4.90 (2H, m, H-3 u~d H-3'), 5.44 (lH, br 8, H-l'), 5.75 (lH, br 8, H-4'), 6.06 (lH, 8, H-l), 6.49 (lH, br d, J ~ 7.S Hz, -NH), 7.78 (2H, m, Ar-H), 8.07 (2H, m, Ar-H), 8.27 (4H, m, PNB), spp~rent signds for (lS, 3R) ~' re: 6.22 (lH, 8, H-l) nd 6.58 (lH, br d, J ~ 7.5 Hz, NH).
Step3: (l'S, lR, 3S) , ~ (2',3',6' ~ 3' ~ ~ . u k L-1~ ) 5,10 ' 3,4,S,10 ~ '' ~ 12,3 cl ~J-BCH-2112) To ~ ~olution of st rtiny p.. ' Icohol from step 2 herein (20 mg; 0.0296 mmol) in -' (.3 ml):
.~b. r (1 ml) ~t 0C w~8 dded sodium ' in - -' (4.37 M; .7 ~1; .1 oq). The 35 mLlcture w 8 stirred ~t 0C for 20 minue~ ~nd w 8 then ;. - d with ~ d NH4C1 solution ~Dd was ' with ~' ' - - The e ' org~nic l~yers were wu;hed with bnne ~d dried over N~2SO4 to ~fford ~ crude ro6idue which w~s purified by column . O . ~ on silic- gel using 10%
~cetone in be~ne yidding the titled ~ . ~ (6.4 mg; 639G).
SuBS ~ E ~ r~ET
~1~6~4 8 lH NMR (CD2C12, 250 MHz), ~: 1.11 (6H, d, J = 6.5 Hz, ~H~CE~3)2), 1.20 (3H, d, J ~ 6.5 Hz, H~'), 1.65 (lH, s, OH), 1.75-2.05 (2H, m, H-2'), 2.48 (lH, dd, J = 11.5 snd l9.S Hz, H-4 a~), 3.01 (lH, dd, J = 4.0 nd l9.S Hz, H-4 oq), 3.15 (lH, 8ept., J = 6.5 Hz, CH~CH3)2), 3.58 (lH, d, J =
2.5 Hz, H 4'), 4.10 (lH, q, J - 7.0 Hz, H-S'), 4.28 (lH, m, H-3'), 4.68 (lH, dd, J ~ 4.0 ~nd ll.S
S Hz, H-3), 5.55 (lH, d, J ~ 3.5 Hz, H-l'), 5.97 (lH, 8, H-l), 6.72 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
E~cample 33: Prepu~on of (1'~;,1.';"~Tt) ~nd (1'~;,1P,~S) 5,10-dioxo-3-1 ~ -~) t~5 10 ~ . lII p~ - [2~cJ-p~:
(BC~-2122) ~d ~BCH-2121) OCH, OCH, ~ ~ol O o O O
~
O o O
HoNHlFA HoNH'lFA
BC~U2~ BG~-2121 1~ S~ep 1: (l'S, lR, 3S), Jnd (l'S, lS, 3R)-S,1~ ~- 3 ~ . bon~l-1-(2',3',6'-tri~eo~q-3',t '~ . ~ ' ~'-O ~ ' oL ,~1 L 1~ ' ,J :) 3,4,S,10-H~aphth)-12,3 ~; ~J
Using the ~ in dep 2, e~uDplc 32, the stuting ' . *~m ~tep 1, ~nplc 32, 20 (300 mg; 1.07 mmol) fforded ~ cmde ~ , d dduct (417 mg) which w~ tre~ted wit~ CAN to givc cmde quinone mL~ re (355 mg) of which 250 mg were re~cted with ~ ~ ~,' t4diene. Thi8 reaction SU~TiT~T~ ET
WO 94/11382 ~ ~ 4 6 ~i ~ 8 Pcr/cAg3~3 yidd~d ~ dightly impure mL~ture of the title ~ - ~ (113 mg; 15% o~er ll) (-55:45) f~roring the (l'S, lR, 3S) isomer.
lH NMR (250 MHz, CDC13) ~: (for l'S, lR, 3S): 1.15-1.42 (9H, m, H-6' Jnd CH{C~,3)2), 1.90-2.20 (2H, m, H-2'), 2.68 (lH"dd, J = 12 ~d 19 Hz, H-4 ~), 3.12 (lH, m, H-4 eq), 4.40 (lH, q, 1 =
6.5 Hz, H-5'), 4.50-4.80 (2H, m, H-3 nd H-3'), 5.18 (lH, m, C_{CH3)2), 5.44 (lH, br 8, H-l'), - 5.74 (lH, br s, H-4'), 6.03 (lH, ~, H-l), 6.55 (lH, br d, J = 7.S Hz, N-H), 7.77 (2H, m, Ar-H), 8.11 (2H, m, ArH), 8.27 (4H, m, PNB); (for l'S, lS, 3R): 1,15-1.42 (9H, m, H-6' uld CH(CH3)2), 1.9 2.20 (2H, m, H-2'), 2.69 (lH, dd, J ~ 12 rnd 19 Hz, H-4 alc), 3.12 (lH, m, H-4 eq), 4.50-4.80 (3H, m, H-3, H-3' ~nd H-5'), 5.18 (lH, m, C~,(CH3)2), 5.45 (lH, br 8, H-l'), 5.65 (lH, d, J = 3 Hz, H-3'), 6.18 (lH, 8, H-l), 6.61 (lH, br d, J--7.5 Hz, -NH), 7.77 (2H, m, Ar-H), 8.11 (2H, m, Ar-H), 8.27 (4H, m, PNB).
Step 2: (l'S, lR, 3S)-S,10 ~ 11 1-(2',3',6' t ' ~-3'-L-'` ~ ~ L 1~ ' rJ~ ) 3,4,S,lO~h~dro-lH-naphtbo ~2,3-c1-pyr~ (BC~-2122) U8i~1g the p,~ ~ A ~ d ill 8top 3, ac~mple 32, the st rti~g p.~ ~ . lcohol f~om ~tep 1 herei~
(113 mg; .16 mmol) fforded (~f~er multiple e' ~ ; using lOX ~cetone in benzene or in ~ e) the pure title _ . ' (7 mg; 8%). M.P.: 93-101C.
lH NMR (CDC13) o: 1.29 ~nd 1.33 (6H, 2d, J = 6.5 Hz, -CH-(C~,3)2), 1.33 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.10 (3H, m, H-2' nd O-H), 2.68 (lH, dd, J ~ ll.S ~nd l9.S Hz, H-4 A)~ 3.11 (lH, td, J
; 4.0 ~nd l9.S Hz, H-4 eq), 3.65 (lH, m, H-4'), 4.21 (lH, q, J--6.5 Hz, H-S'), 4.38 (lH, m, H-3'), 4.66 (lH, dd, J = 4.0 ~nd l l.S Hz, H-3), 5.18 (lH, sept., J = 6.5 Hz, C~CH3)2), 5.56 (lH, br 8, H-1'), 5.98 (lH, 8, H-l), 6.72 (lH, m, N~, 7.75 (2H, m, ~r-H), 8.10 (2H, m, Ar-H).(l'S, lS, 3R)-5,10-dioAo-3 r ~.I~A,~ 1-1-(2'~3'~6' h;~A~-3' 1 '' . mido-L-3,4,S,10 t ~ ' ' - [2,3-c1-pyr n(BCH-2121) w~8 isol ted fter mlllap10 ! ~ (5 mg; 6%). M.P.: 155C (doc).
lH NMR (CDCl3) o: 1.32 (6H, d, J--6.5 Hz, CH-(C~3)2), 1.41 (3H, t, 1 c 6.5 Hz, H-6'), 1.87 (2H, m, H-2'), 2.0S (lH, m, OH), 2.70 (lH, dd, J ~ 12.0 ~nd l9.S Hz, H-4 A)~ 3.10 (lH, dd, J = 4.0 snd l9.S Hz, H-4 oq), 3.63 (lH, m, H-4'), 4.32 (lH, m, H-3'), 4.SS (lH, q, J ~ 6.5 Hz, H-S'), 4.62 (lH, dd, J = 4.0 uld 12.0 Hz, H-3), 5.16 (lH, sept., J ~ 6.5 Hz, C_~CH3)2), 5.47 (lH, br 8, H-l'), 6.14 (lH, ~, H-l), 6.75 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.12 (2H, m, Ar-H).
SU~S~ T~ ET
WO94/11382 21~548 PCT/CA93/00463 F p!- 34~ of (l'S,1S)-5,10 :-- - 3,3 ~ 2',3'6'-L-' ~ (BCH-1697) 0~4 0~4 ~ J , ~H
OM~ Ob D
OMc OM~
¢S~3 ~ OMe ¦ NHIFA
~PNB 14 O O
O O o o H,C~j~ H,C z~
NHIF~ ¦ NHlFA
t~PNB CPNI~
,~
O O
H3C~I
HO NH~A
Under ~rgon ~ , 110 mg (2.90 mmol) of LAH were ~dded to 15 ml of dry ~
10 coolod to 0C. To tbiK ~olution w~s ~dded 0.450 ~ (1.45 mmol) of 5,8- " .r-3,3~is (dic~rbome~o~y)-isochroms~ d ill 15 ml of 1~. The I . ~ llowod to w~rm up toroom i . ~, ~d sti~ring w~s . ' for 3 hours. ~fter thd time, ~nother 160 mg (4.22 mmol) of I~H w~ then dded Jnd thc ~ction mi~c~re wui ~tirred for ~nother hour. After th~t time, the re~ction mi~cture w~ poured into 50 ml of ~ 0.1 N u~ueou~ solution of HCl. r~ - of the ~ueDus SUE~E~!TE S~EET
WO 94/11382 PCI~/CA93/00463 2~46~4~
l~ycr rc douc using CH2C12. The . ' org~nic layers re driod over N~2S04, filtered, 9~ d the solvent i6 removed. The isohted titled ~.--y~- ~ is used without further pu. fi~ (0.333 g; 909~).
NMR 1H (250 MHz) (CDC13.ppm): 6.64 (2H, 2d, ~ ~ ); 4.80 (2H, s, H1a- Hlb); 3.76 (6H, s, 2~0CH3); 3.71 (4H, m, 2{~H2-); 2.53 (2H, 8, 2sOH); 1.85 (2H, m, H4a-H4b).
s Step 2~ 3,3 bi~
Under ugon , ' .;, 0.333 g (1.31 mmol) of tho ~rting rn~i l from step 1 herein were phcod in 70 ml of dry THF. To this solution wcre then added 0.105 g (2.62 mmol) of NsH. After a few minutes 10 of firring, 0.41 ml (6.55 mmol) of McI were dded to the re ction mi~re nd 6tirring W~8 left for 1.5 hour. After that time, uK~ther 0.145 g of NaH nd 0.7 ml of MeI wcre ddod to the re~ction which was , ' ' sfter ~other hour of stirring. Aquoow HCl (0.1 N) wss then ddod snd c were done using CH2C12. Thc . ' ' orgsnic e~tr~cts were wYshod with n queou~ solution of sodium ' : ~ driedoverN 2S04, filtsred, ndthesolventw~sremoved. Theobt inedtitled: , 15 wss u~ed for ne~ct step without further ~ ol~ed pr~duct (0.470 g; ~99%).
NMR lH (250 MHz) (CDC13:ppm): 7.26 (2H, 2d, ~ ); 4.74 (2H, s, Hl~-Hlb); 3.76 (6H, 2~, 2~0CH3); 3.54 (2H, d, J = 9.7 Hz, -CH2- side ch~in); 3.41 (2H, d, J ~ 9.7 Hz, -CH2- side chain);
3.38 (6H, ~, 2~cOCH3); 2.64 (2H, 8, H4a~H4b)-IR (film) (cm~l) 2925 (CH ~ c), 1580 (C~C), 1475 (CH2), 1450 and 1360 (CH3), 1100 ~nd 1248 20 (C-0).
Step 3: (1'S, 1S)-~ -3 ~ ~ ~l 1-(2',3',6'~ -3'-2S Under rgon ,* ~, the ~ " .. g ~gonts: product from step 2 hercin, 0.477 g (1.70 mmol), 2,3,6 t~ -3 ~ - ' q 0 ~ .L .yl ~-L 1~ -' r~ ~ 0.378 g (2.00 mmol) nd DDQ 0.452 g (2.00 mmol) were ~ d in 50 ml of ~' ' '- . ' - The ro ction mi~cture w~s stirred t room i for a period of 16 houra Aher th~t time, n e~ccoss of DDQ w then ~dded to the ro ction misturo nd ~tirri~ w~ left for nothcr hour. The re ction mu~tur~ WS8 tben ~
30 with ~ NH4Cl nd ~ of the qucow l~y W98 done u~ing CH2C12. The ~ org~nic l~yers v~e~e dried ov N~2S04, filterod nd the solvent w~ removed. The crude m~teri~l W~8 purified by fls~h ' ~" . ' ~, ~' ' -- ~h.~l scet~te (70:30) then (60:40). The obt~ined titled ~ , ~ W~8 ~ pdc ycllow solid (0-434 8; 39%)-NMR lH (250 MHz) (C6D6; ppm): 7.89 (2H, m, - . ), 7.68 (2H, m, 9 . '- )~ 6.53 (2H, m, 35 ~ . - ), 6.52 (lH, NH), 6.08 (lH, s, H1), 5.62 (lH, 8, H1.), 4.70 (lH, m, Hs.), 4.60 (lH, m, H3.), 3.82 (2H, m, CH2-OMe), 3.74 (lH, m, H4~), 3.55 (2H, m, CH2-OMe), 3.48 nd 3.42 (6H, 28, 2~c0CH3), 3.40 (2H, m, H2., nd H2.b), 3.18 u~d 3.11 (6H, 2~, 2~c0CH3), 2.13 (lH, m, H4"), 1.86 (lH, m, H4b), 1.21 (3H, d, J e 6.2 Hz, CH3 6ug~r).
SUE~S-r~ t ~
214~8,~
Sbp 4: (l'S, 1S)-5,a~diox~3,3 ~ 1 1-(2',3',6'-trideoxy-3'-l. '' . ~
4'_0 ~ ,I L 1~ ' ~,. ) .
Thc st~ting m~ten~l from dep 3 horein, 0.430 g (0.65 mmol), W~ d in - 1- t 0C. A
S ~olution of N~ICO3 0.107 g (1.30 Dl) in 7 ml of w~tcr w~ then ~dod Jnd the oolution wu~ 8ti rod for 10 ~ute6. Aftcr th~ tunc, l.OS3 g (l.9S mmol) of CAN tilutod in 12 ml of w tor were thcn ~dded to thc rellction ~e in ~ m~ner. The re~tion w c ' ~fter 10 minute~. A very diluted 801ution of N HCO3 in w tcr wrs thcn dded to thc re ction mL~ture. r - Of thc resction mi~ re were dane using CH2C12. The ~ ' ' o~g~nic l~yers ~ driod over N 2S04, filtered nd ihe solvent w~ rsmoved. The titled . ' w~8 u~ed for ne~tt step without funher ~ - (0.387 g;
95%).
NMR lH (250 MHz) (C6D6; ppm): 7.94 (2H, d, J ~ 7.5 Hz, ~ ~ --), 7.75 (2H, d, J ~ 7.5 Hz, - ), 7.42 (lH, m, NH), 6.20 (2H, m, qui~one ring), 5.98 (lH, ~, Hl), 5.92 (lH, 8, Hl~), 5.41 (lH, ~, H4.), 4.90 (lH, q, Hs~), 4.67 (lH, m, H3.), 3.47 (2H, CH2-OMe), 3.29 (2H, CH2-OMe), 3.16 lS (3H, 8, OCH3), 3.11 (3H, 8, OCH3), 2.50 (2H, 2d, H2.~, H2.b), 2.22 (lH, m, H4,), 1.97 (lH, m, H4b), 1.27 (3H, d, J = 6.3 Hz, -CH3 ~ug~r).
StepS: (l'S, lS)-S,10 ~- 3,3 ' ' ~ rl 1-(2',3',6' ~ -3'-1- r ~ Jl L 1~ ) 3,4,S,10 1 III ~ 2~cl P~
Under rrgon ~ . ' 0.173 g (0.27 mmol) of the product from stop 4 ~sin W~ ,d in 10 ml of dry toluene. To thi~ olution w~ ddod 0.2 ml (1.65 mmol) of l~ceto~y-1,3 - The ro ction mu~ture W-8 left stimng o.. t room i . ~. Silic~ gel w~s then ~ddod to the rulction mDC~re 25 nd rir w 8 b~bbled in it for ~ p4riod of 2 hours. Whitout . g the ~olvent, tl~e ro~ction mLl~ture wr8 put on top of ~ gd column uld tolue~e w~ u~ed r8 the f~r~t duent. To- - ~ .~l ~cotde (1:1) v~ then wod to dute the do~ired . , ' The titlod c ' W~ ol-tod (0.06 g, 32%) yellow lid.
NMR lH (2S0 MHz) (CD2C12; wm): 8.29 (4H, m, . ) 8.07 (2H, m, ~ ), 7.76 (2H, m, . ), 6.4S (lH, d, NH), 6.05 (lH, 8, Hl), S.70 (lH, 8, Hl-), S.43 (lH, 8, H3-), 4.82 (lH, m, Hs.), 4.52 (lH, m, H4.), 3.27-3.S2 (4H, m, 2~t CH2- ude Ch~in8), 3.3S (3H, 8, OCH3), 3.27 (3H, 6, OCH3), 2.72 (2H, 2d v. . ' ,1~ - a, H4~ uld H4b), 1.87-2.18 (2H, m, -CH2- sug~r), 1.28 (3H, d, J =
6.5 Hz, -CH3 8Ug r).
3S Step 6: (l'S, lS)-S,10-dioxo-3,3 ~ l 1-(2',3',6'~ -3'-1697) S~ E~T
~0 94/11382 PCI`/CA93/00463 ~ 21gLg~48`
Under rgon 9' ~ the product from dep S hercin, 0.06 g (0.09 mmol~ wu; ~ ~i m mLlcture of S ml of dry ' -' nd 2 ml of dry THF. This solution was cooled to 0C. 2 ~ of ~ 4.37 M
solution of ~odium ' '- in ' -' wcre then ddcd to thc rosction mi~re. Thc re~ction w~s . ' ~ d in 10 minutc6, it w thcn ;, ' ~ ' by rdding quoous NH4Cl. r of the squeous S layer w~u done u6ing ' ' ' ~ ' - Tl~e ' ' org~nic l~yers werc dried o~rer N~2S04, filtered nd thc ~olvont w removed. The crude m tori-l w~ then purificd by fluh ~' . O , ' ~, . ' ' yl - - :" ' ~ ' - (3S:75). Tho i~ol ted titled, . ' w~ yollow solid (0.03 g, 67%).
NMR lH (250 MHz) (CDC13; wm): 8.05 (2H, m~ ~ ), 7.74 (2H, m, - ) 6.81 (lH, d, 10 NH), 6.00 (lH, s, Hl), 5.49 (lH, d, J = 2.8 Hz, Hl.), 4.58 (lH, q, Hs.), 4.23 (lH, m, H4.), 3.60 (lH, d, J = 2.3 Hz, H3~), 3.45 (2H, m, -CH2{0Me, 3.37 (2H, m, -CH2{0Me)), 3.34 (3H, ~, OCH3), 3.25 (3H, 8, OCH3), 2.71 (2H, d, 1 ~ 3.5 Hz, H4y nd H4b), 2.09 (lH, ~d)S, OH), 1.79 (2H, m, -CH2- ~r), 1.32 (3H, d, J = 6.6 Hz, ~H3 sug r).
IR (film) (cm~l): 3450 (OH bo~ded), 2950 (CH liph~tic), 1675 (C=C), 1000 nd 1290 (C-O).
Sll~S ~ ~T~TE ~ ET
WO g4/11382 PCl`/CA93/0(~463 ~1~6548 F. p!- 3S~ of (l'~,lP,~ S,10 ~ ~ . bJI-1-(2',3',6'-trid~eox~-3'-L ~ L l~ ' . J- - - ) 3,4,S,10 ~ b~
P~ (BC~-2091) O~ 4 ~ ~ ~
¢f ~ 1 . ~ 2 ¢h ~ 0~ O~Sc 0~ ~ OM~ ~ OMc ~ + ~'~ ¢~
OA~e O Ol~S O O~b H,C ~ H,C~
NHlF~ N~IP`A
\5 O ~ O ,~
~ ~0 O O O O
}I,C~ H,~
OPNB O~NB
O O
H,C ~
Step 1: 'b~l 2-(2',S'-dimetb /"' ,~
Undcr ~rgon . ~, 3.08 ml (26.16 mmol) of r rJ w~8 sddod to 85 ml of THF
10 ".~ to 0C. Il-BuLi lO.S ml (26.16 mmol) w~ then dded to thi~ solution nd thi8 mi~cture was then stirred for 30 n~inute~;. ~r th~t time, tdle rc~on mLstuse W~18 coolod to -78C ~d the ester S.00 g (23.78 mmol), 208-186-01 in 65 ml of THF w~ then uided ~L. r ~ ;o~. Afte~ tlle - ~ " the mL~ture w~ ~itirrod for 5 m~utes befote HMP~ 4.55 ml (26.16 mmol) w~ ,~dded. AP~ ~nother 10 mmute8 of s~ng r . e ~ ~ ~ s.o ml (47.56 mmol) w s thcn ddod to the re-ction SU~ST~ ~ ~T~ 5~EET
2146~48 ~ ture. The re ction mnltture WY6 then ~tirred for 30 minute6 before rev l of thc dry i~ _ I b~th to ~llow the I . to re c~ room I A ' ~ nd the reYction W~8 - ~ by TLC. The re~ction mLlcture w~s left s~rring ~t room l , ~ for 15 hours. The rction mucture WY6 then q~ ' - ' by ~dding ~queow NH4CI Jnd e with other. The c ' - ' org~ uc l-yers were S w~shed with brine, d ied over N 2S04, filtered nd the sol~ent w~8 . ~l~ The crude w~6 punfied by fl~h ~ u6ing ~ ~1 cot~ 8 eluent; 3.36 g of p~lro titlod c , I ~ white solid were o~ - d NMR lH (250 MHz) (CDC13; ppm): 6.84 (lH, m, uom tic), 6.76 (2H, m, ~ ~ ), 3.90 (lH, t, J
~ 7.6 Hz, H3), 3.77 (3H, 8, OCH3), 3.75 (3H, 8, OCH3), 3.64 (3H, 8, (C02)-CH3), 2.03 (lH, m, 10 H3"), 1.72 (lH, m, H3b), 0.88 (3H, t, J ~ 7.3 Hz, -CH3 termin~l).
step 2: 2-(2',S'~
Under rgon -, ' e, the prodwt frorn step 1 herein, 3.36 g (14.08 mmol) w o ~ d in 100 ml of ~' ' ' ~ This solution wss cooled to 0C ~nd DIBAL-H, 31.0 ml (30.98 mmol) w~6 ~dded ir 15 d,~.. m~nner. Tho ~ction w~u . , ' fter 20 minutos 80 HCI lN w~s ~en ~d to the ro ction mi~ture ~d ~ - wer~ done using ~' ' ' ~ . ' -. The ~ ' - I org nic l-yors were dried over Na2SO4, filtcred, u~(d the oolvent W~8 rernoved. The isol~ted titled ~ ' w96 u6ed for ne~ct step without furhtor ~
NMR lH (250 MHz) (CDC13; ppm): 6.76 (3H, m, ~ ~ ~ ), 3.77 (3H, 8, OCH3), 3.76 (3H, s, 20 OCH3), 3.75 (2H, m, Hl, nd Hlb), 3.19 (lH, m, H2), 1.74 (2H, m, H3, snd H3b), 1.51 (lH, t, J =
6.2 Hz, OH), 0.85 (3H, t, J = 7.4 Hz, -CH3 1 1).
Step 3~ d- ' ~ q ~5JI
2S Under Jrgon ~, ' the product from step 2 ~erein, 2.74 g (13.03 mmol) W98 ~ ~ in 55 ml of dry ether. n- ~ ~ m~ne 1.65 ml (19 55 mmol) nd boron trifluoro o~te 4.9 ml (39.09 rnmol) were thon ~Idded to this lution. The obtuned re~on mLlcture wss left stirring u.. _' The re~ction mL~ture W98 ~1 ' - ' using aqueous N HCO3 nd ~. were done u~ing olher. T~e c ' - ' orgsnic eJtt~cts were dried over Na2S4, filtered, snd the solvent w~8 ~moved. T~e ra~due was 30 punfied by fl~;h ç' . ~pby using ~ dh.~l cot te (80:20) snd (70:30) 8 duent. Tho isolsted titled product wss ~ whito ~olid (1.56 g; 54%).
NMR lH (250 MHz) (CDC13; ppm): 6.64 (2H, m, ~ ), 4.85 (lH, d, J ~ 16.1 Hz, Hl,), 4.55 (lH, d, J--16.0 Hz, Hlb), 4.09 (lH, d, J ~ 11.3 Hz, H3~), 3.79 (3H, 8, OCH3), 3.75 (3H, s, OCH3), 3.58 (lH, dd, J1 = 2.7 Hz, J2 = 11.4 Hz, H3b), 2.62 (lH, m, H4), 1.67 (2H, m, -CH2-35 ethyl), 1.01 (3H, t, J = 7.5 Hz, -CH3).
Step 4: (l'S, lR, 4R)-5~8 ~ 1 1-(2',3',G' h 3 ~-3' 1 '` ~ ' ~'-SU~ S~EEET
21~6~;~8 The titled c ' was obhinod by ~pplying thc ~ 7 from step 3, e~smple 34, t~ the 60cL~
f~om step 3 herein.
NMR lH (2S0 MHz) (C6D6; ppm): 7.81 (2H, d, J = 8.8 Hz, - ~ ~~), 7.65 (2H, d, J = 8.9 Hz, 5 _~ ), 6.48 (2H, dd, Jl= 9-0 Hz, J2 = 18.1 Hz, . ), 6.3S (lH, s, Hl), 6.26 (lH, d, J =
6.9 Hz, NH), S.81 (lH, 5, Hl~), S.S2 (lH, ~, H3.), 4.7S (lH, q, Hs.), 4.S8 (lH, m, H4~), 4.24 (lH, dd, Jl = 2.9 Hz, J2 ~ 11.4 Hz, H3~), 3.88 (lH, d, J = 11,.4 Hz, H3b), 3.38 (3H, 8, OCH3), 3.37 (3H, 8, OCH3), 2.84 (lH, m, H~), 1.89 (2H, m, ~I2~ r), 1.85-l.SS (2H, m, -CH2- side c~i 1.18 (3H, d, J = 6.6 Hz, -CH3 ~ug r), l.OS (3H, t, J 7.3 Hz, -CH3 sido ch-in).
10 (l'S, lS, 4S)-S,8 " ~ 2',3',6' t~;dc~ -3' t ~ . '- ~'-0 p ~ 1 L-NMR lH (250 MHz) (C6D6; ppm): 7.81 (2H, d, J--8.7 Hz, ~ ), 7.61 (2H, d, J - 8.7 Hz, ~ ~ - ), 6.54 (2H, m, a.~ ), 6.55 (lH, NH), 6.09 (lH, s, Hl), 5.69 (lH, 8, Hl~), 5.45 (lH, s, H3-), 4.72 (lH, m, H4~), 4.32 (lH, m, Hs~), 4.26 (lH, dd, Jl = 2.9 Hz, J2 ~ 11.4 Hz, H3a)~ 3.89 lS (lH, d, J c 11.2 Hz, H3b), 3.4S (3H, ~, OCH3), 3.39 (3H, s, OCH3), 2.80 (lH, m, H4), 1.88 (2H, m, -CH2- ~ugar), 1.82 (2H, m, {~H2- side ch in), 1.12 (3H, d, J ~ 6.4 Hz, CH3 sugar), 1.04 (3H, t, J =
7.4 Hz, -CH3 side chain).
Step 5: (l'S, lR, 4R)-S,8 ~ b;.~l 1-(2',3',6' ~ -3~ ~ ~ u df ~'-O-~
~ .11 L 1~
The (l'S,lR,4R) ~ ' *om s~p 4 hescin W9~ d in step4, c~mple34. Thetitlod~ J ~
NMR lH (250 MHz)(C6D6;ppm): 7.80(2H, d, J 8.9 Hz, - ~ ~), 7.62(2H, d, J--8.8 Hz, 25 9 " ), 6.89(lH,d,J--6.9 Hz,NE~,6.04 (2H, dd, Jl = 10.1 Hz, J2 = 18.3 Hz, quinone ring), 5.87(1H,s,Hl),5.63(1H,~,Hl~),S.16(1H,s,H3.),4.80(1H, q, J ~ 6.S Hz,Hs~),4.56(1H,m H4.), 3.75(lH,dd,~l ~ 3.0 Hz J2 ~ 11.6 Hz,H3~), 3.54 (lH, d, J--11.5 Hz,H3b),2.25(lH,m, H4), 1.89(2H,m,-CH2- wgar), 1.47(2H,m,-CH2-sidcch~in), 1.27(3H,d,J = 6.5IIz,-CH3IRlg9 )~ 0.86(3H, t, J . 7.3 Hz,-CH3 ddcc~in).
Skp6: (l'S, ~ 4R)-S,10~ 1 1-(2',3',C'~ -3'~
~b~bou~yl-L1~ ' ~, ~ P 3,4,S,lOt ',.'~ LH~ph~ 2~ ~]~,.
The titled - . ' w_sobbined in 1996 yiddÇo11u. e ~, c - - ~ ~ b~een the quinone from step 5 35 hera~ ~nd 1~CO~OA~L 1~ ~, 98 POr ~ a8 d~ Yd instepS,e~mpb34.
Nn~RlH ~S0 MHz)(C6D6;ppm): 8.02(2H,m,~ --),7.77(2H,d,J = 8.9 Hz,~
7.63(2H,d,J ~ 8.9 ~ ~ ),6.02(2H,m, ~ ),6.53(lH,d,NE~,6.11(lH,s,Hl), 5.67(lH, d, H1~), 4.97(lH, 8, H3~),4.95(1H,m,H4~),4.49(1H,m,Hs~),3.83(1H,dd,H3a),3.60 SU~ ET
WO94/11382 2 1 4654 a PCI/CA93/00463 (lH, d, J--11.4.Hz, H3b), 2.S0 (IH, m, H4), 1.95 ~nd 1.72 (2H, 2dd, -CH2- side chain), 1.58 (Z~, m, -CH2- sugar), 1.31 (3H, d, J - 6.4 Hz, ~H3 sug~r), 0.92 (3H, t, J 5 7.3 Hz, ~H3 side chain).
Step 7: (l'S, lR, 4R)-S,10 ~- ~; b~l 1-(2',3',6'-~rideo~-3'-h ~
1~ ~ . J ' r) 3,4,S,10 ~ ', d a lII ~ p~ ' - t2,3-cJ p~r~n (BCH-2091) Thc titled _ ' was obtainod vi~ of the tricyclic ~54 ~ ~ from step 6 herein a~ per p.~ ' c from step 6, o~mple 34.
NMR lH (250 MHz) (CDC13; ppm): 8.10 (2H, m, ~ _ ), 7.75 (2H, m, . ), 6.72 (lH, d, 10 N~, 5.91 (lH, ~, Hl), S.41 (lH, 8, Hl~), 4.S9 (lH, q, J = 6.6 Hz, Hs.), 4.46 (lH, m, H4~), 4.32 ~lH, m, H3~), 4.03 (lH, dd, Jl ~ 3-0 Hz, J2 = 11.6 Hz, H3~), 3.85 (lH, d, J ~ 11.6 Hz, H3b), 3.64 (lH, m, OH), 2.66 (lH, m, H4), 1.99 (lH, d, J ~ 8.3 Hz, -CH2- side ch in), 1.86 (2H, m, H2.8 and -CH2- side ch~in), 1.65 llH, m, H2,~), 1.41 (3H, d, J = 6.5 Hz, -CH3 sugar), 1.06 (3H, t, J = 7.3 Hz, -CH3 ~ide chain).
15 IR (film) (cm-l): 3422 (OH), 2932 (CH ~liphdic), 1710 (C=O), 1668 (C=C), 1299 nd 1165 (C-O).
SU~S~ ~ .T
2146~8 F ,'r36: E~ of(l'S,lP ~S)-S,lO~oxo-~ p~ (2',3',G'-~ideoxy-3'-~ ~ .' L 1~ ' ~J. - ~) 3,4,5,1C1 ~d lII "r " - 12,3~1 p~ran 0~ Ob~ OMe ¢1 1 ~ f `OPh 2 ~OPb O~Ae Ol~k OMe 0~ 0~
~h ¢Ç~``~OPh O~k O OrAc O
H3~J H,C~
NHlFA NHTF~
OPNB OPNB
O O
~h 5 ~h O O O O
H,(~l H,C~J
llHIFA NHIF~
P~ OPNB
o ~h O O
H~
HO NHIF~
S ~
Sep 1: a-pbeno~gnu~hyl-2,5~d~neLhoxy p~ Icohol To a solution of 1,~ ~ (2.0 g; 14.5 mmol) in l ' .~ ' at 0C was ddod n-butyl-10 lithium (2.5 M in he~ne; 5.8 ml; 14.5 mmol). The mLsture w~6 w rmod to room l . ~ nd s~Ted for 4 hours. It w~ then cooled to -78C nd 1,2 opo~cy-3 r~ y ~ 95 g; 13 mmol) w9s dded followod by bo~on t " ' etherate (1.85 g; 13 mmol). The .~, " e mi~cture wJs stirred at -78C for 2 hours. It w~ t. ' ' unth ~' N~HC03 solution uld ~ ~ with SUBS t ~ ffE~T
WO 94/11382 2 14 6 ~ a PCT/CA93/00463 The ~ ' orgsnic lsyets were ws~hed with ' L brine snd were dried over MgSO4. The crude rosidue wss punfied by column ~ ' ~ O ,nb~ on 8i~ 1 gel using 25 % etbyl s~ehte in he~ne to yidd tbe titlc pmduct (2.4 g; 64!~).
lH NMR (250 MHz, CDC13) ~: 2.75 (lH, d, J ~ 4 Hz, -OH), 2.85-3.10 (2H, m, Ar~2-), 3.71 (3H, 5 8, OCH3), 3.79 (3H, 8, OCH3), 3.95 (2H, m, CH2~), 4.29 (lH, m, ~), 6.7~7.00 (6H, m, Ar-H), 7.28 (2H, m, ~r-H).
Step2: 5~ -3 ,7! ~ ' gl .
To ~ solution of c~-pheno~ymethyl-2,5 :' ' .~ 1 alcollol (2.1 ~; 7.24 mmol) in ether (40 ml) at mom I . ., ws~ ~ded ~ ' ~ (966 111; 10.8 mmol) nd tben boron trifluonde etherste (2.68 ml; 21.6 mmol). Tbe rost of the p.~ ~ i8 id~ntic~l to the second p~rt, step 1, e~mplc 29, to yield tbe title product (715 mg; 33 %).
lH NMR (250 MHz, CDC13) ~: 2.65 (lH, dd, J ~ 11 nd 17 Hz, H4 ~), 2.89 (IH, dd, J = 2 snd 17 15 Hz, H-4 eq), 3.79 (3H, 6, -OCH3), 3.82 (3H, s, ~CH3), 4.00 4.30 (3H, m, ~2-OPh snd H-3), 4.73 (lH, d, J = 16 Hz, H-l), 5.07 (lH, d, J--16 Hz, H-l), 6.68 (2H, AB ~' ' ' Ar-H), 7.01 (3H, m, ~r-H), 7.33 (2H, m, Ar-H).
Step 3: (l'S, lR, 3S)-5~ 3 ,~!g1 ~ b~ (2',3',6' ~1 ~-3'-h-~ '-O p ~a~gl L l~ ' ~.,.~ ) chromsn The ' . f~m step 3 herein wss ~ in 57% yidd ~ per ~ d irl step 3, e~mple 34.
NMR lH (250 MHz) (CDC13; ppm): 8.31 (4H, m, ~ . ~ ), 7.31 (2H, m, - ), 6.97 (3H, m, 25 9 -- ), 6.76(2H,m,- ) 6.22(lH, d, NH), 6.02(1H,s,Hl),5.63(1H, 8, Hl~),5.42(1H, s, H3-),4.67(lH, m, H4.),4.66(1H,m,Hs.),4.57(1H,m,H3),4.18(2H,m,-CH2- side ch~in), 3.82(3H, 8, OCH3),3.81(3H,~,OCH3),2.90(lH, dd, H4a)~ 2.56(lH, dd, H4b), 2.0~2.18(2H,m, -CH2- sug~r), 1.16(3H, d, J = 6.5 Hz,-CH3 sug~).
S~p4: (l'S,lR~3~-SJ8:'- 3 p! ~ /I1-(2',3',C'-~idbox~-3'-L-~ . ' q'~Dp ~ ILI~
The (1 'S, lR,3S)gl~_- ' f~m step 3haein WY8 ' ' ~ ' d 8 pcr p.. ~ din step 4,c~cunple34.
NMR lH(250 MHz) (C6D6;ppm): 7.73(4H, dd, - . ), 7.17(2H,m, ~ - ),6.90(3H, d, ~. ---),6.71(lH,d,NH),6.08(2H, d, quinonc ting), 5.80 (lH, 8, Hl),5.76(lH, 8, Hl.), 5.50 (lH, 8, H3.),4.70(1H,m,H4.),4.62(1H,m,Hs~),4.22(1H,m,H3),3.85(1H,m,CH2 side chain), 3.66(lH, dd, CH2 side ch~in), 2.27(lH, dd, H4a)~ 1.94(lH, dd, H4b), 1.85(2H,m,-CH2 side chain),l.34(2H,m,-CH2- sugar), 1.18(3H, d, -CH3 sugar).
SU~ST~r~lr3~ S3~E~
WO 94/11382 214 ~ PCT/CA93/00463 step 5: (l'S, lR,3S)-S,10 ' ~ ~ 1 1-(2',3',6' .~ ~-3'-b~ -O p .h .~1 L 1~ ~ r~ ) 3,4,5,10 1 lII ' ' - 12~c] pyr~n S
C~ between 1 ~ - nd the q~ one from step 4 herein ~ per in ~tep 5, e~unple 34, fforded the titlod ~ , ~, yidd 148%.
NMR lH (250 MHz) (CDC13; ppm): 8.30 (3H, m, ~ ~ - ), 8.11 (2H, m, ~ ~ ), 7.77 (2H, m, ), 7.30 (4H, m, r . ' ), 6.96 (2H, m, ~ ), 6.40 (lH, d, J c 7.5 Hz, NH), 6.01 (lH, 10 s, Hl), 5.75 (lH, s, Hl.), 5.43 (lH, ~, H3.), 4.63 (lH, m, H4.), 4.61 (lH, m, H3), 4.60 (lH, m, Hs.), 4.20 (2H, m, -CH2- ~ide chrin), 2.89 (lH, dd, Jl = 3.4 Hz, J2 19.3 Hz, H4~, 2.S7 (lH, dd, Jl--11.5 Hz, J2 = 19.4 Hz, H4b), 2.07 (2H, td, -CH2- sug~r), 1.19 (3H, t, J = 6.5 Hz, -CH3 ~ug~r).
step 6: (l'S, ~R,3S)-S,10 .' ~l 1-(2',3',6' I 11 ~-3'-l ~ . - '~ L 1~ ' ,r.. - ~ ) 3,4,5,10 t ~ - ~ 12~3-c]
p~r~ (BCH-2032) The ~ 1~ ' - from dep 5 helein w~s dep ~ ikd in step 6, e3cunple 34, to ~fford the titled _ , ~ in 81 % yidd.
NMR lH (250 MHz) CDC13; ppm): 8.11 (2H, m, ~- ), 7.78 (2H, m, . - ), 7.33 (2H, m, ~ ), 6.98 (lH, m, c), 6.91 (2H, d, J = 8.3 Hz, _ - ), 6.69 (lH, d, N~, 5.95 (lH, s, Hl), S.SS (lH, d, Hl~), 4.61 (lH, m, H4.), 4.41 (lH, m, Hs.), 4.38 (lH, m, H3), 4.16 (2H, m, -CH2- side ch in), 3.64 (lH, m, OH), 2.89 (lH, dd, H4~), 2.57 (lH, dd, H4b), 1.93 (2H, m, ~H2-~ugar), 1.24 (3H, d, J = 6.5 Hz, -CH3 sug r).
25 IR (film) (cm~l): 3425 (OH, N~, 2929 (Ch liph~tic), 1716 (C=O), 1668 (C--C), lS96 ~C-N), 1297 nd 1160 (C-O).
S U ~ S li~ ~ -T
21~6~48 F "re 37: F~., ' of ~Dr " ~ 12,3-c] p~ I ;- ''-~ with ~n ~llyl ~ide chl~in OMc OMe ¢C~4Ph I
O~S 0 OMe 0 ¢C~ + ¢C""~
OMc ~ ) OM
H~C~ ~C~
I NH~A I NHIFA
OPNB OPNB
O O
~' ~
O -H~C~ H~C~
NH~A I NHTFA
O O
O ~ O
H~C~ H~C~
NEnFA I ~nFA
OR OR
~-- -~ R-H 8CH-2031 _ R-H 8CH-2163 S Step 1: S,84~imetbox~r-3-(2 ~ ., ,1rl) ' ' ~
.. To sti~ed solution of ~ (670 mg, 2.0 mmol) in CH2C12 (20 ml) at -78C were added dlr? - ~- ' (636 r~l, 4.0 mmol) ~nd AICI3 (S33 mg, 4.0 mmol). Te , ~, w~i then r~u~ed to -35C few minutos, then HCI (0.1 N, 10 ml) wss dded. The roaction mLlcture wa8 worlcod up with CH2C12 and w ter. Thc org~ic layer was wash~ed with brine and dried over MgS04. The solvel~t was c~ , d to givc the allyl: ~ (450 mg, 96 %).
SUBSTITUTE SHEET
21~6~
lH NMR (250 MHz, CDC13) o: 6.63 (2d, J ~ 8.9 Hz, 2H, Ar-H), 5.96 (m, lH, -CH=C), 5.17 (d, J
= 17 Hz, lH, -CH=CH2), S.10 (d, J = 9.9 Hz, lH, -CH=C~I2), 4.93 (d, J = 16.0 Hz, lH, H-l), 4.58 (d, J = 16.0 Hz, lH, H-l), 3.78 nd 3.75 (2s, 6H, 2~OCH3), 3.65 (m, lH, H-3), 2.75 (brosd d, J
= 17.0 Hz~ lH, H-4), 2.45 (m, 3H, H 1~ ~I2-CH=C)-S
Step 2: (l'S,l~,~S) ~d (l'S,l-R,3-R)-1-(2',3',6', trideo~-3'~
3!r ~1 I,l~ ' .,. ` S,~ -3-(2, . . 91) ' .
To z mL~turc of 5,8 ~ -3~2 ~ l) ' . (400 mg, 1.72 mmol), 2' ,3' ,6'-trideo~y-3-0 1 A ~ _ q O ~ h~ A~ ,J ~ (1.2 oq., 810~g, 2.06 mmol) nd MS4A (500 mg) in CH2C12 (17 ml) t room i . _ w ~ ~od DDQ (1.5 ~q., 586 mg, 2.58 mmol). Thc re~ction mLlcturc W~8 6tirred for 3 hou~ ~nd 30 minutcs, thcn filtered ~d the filtrate w~s wuihod by ~ with N HC03 ~t. ~iolution. E~,, of the ~olvcnt ~nd "~;r.~ E by FC
(CH2C12:~ QAc 8:12: 1) g~ve 427 mg of the titled product (50%) nd 531 mg of it~ ' , -15 (50%). The (l'S,lS,3S) ' wu~ prep red u6ing thc samc ~.. c.
lH NMR (2~0 MHz, ~cetonc d6) (ppm): 8.65 (bd,lH,NH), 8.4 (d,8.9Hz,2H,PNB-H), 8.34 (d,8.9Hz,2H, PNB-H), 6.86 (~ 8 8~7.1H,Ar-H), 6.8 (d,8 8~7.1~,~r-H), 6.0 (m,lH,C=CH-C), S.88 (s,lH,H-l), 5.56 (b6, lH,H-l'), S.47 (b6,lH,H-4'), S.14 (bm,2H,C CH2), 4.6 (m,2H,H-3',H-5'), 4.3 (m,lH,H-3), 3.8 (s,3H,ACOCH3), 3.78 (~,3H,Ar-OCH3), 2.75 (m,lH,H-4), 2.47 (m,2H,C=C-CH2), 20 2.4 (m,lH,lE~ 1), 2.3 (m,lH,H-2'), 1.9 (m,lH,H-2'), 1.16 (d,6.4~7 ~E~,~-6').
Step3: (+) r~ cetoliehydloxy 1 ' ~ q~
To a stirrod solution of the methyl Icotone hydro~ty-l ' . - (3.000g, 11.891~nmol) in 180ml of ~ t 0C w~ ~d d~....... n ~uoous ~olution of C~N (26.076g, 47.56 mmol) nd N~HCO3 (7.19~1, 85.6 ~nol) in water. Tho re~ction mi~cture W~8 then droped in a mL~ture of 200 ml of CH2C12 nd 200 n~ of w ter nd ' with CH2C12 nd b~ I ' with Ethyl Acot~te.
C' ' ' organic l~ycrs wcrc w~ihod wit~ w ter (3~c300 ml)~nd then dried (Na2SO4). pr ' 1l- -of the residu gave 2.237g (8S% ~ridd) of the pure methyl ketonc hydro~cy-l ~ - quinone.
30 PMR (CDC13, 300MH_)~: 2.30 (s, 3H, COCH3), 2.39 (ddd, lH, J = 20.0 Hz, 12.0 Hz ~nd 1.2 Hz, CH~CHCO), 2.88 (dd, lH, J = 19.5 Hz ~nd 3.9 Hz, CHeCHCO), 3.42 (bro~d m, lH, OH-l), 4.64 (dd, lH, J = 11.7 Hz ~nd 4 H_, H-3), 6.03 (bro~d ~, lH, H-l), 6.78 (2~cd, 2H, ~. - Il).
Step 4: (l'S,1.~S) sDd (l'-S,1-R,3-R)-3-(t2',3',6'-trideo%~-3' t ~ n 1'-pu ~ ' Jl L 1~ r~ ~ S,l~ ~ 3,4,S,10 ~ ' ~d . p~ ' -t2~3 ~1 r ~-- 3 ~'1) . ~r To ~ solution of (l,-S,l-R,3-R)-1-(2',3',6'-trideo~y-3'-trifl . '~ 4' ~ - v~l-L-~, - )- 5,8-dio~co-3 ~ 1-1,4,5,8 ' ~ 2,3-c]-Pyran (20~ mg, .34 mmol) in SU~STe~ S~EET
WO 94/11382 2 1~ ~ 4 8 PCT/CA93/00463 toluene (10 ml) t room I ~ w~ dded 1-~o~-1,3 t_ ' - (0.250 ml, 1.72 mmol). The mL~ture w~s sti~ed ~ ' followed by ~dding 6ilic~ gel (4.2 g) ~d bubblillg ur. ~fter 2 hours, the solution wsu filtered ~nt oolvent removed form the filh~te. ~;I~...g of thc cmde by FC (Tol.: EtOAc 15: 1) uld ~ g~ve 133 mg of the titled p~duct. The (1 'S, lS,3S) ~" ~ W~8 p~d 5 the ~me w~y.
lH NMR (250 MHz, CD2C12) ~ (ppm): 8.3 (m,4H,PNB-H), 8.1 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.35 (bd,lH,N~, S.95 (lH,C=CH-C), 5.9 (o,lH,H-l), 5.7 (o~lH~H-l')~ 5.43 (bo,lH,H-4'), 5.25 (m,2H,C--CH2), 4.6 (m,lH,H-3'), 4.43 (q,6.4Hz,lH,H-5'), 4.21 (m,lH,H-3), 2.8 (td,19.4Hz,3.2Hz,lH,H-4), 2.47 (m,2H,C=C-CH2), 2.33 (dd,19.4Hz, llHz,lH,H-4), 2.07 (m,2H,H-10 2'), 1.2 (d,6.4~ ~H,T~-6').
Step 5: (l'S,l~,~S) snt (l'S,l-R,3-R)-3-([2',3',6'-trideo~y-3' t. ^ ~u ' 4'-hydroxy-L-I~' ' . ,. ~] 5,10-dioxo-3,4,5,10-te~h,.' . . ' ''~12,3~]-py~n-3-yl), ~, ~ (BCH-2031) To ~ oolution of (l'-S,l-R,3-R)-3~12',3',6' tl;d~-3'-t~;ll~,, ~ '- ~' ~ ~,I-L-1~ ~' ~, )-5,10 dio~3,4,5,10 1 ~ ' yd ~ 2,3~1-py~-3-yll p~e (133 mg, 0.2mmol) in MoOH (2 ml) t 0C w o dded NaOMe (4.37~ in MeOH, 601~1, .26 mmol) snd otirred for 15 minutos. Tnerctionwss, ' by dding NH4CI o~t. snd~ i with CH2C12. Thcorgonic 20 p~so w~s taen driod over MgSO4, e._. ~ to give 64 mg crude. ~ - e by }".,. ~ TLC
(Tol.: EtOAc 6:1) g~ve 25 mg (2~%) of tae de6irod product. Tne (l'S,lS,3S) ~ BCH-2163 W98 p... d the 8 me w y.
lH-NMR (250MHz,CD2C12) ~ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, lH,C=CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), 5.2 (m,2H,C~CH2), 4.25 (m,4H,H-3,3',4',5'), 2S 3.6 (b6, lH,OH), 2.78 (dd,19.4Hz,3.3H_,lH,H-4), 2.44 (m,2H,C=C-CH2), 2.3 (dd,19.4Hz,11~7 lt~,~l-4), 1.85 ( ~,~-2'), 1.25(~ 6 ~7~,~-6').
F p'~' of ~"'~ t2,3-clPYran ' ;. ' .~with-methyllceloneside chain from ~ bicycl;.c qui~ e ulycsl u ~ ;EEl~
WO 94/11382 PCI`/CA93/004~3 2 ~ 8 o 9 ~
O OH
O O O O
~ + ~o~
O O O O
H3Cj~ H,~jJ
R NH~A R NHIFA
.
O O O O
O O O O
H,Ch~ H,C~
R NHIFA R NHIFA
R - I BCH-1620 R - I BC}~1621 R ~ R - PtlB, p R - OH opi K:~1649 R - OH cp BCH-164t Step 1 ~nd2~ S,l~ S) 1! ~ [2',3',6' d ~-3' 1 ~ P '-4'~L l~ * ,. ] S,10 -3,4,S,10-S I ~. . ~phtho~2,3c] ,J.~ 3~ ' -(BCH-1620) 1) To ~ ~rod . of -' ~ievo~ 4A (1.3y), 2~ ,I t ~ tyl: IYIUAY) 3 iod~2,3,6 L~A~ L l~ ' r~ ~ (478 mg~ 1~02 mmol) nd 3~cetyl-5,8~ioAo-l-hydro~cy-1,4,5,8 t~ ' ~.' J~rl2~3~c]-pyrsn (178 mg, 0.8 mmol) in ~ solution of CH2C12/ cetone (lS.4 ml, 10~ t -50C w~ ~dded . ' ~1 ~1 trifl . ' '' ~IMS-OTf, .222 ml, 1.15 mmol). The reaction miAture ws~ the~ ~tirrod st -30C for 50 minutes, followed by ddition of sq. N~HCO3 5 % nd w rmed up to room t . ~. ~fterfiltering off 801ids, the filtr~te wss ' with CH2C12. The org nic phs~e ws~ then w~hed with brine uld driod ovor MgSO4. E. of the solvent ~ve S63 mg of the cn3de.lS 2) From the cmde product obt iued ~ ' d ~bove, 116 mg vn~ utilizod in the ne~ct step by ~ing with l~cetoAy-1,3 1 ' (98 ~1, .82 mmol) in toluene (10 ml) for u.. ~ t room snd under rgon. Silic~ gel wss neAt sdded ~nd ~ur wss bubbled into the re ution miAture ~md ~itirring for 2 hours. The crude p~duct w~ 1 by filtering ~d ws~;hing of SU~ S~;~ET
~ 21~6548 the silic~ gel with ethyl ~c~te. E~ . of tho ~olvent g~ve 139 mg of the crude product.
F~ ~ by ~ TLC (heA:OAc 4: 1) g ve 7.4 mg of the titlo product nd 2.2 mg of its for ~ tot l of 9% yidd. The (l'S,lS,3R) ~' . BCH-1621 w~s p~d u~ing ~e 8 me metllod.
S lH NMR (250 MHz, cetone) o (ppm): 8.43 (bd,lH,N-H), 8.0 (m,2H,~rH), 7.9 (m,2H,Ar-H), 6.0 (~,lH, H-l), 5.6 (bd, 5.4Hz,lH,H-1'), 4.89 (b~,lH,H-3'), 4.75 (dd,11.6Hz,4.0Hz,lH,H-3), 3.75 (m,lH,H-4'), 3.7 (q,6.1Hz,lH,H-5'), 3.0 (dd,19.6Hz,4~ 4), 2.SS (dd,19.6Hz,11.6Hz,lH,H-4), 2.3 (s,3H,COCH3), 2.26 (m,lH,H-2'), 1.8 (m,lH,H-2'), 1.25 (d,6.1Hz,3H,H-6').
Step 3: (1'-S,l-R,3-S)-3-([2',3',C'~ideQ~-3'-tr;fl~ido4' b, ' . ~-I, Iy~ ~ r~ ~ ~] S,10-di~o-3,4,S,10 ~ ' ' Jd p' ' ~ 12,3 ~ 3~YI)~
propene (BCH-1649) To ~ solution of (1'-S,l-R,3-S~3{12',3',6' ~;d~A~-3~ }'- ' ~J1 L-Iy~ rJ ] 5,10 dio~co-3,4,5,10 h~ . ' ' ~ [2,3-c1-pyl n-3-yl) p~pene (133 mg, 0.2mmol) in MeOH (2 ml) ~t 0C w~s ~dod N~OMe (4.37~ in MeOH, 60 ~1, .26 mmol) ~d ~tirred for 15 minutes. The re ction W98 ~ - ' by ~dding NH4CI ~t. ~nd ~ ' with CH2C12. The org~ruc ph~se w~s th~:n driod over MgS04, c. . 1 d to give 64 mg crude. Purifying by ~ TLC (tol:
EtOAc 6:1) gsve 25 mg (25%) of th~ ;ired product. The (l'S,lS,3R), BCH-1648, ~ w~s obt ined usin~ the s~me method.
lH NMR (250MHz,CD2C12) ~ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, lH,C=CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), S.2 (m,2H,C=CH2), 4.25 (m,4H,H-3,3',4',5'), 3.6 (bs, lH,OH), 2.78 (dd,19.4~7 ~ ~H7 1H,H-4), 2.44 (m,2H,C~C CH2), 2.3 (dd,19.4H_llH_lH,H-4), 1.85 (m,'7~,~-2'), 1.25 (~ 6 6~7~H,H-6').
F ~' 3g: 1.. , '- of 1 ,~'` ~, ,~ l,D' '- - 12,3-c1 p~ ' ;. '-~D
O O O O O O
O OR O OR O OR
R ~ HIC~J R ~ H~C~
OM, OMe OMeO~
K ~2141 ~CH-2149 30 Sep 1: (1'-S,1-R,3-S,4~-S,lOa-S) ' ~1 (1-12',3',4',6' ' ' ~-3' - ~ 4'-O-'' .~1 L 1~ J~ 0 ~ -5,10 :-- 3,45,1 ' ~ D! - - [2,3-c] pyl~3-yl) l~ e (BCH-2141) S1~5 ~ ~ ~f ~8~E ~iEET
WO 94/11382 PCl[/CA93/00463 21~ 4~
To ~solution of (1'-S,l-R,3-S)-methyl-(1-12',3',4',6' 1 ' ~-3'- ' ~ 4' 0 - ~r ~I-L-ly~ ~ )-5,10 dio~co-3,4 ' ' ~.~ . ' ' - [2,3-cl py~n-3-yl) l~otone (15 mg, 30 ~mol) i~ THF
(1 ml) ~t 0C W 8 ddot H202 (30% ~q. olution, 5.2 ~1, 46 ,umol). ~fter 10 mi~ute6, N~OH (.lN, S .364 ml) W~18 Jddet ~nd the ro ction mL~turo w~O ~rot t 0C for 30 minutes. Worlcup w~ cuTiod out by ~dding brine to the mLlcture, - e with CH2C12 nt trying the orpnic ph~se over MgSO4. The crude ob~inot ~fter e. of the aolvellt w~ ~ ~ e by ,~. ~ ' to give 8 mg (50%) of the pure titlod product. The (I'S,lS,3R,4-R,10 R), BCH-2149, ~' W~8 obt~i~d using the 8 mc mothot lH NMR (7~0M~7~ CDC13) o (ppm): 8.Q5 ~nd 7.8 (m,4H,ArH), 6.15 (~,lH,H-l), 5.55 (bd,lH,H-l'), 4.86 (b6,lH,H-4'), 4.3 (td,9H_,3Hz,1H,H-3), 4.05 (q 6 6~7 1H,H-5'), 3.65 (m,lH,H-3'), 3.45 (s,3H,SO2CH3), 3.1S (6,3H,OMc), 2.75 (td,12.3H_,3H_,lH,H-4), 2.35 (m,lH,H-4), 2.3 (o,3H,COCH3), 1.9-2.2 (m,2H,H-2'), 1.25 (d,6.6T~7 ~ 6').
S U ~S ~ S E i E ET
WO 94/11382. 214 ~ ~4 9 PCT/CA93/00463 F ~ gsr 5 ' ' ' ' 3 ~
"~ Q~oSilBuM~2 Z3 ~oSitBuMe2 AcO _ ACO~y HO
OAc S hc / ~,5 O O O O
lVAB~
+1,3 ' . ~
NHIFA
+1,3 '- -O O
O O~
-+1,3 Step 1~ D,~,!;S,6S) ~;nd (2R,~ S,6S)-2-tert L b~ '- ' Y~ -5-A 601ution of rhsmn~l di cetate (0.514 g, 2.4 mmols) in H20 (24 ml) is he~ted at 80C for 30 minutes.
The 601ution i6 then cooled down to 0C nd CH3COSH (0.51 ml, 3 eq.) i6 then ~dded. The cloudy0 601ution is ~irred ~t room I . .i for 2 hours ~A~ter which NltHC03 (1.2 g, 6 e~A.) is ~d to the e~cces6 CII3COSH. Thc w ter is c., - d ~nd the -esidue i6 ~ A in CH2C12 rAnd dried over MgS04. The 60Aids re fiAtered rAnd the solvent c., - ' A 601ution of the oil obt~irAed ~tter c. A in CH2CI2 (24 TAA) is t~ted with (0.33 g, 2 e~A-) nd t BuAUe2SiCI (0.43 g, 1.2 eq.). The 601ution is 6ti-red rAt room I . .i, under rArgon, for 18 hours. It is po~Ared in ~At. aq.
15 NrHC03 nd tlAeA~so~ rAre - . ~ TA2 e queou6 IrAyer is 1 d with CH2C12 (2~) nd the combine~lA o~nic el~t~Acts are dAiet~A over MgS04. The soAid6 rAre fiAAte~ed nd the 801vent6 ~U~ ET
W O 94/11382 PC~r/C~93/00463 2146~48 The oil o~inod i8 purifiod by flssh ' . ., , ' ~ (silics gel, 9: 1 ha~snos/EtOAc) to give ~ 1: 1 misture of titled isomers: 0.50 g (60%) 8 cle~r oil.
lH NMR (CDC13): o 4.90+4.85 (2dd, lH, H-l), 4.73+4.62 (2dd, lH, H-4), 4.30+3.75 (q+m, lH, H-5), 3.71+3.55 (2ddd, lH, H-3), 2.36+2.30 (28, 3H, SAc), 2.19 (m, lH, H-2), 2.03+1.99 (2s, 3H, S OAc), 1.77 (m, lH, H-2), 1.22+1.18 (2d, 3H, H~), 0.88 (8, 9H, t-Bu), 0.09+0.10 (2~, 6H, SiMo2).
Step 2: (~D,~,~) 2 ~ I t ':yl '- ~g! ly~ ~-5 ~ 1 t ' A solution of the thio-wg~r from ~tep 1 horein (51 mg, 0.14 mmol) in oth nol (2 ml) w~s tr~ted with acce6s of ~9 ~ Ni. Tbc . w~ ~;~u.. 1~ ~tinod for 30 minut~ nd W98 then filtered through 10 Cclitc. The othsnol w~ _ . . d to givc 36 m~ (89 X) of the titlod . . ' 98 clc~r oil.
lH NMR (CDCl3): o 4.74 (dd, lH, J = 2.0, 8.6, H-l), 4.42 (ddd, lH, J ~ 4.7, 10.5, 10.5, H~), 3.98 (dq, lH, J ~= 6.16, 9.23, H-5) 2.10 (m, lH, H-2 or H-3), 2.02 (8, 3H, OAc), 1.86-1.35 (m, 3H, H-2 uld H-3), 1.17 (d, 3H, J - 6.16, H-6), 0.88 (8, 9H, t-Bu), 0.10 (8, 3H, SiMe), 0.08 (8, 3H, SiMe).
lS Step 3: ('~D"~,~9 2 l I ~ ' ly1 ~ ~h~.' . ~ ~ b;~l ' ~.' ~ . ,.
To ~olution of the scotste from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), nt room _, V~8 ddod 1 N N OH (0.14 ml, 1.1 oq.) ~d the ~olution W98 sti~ed for 45 minute6. It W95 thon powod in H20 nd tho quoou~ se wss - ' 3~c with CH2C12. The ~ ' orgsnic 20 e~trscts we~e driod ov MgS04, the ~olids wore filterod snt the ~olvent _., ' to give 30 mg (96%) of the pure titled slcohol.
lH NMR (CDC13): ~ 4.72 (dd, lH, J ~ 1.9, 8.7, H-l), 3.28-3.24 (m, 2H, H-4 nd H-5), 2.04-1.41 (m, 4H, H-2 snd H-3), 1.27 (d, 3H, J 5.5, H-6), 0.88 (8, 9H, t-Bu), 0.10 (~, 3H, SiMe), 0.09 (8, 3H, SiMe).
step4: (~,!;S,li~) 2 I I ~ g~l ly~ '~ C ' .~
To solution of the Icohol from step 3 horein (62 m~, 0.25 mmol) in dry THF (2.5 ml), st ~om .i, under u~on, we ~dsd ; .1~ Ph3P (66 IIU, 1 oq.), DE~D (40 ~1, 1 oq.) ~nd 30 (PhO)2PON3 (54 111, 1 oq.) ~nd tbe solution w~s stirred for 18 hours. The THF wss e., d snd the crude oil W~8 purifiod by {b~ ~ (silic~ gel, 95:S he~os/EtOAc) to give 38 mB (569~) of the titlod zide ~ ~ elo r oil.
lH NMR (CDC13): 8 4.71 (dd, lH, J ~ 3.0, 7.9, H-l), 3.64 (dq, lH, J = 1.7, 6.3, H-5), 3.33 (m, lH, H 4), 2.15-1.60 (m, 4H, H-2 ~d H-3), 1.26 (d, 3H, J--6.3, H-6), 0.89 (8, 9H, tl3u), 0.11 (s, 3H, 3S SiMe), 0.09 (s, 3H, S~Ie).
Step 5: (~,SS,f9 2 I ~ y! Iy!( ~ ' h-~ '~ 6 ' ~1 S~Et~ 5~ T
WO 94/11382 2 14 6~ 8 PCT/CA93/00463 To solution of the ~zide from ~ep 4 herei~ (0.20 8, 0.72 rmnol) in dry EtOAc (7.2 rnl) t room h_ r ' ~ w~8 ddodPdlC109~(0.10g,50%wt.) ndtheblcl~ r w9 plcodunder~H2 , ' ~; for 3 hours. The c~t~lyst w s then filtered thr~ugh Celite nd the solvent v~s c., d to dryness. The cmde mine (0.18 y, 0.72 mmol) wss ~ ,d in dry CH2C12 (7.2 ml) _nd Et3N (0.20 5 ml, 2 oq.) W~8 dded. The solution W_8 coolod to 0C nd TFA20 (0.11 ml, 1.1 eq.) w~ ~dded slowly.
The solutio~ W~8 sti~d ~t 0C for S bours Yld wss tben poured in sl ~q. N HC03. The ph~es were '~ ~ nt the _queous l_yer W~8 Y d with CH2C12 (2~). Tbe ~ ' org~nic e~ctr cts were triod ov MgS04, the solids filteret ~d the solvcnt c., ' to give 0.17 ~ (71 X) of the crude titled i ^ ~ ' thst WUI used ~8 ~.
10 lH NMR (CDC13): o 6.70 (b~, lH, NH), 4.75 (tt, IH, H-l), 3.92 (m, lH, H-4), 3.73 (dq, lH, H-5), 2.06-1.45 (m, 4H, H-2 nd H-3), 1.19 (d, 3H, H-6), 0.88 (8, 9H, t-Bu), 0.11 (s, 3H, SiMe), 0.09 (8, 3H, SiMe).
Step C: (lS,3R,l'S,5'S,6'S) nd (1P ~S,l'S,S'S,6'S) yl (1~4'L ~ .P ' 5'-methyltet~hydropy~nyll-S,10 :' 3,4,S,1~ 2,3-c]
py~n-3-yl) lutone (BCH-1673) Tbc titlod ~ - . ' wo~e obbined in 30% yidd by f"ll .. - e tbe ~ - d in step 4, e~csmple 12, on the ~ of step 5 herein. Tbe titled ~ , ' were purified vi~ flu;h 20 ~ " . ' ~ (silic~ gel, 3:1 ha~ /EtOAc). The mLl~ture of jSOD W9S not ~ , ' '- by . ~
lH NMR (CDC13): 8 8.14-8.07 (m, 2H, ArH), 7.79-7.73 (m, 2H, ArH), 6.17+5.99 (2s, lH, H-l), 5.50+5.39 (2bs, lH, H-l'), 4.68+4.24 (2q, lH, J = 6.5, H-5'), 4.56+4.49 (2dd, lH, J ~ 4.2, 11.8, H-3), 4.05 (m, lH, H-4'), 3.08+3.07 (2dd, lH, J = 4.2, 19.9, H-4), 2.S7 (dd, lH, J = 11.8, 19.9, H-2S 4), 2.34+2.33 (2~, 3H, COCH3), 2.00 1.53 (m, 4H, H-2' ~nd H-3'), 1.31+1.13 (2d, 3H, J ~ 6.5, H-6').
~UE~ 5~E~T
W O 94/11382 2 1 ~ 8 P ~ /CA93/00463 (1~ ,3~)-3-(r~ thrl)-s~lo ~ (2,3,6-tr~ 3-tri f 1 ~ ; A~
3,4,5,10--t--tr hrdro-lH ~}'~- ~ 2,3-cl ~rran (~CH-2101) nd 1,3 'i ,~ - (JC~-2115) Ob4 0 01-4 0 H,C~A H,~J~, H,C~A
0~ 0~ ~
~3 =~-~
~ 0~.4 0 0 0 H~ H CZ~ H,C~;J
OPNB OPNB oHN81PA
BC~2115 8t-p ls (1~,3R)-3 (r~ rl)-l (2,3,6-tr~ 3-tr~f~ L. ~~rl-L-l~ )-5,8-a;
To ~ s]~lti~ of h~d~o~ - h~d.ochloride (60 mg; 86 ~mol) in a m~xtur~ of ~th~nol (4 ml) and wat~r ( 4 ml) wa- added St ' i - hydroxide (33 mg) in ethanol (2 ml) The mixtur~ was 3tirrcd at room t~ tUL~
lS for 5 hour Th~ oolution wa~ filt~rod The filtrat- wa~ added to 3-ac~tyl-i---' - glycoside from t~p 1, c S, (92 mg; 147 mmole) Th~ reaction wa- c~ L- in 10 minutc~ The m$xture wa~ o-aLed down to dk~ , dic~olved in mall volume of w~ter (5 ml), x~racted with CH2C12 (3x50 ml), w~h7d with cat ~aCl, dri~d and =~v~a-Qd The crude product wac pa-~ed through a mall column of ff~lica gel 1~ n ~h~
with 0 2% tri-thylam$ne in haxan~ (~lucnt 15~, 20~ and 25~ EtOAc in hexane) y;~ ng purQ oxime (63 mgS 67~) S U ~ ~ 6 ~ t~ SHEET
WO 94/11382 PCI`/C~93~00463 21~6~48 NMR (ac~tone-d6; 8): 1.26 (3H, d, J ~ 6.8 Hzs -CH3), 1.26 (3H, d, J =
8.3 Hz; -CH3), 1.89 (lH, dd, J ~ 4.4, 13.2 Hz; H-2 of the uugar), 1.96 (3H, ~, CH3 of the ide chain), 2.47 (lH, dt, J - 3.6, 13.1 Hz; H-2), 3.81, 3.88 (3H, ach; Ar-OCH3), 4.60-4.66 (lH, m; ~ugar-H), 4.72 (lH, S t, J ~ 7.8 Hz; H-3), 4.83 (lH, q; J ~ 6.S Hz; H-5 of the sugar), 5.51 - (lH, br singl~t; H-1 of the ugar), 5.61 (lH, d, J 8 2.9 Hz; H-4 of the ugar), 6.15 (lH, ~; H-l), 6.87, 6.90 (lH, d nach; J - 8.9 Hz; Ar-H), 8.36, 8.41 (2H, d acht J ~ 8.8 Hz; Ar-H of PN~ ~.ou~), 8.70 (lH, d, J
8.0 Hz; -N~TFA), 10.02 (lH, ~; ~NOH).
~t-p ~s (1'8,1~,3R)-3 (~ --thrl)-5,10 ~ ~-l (2,3,6-tri~ 3-tr~ ^-L~ )-3,4,S,10-t-trahydro-lH ~ 2,3-cl prr n (~CH-2101) lS Acetylation wa- don- on th- oxime from t~p 1 her-in (33mg; 0.051 mmol~) ~n CH2C12 (4ml) u-ing pyridin- (0.2 ml), ac~tic anhydrid~ (0.1 ml) and catalytic amount of DNAP. After tirring at room tr - .L~e for 3 hour~, the mixtur- wa- ~v~, d ~nto ic~, extractQd wLth CH2C12 (3x50 ml), w ~ ' with w~tQr ~15 ml), dri-d and ~GL~Led. Th- crud~ product was ~ _-d for 16 hours ~fG~ u-ing in th- n xt tep.
CAN ~Vi~tiQn was don- on th~ crude ~ -t- (40 mg) u-ing sodium hi r'r~Q~'te following the g-neral pr.c- re ao de~cribed in other ~ . It re~ult-d in 32 mg of crude ~- i n~- . The ~-;-- - wa~
r~acted with acetoxy b~l~r ii - (100 ~1) in toluene following thc gen~ral 2S ~.~i` c. On purifir-ti~n through a col of silica gel (30% EtOAc in tol -, S0% ~tOAc in tol - nd CH2C12~ 9:1 s -1 ~) pure tricyclic gl~c~ - (29 mg) was o~t~ . Finally, d-prot~ction of acetate and PNB y~O~__ was don~ by u-ing ~ meth~Y~de (catalytic) in meth~nol (3 ml) at 0C. Aft-r tirring at 0C for 14 m~nut-s, the mixtur- wa- n-utr~ with dil. HCl to pH-7, diluted with water (Sml), extracted with CH2C12 (3x30 ml), ~ _1^-d with water (10 ml), dried and ~G.~Led. Th~ crude product was purified by column c~ GJ a~hy over a mall col of ~ilica gel (1% methanol ln CH2C12 ~- eluent) and pr~parative TLC (CH2C12s M~OH~9:1) yi~l~in~ pure titled o~ime (3.7 mg;
1 4 1~CH-2027 o To ~ fiolutio~ of S,8 y-3 ~ 1 ' (1 0 g; 45 mmol) in :' ' ' - (30 ml) ~t 10 mom i , ~ were ~Ided ' -' (211 ~1; s.4 mmol), 4A -~ - sieves (2 g) Jnd 2,3-dichloro S,~ " ~ - h . - (1 21 g; S 4 mmol) The ~ulting d~ mi~ture w~ ~tinod for S hou~ nd W~8 then sl ' - ' with ' N~HCO3 olution It W_8 ' with ~' ' ' ' ~d the orgs~c l-yers were w~hod with ~ ine ~nt then driet a~er N 2S04 ~
1.0 g of crute ~,ttuct of which 300 mg (1.19 mmol 9 d) were plscod in pear-shspet fls~c JloDg with - - ' (70 mg; 1.19 mmol). Thc oolid mLstule wss thon he~tod to 130 C for 30 minutes. It w~ then coolot to room I . ~i snd ~' ' . ' wss adtct followot by pe~tane yielting ~ I , (160 mg) of which 120 mg (.43 mmol ~ssumet) wss ~ ,t in ~ - (15 ml) nt tro~ted with solution of CAN I . d by slowly ~ g sotium 1 ~ (384 mg) in w ter (S ml) ~ g cerium ~ nitrste (1.46 g; 2.5 mmol). The . " e mi~ re wss stirrot ~t room i , for 15 t utos ~nd wss ~ - ' with, d NsHC03 solution followed by o ~ with ~' ' ' . - - The _ ' ' osgsnic e~c~cts were wsshe~d wit~ brinc ~nd dnod ovor Ns2S04 to sfford the ti~dod ~ . ~ ~ yollow ~olid (125 mg; 42% ove~ll).
lH NMR (250 MHz, CDC13) o: 0.99 (3H, t, J = 7.5 Hz, C_3-CH2), 1.65 (2H, m, -CH2-CH3), 2.02 (3H, ~, -CH3), 2.20 (lH, m. H 4 alc ). 2.60 (lH, dd, J = 3.5 ~nd 19.5 Hz. H 1 oq), 3.70 (lH, m, H-3), 6.12 (2H, br 8, H-l snd N-H), 6.73 snd 6.78 (2H, AB ~y~Sem, Ar-H).
SUBST~ TÉ SE~ET
2i~6S~8 Step2: Tr~ S,10 dioxo-l = '- 3~thyl-3,4,5,10 ~ ' - [2,3-c]-py~
S To ~ solution of the sturting quinone from step 1 herein (56 mg; .22 mmol) in toluene (S0 ml) W~8 ~dded ceto~cy-1,3 b ' (30 111; 11 eq). The mLl~ture wss stimd o.. y' ~t room I . e nd w~s then ~ ' snd pplied to ~ column of silic gel using l-lS % ~tone in bellzene to dute the product which w s then ~ " ' from ~ ' " g the titlo ~ , ' ~6 -yellow solid (10 mg; 15%).
lH NMR (250 MHz, DMSO-D6), ~: 0.90 (3H, t, J ~ 7.S Hz, C~3-CH2), 1.58 (2H, m, CH2-CH3), 1.82 (3H, s, CH3-C=O), 2.20 (lH, m, H 4 ~), 2.64 (lH, br d, J ~ 16.0 Hz, H-4 eq), 3.71 (lH, m, H-3), 6.17 (lH, d, J = 8.0 Hz, H-l), 7.88 (2H, m, Ar-H), 8.01 (2H, m, Ar-H), 8.78 (lH, d, J = 8.0 Hz, N-H).
Step3: S,J~ ~- 3 ~ J~
To ~ solution of 3-cthyl-5,8~ - ' . (300 mg; 1.35 mmol) in '- (10 ml) t room .; W~8 ~dded ~.. - ~ olution of CAN (prep rod by ~ - e ceric ~ nitr~te (2.22 g; 4.0 mmol) in w~ter (S ml)). The rosulting mi~ture w~s !. ' - ' with ' ~ I
solution nd ~ ~ with 1'- ' ' - ~ ' - The . ' - ' or~ nic hycrs wcre wu hed with brine nd dried over N~2S04 ~'' " e tho cmdc titlc ~ . ' (251 mg; 97X) which w~ used ~8 a~h for ~ps.
lH NMR (250 MHz, CDC13) o: 0.97 (3H, t, J ~ 7.5 Hz, CH2-C_3), 1.60 (2H, m, ~_2-CH3), 2.10 (lH, m, H-4), 2.52 (lH, m, H-4), 3.35 (lH, m, H-3), 4.30 (lH, m, H-l), 4.62 (lH, br d, J = 16 Hz, H-l), 6.68 (2H, m, ~r-H).
Step 4: 3 2~b~1 S,10 ~- 3,4,S,10 1 ' ~ lII . ' ' ~ t2,3-c] p~n F~" .. e the p.. ~ ' ' d in ~tep 4, o~mple 26, the ~;brtiDg quinone from step 3 hereln (250 m~; 1.30 mmol) rnd l~coto~y-1,3 ~ ' - (876 ~1; 7.8 mmol) were re~ctod in toluene (10 ml) to yield 30 fter ~ ing 2X ethyl cet~te in toluene the title . ' (62 mg; 20X) ~long with mi~ed f~ctions c- E Iot of de~iired titled product (230 mg), M.P.: 98-101C.
IR (ne~lt): 2963, 2938, 2876, 1658, 1636, 1593, 1337, 1299, 1176 snd 698 cm~l.
lH NMR (250 MHz, CDC13) ~: 1.04 (3H, t, J ~ 7.5 Hz, CH3-), 1.70 (2H, m, C_2~I3), 2.30 (lH, m, H-4 uc), 2.75 (lH, br d, J = 19.0 Hz, H- eq), 3.45 (lH, m, H-3), 4.50 (lH, dt, J = 4.0 ~nd 18.5 3S Hz, H-l), 4.86 (lH, dd, J = 2.5 ~nd 18.5 Hz, H-l), 7.72 (2H, m, Ar-H), 8.18 (2H, m, Ar-H).
SUBST~ Si~ T
~l~6~a e r ' 2g~ . of (l'S,lR,3S) J~nd (l'S,l~ ,10-dioxo-3 .. ~1-1-(2',3',6'-trideoxy-3'-h ~ .'- L-l, ' ~,. ~) 3,4,5,10-~. ~ lII p! 12,3 cJ ~(BCH-2053) and (BCH-2052) OCH, OCH
[~--CHO I
OCH, OCH, ~ + ~"~
~' PNB~A
o 13 pNB~A PNB~A
ol~ 15 H~A HoNH~
S BCH-2053 B~H-2052 step 1: 3 ~ 59~
To a ~olu~ion of thc st~g ~ ~ (1.16 g; 6.44 mmol) ill; ' ~.~ ' (25 rnl) at 0C w~ added a 10 solutioll of ~ J~l magnesium chloride (2 M in THF; 6.4 r~l; 12.88 r~mol). The re6ultilllg mLl~ture was ~rod t 0C for 1 hour and t room , for 30 minutes. It w~ then ~ with ~ ~ chloridc solutioD nd ~ ' with ether. The . ' - ' orguuc l~ye~ were w shed with brinc nd dried over MgSO4 to yield a crude Icohol (1.29 g) wSicS was !~ l~ed in cther (40 ml). To thi~ oolution werc sdded ~ (777 111; 8.55 rnmol) nd boron I " ' 15 etherate (2.02 ml; 17.1 mrnol). The ro~wlting mi~tture wao stirr~d ~t room i . ., for 20 hou~ and wao then ~ ' - ' with - ~ oodium h- ' solution. It w 6 then ~ ' with ether and the ' - ' org~mic layers were w lihed with bmle nd dried over MgSO4. The cn~de product wa8 then SlJ~STOIl~T~ Si~EE~
WO 94/11382 PCI`/CA93J00463 ~146~4~
punfiod by colu~ on 8il~c~ gd using 20-30% ethyl ~ce~to in haune Y8 duent to give the title - . ' (607 mg; 409G over~ll).
lH NMR (CDC13) ~: 1.00 ~nd 1.05 (6H, 2d, J= 7 Hz, -CH~CH3)2), 1.84 (lH, ~ept., J = 7 Hz, CH-(CH3)2), 2.42 (lH, dd, J = 11 ~nd 17 Hz, H 4 ~s), 2.74 (lH, dm, J = 17 Hz, H~ oq), 3.22 (lH, m, S H-3), 3.76 (3H, ~, OCH3), 3.79 (3H, 8, OCH3), 4.56 (lH, dm, J = 16 Hz, H-l), 4.95 (lH, d, J = 16 Hz, H-l), 6.63 (2H, AB system, Ar-H).
- Step 2: (l'S, lR, 3S) and (l'S, lS, 3R)-~,JI ' 3 , .>~ /l 1-(2',3',6' ~ ~-3'-i~n (40:6~) Using the ~,. ' ~, ~' ' - ' i~ dep 3, o~u~ple 26, tho ~rting ' . from ~p 1 herein (300 mg; 1.27 mmol) ~fforded ~ cmde ' ~ ~ mLsture of gl~ ' ' ' . (515 mg) which w~ ctot with CAN ~ d in d~ 3, ac~mple 26, to ~fford ~ - title ~ ~
15 mLsture (450 mg; 59%) in ~ r~tio of (40:60) f voring the l'S, lS, 3R isomer which were used ~8 such for the ne~t -For minor isomer: lH NMR (250 MHz, CDCI3) o: 0.90-1.40 (9H, m, H-6' nd -CH(~3)2), 1.70-2.35 (4H, m, H-2', H-4 ~s nd C~-CH3), 2.62 (lH, m, H-4 oq), 3.80 (lH, m, H-3), 4.42 (lH, q, J =
6.5 Hz, H-S'), 4.S0-4.70 (lH, m, H-3'), 5.44 (lH, br 8, H-l'), 5.63 (lH, br ~, H-4'), 5.74 (lH, 8, H-20 1), 6.32 (lH, m, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
For m~jor isomer: 0.90-1.40 (9H, m, H-6' nd CH(-C~3)2), 1.70-2.3S (4H, m, H-2', H 4 a~c Jnt C~-CH3), 2.62 (lH, m, H 4 oq), 3.69 (lH, m, H-3), 4.50-4.75 (2H, m, H-3' nd H-S'), 5.42 (lH, br 8, H-1'), S.56 (lH, d, J ~ 3 Hz, H-4'), 5.88 (lH, 8, H-l), 6.43 (lH, br d, 1--7.5 Hz, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
Step3: (l'S, lS,3R)-S,10 :' 3 , ~,JI 1 (2',3',C' '~I ~-3' S -' . u ' d~
~ l L 1~ ~ ~., ) 3,4,S,10 1 ~.'r8 lII~! ' ~ 12,3-c]-p~r~n Using the ~ d- ' 1 in ~p 4, o~mple 26, tho duting quinone mLlcture f~m l~tep 2 herein (100 mg; .167 mmol) w~ tr~ted with l~ceto~y-1,3 b ~ (112 ~1; 1 mmol) in 5 ml of toluene to ~fford the title r . ' (34 mg pure + 9 mg of 1:1 mi~ture of d . ).
lH NMR (250 MHz, CD2C12) o: 1.01 nd 1.04 (6H, 2d, J = 6.5 Hz, ~H-(C~3)2), 1.31 (3H, d, J =
6.5 Hz, H-6'), 1.70-2.02 (2H, m, H-2' ~nd C~CH3)2), 2.13 (lH, t d, J ~ 3.5 nd 13 Hz, H-2'), 2.34 35 (lH, dd, J = 11.5 Ynd 19.5 Hz, H-4 ~), 2.78 (lH, dd, J = 3.5 Jnd l9.S Hz, H-4 oq), 3.76 (lH, m, H-3), 4.55 (lH, m, H-3'), 4.80 (lH, q, J = 6.5 Hz, H-S'), 5.42 (lH, d, J = 2.5 Hz, H-l'), 5.S8 (lH, d, J
--3 Hz, H-4'), 6.03 (lH, 8, H-l), 6.52 (lH, br d, J = 7.5 Hz, ~ , 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.28 (4H, s, PNB).
The socond ~
SU~ Y~ET
21~q8 ~-(l'S, lR, 3S)-5,10-dio~o- 3 . u~ 2'~3'~6' t.;~.~y-3'-t ~ '~ ~ ~UJI-L-~ )-3,4,5,10 1 ~.i.~lII p~ ' ~[2,3~1-pyr~n, obt~ined in 16% yield, h~d lH NMR
(250 MHz, CD2C12) ~: 0.90-1.10 (6H, m, CH~CH3)2), 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.40 (4H, m, H-2', (~CH3)2) ~nd H-4), 2.60 2.90 (lH, m, H-4), 3.87 (lH, m, H-3), 4.44 (lH, q, J = 6.S
S Hz, H-S'), 4.58 (lH, m, H-3'), S.42 (lH, br 8, H-l'), 5.69 (lH, br a, H-4'), S.89 (lH, o, H-l), 6.40 (lH, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.C6 (2H, m, Ar-H), 8.28 (4H, m, PNB).
step 4: (l'S, lR, 3S)-S,10 ' ~ l 1-(2',3',C' ~1 ~-3' ~' ~ . ~ ~ L-1~ ' ., ~ ) 3,4,S,lC I ' '~ lII p' - ~ 12,3 cl ~,. (BCI~-2053) Uoing the ~.. c e ~ dep 5, c~mple 26, the ~ting ~ Icohol from dep 3 herein (11 mg; .017 mmol) w~s t~tod wit~ N~OMe/MeOH (4.37 M; 1 1~1; .26 oq) to yield a~er column ' . O , ' ~ (79~ cetone in b~c) the title ~ , ' (5 mg; 59%), M.P.: 180-185C.
IR (ne~t): 3491, 3423, 3325, 2962, 2938, 1721, 1670, 1596, 1293, 1179, 982 cm~l.lH NMR (250 MHz, CD2C12): 1.00 uld 1.01 (6H, 2d, J ~ 6.5 Hz, -CH~C~3)2), 1.22 (3H, d, J ~
6.5 Hz, H-o'), 1.60-2.00 (4H, m, -C~CH3)2, H-2' uld OH), 2.27 (lH, br dd, J ~ 11.0 ~nd 19.5 Hz, H-4 ~s), 2.74 (lH, dd, J = 3.5 ~nd 19.5 Hz, H 4 oq), 3.58 (lH, d, J - 2.5 Hz, H-4'), 3.85 (lH, m, H-3), 4.25 (2H, m, H-3' ~nd H-S'), 5.52 (lH, d, J = 3.0 Hz, H-l'), 5.82 (lH, 8, H-l), 6.75 (lH, m, NH), 7.74 (2H, m, Ar-H), 8.03 (2H, m, Ar-H).
Step S (l~S~ lS~ 3R)-S,10~o~o-3 r ~ ~ JI 1-(2~3~6~ -31 ~ ~~ ~v I~-) 3~4~S~10 ~ lII p! ' - ~,3 c] 1 J - ~BClH-20S2) U~ing the ~ '- ' d i~ ~tep 5, e~mple 26, the st~rting r ~ ~ Jlcohol from d~p 3 hcrein (32 25 mg; .0495 mmol) ~ffordod ~fter fl~h v ph~ using 7 ~i cotone in ba zenc ~ dualt, ~ gummy product which W~8 ~- h ~1 in ~ nd ~,.. , ~ with pa~ne yielding the title product (16 mg; 6596), M.P.: 212-213C.
IR (ne~t): 3509, 3421, 3333, 2961, 2944, 1718, 1667, 1592, 1292, 1166 ~nd 979 cm~l.
lH NMR (250 MHz, CD2C12): 0.98 ~nd 1.00 (6H, 2d, J ~ 6.7 Hz, ~H(C~3)2), 1.36 (3H, d, J--6.5 30 Hz, H-6'), 1.7~2.00 (4H, m, ~_(CH3)2, H-2' ~d -OH), 2.32 (lH, dd, J--11.5 nd 19.5 Hz, H 1 u~), 2.76 (lH, dd, J 3.5 ~nd 19.5 Hz, H-4 oq), 3.61 (lH, br ~, H-4'), 3.74 (lH, ddd, J ~- 3.5, 6.5 ~nd 11.5 Hz, H-3), 4.24 (lH, m, H-3'), 4.59 (lH, q, J--6.5 Hz H-5'), 5.39 (lH, t, J z 2.0 Hz, H-l'), 5.97 (lH, s, H-l), 6.77 (lH, m, NH), 7.72 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
SU~ST~ EET
.
WO 94/11382 PCT/CA93/~0463 214l~5~3 F . 'r 30~ P tS) u~ S~ S~10 d- - 3 . ~ r .
(2',3',6'-trideo~-3'~ ~ . u ~o L l~ ' ,,. - ~.) 3,4,5,1~
lII p' - 12,3 cl ~, - (BC~-21S3) 9nd (BCH-21S2) 9Dd ~s-S,l~ 3 ~ 3,4,S,10 - 12,3 CJ rJ (B(~-2148) [~ I ~ 2 OCH3 OCH~ OCH~
CH~
CH~O O CH~O o PN80NHIFA PNPoN~FA
O O O O
PNBONHIF~ pNpoNHlFA
O o O O
HoNHlFA . HoNH~A
Sll!p 1: 5J~ ~- ~-3 To ~ solution of ~' ~ 1, ' , ' bromide (2.26 g; 6.4 mmol) in other (75 ml) at room (not totlllly soluble) wss added n-BuLi (2.5 M in he~unes; 2.03 ml; S. l mmol). The ~ulting mi~ture wss sti~rod at room ~ , ~i for 1 hour. A solution of S,8~' ' r-3-(1-acethyl)-' . (1.0 g; 4.2 mmol) w thcn dded to the yellow-or~ngc mL~ture and the ro~ulting solution5 w~ 6tirrod t room i , ~ for 3 hours. The mL~turo w~ then ~. ' d with NH4CI (s~t.) snd d with other. Tho c ' ' organic layer~ were ws~hed with brino and driod over Na2S04. The cn~do mi~cturo w~ then purifiod by column ' . ~ in 6ilica gel using 25% ethyl ~te in he~csno s eluent to afford the title , ' (541 mg; 55%)-SU~5~ L ~ 3~ T
WO 94/11382 PCr/CA93/00463 21 4~8 lH NMR (250 MHz, CDC13) ~: 1.86 (3H, 8, zC-CH3), 2.58 (lH, br dd, J = 11 ~d 17 Hz, H 4 a~), 2.85 (lH, ddd, J = l.S, 3.5 ~nd 17 Hz, H 4 oq), 3.77 nd 3.79 (6H, 2s, ~CH3), 4.00 (lH, dd, J =
3.5 ~nd 11 Hz, H-3), 4.66 (lH, br d, J = 16 Hz, H-l), 4.93 (lH, br 8, =CH2), 4.99 (lH, d, J = 16Hz, H-l), 5.09 (lH, br B, =CH2), 6.62 nd 6.67 (2H, 2d (AB), J -c 9 Hz, Ar-H).
S
Step2: ~ ` S,lQ ' 3 ~ 3,4,5,10 ~ 12,3-2148) U8ing thc ~ d in Btep 3, e~mple 26, t}# ~rting ' . (lS0 mg; .64 ~nol) nd ' -' (25 mg; .76 mmol) wore ~d with DDQ to ~fford ~ cmde ~duct (160 mg) which was then ~ted u ith CAN. ThiA re~ction yiddod n im~ro cmde quiwne (91 mg) which w~s ~d with 1-~ceto~y-1,3 h ~ 8 ~' ~' d in step 4, es~mplc 26, ~ g ~ ~
(0-2% ethyl ~to in toluene) the title ~ ' ~8 18 mg of sUghtly impure form nd S mg of purc product (13 % overdl) lS lH NMR (CDC13, 250 MHz) o 1 87 (3H, 8~ ~C~3), 2 49 (lH, dd, J ~ ll S nd 19 5Hz, H-4 uc), 2 84 (lH, dd, J = 3 5 ~nd 19 5 Hz, H-4 eq), 3 61 (3H, 6~ -OCH3), 4 50 (lH, dd, J = 3 5 ~nd ll S Hz, H-3), S 00 (lH, s, =CH), S lS (lH, 8~ ~CH), 5 63 (lH, 8, H-l), 7 7S (2H, m, ~r-H), 8 10 (2H, m, Ar-H).
20 step 3 (l'S, lS, 3R)-S,~ 3 , , Jl 1-(2',3',~'-trideo~-3'-FO11G.. g the p.. ~ ' ' 'x ~ in the f~;t p~rt of step 3, o~mplc 26, the st~ng ' from ~tep 1 horein (2S0 m~; 1 07 mmol) w s tro tet with ~-2,3,6 t~;~A~-3 t ~ .~ ~ ' 4.~ yl L 1~ ' r ~ ~ (461 mg; 1 17 mmol) nt DDQ (337 mg; 1 49 mmol) in ~ (20 ml) ~ g 4A ~ ieve~ (S00 mg) to yielt ~ ' r on silic~
gd using 2S % othyl Jcotdo in l~ne with 1 % ~ ' the title ~ 8 ~ tu~e with it6 (l'S, lR, 3S) ' - (1 1; 310 mg) Another t~CtiOII g vo pure titlet c ~ (131 mg; 199G) lH NMR (2S0 MHz, CD2C12) o 1 22 (3H, t, J - 6 S Hz, H-6'), 1 83 (3H, B, =C~3), 1 75-2 20 30 (2H, m, H-2'), 2 48 (lH, tt, J ~ 12 nt 17 S Hz, H~ ut), 2 89 (lH, td, J ~ 3 5 Ult 17 5 Hz, H-4 oq), 3 77 (3H, 8, OCH3), 3 78 (3H, ~, OCH3), 4 40-4 65 (2H, m, H-3 ~nd H-3'), 4 73 (lH, q, J--6 5 Hz, H-S'), 4 92 (lH, 8, ~CH), S.O9 (lH, ~,--CH), 5 42 (lH, br 8, H-l'), 5 S7 (lH, d, J--3 Hz, H-4'), 6 12 (lH, 8, H-l), 6 31 (lH, br t, J = 6 Hz, N-H), 6 73 ~nd 6 79 (2H, AB 1 ' ' Ar-H), 8 27 (4H, m, PNB) 3~ The (l'S, lR, 3S)-5,8 ' ' ~~3 r -r ~1 1-(2',3',6' L~IC~A~-3~-t ~ q~_o_p_ ,I-L 1~ t lH NMR (CD2C12, 250 MHz) ~ 1 10 (3H, d, J -6 5 Hz, H-6'), 1 83 (3H, 8, ~C~3), 1 90-2 2tl (2H, m, H-2'), 2 39 (lH, dd, J ~ 12 ~t 17 5 Hz, H-4 ~s), 2 89 (lH, dd, J--3 5 u~d 17 5 Hz, H 4 oq), 3 76 (3H, B, OCH3), 3 77 (3H, 8, OCH3), 4 35 (lH, q, J = 6 5 Hz, H-S'), 4 50-4 70 (2H, m, H-3 ~nd H-3'), 4 90 (lH, br 6, =CH), S 10 (lH, br 6, SUEST~ ~ ~7~ ET
WO 94/11382 2 1 g ~,~ 4 ~ PCI'/CA93il)04i63 =CH), 5.38 (lH, br 8, H-l'), S.54 (lH, br 8, H-4'), 5.94 (lH, 8, H-l), 6.31 (lH, m, N-H), 6.71 ~nd 6.77 (2H, AB sy~tem, Ar-H), 8.27 (4H, m, PNB).
Step 4: (1'S, lR, 3S)-S,10 :'- 3 ~ 1 1-(2',3',6'-1 ~I ~-3'~ " ~ ' ' 4'-0 ~ ' yl L l~ ' IJ - ` 3,4,S,10 1 ~.~. lII ~r " ~ 12,3-c]-p~ll Using th,c ~,mc ~ ~ ' ' - d in step 6 of thi~ _ , ' e, thc ~rting ' . from step 3 hercil~ (80 mg; .13 mmol) fford~ fte,r CAN ~ ,d Diels-Aldcr thc title produc,t (35 mg; 42%
10 ova~ll) cont~ tod by whd loolcs lilce ~gl~_ ~ systcms.
lH NM,R (250 MHz, CDC13) o: 1.17 (3H, d, J = 6.S Hz, H-6'), 1.87 (3H, 8, =C-CH3), 2.09 (2H, m, H-2'), 2.45 (lH, m, H4 u~), 2.90 (lH, m, H4 eq), 4.34 (lH, q, J--6.5 Hz, H-5'), 4.50-4.75 (2H, m, H-3 ~nd H-3'), 5.00 (lH, 8, =C-H), 5.17 (lH, 8, =C-H), 5.44 (lH, br 8, H-l'), 5.72 (lH, ~, H-4'), 5.99 (lH, 8, H-l), 6.40 (lH, br d, J = 7.5 Hz, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H), 8.28 15 (4H, m, PNB).
Step S: (l'S, lR, 3S)-!;,10-dioxo-3 ~ l 1-(2',3',6'~ -3'-L-~
L l~ ' .J. ~) 3,4,S,10 t ~d o llI ~ 12,3 ~] ~. (BCH-21S3) 20 Usmg the ~ , A~ d ill ~tep 3, c~c mple 32, thc d~rting p- ' ~Icohol from ~tep 6 herein (dightly impurc, 30 mg; .047 mmol) ~ffordod thc title ~ . ~ (11 mg; 48%), M.P.: 170C (dec).
IR (ne~t): 3417, 2936, 1716, 1664, 1596, 1293, 1167 ~nd 983 cm~l.
lH NMR (250 MHz, CDC13) o: 1.22 (3H, d, J--6.5 Hz, H-6'), 1.70-2.10 (3H, m, H-2' ~nd O-H), 1.85 (3H, 8, - C-GEI3), 2.41 (lH, dd, J = 11.5 nd 19.5 Hz, H4 as), 2.89 (lH, dd, J = 3.5 and l9.S
Hz, H4 oq), 3.59 (lH, m, H-4'), 4.16 (lH, q, J--6.5 Hz, H-5'), 4.35 (lH, m, H-3'), 4.52 (lH, dd, J
= 3.5 nd ll.S Hz, H-3), 4.96 (lH, 8, ;CEI), 5.13 (lH, 8,--CH), 5.54 (lH, d, J = 3.5 Hz, H-l'), 5.93 (lH, 8, H-l), 6.71 (lH, br d, J = 8.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, ArH).
Step 6: (1'S, lS,3R)-S,10 ;d- 3 ~ 1 1-(2',3',6' i '~ ~-3' ~
4'-O I ~ Jl L ~ .` 3,4,5,10 ~ ' ~d ~ lII p~ ' ~ 12,3-c1-P~
To a solution of the st rting . from stc~ 3 hercin (120 mg; 0.19 mmol) in ~ I~ (4 ml) at 0C was ddod a solution of CAN (p~c~ ~d by ~ e c~c r~it~te (630 mg; l.lS mmol) in water (2 ml) nd th~ adding slowly 60dium ' (169 mg)). After thc ~d " the mi~ture was stined for 10 minutes nd was thcn .. ' - ' with ! ' ' ~ sodium L L solution. The product v~s e d with ~" ' ' - - and the . ' - ' orgsnic e~ctr cts were w~ihed with brine nd dried over Na2SO4 to yield ~ crudc quinone (112 rng) which W~8 ~ d in toluene (5 rnl) and re~cted with l-acoto~cy-1,3 ~ ' - (113 ~1; 1 mmol) ~t room I , c for 15 hours. After this SUBSTITUTE SHEET
W O 94/11382 PCT/CA93/00463 2 1 ~
timo, silict gd w~ ldod nd ir W~8 bubblod through for 30 minutes The rosidue w~ y~plied to silic- gel column ~nd duted with 0-5 % ethyl ~te in toluene ~rru ~g slightly impure title (54 mg) ~long with pu~s product (17 mg; totd yield 575~).
lH Nn~R(250 MHz,CDC13)~: 1.36(3H,d,J = 6.5 Hz, H-6'),1.86(3H, s, =C~H3),1.99(lH,br 5 dd, J = S nd 12.5 Hz,H-2' e~, 2.13(lH, td, J - 3.5 nd 12.5 Hz,H-2'~),2.52 (lH, dd, J = 11.5 - nd 19 Hz, H4 ~), 2.91lH, dd, J = 3.5~nd 19 Hz, H4 o~, 4.48(lH, br d, J ~ ll S Hz,H-3),4.62 (lH, m, H-3'),4.84(lH,q, J ~ 6.S ~ H-S'),S.UO(lH, br s, !CH), S 14 (lH, ~ 8, =C-H),5.47 (lH, br 8, H-l'),S.62(lH, d, J = 2.S ~ H4'), 6.13(lH, B, H-1),6.47(lH, ~ d, J = 7 5 Hz,-NE~, 7.78(2H,m, ~r-H), 8.12(2H, m, ~-H),8.29(4H, m, PNB) Step 7 (l'S, lS, 3R)-S,10 ' 3 ),, , 11 1-t2',3',C' i ~I ~-3' 1 L 1~ ) 3,4,5,10 1 ',d ~ ~ p! ' ~ [2,3-cl-p~n (BCH-21-52) Uung ~c ~ ' - d in dbp 3~o~Iple32,~edhning p ~ ' dcohol fi~m d~p6ho~m(16 15 mg; .0248 mmol) ~ffordod tho titlo ~ ' (11 mg; 9096), M P 102-105C
IR(~t): 3418,2934, 1718, 1669, 1295, 1167,982 nd965cm~l.
lH NnMR(250 MHz,CDC13)o: 1.42(3H,d,J = 6.5 H~ H-6'), 1.84(3H,~, C-CH3), 1.86(2H,m, H-2'),l.99(lH,d,J - 8.0 Hz,~DH),2.51(lH,dd,J = ll.S~ndl9.5 Hz,H-4~),2.89(lH,dd,J =
3.5 ndl9.5 ~ H-4o~,3.65(1H,m,H-4'),4.35(1H,m,H-3'),4.46(1H,dd,J = 3.5 ndll.SH~, H-3),4.63(lH,q,J ~ 6.5 Hz,H-5'),4.98(lH,~, CH~,5.12(lH,~ ~C~,S.43(lH,~ ~,H-l'),6.07(lH, 8, H-1),6.72(1H,m,-Nn~,7.75(2H,m,A~-H),8.12(2H,m,A~-H).
r p! 31~ of(l'S,lP ~S)-S,10 t- 3 ~ L .11 l-t2',3',6'-~ideo~y-3'-~ A ~ L l~ ' .J ~ ~) 3,4,S,10 1 ~d ~ p! ' - ~2,3 cl r.~- ~ (BClI-2128) Sl J~S~ ET
2 14 ~ ~ ~ 8 OCH, ~H, ~,0 OC~, CH~H~ OCH
CH,O O + CH,O o PNBONHIFA PNBONHlFA
.~H~
O O O O
pN~oNslFA PNBoN~FA
o o ~ \4 pNBoNHlFA ~o o ~OCH, O O
HoNHlFA
Step 1: (l'S, lR, 3S) ~nd (l'S, lS, 3R)-S,8 dimetho~-3 ~ 1-(2',3',6'-S i~n.
U~g the r ~ d- - ~ d LG dbp 2, c~Jrople 32, thc o~u~n~ _ (S00 mg; 1.98 mmol) rf~orded ~hkr f~h . , ~ (S-20% codone in benzene . g ~ bRcc of I - ~ -) the mic~ue of ~c ~ . ' (490 mg; 40% (-1:1)).
lH ~n~R (2S0 ~LF~ CD2C~2) ~: (for l'S, lR,3S): l.lS (3H, d, J = 6.5 H~ H-6'),1.7oL2.2S (2H, m, H-2'), 2.65 (lH, m, H-4 ~),3.10 (lH, m, H 4 oq~,3.76-3.78 (9H, I , . d ~Dngle~, CKCH3), 4.38 (lH, q, J = 6.S H~ H-5'),4.4S-4.85 (2H, m, H-3 snd H-3'),5.41 (lH, m, H-1'),5.57 (lH, m, H-4'),5.97 (lH, 8, H-1),6.45 (lH, br d, J ~ 7.5 E~ -NlH~,6.65-6.8S (2H, m, Al-H), 8.26 (4H, m, P~DB); ~ (for l'S, lS,3R): 1.22 ~3H, d, J 6.5 H~ H-6'), 1.70-2.20 (2H, m, H-2'),2.66 (lH, m, H-4 ~),3.10 (lH, m, H ~ oq~,3.76-3.78 (9H, . . - ~ sLngle~, CPCH3),4.45-4.85 (3H, m, H-3, H-llS
SU~ST~lJT~ T
~146~4~ e 3' ~nd H-5'), 5.42 (IH, m, H-1'), 5.57 (lH, m, H-4'), 6.16 (lH, ~, H-l), 6.45 (lH, br d, J = 7.5 Hz, -N-H), 6.65-6.85 (2H, m, ~r-H), 8.26 (4H, m, PNB).
Step 2: (l'S, lR, 3S) ~nd (l'S, 1S, 3R)-S,8 dioxo-~ L yl 1-(2',3',6'-trideoxy-S 3~ O r ~ ~I L l~ ' r~ ) 5J8 ,~
To ~olutio~ of the ~g ' _ from ~p 1 haein (475 mg 0.74 mmol) in ~ D (15 ~1) ~t 0C w~s ~dded ~ solution of C~N (L . d by ~ e ~c nit~tc (2.42 ~) ill w ter (7 10 ml) ~nd th~ ~ with odium ' L (652 mg) ~d olowly). ~fter thc ~ ' " the mi~ture w~ stirred ~t 0C for 15 minute~ nd W98 thell i ' - ' with - ~ sotium b L ~olution l~nd ' w th ~' ' ' . ' - The: ' - ' org~nic layer~ werc w shed with brinc nt dried ovcr Na2S04 giving a cmde mL~re of tlle titlc !, ~ (422 mg; 939G) usod ~ uch for the lle~ct rc~ction.
lH NMR (2SO MHz, CD2C12) o: 1.15 (3H, d, J = 6.5 Hz, H-6'"~), 1.27 (3H, d, J = 6.5 Hz, H-6', 15 O, 1.70 -2.25 (2H, m, H-2', ~ Jnd 2H, m, H-2', O, 2.S5 (lH, m, H~ ~, A nd lH, m, H-4 ~, O, 2.85 (lH, m, H4 oq, A ~nd lH, m, H-4 oq, O, 3~76 (3H, 8, OCH3, O, 3.77 (3H, 8, OCH3, O, 4.34 (lH, q, J 6.5 Hz, H-5', ~), 4.4~4.70 (2H, m, H-3' nd H-3, ~ ~nd 3H, m, H-3', H-3 nd H-5', O, 5.39 (lH, m, H-l', ~ nd lH, m, H-l', O, S.54 (lH, d, J -3H, H~', O, 5.57 (lH, d, J = 3Hz, H-4', ~O, S-80 (lH, 8~ H-l, ~O. S.9S (lH, 8, H-l, O, 6.60 (lH, m, NH, A nd lH, m, NH, O, 6.80 (2H, m, 20 Ar-H, ~ nd 2H, m, ~.r-H, O, 8.26 (4H, m, PNB, ~ nd 4H, m, PNB, O.
~ A i8 (l'S, lR, 3S) d-- nd B i8 (l'S, lS, 3R) :' . .
step 3: (l'S, lR, 3S~-S,10 ~- 3 ' ~ l 1-(2',3',C' ' 11 ~-3'-~ q'- F ~ l L l~ ' ., ~ ` 3,4,S,10 . ~ b 2S III p! '' ~ r~ c] IJ
Using Ihc ~ d in ~p 4, c~lc 26, thc ~tsrting quinonc f~m 8t~p 2 hcrcin (400 mg;
.658 mmol of a 1:1 mi~c of 1'S, lR, 3S ~nd 1'S, lS, 3R) fforded purc titlc product (13 mg) dong wit}l a -1:1 mi~ct~rc of (l'S, lR, 3S) nd (l'S, lS, 3R) i80mer8 (275 mg).
30 lH NMR (2S0 MHz, C1~2C12) ~: 1.18 (3H, d, J ~ 6.5 Hz, H-6'), 1.9~2.20 (2H, m, H-2'), 2.68 (lH, dd, J = 11.5 nd 19 Hz, H4 ~), 3.08 (lH, did, J ~ 4 ~nd 19 Hz, H-4 oq), 3.80 (3H, ~, OCH3), 4.38 (lH, q, J 6.5 Hz, H-5'), 4.57 (lH, m, H-3'), 4.75 (lH, dd, J ~ 4 nd 11.5 Hz, H-3), S.42 (lH, br s, H-l'), S.69 (lH, br s, H-4'), S.99 (lH, s, H-l), 6.42 (lH, br d, J ~ 7 Hz, -N~, 7.7S (2H, m, Ar-H), 8.08 (2H, m, ~r-H), 8.28 (4H, m, PNB).5 Step 4: (l'S, lR, 3S)-5,10-dioxo-3 ' ~ L ~l 1-(2',3',6',trideoxy-3'-h-~ r '~ L l~ ' ~,. ~ ) 3,4,S,10~h~dro-lII ~ID! '- ~ 12,3~1-p~no (BC~I-2128) S~ T~ 3 ~F ~ T
W O 94/11382 21~ ~ A ~ PC~r/CA93~00463 Using the ~.. ' e ~ d ill step 5, e~mple 26, the st rti~g ~ Icohol from ste~ 3 herein (12 mg; 0.018 mmol) ffordot ~fkr column ch.. ~ (10% ~cetone in ~ ), the title . _ ' (5 mg; 54%) ~ ~ ydlow solid. M.P. 92-105C.
lH NMR (250 MHz, CD2C12) o: 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.55 (lH, br 8, OH), 1.70-2.00 (2H, S m, H-2'), 2.66 (lH, dd, J ~ 12.0 ~nd 19.0 Hz, H ~ ~), 3.06 (lH, dd, J ~ 4.0 uld 19.0 Hz, H-4 oq), 3.59 (lH, br 8, H-4'), 3.79 (3H, 8, -CO2CH3), 4.17 (lH, q, J ~ 6.5 Hz, H-S'), 4.28 (lH, m, H-3'), 4.73 (lH, dsl, J = 4.0 nd 11.5 Hz, H-3), 5.52 (lH, br ~, H-l'), 5.92 (lH, 8, H-l), 6.75 (lH, m, -NH), 7.75 (2H, m, ~r-H), 8.05 (2H, m, ~r-H).
S U ~ T
:
2146~
F "r.~ 32: ~ . ' of (l'S,lR,3S) , ~ l [5,10-dioxo-1-(2',3',C'-: ~-3'-L '1l . - '~:t '1 1,-1,~ ' r~ ) 3,4,5,10 1 ~L., l~I l"! " -2,3~] ~". .,1] ' (BCH-2112) + ~0 ~~ .
OCH, OCH, OCH, ~+ ~0"~
O o O O
PNBONHIF~ pNBoNHlFA
O O
HoNH~A
S ~
step 1: 1~ 3-yl)-lce~oDe To ~ olutioo of the ~ting o~ler (1.0 g; 3.97 mmol) ~n t ' ~ ' (30 ml) ~t 0C w~ ~led , , ,1 _ c~loritlc (2M, 4.17 mmol). Thc mLsture w 8 s~d t 0C for 20 minute~i ~d Jlt room i . for 1 hour. It wss then 1 ' ' with L ' ' d chloride solution ~nd e~ ' with ~ Thc ~ ' org~ic l yer~ wer~ w-shed with ~ e uld dried over MgSO4 to fford dter 6. . thc titlc ~ . I (240 mg; 239~ (40% b~ed on S.M. .~._~ d)).
lH NMR (250 MHz, CDC13) o: 1.13 (3H, d, J--6.5 Hz, CH3~, 1.16 (3H, t, J ~ 6.5 Hz, C~3-CH), 2.S9 (lH, br dd, J--11.5 ~d 17 Hz, H 4 ~I-A)~ 3.04 (lH, dm, J ~ 17 Hz, H-4 eq), 3.17 (lH, m, ~-CH3), 3.76 (3H, 8, OCH3), 3.78 (6H, 8, OCH3), 4.17 (lH, dd, J ~ 3.5 nd 11.5 Hz, H-3), 4.64 (lH, br d, J ~ 16 Hz, H-l), 5.03 (lH, d, J = 16 Hz, H-l), 6.65 (2H, ~B system, Ar-H).
5,8 ' ' ~-3 .~ JVA,~ w~sobt~inedu;-b, p..' ~ ' Efirom~ ' of the G- _ ' rcye~lt.
lH NMR (250 MHz, CDC13) ~: 1.29 (3H, d, J = 6Hz, CH3-CH), 1.30 (3H, d, J = 6 Hz, CH3 CH), 2.74 (lH, br dd, J 5 11 ~nd 17 Hz, H-4 ~c), 3.05 (lH, dm, J = 17 Hz, H 1 eq), 3.7S (3H, 8, OCH3), SUI~ST~ 3 ~E ~ E~
WO 94/11382 PCI/CA93~'00463 ~146~8 3.78 (3H, 8, OCH3), 4.19 (lH, dd, J ~ ~, ~d 11 Hz, H-3), 4.65 (lH, br d, J = 16 Hz, H-1), S.04 (lH, d, J = 16 Hz, H-1), 5.15 (lH, ~opt., J = 6 Hz, C~-CH3), 6.64 (2H, AB system, ~r-H).
step 2: (I'S, lR, 3S) . .. ,11 [1-(2',3',6'~ideQ~-3'-t '~ . e~mido~'~p-S ~L ,~1 L 1~ ' ,, ) S,10 ~- 3,4,S,10 1 ' ~ lII "r ' [2,3 cl ,,. ,~II-lcetone To ~solutionof~-2',3',6' 1 ' ~-3' ~ L yl L-ly~r' ., (408 mg; 1.04 mmol) nd st rting Icotonc f~m ~p 1 herein (230 mg; 0.87 mmol) in ~- ' ' ~ (IS
10 ml), werc dded 4A molocul-r uove~ (400 mg) ult 2,3: - ~' ~5,6~ (270 mg; 1.2 mmol). The mL~turo w ~ ctirred t room l . for 14 h~s uld w then q ' - ' with ' ~ solutionuld ' with ~" ' ' . ~ Thc c ' org nic l~yerswerewsshedwith brine nd dried over N~2S04 to ~fford ~ cmde dduct (S90 mg) which W91; ~ d i~ (20 ml) t 0C nd tre~ .. with ~ solution of ceric llitrs~e (3.15 g; 5.7 mmol) in w ter lS (10ml) c g~odiuml L (847mg). ARerthe-'' themi~turew sstin~ddOCfor lS minutes nd w~8 i ' - ' with ~ N HC, 03 nd a ~ with ~ ' ' ' ~ The c ' - ' orgsnic l~yer~ were w~hed with brine ~nd dried over Na2S04 to fford ~ csude quinone mi~cture (SS7 mg) of which 100 mg (.16 mmol) were d l~ _1 in tolueDe (6 ml) u~d t~d with 1-~ceto~cy-1,3 t - (113 ~1; 1 mmol) t rt~om I . .i for 14 hours. Silic ud ws~ dded to the 20 m~ture ~nd ~ir w~s bubbled throu~h for 1 hour while toluene p~ly ~ The residue wss spplied to ~ column of silic~ gd nd dutsd with 0-1096 othyl ~te in tolueno ~ g the title c~ . ' (20 mg) slightly ~ ' by ih (lS, 3R) ' ~ (-3:1).
lH NMR (250 MHz, CDC13) ~: 1.00-1.30 (9H, m, H~' nd CH~C~3)2), 1.60 2.40 ~2H, m, H-2'), 2.52 (lH, m, H-4 ~c), 3.00-3.35 (2H, m, H-4 oq snd C~CH3)2), 4.32 (lH, q, J = 6.5 Hz, H-S'), 25 4.50-4.90 (2H, m, H-3 u~d H-3'), 5.44 (lH, br 8, H-l'), 5.75 (lH, br 8, H-4'), 6.06 (lH, 8, H-l), 6.49 (lH, br d, J ~ 7.S Hz, -NH), 7.78 (2H, m, Ar-H), 8.07 (2H, m, Ar-H), 8.27 (4H, m, PNB), spp~rent signds for (lS, 3R) ~' re: 6.22 (lH, 8, H-l) nd 6.58 (lH, br d, J ~ 7.5 Hz, NH).
Step3: (l'S, lR, 3S) , ~ (2',3',6' ~ 3' ~ ~ . u k L-1~ ) 5,10 ' 3,4,S,10 ~ '' ~ 12,3 cl ~J-BCH-2112) To ~ ~olution of st rtiny p.. ' Icohol from step 2 herein (20 mg; 0.0296 mmol) in -' (.3 ml):
.~b. r (1 ml) ~t 0C w~8 dded sodium ' in - -' (4.37 M; .7 ~1; .1 oq). The 35 mLlcture w 8 stirred ~t 0C for 20 minue~ ~nd w 8 then ;. - d with ~ d NH4C1 solution ~Dd was ' with ~' ' - - The e ' org~nic l~yers were wu;hed with bnne ~d dried over N~2SO4 to ~fford ~ crude ro6idue which w~s purified by column . O . ~ on silic- gel using 10%
~cetone in be~ne yidding the titled ~ . ~ (6.4 mg; 639G).
SuBS ~ E ~ r~ET
~1~6~4 8 lH NMR (CD2C12, 250 MHz), ~: 1.11 (6H, d, J = 6.5 Hz, ~H~CE~3)2), 1.20 (3H, d, J ~ 6.5 Hz, H~'), 1.65 (lH, s, OH), 1.75-2.05 (2H, m, H-2'), 2.48 (lH, dd, J = 11.5 snd l9.S Hz, H-4 a~), 3.01 (lH, dd, J = 4.0 nd l9.S Hz, H-4 oq), 3.15 (lH, 8ept., J = 6.5 Hz, CH~CH3)2), 3.58 (lH, d, J =
2.5 Hz, H 4'), 4.10 (lH, q, J - 7.0 Hz, H-S'), 4.28 (lH, m, H-3'), 4.68 (lH, dd, J ~ 4.0 ~nd ll.S
S Hz, H-3), 5.55 (lH, d, J ~ 3.5 Hz, H-l'), 5.97 (lH, 8, H-l), 6.72 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
E~cample 33: Prepu~on of (1'~;,1.';"~Tt) ~nd (1'~;,1P,~S) 5,10-dioxo-3-1 ~ -~) t~5 10 ~ . lII p~ - [2~cJ-p~:
(BC~-2122) ~d ~BCH-2121) OCH, OCH, ~ ~ol O o O O
~
O o O
HoNHlFA HoNH'lFA
BC~U2~ BG~-2121 1~ S~ep 1: (l'S, lR, 3S), Jnd (l'S, lS, 3R)-S,1~ ~- 3 ~ . bon~l-1-(2',3',6'-tri~eo~q-3',t '~ . ~ ' ~'-O ~ ' oL ,~1 L 1~ ' ,J :) 3,4,S,10-H~aphth)-12,3 ~; ~J
Using the ~ in dep 2, e~uDplc 32, the stuting ' . *~m ~tep 1, ~nplc 32, 20 (300 mg; 1.07 mmol) fforded ~ cmde ~ , d dduct (417 mg) which w~ tre~ted wit~ CAN to givc cmde quinone mL~ re (355 mg) of which 250 mg were re~cted with ~ ~ ~,' t4diene. Thi8 reaction SU~TiT~T~ ET
WO 94/11382 ~ ~ 4 6 ~i ~ 8 Pcr/cAg3~3 yidd~d ~ dightly impure mL~ture of the title ~ - ~ (113 mg; 15% o~er ll) (-55:45) f~roring the (l'S, lR, 3S) isomer.
lH NMR (250 MHz, CDC13) ~: (for l'S, lR, 3S): 1.15-1.42 (9H, m, H-6' Jnd CH{C~,3)2), 1.90-2.20 (2H, m, H-2'), 2.68 (lH"dd, J = 12 ~d 19 Hz, H-4 ~), 3.12 (lH, m, H-4 eq), 4.40 (lH, q, 1 =
6.5 Hz, H-5'), 4.50-4.80 (2H, m, H-3 nd H-3'), 5.18 (lH, m, C_{CH3)2), 5.44 (lH, br 8, H-l'), - 5.74 (lH, br s, H-4'), 6.03 (lH, ~, H-l), 6.55 (lH, br d, J = 7.S Hz, N-H), 7.77 (2H, m, Ar-H), 8.11 (2H, m, ArH), 8.27 (4H, m, PNB); (for l'S, lS, 3R): 1,15-1.42 (9H, m, H-6' uld CH(CH3)2), 1.9 2.20 (2H, m, H-2'), 2.69 (lH, dd, J ~ 12 rnd 19 Hz, H-4 alc), 3.12 (lH, m, H-4 eq), 4.50-4.80 (3H, m, H-3, H-3' ~nd H-5'), 5.18 (lH, m, C~,(CH3)2), 5.45 (lH, br 8, H-l'), 5.65 (lH, d, J = 3 Hz, H-3'), 6.18 (lH, 8, H-l), 6.61 (lH, br d, J--7.5 Hz, -NH), 7.77 (2H, m, Ar-H), 8.11 (2H, m, Ar-H), 8.27 (4H, m, PNB).
Step 2: (l'S, lR, 3S)-S,10 ~ 11 1-(2',3',6' t ' ~-3'-L-'` ~ ~ L 1~ ' rJ~ ) 3,4,S,lO~h~dro-lH-naphtbo ~2,3-c1-pyr~ (BC~-2122) U8i~1g the p,~ ~ A ~ d ill 8top 3, ac~mple 32, the st rti~g p.~ ~ . lcohol f~om ~tep 1 herei~
(113 mg; .16 mmol) fforded (~f~er multiple e' ~ ; using lOX ~cetone in benzene or in ~ e) the pure title _ . ' (7 mg; 8%). M.P.: 93-101C.
lH NMR (CDC13) o: 1.29 ~nd 1.33 (6H, 2d, J = 6.5 Hz, -CH-(C~,3)2), 1.33 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.10 (3H, m, H-2' nd O-H), 2.68 (lH, dd, J ~ ll.S ~nd l9.S Hz, H-4 A)~ 3.11 (lH, td, J
; 4.0 ~nd l9.S Hz, H-4 eq), 3.65 (lH, m, H-4'), 4.21 (lH, q, J--6.5 Hz, H-S'), 4.38 (lH, m, H-3'), 4.66 (lH, dd, J = 4.0 ~nd l l.S Hz, H-3), 5.18 (lH, sept., J = 6.5 Hz, C~CH3)2), 5.56 (lH, br 8, H-1'), 5.98 (lH, 8, H-l), 6.72 (lH, m, N~, 7.75 (2H, m, ~r-H), 8.10 (2H, m, Ar-H).(l'S, lS, 3R)-5,10-dioAo-3 r ~.I~A,~ 1-1-(2'~3'~6' h;~A~-3' 1 '' . mido-L-3,4,S,10 t ~ ' ' - [2,3-c1-pyr n(BCH-2121) w~8 isol ted fter mlllap10 ! ~ (5 mg; 6%). M.P.: 155C (doc).
lH NMR (CDCl3) o: 1.32 (6H, d, J--6.5 Hz, CH-(C~3)2), 1.41 (3H, t, 1 c 6.5 Hz, H-6'), 1.87 (2H, m, H-2'), 2.0S (lH, m, OH), 2.70 (lH, dd, J ~ 12.0 ~nd l9.S Hz, H-4 A)~ 3.10 (lH, dd, J = 4.0 snd l9.S Hz, H-4 oq), 3.63 (lH, m, H-4'), 4.32 (lH, m, H-3'), 4.SS (lH, q, J ~ 6.5 Hz, H-S'), 4.62 (lH, dd, J = 4.0 uld 12.0 Hz, H-3), 5.16 (lH, sept., J ~ 6.5 Hz, C_~CH3)2), 5.47 (lH, br 8, H-l'), 6.14 (lH, ~, H-l), 6.75 (lH, m, N-H), 7.75 (2H, m, Ar-H), 8.12 (2H, m, Ar-H).
SU~S~ T~ ET
WO94/11382 21~548 PCT/CA93/00463 F p!- 34~ of (l'S,1S)-5,10 :-- - 3,3 ~ 2',3'6'-L-' ~ (BCH-1697) 0~4 0~4 ~ J , ~H
OM~ Ob D
OMc OM~
¢S~3 ~ OMe ¦ NHIFA
~PNB 14 O O
O O o o H,C~j~ H,C z~
NHIF~ ¦ NHlFA
t~PNB CPNI~
,~
O O
H3C~I
HO NH~A
Under ~rgon ~ , 110 mg (2.90 mmol) of LAH were ~dded to 15 ml of dry ~
10 coolod to 0C. To tbiK ~olution w~s ~dded 0.450 ~ (1.45 mmol) of 5,8- " .r-3,3~is (dic~rbome~o~y)-isochroms~ d ill 15 ml of 1~. The I . ~ llowod to w~rm up toroom i . ~, ~d sti~ring w~s . ' for 3 hours. ~fter thd time, ~nother 160 mg (4.22 mmol) of I~H w~ then dded Jnd thc ~ction mi~c~re wui ~tirred for ~nother hour. After th~t time, the re~ction mi~cture w~ poured into 50 ml of ~ 0.1 N u~ueou~ solution of HCl. r~ - of the ~ueDus SUE~E~!TE S~EET
WO 94/11382 PCI~/CA93/00463 2~46~4~
l~ycr rc douc using CH2C12. The . ' org~nic layers re driod over N~2S04, filtered, 9~ d the solvent i6 removed. The isohted titled ~.--y~- ~ is used without further pu. fi~ (0.333 g; 909~).
NMR 1H (250 MHz) (CDC13.ppm): 6.64 (2H, 2d, ~ ~ ); 4.80 (2H, s, H1a- Hlb); 3.76 (6H, s, 2~0CH3); 3.71 (4H, m, 2{~H2-); 2.53 (2H, 8, 2sOH); 1.85 (2H, m, H4a-H4b).
s Step 2~ 3,3 bi~
Under ugon , ' .;, 0.333 g (1.31 mmol) of tho ~rting rn~i l from step 1 herein were phcod in 70 ml of dry THF. To this solution wcre then added 0.105 g (2.62 mmol) of NsH. After a few minutes 10 of firring, 0.41 ml (6.55 mmol) of McI were dded to the re ction mi~re nd 6tirring W~8 left for 1.5 hour. After that time, uK~ther 0.145 g of NaH nd 0.7 ml of MeI wcre ddod to the re~ction which was , ' ' sfter ~other hour of stirring. Aquoow HCl (0.1 N) wss then ddod snd c were done using CH2C12. Thc . ' ' orgsnic e~tr~cts were wYshod with n queou~ solution of sodium ' : ~ driedoverN 2S04, filtsred, ndthesolventw~sremoved. Theobt inedtitled: , 15 wss u~ed for ne~ct step without further ~ ol~ed pr~duct (0.470 g; ~99%).
NMR lH (250 MHz) (CDC13:ppm): 7.26 (2H, 2d, ~ ); 4.74 (2H, s, Hl~-Hlb); 3.76 (6H, 2~, 2~0CH3); 3.54 (2H, d, J = 9.7 Hz, -CH2- side ch~in); 3.41 (2H, d, J ~ 9.7 Hz, -CH2- side chain);
3.38 (6H, ~, 2~cOCH3); 2.64 (2H, 8, H4a~H4b)-IR (film) (cm~l) 2925 (CH ~ c), 1580 (C~C), 1475 (CH2), 1450 and 1360 (CH3), 1100 ~nd 1248 20 (C-0).
Step 3: (1'S, 1S)-~ -3 ~ ~ ~l 1-(2',3',6'~ -3'-2S Under rgon ,* ~, the ~ " .. g ~gonts: product from step 2 hercin, 0.477 g (1.70 mmol), 2,3,6 t~ -3 ~ - ' q 0 ~ .L .yl ~-L 1~ -' r~ ~ 0.378 g (2.00 mmol) nd DDQ 0.452 g (2.00 mmol) were ~ d in 50 ml of ~' ' '- . ' - The ro ction mi~cture w~s stirred t room i for a period of 16 houra Aher th~t time, n e~ccoss of DDQ w then ~dded to the ro ction misturo nd ~tirri~ w~ left for nothcr hour. The re ction mu~tur~ WS8 tben ~
30 with ~ NH4Cl nd ~ of the qucow l~y W98 done u~ing CH2C12. The ~ org~nic l~yers v~e~e dried ov N~2S04, filterod nd the solvent w~ removed. The crude m~teri~l W~8 purified by fls~h ' ~" . ' ~, ~' ' -- ~h.~l scet~te (70:30) then (60:40). The obt~ined titled ~ , ~ W~8 ~ pdc ycllow solid (0-434 8; 39%)-NMR lH (250 MHz) (C6D6; ppm): 7.89 (2H, m, - . ), 7.68 (2H, m, 9 . '- )~ 6.53 (2H, m, 35 ~ . - ), 6.52 (lH, NH), 6.08 (lH, s, H1), 5.62 (lH, 8, H1.), 4.70 (lH, m, Hs.), 4.60 (lH, m, H3.), 3.82 (2H, m, CH2-OMe), 3.74 (lH, m, H4~), 3.55 (2H, m, CH2-OMe), 3.48 nd 3.42 (6H, 28, 2~c0CH3), 3.40 (2H, m, H2., nd H2.b), 3.18 u~d 3.11 (6H, 2~, 2~c0CH3), 2.13 (lH, m, H4"), 1.86 (lH, m, H4b), 1.21 (3H, d, J e 6.2 Hz, CH3 6ug~r).
SUE~S-r~ t ~
214~8,~
Sbp 4: (l'S, 1S)-5,a~diox~3,3 ~ 1 1-(2',3',6'-trideoxy-3'-l. '' . ~
4'_0 ~ ,I L 1~ ' ~,. ) .
Thc st~ting m~ten~l from dep 3 horein, 0.430 g (0.65 mmol), W~ d in - 1- t 0C. A
S ~olution of N~ICO3 0.107 g (1.30 Dl) in 7 ml of w~tcr w~ then ~dod Jnd the oolution wu~ 8ti rod for 10 ~ute6. Aftcr th~ tunc, l.OS3 g (l.9S mmol) of CAN tilutod in 12 ml of w tor were thcn ~dded to thc rellction ~e in ~ m~ner. The re~tion w c ' ~fter 10 minute~. A very diluted 801ution of N HCO3 in w tcr wrs thcn dded to thc re ction mL~ture. r - Of thc resction mi~ re were dane using CH2C12. The ~ ' ' o~g~nic l~yers ~ driod over N 2S04, filtered nd ihe solvent w~ rsmoved. The titled . ' w~8 u~ed for ne~tt step without funher ~ - (0.387 g;
95%).
NMR lH (250 MHz) (C6D6; ppm): 7.94 (2H, d, J ~ 7.5 Hz, ~ ~ --), 7.75 (2H, d, J ~ 7.5 Hz, - ), 7.42 (lH, m, NH), 6.20 (2H, m, qui~one ring), 5.98 (lH, ~, Hl), 5.92 (lH, 8, Hl~), 5.41 (lH, ~, H4.), 4.90 (lH, q, Hs~), 4.67 (lH, m, H3.), 3.47 (2H, CH2-OMe), 3.29 (2H, CH2-OMe), 3.16 lS (3H, 8, OCH3), 3.11 (3H, 8, OCH3), 2.50 (2H, 2d, H2.~, H2.b), 2.22 (lH, m, H4,), 1.97 (lH, m, H4b), 1.27 (3H, d, J = 6.3 Hz, -CH3 ~ug~r).
StepS: (l'S, lS)-S,10 ~- 3,3 ' ' ~ rl 1-(2',3',6' ~ -3'-1- r ~ Jl L 1~ ) 3,4,S,10 1 III ~ 2~cl P~
Under rrgon ~ . ' 0.173 g (0.27 mmol) of the product from stop 4 ~sin W~ ,d in 10 ml of dry toluene. To thi~ olution w~ ddod 0.2 ml (1.65 mmol) of l~ceto~y-1,3 - The ro ction mu~ture W-8 left stimng o.. t room i . ~. Silic~ gel w~s then ~ddod to the rulction mDC~re 25 nd rir w 8 b~bbled in it for ~ p4riod of 2 hours. Whitout . g the ~olvent, tl~e ro~ction mLl~ture wr8 put on top of ~ gd column uld tolue~e w~ u~ed r8 the f~r~t duent. To- - ~ .~l ~cotde (1:1) v~ then wod to dute the do~ired . , ' The titlod c ' W~ ol-tod (0.06 g, 32%) yellow lid.
NMR lH (2S0 MHz) (CD2C12; wm): 8.29 (4H, m, . ) 8.07 (2H, m, ~ ), 7.76 (2H, m, . ), 6.4S (lH, d, NH), 6.05 (lH, 8, Hl), S.70 (lH, 8, Hl-), S.43 (lH, 8, H3-), 4.82 (lH, m, Hs.), 4.52 (lH, m, H4.), 3.27-3.S2 (4H, m, 2~t CH2- ude Ch~in8), 3.3S (3H, 8, OCH3), 3.27 (3H, 6, OCH3), 2.72 (2H, 2d v. . ' ,1~ - a, H4~ uld H4b), 1.87-2.18 (2H, m, -CH2- sug~r), 1.28 (3H, d, J =
6.5 Hz, -CH3 8Ug r).
3S Step 6: (l'S, lS)-S,10-dioxo-3,3 ~ l 1-(2',3',6'~ -3'-1697) S~ E~T
~0 94/11382 PCI`/CA93/00463 ~ 21gLg~48`
Under rgon 9' ~ the product from dep S hercin, 0.06 g (0.09 mmol~ wu; ~ ~i m mLlcture of S ml of dry ' -' nd 2 ml of dry THF. This solution was cooled to 0C. 2 ~ of ~ 4.37 M
solution of ~odium ' '- in ' -' wcre then ddcd to thc rosction mi~re. Thc re~ction w~s . ' ~ d in 10 minutc6, it w thcn ;, ' ~ ' by rdding quoous NH4Cl. r of the squeous S layer w~u done u6ing ' ' ' ~ ' - Tl~e ' ' org~nic l~yers werc dried o~rer N~2S04, filtered nd thc ~olvont w removed. The crude m tori-l w~ then purificd by fluh ~' . O , ' ~, . ' ' yl - - :" ' ~ ' - (3S:75). Tho i~ol ted titled, . ' w~ yollow solid (0.03 g, 67%).
NMR lH (250 MHz) (CDC13; wm): 8.05 (2H, m~ ~ ), 7.74 (2H, m, - ) 6.81 (lH, d, 10 NH), 6.00 (lH, s, Hl), 5.49 (lH, d, J = 2.8 Hz, Hl.), 4.58 (lH, q, Hs.), 4.23 (lH, m, H4.), 3.60 (lH, d, J = 2.3 Hz, H3~), 3.45 (2H, m, -CH2{0Me, 3.37 (2H, m, -CH2{0Me)), 3.34 (3H, ~, OCH3), 3.25 (3H, 8, OCH3), 2.71 (2H, d, 1 ~ 3.5 Hz, H4y nd H4b), 2.09 (lH, ~d)S, OH), 1.79 (2H, m, -CH2- ~r), 1.32 (3H, d, J = 6.6 Hz, ~H3 sug r).
IR (film) (cm~l): 3450 (OH bo~ded), 2950 (CH liph~tic), 1675 (C=C), 1000 nd 1290 (C-O).
Sll~S ~ ~T~TE ~ ET
WO g4/11382 PCl`/CA93/0(~463 ~1~6548 F. p!- 3S~ of (l'~,lP,~ S,10 ~ ~ . bJI-1-(2',3',6'-trid~eox~-3'-L ~ L l~ ' . J- - - ) 3,4,S,10 ~ b~
P~ (BC~-2091) O~ 4 ~ ~ ~
¢f ~ 1 . ~ 2 ¢h ~ 0~ O~Sc 0~ ~ OM~ ~ OMc ~ + ~'~ ¢~
OA~e O Ol~S O O~b H,C ~ H,C~
NHlF~ N~IP`A
\5 O ~ O ,~
~ ~0 O O O O
}I,C~ H,~
OPNB O~NB
O O
H,C ~
Step 1: 'b~l 2-(2',S'-dimetb /"' ,~
Undcr ~rgon . ~, 3.08 ml (26.16 mmol) of r rJ w~8 sddod to 85 ml of THF
10 ".~ to 0C. Il-BuLi lO.S ml (26.16 mmol) w~ then dded to thi~ solution nd thi8 mi~cture was then stirred for 30 n~inute~;. ~r th~t time, tdle rc~on mLstuse W~18 coolod to -78C ~d the ester S.00 g (23.78 mmol), 208-186-01 in 65 ml of THF w~ then uided ~L. r ~ ;o~. Afte~ tlle - ~ " the mL~ture w~ ~itirrod for 5 m~utes befote HMP~ 4.55 ml (26.16 mmol) w~ ,~dded. AP~ ~nother 10 mmute8 of s~ng r . e ~ ~ ~ s.o ml (47.56 mmol) w s thcn ddod to the re-ction SU~ST~ ~ ~T~ 5~EET
2146~48 ~ ture. The re ction mnltture WY6 then ~tirred for 30 minute6 before rev l of thc dry i~ _ I b~th to ~llow the I . to re c~ room I A ' ~ nd the reYction W~8 - ~ by TLC. The re~ction mLlcture w~s left s~rring ~t room l , ~ for 15 hours. The rction mucture WY6 then q~ ' - ' by ~dding ~queow NH4CI Jnd e with other. The c ' - ' org~ uc l-yers were S w~shed with brine, d ied over N 2S04, filtered nd the sol~ent w~8 . ~l~ The crude w~6 punfied by fl~h ~ u6ing ~ ~1 cot~ 8 eluent; 3.36 g of p~lro titlod c , I ~ white solid were o~ - d NMR lH (250 MHz) (CDC13; ppm): 6.84 (lH, m, uom tic), 6.76 (2H, m, ~ ~ ), 3.90 (lH, t, J
~ 7.6 Hz, H3), 3.77 (3H, 8, OCH3), 3.75 (3H, 8, OCH3), 3.64 (3H, 8, (C02)-CH3), 2.03 (lH, m, 10 H3"), 1.72 (lH, m, H3b), 0.88 (3H, t, J ~ 7.3 Hz, -CH3 termin~l).
step 2: 2-(2',S'~
Under rgon -, ' e, the prodwt frorn step 1 herein, 3.36 g (14.08 mmol) w o ~ d in 100 ml of ~' ' ' ~ This solution wss cooled to 0C ~nd DIBAL-H, 31.0 ml (30.98 mmol) w~6 ~dded ir 15 d,~.. m~nner. Tho ~ction w~u . , ' fter 20 minutos 80 HCI lN w~s ~en ~d to the ro ction mi~ture ~d ~ - wer~ done using ~' ' ' ~ . ' -. The ~ ' - I org nic l-yors were dried over Na2SO4, filtcred, u~(d the oolvent W~8 rernoved. The isol~ted titled ~ ' w96 u6ed for ne~ct step without furhtor ~
NMR lH (250 MHz) (CDC13; ppm): 6.76 (3H, m, ~ ~ ~ ), 3.77 (3H, 8, OCH3), 3.76 (3H, s, 20 OCH3), 3.75 (2H, m, Hl, nd Hlb), 3.19 (lH, m, H2), 1.74 (2H, m, H3, snd H3b), 1.51 (lH, t, J =
6.2 Hz, OH), 0.85 (3H, t, J = 7.4 Hz, -CH3 1 1).
Step 3~ d- ' ~ q ~5JI
2S Under Jrgon ~, ' the product from step 2 ~erein, 2.74 g (13.03 mmol) W98 ~ ~ in 55 ml of dry ether. n- ~ ~ m~ne 1.65 ml (19 55 mmol) nd boron trifluoro o~te 4.9 ml (39.09 rnmol) were thon ~Idded to this lution. The obtuned re~on mLlcture wss left stirring u.. _' The re~ction mL~ture W98 ~1 ' - ' using aqueous N HCO3 nd ~. were done u~ing olher. T~e c ' - ' orgsnic eJtt~cts were dried over Na2S4, filtered, snd the solvent w~8 ~moved. T~e ra~due was 30 punfied by fl~;h ç' . ~pby using ~ dh.~l cot te (80:20) snd (70:30) 8 duent. Tho isolsted titled product wss ~ whito ~olid (1.56 g; 54%).
NMR lH (250 MHz) (CDC13; ppm): 6.64 (2H, m, ~ ), 4.85 (lH, d, J ~ 16.1 Hz, Hl,), 4.55 (lH, d, J--16.0 Hz, Hlb), 4.09 (lH, d, J ~ 11.3 Hz, H3~), 3.79 (3H, 8, OCH3), 3.75 (3H, s, OCH3), 3.58 (lH, dd, J1 = 2.7 Hz, J2 = 11.4 Hz, H3b), 2.62 (lH, m, H4), 1.67 (2H, m, -CH2-35 ethyl), 1.01 (3H, t, J = 7.5 Hz, -CH3).
Step 4: (l'S, lR, 4R)-5~8 ~ 1 1-(2',3',G' h 3 ~-3' 1 '` ~ ' ~'-SU~ S~EEET
21~6~;~8 The titled c ' was obhinod by ~pplying thc ~ 7 from step 3, e~smple 34, t~ the 60cL~
f~om step 3 herein.
NMR lH (2S0 MHz) (C6D6; ppm): 7.81 (2H, d, J = 8.8 Hz, - ~ ~~), 7.65 (2H, d, J = 8.9 Hz, 5 _~ ), 6.48 (2H, dd, Jl= 9-0 Hz, J2 = 18.1 Hz, . ), 6.3S (lH, s, Hl), 6.26 (lH, d, J =
6.9 Hz, NH), S.81 (lH, 5, Hl~), S.S2 (lH, ~, H3.), 4.7S (lH, q, Hs.), 4.S8 (lH, m, H4~), 4.24 (lH, dd, Jl = 2.9 Hz, J2 ~ 11.4 Hz, H3~), 3.88 (lH, d, J = 11,.4 Hz, H3b), 3.38 (3H, 8, OCH3), 3.37 (3H, 8, OCH3), 2.84 (lH, m, H~), 1.89 (2H, m, ~I2~ r), 1.85-l.SS (2H, m, -CH2- side c~i 1.18 (3H, d, J = 6.6 Hz, -CH3 ~ug r), l.OS (3H, t, J 7.3 Hz, -CH3 sido ch-in).
10 (l'S, lS, 4S)-S,8 " ~ 2',3',6' t~;dc~ -3' t ~ . '- ~'-0 p ~ 1 L-NMR lH (250 MHz) (C6D6; ppm): 7.81 (2H, d, J--8.7 Hz, ~ ), 7.61 (2H, d, J - 8.7 Hz, ~ ~ - ), 6.54 (2H, m, a.~ ), 6.55 (lH, NH), 6.09 (lH, s, Hl), 5.69 (lH, 8, Hl~), 5.45 (lH, s, H3-), 4.72 (lH, m, H4~), 4.32 (lH, m, Hs~), 4.26 (lH, dd, Jl = 2.9 Hz, J2 ~ 11.4 Hz, H3a)~ 3.89 lS (lH, d, J c 11.2 Hz, H3b), 3.4S (3H, ~, OCH3), 3.39 (3H, s, OCH3), 2.80 (lH, m, H4), 1.88 (2H, m, -CH2- ~ugar), 1.82 (2H, m, {~H2- side ch in), 1.12 (3H, d, J ~ 6.4 Hz, CH3 sugar), 1.04 (3H, t, J =
7.4 Hz, -CH3 side chain).
Step 5: (l'S, lR, 4R)-S,8 ~ b;.~l 1-(2',3',6' ~ -3~ ~ ~ u df ~'-O-~
~ .11 L 1~
The (l'S,lR,4R) ~ ' *om s~p 4 hescin W9~ d in step4, c~mple34. Thetitlod~ J ~
NMR lH (250 MHz)(C6D6;ppm): 7.80(2H, d, J 8.9 Hz, - ~ ~), 7.62(2H, d, J--8.8 Hz, 25 9 " ), 6.89(lH,d,J--6.9 Hz,NE~,6.04 (2H, dd, Jl = 10.1 Hz, J2 = 18.3 Hz, quinone ring), 5.87(1H,s,Hl),5.63(1H,~,Hl~),S.16(1H,s,H3.),4.80(1H, q, J ~ 6.S Hz,Hs~),4.56(1H,m H4.), 3.75(lH,dd,~l ~ 3.0 Hz J2 ~ 11.6 Hz,H3~), 3.54 (lH, d, J--11.5 Hz,H3b),2.25(lH,m, H4), 1.89(2H,m,-CH2- wgar), 1.47(2H,m,-CH2-sidcch~in), 1.27(3H,d,J = 6.5IIz,-CH3IRlg9 )~ 0.86(3H, t, J . 7.3 Hz,-CH3 ddcc~in).
Skp6: (l'S, ~ 4R)-S,10~ 1 1-(2',3',C'~ -3'~
~b~bou~yl-L1~ ' ~, ~ P 3,4,S,lOt ',.'~ LH~ph~ 2~ ~]~,.
The titled - . ' w_sobbined in 1996 yiddÇo11u. e ~, c - - ~ ~ b~een the quinone from step 5 35 hera~ ~nd 1~CO~OA~L 1~ ~, 98 POr ~ a8 d~ Yd instepS,e~mpb34.
Nn~RlH ~S0 MHz)(C6D6;ppm): 8.02(2H,m,~ --),7.77(2H,d,J = 8.9 Hz,~
7.63(2H,d,J ~ 8.9 ~ ~ ),6.02(2H,m, ~ ),6.53(lH,d,NE~,6.11(lH,s,Hl), 5.67(lH, d, H1~), 4.97(lH, 8, H3~),4.95(1H,m,H4~),4.49(1H,m,Hs~),3.83(1H,dd,H3a),3.60 SU~ ET
WO94/11382 2 1 4654 a PCI/CA93/00463 (lH, d, J--11.4.Hz, H3b), 2.S0 (IH, m, H4), 1.95 ~nd 1.72 (2H, 2dd, -CH2- side chain), 1.58 (Z~, m, -CH2- sugar), 1.31 (3H, d, J - 6.4 Hz, ~H3 sug~r), 0.92 (3H, t, J 5 7.3 Hz, ~H3 side chain).
Step 7: (l'S, lR, 4R)-S,10 ~- ~; b~l 1-(2',3',6'-~rideo~-3'-h ~
1~ ~ . J ' r) 3,4,S,10 ~ ', d a lII ~ p~ ' - t2,3-cJ p~r~n (BCH-2091) Thc titled _ ' was obtainod vi~ of the tricyclic ~54 ~ ~ from step 6 herein a~ per p.~ ' c from step 6, o~mple 34.
NMR lH (250 MHz) (CDC13; ppm): 8.10 (2H, m, ~ _ ), 7.75 (2H, m, . ), 6.72 (lH, d, 10 N~, 5.91 (lH, ~, Hl), S.41 (lH, 8, Hl~), 4.S9 (lH, q, J = 6.6 Hz, Hs.), 4.46 (lH, m, H4~), 4.32 ~lH, m, H3~), 4.03 (lH, dd, Jl ~ 3-0 Hz, J2 = 11.6 Hz, H3~), 3.85 (lH, d, J ~ 11.6 Hz, H3b), 3.64 (lH, m, OH), 2.66 (lH, m, H4), 1.99 (lH, d, J ~ 8.3 Hz, -CH2- side ch in), 1.86 (2H, m, H2.8 and -CH2- side ch~in), 1.65 llH, m, H2,~), 1.41 (3H, d, J = 6.5 Hz, -CH3 sugar), 1.06 (3H, t, J = 7.3 Hz, -CH3 ~ide chain).
15 IR (film) (cm-l): 3422 (OH), 2932 (CH ~liphdic), 1710 (C=O), 1668 (C=C), 1299 nd 1165 (C-O).
SU~S~ ~ .T
2146~8 F ,'r36: E~ of(l'S,lP ~S)-S,lO~oxo-~ p~ (2',3',G'-~ideoxy-3'-~ ~ .' L 1~ ' ~J. - ~) 3,4,5,1C1 ~d lII "r " - 12,3~1 p~ran 0~ Ob~ OMe ¢1 1 ~ f `OPh 2 ~OPb O~Ae Ol~k OMe 0~ 0~
~h ¢Ç~``~OPh O~k O OrAc O
H3~J H,C~
NHlFA NHTF~
OPNB OPNB
O O
~h 5 ~h O O O O
H,(~l H,C~J
llHIFA NHIF~
P~ OPNB
o ~h O O
H~
HO NHIF~
S ~
Sep 1: a-pbeno~gnu~hyl-2,5~d~neLhoxy p~ Icohol To a solution of 1,~ ~ (2.0 g; 14.5 mmol) in l ' .~ ' at 0C was ddod n-butyl-10 lithium (2.5 M in he~ne; 5.8 ml; 14.5 mmol). The mLsture w~6 w rmod to room l . ~ nd s~Ted for 4 hours. It w~ then cooled to -78C nd 1,2 opo~cy-3 r~ y ~ 95 g; 13 mmol) w9s dded followod by bo~on t " ' etherate (1.85 g; 13 mmol). The .~, " e mi~cture wJs stirred at -78C for 2 hours. It w~ t. ' ' unth ~' N~HC03 solution uld ~ ~ with SUBS t ~ ffE~T
WO 94/11382 2 14 6 ~ a PCT/CA93/00463 The ~ ' orgsnic lsyets were ws~hed with ' L brine snd were dried over MgSO4. The crude rosidue wss punfied by column ~ ' ~ O ,nb~ on 8i~ 1 gel using 25 % etbyl s~ehte in he~ne to yidd tbe titlc pmduct (2.4 g; 64!~).
lH NMR (250 MHz, CDC13) ~: 2.75 (lH, d, J ~ 4 Hz, -OH), 2.85-3.10 (2H, m, Ar~2-), 3.71 (3H, 5 8, OCH3), 3.79 (3H, 8, OCH3), 3.95 (2H, m, CH2~), 4.29 (lH, m, ~), 6.7~7.00 (6H, m, Ar-H), 7.28 (2H, m, ~r-H).
Step2: 5~ -3 ,7! ~ ' gl .
To ~ solution of c~-pheno~ymethyl-2,5 :' ' .~ 1 alcollol (2.1 ~; 7.24 mmol) in ether (40 ml) at mom I . ., ws~ ~ded ~ ' ~ (966 111; 10.8 mmol) nd tben boron trifluonde etherste (2.68 ml; 21.6 mmol). Tbe rost of the p.~ ~ i8 id~ntic~l to the second p~rt, step 1, e~mplc 29, to yield tbe title product (715 mg; 33 %).
lH NMR (250 MHz, CDC13) ~: 2.65 (lH, dd, J ~ 11 nd 17 Hz, H4 ~), 2.89 (IH, dd, J = 2 snd 17 15 Hz, H-4 eq), 3.79 (3H, 6, -OCH3), 3.82 (3H, s, ~CH3), 4.00 4.30 (3H, m, ~2-OPh snd H-3), 4.73 (lH, d, J = 16 Hz, H-l), 5.07 (lH, d, J--16 Hz, H-l), 6.68 (2H, AB ~' ' ' Ar-H), 7.01 (3H, m, ~r-H), 7.33 (2H, m, Ar-H).
Step 3: (l'S, lR, 3S)-5~ 3 ,~!g1 ~ b~ (2',3',6' ~1 ~-3'-h-~ '-O p ~a~gl L l~ ' ~.,.~ ) chromsn The ' . f~m step 3 herein wss ~ in 57% yidd ~ per ~ d irl step 3, e~mple 34.
NMR lH (250 MHz) (CDC13; ppm): 8.31 (4H, m, ~ . ~ ), 7.31 (2H, m, - ), 6.97 (3H, m, 25 9 -- ), 6.76(2H,m,- ) 6.22(lH, d, NH), 6.02(1H,s,Hl),5.63(1H, 8, Hl~),5.42(1H, s, H3-),4.67(lH, m, H4.),4.66(1H,m,Hs.),4.57(1H,m,H3),4.18(2H,m,-CH2- side ch~in), 3.82(3H, 8, OCH3),3.81(3H,~,OCH3),2.90(lH, dd, H4a)~ 2.56(lH, dd, H4b), 2.0~2.18(2H,m, -CH2- sug~r), 1.16(3H, d, J = 6.5 Hz,-CH3 sug~).
S~p4: (l'S,lR~3~-SJ8:'- 3 p! ~ /I1-(2',3',C'-~idbox~-3'-L-~ . ' q'~Dp ~ ILI~
The (1 'S, lR,3S)gl~_- ' f~m step 3haein WY8 ' ' ~ ' d 8 pcr p.. ~ din step 4,c~cunple34.
NMR lH(250 MHz) (C6D6;ppm): 7.73(4H, dd, - . ), 7.17(2H,m, ~ - ),6.90(3H, d, ~. ---),6.71(lH,d,NH),6.08(2H, d, quinonc ting), 5.80 (lH, 8, Hl),5.76(lH, 8, Hl.), 5.50 (lH, 8, H3.),4.70(1H,m,H4.),4.62(1H,m,Hs~),4.22(1H,m,H3),3.85(1H,m,CH2 side chain), 3.66(lH, dd, CH2 side ch~in), 2.27(lH, dd, H4a)~ 1.94(lH, dd, H4b), 1.85(2H,m,-CH2 side chain),l.34(2H,m,-CH2- sugar), 1.18(3H, d, -CH3 sugar).
SU~ST~r~lr3~ S3~E~
WO 94/11382 214 ~ PCT/CA93/00463 step 5: (l'S, lR,3S)-S,10 ' ~ ~ 1 1-(2',3',6' .~ ~-3'-b~ -O p .h .~1 L 1~ ~ r~ ) 3,4,5,10 1 lII ' ' - 12~c] pyr~n S
C~ between 1 ~ - nd the q~ one from step 4 herein ~ per in ~tep 5, e~unple 34, fforded the titlod ~ , ~, yidd 148%.
NMR lH (250 MHz) (CDC13; ppm): 8.30 (3H, m, ~ ~ - ), 8.11 (2H, m, ~ ~ ), 7.77 (2H, m, ), 7.30 (4H, m, r . ' ), 6.96 (2H, m, ~ ), 6.40 (lH, d, J c 7.5 Hz, NH), 6.01 (lH, 10 s, Hl), 5.75 (lH, s, Hl.), 5.43 (lH, ~, H3.), 4.63 (lH, m, H4.), 4.61 (lH, m, H3), 4.60 (lH, m, Hs.), 4.20 (2H, m, -CH2- ~ide chrin), 2.89 (lH, dd, Jl = 3.4 Hz, J2 19.3 Hz, H4~, 2.S7 (lH, dd, Jl--11.5 Hz, J2 = 19.4 Hz, H4b), 2.07 (2H, td, -CH2- sug~r), 1.19 (3H, t, J = 6.5 Hz, -CH3 ~ug~r).
step 6: (l'S, ~R,3S)-S,10 .' ~l 1-(2',3',6' I 11 ~-3'-l ~ . - '~ L 1~ ' ,r.. - ~ ) 3,4,5,10 t ~ - ~ 12~3-c]
p~r~ (BCH-2032) The ~ 1~ ' - from dep 5 helein w~s dep ~ ikd in step 6, e3cunple 34, to ~fford the titled _ , ~ in 81 % yidd.
NMR lH (250 MHz) CDC13; ppm): 8.11 (2H, m, ~- ), 7.78 (2H, m, . - ), 7.33 (2H, m, ~ ), 6.98 (lH, m, c), 6.91 (2H, d, J = 8.3 Hz, _ - ), 6.69 (lH, d, N~, 5.95 (lH, s, Hl), S.SS (lH, d, Hl~), 4.61 (lH, m, H4.), 4.41 (lH, m, Hs.), 4.38 (lH, m, H3), 4.16 (2H, m, -CH2- side ch in), 3.64 (lH, m, OH), 2.89 (lH, dd, H4~), 2.57 (lH, dd, H4b), 1.93 (2H, m, ~H2-~ugar), 1.24 (3H, d, J = 6.5 Hz, -CH3 sug r).
25 IR (film) (cm~l): 3425 (OH, N~, 2929 (Ch liph~tic), 1716 (C=O), 1668 (C--C), lS96 ~C-N), 1297 nd 1160 (C-O).
S U ~ S li~ ~ -T
21~6~48 F "re 37: F~., ' of ~Dr " ~ 12,3-c] p~ I ;- ''-~ with ~n ~llyl ~ide chl~in OMc OMe ¢C~4Ph I
O~S 0 OMe 0 ¢C~ + ¢C""~
OMc ~ ) OM
H~C~ ~C~
I NH~A I NHIFA
OPNB OPNB
O O
~' ~
O -H~C~ H~C~
NH~A I NHTFA
O O
O ~ O
H~C~ H~C~
NEnFA I ~nFA
OR OR
~-- -~ R-H 8CH-2031 _ R-H 8CH-2163 S Step 1: S,84~imetbox~r-3-(2 ~ ., ,1rl) ' ' ~
.. To sti~ed solution of ~ (670 mg, 2.0 mmol) in CH2C12 (20 ml) at -78C were added dlr? - ~- ' (636 r~l, 4.0 mmol) ~nd AICI3 (S33 mg, 4.0 mmol). Te , ~, w~i then r~u~ed to -35C few minutos, then HCI (0.1 N, 10 ml) wss dded. The roaction mLlcture wa8 worlcod up with CH2C12 and w ter. Thc org~ic layer was wash~ed with brine and dried over MgS04. The solvel~t was c~ , d to givc the allyl: ~ (450 mg, 96 %).
SUBSTITUTE SHEET
21~6~
lH NMR (250 MHz, CDC13) o: 6.63 (2d, J ~ 8.9 Hz, 2H, Ar-H), 5.96 (m, lH, -CH=C), 5.17 (d, J
= 17 Hz, lH, -CH=CH2), S.10 (d, J = 9.9 Hz, lH, -CH=C~I2), 4.93 (d, J = 16.0 Hz, lH, H-l), 4.58 (d, J = 16.0 Hz, lH, H-l), 3.78 nd 3.75 (2s, 6H, 2~OCH3), 3.65 (m, lH, H-3), 2.75 (brosd d, J
= 17.0 Hz~ lH, H-4), 2.45 (m, 3H, H 1~ ~I2-CH=C)-S
Step 2: (l'S,l~,~S) ~d (l'S,l-R,3-R)-1-(2',3',6', trideo~-3'~
3!r ~1 I,l~ ' .,. ` S,~ -3-(2, . . 91) ' .
To z mL~turc of 5,8 ~ -3~2 ~ l) ' . (400 mg, 1.72 mmol), 2' ,3' ,6'-trideo~y-3-0 1 A ~ _ q O ~ h~ A~ ,J ~ (1.2 oq., 810~g, 2.06 mmol) nd MS4A (500 mg) in CH2C12 (17 ml) t room i . _ w ~ ~od DDQ (1.5 ~q., 586 mg, 2.58 mmol). Thc re~ction mLlcturc W~8 6tirred for 3 hou~ ~nd 30 minutcs, thcn filtered ~d the filtrate w~s wuihod by ~ with N HC03 ~t. ~iolution. E~,, of the ~olvcnt ~nd "~;r.~ E by FC
(CH2C12:~ QAc 8:12: 1) g~ve 427 mg of the titled product (50%) nd 531 mg of it~ ' , -15 (50%). The (l'S,lS,3S) ' wu~ prep red u6ing thc samc ~.. c.
lH NMR (2~0 MHz, ~cetonc d6) (ppm): 8.65 (bd,lH,NH), 8.4 (d,8.9Hz,2H,PNB-H), 8.34 (d,8.9Hz,2H, PNB-H), 6.86 (~ 8 8~7.1H,Ar-H), 6.8 (d,8 8~7.1~,~r-H), 6.0 (m,lH,C=CH-C), S.88 (s,lH,H-l), 5.56 (b6, lH,H-l'), S.47 (b6,lH,H-4'), S.14 (bm,2H,C CH2), 4.6 (m,2H,H-3',H-5'), 4.3 (m,lH,H-3), 3.8 (s,3H,ACOCH3), 3.78 (~,3H,Ar-OCH3), 2.75 (m,lH,H-4), 2.47 (m,2H,C=C-CH2), 20 2.4 (m,lH,lE~ 1), 2.3 (m,lH,H-2'), 1.9 (m,lH,H-2'), 1.16 (d,6.4~7 ~E~,~-6').
Step3: (+) r~ cetoliehydloxy 1 ' ~ q~
To a stirrod solution of the methyl Icotone hydro~ty-l ' . - (3.000g, 11.891~nmol) in 180ml of ~ t 0C w~ ~d d~....... n ~uoous ~olution of C~N (26.076g, 47.56 mmol) nd N~HCO3 (7.19~1, 85.6 ~nol) in water. Tho re~ction mi~cture W~8 then droped in a mL~ture of 200 ml of CH2C12 nd 200 n~ of w ter nd ' with CH2C12 nd b~ I ' with Ethyl Acot~te.
C' ' ' organic l~ycrs wcrc w~ihod wit~ w ter (3~c300 ml)~nd then dried (Na2SO4). pr ' 1l- -of the residu gave 2.237g (8S% ~ridd) of the pure methyl ketonc hydro~cy-l ~ - quinone.
30 PMR (CDC13, 300MH_)~: 2.30 (s, 3H, COCH3), 2.39 (ddd, lH, J = 20.0 Hz, 12.0 Hz ~nd 1.2 Hz, CH~CHCO), 2.88 (dd, lH, J = 19.5 Hz ~nd 3.9 Hz, CHeCHCO), 3.42 (bro~d m, lH, OH-l), 4.64 (dd, lH, J = 11.7 Hz ~nd 4 H_, H-3), 6.03 (bro~d ~, lH, H-l), 6.78 (2~cd, 2H, ~. - Il).
Step 4: (l'S,1.~S) sDd (l'-S,1-R,3-R)-3-(t2',3',6'-trideo%~-3' t ~ n 1'-pu ~ ' Jl L 1~ r~ ~ S,l~ ~ 3,4,S,10 ~ ' ~d . p~ ' -t2~3 ~1 r ~-- 3 ~'1) . ~r To ~ solution of (l,-S,l-R,3-R)-1-(2',3',6'-trideo~y-3'-trifl . '~ 4' ~ - v~l-L-~, - )- 5,8-dio~co-3 ~ 1-1,4,5,8 ' ~ 2,3-c]-Pyran (20~ mg, .34 mmol) in SU~STe~ S~EET
WO 94/11382 2 1~ ~ 4 8 PCT/CA93/00463 toluene (10 ml) t room I ~ w~ dded 1-~o~-1,3 t_ ' - (0.250 ml, 1.72 mmol). The mL~ture w~s sti~ed ~ ' followed by ~dding 6ilic~ gel (4.2 g) ~d bubblillg ur. ~fter 2 hours, the solution wsu filtered ~nt oolvent removed form the filh~te. ~;I~...g of thc cmde by FC (Tol.: EtOAc 15: 1) uld ~ g~ve 133 mg of the titled p~duct. The (1 'S, lS,3S) ~" ~ W~8 p~d 5 the ~me w~y.
lH NMR (250 MHz, CD2C12) ~ (ppm): 8.3 (m,4H,PNB-H), 8.1 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.35 (bd,lH,N~, S.95 (lH,C=CH-C), 5.9 (o,lH,H-l), 5.7 (o~lH~H-l')~ 5.43 (bo,lH,H-4'), 5.25 (m,2H,C--CH2), 4.6 (m,lH,H-3'), 4.43 (q,6.4Hz,lH,H-5'), 4.21 (m,lH,H-3), 2.8 (td,19.4Hz,3.2Hz,lH,H-4), 2.47 (m,2H,C=C-CH2), 2.33 (dd,19.4Hz, llHz,lH,H-4), 2.07 (m,2H,H-10 2'), 1.2 (d,6.4~ ~H,T~-6').
Step 5: (l'S,l~,~S) snt (l'S,l-R,3-R)-3-([2',3',6'-trideo~y-3' t. ^ ~u ' 4'-hydroxy-L-I~' ' . ,. ~] 5,10-dioxo-3,4,5,10-te~h,.' . . ' ''~12,3~]-py~n-3-yl), ~, ~ (BCH-2031) To ~ oolution of (l'-S,l-R,3-R)-3~12',3',6' tl;d~-3'-t~;ll~,, ~ '- ~' ~ ~,I-L-1~ ~' ~, )-5,10 dio~3,4,5,10 1 ~ ' yd ~ 2,3~1-py~-3-yll p~e (133 mg, 0.2mmol) in MoOH (2 ml) t 0C w o dded NaOMe (4.37~ in MeOH, 601~1, .26 mmol) snd otirred for 15 minutos. Tnerctionwss, ' by dding NH4CI o~t. snd~ i with CH2C12. Thcorgonic 20 p~so w~s taen driod over MgSO4, e._. ~ to give 64 mg crude. ~ - e by }".,. ~ TLC
(Tol.: EtOAc 6:1) g~ve 25 mg (2~%) of tae de6irod product. Tne (l'S,lS,3S) ~ BCH-2163 W98 p... d the 8 me w y.
lH-NMR (250MHz,CD2C12) ~ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, lH,C=CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), 5.2 (m,2H,C~CH2), 4.25 (m,4H,H-3,3',4',5'), 2S 3.6 (b6, lH,OH), 2.78 (dd,19.4Hz,3.3H_,lH,H-4), 2.44 (m,2H,C=C-CH2), 2.3 (dd,19.4Hz,11~7 lt~,~l-4), 1.85 ( ~,~-2'), 1.25(~ 6 ~7~,~-6').
F p'~' of ~"'~ t2,3-clPYran ' ;. ' .~with-methyllceloneside chain from ~ bicycl;.c qui~ e ulycsl u ~ ;EEl~
WO 94/11382 PCI`/CA93/004~3 2 ~ 8 o 9 ~
O OH
O O O O
~ + ~o~
O O O O
H3Cj~ H,~jJ
R NH~A R NHIFA
.
O O O O
O O O O
H,Ch~ H,C~
R NHIFA R NHIFA
R - I BCH-1620 R - I BC}~1621 R ~ R - PtlB, p R - OH opi K:~1649 R - OH cp BCH-164t Step 1 ~nd2~ S,l~ S) 1! ~ [2',3',6' d ~-3' 1 ~ P '-4'~L l~ * ,. ] S,10 -3,4,S,10-S I ~. . ~phtho~2,3c] ,J.~ 3~ ' -(BCH-1620) 1) To ~ ~rod . of -' ~ievo~ 4A (1.3y), 2~ ,I t ~ tyl: IYIUAY) 3 iod~2,3,6 L~A~ L l~ ' r~ ~ (478 mg~ 1~02 mmol) nd 3~cetyl-5,8~ioAo-l-hydro~cy-1,4,5,8 t~ ' ~.' J~rl2~3~c]-pyrsn (178 mg, 0.8 mmol) in ~ solution of CH2C12/ cetone (lS.4 ml, 10~ t -50C w~ ~dded . ' ~1 ~1 trifl . ' '' ~IMS-OTf, .222 ml, 1.15 mmol). The reaction miAture ws~ the~ ~tirrod st -30C for 50 minutes, followed by ddition of sq. N~HCO3 5 % nd w rmed up to room t . ~. ~fterfiltering off 801ids, the filtr~te wss ' with CH2C12. The org nic phs~e ws~ then w~hed with brine uld driod ovor MgSO4. E. of the solvent ~ve S63 mg of the cn3de.lS 2) From the cmde product obt iued ~ ' d ~bove, 116 mg vn~ utilizod in the ne~ct step by ~ing with l~cetoAy-1,3 1 ' (98 ~1, .82 mmol) in toluene (10 ml) for u.. ~ t room snd under rgon. Silic~ gel wss neAt sdded ~nd ~ur wss bubbled into the re ution miAture ~md ~itirring for 2 hours. The crude p~duct w~ 1 by filtering ~d ws~;hing of SU~ S~;~ET
~ 21~6548 the silic~ gel with ethyl ~c~te. E~ . of tho ~olvent g~ve 139 mg of the crude product.
F~ ~ by ~ TLC (heA:OAc 4: 1) g ve 7.4 mg of the titlo product nd 2.2 mg of its for ~ tot l of 9% yidd. The (l'S,lS,3R) ~' . BCH-1621 w~s p~d u~ing ~e 8 me metllod.
S lH NMR (250 MHz, cetone) o (ppm): 8.43 (bd,lH,N-H), 8.0 (m,2H,~rH), 7.9 (m,2H,Ar-H), 6.0 (~,lH, H-l), 5.6 (bd, 5.4Hz,lH,H-1'), 4.89 (b~,lH,H-3'), 4.75 (dd,11.6Hz,4.0Hz,lH,H-3), 3.75 (m,lH,H-4'), 3.7 (q,6.1Hz,lH,H-5'), 3.0 (dd,19.6Hz,4~ 4), 2.SS (dd,19.6Hz,11.6Hz,lH,H-4), 2.3 (s,3H,COCH3), 2.26 (m,lH,H-2'), 1.8 (m,lH,H-2'), 1.25 (d,6.1Hz,3H,H-6').
Step 3: (1'-S,l-R,3-S)-3-([2',3',C'~ideQ~-3'-tr;fl~ido4' b, ' . ~-I, Iy~ ~ r~ ~ ~] S,10-di~o-3,4,S,10 ~ ' ' Jd p' ' ~ 12,3 ~ 3~YI)~
propene (BCH-1649) To ~ solution of (1'-S,l-R,3-S~3{12',3',6' ~;d~A~-3~ }'- ' ~J1 L-Iy~ rJ ] 5,10 dio~co-3,4,5,10 h~ . ' ' ~ [2,3-c1-pyl n-3-yl) p~pene (133 mg, 0.2mmol) in MeOH (2 ml) ~t 0C w~s ~dod N~OMe (4.37~ in MeOH, 60 ~1, .26 mmol) ~d ~tirred for 15 minutes. The re ction W98 ~ - ' by ~dding NH4CI ~t. ~nd ~ ' with CH2C12. The org~ruc ph~se w~s th~:n driod over MgS04, c. . 1 d to give 64 mg crude. Purifying by ~ TLC (tol:
EtOAc 6:1) gsve 25 mg (25%) of th~ ;ired product. The (l'S,lS,3R), BCH-1648, ~ w~s obt ined usin~ the s~me method.
lH NMR (250MHz,CD2C12) ~ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, lH,C=CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), S.2 (m,2H,C=CH2), 4.25 (m,4H,H-3,3',4',5'), 3.6 (bs, lH,OH), 2.78 (dd,19.4~7 ~ ~H7 1H,H-4), 2.44 (m,2H,C~C CH2), 2.3 (dd,19.4H_llH_lH,H-4), 1.85 (m,'7~,~-2'), 1.25 (~ 6 6~7~H,H-6').
F ~' 3g: 1.. , '- of 1 ,~'` ~, ,~ l,D' '- - 12,3-c1 p~ ' ;. '-~D
O O O O O O
O OR O OR O OR
R ~ HIC~J R ~ H~C~
OM, OMe OMeO~
K ~2141 ~CH-2149 30 Sep 1: (1'-S,1-R,3-S,4~-S,lOa-S) ' ~1 (1-12',3',4',6' ' ' ~-3' - ~ 4'-O-'' .~1 L 1~ J~ 0 ~ -5,10 :-- 3,45,1 ' ~ D! - - [2,3-c] pyl~3-yl) l~ e (BCH-2141) S1~5 ~ ~ ~f ~8~E ~iEET
WO 94/11382 PCl[/CA93/00463 21~ 4~
To ~solution of (1'-S,l-R,3-S)-methyl-(1-12',3',4',6' 1 ' ~-3'- ' ~ 4' 0 - ~r ~I-L-ly~ ~ )-5,10 dio~co-3,4 ' ' ~.~ . ' ' - [2,3-cl py~n-3-yl) l~otone (15 mg, 30 ~mol) i~ THF
(1 ml) ~t 0C W 8 ddot H202 (30% ~q. olution, 5.2 ~1, 46 ,umol). ~fter 10 mi~ute6, N~OH (.lN, S .364 ml) W~18 Jddet ~nd the ro ction mL~turo w~O ~rot t 0C for 30 minutes. Worlcup w~ cuTiod out by ~dding brine to the mLlcture, - e with CH2C12 nt trying the orpnic ph~se over MgSO4. The crude ob~inot ~fter e. of the aolvellt w~ ~ ~ e by ,~. ~ ' to give 8 mg (50%) of the pure titlod product. The (I'S,lS,3R,4-R,10 R), BCH-2149, ~' W~8 obt~i~d using the 8 mc mothot lH NMR (7~0M~7~ CDC13) o (ppm): 8.Q5 ~nd 7.8 (m,4H,ArH), 6.15 (~,lH,H-l), 5.55 (bd,lH,H-l'), 4.86 (b6,lH,H-4'), 4.3 (td,9H_,3Hz,1H,H-3), 4.05 (q 6 6~7 1H,H-5'), 3.65 (m,lH,H-3'), 3.45 (s,3H,SO2CH3), 3.1S (6,3H,OMc), 2.75 (td,12.3H_,3H_,lH,H-4), 2.35 (m,lH,H-4), 2.3 (o,3H,COCH3), 1.9-2.2 (m,2H,H-2'), 1.25 (d,6.6T~7 ~ 6').
S U ~S ~ S E i E ET
WO 94/11382. 214 ~ ~4 9 PCT/CA93/00463 F ~ gsr 5 ' ' ' ' 3 ~
"~ Q~oSilBuM~2 Z3 ~oSitBuMe2 AcO _ ACO~y HO
OAc S hc / ~,5 O O O O
lVAB~
+1,3 ' . ~
NHIFA
+1,3 '- -O O
O O~
-+1,3 Step 1~ D,~,!;S,6S) ~;nd (2R,~ S,6S)-2-tert L b~ '- ' Y~ -5-A 601ution of rhsmn~l di cetate (0.514 g, 2.4 mmols) in H20 (24 ml) is he~ted at 80C for 30 minutes.
The 601ution i6 then cooled down to 0C nd CH3COSH (0.51 ml, 3 eq.) i6 then ~dded. The cloudy0 601ution is ~irred ~t room I . .i for 2 hours ~A~ter which NltHC03 (1.2 g, 6 e~A.) is ~d to the e~cces6 CII3COSH. Thc w ter is c., - d ~nd the -esidue i6 ~ A in CH2C12 rAnd dried over MgS04. The 60Aids re fiAtered rAnd the solvent c., - ' A 601ution of the oil obt~irAed ~tter c. A in CH2CI2 (24 TAA) is t~ted with (0.33 g, 2 e~A-) nd t BuAUe2SiCI (0.43 g, 1.2 eq.). The 601ution is 6ti-red rAt room I . .i, under rArgon, for 18 hours. It is po~Ared in ~At. aq.
15 NrHC03 nd tlAeA~so~ rAre - . ~ TA2 e queou6 IrAyer is 1 d with CH2C12 (2~) nd the combine~lA o~nic el~t~Acts are dAiet~A over MgS04. The soAid6 rAre fiAAte~ed nd the 801vent6 ~U~ ET
W O 94/11382 PC~r/C~93/00463 2146~48 The oil o~inod i8 purifiod by flssh ' . ., , ' ~ (silics gel, 9: 1 ha~snos/EtOAc) to give ~ 1: 1 misture of titled isomers: 0.50 g (60%) 8 cle~r oil.
lH NMR (CDC13): o 4.90+4.85 (2dd, lH, H-l), 4.73+4.62 (2dd, lH, H-4), 4.30+3.75 (q+m, lH, H-5), 3.71+3.55 (2ddd, lH, H-3), 2.36+2.30 (28, 3H, SAc), 2.19 (m, lH, H-2), 2.03+1.99 (2s, 3H, S OAc), 1.77 (m, lH, H-2), 1.22+1.18 (2d, 3H, H~), 0.88 (8, 9H, t-Bu), 0.09+0.10 (2~, 6H, SiMo2).
Step 2: (~D,~,~) 2 ~ I t ':yl '- ~g! ly~ ~-5 ~ 1 t ' A solution of the thio-wg~r from ~tep 1 horein (51 mg, 0.14 mmol) in oth nol (2 ml) w~s tr~ted with acce6s of ~9 ~ Ni. Tbc . w~ ~;~u.. 1~ ~tinod for 30 minut~ nd W98 then filtered through 10 Cclitc. The othsnol w~ _ . . d to givc 36 m~ (89 X) of the titlod . . ' 98 clc~r oil.
lH NMR (CDCl3): o 4.74 (dd, lH, J = 2.0, 8.6, H-l), 4.42 (ddd, lH, J ~ 4.7, 10.5, 10.5, H~), 3.98 (dq, lH, J ~= 6.16, 9.23, H-5) 2.10 (m, lH, H-2 or H-3), 2.02 (8, 3H, OAc), 1.86-1.35 (m, 3H, H-2 uld H-3), 1.17 (d, 3H, J - 6.16, H-6), 0.88 (8, 9H, t-Bu), 0.10 (8, 3H, SiMe), 0.08 (8, 3H, SiMe).
lS Step 3: ('~D"~,~9 2 l I ~ ' ly1 ~ ~h~.' . ~ ~ b;~l ' ~.' ~ . ,.
To ~olution of the scotste from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), nt room _, V~8 ddod 1 N N OH (0.14 ml, 1.1 oq.) ~d the ~olution W98 sti~ed for 45 minute6. It W95 thon powod in H20 nd tho quoou~ se wss - ' 3~c with CH2C12. The ~ ' orgsnic 20 e~trscts we~e driod ov MgS04, the ~olids wore filterod snt the ~olvent _., ' to give 30 mg (96%) of the pure titled slcohol.
lH NMR (CDC13): ~ 4.72 (dd, lH, J ~ 1.9, 8.7, H-l), 3.28-3.24 (m, 2H, H-4 nd H-5), 2.04-1.41 (m, 4H, H-2 snd H-3), 1.27 (d, 3H, J 5.5, H-6), 0.88 (8, 9H, t-Bu), 0.10 (~, 3H, SiMe), 0.09 (8, 3H, SiMe).
step4: (~,!;S,li~) 2 I I ~ g~l ly~ '~ C ' .~
To solution of the Icohol from step 3 horein (62 m~, 0.25 mmol) in dry THF (2.5 ml), st ~om .i, under u~on, we ~dsd ; .1~ Ph3P (66 IIU, 1 oq.), DE~D (40 ~1, 1 oq.) ~nd 30 (PhO)2PON3 (54 111, 1 oq.) ~nd tbe solution w~s stirred for 18 hours. The THF wss e., d snd the crude oil W~8 purifiod by {b~ ~ (silic~ gel, 95:S he~os/EtOAc) to give 38 mB (569~) of the titlod zide ~ ~ elo r oil.
lH NMR (CDC13): 8 4.71 (dd, lH, J ~ 3.0, 7.9, H-l), 3.64 (dq, lH, J = 1.7, 6.3, H-5), 3.33 (m, lH, H 4), 2.15-1.60 (m, 4H, H-2 ~d H-3), 1.26 (d, 3H, J--6.3, H-6), 0.89 (8, 9H, tl3u), 0.11 (s, 3H, 3S SiMe), 0.09 (s, 3H, S~Ie).
Step 5: (~,SS,f9 2 I ~ y! Iy!( ~ ' h-~ '~ 6 ' ~1 S~Et~ 5~ T
WO 94/11382 2 14 6~ 8 PCT/CA93/00463 To solution of the ~zide from ~ep 4 herei~ (0.20 8, 0.72 rmnol) in dry EtOAc (7.2 rnl) t room h_ r ' ~ w~8 ddodPdlC109~(0.10g,50%wt.) ndtheblcl~ r w9 plcodunder~H2 , ' ~; for 3 hours. The c~t~lyst w s then filtered thr~ugh Celite nd the solvent v~s c., d to dryness. The cmde mine (0.18 y, 0.72 mmol) wss ~ ,d in dry CH2C12 (7.2 ml) _nd Et3N (0.20 5 ml, 2 oq.) W~8 dded. The solution W_8 coolod to 0C nd TFA20 (0.11 ml, 1.1 eq.) w~ ~dded slowly.
The solutio~ W~8 sti~d ~t 0C for S bours Yld wss tben poured in sl ~q. N HC03. The ph~es were '~ ~ nt the _queous l_yer W~8 Y d with CH2C12 (2~). Tbe ~ ' org~nic e~ctr cts were triod ov MgS04, the solids filteret ~d the solvcnt c., ' to give 0.17 ~ (71 X) of the crude titled i ^ ~ ' thst WUI used ~8 ~.
10 lH NMR (CDC13): o 6.70 (b~, lH, NH), 4.75 (tt, IH, H-l), 3.92 (m, lH, H-4), 3.73 (dq, lH, H-5), 2.06-1.45 (m, 4H, H-2 nd H-3), 1.19 (d, 3H, H-6), 0.88 (8, 9H, t-Bu), 0.11 (s, 3H, SiMe), 0.09 (8, 3H, SiMe).
Step C: (lS,3R,l'S,5'S,6'S) nd (1P ~S,l'S,S'S,6'S) yl (1~4'L ~ .P ' 5'-methyltet~hydropy~nyll-S,10 :' 3,4,S,1~ 2,3-c]
py~n-3-yl) lutone (BCH-1673) Tbc titlod ~ - . ' wo~e obbined in 30% yidd by f"ll .. - e tbe ~ - d in step 4, e~csmple 12, on the ~ of step 5 herein. Tbe titled ~ , ' were purified vi~ flu;h 20 ~ " . ' ~ (silic~ gel, 3:1 ha~ /EtOAc). The mLl~ture of jSOD W9S not ~ , ' '- by . ~
lH NMR (CDC13): 8 8.14-8.07 (m, 2H, ArH), 7.79-7.73 (m, 2H, ArH), 6.17+5.99 (2s, lH, H-l), 5.50+5.39 (2bs, lH, H-l'), 4.68+4.24 (2q, lH, J = 6.5, H-5'), 4.56+4.49 (2dd, lH, J ~ 4.2, 11.8, H-3), 4.05 (m, lH, H-4'), 3.08+3.07 (2dd, lH, J = 4.2, 19.9, H-4), 2.S7 (dd, lH, J = 11.8, 19.9, H-2S 4), 2.34+2.33 (2~, 3H, COCH3), 2.00 1.53 (m, 4H, H-2' ~nd H-3'), 1.31+1.13 (2d, 3H, J ~ 6.5, H-6').
~UE~ 5~E~T
W O 94/11382 2 1 ~ 8 P ~ /CA93/00463 (1~ ,3~)-3-(r~ thrl)-s~lo ~ (2,3,6-tr~ 3-tri f 1 ~ ; A~
3,4,5,10--t--tr hrdro-lH ~}'~- ~ 2,3-cl ~rran (~CH-2101) nd 1,3 'i ,~ - (JC~-2115) Ob4 0 01-4 0 H,C~A H,~J~, H,C~A
0~ 0~ ~
~3 =~-~
~ 0~.4 0 0 0 H~ H CZ~ H,C~;J
OPNB OPNB oHN81PA
BC~2115 8t-p ls (1~,3R)-3 (r~ rl)-l (2,3,6-tr~ 3-tr~f~ L. ~~rl-L-l~ )-5,8-a;
To ~ s]~lti~ of h~d~o~ - h~d.ochloride (60 mg; 86 ~mol) in a m~xtur~ of ~th~nol (4 ml) and wat~r ( 4 ml) wa- added St ' i - hydroxide (33 mg) in ethanol (2 ml) The mixtur~ was 3tirrcd at room t~ tUL~
lS for 5 hour Th~ oolution wa~ filt~rod The filtrat- wa~ added to 3-ac~tyl-i---' - glycoside from t~p 1, c S, (92 mg; 147 mmole) Th~ reaction wa- c~ L- in 10 minutc~ The m$xture wa~ o-aLed down to dk~ , dic~olved in mall volume of w~ter (5 ml), x~racted with CH2C12 (3x50 ml), w~h7d with cat ~aCl, dri~d and =~v~a-Qd The crude product wac pa-~ed through a mall column of ff~lica gel 1~ n ~h~
with 0 2% tri-thylam$ne in haxan~ (~lucnt 15~, 20~ and 25~ EtOAc in hexane) y;~ ng purQ oxime (63 mgS 67~) S U ~ ~ 6 ~ t~ SHEET
WO 94/11382 PCI`/C~93~00463 21~6~48 NMR (ac~tone-d6; 8): 1.26 (3H, d, J ~ 6.8 Hzs -CH3), 1.26 (3H, d, J =
8.3 Hz; -CH3), 1.89 (lH, dd, J ~ 4.4, 13.2 Hz; H-2 of the uugar), 1.96 (3H, ~, CH3 of the ide chain), 2.47 (lH, dt, J - 3.6, 13.1 Hz; H-2), 3.81, 3.88 (3H, ach; Ar-OCH3), 4.60-4.66 (lH, m; ~ugar-H), 4.72 (lH, S t, J ~ 7.8 Hz; H-3), 4.83 (lH, q; J ~ 6.S Hz; H-5 of the sugar), 5.51 - (lH, br singl~t; H-1 of the ugar), 5.61 (lH, d, J 8 2.9 Hz; H-4 of the ugar), 6.15 (lH, ~; H-l), 6.87, 6.90 (lH, d nach; J - 8.9 Hz; Ar-H), 8.36, 8.41 (2H, d acht J ~ 8.8 Hz; Ar-H of PN~ ~.ou~), 8.70 (lH, d, J
8.0 Hz; -N~TFA), 10.02 (lH, ~; ~NOH).
~t-p ~s (1'8,1~,3R)-3 (~ --thrl)-5,10 ~ ~-l (2,3,6-tri~ 3-tr~ ^-L~ )-3,4,S,10-t-trahydro-lH ~ 2,3-cl prr n (~CH-2101) lS Acetylation wa- don- on th- oxime from t~p 1 her-in (33mg; 0.051 mmol~) ~n CH2C12 (4ml) u-ing pyridin- (0.2 ml), ac~tic anhydrid~ (0.1 ml) and catalytic amount of DNAP. After tirring at room tr - .L~e for 3 hour~, the mixtur- wa- ~v~, d ~nto ic~, extractQd wLth CH2C12 (3x50 ml), w ~ ' with w~tQr ~15 ml), dri-d and ~GL~Led. Th- crud~ product was ~ _-d for 16 hours ~fG~ u-ing in th- n xt tep.
CAN ~Vi~tiQn was don- on th~ crude ~ -t- (40 mg) u-ing sodium hi r'r~Q~'te following the g-neral pr.c- re ao de~cribed in other ~ . It re~ult-d in 32 mg of crude ~- i n~- . The ~-;-- - wa~
r~acted with acetoxy b~l~r ii - (100 ~1) in toluene following thc gen~ral 2S ~.~i` c. On purifir-ti~n through a col of silica gel (30% EtOAc in tol -, S0% ~tOAc in tol - nd CH2C12~ 9:1 s -1 ~) pure tricyclic gl~c~ - (29 mg) was o~t~ . Finally, d-prot~ction of acetate and PNB y~O~__ was don~ by u-ing ~ meth~Y~de (catalytic) in meth~nol (3 ml) at 0C. Aft-r tirring at 0C for 14 m~nut-s, the mixtur- wa- n-utr~ with dil. HCl to pH-7, diluted with water (Sml), extracted with CH2C12 (3x30 ml), ~ _1^-d with water (10 ml), dried and ~G.~Led. Th~ crude product was purified by column c~ GJ a~hy over a mall col of ~ilica gel (1% methanol ln CH2C12 ~- eluent) and pr~parative TLC (CH2C12s M~OH~9:1) yi~l~in~ pure titled o~ime (3.7 mg;
14% in 4 ~t~ps), m.p.~l25-27C.
NMR (-cstone-d6) ~: 1.35 (3H,d,J~6.6Hz5 CH3 of the sugar), 1.75 (lH,dd,J-4.6,13.0HztH-2 of th- ugar), l.9S (3H,s,CH3 of the side-chain), 3.71 (lH, br.signal; H-4 of thc sugar), 4.27 (2H,m;-ugar-H), 4.57 (lH,q,J~6.6HztH-S of th- ugar), 4.70 (lH,t,J=7.5HzSH-3), 5.44 Sl~S i i ~ ET
W O 94/11382 PC~r/CA93/004~3 21~65~ ~
(lH,d,J~3.3H~SH-1 of th- ~ugar), 6.07 (lH,S;H-l), 7.87-7.90 (2H,m;Ar-H), 8.08-8.12 (2H,m;Ar-H), 10.15 (lH,bit br. ~Lngl-t~-NOH).
8t-p 3s (lR,38)-3-(~ L~yl)-l (2,3,6-tr~ 3-S tr~f~ p ~ o~l-L-l~ o~-)-5,8-o Ox$mQ wa~ prQpar-d from 3 _c~yl i-~- -n glyco~$d~ (60 mgt .096 ~mol) u-'ng hyd~o~yl mine hyd~ochlor$ds (39 mgs 0.56 ~mol-) in ~tOH (2.6 ml) and wat~r (0.26 ml), and ~ i hydrox'de (21.5 mg) in ~tOH (1.3 ml) follow'ng the pr~c- _ d ~cr$bed 'n ~t-p 1 h-r-_n. Aft-r ch - GJ-~hy ov~r ~ ca g~l p,nt~ wLth tri-thylumine titl~d oxime ($n dLast~ - 'c m~xtur- of 5:1 ratlo) w~- obta$nQd $n 81~ y$~1d (50 mg).
NMR (-~to~-d6; ~): 1.10 (3H, d, J - 6.6 Hz; CH3 of ugar), 1.98 (3H, ; m4thyl of th- ~iA- chain), 2.39 (lH, dt, J - 3.6, 12.9 ~z; H-4), 3.81 (6H, ; Ar-OCH3), 4.63-4.73 (lH, m; H-3 of ~ugar), 5.45 (lH, br ignal;
H-l of ugar; ~am- of th~ oth~r A;-~t~m~ -- ov~rlapp d), 5.56 (lH, br ignal; H-4 of the ugar; ume of th~ other Ai ~t~ `- - overlapped), 5.95 (lH, ~, H-l), 6.81-6.95 (m; Ar-H), 8.30-8.43 (m; A-H of PNB group), 8.66 (lH, br d, J - 5.9 Hz; N~TFA), 10.05 (lH, ~; -N-OH), (~h-ru w-re f-w oth~r ~igr-l~ wh'ch wer- du- to th- oth~r d$a-t;~ - and to a mall impurity wh$ch w~re not ~ ~il r ' ) -5 8t-p 4s (1 ~, lR, 38)-3 (r~ Lhrl)-5,10-d~oro-1 (2,3,6-tr;~ 3-tr~ )-3,~,5,10 L ~._h~dro-r ~ (2,3-~)-prr 3 (~C~-2115) Ac~tyl~t'~ of the ox$m~ (50 mg; .078 D 1~) wa~ done following the p~OCQd~ dQ~cr$bed in tQp 2, f$r-t part. CAN oYi~-t~ wa~ done on the ~ to ~5~ mg) us$ng ~o ' b~ b~-to following th~ g~neral p~ocedu~. It result~d in 50 mg of crude qu$none. QUinnn~ (50 mg) WaB
r-acted w$th -~at~ yL~ i - (0.1 ml) $n tol ~ ~ (2 ml) follow$ng the q~n~ral ~ o~ . On purifi~-t'Qn by column ~ ~hy over ~ilLca 3~ gel (20% ~tOAC in toluene, 50% EtOAc in toluQn~ lnd 5~ m~thanol in CH2C12 a~ ) gave 33 mg of slightly impur~ tricycl$c -~Finally, deprot-ction of ~cst-t~ ~nd PNB group- wa- done by u-$ng o m~hnYi~ (catalytic) in methanol (2 ml) at 0C following the ~,oce~
de-cr$bed in tep 2, last part. Tho t$tled c N de pcod~cL wa~ pa~ed SUBSTITUTE SHEET
2146~
through two column- of ilica gcl (l~ and 2~ methanol in CH2C12 a~
elu-nt~) y;~ldin7 the oxime in 12.5% yi~ld (5 mg) (~ont~ t~d with the other diast;- _ -r in 5.6:1 ratio).
NMR (ac~Lon~ d6; ~): 1.18 (3H,d,J-6.4H~sCH3 of the sugar), 1.76 (lH,dd,J-4.8,12.9H~S~-2 of the ~ugar), 1.98 (3H,~,CH3 of th~ ide chain), 2.18 (lH, dd,J~3.7,12.9Hz,H-4), 3.67 (lH,br.d,J~3.9HzS-ugar-H), 4.21-4.29 (2H,m,~ugar-H), 4.77 (lH,dd,J~5.4, 9.6Hz;H-3), 5.48 (lH,d,J~3.2; H-l of th ugar), 5.91 (lH,-,H-1), 7.86-7.92 (2H,m;Ar-H), 8.06-8.10 (2H,mtAr-H), 10.14 (lH,s,-N-OH) , (th-r- w re mall signal~
duQ to the other dia-t;~m~ ~ p r- ~ $n the p-ctru~ which w~r~ not detailod).
2s Prep~ration of (1'8,18,3R)-3 (t ir~ t~ rl)-s,lo -if - 1 (2,3,6-tr~ 3,~-dLh~d.~A~ '- p~ )-3,4,5,10-t-tr hrdro-lr ~ 2,3-c] prr~n (~C~-2018) OMe O 0~ ?~F~
~ I ~ ~
OMc Ob~e 0~ NHIPA O NHIFA
3, ~o~
01~ 0 0 0 H,C~ B,C~
0~ ~ OH OH
8C~2015 20 ~-p ls 3-(~r~ o ~-hrl)-5,8-~
To a ~olution of hyd~Aylamine-hydrochloride (1.4 g; 20.1 mmole) in a mixtur~ of ethanol (30 ml) and water (3 ml) wa- added ~ i hydroxide (720 mg) in ethanol (15 ml). The mixtur~ wa~ stirred for .5 hour. The 2S solution was filt~red. The filtrate wa- ~dded to 5,8-dimethoxy-3-acetyl-i~oc~ (1 gs 4.23 mmol~). The mixture wa~ ~tirr~d at room t- _- aLu,e for 1.5 hour and _~pG,aLed to dryne~s. The residu~ was S l J ~ T
2 1~`6~A~ ~
dL~solved in small volum~ of water (10 ml), extracted with CH2C12 (3x100 ml), wa~hed with brine (20 ml), dri~d and c~po~aL~d. The crude product (900 mg) obtained was di~aolved in toluene (30 ml) and cooled to -40C.
Rcd-Al (9 ml) was addQd during 25 mLnut~. The mixtur~ wac ~t~rred at -40C for 40 m$nut~. The t~ - atur- of th~ cooling mixtur~ wa~ rai-ed lowly to 25C and the reaction was ~tirred at 25C for 16 hours.
EXC~-8 ~ L wa~ d~stroyad by carQful addition of cold water (6 ml) followed by 10~ ~o'i hydroxide (1 ml). The mixtur~ wa~ extracted with ether (3x100 ml), wr '~-' with brine (25 ml), dried and ~-~Gr-ted. Thc crude product (800 mg) wa~ di-solv~d Ln CH2Cl2 (50 ml). Pyridin~ (8 ml) and D~AP (15 mg) w-r~ added and th~ mixture wa- cooled to 0C.
Trifluoroacetic anhydride (3 ml) was added ~lowly and th~ mixture wa~
tirred at room t~ ~tu ~ for 16 hour~. It was poured into $ce, neutralized with aturated sodium bi~nhon~te~ xtract~d with CH2C12 (3x100 ml), w ~9A with water (25 ml), dried and i~ o~at~d. Th~ solid r~sidue was ,~ r-~ twic~ from a mixture of hex-nQ and nth~r (4sl) yi~lAin7 pur- titled product (purity by NNR: >92~ yi-ld ~ 330 mg;
23.4~ in three t-p~).
NMR (CDCl35 ~)s 1.29 (3H, d, J - 6.8 Hz; -CH3), 2.52 (lH, dd, J - 11.3, 16.9 Hzt H-4), 2.69 (lH, dd, J ~ 2.2, 16.4 Hzs H'-4), 3.65 (lH, ddd, J =
3.2, 6.3, 11.2 Hzs H-3), 3.75, 3.78 (3H, s each, Ar-OCH3), 4.24 (lH, m;
-C~(NHCOCF3)CH3), 4.58 (lH, d, J ~ 15.8 HzS H-l), 4.97 (lH, d, J ~ 15.8 HZ5 H'-l), 6.62, 6.67 ~lH, d each, J ~ 8.9 ~z5 Ar-H).
8t-p 2s (18',18,3R)-3-~trif~ r hyl)-5,~ d (2',3',C'-tr~ 3',4'-d~h,d.~_~ L-l~
Co~rl i nq with sugar wa- done u-ing DDQ in CH2C12 following g~nsral ~.oc~du.c (~tep 1, 1 _le 14). Th~ product wa~ isolated a~
dia.L- ~~ - ic mixtur~ from crude r~action mixtur~ by column ch.~ ~ G~ a~l.y over ilica gel ~ rr~sA with .5% tri-thylamin~
(eluents~ thyl ac~tatc ~ 80s20) in 75~ yi~ld.
To a olution of th~ dia-t~ - ic mixture (100 mg) in CH3CN (6 ml) at 3~ 0C wa~ added 0.1 N NaOH (4 equiv.). The mixture wa- tirrQd at 0C
for .5 hour. Ic~ bath wa~ ~ . d and it wa~ stirr~d ~t room t - aLu. ~ for 1 . 5hr . The mixture wa~ diluted with water ( 10 ml ), extracted with CH2C12 (3xlO0 ml), w h--A with water (20 ml), dried and G.--Led. The crud- product wa- chromatoy.~l;ed over ilica gel SIJBSTI~UTE SHEET
W O 94/11382 PC~r/CA93/00463 2 ~ 4 a (p~a~J~aho~ with .2% trL~thylamine) ~lusnt: 50%, 60%, 70%, 80% ~tOAc in hexan~ and finally by pur~ LtOAc) yi~lding pure title -~ s~nd (yield =
25 mg; 29.4~), and 1,3~ (37 mg; 80~ pure; 34.5~).
NMR (AcQtone-d6t~) of the titl- = _ : 1.28, 1.35 (3H,d ach, J ~ 6.5 S Hz; CH3 of thQ side chain and CH3 of th~ ugar), 1.58 (lH, dd, J - 5.1,12.6 Hz; H-2 of the ugar), 1.91 (lH, dt~ J ~ 3.8, 12.3 Hz7 H-2 of th~ sugar), 2.41 (lH, dd, J ~ 11.6, 17.4 Hz, H-4), 2.79 (lH, dd, J -3.4, 17.6 Hz; H~-4), 3.42 (lH, d, J ~ 4.4, sugar-H), 3.55 (lH, br ~ignal; H-4 of tha ~ugar), 3.64 (lH, d, J ~ 6.7 Hzs ugar-H), 3.77, 3.78 (3H, n, ~ach, Ar-OCH3), 4.16-4.29 (2H, m, -C~(NHTFA)CH3 nd sugar-H), 4.36 (lH, q, J - 6.5 Hz; H-5 of ~ugar), 5.36 (lH, d, J ~ 3.3 Hz; H-l of the ~ugar), 6.04 (lH, s, H-l), 6.79, 6.88 (lH, d each, J - 8.9Hz; Ar-H), 8.50 (lH, br d, J - 7.0; N_TFA).
NMR of 1~3-~is~i - (~ton--d6; ~): 1.21 (3H, d, J ~ 6.5 Hz; CH3), 1.36 (3H, d, J - 6.3 H~; CH3), 2.37 (lH, dd, J - 6.1, 11.3 Hz; H-4), 2.80 (lH, dd, J ~ 3.3, 17.3 Hz; H'-4), 3.45 (lH, d, J - 4.8 Hz; ~ugar-H), 3.S3 (lH, br signal5 ugar-H), 3.66 (lH, d, J - 6.9 Hz; ugar-H), 3.78, 3.81 (3H, acht Ar-OCH3), 4.08 (lH, g, J ~ 6.7 Hzs H-5 of the ugar), 4.16-4.29 (2H, m; C~(NHTFA)CH3 and zugar-H), 5.36 (lH, br inglet, H-l of ugar)~ 5.85 (lH, ~ H-l), 6.78-6.89 (2H, m; A-H), (Th~re w-re f~w ignalz duQ to th~ other dia-te_~ - which are not detail~d.).
~t--p 3s (1'8,18,3R)--3--(tr~ thrl)-S,10--dio~o--1--(2',3',6'-tr~ 3',4'-~,d.~ L-~
3,4,5,10-t--trahrdro-lH ~,~ ~o-t2,3-c]-prr~n (JCJ-2018) CAN ~Yi~-ti~ was done on dimetho~ u ~ following the general ~ - ' r~ (-t~p 3, - l- 12).
The crude ~i n~n~ wa3 r-acted with acetG~ hu~ aA i ~n9 in tolu~ne following the general ~,ocedu~e. Pure titled product wa~ obtained by column ch.. -~oJ-~hy over ~ilica gel (elu~nt: tolu~ne: EtOAc~70:30 and 60:40) followed by pr~paratiVQ TLC (~luent: CH2Cl2: MeOH~9:1) (5 mg;l9%
yield) as a light yQllow ~olid, mp: 180-3C (dec.).
3S NMR (acQtone-d6;~): 1.34 (3H,d,J-6.4Hz;-CH3), 1.38 (3H,d,J~6.7Hz;-CH3), 1.60 (lH,dd,J~4.7,12.6Hz;H-2 of th~ ugar), 1.92 (lH,dd,J~3.7,12.2Hz;H-2 of th~ zugar), 2.47 (lH,dd,J~10.2~19.0Hz;H-4), 2.82 (lH,dd,J~2.9,19.0Hz;H'-4), 3.49 (lH,d,J-4.3Hzt-OH of th~ ~ugar), 3.59 (lH,br.signal which became ~harp on D2O-~Ychange;H-4 of sug_r), 3.68 SUE3STITUT~ T
-WO 94/11382 PCr~CA93/00463 2 ~
(lH,d,J~6.7Hz;-OH of th~ sugar), 3.82 (lH,m;H-3), 4.19 - 4.30 (2H,m,ov2rl~pp;ng-C~CH3(NHTFA) ~nd ug~r-proton), 4.42 (lH,q,J=6.5Hz,H-5 of the sugar), 5 36 (lH,d,J~3.5Hz,H-1 of the ~ugar), 6.0 (lH,-,H-l), 7.86-7.90 (2H,m;Ar-H), 8.05-8.10 (2H,m;Ar-H), 8.56 (lH,br. ~gnal~-S N~TFA). ~St~ try of NHTFA io not y~t det~
_lc ~3s Pr-p~sat~on of (1'~,1~,38)-3 - ~c 5,10-dioso-1-(2-d os~-2-chlc.-~thrln~L,~
3,4,S,10-t-tr-hrdro-111 ~ - t2,3-cl prr~n (BCII-2038) OM. O O~c OM- O
¢~ ~T~,2r~-,rl OMc Ohlc O
HN~O~
0~ O~c ~r~
O O OMc O
~3 o=~Ph o=~Ph ~HrP~
0 ~H
NO)C~2CH2CI
8t--p ls (l'R, lR, 38)--3--~c--to--S,~ 1(2 d- ~ 2--chloro-thylur-ido-3, ~, 6-tri--c-trl ~ ,1 c ~ o o ) S ~ T
WO 94/11382 PCI`/CA93/00463 ~ 2 1 4 ~ J
2-Deoxy-2-chloroethylureido-3,4,6-triacetyl-D-glucopyranose was prepared following known ~oc~d~rQ (Ref: T.P. Johnston, G.S. ~rC-l?b and J.A.
~nntg - y~ J. Med Ch~m. ~ 104 (1975)). Thi~ wa~ couplnd with 3--c~to-5,8-dimethoxy-j~o~ ~ -n u-ing DDQ following th~ general ~.oc~d~r~ outl$ned before (-tep 1, r ~ le 14). Purifie~tion was done - by column cl.~c -tG~ hy over sLlica gel (eluents~ tOAc ~ 7:3) yiel~ing the title - _ ~ (29.4~) and 1,3-~ - (31~).
NMR (aceton~-d6S ~) of the title _ ~: 1.91, 1.95, 2.00 (3H, s ach; acetyl group-) 2.32 (3H, , k to-methyl), 2.50 (lH, dd, J ~ 12.3, 17.6 Hz5 H-4), 3.01 (lH, dd, J ~ 4.0, 17.6 Hzs H'-4), 3.49 (2H, m; -NH-CH2- group), 3.63 (2H, t, J - 6.2 Hz~ -CH2-Cl group); 3.83, 3.88 (3H, each5 Ar-OCH3), 4.14 (4H, m; H-5, H-2, H-6 and H-6 of th- ugar overlapFin~), 4.60 (lH, dd, J - 4.1, 12.2 Hzs H-3), 5.08 (pair of double-~-hl~- overlAppin~; H-3 and H-4 of the ugar), 5.46 (lH, d, J
lS 3.5 Hz; H-l of th- ugar), 5.49 (lH, broad s; -NH-CO-), 6.02 (lH, ; H-1), 6.15 (lH, br ignal; CON~-CH2), 6.87, 6.96 (lH, d each, J - 9.0 Hz;
Ar-H).
NMR (ac~tone-d6t ~) of the 1,3-~pi - : 1.92, 2.00, 2.06 (3H, ~ each;
ac0t~te 9.. ~), 2.28 t3H, S k to-methyl), 2.48 (lH, dd, J - 12.0, 17.8 Hz; H-4), 2.91 (lH, dd, J - 4.2, 11.7 H~s H'-4), 3.26-3.51 (2 multipl-t-, lH ach; -HN-CH2-), 3.56 (2H, t, J ~ 6.2 Hzs -CH2Cl), 3.84 (6H, s; Ar-OCH3), 4.14-4.23 (2H, ms sugar-H), 4.34 (lH, dd, J - 4.7;
12.1 Hz; ugar-H), 4.62 (2H, dd, another proton ov-rl~ ; J - 4.3, 12 Hz; H-3), 5.05-5.18 (2H, m; H-3 and H-4 of sugar), 5.51 (lH, d, J ~ 3.7 Hz; H-l of the ugar), 5.81 (lH, d, J - 9.6 Hz; -NH-CO), 5.98 (lH, ~r, triplet; -N~-CH2), 6.16 (lH, ~; H-l), 6.91, 6.99 (lH, d ach, J - 9.0 Hz; Ar-H).
~t-p ~s (l'R, lR, 3S)-3 ~ ~o 5,8 .; ~ 2-chloro-thy~ ~-4,~ D-g~ -~r~
,~ _ To a cold solution of triacetyl derivative (120 mg; .19 mmol) in CH3CN
wa- add~d .1 N NaOH (8.6 ml; 4.6 eg.). The mixture wa- stirred at 0C
3S until TLC .~ ed c~ e reaction. It was carQfully neutrAli-ed with .1 N HCl to pH -8 and xtracted with ethyl acetat~ (3x100 ml), wi~
with 2.5% NaHCO3-NaCl-~olution (1:1) (10 ml), dried and 2~ ,~Led. To a solution of the crude product in DMF (5 ml), hen~ h~de dimethyl acetal ~30 ~1; 1.2 eq.) and p-TSA (10 mg; catalytic) was added. The 51 1 ~ E~T
W O 94/11382 P ~ /CA93/00463 214~S~8 ~
rnaction flask wa~ connected to w~ter a~pLrator and held at 50C for 15 minute~. So~i bicarbonate ~olution (2.5~; 10 ml) wa~ added and the mixture was extracted with CH2C12 (3x50 ml), wa~hed with saturated NaCl ~olution, dr$cd and evaporat~d. The crude product was ~- ~h~ with A
S mixture of hexane and ether, yislding pure titlad b-nzylidQne derivative (77 mg; 68~).
NMR (a~eton~-d6; ~): 2.33 (3H, ~, k~to-mQthyl), 2.50 (lH, dd, J - 12.2, 17.6 Hz; H-4), 2.99 (lH, dd, J ~ 4.1, 17.6 Hz; H'-4), 3.49 (2H, t, J =
5-8 Hzs -CH2-Cl), 3.63 (2H, m, -NH-CH2-), 3.82, 3.91 (3H, 8, Ar-OCH3), 4.19 (lH, dd, J ~ 4.5, 9.6 Hz; zugar-~), 4.62 (lH, dd, J - 4.1, 12.2 Hz;
H-3), 5.46 (lH, d, J ~ 3.8 Hz; H-l of the zugar)~ 5.62 (lH, ~, -CH Ph), 5.68 (lH, d, J 8 8.5 Hz; -NH-), 6.00 (lH, 8, H-l), 6.18 (lH, br ~, -N~
CH2-), 6.87, 6.95 (lH, d ~ach, J ~ 8.9 Hz; Ar-H), 7.34 (3H, m; Ar-H), 7.46 (2H, mt Ar-H).
St-p 3 (l'R, lR, 3~)-3 ~ o 5,10-dio~o-1-(2 d-- ~ 2-chlG.. ~yl~s-$do-4,6-b-~zr~ - D-gl.~ )-3,~,5,10-t--trahrdro-lH ~ 2,3-CI pyrau To a olution of b~nzyliden~ derivative (77 mg; .127 mmol) in acetonitrile (6 ml) wa- added a olution of ceric ~ -ri nitrate (146 mq; .266 mmol) in water (2.5 ml) at room t~ - ~Lure. The mixture wa~
stirred for 5 minut~, diluted with water (10 ml), oxtracted with CH2C12 (3x75ml), w ~- with water (15 ml), dried, c~o~aLed. The crude product (60 mg) wa~ ~ - for 2 hour~ before going to the next ~tep.
The crud~ product wa~ taken up Ln dry toluene ~3 ml) and acstoxy-bu~r~i - (1.2 ml) wa~ added. Th~ mixture was ~tirred at room t~ - ~Lure for 16 hour~. The ~olution waw not quita } -, ~ and TLC ~howed ~OmQ ~tarting mat-rial. AcQtGA~ bu~ A~ ( . 5 ml) was further _dded and ~tirred for 20 hour~. The mixture wa~ diluted with toluene (10 ml). Silica gel (500 mg) wa~ added and air wa- bubbled through th~ mixture for 1 hour. Th~ crude reaction mixture wa~ pa~ed through a column of ~ilica gel (eluent:toluene:EtOAc ~ 7:3 and CH2C12s~eOH ~ 9:1). Fraction contAinjng the product wa~ further purified by proparative TLC (eluentsEtOAc) yielAin~ 12 mg of pure titled product (15%) (poor yield hec~ e of Deparation problem).
NMR (acQtonQ-d6; ~)s 2.35 (3H, ~S kQto-methyl), 2.58 (lH, dd, J = 11.4, 19.7 Hz; H-4), 3.01 (lH, dd, J ~ 3.9, 19.6 Hz; H'-4) 3.55, 3.67 (m ~ach, HN CH2-CH2Cl), 4.22 (lH, dd, J 8 4.6, 9.7 Hz; ~ugar-H), 4.65 (lH, d, J s S~ r ~ T
WO 94/11382 PCI`JCA93/00463 ~ 2146S~8 3.9 Hz; -OH), 4.73 (lH, dd, J - 4.0, 11.4 Hz; H-3), 5.52 (lH, d, J = 3.8 Hz; H-1 of the ~ugar), 5.63 (2H, ~r n; C~-Ph and -NH-CO), 5.94 (lH, t, J
~ 5.7 Hz; -N~-CH2), 6.04 (lH, ~; H-1), 7.33 (3H, m, Ar-H), 7.46 (3H, m;
Ar-H), 7.91 (2H, m, Ar-H), 8.14 (2H, m; Ar-H).
S
8t-p 4s (l'R, lR, 38)-3-ac-to-S~10-dioxo-1-(2 d-~ ~ 2-chloro-thyl-nit..~ - D _l~c~ )-3,4,5,10-t-tr hydro-1~-~ 2,3-C] prs ~
To a ~olution of ben2ylid-ne derivativQ (6 mg; .01 mmol) in 96% formic acid (1 ml) at 5C wa- added NaNO2 (10 mg) in two portion~. The reaction was ~ o in 2 minut-~. It was dilutod with water (5 ml), extracted with CH2C12 (3x25 ml), wr ~he~ with water (10 ml; 15 ml), dried ov-r Na2S04 and .~o~L-d. The crude product (4.5 mg) wa- pa--ed lS through a ~mall column of ilica gel (-lu~nt:BtOAc and 10~ methanol in CH2C12) yi~ n~ pur- t$tl~d product (yield ~ .9 mg; 17~) (HPLC:92%) NMR (acetone-d6; ~): 2.35 (3H, s, keto-methyl), 2.51 (lH, dd, J ~ 12.9, 19.2 Hz; H-4), 2.98 (lH, dd, J ~ 4.1, 19.6 Hz; H'-4), 3.52-3.89 (two multiplet-; ome of th- ugar protons, and overlArpi ng A2B2 y-tem due to -HN(CH2)2Cl), 4.08 (H, dd, J ~ 3.5, 6.0 Hz; ugar-H), 4.26 (lH, dd, J
- 6.6, 11.3 H~s ugar-H), 4.43 (lH, dd, J - 4.7, 7.5 H2S ugar-H), 4.66 (lH, dd, J ~ 4.0, 11.5 Hz; H-3), 5.66 (lH, d, J ~ 3.6s H-l of the ugar), 5.99 (lH, , H-l), 7.59 (lH, d, J ~ 8.6 Hz; NH-OO), 7.88, 8.08 (two mult~pl-L~, Ar-H).
4s ~. _ ,Lion of 3 ~ 5,lO-dio~o-l-m ~ ~ S,10-d~hrdro-l~ ~p~t~- 12,3-cl pyran (BC~-2129) o o o o ~'1' ~
O 0~ 0 OMe s~top ls 3 ~ ~o S,lO-dio~o-l- ~ S,10-dihydro-1~ ~p~- (2,3-~ c)-prr~n (BCH-2129) To a ~olution of 3-acetyl-5,10-d$oxo-1-methoxy-3,4-5,10-tQtrahydro-lH-35 n~rhtho (2,3-c) pyran (50 mg, .175 mmole) in CH3CN (8 ml) and THF (4 ml) lSl SUE5 ~ t ~ ET
W O 94/11382 PC~r/CA93/00463 2 1 ~
at 0C wa~ added O.5N odium hydroxide (1 equiv.). Tho mixture was ~tirred at 0C for 15 minute~ and $t wa- allowed to come to room t ~_aL~a. After 1.5 hour at room temperature the mixture wa~
acid$f$ed with d$1. HCl to pH-6. Saturated NH4Cl (5 ml) wa~ added and S the mixture wa~ extracted with CH2C12 (3x50 ml), w~Dd wLth water (10 ml), dried and r~a~GLaLed. The crude t$tled product wa- ~ub~ected to preparat$ve TLC (elu-nt: toluene:~tOAc-96:4) and pure product wa~
$~olated a~ a l$ght y~llow ~ol$d, mp. 154-56C (3mg; 6~
NMR (aceton~-d6, ~): 2.50 (3H,~,ketom thyl), 3.63 (3H,~,-OCH3), 6.42 (lH,-,H-l), 7.11 (lH,-;H-4), 7.92 (2H,m;Ar-H), 8.14 (2H,~;Ar-H).
_ 1 t ~5: Pr parat$on of (lR,3S) ~nd (18,3R)-3--c-to-S,10 di~o-1 (4-chloro-th~ln$L~ A~ crclr- ~l-osr)-3,4,5,10-t-tr h~dro-l~ o [2,3-c] prr-n ~BCH-211~) ~ CO~
OMe ~CO~
o o o o \~iCON(NO)r~,r~2~ ~NHC01~,~
s~2ll4 8t-p 1: (lR,3S) ~nd (18,3R)-3 ' ~o 1 (~-chloro-thylur-ido-cro~ lox~)-5,~ ocL,_ 3-Acetyl i-~c' ~ -n wac co~pled to 4-chloroethyl urO$do-cycloh~YAnol (prQpared by known ~ocedu a, ref.: T.P. John~ton, G.S. ~Çal~h~ P.S.
Opliger, W.R. La-ter and J.A. Mont~ -_y~ J. Med ~h~., 1~, 600 (1971)) u~$ng DDQ ~ollow$ng the general P~OCGdU~a (ctep 1, _ le 14).
-nti~ - $c m$0ture of the t$tled productc wac $colated from the crude lS2 i L ~_ ~"f5 ~ S ~
W 0 94/11382 214 ~ ; . PC~r/CA93/00463 react~on mixture by column ch ~ tGJ.a~hy over ~ilica gel (eluent: 50 and 80~ EtOAc in hexane) yield=lOOmg (52~).
NMR (acetone-d6;~): 1.26-1.48 (two multiplet~; CH2 ~o~ of cyclohexyl ring), 1.78-1.80 (multiplet,-CH2 of cyclohexyl ring), 2.27 (3H, ~, keto-S methyl), 2.4S (lH, dd, J c 12.1, 17.8 Hz; H-4), 2.90 (lB, dd, J ~ 4.2, - 17.7 Hz; H'-4), 3.42 ~2H, m; -HNC~2Cl), 3.59 ~2H, t, J ~ 6.0 Hz; -C~2-Cl), 3.78, 3.79 (3H, ach, Ar-OCH3), 3.86 (lH, mt H-1 of the cyclohexyl r~ng), 4.61 (lH, dd, J - 4.2, 12.0 Hz~ H-3), 5.51 ~lH, d, J ~ 7.4 Hz; -NH-Co-), 5.67 (lH, br ignal; -CON~CH2-), S.90 (lH, ~, H-1), 6.79, 6.87 (lH, d ach, J - 8.9 Hz; Ar-H).
8t-p 2s (lR,38) ~nd (18,3R)-3 ' ~o S,10-dio~o-1 (4-chloro-thylur-~do cy~ oxr)-3,4,5,10-t-trahrdro-lH-~ ~ ( 2 ~ 3--c )--prr~
lSCAN oY;~-t;n~ was performed on the dimethoxy-ioochroman from ~tep 1 herein (35 mg; .077 mmole) ollow~ng the gen~ral ~oc~ re ~step 2, exampla 14).
The crude product (32 mg) wa~ di-solved ~n dry toluene (3 ml) and ac~toxybut~ (0.5 ml) wa- added. The m~xture wa- t~rred at room t ~ Lure for 18 hour~. S~lica gel (500 mg) wa- added and air wa~
bubbled for .5 hour. The crude product waB pas~ed through a column of ~ilica gel (30% ~tOAc in tol ---, 50% ~tOAc in Tolu-n~, and CH2Cl2:
MeOH~l9:1 a~ ) y~ ng pur~ tricycl~c t~tled c~ ~ (15 mg;
2S yield 41%).
NMR (~ce~Qn--d6;~): 1.24-1.54 (6H, m, CH2 group of the cyclohexyl r$ng), 2.30 (3H, g, ~st~ hyl), 2.51 (lH, dd, J ~ 11.6, 19.5 Hz; H-4), 3.42 (2H, m; -NHC~2-CH2Cl), 3.60 (2H, t, J ~ 6.2 Hz7 -CH2Cl), 3.95 (lH, m, H-1 of the cycl-~ yl ring), 4.64 (lH, dd, J - 4.2, 11.5 Hzs H-3), 5.54 (lH, br d, J - 6.9 Hzt NHCO-), 5.69 (lH, br ~ignal; -CON~-CH2-), 5.92 (lH, ~; H-l), 7.86-7.91 (2H, mt Ar-H), 8.06-8.10 (2H, mt ArH).
8t-p 3: (lR,38) nd (18,3R)-3 - ~L~ S,10-dio~o-1 (4-chloro-thrlnit.. ~ do crr~ l-o~r) -3, 4, 5 ,10-3S t-trahrdro-lP 1~' '- (2,3-c)-prr n (BC~-~114) To a ~olution of chloroethyl ureido de $vative from ~tep 2 herein (14 mg, .03 mmole) in formic acid (1.2 ml) at 5C waff added ~ nitrite (20 mg) in two portion~. Reaction wa~ complete in 3 minute~. It wa~
lS3 SUB~
W O 94/11382 P ~ /CA93/00463 2146~48 o diluted with w~ter (10 ml), xtr-cted wlth CH2C12 (3x50 ml), w~h~d with water (2xlO ml), dried and ~.~oL~ted. ~he crude product wa~ purified by pas~ing through a ~mall column of sLlica gel (elu~nt: 1% methanol in CH2C12) and finally by ~ ~hi ng with hexane-ether mixture yielding pure titl~d n~t o~o de~ivative, mp~58-63C ~yi-ld~5 mg;34%).
NMR (ac~tone-d6;~): 1.48-1.80 (6H,m;CH2 of the cyclohexyl group), 2.32 (3H,~ Lhyl), 2.52 (lH,dd,J-11.6, 19.6Hs~sH-4), 2.93 (lH,dd,J=4.3,19.7Hz;H'-4), 3.60 (2H,t,J-6.5H~t-CH2-Cl), 3.76-4.05 (m,H-1 and H-4 of th~ cyclc yl group), 4.16 (2H,t,J~6.6H~-N(No)c~2-)~ 4.66 (lH,dd,J~4.3,11.4H~SH-3), 5.97 (l~,~,H-1), 7.77 (lK,br.d, J~7.8Hz5-NHC0-), 7.87-7.90 (2H,mtAr-H), 8.07-8.11 (2H,m;Ar-H).
_1, 46s U~ng th~ c-rbosy~ic c~d a~ d-~crLb-d ~n -16, 1 ~ ~ 5,10 ~ o-3,4,5,10-t-tr-hydro-lH-~ 2,3-c~ 3-c~ w-r- pr-p-r-d o o o o OOCH, O OCH~
Slep: 1, 8CH-204 R~C6H~
2, R~ ,~ul~ BC~2166 3, R--CUl~r-~2~N
4,R~ 2rU2~u~ 1~21~7 8t-p ls 1 ~ ~ 3-~ ~ yl~ 1-S,10-dioxo-5,10-dihydro-lH-~ 2,3-c]-pyran (~C~-2044) U~ing a ~m~lar ~ ac de~cribed in ~tep 7, example 16, the carboxylic acid from ~t~p 6, - - _le 16, wa~ co..v~Led to thc titled dec. 140C; m.p. 200C.
SU~ 5~ ~T
0 94/11382 214 ~ ~4 3 P ~ /CA93/00463 1H NMR (CDC13, 250 MH~, Bruker): ~, 3.68 (3H, ~, OCH3), 6.48 (lH, ~
CH), 7.18 (lH, tr, J ~ 7.6 Hz, p-Ani-H), 7.49 (2H, tr, J - 8.0 Hz, m-Ani-H), 7.50 (lH, B, 4-CH), 7.66 (2H, d, J - 7.8 Hz, O-Ani-H), 7.79 (2H, m, 7, 8-ArH), 8.15 (2H, m, 6, 9-ArH), 8.40 (lH, s, NHCO).
IR (Nicolet , 205 FT, film on NaCl plate): cm~1, 3322.9, 2929.3 2848.3, 1682.9, 1659.8, 1594.2, 1527.7, 1443.7, 1374.2, 1297.0, 1258.4, 1063.2, 947.6, 863.1, 719.7, 693.6.
8t-p 2s 1 ~ ~ 3-(3-N-prrro~ lpropr~ l)-S,10-dioso-s~lo-d~h~dro- m -~- ~~ [2,3-cl-prran (~C~-2166) 60 mq of the acid from step 6, example 16, wao diosolved in 6.8 ml of dry THF, cooled to 0C and 63 ~1 of oxalyl chloride was added. The m$xture was all~ to ~tir at 0C for 20 minutes, and thQn at room lS t~ ~ aLur~ for 20 minutes. The solvent was then ~GL~ted, the residuQ was re~ olved in ~;rhloromethane and ava~G.~Led, and then the residuc was again dissolved into dry THF. The ~olution was cooled to -10C. 29.3 ~1 of triethyl_mine and 19.90 ~1 of 1-~3 . ;~o~,op~1)-2-pyrrol~nrns was added and allowed to stir for 45 minutes at -10C and then 2 hour~ at room tomperature. Tha solvent was then Jv~G aLed to half of it- original volume, the ~ ~;n;ng olution wao ~ onto at.
brine and extractod into ~ichlsromethane. The organic layer was then w ~h9d with at. odium bicarbonate solution, dried over ~odium sulfate, and ~apG~Led to d.~ to give 24 mg of pur~ titlQd product.
2S NMR ~CDC13 250 MHz, Bruker): ~, 1.86 (2H, Quin, J ~ 6.6 Hz, C-CH2-C), 2.08 (2H, Quin, J ~ 7.5 Hz, 4' ~y~ CH2), 2.45 (2H, t, J ~ 7.5 Hz, 3'-pyrr-CH2), 3.15-3.34 (2H, m, C~u~2), 3.36-3.55 (4H, m, CH2-pyrr, 5~-pyrr-CH2), 3.74 (3H, 8, -OCH3), 6.43 (8, lH, 4-CH), 7.32 (s, lH, 1-CH), 7.70-7.78 (2H, m, 6, 9-ArH), 8.08-8.16 (3H, m, 7, 8-ArH, NH).
IR (N;rolet, 205 FT, film on NaCl plate): cm~l, 3320.9, 2936.7, 2871.3, 1679.9, 1658.1, 1597.0, 1527.2, 1335.2, 1291.5, 1278.4, 1082.1, 947.98, 857.41, 801.34, 723.70.
8tep 3: (3-N~ olrlpropyl)-l L~ ~ 5,10-dioxo-5,10-dihydro-lH-3S ~p~t~- 12,3-~] ~-~ 3-c~
To a stirred solution of acod from tep 6, example 16, ~0.185 mmol, S3 mg) and catalytic amounts of DMF in 6 ml of THF at 0C was added oxalyl chloride ~0.426 mmol). After stirring at 0C for one hour, and at room ISS
SUBSTITUTE SHEET
W O 94/11382 PC~rJCA93/00463 2i46~
t~mperature for a further 20 minutes, the solvent wa~ ~aporated to drynes~. 6 ml of THF wa~ then added, and the mixture divided Lnto two.
3 ml of ~olution was then cooled to -10C, and 1-(3-ammino~r~p~l)-~ iAa-Qle (8.39 ~l, 0.20 mmol) di~olved in 1 ml of THF was add~d S dropwi-e. Th~ mixtur~ wau a~ to tir for on~ hour at which time it - was poured onto ~at. ~odium b~ca~hon-t~ ~olution, xtracted into methyl~ne chloride, ~- h~ with brine, dri~d over ~odium sulfat~ and the ~olv~nt _v~G aL~d. Purifi rat~ rn on TLC u~ing 8% m~thanol/chloroform y-tem produced 6 mq of pure titl~d product.
lH N~R (aceton~ -d6, 250 M~z, Bruker), ~: 2.10 (m, 2H, CH2-~ Ql)~
3.42 (m, 2H, C-CH2-C), 3.60 (s, 3H, OCH3), 4.14 (t, 2H, CH2NCO, 6.34 (~, lH, 4-CH), 6.96 (~ lH, 4-CH (i ;~--ol)), 7.16 (~, lH, l-CH), 7.18 (~, lH, 5-CH (i ~ ol)), 7.70 (s, lH, 2-CH (; ~a~ol)), 7.90 (m, 2H, 6, 9-ArH), 8.12 (m, 2H, 7, 8-ArH), 8.29 (m, lH, NH).
IR ~Nicolet 205 FT, film on NaCl plate), cm~l: 3313.5, 2932.1, 2853.4, 1676.1, 1665.4, 1593.2, 1552.8, 1334.1, 1274.0, 1087.5, 950.72, 859.52, 718.64.
8t-p 45 (3-N k~d.~chlor~ ~A-r~lrlpropyl)-l-m-~ l 5,10-d$o~o-S,10-d~hr~ro - 1~ t2,3-cl p~,,~ 3-~- '~ ~f-- (BC8-21S7) 6 mg of product from tQp 3 ~ -i n was di-~olved in 2 ml of sth~r. To this wa~ added 6 ~l of lM HCl/-ther solution (from Aldrich). Th~
mixtur~ wa~ tirr~d, and th~n th- ~olv~nt ~GLaLed to givs 6.7 mg of th~ HCl salt.
H NMR (~reton--d6, 250 MHz, Bruker) for salt, ~: 2.29 (m, 2H, CH2-~ ol), 3.53 (m, 2H, C-CH2-C), 3.62 (8, 3H, OCH3), 4.50 (m, 2H, CH2NHCO), 6.33 (~, lH, 4-CH), ?.14 (~ lH, l-CH), 7.55 (s, lH, 5 CH($mi)), 7.76 (~, lH, 4-CH(imi)), 7.88 (m, 2H, 7, 8-ArH), 8.05 (m, 2H, 6, 9-ArH), 8.64 (m, lH, NH), 9.285 (s, lH, 2-CH(imi)).
IR (NirolQt 205 FT, film on NaCl plate) cm~l: 3345.8, 1676.5, 1652.2, 1527.0, 1280.4, 1090.9, 955.01.
~ 7: ~.~ ~tion of 3~ rl~ l-1,3,4,5,10-~ t-k~ 5,10 '~f ~ [2,3-cl prr~n (BCH-2003) ~nd 3-(S'-tosrl~ olrl)-1,3,~,5,10 ~ 5,10-A~ ~ - t2~3--cl--prr~ 1 (BCII--2155) lS6 SUBSrlTUTE SH~ET
WO 94/11382 2 14 6~4 8 PCI`/CA93/00463 oc~, o oc~, o o o ~0 ~op2 ~
OCHl OCH~ O
p3 r O O
~
OCH3 1~1 0 1~¦ BC~2003 CH~ CH~
l~p6 O O~N
~, 01 BCH~21~5 CH~
8t-p ls 3--thyl~h~ 1-5,8 'i ~hos~
S 5,8~ h~y-3-carboxyi-ochroman (300 mg, 1.26 mmol) in THF (6 ml) was stirred with l,l'-carbonyl~ Ql~ (225 mg, 1.386 mmol) at room t~ ~ aLu.G for 30 minut-~. More THF (6 ml) wa~ addad to d~lute the f~_ ing ~un~ -ion. After one hour, ethanethiol (103 ~1, 1.40 mmol) wa~
added and the mixtur- wa- tirred for 18 hours at room t _- ~t~re.
Solvent was ~ G,,Led and the crude t$tled product was chr~ -~GJ ~hed (hex:EtoAc ~ 4sl) to giv~ desired product as a solid (200 mg, m.p. 99.2 C) .
lH NMR (CDC13, 250 MHz, 8ruker)s ~, 1.28 (3H, tr, J Y 7.6 Hz, CH3), 2.68 (lH, dd, J ~ 17.6 Hz, 11.2 Hz, 4-HCH,), 2.92 (lH, qua, J ~ 7.6 Hz, lS -CH2-), 3.12 (lH, dd, J ~ 11.2 Hz, 3.5 Hz, 4-HCHe), 3.76 (3H, Q~ OCH3), 3.78 (3H, s, OCH3), 4.24 (lH, dd, J ~ 11.2 Hz, 3.0 Hz, 3-CH), 4.70 (lH, d, J ~ 15.3 Hz, l-HCH~), S.06 (lH, d, J ~ 15.3 Hz, l-HCH~), 6.64 (lH, d, J ~ 8.0 Hz, ArH), 6.67 (lH, d, J - 8.0 Hz, ArH).
IR (Nicolet , 205 FT, film on NaCl plate)s cm 1, 2936.2 2836.2, 1679.2 20 1604.8 ~ 1486.8, 1461.8, 1258.5 ,1094.3, 1078.9, 1022.5, 796.81, 714.69.
gt - p 2s 3 - thylt~ 1 - 5~8 ~ - 1~3~4~S~8 ~ ~ ~ - t2~3 -C 1 -pyran SUBS~Ig UTE SHEET
W O 94~11382 P ~ /CA93/00463 21q~ 48 The r n~ from ~tep 1 here~n (100 mg, 0.35 mmol) wa~ di-solved ln aceton~trLl~ ~6 ml), then cooled to 0C. So~i bir~bo~te (58.8 mg, 0.7 mmol) was added. ~his wa~ followed by add~tLon of a solution of S - i cerium nitrat~ (583 mg, .0063 mmol) in 2 ml of w~ter. The r~action mixture wa~ allowed ~tirred for S minute- at 0C. TLC ~howed - _l~ti nn of ths reaction. It wa~ poured to water and xtractsd with methyl-ne chloride. The organic layer wa~ dr$ed over Na25O4 and .v~o ~Led to givQ a crude tltl~d product (83 mg).
lH NMR (CDC13, 250 MHz, Bruk r)s ~, 1.24 (3H, tr, J ~ 7.6 Hz, CH3), 2.51 (lH, dd tr, J - 17.6 Hz, 9.2 Hz, 3 Hz, 4-HCH,), 2.85 (lH, d, J ~
17.6 Hz, 4-HCH~), 2.88 (lH, qua, J ~ 7.6 Hz, -CH2-), 4.18 (lH, dd, J -9.2 Hz, 3 Hz, 3-CH), 4.47 (lH, d tr, J ~ 17.5 Hz, 3 Hz, l-HCHa), 4.81 (lH, br d, J ~ 17.6 Hz, l-HCHe), 6.71 (lH, d, J ~ 9.7 Hz, Quin-H), 6.76 (lH, d, J ~ 9.7 H, Quln-H).
lR (Nicol~t , 205 FT, film on NaCl plate): cm~l, 2972.6, 2929.5, 2882.4, 1678.5, 1655.5, 1599.3, 1418.9,. 1313.1, 1147.5, 1125.6, 993.09, 827.00, 766.77, 729.32, 667.58, 629.13.
8t.p 3: 3-- thrlt~ i o~ - S ~ 8-dioxo-1,3,4,5,10 ~ ~k~O ~r~
[2,3-~]-p~ra~ (BC~-2003) Ths __ - from tep 2 h~rein (42 mg, 0.167 mmol) in tolu~n~ (6 ml) was st~rr~d with l-acetoxy-1,3-but~j ~ (119 ~1, 1.0 mmol) at 60C for 2~ 22 hours. Solvent wa~ ~G~ated and the crude product wa~
ch~ ~phed (tolu-n~/~tOAc ~ 100/15) to give de~ired titled product (41 mg) a~ a zolld (m.p. 95.4-96.5C).
lH NNR (CDCl3, 250 MHz, Bruker): ~, 1.26 (3H, tr, J - 7.6 Hz, CH3), 2.65 (lH, dd tr, J - 19.4 Hz, 9.4 Hz, 3 Hz, 4-HCHa), 2.91 (2H, qua, J
7.6 Hz, CH2), 3.04 (lH, d tr, J ~ 19.4 Hz, 3 Hz, 4-HCHe), 4.25 (lH, dd, J ~ 9.4 Hz, 3 Hz, 3-CH), 4.61 (lH, d tr, J ~ 18.2 Hz, 3 Hz, l-HCHa), 4.97 (lH, dd, J - 18.2 Hz, 1.8 Hz, l-HCHe), 7.71 (2H, m, 7, 8-ArH), 8.04 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm~1, 2969.3, 2931.3, 3S 2874.3, 1680.8, 1661.8, 1641.4, 1594.2, 1334.2, 1296.4, 1175.1, 1108.9, 1027.0, 874.2, 787.5, 694.6.
8t-p ~: 3-(5~-to~yl~ Qlrl)-S,8-~ y i~Gch~ -~
SU~S ~ e f ~T~ S~;EET
W O 94/11382 PC~r/CA93/00463 21~6~8 To 5,8-dimethoxy-3-carboxyi~ochroman (211 mg, 0.887 mmol) dis~olved in THF ~2.0 ml) cooled to 0C was added oxalyl chloride (86.09 ~1, 0.975 mmol). The mixture was ~tirred for 20 minutes then at room t~, ?' a~ure for 20 minutes. The r~action mixture wa~ --va~o~ated to dryne~s to give desir~d acid chloride. It was r ~i~oolved in THF (4 ml) and cooled to -78C. A ~olution of tosylmethyl i~G~y i ~ anion (made from th2 treatment of tosylmethyl i-_~y ~e, 180 mg, 0.92 mmol, by n-butyll~thium, 1.6 M in h~xane, 0.61 ml, 0.975 mmol at -78C for 10 minute~) was added to the abovs cold acid chloride solution. The reaction mixture was tirr~d for 24 hours a- it w -~ to room t= -~ure. Th~n, it wa~ poured to NH4Cl (-at.) and xtracted with methylRne chloride. The organic layer wa~ dri~d (over Na2SO4) and evaporated to give a crude product which was chromatGgcaphed to give the desired titled product a~ a white ~olid 115 mg, m.p. 138-140C.
lS lH NMR (CDC13, 250 MHz, Bruk-r)s ~, 2.41 (3H, s, to~y-CH3), 2.99 (2H, d, J ~ 7.4 Hz, 4-CH2), 3.76 (6H, 8, 2xCH3), 4.85 (lH, d, J ~ 17.5 Hz, 1-HCHa), 4.03 (lH, d, J ~ 17.5 Hz, l-HeCH), 5.54 (lH, tr, J ~ 7.4 Hz, 3-CH), 6.67 (2H, br , 6, 7-ArH), 7.33 (2H, d, J ~ 8.2 Hz, 3', 5', to-yl-H), 7.82 (lH, s, oxa-H), 7.92 (2H, J z 8.2 Hz, 2, 6-tosyl-H).
20 IR (Nicolet 205 FT, film on NaCl plat~): cm~l, 3134.2, 2951.5, 2837.5, 1595.5, 1511.7, 1485.6, 1463.6, 1437.5, 1331.7, 1261.6, 1194.3, 1149.0, 1089.9, 1072.0, 809.60, 798.61.
8t-p Ss 3-(S'-t4~ 1)-5,8 i~-o 1,3,~,5,8 ~ k~d~r -~
2S ~2,3-c~-prr n The ; _ ~ from tep 4 ~-~ in (10 mg, 0.024 mmol) wa~ di--olved in acetonitrLle (2 ml) and cooled to 0C. A solution of ~ - i cerium nitrate (39.5 mg, 0.072 m~ol) in 0.5 ml of water wa~ added dropwi~e.
The reaction mixture wa~ tirred at 0C for 5 minut~s, then poured to water and extract-d with ~i rhl oromethane. The organic layer was w ~d with brine, dried ~nd v.~o ~Led to giva tha titled ~ ~_ as a white solid (9 mg, dec. 150Ct m.p. 177C).
lH NMR (CDC13, 250 MHz, Bruker): ~, 2.42 (3H, s, tosyl-CH3), 2.82 ~2H, 3S m, 4-CH2), 4.65 (lH, d tr, J = 17.6 Hz, 4.1 Hz, 1-HCHa), 4.82 (lH, d tr, J - 17.6 Hz, 1.8 Hz, l-HCHe), 5.52 (lH, tr, J - 7.0 Hz, 3-CH), 6.75 (lH, d, J ~ 9.1 Hz, guin-H), 6.81 (lH, d, J - 9.1 Hz, quin-H), 7.35 (2H, d, J
8.2 Hz, 3', 5'-toayl-H), 7.83 (lH, ~, oxa-H), 7.90 (2H, d, J ~ 8.2 Hz, 2', 6'-tosyl-H).
lS9 SUBSTITUTE SHEET
W O 94/11382 PC~r/cA93/00463 2~&~
~t-p 6t 3-(5'-tosrlr--~olrl)-5,10 i~-o-1,3,4,5,10-p utahydro-~p~ ~~ [2,3-cl-pyr n (BC~-2155) A ~olution of tosyloxa~olyl pyranoquinone from step 5 her~in in 4 ml oftolu~ne and 0.5 ml of t-trahydrofuran (9 mg, 0.023 mmol) wa~ t0~ w$th l-acetoxy 1,3-but~ (55 ~1, 0.47 mmol) at 50C for 20 hours.
Solvent wa~ a~apG~ ed to d.~ -e~ and the crudQ product wa- purified by means of cl,~ - oJ a~hy (Tol:FtOAc~100sl5) to g~v- d~Lred titl~d product a~ a light color~d olid (6.6 mg obtain~d).
M.P. >240C.
1H NMR (CDC13, 250 MHz, Bruker): ~, 2.43 (3H, s, ArCH3), 2.99 (2H, m, 4-CH2), 4.78 (lH, d tr, J ~ 18.8 Hz, 3.3 Hz, l-HCH~), 4.96 (lH, d, J -18.8 Hz, l-HCHQ), 5.57 (lH, dd, J ~ 8.9 Hz, S.0 Hz, 3-CH), 7.36 (2H, d, lS J - 8.2 Hz, 3', 5'-tosyl-H), 7.75 (2H, m, 7, 8-ArH), 7.85 (lH, s, oxa-H), 7.92 (2H, d, J ~ 8.2 Hz, 2', 6'-tozyl-H), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet 205 FT, film on NaCl plate): cm~l, 2955.7, 2921.3, 2854.0, 1662.8 (-tr), 1592.2, 1508.6, 1398.6, 1334.6, 1319.9, 1298. 5, 1147.6, 1106.6, 1086.9, 1013.0, 811.2, 794.8.
8s Pr-parat~on of (l'S,18,3R)-1-(3'-tr~fl 7~0~c-ta-$do-2',3',6'-tr~ lyxo-~ - ~}~ Q~ 3-t~ 1-3-m-th~1-3,4,5,10-t-tr~h~d,o S,10-d~oxo-~p~ ~ [2,3-cl ~yran (BC~-2076) SUBS~lTlJTe ~HE~T
WO 94/11382 PCI`/CA93/00463 2146~48 OCH3 `
3 ~OCH3 OCH3 0 ~
H3C~ H,~
PNBo NHIF~ PNBo NNIFA
O O O O
~H ~ K3 o o o o H,C--~ H,C~J
oHNHlFA Pt~Bo NH'IFA
~t-p ls (1'~, 18, 3~)~ p-~$L~ Qyl-3'-tr~ c~c-t~ ~o-2',3',6'-tr~ )-3 ~ ~ c~ 1-3-S m thrl-S,8-d~o~o-4,S,8-tr~h~dro-1~ 2,3-c]-prr~n (l'S,lS,3R) 1-(2',3',6'-tridQoxy-3-trifluoroacotamido-4'-O-p-niL~ royl-L-l~ r-~s 5,8-dim~thoxy-3-aceto-3-m~thyli~ch~oman ~62 mg, 0.0945 mmol) $n acotonLtrLle (3 ml) wa- tLrred ~t 0c whLl- a ~olut$on of ~ - i cer$um n$trat- (165.5 mg, 0.284 mmol) $n water (1.5 ml), ~. L~.-t-' w$th ~c'i bir~hQn-te (15.1 mg, 0.18 mmol), wa~ added dropwi-e. Th~ zolution waz ctirred for 5 minute~ at 0C then poured to water and extracted w$th ~ich loromQthane. The organic layer wa~ dried ~nd a~o~ed to give de~ired titled product (40 mg, 0.064 mmol).
lS lH NMR (CDC13 250 MHz, Bruker): ~, 1.27 (3H, d, J - 6.5 Hz, 6'-CH3), 1.57 (3H, B, 3-CCH3), 1.91 ~lH, dd, J ~ 11.8 Hz, 4.7 Hz, 2'-CH), 2.10 (lH, d tr, J ~ 11.8 Hz, 3.6 Hz, 2'-CH), 2.72 (lH, d, J - 17.9 Hz, 4-CH), 2.94 (lH, dd, J ~ 17.9 Hz, 0.9 Hz, 4-CH), 3.75 (3H, ~, OCH3), 4.54 (lH, m, 3'-CH), 4.64 (lH, qua, J - 6.5 Hz, 5'-CH), 5.40 (lH, ~, 4'-CH), 5.65 (lH, d, J ~ 2.4 Hz, l'-CH), 6.06 (lH, ~, l-CH), 6.52 (lH, d, J Y 8.2 Hz, NHCOCF3), 6.77 (lH, d, J ~ 10 Hz, Quin-H), 6.83 (lH, d, J ~ 10Hz, Qu$n-H), 8.27 (4H, m, PNB).
~U~ST~ S~ET
~1~6~48 IR (N~colct, 205 FT, film on N~Cl plat~): cm~l, 3336.1, 3083.4, 2956.1, 2849.7, 1734.5, 1664.2, lS29.4, 1352.7, 1272.9, 1162.7, 989.8, 949.9, 839.70, 721.95.
8t-p 2s (1'8, 18, 3R)-1-(4'-p-n~t,. -Q~1-3'-tr~fl~ t~uido-2',3',6'-tr~ -3-n~ 1-3- -~-th~1-5,10 'i~-~-4,S,10-tr~hydro-1~ '- [2,3-cl-prr~n The titl~d _ _ ~ w~- obt-in~d a~ p r ~.~c~ re d--cribed ~n zt~p 2, . - _l~ 5, but u~ing th~ ~-in~n~ from ~tep 1 h~rein.
lH NMR (CDC13 250 MHz, Bruk~r): ~, 1.32 (3H, d, J - 6.6 Hz, 6'-CH3), l.9S (lH, dd, J ~ 12.4 Hz, 5.0 Hz, 2'-CH), 2.10 (lH, d tr, J ~ 12.4 Hz, 3.5 Hz, 2'-CH), 2.88 (lH, d, J ~ 18.2 Hz, 4-CH), 3.13 (lH, dd, J ~ 18.2 Hz, 1.0 Hz, 4-CH), 3.75 (3H, 9, OCH3), 4.56 (lH, m, 3'-CH), 4.76 (lH, lS qua, J ~ 6.6 Hz, 5'-CH), 5.45 (lH, s, 4'-CH), 5.72 (lH, d, J ~ 2.0 Hz, l'-CH), 6.26 (lH, ~, l-CH), 6.45 (lH, d, J ~ 7.1 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH), 8.29 (4H, m, PNB). IR (Nicolet, 205 FT, film on NaCl pl-tc): cm 1, 3329.3, 2955.6, 2926.9, 2855.3, 1732.9, 1709.5, 1668.3, 1596.8, 1532.3, 1349.5, 1272.6, 1217.6, 1184.7, 1164.1, 996.5, 952.5, 729.90, 720.30.
8t-p 35 (1~8, 18, 3R)-1-(3'-tr~fl~o~ zu~do-2',3',6'-tr~ L-)-S,10-d~o~o-4,S,10-tr~h~dro-lH
t2~3-Cl-prran (~CJ-2076) The titl~d ~ w~z obtaincd from th~ gly_~aid~ from t~p 2 h~rein ~ia ba~e hydroly-i~ a~ per ~ OCL l~r~ d~3cribed in ~tep 3, . l~ 5.
lH NMR (CDCl3, 250 MHz, Brukcr): ~, 1.38 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.60 (3H, ~, 3-CCH3), 1.85 (lH, d, J ~ 6.8 Hz, 4'-OH), 1.85 (lH, dd, J =
9.4 Hz, 2.6 Hz, 2'-HCHa), 1.96 (lH, d, J - 9.4 Hz, 2'-HCHe), 2.87 (lH, d, J ~ 18.8 Hz, 4-HCH~), 3.12 (lH, dd, J ~ 18.8 Hz, 0.6 Hz, 4-HCHe), 3.63 (lH, br d, J ~ 6.8 Hz, 4'-CH), 3.75 (3H, ~, OCH3), 4.28 (lH, qua, J
~ 8.8 Hz, 3'-CH), 4.55 (lH, qua, J ~ 6.0 Hz, S'-CH), 5.54 (lH, ~, l'-CH), 6.21 ~lH, ~, l-CH), 6.71 (lH, br d, J ~ 9.4 Hz, ~n~3), 7.75 (2H, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH), IR (N$colet , 205 FT, film on NaCl plate): cm~l, 3420.1 (br ~tr), 2955.6, 1718.7, 1668.3, 1595.5, 1377.3, 1329.7, 1287.7, 1161.8, 982.68, 921.12, 730.64.
SUBSTITUTE SHEET
W O 94~11382 PCT~CA93/00463 2l4~qa i r 1 ~ ~ 9 ( 1~ 3--tr~z ) -n l i ~ ( l~t ~ - ~ S ~ 10--dioso--3 ~ ~ ~ 5 ~ 10-t-tr hrdro-l~ 2,3-~1-pyr n)-3-c~
(BC~-2041) and (1,3-c~ 5,10-dioxo-3,4, S, 10-t-trahrdro-1H ~phi h7_ l2,3-c]-prran)-3-S c---'o - i~~ (JCH-20~2) ~p~CO2M- ~H
O O~
~CO2H ~$CO2H
O O~ O O~
BCH~2045 BCH-2119 ~ ` ~
O O~ O O~
8t-p ls The c __ ' from tep 3, _le 16, ~21 mg, 0.0695 mmol) was dissolved in ~et~nitrile (10 ml) and then cooled to 0C. NaOH (0.1 N, 1.4 ml, 0.14 mmol) ~D~ut;on wa- then added ~lowly. After 10 minutes, the brown solution wa~ poured to water, extract~d with ethyl acetate. The aqueou6 layer wa~ acidifLed with dilute HCl and extracted with ethyl ace~tate.
The organic l-yer co~t~ning acid wa~ dried and _~pG-~Led to give a mixture of 3 product~ (18 mg). ~h.e -tGJ a~hy (CHC13/MeOH/HOAc =
100:15:2) llotJe~ ~paration of the 3 F _ _ '~. One of the products wa~ the ~ame~ a~ tha one~ obtaine~d in tep 6, ~ _le 16, and had:
lH NMR (CD3COCD3, 250 MHz, Bruker): ~, 3.58 (3H, ~, OCH3), 6.36 (lH, s, l-CH), 7.22 (lH, ~, 4-CH), 7.91 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
SUBSTITUTE SHEET
=
WO 94/11382 PCr/CA93/00463 21~6~
ThR ~ocond product (1,3-tran~)-1-mathoxy-3-carboxyl-5,10-dLoxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-cl-pyran, BCH-2045 had:
1H NMR (CD3SOCD3 250 ~Hz, Brukcr): ~, 2.55 (lH, dd, J ~ 18.5 Hz, 12.4 Hz, 4-HCHa), 2.88 (lH, dd, J - 18.S Hz, 3.5 Hz, 4-HCHe), 3.47 (3H, ~, OCH3), 4.49 (lH, dd, J - 12.4 Hz, 3.5 Hz, 3-CH~, 5.55 (lH, s, l-CH), 7.88 (2H, m, 7, 8-ArH), 8.00 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plat~): cm 1, 3549.2-3183.8, 2922.8, 1722.1, 1289.0, 1107.4, 1012.3, 9S1.08, 808.9, 793.5.
The third product: (1,3-ciD)-1 h~Yy-3-carboxyl-S,l0-dioxo-3,4,5,10-tetrahydro-lH-r~rhth~-~2,3-c]-pyran, (BCH-2119), hadt lH NMR (CD3SOCD3 250 ~Hz, Bruker)s ~, 1.28 (lH, dd, J - 15.3 Hz, 11.5 Hz, 4-HCHa), 2.58 (lH, dd, J ~ 11.5 Hz, 2.9 Hz, 4-HCHe), 3.4S (3H, ~, OCH3), 4.17 (lH, dd, J - ll.S Hz, 2.9 Hz, 3-CH), S.62 (lH, ~, 1-CH), 7.89 (4H, m, 6, 7, 8, 9-ArH).
gt-p 2s (1,3-tr n~)-l-~ tho~r-3-N ~ il~ylc~ l-S,10-d~o~o-3,4,S,10-t-trahydro-1~ t2,3-cl-pyran, ~C~-2041s A ~olution of acid from tep 1 h-rein (20 mg, 0.069 mmol) in THF (4 ml) was cool~d to 0C. To the olution w~ added DMF (1 ~ a cataly-t) and then oxalyl chloride (12 ~1, 0.138 mmol). The mLxtur- wa- tirred at 0C for 45 minut~ and at room t~ _- ~L~ for 20 minut-~. Solvent was L~pG a~ed. The residue was redi-~olved in methyl-ne chloride and th~n ~pG.&L-d. Tha r-~idue wa- di-~olved again Ln mnthyl-ne chloride (4 ml) and half of th~ volume wa~ taken for co--rl;nq wlth !ni 1 ;ne (4 ~1, 0.044 ol) a~ foll~ o the ice-cold zolution of th- acid chloride was add~d ~n~ 1 i ~ (1 eg. ) in 1 ml of methylene chloride. The reaction mixture wa~ ~t~rred for 10 minutos. It was poured to water and xtracted with m~thyl-n~ chloride. The organic layer wa~ dried and _~G~Led to give a crude product which wa~ purified by ~ tiQn from methylene chloride and hexane. The de~ired titled product wa~ obtain~d (11 mg) a~ a light yellow olid.
.P. 183-184C.
lH NMR (CDC13, 250 NHz, Bruker): ~, 2.63 (lH, dd, J ~ 19.4 Hz, 12.5 Hz, 3S 1-HCH~), 3.30 (lH, dd, J ~ 19.3 Hz, 4.2 Hz, l-HCHe), 3.67 (3H, ~, OCH3), 4.74 (lH, dd, J ~ 12.5 Hz, 4.5 Hz, 3-CH), 5.77 (lH, s, 1-CH), 7.16 (lH, tr, J ~ 8.5 Hz, 4'-Ani-H), 7.47 (2H, tr, J ~ 8.5 Hz, 3', 5'-Ani-H), 7.52 (2H, d, J ~ 8.5 Hz, 2', 6'-Ani-H), 7.75 ~2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.31 (lH, ~, NHCO).
SU~T; ~ . S~EET
W O 94/11382 21 4 6 ~4 g PC~r/CA93/00463 IR ~NJcolet , 205 FT, f$1m on NnCl pl~te): cm l, 3278.8, 2923.0, 1665.0, 1593.4, 1533.0, 1445.7, 1798.0, 1060.7, 960.0, 755.6, 688.2, 679Ø
S St-p 3s (1,3-c~ ~ thosr-3-~ ~ ~r~ ~^~rl - S~10 -dioso-3,~,5,10-t-tr~h~dro-1~ 2,3-ol-prr~n, JC~-2042, A ~imilar to the ~o~` r~ d~scribed pr~viou~ly in tep 2, the ci~ acid from ~tep 1 herein wa~ C06~_ Led to the titlcd product.
M.P. 217-219C.
lH NMR (CDCl3, 250 ~Hz, BrukQr): ~, 2.49 (lH, dd, J - 15.6 Hz, li.2 Hz, 4-HCHa), 3.08 (lH, dd, J ~ 15.6 Hz, 3.2 Hz, 4-HCHQ), 3.65 (3H, ~, OCH3), 4.50 (lH, dd, J ~ 11.2 Hz, 3.2 H, 3-CH), 5.94 (lH, 8~ l-CH), 7.14 (lH, tr, J - 7.6 Hz, p-Ani-H), 7.35 (2H, tr, J ~ 7.6 Hz, m-Ani-H), 7.56 (2H, d, J - 7.6 Hz, O-An~-H), 7.78 (2H, m, 7, 8-ArH), 8.00 (28, m, 6, 9-ArH), 8.21 (lH, ~, NHCO).
IR (Nioolet , 205 FT, film on NaCl plate): cm~l, 3353.5, 3052.9, 2928.1, 2853.9, 1694.6, 1597.5, 1531.8, 1443.3, 1300.6, 1172.1, 1117.8, 1060.7, 1043.6, 1026.5, 906.7, 750.6, 712.5, 692.6.
_1- S0t ~ r~t~on of (l'~,lR,35)-1-(3'-tr~fl ~ a-ido-2',3',6'-tr~ )-3-(5~-to~rl~ rl)-3,~,5,10-t~tr~L~d.~ S,lO-di~ r~t~-12,3-o] p~r ~ (AC~-2150) SUBSTITUTE SHEE~T
W O 94/11382 P ~ /CA93/00463 ~ OCH~ ~~
~ H~C~ ~ ~
CH, PNB CH PNBO NH~A CH, ~H3 ~ ~ CH, pNB~A PNB~A
O o~
~ o ~ H, H, ~
oHNHl~A
BCH-21~0 ~t-p ls (l'S, 1~, 3R)-1-(4'-p-niL. ~ 1-2~,3',6'-tr~ 3'-tr~ -3-(Sn-to~r~ lrl)-s,a -; ~os~ c~
s To the ~ ' from ~t~p 4, _le 47, (50 mg, 0 120 mmol) in ~ i ~h 1 oromethane (15 ml) stirred wLth 5'-p-nitrobenzoyl-3',4',7'-trideoxy-3~-trifluoro~ o-L-ly~ohe~py~anose (49 mg, 0 125 mmol) was added 1,2-~ichloro-4,5-dicyano-b~nzoquinone (35 6 mg, 0 157 mmol) The resultLng mixture wa- stirred for 18 hours at 40C Solvent was e~G ~Led and th~ crude product w~ el,, -~Gy~hed (hexane/ethyl acetate~3/2) to gi~ the titled _ _ d (17 mg) and the (l'S,lR,3S) diast~,~ - (12 mg) ~he titled : _ ~ had lH NMR (acetonQ-d6, 250 NHz, B N ker) ~, 1 27 (3H, d, J ~ 5 9 Hz, 6'-CH3), 2 14-2 30 (2H, m, 2'-CH2), 2 44 (3H, ~, to~yl-CH3), 3 01 (2H, d, J
SUBSTITUTE SHEET
WO 94J11382 PCr/CA93/00463 ~1~6~4~
= 6.5 Hz, 4-CH2), 3.82 (3H, ~, OCH3), 3.92 (3H, s, OCH3), 4.65 (lH, m, 3'-CH), 4.86 (lH, qua, J ~ 5.9 Hz, 5'-CH), 5.71 (lH, d, J ~ 2.4 Hz, 4-CH), 6.17 (lH, tr, J ~ 6.5 Hz, 3-CH), 6.24 (lH, n, l-CH), 6.95 (2H, m, 6, 7-ArH), 7.48 (2H, d, J = 7.4 Hz, 3"~5n-tosyl-H)~ 7.95 (2H, d, J = 7.4 S Hz, 2n, 6"-tosyl-H), 8.38 (4H, m, PNB), 8.37 (lH, s, oxa-H), 8.66 (lH, - d, J - 7.4 Hz, NHCOCF3).
The (l'S, lR, 3S)-1-(4'-p-nitrobenzoyl-2',3',6'-tr~ 3'-trifluoroacetamido-L-lyYoh~ y~ano~e)-3-(5~-tosyloxa-zolyl)-s~8 dimethoxy i r ~ n h~ds lH NNR (acetone-d6, 250 ~Hz, Bruker)s ~, 0.80 (3H, d, J ~ 6.8 Hz, 6'-CH3), 2.19 (lH, m, 2'-HCHa), 2.48 (lH, d tr, J - 11.8 Hz, 4.1 az, 2'-HCHe), 2.46 (3H, 8, to~yl-CH3), 2.88 (lH, dd, J - 17.6 Hz, 11.8 Hz, 4-HCHa), 3.04 (lH, dd, J ~ 17.6 Hz, 4.4 Hz, 4-HCH~), 3.83 (3H, ~, OCH3), 3.86 (3H, 8, OCH3), 4.42 (lH, qua, J ~ 6.8 Hz, 5'-CH), 4.84 (lH, m, 3'-CH), 5.48 (lH, ~, 4~-CH), 5.58 (lH, d, J ~ 3.5 Hz, l'-CH), 6.01 (lH, 8, l-CH), 6.92 (lH, d, J ~ 6.5 Hz, ArH), 6.96 (lH, d, J ~ 6.5 Hz, ArH), 7.54 (2H, d, J ~ 9.1 Hz, 3", 5n-to8yl-H), 8.06 (2H, d, J ~ 9.1 Hz, 2~, 6~-to~yl-H), 8.35 (lH, ~, oxa-H), 8.49 (4H, m, PNB), 8.62 (lH, d, J -6.8 Hz, NHCOCF3).
8t-p 2: (1'8, 18, 3R)-1-(4'-p-niL.~ ~orl-2',3',6'-tr~ 3'-tr~ t~ -L-l~ )-3-(5~-to~r~ Qlrl) S,8 'i~ 3,4,S,8-t-tr~ ' ~o [2~3-~1-prrzn.
25 The _ _~ ~ from tep 1 herein (17 mg, 0.021 mmol) $n ~ onitr$1e (2 ml) was cooled to 0C and - -i cerium nitrate (35.5 mg, 0.0648 mmol, protreatQd with ~'i b~ on-~e, 3.6 mg, 0.042 mmol) wa~ added dropwi~e. The reaction mixtur~ was ~tirred for 15 minute~ at 0C then poured to water. It was extracted with ~i c-hl o~ han~. The organic phase wa~ with brine, dried (over ~odium ~ulfate) and ~apG~&ted to give a cruda product which wa~ purified on ~ilica gel (hexane/EtOAc -2sl) to give the de-ired titled product (7 mg).
lH NMR (acetone-d6, 250 MHz, Bruker): ~, 1.04 (3H, d, J ~ 6.5 Hz, 6'-CH3), 2.12-2.35 (2H, m, 2'-CH2), 2.45 (3H, 8, to~yl-CH3), 2.80-2.93 (2H, m, 4-CH2), 4.55 (lH, qua, J ~ 6.5 Hz, 5'-CH), 4.86 (lH, m, 3'-CH), 5.49 (lH, ~, 4'-CH), 5.61 (lH, d, J = 2.1 Hz, l'-CH), 5.85 (lH, ~, l-CH), 6.12 (lH, dd, J ~ 10.6 Hz, 4.7 Hz, 3-CH), 6.80 (lH, d, J ~ 10.6 Hz, Quin-H), 6.85 (lH, d, J = 10.6 Hz, QuLn-H), 7.48 (2H, d, J ~ 8.8 Hz, 3n, SUBST)TU,TE SHET
W O 94/11382 2 14 6 ~4 ~ PC~r/CA93/00463 5"-tosyl-H)~ 7.88 (lH, s, oxa-H), 7.94 (2H, ~, J ~ 8.8 Hz, 2~, 6"-to~yl-H), 8.28 (4H, m, PNB).
8t-p 3: (1'8, lR, 3S)-1-(4'-p-nit,.~- -Qyl-3-trlfluoroac-t $do-2',3~,6~-tri~ ~ L-l~ )-3-(5n-tosrl-o~a~olyl)-S,10 'i- 3,4,5,10-t-tr-~d.~ lH ~ ~p~ 2,3-c]-pyra~
ThQ c~ from ztep 2 her~in (9 mg, 0.012 mmol) wa~ tirred wLth 1-acQtoxy-l ~ 3-but~ i r ~ ( 28 ~1, 0.236 ~mol) $n tolu-na (4 ml) and THF (0.5 ml) at 50C for 18 hours. Solv~nt wa- .-~G-.L-d nd th~ crude product was ch -~o~ ' (tolu~n~/ethyl ~ - 5/1) to give the de~red titled product (4.8 mg).
lH NMR (CDC13 250 MHz, Bruker): ~, 1.06 (3H, d, J ~ 6.2 Hz, 6'-CH3), 2.00 (lH, d tr, J ~ 11.5 Hz, 2.9 Hz, 2'-HCHa), 2.25 (lH, dd, J ~ 11.5
NMR (-cstone-d6) ~: 1.35 (3H,d,J~6.6Hz5 CH3 of the sugar), 1.75 (lH,dd,J-4.6,13.0HztH-2 of th- ugar), l.9S (3H,s,CH3 of the side-chain), 3.71 (lH, br.signal; H-4 of thc sugar), 4.27 (2H,m;-ugar-H), 4.57 (lH,q,J~6.6HztH-S of th- ugar), 4.70 (lH,t,J=7.5HzSH-3), 5.44 Sl~S i i ~ ET
W O 94/11382 PC~r/CA93/004~3 21~65~ ~
(lH,d,J~3.3H~SH-1 of th- ~ugar), 6.07 (lH,S;H-l), 7.87-7.90 (2H,m;Ar-H), 8.08-8.12 (2H,m;Ar-H), 10.15 (lH,bit br. ~Lngl-t~-NOH).
8t-p 3s (lR,38)-3-(~ L~yl)-l (2,3,6-tr~ 3-S tr~f~ p ~ o~l-L-l~ o~-)-5,8-o Ox$mQ wa~ prQpar-d from 3 _c~yl i-~- -n glyco~$d~ (60 mgt .096 ~mol) u-'ng hyd~o~yl mine hyd~ochlor$ds (39 mgs 0.56 ~mol-) in ~tOH (2.6 ml) and wat~r (0.26 ml), and ~ i hydrox'de (21.5 mg) in ~tOH (1.3 ml) follow'ng the pr~c- _ d ~cr$bed 'n ~t-p 1 h-r-_n. Aft-r ch - GJ-~hy ov~r ~ ca g~l p,nt~ wLth tri-thylumine titl~d oxime ($n dLast~ - 'c m~xtur- of 5:1 ratlo) w~- obta$nQd $n 81~ y$~1d (50 mg).
NMR (-~to~-d6; ~): 1.10 (3H, d, J - 6.6 Hz; CH3 of ugar), 1.98 (3H, ; m4thyl of th- ~iA- chain), 2.39 (lH, dt, J - 3.6, 12.9 ~z; H-4), 3.81 (6H, ; Ar-OCH3), 4.63-4.73 (lH, m; H-3 of ~ugar), 5.45 (lH, br ignal;
H-l of ugar; ~am- of th~ oth~r A;-~t~m~ -- ov~rlapp d), 5.56 (lH, br ignal; H-4 of the ugar; ume of th~ other Ai ~t~ `- - overlapped), 5.95 (lH, ~, H-l), 6.81-6.95 (m; Ar-H), 8.30-8.43 (m; A-H of PNB group), 8.66 (lH, br d, J - 5.9 Hz; N~TFA), 10.05 (lH, ~; -N-OH), (~h-ru w-re f-w oth~r ~igr-l~ wh'ch wer- du- to th- oth~r d$a-t;~ - and to a mall impurity wh$ch w~re not ~ ~il r ' ) -5 8t-p 4s (1 ~, lR, 38)-3 (r~ Lhrl)-5,10-d~oro-1 (2,3,6-tr;~ 3-tr~ )-3,~,5,10 L ~._h~dro-r ~ (2,3-~)-prr 3 (~C~-2115) Ac~tyl~t'~ of the ox$m~ (50 mg; .078 D 1~) wa~ done following the p~OCQd~ dQ~cr$bed in tQp 2, f$r-t part. CAN oYi~-t~ wa~ done on the ~ to ~5~ mg) us$ng ~o ' b~ b~-to following th~ g~neral p~ocedu~. It result~d in 50 mg of crude qu$none. QUinnn~ (50 mg) WaB
r-acted w$th -~at~ yL~ i - (0.1 ml) $n tol ~ ~ (2 ml) follow$ng the q~n~ral ~ o~ . On purifi~-t'Qn by column ~ ~hy over ~ilLca 3~ gel (20% ~tOAC in toluene, 50% EtOAc in toluQn~ lnd 5~ m~thanol in CH2C12 a~ ) gave 33 mg of slightly impur~ tricycl$c -~Finally, deprot-ction of ~cst-t~ ~nd PNB group- wa- done by u-$ng o m~hnYi~ (catalytic) in methanol (2 ml) at 0C following the ~,oce~
de-cr$bed in tep 2, last part. Tho t$tled c N de pcod~cL wa~ pa~ed SUBSTITUTE SHEET
2146~
through two column- of ilica gcl (l~ and 2~ methanol in CH2C12 a~
elu-nt~) y;~ldin7 the oxime in 12.5% yi~ld (5 mg) (~ont~ t~d with the other diast;- _ -r in 5.6:1 ratio).
NMR (ac~Lon~ d6; ~): 1.18 (3H,d,J-6.4H~sCH3 of the sugar), 1.76 (lH,dd,J-4.8,12.9H~S~-2 of the ~ugar), 1.98 (3H,~,CH3 of th~ ide chain), 2.18 (lH, dd,J~3.7,12.9Hz,H-4), 3.67 (lH,br.d,J~3.9HzS-ugar-H), 4.21-4.29 (2H,m,~ugar-H), 4.77 (lH,dd,J~5.4, 9.6Hz;H-3), 5.48 (lH,d,J~3.2; H-l of th ugar), 5.91 (lH,-,H-1), 7.86-7.92 (2H,m;Ar-H), 8.06-8.10 (2H,mtAr-H), 10.14 (lH,s,-N-OH) , (th-r- w re mall signal~
duQ to the other dia-t;~m~ ~ p r- ~ $n the p-ctru~ which w~r~ not detailod).
2s Prep~ration of (1'8,18,3R)-3 (t ir~ t~ rl)-s,lo -if - 1 (2,3,6-tr~ 3,~-dLh~d.~A~ '- p~ )-3,4,5,10-t-tr hrdro-lr ~ 2,3-c] prr~n (~C~-2018) OMe O 0~ ?~F~
~ I ~ ~
OMc Ob~e 0~ NHIPA O NHIFA
3, ~o~
01~ 0 0 0 H,C~ B,C~
0~ ~ OH OH
8C~2015 20 ~-p ls 3-(~r~ o ~-hrl)-5,8-~
To a ~olution of hyd~Aylamine-hydrochloride (1.4 g; 20.1 mmole) in a mixtur~ of ethanol (30 ml) and water (3 ml) wa- added ~ i hydroxide (720 mg) in ethanol (15 ml). The mixtur~ wa~ stirred for .5 hour. The 2S solution was filt~red. The filtrate wa- ~dded to 5,8-dimethoxy-3-acetyl-i~oc~ (1 gs 4.23 mmol~). The mixture wa~ ~tirr~d at room t- _- aLu,e for 1.5 hour and _~pG,aLed to dryne~s. The residu~ was S l J ~ T
2 1~`6~A~ ~
dL~solved in small volum~ of water (10 ml), extracted with CH2C12 (3x100 ml), wa~hed with brine (20 ml), dri~d and c~po~aL~d. The crude product (900 mg) obtained was di~aolved in toluene (30 ml) and cooled to -40C.
Rcd-Al (9 ml) was addQd during 25 mLnut~. The mixtur~ wac ~t~rred at -40C for 40 m$nut~. The t~ - atur- of th~ cooling mixtur~ wa~ rai-ed lowly to 25C and the reaction was ~tirred at 25C for 16 hours.
EXC~-8 ~ L wa~ d~stroyad by carQful addition of cold water (6 ml) followed by 10~ ~o'i hydroxide (1 ml). The mixtur~ wa~ extracted with ether (3x100 ml), wr '~-' with brine (25 ml), dried and ~-~Gr-ted. Thc crude product (800 mg) wa~ di-solv~d Ln CH2Cl2 (50 ml). Pyridin~ (8 ml) and D~AP (15 mg) w-r~ added and th~ mixture wa- cooled to 0C.
Trifluoroacetic anhydride (3 ml) was added ~lowly and th~ mixture wa~
tirred at room t~ ~tu ~ for 16 hour~. It was poured into $ce, neutralized with aturated sodium bi~nhon~te~ xtract~d with CH2C12 (3x100 ml), w ~9A with water (25 ml), dried and i~ o~at~d. Th~ solid r~sidue was ,~ r-~ twic~ from a mixture of hex-nQ and nth~r (4sl) yi~lAin7 pur- titled product (purity by NNR: >92~ yi-ld ~ 330 mg;
23.4~ in three t-p~).
NMR (CDCl35 ~)s 1.29 (3H, d, J - 6.8 Hz; -CH3), 2.52 (lH, dd, J - 11.3, 16.9 Hzt H-4), 2.69 (lH, dd, J ~ 2.2, 16.4 Hzs H'-4), 3.65 (lH, ddd, J =
3.2, 6.3, 11.2 Hzs H-3), 3.75, 3.78 (3H, s each, Ar-OCH3), 4.24 (lH, m;
-C~(NHCOCF3)CH3), 4.58 (lH, d, J ~ 15.8 HzS H-l), 4.97 (lH, d, J ~ 15.8 HZ5 H'-l), 6.62, 6.67 ~lH, d each, J ~ 8.9 ~z5 Ar-H).
8t-p 2s (18',18,3R)-3-~trif~ r hyl)-5,~ d (2',3',C'-tr~ 3',4'-d~h,d.~_~ L-l~
Co~rl i nq with sugar wa- done u-ing DDQ in CH2C12 following g~nsral ~.oc~du.c (~tep 1, 1 _le 14). Th~ product wa~ isolated a~
dia.L- ~~ - ic mixtur~ from crude r~action mixtur~ by column ch.~ ~ G~ a~l.y over ilica gel ~ rr~sA with .5% tri-thylamin~
(eluents~ thyl ac~tatc ~ 80s20) in 75~ yi~ld.
To a olution of th~ dia-t~ - ic mixture (100 mg) in CH3CN (6 ml) at 3~ 0C wa~ added 0.1 N NaOH (4 equiv.). The mixture wa- tirrQd at 0C
for .5 hour. Ic~ bath wa~ ~ . d and it wa~ stirr~d ~t room t - aLu. ~ for 1 . 5hr . The mixture wa~ diluted with water ( 10 ml ), extracted with CH2C12 (3xlO0 ml), w h--A with water (20 ml), dried and G.--Led. The crud- product wa- chromatoy.~l;ed over ilica gel SIJBSTI~UTE SHEET
W O 94/11382 PC~r/CA93/00463 2 ~ 4 a (p~a~J~aho~ with .2% trL~thylamine) ~lusnt: 50%, 60%, 70%, 80% ~tOAc in hexan~ and finally by pur~ LtOAc) yi~lding pure title -~ s~nd (yield =
25 mg; 29.4~), and 1,3~ (37 mg; 80~ pure; 34.5~).
NMR (AcQtone-d6t~) of the titl- = _ : 1.28, 1.35 (3H,d ach, J ~ 6.5 S Hz; CH3 of thQ side chain and CH3 of th~ ugar), 1.58 (lH, dd, J - 5.1,12.6 Hz; H-2 of the ugar), 1.91 (lH, dt~ J ~ 3.8, 12.3 Hz7 H-2 of th~ sugar), 2.41 (lH, dd, J ~ 11.6, 17.4 Hz, H-4), 2.79 (lH, dd, J -3.4, 17.6 Hz; H~-4), 3.42 (lH, d, J ~ 4.4, sugar-H), 3.55 (lH, br ~ignal; H-4 of tha ~ugar), 3.64 (lH, d, J ~ 6.7 Hzs ugar-H), 3.77, 3.78 (3H, n, ~ach, Ar-OCH3), 4.16-4.29 (2H, m, -C~(NHTFA)CH3 nd sugar-H), 4.36 (lH, q, J - 6.5 Hz; H-5 of ~ugar), 5.36 (lH, d, J ~ 3.3 Hz; H-l of the ~ugar), 6.04 (lH, s, H-l), 6.79, 6.88 (lH, d each, J - 8.9Hz; Ar-H), 8.50 (lH, br d, J - 7.0; N_TFA).
NMR of 1~3-~is~i - (~ton--d6; ~): 1.21 (3H, d, J ~ 6.5 Hz; CH3), 1.36 (3H, d, J - 6.3 H~; CH3), 2.37 (lH, dd, J - 6.1, 11.3 Hz; H-4), 2.80 (lH, dd, J ~ 3.3, 17.3 Hz; H'-4), 3.45 (lH, d, J - 4.8 Hz; ~ugar-H), 3.S3 (lH, br signal5 ugar-H), 3.66 (lH, d, J - 6.9 Hz; ugar-H), 3.78, 3.81 (3H, acht Ar-OCH3), 4.08 (lH, g, J ~ 6.7 Hzs H-5 of the ugar), 4.16-4.29 (2H, m; C~(NHTFA)CH3 and zugar-H), 5.36 (lH, br inglet, H-l of ugar)~ 5.85 (lH, ~ H-l), 6.78-6.89 (2H, m; A-H), (Th~re w-re f~w ignalz duQ to th~ other dia-te_~ - which are not detail~d.).
~t--p 3s (1'8,18,3R)--3--(tr~ thrl)-S,10--dio~o--1--(2',3',6'-tr~ 3',4'-~,d.~ L-~
3,4,5,10-t--trahrdro-lH ~,~ ~o-t2,3-c]-prr~n (JCJ-2018) CAN ~Yi~-ti~ was done on dimetho~ u ~ following the general ~ - ' r~ (-t~p 3, - l- 12).
The crude ~i n~n~ wa3 r-acted with acetG~ hu~ aA i ~n9 in tolu~ne following the general ~,ocedu~e. Pure titled product wa~ obtained by column ch.. -~oJ-~hy over ~ilica gel (elu~nt: tolu~ne: EtOAc~70:30 and 60:40) followed by pr~paratiVQ TLC (~luent: CH2Cl2: MeOH~9:1) (5 mg;l9%
yield) as a light yQllow ~olid, mp: 180-3C (dec.).
3S NMR (acQtone-d6;~): 1.34 (3H,d,J-6.4Hz;-CH3), 1.38 (3H,d,J~6.7Hz;-CH3), 1.60 (lH,dd,J~4.7,12.6Hz;H-2 of th~ ugar), 1.92 (lH,dd,J~3.7,12.2Hz;H-2 of th~ zugar), 2.47 (lH,dd,J~10.2~19.0Hz;H-4), 2.82 (lH,dd,J~2.9,19.0Hz;H'-4), 3.49 (lH,d,J-4.3Hzt-OH of th~ ~ugar), 3.59 (lH,br.signal which became ~harp on D2O-~Ychange;H-4 of sug_r), 3.68 SUE3STITUT~ T
-WO 94/11382 PCr~CA93/00463 2 ~
(lH,d,J~6.7Hz;-OH of th~ sugar), 3.82 (lH,m;H-3), 4.19 - 4.30 (2H,m,ov2rl~pp;ng-C~CH3(NHTFA) ~nd ug~r-proton), 4.42 (lH,q,J=6.5Hz,H-5 of the sugar), 5 36 (lH,d,J~3.5Hz,H-1 of the ~ugar), 6.0 (lH,-,H-l), 7.86-7.90 (2H,m;Ar-H), 8.05-8.10 (2H,m;Ar-H), 8.56 (lH,br. ~gnal~-S N~TFA). ~St~ try of NHTFA io not y~t det~
_lc ~3s Pr-p~sat~on of (1'~,1~,38)-3 - ~c 5,10-dioso-1-(2-d os~-2-chlc.-~thrln~L,~
3,4,S,10-t-tr-hrdro-111 ~ - t2,3-cl prr~n (BCII-2038) OM. O O~c OM- O
¢~ ~T~,2r~-,rl OMc Ohlc O
HN~O~
0~ O~c ~r~
O O OMc O
~3 o=~Ph o=~Ph ~HrP~
0 ~H
NO)C~2CH2CI
8t--p ls (l'R, lR, 38)--3--~c--to--S,~ 1(2 d- ~ 2--chloro-thylur-ido-3, ~, 6-tri--c-trl ~ ,1 c ~ o o ) S ~ T
WO 94/11382 PCI`/CA93/00463 ~ 2 1 4 ~ J
2-Deoxy-2-chloroethylureido-3,4,6-triacetyl-D-glucopyranose was prepared following known ~oc~d~rQ (Ref: T.P. Johnston, G.S. ~rC-l?b and J.A.
~nntg - y~ J. Med Ch~m. ~ 104 (1975)). Thi~ wa~ couplnd with 3--c~to-5,8-dimethoxy-j~o~ ~ -n u-ing DDQ following th~ general ~.oc~d~r~ outl$ned before (-tep 1, r ~ le 14). Purifie~tion was done - by column cl.~c -tG~ hy over sLlica gel (eluents~ tOAc ~ 7:3) yiel~ing the title - _ ~ (29.4~) and 1,3-~ - (31~).
NMR (aceton~-d6S ~) of the title _ ~: 1.91, 1.95, 2.00 (3H, s ach; acetyl group-) 2.32 (3H, , k to-methyl), 2.50 (lH, dd, J ~ 12.3, 17.6 Hz5 H-4), 3.01 (lH, dd, J ~ 4.0, 17.6 Hzs H'-4), 3.49 (2H, m; -NH-CH2- group), 3.63 (2H, t, J - 6.2 Hz~ -CH2-Cl group); 3.83, 3.88 (3H, each5 Ar-OCH3), 4.14 (4H, m; H-5, H-2, H-6 and H-6 of th- ugar overlapFin~), 4.60 (lH, dd, J - 4.1, 12.2 Hzs H-3), 5.08 (pair of double-~-hl~- overlAppin~; H-3 and H-4 of the ugar), 5.46 (lH, d, J
lS 3.5 Hz; H-l of th- ugar), 5.49 (lH, broad s; -NH-CO-), 6.02 (lH, ; H-1), 6.15 (lH, br ignal; CON~-CH2), 6.87, 6.96 (lH, d each, J - 9.0 Hz;
Ar-H).
NMR (ac~tone-d6t ~) of the 1,3-~pi - : 1.92, 2.00, 2.06 (3H, ~ each;
ac0t~te 9.. ~), 2.28 t3H, S k to-methyl), 2.48 (lH, dd, J - 12.0, 17.8 Hz; H-4), 2.91 (lH, dd, J - 4.2, 11.7 H~s H'-4), 3.26-3.51 (2 multipl-t-, lH ach; -HN-CH2-), 3.56 (2H, t, J ~ 6.2 Hzs -CH2Cl), 3.84 (6H, s; Ar-OCH3), 4.14-4.23 (2H, ms sugar-H), 4.34 (lH, dd, J - 4.7;
12.1 Hz; ugar-H), 4.62 (2H, dd, another proton ov-rl~ ; J - 4.3, 12 Hz; H-3), 5.05-5.18 (2H, m; H-3 and H-4 of sugar), 5.51 (lH, d, J ~ 3.7 Hz; H-l of the ugar), 5.81 (lH, d, J - 9.6 Hz; -NH-CO), 5.98 (lH, ~r, triplet; -N~-CH2), 6.16 (lH, ~; H-l), 6.91, 6.99 (lH, d ach, J - 9.0 Hz; Ar-H).
~t-p ~s (l'R, lR, 3S)-3 ~ ~o 5,8 .; ~ 2-chloro-thy~ ~-4,~ D-g~ -~r~
,~ _ To a cold solution of triacetyl derivative (120 mg; .19 mmol) in CH3CN
wa- add~d .1 N NaOH (8.6 ml; 4.6 eg.). The mixture wa- stirred at 0C
3S until TLC .~ ed c~ e reaction. It was carQfully neutrAli-ed with .1 N HCl to pH -8 and xtracted with ethyl acetat~ (3x100 ml), wi~
with 2.5% NaHCO3-NaCl-~olution (1:1) (10 ml), dried and 2~ ,~Led. To a solution of the crude product in DMF (5 ml), hen~ h~de dimethyl acetal ~30 ~1; 1.2 eq.) and p-TSA (10 mg; catalytic) was added. The 51 1 ~ E~T
W O 94/11382 P ~ /CA93/00463 214~S~8 ~
rnaction flask wa~ connected to w~ter a~pLrator and held at 50C for 15 minute~. So~i bicarbonate ~olution (2.5~; 10 ml) wa~ added and the mixture was extracted with CH2C12 (3x50 ml), wa~hed with saturated NaCl ~olution, dr$cd and evaporat~d. The crude product was ~- ~h~ with A
S mixture of hexane and ether, yislding pure titlad b-nzylidQne derivative (77 mg; 68~).
NMR (a~eton~-d6; ~): 2.33 (3H, ~, k~to-mQthyl), 2.50 (lH, dd, J - 12.2, 17.6 Hz; H-4), 2.99 (lH, dd, J ~ 4.1, 17.6 Hz; H'-4), 3.49 (2H, t, J =
5-8 Hzs -CH2-Cl), 3.63 (2H, m, -NH-CH2-), 3.82, 3.91 (3H, 8, Ar-OCH3), 4.19 (lH, dd, J ~ 4.5, 9.6 Hz; zugar-~), 4.62 (lH, dd, J - 4.1, 12.2 Hz;
H-3), 5.46 (lH, d, J ~ 3.8 Hz; H-l of the zugar)~ 5.62 (lH, ~, -CH Ph), 5.68 (lH, d, J 8 8.5 Hz; -NH-), 6.00 (lH, 8, H-l), 6.18 (lH, br ~, -N~
CH2-), 6.87, 6.95 (lH, d ~ach, J ~ 8.9 Hz; Ar-H), 7.34 (3H, m; Ar-H), 7.46 (2H, mt Ar-H).
St-p 3 (l'R, lR, 3~)-3 ~ o 5,10-dio~o-1-(2 d-- ~ 2-chlG.. ~yl~s-$do-4,6-b-~zr~ - D-gl.~ )-3,~,5,10-t--trahrdro-lH ~ 2,3-CI pyrau To a olution of b~nzyliden~ derivative (77 mg; .127 mmol) in acetonitrile (6 ml) wa- added a olution of ceric ~ -ri nitrate (146 mq; .266 mmol) in water (2.5 ml) at room t~ - ~Lure. The mixture wa~
stirred for 5 minut~, diluted with water (10 ml), oxtracted with CH2C12 (3x75ml), w ~- with water (15 ml), dried, c~o~aLed. The crude product (60 mg) wa~ ~ - for 2 hour~ before going to the next ~tep.
The crud~ product wa~ taken up Ln dry toluene ~3 ml) and acstoxy-bu~r~i - (1.2 ml) wa~ added. Th~ mixture was ~tirred at room t~ - ~Lure for 16 hour~. The ~olution waw not quita } -, ~ and TLC ~howed ~OmQ ~tarting mat-rial. AcQtGA~ bu~ A~ ( . 5 ml) was further _dded and ~tirred for 20 hour~. The mixture wa~ diluted with toluene (10 ml). Silica gel (500 mg) wa~ added and air wa- bubbled through th~ mixture for 1 hour. Th~ crude reaction mixture wa~ pa~ed through a column of ~ilica gel (eluent:toluene:EtOAc ~ 7:3 and CH2C12s~eOH ~ 9:1). Fraction contAinjng the product wa~ further purified by proparative TLC (eluentsEtOAc) yielAin~ 12 mg of pure titled product (15%) (poor yield hec~ e of Deparation problem).
NMR (acQtonQ-d6; ~)s 2.35 (3H, ~S kQto-methyl), 2.58 (lH, dd, J = 11.4, 19.7 Hz; H-4), 3.01 (lH, dd, J ~ 3.9, 19.6 Hz; H'-4) 3.55, 3.67 (m ~ach, HN CH2-CH2Cl), 4.22 (lH, dd, J 8 4.6, 9.7 Hz; ~ugar-H), 4.65 (lH, d, J s S~ r ~ T
WO 94/11382 PCI`JCA93/00463 ~ 2146S~8 3.9 Hz; -OH), 4.73 (lH, dd, J - 4.0, 11.4 Hz; H-3), 5.52 (lH, d, J = 3.8 Hz; H-1 of the ~ugar), 5.63 (2H, ~r n; C~-Ph and -NH-CO), 5.94 (lH, t, J
~ 5.7 Hz; -N~-CH2), 6.04 (lH, ~; H-1), 7.33 (3H, m, Ar-H), 7.46 (3H, m;
Ar-H), 7.91 (2H, m, Ar-H), 8.14 (2H, m; Ar-H).
S
8t-p 4s (l'R, lR, 38)-3-ac-to-S~10-dioxo-1-(2 d-~ ~ 2-chloro-thyl-nit..~ - D _l~c~ )-3,4,5,10-t-tr hydro-1~-~ 2,3-C] prs ~
To a ~olution of ben2ylid-ne derivativQ (6 mg; .01 mmol) in 96% formic acid (1 ml) at 5C wa- added NaNO2 (10 mg) in two portion~. The reaction was ~ o in 2 minut-~. It was dilutod with water (5 ml), extracted with CH2C12 (3x25 ml), wr ~he~ with water (10 ml; 15 ml), dried ov-r Na2S04 and .~o~L-d. The crude product (4.5 mg) wa- pa--ed lS through a ~mall column of ilica gel (-lu~nt:BtOAc and 10~ methanol in CH2C12) yi~ n~ pur- t$tl~d product (yield ~ .9 mg; 17~) (HPLC:92%) NMR (acetone-d6; ~): 2.35 (3H, s, keto-methyl), 2.51 (lH, dd, J ~ 12.9, 19.2 Hz; H-4), 2.98 (lH, dd, J ~ 4.1, 19.6 Hz; H'-4), 3.52-3.89 (two multiplet-; ome of th- ugar protons, and overlArpi ng A2B2 y-tem due to -HN(CH2)2Cl), 4.08 (H, dd, J ~ 3.5, 6.0 Hz; ugar-H), 4.26 (lH, dd, J
- 6.6, 11.3 H~s ugar-H), 4.43 (lH, dd, J - 4.7, 7.5 H2S ugar-H), 4.66 (lH, dd, J ~ 4.0, 11.5 Hz; H-3), 5.66 (lH, d, J ~ 3.6s H-l of the ugar), 5.99 (lH, , H-l), 7.59 (lH, d, J ~ 8.6 Hz; NH-OO), 7.88, 8.08 (two mult~pl-L~, Ar-H).
4s ~. _ ,Lion of 3 ~ 5,lO-dio~o-l-m ~ ~ S,10-d~hrdro-l~ ~p~t~- 12,3-cl pyran (BC~-2129) o o o o ~'1' ~
O 0~ 0 OMe s~top ls 3 ~ ~o S,lO-dio~o-l- ~ S,10-dihydro-1~ ~p~- (2,3-~ c)-prr~n (BCH-2129) To a ~olution of 3-acetyl-5,10-d$oxo-1-methoxy-3,4-5,10-tQtrahydro-lH-35 n~rhtho (2,3-c) pyran (50 mg, .175 mmole) in CH3CN (8 ml) and THF (4 ml) lSl SUE5 ~ t ~ ET
W O 94/11382 PC~r/CA93/00463 2 1 ~
at 0C wa~ added O.5N odium hydroxide (1 equiv.). Tho mixture was ~tirred at 0C for 15 minute~ and $t wa- allowed to come to room t ~_aL~a. After 1.5 hour at room temperature the mixture wa~
acid$f$ed with d$1. HCl to pH-6. Saturated NH4Cl (5 ml) wa~ added and S the mixture wa~ extracted with CH2C12 (3x50 ml), w~Dd wLth water (10 ml), dried and r~a~GLaLed. The crude t$tled product wa- ~ub~ected to preparat$ve TLC (elu-nt: toluene:~tOAc-96:4) and pure product wa~
$~olated a~ a l$ght y~llow ~ol$d, mp. 154-56C (3mg; 6~
NMR (aceton~-d6, ~): 2.50 (3H,~,ketom thyl), 3.63 (3H,~,-OCH3), 6.42 (lH,-,H-l), 7.11 (lH,-;H-4), 7.92 (2H,m;Ar-H), 8.14 (2H,~;Ar-H).
_ 1 t ~5: Pr parat$on of (lR,3S) ~nd (18,3R)-3--c-to-S,10 di~o-1 (4-chloro-th~ln$L~ A~ crclr- ~l-osr)-3,4,5,10-t-tr h~dro-l~ o [2,3-c] prr-n ~BCH-211~) ~ CO~
OMe ~CO~
o o o o \~iCON(NO)r~,r~2~ ~NHC01~,~
s~2ll4 8t-p 1: (lR,3S) ~nd (18,3R)-3 ' ~o 1 (~-chloro-thylur-ido-cro~ lox~)-5,~ ocL,_ 3-Acetyl i-~c' ~ -n wac co~pled to 4-chloroethyl urO$do-cycloh~YAnol (prQpared by known ~ocedu a, ref.: T.P. John~ton, G.S. ~Çal~h~ P.S.
Opliger, W.R. La-ter and J.A. Mont~ -_y~ J. Med ~h~., 1~, 600 (1971)) u~$ng DDQ ~ollow$ng the general P~OCGdU~a (ctep 1, _ le 14).
-nti~ - $c m$0ture of the t$tled productc wac $colated from the crude lS2 i L ~_ ~"f5 ~ S ~
W 0 94/11382 214 ~ ; . PC~r/CA93/00463 react~on mixture by column ch ~ tGJ.a~hy over ~ilica gel (eluent: 50 and 80~ EtOAc in hexane) yield=lOOmg (52~).
NMR (acetone-d6;~): 1.26-1.48 (two multiplet~; CH2 ~o~ of cyclohexyl ring), 1.78-1.80 (multiplet,-CH2 of cyclohexyl ring), 2.27 (3H, ~, keto-S methyl), 2.4S (lH, dd, J c 12.1, 17.8 Hz; H-4), 2.90 (lB, dd, J ~ 4.2, - 17.7 Hz; H'-4), 3.42 ~2H, m; -HNC~2Cl), 3.59 ~2H, t, J ~ 6.0 Hz; -C~2-Cl), 3.78, 3.79 (3H, ach, Ar-OCH3), 3.86 (lH, mt H-1 of the cyclohexyl r~ng), 4.61 (lH, dd, J - 4.2, 12.0 Hz~ H-3), 5.51 ~lH, d, J ~ 7.4 Hz; -NH-Co-), 5.67 (lH, br ignal; -CON~CH2-), S.90 (lH, ~, H-1), 6.79, 6.87 (lH, d ach, J - 8.9 Hz; Ar-H).
8t-p 2s (lR,38) ~nd (18,3R)-3 ' ~o S,10-dio~o-1 (4-chloro-thylur-~do cy~ oxr)-3,4,5,10-t-trahrdro-lH-~ ~ ( 2 ~ 3--c )--prr~
lSCAN oY;~-t;n~ was performed on the dimethoxy-ioochroman from ~tep 1 herein (35 mg; .077 mmole) ollow~ng the gen~ral ~oc~ re ~step 2, exampla 14).
The crude product (32 mg) wa~ di-solved ~n dry toluene (3 ml) and ac~toxybut~ (0.5 ml) wa- added. The m~xture wa- t~rred at room t ~ Lure for 18 hour~. S~lica gel (500 mg) wa- added and air wa~
bubbled for .5 hour. The crude product waB pas~ed through a column of ~ilica gel (30% ~tOAc in tol ---, 50% ~tOAc in Tolu-n~, and CH2Cl2:
MeOH~l9:1 a~ ) y~ ng pur~ tricycl~c t~tled c~ ~ (15 mg;
2S yield 41%).
NMR (~ce~Qn--d6;~): 1.24-1.54 (6H, m, CH2 group of the cyclohexyl r$ng), 2.30 (3H, g, ~st~ hyl), 2.51 (lH, dd, J ~ 11.6, 19.5 Hz; H-4), 3.42 (2H, m; -NHC~2-CH2Cl), 3.60 (2H, t, J ~ 6.2 Hz7 -CH2Cl), 3.95 (lH, m, H-1 of the cycl-~ yl ring), 4.64 (lH, dd, J - 4.2, 11.5 Hzs H-3), 5.54 (lH, br d, J - 6.9 Hzt NHCO-), 5.69 (lH, br ~ignal; -CON~-CH2-), 5.92 (lH, ~; H-l), 7.86-7.91 (2H, mt Ar-H), 8.06-8.10 (2H, mt ArH).
8t-p 3: (lR,38) nd (18,3R)-3 - ~L~ S,10-dio~o-1 (4-chloro-thrlnit.. ~ do crr~ l-o~r) -3, 4, 5 ,10-3S t-trahrdro-lP 1~' '- (2,3-c)-prr n (BC~-~114) To a ~olution of chloroethyl ureido de $vative from ~tep 2 herein (14 mg, .03 mmole) in formic acid (1.2 ml) at 5C waff added ~ nitrite (20 mg) in two portion~. Reaction wa~ complete in 3 minute~. It wa~
lS3 SUB~
W O 94/11382 P ~ /CA93/00463 2146~48 o diluted with w~ter (10 ml), xtr-cted wlth CH2C12 (3x50 ml), w~h~d with water (2xlO ml), dried and ~.~oL~ted. ~he crude product wa~ purified by pas~ing through a ~mall column of sLlica gel (elu~nt: 1% methanol in CH2C12) and finally by ~ ~hi ng with hexane-ether mixture yielding pure titl~d n~t o~o de~ivative, mp~58-63C ~yi-ld~5 mg;34%).
NMR (ac~tone-d6;~): 1.48-1.80 (6H,m;CH2 of the cyclohexyl group), 2.32 (3H,~ Lhyl), 2.52 (lH,dd,J-11.6, 19.6Hs~sH-4), 2.93 (lH,dd,J=4.3,19.7Hz;H'-4), 3.60 (2H,t,J-6.5H~t-CH2-Cl), 3.76-4.05 (m,H-1 and H-4 of th~ cyclc yl group), 4.16 (2H,t,J~6.6H~-N(No)c~2-)~ 4.66 (lH,dd,J~4.3,11.4H~SH-3), 5.97 (l~,~,H-1), 7.77 (lK,br.d, J~7.8Hz5-NHC0-), 7.87-7.90 (2H,mtAr-H), 8.07-8.11 (2H,m;Ar-H).
_1, 46s U~ng th~ c-rbosy~ic c~d a~ d-~crLb-d ~n -16, 1 ~ ~ 5,10 ~ o-3,4,5,10-t-tr-hydro-lH-~ 2,3-c~ 3-c~ w-r- pr-p-r-d o o o o OOCH, O OCH~
Slep: 1, 8CH-204 R~C6H~
2, R~ ,~ul~ BC~2166 3, R--CUl~r-~2~N
4,R~ 2rU2~u~ 1~21~7 8t-p ls 1 ~ ~ 3-~ ~ yl~ 1-S,10-dioxo-5,10-dihydro-lH-~ 2,3-c]-pyran (~C~-2044) U~ing a ~m~lar ~ ac de~cribed in ~tep 7, example 16, the carboxylic acid from ~t~p 6, - - _le 16, wa~ co..v~Led to thc titled dec. 140C; m.p. 200C.
SU~ 5~ ~T
0 94/11382 214 ~ ~4 3 P ~ /CA93/00463 1H NMR (CDC13, 250 MH~, Bruker): ~, 3.68 (3H, ~, OCH3), 6.48 (lH, ~
CH), 7.18 (lH, tr, J ~ 7.6 Hz, p-Ani-H), 7.49 (2H, tr, J - 8.0 Hz, m-Ani-H), 7.50 (lH, B, 4-CH), 7.66 (2H, d, J - 7.8 Hz, O-Ani-H), 7.79 (2H, m, 7, 8-ArH), 8.15 (2H, m, 6, 9-ArH), 8.40 (lH, s, NHCO).
IR (Nicolet , 205 FT, film on NaCl plate): cm~1, 3322.9, 2929.3 2848.3, 1682.9, 1659.8, 1594.2, 1527.7, 1443.7, 1374.2, 1297.0, 1258.4, 1063.2, 947.6, 863.1, 719.7, 693.6.
8t-p 2s 1 ~ ~ 3-(3-N-prrro~ lpropr~ l)-S,10-dioso-s~lo-d~h~dro- m -~- ~~ [2,3-cl-prran (~C~-2166) 60 mq of the acid from step 6, example 16, wao diosolved in 6.8 ml of dry THF, cooled to 0C and 63 ~1 of oxalyl chloride was added. The m$xture was all~ to ~tir at 0C for 20 minutes, and thQn at room lS t~ ~ aLur~ for 20 minutes. The solvent was then ~GL~ted, the residuQ was re~ olved in ~;rhloromethane and ava~G.~Led, and then the residuc was again dissolved into dry THF. The ~olution was cooled to -10C. 29.3 ~1 of triethyl_mine and 19.90 ~1 of 1-~3 . ;~o~,op~1)-2-pyrrol~nrns was added and allowed to stir for 45 minutes at -10C and then 2 hour~ at room tomperature. Tha solvent was then Jv~G aLed to half of it- original volume, the ~ ~;n;ng olution wao ~ onto at.
brine and extractod into ~ichlsromethane. The organic layer was then w ~h9d with at. odium bicarbonate solution, dried over ~odium sulfate, and ~apG~Led to d.~ to give 24 mg of pur~ titlQd product.
2S NMR ~CDC13 250 MHz, Bruker): ~, 1.86 (2H, Quin, J ~ 6.6 Hz, C-CH2-C), 2.08 (2H, Quin, J ~ 7.5 Hz, 4' ~y~ CH2), 2.45 (2H, t, J ~ 7.5 Hz, 3'-pyrr-CH2), 3.15-3.34 (2H, m, C~u~2), 3.36-3.55 (4H, m, CH2-pyrr, 5~-pyrr-CH2), 3.74 (3H, 8, -OCH3), 6.43 (8, lH, 4-CH), 7.32 (s, lH, 1-CH), 7.70-7.78 (2H, m, 6, 9-ArH), 8.08-8.16 (3H, m, 7, 8-ArH, NH).
IR (N;rolet, 205 FT, film on NaCl plate): cm~l, 3320.9, 2936.7, 2871.3, 1679.9, 1658.1, 1597.0, 1527.2, 1335.2, 1291.5, 1278.4, 1082.1, 947.98, 857.41, 801.34, 723.70.
8tep 3: (3-N~ olrlpropyl)-l L~ ~ 5,10-dioxo-5,10-dihydro-lH-3S ~p~t~- 12,3-~] ~-~ 3-c~
To a stirred solution of acod from tep 6, example 16, ~0.185 mmol, S3 mg) and catalytic amounts of DMF in 6 ml of THF at 0C was added oxalyl chloride ~0.426 mmol). After stirring at 0C for one hour, and at room ISS
SUBSTITUTE SHEET
W O 94/11382 PC~rJCA93/00463 2i46~
t~mperature for a further 20 minutes, the solvent wa~ ~aporated to drynes~. 6 ml of THF wa~ then added, and the mixture divided Lnto two.
3 ml of ~olution was then cooled to -10C, and 1-(3-ammino~r~p~l)-~ iAa-Qle (8.39 ~l, 0.20 mmol) di~olved in 1 ml of THF was add~d S dropwi-e. Th~ mixtur~ wau a~ to tir for on~ hour at which time it - was poured onto ~at. ~odium b~ca~hon-t~ ~olution, xtracted into methyl~ne chloride, ~- h~ with brine, dri~d over ~odium sulfat~ and the ~olv~nt _v~G aL~d. Purifi rat~ rn on TLC u~ing 8% m~thanol/chloroform y-tem produced 6 mq of pure titl~d product.
lH N~R (aceton~ -d6, 250 M~z, Bruker), ~: 2.10 (m, 2H, CH2-~ Ql)~
3.42 (m, 2H, C-CH2-C), 3.60 (s, 3H, OCH3), 4.14 (t, 2H, CH2NCO, 6.34 (~, lH, 4-CH), 6.96 (~ lH, 4-CH (i ;~--ol)), 7.16 (~, lH, l-CH), 7.18 (~, lH, 5-CH (i ~ ol)), 7.70 (s, lH, 2-CH (; ~a~ol)), 7.90 (m, 2H, 6, 9-ArH), 8.12 (m, 2H, 7, 8-ArH), 8.29 (m, lH, NH).
IR ~Nicolet 205 FT, film on NaCl plate), cm~l: 3313.5, 2932.1, 2853.4, 1676.1, 1665.4, 1593.2, 1552.8, 1334.1, 1274.0, 1087.5, 950.72, 859.52, 718.64.
8t-p 45 (3-N k~d.~chlor~ ~A-r~lrlpropyl)-l-m-~ l 5,10-d$o~o-S,10-d~hr~ro - 1~ t2,3-cl p~,,~ 3-~- '~ ~f-- (BC8-21S7) 6 mg of product from tQp 3 ~ -i n was di-~olved in 2 ml of sth~r. To this wa~ added 6 ~l of lM HCl/-ther solution (from Aldrich). Th~
mixtur~ wa~ tirr~d, and th~n th- ~olv~nt ~GLaLed to givs 6.7 mg of th~ HCl salt.
H NMR (~reton--d6, 250 MHz, Bruker) for salt, ~: 2.29 (m, 2H, CH2-~ ol), 3.53 (m, 2H, C-CH2-C), 3.62 (8, 3H, OCH3), 4.50 (m, 2H, CH2NHCO), 6.33 (~, lH, 4-CH), ?.14 (~ lH, l-CH), 7.55 (s, lH, 5 CH($mi)), 7.76 (~, lH, 4-CH(imi)), 7.88 (m, 2H, 7, 8-ArH), 8.05 (m, 2H, 6, 9-ArH), 8.64 (m, lH, NH), 9.285 (s, lH, 2-CH(imi)).
IR (NirolQt 205 FT, film on NaCl plate) cm~l: 3345.8, 1676.5, 1652.2, 1527.0, 1280.4, 1090.9, 955.01.
~ 7: ~.~ ~tion of 3~ rl~ l-1,3,4,5,10-~ t-k~ 5,10 '~f ~ [2,3-cl prr~n (BCH-2003) ~nd 3-(S'-tosrl~ olrl)-1,3,~,5,10 ~ 5,10-A~ ~ - t2~3--cl--prr~ 1 (BCII--2155) lS6 SUBSrlTUTE SH~ET
WO 94/11382 2 14 6~4 8 PCI`/CA93/00463 oc~, o oc~, o o o ~0 ~op2 ~
OCHl OCH~ O
p3 r O O
~
OCH3 1~1 0 1~¦ BC~2003 CH~ CH~
l~p6 O O~N
~, 01 BCH~21~5 CH~
8t-p ls 3--thyl~h~ 1-5,8 'i ~hos~
S 5,8~ h~y-3-carboxyi-ochroman (300 mg, 1.26 mmol) in THF (6 ml) was stirred with l,l'-carbonyl~ Ql~ (225 mg, 1.386 mmol) at room t~ ~ aLu.G for 30 minut-~. More THF (6 ml) wa~ addad to d~lute the f~_ ing ~un~ -ion. After one hour, ethanethiol (103 ~1, 1.40 mmol) wa~
added and the mixtur- wa- tirred for 18 hours at room t _- ~t~re.
Solvent was ~ G,,Led and the crude t$tled product was chr~ -~GJ ~hed (hex:EtoAc ~ 4sl) to giv~ desired product as a solid (200 mg, m.p. 99.2 C) .
lH NMR (CDC13, 250 MHz, 8ruker)s ~, 1.28 (3H, tr, J Y 7.6 Hz, CH3), 2.68 (lH, dd, J ~ 17.6 Hz, 11.2 Hz, 4-HCH,), 2.92 (lH, qua, J ~ 7.6 Hz, lS -CH2-), 3.12 (lH, dd, J ~ 11.2 Hz, 3.5 Hz, 4-HCHe), 3.76 (3H, Q~ OCH3), 3.78 (3H, s, OCH3), 4.24 (lH, dd, J ~ 11.2 Hz, 3.0 Hz, 3-CH), 4.70 (lH, d, J ~ 15.3 Hz, l-HCH~), S.06 (lH, d, J ~ 15.3 Hz, l-HCH~), 6.64 (lH, d, J ~ 8.0 Hz, ArH), 6.67 (lH, d, J - 8.0 Hz, ArH).
IR (Nicolet , 205 FT, film on NaCl plate)s cm 1, 2936.2 2836.2, 1679.2 20 1604.8 ~ 1486.8, 1461.8, 1258.5 ,1094.3, 1078.9, 1022.5, 796.81, 714.69.
gt - p 2s 3 - thylt~ 1 - 5~8 ~ - 1~3~4~S~8 ~ ~ ~ - t2~3 -C 1 -pyran SUBS~Ig UTE SHEET
W O 94~11382 P ~ /CA93/00463 21q~ 48 The r n~ from ~tep 1 here~n (100 mg, 0.35 mmol) wa~ di-solved ln aceton~trLl~ ~6 ml), then cooled to 0C. So~i bir~bo~te (58.8 mg, 0.7 mmol) was added. ~his wa~ followed by add~tLon of a solution of S - i cerium nitrat~ (583 mg, .0063 mmol) in 2 ml of w~ter. The r~action mixture wa~ allowed ~tirred for S minute- at 0C. TLC ~howed - _l~ti nn of ths reaction. It wa~ poured to water and xtractsd with methyl-ne chloride. The organic layer wa~ dr$ed over Na25O4 and .v~o ~Led to givQ a crude tltl~d product (83 mg).
lH NMR (CDC13, 250 MHz, Bruk r)s ~, 1.24 (3H, tr, J ~ 7.6 Hz, CH3), 2.51 (lH, dd tr, J - 17.6 Hz, 9.2 Hz, 3 Hz, 4-HCH,), 2.85 (lH, d, J ~
17.6 Hz, 4-HCH~), 2.88 (lH, qua, J ~ 7.6 Hz, -CH2-), 4.18 (lH, dd, J -9.2 Hz, 3 Hz, 3-CH), 4.47 (lH, d tr, J ~ 17.5 Hz, 3 Hz, l-HCHa), 4.81 (lH, br d, J ~ 17.6 Hz, l-HCHe), 6.71 (lH, d, J ~ 9.7 Hz, Quin-H), 6.76 (lH, d, J ~ 9.7 H, Quln-H).
lR (Nicol~t , 205 FT, film on NaCl plate): cm~l, 2972.6, 2929.5, 2882.4, 1678.5, 1655.5, 1599.3, 1418.9,. 1313.1, 1147.5, 1125.6, 993.09, 827.00, 766.77, 729.32, 667.58, 629.13.
8t.p 3: 3-- thrlt~ i o~ - S ~ 8-dioxo-1,3,4,5,10 ~ ~k~O ~r~
[2,3-~]-p~ra~ (BC~-2003) Ths __ - from tep 2 h~rein (42 mg, 0.167 mmol) in tolu~n~ (6 ml) was st~rr~d with l-acetoxy-1,3-but~j ~ (119 ~1, 1.0 mmol) at 60C for 2~ 22 hours. Solvent wa~ ~G~ated and the crude product wa~
ch~ ~phed (tolu-n~/~tOAc ~ 100/15) to give de~ired titled product (41 mg) a~ a zolld (m.p. 95.4-96.5C).
lH NNR (CDCl3, 250 MHz, Bruker): ~, 1.26 (3H, tr, J - 7.6 Hz, CH3), 2.65 (lH, dd tr, J - 19.4 Hz, 9.4 Hz, 3 Hz, 4-HCHa), 2.91 (2H, qua, J
7.6 Hz, CH2), 3.04 (lH, d tr, J ~ 19.4 Hz, 3 Hz, 4-HCHe), 4.25 (lH, dd, J ~ 9.4 Hz, 3 Hz, 3-CH), 4.61 (lH, d tr, J ~ 18.2 Hz, 3 Hz, l-HCHa), 4.97 (lH, dd, J - 18.2 Hz, 1.8 Hz, l-HCHe), 7.71 (2H, m, 7, 8-ArH), 8.04 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm~1, 2969.3, 2931.3, 3S 2874.3, 1680.8, 1661.8, 1641.4, 1594.2, 1334.2, 1296.4, 1175.1, 1108.9, 1027.0, 874.2, 787.5, 694.6.
8t-p ~: 3-(5~-to~yl~ Qlrl)-S,8-~ y i~Gch~ -~
SU~S ~ e f ~T~ S~;EET
W O 94/11382 PC~r/CA93/00463 21~6~8 To 5,8-dimethoxy-3-carboxyi~ochroman (211 mg, 0.887 mmol) dis~olved in THF ~2.0 ml) cooled to 0C was added oxalyl chloride (86.09 ~1, 0.975 mmol). The mixture was ~tirred for 20 minutes then at room t~, ?' a~ure for 20 minutes. The r~action mixture wa~ --va~o~ated to dryne~s to give desir~d acid chloride. It was r ~i~oolved in THF (4 ml) and cooled to -78C. A ~olution of tosylmethyl i~G~y i ~ anion (made from th2 treatment of tosylmethyl i-_~y ~e, 180 mg, 0.92 mmol, by n-butyll~thium, 1.6 M in h~xane, 0.61 ml, 0.975 mmol at -78C for 10 minute~) was added to the abovs cold acid chloride solution. The reaction mixture was tirr~d for 24 hours a- it w -~ to room t= -~ure. Th~n, it wa~ poured to NH4Cl (-at.) and xtracted with methylRne chloride. The organic layer wa~ dri~d (over Na2SO4) and evaporated to give a crude product which was chromatGgcaphed to give the desired titled product a~ a white ~olid 115 mg, m.p. 138-140C.
lS lH NMR (CDC13, 250 MHz, Bruk-r)s ~, 2.41 (3H, s, to~y-CH3), 2.99 (2H, d, J ~ 7.4 Hz, 4-CH2), 3.76 (6H, 8, 2xCH3), 4.85 (lH, d, J ~ 17.5 Hz, 1-HCHa), 4.03 (lH, d, J ~ 17.5 Hz, l-HeCH), 5.54 (lH, tr, J ~ 7.4 Hz, 3-CH), 6.67 (2H, br , 6, 7-ArH), 7.33 (2H, d, J ~ 8.2 Hz, 3', 5', to-yl-H), 7.82 (lH, s, oxa-H), 7.92 (2H, J z 8.2 Hz, 2, 6-tosyl-H).
20 IR (Nicolet 205 FT, film on NaCl plat~): cm~l, 3134.2, 2951.5, 2837.5, 1595.5, 1511.7, 1485.6, 1463.6, 1437.5, 1331.7, 1261.6, 1194.3, 1149.0, 1089.9, 1072.0, 809.60, 798.61.
8t-p Ss 3-(S'-t4~ 1)-5,8 i~-o 1,3,~,5,8 ~ k~d~r -~
2S ~2,3-c~-prr n The ; _ ~ from tep 4 ~-~ in (10 mg, 0.024 mmol) wa~ di--olved in acetonitrLle (2 ml) and cooled to 0C. A solution of ~ - i cerium nitrate (39.5 mg, 0.072 m~ol) in 0.5 ml of water wa~ added dropwi~e.
The reaction mixture wa~ tirred at 0C for 5 minut~s, then poured to water and extract-d with ~i rhl oromethane. The organic layer was w ~d with brine, dried ~nd v.~o ~Led to giva tha titled ~ ~_ as a white solid (9 mg, dec. 150Ct m.p. 177C).
lH NMR (CDC13, 250 MHz, Bruker): ~, 2.42 (3H, s, tosyl-CH3), 2.82 ~2H, 3S m, 4-CH2), 4.65 (lH, d tr, J = 17.6 Hz, 4.1 Hz, 1-HCHa), 4.82 (lH, d tr, J - 17.6 Hz, 1.8 Hz, l-HCHe), 5.52 (lH, tr, J - 7.0 Hz, 3-CH), 6.75 (lH, d, J ~ 9.1 Hz, guin-H), 6.81 (lH, d, J - 9.1 Hz, quin-H), 7.35 (2H, d, J
8.2 Hz, 3', 5'-toayl-H), 7.83 (lH, ~, oxa-H), 7.90 (2H, d, J ~ 8.2 Hz, 2', 6'-tosyl-H).
lS9 SUBSTITUTE SHEET
W O 94/11382 PC~r/cA93/00463 2~&~
~t-p 6t 3-(5'-tosrlr--~olrl)-5,10 i~-o-1,3,4,5,10-p utahydro-~p~ ~~ [2,3-cl-pyr n (BC~-2155) A ~olution of tosyloxa~olyl pyranoquinone from step 5 her~in in 4 ml oftolu~ne and 0.5 ml of t-trahydrofuran (9 mg, 0.023 mmol) wa~ t0~ w$th l-acetoxy 1,3-but~ (55 ~1, 0.47 mmol) at 50C for 20 hours.
Solvent wa~ a~apG~ ed to d.~ -e~ and the crudQ product wa- purified by means of cl,~ - oJ a~hy (Tol:FtOAc~100sl5) to g~v- d~Lred titl~d product a~ a light color~d olid (6.6 mg obtain~d).
M.P. >240C.
1H NMR (CDC13, 250 MHz, Bruker): ~, 2.43 (3H, s, ArCH3), 2.99 (2H, m, 4-CH2), 4.78 (lH, d tr, J ~ 18.8 Hz, 3.3 Hz, l-HCH~), 4.96 (lH, d, J -18.8 Hz, l-HCHQ), 5.57 (lH, dd, J ~ 8.9 Hz, S.0 Hz, 3-CH), 7.36 (2H, d, lS J - 8.2 Hz, 3', 5'-tosyl-H), 7.75 (2H, m, 7, 8-ArH), 7.85 (lH, s, oxa-H), 7.92 (2H, d, J ~ 8.2 Hz, 2', 6'-tozyl-H), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet 205 FT, film on NaCl plate): cm~l, 2955.7, 2921.3, 2854.0, 1662.8 (-tr), 1592.2, 1508.6, 1398.6, 1334.6, 1319.9, 1298. 5, 1147.6, 1106.6, 1086.9, 1013.0, 811.2, 794.8.
8s Pr-parat~on of (l'S,18,3R)-1-(3'-tr~fl 7~0~c-ta-$do-2',3',6'-tr~ lyxo-~ - ~}~ Q~ 3-t~ 1-3-m-th~1-3,4,5,10-t-tr~h~d,o S,10-d~oxo-~p~ ~ [2,3-cl ~yran (BC~-2076) SUBS~lTlJTe ~HE~T
WO 94/11382 PCI`/CA93/00463 2146~48 OCH3 `
3 ~OCH3 OCH3 0 ~
H3C~ H,~
PNBo NHIF~ PNBo NNIFA
O O O O
~H ~ K3 o o o o H,C--~ H,C~J
oHNHlFA Pt~Bo NH'IFA
~t-p ls (1'~, 18, 3~)~ p-~$L~ Qyl-3'-tr~ c~c-t~ ~o-2',3',6'-tr~ )-3 ~ ~ c~ 1-3-S m thrl-S,8-d~o~o-4,S,8-tr~h~dro-1~ 2,3-c]-prr~n (l'S,lS,3R) 1-(2',3',6'-tridQoxy-3-trifluoroacotamido-4'-O-p-niL~ royl-L-l~ r-~s 5,8-dim~thoxy-3-aceto-3-m~thyli~ch~oman ~62 mg, 0.0945 mmol) $n acotonLtrLle (3 ml) wa- tLrred ~t 0c whLl- a ~olut$on of ~ - i cer$um n$trat- (165.5 mg, 0.284 mmol) $n water (1.5 ml), ~. L~.-t-' w$th ~c'i bir~hQn-te (15.1 mg, 0.18 mmol), wa~ added dropwi-e. Th~ zolution waz ctirred for 5 minute~ at 0C then poured to water and extracted w$th ~ich loromQthane. The organic layer wa~ dried ~nd a~o~ed to give de~ired titled product (40 mg, 0.064 mmol).
lS lH NMR (CDC13 250 MHz, Bruker): ~, 1.27 (3H, d, J - 6.5 Hz, 6'-CH3), 1.57 (3H, B, 3-CCH3), 1.91 ~lH, dd, J ~ 11.8 Hz, 4.7 Hz, 2'-CH), 2.10 (lH, d tr, J ~ 11.8 Hz, 3.6 Hz, 2'-CH), 2.72 (lH, d, J - 17.9 Hz, 4-CH), 2.94 (lH, dd, J ~ 17.9 Hz, 0.9 Hz, 4-CH), 3.75 (3H, ~, OCH3), 4.54 (lH, m, 3'-CH), 4.64 (lH, qua, J - 6.5 Hz, 5'-CH), 5.40 (lH, ~, 4'-CH), 5.65 (lH, d, J ~ 2.4 Hz, l'-CH), 6.06 (lH, ~, l-CH), 6.52 (lH, d, J Y 8.2 Hz, NHCOCF3), 6.77 (lH, d, J ~ 10 Hz, Quin-H), 6.83 (lH, d, J ~ 10Hz, Qu$n-H), 8.27 (4H, m, PNB).
~U~ST~ S~ET
~1~6~48 IR (N~colct, 205 FT, film on N~Cl plat~): cm~l, 3336.1, 3083.4, 2956.1, 2849.7, 1734.5, 1664.2, lS29.4, 1352.7, 1272.9, 1162.7, 989.8, 949.9, 839.70, 721.95.
8t-p 2s (1'8, 18, 3R)-1-(4'-p-n~t,. -Q~1-3'-tr~fl~ t~uido-2',3',6'-tr~ -3-n~ 1-3- -~-th~1-5,10 'i~-~-4,S,10-tr~hydro-1~ '- [2,3-cl-prr~n The titl~d _ _ ~ w~- obt-in~d a~ p r ~.~c~ re d--cribed ~n zt~p 2, . - _l~ 5, but u~ing th~ ~-in~n~ from ~tep 1 h~rein.
lH NMR (CDC13 250 MHz, Bruk~r): ~, 1.32 (3H, d, J - 6.6 Hz, 6'-CH3), l.9S (lH, dd, J ~ 12.4 Hz, 5.0 Hz, 2'-CH), 2.10 (lH, d tr, J ~ 12.4 Hz, 3.5 Hz, 2'-CH), 2.88 (lH, d, J ~ 18.2 Hz, 4-CH), 3.13 (lH, dd, J ~ 18.2 Hz, 1.0 Hz, 4-CH), 3.75 (3H, 9, OCH3), 4.56 (lH, m, 3'-CH), 4.76 (lH, lS qua, J ~ 6.6 Hz, 5'-CH), 5.45 (lH, s, 4'-CH), 5.72 (lH, d, J ~ 2.0 Hz, l'-CH), 6.26 (lH, ~, l-CH), 6.45 (lH, d, J ~ 7.1 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH), 8.29 (4H, m, PNB). IR (Nicolet, 205 FT, film on NaCl pl-tc): cm 1, 3329.3, 2955.6, 2926.9, 2855.3, 1732.9, 1709.5, 1668.3, 1596.8, 1532.3, 1349.5, 1272.6, 1217.6, 1184.7, 1164.1, 996.5, 952.5, 729.90, 720.30.
8t-p 35 (1~8, 18, 3R)-1-(3'-tr~fl~o~ zu~do-2',3',6'-tr~ L-)-S,10-d~o~o-4,S,10-tr~h~dro-lH
t2~3-Cl-prran (~CJ-2076) The titl~d ~ w~z obtaincd from th~ gly_~aid~ from t~p 2 h~rein ~ia ba~e hydroly-i~ a~ per ~ OCL l~r~ d~3cribed in ~tep 3, . l~ 5.
lH NMR (CDCl3, 250 MHz, Brukcr): ~, 1.38 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.60 (3H, ~, 3-CCH3), 1.85 (lH, d, J ~ 6.8 Hz, 4'-OH), 1.85 (lH, dd, J =
9.4 Hz, 2.6 Hz, 2'-HCHa), 1.96 (lH, d, J - 9.4 Hz, 2'-HCHe), 2.87 (lH, d, J ~ 18.8 Hz, 4-HCH~), 3.12 (lH, dd, J ~ 18.8 Hz, 0.6 Hz, 4-HCHe), 3.63 (lH, br d, J ~ 6.8 Hz, 4'-CH), 3.75 (3H, ~, OCH3), 4.28 (lH, qua, J
~ 8.8 Hz, 3'-CH), 4.55 (lH, qua, J ~ 6.0 Hz, S'-CH), 5.54 (lH, ~, l'-CH), 6.21 ~lH, ~, l-CH), 6.71 (lH, br d, J ~ 9.4 Hz, ~n~3), 7.75 (2H, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH), IR (N$colet , 205 FT, film on NaCl plate): cm~l, 3420.1 (br ~tr), 2955.6, 1718.7, 1668.3, 1595.5, 1377.3, 1329.7, 1287.7, 1161.8, 982.68, 921.12, 730.64.
SUBSTITUTE SHEET
W O 94~11382 PCT~CA93/00463 2l4~qa i r 1 ~ ~ 9 ( 1~ 3--tr~z ) -n l i ~ ( l~t ~ - ~ S ~ 10--dioso--3 ~ ~ ~ 5 ~ 10-t-tr hrdro-l~ 2,3-~1-pyr n)-3-c~
(BC~-2041) and (1,3-c~ 5,10-dioxo-3,4, S, 10-t-trahrdro-1H ~phi h7_ l2,3-c]-prran)-3-S c---'o - i~~ (JCH-20~2) ~p~CO2M- ~H
O O~
~CO2H ~$CO2H
O O~ O O~
BCH~2045 BCH-2119 ~ ` ~
O O~ O O~
8t-p ls The c __ ' from tep 3, _le 16, ~21 mg, 0.0695 mmol) was dissolved in ~et~nitrile (10 ml) and then cooled to 0C. NaOH (0.1 N, 1.4 ml, 0.14 mmol) ~D~ut;on wa- then added ~lowly. After 10 minutes, the brown solution wa~ poured to water, extract~d with ethyl acetate. The aqueou6 layer wa~ acidifLed with dilute HCl and extracted with ethyl ace~tate.
The organic l-yer co~t~ning acid wa~ dried and _~pG-~Led to give a mixture of 3 product~ (18 mg). ~h.e -tGJ a~hy (CHC13/MeOH/HOAc =
100:15:2) llotJe~ ~paration of the 3 F _ _ '~. One of the products wa~ the ~ame~ a~ tha one~ obtaine~d in tep 6, ~ _le 16, and had:
lH NMR (CD3COCD3, 250 MHz, Bruker): ~, 3.58 (3H, ~, OCH3), 6.36 (lH, s, l-CH), 7.22 (lH, ~, 4-CH), 7.91 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
SUBSTITUTE SHEET
=
WO 94/11382 PCr/CA93/00463 21~6~
ThR ~ocond product (1,3-tran~)-1-mathoxy-3-carboxyl-5,10-dLoxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-cl-pyran, BCH-2045 had:
1H NMR (CD3SOCD3 250 ~Hz, Brukcr): ~, 2.55 (lH, dd, J ~ 18.5 Hz, 12.4 Hz, 4-HCHa), 2.88 (lH, dd, J - 18.S Hz, 3.5 Hz, 4-HCHe), 3.47 (3H, ~, OCH3), 4.49 (lH, dd, J - 12.4 Hz, 3.5 Hz, 3-CH~, 5.55 (lH, s, l-CH), 7.88 (2H, m, 7, 8-ArH), 8.00 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plat~): cm 1, 3549.2-3183.8, 2922.8, 1722.1, 1289.0, 1107.4, 1012.3, 9S1.08, 808.9, 793.5.
The third product: (1,3-ciD)-1 h~Yy-3-carboxyl-S,l0-dioxo-3,4,5,10-tetrahydro-lH-r~rhth~-~2,3-c]-pyran, (BCH-2119), hadt lH NMR (CD3SOCD3 250 ~Hz, Bruker)s ~, 1.28 (lH, dd, J - 15.3 Hz, 11.5 Hz, 4-HCHa), 2.58 (lH, dd, J ~ 11.5 Hz, 2.9 Hz, 4-HCHe), 3.4S (3H, ~, OCH3), 4.17 (lH, dd, J - ll.S Hz, 2.9 Hz, 3-CH), S.62 (lH, ~, 1-CH), 7.89 (4H, m, 6, 7, 8, 9-ArH).
gt-p 2s (1,3-tr n~)-l-~ tho~r-3-N ~ il~ylc~ l-S,10-d~o~o-3,4,S,10-t-trahydro-1~ t2,3-cl-pyran, ~C~-2041s A ~olution of acid from tep 1 h-rein (20 mg, 0.069 mmol) in THF (4 ml) was cool~d to 0C. To the olution w~ added DMF (1 ~ a cataly-t) and then oxalyl chloride (12 ~1, 0.138 mmol). The mLxtur- wa- tirred at 0C for 45 minut~ and at room t~ _- ~L~ for 20 minut-~. Solvent was L~pG a~ed. The residue was redi-~olved in methyl-ne chloride and th~n ~pG.&L-d. Tha r-~idue wa- di-~olved again Ln mnthyl-ne chloride (4 ml) and half of th~ volume wa~ taken for co--rl;nq wlth !ni 1 ;ne (4 ~1, 0.044 ol) a~ foll~ o the ice-cold zolution of th- acid chloride was add~d ~n~ 1 i ~ (1 eg. ) in 1 ml of methylene chloride. The reaction mixture wa~ ~t~rred for 10 minutos. It was poured to water and xtracted with m~thyl-n~ chloride. The organic layer wa~ dried and _~G~Led to give a crude product which wa~ purified by ~ tiQn from methylene chloride and hexane. The de~ired titled product wa~ obtain~d (11 mg) a~ a light yellow olid.
.P. 183-184C.
lH NMR (CDC13, 250 NHz, Bruker): ~, 2.63 (lH, dd, J ~ 19.4 Hz, 12.5 Hz, 3S 1-HCH~), 3.30 (lH, dd, J ~ 19.3 Hz, 4.2 Hz, l-HCHe), 3.67 (3H, ~, OCH3), 4.74 (lH, dd, J ~ 12.5 Hz, 4.5 Hz, 3-CH), 5.77 (lH, s, 1-CH), 7.16 (lH, tr, J ~ 8.5 Hz, 4'-Ani-H), 7.47 (2H, tr, J ~ 8.5 Hz, 3', 5'-Ani-H), 7.52 (2H, d, J ~ 8.5 Hz, 2', 6'-Ani-H), 7.75 ~2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.31 (lH, ~, NHCO).
SU~T; ~ . S~EET
W O 94/11382 21 4 6 ~4 g PC~r/CA93/00463 IR ~NJcolet , 205 FT, f$1m on NnCl pl~te): cm l, 3278.8, 2923.0, 1665.0, 1593.4, 1533.0, 1445.7, 1798.0, 1060.7, 960.0, 755.6, 688.2, 679Ø
S St-p 3s (1,3-c~ ~ thosr-3-~ ~ ~r~ ~^~rl - S~10 -dioso-3,~,5,10-t-tr~h~dro-1~ 2,3-ol-prr~n, JC~-2042, A ~imilar to the ~o~` r~ d~scribed pr~viou~ly in tep 2, the ci~ acid from ~tep 1 herein wa~ C06~_ Led to the titlcd product.
M.P. 217-219C.
lH NMR (CDCl3, 250 ~Hz, BrukQr): ~, 2.49 (lH, dd, J - 15.6 Hz, li.2 Hz, 4-HCHa), 3.08 (lH, dd, J ~ 15.6 Hz, 3.2 Hz, 4-HCHQ), 3.65 (3H, ~, OCH3), 4.50 (lH, dd, J ~ 11.2 Hz, 3.2 H, 3-CH), 5.94 (lH, 8~ l-CH), 7.14 (lH, tr, J - 7.6 Hz, p-Ani-H), 7.35 (2H, tr, J ~ 7.6 Hz, m-Ani-H), 7.56 (2H, d, J - 7.6 Hz, O-An~-H), 7.78 (2H, m, 7, 8-ArH), 8.00 (28, m, 6, 9-ArH), 8.21 (lH, ~, NHCO).
IR (Nioolet , 205 FT, film on NaCl plate): cm~l, 3353.5, 3052.9, 2928.1, 2853.9, 1694.6, 1597.5, 1531.8, 1443.3, 1300.6, 1172.1, 1117.8, 1060.7, 1043.6, 1026.5, 906.7, 750.6, 712.5, 692.6.
_1- S0t ~ r~t~on of (l'~,lR,35)-1-(3'-tr~fl ~ a-ido-2',3',6'-tr~ )-3-(5~-to~rl~ rl)-3,~,5,10-t~tr~L~d.~ S,lO-di~ r~t~-12,3-o] p~r ~ (AC~-2150) SUBSTITUTE SHEE~T
W O 94/11382 P ~ /CA93/00463 ~ OCH~ ~~
~ H~C~ ~ ~
CH, PNB CH PNBO NH~A CH, ~H3 ~ ~ CH, pNB~A PNB~A
O o~
~ o ~ H, H, ~
oHNHl~A
BCH-21~0 ~t-p ls (l'S, 1~, 3R)-1-(4'-p-niL. ~ 1-2~,3',6'-tr~ 3'-tr~ -3-(Sn-to~r~ lrl)-s,a -; ~os~ c~
s To the ~ ' from ~t~p 4, _le 47, (50 mg, 0 120 mmol) in ~ i ~h 1 oromethane (15 ml) stirred wLth 5'-p-nitrobenzoyl-3',4',7'-trideoxy-3~-trifluoro~ o-L-ly~ohe~py~anose (49 mg, 0 125 mmol) was added 1,2-~ichloro-4,5-dicyano-b~nzoquinone (35 6 mg, 0 157 mmol) The resultLng mixture wa- stirred for 18 hours at 40C Solvent was e~G ~Led and th~ crude product w~ el,, -~Gy~hed (hexane/ethyl acetate~3/2) to gi~ the titled _ _ d (17 mg) and the (l'S,lR,3S) diast~,~ - (12 mg) ~he titled : _ ~ had lH NMR (acetonQ-d6, 250 NHz, B N ker) ~, 1 27 (3H, d, J ~ 5 9 Hz, 6'-CH3), 2 14-2 30 (2H, m, 2'-CH2), 2 44 (3H, ~, to~yl-CH3), 3 01 (2H, d, J
SUBSTITUTE SHEET
WO 94J11382 PCr/CA93/00463 ~1~6~4~
= 6.5 Hz, 4-CH2), 3.82 (3H, ~, OCH3), 3.92 (3H, s, OCH3), 4.65 (lH, m, 3'-CH), 4.86 (lH, qua, J ~ 5.9 Hz, 5'-CH), 5.71 (lH, d, J ~ 2.4 Hz, 4-CH), 6.17 (lH, tr, J ~ 6.5 Hz, 3-CH), 6.24 (lH, n, l-CH), 6.95 (2H, m, 6, 7-ArH), 7.48 (2H, d, J = 7.4 Hz, 3"~5n-tosyl-H)~ 7.95 (2H, d, J = 7.4 S Hz, 2n, 6"-tosyl-H), 8.38 (4H, m, PNB), 8.37 (lH, s, oxa-H), 8.66 (lH, - d, J - 7.4 Hz, NHCOCF3).
The (l'S, lR, 3S)-1-(4'-p-nitrobenzoyl-2',3',6'-tr~ 3'-trifluoroacetamido-L-lyYoh~ y~ano~e)-3-(5~-tosyloxa-zolyl)-s~8 dimethoxy i r ~ n h~ds lH NNR (acetone-d6, 250 ~Hz, Bruker)s ~, 0.80 (3H, d, J ~ 6.8 Hz, 6'-CH3), 2.19 (lH, m, 2'-HCHa), 2.48 (lH, d tr, J - 11.8 Hz, 4.1 az, 2'-HCHe), 2.46 (3H, 8, to~yl-CH3), 2.88 (lH, dd, J - 17.6 Hz, 11.8 Hz, 4-HCHa), 3.04 (lH, dd, J ~ 17.6 Hz, 4.4 Hz, 4-HCH~), 3.83 (3H, ~, OCH3), 3.86 (3H, 8, OCH3), 4.42 (lH, qua, J ~ 6.8 Hz, 5'-CH), 4.84 (lH, m, 3'-CH), 5.48 (lH, ~, 4~-CH), 5.58 (lH, d, J ~ 3.5 Hz, l'-CH), 6.01 (lH, 8, l-CH), 6.92 (lH, d, J ~ 6.5 Hz, ArH), 6.96 (lH, d, J ~ 6.5 Hz, ArH), 7.54 (2H, d, J ~ 9.1 Hz, 3", 5n-to8yl-H), 8.06 (2H, d, J ~ 9.1 Hz, 2~, 6~-to~yl-H), 8.35 (lH, ~, oxa-H), 8.49 (4H, m, PNB), 8.62 (lH, d, J -6.8 Hz, NHCOCF3).
8t-p 2: (1'8, 18, 3R)-1-(4'-p-niL.~ ~orl-2',3',6'-tr~ 3'-tr~ t~ -L-l~ )-3-(5~-to~r~ Qlrl) S,8 'i~ 3,4,S,8-t-tr~ ' ~o [2~3-~1-prrzn.
25 The _ _~ ~ from tep 1 herein (17 mg, 0.021 mmol) $n ~ onitr$1e (2 ml) was cooled to 0C and - -i cerium nitrate (35.5 mg, 0.0648 mmol, protreatQd with ~'i b~ on-~e, 3.6 mg, 0.042 mmol) wa~ added dropwi~e. The reaction mixtur~ was ~tirred for 15 minute~ at 0C then poured to water. It was extracted with ~i c-hl o~ han~. The organic phase wa~ with brine, dried (over ~odium ~ulfate) and ~apG~&ted to give a cruda product which wa~ purified on ~ilica gel (hexane/EtOAc -2sl) to give the de-ired titled product (7 mg).
lH NMR (acetone-d6, 250 MHz, Bruker): ~, 1.04 (3H, d, J ~ 6.5 Hz, 6'-CH3), 2.12-2.35 (2H, m, 2'-CH2), 2.45 (3H, 8, to~yl-CH3), 2.80-2.93 (2H, m, 4-CH2), 4.55 (lH, qua, J ~ 6.5 Hz, 5'-CH), 4.86 (lH, m, 3'-CH), 5.49 (lH, ~, 4'-CH), 5.61 (lH, d, J = 2.1 Hz, l'-CH), 5.85 (lH, ~, l-CH), 6.12 (lH, dd, J ~ 10.6 Hz, 4.7 Hz, 3-CH), 6.80 (lH, d, J ~ 10.6 Hz, Quin-H), 6.85 (lH, d, J = 10.6 Hz, QuLn-H), 7.48 (2H, d, J ~ 8.8 Hz, 3n, SUBST)TU,TE SHET
W O 94/11382 2 14 6 ~4 ~ PC~r/CA93/00463 5"-tosyl-H)~ 7.88 (lH, s, oxa-H), 7.94 (2H, ~, J ~ 8.8 Hz, 2~, 6"-to~yl-H), 8.28 (4H, m, PNB).
8t-p 3: (1'8, lR, 3S)-1-(4'-p-nit,.~- -Qyl-3-trlfluoroac-t $do-2',3~,6~-tri~ ~ L-l~ )-3-(5n-tosrl-o~a~olyl)-S,10 'i- 3,4,5,10-t-tr-~d.~ lH ~ ~p~ 2,3-c]-pyra~
ThQ c~ from ztep 2 her~in (9 mg, 0.012 mmol) wa~ tirred wLth 1-acQtoxy-l ~ 3-but~ i r ~ ( 28 ~1, 0.236 ~mol) $n tolu-na (4 ml) and THF (0.5 ml) at 50C for 18 hours. Solv~nt wa- .-~G-.L-d nd th~ crude product was ch -~o~ ' (tolu~n~/ethyl ~ - 5/1) to give the de~red titled product (4.8 mg).
lH NMR (CDC13 250 MHz, Bruker): ~, 1.06 (3H, d, J ~ 6.2 Hz, 6'-CH3), 2.00 (lH, d tr, J ~ 11.5 Hz, 2.9 Hz, 2'-HCHa), 2.25 (lH, dd, J ~ 11.5
15 Hz, 4.4 Hz, 2'-HCHe), 2.44 (3H, ~, tosyl-CH3), 2.98 (lH, d, J - 5.6 Hz, 4-CH), 2.99 ~lH, d, J - 11.0 Hz, 4-CH), 4.60 (lH, qua, J - 6.2 Hz, 5'-CH), 4.87 (lH, m, 3~-CH), 5.40 (lH, s, 4'-CH), 5.72 (lH, d, J ~ 2.0 Hz, 1'-CH), 6.05 (lH, s, 1-CH), 6.19 (lH, dd, J - 11.0 Hz, 5.6 Hz, 3-CH), 6.66 (H, d, J ~ 6.5 Hz, NHCOCF3), 7.49 (2H, d, J ~ 8.8 Hz, 3n, 5"-to~yl-20 H), 7.79 (2H, m, 7, 8-ArH), 7.90 (lH, , oxa-H), 7.95 (2H, d, J ~ 8.8 Hz, 2n, 6n-to-yl-H), 8.13 (2H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
8t-p 4s (1'~, lR, 3~)-2',3',6'-tr~ 3'-tr~fl ~ w~ a~do-~-~ 3-[S'-tozr~ Qlrl]-5,10 '~ -3,6,5,10-2S t~ - [2,3-c]-pyr ~ (JCH-21S0) To th~ ~ _: ' from step 3 ~ n (4.8 mg, 5.92 ~mol) in THF (0.5 ml) and mQthanol (1.5 ml) coolsd to 0C wa~ added ~odium ~h~Y;~Q (4.37 M,1.4 ~1, 5.g2 ~mol). Aft~r 5 m$nutes, the r~action was ~ d with d$1utc h~ cl.loridQ acid and xtracted with methyl~ne chlorideO The organic layer wa- dried (ov~r Na2S04) and ~ uLaL~d to giva a crude product which was purified on T~C (CHC13sMeOH - 100:7) to givc desired titled product a~ an off-whit~ solid (1.3 mg).
M.P. 130-135C.
lH NMR (CDC13, 250 MHz, Bruk r)s ~, 1.13 (3H, d, J - 6.S Hz, 6'-CH3), 1.78 (lH, tr d, J ~ 11.2 Hz, 2'-HCHa), 2.05 (lH, m, 2'-HCHe, due to ~olvcnt overlap, thi~ is an ost~ -tj~), 2.43 ~3H, s, tol-cH3)~ 2.92 (lH, d, J ~ 5.9 Hz, 4-HCHa), 2.94 (lH, d, J - 10.5 Hz, 4-HCHe), 3.71 (lH, m, 4~-OH), 4.20 (lH, dd, J ~ 5.9 Hz, 3-2 Hz, 4'-OH), 4.47 (lH, qua, SU~TliT~JT~- 5~EET
~ 2146~8 J ~ 6.S Hz, 5'--CH3), 4.58 ~lH, m, 3'--CH), 5.55 (lH, d, J ~ 3.0 Hz, 1'-CH), 5.99 (lH, ~, 1--CH), 6.16 (lH, dd, J -- 10.6 Hz, 5.9 Hz, 3--CH), 6.77 (lH, d, J ~ 10.6 Hz, NHCOCF3), 7.36 (2H, d, J ~ 8.8 Hz, to~lyl--H), 7.79 (2H, m, 7, 8-ArH), 7.90 (lH, u, oxa-H), 7.91 (2H, d, J ~ 8.8 Hz, to~yl-S H), 8.11 (2H, m, 6, 9-ArH).
IR (Nicol~t 205 FT, film on NaCl plat--): cm~l, 3379.1, 2956.4, 2927.8, 2854.7, 1716.9, 1669.3, 1335.6, 1297.4~ 1148.0, 985.2.
-_1- Sls Pr parat$on of (1'8,121,31~)-l-(3'tr~ t ~o-2 ',3 ',6 ' -tr~ ly o-L ~ ~ ) -3- ( S ~ _ to~ 1)--3,~,S,10--t~ l ~d,o S,10 'i~
[2,3-cl pyran (~-21Sl) OCH, O~ ~
~N J~ ~N
~ S2~ ~
H~C~;J H~
NBO NHlFJ~ PNBO N~PA
l~p2 O 0~ 0 0 H~ H~C~i oHNHlFA PNBo NHJFA
lS
sStep ls (1's5, 18, 3R)-1-(4'-p-n$~.,. ' -orl-2' ,3' ,6'-tr~ 3'-~r~ A^-L-l~ J-)-3-(S~-to-rl~ lrl)-S,8 i~-o-3,4,5,8-t-trah~d~ c [2,3-c]-prran -Starting wLth the (l~S,lS,3R) dia~L~. from ~tep 1, r le 50, (12 my, 0 015 mmol), using the ame material~ (- --; cerium nitrate, 25 mg, 0 046 mmol; NaHC03, 2 55 mg, 0 0304 mmol; -~Lo~trile, 1 5 ml; H20, O 4 ml) and following the ~me ~.~c~d~ ~c as described in step 2, example 50, the desired titled product was obtained (9 mg) SUB~T~ SI~E-T
WO 94/11382 PCI'/CA93/00463 21~X~48 ~
lH NMR (~ s - d6, 2S0 MHz, Bru~er): ~, 1.27 (3H, d, J ~ 6.6 Hz, 6~-CH3), 2.20 (2H, m, 2'-CH2), 2.45 (3H, s, tosyl-CH3), 2.95 (lH, d, J ~
6.8 Hz, 4-CH), 2.95 (lH, d, J ~ 8.8 Hz, 4-CH), 4.56 (lH, m, 3'-CH), 4.74 (lH, qua, J = 6.6 Hz, 5'-CH), 5.53 (lH, s, 4'-CH), 5.68 (lH, d, J ~ 2.9 S Hz, l'-CH), 6.01 (lH, s, l-CH), 6.09 (lH, dd, J ~ 8.8 Hz, 6.8 Hz, 3-CH), 6.93 (lH, d, J = 11.8 Hz, Quin-H), 6.96 (lH, d, J ~ 11.8 Hz, Quin-H), 7.49 (2H, d, J ~ 8.8 Hz, 3~, 5"-to-yl-H), 7.93 (2H, d, J ~ 8.8 Hz, 2", 6"-tosyl-H), 8.36 (lH, ~, oxa-H), 8.39 (4H, m, PNB), 8.68 (lH, d, J =
8.8 Hz, h~4~3).
8t-p 2s (1'~, 18, 3R)~ 4'-p-~it,. ~ - D~1 -3-tr~fl~G~ do-2',3',6~-tr~ L-l~ )_3_(5 n -to~rl-o~olyl ) ~
5,10-d~oxo-3,4,S,10-t-tr~hydro-lH ~r~t~ - [ 2,3-~1-pyr n The _ ~su ~ from tep 2 herein (7 mg, 0.009 mmol) was reacted wLth 1-acetoxy-l,3-but~if-- (21 ~1, 0.184 mmol) in tolu-ne (3 ml) at 50C for 18 hours. The solvent was _~p~,aLed to give a crude product. After chromatoy~a~hy (toluene/-thyl acetate ~ 5:1) desired titled product was obtained (6.4 mg).
lH NMR (CDC13 250 MHz, Bruk r)s ~, 1.34 (3H, d, J - 7.1 Hz, 6'-CH3), 2.15 (lH, d tr, J - 12.9 Hz, 4.1 Hz, 2'-HCHa), 2.32 (lH, dd, J ~ 12.9 Hz, 4.1 Hz, 2'-HCH~), 2.45 (3H, s, to~yl-CH3), Z.96 (lH, dd, J ~ 18.2 Hz, 4.1 Hz, 4-HCHa), 3.13 (lH, dd, J ~ 18.2 Hz, 11.2 Hz, 4-HCHe), 4.64 (lH, m, 3'-CH), 4.77 (lH, qu~, J - 7.1 Hz, 5'-CH), 5.52 (lH, s, 4'-CH), 2S 5.76 (lH, d, J ~ 2.0 Hz, l~-CH), 6.08 (lH, dd, J = 11.2 Hz, 4.1 Hz, 3-CH), 6.20 (lH, ~, l-CH), 6.21 (lH, m, HNCOCF3), 7.37 (2H, d, J ~ 8.2 Hz, 3", 5~-tosyl-H), 7.71 (2H, m, 7, 8-ArH), 7.89 (2H, d, J ~ 8.2 Hz, 2", 6n-tosyl-H), 7.90 (lH, ~, oxa-H), 8.15 (lH, m, 6, 9-ArH), 8.31 (4H, m, PNB).
~t-p 3: (l'S, lS, 3R)-2',3',6'-tr~ 3'-tr~fl v_s~-- i~o-L-~ 3-lS~-to~ Qlrl)]-5~lo t~ -3,~,S,10-t-tr hydro~ ~ t2~3-CI-prran (~C~-2151) To PNB derivative ~rom tep 2 herein (6.4 mg, 0.0079 mmol) tirrnd in tetrahydrofuran (0.5 ml) and methanol (1.5 ml) at 0C was ldded ~odium meth~Y~do (4.373 M, 1.8 ~1, 0.0079 mmol). After 5 minutes, the pink solution wa~ g~len~h~ with dilute HCl. The product wa~ extracted with methylRne chloride. The organic layer was dried and ~a~G,aLed to give SuBsTlTuTE SHEET
W O 94~11382 PC~r/CA93/00463 214~4g a crud~ product which wa~ pur~f~d by thin~ tG-~- ~phy (CHC13s~0H ~ 100:7) to d~s~red titl-d product ~ an off-whLt~ ~olid (0.8 mg).
M.P. 100-105C.
S ~H NMR (CDC13, 250 HHz, Bruk-r)s ~, 1.41 (3H, d, J - S.9 Hz, 6'-CH3), 1.92 (lH, tr d, J - 11 Hz, 3.5 ~z, 2'-HCHa, o~tim~tlon), 2.20 (lH, m, 2'-HCHe, ~tj -~io~), 2.44 (3H, ~, tol-CH3), 2.95 (lH, dd, J - 18.5 Hz, 4.7 Hz, 4-HCHe), 3.12 (lH, dd~ J - 18.5 ~, 11.2 Hz, 4-HCHa), 4.00 (lH, m, 4'-CH), 4.37 (m, lH, 3'-CH), 4.60 (lH, qua, J - 5.9 Hz, 5'-CH), 5.10 (lH, br ~, 4'-OH, ~ti - j~n)~ 5.58 (lH, d, J - 3.5 Hz, l'-CH), 6.05 (lH, dd, J - 11.2 Hsc, 4.7 Hz, 3-CH), 6.15 (lH, ~, l-CH), 6.66 (lH, m, ~O~r3), 7.36 (2H, d, J ~ 8.8 Hz, to~yl-H), 7.78 (2H, m, 7, 8-ArH), 7.87 (lH, ~, oxa-H), 7.88 (2H, d, J - 8.8 Hz, to~yl-H), 8.12 (2H, m, 6, g-ArH ) .
IR (Nicol~t 205 FT, f~lm on N~Cl pl~t-)s cm~l, 3368.3 2961.8, 2930.2, 2848.9, 1715.0, 1669.9, 1463.0, 1332.8, 1289.0, 1153.4, 975.46.
1~ S2s ~ ion of (1,3-tr~n-)-1-~-thosr-3-(3'-~ l rl)-s, lo . i . 3,4,5,10-totr~hrdro-lH-~ ~~ t2~3-cl-Pqr~n (BC~-1616) ~d (1,3-tr~n~)-1-~ 3 ~ 1-S,10-d~oso-3,~,5,10-t-tr h~dro-1~~ [2,3-cl-prr~3 (BCH-lC7~) OCHI O o O
OCH~ OH O oCH~ O OCH~
~/ O N--~~~Br ~ O OCH~ BCH-1616 O OCH~ \
\~p5 O O O
\~ G[~H21~(POCH,)~
O OCH
~ UTE SHEET
WO 94/11382 PCr/C~93/00463 21~4~
~t-p 1 1 ~- ~ 3 -- L~l-S,8 ~ -3,4,5,8-t-tr--h~d. ~ -o-t2,3-C 1--prr S A ~ampl~ of 5,8-d~m~thoxy-1-hyd OAY 3-ac~to~ -n (200 mg, 0.79 mmol) ~n ~eOH (10 ml) wa~ t~rr~d at room t- - ~Lur- whil- a olution of CAN (2.16 q, 3.95 ~mol) ln water (9 ml) wa~ add~d dropwl-e. Aft~r S
minut-~, tha r-actLon mixtur- wa- pourQd to wat~r nd th-n xtract~d with m~thyl-nc chloride. Th- organic layer wa~ dr~-d (over ~
sulfate), and J~o~atQd to q~v- a ~ 1 low st~cky ol~d (157 mg). lH NMR
howad that de-~red tltlsd product w-~ o~t~i~~' w~th 89% purity.
lH NMR (CDC13, 250 MHz Bruk r), ~: 2.28 (8, 3H, COCH3), 2.35 (dd, lH, J
- 20.5 Hz, 12.1 Hz, 4-Ha), 2.78 (dd, lH, J ~ 20.5 Hz, 4.3 Hz, 4-He), 3.56 (s, 3H, OC~3), 4.44 (dd, lH, J ~ 12.1 Hz, 4.3 Hz, 3-H), 5.46 (~, lS lH, 1-H), 6.73 (m, 2H, 6.7-~
~t-p 2 1_-thosr-3 ~ 1-5,10 'i ~o-3,~,5,10-t-tr~hrdro-lH-~p~~~ [2,3-e]-prran The bicycllc ~-in~n~ from step 1 hera$n (157 mg, 0.66 mmol) was tfrredwith l-acetoxy-1,3-but-'~ (632 ~1, 5.32 mmol) in tol --~ (20 ml) ~t 40C for 16 hours. Solvent wa~ ~G~ated and the crude ~.~duuL was cl.,~ - oJ~a~h~d (tol - -s~tOAc ~ 100s25) to gl~e d s~rcd t~tl-d tr$cyclic ~i - - a- a yellow ~olid (190 mg).
2S ~.P. 169.8-170.8C.
H NMR (CDC13, 250 ~H~ 8ruker), ~s 2.34 (s, 3H, COCH3), 2.53 (dd, lH, J
20.7 Hz, 10.7 ~z, 4-Ha), 3.00 (dd, lH, J ~ 10.7 Hz, 4.3 ~z, 4-He), 3.63 (8, 3H, OCH3), 4.54 (dd, lH, J ~ 10.7 Hz, 4.3 Hz, 3-H), 5.66 (~, lH, l-H), 7.73 (m, 2H, 7.8-As~), 8.06 (m, 2H, 6.8-ArH).
IR (N~colet 205 FT, f~lm on NaCl plate), cm~l: 2923.4, 2827.6, 1717.7, 1668.2, 1637.3, 1597.1, 1368.3, 1331.3, 1300.3, 1281.8, 1179.8, 1105.6, 1083.9, 1046.8, 875.5, 799.8, 714.2, 686.1.
s~t - p 3s 3 _ -- ~ ~rl-l ~ ~ 5,10-dio~o-3,-,5,10-t-tr~h~dro-lH-~P~ ~~ t2~3~Cl-prr~n To a solut~on of product from step 2 herein (50 mg, 0.175 mmol) in THF
(3 ml) at room t- ~ aLu . was added pyri~ini- ~ydro~ .L.~ i~e (1.3 eq.) in THF (2 ml). The mixtura was stirred for 45 minutes at room SUBSTITVTE SHEET
W O 94/11382 PC~rJcA93/00463 ~46~
t~ - ~ture. It wa~ poured to water and extracted wLth methyl~ne chloride. The organic layer wa~ dried and _~a~o,ated to qive a product.
TLC and lH NMR both ~howed that th~ de~ired t$tled product (76 mg) wa~
obtained with purity ~90~.
M.P. 169.8-170.8C.
H NMR (CDC13, 250 MHz Bruker), ~: 2.53 ~dd, lH, J - 20.3 Hz, 11.0 Hz, 4-Ha), 3.02 (dd, lH, J ~ 20.3 Hz, 4.1 Hz, 4-He), 3.64 ~u, 3H, OCH3), 4.15 (d, lH, J ~ 12.7 Hz, BrCHAH), 4.35 (d, lH, J ~ 12.7 Hz, Br CHHB), 4.84 (dd, lH, J - 11.0 Hz, 4.1 Hz, 3-H), 5.65 (s, lH, l-H), 7.72 (m, 2H, 7.8-ArH), 8.02 ~m, 2H, 6.9-ArH).
8t--p ~s (1,3-tr--nz)-1-~ tho--r-3--(3' _ ~ -~h~--~lyl)-S~l0-d 3,4,5,10-t-trahydro-1~ ~ [2,3-c] pyran (BC~-1616) ~.~ Lhyl ketone from step 3 her~in (20 mg, 0.054 mmol) waz ztirred with thioure~ at room t - a~ure for 3.5 hours in ther (2 ml) and oromethane (2 ml). It wa- poured to at. ~dj- bic~rhQn-t~ and xtracted with ~ i ~h l o~ - . Th~ organic layer wa~ ~v~.t-d to give crude product which wa~ -tr ~had (MeOHsCHC13sHOAc ~ 4:100:1) to give de~Lred tLtl-d p,v~u~L (5.3 mg). A polar b~ ~.oluct was al~o obtained (8 mg).
lH NMR (CDC13, 250 MHz Bruker), ~: 2.77 (lH, dd, J ~ 18.8 Hz, 11.8 Hz, 4-HCHa), 3.00 (lH, dd, J - 18.8 Hz, 5.2 Hz, 4-HCH~), 3.63 (3H, ~, OCH3), 5.03 (lH, dd, J ~ 11.8 Hz, 5.2 Hz, 3-CH), 5.67 (lH, , l-CH), 6.53 (lH, 2S ~, thia-H), 7.73 (2H, m, 6, 9-ArH), 8.08 (2H, m, 7, 8-ArH).
IR (Nicolet 205 FT, fLlm on NaCl plat-), cm~l: 3429.8, 3346.7, 3130.7, 2957.8, 2921.3, 2854.8, 1664.9, 1641.6, 1591.7, 1521.9, 1455.5, 1408.9, 1327.1, 1294.1, 1102.0, 1039.9, 731.92, 708.07.
0 8tep 5: 1- tho~r-3 ~; -thrl ~ s~t~1-5,10-dLoxo-3,~,S,10-t--tr bydro-lr ~ ~ t2~3-c]-pyran (~CX-167-) A ~olution of b.~ thyl`-Lone from ztep 3 herein (10 mg, 0.027 mmol) wa~ refluxed with trimQthylpho~phite (3.54 ~1, 0.03 mmol) and odium iodide (0.2 mg, 0.05 mmol) in THF at 70C ov~rnight. Solvent wa~
L~po~ated and the brown ~3~i~ - wa~ cl... ~to~.~hed (CHC13:MeOH 50:1) to give de~ir~d titled product a~ a light-colored solid (2 mg).
1H NMR (CDC13, 250 MHz, Bruker): ~, 2.60 (lH, dd, J ~ 19.8 Hz, 11.6 Hz 4-HCH~), 2.94 (lH, dd, J ~ 19.8 Hz, 3.5 Hz, 4-HeCH), 3.62 (3H, ~, 1-SUBSTIT~JTE SHEEt 21~ 8 ~
OCH3), 3.85 (3H, ~, POCH3), 3.88 (3H, ~, POCH3), 4.59 (lH, dd, J ~ 11.6 Hz, 3.5 Hz, 3-CH), 5.02 (lH, br ~, CHP), 5.15 (lH, br ~, CHP), 5.62 (lH, 8, l-CH), 7.73 (2H, m, 6, 9-ArH), 8.08 (2H, m, 7, 8-ArH).
S _1- 53s Pr~p~r~tion of (1'8,1~,38)-1-(3~-trifl ~ c~t~
2',3',6'-tr~ )-3--t~- ~c~ 3---thrl-3,4,5,10-t-tr h~l.~ S,10-d~o~o-l~ -~rht~- [2,3-cl prr n (~C~-2077) ~' OCH,O
X 11 OCH, O + OCH, O +
~OCH, 2p~lA PNB~A
OCH, 1 ~ X-H ~H~ ¢~;~U3 OCH, o OCH, O
H3C~A C PNBC~ D
O O
o o Ll--- Ll ~H 4 Ç~
H3C~IA
PNBO NH~A ~ o o ~J~H, O O
H,C~;J
oHNHlFA 8CH-20n 8t-p ls 3- ~ 1-3-~ thrl-5,~ ; -Lhoxy ;~
A ~olutLon of di-~.o~ylamine (616.8 ~1, 4.37 ~,ol) in THF (10 ~1) wa~
cooled to 0C and 1-3 ~ae~ briefly. n ~Lyl lithium (1.6 M in hexane, 2.60 ml, 4.17 ~mol) wa- added. After stirred for 30 minutes at 0C, the SUBSr1TUTE SHEET
~ 214~4~
olution wa~ furthQr cool~d to -78c. A Rolution of 5,8-d$methoxy-3-methoxycarbonyli~o-hroman (1.0 g, 3.97 mmol) in THF (10 ml), pre-~sg~Ed, wa~ added ~lowly. The r-~ulting yellow Rolution was stirred for 1 hour at -78C before the addition of methyliodide (1.01 ml, 16 S mmol). After ~tirred further for 45 minutes, ~at. NH4Cl Rolution wa~
added. The mixturc wa~ diluted with water and extracted with ethyl acctate. The organic layer was dried and _~pG.ated to givs a crude product which was ch~ -LoJ-a~h~d (hoxan~:~tOAc ~ 3sl) to give the des~rQd product as a olid (650 mg, m p. 73.0-74.5C) and another fraction (192 mg) which con~in~d 66~ of titled product and 34% of the tarting materlal.
M.P. 73-74.5C
H NMR (CDC13 250 MHz, Bruker): 8, 1.50 (3H, 8, 3-CCH3), 2.58 (lH, d, J
~ 17.1 Hz, 4-CH), 3.25 (lH, d, J ~ 17.1 Hz, 4-CH), 3.64 (3H, s, OCH3), 3.68 (3H, 8, OCH3), 3.72 (3H, s, OCH3), 4.76 (lH, d, J - 17.1 Hz, l-CH), 4.84 (lH, d, J ~ 17.1 H, l-CH), 6.53 (lH, d, J ~ 7.1 Hz, ArH), 6.59 (lH, d, J ~ 7.1 Hz, ArH).
IR (~icolet, 205 FT, film on NaCl plate): cm~1, 2949.9, 2833.2, 1736.6, 1489.0, 1365.2, 1344.0, 1259.1, 1206.0, 1142.3, 1114.0, 1060.7, 295.7, 713.8.
8t-p 2s (1'8, lR, 38)-l-(~ ~yl-3'-tr~f~
2',3',6'-tr~ Ll~ )-3 ~ yl-3-~ thrl-S, ~ r-~-o~
The _ _ ' from ~tep 1 ~ .i n ( 133 mg, 0.5 mmol) wa~ r-acted with DDQ
(136 mg, 0.6 mmol) and 5'-p-ni~.~b~ ~oyl-3',4',7'-tridQoxy-3'-trifluoroacotamido-L-ly~oh--.,pyL- -~e (196 mg, 0.5 mmol) at 45C for 16 hours, the ~ame way a- d~cribed in ~tep 2, example 13. After cl..~ -tGy~hy (hexane:EtOAc - 2.521), four ;R - ~ were obtained: C, 49 mgJ B, 24 mgS D, 73 mg; A, 56 mg.
For C, lH NMR (CDC13 250 MHz, Bruker): 8, 1.22 (3H, d, J - 6.1 Hz, 6~-CH3), 1.45 (3H, 8, 3-CCH3), 1.89 (lH, dd, J - 11.8 Hz, 4.7 Hz, 2'-CH), 2.05 (lH, d, tr, J ~ 11.8 Hz, 3.0 Hz, 2'-CH), 2.77 (lH, d, J ~ 17.1 Hz, 4-CH), 3.82 (lH, d, J ~ 17.1 Hz, 4-CH), 3.64 (3H, 8, OCH3), 3.78 (3H, s, OCH3), 3.81 (3H, ~, OCH3), 4.52 (lH, m, 3'-CH), 4.60 (lH, qua, J ~ 6.1 Hz, 5'-CH), 5.42 (lH, s, 4'-CH), 5~74 (lH, d, J ~ 1.7 Hz, l'-CH), 6.22 (lH, ~, l-CH), 6.36 (lH, d, J - 8.2 Hz, NHCOCF3), 6.71 (lH, d, J = 8.8 Hz, ArH), 6.80 (lH, d, J ~ 8.8 Hz, ArH), 8.28 (4H, m, PNB).
SUBS~iTUTE SHEET
WO 94/11382 PCI/CA93/004~3 2 1 ~ e IR (Nicolet, 205 F~, f;lm on NaCl plate): cm~l, 3328.4, 3077.3, 2946.4, 2843.8, 1740.1, lS27.9, 1492.5, 1259.1, 1114.0, 1054.2, 974.90, 947.90, 803.50, 716.80 The (l'S, lS, 3s)~ 4~-p-nitrobenzoyl-3~-trifluoroacQtamido-2~3~6 trideoxyly ' ~y~.no-e)-3-m~thvA~ carbonyl-3-methyl-5,8-dimethoxy-$-oc}..~ - n hads H NMR (CDC13 250 MHz, Brukcr): ~, 1.16 (3H, d, J ~ 7.3 Hz, 6~-CH3), 1.63 (3H, ~, 3-CCH3), 2.02 (2H, m, 2'-CH2), 2.86 (lH, d, J ~ lS.9 Hz, 4-CH), 3.21 (lH, d, J - lS.9 Hz, 4-CH), 3.65 (3H, s, OCH3), 3.76 (6H, s, 2xOCH3), 4.10 (lH, qua, J ~ 7.2 ~z, 5'-CH), 4.61 (lH, m, 3'-CH), 5.45 (lH, 8~ 4'-CH), 5.55 (lH, s, l'-CH), 6.24 (lH, ~, l-CH), 6.68 (lH, d, J ~ 9.4 Hz, ArH), 6.76 (lH, d, J ~ 9.4 Hz, ArH), 6.23 (lH, o, hn~r3), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, f$1m on NaCl plat-): cm~l, 3332.0, 2924.7, 2857.1, 1732.5, 1708.0, 1531.6, 1488.5, 1353.3, 1265.1, 1167.0, g57.18, 718.76.
Th~ (l'S, lS, 3R)-1-(4'-p-nit.~ ~oyl-3'-trifluorQ~r~ ~-2',3',6'-tr;~oc y L-ly-~h ~ - O~y ~ nr-~)-3-methoxy-carbonyl-3-methyl-5,8-di~ethoxy-~GCh~. -n had:
lH NMR (CDC13 250 MHz, Bruker): ~, 1.19 (3H, d, J - 6.1 Hz, 6' CH3), 1.60 (3H, s, 3-CCH3), 1.87 (lH, dd, J ~ 12.4 Hz, 4.7 Hz, 2'-CH), 2.11 (lH, d tr, J Y 12.4 Hz, 3.0 Hz, 2'-CH), 2.86 (lH, d, J ~ 16.5 Hz, 4-CH), 3.33 (lH, d, J ~ 16.5 Hz, 4-CH), 3.62 (3H, s,OCH3), 3.78 (6H, , 2XOCH3), 4.54 (lH, q~, J - 6.1 Hz, 5'-CH), 4.57 (lH, m, 3'-CH), 5.41 (lH, o, 4'-CH), 5.69 (lH, d, J - 2.9 Hz, l'-CH), 6.40 (lH, s, l-CH), 6.45 (lH, d, J ~ 7.6 Hz, NHCOCF3), 6.71 (lH, d, J ~ 8.9 Hz, ArH), 6.81 (lH, d, J ~ 8.9 ~z, ArH), 8.24 (4H, s, PNB).
IR ~ ol-t, 205 FT, f~lm on NaCl plat~): cm~l, 3325.5, 3077.2 2951.9, 2541.1, 1737.3, 1705.9, 1609.5, 1530.0, 1489.0, 1354.1, 1264.9, 970.9, 951.60, 804.80, 720.90.
The (l'S, lR, 3R)-1-(4'-p-nitrobenzoyl-3'-tr;fluoroacetam~do-2',3',6'-tr;~c ~ L-ly '~ . r~re)-3 -~ carbonyl-3-methyl-5,8-dim~thoxy-~- hads H NMR (CDC13 250 MHz, Bruker): ~, 1.20 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.53 (3H, s, 3-CCH3), 1.93 (lH, dd, J ~ 11.8 Hz, 2.9 Hz, 2'-CH), 2.05 (lH, m, 2'-CH), 2.60 (lH, d, J ~ 16.5 Hz, 4-CH), 3.39 (lH, d, J ~ 16.5 Hz, 4-CH), 3.73 (3H, ~, OCH3), 3.76 (3H, o, OCH3), 3.80 (3H, o, OCH3), 4.71 (lH, m, 3'-CH), 4.86 (lH, qua, J ~ 6.0 Hz, 5'-CH), 5.45 (lH, s, 4'-CH), 5.55 (lH, d, J ~ 1.74 Hz, l'-CH), 6.01 (lH, 8~ l-CH), 6.49 (lH, U ~ S ~
W O 94/11382 2 1~ ~ ~4 ~ PC~r/CA93/00463 d, J ~ 6.8 Hz, NHCO~r3), 6.24 (lH, d, J - 10.2 Hz, ArH), 6.82 (lH, d, J
= 10.2 Hz, ArH), 8.29 (4H, s, PN8).
8t~p 3s (1'8, lR, 38)~ p-n~ orl-3'-trifluoro-c-t~ ido-S 2~,3~,6~-tr~ )-3 ~ 3-m thrl-S, a -; ~-~-4, s, 8-tr~h~dro-lH ~-o-[2,3-c]-prr The titled c _~ ~' w~s obtain~d via Q N oY~-tinn (-t-p 3, .-- 1~ 13) of the (l'S,lR,3S) y,~cu.~GL from ztep 2 ~ ~in.
lH NMR (CDC13 250 MHz, Brukor)s ~, 1.30 (3H, d, J - 6.5 Hz, 6'-CH3), 1.57 (3H, B, 3-CCH3), 1.93-2.05 (2H, m, 2'-CH2), 2.36 (lH, d, J ~ 20 Hz, 4-CH), 3.31 (lH, d, J ~ 20 Hz, 4-CH), 3.67 (3H, s, OCH3), 4.46 (lH, m, 3'-CH), 4.66 (lH, qu~, J ~ 6.5 Hz, 5'-CH), 5.36 (lH, ~, 4'-CH), 5.62 (lH, s, l'-CH), 5.93 (lH, ~, l-CH), 6.56 (lH, d, J ~ 7.1 Hz, NHCOCF3), lS 6.77 (lH, d, J - 9.7 Hz, Quin-H). 6.85 (lH, d, J - 9.7 Hz, Quin-H), 8.30 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plat~): cm~l, 3347.1, 2924.7, 2851.4, 1736.3, 1663.1, 1527.9, 1351.4, 1272.6, 1167.4, 951.60, 837.00, 718.80.
8t-p 4s (1'8, lR, 38~-1-(4'-p-niL..~-~-Qrl-3'-tr~ m~do-2',3',6'-tr~ )-3--~t~ 1-3--thyl-S,10 d~-o-4,5,10-tr~hydro-1~ ~p~-~ [2~3-c]-prr~n Th~ titl~d ~ : ' wa- obt~in~d following cyclo~~ti~n ~
2S ~c-toxybu~ nd th- pr-cur-or from t-p 3 ~ n ~ per previou-ly described ~,oc- ~.
lH NMR (CDC13 250 MHz, Bruk-r)s ~, 1.34 (3H, d, J ~ 6.5 Hz, 6'-CH3), 1.59 (3H, ~, 3-CCH3), 1.90-2.10 (2H, m, 2'-CH2), 2.50 (lH, d, J ~ 19.4 Hz, 4-CH), 3.49 (lH, d, J - 19.4 Hz, 4-CH), 3.65 (3H, ~, OCH3), 4.46 (lH, m, 3'-CH), 4.79 (lH, qua, J ~ 6.5 Hz, 5'-CH), 5.40 (lH, br s, 4'-CH), 5.65 (lH, d, J z 2.5 Hz, l'-CH), 6.10 (lH, ~, l-CH), 6.51 (lH, d, J ~ 7.6 Hz, ~n~G~r3), 7.76 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
IR (Nicolet, 205 FT, film on N~Cl plate): cm 1, 3333.8, 2919.5, 2851.0, 3S 1739.0, 1667.4, 1533.4, 1790.5, 1271.8, 1212.6, 1187.7, 1103.6, 994.58, 949.75, 723.70.
SUBSTITUTE SHEET
W O 94/11382 P ~ /CA93/00463 2146~8 1~
8t-p S~ 8, lR, 3~)-1-(3~-trifl ~ o~L~do-2~,3',6~-tr~ L-)-5,10-dioxo-~,5,10-tr$hrdro-lH
~2,3-cl-prran (BC~-2077) S Th~ tLtl~d c -~ waz obt~Lned followLng mRth~nolyz~ of thc pr~cur~or from tcp 4.
1H NMR (CDC13, 250 MHz, Brukor): ~, 1.39 (3H, d, J - 6.0 Hz, 6'-CH3), 1.58 (3H, s, 3-CCH3), 1.77 (lH, dd, J ~ 12.0 Hz, 4.1 Hz, 2'-HCHa), 1.84 (lH, dd, J ~ 12.1 Hz, 5.9 ~z, 2'-HCHa), 1.96 (lH, d, J ~ 8.7 Hz, 4'-OH), 2.48 (lH, d, J - 19.5 Hz, 4-HCHa), 3.47 (lH, d, J ~ 19.5 Hz, 4-HCHe), 3.60 (lH, d, J ~ 8.7 Hz, 4'-CH), 3.64 (3H, , OCH3), 4.17 (lH, m, 3'-CH), 3.56 (lH, qu~, J ~ 6.0 Hz, 5'-CH), 5.46 (lH, d, J ~ 2.9 Hz, 1'-CH), 6.05 (lH, ~, 1-CH), 6.71 (lH, d, J - 8.8 Hz, ~ iLF3), 7.75 (2H, m, 7, 8-AsH), 8.10 (2H, m, 6, 9-ArH).
lS IR (NLcolet , 205 FT, film on NaCl plate): cm~1, 3420.6, 2934.5, 1735, 1721.8, 1665.8, 1291.8, 1182.3, 1166.3, 1112.9, 776.7, 944.6, 912.6, 728.97.
~ s~S Pr p~rat$on of (1'~,18,3R)-1-(3~-tr~fl -_o~c-t~$do-2',3',6'-tr~ lrxo-L '- ~ )~3 ~ 1-3--th~1-3,~,S,10 ~r-k~d~o 5,10 ~ o ~~"~ ~~ t2,3-c]
Prr~ (BC~-2082) ~ ~ 0~
Hl~ H,(~
PNBO NH~AOHNHlF
B~2082 8t-p 1: (l'S, lS, 3R~-1-(3'-tr~ -2',3',6'-tr~ L-~ )-3 ~ 1-3-m-thyl-5,10 ~ ,5,10-tr$hrdro-l~ ~E~t~- t2,3-c]-prran (~CH-2082) Methanoly~i~ of the p-nitrobenzoylated ~ UL 60r yielded the titled product.
H NMR (CDC13, 250 MHz, Bruker): ~, 1.31 (lH, d, J - 6.6 Hz, 6'-CH3), 1.45 (3H, 6, 3-CCH3), 1.80 (lH, d, J ~ 8.8 Hz, 2'-CH), 1.81 (lH, d, J =
SUBSriTUTE SHEET
WO 94/11382 PCI~/CA93/00463 21,96~4 8 10 Hz, 2~-CH), 2.24 (3H, 8, COCH3), 2.52 (lH, d, J = 18.5 HZ, 4 - HCHa), 3.38 ~lH, d, J ~ 18.5 Hz, 4-HCHe), 3.60 (lH, br 8, 4'-CH), 4.19 (lH, br qua, J ~ 10 Hz, 3'-CH), 4.41 (lH, qua, J ~ 6.6 Hz, S'-CH), 5.45 (lH, s, l'-CH), 6.13 (lH, ~, l-CH), 6.63 (lH, d, J = 10 Hz), 7.75 (2H, m, 7, 8-S ArH), 8.09 (2H, m, 6, 9-ArH).
- IR (Nicolet , 205 FT, f~lm on NaCl plat-): cm 1, 3375.1 (br str), 3091.1, 2929.6, 1715.2, 1671.2, 1597.7, 1293.3, 1172.9, 981.5, 729.22.
_1- SSs Pr-p-r-t~on of (1'8,18,3R)-1-(3'-trlfl ~ ido-2',3',6'-tr~ lyso-L ~ ,~ )-3-d~m~ ,1-3,4,5,10-t-tr-h~d.~ 5,10-~ - [2,3-c] pyran (8C~-1690 o o (oCH,)~ ~o(ocH~)2 o o pNCB~A H3C~A
lS
8t-p ls (1'~,18,3R)-1-(2',3',6'-tri ~c ~ 3'-tr~ _~a~ do-~-~ )-3 ~ hyl~ 1-5,10-dio~o-3,4,S-10-t-tr~ lH-~ - [2~3-c]-pyran (~CH-1690) The p-nltrobenzoyl ~ ___ .G wa~ hydrolyzed wlth catalytic odLum me~ d~ ln methanol a~ per prevlou~ly de~crlbed p c_ ` re. The tltled cl __ ' had:
.P. 91-93C, lH ~MR (CDC13, 250 MHz, Bruker)s ~, 1.40 (3H, d, J ~ 7.6 Hz, 6'-CH3), 2S 1.89 (2H, m, 2'-CH2), 2.62 (lH, dd, J - 18.2 Hz, 11.8 Hz, 4-HCHa), 3.00 (lH, dd, J ~ 18.2 Hz, 4.1 Hz, 4-HCHe), 3.65 (lH, br s, 4-CH), 3.83 (3H, s, POCH3), 3.87 (3H, s, POCH3), 4.32 (lH, qua, J ~ 7.6 Hz, 5'-CH), 4.56 - (lH, m, 3-CH), 4.99 (lH, br ~ CHP), 5.13 (lH, br 8, CHP), 5.44 (lH, s, l'-CH), 6.09 (lH, 3, l-CH), 6.83 (lH, br d, J ~ 7.6 Hz, ~n~r3), 7.77 (2H, m, 7, 8-ArH), 8.09 (2H, m, 6, 9-ArH).
IR (Nlcolet 205 FT, fllm on NaCl plate): cm 1, 3421.9, 2958.3, 1716.0, 1665.6, 1592.5, 1287.6, 1181.8, 1045.7, 977.7, 858.4, 727.5.
SUBS~IT!JTE SHEET
WO 94/11382 PCr/CA93/00463 ~&~4~ --_1- 56s Pr-p~r~tion of (1'8,18,3~)-1-(3'-trifluoro~ iA~_ 2~,3',6~-tr~ lrso-L ~ )-3-~t~ - ~C~ 1-3- -thyl-3 ~ 4 ~ S, lO-t-tr~hrdro-5 ~ 10-diGao -.pht~- ~2,3-c] pyrzn (BCH-2081) S
OCH O
~1~ ~H, OCH,O .
PNBO ~ PNBO ~
o o o o O O O O
H,~ H,C~
o~Nl~lFA PNBO NHIFA
BCH~2081 8t-p ls (l's~, 18, 38)-1-(4~-p-u$L,.' -_~1-3'-tr~f~ t 2~,3~,6'-tr~ )-3-~ h~yl-3--thrl-5,8-d$oso-4,5,8-trihrdro-1~ 0 t2,3-c]-prr n.
CAN ~V~at~on of the (l'S,lR,3S) ~cu~ from t~p 2, le 53, yielded the t~tled _ '.
lH NMR (CDC13 250 MHz, Bruker): ~, 1.14 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.61 (3H, ~, 3-CCH3), 1.96 (lH, d tr, J - 11.7 Hz, 4.1 Hz, 2'-CH), 2.10 (lH, dd, J ~ 11.7 Hz, 2.9 Hz, 2'-CH), 2.58 (lH, d, J ~ 18.2 Hz, 4-CH), 3.00 llH, d, J ~ 18.2 Hz, 4-CH), 3.71 (3H, ~, OCH3) 4.50 (lH, gua, J e 6.0 Hz, 5'-CH), 4.60 (lH, m, 3'-CH), 5.42 (lH, ~, 4'-CH), 5.56 ~lH, ~, l'-CH), 6.03 (lH, ~, l-CH), 6.58 (lH, d, J ~ 7.4 Hz, ~3), 6.72 (lH, d, J ~ 8.8 Hz, Qu~n-H), 6.78 (lH, d, J ~ 8.8 Hz, QuLn-H), 8.24 (4H, br ~, PNB).
IR (Nicolat, 205 FT, film on NaCl plat~): cm~l, 3340.0, 3084.6, 2950.7,2857.2, 1732.8, 1664.3, 1533.4, 1349.7, 1268.7, 1159.7, 1013.3, 955.70, 837.03, 735.00.
~ ~ ~ â ~ ~ . q~ T
W O 94/11382 PC~r/cA93/00463 2 1 ~
st-p 2s (1'8, 1~, 38)-1-(4'-p-ni~ Qyl-3'-tr~fluorr-c~ - iA~_ 2',3',6'-tr~ '- a~ )-3~ arbonrl-3-m-thyl-S,10 di~-o-4,S,10-trih~dro-lH ; s~ 2,3-cl-prran S
The titled c _~ ' wa- obtained following cycloaddition bat ~-- 1-acntosybutr~i - and th~ n~n9 from step 1 ~- ~in.
H NMR (CDC13 250 MHz, Bruk~r~: ~, 1.16 (3H, d, J - 6.0 Hz, 6'-CH3), 1.67 (3H, ~, 3-CCH3), 2.05 (2H, m, 2'-CH2), 2.77 (lH, dd, J - 17.6 Hz, 0.6 Hz, 4-HCHa), 3.22 (lH, dd, J - 17.6 Hz, 1.8 Hz, 4-HCH~), 3.73 (3H, s, OCH3), 4.57 (lH, qua, J - 6.0 Hz, 5'-CH), 4.64 (lH, m, 3'-CH), 5.45 (lH, d, J ~ 2.1 Hz, 4'-CH), 5.67 (lH, B, l'-CH), 6.22 (lH, 8~ l-CH), 6.34 (lH, d, J - 8.2 Hz, hn~r3), 7.76 (2H, m, 7, 8-ArH), 8.08 (2H, m, 6, 9-ArH), 8.28 (4H, m, PN8).
lS IR (Nlcolet, 205 FT, film on NaCl plate): cm~l, 3331.7, 2957.1, 1734.1, 1708.5, 1666.4, 1595.6, 1527.9, 1271,3, 1216.2, 1181.61, 1165.8, 1104.5, 1013.2, 954.94, 731.40, 721.98.
8t-p 3s (1'8, 18, 38)-1-(3'-tr~f~ c-t~o~do-2',3',6'-tr~
1~ '- ~,_ -a-)-3-m-t'~ ~ 1-3- ~thrl-5,10-dioso-4,S,10-tr~hrdro-1~ - 12,3-cl-prr n (BCH-2081) The ~ o~ from trp 2 herein wa~ hydrolyzed with D~ hnYiA~
(catalytic) as per previou-ly de~cribed ~ ocL~ure. Th~ product had:
lH NMR (CDC13 250 ~Hz, Bruk~r): ~, 1.23 (3H, d, J - 6.1 Hz, 6'-CH3), 1.64 (3H, s, 3-CH3), 1.79 (lH, d tr, J ~ 12.9 Hz, 3.8 Hz, 2'-HCHa), 1.88 (lH, dd, J ~ 13.0 Hz, 4.7 Hz, -2'-HCH~), 1.94 (lH, d, J - 7.6 Hz, 2'-OH), 2.74 (lH, d, J - 18.8 Hz, 4-HCHa), 3.17 (lH, d, J Y 18.8 Hz, 4-HCHQ), 3.61 (lH, d, J - 7.8 Hz, 4'-CH), 3.71 (3H, s, OCH3), 4.32 (lH, m, 3'-CH), 4.40 (lH, qua, J - 6.1 Hz, 5'-CH), 5.50 (lH, d, J ~ 3.5 Hz, 1'-CH), 6.15 (lH, s, l-CH), 6.67 (lH, d, J ~ 8.8 Hz, NHCOCF3), 7.74 (2H, m, 7, 8-ArH),8.07 (2H, m, 6,9-ArH).
IR (N~colet, 20S FT, f~lm on NaCl plate): cm~1, 3422.1 (br str), 2928.1, 2853.9, 1720.3, 1668.9, 1594.7, 1292.0, 1183.5, 1166.4, 1009.3, 3S 986.49, 728.24.
~- S7: ~ Y~ of (1~8~18~38)-1-(3--trif~ . iA~_ 2',3',6'-tr~ lrso-L ' ~,. -~)-3-W 0 94/11382 2 ~ 4 ~ P ~ /CA93/00463 ~ p~ t~l-3~s~lo-t-trahrdro-s~
diGaO ~~p~t~~ 12,3-cI thioprr~n (BC~-2037 001 OCH~ O OCH~ O
~+ (lS 3R~or 2 OCH~ OCN, O
rl~R~A
+ (IS 3R)_ol 3 H~
PNBO NHIFA +
H,C--PNBO NHI~A
O O
~ H~C~
O O
H,C~
oHNHlFA
BCH-2037.001 S
St-p ls Pr par~t~on of (1'~,18,38) and (1'8,1R,3R)-1-(3'-~r~fl ~ 2',3',C'-~r~ c' ,,~ )-3-~c~trl-5,8'i ~
The _ ,_ ' from t~p 1, ~ 13, and A - -- - - ~ i n~ precur-or (259 mg, 0 66 mmole) w~r- di-~olved in CH2C12 (25 ml) and l-ft ~tirring ~n p~-a ~a of mol~ r i-ve for 30 minute~ b~forQ DDQ (150 mq, 0 66 lS mmole) wa- added The re~ulting mixture wa~ stirred for 2 1/2 hours NaHC03 (5% ~olution) wa~ added and th~ e: ~ layer wao extracted with CH2C12 The combin~d organic pha-e~ w~re w ~ with H20, dried over MgS04, filtered and ~ aLed in vacuo The crudc obtained was flash cl.~ ~hed u-ing TolsEE (9sl) to give a pure mixtur- of two titled 20 ~r- ~~c (in 60~ yield) which wa~ u~ed to carry out the next tep S U E~ r ~
W 0 94/11382 214 6 ~ ~ PC~r/CA93~00463 8t-p 2s Pr p~ration of (1'8,18,38) a~d (1'8,1R,3R)-1-(4'-p-n~Lc~ Qrl-3'-trifl~ tar~do-2',3~,6~-tr~ L-~ )-3 ~ 1-5,8-dio~o-~,S,8-tr~hpdro-lX-b-nzo-[2,3-c]-prr-n The c _ -~ from ~tep 1 herein (112.7 mg, 0.18 mmole) wa~ di-~olved in acetonitrile (5 ml), cooled to 0C, followod by th~ addition of NaHCO3 (29 mg, 0.34 mmole) and om~ H2O. ~h~ r-~ulting mixtur~ wa~ ~tirred for 5 minute~ before CAN (296 mg, 0.54 mmolc) was added. After all CAN wa~
added, the r-action mixture wa- ~tirred 10 minut-~ extra 0C, th~n ~- -d to room t~ ~- .Lu ~. H2O wa- addQd and Lt w~- extracted with CH2C12. Tho combined organic pha-o~ wero wa-hed with H2O, dried ovQr MgSO4, filtered and col~a~L~-ed in vacuo. The crude co~t~inin~ a mixtur- of two titled dia-t-roo~- - a wa~ u~ed in th~ following ~tep.
lS
8t-p 3s (1'8,18,3s~)-1-(4'-p-niL~ ~yl-3'-trif~ do-2',3',6'-tr;~ )-3 ~ 1-S,10 .';~
3, 4, S, 10-t-trahrdro- lH ~ - [ 2, 3-c ] -th~ oprr~
Following tha - ~ 1, tap 1, a mixture of th~ two titled adduct- wa~
obtain~d which could b~ v .Led via fla-h ch,~ --G~ph~. Th~ fir~t elu~nt had:
lH NNR (ac~tone-d6, 250 ~Hz, Brukor): ~, 1.23 (3H, d, J ~ 5.6 Hz, 6'-CH3), 1.70-1.90 (2H, m, 2'-CH2), 2.44 (3H, , COCH3), 2.84 (lH, dd, J
2S 17.8 Hz, 11.8 Hz, 4-HCHa), 3.36 (lH, dd, J ~ 17.8 Hz, 4.1 Hz, 4'-HCHe), 4.53 (lH, dd, J - 11.8 Hz, 4.1 Hz, 3-CH), 4.60 (lH, m, 3'-CH), 4.75 (lH, qua, J ~ 5.6 Hz, 5'-CH), 5.53 (lH, ~, 4'-CH), 5.70 (lH, d, J ~ 2.3 Hz, l'-CH), 6.13 (lH, ~, l-CH), 7.90 (2H, m, 7, 8-ArH), 8.12 ~2H, m, 6, 9-ArH), 8.39 (4H, m, PNB), 8.65 (lH, d, J ~ 5.8 Hz, NHCOCF3).
The ~econd luent had:
lH NMR (-~ ~ - d6, 250 ~Hz, 8ruker): ~, 1.32 (3H, d, J ~ 6.8 Hz, 6'-CH3), 2.39 (3H, ~, COCH3), 1.94 (lH, dd, J = 12.3 Hz, 4.1 Hz, 2'-HCHa), 2.50 (lH, tr d, J - 12.3 Hz, 2.9 Hz, 2'-HCHe), 2.89 (lH, dd, J ~ 18.2 Hz, 11.2 Hz, 4-HCHa), 3.35 (lH, dd, J ~ 18.2 Hz, 3.5 Hz, 4-HCHe), 4.41 3S (lH, dd, J ~ 11.2 Hz, 3.5 Hz, 3-CH), 4.52 (lH, m, 3'-CH), 4.66 (lH, qua, J ~ 6.8 Hz, 5'-CH), 5.47 (lH, ~, 4'-CH), 5.74 (lH, d, J ~ 2.9 Hz, 1'-CH), 6.31 (lH, ~, l-CH), 7.91 (2H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH), 8.38 (4H, m, PNB), 8.68 (lH, d, J ~ 7.1 Hz, ~.A ~Cr3).
S I~ ~T~ ~ q~ ~
W O 94/11382 2 1 4 6~ ~ ~ PC~r/CA93/00463 s~t~p 4s (1'8,1s~,38)-1-(3'-ts~fl~ -2',3~,6'-tr~
) -S ,10-~l~o-ao-3, 4, 5 ,10-t-tr~h~dro-1 [2,3-cl-thLoprran ~C8-2037.001) S lB NMR ~CDC13 250 MHz, Brukcr)s ~, 1.43 (3H, ~, 6'-CH3), 1.83-1.98 (2H, m, 2'-CH2), 2.37 (3H, , COCH3), 2.90 (lH, dd, J - 17.8 Hz, 12 Hz, 4-HCH~), 3.32 (lH, dd, J - 17.8 Hz, 4.1 Hz, 4-HCH~), 3.61 ~lH, br s, 4'-CB), 4.07 (lH, dd, J - 12.0 Bz, J - 4.1 Hz, 3-CH), 5.53 ~lH, ~, l'-CH), 6.21 ~lH, s, l-CH), 6.74 (lH, d, J ~ 7.6 Hz, ~n~G~F3), 7.76 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
_1- S8s Pr parat~on of (1'8,1R,3R)-1-(3'tr~f~ do-2',3',6'-tr~ lrso-L ~ 3-~ r-~~L~1-3,4,S,lO-t-tr-~d~ 5,10-~i~a~ ~ [2~3-cl prr~n (~C~-2127) O o o o o o o o HIC~ H,C~
PNBo NHIP~ oHNHlFA
t-p ls (1'~, lR, 3R)-1-(3'-tr~fl ~ 2',3',6'-tr~ r~ ~ T-_ 1~ . r~ z~ 1-5,10-d~o~o-3,4,5,10-t-tr h~ro-~r -~p~ 2,3-c]-~ (BC~-2127) Th~ ~cond ~luent from zt-p 3, _ 1A 57, wa- hydrolyzed wLth c~talytLc ~d~ - h~ Ln ~h-~ol. The tLtled c~ ~aurd h~d:
2S lH NMR (CDC13 2S0 H~z, Bruksr): ~, 1.43 (3H, d, J - 6.5 Hz, 6~-CH3), 1.80-2.00 (2H, m, 2'-CH2), 2.37 (3H, ~, COCH3), 2.91 (lH, dd, J ~ 18.3 Hz, 11.8 Hz, 4-HCHa), 3.33 (lH, dd, J = 18.3 Hz, 4.7 Hz, 4-HCHe), 3.60 (lH, br ~, 4-CH), 4.07 (lH, dd, J = 11.8 Hz, 4.7 Hz, 3-CH), 4.25 (lH, m, 3'-CH), 4.35 (lH, qua, J ~ 6.5 Hz, 5'-CH), 5.53 (lH, d, J ~ 2.4 Hz, 1'-CH), 6.21 (lH, ~, l-CH), 6.74 (lH, d, J - 7.6 Hz, ~ 3), 7.76 (lH, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH).
_1- S9s Pr-paration of (1'8,18,3~-1-(3'-~r~f~ tr ~
2',3',6'-tr~ lr~o-L '- ~ )-3 -~ 1-3-O ~3 ~
21~4~
m thrl-3,4,S,10-t-tr~h~d,~ 5,10 ';~-~- lH - ~ ~} ~ t 2, 3 -cl pqran (BC~-2090) OCH~ O OCH~ O
~CH, ~J~CH, OCH, OCH, O OCH, X~ H3~ H3c jZj~
1 ~ X-C4 PNI~O NHlp~ PNBo NRIF~
~ 4 PNBO ~ ~
+ H3C~
O O
PNBO ~ \~ ~H3 O O
H3~J
BC~2090 S
8t-p 1s 3 ~ 3-m thyl-5,8 '; -~ c~- -The _ __ ~ from ~t-p 1, ~ 53, (126 5 mg, 0 474 mmol) was di-solved $n ther nd then cool~d to -78C Msthyll$th$um (1 4 M Ln ether (0 71 ml, 0 995 mmol) wa- add-d Aft-r 10 m$nut-- methanol was added The r-act$on m$xtur- wa- ac$d$f~ed w$th HCl (0 5 N) and extracted w$th thyl -~~t~te The organic layer was dri~d over sodium ~ ~ulfat~ ~nd then o~a~. t-' to give a crude product (121 mg) lH NNR
~howed that it wa- a mixtur- of tarting mat~rial and product in 1 1 1~ ratio Ch,~ - o~ ~phy ~11 e~ jr~luti~n of the desLred tLtled product as a gel lH NMR (CDC13 250 NHz, BrukQr)s 8, 1 37 (3H, ~, 3-CCH3), 2 24 (3H, s, COCH3), 2 59 (lH, d, J ~ 17 6 Hz, 4-CH), 2 99 (lH, d, J - 17 6 Hz, 4-SU~ ET
WO 94/11382 PCI/CA93/004~3 2 1 ~
CH), 3.74 (3H, ~, OCH3), 3.76 (3H, s, OCH3), 4.77 (2H, ~, l-CH2), 6.57 (lH, d, J ~ 9.4 Hz, ArH), 6.62 (lH, d, J ~ 9.4 Hz, ArH).
IR (Nicolet, film on NaCl plate): cm-l, 2941.9, 2834.4, 1721.6, 1482.4, 1340.2, 1257.0, 1061.4, 795.30, 716.80 - 8t-p 2s (~S,lS,38) ~d (1'8,1S,3R~-1-(4'-p-~ 1-3~-tri f 1~ ~e~do-2',3',6'-tr~c ~ L-l~ o~)-3-~c-t~1-3---th~1-5,8 'i - ~ ~ i.~ -10 The ~ from st~p 1 herein (67 mg, 0.268 mmol) wa~ ~tirr~d with DDQ
(91.3 mg, 0.422 mmol) and 4',5'-prot-cted ~ in^ (157 mg, 0.402 mmol) in methyl-no chloride at 40C for 24 hour~. The olvent wa~
_v~p~.~L-d. The crude product wac chromato~phod (h-xsEtOAc ~ 10s4) to give the titled = au '- (88 mg co~tainin~ two i~ n 2sl ratio lS i n - ~ ~rable).
lH NMR (CDC13 250 MHz, Bruker): ~, 1.23 (3H, d, J - 6.0 Hz, A-6'-CH3), 1.22 (3H, d, J - 6.0 Hz, B-6~-CH3), 1.44 (3H, s, A-3-CCH3), 1.66 (3H, ~, B-3-CCH3), 1.84 (lH, m, A-2'-CH), 1.84 (lH, m, A-2'-CH), 1.84 (lH, m, B-2'-CH), 2.14 (lH, m, A-2'-CH), 2.15 (lH, m, B-2'-CH), 2.80 (lH, d, J
15.9 Hz, A-4-CH), 3.02 (2H, a, B-4-CH2), 3.14 llH, d, J ~ 15.9 ~z, A-4 CH), 3.77 (6H, z, B-OCH3), 3.80 (6H, , A-OCH3), 4.41 (lH, qua, J - 6.0 Hz, B-5'-CH), 4.47 (lH, m, B-3'-CH), 4.56 (lH, qua, J ~ 6.0 Hz, A-5'-CH), 4.61 (lH, m, A-3~-CH), S.40 (lH, s, B-4'-C~), 5.44 (lH, c, A-4'-CH), 5.61 (lH, d, ~ - 2.5 Hz, B-l'-CH), 5.70 (lH, d, J ~ 2.2 Hz, A-l'-CH), 6.35 (lH, , B-l-CH), 6.37 (lH, s, A-l-CH), 6.41 (lH, d, J - 7.6 Hz, B-N~COCF3), 6.46 (lH, d, J - 7.8 Hz, A-NHCOCF3), 6.76 (2H, m, B-ArH), 6.81 (2H, m, A-ArH), 8.25 (8H, br ~, A-PNB, B-PNB~.
IR (N~colet, 205 FT, film on NaCl plate): cm~l, 3327.9, 2945.2, 2840.3, 1732.6, 1528.4, 1489.4, 1351.8, 1263.4, 1167.8, 1116.3, 1105.2, 969.06, 948.80, 801.62, 720.66.
Al~o ~bt~ l from thi- reaction (34 mg) wa~ (l'S, lR, 3S)-1-(4'-p-n$troben~oyl-3'-trifluoroac~tamido-2',3',6'-trideoxyly ~ y~_n~e)-3-acetyl-3-methyl-5,8-d~methoxy-irac'r~ -n which had:
lH NMR (CDC13 250 MHz, Bruk~r): ~, 1.18 (3H, d, J - 7.6 Hz, 6' CX3), 3S 1.51 (3H, ~, 3-CCH3), 2.00-2.10 (2H, m, 2'-CH2), 2.84 (lH, d, J = 17.1 Hz, 4-CH), 2.96 (lH, d, J Y 17.1 Hz, 4-CH), 3.77 (3H, ~, OCH3), i.78 (3H, ~, OCH3), 4.54 (lH, qua, J ~ 7.6 Hz, 5'-CH), 4.62 (lH, m, 3'-CH), 5.46 ~lH, d, J - 2.1 Hz, 4'-CH), 5.56 (lH, c, l'-CH), 6.14 (lH, ~, t~ ET
WO 94/11382 PCI`/CA93/00463 -~ 1 46~ ~
1 - CH), 6.41 (lH, d, J ~ 7.6 Hz, NHCOCF3), 6.70 (lH, d, J - 8.8 Hz, ArH), 6.76 (lH, d, J ~ 8.8 Hz, ArH), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm 1, 3336.5, 2940.0, 2834.3, 1730.3, 1527.2, 1481.4, 1266.3, 1163.6, 975.8, 718.02.
S
8t-p 3s (l~S,18~38) znd (1'8, 18, 3R)-1-(4'-p-ni~o~ Qrl-3'-tr~f~ do-2',3',6'-tr~ )-3-ac-t~1-3-~ th~1-S,8 '~o-4,5,8-tr~hrdro-1~ o-~2,3-c]-prran CAN ~Y~t1~ of th- productz from t-p 2 h-rein gave the titl-d ~s (a~ per ~ec~ tep 2, exumple 14).
lH NMR (CDC13 250 MHz, Bruker)s ~, 1.30 (3H, d, J ~ 6.0 Hz, A-6'-CH3), 1.27 (3H, d, J ~ 6.1 Hz, 8-6'-CH3), 1.44 (3H, B, A-3-CCH3), 1.44 (3H, 8, lS B-3-CCH3), 1.80-2.30 (4~, m, A-2'-CH2, B-2'-CH2), 2.62 (lH, d, J -18.1 Hz, A-4-HCHa), 2.72 (lH, d, J - 18.1 Hz, A-4-HCH~), 2.70 (lH, d, J
~ 18.0 Hz, B-4-CH), 3.25 (lH, d, J ~ 18 Hz, B-4'-CH), 4.41 (lH, m, B-3'-CH), 4.56 (lH, m, A-3'-CH), 4.57 (lH, gua, J - 6 Hz, B-5'-CH), 4.72 (lH, qua, J - 6 Hz, A-5'-CH), 5.38 (lH, ~, B-4'-CH), 5.42 (lH, s, A-4~-CH), 5.58 (lH, d, J ~ 2.4 Hz, B-l'-CH), 5.66 (lH, d, J ~ 2.9 Hz, A-l'-CH), 5.98 (lH, ~, B-l-CH), 6.02 (lH, ~, A-l-CH), 6.45 (lH, d, J - 8.1 Hz, B-NHCOCF3), 6.55 (lH, d, J - 8 Hz, A-NHCOCF3), 6.70-6.87 (4H, m, A-6, 7-Quin, B-6, 7-Qu$n), 8.28 (8H, m, A-PNB, B-PNB).
IR (Nicol~t, 205 FT, film on NaCl plate): cm~l, 3327.5, 3084.6, 2984.9, 2S 2938.2, 1723.4, 1661.1, 1533.4, 1352.8, 1278.0, 1215.7, 1169.0, 1122.3, 948.30, 730.86.
8t-p 4s (1'8,18,38) nd (1'8, 18, 3R)-1-(4' ~ ~L-.b -orl-3'-tr~fl ~_o~ 2',3',6'-tr~ )-3-ac-trl-3-m-thrl-5,10 '~-o-4,5,10-trihydro-lH-~ 2,3-c3-yqr n The gu$none from ztep 3 herein wa~ cyc~o~d~ed with l-acetoxybut~'inns a~
per ~,ocedu,_ de~cribed in step 3, _ - _le 14. The (l'S,lS,3R) titled c __ ' had:
H NMR (CDC13 250 MHz, Bruker): ~, 1.35 (3H, d, J ~ 5.9 Hz, 6'-CH3), 1.49 (3H, 8, 3-CCH3), 1.95 (lH, dd, J = 12.6 Hz, 4.7 Hz, 2'-CH), 2.12 (lH, d tr, J - 12.6 Hz, 2.9 Hz, 2'-CH), 2.71 (lH, d, J ~ 18.2 Hz, 4-CH), 2.89 (lH, d, J - 18.2 Hz, 4-CH), 4.60 (lH, m, 3'-CH), 4.85 (lH, qua, J
5 ~ E ~ ~F
PCI`/CA93/00463 W0 94~ll382 ~ 8 5.9 Hz, 5'-CH), 5.47 (lH, br ~, 4'-CH~, 5.71 (lH, d, ~ - 2 Hz, l'-CH), 6.21 (lH, d, J - 1.2 Hz, l-CH~, 6.42 (lH, d, J ~ 7.6 Hz, NHCOCF3~, 7.78 (2H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH~, 8.31 ~4H, m, PNB~.
IR (NiCo~t~ 205 FT, film on NaCl plate): cm~l, 3336.3, 2922.6, 2852.6, S 1728.0, 1666.8, 1532.8, 1346.3, 1273.5, 1212.3, 1165.6, 1119.0, 1098.6, 996.7, 952.96, 836.3, 722.58.
Th~ (l'S,15,3S~ dlast~.~ ~ had:
lH NMR (CDC13 250 MHz, Bruk r~s ~, 1.31 (3H, d, J - 5.9 Xz, 6'-CH3), 1.47 (3H, , 3-CCH3~, 1.89 (lH, dd, J - 11.8 Hz, 5.3 Hz, 2'-HCHa), 2.06 (lH, d tr, J - 11.8 Hz, 4.1 Hz, 2'-HCH~), 2.55 (lH, d, J - 17.8 Hz, 4-HCHA~, 3.40 (lH, d, J - 17.8 ~z, 4-HCH~), 4.45 (lH, m, 3'-CH), 4.66 (1~, qua, J - 5.9 Hz, 5'-CH), 5.43 (lH, ~, 4'-CH), 5.63 (lH, d, J - 2.3 Xz, l'-CH), 6.17 (lH, , l-CH), 6.30 (lH, d, J - 11.8 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 3.30 (4H, m, PNB).
8t-p 5s (1'8, 18, 3~)-1-(3'-trifl r~ -2',3',6'-tr;~
~ 3 ~ 1-3-u~thrl-5,10 ~i9-~-q,S,10-tr~hrdro-l~ ~ 12,3-cl-prr n ( Q -2090) Hydroly-i- of th~ (l'S,lS,3S) ~,~_ ~o~ from st~p 4 ~- ~in g~v~ thQ
titl~d c _ '.
M.P. 95C.
lH NMR ~CDC13, 2S0 N~z, Bruk~r)s ~, 1.41 (3H, d, J - 5.9 Hz, 6'-CH3), 1.46 (3H, ~, 3-CCH3), 1.85 (2H, m, 2'-CH2), 2.27 (3H, ~, COCH3), 2.84 ~2H, d, J - 5.9 Hz, 4-CH2), 3.65 (lH, s, 4'-CH), 4.31 (lH, m, 3'-CH), 4.64 (lH, gua, J ~ 6.0 Xz, 5'-CH), 5.53 (lH, br , l'-CH), 6.15 (lH, s, l-CH),-6.71 (lH, br d, J - 8.8 Hz, NHCOCF3), 7.75 (2X, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH).
IR (Ni~ol ~ , 205 FT, f~lm on NaCl plat-): cm~l, 3423.2, 3342.2, 3087.5, 2987.2, 2933.2, 1717.6, 1667.5, 1590.3, 1289.3, 1216.0, 1179.1, 1167.6, 1124.2, 980.89, 940.05, 918.55, 734.22.
- 60s Pr paration of (1'8~1R~38)-1-(3'-tr~f) -_.~- L- i~_ 2',3',6'-tr~ lrso-L ' ~ )-3-~ 1-3,4,S,lO L~ d-o 5,10-~ [2~3-c] prran (~C~-1689) ~"~ ~ r q~ ~ r _~ C" ~ ~ 11 ~~ ~r '~
WO 94/11382 21~ PCT/CA93/00463 (OCH,)2 ~(OCH,), C X~Br OCH~ OCH~
OCH~ ~po(ocH~)2 O O
~,~o(OCH~)2 ~W;~
+ (IS 3R~e ~ + (lS 3R}i~ooc I _ r 4 OCH, O
O O
pNCB~A PNBC;~A
0~o(ocH~)2 ~``~po(ocH~)2 O O O o H,C~;11 ~ H~C~J
PNBO NHlFA O O PNBo NHlE~A
0~0(0CH,)2 O O
BC~16119 o}{NNlFA
8t-p lt 3 ~ t~1-5,8 ~; Lho~-;~- . -S Tha titl~d cc _ wa- pr-par-d by uz$ng 5,8-dimathoxy-3---e~o~o_ ~ - n and th~ r a from tep 1, - 1~- 8.
lH NMR (CDC13, 2SO MHz, 8ruker)s 2.59 (lH, dd, J - 15.9 Hz, 11.8 Hz, 4-HCHa), 3.03 (lH, dd, J - 15.9 Hz, 2.9 Hz, 4-HCH~), 3.74 (3H, o, OCH3), 3.75 (3H, ~, OCH3), 4.23 (lH, dd, J ~ 11.8 Hz, 2.9 Hz), 4.27 (lH, d, J
13.5 Hz, CHBr), 4.34 (lH, d, J ~ 13.5 Hz, CHBr), 4.63 (lH, d, J ~ 15.9 Hz, 1-HCH~), 4.96 (lH, d, J ~ 15.9 Hz, l-HCHe), 6.63 (2H, m, ArH).
8t - p 2s 3 d; ~ t~l - 5,8 - d~ otho~y-i~och~. -The titl~d ~ wa- obta~ned following troatment of the product from t~p 1 h~rein w1th P(OCH3)3.
lHNMR (CDC13, 250 MHz, Bruker), ~:2.57 (dd, 1 H, J - 16.9 Hz, 11 Hz, 4 -HCHa), 2.98 (dd, 1 H, J ~ 16.9 Hz, 2.9 Hz, 4 - HCH~), 3.26 (dd, 1 H, J =
21.5 Hz, 14.5 Hz, COCHP), 3.54 (dd, 1 H, J ~ 21.5 Hz, 14.5 Hz, COCHP), ~U~ 5i, ~
WO 94/11382 PCl/CA93/00463 3.71 (s, 3 H, ArOCH3), 3.72 (~, 3 H, ArOCH3), 3.74 (d, 3 H, J ~ 4.3 Hz, POCH3), 3.78 (d, 3 H, J - 4.3 Hz, POCH3), 4.11 (dd, 1 H, J ~ 11 Hz, 3.4 Hz, 3 - CH), 4.63 (d, 1 H, J ~ 16.3 Hz, 1 HCHa), 4.97 (d, 1 H, J - 16.3 Hz, 1 - HCH~), 6.60 (m, 2 H, 6.7 - ArH).
S IR (NLcol~t, 205FT, fLlm on NaCl platn), cm~l: 2954.3, 2836.7, 1725.5 (str), 1603.9 (W), 1482.2, 1259.2 (ztr), 1034.7, 799.10, 715.8.
St-p 3t (1'8,18,3R) (1~8,1~,38)-S,~ 1(2',3',6'-tr~qc ~ 3'-tr~ fl ~ do-4~-p-nl~ Qyl-~-l~ )-3-d~--thy~ zochro ~
To a ~tLrred solut~on of the ~b-sph~ate from ~tep 2 h~r-Ln (199 mg, 0.58 mmole) wLth 4 - PNB - 3 - TFA - ~ ne (270 mg, 0.69 mmole) Ln cl~hlorom~thane (60 ml) wa- added 4 pel~t- of mol- l~r Love~ (4A-).
lS ThL~ wa~ followed by ~ddLtLon of ~hl~rodLzyanoquLnon~ (DDQ, 170 mg, 0.75 mmole) in on~ portLon. The rezultLng green lLqu~d waa ~tLrred at 40 C (controll~d by an T~ -~ Ra~ C ~~-t~n~-Stirring y-t~m) Ln a nclo-ed y-tem for 25 hours then at room tr - ~Lu~ (wLthout hsatLng) for 48 hour~. The r~zulting muddy mLxture wa~ .~po~L~d ~nd then dLr-ctly ch~. -to~ (HexsEA ~ 1:1.5) to yLeld the d~Lred tLtl~d gly-c=~-7 (dia~t-~ - Lc mLxture A and B, a~ lLght-color~d gla-~y materLal, 407 mg) .
lHNMR (CDC13, 250 M~z, Bruker), ~:1.20 (d, 3 H, J - 7.0 Hz, 6' - CH3A), 1.23 (d, 3 H, J - 7.0 Hz 6~ - CH3B), 1.82 ~dd, 1 H, J - 12.2 Hz, 4.5 Hz, 2S 2' - HCHAa), 1.91 (dd, 1 H, J ~ 12.3 H~, 4.6 Hz, 2' - HCHBa), 2.07 (dt, 1 H, J - 12.3 Hz, 3.5 Hz, 2' - HCHA~), 2.20 (dt, 1 H, J - 12.4 Hz, 4 Hz, 2' - HCHBe), 2.54 (dd, 1 H, J ~ 16.9 Hz, 13.4 Hz, 4 - HCH8a), 2.60 (dd, 1 H, J - 17 Hz, 11 Hz, 4 - HCHAa), 2.96 (dd, 1 H, J ~ 11 Hz, 3.5 Hz, 4 -HCHA~), 3.03 (dd, 1 H, J - 11.1 Hz, 3.3 Hz, 4 - HCHB~), 3.74 - 3087 (8x~, 24 H, 2 x ArOCH3A, 2 x ArOCH3B, 2 x POCH3A, 2 x POCH3B), 4.41 (qua, 1 H, J ~ 6.0 ~z, 5' - CHB), 4.50 - 4.68 (M, 4 H, 3' - CHA, 3' -CHB, 3 - CHA, 3 - CHB), 4.70 (qua, 1 ~, J ~ 7.0 Hz, S' - CHA), 4O99 (d, 2 H, J - 16 Hz, COCH2AP), 5.03 (d, 2 H, J ~ 16.7 Hz, CoCH2BP), 5.41 (-, 1 H, 4' - CHB), 5.47 (~, 1 H, 4' - CHA), 5.57 (B, 1 H, 1' - CHB), 5.61 3S (~, 1 H, 1~ - CHA), 5.98 (~, 1 H, 1 - CHB), 6.15 (~, 1 H, 1 - CHA), 6.71 (qua~ 2 H, J ~ 8.7 Hz, 6.7 - ArHB), 6.75 (qua, 2 H, J ~ 8.5 Hz, 6.7 -ArHA)~ 6.89 (d, 1 H, J ~ 7.0 Hz, rH~OCF3), 7.05 (d, 1 H, J ~ 7.0 Hz, NHACOCF3), 8.21 (m, 8 H, 4 x COArHANO2, 4 x C~rHBNO2).
Sl~ t ~ ~ L 5~ ~_ T
W O 94~11382 PC~r/CA93/00463 ~ 2146~48 8t-p ~s [~1'8,1S,3R) and (l~s~lR~3s)-l-(a~3~6 -tr~ 3~-tri fl ~ c-tam~do-~'-p-nit~ )-3-dim thr~ Lhyl-3,4,S,8-t-trahydre- ~ -L~ [2,3-c]-pyr S
To a ~olution of glyco-ide from ~tep 3 her-in (98 mg, 0 13 mmole) in 8 ml of ac~tonitrile cooled to 0C wa~ added ~odium bi~rhon-t- ~_ e_ (22 mg, 0 27 mmol-) Thi- wa- fol ~ ' by dropwi-e addition Of ~
cerium ~ nitrate (CAN, 298 mg, 0 54 mmol- in 3 0 ml of wat~r) After 10 ;n~lt;~ at 0C, the r-action mixtur- wa~ pour~d to water (20 ml) and extract-d with ~1~hlG ~~ ~ (4 x 10 ml) The organic layer wa~ dried (over odium ulfate) and ~ o~ated to give the titled a~ a gla~y mixture (85 mg) lHNMR (CDC13, 250 MHz, Bruk r), ~ 1 15 (d, 1 H, J - 6 4 Hz, 6' - CH3B), lS 1 30 (d, 1 H, J - 6 4 H~ 6' - CH3A), 2 44-1 80 (M, 4 H, 2 - HCHAa, 2 -HCHBa, 2 - HCHA~, 2 - HCHB~), 2 41 (dd, 1 H, J - 16 6 Hz, 11 6 Hz, 4 -HCHBa), 2 48 (dd, 1 H, J - 16 6 Hz, 11 3 Hz, 4 - HCHAa), 2 83 (dd, 1 H, J - 17 0 Hz, 5 23 Hz, 4 - HCHAe), 2 85 (dd, 1 H, J - 16 8 Hz, 5 0 Hz, 4 - HCHBe), 3 79 (-, 3 H, POCH3A), 3 84 (-, 3 H, POCH3A), 3 82 (d, 3 H, J
~ 2 1 Hz, POCH3B), 3 87 (d, 3 H, J ~ 2 1 H~, POCH3B), 4 34 (qua, 1 H, J
~ 7 0 _z, 5' CHB), 4 48 - 4 60 (m, 4 H, 3 - CHA, 3 CHB, 3' - CHA, 3' -CHB), 4 64 (qua, 1 H, J ~ 7 0 Hz, 5' - CHA), 5 04 (d, 2 H, J - 25 Hz, COCH2AP), 5 05 (d, 2 H, J ~ 31 Hz, COCH2BP), 5 43 (~, 2 H, 4', CHA, 4' -CHB), 5 55 (-, 1 H, 1'- CHA), 5 61 (~, 1 H, 1' - C_B), 5 81 (~, 1 H , 1 2S - CHB), 5 97 (-, 1 H, 1 - CHA), 6 79 (m, 2 H, 6 7 - ArHB), 6 82 (m, 2 H, 6 7 - ArHA), 8 27 (8, 8 H, 4 x Cn`rRAN02, 4 x QO~rRBN02) ~t-p Ss (1'8,1R,3S)-1-~2',3',6'-tr~ t~ oyl-3'-tri f ~ 7~ -L-~ ) -3 ; ~hyl E~ -c_Lyl-5,10-dioso-3,4,5,10-t-trahrdro-lH-~ '~[2,3--cl--prr n The ~ nd~ from ~tQp 4 hsrein (85 mg, 0 121 mmol) were h~t;~d with 1-ac~Lo~y 1,3-~utr~i~ ~ (86 ~1, 0 723 ol) in toluene at 45C for 28 3S hours Solvent wa~ ~v~aLed and the crude product wa~ ch,. - G~ ~hed three time~ (tol~e -sEtOAc HOMes ~eton~ sHOAc ~ 240 75 10 10 1) to give the (l'S,lR,3S) i~omer (21 mg) and'the (l'S,15,3R) i~omer (18 mg) The titled . _ had r r~ ~~ s~ .~ ~ I~ T
t~ ~ ~ L
~ ~:4 ~
lH N~R (CDC13, 250 MHz, Bruk r): 8, 1.19 (3H, d, J - 7.0 ~z, 6~-CH3), 2.03 ~lH, m, 2-HCH,), 2.07 (lH, m, 2-HCH~), 2.56 (lH, dd, J ~ 18.2 Hz, 11.8 Hz, 4-HCHa), 3.05 (lH, dd, J ~ 18.2 Hz, 4.7 Hz, 4-HCH_), 3.85 (3H, d, J - 2.0 Hz, POC~3), 3.91 (3H, d, J 8 2.0 Hz, POCH3), 4.40 (lH, qua, J
S ~ 7.0 ~z, 5'-CH), 4.60 (lH, m, 3'-C~), 4.65 (lH, dd, J - 11.8 ~z, 4.7 Hz), 5.04 (lH, br ~, CHP), 5.17 (lH, tr, J - 2.0 Hz, CHP), 5.42 (lH, n, 4'-CH), 5.71 (lH, , l'-CH), 6.00 (lH, , l-CH), 6.48 (lH, d, J ~ 7.6 Hz, ~u~r3), 7.76 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.27 (2H, d, J ~ 8.0 Hz, PNB), 8.32 (2X, d, J - 8.0 Hz, PNB).
IR (Nieolet 205 FT, f~lm on N-Cl plat-): em~l, 3323.0, 3242.5, 3077.6, 2965.0, 1730.3, 1661.9, 1593.5, 1529.2, 1271.8, 1193.2, 1050.8, 864.0, 835.7, 722.1.
The eeond ~ -', (l'S,lS,3R)-1-(2',3',6'-tridc-A~ 4'-p-niprob~nzoyl-3'-trifluorc~ r.~-L-l,y ~'~ ~ pyranos~)-3-~i -Lhyl ~;!hr_ph~ Aty lS 5,10-dioxo-3,4,5,10 t~ hydro-lH-~ph~hot2,3-e]-pyran had:
M.P. 135-137C.
lH NMR (CDC13, 250 ~Hz, Bruk r): ~, 1.33 (3H, d, J - 6.4 Hz, 6'-CH3), 2.01 (lH, ~r tr, J ~ 11.8 ~z, 3'-HCH~), 2.15 (lH, br tr, J - 11.8 Hz, 3'-HCH~), 2.62 (lH, dd, J ~ 18.8 Hz, 12.1 Hz, 4-HCH~), 3.01 (lH, dd, J =
18.8 Hz, 4.4 ~z, 4-HCH~), 3.81 (3H, ~, POCH3), 3.86 (3H, ~, POC~3), 4.58 ~lH, ~, 4'-CH), 4.60 (lH, dd, J - 12.1 Hz, 4.4 ~z, 3-CH), 4.79 (lH, qun, J - 6.4 Hz, 6-CH), 5.02 (lH, br ~, PCH), 5.13 (lH, br , PCH), 5.46 (lH, ~, s~-CH ), 5.62 (lH, s, l'-CH), 6.14 (lH, ~, l-CH), 6.63 (lH, d, J -8.2 Hz, NHCOCF3), 7.79 (2H, m, 7, 8-ArH), 8.16 (2H, m, 6, 9-ArH), 8.30 ~4H, m, PNB).
IR (Ni~ol~t 205 FT, f~lm on NaCl plato)s em~l, 3322.0, 3242.5, 3083.5, 2959.0, 2853.0, 1729.5, 1668.6, 1597.0, 1525.5, 1276.4, 1183.7, 1045.9, 853.9, 724.2.
~t-p 6: (1'8,1R,38)-1-(2',3',6'-tr~ 3'-tr~f~ ;A~-L-~ )-3 ~ t~rl '~ 1-5,10 ';~
3~S-lO-t-tr~h~dro-lr ~ '- t2,3-e]-prr n ~JC~-1~89) The PND ~,~Lc~ L_~h~ t~ frem t-p 5 ~- ~in ~21 ~g, 0.028 mmol) wa~ di~olvod in ~HF-~ OH (3 ml of aeh) ~nd eoolf~ to 0C. 8Odium -- h~ (4.3 m, 6.5 ~1) wa~ added. Aftor ~tLrred for 5 in~t~- at 0 C, the erud~ mixture (pink) wa- aeidifiod with 0.1 N ~ g ~ hyd ogon chloride. It wa~ extracted w$th ~ethyl-ne chloride, dri~d (over ~odium ulfate) and _.apo-aLed to givs a crud~ product which wa~
SIE~ T
21~6~8 from m thylonc chlor$d- ~nd h-x~n~ to q$v~ th- d~$rcd product (10 mg) ~ n of f -whit~ olid .
.P. 95-97C.
lH NMR (CDC13, 250 MBz, Bruk~r)s ~, 1.25 (3H, d, J ~ 8.2 Hz, 6'-CH3), 1.83-1.98 (2H, m, 2'-CB2), 2.53 (lH, dd, J - 17.6, 11.8 Hz, 4-HCHa), - 3.00 (lH, dd, J ~ 17.6 Hz, 3.5 Hz, 4-HCHe), 3.62 (lH, br ~, 4'-CH), 3.82 (3B, , POCH3), 3.86 (3H, 8, POCB3), 4.16 (lH, gu~, J - 8.2 Hz, S'-CH), 4.34 (lH, m, 3'-CH), 4.62 (lH, dd, J - 11.8 Hz, 3.5 Hz, 3-CH), 5.01 (lH, s, CHP), 5.12 (lH, ~, CHP), 5.54 (lH, , l'-CH), 5.94 (lH, , l-CH), 6.82 (lH, d, J ~ 7.1 Hz, NHCOCF3), 7.74 ~2H, m, 7, 8-ArH), 8.06 (2H, m, 6, 9-ArH).
IR (Nicolet 205F~, film on N~Cl pl~t-): cm~l, 3421.4 (br), 3080.8, 2960.1, 1718.4, 1664.5, 1556.7, 1457.6, 1283.0, 1188.1, 1043.7, 983.4, 858.9, 728.4.
lS
~U~STi ~ JTE S~EET
WO 94/11382 PCI`/CA93/00463 214~4~
r ~ 615 . V~S~ou~ ~--2 ' ~Alr i~i~ ~pl~
g H~C~ H,Cj~ + ~C}~
,,~0 ~0 H~CO
OCHJ OCHJ O OCH~ O OCH~ O
Wa~ 3 ¢Ç~ ~10 ~CH~ ~
H~CO O HJC O HJCO OHJCO O
~C~ ~C~ H~C~ HJC~
rO~ .eOO~ I AcOO~ I HooH
~4 ~6 ~8 WLCII~ ~CH, ~aCH,~'`~
HJHCO~ H~CO~ ~0I HJHCO~
~5 l7 ~9 l 12 oo oo oo oo ~} ~ ~p~CH~ CH, O O O o o H~C~ HJC~ HJC~ H~C~;t HO I ~oOOAC ~.coA~ ~ I
BCH-20lS BCH I666 BCH-1667 BCH 2014 s ~t-p ls 3,4-D~ O ~ l-2-~odo-2,C '~
To a mixture of dL-O-acetyl fucal ~3 029 g, 14 140 mmol) ln 180 ml of ~-~t~itrile and 18 ~1 of water wa~ added portionwi-~ the NIS ~3 590 g, 15 554 m~ol) Aft-r tirr~ng for 30 minut~ th- mixtur- wa- xtracted with CH2C12 ~2x) and the combined organic extract- w r~ ^d wLth 10%
odium thir- lf- ~ ~olut~on, water and finally dr~ed (Na2SO4) to give 4 403 g (87~ yi~ld) of the dQ-ir-d ugar PNR (~c~L~ d6, 250 H~z) ~ 1 12 (d, 3H, J~6 4Hz, CH3-6'), 1 99 ~nd lS 2 11 (2-, 2X3H, 2XOAc), 4 36 (d, 1~, J-5 1Hz, H-2), 4 48 (q, lH, J~6 6Hz, ~-5), 4 98 (unre~olved dd, lH, H-3), 5 18 (broad ~,lH, H-4), 5 59 (broad ~, lH, H-l), 5 94 (d, lH, OH) S U ~ , T ~
~ 214;65~8 ~t-p 2:(1'8,1R,38) ~Dd (1's~,18,3R) - 2,S ri Lhoxy-1-(~',6'-"~ 2'-~odo~ )-3-a~-to~oc~ro ~n ~o a mixtur- of ugar frDm ~t-p 1 ~- _in ~910 mg, 2.539 mmol) and methyl - ketone i~e:' ~ -n (500 mg, 2.116 mmol) ~n dry CH2C12 under argon a~ -r,'- ~ and room t~ re wa~ added Dms mol~ r ~i-VQ (4A).
After stirring for 20 minut-- DDQ (577 mg, 2.539 mmol) wa~ added.
Aft-r tirring for 72 hour~, whil- addition- of 0.5 guivalent of ugar and 0.5 quival-nt of DDQ w-r- don- after 24 nd 48 hour~, the reaction wa~ up by addition of 100 ml of NaHCO3 5~ and water mixtur~
(ls3). ~xtraction- with CH2C12 (3x100 ml) following by w ~h~ng with the ame ~ mixtur- and drying (Na28O4). Flash ch.. -tG~ap}~y of the crude (CH2C12sH-xs~tOAc~ 9s4sl) gave 361 mg of the non-natural lS (l~S,lS,3R) gl~cc~id~ ~nd 435 mg of th- natural (l'S,lR,3S) one. The arbLtrar$1y ~ (l'S,lS,3R) t~tled _ __ ~ had:
PMR (-cetonQ-d6, 250 MHz) ~: 1.27 (d,3H, J~6.5Hz, CH3-6'), 1.94 and 2.16 (2~, 2X3H, 2XOAc), 2.30 (~,3H,COCH3), 2.50 (dd, lH, J-17.8Hz and 12.1Hz, CH~CHO), 2.95 (dd, lH, J~17.8 and 4.3Hz, CHeCHO), 3.80 and 3.83 (2s, 2X3H, 2XOCH3~, 5.52 (d, lH, J~5.0Hz, H-2'), 4.75 (m, 3H, H-3, H-3' and H-5'), 5.24 (broad ~, lH, H-4'), 5.89 (ss, lH, H-l'), 6.15 (-, lH, H-l), 6.90 (2d, 2H, Ar-H).
The ~econd (l~S,lS,3R) titled ~ _ -' had:
PMR (-~etc - d6, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 1.97 and 2S 2.15 (28, 2Y3H, 2XOAc), 2.30 (8, 3H, COCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CH~CHO), 2.96 (dd, lH, J-17.6Hz and 4.1H~, CHeCHO), 3.80 and 3.82 (2~, 2X3H, 2XOCH3), 4.48 (d, lH, J~5.0Hz, H-2'), 4.54 (m, 2H, H-3, H-5'), 4.83 (un.~Dlved dd, lH, H-3'), 5.20 (broad 8, lH, H-4'), 5.86 (~, lH, H-l'), 6.03 (~, lH, H-l), 6.88 (2d, 2H, Ar-H).
8t-p 3s (l's~,lR,38)-5,8-~ 3 ~ o 1-(2',6'-~ 2'-~odo-L-l~ o~h.
To mixture of the ~ from tep 2 herein (500 mg, 0.844 mmol) in 90 ml of dry THF -i n~ 1 n~ at 0C and undsr argon a; ~_~ha._ were added 90 ml of NaOH 0.5N. After ~tirrin~ for 1 hour the reactLon mixture was n~utr~l--e~ with 160 ml of NH4Cl ~at.sNaHCO3 at. (4:1) and extracted with CH2C12 (3x200 ml). Th~ combined organic layer~ were dried over r ~ s W O 94~11382 PC~r/cA93/00463 5~ ~ --MgSO4. Flash ch~ Gy aphy (toluene:ethyl acetate; 8:2) of the crude gave 248 mg (49% yiQld) of pure titled ~
PMR (aceton~-d6, 2S0 MHz) ~: 1.26 (d, 3H, J~6.5Hz, CH3-6'), 2.29 (s, 3H, COCH3), 2.44 (dd, lH, J~17.5Hz and 12.2Hz, CHaCHO), 2.93 (dd, lH, S J-17.7Hz and 4.1Hz, CH~CHO), 3.16 (d, lH, J-6.0~z, OH), 3.49 (m, lH, H-3'), 3.77 (m, lH, H-4'), 3.79 and 3.84 (2X~, 2X3H, OCH3), 4.09 (d, lH, J=7.4Hz, OH), 4.25 (q, lH, J-6.6Hz, H-5'), 4.37 (d, lH, J~5.0Hz, H-2'), 4.54 (dd, lH, J-12.2Hz, 4.1~z, H-3), 5.84 (~, lH, H-l'), 5.99 (B, lH, H-1), 6.88 (2Xd, 2XH, ArH) 8t-p ~s ~ ,1~,3~)-3 ~ ~t~ 1-(2',6' ~ 2'-~odo-~-~ )-S,8 ~i~ 5,8-dih~drc~
The tLtl~d _ _ ' wa- obtain~d following CAN oxidat~on of th2 product from tep 3 ~- i n aS per pr~vious pr~CEdU~e.
PMR (CDC13, 250 MHz) 8: 1.32 (d, 3H~ J-6.6Hz, CH3-6'), 1.86 (larg~ d, lH, OH), 2.33 (-, 3H, COCH3), 2.39 (dd, lH, J-l9.9 and ll.9Hz, CHa-CHO), 2.81 (larg~ ~, lH, OH), 2.90 (dd, lH, J-19.7Hz and 3.9Hz, CHe-CHO), 3.32 (larg- , lH, H-3'), 3.78 (larg~ ~..~ lv d d, lH, H-4'), 4.17 (broad q, lH, J-5.0Hz, H-5'), 4.39 (m, 2H, H-3 and H-2'), 6.81 (s, lH, H-l'), 6.89 (~, lH, H-l), 6.81 (2Xd, 2H, ~u~n~9 ring-H).
IR (film) Vmaxs 3486, 3400, 2937, 1711, 1657, 1307, 968 cm~l.
~t-~ 5s (l'~,lR,38)- mathyl-~1-t2',6' ~ 3',4'-d~h~d.~ 2~-~odo-L-l~ -S,10 i~-~-3,~,S,10-L- ~ - [2,3-c] ~-c 3-rl) ' t - (~CH-~01S) Starting from 50 mg (0.105 mmol) of th~ c~ ' from t~p 4 h-rein and 1 ml of 1 r~t ~L~ -, th~ ~ d~cribQd in ~t-p 2, -- _ 18 5, has b~en followQd. After pur$fic~ti~, 15.8 mg (29~ y~ld) of pur~
titled c~ was j~~lrt~.
PMR (CDCl3, 250 MHz) ~s 1.32 (d, 3H, J~6.7Hz, CH3-6'), 1.91 (large d, lH, J~ll.OHz, OH), 2.36 (s, 3H, COCH3), 2.53 (dd, lH, J-19.5Hz, 11.4Hz, C~aCHO), 2.81 (larg~ d, lH, J-10.4Hz, OH), 3.08 (dd, lH, J~19.9Hz and 3S 4.1Hz, CH~CHO), 3.34 (m, lH, H-3'), 3.80 ~m, lH, H-4'), 4.17 (broad q, lH, 6.9Hz, H-5'), 4.45 (m, 2H, ~-3 and H-4'), 5.98 (2Xs, 2XlH, H-l and H-l'), 7.78 and 8.11 (2Xm, 2X2H, ArH).
IR (film) Vm~xs 3477 broad, 2928, 1722, 1670, 1298, 961, 732 cm~l.
W O 94/11382 P ~ /CA93/00463 2i~48 8t-p 6~ ,lR,3$)- 5,1~ rio~ 3-ac-to-l-(2~6~-A~ 3',~'-diac-tos~-2'-iodo-~)-5,8-dihrdroi~ochrD ~n CAN ~Yi~tion of the (l'S,lR,3S) dia~t~ Lc product from ~tep 2, S example 61, yLelded the titled ~
- PMR ~CDC13, 250 MHz) ~s 1.21 ~d, 3H, J-6.6Hz, CH3-6'), 2.07 and 2.22 ~2~, 2X3H, 2XOAc), 2.32 (~, 3H, COCH3), 2.41 ~dd, lH, J-24.1Hz, 11.8Hz, CHaCHO), 2.92 (dd, lH, J~19.7Hz nd 3.9Hz, CHeCHO), 4.29 (q, lH, J-6.5 Hz, H-5'), 4.36 (d, lH, J-5.1Hz, H-2'), 4.41 (dd, lH, J-11.2Hz nd 4.0Hz, H-3), 4.78 ~dd, lH, J-4.0Hz, H-3'), 5.23 (broad ~, lH, H-4'), 5.82 (18, lH, H-l'), 5.87 (18, lH, H-l), 6.81 (2d, 2H, qv~nnne ring-H).
8t--p 7t (1'8,1R,38)-~--thyl-(1-[2',6'-~~ 3~~4~ Ga~ 2'--iodo-L-l~ -5,10 io-o-3,4,S,10-t-tr h~d. ~ 2,3-cl ~,........ ~ 3-yl) ~ ~ - (BC~-1666) To a mixture of glyco~ide from tep 6 herein ~55 mg, 0.098 mmol) in 1.5 ml of dry tolu-n~ and under argon ~ -_~hc~, wa~ added 1-acetoxybut~i- - (66 mg, 0.587 mmol). After 18 hour~ of tirring the mixtur- was directly fla~h cl... LO~J,~h~d (tolu-nes~thyl ac~tate; 9:1) to give 17 mg of pur~ titl-d _ __ ' (28~ yi-ld).
PMR (CD2C12, 250 MHz) ~: 1.20 (d, 3H, J-1.20Hz, CH3-6'), 2.13 and 2.44 (28, 2X3H, 2XOCH3), 2.31 (8, 3H, COCH3), 2.62 (dd, lH, J~19.5Hz and 11.5Hz, HC~aCHC~O), 3.16 (dd, lH, J~19.5Hz, 4.0Hz, HCHeCHC~O), 4.45 2S (broad q, lH, J-6.6Hz, H-5'), 4.51 (d, lH, J~5.0Hz, H-2'), 4.62 ~ lved dd, lH, J-11.7Hz nd 4.0Hz, H-3), 4.88 (dd, lH, J~4.0Hz, H-3'), 5.32 (broad ~, lH, H-4'), 6.06 (~, lH, H-l'), 6.16 (~, lH, H-l), 7.71 and 8.22 (2Xm, 2Y2H, ArH).
lR (fi}m) Vmaxs 2991, 2935, 1746, 1668, 1238, 970, 730 cm 1.
~t-p 8s (l'~,lS,3R)-5,8-Dioso-3 -~-~o 1-(2',6'-~;~ ~ 3',4'-~ 2'-~odo-L-1~ )-5,8 di~d.o~
CAN ~Y~'t~ of the (l'S,lS,3R) gly~:a~de from tep 2, . _le 61, gave the titled a _ ~.
PMR (CDC13, 250 MHz) ~s 1.35 (d, 3H, J-6.6Hz, CH3-6'), 2.07 and 2.23 (28, 2X3H, 2XOAc), 2.32 (~, 3H, COCH3), 2.46 (dd, lH, J~20.3 Hz and 11.7 Hz, CHaCHO), 2.90 (dd, lH, J~19.7Hz and 4.1Hz, CHeCHO), 4.25 ~d, lH, JY5.2Hz, H-2'), 4.43 (dd, lH, J-11.6Hz and 4.1Hz, H-3), 4.61 (q, lH, W O 94/11382 21~6S48 PC~r/CA93/00463 J~6.2Hz, H-5'), 4.75 (dd, lH, J~3.6 Hz, H-3'), 5.26 (broad ~, lH, H-4'), 5.82 (s, lH, H-l'), S.97 (~, lH, H-l), 6.81 (2d, 2H, quinone ring-H).
IR (film) Vmax: 2945, 1747 broad, 1663, 1237, 969 cm-l.
S
8t-p 9s (1'8,1s5,3R~-~ ~hrl-(1-[2',6'-A~ 3',4'-~i~ G~ 2'-~odo-L-l~ -S,10 'it~Y^-3,~,S,10-t-tr k~ [2,3-c~ 3-rl) ~-ton- (BC~ 67) Starting from 70 mg (0.118 mmol) of _ _ ' from ztep 8 herein and 79.6 mg of l-aceto~y~ut~ and following the ~ c~_' r- d~scr~bed in tep 2, s l~ 5, we obtained after purification 25 mg (35~ yield) of titled ~
PMR (CDC13, 250 MHz) ~s 1.40 (d, 3H, J~6.4 Hz, CH3-6'), 2.05 and 2.24 (2g, 2x3H, 2xOCH3), 2.35 (~, 3H, COCH3), 2.57 (dd, lH, J-20.0 nd 12.4Hz, HC~aCHCO), 3.07 (dd, lH, J~20.0Hz and 4.2Hz, HCHeCHC~O), 4.27 ~d, lH, J~5.0Hz, H-2~), 4.49 (dd, lH, J~11.6, 4.2 Hz, H-3), 4.75 (m, 2H, H-3' and H-5~), 5.28 (larg- ~, lH, H-4~), 5.86 (8, lH, H-l'), 6~14 (-, lH, H-l), 7.77 and 8.11 (2m, 2X2H, ArH).
IR (film) Vmax: 2945, 1743 broad, 1668, 1236 bro~d, 958, 734 cm 1 8t-p 10s (l'S,18,3R)-5,8 r~ ~ , 3 ~-~o 1-(2',6'-~ 2'-iodo-The titled ~ ' wa- obtained via ba~e hydroly-i- of th~ (l'S,lS,lR) pr-cur~or from t-p 2 h-rein a- p-r ~ r~ from tep 3 ~- ~i n, PMR (~cetone-d6, 250 NHz) ~: 1.35 (d, 3H, J-6.6Hz, CH3-6'), 2.30 (8 3H, COCH3), 2.50 (dd, lH, J~17.6 and 11.5 Hz, CHaCHO), 2.94 (dd, lH, J~17.9 and 4.3Hz, CH~CHO), 3.20 ~d, lH, OH), 4.44 (m, lH, H-3'), 3.80 (large ~, 7H, 2XOCH3 and H-4~), 4.12 (d, lH, OH), 4.41 (d, lH, J~5.0Hz, H-2'), 4.55 (q, lH, J~6.4Hz, H-5'), 4.70 (dd, lH, J~12.1 Hz and 4.5 Hz, H-3), 5.87 (lS, lH, H-l'), 6.14 (1~, lH, H-l), 6.88 (2d, 2H, ArH).
8t-p lls (l'sS,18,3R)-3 ~ o 1-(2',6'-~~ 2'-iodo-L-1~ )-S,8 'i~-~-S,8-di~rdro~
The titl~d _ ~ wa- obtained ~following CAN ~Yi~-tinn of thc product from ztep 10 her~in a~ per previou~ ~soc~
Y` ~ E~Y~-T
W O 94/11382 2 ~4 ~ ~ 8 Pc~r/cAg3/00463 PMR (CDCl3, 250 MHz) ~: 1.45 ~d, 3H, Js6.6Hz, CH3-6~), 1.90 (bro~d B, lH, OH), 2.31 (~, 3H, COCH3), 2.43 (dd, lH, J-20.1Hz and 11.8 Hz, CHaCHO), 2.80 (m, 1-, OH), 2.88 (dd, lH, J~19.8Hz and 4.1Hz, CHeCHO), 3.32 (m, lH, H-3'), 3.84 (m, lH, H-4'), 4.24 (d, lH, J~4.4Hz, H-2'), S 4.42 (dd, lH, J~11.8Hz ~nd 4.2Hz, H-3), 5.82 (~, lH, H-l'), 5.95 (~, - lH, H-l), 6.79 (ZXd, 2H, ~-~n~n~ r~ng-X).
gt-p 12s (1'8,1~,3R~ _ th~l-(1-[2'~C' ~ 3'~4'~d~d~_a~ 2'-~odo-L-l~ ~5~0 '~-3~4~5~10-t-trah~ 2,3-c~ 3-yl) ' ~ ~ (~C8-2014) A mixtur- of ~ _ ' from t-p 11 ~ rin (1 mlJ nd l-acetGA~ bu~r~i ~
(96 mg, 0.201 mmol) ~n 2 ml of dry tolu-n~ wa~ t~rr~d for 18 hour~
under argon ~ nd then fla~h cl~ ~ ~hed (Toluene:Ethyl lS aoetate; 8s2) to g~- 42 mg (40% yield) of pure titl~d c PMR (CDCl3, 250 MHz) ~: 1.52 (d, 3H, CH3-6'), 2.36 (B, 3H, COCH3), 2.58 (dd, lH, J-19.7Hz and 11.4Hz, HCH~CHCO), 2.78 (broad m, lH, OH), 3.09 (dd, lH, J-20.0Hz and 4.2Hz, HCHeCHCO), 3.34 (m, lH, H-3'), 3.89 (m, lH, H-4'), 4.27 (d, lH, J-4.5Hz, H-2'), 4.49 (dd, lH, J~11.7Hz and 4.2Hz, H-3), 4.66 (broad q, lH, J-6.4Hz, H-S~), 5.30 (~, lH, H-l'), 5.89 (~, lH, H-l), 7.53 and 8.13 (2m, 2X2H, Ar-H).
IR (f~lm) Vmaxs 3434 broad, 2934 broad, 1720, 1669, 1292, 995, 955 om~l.
sues~ T~ ~ff~T
W O 94/11382 2 ~ 4 ~ PCT/CA93/00463 _1~ 62 V~riou- C-2' ~sial~ t-d ~ rh~ ino~e gl~co~
HIC~/ 1 H~C~O + ~CH
AcOO~C ACoOA~ Br - H~CO
OCH~ O OCH3 O
H~CO + H~CO O
H~Cj~ H~Co~ i ~ CH~
H~C~ H~C~;
OAI: Br AcO
O O O O
~CH~ ~o~ C
O O O O
H~C~ H,C~
~oOh Br ~oOA~: Br 8t-p 1 3,4-D~ C ~ 1-2 ~. - 2,6-~;~
Following the p,.--` - de~cribed in tcp 1, ~ 61, we obtained after work-up 89% yield of a mixture of four ~ _ _"d~ Probably axi-al 10 and equatorial bromo ugar- and ~ and ~ of ach 8t-p 2s (1'8,1~,38) ~nd (1'8,18,3R)-2,5-Di t~os~-1-(2',6~-3',4' i~L- ~ 2' ~ )-3-~c-t~ h-~o~n Followin~ the proc.dur~ described in ~tep 2, examplQ 61, w~ obtained aft~r purifir-tinn (Dichlo -'~-n~sH~xane Ethyl aC~tatet 12s7 1) 35%
yield of a ~eparable (l'S,lR,3S and l'S,lS,3R) 1 1 mixture of titled diastereoi r ~ S.
SUBSTITUTE SHEE~T
WO 94/11382 PCI`/CA93/00463 2l4~4~
(l~S,lS,3R): PMR (acetone-d6~ Z50 MHz) ~: 1.27 (d, 3H, JY6.5Hz, CH3-6'), 1.94 and 2.11 (2Xs, 2X3H, 2XOAc), 2.29 (B, 3H, COCH3), 2.50 (dd, lH, J~17.7Hz and 12.1Hz, CHaCHO), 2.96 (dd, lH, J-17.8 and 4.2Hz, CHeCHO), 3.80 and 3.84 (2Xs, 2X3H, 2XOCH3), 4.42 (d, lH, J-4.2Hz, H-S 2'), 4.71 (dd, lH, J~12.2Hz and 4.2 Hz,H-3), 4.81 (q, lH, J~6.4Hz, H-- 5'), 5.22 (m, 2H, H-3' and H-4'), 5.74 (s,lH, H-l'), 6.17 (8, lH, H-l), 6.90 (2Xd, 2H, Ar-H).
SR (film) Vm~x: 2937, 1748, 1486, 1260 and 1237, 970 cm~l.
(l'S,lR,3S~: PMR (acQtone, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 1.97 and 2.10 (2Xs, 2X3H, 2XOAc), 2.30 (8, 3H, COCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CHaCHO), 2.97 (dd, lH, J~17.6Hz and 4.0Hz, CHeCHO), 3.80 and 3.82 (2xs~ 2X3H, 2XOCH3), 4.38 (d, lH, J~4.6Hz, H-2'), 4.53 (q, lH, J-6.4Hz, H-5'), 5.16 (broad 8, lH, H-4'), 5.27 (dd, lH, J~4.2Hz, H-3'), 5.71 (8~ lH, H-l'), 6.05 (8~ lH, H-l), 6.89 (2Xd, 2H, Ar-H)~
lS
St-p 3: (l'S,lR,35)-5,8-dioso-1-(2',6'-~~ 3',4' '~ toA~ 2~-~ )-5,8-dihydroi~Qchro -n CAN oxidat$on of the _ _ ~ from ~tep 2 here$n yielded the t$tled ~ _ .
PMR (CDC13, 2S0 MHz) ~: 1.19 (d, 3H, J-6.6Hz, CH3-6'), 2.04 and 2.16 (2X~, 2Y3H, 2YOAc), 2.29 (~, 3H, COCH3), 2.38 ~dd, lH, J-19.9Hz and 11.6Hz, CHaCHO), 2.88 (dd, lH, J~19.8Hz and 3.9Hz, CHeCHO), 4.25 (m, 2H, H-2' and H-5'), 4.39 (dd, lH, J~11.6Hz and 3.8Hz, H-3), 5.16 (broad 8, lH, H-4'), 5.19 (dd, lH, J~4.0Hz, H-3'), 5.71 (8, lH, H-l'), 5.81 (~, lH,H-l), 6.79 (2Yd, 2H, Ar-H).
St-p 4: (l'~,lR,38)-m th~ 1-[2',6'-~~ s 3~ o~ 2'-~ p~ ]-S,lO-dioso-3,4,S,10-t-tr~d... ~p~b- ~2,3-c] ~ a 3-~1) k-tone (BCH-2100) The tltled _ __ ' wa~ obtained follow$ng the ~---e re described in ~tep 2, ~ _1~ 5, from the ~ ' from step 3 herein. HPLC
purifi~ti nn gav- 9~ of desired (l'S,lR,35) natural titled glycoside.
3S PMR (CDC13, 250 MHz) ~: 1.23 (d, 3H, J~6.4Hz, CH3-6'), 2.06 and 2.19 (2~,2X3B, 2XOAc), 2.35 (8, 3H, COCH3), 2.54 (dd, lH, J~19.7Hz and 11.7Hz, CHaCBO), 3.09 (dd, lH, J-19.8Hz and 4.0Hz, CHeCHO), 4.29 (m, 2H, H-2' and H-5'), 4.47 (dd, lH, J~11.7Hz and 4.0Hz, H-3), 5.18 (broad 8, SU~ E~T
WO 94/11382 PCI/C~93/00463 21~6~4~ ~
lH, H-4'), 5.23 (unr~solv~d dd, lH, H-3'), 5.83 (~ lH, H-l'), 6.01 (8, lH, H-l), 7.77 and 8.11 (2m, 2X2H, Ar-H).
IR (film) Vmax: 2991 and 2943, 1748,1665, 1241, 975 cm 1.
~t-p 5s (1'8,1R,3~)-5,8-dloxo-3 - ~Lo 1-(2',6~ 3~
~ 2' _. - L-l~ -)-S,8-dihrdroi-o~h CAN oY~ n~ of the (l'S,lR,3S) dia-tc ~ - from tep 2 h~rein yielded the titled product.
IR (film) Vm~x: 2939, 1743, 1674, 1241, 968 cm~l.
Bt-p 6s (1'8,18,3R)---thrl-(1-[2',6'-~;~- ~ 3',4'-~i~--tG~ 2'-~.. - L-l~ 1-5,10-dioxo-3,4,S,lO-t-ts~L~d.. ~ - [2,3-~]-pyraQ-3-yl) ~-ton- (~Ca-2099) The titl~d . _ ' wa~ obt~in~d following thQ ~~ d~3crib~d in t~p 2, ~ 5, from th~ quinon~ from tcp 5 h-r-in. Flash ch.. - o~L.~hy (Toluonc:Ethyl aootat~ 9sl) gav- 30% of do~irQd titl~d C~, ~L ~.
PMR (CDC13, 250 ~z) ~: 1.41 (d, 3H, J~6.4Hz, CH3-6'), 2.05 and 2.21 (2-, 2X3H, 2xoAc)~ 2.34 (~, 3H, COCH3), 2.58 (dd, lH, J-20.1Hz and 11.6Hz, CH~CHO), 3.08 (dd, lH, J-20.0Hz ~nd 4.2Hz, C~CHO), 4.16 (d, lH, J~4.5Hz, H-2'), 4.48 (dd, lH, J-11.6Hz and 4.1Hz, H-3), 4.76 (q, lH, J-5.9Hz, H-5'), 5.20 (unr--olv-d dd, lH, H-3'), 5.25 ~bro~d , lH, H-4'), 5.72 (1~, lH, H-l'), 6.17 (1~, lH, H-l), 7.78 and 8.12 (2m, 2X2H, Ar-H).
IR (film) Umax: 2937, 1750, 1672, 1243, 964 cm~l.
r _1- 63s C-2'-ax~-lr ~^A~ rl ~ ,"~ ~ glrco~
SUBSTITUTE StlEET
WO 94/11382 ~ PCT/CA93/00463 2146~48 H3C ~ / _ H,C ~ + ~ CH, ACoNHCOCF, ACoNH ~ H,CO
OCH, O OCH, O OCH, O OCH, O
_ ~ CH, ~ CH, ~ ~CH, ~ ~CH3 ~ 3 ~ ~ 6 ~
H,CO O ~ H,CO O+ H3CO O ____~ H,CO O
H,C ~ ~,C ~H,C ~ H,C
HoNH I A~ONH ICOCF, HoNH I
O O O O
CH, ~ "~CH
o O O O
H,C ~ H,C
HOCOCF, ~ ~ HoNH I
O O O O
H~
O O o O
H,C ~ H,C
COCF3 HoNH I
~CH~U23 HCH-2022 8t-p ls~',3',6'-tr~ 2'-~odo-3'-trifl~ z~ do-~'-c -~ L~l-L-l~
S
Following th~ ~r~9~ ~ dQscribed in step 1, xample 61, we obtained after w~_ up 94~ y~eld of a AOA ~e~-rable ~-~ m$xture (2:1) of t~tled h- l99 -tr~ ~ugar.
PMR ~acetone-d6, 250 NHz) ~: 1.08 (d, 3H, J=6.6Hz, CH3-6), 2.13 (8, 3H, OAc-4), 4.47 (m, lH, H-3), 4.53 (d, lH, J~4.3Hz, H-2), 4.56 (broad q, lH, J~5.2Hz, H-5), 5.17 (broad 8, lH, H-4), 5.65 (d, lH, J~3.8Hz, H-l), 6.04 (d, lH, J~3.8Hz, OH).
8t-p 2: (1'8,1R,3~) ~Td (1'8,15,3R)-2,5-D-o-tho~-3 !~to 1 -lS (2',3',6'-tr;~ 2'-iodo-3'-tr~f~ t- ;~o-4'-O-ac--tyl--L--l~ "_~o~ ocl~
SUBSTITUTE SHEET
W O 94/11382 P ~ rC~93/00463 Following thQ s mc ~rcs~' r~ a~ d~scribed in st~p 2, xampla 61, we obtained after purif~c~tjs~ (~olucne:Ethyl acctate7 9:1) 38~ yield of a separable (l~S,lR,3S and l'S,lS,3R) mixtur~ of titlcd diartcreo~ a S (1:1).
The natural (l~S,lR,3S) glycor~de: PMR ~aceton~-d6, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 2.15 (r, 3H, Ac0-4'), 2.30 (~ 3H, OOCH3), 2.41 (unr~solv~d dd, lH, CHaCHCO), 2.97 (dd, lH, J-17.7Hz and 3.89Hz, CHeCHO), 3.80 and 3.84 (2xs, 2x3H, 2xOCH3), 4.36 (m, lH, H-3'), 4.63 (m, 3H, H-3, H-2~ and H-5~), 5.19 (broad r, lH, H-4'), 5.90 (r, lH, H-l'), 6.06 (s, lH, H-l), 6.87 (2xd, 2H, Ar-H), 7.95 (broad r, lH, ~O~r3).
Th~ non-natural glyco-id~ (l'S,15,3R): PMR (ac~ton~-d6, 250 MHz) ~:
1.23 (s, 3H, J~6.5Hz, CH3-6'), 2.16 (s, 3H, Ac0-4'), 2.30 (s, 3H, COCH3), 2.51 (dd, lH, J~18.2Hz and 12.0Hz, C~aCHO), 2.97 (dd, lH, J=17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.83 (2X~, 2X3H, 2XOCH3), 4.30 (m, lH, H-3~), 4.69 (d, lH, Js4.72Hz, H-2'), 4.74 (dd, lH, J~12.1Hz and 4.3Hz, H-3), 4.88 (q, lH, J~5.0Hz, H-5'), 5.24 (broad 8, lH, H-4'), 5.92 (r, lH, H-l'), 6.18 (s, lH, H-l), 6.90 (2Xd, 2XlH, Ar-H), 7.9S (broad s, lH, ~nCG~r3).
8t-p 3s (l'~,lR,38)-5,8-D; thoxr-3 --~Lc 1-(2',3',6'-tr;~-- ~ 3'-tr~fl ~ La~do-2'-~odo-~-1~ ,, -r~ 6~h..
Ba~ hydrolyris of th~ from rt~p 2 h~r~in as p~r ~Loc~dure from tep 3, xampl- 61, yi-lded th~ titl~d ~ . PMR (~ one d6, 250 MHz) ~: 1.28 (d, 3H, J-6.6Hz, CH3-6'), 2.30 (~, 3H, OOCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CHaCHO), 2.95 (dd, lH, J~17.6Hz ~nd 4.0Hz, CHeCHO), 3.79 and 3.84 (2s, 2X3H, 2XOCH3), 4.03 (m, 2H, H-4' and OH-4~), 4.44 (broad q, lH, J~6.4Hz, H-5'), 4.58 (m, 2H, H-3 and H-2'), 5.89 (~, lH, H-l'), 6.04 (s, lH, H-l), 6.89 (2d, 2XH, Ar-H), 7.65 (broad s, lH, h~C:C~r 3 ) -IR (f~lm) Vm~x: 3539 and 3414, 2941 and 2844, 1728, 1488, 1260, 1175, 970 cm-l.
35 ~t-p 4s (1'8,1~,3~)-3 ~-~o 1-(2',3',6'-trid-ox~ -2'-~odo-3'-trifl -_~r~ -L-l~ )-S,8-dioxo-S,8-d.~ C~o--~n SUBSTiTUTE SHEET
WO 94/11382 PCI`/CA93/00463 21~6~
CAN ~yi~at1nn of the product ~rom ~tep 3 herein yielded the titled product.
P~R (CDC13, 250 ~Hz) ~: 1.32 (d, 3H, J~6.6Hz, CH3-6'), 2.06 (broad d, lH, OH-4'), 2.32 (~, 3H, COCH3), 2.41 (dd, lH, J~20.4Hz and 11.7Hz, S CHaCHO), 2.93 (dd, lH, J~19.6 and 3.9Hz, CHeCHO), 3.75 (broad d, lH, H-4'), 3.96 (m, lH, H-3'), 4.28 (q, lH, J-6.7Hz, H-5'), 4.42 (m, 2H, H-3 and H-2'), 5.82 (8, lH, H-l'), 5.90 (s, lH, H-l), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, lH, NHCOCF3).
IR (film) Vmax 3541 and 3417, 2992 and 2944, 1729, 1664, 1174, 967 cm~
10 1.
St-p 5s (1'8,1R,38)---thyl-(1-[2',3',6'-tr{~- ~ 2'-iodo-3'-tr~ $do-4' k~.OA~ L~ -5,1O-dioxo-3,4,S,lO-t-tr h~d.. ~rh~ 2,3-cl rJ~ 3-yl) k-tone (BCH-2023) The tLtled ~ _ l wa- obtained aB per ~.oc~dure de~cribed in ~tep 2, le 5, but u-lng the product from ~tep 4 ber-in. Purification was ffectQd by fla-h cl..~ -to~-a~h~ (Toluene:Ethyl ac~t~ 8:2).
PMR (CDC13, 250 ~H~) ~: 1.34 (d, 3H, J-6.6Hz, CH3-6'), 2.35 (8, 3H, COCH3), 2.53 (dd, lH, J~19.6Hz and 11.5Hz, CH~CHO), 3.11 (dd, lH, J-19.6Hz and 4.1Hz, CHeCHO), 3.76 (broad s, lH, H-4'), 3.97 (m, lH, H-3'), 4.30 (q, lH, J~6.6Hz, H-5~), 4.49 (dd+d, 2H, H-3 and H-2'), 6.00 (13, 2H, H-l and H-l'), 7.01 (broad d, lH, NHCOCF3), 7.78 and 8.13 (2Xm, 2S 2X2H, Ar-H).
IR (film) Vm~xs 3529 and 3414, 2991 and 2930, 1727, 1666, 1298, 1177, 963 cm~l.
8~-p 6: (1'8,18,3R)-5,8 'i ~ ~ 3 ~ o 1-(2',3',6'-~r~d~ ~ 3~-tri~ - t- '~-2'-iodo-L-l~ ochro n To a m$xture of (l'S,lS,3R) glyco~ide from ~tep 2 herain (103 mg, 0.16 mmol) in 15 ml of anhydrou~ h-nol wa~ added, at 0C and under argon ~~phe~e, 2 drop~ of NaOCH3, 4.37M (cat.). After fftirring for 45 3S minutes, the reaction wa- worked up by adding 10 ml of a mixture NH4Cl ~at.sNaHCO3 ~at. (8:3) and extracted with CH2C12 (2x30 ml). The ~ `in~d organic layer~ were w ~ with the ame aqueou~ mixture (30 ml) and dried (~gSO4). Fla~h ch~ -toJ-a~hy (Toluene:Ethyl acetate;
9:1) gave 70 mg of pure titled glycoaide (73% yield).
SUBSTITUTE SHEET
WO 94/11382 PCr/CA93/00463 21g6~
PMR (acstone-d6, 250 MHz) ~: 1.38 (d, 3H, J~6.5Hz, CH3-6'), 2.30 (u, 3H, COCH3), 2.50 (dd, lH, J~17.7Hz and 12.0Hz, CHaCHO), 2.97 (dd, J~17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.81 (2Xs, 2X3H, 2XOCH3), 4.00 (m, 3H, H-3', H-4~ and OH-4'), 4.62 (d, lH, J~4.8~z, H-2'), 4.74 (m, 2H, H-3 and S H-5'), 5.92 (1~, lH, H-l'), 6.18 (1~, lH, H-l), 6.88 (2Xd, 2H, Ar-H), 7.65 (broad ~, lH, NHOOCF3).
IR (film) Vmax: 3530, 3410, 2942 and 2837, 1723 broad, 1491, 1263, 1175, 958 cm~1.
~t-p 7: (1~8,1S,3R)-3--c-to-1-(2~3~,6~-trid~ ~ 2'-iodo-3~-tr~ f 1 ~ a~$do-L-l~ )-5,8-~$oso-S,8-dihydrQ~ h ~
CAN nYi~'ti~n of the product from ztep 6 herein yieldQd the t15 product.
PMR (CDC13, 250 KHz) ~: 1.47 (d, 3H, J-6.61Hz, CH3-6'), 2.22 (broad d, lH, OH-4'), 2.32 (1~, 3H, OOCH3), 2.46 (dd, lH, J~19.6Hz and 11.7Hz, CHaCHO), 2.92 (dd, lH, J-19.9Hz and 4.2Hz), 3.78 ~broad d, lH, H-4'), 3.91 (m, lH, H-3'), 4.37 (d, lH, J~4.8Hz, H-2'), 4.43 (dd, lH, ~-11.7Hz 20 and 4.1Hz, H-3), 4.64 (q, lH, J~6.3Hz, H-5'), 5.84 (s, lH, H-l'), 5.97 (~, lH, H-l), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, lH, NHCOCF3).
IR (film) VmaX 3531 and 3406, 2929, 1726, 1663, 1181 broad, 960 cm~l.
8~-p 8s (1'-,18,3~ thyl-(l-[2',3',5'-tr;~ ~ 2'-$odo-3'-2S ~r~f~ a~ d.~ ]-5,10-d$oxo-3,4,S,10-t-tr~d. ~ - [2,3-c] ~_ 3-yl) k-ton-(~ca-~022) The titled _ ' waz obtained a~ per ~.oced~re de-cribed in tep 2, _le 5, but u~ing the product from tep 7 h~rein. Purif~ o~ by fla~h ch.~ - - a~hy (Tolu-ne:Ethyl acetate; 9:1).
PMR (CDC13, 250 ~Hz) ~: 1.51 (d, 3H, J~6.5Hz, CH3-6'), 2.11 (broad d, lH, OH-4'), 2.34 (~, 3H, COCH3), 2.58 (dd, lH, J~19.4Hz and 11.6Hz, CHaCHO), 3.10 (dd, lH, J~19.8Hz and 4.1Hz, CHeCHO), 3.82 (broad d, lH, 3S H-4'), 3.92 (dd, lH, J~11.6Hz and 4.1Hz, H-3), 4.79 (g, lH, J-6.5Hz, H-5'), 5.88 (~, lH, H-l'), 6.14 (~, lH, H-l), 7.07 (broad d, lH, ~ 3), 7.78 and 8.11 (2Xm, 2X2H, Ar-H).
IR (film) Vmax: 3539 and 3414, 2946, 1731, 1666, 1293, 1174, 961 cm~l.
~UBSTmlTE SHEET
!
r ~ 6~: 2 1~ ~ ~ 4 ~
Hd~/ I ~1 + ~CH, H,CO
~ 2 OCH~ O OCHI O
~CH, ~"~CH~
HICO O H~CO O
Ac~ ~ 0~
o o o o ~CH~ ~"~CH, O O o O
~ O~AC I ~ O~A~
o o o o ~0 o O + o o IK~E-2~65 8t-p ls 2',6~ di~-- ~ 3',4'-~;a-~tGa~ 2'-iodo-~-~r~
Following the p,ocedu~ de~cribed in tep 1, ~ Q 61, we obtained after w__~ up a quantitative yi~ld of th~ de~$red _ _ ' which w_~
used in th~ next tep without purification:
PMR ~P~ - - d6, 250 MXz) ~: 1.17 (d, 3H, J~6.2Hz, CH3-6), 4.04 (m, lH, R-5), 4.48 (d, lH, J~4.2Hz, H-2), 4.84 (dd, lH, J~9.5Hz and 4.2Hz, H-3), 5.01 (large ~, lH, H-l), 5.51 (dd, lH, J~9.7Hz, H-4).
8t-p 2s (1'8,18,3R) nd (1'8,1R,38)-5,8-D$m-tho~r-3 ~ ~o 1-(2~,6~-~ - r 3~,4~ c~t~ ~ 2'-$odo-L-ar~
$ZG~ ~, - n WO 94/11382 PCr/CA93/00463 2 14 ~
Following the ame p,~ a~ de~cribed in tep 2, example 61, we obtained after fla~h chromatography (Toluene:Ethyl acetate; 9:1) a mixture of the tLtled ~tereoisomers (non ~ rable).
PMR (Ren~e d6, 250 HHz) ~: 1.20 and 1.38 (2d, 2X3H, 2XCH3-6'), 1.61, S 1.66, 1.67 and 1.69 (4~, 4X3H, 4XOAc), l.9S and 2.12 (2~, 2X3H, 2XOCH3), 2.76 (m, 2XH, 2XCHaCHO), 3.20 (m, 2H, 2XCHeCHO), 2.30, 2.31 and 2.32 (38, 4X3H, 4XOCH3), 4.18 (m, lH, H-5'), 4.35 and 4.47 (2Xdd, 2H, J~12.0Hz and 4.2Hz, 2XH-3), 4.82 (m, 5H, 2XH-3', 2XH-2's and H-5'), 5.62 and 5.70 (2Xdd, 2H, J~9.5Hz, 2XH-4'), 5.84 and 5.93 (2 larg~ ~, 2H, 2XH-1'), 5.95 (8~ lH, H-l), 6.33 (m, 5H, 2X2 Ar-H and H-l).
8t-p 3s (1'8,1~,38) d (1'~,18,3R)-3 ~ o 1-(2~,6'-Ai~- ~ 2'-iodo--L--~r~h; ~ ~ A~ )--S~8--dio~co--S~8--d~hrdroj9~cc~h~o~n lS The tltled - c ~- w~r~ o~t~in~ following CAN oY~Ati~ of the products from t~p 2 here~n as per previou~ ~c~
PMR (CDC13, 250 M~z) ~: 1.23 and 1.36 (2d, 2X3H, J~6.2Hz, 2XCH3-6'), 2.03, 2.04, 2.06 and 2.07 (4s, 4X3H, 4XOAc), 2.29 and 2.30 (2S, 2X3H, 2XCOCH3), 2.46 (m, 2H, 2XCHaCHO), 2.90 (dd, 2H, J-19.7Hz and 3.8Hz, 2XCHeCHO), 4.02 (m, lH, H-5'), 4.49 (m, 7H, 2XH-2', 2XH-3', 2XH-3 and H-5'), 5.15 (m, 2H, 2XH-4'), 5.62 and 5.68 (2S, 2H, 2XH-1'), 5.79 and 5.95 (28, 2H, 2XH-1), 6.75 (2X2d, 4H, 4XAr-H).
8t-p 4s (1'8,1R,18) - d (1'8,18,3R)-m-thrl-(1-[2',6' d~-- J-3',~-2S ~i ~ ~ tOa~ 2 ~ ~i odo-L ~ -5,10-d~o~o-3,4,S,lO L~t l~d-. ~p~~ t2,3-cl ~--~ 3-rl) k ton- (~CH-~065) FollowLng the r-ported ~c.c-' L $n ~tep 2, ~ 5, and ~tarting from the two ~t-reoi~- ?~ from ~tep 3 herein, tLtled r , __ 'n (9~) were isolated after fla~h c~ togra~hy (Toluene:Ethyl acetate; 19:1).
PMR (CDC13, 250 MHz) ~: 1.41 (d, 3H, J~6.2Hz, CH3-6'), 2.06 and 2.08 (2~, 2X3H, 2XOAc), 2.33 (~, 3H, COCH3), 2.57 (dd, lH, J~19.5Hz and 11.7Hz, CHaCHO), 3.09 (dd, lH, J~19.8Hz and 4.2Hz, CHeCHO), 4.46 (m, 4H, 3S H-3, H-2', H-3' and H-5~), 5.21 (dd, lH, J~9.5Hz, H-4'), 5.67 ~8~ lH, H-1'), 6.14 (8, lH, H-l), 7.78 and 8.13 (2m, 2X2H, Ar-H).
IR (film) Vmax: 2941, 1750 and 1739, 1665, 1298, 1236 large, 971 cm~1.
_l~ 65: C-2 ~ ,c~ L~_n~ inon- gl~ro~id--S~ ET
~ 2 1 4 ~
HJC~ + ~ Q~ ~ H3 ~ H~CO H~CO ol +1 H,C~
OCH, O ~ ~0~
HIC ~ r ~ CH3 ~,~ HO H~C~ r o ~cOOAC
~J 6 C ~ r ~ O H~
o o +l.3-~i~
H~C ~ r ~ +l~ x BCH21~t H~C~7 r HoOH
scH~ll7 8tep ls ~1'8,1~,3R) d (1'8,1R,38)-5,8-~ 3 ~r Lo 1-(2',6'-5 ~ 3'~ 6a~ L-l~
~he ~.._-' ~ de-cr$bed $n ~tep 2, - - ~le 61, wa- arplii~l to 5,8-dimethoxy-3-acctoi~ n and 3,4-~ YY-2,6-~;~ G- y ~uco~e. Fla~h Ch~ oJ~phy (~hloromethane:R~x ~n~: Fthyl acetate; 6:3:1) gave a 50%
yield of the two non ~ able titled ~tereolr D mixture (1:1).
PMR (~cqton~-d6, 250 MHz) ~: 1.11 and 1.20 (2d, 2X3H, J~6.6Hz, CH3-6'), 1.87, 1.88, 2.10 and 2.10 (48, 4X3H, 4xOAc), 2.28 ~nd 2.29 (2~, 2X3H, ~YrO~R3) ~ 2.45 (m, 2X3H, 2XCHaCHO), 2.94 (m, 2H, 2XCHeCHO), 3.79, 3.81 and 3.83 (3~, 4X3H, 4XOCH3), 4.34 (q, lH, J~6.53Hz, H-S'), 4.62 (m, 3H, lS 2XH-3 and H-S'), 5.14 (m, 4H, 2xH-3' ~nd 2XH-4'), 5.54 and 5.61 (2 broad ~, 2H, 2XH-1'), 5.97 and 6.16 (2~, 2H,H-1), 6.88 (m, 2X2H, 2XAr-H)-8t-p 2s (1'8,18,3R) and (1'8,1R,38)-5,8 di -thosr-3 ~ 1-(2',6'-~;~- ~ L-l~ '- ~,- ~~-) i-~ ~-SlJ~ T~- S~'E~.T
W O 94~11382 PC~r/cA93/00463 2 ~
Th~ ~ame p-~ d-~cribod in ~tep 3, example 61, wa~ applied to the product~ from ~tep 1 h-rein. Fla~h chromatGg-a~hy of the crude (Toluen~:~thyl acQtate; 6s4) gave 39% yield of no.l ~_~~rable titled dia~t~reoi- ~ (lsl).
S PMR (acQtonc-d6~ 2S0 MH~ 1.16 ~nd 1.25 (2d, 2X3H, J-6.6Hz, 2XCH3-6'), 1.80 (m, 4H, 4XH-2'), 2.24 (~, 2X3H, 2XCOCH3), 2.45 (unre~olved dd, 2H, CHaCHO), 2.87 (dd, 2H, CH~CHO), 3.37 (ff, lH, H-3'), 3.56 (m, 3H, ~-3' ~nd 2XH-4'), 3.75 (~, 3X3H, 3xOCH3), 3.77 (~, 3H, OCH3), 4.00 and 4.34 (2d, 2H, J-6.6Hz, 2XH-5'), 4.54 (2 u.~olved dd, 2H, H-3), 5.35 and 5.41 ( 2 broad ~, 2H, 2XH-1'), 5.89 and 6.10 (2~, 2H, 2XH-1), 6.83 (2X2d, 4H, Ar-H).
8t-p 3s (1'8,18,3R) and (1'8,1R,38)-S,8-d;oso-3-ac-to-1-(2',6~-~ L~ ,. - )-5,8-d~hydroi~ochro~
lS
The titlad ~.odu~L- w re obt~no~ following CAN ~Y~ti~ of the ~-o~cL~ from ~tep 2 ~- ~i n, PMR (CDC13, 250 ~H~) ~s 1.29 and 1.42 (2d, 2X2H, J-6.6Hz, 2XCH3-6'), 1.70 (m, 4H, 4XOH), 1.89 (m, 4H, 4XH-2'), 2.30 ~nd 2.31 (2~, 2X3H, ~Scoc~3)~ 2.43 (2 overlapping dd, 2H, 2XCHaCHO), 2.89 (2 ov~rlappLng dd, 2H, 7~C~L~ 3.65 nd 3.70 (2 broad , 2H, 2XH-4'), 3.90 (m, 2H, 2XH-3'), 3.99 (u-, olved q, lH, H-S'), 4.36 (g, lH, J-6.8Hz, H-S'), 4.43 (2 overlarping, 2H, 2X~-3), 5.41 ~nd 5.49 (2 broad ~, 2H, 2XH-1'), 5.81 and 5.98 (2s, 2H, 2xH-1), 6.79 (2X2d, 4H, Ar-H).
8t-p 4s (1'8,18,3R) ~nd (l'~,lR,38~ thrl-(1-[~;~-- ~ 2~,6~-d~h~d.o~ 3',4'-~ -S,10-dioso-3,4,5,10-t-tr ~ ~ [2,3-c] ~ 3-yl) ~-ton- (BCH-2117) The titled ~ wer- obtained in 43% yield by following the p.o~' e de~crib~d in ~t~p 2, . 1~ S, and u-ing the products fro~
~tep 3 herein. Fl~h cb., -t~_ .~hy (ToluenesEthyl acetat~; 4~6) and final purific~ti~ by preparative TLC (sam~ solvent conditions) wa~
r-quired.
PMR (DMSO-d6, 250 ~Hz) ~s 1.10 and 1.23 (2d, 2X3H, J~6.3Hz, 2XCH3-6~), 1.54 ~nd 1.87 (2m, 2X2H, 2X2H-2'), 2.25 (~, 6H, 2yoor-~3)~ 2.46 (m, 2~, 2XCH~cHo)~ 2.86 (2 overl~rp~ n~ dd, 2H, CHeCHO), 3.73 (m, 2H, 2XH-3'), 3.89 (q, lH, J~6.5Hz, H-5'), 4.28 (q, lH, J~6.3Hz, H-5'), 4.38 (broad ~, lH, H-4'), 4.52 (2X unre~olved dd, 2H, 2XH-3), 4.54 (broad ~, lH, H-4'), SUBSTIT~ITE StlEET
WO g4/11382 PCI'/CA93/00463 ~ 214~4g 5.11 ~m, 2H~ 2XOH) ~ 5.31 nd 5.38 (2 broad s, 2H, 2XH-1'), 5.49 ~m, 2H~
2XOH), 5.86 and 5.94 (2s, 2H, 2XH-1), 8.32 and 9.58 (2m, 8H, Ar-H).
8t-p 5s (1'8,18,3~) d (1'8,1R,38)-S,8-d$o~o-3 -- Lo 1-(2',6'-S ~~ 3~ a-~a~ L-l~ oc~ro n The titled r ,_ ~ w r~ obta~ned following CAN oY~-tisn of the product- obtain~d from t-p 1 herein.
PMR (CDCL3, 250 ~Hz) ~s 1.10 nd 1.22 (2d, 2X3H, J~6.5Hz, 2XCH3-6'), 1.93 (largs m, 2X2H, 2X2H-2'), 1.92, 1.96, 2.11 _nd 2.12 (4s, 4X3H, 4XOAc), 2.23 and 2.25 (2~, 2X3H, 2XCOCH3), 2.39 (2 overlarpin~ dd, 2H, 2XCHaCHO), 2.80 (2 overlappin~ dd, 2H, 2XCHeCHO), 4.10 (g, lH, J=6.5Hz, H-5'), 4.40 (m, 3H, 2XH-3 and H-5'), 5.10 (m, 4H, 2XH-3', and 2XH-4'), 5.44 and 5.50 (2 broad s, 2H, 2XH-1'), 5.76 and 5.94 (2s, 2H, 2XH-1), lS 6.57 (2X2d, 4H, Ar-H).
8tap 6s (1'~,18,3R) ~d (1'8,1R,38)-m-thrl-(1-~ 2',6'-~i~- LGa~ 3~ ~4~ --5~10--dioso--3,4,5,10--t-tr L~d.. ~'h~-[2,3-c~ ~ 3-yl) ~L - (BC~-2118) The titled c~ w-re obtained Ln S1~ yield by follow$ng the .ocad~rQ d-scribed Ln t~p 2, - le 5, and u-ing the products from tep 5 hQrein. A~ -Li--t~nn by flash cl.~ -LG~.a~h~ (Toluone:~thyl ac~t_t~ 8:2). Final purifi~ti~n by preparativ~ TLC (-ame solvent 2S cond~tions).
PMR (CDC13, 250 MHz) ~s 1.17 and 1.33 (2d, 2Y3H, J~6.6Hz, 2YCH3-6'), 1.88 ~m, 2H, 2XH-2'), 1.96 (s, 2X3H, 2XOAc), 2.16 (l_rge m, 2H, 2XH-2'), 2.18 and 2.19 (2s, 2X3H, 2XOAc), 2.32 and 2.34 (2s, 2X3H, 2XCOCH3), 2.54 (2X overlArping dd, 2H, 2XC~ CHO), 3.07 (2X over~app~ng dd, 2H, 2XCHeCHO), 4.17 (q, lH, J-6.7Hz, H-5'), 4.51 (2X aoverl~rp~n7 dd, 2H, 2X
H-3), 4.63 (q, lH, J~6.4Hz, H-5'), 5.19 (m~ 4H, 2XH-3'~ and 2XH-4'), S.SS and 5.67 (2 broad s, 2H, 2XH-1'), 6.00 and 6.18 (2~, 2H, 2XH-1), 7.76 and 8.10 ~2m, 8H, Ar-H).
SUBSTITUTE SHEE~T
65 P ~ Prr~rl ~ - slr~
CH~
0~5 i-CH~ O O HO O O
CH~ + ~CH, I ~ ~CH~
O O
CH~
O--S i-CH, o O HO O O
[~ CH~ + ~ 2 [~CH~
O O O O
H~C~ H~C~g PNBON~H PNBON`H
+}~C-10 HO O O
~CH, O O
,J 8CH~7 H,C~J
COCF~
+ H~y C-10 ~io~
S ~t-p ls l~-thrl-(6 ~ d~_a~ S ~10 ~ o-3 ~ 4 ~ S ~10-t-tr~h~d~
[2,3-c~ ~ 3-rl) ~-ton- d ~-thrl-(9 h~a~ S,10-dioso-3,4,5,10-t-trah~ 2,3-c~ 3-rl) ~-ton-(JC~-20C2) ~h~ titlsd c ~_ ~ were oht~i~s~ by following the ~..cv . described in tQp 2 ~ nd u~ing l-acetoxybut~ - ~nd 3-~oetoi-c-~ ~ -- 5,8-dion~.
PMR (CDC13, 250 MHz) ~: 2.33 (2~, 2X3H, COCF3), 2.56 (m, 2H, CHaCHO), 3.00 (m, 2H, CH~CHO), 4.07 (dd, 2H, J~lO.lHz ~nd 3.9Hz, H-3), 4.60 (m, 2H, H-l), 4.95 (m, 2H, H-l), 7.26 (m, 2H, Ar-H), 7.62 (m, 2X2H, Ar-H), 11.84 and 11.96 ~2~, 2H, OH-5 and OH-8).
~t-p 2s (1'~,18,3R)-m thrl-(6 and S ~d~a~ 1-(2',3',6'-tr~ 3'-tr~f~ o-4 -0-p-~t.J~- ~orl-L-l~
S,10-dio~o-3,4,5,10-t-trzh~dro-1~ 2,3-cl ~ ~ 3~
yl) ~-ton~
sue~ ~ r~ A j~ ET
WO 94/11382 PCr/CA93/00463 ` 214~48 To a mixture of (l~S,lS,3R) glyco~ide from ztep 1, example 5, (200 mg, 0.335 mmol) in dry tolu-ne (2.5 ml) undQr argon aL -rl'~.e, wa_ added dropwi~s the l-trimethyl-ilyloxy-1,3-but~ . After stirring for 18 hour~ at room t ~ ~L2, the ~olv-nt was ~ .~d in vacuo. The re~idue wa~ dried over vacuum for 10 minutes, di-zolved in 5 ml of THF
and cooled to 0C. Add$tion of HCl lN (5 ml) gave after 30 minute~
stirring a ~ L~ cloavag~ of the ~ilyl group. ~xtraction~ were done with CH2C12 (3x30 ml) and the combined organic lay-r~ were dried with Na2S04 and then _~p~ated. The L~ wa- di--olved with 10 ml of dry CH2C12, at room ~ _- a~u._ and under argon, ~nd tr-ated with 200 mg of PCC. After 30 minute- tirring, the reaction mixture wa~ d.~ed on SiO2 and fla~h cl.~. LG~ had (Toluen~:~thyl acetatet 8:2) to give 162 mg (72% yield) of a non ~e~-rable titl~d regioi~( ~r~ (1:1).
PMR (CDC13, 250 MHz) ~: 1.36 and 1.37 (2d, 2X3H, J-6.4Hz, CH3-6'), 2.14 (2X m, 2X2H, H-2'), 2.34 and 2.35 (2s, 2X3H, COCH3), 2.S7 (dd, 2XlH, J~20.1Hz and 11.8Hz, CHaCHO), 3.09 (dd, 2XlH, J-19.9Hz and 4.1Hz, CHeCHO), 4.53 (2X ~ Dlv d dd, 2XlH, H-3), 4.61 (2Xm, 2XlH, H-3'), 4.77 (2X ~n~ VQd q, 2XlH, H-S'), S.45 (broad ~, 2XlH, H-4'), S.63 (broad s, 2XH, H-l'), 6.19 and 6.21 (28, 2H, H-l), 6.46 (broad B~ 2H, NHCOCF3), 7.32 (m, 2H, Ar-H), 7.67 (m, 2X2H, Ar-H), 8.32 ~m, 2X2H, Ar-H), 11.89 and 11.90 (2~, 2H, OH-S and OH-8).
8t-p 3s (1'~,18,3R) _ thrl-(6 ~d ~ k~d.~,~ 2',3',6'-tr~ 3'-2S tr~ f ~ d,o~ -S,10-- 3,4,5,10-t-tr~ 2,3-cl .,. 3-~1-k-ton-(~C~-2078) Hydroly~i~ of the gl~c~ -~ from tep 2 herein with catalytic u- h~Yida in Lh-n~l y$-lded th~ titled ~ _ -a. Fla~h cl~. -~oJ-aphy (Tol -sFthyl r-~L~ ~s~~~L~ne; 6s4:2) of the crude gave 83% yield of pure titled .~ mixture ( 121 ) .
PMR (CDC13, 250 HHz) ~: 1.40 and 1.42 (2Xd, 2X3H, J-6.4Hz, CH3-6'), 1.91 (m, 2X2H, H-2'), 2.31 ~nd 2.32 (2X~, 2X3H, COCH3), 2.S6 (dd, 2XlH, J~19.7Hz nd 11.4Hz, CHaCHO), 3.08 (dd, 2H, J~19.9Hz and 4.2Hz, CHeCHO), 3.67 (broad d, 2H, H-4'), 4.33 (m, 2H, H-3'), 4.53 (m, 4H, H-3 and H-5'), 5.44 and 5.45 (2s, 2H, H-l'), 6.13 and 6.15 (2S, 2H, H-l), 6.74 (broad d, 2H, NHCOCF3), 7.30 (m, 2H, Ar-H), 7.65 (m, 2X2H, Ar-H), 11.89 and 11.91 (2~, 2H, OH-5 and OH-8).
~ U E~ h ~
WO 94/11382 PCI'/CA93/00463 %
67: 3-(3~ h;~Qlyl) - 5~10 - dio~o-1,3,4,S,10-p-nta~d.o -~ 2,3-c]-prran (~CH) OCH, O
oc~,i, o ~
HCH
rx~
3 L~X~8r 8t-p 1s 3 -~Lo 5,8 'i~-~-3,4,S,8-t-trahrdro-1~ t -o-12,3-cl-prr n CAN oxidation of 5,8-Dimethoxy-3-acetoi~ochroman yieldQd the tltled 10 = _ .
lH NMR (CDC13, 250 HHz, Bruk~r) ~: 2.23 (3H, , COCH3), 2.36 (lH, dd tr, J-17.8Hz, 11.0~z, 2.9Hz, 4-HCHa), 2.75 (lH, d tr, J~17.8Hz, 2.9Hz, 4-HCH~), 3.96 (lH, dd, J-llHz, 5.3Hz, 3-CH), 4.41 (lH, d tr, J~17.8Hz, 3.5Hz, l-HCHa), 4.72 (lH, d tr, J~17.5Hz, lHz, l-HCH~), 6.71 (2H, m, 15 ArH).
~t-p 2: 3 -- ~o S,10-dio~o-3,4,5,10-t-trahydrD-l~ -~r~t~- 12,3-cl-prr~n The titled _ __ ' wa- ~ht~ i n~ by following the ~,ocodu o described in tep 2, _ _le S, and using the product from step 1 herein.
lH NNRs (CDC13, 250 MHz, Bruker) ~: 2.30 (3H, B, COCH3), 2.56 (lH, dd tr, J-18Hz, 11.2Hz, 2.9Hz, 4-HCHa), 3.01 (lH, d, J~18.0Hz, 4-HCHe), 4.0S
(lH, dd, J-11.2Hz, 3.8Hz, 3-CH), 4.60 (lH, d tr, J=17.8Hz, 4.1Hz, 1-25 HCHa), 4.9S (lH, d m, J~17.8Hz, l-HCHe), 7.73 (2H, m, 7, 8-ArH), 8.08 ~2H, m, ArH).
SUE~` s ~ c ''~-5'~
W O 94/11382 PC~r/CA93/00463 ~ 2146~48 st-p 3: 3 ~ 5,10-dio~o-3,4,5,10-t-~rahrdro-1~ ; -~2,3-cl-prr~
The titled c _~nd w~ obtain~d by following the ~LIure described in ~tep 1, example 7, and uzing the product from ~tep 2 h~r-$n.
lH NMR (CDCl3, 250 MHz, Bruker) ~s 2.57 (lH, dd tr, J~18.8Hz, 11.2Hz, 3Hz, 4-HCHa), 3.02 (lH, d m, J-18.8Hz, 4-HCH~), 4.21 (lH, d, J~12.9Hz, CHBr), 4.30 (lH, d, J~12.9Hz, CHBr), 4.34 (lH, dd, J~11.2Hz, 4.7Hz, 3-CH), 4.58 (lH, d tr, J-18.0Hz, 3.0Hz, l-HCHa), 4.90 (lH, d m, J-18.0Hz, l-HCHe), 7.70 (2H, m, 7, 8-ArH), 8.04 (2H, m, 6, 9-ArH).
8t-p ~s 3~(3~ rl)-s~lo-dio~o-l~3~5~lo ~ -~rdro-~aphtho-[2,3-ol-prr n B.l Lhyl keton- from st-p 3 h~r~in (270 mg, 0.81 mmol) waz stirred with thiourea (60 mg, 0.88 mmol) inj ether (80 ml) and methylenQ chloride (10 ml) at room t - aLu-e for 4 hours. Three ~ e~ of molec~ r ~ieve- werQ u~ed to take up water. Solvent wa~ ated to give a white olid. The crude product wa~ wa~hed with chloroform/ether (8:1) fir~t, then basifi~d with pot~ c~rhon-te. It was extracted with chlo.ofo. . The organic pha-e wa~ ~GL~ted to giv- a crude product which was chromatG~.~hsd to give desired titled product.
.
dec. 130C.
lH NMR (CDC13, 250 MHz, Bruker), 2.80 (lH, m, 4-HCH~), 3.09 (lH, br d, J ~ 18.2 Hz, 4-HCH,), 4.58 (lH, dd, J - 10.0 Hz, 3.S Hz, 3-CH), 4.68 (lH, d tr, J ~ 18.8, 2.9 Hz, l-HCH~), 4.95 (lH, dd, J ~ 18.8 Hz, 2.3 Hz, l-HCHe), 5.54 (lH, br ~, NH), 6.54 (lH, s, thia-H), 7.73 (lH, m, ArH), 8.08 (lH, m, ArH).
S~ w 5~ r.T
W O 94/11382 2146 ~ ~ PCT/CA93/0n463 r _1~ 68s C~cl~c a ~n- ~ub~t~ 4 i - - d-ri~ti~-BOC
COS~H COOH
OMk o BOC OM~ o 3 ~ +
o~s ~
BOC
1~
o o o o o ~ -~1 ~CI soc +~ +I,3~
so~2~s sc~2~s ~t-p ls N-~OC-~ -_c~ic ac$d The titl-d _ _ ' wa- obtained following standard conditions H NMR (CDC13) ~ 4 02 (m, 2H, CH2N), 2 73 (m, 2H, CH2N), 2 50 (m, lH, ~noou)~ 1 91 (m, 2H, S~2CHCOOH), 1 64 (m, 2H, ~2CHCOOH) ~t-p 2s N-80C-~-pip~r~
To a ~olution of the acid from ~tep 1 (0 11 g, 0 48 mmol) in dry THF
(4 8 ml), under argon, at 0C, wac added dropwi-~ BH3-THF 1 0 M/THF
(0 72 ml, 1 5 q) Th~ ~olution wa~ stirred at 0C for 30 minute~ and at room t~ --a0~re for 15 hours MQthanol (10 ml) wa~ then carefully SUBSTIT~JTE SHEEI
WO 94/11382 2 14 ~ 5 ~ ~ PCI/CA93/00463 added to destroy the exc~s BH3 and the ~olv~nt~ were evaporated. The residue wa~ poured in CH2C12/-at. aq. NaHCO3 and the pha~e~ were separated. The ~ layer wao extracted with CH2C12 (2x) and the combined organic ~xtract~ were dried over MgSO4. The ~olids were filtered and the olv-nt ~oLated to give the tltled alcohol as a - clear oil (0.092 g, 89~).
lH NMR (CDC13): ~ 4.09 (m, 2H, CH2N), 3.44 (d, 2H, ~20H), 2.67 ~m, 2H, CH2N), 2.08 (bs, lH, OH), 1.73-1.52 (m, 2H, S~2-CH2N)~ 1-48 (8~ 9H, BOC), 1.22-1.01 (m, 2H, S~2-CH2N).
~t-p 3s 1-O-[N-B4C-4-pip-r~ 1]_3 ~~~t~l-S,8-dimethosr ~sochro ~n . - ~ r The titled _ ~ was obtained via DDQ in~ured coupling of the alcohol lS ~rom ~t~p 2 her-in with 3-ac~to-5,8-dimethoxy i-ochroman. Purifi~ti~n:
flash c~ Lo~a~hy (silica gel, 2:1 Hex/EtOAc).
lH NMR (CDC13): ~ 6.76 (d, lH, J ~ 8.8, ArH), 6.70 (d, lH, J - 8.8, ArH), 5.77 (~, lH, H-1~, 4.59 (dd, lH, J - 4.2, 12.2, H-3), 4.08 (m, 2H, CH2N), 3.78 (8, 3H, ArOMe), 3.77 (8, 3H, ArOMe), 3.72 (dd, lH, J - 6.4, 9.7, H-l'), 3.57 (dd, lH, J - 6.4, 9.7, H-l'), 3.04 (dd, lH, J e 4.2, 17.6, H-4), 2.70 (m, 2H, CH2N), 2.53 (dd, lH, J - 12.2, 17.6, H-4), 2.33 (8, 3H, COCH3), 1.76 (m, 3H, ~2~-CH20), 1.21 (m, 2H, ~2CHCH20).
8t-p 4: ~ thrl-~1-0-[2'-pip~r;~; - Lhanoll-S,10 d;~-o-3,4,S,10-t-tr~h~d.~ 1 - [2,3-cl p,.~n 3-~ t h~d.~chlor~d- (~CH-2069) The titled c ~ was obtained from the precur~or from step 3 herein a~ per previou~ly describQd p a~
lH NMR (DMSO): ~ 8.05-7.80 (m, 4H, ArH), 5.69 (8, lH, H-l), 4.48 (m, lH, H-3), 3.88 (m, 4H, CH2N and NH2Cl), 3.74 (m, lH, H-l'), 3.60 (m, lH, H-1'), 3.25 (m, lH, H-4+H2O), 2.82 (m~ 3H, CH2N and H-4), 2.31 (~, 3H, COCH3), 2.01-1.70 (m, 3H, S~2~-CH2O), 1.57-1.38 (m, 2H, ~2CHCH20).
_1- 69 ~ ub~t~t~ ~ ; - d-r~v-t~e SUBSTITUTE SHEET
WO 94/11382 PCI`/CA93/00463 ~14~4~ --~", l~O~ OH . , ~f~ OS i~BI~ 2 HO ~ ~ N3 NHlFA NHl~A
O O O O
OS hB~4 1 4 ~
O OH NHIFA O O~ NHl~A
+1,3~ net 0 ~
~ NHlFA
+1~ " . ' O O
f~
o O~ NHIFA
~NHl~A
+1,3 J' , BC~2102 ~t--p 1~ (2R,~8,5S,68)-2-t-rt-butrld;l thrlsi l~lo,.
tr~fl ~ L~d~ S krl.~ C Lhrl-t-tr-l ~1.~,.
S
To a oolution of the ia-~tal ~0 51 g, 2 08 ~ol) $n dry CH2C12 (20 ml), under argon, at room ~ Lure, were added ~ls~ iv~ly ~ ir3-701e (0 28 g, 2 eg) and t-Bu~5e2S~Cl (0 34 g, 1 1 eg) The ~olution was stirred at room t~ ~ aL~r~ for 15 hour~ after which it was poured in 10 ~at aq NaHCO3 The pha-e~ were ~eparated and the ~-, 9: ~! layer was extracted with CH2C12 (2x) The combined organic xtracts w~re dried over MgS04, the ~olid- were filt~red and the solvent _~.~Grat~d to give O 72 g (97~ ) of the t~tled silyloxy-sugar as a white solid lH N~SR (CDC13) ~ 6 82 (bd, lH, NH), 4 78 (dd, lH, J Y 2 2, 9 2, H--1), 15 4 09 ~m, lH, H-3), 3 62 ~g, lH, J ~ 6 6, H-5), 3 48 ~d, lH, J ~ 2 6, H-4), 2 44 (bB, lH, OH), 2 08 (dd, lH, J - 5 0, 13 0, H-2), 1 55 (ddd, lH, J ~ 9 2, 13 0, 13 0, H--2), 1 29 (d, 3H, J -- 6 6, H--6), 0 89 (s, 9H, t--Bu) , 0 12 ~t, 3H, S~B) , 0.11 ~E~, 3H, S~e) SUBSTITUTE SHEET
W O 94/11382 PC~r/CA93/00463 2~45~
8t--p 2 (2R,48,SR,68)-2-t--rt-butrld~-thyl~ilrlosr-4-tr~fl ~ c~u~$do 5 ~~j~o 6 thyl-t-tr-h~d~p,..~
S To a ~olution of th~ alcohol (O 40 g, 1 11 mmol) in dry CH2Cl2 (11 1 ml), under argon, at -30Cjw-re ~dded ~ c~ vely pyridin~ ~0 45 ml, 5 ¢q) and Tf20 (0 37 ml, 2 eg) and the solution wa~ tirr~d at -10C for 1 hour It was then poured in at aq NaHCO3 and the pha~es were ~ep~rated Th~ aqu~ou~ lay~r wa- extract~d with CH2Cl2 (2x) and the combined organic extract~ wQre driQd ovQr MgSO4 The olids were filter~d and th~ olvent- were ~oL~L~d to d,y ~-~ Th~ r-d oil obtained wa~ di~solv~d in dry DMF (11 1 ml), under ~rgon, at room t _ aLur~, and NaN3 (0 36 g, 5 q) wa~ added Th- ~ lon was ~tirred for 5 hours after which it was poured in FtOAc Thi~ organic pha~ wa~ w ~-l with water (3x) and brine It was then dried over MgS04, thQ ~olid~ wer~ f$1t-red and the olvent ~ B ~ to give the titled azido-tr~fluoroacetamide as a cl~ar oil (0 27 g, 68~) 1H NMR (CDC13)s ~ 6 44 (bd, lH, J ~ 8 6, NH), 4 82 (dd, lH, J - 2 1, 8 8, H-1), 4 09 (ddd, lH, J - 4 7, 9 7, 12 8, H-3), 3 41 (dq, lH, J -6 1, 9 2, H-5), 2 97 (dd, lH, J - 9 7, 9 7, H-4), 2 21 (ddd, lH, J ~
2 1, 4 7, 12 8, H-2), 1 67 (ddd, lH, J - 8 8, 12 8, 12 8, H-2), 1 39 (d, 3H, J ~ 6 1, H-6), 0 89 (8, 9H, tBu), 0 12 (8, 3H, SLMe), 0 10 (~, 3H, SLMe ) .
2S 8t-p 3s (2R,4~,SR,~8)-2-t-rt-butrld$m-thrl-il~losr-4,5-bi--trif~ ~ 6 ~Lhrl-t-tr-l~d.~
The azLdo ~-rch~ride from step 2 was reduced a~ per ~tandard conti~itOn~ PurLf~c-t~ flash c}~. tG~a~}y (0Ll$ca g~l, 85:15 30 T~ tOAC) 1H NMR ~CDCl3) ~ 7 85 (bd, lH, J - 9 4, NH), 7 48 (bd, lH, J - 9 7, NH), 4 84 (d, lH, J ~ 7 8, H-l), 4 38 (m, lH, H-3), 3 96 (m, lH, H-4), 3 56 (dq, lH, J ~ 6 1, 9 6, H-5), 2 19 (m, lH, H-2), 1 78 (m, lH, H-2), 1 29 (d, 3H, J ~ 6 1, H-6), 0 89 (~, 9H, t-Bu), 0 12 (8, 3H, SLMe), 0 11 3~ (8, 3H, SLMe) -tep gs (lR,3s8,1'8) d (18,3~,1'8)-~ thrl-(1-~2',3',4',6'-t L -~c 1 3',~'-b$~-trif1 r .- ~a-$do-L--5, 10-dioso-3, 4, 5 ,10-SUBSTITUTE SHEET
W O 94/11382 P ~ /CA93/00463 2~6~48 ~
t-tr-h~ r~ Z,3-c~ ~ 3-~ ~ton- (~CH-210 ~nd ~C8-2102) To a solution of the hyd ~y~inone (72 mg, 0.33 mmole) and di-S trifluoroacetamido ugar from ~t-p 3 ~-L-i~ (162 mg, 1.1 q) in 6.5 mLof a 9:1 mixture of ~nhydrous CH2Cl2/Ac-ton~, under argon, at -30 C, w-re add~d activ-t-d 4A M.S. (200 mg) and THSOTf (94 ~L). The solution wa~ ~t~rrod at -30 C for 4 hr and 5~ N~XCO3 (5mL) wa~ added.
The ~irha~iC olution wa~ tirred for 15 min while the t~ ~- aLu ~ wa~
al 1~J~ to go back to r.t. It was then filtered through CQlite and pour~d in wat-r. Th- pha-e~ were ~eparatod nd the r,~ q layer was ~xtracted with CH2Cl2 ~2x). The combined organic extract- were dried ov~r MgS04, Th~ ~olid~ wer~ filt-red nd the olvant- ~ap~a~ed. The pal~ brown olid obtainod wa- di-~olved in dry toluen~ ~6.5 mL) and 1-lS acetoxybut~ 0.19 mL, 5 eq) waB added. The ~olution was ~tirred ~t r.t. , under argon for 15 hr. Silica gel wa- added and air wan bubbled through the olution. Thi~ p~n-ion was th-n placQd on top of a ilica gel column and the column wa~ luted with ~
~ oir). When th~ h~ r~ waB all gone , it wa~ r~pl~ce~ with 2:1 h~-~r~/othyl ~c-tate and ~ t~re of j~ a wa- coll~L~d. Thi~
mixture wa~ further purified by ChL~ ~LG~ a~l,Y ~10~ LQns/tolu~ne) to give 58 mg ~30%) of the titlQd ~parat~d ~
The fa-ter running fraction had: 33 mg, m.p.: 180-195 C d~c.
lH NMR ~6~_ ~ d6) s d 8.47 ~d, lH, J- 9.1, NH), 8.36 ~d, lH, J~ 9.4, NH), 8.11-8.04 (m, ZH, ArH), 7.92-7.85 (m, 2H, ArH), 6.03 (~, lH, H-1), 5.65 (~, lH, H-l'), 4.68 (dd, lH, J~ 4.1, 11.6, H-3), 4.58-4.36 (m~ 2H, H-3' and H-4'), 3.85 (g, lH, J~ 10.1, H-5'), 3.02 (dd, lH, J-4.1, 19.6, H-4), 2.51 ~dd, lH, J- 11.6, 19.6, H-4), 2.32 (~, 3H, coMe)r 2.28-2.09 (m, 2H, H-2'), 1.28 (d, 3H, J~ 6.3, H-6').
~h~ ~low2r running fraction had: 25 mg, m.p.: 143-153 dQc.
1H NMR ~CDCl3) : d 8.55 ~d, lH, J~ 9.2, NH), 8.46 ~d, lH, J- 9.1, NH), 8.13-8.07 ~m, 2H, ArH), 7.95-7.88 ~m, 2H, ArH), 6.17 ~8~ lH, H-1), 5.63 ~t, lH, J- 2.5, H-1'), 4.71 ~dd, lH, J~ 4.3, 11.6, H-3), 4.61-4.34 (m, 2H, H-~' ~nd H-4'), 3.86 (q, lH, J~ 10.2, H-S'), 2.99 (dd, lH, J~ 4.3, 19.7, H-4), 2.58 ~dd, lH, J- 11.6, 19.7, H-4), 2.32 (n, 3H, COMe), 2.28-2.13 (m, 2H, H-2'), 1.37 (d, 3H, J~ 6.2, H-6').
_1~ 70s 4'-;~c'~ ub~t~tut~d ~ tc, i d-rL -ti~
WO 94/11382 PCI~/CA93/00463 ~X~ ~ ositsuM
Br N~ N~
O O O O
SitE~u~
O OH N}I~P~ q~
,3 1- O~Hr +~
O O
O O~
-+1~
Bt ~2047 8t-p ls (2~,48,58,~ 2-(2' - ~ ~ 2' ~ a~ S ~ 6 -thyl-tetr h~d._ ~.. n To a colution of th~ triflat~ (1.06 g, 2.80 mmol) in a 1:1 mixture of CH2C12/tol --- (lS ml), under argon, at room t- ~~~a~u.a, wa~ added nBu4NBr (1.34 g, 1.5 q) and the ~olution wa~ ~tirred for 3 hours. It was then poured in ~at. aq. NaHCO3 and the pha~Q~ w~re eparated. The aqueous layer wa- xtracted wLth CH2C12 (2x) and thQ combined organic ~xtract~ were dried over MgSO4. ThQ ~olid~ wQre filt~red and the ~olvent~ -~a~G ~Led to g$ve a crude oil that wa~ pur~f$ed by flaRh ch,. -Lo~ ~hy (~ ca gel, 85:15 r ~ tOAc). The titled bL~ ~ azide lS was obtained in 66% yield (0.57 g).
H NMR (CDC13): ~ 5.34 (d, lH, J - 3.4, H-l), 4.27 (~, lH, H-4), 4.02 (g, lH, J ~ 6.2, H-5), 3.96 (m, lH, H-3), 3.20 (~, 3H, OMe), 2.23 (ddd, lH, J - 3.4, 12.5, 12.5, H-2), 1.74 (dd, lH, J ~ 4.26, 12.5, H-2), 1.40 Sl~B~ ~ L~ T
-W O 94/11382 PC~r/cA93/00463 21~6~48 ~
(~, 3H, , i Lhyl), 1 35 (8, 3H, , i Lhyl), 1 25 (d, 3H, J ~ 6 2, H-6) 8t-p 2 (2R,48,S8,6S)-2-t-rt-~utrl~i hrls~lrlca~ ^ 5 ~. -S 6-~-thyl-t--tr~d.~r, ~
To a ~olution of the bromo-azide from st~p 1 (0 57 g, 1 84 mmol) in dry CH2Cl2 (9 0 ml), under argon, at 0C, wa- added lowly CF3COOH (7 ~l, 0 05 eg) and th~ ~olution was ~tirred for 60 minut-s Th~ solvent and reagent w~re then _~G~aLed to dL~ ~rc and the crude ~ etal wa~
di~solved in a dry mixture (15 1) of CH2C12/DNF (9 2 ml) T i~-70le (0 25 g, 2 eq) was then added followed by t-BuMe2SiCl (0 31 g, 1 1 eg) The solution was ~t$rr~d at room t - ature for 15 hours after which it was poured in at aq NaHCO3 The phases were s~paratQd, the aqueous layer was extract~d w$th CH2C12 ~2x) and the combined organic extract~
WQre dr~ed over MgS04 Th~ solid- were filtcred and th~ ~olvent ~pG ~Lod to g~ve the titled T8DMS protected b,~ - azide ~0 30 g, 46~) as a clear oil 1H NMR ~CDCl3) ~ 4 80 ~dd, lH, J ~ 2 5, 8 7, H-1), 4 15 ~dd, lH, J ~
1 2, 3 3, H-4), 3 57 ~ddd, lH, J ~ 3 3, 4 4, 11 8, H-3), 3 44 (dq, lH, J
= 1 2, 6 1, H-5), 2 11-1 88 (m, 2H, H-2), 1 33 (d, 3H, J ~ 6 1, H-6), 0 90 (~, 9H, t-Bu), 0 14 ~s, 3H, S$Me), 0 11 (s, 3H, SiMe) ~t-p 3s (~ B,5~,68)-2-t-rt-butrl~; hyl~lrlo~ -tr~ ~~at-~$ao 5 ~.~ - 6 hyl-t-tr L~d--~
To a ~olu~;~n of the a~ide from tep 2 herein (0 30 g, 0 84 mmol) in a 19 1 mixture of THF/H2O ~8 4 ml) was added Ph3P (0 33 g, 1 5 og) and the olution wa~ tod at 50C for 3 hour~ It wa~ then ~ou ~d in at aq NaHCO3 and the ~ pha~ wa- extracted with CH2Cl2 ~3x) The combin~d organ~c ~xtract- were dried over MgS04 The ol~d- were filt-red and th~ olvent _~.~4 ~Led to drynes~ to giv~ a crud~ amine th~t wa~ dis~olved in dry CH2Cl2 ~8 4 ml) To thi- solution, under ~rgon, at -30C, wQre added .~ccaesively dry pyridine ~0 14 ml, 2 eq) and TFA2O ~0 13 ml, 1 1 eg) The solution wa~ ~tirred for 90 minute~ at -30C and was then poured in ~at aq NaHCO3 The pha~es were eparatQd, the r ~ n layer wa~ extracted with CH2Cl2 ~2x) and the combined organic extracts were dried over MgS04 The ~olid~ were SU~ r~T
W O 94/11382 21465A~ PC~r/CA93/00463 filt~red and th~ ~olv~nt wa- ~G ~tcd to givc the titled crude bromo-trifluoroacetamidQ in 72~ yi~ld (0.26 g).
H NMR (CDC13): ~ 6.67 (bd, lH, J - 7.3, NH), 4.84 (dd, lH, J - 5.4, 6.5, H-l), 4.28-4.17 (m, 2H, H-3 and H-4), 3.58 (g, lH, J - 6.1, H-5), 1.89-1.83 (m, 2H, H-2), 1.32 ~d, 3H, J - 6.1, H-6), 0.88 (s, 9H, t-Bu), 0.12 (8, 3H, SiMe), 0.10 (s~ 3H, SiMe).
8t~p ~s (1~,3~,1'~)--~--th~l--(1--t2',3',~',6'--t--t~ 3--tr~ t-~ido-~ ]-5,10-dioso-3,4,5,10-t-traL~d,~ ~p~t~ [2, 3-cl L~ ~-~ 3-rl) ~-tone The t$tled _ ~_ ' wa~ obtained a~ per previou~ ~,occdu~ from the ~ugar of tep 3 and the isochl~ -n~ . Purification: fla~h chromatG~ hy (-ilica gel, toluene/acetone 95:5). The two i~ s are ~eparable by cl~ -Lo~.aph~.
H NMR (CDC13): ~ 8.15-8.07 (m, 2H, ArH), 7.81 -7.76 (m, 2H, ArH), 6.46 (bd, lH, J - 8.4, NH), 6.01 (8, lH, H-l), 5.62 (d, lH, J - 3.2, H-l'), 4.54 (dd, lH, J ~ 4.0, 11.7, H-3), 4.42 (m, lH, H-3'), 4.37 (s, lH, H-4'), 4.11 (g, lH, J - 6.5, H-5'), 3.11 (dd, lH, J - 4.0, 19.7, H-4), 2.53 (dd, lH, J - 11.7, 19.7, H-4), 2.35 (s, 3H, COMe), 2.14 (td, lH, J
3.2, 12.9, H-2'), 1.91 (dd, lH, J ~ 4.5, 12.9, H-2'), 1.32 (d, 3H, J -6.5, H-6').
Th~ (lS,3R,l'S)-Methyl-(l-t2',3',4',6'-tetr~ 3'-trifluoroac~tamido-4' ~,~ - L-l~ nos~-s~lo-dioxo-3~4~5~lo-t~trahydrQn~rht ~2,3-cl py.an 3-yl) k~tone (BCH-2047) had:
H NMR (CDC13): ~ 8.15-8.08 (m, 2H, ArH), 7.82-7.74 (m, 2H, ArH), 6.50 (bd, lH, J ~ 8.5, NH), 6.18 (s, lH, H-l), 5.49 (d, lH, J ~ 3.4, H-l'), 4.58 (q, lH, J ~ 6.4, H-5'), 4.48 (dd, lH, J ~ 4.2, 11.6, H-3), 4.40 (8, lH, H-4'), 4.40 (m, lH, H-3'), 3.08 (dd, lH, J - 4.2, 19.7, H-4), 2.57 (dd, lH, J ~ 11.6, 19.7, H-4), 2.32 (s, 3H, COMe), 2.18 (td, lH, J ~
3.4, 13.0, H-2'), 1.79 (dd, lH, J ~ 4.4, 13.0, H-2'), 1.49 (d, 3H, J =
6.4, H-6').
_1- 71: Cyclic ~ in- sub~t~tuted ~ d-ri-ati-e W 0 94/11382 P ~ /CA93/00463 H 2~ ~ 6 5~ ~
[~)H
o~ o BOC o~ O
~ + ~ ~ ~
0~ 0~ O~ .
h ~BOC
O O O O
O O~ ` O O~
NH2CI ~OC
BCH 2061 BC~2060 ~t-p 1: N-~OC-3-pip-r~
S The t$tled _ __ ' obtainQd follow$ng prot-ction with BOC had:
1H NMR ~CDC13): ~ 3.90-3.65 (m, 2H), 3.48 (d, 2H, CH20H), 3.25-2.75 (m, 2H), 2.28 (b~, lH, OH), 1.86-1.54 (m, 4H), 1.25 (m, lH).
~t-p 2: l-o-IN-BoC-3-p~ - ai L~ -ll-3 ~ ,1-5,8-Ai ~ y i~ t~r- of ~- -The titled ~ wa- obtained from the ~ of t-p 1 her~in and 5,8-d~methoxy-3 .-~to~ n a~ per ~ ocLIurQ de~cribed ~rli~r.
Pur$fic~tion: fla3h ~ ap}.~ lica gel, 2:1 RsY~--/2tOAc)~
lS The ;- - ~ wsr~ not ~parable by flash cl~- -~o~Laphy.
H NNR (CDCl3)s ~ 6.75-6.65 (m, 2H, ArH), 5.74+5.73 (2~, lH, H-l), 4.60 (m, lH, H-3), 4.05-3.56 (m, 4H, H-1' and CH2N), 3.04 (dd, lH, H-4), 2.86-2.62 (m, 2H, CH2N), 2.53 (dd, lH, H-4), 2.33 (~, 3H, COCH3), 1.94-1.79 (m, 2H), 1.68 (m, lH), 1.48 (~ 9H, BOC), 1.37-1.24 (m,2 H)~
S U ~ . U 1, ~ .: ~ ï
WO 94/11382 PCI~/CA93/00463 ~ j 2146~
8t-p 3s ~ thr~ - o-1 N-BOC-3-pip ri Ai - th nol]-5,6-dioso-3,4,5,10-t-tr~hyd,. ~p~ 2,3-c] prran-3-yl) k-ton~ stur- of ~ C8-2060) The t$tled _ __-' wa~ obta~ned from thc product from ~tap 2 herein, - follow$ng previou-ly d--cr$bed ~co-` ~ 6. Pur$f$cat$on: fla~h chromatoy.a~.y (~$1$ca gel, 2:1 ~ /EtOAc). The i~om~r~ were not ~eparable by fla~h chromato~.aphy.
lH NMR (CDC13): ~ 8.12-8.03 (m, 2H, ArH), 7.78-7.67 (m, 2H, ArH), 6.72 10 (8, lH, H-l), 4.54 (m, lH, H-3), 4.10-3.55 (m, 4H, H-l' nd CH2N), 3.04 (dd, lH, H-4), 2.90-2.60 (m, 2H, CH2N), 2.51 (dd, lH, H-4), 2.30 (8, 3H, COCH3), 1.97-1.72 (m, 2H), 1.61 (m, lH), 1.48 (8, 9H, BOC), 1.34-1.15 (m, 2H).
15 st-p 4: M th~1-(1-0-[3-pip-r~ ]-5,10-dioso-3,4,5,10-t-tr~hyd~ 2,3-c] pyr-n-3-yl) ~t~ -L~-~,ocLlor~d- ~alt, m$stur- of i- ~. (BCH-2061) The tLtled c ~u ' wa- obta$ned from the tr$cyclic product from ~tep 3 here$n follow$ng acid$c hydroly-$~.
lH NMR (DMSO-d6): ~ 8.23-7.84 ~m, 4H, ArH), 5.68+5.67 (2B, lH, H-l), 4.48 (m, lH, H-3), 3.83-3.57 (m, 2H, H-l'), 3.29-3.15 (m, 2H, CH2N), 2.84 (dd, lH, H-4), 2.66 (m, 2H, CH2N), 2.43 (m, lH, H-4), 2.29 (~ 3H, COCH3), 1.74-1.72 (m, 4H), 1.25 (m, lH).
-~U~ST~ ~ ~ f ~ S ~ r E T
8t-p 4s (1'~, lR, 3~)-2',3',6'-tr~ 3'-tr~fl ~ w~ a~do-~-~ 3-[S'-tozr~ Qlrl]-5,10 '~ -3,6,5,10-2S t~ - [2,3-c]-pyr ~ (JCH-21S0) To th~ ~ _: ' from step 3 ~ n (4.8 mg, 5.92 ~mol) in THF (0.5 ml) and mQthanol (1.5 ml) coolsd to 0C wa~ added ~odium ~h~Y;~Q (4.37 M,1.4 ~1, 5.g2 ~mol). Aft~r 5 m$nutes, the r~action was ~ d with d$1utc h~ cl.loridQ acid and xtracted with methyl~ne chlorideO The organic layer wa- dried (ov~r Na2S04) and ~ uLaL~d to giva a crude product which was purified on T~C (CHC13sMeOH - 100:7) to givc desired titled product a~ an off-whit~ solid (1.3 mg).
M.P. 130-135C.
lH NMR (CDC13, 250 MHz, Bruk r)s ~, 1.13 (3H, d, J - 6.S Hz, 6'-CH3), 1.78 (lH, tr d, J ~ 11.2 Hz, 2'-HCHa), 2.05 (lH, m, 2'-HCHe, due to ~olvcnt overlap, thi~ is an ost~ -tj~), 2.43 ~3H, s, tol-cH3)~ 2.92 (lH, d, J ~ 5.9 Hz, 4-HCHa), 2.94 (lH, d, J - 10.5 Hz, 4-HCHe), 3.71 (lH, m, 4~-OH), 4.20 (lH, dd, J ~ 5.9 Hz, 3-2 Hz, 4'-OH), 4.47 (lH, qua, SU~TliT~JT~- 5~EET
~ 2146~8 J ~ 6.S Hz, 5'--CH3), 4.58 ~lH, m, 3'--CH), 5.55 (lH, d, J ~ 3.0 Hz, 1'-CH), 5.99 (lH, ~, 1--CH), 6.16 (lH, dd, J -- 10.6 Hz, 5.9 Hz, 3--CH), 6.77 (lH, d, J ~ 10.6 Hz, NHCOCF3), 7.36 (2H, d, J ~ 8.8 Hz, to~lyl--H), 7.79 (2H, m, 7, 8-ArH), 7.90 (lH, u, oxa-H), 7.91 (2H, d, J ~ 8.8 Hz, to~yl-S H), 8.11 (2H, m, 6, 9-ArH).
IR (Nicol~t 205 FT, film on NaCl plat--): cm~l, 3379.1, 2956.4, 2927.8, 2854.7, 1716.9, 1669.3, 1335.6, 1297.4~ 1148.0, 985.2.
-_1- Sls Pr parat$on of (1'8,121,31~)-l-(3'tr~ t ~o-2 ',3 ',6 ' -tr~ ly o-L ~ ~ ) -3- ( S ~ _ to~ 1)--3,~,S,10--t~ l ~d,o S,10 'i~
[2,3-cl pyran (~-21Sl) OCH, O~ ~
~N J~ ~N
~ S2~ ~
H~C~;J H~
NBO NHlFJ~ PNBO N~PA
l~p2 O 0~ 0 0 H~ H~C~i oHNHlFA PNBo NHJFA
lS
sStep ls (1's5, 18, 3R)-1-(4'-p-n$~.,. ' -orl-2' ,3' ,6'-tr~ 3'-~r~ A^-L-l~ J-)-3-(S~-to-rl~ lrl)-S,8 i~-o-3,4,5,8-t-trah~d~ c [2,3-c]-prran -Starting wLth the (l~S,lS,3R) dia~L~. from ~tep 1, r le 50, (12 my, 0 015 mmol), using the ame material~ (- --; cerium nitrate, 25 mg, 0 046 mmol; NaHC03, 2 55 mg, 0 0304 mmol; -~Lo~trile, 1 5 ml; H20, O 4 ml) and following the ~me ~.~c~d~ ~c as described in step 2, example 50, the desired titled product was obtained (9 mg) SUB~T~ SI~E-T
WO 94/11382 PCI'/CA93/00463 21~X~48 ~
lH NMR (~ s - d6, 2S0 MHz, Bru~er): ~, 1.27 (3H, d, J ~ 6.6 Hz, 6~-CH3), 2.20 (2H, m, 2'-CH2), 2.45 (3H, s, tosyl-CH3), 2.95 (lH, d, J ~
6.8 Hz, 4-CH), 2.95 (lH, d, J ~ 8.8 Hz, 4-CH), 4.56 (lH, m, 3'-CH), 4.74 (lH, qua, J = 6.6 Hz, 5'-CH), 5.53 (lH, s, 4'-CH), 5.68 (lH, d, J ~ 2.9 S Hz, l'-CH), 6.01 (lH, s, l-CH), 6.09 (lH, dd, J ~ 8.8 Hz, 6.8 Hz, 3-CH), 6.93 (lH, d, J = 11.8 Hz, Quin-H), 6.96 (lH, d, J ~ 11.8 Hz, Quin-H), 7.49 (2H, d, J ~ 8.8 Hz, 3~, 5"-to-yl-H), 7.93 (2H, d, J ~ 8.8 Hz, 2", 6"-tosyl-H), 8.36 (lH, ~, oxa-H), 8.39 (4H, m, PNB), 8.68 (lH, d, J =
8.8 Hz, h~4~3).
8t-p 2s (1'~, 18, 3R)~ 4'-p-~it,. ~ - D~1 -3-tr~fl~G~ do-2',3',6~-tr~ L-l~ )_3_(5 n -to~rl-o~olyl ) ~
5,10-d~oxo-3,4,S,10-t-tr~hydro-lH ~r~t~ - [ 2,3-~1-pyr n The _ ~su ~ from tep 2 herein (7 mg, 0.009 mmol) was reacted wLth 1-acetoxy-l,3-but~if-- (21 ~1, 0.184 mmol) in tolu-ne (3 ml) at 50C for 18 hours. The solvent was _~p~,aLed to give a crude product. After chromatoy~a~hy (toluene/-thyl acetate ~ 5:1) desired titled product was obtained (6.4 mg).
lH NMR (CDC13 250 MHz, Bruk r)s ~, 1.34 (3H, d, J - 7.1 Hz, 6'-CH3), 2.15 (lH, d tr, J - 12.9 Hz, 4.1 Hz, 2'-HCHa), 2.32 (lH, dd, J ~ 12.9 Hz, 4.1 Hz, 2'-HCH~), 2.45 (3H, s, to~yl-CH3), Z.96 (lH, dd, J ~ 18.2 Hz, 4.1 Hz, 4-HCHa), 3.13 (lH, dd, J ~ 18.2 Hz, 11.2 Hz, 4-HCHe), 4.64 (lH, m, 3'-CH), 4.77 (lH, qu~, J - 7.1 Hz, 5'-CH), 5.52 (lH, s, 4'-CH), 2S 5.76 (lH, d, J ~ 2.0 Hz, l~-CH), 6.08 (lH, dd, J = 11.2 Hz, 4.1 Hz, 3-CH), 6.20 (lH, ~, l-CH), 6.21 (lH, m, HNCOCF3), 7.37 (2H, d, J ~ 8.2 Hz, 3", 5~-tosyl-H), 7.71 (2H, m, 7, 8-ArH), 7.89 (2H, d, J ~ 8.2 Hz, 2", 6n-tosyl-H), 7.90 (lH, ~, oxa-H), 8.15 (lH, m, 6, 9-ArH), 8.31 (4H, m, PNB).
~t-p 3: (l'S, lS, 3R)-2',3',6'-tr~ 3'-tr~fl v_s~-- i~o-L-~ 3-lS~-to~ Qlrl)]-5~lo t~ -3,~,S,10-t-tr hydro~ ~ t2~3-CI-prran (~C~-2151) To PNB derivative ~rom tep 2 herein (6.4 mg, 0.0079 mmol) tirrnd in tetrahydrofuran (0.5 ml) and methanol (1.5 ml) at 0C was ldded ~odium meth~Y~do (4.373 M, 1.8 ~1, 0.0079 mmol). After 5 minutes, the pink solution wa~ g~len~h~ with dilute HCl. The product wa~ extracted with methylRne chloride. The organic layer was dried and ~a~G,aLed to give SuBsTlTuTE SHEET
W O 94~11382 PC~r/CA93/00463 214~4g a crud~ product which wa~ pur~f~d by thin~ tG-~- ~phy (CHC13s~0H ~ 100:7) to d~s~red titl-d product ~ an off-whLt~ ~olid (0.8 mg).
M.P. 100-105C.
S ~H NMR (CDC13, 250 HHz, Bruk-r)s ~, 1.41 (3H, d, J - S.9 Hz, 6'-CH3), 1.92 (lH, tr d, J - 11 Hz, 3.5 ~z, 2'-HCHa, o~tim~tlon), 2.20 (lH, m, 2'-HCHe, ~tj -~io~), 2.44 (3H, ~, tol-CH3), 2.95 (lH, dd, J - 18.5 Hz, 4.7 Hz, 4-HCHe), 3.12 (lH, dd~ J - 18.5 ~, 11.2 Hz, 4-HCHa), 4.00 (lH, m, 4'-CH), 4.37 (m, lH, 3'-CH), 4.60 (lH, qua, J - 5.9 Hz, 5'-CH), 5.10 (lH, br ~, 4'-OH, ~ti - j~n)~ 5.58 (lH, d, J - 3.5 Hz, l'-CH), 6.05 (lH, dd, J - 11.2 Hsc, 4.7 Hz, 3-CH), 6.15 (lH, ~, l-CH), 6.66 (lH, m, ~O~r3), 7.36 (2H, d, J ~ 8.8 Hz, to~yl-H), 7.78 (2H, m, 7, 8-ArH), 7.87 (lH, ~, oxa-H), 7.88 (2H, d, J - 8.8 Hz, to~yl-H), 8.12 (2H, m, 6, g-ArH ) .
IR (Nicol~t 205 FT, f~lm on N~Cl pl~t-)s cm~l, 3368.3 2961.8, 2930.2, 2848.9, 1715.0, 1669.9, 1463.0, 1332.8, 1289.0, 1153.4, 975.46.
1~ S2s ~ ion of (1,3-tr~n-)-1-~-thosr-3-(3'-~ l rl)-s, lo . i . 3,4,5,10-totr~hrdro-lH-~ ~~ t2~3-cl-Pqr~n (BC~-1616) ~d (1,3-tr~n~)-1-~ 3 ~ 1-S,10-d~oso-3,~,5,10-t-tr h~dro-1~~ [2,3-cl-prr~3 (BCH-lC7~) OCHI O o O
OCH~ OH O oCH~ O OCH~
~/ O N--~~~Br ~ O OCH~ BCH-1616 O OCH~ \
\~p5 O O O
\~ G[~H21~(POCH,)~
O OCH
~ UTE SHEET
WO 94/11382 PCr/C~93/00463 21~4~
~t-p 1 1 ~- ~ 3 -- L~l-S,8 ~ -3,4,5,8-t-tr--h~d. ~ -o-t2,3-C 1--prr S A ~ampl~ of 5,8-d~m~thoxy-1-hyd OAY 3-ac~to~ -n (200 mg, 0.79 mmol) ~n ~eOH (10 ml) wa~ t~rr~d at room t- - ~Lur- whil- a olution of CAN (2.16 q, 3.95 ~mol) ln water (9 ml) wa~ add~d dropwl-e. Aft~r S
minut-~, tha r-actLon mixtur- wa- pourQd to wat~r nd th-n xtract~d with m~thyl-nc chloride. Th- organic layer wa~ dr~-d (over ~
sulfate), and J~o~atQd to q~v- a ~ 1 low st~cky ol~d (157 mg). lH NMR
howad that de-~red tltlsd product w-~ o~t~i~~' w~th 89% purity.
lH NMR (CDC13, 250 MHz Bruk r), ~: 2.28 (8, 3H, COCH3), 2.35 (dd, lH, J
- 20.5 Hz, 12.1 Hz, 4-Ha), 2.78 (dd, lH, J ~ 20.5 Hz, 4.3 Hz, 4-He), 3.56 (s, 3H, OC~3), 4.44 (dd, lH, J ~ 12.1 Hz, 4.3 Hz, 3-H), 5.46 (~, lS lH, 1-H), 6.73 (m, 2H, 6.7-~
~t-p 2 1_-thosr-3 ~ 1-5,10 'i ~o-3,~,5,10-t-tr~hrdro-lH-~p~~~ [2,3-e]-prran The bicycllc ~-in~n~ from step 1 hera$n (157 mg, 0.66 mmol) was tfrredwith l-acetoxy-1,3-but-'~ (632 ~1, 5.32 mmol) in tol --~ (20 ml) ~t 40C for 16 hours. Solvent wa~ ~G~ated and the crude ~.~duuL was cl.,~ - oJ~a~h~d (tol - -s~tOAc ~ 100s25) to gl~e d s~rcd t~tl-d tr$cyclic ~i - - a- a yellow ~olid (190 mg).
2S ~.P. 169.8-170.8C.
H NMR (CDC13, 250 ~H~ 8ruker), ~s 2.34 (s, 3H, COCH3), 2.53 (dd, lH, J
20.7 Hz, 10.7 ~z, 4-Ha), 3.00 (dd, lH, J ~ 10.7 Hz, 4.3 ~z, 4-He), 3.63 (8, 3H, OCH3), 4.54 (dd, lH, J ~ 10.7 Hz, 4.3 Hz, 3-H), 5.66 (~, lH, l-H), 7.73 (m, 2H, 7.8-As~), 8.06 (m, 2H, 6.8-ArH).
IR (N~colet 205 FT, f~lm on NaCl plate), cm~l: 2923.4, 2827.6, 1717.7, 1668.2, 1637.3, 1597.1, 1368.3, 1331.3, 1300.3, 1281.8, 1179.8, 1105.6, 1083.9, 1046.8, 875.5, 799.8, 714.2, 686.1.
s~t - p 3s 3 _ -- ~ ~rl-l ~ ~ 5,10-dio~o-3,-,5,10-t-tr~h~dro-lH-~P~ ~~ t2~3~Cl-prr~n To a solut~on of product from step 2 herein (50 mg, 0.175 mmol) in THF
(3 ml) at room t- ~ aLu . was added pyri~ini- ~ydro~ .L.~ i~e (1.3 eq.) in THF (2 ml). The mixtura was stirred for 45 minutes at room SUBSTITVTE SHEET
W O 94/11382 PC~rJcA93/00463 ~46~
t~ - ~ture. It wa~ poured to water and extracted wLth methyl~ne chloride. The organic layer wa~ dried and _~a~o,ated to qive a product.
TLC and lH NMR both ~howed that th~ de~ired t$tled product (76 mg) wa~
obtained with purity ~90~.
M.P. 169.8-170.8C.
H NMR (CDC13, 250 MHz Bruker), ~: 2.53 ~dd, lH, J - 20.3 Hz, 11.0 Hz, 4-Ha), 3.02 (dd, lH, J ~ 20.3 Hz, 4.1 Hz, 4-He), 3.64 ~u, 3H, OCH3), 4.15 (d, lH, J ~ 12.7 Hz, BrCHAH), 4.35 (d, lH, J ~ 12.7 Hz, Br CHHB), 4.84 (dd, lH, J - 11.0 Hz, 4.1 Hz, 3-H), 5.65 (s, lH, l-H), 7.72 (m, 2H, 7.8-ArH), 8.02 ~m, 2H, 6.9-ArH).
8t--p ~s (1,3-tr--nz)-1-~ tho--r-3--(3' _ ~ -~h~--~lyl)-S~l0-d 3,4,5,10-t-trahydro-1~ ~ [2,3-c] pyran (BC~-1616) ~.~ Lhyl ketone from step 3 her~in (20 mg, 0.054 mmol) waz ztirred with thioure~ at room t - a~ure for 3.5 hours in ther (2 ml) and oromethane (2 ml). It wa- poured to at. ~dj- bic~rhQn-t~ and xtracted with ~ i ~h l o~ - . Th~ organic layer wa~ ~v~.t-d to give crude product which wa~ -tr ~had (MeOHsCHC13sHOAc ~ 4:100:1) to give de~Lred tLtl-d p,v~u~L (5.3 mg). A polar b~ ~.oluct was al~o obtained (8 mg).
lH NMR (CDC13, 250 MHz Bruker), ~: 2.77 (lH, dd, J ~ 18.8 Hz, 11.8 Hz, 4-HCHa), 3.00 (lH, dd, J - 18.8 Hz, 5.2 Hz, 4-HCH~), 3.63 (3H, ~, OCH3), 5.03 (lH, dd, J ~ 11.8 Hz, 5.2 Hz, 3-CH), 5.67 (lH, , l-CH), 6.53 (lH, 2S ~, thia-H), 7.73 (2H, m, 6, 9-ArH), 8.08 (2H, m, 7, 8-ArH).
IR (Nicolet 205 FT, fLlm on NaCl plat-), cm~l: 3429.8, 3346.7, 3130.7, 2957.8, 2921.3, 2854.8, 1664.9, 1641.6, 1591.7, 1521.9, 1455.5, 1408.9, 1327.1, 1294.1, 1102.0, 1039.9, 731.92, 708.07.
0 8tep 5: 1- tho~r-3 ~; -thrl ~ s~t~1-5,10-dLoxo-3,~,S,10-t--tr bydro-lr ~ ~ t2~3-c]-pyran (~CX-167-) A ~olution of b.~ thyl`-Lone from ztep 3 herein (10 mg, 0.027 mmol) wa~ refluxed with trimQthylpho~phite (3.54 ~1, 0.03 mmol) and odium iodide (0.2 mg, 0.05 mmol) in THF at 70C ov~rnight. Solvent wa~
L~po~ated and the brown ~3~i~ - wa~ cl... ~to~.~hed (CHC13:MeOH 50:1) to give de~ir~d titled product a~ a light-colored solid (2 mg).
1H NMR (CDC13, 250 MHz, Bruker): ~, 2.60 (lH, dd, J ~ 19.8 Hz, 11.6 Hz 4-HCH~), 2.94 (lH, dd, J ~ 19.8 Hz, 3.5 Hz, 4-HeCH), 3.62 (3H, ~, 1-SUBSTIT~JTE SHEEt 21~ 8 ~
OCH3), 3.85 (3H, ~, POCH3), 3.88 (3H, ~, POCH3), 4.59 (lH, dd, J ~ 11.6 Hz, 3.5 Hz, 3-CH), 5.02 (lH, br ~, CHP), 5.15 (lH, br ~, CHP), 5.62 (lH, 8, l-CH), 7.73 (2H, m, 6, 9-ArH), 8.08 (2H, m, 7, 8-ArH).
S _1- 53s Pr~p~r~tion of (1'8,1~,38)-1-(3~-trifl ~ c~t~
2',3',6'-tr~ )-3--t~- ~c~ 3---thrl-3,4,5,10-t-tr h~l.~ S,10-d~o~o-l~ -~rht~- [2,3-cl prr n (~C~-2077) ~' OCH,O
X 11 OCH, O + OCH, O +
~OCH, 2p~lA PNB~A
OCH, 1 ~ X-H ~H~ ¢~;~U3 OCH, o OCH, O
H3C~A C PNBC~ D
O O
o o Ll--- Ll ~H 4 Ç~
H3C~IA
PNBO NH~A ~ o o ~J~H, O O
H,C~;J
oHNHlFA 8CH-20n 8t-p ls 3- ~ 1-3-~ thrl-5,~ ; -Lhoxy ;~
A ~olutLon of di-~.o~ylamine (616.8 ~1, 4.37 ~,ol) in THF (10 ~1) wa~
cooled to 0C and 1-3 ~ae~ briefly. n ~Lyl lithium (1.6 M in hexane, 2.60 ml, 4.17 ~mol) wa- added. After stirred for 30 minutes at 0C, the SUBSr1TUTE SHEET
~ 214~4~
olution wa~ furthQr cool~d to -78c. A Rolution of 5,8-d$methoxy-3-methoxycarbonyli~o-hroman (1.0 g, 3.97 mmol) in THF (10 ml), pre-~sg~Ed, wa~ added ~lowly. The r-~ulting yellow Rolution was stirred for 1 hour at -78C before the addition of methyliodide (1.01 ml, 16 S mmol). After ~tirred further for 45 minutes, ~at. NH4Cl Rolution wa~
added. The mixturc wa~ diluted with water and extracted with ethyl acctate. The organic layer was dried and _~pG.ated to givs a crude product which was ch~ -LoJ-a~h~d (hoxan~:~tOAc ~ 3sl) to give the des~rQd product as a olid (650 mg, m p. 73.0-74.5C) and another fraction (192 mg) which con~in~d 66~ of titled product and 34% of the tarting materlal.
M.P. 73-74.5C
H NMR (CDC13 250 MHz, Bruker): 8, 1.50 (3H, 8, 3-CCH3), 2.58 (lH, d, J
~ 17.1 Hz, 4-CH), 3.25 (lH, d, J ~ 17.1 Hz, 4-CH), 3.64 (3H, s, OCH3), 3.68 (3H, 8, OCH3), 3.72 (3H, s, OCH3), 4.76 (lH, d, J - 17.1 Hz, l-CH), 4.84 (lH, d, J ~ 17.1 H, l-CH), 6.53 (lH, d, J ~ 7.1 Hz, ArH), 6.59 (lH, d, J ~ 7.1 Hz, ArH).
IR (~icolet, 205 FT, film on NaCl plate): cm~1, 2949.9, 2833.2, 1736.6, 1489.0, 1365.2, 1344.0, 1259.1, 1206.0, 1142.3, 1114.0, 1060.7, 295.7, 713.8.
8t-p 2s (1'8, lR, 38)-l-(~ ~yl-3'-tr~f~
2',3',6'-tr~ Ll~ )-3 ~ yl-3-~ thrl-S, ~ r-~-o~
The _ _ ' from ~tep 1 ~ .i n ( 133 mg, 0.5 mmol) wa~ r-acted with DDQ
(136 mg, 0.6 mmol) and 5'-p-ni~.~b~ ~oyl-3',4',7'-tridQoxy-3'-trifluoroacotamido-L-ly~oh--.,pyL- -~e (196 mg, 0.5 mmol) at 45C for 16 hours, the ~ame way a- d~cribed in ~tep 2, example 13. After cl..~ -tGy~hy (hexane:EtOAc - 2.521), four ;R - ~ were obtained: C, 49 mgJ B, 24 mgS D, 73 mg; A, 56 mg.
For C, lH NMR (CDC13 250 MHz, Bruker): 8, 1.22 (3H, d, J - 6.1 Hz, 6~-CH3), 1.45 (3H, 8, 3-CCH3), 1.89 (lH, dd, J - 11.8 Hz, 4.7 Hz, 2'-CH), 2.05 (lH, d, tr, J ~ 11.8 Hz, 3.0 Hz, 2'-CH), 2.77 (lH, d, J ~ 17.1 Hz, 4-CH), 3.82 (lH, d, J ~ 17.1 Hz, 4-CH), 3.64 (3H, 8, OCH3), 3.78 (3H, s, OCH3), 3.81 (3H, ~, OCH3), 4.52 (lH, m, 3'-CH), 4.60 (lH, qua, J ~ 6.1 Hz, 5'-CH), 5.42 (lH, s, 4'-CH), 5~74 (lH, d, J ~ 1.7 Hz, l'-CH), 6.22 (lH, ~, l-CH), 6.36 (lH, d, J - 8.2 Hz, NHCOCF3), 6.71 (lH, d, J = 8.8 Hz, ArH), 6.80 (lH, d, J ~ 8.8 Hz, ArH), 8.28 (4H, m, PNB).
SUBS~iTUTE SHEET
WO 94/11382 PCI/CA93/004~3 2 1 ~ e IR (Nicolet, 205 F~, f;lm on NaCl plate): cm~l, 3328.4, 3077.3, 2946.4, 2843.8, 1740.1, lS27.9, 1492.5, 1259.1, 1114.0, 1054.2, 974.90, 947.90, 803.50, 716.80 The (l'S, lS, 3s)~ 4~-p-nitrobenzoyl-3~-trifluoroacQtamido-2~3~6 trideoxyly ' ~y~.no-e)-3-m~thvA~ carbonyl-3-methyl-5,8-dimethoxy-$-oc}..~ - n hads H NMR (CDC13 250 MHz, Brukcr): ~, 1.16 (3H, d, J ~ 7.3 Hz, 6~-CH3), 1.63 (3H, ~, 3-CCH3), 2.02 (2H, m, 2'-CH2), 2.86 (lH, d, J ~ lS.9 Hz, 4-CH), 3.21 (lH, d, J - lS.9 Hz, 4-CH), 3.65 (3H, s, OCH3), 3.76 (6H, s, 2xOCH3), 4.10 (lH, qua, J ~ 7.2 ~z, 5'-CH), 4.61 (lH, m, 3'-CH), 5.45 (lH, 8~ 4'-CH), 5.55 (lH, s, l'-CH), 6.24 (lH, ~, l-CH), 6.68 (lH, d, J ~ 9.4 Hz, ArH), 6.76 (lH, d, J ~ 9.4 Hz, ArH), 6.23 (lH, o, hn~r3), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, f$1m on NaCl plat-): cm~l, 3332.0, 2924.7, 2857.1, 1732.5, 1708.0, 1531.6, 1488.5, 1353.3, 1265.1, 1167.0, g57.18, 718.76.
Th~ (l'S, lS, 3R)-1-(4'-p-nit.~ ~oyl-3'-trifluorQ~r~ ~-2',3',6'-tr;~oc y L-ly-~h ~ - O~y ~ nr-~)-3-methoxy-carbonyl-3-methyl-5,8-di~ethoxy-~GCh~. -n had:
lH NMR (CDC13 250 MHz, Bruker): ~, 1.19 (3H, d, J - 6.1 Hz, 6' CH3), 1.60 (3H, s, 3-CCH3), 1.87 (lH, dd, J ~ 12.4 Hz, 4.7 Hz, 2'-CH), 2.11 (lH, d tr, J Y 12.4 Hz, 3.0 Hz, 2'-CH), 2.86 (lH, d, J ~ 16.5 Hz, 4-CH), 3.33 (lH, d, J ~ 16.5 Hz, 4-CH), 3.62 (3H, s,OCH3), 3.78 (6H, , 2XOCH3), 4.54 (lH, q~, J - 6.1 Hz, 5'-CH), 4.57 (lH, m, 3'-CH), 5.41 (lH, o, 4'-CH), 5.69 (lH, d, J - 2.9 Hz, l'-CH), 6.40 (lH, s, l-CH), 6.45 (lH, d, J ~ 7.6 Hz, NHCOCF3), 6.71 (lH, d, J ~ 8.9 Hz, ArH), 6.81 (lH, d, J ~ 8.9 ~z, ArH), 8.24 (4H, s, PNB).
IR ~ ol-t, 205 FT, f~lm on NaCl plat~): cm~l, 3325.5, 3077.2 2951.9, 2541.1, 1737.3, 1705.9, 1609.5, 1530.0, 1489.0, 1354.1, 1264.9, 970.9, 951.60, 804.80, 720.90.
The (l'S, lR, 3R)-1-(4'-p-nitrobenzoyl-3'-tr;fluoroacetam~do-2',3',6'-tr;~c ~ L-ly '~ . r~re)-3 -~ carbonyl-3-methyl-5,8-dim~thoxy-~- hads H NMR (CDC13 250 MHz, Bruker): ~, 1.20 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.53 (3H, s, 3-CCH3), 1.93 (lH, dd, J ~ 11.8 Hz, 2.9 Hz, 2'-CH), 2.05 (lH, m, 2'-CH), 2.60 (lH, d, J ~ 16.5 Hz, 4-CH), 3.39 (lH, d, J ~ 16.5 Hz, 4-CH), 3.73 (3H, ~, OCH3), 3.76 (3H, o, OCH3), 3.80 (3H, o, OCH3), 4.71 (lH, m, 3'-CH), 4.86 (lH, qua, J ~ 6.0 Hz, 5'-CH), 5.45 (lH, s, 4'-CH), 5.55 (lH, d, J ~ 1.74 Hz, l'-CH), 6.01 (lH, 8~ l-CH), 6.49 (lH, U ~ S ~
W O 94/11382 2 1~ ~ ~4 ~ PC~r/CA93/00463 d, J ~ 6.8 Hz, NHCO~r3), 6.24 (lH, d, J - 10.2 Hz, ArH), 6.82 (lH, d, J
= 10.2 Hz, ArH), 8.29 (4H, s, PN8).
8t~p 3s (1'8, lR, 38)~ p-n~ orl-3'-trifluoro-c-t~ ido-S 2~,3~,6~-tr~ )-3 ~ 3-m thrl-S, a -; ~-~-4, s, 8-tr~h~dro-lH ~-o-[2,3-c]-prr The titled c _~ ~' w~s obtain~d via Q N oY~-tinn (-t-p 3, .-- 1~ 13) of the (l'S,lR,3S) y,~cu.~GL from ztep 2 ~ ~in.
lH NMR (CDC13 250 MHz, Brukor)s ~, 1.30 (3H, d, J - 6.5 Hz, 6'-CH3), 1.57 (3H, B, 3-CCH3), 1.93-2.05 (2H, m, 2'-CH2), 2.36 (lH, d, J ~ 20 Hz, 4-CH), 3.31 (lH, d, J ~ 20 Hz, 4-CH), 3.67 (3H, s, OCH3), 4.46 (lH, m, 3'-CH), 4.66 (lH, qu~, J ~ 6.5 Hz, 5'-CH), 5.36 (lH, ~, 4'-CH), 5.62 (lH, s, l'-CH), 5.93 (lH, ~, l-CH), 6.56 (lH, d, J ~ 7.1 Hz, NHCOCF3), lS 6.77 (lH, d, J - 9.7 Hz, Quin-H). 6.85 (lH, d, J - 9.7 Hz, Quin-H), 8.30 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plat~): cm~l, 3347.1, 2924.7, 2851.4, 1736.3, 1663.1, 1527.9, 1351.4, 1272.6, 1167.4, 951.60, 837.00, 718.80.
8t-p 4s (1'8, lR, 38~-1-(4'-p-niL..~-~-Qrl-3'-tr~ m~do-2',3',6'-tr~ )-3--~t~ 1-3--thyl-S,10 d~-o-4,5,10-tr~hydro-1~ ~p~-~ [2~3-c]-prr~n Th~ titl~d ~ : ' wa- obt~in~d following cyclo~~ti~n ~
2S ~c-toxybu~ nd th- pr-cur-or from t-p 3 ~ n ~ per previou-ly described ~,oc- ~.
lH NMR (CDC13 250 MHz, Bruk-r)s ~, 1.34 (3H, d, J ~ 6.5 Hz, 6'-CH3), 1.59 (3H, ~, 3-CCH3), 1.90-2.10 (2H, m, 2'-CH2), 2.50 (lH, d, J ~ 19.4 Hz, 4-CH), 3.49 (lH, d, J - 19.4 Hz, 4-CH), 3.65 (3H, ~, OCH3), 4.46 (lH, m, 3'-CH), 4.79 (lH, qua, J ~ 6.5 Hz, 5'-CH), 5.40 (lH, br s, 4'-CH), 5.65 (lH, d, J z 2.5 Hz, l'-CH), 6.10 (lH, ~, l-CH), 6.51 (lH, d, J ~ 7.6 Hz, ~n~G~r3), 7.76 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
IR (Nicolet, 205 FT, film on N~Cl plate): cm 1, 3333.8, 2919.5, 2851.0, 3S 1739.0, 1667.4, 1533.4, 1790.5, 1271.8, 1212.6, 1187.7, 1103.6, 994.58, 949.75, 723.70.
SUBSTITUTE SHEET
W O 94/11382 P ~ /CA93/00463 2146~8 1~
8t-p S~ 8, lR, 3~)-1-(3~-trifl ~ o~L~do-2~,3',6~-tr~ L-)-5,10-dioxo-~,5,10-tr$hrdro-lH
~2,3-cl-prran (BC~-2077) S Th~ tLtl~d c -~ waz obt~Lned followLng mRth~nolyz~ of thc pr~cur~or from tcp 4.
1H NMR (CDC13, 250 MHz, Brukor): ~, 1.39 (3H, d, J - 6.0 Hz, 6'-CH3), 1.58 (3H, s, 3-CCH3), 1.77 (lH, dd, J ~ 12.0 Hz, 4.1 Hz, 2'-HCHa), 1.84 (lH, dd, J ~ 12.1 Hz, 5.9 ~z, 2'-HCHa), 1.96 (lH, d, J ~ 8.7 Hz, 4'-OH), 2.48 (lH, d, J - 19.5 Hz, 4-HCHa), 3.47 (lH, d, J ~ 19.5 Hz, 4-HCHe), 3.60 (lH, d, J ~ 8.7 Hz, 4'-CH), 3.64 (3H, , OCH3), 4.17 (lH, m, 3'-CH), 3.56 (lH, qu~, J ~ 6.0 Hz, 5'-CH), 5.46 (lH, d, J ~ 2.9 Hz, 1'-CH), 6.05 (lH, ~, 1-CH), 6.71 (lH, d, J - 8.8 Hz, ~ iLF3), 7.75 (2H, m, 7, 8-AsH), 8.10 (2H, m, 6, 9-ArH).
lS IR (NLcolet , 205 FT, film on NaCl plate): cm~1, 3420.6, 2934.5, 1735, 1721.8, 1665.8, 1291.8, 1182.3, 1166.3, 1112.9, 776.7, 944.6, 912.6, 728.97.
~ s~S Pr p~rat$on of (1'~,18,3R)-1-(3~-tr~fl -_o~c-t~$do-2',3',6'-tr~ lrxo-L '- ~ )~3 ~ 1-3--th~1-3,~,S,10 ~r-k~d~o 5,10 ~ o ~~"~ ~~ t2,3-c]
Prr~ (BC~-2082) ~ ~ 0~
Hl~ H,(~
PNBO NH~AOHNHlF
B~2082 8t-p 1: (l'S, lS, 3R~-1-(3'-tr~ -2',3',6'-tr~ L-~ )-3 ~ 1-3-m-thyl-5,10 ~ ,5,10-tr$hrdro-l~ ~E~t~- t2,3-c]-prran (~CH-2082) Methanoly~i~ of the p-nitrobenzoylated ~ UL 60r yielded the titled product.
H NMR (CDC13, 250 MHz, Bruker): ~, 1.31 (lH, d, J - 6.6 Hz, 6'-CH3), 1.45 (3H, 6, 3-CCH3), 1.80 (lH, d, J ~ 8.8 Hz, 2'-CH), 1.81 (lH, d, J =
SUBSriTUTE SHEET
WO 94/11382 PCI~/CA93/00463 21,96~4 8 10 Hz, 2~-CH), 2.24 (3H, 8, COCH3), 2.52 (lH, d, J = 18.5 HZ, 4 - HCHa), 3.38 ~lH, d, J ~ 18.5 Hz, 4-HCHe), 3.60 (lH, br 8, 4'-CH), 4.19 (lH, br qua, J ~ 10 Hz, 3'-CH), 4.41 (lH, qua, J ~ 6.6 Hz, S'-CH), 5.45 (lH, s, l'-CH), 6.13 (lH, ~, l-CH), 6.63 (lH, d, J = 10 Hz), 7.75 (2H, m, 7, 8-S ArH), 8.09 (2H, m, 6, 9-ArH).
- IR (Nicolet , 205 FT, f~lm on NaCl plat-): cm 1, 3375.1 (br str), 3091.1, 2929.6, 1715.2, 1671.2, 1597.7, 1293.3, 1172.9, 981.5, 729.22.
_1- SSs Pr-p-r-t~on of (1'8,18,3R)-1-(3'-trlfl ~ ido-2',3',6'-tr~ lyso-L ~ ,~ )-3-d~m~ ,1-3,4,5,10-t-tr-h~d.~ 5,10-~ - [2,3-c] pyran (8C~-1690 o o (oCH,)~ ~o(ocH~)2 o o pNCB~A H3C~A
lS
8t-p ls (1'~,18,3R)-1-(2',3',6'-tri ~c ~ 3'-tr~ _~a~ do-~-~ )-3 ~ hyl~ 1-5,10-dio~o-3,4,S-10-t-tr~ lH-~ - [2~3-c]-pyran (~CH-1690) The p-nltrobenzoyl ~ ___ .G wa~ hydrolyzed wlth catalytic odLum me~ d~ ln methanol a~ per prevlou~ly de~crlbed p c_ ` re. The tltled cl __ ' had:
.P. 91-93C, lH ~MR (CDC13, 250 MHz, Bruker)s ~, 1.40 (3H, d, J ~ 7.6 Hz, 6'-CH3), 2S 1.89 (2H, m, 2'-CH2), 2.62 (lH, dd, J - 18.2 Hz, 11.8 Hz, 4-HCHa), 3.00 (lH, dd, J ~ 18.2 Hz, 4.1 Hz, 4-HCHe), 3.65 (lH, br s, 4-CH), 3.83 (3H, s, POCH3), 3.87 (3H, s, POCH3), 4.32 (lH, qua, J ~ 7.6 Hz, 5'-CH), 4.56 - (lH, m, 3-CH), 4.99 (lH, br ~ CHP), 5.13 (lH, br 8, CHP), 5.44 (lH, s, l'-CH), 6.09 (lH, 3, l-CH), 6.83 (lH, br d, J ~ 7.6 Hz, ~n~r3), 7.77 (2H, m, 7, 8-ArH), 8.09 (2H, m, 6, 9-ArH).
IR (Nlcolet 205 FT, fllm on NaCl plate): cm 1, 3421.9, 2958.3, 1716.0, 1665.6, 1592.5, 1287.6, 1181.8, 1045.7, 977.7, 858.4, 727.5.
SUBS~IT!JTE SHEET
WO 94/11382 PCr/CA93/00463 ~&~4~ --_1- 56s Pr-p~r~tion of (1'8,18,3~)-1-(3'-trifluoro~ iA~_ 2~,3',6~-tr~ lrso-L ~ )-3-~t~ - ~C~ 1-3- -thyl-3 ~ 4 ~ S, lO-t-tr~hrdro-5 ~ 10-diGao -.pht~- ~2,3-c] pyrzn (BCH-2081) S
OCH O
~1~ ~H, OCH,O .
PNBO ~ PNBO ~
o o o o O O O O
H,~ H,C~
o~Nl~lFA PNBO NHIFA
BCH~2081 8t-p ls (l's~, 18, 38)-1-(4~-p-u$L,.' -_~1-3'-tr~f~ t 2~,3~,6'-tr~ )-3-~ h~yl-3--thrl-5,8-d$oso-4,5,8-trihrdro-1~ 0 t2,3-c]-prr n.
CAN ~V~at~on of the (l'S,lR,3S) ~cu~ from t~p 2, le 53, yielded the t~tled _ '.
lH NMR (CDC13 250 MHz, Bruker): ~, 1.14 (3H, d, J ~ 6.0 Hz, 6'-CH3), 1.61 (3H, ~, 3-CCH3), 1.96 (lH, d tr, J - 11.7 Hz, 4.1 Hz, 2'-CH), 2.10 (lH, dd, J ~ 11.7 Hz, 2.9 Hz, 2'-CH), 2.58 (lH, d, J ~ 18.2 Hz, 4-CH), 3.00 llH, d, J ~ 18.2 Hz, 4-CH), 3.71 (3H, ~, OCH3) 4.50 (lH, gua, J e 6.0 Hz, 5'-CH), 4.60 (lH, m, 3'-CH), 5.42 (lH, ~, 4'-CH), 5.56 ~lH, ~, l'-CH), 6.03 (lH, ~, l-CH), 6.58 (lH, d, J ~ 7.4 Hz, ~3), 6.72 (lH, d, J ~ 8.8 Hz, Qu~n-H), 6.78 (lH, d, J ~ 8.8 Hz, QuLn-H), 8.24 (4H, br ~, PNB).
IR (Nicolat, 205 FT, film on NaCl plat~): cm~l, 3340.0, 3084.6, 2950.7,2857.2, 1732.8, 1664.3, 1533.4, 1349.7, 1268.7, 1159.7, 1013.3, 955.70, 837.03, 735.00.
~ ~ ~ â ~ ~ . q~ T
W O 94/11382 PC~r/cA93/00463 2 1 ~
st-p 2s (1'8, 1~, 38)-1-(4'-p-ni~ Qyl-3'-tr~fluorr-c~ - iA~_ 2',3',6'-tr~ '- a~ )-3~ arbonrl-3-m-thyl-S,10 di~-o-4,S,10-trih~dro-lH ; s~ 2,3-cl-prran S
The titled c _~ ' wa- obtained following cycloaddition bat ~-- 1-acntosybutr~i - and th~ n~n9 from step 1 ~- ~in.
H NMR (CDC13 250 MHz, Bruk~r~: ~, 1.16 (3H, d, J - 6.0 Hz, 6'-CH3), 1.67 (3H, ~, 3-CCH3), 2.05 (2H, m, 2'-CH2), 2.77 (lH, dd, J - 17.6 Hz, 0.6 Hz, 4-HCHa), 3.22 (lH, dd, J - 17.6 Hz, 1.8 Hz, 4-HCH~), 3.73 (3H, s, OCH3), 4.57 (lH, qua, J - 6.0 Hz, 5'-CH), 4.64 (lH, m, 3'-CH), 5.45 (lH, d, J ~ 2.1 Hz, 4'-CH), 5.67 (lH, B, l'-CH), 6.22 (lH, 8~ l-CH), 6.34 (lH, d, J - 8.2 Hz, hn~r3), 7.76 (2H, m, 7, 8-ArH), 8.08 (2H, m, 6, 9-ArH), 8.28 (4H, m, PN8).
lS IR (Nlcolet, 205 FT, film on NaCl plate): cm~l, 3331.7, 2957.1, 1734.1, 1708.5, 1666.4, 1595.6, 1527.9, 1271,3, 1216.2, 1181.61, 1165.8, 1104.5, 1013.2, 954.94, 731.40, 721.98.
8t-p 3s (1'8, 18, 38)-1-(3'-tr~f~ c-t~o~do-2',3',6'-tr~
1~ '- ~,_ -a-)-3-m-t'~ ~ 1-3- ~thrl-5,10-dioso-4,S,10-tr~hrdro-1~ - 12,3-cl-prr n (BCH-2081) The ~ o~ from trp 2 herein wa~ hydrolyzed with D~ hnYiA~
(catalytic) as per previou-ly de~cribed ~ ocL~ure. Th~ product had:
lH NMR (CDC13 250 ~Hz, Bruk~r): ~, 1.23 (3H, d, J - 6.1 Hz, 6'-CH3), 1.64 (3H, s, 3-CH3), 1.79 (lH, d tr, J ~ 12.9 Hz, 3.8 Hz, 2'-HCHa), 1.88 (lH, dd, J ~ 13.0 Hz, 4.7 Hz, -2'-HCH~), 1.94 (lH, d, J - 7.6 Hz, 2'-OH), 2.74 (lH, d, J - 18.8 Hz, 4-HCHa), 3.17 (lH, d, J Y 18.8 Hz, 4-HCHQ), 3.61 (lH, d, J - 7.8 Hz, 4'-CH), 3.71 (3H, s, OCH3), 4.32 (lH, m, 3'-CH), 4.40 (lH, qua, J - 6.1 Hz, 5'-CH), 5.50 (lH, d, J ~ 3.5 Hz, 1'-CH), 6.15 (lH, s, l-CH), 6.67 (lH, d, J ~ 8.8 Hz, NHCOCF3), 7.74 (2H, m, 7, 8-ArH),8.07 (2H, m, 6,9-ArH).
IR (N~colet, 20S FT, f~lm on NaCl plate): cm~1, 3422.1 (br str), 2928.1, 2853.9, 1720.3, 1668.9, 1594.7, 1292.0, 1183.5, 1166.4, 1009.3, 3S 986.49, 728.24.
~- S7: ~ Y~ of (1~8~18~38)-1-(3--trif~ . iA~_ 2',3',6'-tr~ lrso-L ' ~,. -~)-3-W 0 94/11382 2 ~ 4 ~ P ~ /CA93/00463 ~ p~ t~l-3~s~lo-t-trahrdro-s~
diGaO ~~p~t~~ 12,3-cI thioprr~n (BC~-2037 001 OCH~ O OCH~ O
~+ (lS 3R~or 2 OCH~ OCN, O
rl~R~A
+ (IS 3R)_ol 3 H~
PNBO NHIFA +
H,C--PNBO NHI~A
O O
~ H~C~
O O
H,C~
oHNHlFA
BCH-2037.001 S
St-p ls Pr par~t~on of (1'~,18,38) and (1'8,1R,3R)-1-(3'-~r~fl ~ 2',3',C'-~r~ c' ,,~ )-3-~c~trl-5,8'i ~
The _ ,_ ' from t~p 1, ~ 13, and A - -- - - ~ i n~ precur-or (259 mg, 0 66 mmole) w~r- di-~olved in CH2C12 (25 ml) and l-ft ~tirring ~n p~-a ~a of mol~ r i-ve for 30 minute~ b~forQ DDQ (150 mq, 0 66 lS mmole) wa- added The re~ulting mixture wa~ stirred for 2 1/2 hours NaHC03 (5% ~olution) wa~ added and th~ e: ~ layer wao extracted with CH2C12 The combin~d organic pha-e~ w~re w ~ with H20, dried over MgS04, filtered and ~ aLed in vacuo The crudc obtained was flash cl.~ ~hed u-ing TolsEE (9sl) to give a pure mixtur- of two titled 20 ~r- ~~c (in 60~ yield) which wa~ u~ed to carry out the next tep S U E~ r ~
W 0 94/11382 214 6 ~ ~ PC~r/CA93~00463 8t-p 2s Pr p~ration of (1'8,18,38) a~d (1'8,1R,3R)-1-(4'-p-n~Lc~ Qrl-3'-trifl~ tar~do-2',3~,6~-tr~ L-~ )-3 ~ 1-5,8-dio~o-~,S,8-tr~hpdro-lX-b-nzo-[2,3-c]-prr-n The c _ -~ from ~tep 1 herein (112.7 mg, 0.18 mmole) wa~ di-~olved in acetonitrile (5 ml), cooled to 0C, followod by th~ addition of NaHCO3 (29 mg, 0.34 mmole) and om~ H2O. ~h~ r-~ulting mixtur~ wa~ ~tirred for 5 minute~ before CAN (296 mg, 0.54 mmolc) was added. After all CAN wa~
added, the r-action mixture wa- ~tirred 10 minut-~ extra 0C, th~n ~- -d to room t~ ~- .Lu ~. H2O wa- addQd and Lt w~- extracted with CH2C12. Tho combined organic pha-o~ wero wa-hed with H2O, dried ovQr MgSO4, filtered and col~a~L~-ed in vacuo. The crude co~t~inin~ a mixtur- of two titled dia-t-roo~- - a wa~ u~ed in th~ following ~tep.
lS
8t-p 3s (1'8,18,3s~)-1-(4'-p-niL~ ~yl-3'-trif~ do-2',3',6'-tr;~ )-3 ~ 1-S,10 .';~
3, 4, S, 10-t-trahrdro- lH ~ - [ 2, 3-c ] -th~ oprr~
Following tha - ~ 1, tap 1, a mixture of th~ two titled adduct- wa~
obtain~d which could b~ v .Led via fla-h ch,~ --G~ph~. Th~ fir~t elu~nt had:
lH NNR (ac~tone-d6, 250 ~Hz, Brukor): ~, 1.23 (3H, d, J ~ 5.6 Hz, 6'-CH3), 1.70-1.90 (2H, m, 2'-CH2), 2.44 (3H, , COCH3), 2.84 (lH, dd, J
2S 17.8 Hz, 11.8 Hz, 4-HCHa), 3.36 (lH, dd, J ~ 17.8 Hz, 4.1 Hz, 4'-HCHe), 4.53 (lH, dd, J - 11.8 Hz, 4.1 Hz, 3-CH), 4.60 (lH, m, 3'-CH), 4.75 (lH, qua, J ~ 5.6 Hz, 5'-CH), 5.53 (lH, ~, 4'-CH), 5.70 (lH, d, J ~ 2.3 Hz, l'-CH), 6.13 (lH, ~, l-CH), 7.90 (2H, m, 7, 8-ArH), 8.12 ~2H, m, 6, 9-ArH), 8.39 (4H, m, PNB), 8.65 (lH, d, J ~ 5.8 Hz, NHCOCF3).
The ~econd luent had:
lH NMR (-~ ~ - d6, 250 ~Hz, 8ruker): ~, 1.32 (3H, d, J ~ 6.8 Hz, 6'-CH3), 2.39 (3H, ~, COCH3), 1.94 (lH, dd, J = 12.3 Hz, 4.1 Hz, 2'-HCHa), 2.50 (lH, tr d, J - 12.3 Hz, 2.9 Hz, 2'-HCHe), 2.89 (lH, dd, J ~ 18.2 Hz, 11.2 Hz, 4-HCHa), 3.35 (lH, dd, J ~ 18.2 Hz, 3.5 Hz, 4-HCHe), 4.41 3S (lH, dd, J ~ 11.2 Hz, 3.5 Hz, 3-CH), 4.52 (lH, m, 3'-CH), 4.66 (lH, qua, J ~ 6.8 Hz, 5'-CH), 5.47 (lH, ~, 4'-CH), 5.74 (lH, d, J ~ 2.9 Hz, 1'-CH), 6.31 (lH, ~, l-CH), 7.91 (2H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH), 8.38 (4H, m, PNB), 8.68 (lH, d, J ~ 7.1 Hz, ~.A ~Cr3).
S I~ ~T~ ~ q~ ~
W O 94/11382 2 1 4 6~ ~ ~ PC~r/CA93/00463 s~t~p 4s (1'8,1s~,38)-1-(3'-ts~fl~ -2',3~,6'-tr~
) -S ,10-~l~o-ao-3, 4, 5 ,10-t-tr~h~dro-1 [2,3-cl-thLoprran ~C8-2037.001) S lB NMR ~CDC13 250 MHz, Brukcr)s ~, 1.43 (3H, ~, 6'-CH3), 1.83-1.98 (2H, m, 2'-CH2), 2.37 (3H, , COCH3), 2.90 (lH, dd, J - 17.8 Hz, 12 Hz, 4-HCH~), 3.32 (lH, dd, J - 17.8 Hz, 4.1 Hz, 4-HCH~), 3.61 ~lH, br s, 4'-CB), 4.07 (lH, dd, J - 12.0 Bz, J - 4.1 Hz, 3-CH), 5.53 ~lH, ~, l'-CH), 6.21 ~lH, s, l-CH), 6.74 (lH, d, J ~ 7.6 Hz, ~n~G~F3), 7.76 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
_1- S8s Pr parat~on of (1'8,1R,3R)-1-(3'tr~f~ do-2',3',6'-tr~ lrso-L ~ 3-~ r-~~L~1-3,4,S,lO-t-tr-~d~ 5,10-~i~a~ ~ [2~3-cl prr~n (~C~-2127) O o o o o o o o HIC~ H,C~
PNBo NHIP~ oHNHlFA
t-p ls (1'~, lR, 3R)-1-(3'-tr~fl ~ 2',3',6'-tr~ r~ ~ T-_ 1~ . r~ z~ 1-5,10-d~o~o-3,4,5,10-t-tr h~ro-~r -~p~ 2,3-c]-~ (BC~-2127) Th~ ~cond ~luent from zt-p 3, _ 1A 57, wa- hydrolyzed wLth c~talytLc ~d~ - h~ Ln ~h-~ol. The tLtled c~ ~aurd h~d:
2S lH NMR (CDC13 2S0 H~z, Bruksr): ~, 1.43 (3H, d, J - 6.5 Hz, 6~-CH3), 1.80-2.00 (2H, m, 2'-CH2), 2.37 (3H, ~, COCH3), 2.91 (lH, dd, J ~ 18.3 Hz, 11.8 Hz, 4-HCHa), 3.33 (lH, dd, J = 18.3 Hz, 4.7 Hz, 4-HCHe), 3.60 (lH, br ~, 4-CH), 4.07 (lH, dd, J = 11.8 Hz, 4.7 Hz, 3-CH), 4.25 (lH, m, 3'-CH), 4.35 (lH, qua, J ~ 6.5 Hz, 5'-CH), 5.53 (lH, d, J ~ 2.4 Hz, 1'-CH), 6.21 (lH, ~, l-CH), 6.74 (lH, d, J - 7.6 Hz, ~ 3), 7.76 (lH, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH).
_1- S9s Pr-paration of (1'8,18,3~-1-(3'-~r~f~ tr ~
2',3',6'-tr~ lr~o-L '- ~ )-3 -~ 1-3-O ~3 ~
21~4~
m thrl-3,4,S,10-t-tr~h~d,~ 5,10 ';~-~- lH - ~ ~} ~ t 2, 3 -cl pqran (BC~-2090) OCH~ O OCH~ O
~CH, ~J~CH, OCH, OCH, O OCH, X~ H3~ H3c jZj~
1 ~ X-C4 PNI~O NHlp~ PNBo NRIF~
~ 4 PNBO ~ ~
+ H3C~
O O
PNBO ~ \~ ~H3 O O
H3~J
BC~2090 S
8t-p 1s 3 ~ 3-m thyl-5,8 '; -~ c~- -The _ __ ~ from ~t-p 1, ~ 53, (126 5 mg, 0 474 mmol) was di-solved $n ther nd then cool~d to -78C Msthyll$th$um (1 4 M Ln ether (0 71 ml, 0 995 mmol) wa- add-d Aft-r 10 m$nut-- methanol was added The r-act$on m$xtur- wa- ac$d$f~ed w$th HCl (0 5 N) and extracted w$th thyl -~~t~te The organic layer was dri~d over sodium ~ ~ulfat~ ~nd then o~a~. t-' to give a crude product (121 mg) lH NNR
~howed that it wa- a mixtur- of tarting mat~rial and product in 1 1 1~ ratio Ch,~ - o~ ~phy ~11 e~ jr~luti~n of the desLred tLtled product as a gel lH NMR (CDC13 250 NHz, BrukQr)s 8, 1 37 (3H, ~, 3-CCH3), 2 24 (3H, s, COCH3), 2 59 (lH, d, J ~ 17 6 Hz, 4-CH), 2 99 (lH, d, J - 17 6 Hz, 4-SU~ ET
WO 94/11382 PCI/CA93/004~3 2 1 ~
CH), 3.74 (3H, ~, OCH3), 3.76 (3H, s, OCH3), 4.77 (2H, ~, l-CH2), 6.57 (lH, d, J ~ 9.4 Hz, ArH), 6.62 (lH, d, J ~ 9.4 Hz, ArH).
IR (Nicolet, film on NaCl plate): cm-l, 2941.9, 2834.4, 1721.6, 1482.4, 1340.2, 1257.0, 1061.4, 795.30, 716.80 - 8t-p 2s (~S,lS,38) ~d (1'8,1S,3R~-1-(4'-p-~ 1-3~-tri f 1~ ~e~do-2',3',6'-tr~c ~ L-l~ o~)-3-~c-t~1-3---th~1-5,8 'i - ~ ~ i.~ -10 The ~ from st~p 1 herein (67 mg, 0.268 mmol) wa~ ~tirr~d with DDQ
(91.3 mg, 0.422 mmol) and 4',5'-prot-cted ~ in^ (157 mg, 0.402 mmol) in methyl-no chloride at 40C for 24 hour~. The olvent wa~
_v~p~.~L-d. The crude product wac chromato~phod (h-xsEtOAc ~ 10s4) to give the titled = au '- (88 mg co~tainin~ two i~ n 2sl ratio lS i n - ~ ~rable).
lH NMR (CDC13 250 MHz, Bruker): ~, 1.23 (3H, d, J - 6.0 Hz, A-6'-CH3), 1.22 (3H, d, J - 6.0 Hz, B-6~-CH3), 1.44 (3H, s, A-3-CCH3), 1.66 (3H, ~, B-3-CCH3), 1.84 (lH, m, A-2'-CH), 1.84 (lH, m, A-2'-CH), 1.84 (lH, m, B-2'-CH), 2.14 (lH, m, A-2'-CH), 2.15 (lH, m, B-2'-CH), 2.80 (lH, d, J
15.9 Hz, A-4-CH), 3.02 (2H, a, B-4-CH2), 3.14 llH, d, J ~ 15.9 ~z, A-4 CH), 3.77 (6H, z, B-OCH3), 3.80 (6H, , A-OCH3), 4.41 (lH, qua, J - 6.0 Hz, B-5'-CH), 4.47 (lH, m, B-3'-CH), 4.56 (lH, qua, J ~ 6.0 Hz, A-5'-CH), 4.61 (lH, m, A-3~-CH), S.40 (lH, s, B-4'-C~), 5.44 (lH, c, A-4'-CH), 5.61 (lH, d, ~ - 2.5 Hz, B-l'-CH), 5.70 (lH, d, J ~ 2.2 Hz, A-l'-CH), 6.35 (lH, , B-l-CH), 6.37 (lH, s, A-l-CH), 6.41 (lH, d, J - 7.6 Hz, B-N~COCF3), 6.46 (lH, d, J - 7.8 Hz, A-NHCOCF3), 6.76 (2H, m, B-ArH), 6.81 (2H, m, A-ArH), 8.25 (8H, br ~, A-PNB, B-PNB~.
IR (N~colet, 205 FT, film on NaCl plate): cm~l, 3327.9, 2945.2, 2840.3, 1732.6, 1528.4, 1489.4, 1351.8, 1263.4, 1167.8, 1116.3, 1105.2, 969.06, 948.80, 801.62, 720.66.
Al~o ~bt~ l from thi- reaction (34 mg) wa~ (l'S, lR, 3S)-1-(4'-p-n$troben~oyl-3'-trifluoroac~tamido-2',3',6'-trideoxyly ~ y~_n~e)-3-acetyl-3-methyl-5,8-d~methoxy-irac'r~ -n which had:
lH NMR (CDC13 250 MHz, Bruk~r): ~, 1.18 (3H, d, J - 7.6 Hz, 6' CX3), 3S 1.51 (3H, ~, 3-CCH3), 2.00-2.10 (2H, m, 2'-CH2), 2.84 (lH, d, J = 17.1 Hz, 4-CH), 2.96 (lH, d, J Y 17.1 Hz, 4-CH), 3.77 (3H, ~, OCH3), i.78 (3H, ~, OCH3), 4.54 (lH, qua, J ~ 7.6 Hz, 5'-CH), 4.62 (lH, m, 3'-CH), 5.46 ~lH, d, J - 2.1 Hz, 4'-CH), 5.56 (lH, c, l'-CH), 6.14 (lH, ~, t~ ET
WO 94/11382 PCI`/CA93/00463 -~ 1 46~ ~
1 - CH), 6.41 (lH, d, J ~ 7.6 Hz, NHCOCF3), 6.70 (lH, d, J - 8.8 Hz, ArH), 6.76 (lH, d, J ~ 8.8 Hz, ArH), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm 1, 3336.5, 2940.0, 2834.3, 1730.3, 1527.2, 1481.4, 1266.3, 1163.6, 975.8, 718.02.
S
8t-p 3s (l~S,18~38) znd (1'8, 18, 3R)-1-(4'-p-ni~o~ Qrl-3'-tr~f~ do-2',3',6'-tr~ )-3-ac-t~1-3-~ th~1-S,8 '~o-4,5,8-tr~hrdro-1~ o-~2,3-c]-prran CAN ~Y~t1~ of th- productz from t-p 2 h-rein gave the titl-d ~s (a~ per ~ec~ tep 2, exumple 14).
lH NMR (CDC13 250 MHz, Bruker)s ~, 1.30 (3H, d, J ~ 6.0 Hz, A-6'-CH3), 1.27 (3H, d, J ~ 6.1 Hz, 8-6'-CH3), 1.44 (3H, B, A-3-CCH3), 1.44 (3H, 8, lS B-3-CCH3), 1.80-2.30 (4~, m, A-2'-CH2, B-2'-CH2), 2.62 (lH, d, J -18.1 Hz, A-4-HCHa), 2.72 (lH, d, J - 18.1 Hz, A-4-HCH~), 2.70 (lH, d, J
~ 18.0 Hz, B-4-CH), 3.25 (lH, d, J ~ 18 Hz, B-4'-CH), 4.41 (lH, m, B-3'-CH), 4.56 (lH, m, A-3'-CH), 4.57 (lH, gua, J - 6 Hz, B-5'-CH), 4.72 (lH, qua, J - 6 Hz, A-5'-CH), 5.38 (lH, ~, B-4'-CH), 5.42 (lH, s, A-4~-CH), 5.58 (lH, d, J ~ 2.4 Hz, B-l'-CH), 5.66 (lH, d, J ~ 2.9 Hz, A-l'-CH), 5.98 (lH, ~, B-l-CH), 6.02 (lH, ~, A-l-CH), 6.45 (lH, d, J - 8.1 Hz, B-NHCOCF3), 6.55 (lH, d, J - 8 Hz, A-NHCOCF3), 6.70-6.87 (4H, m, A-6, 7-Quin, B-6, 7-Qu$n), 8.28 (8H, m, A-PNB, B-PNB).
IR (Nicol~t, 205 FT, film on NaCl plate): cm~l, 3327.5, 3084.6, 2984.9, 2S 2938.2, 1723.4, 1661.1, 1533.4, 1352.8, 1278.0, 1215.7, 1169.0, 1122.3, 948.30, 730.86.
8t-p 4s (1'8,18,38) nd (1'8, 18, 3R)-1-(4' ~ ~L-.b -orl-3'-tr~fl ~_o~ 2',3',6'-tr~ )-3-ac-trl-3-m-thrl-5,10 '~-o-4,5,10-trihydro-lH-~ 2,3-c3-yqr n The gu$none from ztep 3 herein wa~ cyc~o~d~ed with l-acetoxybut~'inns a~
per ~,ocedu,_ de~cribed in step 3, _ - _le 14. The (l'S,lS,3R) titled c __ ' had:
H NMR (CDC13 250 MHz, Bruker): ~, 1.35 (3H, d, J ~ 5.9 Hz, 6'-CH3), 1.49 (3H, 8, 3-CCH3), 1.95 (lH, dd, J = 12.6 Hz, 4.7 Hz, 2'-CH), 2.12 (lH, d tr, J - 12.6 Hz, 2.9 Hz, 2'-CH), 2.71 (lH, d, J ~ 18.2 Hz, 4-CH), 2.89 (lH, d, J - 18.2 Hz, 4-CH), 4.60 (lH, m, 3'-CH), 4.85 (lH, qua, J
5 ~ E ~ ~F
PCI`/CA93/00463 W0 94~ll382 ~ 8 5.9 Hz, 5'-CH), 5.47 (lH, br ~, 4'-CH~, 5.71 (lH, d, ~ - 2 Hz, l'-CH), 6.21 (lH, d, J - 1.2 Hz, l-CH~, 6.42 (lH, d, J ~ 7.6 Hz, NHCOCF3~, 7.78 (2H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH~, 8.31 ~4H, m, PNB~.
IR (NiCo~t~ 205 FT, film on NaCl plate): cm~l, 3336.3, 2922.6, 2852.6, S 1728.0, 1666.8, 1532.8, 1346.3, 1273.5, 1212.3, 1165.6, 1119.0, 1098.6, 996.7, 952.96, 836.3, 722.58.
Th~ (l'S,15,3S~ dlast~.~ ~ had:
lH NMR (CDC13 250 MHz, Bruk r~s ~, 1.31 (3H, d, J - 5.9 Xz, 6'-CH3), 1.47 (3H, , 3-CCH3~, 1.89 (lH, dd, J - 11.8 Hz, 5.3 Hz, 2'-HCHa), 2.06 (lH, d tr, J - 11.8 Hz, 4.1 Hz, 2'-HCH~), 2.55 (lH, d, J - 17.8 Hz, 4-HCHA~, 3.40 (lH, d, J - 17.8 ~z, 4-HCH~), 4.45 (lH, m, 3'-CH), 4.66 (1~, qua, J - 5.9 Hz, 5'-CH), 5.43 (lH, ~, 4'-CH), 5.63 (lH, d, J - 2.3 Xz, l'-CH), 6.17 (lH, , l-CH), 6.30 (lH, d, J - 11.8 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 3.30 (4H, m, PNB).
8t-p 5s (1'8, 18, 3~)-1-(3'-trifl r~ -2',3',6'-tr;~
~ 3 ~ 1-3-u~thrl-5,10 ~i9-~-q,S,10-tr~hrdro-l~ ~ 12,3-cl-prr n ( Q -2090) Hydroly-i- of th~ (l'S,lS,3S) ~,~_ ~o~ from st~p 4 ~- ~in g~v~ thQ
titl~d c _ '.
M.P. 95C.
lH NMR ~CDC13, 2S0 N~z, Bruk~r)s ~, 1.41 (3H, d, J - 5.9 Hz, 6'-CH3), 1.46 (3H, ~, 3-CCH3), 1.85 (2H, m, 2'-CH2), 2.27 (3H, ~, COCH3), 2.84 ~2H, d, J - 5.9 Hz, 4-CH2), 3.65 (lH, s, 4'-CH), 4.31 (lH, m, 3'-CH), 4.64 (lH, gua, J ~ 6.0 Xz, 5'-CH), 5.53 (lH, br , l'-CH), 6.15 (lH, s, l-CH),-6.71 (lH, br d, J - 8.8 Hz, NHCOCF3), 7.75 (2X, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH).
IR (Ni~ol ~ , 205 FT, f~lm on NaCl plat-): cm~l, 3423.2, 3342.2, 3087.5, 2987.2, 2933.2, 1717.6, 1667.5, 1590.3, 1289.3, 1216.0, 1179.1, 1167.6, 1124.2, 980.89, 940.05, 918.55, 734.22.
- 60s Pr paration of (1'8~1R~38)-1-(3'-tr~f) -_.~- L- i~_ 2',3',6'-tr~ lrso-L ' ~ )-3-~ 1-3,4,S,lO L~ d-o 5,10-~ [2~3-c] prran (~C~-1689) ~"~ ~ r q~ ~ r _~ C" ~ ~ 11 ~~ ~r '~
WO 94/11382 21~ PCT/CA93/00463 (OCH,)2 ~(OCH,), C X~Br OCH~ OCH~
OCH~ ~po(ocH~)2 O O
~,~o(OCH~)2 ~W;~
+ (IS 3R~e ~ + (lS 3R}i~ooc I _ r 4 OCH, O
O O
pNCB~A PNBC;~A
0~o(ocH~)2 ~``~po(ocH~)2 O O O o H,C~;11 ~ H~C~J
PNBO NHlFA O O PNBo NHlE~A
0~0(0CH,)2 O O
BC~16119 o}{NNlFA
8t-p lt 3 ~ t~1-5,8 ~; Lho~-;~- . -S Tha titl~d cc _ wa- pr-par-d by uz$ng 5,8-dimathoxy-3---e~o~o_ ~ - n and th~ r a from tep 1, - 1~- 8.
lH NMR (CDC13, 2SO MHz, 8ruker)s 2.59 (lH, dd, J - 15.9 Hz, 11.8 Hz, 4-HCHa), 3.03 (lH, dd, J - 15.9 Hz, 2.9 Hz, 4-HCH~), 3.74 (3H, o, OCH3), 3.75 (3H, ~, OCH3), 4.23 (lH, dd, J ~ 11.8 Hz, 2.9 Hz), 4.27 (lH, d, J
13.5 Hz, CHBr), 4.34 (lH, d, J ~ 13.5 Hz, CHBr), 4.63 (lH, d, J ~ 15.9 Hz, 1-HCH~), 4.96 (lH, d, J ~ 15.9 Hz, l-HCHe), 6.63 (2H, m, ArH).
8t - p 2s 3 d; ~ t~l - 5,8 - d~ otho~y-i~och~. -The titl~d ~ wa- obta~ned following troatment of the product from t~p 1 h~rein w1th P(OCH3)3.
lHNMR (CDC13, 250 MHz, Bruker), ~:2.57 (dd, 1 H, J - 16.9 Hz, 11 Hz, 4 -HCHa), 2.98 (dd, 1 H, J ~ 16.9 Hz, 2.9 Hz, 4 - HCH~), 3.26 (dd, 1 H, J =
21.5 Hz, 14.5 Hz, COCHP), 3.54 (dd, 1 H, J ~ 21.5 Hz, 14.5 Hz, COCHP), ~U~ 5i, ~
WO 94/11382 PCl/CA93/00463 3.71 (s, 3 H, ArOCH3), 3.72 (~, 3 H, ArOCH3), 3.74 (d, 3 H, J ~ 4.3 Hz, POCH3), 3.78 (d, 3 H, J - 4.3 Hz, POCH3), 4.11 (dd, 1 H, J ~ 11 Hz, 3.4 Hz, 3 - CH), 4.63 (d, 1 H, J ~ 16.3 Hz, 1 HCHa), 4.97 (d, 1 H, J - 16.3 Hz, 1 - HCH~), 6.60 (m, 2 H, 6.7 - ArH).
S IR (NLcol~t, 205FT, fLlm on NaCl platn), cm~l: 2954.3, 2836.7, 1725.5 (str), 1603.9 (W), 1482.2, 1259.2 (ztr), 1034.7, 799.10, 715.8.
St-p 3t (1'8,18,3R) (1~8,1~,38)-S,~ 1(2',3',6'-tr~qc ~ 3'-tr~ fl ~ do-4~-p-nl~ Qyl-~-l~ )-3-d~--thy~ zochro ~
To a ~tLrred solut~on of the ~b-sph~ate from ~tep 2 h~r-Ln (199 mg, 0.58 mmole) wLth 4 - PNB - 3 - TFA - ~ ne (270 mg, 0.69 mmole) Ln cl~hlorom~thane (60 ml) wa- added 4 pel~t- of mol- l~r Love~ (4A-).
lS ThL~ wa~ followed by ~ddLtLon of ~hl~rodLzyanoquLnon~ (DDQ, 170 mg, 0.75 mmole) in on~ portLon. The rezultLng green lLqu~d waa ~tLrred at 40 C (controll~d by an T~ -~ Ra~ C ~~-t~n~-Stirring y-t~m) Ln a nclo-ed y-tem for 25 hours then at room tr - ~Lu~ (wLthout hsatLng) for 48 hour~. The r~zulting muddy mLxture wa~ .~po~L~d ~nd then dLr-ctly ch~. -to~ (HexsEA ~ 1:1.5) to yLeld the d~Lred tLtl~d gly-c=~-7 (dia~t-~ - Lc mLxture A and B, a~ lLght-color~d gla-~y materLal, 407 mg) .
lHNMR (CDC13, 250 M~z, Bruker), ~:1.20 (d, 3 H, J - 7.0 Hz, 6' - CH3A), 1.23 (d, 3 H, J - 7.0 Hz 6~ - CH3B), 1.82 ~dd, 1 H, J - 12.2 Hz, 4.5 Hz, 2S 2' - HCHAa), 1.91 (dd, 1 H, J ~ 12.3 H~, 4.6 Hz, 2' - HCHBa), 2.07 (dt, 1 H, J - 12.3 Hz, 3.5 Hz, 2' - HCHA~), 2.20 (dt, 1 H, J - 12.4 Hz, 4 Hz, 2' - HCHBe), 2.54 (dd, 1 H, J ~ 16.9 Hz, 13.4 Hz, 4 - HCH8a), 2.60 (dd, 1 H, J - 17 Hz, 11 Hz, 4 - HCHAa), 2.96 (dd, 1 H, J ~ 11 Hz, 3.5 Hz, 4 -HCHA~), 3.03 (dd, 1 H, J - 11.1 Hz, 3.3 Hz, 4 - HCHB~), 3.74 - 3087 (8x~, 24 H, 2 x ArOCH3A, 2 x ArOCH3B, 2 x POCH3A, 2 x POCH3B), 4.41 (qua, 1 H, J ~ 6.0 ~z, 5' - CHB), 4.50 - 4.68 (M, 4 H, 3' - CHA, 3' -CHB, 3 - CHA, 3 - CHB), 4.70 (qua, 1 ~, J ~ 7.0 Hz, S' - CHA), 4O99 (d, 2 H, J - 16 Hz, COCH2AP), 5.03 (d, 2 H, J ~ 16.7 Hz, CoCH2BP), 5.41 (-, 1 H, 4' - CHB), 5.47 (~, 1 H, 4' - CHA), 5.57 (B, 1 H, 1' - CHB), 5.61 3S (~, 1 H, 1~ - CHA), 5.98 (~, 1 H, 1 - CHB), 6.15 (~, 1 H, 1 - CHA), 6.71 (qua~ 2 H, J ~ 8.7 Hz, 6.7 - ArHB), 6.75 (qua, 2 H, J ~ 8.5 Hz, 6.7 -ArHA)~ 6.89 (d, 1 H, J ~ 7.0 Hz, rH~OCF3), 7.05 (d, 1 H, J ~ 7.0 Hz, NHACOCF3), 8.21 (m, 8 H, 4 x COArHANO2, 4 x C~rHBNO2).
Sl~ t ~ ~ L 5~ ~_ T
W O 94~11382 PC~r/CA93/00463 ~ 2146~48 8t-p ~s [~1'8,1S,3R) and (l~s~lR~3s)-l-(a~3~6 -tr~ 3~-tri fl ~ c-tam~do-~'-p-nit~ )-3-dim thr~ Lhyl-3,4,S,8-t-trahydre- ~ -L~ [2,3-c]-pyr S
To a ~olution of glyco-ide from ~tep 3 her-in (98 mg, 0 13 mmole) in 8 ml of ac~tonitrile cooled to 0C wa~ added ~odium bi~rhon-t- ~_ e_ (22 mg, 0 27 mmol-) Thi- wa- fol ~ ' by dropwi-e addition Of ~
cerium ~ nitrate (CAN, 298 mg, 0 54 mmol- in 3 0 ml of wat~r) After 10 ;n~lt;~ at 0C, the r-action mixtur- wa~ pour~d to water (20 ml) and extract-d with ~1~hlG ~~ ~ (4 x 10 ml) The organic layer wa~ dried (over odium ulfate) and ~ o~ated to give the titled a~ a gla~y mixture (85 mg) lHNMR (CDC13, 250 MHz, Bruk r), ~ 1 15 (d, 1 H, J - 6 4 Hz, 6' - CH3B), lS 1 30 (d, 1 H, J - 6 4 H~ 6' - CH3A), 2 44-1 80 (M, 4 H, 2 - HCHAa, 2 -HCHBa, 2 - HCHA~, 2 - HCHB~), 2 41 (dd, 1 H, J - 16 6 Hz, 11 6 Hz, 4 -HCHBa), 2 48 (dd, 1 H, J - 16 6 Hz, 11 3 Hz, 4 - HCHAa), 2 83 (dd, 1 H, J - 17 0 Hz, 5 23 Hz, 4 - HCHAe), 2 85 (dd, 1 H, J - 16 8 Hz, 5 0 Hz, 4 - HCHBe), 3 79 (-, 3 H, POCH3A), 3 84 (-, 3 H, POCH3A), 3 82 (d, 3 H, J
~ 2 1 Hz, POCH3B), 3 87 (d, 3 H, J ~ 2 1 H~, POCH3B), 4 34 (qua, 1 H, J
~ 7 0 _z, 5' CHB), 4 48 - 4 60 (m, 4 H, 3 - CHA, 3 CHB, 3' - CHA, 3' -CHB), 4 64 (qua, 1 H, J ~ 7 0 Hz, 5' - CHA), 5 04 (d, 2 H, J - 25 Hz, COCH2AP), 5 05 (d, 2 H, J ~ 31 Hz, COCH2BP), 5 43 (~, 2 H, 4', CHA, 4' -CHB), 5 55 (-, 1 H, 1'- CHA), 5 61 (~, 1 H, 1' - C_B), 5 81 (~, 1 H , 1 2S - CHB), 5 97 (-, 1 H, 1 - CHA), 6 79 (m, 2 H, 6 7 - ArHB), 6 82 (m, 2 H, 6 7 - ArHA), 8 27 (8, 8 H, 4 x Cn`rRAN02, 4 x QO~rRBN02) ~t-p Ss (1'8,1R,3S)-1-~2',3',6'-tr~ t~ oyl-3'-tri f ~ 7~ -L-~ ) -3 ; ~hyl E~ -c_Lyl-5,10-dioso-3,4,5,10-t-trahrdro-lH-~ '~[2,3--cl--prr n The ~ nd~ from ~tQp 4 hsrein (85 mg, 0 121 mmol) were h~t;~d with 1-ac~Lo~y 1,3-~utr~i~ ~ (86 ~1, 0 723 ol) in toluene at 45C for 28 3S hours Solvent wa~ ~v~aLed and the crude product wa~ ch,. - G~ ~hed three time~ (tol~e -sEtOAc HOMes ~eton~ sHOAc ~ 240 75 10 10 1) to give the (l'S,lR,3S) i~omer (21 mg) and'the (l'S,15,3R) i~omer (18 mg) The titled . _ had r r~ ~~ s~ .~ ~ I~ T
t~ ~ ~ L
~ ~:4 ~
lH N~R (CDC13, 250 MHz, Bruk r): 8, 1.19 (3H, d, J - 7.0 ~z, 6~-CH3), 2.03 ~lH, m, 2-HCH,), 2.07 (lH, m, 2-HCH~), 2.56 (lH, dd, J ~ 18.2 Hz, 11.8 Hz, 4-HCHa), 3.05 (lH, dd, J ~ 18.2 Hz, 4.7 Hz, 4-HCH_), 3.85 (3H, d, J - 2.0 Hz, POC~3), 3.91 (3H, d, J 8 2.0 Hz, POCH3), 4.40 (lH, qua, J
S ~ 7.0 ~z, 5'-CH), 4.60 (lH, m, 3'-C~), 4.65 (lH, dd, J - 11.8 ~z, 4.7 Hz), 5.04 (lH, br ~, CHP), 5.17 (lH, tr, J - 2.0 Hz, CHP), 5.42 (lH, n, 4'-CH), 5.71 (lH, , l'-CH), 6.00 (lH, , l-CH), 6.48 (lH, d, J ~ 7.6 Hz, ~u~r3), 7.76 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.27 (2H, d, J ~ 8.0 Hz, PNB), 8.32 (2X, d, J - 8.0 Hz, PNB).
IR (Nieolet 205 FT, f~lm on N-Cl plat-): em~l, 3323.0, 3242.5, 3077.6, 2965.0, 1730.3, 1661.9, 1593.5, 1529.2, 1271.8, 1193.2, 1050.8, 864.0, 835.7, 722.1.
The eeond ~ -', (l'S,lS,3R)-1-(2',3',6'-tridc-A~ 4'-p-niprob~nzoyl-3'-trifluorc~ r.~-L-l,y ~'~ ~ pyranos~)-3-~i -Lhyl ~;!hr_ph~ Aty lS 5,10-dioxo-3,4,5,10 t~ hydro-lH-~ph~hot2,3-e]-pyran had:
M.P. 135-137C.
lH NMR (CDC13, 250 ~Hz, Bruk r): ~, 1.33 (3H, d, J - 6.4 Hz, 6'-CH3), 2.01 (lH, ~r tr, J ~ 11.8 ~z, 3'-HCH~), 2.15 (lH, br tr, J - 11.8 Hz, 3'-HCH~), 2.62 (lH, dd, J ~ 18.8 Hz, 12.1 Hz, 4-HCH~), 3.01 (lH, dd, J =
18.8 Hz, 4.4 ~z, 4-HCH~), 3.81 (3H, ~, POCH3), 3.86 (3H, ~, POC~3), 4.58 ~lH, ~, 4'-CH), 4.60 (lH, dd, J - 12.1 Hz, 4.4 ~z, 3-CH), 4.79 (lH, qun, J - 6.4 Hz, 6-CH), 5.02 (lH, br ~, PCH), 5.13 (lH, br , PCH), 5.46 (lH, ~, s~-CH ), 5.62 (lH, s, l'-CH), 6.14 (lH, ~, l-CH), 6.63 (lH, d, J -8.2 Hz, NHCOCF3), 7.79 (2H, m, 7, 8-ArH), 8.16 (2H, m, 6, 9-ArH), 8.30 ~4H, m, PNB).
IR (Ni~ol~t 205 FT, f~lm on NaCl plato)s em~l, 3322.0, 3242.5, 3083.5, 2959.0, 2853.0, 1729.5, 1668.6, 1597.0, 1525.5, 1276.4, 1183.7, 1045.9, 853.9, 724.2.
~t-p 6: (1'8,1R,38)-1-(2',3',6'-tr~ 3'-tr~f~ ;A~-L-~ )-3 ~ t~rl '~ 1-5,10 ';~
3~S-lO-t-tr~h~dro-lr ~ '- t2,3-e]-prr n ~JC~-1~89) The PND ~,~Lc~ L_~h~ t~ frem t-p 5 ~- ~in ~21 ~g, 0.028 mmol) wa~ di~olvod in ~HF-~ OH (3 ml of aeh) ~nd eoolf~ to 0C. 8Odium -- h~ (4.3 m, 6.5 ~1) wa~ added. Aftor ~tLrred for 5 in~t~- at 0 C, the erud~ mixture (pink) wa- aeidifiod with 0.1 N ~ g ~ hyd ogon chloride. It wa~ extracted w$th ~ethyl-ne chloride, dri~d (over ~odium ulfate) and _.apo-aLed to givs a crud~ product which wa~
SIE~ T
21~6~8 from m thylonc chlor$d- ~nd h-x~n~ to q$v~ th- d~$rcd product (10 mg) ~ n of f -whit~ olid .
.P. 95-97C.
lH NMR (CDC13, 250 MBz, Bruk~r)s ~, 1.25 (3H, d, J ~ 8.2 Hz, 6'-CH3), 1.83-1.98 (2H, m, 2'-CB2), 2.53 (lH, dd, J - 17.6, 11.8 Hz, 4-HCHa), - 3.00 (lH, dd, J ~ 17.6 Hz, 3.5 Hz, 4-HCHe), 3.62 (lH, br ~, 4'-CH), 3.82 (3B, , POCH3), 3.86 (3H, 8, POCB3), 4.16 (lH, gu~, J - 8.2 Hz, S'-CH), 4.34 (lH, m, 3'-CH), 4.62 (lH, dd, J - 11.8 Hz, 3.5 Hz, 3-CH), 5.01 (lH, s, CHP), 5.12 (lH, ~, CHP), 5.54 (lH, , l'-CH), 5.94 (lH, , l-CH), 6.82 (lH, d, J ~ 7.1 Hz, NHCOCF3), 7.74 ~2H, m, 7, 8-ArH), 8.06 (2H, m, 6, 9-ArH).
IR (Nicolet 205F~, film on N~Cl pl~t-): cm~l, 3421.4 (br), 3080.8, 2960.1, 1718.4, 1664.5, 1556.7, 1457.6, 1283.0, 1188.1, 1043.7, 983.4, 858.9, 728.4.
lS
~U~STi ~ JTE S~EET
WO 94/11382 PCI`/CA93/00463 214~4~
r ~ 615 . V~S~ou~ ~--2 ' ~Alr i~i~ ~pl~
g H~C~ H,Cj~ + ~C}~
,,~0 ~0 H~CO
OCHJ OCHJ O OCH~ O OCH~ O
Wa~ 3 ¢Ç~ ~10 ~CH~ ~
H~CO O HJC O HJCO OHJCO O
~C~ ~C~ H~C~ HJC~
rO~ .eOO~ I AcOO~ I HooH
~4 ~6 ~8 WLCII~ ~CH, ~aCH,~'`~
HJHCO~ H~CO~ ~0I HJHCO~
~5 l7 ~9 l 12 oo oo oo oo ~} ~ ~p~CH~ CH, O O O o o H~C~ HJC~ HJC~ H~C~;t HO I ~oOOAC ~.coA~ ~ I
BCH-20lS BCH I666 BCH-1667 BCH 2014 s ~t-p ls 3,4-D~ O ~ l-2-~odo-2,C '~
To a mixture of dL-O-acetyl fucal ~3 029 g, 14 140 mmol) ln 180 ml of ~-~t~itrile and 18 ~1 of water wa~ added portionwi-~ the NIS ~3 590 g, 15 554 m~ol) Aft-r tirr~ng for 30 minut~ th- mixtur- wa- xtracted with CH2C12 ~2x) and the combined organic extract- w r~ ^d wLth 10%
odium thir- lf- ~ ~olut~on, water and finally dr~ed (Na2SO4) to give 4 403 g (87~ yi~ld) of the dQ-ir-d ugar PNR (~c~L~ d6, 250 H~z) ~ 1 12 (d, 3H, J~6 4Hz, CH3-6'), 1 99 ~nd lS 2 11 (2-, 2X3H, 2XOAc), 4 36 (d, 1~, J-5 1Hz, H-2), 4 48 (q, lH, J~6 6Hz, ~-5), 4 98 (unre~olved dd, lH, H-3), 5 18 (broad ~,lH, H-4), 5 59 (broad ~, lH, H-l), 5 94 (d, lH, OH) S U ~ , T ~
~ 214;65~8 ~t-p 2:(1'8,1R,38) ~Dd (1's~,18,3R) - 2,S ri Lhoxy-1-(~',6'-"~ 2'-~odo~ )-3-a~-to~oc~ro ~n ~o a mixtur- of ugar frDm ~t-p 1 ~- _in ~910 mg, 2.539 mmol) and methyl - ketone i~e:' ~ -n (500 mg, 2.116 mmol) ~n dry CH2C12 under argon a~ -r,'- ~ and room t~ re wa~ added Dms mol~ r ~i-VQ (4A).
After stirring for 20 minut-- DDQ (577 mg, 2.539 mmol) wa~ added.
Aft-r tirring for 72 hour~, whil- addition- of 0.5 guivalent of ugar and 0.5 quival-nt of DDQ w-r- don- after 24 nd 48 hour~, the reaction wa~ up by addition of 100 ml of NaHCO3 5~ and water mixtur~
(ls3). ~xtraction- with CH2C12 (3x100 ml) following by w ~h~ng with the ame ~ mixtur- and drying (Na28O4). Flash ch.. -tG~ap}~y of the crude (CH2C12sH-xs~tOAc~ 9s4sl) gave 361 mg of the non-natural lS (l~S,lS,3R) gl~cc~id~ ~nd 435 mg of th- natural (l'S,lR,3S) one. The arbLtrar$1y ~ (l'S,lS,3R) t~tled _ __ ~ had:
PMR (-cetonQ-d6, 250 MHz) ~: 1.27 (d,3H, J~6.5Hz, CH3-6'), 1.94 and 2.16 (2~, 2X3H, 2XOAc), 2.30 (~,3H,COCH3), 2.50 (dd, lH, J-17.8Hz and 12.1Hz, CH~CHO), 2.95 (dd, lH, J~17.8 and 4.3Hz, CHeCHO), 3.80 and 3.83 (2s, 2X3H, 2XOCH3~, 5.52 (d, lH, J~5.0Hz, H-2'), 4.75 (m, 3H, H-3, H-3' and H-5'), 5.24 (broad ~, lH, H-4'), 5.89 (ss, lH, H-l'), 6.15 (-, lH, H-l), 6.90 (2d, 2H, Ar-H).
The ~econd (l~S,lS,3R) titled ~ _ -' had:
PMR (-~etc - d6, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 1.97 and 2S 2.15 (28, 2Y3H, 2XOAc), 2.30 (8, 3H, COCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CH~CHO), 2.96 (dd, lH, J-17.6Hz and 4.1H~, CHeCHO), 3.80 and 3.82 (2~, 2X3H, 2XOCH3), 4.48 (d, lH, J~5.0Hz, H-2'), 4.54 (m, 2H, H-3, H-5'), 4.83 (un.~Dlved dd, lH, H-3'), 5.20 (broad 8, lH, H-4'), 5.86 (~, lH, H-l'), 6.03 (~, lH, H-l), 6.88 (2d, 2H, Ar-H).
8t-p 3s (l's~,lR,38)-5,8-~ 3 ~ o 1-(2',6'-~ 2'-~odo-L-l~ o~h.
To mixture of the ~ from tep 2 herein (500 mg, 0.844 mmol) in 90 ml of dry THF -i n~ 1 n~ at 0C and undsr argon a; ~_~ha._ were added 90 ml of NaOH 0.5N. After ~tirrin~ for 1 hour the reactLon mixture was n~utr~l--e~ with 160 ml of NH4Cl ~at.sNaHCO3 at. (4:1) and extracted with CH2C12 (3x200 ml). Th~ combined organic layer~ were dried over r ~ s W O 94~11382 PC~r/cA93/00463 5~ ~ --MgSO4. Flash ch~ Gy aphy (toluene:ethyl acetate; 8:2) of the crude gave 248 mg (49% yiQld) of pure titled ~
PMR (aceton~-d6, 2S0 MHz) ~: 1.26 (d, 3H, J~6.5Hz, CH3-6'), 2.29 (s, 3H, COCH3), 2.44 (dd, lH, J~17.5Hz and 12.2Hz, CHaCHO), 2.93 (dd, lH, S J-17.7Hz and 4.1Hz, CH~CHO), 3.16 (d, lH, J-6.0~z, OH), 3.49 (m, lH, H-3'), 3.77 (m, lH, H-4'), 3.79 and 3.84 (2X~, 2X3H, OCH3), 4.09 (d, lH, J=7.4Hz, OH), 4.25 (q, lH, J-6.6Hz, H-5'), 4.37 (d, lH, J~5.0Hz, H-2'), 4.54 (dd, lH, J-12.2Hz, 4.1~z, H-3), 5.84 (~, lH, H-l'), 5.99 (B, lH, H-1), 6.88 (2Xd, 2XH, ArH) 8t-p ~s ~ ,1~,3~)-3 ~ ~t~ 1-(2',6' ~ 2'-~odo-~-~ )-S,8 ~i~ 5,8-dih~drc~
The tLtl~d _ _ ' wa- obtain~d following CAN oxidat~on of th2 product from tep 3 ~- i n aS per pr~vious pr~CEdU~e.
PMR (CDC13, 250 MHz) 8: 1.32 (d, 3H~ J-6.6Hz, CH3-6'), 1.86 (larg~ d, lH, OH), 2.33 (-, 3H, COCH3), 2.39 (dd, lH, J-l9.9 and ll.9Hz, CHa-CHO), 2.81 (larg~ ~, lH, OH), 2.90 (dd, lH, J-19.7Hz and 3.9Hz, CHe-CHO), 3.32 (larg- , lH, H-3'), 3.78 (larg~ ~..~ lv d d, lH, H-4'), 4.17 (broad q, lH, J-5.0Hz, H-5'), 4.39 (m, 2H, H-3 and H-2'), 6.81 (s, lH, H-l'), 6.89 (~, lH, H-l), 6.81 (2Xd, 2H, ~u~n~9 ring-H).
IR (film) Vmaxs 3486, 3400, 2937, 1711, 1657, 1307, 968 cm~l.
~t-~ 5s (l'~,lR,38)- mathyl-~1-t2',6' ~ 3',4'-d~h~d.~ 2~-~odo-L-l~ -S,10 i~-~-3,~,S,10-L- ~ - [2,3-c] ~-c 3-rl) ' t - (~CH-~01S) Starting from 50 mg (0.105 mmol) of th~ c~ ' from t~p 4 h-rein and 1 ml of 1 r~t ~L~ -, th~ ~ d~cribQd in ~t-p 2, -- _ 18 5, has b~en followQd. After pur$fic~ti~, 15.8 mg (29~ y~ld) of pur~
titled c~ was j~~lrt~.
PMR (CDCl3, 250 MHz) ~s 1.32 (d, 3H, J~6.7Hz, CH3-6'), 1.91 (large d, lH, J~ll.OHz, OH), 2.36 (s, 3H, COCH3), 2.53 (dd, lH, J-19.5Hz, 11.4Hz, C~aCHO), 2.81 (larg~ d, lH, J-10.4Hz, OH), 3.08 (dd, lH, J~19.9Hz and 3S 4.1Hz, CH~CHO), 3.34 (m, lH, H-3'), 3.80 ~m, lH, H-4'), 4.17 (broad q, lH, 6.9Hz, H-5'), 4.45 (m, 2H, ~-3 and H-4'), 5.98 (2Xs, 2XlH, H-l and H-l'), 7.78 and 8.11 (2Xm, 2X2H, ArH).
IR (film) Vm~xs 3477 broad, 2928, 1722, 1670, 1298, 961, 732 cm~l.
W O 94/11382 P ~ /CA93/00463 2i~48 8t-p 6~ ,lR,3$)- 5,1~ rio~ 3-ac-to-l-(2~6~-A~ 3',~'-diac-tos~-2'-iodo-~)-5,8-dihrdroi~ochrD ~n CAN ~Yi~tion of the (l'S,lR,3S) dia~t~ Lc product from ~tep 2, S example 61, yLelded the titled ~
- PMR ~CDC13, 250 MHz) ~s 1.21 ~d, 3H, J-6.6Hz, CH3-6'), 2.07 and 2.22 ~2~, 2X3H, 2XOAc), 2.32 (~, 3H, COCH3), 2.41 ~dd, lH, J-24.1Hz, 11.8Hz, CHaCHO), 2.92 (dd, lH, J~19.7Hz nd 3.9Hz, CHeCHO), 4.29 (q, lH, J-6.5 Hz, H-5'), 4.36 (d, lH, J-5.1Hz, H-2'), 4.41 (dd, lH, J-11.2Hz nd 4.0Hz, H-3), 4.78 ~dd, lH, J-4.0Hz, H-3'), 5.23 (broad ~, lH, H-4'), 5.82 (18, lH, H-l'), 5.87 (18, lH, H-l), 6.81 (2d, 2H, qv~nnne ring-H).
8t--p 7t (1'8,1R,38)-~--thyl-(1-[2',6'-~~ 3~~4~ Ga~ 2'--iodo-L-l~ -5,10 io-o-3,4,S,10-t-tr h~d. ~ 2,3-cl ~,........ ~ 3-yl) ~ ~ - (BC~-1666) To a mixture of glyco~ide from tep 6 herein ~55 mg, 0.098 mmol) in 1.5 ml of dry tolu-n~ and under argon ~ -_~hc~, wa~ added 1-acetoxybut~i- - (66 mg, 0.587 mmol). After 18 hour~ of tirring the mixtur- was directly fla~h cl... LO~J,~h~d (tolu-nes~thyl ac~tate; 9:1) to give 17 mg of pur~ titl-d _ __ ' (28~ yi-ld).
PMR (CD2C12, 250 MHz) ~: 1.20 (d, 3H, J-1.20Hz, CH3-6'), 2.13 and 2.44 (28, 2X3H, 2XOCH3), 2.31 (8, 3H, COCH3), 2.62 (dd, lH, J~19.5Hz and 11.5Hz, HC~aCHC~O), 3.16 (dd, lH, J~19.5Hz, 4.0Hz, HCHeCHC~O), 4.45 2S (broad q, lH, J-6.6Hz, H-5'), 4.51 (d, lH, J~5.0Hz, H-2'), 4.62 ~ lved dd, lH, J-11.7Hz nd 4.0Hz, H-3), 4.88 (dd, lH, J~4.0Hz, H-3'), 5.32 (broad ~, lH, H-4'), 6.06 (~, lH, H-l'), 6.16 (~, lH, H-l), 7.71 and 8.22 (2Xm, 2Y2H, ArH).
lR (fi}m) Vmaxs 2991, 2935, 1746, 1668, 1238, 970, 730 cm 1.
~t-p 8s (l'~,lS,3R)-5,8-Dioso-3 -~-~o 1-(2',6'-~;~ ~ 3',4'-~ 2'-~odo-L-1~ )-5,8 di~d.o~
CAN ~Y~'t~ of the (l'S,lS,3R) gly~:a~de from tep 2, . _le 61, gave the titled a _ ~.
PMR (CDC13, 250 MHz) ~s 1.35 (d, 3H, J-6.6Hz, CH3-6'), 2.07 and 2.23 (28, 2X3H, 2XOAc), 2.32 (~, 3H, COCH3), 2.46 (dd, lH, J~20.3 Hz and 11.7 Hz, CHaCHO), 2.90 (dd, lH, J~19.7Hz and 4.1Hz, CHeCHO), 4.25 ~d, lH, JY5.2Hz, H-2'), 4.43 (dd, lH, J-11.6Hz and 4.1Hz, H-3), 4.61 (q, lH, W O 94/11382 21~6S48 PC~r/CA93/00463 J~6.2Hz, H-5'), 4.75 (dd, lH, J~3.6 Hz, H-3'), 5.26 (broad ~, lH, H-4'), 5.82 (s, lH, H-l'), S.97 (~, lH, H-l), 6.81 (2d, 2H, quinone ring-H).
IR (film) Vmax: 2945, 1747 broad, 1663, 1237, 969 cm-l.
S
8t-p 9s (1'8,1s5,3R~-~ ~hrl-(1-[2',6'-A~ 3',4'-~i~ G~ 2'-~odo-L-l~ -S,10 'it~Y^-3,~,S,10-t-tr k~ [2,3-c~ 3-rl) ~-ton- (BC~ 67) Starting from 70 mg (0.118 mmol) of _ _ ' from ztep 8 herein and 79.6 mg of l-aceto~y~ut~ and following the ~ c~_' r- d~scr~bed in tep 2, s l~ 5, we obtained after purification 25 mg (35~ yield) of titled ~
PMR (CDC13, 250 MHz) ~s 1.40 (d, 3H, J~6.4 Hz, CH3-6'), 2.05 and 2.24 (2g, 2x3H, 2xOCH3), 2.35 (~, 3H, COCH3), 2.57 (dd, lH, J-20.0 nd 12.4Hz, HC~aCHCO), 3.07 (dd, lH, J~20.0Hz and 4.2Hz, HCHeCHC~O), 4.27 ~d, lH, J~5.0Hz, H-2~), 4.49 (dd, lH, J~11.6, 4.2 Hz, H-3), 4.75 (m, 2H, H-3' and H-5~), 5.28 (larg- ~, lH, H-4~), 5.86 (8, lH, H-l'), 6~14 (-, lH, H-l), 7.77 and 8.11 (2m, 2X2H, ArH).
IR (film) Vmax: 2945, 1743 broad, 1668, 1236 bro~d, 958, 734 cm 1 8t-p 10s (l'S,18,3R)-5,8 r~ ~ , 3 ~-~o 1-(2',6'-~ 2'-iodo-The titled ~ ' wa- obtained via ba~e hydroly-i- of th~ (l'S,lS,lR) pr-cur~or from t-p 2 h-rein a- p-r ~ r~ from tep 3 ~- ~i n, PMR (~cetone-d6, 250 NHz) ~: 1.35 (d, 3H, J-6.6Hz, CH3-6'), 2.30 (8 3H, COCH3), 2.50 (dd, lH, J~17.6 and 11.5 Hz, CHaCHO), 2.94 (dd, lH, J~17.9 and 4.3Hz, CH~CHO), 3.20 ~d, lH, OH), 4.44 (m, lH, H-3'), 3.80 (large ~, 7H, 2XOCH3 and H-4~), 4.12 (d, lH, OH), 4.41 (d, lH, J~5.0Hz, H-2'), 4.55 (q, lH, J~6.4Hz, H-5'), 4.70 (dd, lH, J~12.1 Hz and 4.5 Hz, H-3), 5.87 (lS, lH, H-l'), 6.14 (1~, lH, H-l), 6.88 (2d, 2H, ArH).
8t-p lls (l'sS,18,3R)-3 ~ o 1-(2',6'-~~ 2'-iodo-L-1~ )-S,8 'i~-~-S,8-di~rdro~
The titl~d _ ~ wa- obtained ~following CAN ~Yi~-tinn of thc product from ztep 10 her~in a~ per previou~ ~soc~
Y` ~ E~Y~-T
W O 94/11382 2 ~4 ~ ~ 8 Pc~r/cAg3/00463 PMR (CDCl3, 250 MHz) ~: 1.45 ~d, 3H, Js6.6Hz, CH3-6~), 1.90 (bro~d B, lH, OH), 2.31 (~, 3H, COCH3), 2.43 (dd, lH, J-20.1Hz and 11.8 Hz, CHaCHO), 2.80 (m, 1-, OH), 2.88 (dd, lH, J~19.8Hz and 4.1Hz, CHeCHO), 3.32 (m, lH, H-3'), 3.84 (m, lH, H-4'), 4.24 (d, lH, J~4.4Hz, H-2'), S 4.42 (dd, lH, J~11.8Hz ~nd 4.2Hz, H-3), 5.82 (~, lH, H-l'), 5.95 (~, - lH, H-l), 6.79 (ZXd, 2H, ~-~n~n~ r~ng-X).
gt-p 12s (1'8,1~,3R~ _ th~l-(1-[2'~C' ~ 3'~4'~d~d~_a~ 2'-~odo-L-l~ ~5~0 '~-3~4~5~10-t-trah~ 2,3-c~ 3-yl) ' ~ ~ (~C8-2014) A mixtur- of ~ _ ' from t-p 11 ~ rin (1 mlJ nd l-acetGA~ bu~r~i ~
(96 mg, 0.201 mmol) ~n 2 ml of dry tolu-n~ wa~ t~rr~d for 18 hour~
under argon ~ nd then fla~h cl~ ~ ~hed (Toluene:Ethyl lS aoetate; 8s2) to g~- 42 mg (40% yield) of pure titl~d c PMR (CDCl3, 250 MHz) ~: 1.52 (d, 3H, CH3-6'), 2.36 (B, 3H, COCH3), 2.58 (dd, lH, J-19.7Hz and 11.4Hz, HCH~CHCO), 2.78 (broad m, lH, OH), 3.09 (dd, lH, J-20.0Hz and 4.2Hz, HCHeCHCO), 3.34 (m, lH, H-3'), 3.89 (m, lH, H-4'), 4.27 (d, lH, J-4.5Hz, H-2'), 4.49 (dd, lH, J~11.7Hz and 4.2Hz, H-3), 4.66 (broad q, lH, J-6.4Hz, H-S~), 5.30 (~, lH, H-l'), 5.89 (~, lH, H-l), 7.53 and 8.13 (2m, 2X2H, Ar-H).
IR (f~lm) Vmaxs 3434 broad, 2934 broad, 1720, 1669, 1292, 995, 955 om~l.
sues~ T~ ~ff~T
W O 94/11382 2 ~ 4 ~ PCT/CA93/00463 _1~ 62 V~riou- C-2' ~sial~ t-d ~ rh~ ino~e gl~co~
HIC~/ 1 H~C~O + ~CH
AcOO~C ACoOA~ Br - H~CO
OCH~ O OCH3 O
H~CO + H~CO O
H~Cj~ H~Co~ i ~ CH~
H~C~ H~C~;
OAI: Br AcO
O O O O
~CH~ ~o~ C
O O O O
H~C~ H,C~
~oOh Br ~oOA~: Br 8t-p 1 3,4-D~ C ~ 1-2 ~. - 2,6-~;~
Following the p,.--` - de~cribed in tcp 1, ~ 61, we obtained after work-up 89% yield of a mixture of four ~ _ _"d~ Probably axi-al 10 and equatorial bromo ugar- and ~ and ~ of ach 8t-p 2s (1'8,1~,38) ~nd (1'8,18,3R)-2,5-Di t~os~-1-(2',6~-3',4' i~L- ~ 2' ~ )-3-~c-t~ h-~o~n Followin~ the proc.dur~ described in ~tep 2, examplQ 61, w~ obtained aft~r purifir-tinn (Dichlo -'~-n~sH~xane Ethyl aC~tatet 12s7 1) 35%
yield of a ~eparable (l'S,lR,3S and l'S,lS,3R) 1 1 mixture of titled diastereoi r ~ S.
SUBSTITUTE SHEE~T
WO 94/11382 PCI`/CA93/00463 2l4~4~
(l~S,lS,3R): PMR (acetone-d6~ Z50 MHz) ~: 1.27 (d, 3H, JY6.5Hz, CH3-6'), 1.94 and 2.11 (2Xs, 2X3H, 2XOAc), 2.29 (B, 3H, COCH3), 2.50 (dd, lH, J~17.7Hz and 12.1Hz, CHaCHO), 2.96 (dd, lH, J-17.8 and 4.2Hz, CHeCHO), 3.80 and 3.84 (2Xs, 2X3H, 2XOCH3), 4.42 (d, lH, J-4.2Hz, H-S 2'), 4.71 (dd, lH, J~12.2Hz and 4.2 Hz,H-3), 4.81 (q, lH, J~6.4Hz, H-- 5'), 5.22 (m, 2H, H-3' and H-4'), 5.74 (s,lH, H-l'), 6.17 (8, lH, H-l), 6.90 (2Xd, 2H, Ar-H).
SR (film) Vm~x: 2937, 1748, 1486, 1260 and 1237, 970 cm~l.
(l'S,lR,3S~: PMR (acQtone, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 1.97 and 2.10 (2Xs, 2X3H, 2XOAc), 2.30 (8, 3H, COCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CHaCHO), 2.97 (dd, lH, J~17.6Hz and 4.0Hz, CHeCHO), 3.80 and 3.82 (2xs~ 2X3H, 2XOCH3), 4.38 (d, lH, J~4.6Hz, H-2'), 4.53 (q, lH, J-6.4Hz, H-5'), 5.16 (broad 8, lH, H-4'), 5.27 (dd, lH, J~4.2Hz, H-3'), 5.71 (8~ lH, H-l'), 6.05 (8~ lH, H-l), 6.89 (2Xd, 2H, Ar-H)~
lS
St-p 3: (l'S,lR,35)-5,8-dioso-1-(2',6'-~~ 3',4' '~ toA~ 2~-~ )-5,8-dihydroi~Qchro -n CAN oxidat$on of the _ _ ~ from ~tep 2 here$n yielded the t$tled ~ _ .
PMR (CDC13, 2S0 MHz) ~: 1.19 (d, 3H, J-6.6Hz, CH3-6'), 2.04 and 2.16 (2X~, 2Y3H, 2YOAc), 2.29 (~, 3H, COCH3), 2.38 ~dd, lH, J-19.9Hz and 11.6Hz, CHaCHO), 2.88 (dd, lH, J~19.8Hz and 3.9Hz, CHeCHO), 4.25 (m, 2H, H-2' and H-5'), 4.39 (dd, lH, J~11.6Hz and 3.8Hz, H-3), 5.16 (broad 8, lH, H-4'), 5.19 (dd, lH, J~4.0Hz, H-3'), 5.71 (8, lH, H-l'), 5.81 (~, lH,H-l), 6.79 (2Yd, 2H, Ar-H).
St-p 4: (l'~,lR,38)-m th~ 1-[2',6'-~~ s 3~ o~ 2'-~ p~ ]-S,lO-dioso-3,4,S,10-t-tr~d... ~p~b- ~2,3-c] ~ a 3-~1) k-tone (BCH-2100) The tltled _ __ ' wa~ obtained follow$ng the ~---e re described in ~tep 2, ~ _1~ 5, from the ~ ' from step 3 herein. HPLC
purifi~ti nn gav- 9~ of desired (l'S,lR,35) natural titled glycoside.
3S PMR (CDC13, 250 MHz) ~: 1.23 (d, 3H, J~6.4Hz, CH3-6'), 2.06 and 2.19 (2~,2X3B, 2XOAc), 2.35 (8, 3H, COCH3), 2.54 (dd, lH, J~19.7Hz and 11.7Hz, CHaCBO), 3.09 (dd, lH, J-19.8Hz and 4.0Hz, CHeCHO), 4.29 (m, 2H, H-2' and H-5'), 4.47 (dd, lH, J~11.7Hz and 4.0Hz, H-3), 5.18 (broad 8, SU~ E~T
WO 94/11382 PCI/C~93/00463 21~6~4~ ~
lH, H-4'), 5.23 (unr~solv~d dd, lH, H-3'), 5.83 (~ lH, H-l'), 6.01 (8, lH, H-l), 7.77 and 8.11 (2m, 2X2H, Ar-H).
IR (film) Vmax: 2991 and 2943, 1748,1665, 1241, 975 cm 1.
~t-p 5s (1'8,1R,3~)-5,8-dloxo-3 - ~Lo 1-(2',6~ 3~
~ 2' _. - L-l~ -)-S,8-dihrdroi-o~h CAN oY~ n~ of the (l'S,lR,3S) dia-tc ~ - from tep 2 h~rein yielded the titled product.
IR (film) Vm~x: 2939, 1743, 1674, 1241, 968 cm~l.
Bt-p 6s (1'8,18,3R)---thrl-(1-[2',6'-~;~- ~ 3',4'-~i~--tG~ 2'-~.. - L-l~ 1-5,10-dioxo-3,4,S,lO-t-ts~L~d.. ~ - [2,3-~]-pyraQ-3-yl) ~-ton- (~Ca-2099) The titl~d . _ ' wa~ obt~in~d following thQ ~~ d~3crib~d in t~p 2, ~ 5, from th~ quinon~ from tcp 5 h-r-in. Flash ch.. - o~L.~hy (Toluonc:Ethyl aootat~ 9sl) gav- 30% of do~irQd titl~d C~, ~L ~.
PMR (CDC13, 250 ~z) ~: 1.41 (d, 3H, J~6.4Hz, CH3-6'), 2.05 and 2.21 (2-, 2X3H, 2xoAc)~ 2.34 (~, 3H, COCH3), 2.58 (dd, lH, J-20.1Hz and 11.6Hz, CH~CHO), 3.08 (dd, lH, J-20.0Hz ~nd 4.2Hz, C~CHO), 4.16 (d, lH, J~4.5Hz, H-2'), 4.48 (dd, lH, J-11.6Hz and 4.1Hz, H-3), 4.76 (q, lH, J-5.9Hz, H-5'), 5.20 (unr--olv-d dd, lH, H-3'), 5.25 ~bro~d , lH, H-4'), 5.72 (1~, lH, H-l'), 6.17 (1~, lH, H-l), 7.78 and 8.12 (2m, 2X2H, Ar-H).
IR (film) Umax: 2937, 1750, 1672, 1243, 964 cm~l.
r _1- 63s C-2'-ax~-lr ~^A~ rl ~ ,"~ ~ glrco~
SUBSTITUTE StlEET
WO 94/11382 ~ PCT/CA93/00463 2146~48 H3C ~ / _ H,C ~ + ~ CH, ACoNHCOCF, ACoNH ~ H,CO
OCH, O OCH, O OCH, O OCH, O
_ ~ CH, ~ CH, ~ ~CH, ~ ~CH3 ~ 3 ~ ~ 6 ~
H,CO O ~ H,CO O+ H3CO O ____~ H,CO O
H,C ~ ~,C ~H,C ~ H,C
HoNH I A~ONH ICOCF, HoNH I
O O O O
CH, ~ "~CH
o O O O
H,C ~ H,C
HOCOCF, ~ ~ HoNH I
O O O O
H~
O O o O
H,C ~ H,C
COCF3 HoNH I
~CH~U23 HCH-2022 8t-p ls~',3',6'-tr~ 2'-~odo-3'-trifl~ z~ do-~'-c -~ L~l-L-l~
S
Following th~ ~r~9~ ~ dQscribed in step 1, xample 61, we obtained after w~_ up 94~ y~eld of a AOA ~e~-rable ~-~ m$xture (2:1) of t~tled h- l99 -tr~ ~ugar.
PMR ~acetone-d6, 250 NHz) ~: 1.08 (d, 3H, J=6.6Hz, CH3-6), 2.13 (8, 3H, OAc-4), 4.47 (m, lH, H-3), 4.53 (d, lH, J~4.3Hz, H-2), 4.56 (broad q, lH, J~5.2Hz, H-5), 5.17 (broad 8, lH, H-4), 5.65 (d, lH, J~3.8Hz, H-l), 6.04 (d, lH, J~3.8Hz, OH).
8t-p 2: (1'8,1R,3~) ~Td (1'8,15,3R)-2,5-D-o-tho~-3 !~to 1 -lS (2',3',6'-tr;~ 2'-iodo-3'-tr~f~ t- ;~o-4'-O-ac--tyl--L--l~ "_~o~ ocl~
SUBSTITUTE SHEET
W O 94/11382 P ~ rC~93/00463 Following thQ s mc ~rcs~' r~ a~ d~scribed in st~p 2, xampla 61, we obtained after purif~c~tjs~ (~olucne:Ethyl acctate7 9:1) 38~ yield of a separable (l~S,lR,3S and l'S,lS,3R) mixtur~ of titlcd diartcreo~ a S (1:1).
The natural (l~S,lR,3S) glycor~de: PMR ~aceton~-d6, 250 MHz) ~: 1.16 (d, 3H, J~6.6Hz, CH3-6'), 2.15 (r, 3H, Ac0-4'), 2.30 (~ 3H, OOCH3), 2.41 (unr~solv~d dd, lH, CHaCHCO), 2.97 (dd, lH, J-17.7Hz and 3.89Hz, CHeCHO), 3.80 and 3.84 (2xs, 2x3H, 2xOCH3), 4.36 (m, lH, H-3'), 4.63 (m, 3H, H-3, H-2~ and H-5~), 5.19 (broad r, lH, H-4'), 5.90 (r, lH, H-l'), 6.06 (s, lH, H-l), 6.87 (2xd, 2H, Ar-H), 7.95 (broad r, lH, ~O~r3).
Th~ non-natural glyco-id~ (l'S,15,3R): PMR (ac~ton~-d6, 250 MHz) ~:
1.23 (s, 3H, J~6.5Hz, CH3-6'), 2.16 (s, 3H, Ac0-4'), 2.30 (s, 3H, COCH3), 2.51 (dd, lH, J~18.2Hz and 12.0Hz, C~aCHO), 2.97 (dd, lH, J=17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.83 (2X~, 2X3H, 2XOCH3), 4.30 (m, lH, H-3~), 4.69 (d, lH, Js4.72Hz, H-2'), 4.74 (dd, lH, J~12.1Hz and 4.3Hz, H-3), 4.88 (q, lH, J~5.0Hz, H-5'), 5.24 (broad 8, lH, H-4'), 5.92 (r, lH, H-l'), 6.18 (s, lH, H-l), 6.90 (2Xd, 2XlH, Ar-H), 7.9S (broad s, lH, ~nCG~r3).
8t-p 3s (l'~,lR,38)-5,8-D; thoxr-3 --~Lc 1-(2',3',6'-tr;~-- ~ 3'-tr~fl ~ La~do-2'-~odo-~-1~ ,, -r~ 6~h..
Ba~ hydrolyris of th~ from rt~p 2 h~r~in as p~r ~Loc~dure from tep 3, xampl- 61, yi-lded th~ titl~d ~ . PMR (~ one d6, 250 MHz) ~: 1.28 (d, 3H, J-6.6Hz, CH3-6'), 2.30 (~, 3H, OOCH3), 2.45 (dd, lH, J~17.6Hz and 12.2Hz, CHaCHO), 2.95 (dd, lH, J~17.6Hz ~nd 4.0Hz, CHeCHO), 3.79 and 3.84 (2s, 2X3H, 2XOCH3), 4.03 (m, 2H, H-4' and OH-4~), 4.44 (broad q, lH, J~6.4Hz, H-5'), 4.58 (m, 2H, H-3 and H-2'), 5.89 (~, lH, H-l'), 6.04 (s, lH, H-l), 6.89 (2d, 2XH, Ar-H), 7.65 (broad s, lH, h~C:C~r 3 ) -IR (f~lm) Vm~x: 3539 and 3414, 2941 and 2844, 1728, 1488, 1260, 1175, 970 cm-l.
35 ~t-p 4s (1'8,1~,3~)-3 ~-~o 1-(2',3',6'-trid-ox~ -2'-~odo-3'-trifl -_~r~ -L-l~ )-S,8-dioxo-S,8-d.~ C~o--~n SUBSTiTUTE SHEET
WO 94/11382 PCI`/CA93/00463 21~6~
CAN ~yi~at1nn of the product ~rom ~tep 3 herein yielded the titled product.
P~R (CDC13, 250 ~Hz) ~: 1.32 (d, 3H, J~6.6Hz, CH3-6'), 2.06 (broad d, lH, OH-4'), 2.32 (~, 3H, COCH3), 2.41 (dd, lH, J~20.4Hz and 11.7Hz, S CHaCHO), 2.93 (dd, lH, J~19.6 and 3.9Hz, CHeCHO), 3.75 (broad d, lH, H-4'), 3.96 (m, lH, H-3'), 4.28 (q, lH, J-6.7Hz, H-5'), 4.42 (m, 2H, H-3 and H-2'), 5.82 (8, lH, H-l'), 5.90 (s, lH, H-l), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, lH, NHCOCF3).
IR (film) Vmax 3541 and 3417, 2992 and 2944, 1729, 1664, 1174, 967 cm~
10 1.
St-p 5s (1'8,1R,38)---thyl-(1-[2',3',6'-tr{~- ~ 2'-iodo-3'-tr~ $do-4' k~.OA~ L~ -5,1O-dioxo-3,4,S,lO-t-tr h~d.. ~rh~ 2,3-cl rJ~ 3-yl) k-tone (BCH-2023) The tLtled ~ _ l wa- obtained aB per ~.oc~dure de~cribed in ~tep 2, le 5, but u-lng the product from ~tep 4 ber-in. Purification was ffectQd by fla-h cl..~ -to~-a~h~ (Toluene:Ethyl ac~t~ 8:2).
PMR (CDC13, 250 ~H~) ~: 1.34 (d, 3H, J-6.6Hz, CH3-6'), 2.35 (8, 3H, COCH3), 2.53 (dd, lH, J~19.6Hz and 11.5Hz, CH~CHO), 3.11 (dd, lH, J-19.6Hz and 4.1Hz, CHeCHO), 3.76 (broad s, lH, H-4'), 3.97 (m, lH, H-3'), 4.30 (q, lH, J~6.6Hz, H-5~), 4.49 (dd+d, 2H, H-3 and H-2'), 6.00 (13, 2H, H-l and H-l'), 7.01 (broad d, lH, NHCOCF3), 7.78 and 8.13 (2Xm, 2S 2X2H, Ar-H).
IR (film) Vm~xs 3529 and 3414, 2991 and 2930, 1727, 1666, 1298, 1177, 963 cm~l.
8~-p 6: (1'8,18,3R)-5,8 'i ~ ~ 3 ~ o 1-(2',3',6'-~r~d~ ~ 3~-tri~ - t- '~-2'-iodo-L-l~ ochro n To a m$xture of (l'S,lS,3R) glyco~ide from ~tep 2 herain (103 mg, 0.16 mmol) in 15 ml of anhydrou~ h-nol wa~ added, at 0C and under argon ~~phe~e, 2 drop~ of NaOCH3, 4.37M (cat.). After fftirring for 45 3S minutes, the reaction wa- worked up by adding 10 ml of a mixture NH4Cl ~at.sNaHCO3 ~at. (8:3) and extracted with CH2C12 (2x30 ml). The ~ `in~d organic layer~ were w ~ with the ame aqueou~ mixture (30 ml) and dried (~gSO4). Fla~h ch~ -toJ-a~hy (Toluene:Ethyl acetate;
9:1) gave 70 mg of pure titled glycoaide (73% yield).
SUBSTITUTE SHEET
WO 94/11382 PCr/CA93/00463 21g6~
PMR (acstone-d6, 250 MHz) ~: 1.38 (d, 3H, J~6.5Hz, CH3-6'), 2.30 (u, 3H, COCH3), 2.50 (dd, lH, J~17.7Hz and 12.0Hz, CHaCHO), 2.97 (dd, J~17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.81 (2Xs, 2X3H, 2XOCH3), 4.00 (m, 3H, H-3', H-4~ and OH-4'), 4.62 (d, lH, J~4.8~z, H-2'), 4.74 (m, 2H, H-3 and S H-5'), 5.92 (1~, lH, H-l'), 6.18 (1~, lH, H-l), 6.88 (2Xd, 2H, Ar-H), 7.65 (broad ~, lH, NHOOCF3).
IR (film) Vmax: 3530, 3410, 2942 and 2837, 1723 broad, 1491, 1263, 1175, 958 cm~1.
~t-p 7: (1~8,1S,3R)-3--c-to-1-(2~3~,6~-trid~ ~ 2'-iodo-3~-tr~ f 1 ~ a~$do-L-l~ )-5,8-~$oso-S,8-dihydrQ~ h ~
CAN nYi~'ti~n of the product from ztep 6 herein yieldQd the t15 product.
PMR (CDC13, 250 KHz) ~: 1.47 (d, 3H, J-6.61Hz, CH3-6'), 2.22 (broad d, lH, OH-4'), 2.32 (1~, 3H, OOCH3), 2.46 (dd, lH, J~19.6Hz and 11.7Hz, CHaCHO), 2.92 (dd, lH, J-19.9Hz and 4.2Hz), 3.78 ~broad d, lH, H-4'), 3.91 (m, lH, H-3'), 4.37 (d, lH, J~4.8Hz, H-2'), 4.43 (dd, lH, ~-11.7Hz 20 and 4.1Hz, H-3), 4.64 (q, lH, J~6.3Hz, H-5'), 5.84 (s, lH, H-l'), 5.97 (~, lH, H-l), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, lH, NHCOCF3).
IR (film) VmaX 3531 and 3406, 2929, 1726, 1663, 1181 broad, 960 cm~l.
8~-p 8s (1'-,18,3~ thyl-(l-[2',3',5'-tr;~ ~ 2'-$odo-3'-2S ~r~f~ a~ d.~ ]-5,10-d$oxo-3,4,S,10-t-tr~d. ~ - [2,3-c] ~_ 3-yl) k-ton-(~ca-~022) The titled _ ' waz obtained a~ per ~.oced~re de-cribed in tep 2, _le 5, but u~ing the product from tep 7 h~rein. Purif~ o~ by fla~h ch.~ - - a~hy (Tolu-ne:Ethyl acetate; 9:1).
PMR (CDC13, 250 ~Hz) ~: 1.51 (d, 3H, J~6.5Hz, CH3-6'), 2.11 (broad d, lH, OH-4'), 2.34 (~, 3H, COCH3), 2.58 (dd, lH, J~19.4Hz and 11.6Hz, CHaCHO), 3.10 (dd, lH, J~19.8Hz and 4.1Hz, CHeCHO), 3.82 (broad d, lH, 3S H-4'), 3.92 (dd, lH, J~11.6Hz and 4.1Hz, H-3), 4.79 (g, lH, J-6.5Hz, H-5'), 5.88 (~, lH, H-l'), 6.14 (~, lH, H-l), 7.07 (broad d, lH, ~ 3), 7.78 and 8.11 (2Xm, 2X2H, Ar-H).
IR (film) Vmax: 3539 and 3414, 2946, 1731, 1666, 1293, 1174, 961 cm~l.
~UBSTmlTE SHEET
!
r ~ 6~: 2 1~ ~ ~ 4 ~
Hd~/ I ~1 + ~CH, H,CO
~ 2 OCH~ O OCHI O
~CH, ~"~CH~
HICO O H~CO O
Ac~ ~ 0~
o o o o ~CH~ ~"~CH, O O o O
~ O~AC I ~ O~A~
o o o o ~0 o O + o o IK~E-2~65 8t-p ls 2',6~ di~-- ~ 3',4'-~;a-~tGa~ 2'-iodo-~-~r~
Following the p,ocedu~ de~cribed in tep 1, ~ Q 61, we obtained after w__~ up a quantitative yi~ld of th~ de~$red _ _ ' which w_~
used in th~ next tep without purification:
PMR ~P~ - - d6, 250 MXz) ~: 1.17 (d, 3H, J~6.2Hz, CH3-6), 4.04 (m, lH, R-5), 4.48 (d, lH, J~4.2Hz, H-2), 4.84 (dd, lH, J~9.5Hz and 4.2Hz, H-3), 5.01 (large ~, lH, H-l), 5.51 (dd, lH, J~9.7Hz, H-4).
8t-p 2s (1'8,18,3R) nd (1'8,1R,38)-5,8-D$m-tho~r-3 ~ ~o 1-(2~,6~-~ - r 3~,4~ c~t~ ~ 2'-$odo-L-ar~
$ZG~ ~, - n WO 94/11382 PCr/CA93/00463 2 14 ~
Following the ame p,~ a~ de~cribed in tep 2, example 61, we obtained after fla~h chromatography (Toluene:Ethyl acetate; 9:1) a mixture of the tLtled ~tereoisomers (non ~ rable).
PMR (Ren~e d6, 250 HHz) ~: 1.20 and 1.38 (2d, 2X3H, 2XCH3-6'), 1.61, S 1.66, 1.67 and 1.69 (4~, 4X3H, 4XOAc), l.9S and 2.12 (2~, 2X3H, 2XOCH3), 2.76 (m, 2XH, 2XCHaCHO), 3.20 (m, 2H, 2XCHeCHO), 2.30, 2.31 and 2.32 (38, 4X3H, 4XOCH3), 4.18 (m, lH, H-5'), 4.35 and 4.47 (2Xdd, 2H, J~12.0Hz and 4.2Hz, 2XH-3), 4.82 (m, 5H, 2XH-3', 2XH-2's and H-5'), 5.62 and 5.70 (2Xdd, 2H, J~9.5Hz, 2XH-4'), 5.84 and 5.93 (2 larg~ ~, 2H, 2XH-1'), 5.95 (8~ lH, H-l), 6.33 (m, 5H, 2X2 Ar-H and H-l).
8t-p 3s (1'8,1~,38) d (1'~,18,3R)-3 ~ o 1-(2~,6'-Ai~- ~ 2'-iodo--L--~r~h; ~ ~ A~ )--S~8--dio~co--S~8--d~hrdroj9~cc~h~o~n lS The tltled - c ~- w~r~ o~t~in~ following CAN oY~Ati~ of the products from t~p 2 here~n as per previou~ ~c~
PMR (CDC13, 250 M~z) ~: 1.23 and 1.36 (2d, 2X3H, J~6.2Hz, 2XCH3-6'), 2.03, 2.04, 2.06 and 2.07 (4s, 4X3H, 4XOAc), 2.29 and 2.30 (2S, 2X3H, 2XCOCH3), 2.46 (m, 2H, 2XCHaCHO), 2.90 (dd, 2H, J-19.7Hz and 3.8Hz, 2XCHeCHO), 4.02 (m, lH, H-5'), 4.49 (m, 7H, 2XH-2', 2XH-3', 2XH-3 and H-5'), 5.15 (m, 2H, 2XH-4'), 5.62 and 5.68 (2S, 2H, 2XH-1'), 5.79 and 5.95 (28, 2H, 2XH-1), 6.75 (2X2d, 4H, 4XAr-H).
8t-p 4s (1'8,1R,18) - d (1'8,18,3R)-m-thrl-(1-[2',6' d~-- J-3',~-2S ~i ~ ~ tOa~ 2 ~ ~i odo-L ~ -5,10-d~o~o-3,4,S,lO L~t l~d-. ~p~~ t2,3-cl ~--~ 3-rl) k ton- (~CH-~065) FollowLng the r-ported ~c.c-' L $n ~tep 2, ~ 5, and ~tarting from the two ~t-reoi~- ?~ from ~tep 3 herein, tLtled r , __ 'n (9~) were isolated after fla~h c~ togra~hy (Toluene:Ethyl acetate; 19:1).
PMR (CDC13, 250 MHz) ~: 1.41 (d, 3H, J~6.2Hz, CH3-6'), 2.06 and 2.08 (2~, 2X3H, 2XOAc), 2.33 (~, 3H, COCH3), 2.57 (dd, lH, J~19.5Hz and 11.7Hz, CHaCHO), 3.09 (dd, lH, J~19.8Hz and 4.2Hz, CHeCHO), 4.46 (m, 4H, 3S H-3, H-2', H-3' and H-5~), 5.21 (dd, lH, J~9.5Hz, H-4'), 5.67 ~8~ lH, H-1'), 6.14 (8, lH, H-l), 7.78 and 8.13 (2m, 2X2H, Ar-H).
IR (film) Vmax: 2941, 1750 and 1739, 1665, 1298, 1236 large, 971 cm~1.
_l~ 65: C-2 ~ ,c~ L~_n~ inon- gl~ro~id--S~ ET
~ 2 1 4 ~
HJC~ + ~ Q~ ~ H3 ~ H~CO H~CO ol +1 H,C~
OCH, O ~ ~0~
HIC ~ r ~ CH3 ~,~ HO H~C~ r o ~cOOAC
~J 6 C ~ r ~ O H~
o o +l.3-~i~
H~C ~ r ~ +l~ x BCH21~t H~C~7 r HoOH
scH~ll7 8tep ls ~1'8,1~,3R) d (1'8,1R,38)-5,8-~ 3 ~r Lo 1-(2',6'-5 ~ 3'~ 6a~ L-l~
~he ~.._-' ~ de-cr$bed $n ~tep 2, - - ~le 61, wa- arplii~l to 5,8-dimethoxy-3-acctoi~ n and 3,4-~ YY-2,6-~;~ G- y ~uco~e. Fla~h Ch~ oJ~phy (~hloromethane:R~x ~n~: Fthyl acetate; 6:3:1) gave a 50%
yield of the two non ~ able titled ~tereolr D mixture (1:1).
PMR (~cqton~-d6, 250 MHz) ~: 1.11 and 1.20 (2d, 2X3H, J~6.6Hz, CH3-6'), 1.87, 1.88, 2.10 and 2.10 (48, 4X3H, 4xOAc), 2.28 ~nd 2.29 (2~, 2X3H, ~YrO~R3) ~ 2.45 (m, 2X3H, 2XCHaCHO), 2.94 (m, 2H, 2XCHeCHO), 3.79, 3.81 and 3.83 (3~, 4X3H, 4XOCH3), 4.34 (q, lH, J~6.53Hz, H-S'), 4.62 (m, 3H, lS 2XH-3 and H-S'), 5.14 (m, 4H, 2xH-3' ~nd 2XH-4'), 5.54 and 5.61 (2 broad ~, 2H, 2XH-1'), 5.97 and 6.16 (2~, 2H,H-1), 6.88 (m, 2X2H, 2XAr-H)-8t-p 2s (1'8,18,3R) and (1'8,1R,38)-5,8 di -thosr-3 ~ 1-(2',6'-~;~- ~ L-l~ '- ~,- ~~-) i-~ ~-SlJ~ T~- S~'E~.T
W O 94~11382 PC~r/cA93/00463 2 ~
Th~ ~ame p-~ d-~cribod in ~tep 3, example 61, wa~ applied to the product~ from ~tep 1 h-rein. Fla~h chromatGg-a~hy of the crude (Toluen~:~thyl acQtate; 6s4) gave 39% yield of no.l ~_~~rable titled dia~t~reoi- ~ (lsl).
S PMR (acQtonc-d6~ 2S0 MH~ 1.16 ~nd 1.25 (2d, 2X3H, J-6.6Hz, 2XCH3-6'), 1.80 (m, 4H, 4XH-2'), 2.24 (~, 2X3H, 2XCOCH3), 2.45 (unre~olved dd, 2H, CHaCHO), 2.87 (dd, 2H, CH~CHO), 3.37 (ff, lH, H-3'), 3.56 (m, 3H, ~-3' ~nd 2XH-4'), 3.75 (~, 3X3H, 3xOCH3), 3.77 (~, 3H, OCH3), 4.00 and 4.34 (2d, 2H, J-6.6Hz, 2XH-5'), 4.54 (2 u.~olved dd, 2H, H-3), 5.35 and 5.41 ( 2 broad ~, 2H, 2XH-1'), 5.89 and 6.10 (2~, 2H, 2XH-1), 6.83 (2X2d, 4H, Ar-H).
8t-p 3s (1'8,18,3R) and (1'8,1R,38)-S,8-d;oso-3-ac-to-1-(2',6~-~ L~ ,. - )-5,8-d~hydroi~ochro~
lS
The titlad ~.odu~L- w re obt~no~ following CAN ~Y~ti~ of the ~-o~cL~ from ~tep 2 ~- ~i n, PMR (CDC13, 250 ~H~) ~s 1.29 and 1.42 (2d, 2X2H, J-6.6Hz, 2XCH3-6'), 1.70 (m, 4H, 4XOH), 1.89 (m, 4H, 4XH-2'), 2.30 ~nd 2.31 (2~, 2X3H, ~Scoc~3)~ 2.43 (2 overlapping dd, 2H, 2XCHaCHO), 2.89 (2 ov~rlappLng dd, 2H, 7~C~L~ 3.65 nd 3.70 (2 broad , 2H, 2XH-4'), 3.90 (m, 2H, 2XH-3'), 3.99 (u-, olved q, lH, H-S'), 4.36 (g, lH, J-6.8Hz, H-S'), 4.43 (2 overlarping, 2H, 2X~-3), 5.41 ~nd 5.49 (2 broad ~, 2H, 2XH-1'), 5.81 and 5.98 (2s, 2H, 2xH-1), 6.79 (2X2d, 4H, Ar-H).
8t-p 4s (1'8,18,3R) ~nd (l'~,lR,38~ thrl-(1-[~;~-- ~ 2~,6~-d~h~d.o~ 3',4'-~ -S,10-dioso-3,4,5,10-t-tr ~ ~ [2,3-c] ~ 3-yl) ~-ton- (BCH-2117) The titled ~ wer- obtained in 43% yield by following the p.o~' e de~crib~d in ~t~p 2, . 1~ S, and u-ing the products fro~
~tep 3 herein. Fl~h cb., -t~_ .~hy (ToluenesEthyl acetat~; 4~6) and final purific~ti~ by preparative TLC (sam~ solvent conditions) wa~
r-quired.
PMR (DMSO-d6, 250 ~Hz) ~s 1.10 and 1.23 (2d, 2X3H, J~6.3Hz, 2XCH3-6~), 1.54 ~nd 1.87 (2m, 2X2H, 2X2H-2'), 2.25 (~, 6H, 2yoor-~3)~ 2.46 (m, 2~, 2XCH~cHo)~ 2.86 (2 overl~rp~ n~ dd, 2H, CHeCHO), 3.73 (m, 2H, 2XH-3'), 3.89 (q, lH, J~6.5Hz, H-5'), 4.28 (q, lH, J~6.3Hz, H-5'), 4.38 (broad ~, lH, H-4'), 4.52 (2X unre~olved dd, 2H, 2XH-3), 4.54 (broad ~, lH, H-4'), SUBSTIT~ITE StlEET
WO g4/11382 PCI'/CA93/00463 ~ 214~4g 5.11 ~m, 2H~ 2XOH) ~ 5.31 nd 5.38 (2 broad s, 2H, 2XH-1'), 5.49 ~m, 2H~
2XOH), 5.86 and 5.94 (2s, 2H, 2XH-1), 8.32 and 9.58 (2m, 8H, Ar-H).
8t-p 5s (1'8,18,3~) d (1'8,1R,38)-S,8-d$o~o-3 -- Lo 1-(2',6'-S ~~ 3~ a-~a~ L-l~ oc~ro n The titled r ,_ ~ w r~ obta~ned following CAN oY~-tisn of the product- obtain~d from t-p 1 herein.
PMR (CDCL3, 250 ~Hz) ~s 1.10 nd 1.22 (2d, 2X3H, J~6.5Hz, 2XCH3-6'), 1.93 (largs m, 2X2H, 2X2H-2'), 1.92, 1.96, 2.11 _nd 2.12 (4s, 4X3H, 4XOAc), 2.23 and 2.25 (2~, 2X3H, 2XCOCH3), 2.39 (2 overlarpin~ dd, 2H, 2XCHaCHO), 2.80 (2 overlappin~ dd, 2H, 2XCHeCHO), 4.10 (g, lH, J=6.5Hz, H-5'), 4.40 (m, 3H, 2XH-3 and H-5'), 5.10 (m, 4H, 2XH-3', and 2XH-4'), 5.44 and 5.50 (2 broad s, 2H, 2XH-1'), 5.76 and 5.94 (2s, 2H, 2XH-1), lS 6.57 (2X2d, 4H, Ar-H).
8tap 6s (1'~,18,3R) ~d (1'8,1R,38)-m-thrl-(1-~ 2',6'-~i~- LGa~ 3~ ~4~ --5~10--dioso--3,4,5,10--t-tr L~d.. ~'h~-[2,3-c~ ~ 3-yl) ~L - (BC~-2118) The titled c~ w-re obtained Ln S1~ yield by follow$ng the .ocad~rQ d-scribed Ln t~p 2, - le 5, and u-ing the products from tep 5 hQrein. A~ -Li--t~nn by flash cl.~ -LG~.a~h~ (Toluone:~thyl ac~t_t~ 8:2). Final purifi~ti~n by preparativ~ TLC (-ame solvent 2S cond~tions).
PMR (CDC13, 250 MHz) ~s 1.17 and 1.33 (2d, 2Y3H, J~6.6Hz, 2YCH3-6'), 1.88 ~m, 2H, 2XH-2'), 1.96 (s, 2X3H, 2XOAc), 2.16 (l_rge m, 2H, 2XH-2'), 2.18 and 2.19 (2s, 2X3H, 2XOAc), 2.32 and 2.34 (2s, 2X3H, 2XCOCH3), 2.54 (2X overlArping dd, 2H, 2XC~ CHO), 3.07 (2X over~app~ng dd, 2H, 2XCHeCHO), 4.17 (q, lH, J-6.7Hz, H-5'), 4.51 (2X aoverl~rp~n7 dd, 2H, 2X
H-3), 4.63 (q, lH, J~6.4Hz, H-5'), 5.19 (m~ 4H, 2XH-3'~ and 2XH-4'), S.SS and 5.67 (2 broad s, 2H, 2XH-1'), 6.00 and 6.18 (2~, 2H, 2XH-1), 7.76 and 8.10 ~2m, 8H, Ar-H).
SUBSTITUTE SHEE~T
65 P ~ Prr~rl ~ - slr~
CH~
0~5 i-CH~ O O HO O O
CH~ + ~CH, I ~ ~CH~
O O
CH~
O--S i-CH, o O HO O O
[~ CH~ + ~ 2 [~CH~
O O O O
H~C~ H~C~g PNBON~H PNBON`H
+}~C-10 HO O O
~CH, O O
,J 8CH~7 H,C~J
COCF~
+ H~y C-10 ~io~
S ~t-p ls l~-thrl-(6 ~ d~_a~ S ~10 ~ o-3 ~ 4 ~ S ~10-t-tr~h~d~
[2,3-c~ ~ 3-rl) ~-ton- d ~-thrl-(9 h~a~ S,10-dioso-3,4,5,10-t-trah~ 2,3-c~ 3-rl) ~-ton-(JC~-20C2) ~h~ titlsd c ~_ ~ were oht~i~s~ by following the ~..cv . described in tQp 2 ~ nd u~ing l-acetoxybut~ - ~nd 3-~oetoi-c-~ ~ -- 5,8-dion~.
PMR (CDC13, 250 MHz) ~: 2.33 (2~, 2X3H, COCF3), 2.56 (m, 2H, CHaCHO), 3.00 (m, 2H, CH~CHO), 4.07 (dd, 2H, J~lO.lHz ~nd 3.9Hz, H-3), 4.60 (m, 2H, H-l), 4.95 (m, 2H, H-l), 7.26 (m, 2H, Ar-H), 7.62 (m, 2X2H, Ar-H), 11.84 and 11.96 ~2~, 2H, OH-5 and OH-8).
~t-p 2s (1'~,18,3R)-m thrl-(6 and S ~d~a~ 1-(2',3',6'-tr~ 3'-tr~f~ o-4 -0-p-~t.J~- ~orl-L-l~
S,10-dio~o-3,4,5,10-t-trzh~dro-1~ 2,3-cl ~ ~ 3~
yl) ~-ton~
sue~ ~ r~ A j~ ET
WO 94/11382 PCr/CA93/00463 ` 214~48 To a mixture of (l~S,lS,3R) glyco~ide from ztep 1, example 5, (200 mg, 0.335 mmol) in dry tolu-ne (2.5 ml) undQr argon aL -rl'~.e, wa_ added dropwi~s the l-trimethyl-ilyloxy-1,3-but~ . After stirring for 18 hour~ at room t ~ ~L2, the ~olv-nt was ~ .~d in vacuo. The re~idue wa~ dried over vacuum for 10 minutes, di-zolved in 5 ml of THF
and cooled to 0C. Add$tion of HCl lN (5 ml) gave after 30 minute~
stirring a ~ L~ cloavag~ of the ~ilyl group. ~xtraction~ were done with CH2C12 (3x30 ml) and the combined organic lay-r~ were dried with Na2S04 and then _~p~ated. The L~ wa- di--olved with 10 ml of dry CH2C12, at room ~ _- a~u._ and under argon, ~nd tr-ated with 200 mg of PCC. After 30 minute- tirring, the reaction mixture wa~ d.~ed on SiO2 and fla~h cl.~. LG~ had (Toluen~:~thyl acetatet 8:2) to give 162 mg (72% yield) of a non ~e~-rable titl~d regioi~( ~r~ (1:1).
PMR (CDC13, 250 MHz) ~: 1.36 and 1.37 (2d, 2X3H, J-6.4Hz, CH3-6'), 2.14 (2X m, 2X2H, H-2'), 2.34 and 2.35 (2s, 2X3H, COCH3), 2.S7 (dd, 2XlH, J~20.1Hz and 11.8Hz, CHaCHO), 3.09 (dd, 2XlH, J-19.9Hz and 4.1Hz, CHeCHO), 4.53 (2X ~ Dlv d dd, 2XlH, H-3), 4.61 (2Xm, 2XlH, H-3'), 4.77 (2X ~n~ VQd q, 2XlH, H-S'), S.45 (broad ~, 2XlH, H-4'), S.63 (broad s, 2XH, H-l'), 6.19 and 6.21 (28, 2H, H-l), 6.46 (broad B~ 2H, NHCOCF3), 7.32 (m, 2H, Ar-H), 7.67 (m, 2X2H, Ar-H), 8.32 ~m, 2X2H, Ar-H), 11.89 and 11.90 (2~, 2H, OH-S and OH-8).
8t-p 3s (1'~,18,3R) _ thrl-(6 ~d ~ k~d.~,~ 2',3',6'-tr~ 3'-2S tr~ f ~ d,o~ -S,10-- 3,4,5,10-t-tr~ 2,3-cl .,. 3-~1-k-ton-(~C~-2078) Hydroly~i~ of the gl~c~ -~ from tep 2 herein with catalytic u- h~Yida in Lh-n~l y$-lded th~ titled ~ _ -a. Fla~h cl~. -~oJ-aphy (Tol -sFthyl r-~L~ ~s~~~L~ne; 6s4:2) of the crude gave 83% yield of pure titled .~ mixture ( 121 ) .
PMR (CDC13, 250 HHz) ~: 1.40 and 1.42 (2Xd, 2X3H, J-6.4Hz, CH3-6'), 1.91 (m, 2X2H, H-2'), 2.31 ~nd 2.32 (2X~, 2X3H, COCH3), 2.S6 (dd, 2XlH, J~19.7Hz nd 11.4Hz, CHaCHO), 3.08 (dd, 2H, J~19.9Hz and 4.2Hz, CHeCHO), 3.67 (broad d, 2H, H-4'), 4.33 (m, 2H, H-3'), 4.53 (m, 4H, H-3 and H-5'), 5.44 and 5.45 (2s, 2H, H-l'), 6.13 and 6.15 (2S, 2H, H-l), 6.74 (broad d, 2H, NHCOCF3), 7.30 (m, 2H, Ar-H), 7.65 (m, 2X2H, Ar-H), 11.89 and 11.91 (2~, 2H, OH-5 and OH-8).
~ U E~ h ~
WO 94/11382 PCI'/CA93/00463 %
67: 3-(3~ h;~Qlyl) - 5~10 - dio~o-1,3,4,S,10-p-nta~d.o -~ 2,3-c]-prran (~CH) OCH, O
oc~,i, o ~
HCH
rx~
3 L~X~8r 8t-p 1s 3 -~Lo 5,8 'i~-~-3,4,S,8-t-trahrdro-1~ t -o-12,3-cl-prr n CAN oxidation of 5,8-Dimethoxy-3-acetoi~ochroman yieldQd the tltled 10 = _ .
lH NMR (CDC13, 250 HHz, Bruk~r) ~: 2.23 (3H, , COCH3), 2.36 (lH, dd tr, J-17.8Hz, 11.0~z, 2.9Hz, 4-HCHa), 2.75 (lH, d tr, J~17.8Hz, 2.9Hz, 4-HCH~), 3.96 (lH, dd, J-llHz, 5.3Hz, 3-CH), 4.41 (lH, d tr, J~17.8Hz, 3.5Hz, l-HCHa), 4.72 (lH, d tr, J~17.5Hz, lHz, l-HCH~), 6.71 (2H, m, 15 ArH).
~t-p 2: 3 -- ~o S,10-dio~o-3,4,5,10-t-trahydrD-l~ -~r~t~- 12,3-cl-prr~n The titled _ __ ' wa- ~ht~ i n~ by following the ~,ocodu o described in tep 2, _ _le S, and using the product from step 1 herein.
lH NNRs (CDC13, 250 MHz, Bruker) ~: 2.30 (3H, B, COCH3), 2.56 (lH, dd tr, J-18Hz, 11.2Hz, 2.9Hz, 4-HCHa), 3.01 (lH, d, J~18.0Hz, 4-HCHe), 4.0S
(lH, dd, J-11.2Hz, 3.8Hz, 3-CH), 4.60 (lH, d tr, J=17.8Hz, 4.1Hz, 1-25 HCHa), 4.9S (lH, d m, J~17.8Hz, l-HCHe), 7.73 (2H, m, 7, 8-ArH), 8.08 ~2H, m, ArH).
SUE~` s ~ c ''~-5'~
W O 94/11382 PC~r/CA93/00463 ~ 2146~48 st-p 3: 3 ~ 5,10-dio~o-3,4,5,10-t-~rahrdro-1~ ; -~2,3-cl-prr~
The titled c _~nd w~ obtain~d by following the ~LIure described in ~tep 1, example 7, and uzing the product from ~tep 2 h~r-$n.
lH NMR (CDCl3, 250 MHz, Bruker) ~s 2.57 (lH, dd tr, J~18.8Hz, 11.2Hz, 3Hz, 4-HCHa), 3.02 (lH, d m, J-18.8Hz, 4-HCH~), 4.21 (lH, d, J~12.9Hz, CHBr), 4.30 (lH, d, J~12.9Hz, CHBr), 4.34 (lH, dd, J~11.2Hz, 4.7Hz, 3-CH), 4.58 (lH, d tr, J-18.0Hz, 3.0Hz, l-HCHa), 4.90 (lH, d m, J-18.0Hz, l-HCHe), 7.70 (2H, m, 7, 8-ArH), 8.04 (2H, m, 6, 9-ArH).
8t-p ~s 3~(3~ rl)-s~lo-dio~o-l~3~5~lo ~ -~rdro-~aphtho-[2,3-ol-prr n B.l Lhyl keton- from st-p 3 h~r~in (270 mg, 0.81 mmol) waz stirred with thiourea (60 mg, 0.88 mmol) inj ether (80 ml) and methylenQ chloride (10 ml) at room t - aLu-e for 4 hours. Three ~ e~ of molec~ r ~ieve- werQ u~ed to take up water. Solvent wa~ ated to give a white olid. The crude product wa~ wa~hed with chloroform/ether (8:1) fir~t, then basifi~d with pot~ c~rhon-te. It was extracted with chlo.ofo. . The organic pha-e wa~ ~GL~ted to giv- a crude product which was chromatG~.~hsd to give desired titled product.
.
dec. 130C.
lH NMR (CDC13, 250 MHz, Bruker), 2.80 (lH, m, 4-HCH~), 3.09 (lH, br d, J ~ 18.2 Hz, 4-HCH,), 4.58 (lH, dd, J - 10.0 Hz, 3.S Hz, 3-CH), 4.68 (lH, d tr, J ~ 18.8, 2.9 Hz, l-HCH~), 4.95 (lH, dd, J ~ 18.8 Hz, 2.3 Hz, l-HCHe), 5.54 (lH, br ~, NH), 6.54 (lH, s, thia-H), 7.73 (lH, m, ArH), 8.08 (lH, m, ArH).
S~ w 5~ r.T
W O 94/11382 2146 ~ ~ PCT/CA93/0n463 r _1~ 68s C~cl~c a ~n- ~ub~t~ 4 i - - d-ri~ti~-BOC
COS~H COOH
OMk o BOC OM~ o 3 ~ +
o~s ~
BOC
1~
o o o o o ~ -~1 ~CI soc +~ +I,3~
so~2~s sc~2~s ~t-p ls N-~OC-~ -_c~ic ac$d The titl-d _ _ ' wa- obtained following standard conditions H NMR (CDC13) ~ 4 02 (m, 2H, CH2N), 2 73 (m, 2H, CH2N), 2 50 (m, lH, ~noou)~ 1 91 (m, 2H, S~2CHCOOH), 1 64 (m, 2H, ~2CHCOOH) ~t-p 2s N-80C-~-pip~r~
To a ~olution of the acid from ~tep 1 (0 11 g, 0 48 mmol) in dry THF
(4 8 ml), under argon, at 0C, wac added dropwi-~ BH3-THF 1 0 M/THF
(0 72 ml, 1 5 q) Th~ ~olution wa~ stirred at 0C for 30 minute~ and at room t~ --a0~re for 15 hours MQthanol (10 ml) wa~ then carefully SUBSTIT~JTE SHEEI
WO 94/11382 2 14 ~ 5 ~ ~ PCI/CA93/00463 added to destroy the exc~s BH3 and the ~olv~nt~ were evaporated. The residue wa~ poured in CH2C12/-at. aq. NaHCO3 and the pha~e~ were separated. The ~ layer wao extracted with CH2C12 (2x) and the combined organic ~xtract~ were dried over MgSO4. The ~olids were filtered and the olv-nt ~oLated to give the tltled alcohol as a - clear oil (0.092 g, 89~).
lH NMR (CDC13): ~ 4.09 (m, 2H, CH2N), 3.44 (d, 2H, ~20H), 2.67 ~m, 2H, CH2N), 2.08 (bs, lH, OH), 1.73-1.52 (m, 2H, S~2-CH2N)~ 1-48 (8~ 9H, BOC), 1.22-1.01 (m, 2H, S~2-CH2N).
~t-p 3s 1-O-[N-B4C-4-pip-r~ 1]_3 ~~~t~l-S,8-dimethosr ~sochro ~n . - ~ r The titled _ ~ was obtained via DDQ in~ured coupling of the alcohol lS ~rom ~t~p 2 her-in with 3-ac~to-5,8-dimethoxy i-ochroman. Purifi~ti~n:
flash c~ Lo~a~hy (silica gel, 2:1 Hex/EtOAc).
lH NMR (CDC13): ~ 6.76 (d, lH, J ~ 8.8, ArH), 6.70 (d, lH, J - 8.8, ArH), 5.77 (~, lH, H-1~, 4.59 (dd, lH, J - 4.2, 12.2, H-3), 4.08 (m, 2H, CH2N), 3.78 (8, 3H, ArOMe), 3.77 (8, 3H, ArOMe), 3.72 (dd, lH, J - 6.4, 9.7, H-l'), 3.57 (dd, lH, J - 6.4, 9.7, H-l'), 3.04 (dd, lH, J e 4.2, 17.6, H-4), 2.70 (m, 2H, CH2N), 2.53 (dd, lH, J - 12.2, 17.6, H-4), 2.33 (8, 3H, COCH3), 1.76 (m, 3H, ~2~-CH20), 1.21 (m, 2H, ~2CHCH20).
8t-p 4: ~ thrl-~1-0-[2'-pip~r;~; - Lhanoll-S,10 d;~-o-3,4,S,10-t-tr~h~d.~ 1 - [2,3-cl p,.~n 3-~ t h~d.~chlor~d- (~CH-2069) The titled c ~ was obtained from the precur~or from step 3 herein a~ per previou~ly describQd p a~
lH NMR (DMSO): ~ 8.05-7.80 (m, 4H, ArH), 5.69 (8, lH, H-l), 4.48 (m, lH, H-3), 3.88 (m, 4H, CH2N and NH2Cl), 3.74 (m, lH, H-l'), 3.60 (m, lH, H-1'), 3.25 (m, lH, H-4+H2O), 2.82 (m~ 3H, CH2N and H-4), 2.31 (~, 3H, COCH3), 2.01-1.70 (m, 3H, S~2~-CH2O), 1.57-1.38 (m, 2H, ~2CHCH20).
_1- 69 ~ ub~t~t~ ~ ; - d-r~v-t~e SUBSTITUTE SHEET
WO 94/11382 PCI`/CA93/00463 ~14~4~ --~", l~O~ OH . , ~f~ OS i~BI~ 2 HO ~ ~ N3 NHlFA NHl~A
O O O O
OS hB~4 1 4 ~
O OH NHIFA O O~ NHl~A
+1,3~ net 0 ~
~ NHlFA
+1~ " . ' O O
f~
o O~ NHIFA
~NHl~A
+1,3 J' , BC~2102 ~t--p 1~ (2R,~8,5S,68)-2-t-rt-butrld;l thrlsi l~lo,.
tr~fl ~ L~d~ S krl.~ C Lhrl-t-tr-l ~1.~,.
S
To a oolution of the ia-~tal ~0 51 g, 2 08 ~ol) $n dry CH2C12 (20 ml), under argon, at room ~ Lure, were added ~ls~ iv~ly ~ ir3-701e (0 28 g, 2 eg) and t-Bu~5e2S~Cl (0 34 g, 1 1 eg) The ~olution was stirred at room t~ ~ aL~r~ for 15 hour~ after which it was poured in 10 ~at aq NaHCO3 The pha-e~ were ~eparated and the ~-, 9: ~! layer was extracted with CH2C12 (2x) The combined organic xtracts w~re dried over MgS04, the ~olid- were filt~red and the solvent _~.~Grat~d to give O 72 g (97~ ) of the t~tled silyloxy-sugar as a white solid lH N~SR (CDC13) ~ 6 82 (bd, lH, NH), 4 78 (dd, lH, J Y 2 2, 9 2, H--1), 15 4 09 ~m, lH, H-3), 3 62 ~g, lH, J ~ 6 6, H-5), 3 48 ~d, lH, J ~ 2 6, H-4), 2 44 (bB, lH, OH), 2 08 (dd, lH, J - 5 0, 13 0, H-2), 1 55 (ddd, lH, J ~ 9 2, 13 0, 13 0, H--2), 1 29 (d, 3H, J -- 6 6, H--6), 0 89 (s, 9H, t--Bu) , 0 12 ~t, 3H, S~B) , 0.11 ~E~, 3H, S~e) SUBSTITUTE SHEET
W O 94/11382 PC~r/CA93/00463 2~45~
8t--p 2 (2R,48,SR,68)-2-t--rt-butrld~-thyl~ilrlosr-4-tr~fl ~ c~u~$do 5 ~~j~o 6 thyl-t-tr-h~d~p,..~
S To a ~olution of th~ alcohol (O 40 g, 1 11 mmol) in dry CH2Cl2 (11 1 ml), under argon, at -30Cjw-re ~dded ~ c~ vely pyridin~ ~0 45 ml, 5 ¢q) and Tf20 (0 37 ml, 2 eg) and the solution wa~ tirr~d at -10C for 1 hour It was then poured in at aq NaHCO3 and the pha~es were ~ep~rated Th~ aqu~ou~ lay~r wa- extract~d with CH2Cl2 (2x) and the combined organic extract~ wQre driQd ovQr MgSO4 The olids were filter~d and th~ olvent- were ~oL~L~d to d,y ~-~ Th~ r-d oil obtained wa~ di~solv~d in dry DMF (11 1 ml), under ~rgon, at room t _ aLur~, and NaN3 (0 36 g, 5 q) wa~ added Th- ~ lon was ~tirred for 5 hours after which it was poured in FtOAc Thi~ organic pha~ wa~ w ~-l with water (3x) and brine It was then dried over MgS04, thQ ~olid~ wer~ f$1t-red and the olvent ~ B ~ to give the titled azido-tr~fluoroacetamide as a cl~ar oil (0 27 g, 68~) 1H NMR (CDC13)s ~ 6 44 (bd, lH, J ~ 8 6, NH), 4 82 (dd, lH, J - 2 1, 8 8, H-1), 4 09 (ddd, lH, J - 4 7, 9 7, 12 8, H-3), 3 41 (dq, lH, J -6 1, 9 2, H-5), 2 97 (dd, lH, J - 9 7, 9 7, H-4), 2 21 (ddd, lH, J ~
2 1, 4 7, 12 8, H-2), 1 67 (ddd, lH, J - 8 8, 12 8, 12 8, H-2), 1 39 (d, 3H, J ~ 6 1, H-6), 0 89 (8, 9H, tBu), 0 12 (8, 3H, SLMe), 0 10 (~, 3H, SLMe ) .
2S 8t-p 3s (2R,4~,SR,~8)-2-t-rt-butrld$m-thrl-il~losr-4,5-bi--trif~ ~ 6 ~Lhrl-t-tr-l~d.~
The azLdo ~-rch~ride from step 2 was reduced a~ per ~tandard conti~itOn~ PurLf~c-t~ flash c}~. tG~a~}y (0Ll$ca g~l, 85:15 30 T~ tOAC) 1H NMR ~CDCl3) ~ 7 85 (bd, lH, J - 9 4, NH), 7 48 (bd, lH, J - 9 7, NH), 4 84 (d, lH, J ~ 7 8, H-l), 4 38 (m, lH, H-3), 3 96 (m, lH, H-4), 3 56 (dq, lH, J ~ 6 1, 9 6, H-5), 2 19 (m, lH, H-2), 1 78 (m, lH, H-2), 1 29 (d, 3H, J ~ 6 1, H-6), 0 89 (~, 9H, t-Bu), 0 12 (8, 3H, SLMe), 0 11 3~ (8, 3H, SLMe) -tep gs (lR,3s8,1'8) d (18,3~,1'8)-~ thrl-(1-~2',3',4',6'-t L -~c 1 3',~'-b$~-trif1 r .- ~a-$do-L--5, 10-dioso-3, 4, 5 ,10-SUBSTITUTE SHEET
W O 94/11382 P ~ /CA93/00463 2~6~48 ~
t-tr-h~ r~ Z,3-c~ ~ 3-~ ~ton- (~CH-210 ~nd ~C8-2102) To a solution of the hyd ~y~inone (72 mg, 0.33 mmole) and di-S trifluoroacetamido ugar from ~t-p 3 ~-L-i~ (162 mg, 1.1 q) in 6.5 mLof a 9:1 mixture of ~nhydrous CH2Cl2/Ac-ton~, under argon, at -30 C, w-re add~d activ-t-d 4A M.S. (200 mg) and THSOTf (94 ~L). The solution wa~ ~t~rrod at -30 C for 4 hr and 5~ N~XCO3 (5mL) wa~ added.
The ~irha~iC olution wa~ tirred for 15 min while the t~ ~- aLu ~ wa~
al 1~J~ to go back to r.t. It was then filtered through CQlite and pour~d in wat-r. Th- pha-e~ were ~eparatod nd the r,~ q layer was ~xtracted with CH2Cl2 ~2x). The combined organic extract- were dried ov~r MgS04, Th~ ~olid~ wer~ filt-red nd the olvant- ~ap~a~ed. The pal~ brown olid obtainod wa- di-~olved in dry toluen~ ~6.5 mL) and 1-lS acetoxybut~ 0.19 mL, 5 eq) waB added. The ~olution was ~tirred ~t r.t. , under argon for 15 hr. Silica gel wa- added and air wan bubbled through the olution. Thi~ p~n-ion was th-n placQd on top of a ilica gel column and the column wa~ luted with ~
~ oir). When th~ h~ r~ waB all gone , it wa~ r~pl~ce~ with 2:1 h~-~r~/othyl ~c-tate and ~ t~re of j~ a wa- coll~L~d. Thi~
mixture wa~ further purified by ChL~ ~LG~ a~l,Y ~10~ LQns/tolu~ne) to give 58 mg ~30%) of the titlQd ~parat~d ~
The fa-ter running fraction had: 33 mg, m.p.: 180-195 C d~c.
lH NMR ~6~_ ~ d6) s d 8.47 ~d, lH, J- 9.1, NH), 8.36 ~d, lH, J~ 9.4, NH), 8.11-8.04 (m, ZH, ArH), 7.92-7.85 (m, 2H, ArH), 6.03 (~, lH, H-1), 5.65 (~, lH, H-l'), 4.68 (dd, lH, J~ 4.1, 11.6, H-3), 4.58-4.36 (m~ 2H, H-3' and H-4'), 3.85 (g, lH, J~ 10.1, H-5'), 3.02 (dd, lH, J-4.1, 19.6, H-4), 2.51 ~dd, lH, J- 11.6, 19.6, H-4), 2.32 (~, 3H, coMe)r 2.28-2.09 (m, 2H, H-2'), 1.28 (d, 3H, J~ 6.3, H-6').
~h~ ~low2r running fraction had: 25 mg, m.p.: 143-153 dQc.
1H NMR ~CDCl3) : d 8.55 ~d, lH, J~ 9.2, NH), 8.46 ~d, lH, J- 9.1, NH), 8.13-8.07 ~m, 2H, ArH), 7.95-7.88 ~m, 2H, ArH), 6.17 ~8~ lH, H-1), 5.63 ~t, lH, J- 2.5, H-1'), 4.71 ~dd, lH, J~ 4.3, 11.6, H-3), 4.61-4.34 (m, 2H, H-~' ~nd H-4'), 3.86 (q, lH, J~ 10.2, H-S'), 2.99 (dd, lH, J~ 4.3, 19.7, H-4), 2.58 ~dd, lH, J- 11.6, 19.7, H-4), 2.32 (n, 3H, COMe), 2.28-2.13 (m, 2H, H-2'), 1.37 (d, 3H, J~ 6.2, H-6').
_1~ 70s 4'-;~c'~ ub~t~tut~d ~ tc, i d-rL -ti~
WO 94/11382 PCI~/CA93/00463 ~X~ ~ ositsuM
Br N~ N~
O O O O
SitE~u~
O OH N}I~P~ q~
,3 1- O~Hr +~
O O
O O~
-+1~
Bt ~2047 8t-p ls (2~,48,58,~ 2-(2' - ~ ~ 2' ~ a~ S ~ 6 -thyl-tetr h~d._ ~.. n To a colution of th~ triflat~ (1.06 g, 2.80 mmol) in a 1:1 mixture of CH2C12/tol --- (lS ml), under argon, at room t- ~~~a~u.a, wa~ added nBu4NBr (1.34 g, 1.5 q) and the ~olution wa~ ~tirred for 3 hours. It was then poured in ~at. aq. NaHCO3 and the pha~Q~ w~re eparated. The aqueous layer wa- xtracted wLth CH2C12 (2x) and thQ combined organic ~xtract~ were dried over MgSO4. ThQ ~olid~ wQre filt~red and the ~olvent~ -~a~G ~Led to g$ve a crude oil that wa~ pur~f$ed by flaRh ch,. -Lo~ ~hy (~ ca gel, 85:15 r ~ tOAc). The titled bL~ ~ azide lS was obtained in 66% yield (0.57 g).
H NMR (CDC13): ~ 5.34 (d, lH, J - 3.4, H-l), 4.27 (~, lH, H-4), 4.02 (g, lH, J ~ 6.2, H-5), 3.96 (m, lH, H-3), 3.20 (~, 3H, OMe), 2.23 (ddd, lH, J - 3.4, 12.5, 12.5, H-2), 1.74 (dd, lH, J ~ 4.26, 12.5, H-2), 1.40 Sl~B~ ~ L~ T
-W O 94/11382 PC~r/cA93/00463 21~6~48 ~
(~, 3H, , i Lhyl), 1 35 (8, 3H, , i Lhyl), 1 25 (d, 3H, J ~ 6 2, H-6) 8t-p 2 (2R,48,S8,6S)-2-t-rt-~utrl~i hrls~lrlca~ ^ 5 ~. -S 6-~-thyl-t--tr~d.~r, ~
To a ~olution of the bromo-azide from st~p 1 (0 57 g, 1 84 mmol) in dry CH2Cl2 (9 0 ml), under argon, at 0C, wa- added lowly CF3COOH (7 ~l, 0 05 eg) and th~ ~olution was ~tirred for 60 minut-s Th~ solvent and reagent w~re then _~G~aLed to dL~ ~rc and the crude ~ etal wa~
di~solved in a dry mixture (15 1) of CH2C12/DNF (9 2 ml) T i~-70le (0 25 g, 2 eq) was then added followed by t-BuMe2SiCl (0 31 g, 1 1 eg) The solution was ~t$rr~d at room t - ature for 15 hours after which it was poured in at aq NaHCO3 The phases were s~paratQd, the aqueous layer was extract~d w$th CH2C12 ~2x) and the combined organic extract~
WQre dr~ed over MgS04 Th~ solid- were filtcred and th~ ~olvent ~pG ~Lod to g~ve the titled T8DMS protected b,~ - azide ~0 30 g, 46~) as a clear oil 1H NMR ~CDCl3) ~ 4 80 ~dd, lH, J ~ 2 5, 8 7, H-1), 4 15 ~dd, lH, J ~
1 2, 3 3, H-4), 3 57 ~ddd, lH, J ~ 3 3, 4 4, 11 8, H-3), 3 44 (dq, lH, J
= 1 2, 6 1, H-5), 2 11-1 88 (m, 2H, H-2), 1 33 (d, 3H, J ~ 6 1, H-6), 0 90 (~, 9H, t-Bu), 0 14 ~s, 3H, S$Me), 0 11 (s, 3H, SiMe) ~t-p 3s (~ B,5~,68)-2-t-rt-butrl~; hyl~lrlo~ -tr~ ~~at-~$ao 5 ~.~ - 6 hyl-t-tr L~d--~
To a ~olu~;~n of the a~ide from tep 2 herein (0 30 g, 0 84 mmol) in a 19 1 mixture of THF/H2O ~8 4 ml) was added Ph3P (0 33 g, 1 5 og) and the olution wa~ tod at 50C for 3 hour~ It wa~ then ~ou ~d in at aq NaHCO3 and the ~ pha~ wa- extracted with CH2Cl2 ~3x) The combin~d organ~c ~xtract- were dried over MgS04 The ol~d- were filt-red and th~ olvent _~.~4 ~Led to drynes~ to giv~ a crud~ amine th~t wa~ dis~olved in dry CH2Cl2 ~8 4 ml) To thi- solution, under ~rgon, at -30C, wQre added .~ccaesively dry pyridine ~0 14 ml, 2 eq) and TFA2O ~0 13 ml, 1 1 eg) The solution wa~ ~tirred for 90 minute~ at -30C and was then poured in ~at aq NaHCO3 The pha~es were eparatQd, the r ~ n layer wa~ extracted with CH2Cl2 ~2x) and the combined organic extracts were dried over MgS04 The ~olid~ were SU~ r~T
W O 94/11382 21465A~ PC~r/CA93/00463 filt~red and th~ ~olv~nt wa- ~G ~tcd to givc the titled crude bromo-trifluoroacetamidQ in 72~ yi~ld (0.26 g).
H NMR (CDC13): ~ 6.67 (bd, lH, J - 7.3, NH), 4.84 (dd, lH, J - 5.4, 6.5, H-l), 4.28-4.17 (m, 2H, H-3 and H-4), 3.58 (g, lH, J - 6.1, H-5), 1.89-1.83 (m, 2H, H-2), 1.32 ~d, 3H, J - 6.1, H-6), 0.88 (s, 9H, t-Bu), 0.12 (8, 3H, SiMe), 0.10 (s~ 3H, SiMe).
8t~p ~s (1~,3~,1'~)--~--th~l--(1--t2',3',~',6'--t--t~ 3--tr~ t-~ido-~ ]-5,10-dioso-3,4,5,10-t-traL~d,~ ~p~t~ [2, 3-cl L~ ~-~ 3-rl) ~-tone The t$tled _ ~_ ' wa~ obtained a~ per previou~ ~,occdu~ from the ~ugar of tep 3 and the isochl~ -n~ . Purification: fla~h chromatG~ hy (-ilica gel, toluene/acetone 95:5). The two i~ s are ~eparable by cl~ -Lo~.aph~.
H NMR (CDC13): ~ 8.15-8.07 (m, 2H, ArH), 7.81 -7.76 (m, 2H, ArH), 6.46 (bd, lH, J - 8.4, NH), 6.01 (8, lH, H-l), 5.62 (d, lH, J - 3.2, H-l'), 4.54 (dd, lH, J ~ 4.0, 11.7, H-3), 4.42 (m, lH, H-3'), 4.37 (s, lH, H-4'), 4.11 (g, lH, J - 6.5, H-5'), 3.11 (dd, lH, J - 4.0, 19.7, H-4), 2.53 (dd, lH, J - 11.7, 19.7, H-4), 2.35 (s, 3H, COMe), 2.14 (td, lH, J
3.2, 12.9, H-2'), 1.91 (dd, lH, J ~ 4.5, 12.9, H-2'), 1.32 (d, 3H, J -6.5, H-6').
Th~ (lS,3R,l'S)-Methyl-(l-t2',3',4',6'-tetr~ 3'-trifluoroac~tamido-4' ~,~ - L-l~ nos~-s~lo-dioxo-3~4~5~lo-t~trahydrQn~rht ~2,3-cl py.an 3-yl) k~tone (BCH-2047) had:
H NMR (CDC13): ~ 8.15-8.08 (m, 2H, ArH), 7.82-7.74 (m, 2H, ArH), 6.50 (bd, lH, J ~ 8.5, NH), 6.18 (s, lH, H-l), 5.49 (d, lH, J ~ 3.4, H-l'), 4.58 (q, lH, J ~ 6.4, H-5'), 4.48 (dd, lH, J ~ 4.2, 11.6, H-3), 4.40 (8, lH, H-4'), 4.40 (m, lH, H-3'), 3.08 (dd, lH, J - 4.2, 19.7, H-4), 2.57 (dd, lH, J ~ 11.6, 19.7, H-4), 2.32 (s, 3H, COMe), 2.18 (td, lH, J ~
3.4, 13.0, H-2'), 1.79 (dd, lH, J ~ 4.4, 13.0, H-2'), 1.49 (d, 3H, J =
6.4, H-6').
_1- 71: Cyclic ~ in- sub~t~tuted ~ d-ri-ati-e W 0 94/11382 P ~ /CA93/00463 H 2~ ~ 6 5~ ~
[~)H
o~ o BOC o~ O
~ + ~ ~ ~
0~ 0~ O~ .
h ~BOC
O O O O
O O~ ` O O~
NH2CI ~OC
BCH 2061 BC~2060 ~t-p 1: N-~OC-3-pip-r~
S The t$tled _ __ ' obtainQd follow$ng prot-ction with BOC had:
1H NMR ~CDC13): ~ 3.90-3.65 (m, 2H), 3.48 (d, 2H, CH20H), 3.25-2.75 (m, 2H), 2.28 (b~, lH, OH), 1.86-1.54 (m, 4H), 1.25 (m, lH).
~t-p 2: l-o-IN-BoC-3-p~ - ai L~ -ll-3 ~ ,1-5,8-Ai ~ y i~ t~r- of ~- -The titled ~ wa- obtained from the ~ of t-p 1 her~in and 5,8-d~methoxy-3 .-~to~ n a~ per ~ ocLIurQ de~cribed ~rli~r.
Pur$fic~tion: fla3h ~ ap}.~ lica gel, 2:1 RsY~--/2tOAc)~
lS The ;- - ~ wsr~ not ~parable by flash cl~- -~o~Laphy.
H NNR (CDCl3)s ~ 6.75-6.65 (m, 2H, ArH), 5.74+5.73 (2~, lH, H-l), 4.60 (m, lH, H-3), 4.05-3.56 (m, 4H, H-1' and CH2N), 3.04 (dd, lH, H-4), 2.86-2.62 (m, 2H, CH2N), 2.53 (dd, lH, H-4), 2.33 (~, 3H, COCH3), 1.94-1.79 (m, 2H), 1.68 (m, lH), 1.48 (~ 9H, BOC), 1.37-1.24 (m,2 H)~
S U ~ . U 1, ~ .: ~ ï
WO 94/11382 PCI~/CA93/00463 ~ j 2146~
8t-p 3s ~ thr~ - o-1 N-BOC-3-pip ri Ai - th nol]-5,6-dioso-3,4,5,10-t-tr~hyd,. ~p~ 2,3-c] prran-3-yl) k-ton~ stur- of ~ C8-2060) The t$tled _ __-' wa~ obta~ned from thc product from ~tap 2 herein, - follow$ng previou-ly d--cr$bed ~co-` ~ 6. Pur$f$cat$on: fla~h chromatoy.a~.y (~$1$ca gel, 2:1 ~ /EtOAc). The i~om~r~ were not ~eparable by fla~h chromato~.aphy.
lH NMR (CDC13): ~ 8.12-8.03 (m, 2H, ArH), 7.78-7.67 (m, 2H, ArH), 6.72 10 (8, lH, H-l), 4.54 (m, lH, H-3), 4.10-3.55 (m, 4H, H-l' nd CH2N), 3.04 (dd, lH, H-4), 2.90-2.60 (m, 2H, CH2N), 2.51 (dd, lH, H-4), 2.30 (8, 3H, COCH3), 1.97-1.72 (m, 2H), 1.61 (m, lH), 1.48 (8, 9H, BOC), 1.34-1.15 (m, 2H).
15 st-p 4: M th~1-(1-0-[3-pip-r~ ]-5,10-dioso-3,4,5,10-t-tr~hyd~ 2,3-c] pyr-n-3-yl) ~t~ -L~-~,ocLlor~d- ~alt, m$stur- of i- ~. (BCH-2061) The tLtled c ~u ' wa- obta$ned from the tr$cyclic product from ~tep 3 here$n follow$ng acid$c hydroly-$~.
lH NMR (DMSO-d6): ~ 8.23-7.84 ~m, 4H, ArH), 5.68+5.67 (2B, lH, H-l), 4.48 (m, lH, H-3), 3.83-3.57 (m, 2H, H-l'), 3.29-3.15 (m, 2H, CH2N), 2.84 (dd, lH, H-4), 2.66 (m, 2H, CH2N), 2.43 (m, lH, H-4), 2.29 (~ 3H, COCH3), 1.74-1.72 (m, 4H), 1.25 (m, lH).
-~U~ST~ ~ ~ f ~ S ~ r E T
Claims (16)
1. A compound of the formula:
or wherein X1 and X2 are independently selected from: O or S;
X3 is O or S;
X4 is selected from the group consisting of C-Q, nitrogen, and NO:
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1-16 alkyl, C1-16 alkoxy, halogen, nitro, cyano, and amino which may be unsubstituted or substituted with C1-8 alkyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1-16 hydroxime, C2-8 alkenyl, C2-8 alkynyl, amino, cyano, dimethylphosphonato, and C1-8 acetyl, a group of the formula -C(R)=R* wherein R* is O and R is selected from the groupconsisting of: hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8 cycloalkyl, C6-18 aryl, C7-18 aralkyl, fluoromethyl, C2-16 alkene, C2-16 alkyne, C6-18 thioaryl, C2-8 alkoxyalkyl, C1-8 alkoxy, hydroxy, acetoxymethyl, bromoethyl, and amino which may be unsubstitutedor substituted with C1-8 alkyl, and C1-8 acyl, a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1-8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, and C1-8 alkyl, a group of the formula -(CH2)nZ* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl, said heterocycle beingoptionally substituted with one or more halogen, hydroxy, C6-18 aryl sulfone, nitro, and amino, a group of the formula -C(OR)=O, where R is selected from the group consisting of hydrogen, C1-16 alkyl, C6-18 aryl, and C7-18 aralkyl, a group of the formula -(CH2)n C(R)=O, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C6-18 aryl, C7-18 aralkyl, amino which may be unsubstituted, mono- or di-substituted by C1-8 alkyl, acyl, a5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl, and aryl;
R7 is selected from the group consisting of: hydrogen, C1-16 alkyl, halogen, amino, hydroxy, C1-16 alkoxy, and an acyl of the formula -C(R)=O wherein R is selected from the group consisting of:
hydrogen, C1-16 alkyl, C1-16 alkoxy, C3-8 cycloalkyl;
R8 is selected from the group consisting of: hydrogen, halogen, C1-16 alkyl; andR5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C1-16 alkoxyl, C1-16 alkyl, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selected from the group consisting of: O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of:
hydrogen, hydroxyl, C1-8 acyl, and C1-4 alkyl, said heterocycle being optionallysubstituted with one or more halogen, hydroxy, cyano, C1-16 alkoxy, C1-16 alkyl,nitro, amino which may be unsubstituted or mono-or di-substituted by C1-8 alkyl,C1-8 acyl, trifluoroacyl, C2-8 alkenyl, C2-8 alkynyl, and hydroxy, R5 can also be a naturally occurring amino acid or a synthetic amino acid, mono or oligosaccharides of the formula:
wherein Y is oxygen;
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol, amino, trifluoroacetamiso, chloroethylnitrosoureido, and chloroethylureido;
R11 is selected from the group consisting of hydrogen, acylated amino, hydroxy, halogen, acetoxy, C1-16 alkoxy, and amino which may be unsubstituted or mono or di-substituted by C1-8 alkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, and trifluoroacyl,;
R12 is selected from the group consisting of: hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, C1-8 alkoxy, amino,mono- or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, C1-16 alkoxy, C2-8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4.
or wherein X1 and X2 are independently selected from: O or S;
X3 is O or S;
X4 is selected from the group consisting of C-Q, nitrogen, and NO:
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1-16 alkyl, C1-16 alkoxy, halogen, nitro, cyano, and amino which may be unsubstituted or substituted with C1-8 alkyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1-16 hydroxime, C2-8 alkenyl, C2-8 alkynyl, amino, cyano, dimethylphosphonato, and C1-8 acetyl, a group of the formula -C(R)=R* wherein R* is O and R is selected from the groupconsisting of: hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8 cycloalkyl, C6-18 aryl, C7-18 aralkyl, fluoromethyl, C2-16 alkene, C2-16 alkyne, C6-18 thioaryl, C2-8 alkoxyalkyl, C1-8 alkoxy, hydroxy, acetoxymethyl, bromoethyl, and amino which may be unsubstitutedor substituted with C1-8 alkyl, and C1-8 acyl, a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1-8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, and C1-8 alkyl, a group of the formula -(CH2)nZ* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl, said heterocycle beingoptionally substituted with one or more halogen, hydroxy, C6-18 aryl sulfone, nitro, and amino, a group of the formula -C(OR)=O, where R is selected from the group consisting of hydrogen, C1-16 alkyl, C6-18 aryl, and C7-18 aralkyl, a group of the formula -(CH2)n C(R)=O, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C6-18 aryl, C7-18 aralkyl, amino which may be unsubstituted, mono- or di-substituted by C1-8 alkyl, acyl, a5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl, and aryl;
R7 is selected from the group consisting of: hydrogen, C1-16 alkyl, halogen, amino, hydroxy, C1-16 alkoxy, and an acyl of the formula -C(R)=O wherein R is selected from the group consisting of:
hydrogen, C1-16 alkyl, C1-16 alkoxy, C3-8 cycloalkyl;
R8 is selected from the group consisting of: hydrogen, halogen, C1-16 alkyl; andR5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C1-16 alkoxyl, C1-16 alkyl, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selected from the group consisting of: O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of:
hydrogen, hydroxyl, C1-8 acyl, and C1-4 alkyl, said heterocycle being optionallysubstituted with one or more halogen, hydroxy, cyano, C1-16 alkoxy, C1-16 alkyl,nitro, amino which may be unsubstituted or mono-or di-substituted by C1-8 alkyl,C1-8 acyl, trifluoroacyl, C2-8 alkenyl, C2-8 alkynyl, and hydroxy, R5 can also be a naturally occurring amino acid or a synthetic amino acid, mono or oligosaccharides of the formula:
wherein Y is oxygen;
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol, amino, trifluoroacetamiso, chloroethylnitrosoureido, and chloroethylureido;
R11 is selected from the group consisting of hydrogen, acylated amino, hydroxy, halogen, acetoxy, C1-16 alkoxy, and amino which may be unsubstituted or mono or di-substituted by C1-8 alkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, and trifluoroacyl,;
R12 is selected from the group consisting of: hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, C1-8 alkoxy, amino,mono- or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, C1-16 alkoxy, C2-8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4.
2. A compound according to claim 1 wherein X, and X2 are both O;
X3 is selected from the group consisting of: O, or S;
X4 is CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1-4 alkoxyl, fluorine, chlorine, and amino;
Z is one of C-R6, or C-R7;
R6 is selected from the group consisting of: hydrogen, C1-4 alkyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of:
hydrogen, C1-8 alkyl, C2-8 alkoxyalkyl, C2-12 acyloxyalkyl, and amino which may be unsubstituted or mono-or di-substituted with C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, C1-8 trifluroacyl, C7-12 aralkyl or C6-12 aryl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, and C1-8 alkyl, a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of: hydrogen, straight or branched C1-8 alkyl, and amino which may be unsubstituted or mono- or di-substituted with C1-8 alkyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, and NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-8alkoxy, C1-8 alkyl, amino which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, trifluoroacyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, C1-4 alkyl, and C1-4 alkoxy;
R8 is selected from the group consisting of: hydrogen, halogen, hydroxy, C1-8 alkoxy;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxyl, C1-8 alkoxy, amino, mono or dimethylated amino, C1-8 alkoxy, and benzoate, and a mono or oligosaccharide selected from the group consisting of from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, and trifluoroacetyldaunosamine, and a saccharide of formula wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, and hydroxyl;
R11 is selected from the group consisting of: hydroxyl, C1-8 alkoxy, and amino which may be unsubstituted or mono-or di-substituted with C1-8 acetoxy, or trifluoroacyl;
and R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, halogen, amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkylnitrosourea, acetoxy, and trifluoroacetoxy.
X3 is selected from the group consisting of: O, or S;
X4 is CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxyl, C1-4 alkoxyl, fluorine, chlorine, and amino;
Z is one of C-R6, or C-R7;
R6 is selected from the group consisting of: hydrogen, C1-4 alkyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of:
hydrogen, C1-8 alkyl, C2-8 alkoxyalkyl, C2-12 acyloxyalkyl, and amino which may be unsubstituted or mono-or di-substituted with C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, C1-8 trifluroacyl, C7-12 aralkyl or C6-12 aryl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, and C1-8 alkyl, a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of: hydrogen, straight or branched C1-8 alkyl, and amino which may be unsubstituted or mono- or di-substituted with C1-8 alkyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, and NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-8alkoxy, C1-8 alkyl, amino which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, trifluoroacyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, C1-4 alkyl, and C1-4 alkoxy;
R8 is selected from the group consisting of: hydrogen, halogen, hydroxy, C1-8 alkoxy;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxyl, C1-8 alkoxy, amino, mono or dimethylated amino, C1-8 alkoxy, and benzoate, and a mono or oligosaccharide selected from the group consisting of from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, and trifluoroacetyldaunosamine, and a saccharide of formula wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, and hydroxyl;
R11 is selected from the group consisting of: hydroxyl, C1-8 alkoxy, and amino which may be unsubstituted or mono-or di-substituted with C1-8 acetoxy, or trifluoroacyl;
and R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, halogen, amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkylnitrosourea, acetoxy, and trifluoroacetoxy.
3. A compound of the formula or wherein X1 and X2 are both O;
X3 is selected O;
X4 is CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxy, methoxy, amino, and fluorine;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1-4 alkyl, acyl of the formula -C(R) =O, wherein R is selected from the group consisting of: methyl, acyloxymethyl, and amino; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of: hydrogen, methyl, and ethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O,S, N, NO, and NH said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-4alkoxy, C1-4 alkyl, amino which may be unsubstituted or mono- or disubstituted by methyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: hydrogen, C1-5 alkyl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, C1-5 alkyl;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, methoxy, cyano, acetate, acetyl, and a saccharide of formula wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxyl, acetoxy, amino,trifluoroacetamido;
R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine.
X3 is selected O;
X4 is CQ;
R1, R2, R3, and Q are independently selected from the group consisting of: hydrogen, hydroxy, methoxy, amino, and fluorine;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: C1-4 alkyl, acyl of the formula -C(R) =O, wherein R is selected from the group consisting of: methyl, acyloxymethyl, and amino; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of: hydrogen, methyl, and ethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O,S, N, NO, and NH said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-4alkoxy, C1-4 alkyl, amino which may be unsubstituted or mono- or disubstituted by methyl, and hydroxy;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: hydrogen, C1-5 alkyl, a group of the formula -C(OR)=O, wherein R is selected from the group consisting of:
hydrogen, C1-5 alkyl;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, methoxy, cyano, acetate, acetyl, and a saccharide of formula wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxyl, acetoxy, amino,trifluoroacetamido;
R12 is selected from the group consisting of: hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine.
4. A compound according to claim 1, wherein X1 and X2 are both oxygen;
X3 is O;
X4 is CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: methyl, ethyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of:
methyl, fluoromethyl, and difluoromethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NH, said heterocycle being optionally substituted with one or more hydroxy, methyl, and amino;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, and cyano;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, hydroxy, bromine, chlorine, cyano, acetate, acetyl, and a saccharide of the formula:
wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: amino, hydroxy, and acetoxy;
and R12 is hydroxy, or iodine.
X3 is O;
X4 is CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: methyl, ethyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of:
methyl, fluoromethyl, and difluoromethyl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NH, said heterocycle being optionally substituted with one or more hydroxy, methyl, and amino;
R7 is selected from the group consisting of: hydrogen, fluorine, methyl, and cyano;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, hydroxy, bromine, chlorine, cyano, acetate, acetyl, and a saccharide of the formula:
wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: amino, hydroxy, and acetoxy;
and R12 is hydroxy, or iodine.
5. A compound according to claim 1 wherein:
X1 and X2 are both oxygen;
X3 is O, or S;
X4 is CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is hydrogen;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, and hydroxy.
X1 and X2 are both oxygen;
X3 is O, or S;
X4 is CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is hydrogen;
R8 is hydrogen;
R5 is selected from the group consisting of: hydrogen, and hydroxy.
6. A compound according to claim 1 wherein:
X1 and X2 are both oxygen;
X3 is O;
X4 iS CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, and an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is selected from the group consisting of: hydrogen, methyl, or fluorine;
R8 is hydrogen, hydroxyl, acetate, and acetyl;
R5 is a saccharide of the formula:
wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxy, acetoxy, amino, and trifluoroacetamido;
R12 is selected from the group consisting of: acetoxy, hydroxyl, hydrogen, and iodine.
X1 and X2 are both oxygen;
X3 is O;
X4 iS CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of: hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of: ethyl, and an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of: methyl, fluoromethyl, and difluoromethyl;
R7 is selected from the group consisting of: hydrogen, methyl, or fluorine;
R8 is hydrogen, hydroxyl, acetate, and acetyl;
R5 is a saccharide of the formula:
wherein R9 and R10 are independently selected from the group consisting of: hydrogen, fluorine, and iodine;
R11 is selected from the group consisting of: hydroxy, acetoxy, amino, and trifluoroacetamido;
R12 is selected from the group consisting of: acetoxy, hydroxyl, hydrogen, and iodine.
7. A compound according to Claim 5 wherein R5 is hydrogen.
8. A compound according to Claim 5 wherein R5 is hydroxyl.
9. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 1 and a pharmaceutical acceptable carrier.
10. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 2 and a pharmaceutical acceptable carrier.
11. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 3 and a pharmaceutical acceptable carrier.
12. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 4 and a pharmaceutical acceptable carrier.
13. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 5 and a pharmaceutical acceptable carrier.
14. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 6 and a pharmaceutical acceptable carrier.
15. A compound selected from the group consisting of (1'-S, 1'S, 3-R)-methyl-(1 -(2',3',4',6' tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2072);
1 -Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] (BCH-2167) 1 -Methoxy-5,10-dioxo-5,10-dihydro- 1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate (BCH-2051);
(1S,2'S,3S,5'S)-Methyl-(1-0-[N-BOC-Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-c] pyran-3-yl) ketone (BCH-1998);
(1S,2'S,3S,5'S)-Methyl-(1-0-[Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-c] pyran-3-yl) ketone hydrochloride (BCH-2000);
(1S,2'S,3R) and (1R, 2'S, 3S)-methyl-(1-[O-serine methyl ester]-5,10-dioxo-3,4,5,10-tetrahydronaphtaleno [2,3-C] pyran-3-yl) ketone hydrochloride. (BCH-1654);
(1S,2'S,3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone (BCH-2067); (1S,2'S,3R) and (1R, 2'S,3S)-methyl-(1-[O-prolinol]-3,4,5,12-tetrahydronaphto-[2,3-C] pyran-3-yl) ketone hydrochloride salt (BCH-1658);
(1'S, 1-R, 3-S) and (1'-S, 1-S, 3-R)-3-cyano-1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]
pyran-3-yl) (BCH-1688);
(1'-S, 1-S,3-R) and (1'-S, 1-R,3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetimido-4'-O-methane-sulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5, 10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2095);
(1'-S, 1-S,3-R)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetimido-4'-O-(2-bromo-acetyl)-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2105);
(1'-S, 1-R,3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2070);
(1-S,3-R) and (1-R, 3-S)-methyl-(1-(1-methoxy-4-oxocyclohexyloxy)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2096);
(1-R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-5, 10-dioxo-3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c] pyran(BCH-2144);
(1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2145);
(1'S, 1R, 3S)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1691);
(1'S, 1S, 3R)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-1693);
(1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1 -(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2026);
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2020);
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2021);
Trans-5,10-dioxo-acetamido-3-ethyl-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2027);
3-ethyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphto-[2,3-c] pyran (BCH-2154);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1 -(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2053);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphto-[2,3-c]-pyran (BCH-2052);
trans-5,10-dioxo-3-isopropenyl-1-methoxy-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2148);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphto-[2,3-c]-pyran (BCH-2153);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2152);
(1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyrano (BCH-2128);
(1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyranyl]-ketone (BCH-2112);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2122);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2121);
(1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman (BCH-1697);
(1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2091);
(1'S, 1R, 3S)-5,10-dioxo-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2032);
(1'S,1S,3S) and (1'S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene (BCH-2031);
(1'S, 1-R, 3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene (BCH-2163);
(1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1649);
(1'S,1S,3R) and (1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5, 10-dioxo-3,4,5, 10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1648);
(1'-S,1-R,3-S,4a-S, 10a-S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-4a, 10a-epoxy-5, 10-dioxo-3,4,5, 10-tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2141);
(1'-S,1-S,3-R,4a-R,10a-R)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-4a,10a-epoxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2149);
(1S,3R,1'S,5'S,6'S) and (1R,3S,1'S,5'S,6'S)-methyl-(1-[4'trifluoroacetamido-5'-methyltetrahydropyranyl]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-1673);
(1'S,1S,3R)-3 (oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2101);
(1'S,1R,3S)-3(oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2115);
(1's,1S,3R)-3-(trifluoroacetamidoethyl)(-5,10-dioxo-1-(2',3','-trideoxy-3',4'-dihydroxy-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2018);
(1'R,1R,3S)-3-aceto-5,10-dioxo-1-(2-deoxy-2-chloroethylnitrosoureido-D-glucopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]pyran (BCH-2038);
3-Aceto-5,10-dioxo-1-methoxy-5,19-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2129);
(1R,3S) and (1S,3R)-3-aceto-5,10-dioxo-1 (4-chloroethylnitrosoureido cyclohexyl-oxy)-3,4,5,10 tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2114);
1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2044);
1-methoxy-3-(3-N-pyrrolidinomylpropylaminocarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-yran (BCH-2166);
(3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-carboxamide (BCH-2157);
3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2003);
3-(5'-tosyloxazolyl)-5,10-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2155);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-methoxycarbonyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2076);
Methyl(1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]pyran-3-yl) formate (BCH-2043);
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]pyran-3-carboxylic acid (BCH-2161);
(1,3-trans)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2045);
(1,3-cis)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2119);
(1,3-trans)-1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2041);
(1,3-cis)-1-methoxy-3-N-anilirylcarbonyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2042);
(1'S,1R,3S)-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2150);
(1'S,1S,3R)-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2151);
(1,3-trans)-1-methoxy-3-(3'-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1616);
(1,3-trans)-1-methoxy-3-dimethoxyphosphonoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1674);
(1'S,1R,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (BCH-2077);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2082);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-1690);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-methoxy-carbonyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2081);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-thiopyran (BCH-2037);
(1'S,1R,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2127);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2090);
(1'S,1R,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)3-dimethylphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-1689);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2015);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1666);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-1667);
(1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl)- ketone (BCH-2014);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2100);
(1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2099);
(1'S,1R,3S)-methyl-(1-[2',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2023);
(1'S,1S,3R)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2022);
(1'S,1R,1S) and (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-arabino-hexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2065);
(1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'-dihydroxy-3',4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2117);
(1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'-diacetoxy-3'4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2118);
(1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-ketone (BCH-2078);
Methyl-(1-0-[2'-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, racemic, hydrochloride (BCH-2069);
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L-arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104 and BCH-2102);
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L-arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2047);
Methyl-(1-O-[N-BOC-3-piperidinemethanol]-5,6-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, mixture of isomers (BCH-2060); and Methyl-(1-O-[3-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c]
pyran-3-yl) ketone hydrochloride salt, mixture of isomers (BCH-2061).
1 -Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] (BCH-2167) 1 -Methoxy-5,10-dioxo-5,10-dihydro- 1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate (BCH-2051);
(1S,2'S,3S,5'S)-Methyl-(1-0-[N-BOC-Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-c] pyran-3-yl) ketone (BCH-1998);
(1S,2'S,3S,5'S)-Methyl-(1-0-[Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-c] pyran-3-yl) ketone hydrochloride (BCH-2000);
(1S,2'S,3R) and (1R, 2'S, 3S)-methyl-(1-[O-serine methyl ester]-5,10-dioxo-3,4,5,10-tetrahydronaphtaleno [2,3-C] pyran-3-yl) ketone hydrochloride. (BCH-1654);
(1S,2'S,3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone (BCH-2067); (1S,2'S,3R) and (1R, 2'S,3S)-methyl-(1-[O-prolinol]-3,4,5,12-tetrahydronaphto-[2,3-C] pyran-3-yl) ketone hydrochloride salt (BCH-1658);
(1'S, 1-R, 3-S) and (1'-S, 1-S, 3-R)-3-cyano-1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]
pyran-3-yl) (BCH-1688);
(1'-S, 1-S,3-R) and (1'-S, 1-R,3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetimido-4'-O-methane-sulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5, 10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2095);
(1'-S, 1-S,3-R)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetimido-4'-O-(2-bromo-acetyl)-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2105);
(1'-S, 1-R,3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2070);
(1-S,3-R) and (1-R, 3-S)-methyl-(1-(1-methoxy-4-oxocyclohexyloxy)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2096);
(1-R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-5, 10-dioxo-3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c] pyran(BCH-2144);
(1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2145);
(1'S, 1R, 3S)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1691);
(1'S, 1S, 3R)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-1693);
(1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1 -(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2026);
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2020);
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2021);
Trans-5,10-dioxo-acetamido-3-ethyl-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2027);
3-ethyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphto-[2,3-c] pyran (BCH-2154);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1 -(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2053);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphto-[2,3-c]-pyran (BCH-2052);
trans-5,10-dioxo-3-isopropenyl-1-methoxy-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2148);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphto-[2,3-c]-pyran (BCH-2153);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2152);
(1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyrano (BCH-2128);
(1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyranyl]-ketone (BCH-2112);
(1'S, 1R, 3S)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2122);
(1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2121);
(1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman (BCH-1697);
(1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2091);
(1'S, 1R, 3S)-5,10-dioxo-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2032);
(1'S,1S,3S) and (1'S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene (BCH-2031);
(1'S, 1-R, 3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene (BCH-2163);
(1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1649);
(1'S,1S,3R) and (1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5, 10-dioxo-3,4,5, 10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1648);
(1'-S,1-R,3-S,4a-S, 10a-S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-4a, 10a-epoxy-5, 10-dioxo-3,4,5, 10-tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2141);
(1'-S,1-S,3-R,4a-R,10a-R)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L-lyxohexopyranose)-4a,10a-epoxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2149);
(1S,3R,1'S,5'S,6'S) and (1R,3S,1'S,5'S,6'S)-methyl-(1-[4'trifluoroacetamido-5'-methyltetrahydropyranyl]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-1673);
(1'S,1S,3R)-3 (oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2101);
(1'S,1R,3S)-3(oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2115);
(1's,1S,3R)-3-(trifluoroacetamidoethyl)(-5,10-dioxo-1-(2',3','-trideoxy-3',4'-dihydroxy-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2018);
(1'R,1R,3S)-3-aceto-5,10-dioxo-1-(2-deoxy-2-chloroethylnitrosoureido-D-glucopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]pyran (BCH-2038);
3-Aceto-5,10-dioxo-1-methoxy-5,19-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2129);
(1R,3S) and (1S,3R)-3-aceto-5,10-dioxo-1 (4-chloroethylnitrosoureido cyclohexyl-oxy)-3,4,5,10 tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2114);
1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2044);
1-methoxy-3-(3-N-pyrrolidinomylpropylaminocarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-yran (BCH-2166);
(3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-carboxamide (BCH-2157);
3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2003);
3-(5'-tosyloxazolyl)-5,10-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2155);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-methoxycarbonyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2076);
Methyl(1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]pyran-3-yl) formate (BCH-2043);
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]pyran-3-carboxylic acid (BCH-2161);
(1,3-trans)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2045);
(1,3-cis)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2119);
(1,3-trans)-1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2041);
(1,3-cis)-1-methoxy-3-N-anilirylcarbonyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2042);
(1'S,1R,3S)-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2150);
(1'S,1S,3R)-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2151);
(1,3-trans)-1-methoxy-3-(3'-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1616);
(1,3-trans)-1-methoxy-3-dimethoxyphosphonoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1674);
(1'S,1R,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (BCH-2077);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2082);
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-1690);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-methoxy-carbonyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2081);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-thiopyran (BCH-2037);
(1'S,1R,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2127);
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2090);
(1'S,1R,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)3-dimethylphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-1689);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2015);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1666);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-1667);
(1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl)- ketone (BCH-2014);
(1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2100);
(1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2099);
(1'S,1R,3S)-methyl-(1-[2',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2023);
(1'S,1S,3R)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2022);
(1'S,1R,1S) and (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-arabino-hexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2065);
(1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'-dihydroxy-3',4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2117);
(1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'-diacetoxy-3'4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2118);
(1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-ketone (BCH-2078);
Methyl-(1-0-[2'-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, racemic, hydrochloride (BCH-2069);
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L-arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104 and BCH-2102);
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L-arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2047);
Methyl-(1-O-[N-BOC-3-piperidinemethanol]-5,6-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, mixture of isomers (BCH-2060); and Methyl-(1-O-[3-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c]
pyran-3-yl) ketone hydrochloride salt, mixture of isomers (BCH-2061).
16. A method for the treatment of tumors or cancer said method comprising the step of administering to a mammal, a therapeutically effective amount of at least onecompound according to claim 15.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97323392A | 1992-11-09 | 1992-11-09 | |
| US973,233 | 1992-11-09 | ||
| PCT/CA1993/000463 WO1994011382A1 (en) | 1992-11-09 | 1993-11-05 | Antineoplastic heteronaphthoquinones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2146548A1 true CA2146548A1 (en) | 1994-05-26 |
Family
ID=25520651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002146548A Abandoned CA2146548A1 (en) | 1992-11-09 | 1993-11-05 | Antineoplastic heteronaphthoquinones |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0659190A1 (en) |
| CN (1) | CN1094402A (en) |
| AU (1) | AU5414094A (en) |
| CA (1) | CA2146548A1 (en) |
| WO (1) | WO1994011382A1 (en) |
| ZA (1) | ZA938350B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6672794A (en) * | 1993-11-05 | 1995-05-23 | Biochem Pharma Inc. | Antineoplastic heteronaphthoquinones |
| US5883270A (en) * | 1996-02-20 | 1999-03-16 | Wisconsin Alumni Research Foundation | 4-substituted-1, 2-naphthoquinones and their use in the inhibition of neoplastic cell growth |
| US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
| CN102731464B (en) * | 2011-04-12 | 2014-07-23 | 沈阳药科大学 | Sesquiterpene lactone compound, its preparation methods and application |
| CN102911177B (en) * | 2012-11-07 | 2014-07-09 | 新乡医学院 | 7-(4-chlorphenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone and synthetic method thereof |
| CN113278026B (en) * | 2021-05-29 | 2022-05-13 | 南京中医药大学 | Lignin compound with anti-tumor activity and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62120379A (en) * | 1985-11-19 | 1987-06-01 | Hoechst Japan Kk | Fusarbin derivative and production thereof |
| AP340A (en) * | 1990-06-11 | 1994-05-13 | Iaf Biochem Int | Heterocyclic anathracyclinone and anathracycline analogs |
| NL9001834A (en) * | 1990-08-16 | 1992-03-16 | Pharmachemie Bv | NEW ANTRACYCLINE COMPOUNDS WITH ANTI-TUMOR EFFICACY, NEW INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF THESE ANTRACYCLINE COMPOUNDS, AND PREPARATIONS CONTAINING THE ACTIVE ANTRACYCLINE COMPOUNDS. |
-
1993
- 1993-11-05 EP EP93924460A patent/EP0659190A1/en not_active Withdrawn
- 1993-11-05 CA CA002146548A patent/CA2146548A1/en not_active Abandoned
- 1993-11-05 AU AU54140/94A patent/AU5414094A/en not_active Abandoned
- 1993-11-05 WO PCT/CA1993/000463 patent/WO1994011382A1/en not_active Application Discontinuation
- 1993-11-08 CN CN93112945A patent/CN1094402A/en active Pending
- 1993-11-09 ZA ZA938350A patent/ZA938350B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0659190A1 (en) | 1995-06-28 |
| ZA938350B (en) | 1994-06-21 |
| CN1094402A (en) | 1994-11-02 |
| WO1994011382A1 (en) | 1994-05-26 |
| AU5414094A (en) | 1994-06-08 |
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