CA2676512A1 - Synthesis of 1.alpha.-fluoro-25-hydroxy-16-23e-diene-26,27-bishomo-20-epi-cholecalciferol - Google Patents
Synthesis of 1.alpha.-fluoro-25-hydroxy-16-23e-diene-26,27-bishomo-20-epi-cholecalciferol Download PDFInfo
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Abstract
The invention provides a method of producing 20-methyl vitamin D3 compounds of formula (I). The method includes hydroxylation, carbonyl reduction, fluoride substitution, epoxide deoxygenation, and Wittig-type couplings.
Description
SYNTHESIS OF 1 a-FLUORO-25-HYDROXY-16-23E-DIENE-26,27-Related Applications This application claims priority to U.S. provisional patent application Ser.
No.
60/897,609, filed January 25, 2007. This application contains subject matter that is related to that disclosed in International application Ser. No.
PCT/tJS2006/032381, filed August 18, 2006, which claims the benefit of U.S. provisional patent application Ser. No. 60/709,703, filed August 18, 2005. The disclosures of the aforementioned patent applications are incorporated herein in their entireties by this reference.
Background of the Invention The importance of vitamin D (cholecalciferol) in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified as a"vitamin"
essential for the normal development of the skeleton and maintenance of calcium and phosphorous homeostasis.
Studies involving the metabolism of vitamin D3 were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin D3 [25(OH)D3] (Blunt, J.W. et al. (1968) Biochemistry 6:3317-3322) and the hormonally active form, 1a,25(OH)2D3 (Myrtle, J.F. et al. (1970) J. Biol.
Chem.
245:1190-1196; Norman, A.W. et al. (1971) Science 173:51-54; Lawson, D.E.M. et al. (1971) Nature 230:228-230; Holick, M.F. (1971) Proc. Natl. Acad. Sci. USA
68:803-804). The formulation of the concept of a vitamin D endocrine system was dependent upon the appreciation of the key role of the kidney in producing 1 a, 25(OH)2D3 in a carefully regulated fashion (Fraser, D.R. and Kodicek, E (1970) Nature 288:764-766; Wong, R.G. et al. (1972) J Clin. Invest. 51:1287-1291), and the discovery of a nuclear receptor for 1a,25(OH)2D3 (VD3R) in the intestine (Haussler, M.R. et al. (1969) Exp. Cell Res. 58:234-242; Tsai, H.C. and Norman, A.W.
(1972) J Biol. Chem. 248:5967-5975).
The operation of the vitamin D endocrine system depends on the following:
first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T.
and Postlind, H. (1991) Biochem. J. 276:427-432; Ohyama, Y and Okuda, K. (1991) J.
Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J.
Biol. Chem. 249:7529-7535; Gray, R.W. and Ghazarian, J.G. (1989) Biochem. J.
259:561-568), and in a variety of other tissues to effect the conversion of vitamin D3 into biologically active metabolites such as la, 25(OH)2D3 and 24R,25(OH)2D3;
second, on the existence of the plasma vitamin D binding protein (DBP) to effect the selective transport and delivery of these hydrophobic molecules to the various tissue components of the vitamin D endocrine system (Van Baelen, H. et al. (1988) Ann NY
Acad. Sci. 538:60-68; Cooke, N.E. and Haddad, J.G. (1989) Endocr. Rev. 10:294-307;
Bikle, D.D. et al. (1986) J. Clin. Endocrinol. Metab. 63:954-959); and third, upon the existence of stereoselective receptors in a wide variety of target tissues that interact with the agonist 1a,25(OH)2D3 to generate the requisite specific biological responses for this secosteroid hormone (Pike, J.W. (1991) Annu. Rev. Nutr. 11:189-216).
To date, there is evidence that nuclear receptors for 1a,25(OH)2D3 (VD3R) exist in more than 30 tissues and cancer cell lines (Reichel, H. and Norman, A.W. (1989) Annu.
Rev. Med. 40:71-78).
Vitamin D3 and its hormonally active forms are well-known regulators of calcium and phosphorous homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D3 as a pluripotent regulator outside its classical role in calcium/bone homeostasis.
A paracrine role for 1a,25(OH)Z D3 (structure shown below) has been suggested by the combined presence of enzymes capable of oxidizing vitamin D3 into its active forms, e.g., 25-OHD-1 a-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells. Moreover, vitamin D3 hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al.
(1989) Ann. Rev. Med. 40: 71-78).
OH
H
HO' OH
1,25(OH )2D3 Thus, vitamin D3 compounds exert a full spectrum of 1,25(OH)2D3 biological activities such as binding to the specific nuclear receptor VDR, suppression of the increased parathyroid hormone levels in 5,6-nephrectomized rats, suppression of INF-y release in MLR cells, stimulation of HL-601eukemia cell differentiation and inhibition of solid tumor cell proliferation (Uskokovic, M.R et al., "
Synthesis and preliminary evaluation of the biological properties of a 1a,25-dihydroxyvitamin D3 analogue with two side-chains." Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone; Norman, A.W., et al., Eds.; University of California: Riverside, 1997; pp 19-2 1; Norman et al., J. Med. Chem. 2000, Vol. 43, 2719-2730).
In both in vivo and cellular cultures, 1,25-(OH)ZD3 undergoes a cascade of metabolic modifications initiated by the influence of 24R-hydroxylase enzyme.
First 24R-hydroxy metabolite is formed, which is oxydized to 24-keto intermediate, and then 23S-hydroxylation and fragmentation produce the fully inactive calcitroic acid.
Given the activities of vitamin D3 and its metabolites, much attention has focused on the development of synthetic analogs of these compounds. A large number of these analogs involves structural modifications in the A ring, B
ring, C/D
rings, and, primarily, the side chain (Bouillon, R. et al. , Endocrine Reviews 16(2):201-204). Although a vast majority of the vitamin D3 analogs developed to date involves structural modifications in the side chain, a few studies have reported the biological profile of A-ring diastereomers (Norman, A.W. et al. J. Biol. Chem.
(27): 20022-20030). Furthermore, biological esterification of steroids has been studied (Hochberg, R.B., (1998) Endocr Rev. 19(3): 331-348), and esters of vitamin D3 are known (WO 97/11053).
Processes for manufacturing vitamin D analogs typically require multiple steps and chromatographic purifications. Previous processes have the disadvantages that, owing to the large number of process steps involved in the synthesis, they are very complex and lead to an unsatisfactory yield. See, Norman, A. W.; Okamura, W.
H. PCT Int. Appl. WO 9916452 Al 990408; Chem Abstr. 130:282223. Batcho, A. D.;
Bryce, G. F.; Hennessy, B. M.; lacobelli, J. A.; Uskokovic, M. R. Eur. Pat.
Appl. EP
808833, 1997; Chem. Abstr. 128:48406. Nestor, J. J.; Manchand, P. S.;
Uskokovic, M. R. Vickery, B. H. U.S. Pat. No. 5,872,113, 1997; Chem. Abstr. 130:168545.
For example, the synthesis of 1a-fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) OH
HO F
No.
60/897,609, filed January 25, 2007. This application contains subject matter that is related to that disclosed in International application Ser. No.
PCT/tJS2006/032381, filed August 18, 2006, which claims the benefit of U.S. provisional patent application Ser. No. 60/709,703, filed August 18, 2005. The disclosures of the aforementioned patent applications are incorporated herein in their entireties by this reference.
Background of the Invention The importance of vitamin D (cholecalciferol) in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified as a"vitamin"
essential for the normal development of the skeleton and maintenance of calcium and phosphorous homeostasis.
Studies involving the metabolism of vitamin D3 were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin D3 [25(OH)D3] (Blunt, J.W. et al. (1968) Biochemistry 6:3317-3322) and the hormonally active form, 1a,25(OH)2D3 (Myrtle, J.F. et al. (1970) J. Biol.
Chem.
245:1190-1196; Norman, A.W. et al. (1971) Science 173:51-54; Lawson, D.E.M. et al. (1971) Nature 230:228-230; Holick, M.F. (1971) Proc. Natl. Acad. Sci. USA
68:803-804). The formulation of the concept of a vitamin D endocrine system was dependent upon the appreciation of the key role of the kidney in producing 1 a, 25(OH)2D3 in a carefully regulated fashion (Fraser, D.R. and Kodicek, E (1970) Nature 288:764-766; Wong, R.G. et al. (1972) J Clin. Invest. 51:1287-1291), and the discovery of a nuclear receptor for 1a,25(OH)2D3 (VD3R) in the intestine (Haussler, M.R. et al. (1969) Exp. Cell Res. 58:234-242; Tsai, H.C. and Norman, A.W.
(1972) J Biol. Chem. 248:5967-5975).
The operation of the vitamin D endocrine system depends on the following:
first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T.
and Postlind, H. (1991) Biochem. J. 276:427-432; Ohyama, Y and Okuda, K. (1991) J.
Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J.
Biol. Chem. 249:7529-7535; Gray, R.W. and Ghazarian, J.G. (1989) Biochem. J.
259:561-568), and in a variety of other tissues to effect the conversion of vitamin D3 into biologically active metabolites such as la, 25(OH)2D3 and 24R,25(OH)2D3;
second, on the existence of the plasma vitamin D binding protein (DBP) to effect the selective transport and delivery of these hydrophobic molecules to the various tissue components of the vitamin D endocrine system (Van Baelen, H. et al. (1988) Ann NY
Acad. Sci. 538:60-68; Cooke, N.E. and Haddad, J.G. (1989) Endocr. Rev. 10:294-307;
Bikle, D.D. et al. (1986) J. Clin. Endocrinol. Metab. 63:954-959); and third, upon the existence of stereoselective receptors in a wide variety of target tissues that interact with the agonist 1a,25(OH)2D3 to generate the requisite specific biological responses for this secosteroid hormone (Pike, J.W. (1991) Annu. Rev. Nutr. 11:189-216).
To date, there is evidence that nuclear receptors for 1a,25(OH)2D3 (VD3R) exist in more than 30 tissues and cancer cell lines (Reichel, H. and Norman, A.W. (1989) Annu.
Rev. Med. 40:71-78).
Vitamin D3 and its hormonally active forms are well-known regulators of calcium and phosphorous homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D3 as a pluripotent regulator outside its classical role in calcium/bone homeostasis.
A paracrine role for 1a,25(OH)Z D3 (structure shown below) has been suggested by the combined presence of enzymes capable of oxidizing vitamin D3 into its active forms, e.g., 25-OHD-1 a-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells. Moreover, vitamin D3 hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al.
(1989) Ann. Rev. Med. 40: 71-78).
OH
H
HO' OH
1,25(OH )2D3 Thus, vitamin D3 compounds exert a full spectrum of 1,25(OH)2D3 biological activities such as binding to the specific nuclear receptor VDR, suppression of the increased parathyroid hormone levels in 5,6-nephrectomized rats, suppression of INF-y release in MLR cells, stimulation of HL-601eukemia cell differentiation and inhibition of solid tumor cell proliferation (Uskokovic, M.R et al., "
Synthesis and preliminary evaluation of the biological properties of a 1a,25-dihydroxyvitamin D3 analogue with two side-chains." Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone; Norman, A.W., et al., Eds.; University of California: Riverside, 1997; pp 19-2 1; Norman et al., J. Med. Chem. 2000, Vol. 43, 2719-2730).
In both in vivo and cellular cultures, 1,25-(OH)ZD3 undergoes a cascade of metabolic modifications initiated by the influence of 24R-hydroxylase enzyme.
First 24R-hydroxy metabolite is formed, which is oxydized to 24-keto intermediate, and then 23S-hydroxylation and fragmentation produce the fully inactive calcitroic acid.
Given the activities of vitamin D3 and its metabolites, much attention has focused on the development of synthetic analogs of these compounds. A large number of these analogs involves structural modifications in the A ring, B
ring, C/D
rings, and, primarily, the side chain (Bouillon, R. et al. , Endocrine Reviews 16(2):201-204). Although a vast majority of the vitamin D3 analogs developed to date involves structural modifications in the side chain, a few studies have reported the biological profile of A-ring diastereomers (Norman, A.W. et al. J. Biol. Chem.
(27): 20022-20030). Furthermore, biological esterification of steroids has been studied (Hochberg, R.B., (1998) Endocr Rev. 19(3): 331-348), and esters of vitamin D3 are known (WO 97/11053).
Processes for manufacturing vitamin D analogs typically require multiple steps and chromatographic purifications. Previous processes have the disadvantages that, owing to the large number of process steps involved in the synthesis, they are very complex and lead to an unsatisfactory yield. See, Norman, A. W.; Okamura, W.
H. PCT Int. Appl. WO 9916452 Al 990408; Chem Abstr. 130:282223. Batcho, A. D.;
Bryce, G. F.; Hennessy, B. M.; lacobelli, J. A.; Uskokovic, M. R. Eur. Pat.
Appl. EP
808833, 1997; Chem. Abstr. 128:48406. Nestor, J. J.; Manchand, P. S.;
Uskokovic, M. R. Vickery, B. H. U.S. Pat. No. 5,872,113, 1997; Chem. Abstr. 130:168545.
For example, the synthesis of 1a-fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) OH
HO F
which may be utilized to treat a number of diseases including hyperproliferative skin diseases, neoplastic diseases, and sebaceous gland diseases (U.S. Pat No.
5,939,408) has been accomplished. The synthesis started from 1-(2-hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol OH
OH
Steps of interest include a two-part addition of the side chain, including addition of an alkyne substitutent, followed by selective reduction to provide alkene side chains; and subsequent installation of the side chain quaternary carbon (carbon 25). The synthesis of the A-ring portion was not included.
Alternatively, the CD-ring portion has been synthesized by Daniewski et al.
(U.S. Pat. No. 6,255,501) starting from 3a-methyl-octahydro-l-oxa-cyclopropa[e] inden-4-one O
O
In this synthesis, a distinct starting material was utilized, presumably to allow for installation of a pre-synthesized side chain incorporating the alkene functionality.
However, four additional steps were required to synthesize the alkene substituent, which included selective reduction of the corresponding alkyne, resulting in a synthesis of the CD-ring substituent over 11 steps. The A-ring portion was not included in the discussion.
The synthesis of the A-ring portion has been accomplished with modest success. One noteworthy example includes at least the steps of olefin epoxidation, allylic oxidation, and de-epoxidation, but suffers from low yields, side product formation, and difficult purifications. Other synthetic routes begin with (S)-carvone, and can be converted to the appropriate phosphine oxide over a multitude of steps.
Other methodologies, including one starting from vitamin D3 and others starting from (S)-carvone, have proven to be more tedious.
The present invention provides an improved and efficient synthesis of vitamin D compounds as compared to prior art syntheses.
5,939,408) has been accomplished. The synthesis started from 1-(2-hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol OH
OH
Steps of interest include a two-part addition of the side chain, including addition of an alkyne substitutent, followed by selective reduction to provide alkene side chains; and subsequent installation of the side chain quaternary carbon (carbon 25). The synthesis of the A-ring portion was not included.
Alternatively, the CD-ring portion has been synthesized by Daniewski et al.
(U.S. Pat. No. 6,255,501) starting from 3a-methyl-octahydro-l-oxa-cyclopropa[e] inden-4-one O
O
In this synthesis, a distinct starting material was utilized, presumably to allow for installation of a pre-synthesized side chain incorporating the alkene functionality.
However, four additional steps were required to synthesize the alkene substituent, which included selective reduction of the corresponding alkyne, resulting in a synthesis of the CD-ring substituent over 11 steps. The A-ring portion was not included in the discussion.
The synthesis of the A-ring portion has been accomplished with modest success. One noteworthy example includes at least the steps of olefin epoxidation, allylic oxidation, and de-epoxidation, but suffers from low yields, side product formation, and difficult purifications. Other synthetic routes begin with (S)-carvone, and can be converted to the appropriate phosphine oxide over a multitude of steps.
Other methodologies, including one starting from vitamin D3 and others starting from (S)-carvone, have proven to be more tedious.
The present invention provides an improved and efficient synthesis of vitamin D compounds as compared to prior art syntheses.
Summary of the Invention In one aspect, the invention provides a method of producing a vitamin D3 compound of formula I
RI
Ri OH
,,.
HO F I
wherein each R1 is independently alkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof; which comprises converting a compound of formula VI
/
H
ORa VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
ORe H
ORa VII;
wherein Ra is a hydroxy protecting group and Re is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
H
OH X;
converting the compound of formula X to a compound of formula II
R, RjOH
OH Il;and reacting the compound of formula II with a compound of formula III
RI
Ri OH
,,.
HO F I
wherein each R1 is independently alkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof; which comprises converting a compound of formula VI
/
H
ORa VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
ORe H
ORa VII;
wherein Ra is a hydroxy protecting group and Re is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
H
OH X;
converting the compound of formula X to a compound of formula II
R, RjOH
OH Il;and reacting the compound of formula II with a compound of formula III
Q
Ra0"' F III, wherein Ra is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
In another aspect, the invention provides a method of producing a compound of formula X
, H
OH " X
wherein each Rl is independently alkyl; which comprises converting a compound of formula VI
H
FZ, VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
~f"ORe H
ORa VII;
wherein Ra is hydroxyl protecting group and Re is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X, to thereby produce a compound of formula X.
Detailed Description of the Invention 1. DEFINITIONS
Before further description of the present invention, and in order that the invention may be more readily understood, certain terms are first defined and collected here for convenience.
The terms "agent" and "reagent" are terms known to those of ordinary skill in the art. As used herein, each term is synonymous with the other.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above.
An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
The term "alkyl" also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and still more preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, heptyl, octyl and so forth.
Ra0"' F III, wherein Ra is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
In another aspect, the invention provides a method of producing a compound of formula X
, H
OH " X
wherein each Rl is independently alkyl; which comprises converting a compound of formula VI
H
FZ, VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
~f"ORe H
ORa VII;
wherein Ra is hydroxyl protecting group and Re is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X, to thereby produce a compound of formula X.
Detailed Description of the Invention 1. DEFINITIONS
Before further description of the present invention, and in order that the invention may be more readily understood, certain terms are first defined and collected here for convenience.
The terms "agent" and "reagent" are terms known to those of ordinary skill in the art. As used herein, each term is synonymous with the other.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above.
An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
The term "alkyl" also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and still more preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, heptyl, octyl and so forth.
In a preferred embodiment, the term "lower alkyl" includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., CI -C4 alkyl.
The terms "alkoxyalkyl," "polyaminoalkyl" and "thioalkoxyalkyl" refer to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. For example, the invention contemplates cyano and propargyl groups.
The term "aryl" as used herein, refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles,"
"heteroaryls" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "diastereomers" refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
The term "deuteroalkyl" refers to alkyl groups in which one or more of the of the hydrogens has been replaced with deuterium.
The terms "alkoxyalkyl," "polyaminoalkyl" and "thioalkoxyalkyl" refer to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. For example, the invention contemplates cyano and propargyl groups.
The term "aryl" as used herein, refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles,"
"heteroaryls" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "diastereomers" refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
The term "deuteroalkyl" refers to alkyl groups in which one or more of the of the hydrogens has been replaced with deuterium.
The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."
The term "halogen" designates -F, -Cl, -Br or -I.
The term "haloalkyl" is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by halogen, e.g., fluoromethyl and trifluoromethyl.
The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
The terrn "hydroxyl" means -OH.
The term "hydroxy-protecting group" signifies any group commonly used for the protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as "silyl"
groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups include but are not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. The term "acyl" signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group. Alkoxyalkyl protecting groups include but are not limited to methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups include but are not limited to trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
The term "obtaining" as in "obtaining a compound" is intended to include purchasing, synthesizing or otherwise acquiring the compound.
The term "phosphorous-containing reagent" refers to a reagent that contains phosphorus and can be reacted with a compound to provide the compound with a phosphorus-group. Compounds with phosphorus-containing groups can couple with compounds having carbonyl functionalities via, e.g., Wittig-type reactions, to provide compounds with alkene and alkyne groups. Typical phospohorous containing reagents used to make Wittig-type reagents include, but are not limited to, triphenylphosphine, trialkylphosphine, diphenylphosphine oxide, and triethyl phosphonoacetate.
The terms "polycyclyl" or "polycyclic radical" refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "prodrug" includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J.
Pharm. Sci.
66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
The term "secosteroid" is art-recognized and includes compounds in which one of the cyclopentanoperhydro-phenanthrene rings of the steroid ring structure is broken. 1a,25(OH)ZD3 and analogs thereof are hormonally active secosteroids.
In the case of vitamin D3, the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B-steroid. The official IUPAC name for vitamin D3 is 9,10-secocholesta-5,7,10(19)-trien-3B-ol. For convenience, a 6-s-trans conformer of 1a,25(OH)2D3 is illustrated herein having all carbon atoms numbered using standard steroid notation.
The term "halogen" designates -F, -Cl, -Br or -I.
The term "haloalkyl" is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by halogen, e.g., fluoromethyl and trifluoromethyl.
The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
The terrn "hydroxyl" means -OH.
The term "hydroxy-protecting group" signifies any group commonly used for the protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as "silyl"
groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups include but are not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. The term "acyl" signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group. Alkoxyalkyl protecting groups include but are not limited to methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups include but are not limited to trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
The term "obtaining" as in "obtaining a compound" is intended to include purchasing, synthesizing or otherwise acquiring the compound.
The term "phosphorous-containing reagent" refers to a reagent that contains phosphorus and can be reacted with a compound to provide the compound with a phosphorus-group. Compounds with phosphorus-containing groups can couple with compounds having carbonyl functionalities via, e.g., Wittig-type reactions, to provide compounds with alkene and alkyne groups. Typical phospohorous containing reagents used to make Wittig-type reagents include, but are not limited to, triphenylphosphine, trialkylphosphine, diphenylphosphine oxide, and triethyl phosphonoacetate.
The terms "polycyclyl" or "polycyclic radical" refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "prodrug" includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J.
Pharm. Sci.
66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
The term "secosteroid" is art-recognized and includes compounds in which one of the cyclopentanoperhydro-phenanthrene rings of the steroid ring structure is broken. 1a,25(OH)ZD3 and analogs thereof are hormonally active secosteroids.
In the case of vitamin D3, the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B-steroid. The official IUPAC name for vitamin D3 is 9,10-secocholesta-5,7,10(19)-trien-3B-ol. For convenience, a 6-s-trans conformer of 1a,25(OH)2D3 is illustrated herein having all carbon atoms numbered using standard steroid notation.
~
: 15 I H
&5119 HU' /OH
In the formulas presented herein, the various substituents on ring A are illustrated as joined to the steroid nucleus by one of these notations: a dotted line (----) indicating a substituent, which is below the plane of the ring, a wedged solid line (~) indicating a substituent which is above the plane of the molecule, or a wavy line ('"~ ) indicating that a substituent may be either above or below the plane of the ring. As shown, the A ring of the hormone 1a,25(OH)2D3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1 a- and 3p- hydroxyl groups. In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "stereo centers".
Furthermore the indication of stereochemistry across a carbon-carbon double bond designated "Z" refers to "cis" conformation whereas "E" refers to "trans"
conformation. As shown, the A ring of the hormone 1-alpha,25(OH)2D3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1-alpha- and 3-beta- hydroxyl groups.
In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "chiral carbon centers." Regardless, both configurations, cis/trans and/or Z/E are encompassed by the compounds of the present invention.
The term "a" refers to conformations wherein the hydrogen substituent is positioned below the plane. Likewise, the term "(3" refers to conformations wherein the hydrogen substituent is positioned above the plane.
With respect to the nomenclature of a chiral center, the terms "d" and "1"
configuration are as defined by the IUPAC Recommendations. As to the use of the terms diastereomer, racemate, epimer and enantiomer, these will be used in their normal context to describe the stereochemistry of preparations.
The term "subject" includes organisms which are capable of suffering from a vitamin D3 associated state or who could otherwise benefit from the administration of a vitamin D3 compound of the invention, such as human and non-human animals.
Preferred human animals include human patients suffering from or prone to suffering from a vitamin D3 associated state, as described herein. The term "non-human animals" of the invention includes all vertebrates, e.g., , mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
The term "sulfhydryl" or "thiol" means -SH.
2. OVERVIEW OF SYNTHESES OF THE INVENTION
The synthesis of the vitamin D3 analogue 1, shown below in Scheme 1, has been previously reported in the literature (Batcho et al. US patent 5,939,408;
Radinov et al. J. Org. Chem. 2001, 66, 6141; and Daniewski et al. USpatent 6,255,501).
The prior art synthesis of vitamin D3 analogue 1 requires 28 process steps. In contast, the improved synthesis of the instant invention, as embodied in Schemes 2-4 below, provides the total synthesis of vitamin D3 analogue 1, in one embodiment, in 19 steps and, in another embodiment, 21 steps.
As shown in Schemes 1-5, the synthesis of vitamin D3 analogue 1 in accordance with the invention includes reductive ozonolysis of 2, chain length extension, and Homer-Wittig type coupling. Although the invention is described by reference to Schemes 1-5, which exemplify a specific emobodment of the synthesis of vitamin D3 analogue 1, a number of vitamin D3 compounds can be synthesized using the methods described in this section and the following working examples without undue experimentation.
Scheme 1 provides a summary of the conversion of vitamin D2 (2) to compound 1. Compound 2 was initially hydroxyl protected. Oxidation with ozone, followed by a reductive workup provided intermediates 3 and 4. The conversion of 4 to 6 took place over eight steps, and included olefin epoxidation, allylic oxidation, and deoxygenation. The conversion of 3 to 5 was accomplished over eight steps and included oxidation, decarbonylation, ene-hydroxymethylation, and a three step chain elongation. The final coupling of 5 and 6 took place under standard Horner-Wittig conditions to complete the novel synthesis of 1.
: 15 I H
&5119 HU' /OH
In the formulas presented herein, the various substituents on ring A are illustrated as joined to the steroid nucleus by one of these notations: a dotted line (----) indicating a substituent, which is below the plane of the ring, a wedged solid line (~) indicating a substituent which is above the plane of the molecule, or a wavy line ('"~ ) indicating that a substituent may be either above or below the plane of the ring. As shown, the A ring of the hormone 1a,25(OH)2D3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1 a- and 3p- hydroxyl groups. In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "stereo centers".
Furthermore the indication of stereochemistry across a carbon-carbon double bond designated "Z" refers to "cis" conformation whereas "E" refers to "trans"
conformation. As shown, the A ring of the hormone 1-alpha,25(OH)2D3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1-alpha- and 3-beta- hydroxyl groups.
In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "chiral carbon centers." Regardless, both configurations, cis/trans and/or Z/E are encompassed by the compounds of the present invention.
The term "a" refers to conformations wherein the hydrogen substituent is positioned below the plane. Likewise, the term "(3" refers to conformations wherein the hydrogen substituent is positioned above the plane.
With respect to the nomenclature of a chiral center, the terms "d" and "1"
configuration are as defined by the IUPAC Recommendations. As to the use of the terms diastereomer, racemate, epimer and enantiomer, these will be used in their normal context to describe the stereochemistry of preparations.
The term "subject" includes organisms which are capable of suffering from a vitamin D3 associated state or who could otherwise benefit from the administration of a vitamin D3 compound of the invention, such as human and non-human animals.
Preferred human animals include human patients suffering from or prone to suffering from a vitamin D3 associated state, as described herein. The term "non-human animals" of the invention includes all vertebrates, e.g., , mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
The term "sulfhydryl" or "thiol" means -SH.
2. OVERVIEW OF SYNTHESES OF THE INVENTION
The synthesis of the vitamin D3 analogue 1, shown below in Scheme 1, has been previously reported in the literature (Batcho et al. US patent 5,939,408;
Radinov et al. J. Org. Chem. 2001, 66, 6141; and Daniewski et al. USpatent 6,255,501).
The prior art synthesis of vitamin D3 analogue 1 requires 28 process steps. In contast, the improved synthesis of the instant invention, as embodied in Schemes 2-4 below, provides the total synthesis of vitamin D3 analogue 1, in one embodiment, in 19 steps and, in another embodiment, 21 steps.
As shown in Schemes 1-5, the synthesis of vitamin D3 analogue 1 in accordance with the invention includes reductive ozonolysis of 2, chain length extension, and Homer-Wittig type coupling. Although the invention is described by reference to Schemes 1-5, which exemplify a specific emobodment of the synthesis of vitamin D3 analogue 1, a number of vitamin D3 compounds can be synthesized using the methods described in this section and the following working examples without undue experimentation.
Scheme 1 provides a summary of the conversion of vitamin D2 (2) to compound 1. Compound 2 was initially hydroxyl protected. Oxidation with ozone, followed by a reductive workup provided intermediates 3 and 4. The conversion of 4 to 6 took place over eight steps, and included olefin epoxidation, allylic oxidation, and deoxygenation. The conversion of 3 to 5 was accomplished over eight steps and included oxidation, decarbonylation, ene-hydroxymethylation, and a three step chain elongation. The final coupling of 5 and 6 took place under standard Horner-Wittig conditions to complete the novel synthesis of 1.
Scheme 1. Summary of Synthesis OH
~y \ O H
HO O
~ , 5 ~ OH
~
H O''*"
HO F
OH Ph2P=O
TBSO""'6 TBSO-" F
Scheme 2 outlines the cleavage of compound 2 to synthetic precursors 3 and 4.
The hydroxyl group of 2 was initially protected with a t-butyldimethylsilyl group, and ozonolysis was followed by a reductive workup with sodium borohydride to provide dio13 in 60% yield, and alcohol 4 in 40% yield.
Scheme 2. Ozonolysis c OH
H
H Fi -.~
9200 ~ CHZCIZ TBSO' OH 60%
40%
HO' TBSOr In another embodiment, compound 2 can be cleaved in the first step to provide compound 3 and compound 4a, which is followed by a two step protection-deprotection protocol to provide compound 4 (Scheme 2a).
~y \ O H
HO O
~ , 5 ~ OH
~
H O''*"
HO F
OH Ph2P=O
TBSO""'6 TBSO-" F
Scheme 2 outlines the cleavage of compound 2 to synthetic precursors 3 and 4.
The hydroxyl group of 2 was initially protected with a t-butyldimethylsilyl group, and ozonolysis was followed by a reductive workup with sodium borohydride to provide dio13 in 60% yield, and alcohol 4 in 40% yield.
Scheme 2. Ozonolysis c OH
H
H Fi -.~
9200 ~ CHZCIZ TBSO' OH 60%
40%
HO' TBSOr In another embodiment, compound 2 can be cleaved in the first step to provide compound 3 and compound 4a, which is followed by a two step protection-deprotection protocol to provide compound 4 (Scheme 2a).
Scheme 2a. Ozonolysis OH
H
~ I
H
+
I -' HO'' OH
HO' 4a 3 OH OTBS OH
-- -> ~
HO''\\6 TBSO''\\6 TBSO''~~
4a 4b 4 Scheme 3 details the conversion of 4 to the A-ring phosphine oxide 6.
Compound 4 was epoxidized in the presence of mCPBA in methylene chloride to provide 8 in 84% yield. Benzoyl protection of the primary hydroxyl group provided compound 9 in 91 % yield, and was followed by allylic oxidation in the presence of selenium dioxide and t-butyl hydrogen peroxide in dioxane to give 10 as a mixture of epimeric compounds. A preferred isomer, shown as 10, was reacted with diethylaminosulfur trifluoride (DAST) to provide fluorinated 11 in 75% yield.
The conversion of 11 to 12 was accomplished in 61% yield in the presence of tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide and triphenyl phosphine in a sealed tube at 100 C over 14 h. Benzoyl hydrolysis in sodium methoxide solution provided hydroxyl compound 13 in 73% yield. The hydroxyl group of 13 was converted to the chloride compound 23 in the presence of triphosgene and pyridine, and subsequently converted to the Horner-Wittig reagent 6 by substitution of the chloride with diphenyl phosphine oxide. The conversion of 13 to 6 was accomplished in 76% yield.
Scheme 3. A-ring OH OH O
a;~ O`;
=~ -- --84% 91% 58%
TBSO'~~~ TBSCr'%\ 8 TBSO9 O Ph 0 I \ O / 6-1-0 ~
~
0'61% 0- 73%
75%
TBSO'F
TBSO'~\ 'OH 10 TBSO'F 12 OH CI O- PhZ
76%
TBSO'`\\IF TBSO't%\ F TBSO F
In another embodiment, the conversion of 8 to 13 can be carried out by intially protecting the hydroxyl group of 8 with a substituted or unsubstituted benzoyl group.
Substitution of the benzoyl group inlcuded iodine and phenyl, as shown in compounds 9A, 9B, 10A, lOB, 11A, and 11B. The conversion of 11A or 11B to 13 takes place via a tungsten chloride mediated olefination of 11, which also deprotects the primary alcohol to yield 13a. Epimerization of 13a with radiation and 9-fluoronone provided compound 13 in a distinct two step procedure (Scheme 3a).
Scheme 3a. A-ring OH O I a;" O
a;i 0:;~ RZ aa Rz , TBSO"N\ TBSO''\\ RZ H 9 ~\ q RZ H 10 8 RZ I 9A TBSO' OH RZ 1 10A
RZ Ph 9B RZ Ph 10B
OH OH
O \
a RZ
\\
TBSO'F TBSO'F R
& l 13 13a TBSCrt F RZ I 11A
RZ Ph 11 B
Scheme 4 describes the converson of diol 3 to precursor 5. Compound 3 was converted to 15 by an intial acetate protection of the ring alcohol to produce 3a, followed by oxidation of the primary alcohol under Swem conditions (Scheme 4).
The aldehyde was converted to the alkene mixture 16 in the presence of palladium and benzalacetone. Reaction with paraformaldehyde in the presence of dimethyl aluminum chloride afforded compound 17. Compound 17 together with lesser quantities of isomers generated during the decarboxylation reaction were hydroxyl protected with a tosyl group to form 18 and the tosyl group was displaced with sodium cyanide to produce 19. This compound was crystalline and thus permitted its isolation in pure form. Reduction with DIBAL-H provided the aldehyde 20, which was subjected to olefination chain extension conditions to provide ester 21.
Grignard reaction provided diol 22, which was oxidized in the presence of PDC to provide intermediate 5.
Scheme 4. C,D ring ,,.H OH ~'HOH
~b'H\O 8 9% H H
40%
OH H OAc OAc OAc 3 3a 15 16 ~ -O ~ ~CN ~foTs ~jOH
OAc 20 OAc OAc OAc O-- ~ 69% H Et0 H OH H OH
OAc 21 OH 22 O 5 In one embodiment, compound 5 was further protected with a trimethyl silyl group, and the resulting 5a was then coupled with 6 in the presence of base (Scheme 5). The silyl protecting groups were removed in the presence of tetrabutylammonium fluoride to afford 1. In another embodiment, compound 5 was coupled with 6 in the presence of base, followed by in situ deprotection of the silyl group with tetrabutylammonium fluoride to afford 1 (Scheme 5). The second embodiment therefore provides a one-step, one-pot synthesis of 1 starting from 5 and 6.
Scheme 5. Coupling O=PPh2 +
TMS
TBSO''~ F
5a 6 HO'F
or PPh2 O rOH
C H + I O TBSO' "~ F 18% HO''\ Including the coupling steps of 5 and 6, the invention provides for a novel 19-step synthesis of 1. Alternatively, the invention also provides for a 21-step synthesis of 1. The current method represents a significant simplification of the protocol described and practiced previously which required 28 steps.
3. DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
The subject invention will now be described in terms of certain preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject invention is concerned generally with a stereospecific and regioselective process for preparing vitamin D3 compounds of formula I. Thus, in one aspect, the invention provides a method of producing a vitamin D3 compound of formula I
H
~ I
H
+
I -' HO'' OH
HO' 4a 3 OH OTBS OH
-- -> ~
HO''\\6 TBSO''\\6 TBSO''~~
4a 4b 4 Scheme 3 details the conversion of 4 to the A-ring phosphine oxide 6.
Compound 4 was epoxidized in the presence of mCPBA in methylene chloride to provide 8 in 84% yield. Benzoyl protection of the primary hydroxyl group provided compound 9 in 91 % yield, and was followed by allylic oxidation in the presence of selenium dioxide and t-butyl hydrogen peroxide in dioxane to give 10 as a mixture of epimeric compounds. A preferred isomer, shown as 10, was reacted with diethylaminosulfur trifluoride (DAST) to provide fluorinated 11 in 75% yield.
The conversion of 11 to 12 was accomplished in 61% yield in the presence of tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide and triphenyl phosphine in a sealed tube at 100 C over 14 h. Benzoyl hydrolysis in sodium methoxide solution provided hydroxyl compound 13 in 73% yield. The hydroxyl group of 13 was converted to the chloride compound 23 in the presence of triphosgene and pyridine, and subsequently converted to the Horner-Wittig reagent 6 by substitution of the chloride with diphenyl phosphine oxide. The conversion of 13 to 6 was accomplished in 76% yield.
Scheme 3. A-ring OH OH O
a;~ O`;
=~ -- --84% 91% 58%
TBSO'~~~ TBSCr'%\ 8 TBSO9 O Ph 0 I \ O / 6-1-0 ~
~
0'61% 0- 73%
75%
TBSO'F
TBSO'~\ 'OH 10 TBSO'F 12 OH CI O- PhZ
76%
TBSO'`\\IF TBSO't%\ F TBSO F
In another embodiment, the conversion of 8 to 13 can be carried out by intially protecting the hydroxyl group of 8 with a substituted or unsubstituted benzoyl group.
Substitution of the benzoyl group inlcuded iodine and phenyl, as shown in compounds 9A, 9B, 10A, lOB, 11A, and 11B. The conversion of 11A or 11B to 13 takes place via a tungsten chloride mediated olefination of 11, which also deprotects the primary alcohol to yield 13a. Epimerization of 13a with radiation and 9-fluoronone provided compound 13 in a distinct two step procedure (Scheme 3a).
Scheme 3a. A-ring OH O I a;" O
a;i 0:;~ RZ aa Rz , TBSO"N\ TBSO''\\ RZ H 9 ~\ q RZ H 10 8 RZ I 9A TBSO' OH RZ 1 10A
RZ Ph 9B RZ Ph 10B
OH OH
O \
a RZ
\\
TBSO'F TBSO'F R
& l 13 13a TBSCrt F RZ I 11A
RZ Ph 11 B
Scheme 4 describes the converson of diol 3 to precursor 5. Compound 3 was converted to 15 by an intial acetate protection of the ring alcohol to produce 3a, followed by oxidation of the primary alcohol under Swem conditions (Scheme 4).
The aldehyde was converted to the alkene mixture 16 in the presence of palladium and benzalacetone. Reaction with paraformaldehyde in the presence of dimethyl aluminum chloride afforded compound 17. Compound 17 together with lesser quantities of isomers generated during the decarboxylation reaction were hydroxyl protected with a tosyl group to form 18 and the tosyl group was displaced with sodium cyanide to produce 19. This compound was crystalline and thus permitted its isolation in pure form. Reduction with DIBAL-H provided the aldehyde 20, which was subjected to olefination chain extension conditions to provide ester 21.
Grignard reaction provided diol 22, which was oxidized in the presence of PDC to provide intermediate 5.
Scheme 4. C,D ring ,,.H OH ~'HOH
~b'H\O 8 9% H H
40%
OH H OAc OAc OAc 3 3a 15 16 ~ -O ~ ~CN ~foTs ~jOH
OAc 20 OAc OAc OAc O-- ~ 69% H Et0 H OH H OH
OAc 21 OH 22 O 5 In one embodiment, compound 5 was further protected with a trimethyl silyl group, and the resulting 5a was then coupled with 6 in the presence of base (Scheme 5). The silyl protecting groups were removed in the presence of tetrabutylammonium fluoride to afford 1. In another embodiment, compound 5 was coupled with 6 in the presence of base, followed by in situ deprotection of the silyl group with tetrabutylammonium fluoride to afford 1 (Scheme 5). The second embodiment therefore provides a one-step, one-pot synthesis of 1 starting from 5 and 6.
Scheme 5. Coupling O=PPh2 +
TMS
TBSO''~ F
5a 6 HO'F
or PPh2 O rOH
C H + I O TBSO' "~ F 18% HO''\ Including the coupling steps of 5 and 6, the invention provides for a novel 19-step synthesis of 1. Alternatively, the invention also provides for a 21-step synthesis of 1. The current method represents a significant simplification of the protocol described and practiced previously which required 28 steps.
3. DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
The subject invention will now be described in terms of certain preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject invention is concerned generally with a stereospecific and regioselective process for preparing vitamin D3 compounds of formula I. Thus, in one aspect, the invention provides a method of producing a vitamin D3 compound of formula I
tR RI
H
HO~~~ ,.~
I
wherein each R, is independently alkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof; which comprises converting a compound of formula VI
/
H
OR, VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
ORe ORa VII;
wherein Ra is a hydroxy protecting group and Re is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
, H
OH X;
converting the compound of formula X to a compound of formula II
Ri R, OH
0 11; and reacting the compound of formula II with a compound of formula III
H
HO~~~ ,.~
I
wherein each R, is independently alkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof; which comprises converting a compound of formula VI
/
H
OR, VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
ORe ORa VII;
wherein Ra is a hydroxy protecting group and Re is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
, H
OH X;
converting the compound of formula X to a compound of formula II
Ri R, OH
0 11; and reacting the compound of formula II with a compound of formula III
Q
Ra0'"% F III, wherein R. is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
In another aspect, the invention provides a method of producing a compound of formula X
H
OH X
wherein each Rl is independently alkyl; which comprises converting a compound of formula VI
QF~ VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
oRe QRa VII;
wherein Ra is a hydroxyl protecting group and RQ is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X.
In one embodiment, the invention provides a method, further comprising reacting the compound of formula VI
R, VI, wherein Ra is a hydroxy protecting group, with an ene reagent, e.g., formaldehyde, to form a compound of formula VII
Ra0'"% F III, wherein R. is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
In another aspect, the invention provides a method of producing a compound of formula X
H
OH X
wherein each Rl is independently alkyl; which comprises converting a compound of formula VI
QF~ VI, wherein Ra is a hydroxy protecting group, to a compound of formula VII
oRe QRa VII;
wherein Ra is a hydroxyl protecting group and RQ is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X.
In one embodiment, the invention provides a method, further comprising reacting the compound of formula VI
R, VI, wherein Ra is a hydroxy protecting group, with an ene reagent, e.g., formaldehyde, to form a compound of formula VII
ORe ORa VII.
In another embodiment, the invention provides a method, further comprising subjecting the compound of formula VII
ORe ORa VII
wherein Ra is a hydroxy protecting group; to nucleophilic displacement conditions to form a compound of formula VIII-a i C,r, ORa VIII-a or a compound of formula VIII-b O
ORa VIII-b.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula VIII-b O
ORa VIII-b with a phosphorous-containing reagent of formula VIII-c Rd .
Rd OP0 VIII-c, wherein Y is ORb, NRbRb, or S(O)nRb; each Rd is independently alkyl, aryl, or alkoxy;
each Rb is independently H, alkyl, or aryl; and n is 0-2; in the presence of a base to form a compound of formula IX
Y
O
ORa ix, wherein Ra and Y are as defined above.
In yet another embodiment, the invention provides a method, further comprising reacting the compound of formula IX
Y
O
ORa IX, with an organometallic reagent to form a compound of formula X
R, Ri OH
OH X
wherein each R, is independently alkyl.
In one embodiment, the invention provides the hydroxylating reagent comprising butylhydrogenperoxideparaformaldehyde and an organometallic Lewis Acid.
In another embodiment, the invention provides a method, wherein the Lewis Acid is, e.g., aluminum chloride, diethylaluminum chloride, or ethylaluminim dichloride.
In another embodiment, the invention provides a method, further comprising subjecting the compound of formula VII
ORe ORa VII
wherein Ra is a hydroxy protecting group; to nucleophilic displacement conditions to form a compound of formula VIII-a i C,r, ORa VIII-a or a compound of formula VIII-b O
ORa VIII-b.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula VIII-b O
ORa VIII-b with a phosphorous-containing reagent of formula VIII-c Rd .
Rd OP0 VIII-c, wherein Y is ORb, NRbRb, or S(O)nRb; each Rd is independently alkyl, aryl, or alkoxy;
each Rb is independently H, alkyl, or aryl; and n is 0-2; in the presence of a base to form a compound of formula IX
Y
O
ORa ix, wherein Ra and Y are as defined above.
In yet another embodiment, the invention provides a method, further comprising reacting the compound of formula IX
Y
O
ORa IX, with an organometallic reagent to form a compound of formula X
R, Ri OH
OH X
wherein each R, is independently alkyl.
In one embodiment, the invention provides the hydroxylating reagent comprising butylhydrogenperoxideparaformaldehyde and an organometallic Lewis Acid.
In another embodiment, the invention provides a method, wherein the Lewis Acid is, e.g., aluminum chloride, diethylaluminum chloride, or ethylaluminim dichloride.
In still another embodiment, the invention provides a method, wherein the nucleophilic displacement compound is an alkali cyanide such as lithium cyanide, sodium cyanide (NaCN), or potassium cyanide.
In another embodiment, the invention provides a method, wherein the compound of formula VIII-a is converted to a compound of formula VIII-b by a reducing agent.
In a further embodiment, the reducing agent is, e.g., disobutyl aluminum hydride (DIBAL-H).
In still another embodiment, the invention provides a method, wherein the phosphorus-containing compound of formula VIII-a is triethyl phosphonoacetate and the base is lithium hexamethyldisalazide (LiHMDS).
In another embodiment, the invention provides a method, wherein the organometallic reagent is ethyl magnesium bromide (EtMgBr) .
In another further embodiment, the invention provides a method, further comprising the addition of cerium trichloride (CeC13).
In one embodiment, the invention provides a method, wherein the compound of formula VI is Acetic acid 1-ethylidene-7a-methyl-octahydro-inden-4-yl ester:
/
OAc In another embodiment, the invention provides a method, wherein the compound of formula VII is Acetic acid 1-(2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester or Acetic acid 7a-methyl-l-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
oFi ~~
o or o"r O"r In yet another embodiment, the invention provides a method, wherein the compound of formula VIII is Acetic acid 1-(2-cyano-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-a) or Acetic acid 7a-methyl-l-(1-methyl-3-oxo-propyl)-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-b):
In another embodiment, the invention provides a method, wherein the compound of formula VIII-a is converted to a compound of formula VIII-b by a reducing agent.
In a further embodiment, the reducing agent is, e.g., disobutyl aluminum hydride (DIBAL-H).
In still another embodiment, the invention provides a method, wherein the phosphorus-containing compound of formula VIII-a is triethyl phosphonoacetate and the base is lithium hexamethyldisalazide (LiHMDS).
In another embodiment, the invention provides a method, wherein the organometallic reagent is ethyl magnesium bromide (EtMgBr) .
In another further embodiment, the invention provides a method, further comprising the addition of cerium trichloride (CeC13).
In one embodiment, the invention provides a method, wherein the compound of formula VI is Acetic acid 1-ethylidene-7a-methyl-octahydro-inden-4-yl ester:
/
OAc In another embodiment, the invention provides a method, wherein the compound of formula VII is Acetic acid 1-(2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester or Acetic acid 7a-methyl-l-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
oFi ~~
o or o"r O"r In yet another embodiment, the invention provides a method, wherein the compound of formula VIII is Acetic acid 1-(2-cyano-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-a) or Acetic acid 7a-methyl-l-(1-methyl-3-oxo-propyl)-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-b):
O
N
or O~ 0 (VIII-a) (VIII-b) In still another embodiment, the invention provides a method, wherein the compound of formula IX is 5-(4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-hex-2-enoic acid ethyl ester:
Et OH
In another embodiment, the invention provides a method, wherein the compound of formula X is 1-(5-Ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol:
H
OH
In another embodiment, the invention provides a method of producing a vitamin D3 compound of formula I, further comprising obtaining a compound of formula VI.
In another embodiment, the the compound of formula VI is obtained by synthesis by a method comprising:
converting compound 3 ~~.H H
to a compound of formula XXI
WH H
ORa XXI;
wherein Ra is a hydroxy protecting group;
N
or O~ 0 (VIII-a) (VIII-b) In still another embodiment, the invention provides a method, wherein the compound of formula IX is 5-(4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-hex-2-enoic acid ethyl ester:
Et OH
In another embodiment, the invention provides a method, wherein the compound of formula X is 1-(5-Ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol:
H
OH
In another embodiment, the invention provides a method of producing a vitamin D3 compound of formula I, further comprising obtaining a compound of formula VI.
In another embodiment, the the compound of formula VI is obtained by synthesis by a method comprising:
converting compound 3 ~~.H H
to a compound of formula XXI
WH H
ORa XXI;
wherein Ra is a hydroxy protecting group;
converting a compound of formula XXI to compound of formula XX
~~=H
ORa XX;
wherein Ra is a hydroxy protecting group; and convering compound of formula XX to a compound of formula VI. In certain embodiments, the oxidation reagent for the conversion of XXI to XX comprises oxalyl chloride or the radical TEMPO with a suitable electron acceptor. In another embodiment, the invention provides a method wherein the compound of formula XXI is Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-octahydro-inden-4-yl ester:
~I.bH
In one embodiment, the invention provides a method further comprising converting a compound of formula XII
OH
,~
0:,, RaO ` XII, wherein Ra is a hydroxy protecting group, to a compound of formula XII-a o a` Rz 0:,, Ra0 '~XII-a;
wherein RZ is H, I, or Ph;
converting the compound of formula XII-a to a compound of formula XV
OR, RaO.," F XV, wherein R, is H or benzoyl; converting the compound of formula XV to a compound of formula III
~~=H
ORa XX;
wherein Ra is a hydroxy protecting group; and convering compound of formula XX to a compound of formula VI. In certain embodiments, the oxidation reagent for the conversion of XXI to XX comprises oxalyl chloride or the radical TEMPO with a suitable electron acceptor. In another embodiment, the invention provides a method wherein the compound of formula XXI is Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-octahydro-inden-4-yl ester:
~I.bH
In one embodiment, the invention provides a method further comprising converting a compound of formula XII
OH
,~
0:,, RaO ` XII, wherein Ra is a hydroxy protecting group, to a compound of formula XII-a o a` Rz 0:,, Ra0 '~XII-a;
wherein RZ is H, I, or Ph;
converting the compound of formula XII-a to a compound of formula XV
OR, RaO.," F XV, wherein R, is H or benzoyl; converting the compound of formula XV to a compound of formula III
Q
Ra0 " F III, wherein Q is a phosphorus-containing group.
In one embodiment, the invention provides a method, wherein the conversion of the compound of formula XII to the compound of formula XII-a is carried out in the presence of benzoyl chloride and base.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XII-a O ~ ~
~ ~ RZ
0:;~
RaO \ XII-a, with an oxidizing agent, to provide a compound of formula XIII
O ~
RZ
RaO"" i,..OH XIII.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula XIII
O I
~` / Rz Q:,~
RaQ'.'\6'"~oH XIII, with a fluorinating agent, to provide a compound of formula XIV
O I ~
0: ~ ;\ RZ
Rao F XIV.
Ra0 " F III, wherein Q is a phosphorus-containing group.
In one embodiment, the invention provides a method, wherein the conversion of the compound of formula XII to the compound of formula XII-a is carried out in the presence of benzoyl chloride and base.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XII-a O ~ ~
~ ~ RZ
0:;~
RaO \ XII-a, with an oxidizing agent, to provide a compound of formula XIII
O ~
RZ
RaO"" i,..OH XIII.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula XIII
O I
~` / Rz Q:,~
RaQ'.'\6'"~oH XIII, with a fluorinating agent, to provide a compound of formula XIV
O I ~
0: ~ ;\ RZ
Rao F XIV.
In yet another embodiment, the invention provides a method, further comprising reacting the compound of formula XIV
o I-~
/ Rz RaO - F XN, with a deoxygenation agent, to provide a compound of formula XV
o ~ R
Z
Ra0 '` F XV.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XV
o ~ R
Z
RaO.," F XV, with a deprotection agent, to provide a compound of formula XV
OH
RaO ` F XV.
In another embodiment, the invention provides a method, further comprising:
reacting the compound of formula XIV
.
0: ~ RZ
Ra0 ' F XIV, with a deoxygenation agent, to provide a compound of formula XVa OH
Ra0''' F XVa.
In another embodiment, the invention provides a method, further comprising:
reacting the compound of formula XVa OH
RaO,," F XVa, with an epimerization agent, to provide a compound of formula XV
OH
RaO.,a F XV.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula XV
OH
Ra0 "\ F XV, with a chlorinating agent, to provide a compound of formula XVI
ci Ra0.,,' F XVI.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XVI
ci Ra0C" F XVI, with a phosphorous containing agent in the presence of a base, to provide a compound of formula III
Q
Ra0"1% F III.
In a further embodiment, the invention provides a method, wherein the base is pyridine.
In one embodiment, the invention provides a method, wherein the oxidizing reagent comprises selenium dioxide and t-butyl hydrogen peroxide.
In another embodiment, the invention provides a method, wherein the fluorinating agent is diethylaminosulfur trifluoride (DAST).
In yet another embodiment, the invention provides a method, wherein the deoxygenation reagent is tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide or tungsten hexachloride/nBuLi.
In still another embodiment, the invention provides a method, wherein the deprotection agent is sodium methoxide.
In yet another embodiment, the invention provides a method, wherein the epimerization agent is hv and 9-fluorenone.
In another embodiment, the invention provides a method, wherein the chlorinating agent comprises triphosgene and pyridine.
In yet another embodiment, the invention provides a method, wherein the phosphorous containing agent is diphenyl phosphine oxide.
In another further embodiment, the invention provides a method, wherein the base is sodium hydride.
In one embodiment, the invention provides a method, wherein the compound of formula XII-a is benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-ylmethyl ester:
o I~
a;;
TBSO'"\
o I-~
/ Rz RaO - F XN, with a deoxygenation agent, to provide a compound of formula XV
o ~ R
Z
Ra0 '` F XV.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XV
o ~ R
Z
RaO.," F XV, with a deprotection agent, to provide a compound of formula XV
OH
RaO ` F XV.
In another embodiment, the invention provides a method, further comprising:
reacting the compound of formula XIV
.
0: ~ RZ
Ra0 ' F XIV, with a deoxygenation agent, to provide a compound of formula XVa OH
Ra0''' F XVa.
In another embodiment, the invention provides a method, further comprising:
reacting the compound of formula XVa OH
RaO,," F XVa, with an epimerization agent, to provide a compound of formula XV
OH
RaO.,a F XV.
In still another embodiment, the invention provides a method, further comprising reacting the compound of formula XV
OH
Ra0 "\ F XV, with a chlorinating agent, to provide a compound of formula XVI
ci Ra0.,,' F XVI.
In another embodiment, the invention provides a method, further comprising reacting the compound of formula XVI
ci Ra0C" F XVI, with a phosphorous containing agent in the presence of a base, to provide a compound of formula III
Q
Ra0"1% F III.
In a further embodiment, the invention provides a method, wherein the base is pyridine.
In one embodiment, the invention provides a method, wherein the oxidizing reagent comprises selenium dioxide and t-butyl hydrogen peroxide.
In another embodiment, the invention provides a method, wherein the fluorinating agent is diethylaminosulfur trifluoride (DAST).
In yet another embodiment, the invention provides a method, wherein the deoxygenation reagent is tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide or tungsten hexachloride/nBuLi.
In still another embodiment, the invention provides a method, wherein the deprotection agent is sodium methoxide.
In yet another embodiment, the invention provides a method, wherein the epimerization agent is hv and 9-fluorenone.
In another embodiment, the invention provides a method, wherein the chlorinating agent comprises triphosgene and pyridine.
In yet another embodiment, the invention provides a method, wherein the phosphorous containing agent is diphenyl phosphine oxide.
In another further embodiment, the invention provides a method, wherein the base is sodium hydride.
In one embodiment, the invention provides a method, wherein the compound of formula XII-a is benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-ylmethyl ester:
o I~
a;;
TBSO'"\
In another embodiment, the invention provides a method, wherein the compound of formula XIII is benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro[2.5]oct-2-ylmethyl ester:
o 0 a;;
TBSO' /~~'OH
In yet another embodiment, the invention provides a method, wherein the compound of formula XIV is benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-5-fluoro-4-methylene-l-oxa-spiro[2.5]oct-2-ylmethyl ester:
o I~
~
TBSO''\\a F
In still another embodiment, the invention provides a method, wherein the compound of formula XV is benzoic acid 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethyl ester:
o I ~
i TBSO' F
In another embodiment, the invention provides a method, wherein the compound of formula XV is 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethanol:
OH
TBSO''\\ F , In another embodiment, the invention provides a method, wherein the compound of formula XVa is 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethanol:
OH
TBSOF , In still another embodiment, the invention provides a method, wherein the compound of formula XVI is tert-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy] -dimethyl-si lane:
ci TBSO'F
In yet another embodiment, the invention provides a method, wherein the compound of formula III is tert-butyl-{3-[2-(diphenyl-phosphinoyl)-ethylidene]-fluoro-4-methylene-cyclohexyloxy}-dimethyl-silane:
P(O)PhZ
TBSO''\\F
&
In one embodiment, the invention provides a method, wherein the coupling reaction of the compound of formula II and the compound of formula III to form the compound of formula I comprises converting the compound of formula II
Ri RIOH
O II
to a compound of formula XVII
o 0 a;;
TBSO' /~~'OH
In yet another embodiment, the invention provides a method, wherein the compound of formula XIV is benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-5-fluoro-4-methylene-l-oxa-spiro[2.5]oct-2-ylmethyl ester:
o I~
~
TBSO''\\a F
In still another embodiment, the invention provides a method, wherein the compound of formula XV is benzoic acid 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethyl ester:
o I ~
i TBSO' F
In another embodiment, the invention provides a method, wherein the compound of formula XV is 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethanol:
OH
TBSO''\\ F , In another embodiment, the invention provides a method, wherein the compound of formula XVa is 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene] -ethanol:
OH
TBSOF , In still another embodiment, the invention provides a method, wherein the compound of formula XVI is tert-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy] -dimethyl-si lane:
ci TBSO'F
In yet another embodiment, the invention provides a method, wherein the compound of formula III is tert-butyl-{3-[2-(diphenyl-phosphinoyl)-ethylidene]-fluoro-4-methylene-cyclohexyloxy}-dimethyl-silane:
P(O)PhZ
TBSO''\\F
&
In one embodiment, the invention provides a method, wherein the coupling reaction of the compound of formula II and the compound of formula III to form the compound of formula I comprises converting the compound of formula II
Ri RIOH
O II
to a compound of formula XVII
R, RIORa 0 XVII, wherein Ra is hydroxy protecting group; reacting the compound of formula XVII
with a compound of formula III in the presence of base Q
RaCC F III, wherein Q is a. phosphorus-containing group, to form a compound of formula XVIII
Rt R
t 0Ra RaG" F XVIII; and converting the compound of formula XVIII to the compound of formula I.
In another embodiment, the invention provides a method, wherein the reaction of the compound of formula II and the compound of formula III to produce the compound of formula I is carried out in a single process step.
In still another embodiment, the invention provides a method, wherein the compound of formula I is produced in 21 process steps.
In yet another embodiment, the invention provides a method, wherein the compound of formula I is produced in 19 process steps.
In one embodiment, the invention provides the methods described herein, wherein each Rt is ethyl in the compound of formula I.
In another embodiment, the invention provides a method, wherein the compound of formula I is r~H
HO'~In another embodiment, the invention provides a method for reacting a compound of formula II
Ri RIOH
o II
with a compound of formula III
Q
RaO"\' F III, wherein Ra is defined as above and Q is a phosphorus-containing group in the presence of a strong base to thereby produce a compound of formula I. In certain embodiments, the strong base is n-BuLi.
In certain embodiments, the method includes the step of obtaining compound 3. In one embodiment, compound 3 is obtained by synthesis by a method comprising:
converting compound 2 .,,-\
H
HO
2 2, to compound 7 IH
I
TBSOr 7 7;
and converting compound 7 to compound 3.
In other embodiments, the method includes the step of obtaining the compound of formula XII. In one embodiment, the compound of formula XII is obtained by synthesis by a method comprising:
converting compound 2 u-H\
H
HO' 2 2, to compound 4a OH
HO'`\\ , ~
converting compound 4a to compound 4 OH
TBSa'\\ 4;
and converting compound 4 to a compound of formula XII. In certain embodiments, the epoxidation reagent is m-chloroperoxybenzoic acid (M-CPBA).
In carrying out the methods of the invention, a number of reagents and reaction conditions can be used. Although the following is a description of certain preferred reagents and reaction conditions, one of ordinary skill in the art will readily appreciate that reagents and reaction conditions can be varied without undue experimentation and without departing from the spirit of the invention.
Oxidizing agents known in the art include, but are not limited to Se02/t-BuOOH, Jones reagent (H2CrO4, Cr03), VO(acac)2/tBuOOH, dipyridine Cr(VI) oxide, pyridinium chlorochromate, pyridnium dichromate (PDC), sodium hypochlorite/acetic acid NaOCUHOAc), C12-pyridine, hydrogen peroxide/ammonium molybdate, NaBrO3/CAN, KMnO4, Br2, MnO2, NBS/tetrabutylammonium iodide, ruthenium tetroxide, mCPBA, TEMPO/NCS. Preferably, the oxidizing agents of the present invention are Se02/t-BuOOH, mCPBA, TEMPO/NCS, and PDC.
Oxidation reaction times range from 0.5 h to 72 h. In certain embodiments, the TEMPO/NCS oxidation was carried out over 24-48 h, preferably 24-38 h. In certain embodiments, the Se02/t-BuOOH oxidation was carried out over 24-72 h, preferably 72 h. In other embodiment, the Se02/t-BuOOH oxidation was carried out over 24-36 h, preferably 36 h. Typical reaction conditions include high temperatures of from about 0 C to about 150 C. Preferred temperatures include a range of from about 25 C to about 150 C.
Decarbonylation reagents include combinations of metal catalysts and ligands.
Metal catalysts include, but are not limited to Rh/C, Ru/C, Pd(OAc)2, Pd(PPh3)4, Rh(PPh3)3C1, A1203, and Pd/C. Other catalyst/ligand systems include Rh2(OAc)4/N2C(CO2Me)2, and tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide/ triphenylphosphine. Co-reactants include but are not limited to dibenzylideneacetone (dba) and benzylideneacetone. High reaction temperatures provided the desired product in high yields with reduced byproduct formation.
Temperatures for decarbonylation reactions range from about 25 C to about 250 C, preferably about 100 C to about 250 C, preferably about 100 C or 230 C.
Phosphorous containing reagents are phosphorous containing compounds utilized to form compounds used in coupling reactions with carbonyl functionalities to provide compounds with alkene groups, e.g. Wittig-type reactions. Typical phospohorous containing reagents used to make Wittig-type reagents include, but are not limited to, triphenylphosphine, trialkylphosphine, and diphenylphosphine oxide.
Wittig-type reactions are carried out in the presence of a phosphorus-containing compound and carbonyl compound. The present invention provides for the formation of E-double bonds, which are selectively produced from a combination of Wittig reagent, base, and a suitable reaction temperature. It is advantageous that (EtO)2POCH2COOEt is the Wittig-type agent, lithium hexamethyl disalazide (LiHMDS) is the base, and the reaction is carried out at a temperature of about -100 C to about 0 C, preferably about -85 C to about -78 C.
The 1,2 reduction of unsaturated esters is carried out in the presence of organometallic reagents mediated by Lewis acids. Organometallic reagents include but are not limited to Grignard reagents and organolithium reagents such as ethyl magnesium bromide and ethyl lithium. Lewis acids utililized in this reduction include, but are not limited to CeC13, Al(Oi-Pr)3, A1C13i TiC14, BF3, SnC14, and FeC13, preferably CeC13. In certain embodiments, CeC13 was dried in vacuo prior to use.
Benzoyl group deprotection agents known in the art include, but are not limited to sodium methoxide, triethyl amine/water/methanol, potassium cyanide, boron trifluoride/etherate/dimethyl sulfide, and electrolytic cleavage.
Preferably, the benzoyl group deprotection agent of the invention is sodium methoxide.
Chlorinating reagents known in the art include, but are not limited to hydrochloric acid (HCl), thionyl chloride (SOC12), tosylchloride and lithium chloride;
and triphosgene and pyridine. Preferably, triphosgene and pyridine is utilized.
4. NOVEL INERMEDIATES
The methods of the invention involve the generation and use of certain novel intermediate compounds. Novel intermediates of the invention include the following compounds:
Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
OH
O"r O
Acetic acid 7a-methyl-l-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester o o o"r O
with a compound of formula III in the presence of base Q
RaCC F III, wherein Q is a. phosphorus-containing group, to form a compound of formula XVIII
Rt R
t 0Ra RaG" F XVIII; and converting the compound of formula XVIII to the compound of formula I.
In another embodiment, the invention provides a method, wherein the reaction of the compound of formula II and the compound of formula III to produce the compound of formula I is carried out in a single process step.
In still another embodiment, the invention provides a method, wherein the compound of formula I is produced in 21 process steps.
In yet another embodiment, the invention provides a method, wherein the compound of formula I is produced in 19 process steps.
In one embodiment, the invention provides the methods described herein, wherein each Rt is ethyl in the compound of formula I.
In another embodiment, the invention provides a method, wherein the compound of formula I is r~H
HO'~In another embodiment, the invention provides a method for reacting a compound of formula II
Ri RIOH
o II
with a compound of formula III
Q
RaO"\' F III, wherein Ra is defined as above and Q is a phosphorus-containing group in the presence of a strong base to thereby produce a compound of formula I. In certain embodiments, the strong base is n-BuLi.
In certain embodiments, the method includes the step of obtaining compound 3. In one embodiment, compound 3 is obtained by synthesis by a method comprising:
converting compound 2 .,,-\
H
HO
2 2, to compound 7 IH
I
TBSOr 7 7;
and converting compound 7 to compound 3.
In other embodiments, the method includes the step of obtaining the compound of formula XII. In one embodiment, the compound of formula XII is obtained by synthesis by a method comprising:
converting compound 2 u-H\
H
HO' 2 2, to compound 4a OH
HO'`\\ , ~
converting compound 4a to compound 4 OH
TBSa'\\ 4;
and converting compound 4 to a compound of formula XII. In certain embodiments, the epoxidation reagent is m-chloroperoxybenzoic acid (M-CPBA).
In carrying out the methods of the invention, a number of reagents and reaction conditions can be used. Although the following is a description of certain preferred reagents and reaction conditions, one of ordinary skill in the art will readily appreciate that reagents and reaction conditions can be varied without undue experimentation and without departing from the spirit of the invention.
Oxidizing agents known in the art include, but are not limited to Se02/t-BuOOH, Jones reagent (H2CrO4, Cr03), VO(acac)2/tBuOOH, dipyridine Cr(VI) oxide, pyridinium chlorochromate, pyridnium dichromate (PDC), sodium hypochlorite/acetic acid NaOCUHOAc), C12-pyridine, hydrogen peroxide/ammonium molybdate, NaBrO3/CAN, KMnO4, Br2, MnO2, NBS/tetrabutylammonium iodide, ruthenium tetroxide, mCPBA, TEMPO/NCS. Preferably, the oxidizing agents of the present invention are Se02/t-BuOOH, mCPBA, TEMPO/NCS, and PDC.
Oxidation reaction times range from 0.5 h to 72 h. In certain embodiments, the TEMPO/NCS oxidation was carried out over 24-48 h, preferably 24-38 h. In certain embodiments, the Se02/t-BuOOH oxidation was carried out over 24-72 h, preferably 72 h. In other embodiment, the Se02/t-BuOOH oxidation was carried out over 24-36 h, preferably 36 h. Typical reaction conditions include high temperatures of from about 0 C to about 150 C. Preferred temperatures include a range of from about 25 C to about 150 C.
Decarbonylation reagents include combinations of metal catalysts and ligands.
Metal catalysts include, but are not limited to Rh/C, Ru/C, Pd(OAc)2, Pd(PPh3)4, Rh(PPh3)3C1, A1203, and Pd/C. Other catalyst/ligand systems include Rh2(OAc)4/N2C(CO2Me)2, and tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide/ triphenylphosphine. Co-reactants include but are not limited to dibenzylideneacetone (dba) and benzylideneacetone. High reaction temperatures provided the desired product in high yields with reduced byproduct formation.
Temperatures for decarbonylation reactions range from about 25 C to about 250 C, preferably about 100 C to about 250 C, preferably about 100 C or 230 C.
Phosphorous containing reagents are phosphorous containing compounds utilized to form compounds used in coupling reactions with carbonyl functionalities to provide compounds with alkene groups, e.g. Wittig-type reactions. Typical phospohorous containing reagents used to make Wittig-type reagents include, but are not limited to, triphenylphosphine, trialkylphosphine, and diphenylphosphine oxide.
Wittig-type reactions are carried out in the presence of a phosphorus-containing compound and carbonyl compound. The present invention provides for the formation of E-double bonds, which are selectively produced from a combination of Wittig reagent, base, and a suitable reaction temperature. It is advantageous that (EtO)2POCH2COOEt is the Wittig-type agent, lithium hexamethyl disalazide (LiHMDS) is the base, and the reaction is carried out at a temperature of about -100 C to about 0 C, preferably about -85 C to about -78 C.
The 1,2 reduction of unsaturated esters is carried out in the presence of organometallic reagents mediated by Lewis acids. Organometallic reagents include but are not limited to Grignard reagents and organolithium reagents such as ethyl magnesium bromide and ethyl lithium. Lewis acids utililized in this reduction include, but are not limited to CeC13, Al(Oi-Pr)3, A1C13i TiC14, BF3, SnC14, and FeC13, preferably CeC13. In certain embodiments, CeC13 was dried in vacuo prior to use.
Benzoyl group deprotection agents known in the art include, but are not limited to sodium methoxide, triethyl amine/water/methanol, potassium cyanide, boron trifluoride/etherate/dimethyl sulfide, and electrolytic cleavage.
Preferably, the benzoyl group deprotection agent of the invention is sodium methoxide.
Chlorinating reagents known in the art include, but are not limited to hydrochloric acid (HCl), thionyl chloride (SOC12), tosylchloride and lithium chloride;
and triphosgene and pyridine. Preferably, triphosgene and pyridine is utilized.
4. NOVEL INERMEDIATES
The methods of the invention involve the generation and use of certain novel intermediate compounds. Novel intermediates of the invention include the following compounds:
Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
OH
O"r O
Acetic acid 7a-methyl-l-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester o o o"r O
Acetic acid 1-(2-cyano-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester N
Olir O
Acetic acid 7a-methyl-l-(1-methyl-3-oxo-propyl)-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester :
o ~ ; and 4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-hex-2-enoic acid ethyl ester:
Et OH
In another embodiment, the invention provides a method of obtaining any of the aforementioned compounds.
EXEMPLIFICATION OF THE INVENTION
The invention is further illustrated by the following examples which should in no way should be construed as being further limiting.
Synthesis of Compounds of the Invention Experimental All operations involving vitamin D3 analogs were conducted in amber-colored glassware in a nitrogen atmosphere. Tetrahydrofuran was distilled from sodium-benzophenone ketyl just prior to its use and solutions of solutes were dried with sodium sulfate. Melting points were determined on a Thomas-Hoover capillary apparatus and are uncorrected. Optical rotations were measured at 25 C. 'H
NMR
spectra were recorded at 400 MHz in CDC13 unless indicated otherwise. TLC was carried out on silica gel plates (Merck PF-254) with visualization under short-wavelength UV light or by spraying the plates with 10% phosphomolybdic acid in methanol followed by heating. Flash chromatography was carried out on 40-65 m mesh silica gel. Preparative HPLC was performed on a 5x50 cm colunm and 15-30 m mesh silica gel at a flow rate of 100 mL/min.
Cleavage of the Vitamin D2 Starting Material t-Butyl-dimethyl-(4-methylene-3-{2-[7a-methyl-l-(1,4,5-trimethyl-hex-2-enyl)-octahydro-inden-4-ylidene]-ethylidene}-cyclohexyloxy)-silane (7) =, - -~ _ ~ _ I tBuMe2SiCl I
~ DMF ~
HO'~"TBSO'~'2 7 To a stirred solution of 2 (100.00 g, 0.25 mol) in DMF (250 mL), imidazole (40.80 g, 0.6 mol) and (t-butyldimethyl)silyl chloride (45.40 g, 0.3 mol) were added successively. The reaction mixture was stirred at room temperature for lh, diluted with hexane (750 mL), washed with water (500 mL), 1N HCl (500 mL), brine (500 mL) and dried over NazSO4. The residue (155 g) after evaporation of the solvent was filtered through a plug of silica gel (500 g, 5% AcOEt in hexane) to give the title compound (115.98 g, 0.23 mol, 92%).
'H-NMR: 8 0.04 and 0.08 (2s, 6H), 0.59 (s, 3H), 0.90 (d, 3H, J=6.6 Hz), 0.92 (d, 3H, J=6.6 Hz), 0.98 (s, 9H), 0.99 (d, 3H, J=7.0 Hz), 1.06 (d, 3H, J=6.8 Hz), 1.10-2.95 (m, 21H), 5.11 (br s, 2H), 5.22 (m, 2H), 6.49 (br s, 2H).
Olir O
Acetic acid 7a-methyl-l-(1-methyl-3-oxo-propyl)-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester :
o ~ ; and 4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-hex-2-enoic acid ethyl ester:
Et OH
In another embodiment, the invention provides a method of obtaining any of the aforementioned compounds.
EXEMPLIFICATION OF THE INVENTION
The invention is further illustrated by the following examples which should in no way should be construed as being further limiting.
Synthesis of Compounds of the Invention Experimental All operations involving vitamin D3 analogs were conducted in amber-colored glassware in a nitrogen atmosphere. Tetrahydrofuran was distilled from sodium-benzophenone ketyl just prior to its use and solutions of solutes were dried with sodium sulfate. Melting points were determined on a Thomas-Hoover capillary apparatus and are uncorrected. Optical rotations were measured at 25 C. 'H
NMR
spectra were recorded at 400 MHz in CDC13 unless indicated otherwise. TLC was carried out on silica gel plates (Merck PF-254) with visualization under short-wavelength UV light or by spraying the plates with 10% phosphomolybdic acid in methanol followed by heating. Flash chromatography was carried out on 40-65 m mesh silica gel. Preparative HPLC was performed on a 5x50 cm colunm and 15-30 m mesh silica gel at a flow rate of 100 mL/min.
Cleavage of the Vitamin D2 Starting Material t-Butyl-dimethyl-(4-methylene-3-{2-[7a-methyl-l-(1,4,5-trimethyl-hex-2-enyl)-octahydro-inden-4-ylidene]-ethylidene}-cyclohexyloxy)-silane (7) =, - -~ _ ~ _ I tBuMe2SiCl I
~ DMF ~
HO'~"TBSO'~'2 7 To a stirred solution of 2 (100.00 g, 0.25 mol) in DMF (250 mL), imidazole (40.80 g, 0.6 mol) and (t-butyldimethyl)silyl chloride (45.40 g, 0.3 mol) were added successively. The reaction mixture was stirred at room temperature for lh, diluted with hexane (750 mL), washed with water (500 mL), 1N HCl (500 mL), brine (500 mL) and dried over NazSO4. The residue (155 g) after evaporation of the solvent was filtered through a plug of silica gel (500 g, 5% AcOEt in hexane) to give the title compound (115.98 g, 0.23 mol, 92%).
'H-NMR: 8 0.04 and 0.08 (2s, 6H), 0.59 (s, 3H), 0.90 (d, 3H, J=6.6 Hz), 0.92 (d, 3H, J=6.6 Hz), 0.98 (s, 9H), 0.99 (d, 3H, J=7.0 Hz), 1.06 (d, 3H, J=6.8 Hz), 1.10-2.95 (m, 21H), 5.11 (br s, 2H), 5.22 (m, 2H), 6.49 (br s, 2H).
2-[5-(tert-Butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-ethanol (4) and 1-(2-Hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol (3) OH
~ Os OH
\ 3 4 ~ CH2CI2 +
OH TBSO'~' ~
TBSO'~~
A stream of ozone was passed through a stirred solution of 7 (23.4 g, 45.8 mmol), pyridine (5.0 mL) and Sudane Red 7B (15.0 mg) in dichloromethane (550 mL), at -to -60 C until Sudane Red decolorized ( 55 min). Sodium borohydride (6.75 g, mmol) was then added followed by ethanol (250 mL). The reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (15 mL) was added and, after 30 min brine (300 mL) was added. The mixture was diluted with ethyl acetate (500 mL) and washed with water (600 mL). The aqueous phase was extracted with AcOEt (300 mL). The combined organic phases were dried over Na2SO4. The residue (26.5 g), after evaporation of the solvent, was filtered through a plug of silica gel (500 g, 15%, 30% and 50% AcOEt in hexane) to give: Fraction A
(5.9 g, mixture containing the desired A-ring (ca 83% pure by NMR) 'H NMR
S 5.3 8(1 H, t, J=6.4Hz), 4.90 (1 H, brs), 4.5 7(1 H, brs), 4.22 (1 H, dd, J=7.3, 12.5 Hz), 4.13 (1 H, dd, J=6.3, 12.5 Hz), 3.78 (1 H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s); Fraction A was used for the synthesis of the A-ring precursor.
Fraction B (14.6 g, mixture containing a CD-rings fragments on a different stage of oxidation). Fraction B was further ozonolyzed in order to obtain the Lythgoe diol (3).
A stream of ozone was passed through a stirred solution of Fraction B (14.6 g) and Sudane Red 7B (3.0 mg) in ethanol (225 mL) at -55 to -60 C for 30min ( Sudane Red decolorized). Sodium borohydride (3.75 g, 100 mmol) was added and the reaction was allowed to warm to room temperature and stirred at room temperature for lh.
Acetone (5 mL) was added and, after 30 min brine (200 mL) was added. The mixture was diluted with dichloromethane (300 mL) and washed with water (250 mL). The aqueous phase was extracted with dichloromethane (200 mL). The combined organic phases were, evaporated to dryness (the last portion was evaporated with addition of toluene 100 mL). The residue (16.2 g) was dissolved in dichloromethane (100 mL), concentrated to a volume of ca 20 mL diluted with petroleum ether (30 mL) and set aside in the fridge for crystallization. The white powder was filtered of (4.05 g), the mother liquor was concentrated and filtered through silica gel (100g, 5% MeOH
in CH2ClZ) to give yellow oil (9.4 g), which was recrystallized (20 mL, dichloromethane; petroleum ether 1:2) to give white powder (1.79 g). Thus the total yield of the Lythgoe dio13 was (5.84 g, 27.5 mmol, 60 % from D2) 'H NMR : S
4.08 (1 H, m), 3.64 (1 H, dd, J=3.3, 10.6 Hz), 3.39 (1 H, dd, J=6.6, 10.6 Hz), 2.04-1.14 (15H, m), 1.03 (3H, d, J=6.6 Hz), 0.96 (3H, s).
1-(2-Hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol (4a) and 1-(2-Hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol (3) OH
~ 03 OH
~ CH2CI2 \ 3 4a OH HO'~\
Ho~~Compound 2 (98.8 g, 249 mmol) was dissolved in dichloromethane (900 mL) and ethanol (400 mL), pyridine (25.0 mL) and Sudane Red 7B (30.0 mg) were added and the mixture was cooled down to -65 to -70 C. A stream of ozone was passed through for 3h. (until Sudane Red decolorized, reaction was also followed by TLC and decolorization of Sudane Red corresponds to consumption of Vitamin D2). Sodium borohydride (24.0g, 0.64 mol) was added portion-wise and the reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (75 mL) was added portion-wise (to keep temperature under 35 C) and the reaction mixture was stored overnight in the fridge. The mixture was washed with water (600 mL). The aqueous phase was extracted with dichloromethane (6x 300 mL). The combined organic phases were dried over Na2SO4. The residue (118 g) after evaporation of the solvent was passed through a plug of silica gel (0.5 kg, 30%, 50%
AcOEt in hexane) to give: Fraction A (69.7 g, CD-rings fragments); Fraction B
(4.8 g of a pure Lythgoe dio13 after crystallization from hexane:AcOEt 3:1);
Fraction C (12.3 g of a pure compound 4a, after crystallization from AcOEt); Fraction D(11.5 g, mixture of the desired compound 4a and 4-Methylene-cyclohexane-1,3-diol).
Fraction A was further ozonolyzed in order to obtain (3). A stream of ozone was passed through a stirred solution of Fraction A (69.7 g) in ethanol (500 mL), dichloromethane (600 mL) and Sudane Red 7B (3.0 mg) at -65 to -70 C for 3h. ( Sudane Red decolorized). Sodium borohydride (22.5g, 0.6 mol) was added and the reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (125 mL) was added portion-wise (to keep temperature under 35 C) and the reaction mixture was stored overnight in the fridge. The mixture was washed with water (600 mL). The aqueous phase was extracted with dichloromethane (2x mL) and with AcOEt (300 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The residue (55.0g) was purified by crystallization (AcOEt :hexane 1:2) to give: Fraction E (15.7 g of a pure crystalline 3);
Fraction F
(35 g, of mixture containing Lythgoe diol 3). Fraction F (35 g) was passed through a plug of silica gel (0.5 kg, 30%, 50% AcOEt in hexane) to give after crystallization (AcOEt :hexane 1:2) Fraction G (18.9 g), thus the overall yield of (3)was 39.4g 74.5% from 2).
' H NMR : 8 5.3 8(1 H, t, J=6.4Hz), 4.90 (1 H, brs), 4.57 (1 H, brs), 4.22 (1 H, dd, J=7.3, 12.5 Hz), 4.13 (1H, dd, J=6.3, 12.5 Hz), 3.78 (1H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s);
Fraction D (11.5 g) was passed through a plug of silica gel (0.3 kg, 50% AcOEt in hexane) to give (after crystallization (AcOEt): Fraction H(1.1 g of a pure crystalline compound 4a, 2.8%); Fraction I(10.2 g, mixture of the desired compound 4a.
Thus the overall yield of the isolated (S)-(Z)-3-(2-Hydroxy-ethylidene)-4-methylene-cyclohexanol (4a) is 13.4 g, 34.8%
'H NMR : 8 5.51 (1 H, t, J=6.6Hz), 5.03 (1 H, brs), 4.66 (1 H, brs), 4.24 (2H, m), , 3.94 (1 H, m), 2.55 (1 H, dd, J=3.9, 13.2 Hz), 2.41 (1H, m), 2.25 (1 H, dd, J=7.8, 12.9 Hz), 1.94 (1H, m), 1.65 (1H, m).
An alternative workup can be used. After the first ozonolysis the organic phase was extracted with water (4 x 800 mL). The combined water phases were back extracted with hexane (500 mL). The organic phases were dried over Na2SO4, concentrated in vacuo and used for the second 6zonolysis in order to obtain compound 3. The water phase was extracted with EtOAc (5 x 750 mL) and dried over Na2SO4. The residue after evaporation of the solvent was crystallized (EtOAc, 120 mL) to give pure diol 4a.
~ Os OH
\ 3 4 ~ CH2CI2 +
OH TBSO'~' ~
TBSO'~~
A stream of ozone was passed through a stirred solution of 7 (23.4 g, 45.8 mmol), pyridine (5.0 mL) and Sudane Red 7B (15.0 mg) in dichloromethane (550 mL), at -to -60 C until Sudane Red decolorized ( 55 min). Sodium borohydride (6.75 g, mmol) was then added followed by ethanol (250 mL). The reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (15 mL) was added and, after 30 min brine (300 mL) was added. The mixture was diluted with ethyl acetate (500 mL) and washed with water (600 mL). The aqueous phase was extracted with AcOEt (300 mL). The combined organic phases were dried over Na2SO4. The residue (26.5 g), after evaporation of the solvent, was filtered through a plug of silica gel (500 g, 15%, 30% and 50% AcOEt in hexane) to give: Fraction A
(5.9 g, mixture containing the desired A-ring (ca 83% pure by NMR) 'H NMR
S 5.3 8(1 H, t, J=6.4Hz), 4.90 (1 H, brs), 4.5 7(1 H, brs), 4.22 (1 H, dd, J=7.3, 12.5 Hz), 4.13 (1 H, dd, J=6.3, 12.5 Hz), 3.78 (1 H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s); Fraction A was used for the synthesis of the A-ring precursor.
Fraction B (14.6 g, mixture containing a CD-rings fragments on a different stage of oxidation). Fraction B was further ozonolyzed in order to obtain the Lythgoe diol (3).
A stream of ozone was passed through a stirred solution of Fraction B (14.6 g) and Sudane Red 7B (3.0 mg) in ethanol (225 mL) at -55 to -60 C for 30min ( Sudane Red decolorized). Sodium borohydride (3.75 g, 100 mmol) was added and the reaction was allowed to warm to room temperature and stirred at room temperature for lh.
Acetone (5 mL) was added and, after 30 min brine (200 mL) was added. The mixture was diluted with dichloromethane (300 mL) and washed with water (250 mL). The aqueous phase was extracted with dichloromethane (200 mL). The combined organic phases were, evaporated to dryness (the last portion was evaporated with addition of toluene 100 mL). The residue (16.2 g) was dissolved in dichloromethane (100 mL), concentrated to a volume of ca 20 mL diluted with petroleum ether (30 mL) and set aside in the fridge for crystallization. The white powder was filtered of (4.05 g), the mother liquor was concentrated and filtered through silica gel (100g, 5% MeOH
in CH2ClZ) to give yellow oil (9.4 g), which was recrystallized (20 mL, dichloromethane; petroleum ether 1:2) to give white powder (1.79 g). Thus the total yield of the Lythgoe dio13 was (5.84 g, 27.5 mmol, 60 % from D2) 'H NMR : S
4.08 (1 H, m), 3.64 (1 H, dd, J=3.3, 10.6 Hz), 3.39 (1 H, dd, J=6.6, 10.6 Hz), 2.04-1.14 (15H, m), 1.03 (3H, d, J=6.6 Hz), 0.96 (3H, s).
1-(2-Hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol (4a) and 1-(2-Hydroxy-l-methyl-ethyl)-7a-methyl-octahydro-inden-4-ol (3) OH
~ 03 OH
~ CH2CI2 \ 3 4a OH HO'~\
Ho~~Compound 2 (98.8 g, 249 mmol) was dissolved in dichloromethane (900 mL) and ethanol (400 mL), pyridine (25.0 mL) and Sudane Red 7B (30.0 mg) were added and the mixture was cooled down to -65 to -70 C. A stream of ozone was passed through for 3h. (until Sudane Red decolorized, reaction was also followed by TLC and decolorization of Sudane Red corresponds to consumption of Vitamin D2). Sodium borohydride (24.0g, 0.64 mol) was added portion-wise and the reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (75 mL) was added portion-wise (to keep temperature under 35 C) and the reaction mixture was stored overnight in the fridge. The mixture was washed with water (600 mL). The aqueous phase was extracted with dichloromethane (6x 300 mL). The combined organic phases were dried over Na2SO4. The residue (118 g) after evaporation of the solvent was passed through a plug of silica gel (0.5 kg, 30%, 50%
AcOEt in hexane) to give: Fraction A (69.7 g, CD-rings fragments); Fraction B
(4.8 g of a pure Lythgoe dio13 after crystallization from hexane:AcOEt 3:1);
Fraction C (12.3 g of a pure compound 4a, after crystallization from AcOEt); Fraction D(11.5 g, mixture of the desired compound 4a and 4-Methylene-cyclohexane-1,3-diol).
Fraction A was further ozonolyzed in order to obtain (3). A stream of ozone was passed through a stirred solution of Fraction A (69.7 g) in ethanol (500 mL), dichloromethane (600 mL) and Sudane Red 7B (3.0 mg) at -65 to -70 C for 3h. ( Sudane Red decolorized). Sodium borohydride (22.5g, 0.6 mol) was added and the reaction was allowed to warm to room temperature and stirred at room temperature for lh. Acetone (125 mL) was added portion-wise (to keep temperature under 35 C) and the reaction mixture was stored overnight in the fridge. The mixture was washed with water (600 mL). The aqueous phase was extracted with dichloromethane (2x mL) and with AcOEt (300 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The residue (55.0g) was purified by crystallization (AcOEt :hexane 1:2) to give: Fraction E (15.7 g of a pure crystalline 3);
Fraction F
(35 g, of mixture containing Lythgoe diol 3). Fraction F (35 g) was passed through a plug of silica gel (0.5 kg, 30%, 50% AcOEt in hexane) to give after crystallization (AcOEt :hexane 1:2) Fraction G (18.9 g), thus the overall yield of (3)was 39.4g 74.5% from 2).
' H NMR : 8 5.3 8(1 H, t, J=6.4Hz), 4.90 (1 H, brs), 4.57 (1 H, brs), 4.22 (1 H, dd, J=7.3, 12.5 Hz), 4.13 (1H, dd, J=6.3, 12.5 Hz), 3.78 (1H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s);
Fraction D (11.5 g) was passed through a plug of silica gel (0.3 kg, 50% AcOEt in hexane) to give (after crystallization (AcOEt): Fraction H(1.1 g of a pure crystalline compound 4a, 2.8%); Fraction I(10.2 g, mixture of the desired compound 4a.
Thus the overall yield of the isolated (S)-(Z)-3-(2-Hydroxy-ethylidene)-4-methylene-cyclohexanol (4a) is 13.4 g, 34.8%
'H NMR : 8 5.51 (1 H, t, J=6.6Hz), 5.03 (1 H, brs), 4.66 (1 H, brs), 4.24 (2H, m), , 3.94 (1 H, m), 2.55 (1 H, dd, J=3.9, 13.2 Hz), 2.41 (1H, m), 2.25 (1 H, dd, J=7.8, 12.9 Hz), 1.94 (1H, m), 1.65 (1H, m).
An alternative workup can be used. After the first ozonolysis the organic phase was extracted with water (4 x 800 mL). The combined water phases were back extracted with hexane (500 mL). The organic phases were dried over Na2SO4, concentrated in vacuo and used for the second 6zonolysis in order to obtain compound 3. The water phase was extracted with EtOAc (5 x 750 mL) and dried over Na2SO4. The residue after evaporation of the solvent was crystallized (EtOAc, 120 mL) to give pure diol 4a.
(S)-(Z)-2-[5-(tert-butyldimethyl)silanyloxy)-2-methylene-cyclohexylidene]-ethanol (4) OH OTBS OH
- --a CH2CI2 \ THF TBSO,\
HO'~~~ 4a TBSO'~ 4b '~ 4 To a stirred solution (S)-(Z)-3-(2-Hydroxy-ethylidene)-4-methylene-cyclohexanol (4a) (4.04 g, 26.3 mmol) in dichloromethane (40 mL), imidazole (5.36 g, 78.7 mmol) and (tert-butyldimethyl)silyl chloride (9.50 g, 63.0 mmol) were added successively.
The reaction mixture was stirred at room temperature for 100 min. after which water (25 mL) was added. After 15 min. the mixture was diluted with hexane (350 mL), washed with water (2x100 mL) and brine (50 mL) and dried over Na2SO4. The residue (10.7 g) after evaporation of the solvent was dissolved in tetrahydofurane (50 mL), Bu4NF (26.5 mL, 1M/THF) was added at +5 C and the mixture was stirred at +5 C for 45 min. and additiona130 min. at room temperature. The mixture was diluted with water (100 mL) and ethyl acetate (250 mL). After separation organic layer was washed with water (100 mL) and brine (50 mL). Aqueous layers were extracted with ethyl acetate (5x50 mL). The combined organic layers were dried over NaZSO4. The residue after evaporation of the solvent was purified by FC (150g, 10%
and 50% AcOEt in hexane and neat AcOEt) to give the titled compound 4. (6.43 g, 85% pure by NMR, 78% of the title compound).
I H NMR : S 5.38 (1H, t, J=6.4Hz), 4.90 (1H, brs), 4.57 (1H, brs), 4.22 (1H, dd, J=7.3, 12.5 Hz), 4.13 (1H, dd, J=6.3, 12.5 Hz), 3.78 (1H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
1. Synthesis of the A-ring precursor (2R,3S,7S)- [7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl]-methanol (8) OH OH
mCPBA
TBSO'*,6 CH2CI2 TBSO"'6 To a stirred solution of a crude 4 (5.9 g, ca 18.3 mmol, Fraction A from ozonolsysis) in dichloro-methane (120 mL) at room temperature, AcONa (2.14 g, 26.1 mmol) was added followed by 72% mCPBA (4.32 g, 18.0 mmol). The reaction mixture was then stirred at 10 C for 1/2h then diluted with hexane (200 mL) washed with 10%
K2CO3 (3x150 mL), and dried over NaZSO4. The residue after evaporation of solvent (6.6 g) was filtered through a plug of silica gel (150 g, 10% AcOEt in hexane) to give the crude title compound (4.87 g, ca 15.4 mmol, 84%) 1H-NMR: S 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J = 5.6 Hz), 3.60 (m, 2H), 3.86 (m, 1H), 4.91 (m, 1 H).
Benzoic acid (2R,3S,7S)-7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (9) O
OH O
0:, RZ O: ~ Rz " Pyridine '% R -H 9 TBSO' 8 TBSO' RZ=1 9A
RZ=Ph 9B
To a stirred solution of 8 (4.87 g, ca 15.4 mmol) in pyridine (25 mL) at room temperature, benzoyl chloride (2.14 mL, 18.4 mmol) was added and the reaction mixture was stirred for lh. Water (25 mL) was added and after stirring for 45 min at room temperature the mixture was diluted with hexane (80 mL), washed with saturated NaHCO3 solution (50 mL), and dried over Na2SO4. The residue after evaporation of solvent (17.5 g) was purified by FC (150 g, 10% AcOEt in hexane) to give the title compound (5.44 g, 14.0 mmol, 91%) 'H NMR: S 8.04-7.80 (2H, m), 7.56-7.50 (1H, m), 7.44-7.37 (2H, m), 4.94 (1H, brs), 4.92 (1H, brs), 4.32 (1H, dd, J=4.8, 11.9 Hz), 4.14 (1 H, dd, J=6.2, 11.9 Hz), 3.83 (1 H, m), 3.21 (1 H, dd, J=4.8, 6.2 Hz), 2.42 (1H, m), 2.04-1.90 (3H, m), 1.64-1.34 (2H, m), 0.83 (9H, s), 0.02 (3H, s), 0.01 (3H, s).
- --a CH2CI2 \ THF TBSO,\
HO'~~~ 4a TBSO'~ 4b '~ 4 To a stirred solution (S)-(Z)-3-(2-Hydroxy-ethylidene)-4-methylene-cyclohexanol (4a) (4.04 g, 26.3 mmol) in dichloromethane (40 mL), imidazole (5.36 g, 78.7 mmol) and (tert-butyldimethyl)silyl chloride (9.50 g, 63.0 mmol) were added successively.
The reaction mixture was stirred at room temperature for 100 min. after which water (25 mL) was added. After 15 min. the mixture was diluted with hexane (350 mL), washed with water (2x100 mL) and brine (50 mL) and dried over Na2SO4. The residue (10.7 g) after evaporation of the solvent was dissolved in tetrahydofurane (50 mL), Bu4NF (26.5 mL, 1M/THF) was added at +5 C and the mixture was stirred at +5 C for 45 min. and additiona130 min. at room temperature. The mixture was diluted with water (100 mL) and ethyl acetate (250 mL). After separation organic layer was washed with water (100 mL) and brine (50 mL). Aqueous layers were extracted with ethyl acetate (5x50 mL). The combined organic layers were dried over NaZSO4. The residue after evaporation of the solvent was purified by FC (150g, 10%
and 50% AcOEt in hexane and neat AcOEt) to give the titled compound 4. (6.43 g, 85% pure by NMR, 78% of the title compound).
I H NMR : S 5.38 (1H, t, J=6.4Hz), 4.90 (1H, brs), 4.57 (1H, brs), 4.22 (1H, dd, J=7.3, 12.5 Hz), 4.13 (1H, dd, J=6.3, 12.5 Hz), 3.78 (1H, m), 2.40-1.30 (6H, m), 0.83 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
1. Synthesis of the A-ring precursor (2R,3S,7S)- [7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl]-methanol (8) OH OH
mCPBA
TBSO'*,6 CH2CI2 TBSO"'6 To a stirred solution of a crude 4 (5.9 g, ca 18.3 mmol, Fraction A from ozonolsysis) in dichloro-methane (120 mL) at room temperature, AcONa (2.14 g, 26.1 mmol) was added followed by 72% mCPBA (4.32 g, 18.0 mmol). The reaction mixture was then stirred at 10 C for 1/2h then diluted with hexane (200 mL) washed with 10%
K2CO3 (3x150 mL), and dried over NaZSO4. The residue after evaporation of solvent (6.6 g) was filtered through a plug of silica gel (150 g, 10% AcOEt in hexane) to give the crude title compound (4.87 g, ca 15.4 mmol, 84%) 1H-NMR: S 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J = 5.6 Hz), 3.60 (m, 2H), 3.86 (m, 1H), 4.91 (m, 1 H).
Benzoic acid (2R,3S,7S)-7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (9) O
OH O
0:, RZ O: ~ Rz " Pyridine '% R -H 9 TBSO' 8 TBSO' RZ=1 9A
RZ=Ph 9B
To a stirred solution of 8 (4.87 g, ca 15.4 mmol) in pyridine (25 mL) at room temperature, benzoyl chloride (2.14 mL, 18.4 mmol) was added and the reaction mixture was stirred for lh. Water (25 mL) was added and after stirring for 45 min at room temperature the mixture was diluted with hexane (80 mL), washed with saturated NaHCO3 solution (50 mL), and dried over Na2SO4. The residue after evaporation of solvent (17.5 g) was purified by FC (150 g, 10% AcOEt in hexane) to give the title compound (5.44 g, 14.0 mmol, 91%) 'H NMR: S 8.04-7.80 (2H, m), 7.56-7.50 (1H, m), 7.44-7.37 (2H, m), 4.94 (1H, brs), 4.92 (1H, brs), 4.32 (1H, dd, J=4.8, 11.9 Hz), 4.14 (1 H, dd, J=6.2, 11.9 Hz), 3.83 (1 H, m), 3.21 (1 H, dd, J=4.8, 6.2 Hz), 2.42 (1H, m), 2.04-1.90 (3H, m), 1.64-1.34 (2H, m), 0.83 (9H, s), 0.02 (3H, s), 0.01 (3H, s).
Benzoic acid (2R,3S,5R,7S)-7-(t-butyldimethyl)silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro[2.5]oct-2-yI methyl ester (10) o ~
I ~ / ~
~
'~ Rz O:. R
O: ~ Rz Se02 dioxane z TBSO'~~~ \\ ''' 9 TBSO' OH 5 TBSO' ~ OH 10b RZ H 10(a) RZ I IOA(a) RZ Ph IOB(a) To a stirred solution of 9 (10.0 g, 25.7 mmol) ) in dioxane (550 mL) at 85 C
was added selenium dioxide, (3.33 g, 30.0 mmol) followed by t-butyl hydrogen peroxide (9.0 mL, 45.0 mmol, 5-6 M in nonane) and the reaction mixture was stirred at for 16 h, after which selenium dioxide (1.11 g, 10.0 mmol) was added followed by t-butyl hydrogen peroxide (3.0 mL, 15.0 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for additional 6 h. The solvent was removed under vacuum and the residue (15.3 g) was filtered through a plug of silica gel (300g, 20%
AcOEt in hexane) to give: starting material (970 mg, 10% ) and a mixture of l0a and lOb (8.7g). This mixture was divided into 3 portion (2.9 g each) and purified twice by FC (200 g, 5% isopropanol in hexane, same colunm was used for all six chromatographs) to give: lOb (1.83 g, as a 10:1 mixture of lOb:lOa ca 16% of 5a-hydroxy compound); l0a (6.0 g, 14.8 mmol, 58%) as white crystals. The structure of l0a was confirmed by X-ray crystallography.
'H NMR: S 8.02-7.90 (2H, m), 7.58-7.50 (1H, m), 7.46-7.38 (2H, m), 5.25 (1H, br s), 5.11 (1 H, br s), 4.26 (1 H, dd, J=5.5, 12.1 Hz), 4.15 (1 H, dd, J=5.9, 12.1 Hz), 4.07 (1 H, m), 3.8 7(1 H, m), 3.19 (1 H, dd, J=5.5, 5.9 Hz), 2.34-1.10 (5H, m), 0.81 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
I ~ / ~
~
'~ Rz O:. R
O: ~ Rz Se02 dioxane z TBSO'~~~ \\ ''' 9 TBSO' OH 5 TBSO' ~ OH 10b RZ H 10(a) RZ I IOA(a) RZ Ph IOB(a) To a stirred solution of 9 (10.0 g, 25.7 mmol) ) in dioxane (550 mL) at 85 C
was added selenium dioxide, (3.33 g, 30.0 mmol) followed by t-butyl hydrogen peroxide (9.0 mL, 45.0 mmol, 5-6 M in nonane) and the reaction mixture was stirred at for 16 h, after which selenium dioxide (1.11 g, 10.0 mmol) was added followed by t-butyl hydrogen peroxide (3.0 mL, 15.0 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for additional 6 h. The solvent was removed under vacuum and the residue (15.3 g) was filtered through a plug of silica gel (300g, 20%
AcOEt in hexane) to give: starting material (970 mg, 10% ) and a mixture of l0a and lOb (8.7g). This mixture was divided into 3 portion (2.9 g each) and purified twice by FC (200 g, 5% isopropanol in hexane, same colunm was used for all six chromatographs) to give: lOb (1.83 g, as a 10:1 mixture of lOb:lOa ca 16% of 5a-hydroxy compound); l0a (6.0 g, 14.8 mmol, 58%) as white crystals. The structure of l0a was confirmed by X-ray crystallography.
'H NMR: S 8.02-7.90 (2H, m), 7.58-7.50 (1H, m), 7.46-7.38 (2H, m), 5.25 (1H, br s), 5.11 (1 H, br s), 4.26 (1 H, dd, J=5.5, 12.1 Hz), 4.15 (1 H, dd, J=5.9, 12.1 Hz), 4.07 (1 H, m), 3.8 7(1 H, m), 3.19 (1 H, dd, J=5.5, 5.9 Hz), 2.34-1.10 (5H, m), 0.81 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
Benzoic acid (2R,3S,5S,7R)-7-(t-butyldimethyl)silanyloxy)-5-fluoro-4-methylene-1-oxa-spiro[2.5]oct-2-ylmethyl ester (11) O O
60H 0:;RZ DAST Rz trichloroethylene TBSO*'\\ F RZ=H 11 TBSO'10a RZ=1 11A
10A(a) 10B(a) RZ Ph 11 B
To a stirred solution of a diethylaminosulfur trifluoride (DAST) (2.0 mL, 16.0 mmol) in trichloroethylene (20 mL) a solution of 10 (2.78 g, 6.87 mmol) in trichloroethylene (126 mL was added at -75 C. After stirring for 20 min at -75 C methanol (5.5 mL) was added followed by saturated NaHCO3 solution (6 mL) and the resulting mixture was diluted with hexane (150 mL) and washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4 and concentrated. The residue (4.5 g) was purified by FC
(150 g, DCM:hexane:AcOEt 10:20:0.2) to give the title compound (2.09 g, 5.14 mmol, 75%) 'H NMR: S 8.02-7.99 (2H, m), 7.53-7.45 (1H, m), 7.40-7.33 (2H, m), 5.26 (2H, m), 5.11 (1 H, dt, J=3.0, 48.0 Hz), 4.46 (1 H, dd, J=3.3, 12.5 Hz), 4.21 (1H, m), 3.94 (1 H, dd, J=7.7, 12.5 Hz), 3.29 (1 H, dd, J=3.3, 7.7 Hz), 2.44-1.44 (4H, m), 0.80 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
Benzoic acid 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethyl ester (12) O O
O \ O
TpReO3/PPh3 O' ~ R I
PhMe RZ
TBSO"N\ F RZ=H 11 TBSO"%\ F RZ=H 12 RZ=I 11 A RZ= I 12A
RZ=Ph 11 B RZ=Ph 12B
A mixture of tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide (265 mg, 0.50 mmol), triphenylphosphine (158 mg, 0.6 mmol), epoxide 11 (203 mg, 0.5 mmol) and toluene (8 mL) was sealed in an ampule under argon and heated at 100 C for 14h.
60H 0:;RZ DAST Rz trichloroethylene TBSO*'\\ F RZ=H 11 TBSO'10a RZ=1 11A
10A(a) 10B(a) RZ Ph 11 B
To a stirred solution of a diethylaminosulfur trifluoride (DAST) (2.0 mL, 16.0 mmol) in trichloroethylene (20 mL) a solution of 10 (2.78 g, 6.87 mmol) in trichloroethylene (126 mL was added at -75 C. After stirring for 20 min at -75 C methanol (5.5 mL) was added followed by saturated NaHCO3 solution (6 mL) and the resulting mixture was diluted with hexane (150 mL) and washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4 and concentrated. The residue (4.5 g) was purified by FC
(150 g, DCM:hexane:AcOEt 10:20:0.2) to give the title compound (2.09 g, 5.14 mmol, 75%) 'H NMR: S 8.02-7.99 (2H, m), 7.53-7.45 (1H, m), 7.40-7.33 (2H, m), 5.26 (2H, m), 5.11 (1 H, dt, J=3.0, 48.0 Hz), 4.46 (1 H, dd, J=3.3, 12.5 Hz), 4.21 (1H, m), 3.94 (1 H, dd, J=7.7, 12.5 Hz), 3.29 (1 H, dd, J=3.3, 7.7 Hz), 2.44-1.44 (4H, m), 0.80 (9H, s), 0.01 (3H, s), 0.00 (3H, s).
Benzoic acid 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethyl ester (12) O O
O \ O
TpReO3/PPh3 O' ~ R I
PhMe RZ
TBSO"N\ F RZ=H 11 TBSO"%\ F RZ=H 12 RZ=I 11 A RZ= I 12A
RZ=Ph 11 B RZ=Ph 12B
A mixture of tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide (265 mg, 0.50 mmol), triphenylphosphine (158 mg, 0.6 mmol), epoxide 11 (203 mg, 0.5 mmol) and toluene (8 mL) was sealed in an ampule under argon and heated at 100 C for 14h.
(TLC, 10% AcOEt in hexane, mixture of substrate and product, ca 1:1). Rhenium oxide did not completely solubilized. A solution of triphenylphosphine (158 mg, 0.6 mmol) in toluene (4 mL) was added and the heating continued for 6h. The reaction mixture was cooled to room temperature filtered through a plug of silica gel and then the residue after evaporation of the solvent was purified by FC (20g, 5% AcOEt in hexane) to give : 12 (120 mg, 0.31 mmol, 61% of the desire product) and 70 mg of the starting material plus minor contaminations, ca 34 %.
(1 Z,3S,5R)- 2-[5-(t-butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13) MeONa I
RZ
MeOH TBSO"N\ F
TBSO" F RZ=H 12 RZ=I 12A 13 RZ=Ph 12B
To a solution of a benzoate 12 (150 mg, 0.38 mmol) in methanol (3mL) was added sodium methoxide (0.5 mL, 15% in methanol). After stirring for lh at room temperature water was added (6 mL) and the mixture was extracted with methylene chloride (3x 10 mL). The combined organic layers was dried over NaZSO4 and evaporated to dryness. The residue (0.2 g) was purified by FC (20g, 15% AcOEt in hexane) to give 13 (80 mg, 0.28 mmol, 73% of the product).
(1R,3Z,5S)-t-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy]-dimethylsilane (23) OH CI
Triphosgene Pyridine Hexane TBSO'~\\ F
TBSO'~~~ F 13 23 To a solution of 13 (8.07 g, 28.2 mmol) and triphosgene (4.18 g, 14.1 mmol) in hexane (150 mL) at 0 C was added over 30 min a solution of pyridine (4.5 mL, 55.6 mmol) in hexane (20 mL) and the reaction mixture was stirred at this temperature for 30 min and at room temperature for another 30 min. The reaction mixture was washed with CuSO4 aq (3 x 200 mL). The combined aqueous layers were back-extracted with hexane (2 x 100 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to give the title compound (9.0 g, overweight). This material was used immediately in the next step without further purification. [a]25D +
73.0 (c 0.28, CHC13); IR (CHC13) 1643, 838 cm 1; 'H-NMR S 0.08 (s, 6H), 0.88 (s, 9H), 1.84-2.03 (m, 1 H), 2.12 (br s, 1 H), 2.24 (m, 1 H), 2.48 (br d, J = 13 Hz, 1 H), 4.06-4.26 (m, 3H), 5.10 (br d, J = 48 Hz), 5.16 (s, 1 H), 5.35 (s, 1 H), 5.63 (br t, J = 6 Hz, 1 H).
(1S,3Z,5R)-1-fluoro-5-(t-butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane (6) ci P(O)Ph2 Ph2P(O)H
~ NaH
DMF TBSO',,\ F
TBSO", F 23 6 Diphenylphosphine oxide (6.70 g, 33.1 mmol) was added portionwise, over 15 min to a suspension of NaH (1.33 g, 33.1 mmol, 60% dispersion in mineral oil) in DMF
(50 mL) at 10 C. The resulting solution was stirred at room temperature for 30 min and cooled to - 60 C. The solution of crude 23 (9.0 g) in DMF (20 mL)was then added dropwise. The reaction mixture was stirred at -60 C for 2h and at room temperature for lh, diluted with diethyl ether (600 mL) and washed with water (3x200 mL).
The aqueous layers were extracted with diethyl ether (200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give white solid. The crude product was recrystallized from diisopropyl ether (25 mL).
The resulting solid was collected by filtration, washed with cold diisopropyl ether (5 mL) and dried under high vacuum to give the title compound (7.93 g). The mother liquor was concentrated and the residue was subjected to chromatography on silca gel (50 g, 30%-50% AcOEt in hexane) to give title compound (2.22 g). Thus the total yield of the of 6 was (10.1 g, 21.5 mmol, 76% overall from 13. [a]25p + 50.2 (c 0.84, CHC13); IR (CHC13) 835, 692 cm 1 ; UVX ,,aX (ethanol) 223 (E 22770), 258 (1950), 265 (1750), 272 nm (1280); MS, m/e 470 (M+), 455 (4), 450 (8), 413 (98), 338 (9), (100); IH-NMR: S 0.02 (s, 6 H), 0.84 (s, 9H), 1.76-1.93 (m, 1 H), 2.16 (m, 2 H), 2.42 (br d, 1 H), 3.28 (m, 2 H), 4.01 (m, 1 H), 5.02 (dm, J = 44 Hz, 1 H), 5.14 (s, 1 H), 5.30 (s, 1 H), 5.5 (m, 1 H), 7.5 (m, 6 H), 7.73 (m, 4 H). Analysis Calcd for CZ7H36O2FPSi:
C 68.91, H 7.71; F 4.04; Found: C 68.69, H 7.80, F 3.88.
Applying the same procedure by using 4-iodobenzoyl chloride and 4-biphenylcarbonyl chloride respetively, provided compounds 9A, 1 OA, 11 A, 12A
and 9B, lOB,11B and 12B in similar yields.
2. Larger Scale Synthesis of the A-ring precursor (2R,3S,7S)- [7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.51 oct-2-yl]-methanol (8) OH OH
\
O'=~~
mCPBA
TBSO'~\\6 CH2CI2 TBSO'~\\4 8 To a stirred solution of crude (S)-(Z)-2-[5-(tert-butyldimethyl)silanyloxy)-2-methylene-cyclohexylidene]-ethanol (4) (13.5 g, ca 40 mmol) in dichloromethane (100 mL) at room temperature, was added AcONa (4.5 g, 54.8 mmol), followed by 77% mCPBA (8.96 g, 40.0 mmol) at +5 C. The reaction mixture was then stirred at +5 C for 1.5h, diluted with hexane (500 mL), washed with water (200 mL) and saturated NaHCO3 solution (2x 200 mL) and dried over Na2SO4. The residue after evaporation of solvent (12.36 g) was used for the next step without further purification. 'H-NMR: S 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J =
5.6 Hz), 3.60 (m, 2H), 3.86 (m, 1 H), 4.91 (m, 1H).
(1 Z,3S,5R)- 2-[5-(t-butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13) MeONa I
RZ
MeOH TBSO"N\ F
TBSO" F RZ=H 12 RZ=I 12A 13 RZ=Ph 12B
To a solution of a benzoate 12 (150 mg, 0.38 mmol) in methanol (3mL) was added sodium methoxide (0.5 mL, 15% in methanol). After stirring for lh at room temperature water was added (6 mL) and the mixture was extracted with methylene chloride (3x 10 mL). The combined organic layers was dried over NaZSO4 and evaporated to dryness. The residue (0.2 g) was purified by FC (20g, 15% AcOEt in hexane) to give 13 (80 mg, 0.28 mmol, 73% of the product).
(1R,3Z,5S)-t-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy]-dimethylsilane (23) OH CI
Triphosgene Pyridine Hexane TBSO'~\\ F
TBSO'~~~ F 13 23 To a solution of 13 (8.07 g, 28.2 mmol) and triphosgene (4.18 g, 14.1 mmol) in hexane (150 mL) at 0 C was added over 30 min a solution of pyridine (4.5 mL, 55.6 mmol) in hexane (20 mL) and the reaction mixture was stirred at this temperature for 30 min and at room temperature for another 30 min. The reaction mixture was washed with CuSO4 aq (3 x 200 mL). The combined aqueous layers were back-extracted with hexane (2 x 100 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to give the title compound (9.0 g, overweight). This material was used immediately in the next step without further purification. [a]25D +
73.0 (c 0.28, CHC13); IR (CHC13) 1643, 838 cm 1; 'H-NMR S 0.08 (s, 6H), 0.88 (s, 9H), 1.84-2.03 (m, 1 H), 2.12 (br s, 1 H), 2.24 (m, 1 H), 2.48 (br d, J = 13 Hz, 1 H), 4.06-4.26 (m, 3H), 5.10 (br d, J = 48 Hz), 5.16 (s, 1 H), 5.35 (s, 1 H), 5.63 (br t, J = 6 Hz, 1 H).
(1S,3Z,5R)-1-fluoro-5-(t-butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane (6) ci P(O)Ph2 Ph2P(O)H
~ NaH
DMF TBSO',,\ F
TBSO", F 23 6 Diphenylphosphine oxide (6.70 g, 33.1 mmol) was added portionwise, over 15 min to a suspension of NaH (1.33 g, 33.1 mmol, 60% dispersion in mineral oil) in DMF
(50 mL) at 10 C. The resulting solution was stirred at room temperature for 30 min and cooled to - 60 C. The solution of crude 23 (9.0 g) in DMF (20 mL)was then added dropwise. The reaction mixture was stirred at -60 C for 2h and at room temperature for lh, diluted with diethyl ether (600 mL) and washed with water (3x200 mL).
The aqueous layers were extracted with diethyl ether (200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give white solid. The crude product was recrystallized from diisopropyl ether (25 mL).
The resulting solid was collected by filtration, washed with cold diisopropyl ether (5 mL) and dried under high vacuum to give the title compound (7.93 g). The mother liquor was concentrated and the residue was subjected to chromatography on silca gel (50 g, 30%-50% AcOEt in hexane) to give title compound (2.22 g). Thus the total yield of the of 6 was (10.1 g, 21.5 mmol, 76% overall from 13. [a]25p + 50.2 (c 0.84, CHC13); IR (CHC13) 835, 692 cm 1 ; UVX ,,aX (ethanol) 223 (E 22770), 258 (1950), 265 (1750), 272 nm (1280); MS, m/e 470 (M+), 455 (4), 450 (8), 413 (98), 338 (9), (100); IH-NMR: S 0.02 (s, 6 H), 0.84 (s, 9H), 1.76-1.93 (m, 1 H), 2.16 (m, 2 H), 2.42 (br d, 1 H), 3.28 (m, 2 H), 4.01 (m, 1 H), 5.02 (dm, J = 44 Hz, 1 H), 5.14 (s, 1 H), 5.30 (s, 1 H), 5.5 (m, 1 H), 7.5 (m, 6 H), 7.73 (m, 4 H). Analysis Calcd for CZ7H36O2FPSi:
C 68.91, H 7.71; F 4.04; Found: C 68.69, H 7.80, F 3.88.
Applying the same procedure by using 4-iodobenzoyl chloride and 4-biphenylcarbonyl chloride respetively, provided compounds 9A, 1 OA, 11 A, 12A
and 9B, lOB,11B and 12B in similar yields.
2. Larger Scale Synthesis of the A-ring precursor (2R,3S,7S)- [7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.51 oct-2-yl]-methanol (8) OH OH
\
O'=~~
mCPBA
TBSO'~\\6 CH2CI2 TBSO'~\\4 8 To a stirred solution of crude (S)-(Z)-2-[5-(tert-butyldimethyl)silanyloxy)-2-methylene-cyclohexylidene]-ethanol (4) (13.5 g, ca 40 mmol) in dichloromethane (100 mL) at room temperature, was added AcONa (4.5 g, 54.8 mmol), followed by 77% mCPBA (8.96 g, 40.0 mmol) at +5 C. The reaction mixture was then stirred at +5 C for 1.5h, diluted with hexane (500 mL), washed with water (200 mL) and saturated NaHCO3 solution (2x 200 mL) and dried over Na2SO4. The residue after evaporation of solvent (12.36 g) was used for the next step without further purification. 'H-NMR: S 0.063 and 0.068 (2s, 6H), 0.88 (s, 9H), 1.38-1.49 (m, 1H), 1.54 (m, 1H, OH), 1.62 (m, 1H), 1.96 (m, 3H), 2.43 (m, 1H), 3.095 (t, 1H, J =
5.6 Hz), 3.60 (m, 2H), 3.86 (m, 1 H), 4.91 (m, 1H).
Benzoic acid (2R,3S,7S)-7-(t-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (9) OH 0 0.,RZ
, Pyridine \ R -H 9 TBSO 8 TBSO RZ=1 9A
RZPh9B
To a stirred solution of (2R,3S,7S)-[7-(tert-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl]-methanol (8) (12.36 g) in pyridine (50 mL) at room temperature, was added benzoyl chloride (8.5 mL, 73 mmol) and the reaction mixture was stirred for 2h. Water (60 mL) was added and after stirring for 45 min at room temperature the mixture was diluted with hexane (250 mL), washed with saturated NaHCO3 solution (2x250 mL), brine (250 mL) and dried over Na2SO4. The residue after evaporation of the solvent (15.28 g) was used for the next step without further purification. 'H NMR: S 8.04-7.80 (2H, m), 7.56-7.50 (1H, m), 7.44-7.37 (2H, m), 4.94 (1 H, brs), 4.92 (1 H, brs), 4.32 (1 H, dd, J=4.8, 11.9 Hz), 4.14 (1 H, dd, J=6.2, 11.9 Hz), 3.83 (1 H, m), 3.21 (1 H, dd, J=4.8, 6.2 Hz), 2.42 (1 H, m), 2.04-1.90 (3H, m), 1.64-1.34 (2H, m), 0.83 (9H, s), 0.02 (3H, s), 0.01 (3H, s).
Benzoic acid (2R,3S,5R,7S)-7-(t-butyldimethyl)silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (10) ~
~ / ~ 0\
i /
O: ~ o Rz Se02 O
~ ~
Rz O:. R
z TBSO',\dioxane 9 TBSO*'\\ OH 5 TBSO" OH 10b RZ H 10(a) RZ I 10A(a) RZ Ph 10B(a) To a stirred solution of benzoic acid (2R,3S,7S)-7-(tert-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (9) (15.28 g) ) in dioxane (450 mL) at 85 C was added selenium dioxide (4.26 g, 38.4 mmol), followed by tert-butyl hydrogen peroxide (7.7 mL, 38.4 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for 13h, after which selenium dioxide (2.39 g, 21.5 mmol) was added, followed by tert-butyl hydrogen peroxide (4.3 mL, 21.5 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for additiona124h. The mixture was filtered off through a plug of silica gel (0.5 kg, AcOEt). The solvent was removed under vacuum and the residue was dissolved in AcOEt (250 mL) and washed with water (3x 100 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue (16 g) was purified by flash chromatography (0.5 kg, 10, 15 and 20% AcOEt in hexane) to give: Fraction A(1.1 g, of a starting material);
Fraction B
(0.78 g, of lOb); Fraction C (3.01 g, 65:35 (lOb:lOa); Fraction D (6.22 g, 5:95 (lOb:lOa); Fraction D was crystallized two times (each time using the remaining oil) from hexane to give pale yellow solid Fraction E (6.0 g in total) and yellow-red oil Fraction F (0.2 g in total). Fractions C and F were purified by flash chromatography (300 g, 20% AcOEt in hexane) to give: Fraction G (0.8 g, of lOb); Fraction H
(2.4 g, 8:92 lOb:lOa). Fraction H was crystallized two times (each time using the remaining oil) from hexane to give pale yellow solid Fraction I(2.2 g in total) and yellow-red oil Fraction J (0.2 g in total). Fractions E and I were combined to give l0a (8.2 g, 20.3 mmol, 50.7% total yield from compound 4). [a]22D -10.6 (c 0.35, EtOH); 'H
NMR:
8 8.04 (2H, m), 7. 5 8(1 H, m), 7.46 (2H, m), 5.32 (1 H, br s), 5.18 (1 H, br s), 4. 3 3(1 H, dd, J=5.2, 11.9 Hz), 4.21 (1 H, dd, J=6.0, 11.9 Hz), 4.14 (1H, ddd, J=2.6,4.9, 10.0 Hz), 3.94 (1 H, m), 3.25 (1 H, dd, J=5.5, 5.9 Hz), 2.3 8(1 H, m), 2.05 (1 H, t, J=11.5 Hz), 1.64 (1H, ddd, J=1.9, 4.3, 12.2 Hz), 1.52 dt, J=11.1, 11.7 Hz), 1.28 (1H, m), 0.87 (9H, s), 0.07 (3H, s), 0.06 (3H, s);
13C NMR : 166.31(0), 145.52(0), 133.29(1), 129.65(1), 129.54(0), 128.46(1), 107.44(2),68.51(1), 65.95(1), 62.75(2), 61.62(1), 61.09(0), 45.23(2), 44.33(2), 25.72(3), 18.06(0), -4.72(3); MS HR-ES: Calcd. For C2ZH32O5Si: M+Na 427.1911 Found: 427.1909.
In the case of esters 9A and 9B, the isomeric mixtures of 10A(a) and 10B(a) were purified by crystallization (hexane EtOAc) to give pure epimers, avoiding tedious chromatographic purifications.
, Pyridine \ R -H 9 TBSO 8 TBSO RZ=1 9A
RZPh9B
To a stirred solution of (2R,3S,7S)-[7-(tert-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl]-methanol (8) (12.36 g) in pyridine (50 mL) at room temperature, was added benzoyl chloride (8.5 mL, 73 mmol) and the reaction mixture was stirred for 2h. Water (60 mL) was added and after stirring for 45 min at room temperature the mixture was diluted with hexane (250 mL), washed with saturated NaHCO3 solution (2x250 mL), brine (250 mL) and dried over Na2SO4. The residue after evaporation of the solvent (15.28 g) was used for the next step without further purification. 'H NMR: S 8.04-7.80 (2H, m), 7.56-7.50 (1H, m), 7.44-7.37 (2H, m), 4.94 (1 H, brs), 4.92 (1 H, brs), 4.32 (1 H, dd, J=4.8, 11.9 Hz), 4.14 (1 H, dd, J=6.2, 11.9 Hz), 3.83 (1 H, m), 3.21 (1 H, dd, J=4.8, 6.2 Hz), 2.42 (1 H, m), 2.04-1.90 (3H, m), 1.64-1.34 (2H, m), 0.83 (9H, s), 0.02 (3H, s), 0.01 (3H, s).
Benzoic acid (2R,3S,5R,7S)-7-(t-butyldimethyl)silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (10) ~
~ / ~ 0\
i /
O: ~ o Rz Se02 O
~ ~
Rz O:. R
z TBSO',\dioxane 9 TBSO*'\\ OH 5 TBSO" OH 10b RZ H 10(a) RZ I 10A(a) RZ Ph 10B(a) To a stirred solution of benzoic acid (2R,3S,7S)-7-(tert-butyldimethyl)silanyloxy)-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (9) (15.28 g) ) in dioxane (450 mL) at 85 C was added selenium dioxide (4.26 g, 38.4 mmol), followed by tert-butyl hydrogen peroxide (7.7 mL, 38.4 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for 13h, after which selenium dioxide (2.39 g, 21.5 mmol) was added, followed by tert-butyl hydrogen peroxide (4.3 mL, 21.5 mmol, 5-6 M in nonane) and the reaction mixture was stirred at 85 C for additiona124h. The mixture was filtered off through a plug of silica gel (0.5 kg, AcOEt). The solvent was removed under vacuum and the residue was dissolved in AcOEt (250 mL) and washed with water (3x 100 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue (16 g) was purified by flash chromatography (0.5 kg, 10, 15 and 20% AcOEt in hexane) to give: Fraction A(1.1 g, of a starting material);
Fraction B
(0.78 g, of lOb); Fraction C (3.01 g, 65:35 (lOb:lOa); Fraction D (6.22 g, 5:95 (lOb:lOa); Fraction D was crystallized two times (each time using the remaining oil) from hexane to give pale yellow solid Fraction E (6.0 g in total) and yellow-red oil Fraction F (0.2 g in total). Fractions C and F were purified by flash chromatography (300 g, 20% AcOEt in hexane) to give: Fraction G (0.8 g, of lOb); Fraction H
(2.4 g, 8:92 lOb:lOa). Fraction H was crystallized two times (each time using the remaining oil) from hexane to give pale yellow solid Fraction I(2.2 g in total) and yellow-red oil Fraction J (0.2 g in total). Fractions E and I were combined to give l0a (8.2 g, 20.3 mmol, 50.7% total yield from compound 4). [a]22D -10.6 (c 0.35, EtOH); 'H
NMR:
8 8.04 (2H, m), 7. 5 8(1 H, m), 7.46 (2H, m), 5.32 (1 H, br s), 5.18 (1 H, br s), 4. 3 3(1 H, dd, J=5.2, 11.9 Hz), 4.21 (1 H, dd, J=6.0, 11.9 Hz), 4.14 (1H, ddd, J=2.6,4.9, 10.0 Hz), 3.94 (1 H, m), 3.25 (1 H, dd, J=5.5, 5.9 Hz), 2.3 8(1 H, m), 2.05 (1 H, t, J=11.5 Hz), 1.64 (1H, ddd, J=1.9, 4.3, 12.2 Hz), 1.52 dt, J=11.1, 11.7 Hz), 1.28 (1H, m), 0.87 (9H, s), 0.07 (3H, s), 0.06 (3H, s);
13C NMR : 166.31(0), 145.52(0), 133.29(1), 129.65(1), 129.54(0), 128.46(1), 107.44(2),68.51(1), 65.95(1), 62.75(2), 61.62(1), 61.09(0), 45.23(2), 44.33(2), 25.72(3), 18.06(0), -4.72(3); MS HR-ES: Calcd. For C2ZH32O5Si: M+Na 427.1911 Found: 427.1909.
In the case of esters 9A and 9B, the isomeric mixtures of 10A(a) and 10B(a) were purified by crystallization (hexane EtOAc) to give pure epimers, avoiding tedious chromatographic purifications.
Benzoic acid (2R,3S,5S,7R)-7-(t-butyldimethyl)silanyloxy)-5-fluoro-4-methylene-1-oxa-spiro[2.5]oct-2-ylmethyl ester (11) O
O O
60H O;'RZ DAST Rz trichloroethylene TBSO~~\\ F RZ=H 11 TBS10a RZ=I 11A
10A(a) 10B(a) RZ=Ph 11 B
To a stirred solution of diethylaminosulfur trifluoride (16.5 mL, 126.0 mmol) in trichloroethylene (140 mL) was added a solution of benzoic acid (2R,3S,5R,7S)-(tert-butyldimethyl)silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro [2.5]oct-2-yl methyl ester (l0a) (18.7 g, 46.2 mmol) in trichloroethylene (100 mL at -75 C.
After stirring for 20 min. at -75 C methanol (40 mL) was added, followed by NaHCO3ay (50 mL) and the resulting mixture was diluted with hexane (700 mL) and washed with saturated NaHCO3 solution (600 mL), dried over Na2SO4 and concentrated on rotary evaporator. The residue (25.6 g) was purified by flash chromatography (500g, DCM:hexane:AcOEt 10:20:0.2) to give 11 (13.9 g, 34.2 mmol, 74%); [a]29D +38.9 (c 0.8, CHC13);'H NMR: 8 8.07 (2H, m), 7.57 (1H, m), 7.44 (2H, m), 5.33 (2H, m), 5.20 (1 H, dt, J=2.9, 48Hz), 4.55 (1 H, dd, J=3.2, 12.3 Hz), 4.29 (1 H, m), 4.02 (1 H, dd, J=7.9, 12.3 Hz), 3.37 (1 H, dd, J=3.2, 7.7 Hz), 2.45 (1 H, m), 2.05 (1 H, t, J=11.9 Hz), 1.73 (1H, dm), 1.62 (1H, m), 0.88 (9H, s), 0.08 (3H, s), 0.06 (3H, s); 13C NMR
:
166.25(0), 139.95(0, d, J=17Hz), 132.97(1), 129.75(0), 129.62(1), 128.24(1), 116.32(2, d, J=9Hz), 92.11 (1, d, J=162Hz), 65.23(1), 63.78(2), 62.29(1), 60.35(0), 44.38(2), 41.26(2, d, J=23Hz), 25.81(3), 18.13(0), -4.66(3); MS HR-ES: Calcd.
For C22H31O4SiF: M+H 407.2049 Found: 407.2046.
(1 E,3S,5R)- 2-[5-(tert-Butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13a) OH
Rz ~
WCI6/nBuLi TBSO' ~~ F RZ=H 11 THF TBSO'~F 13a RZ=1 11A
RZ=Ph 11 B
O O
60H O;'RZ DAST Rz trichloroethylene TBSO~~\\ F RZ=H 11 TBS10a RZ=I 11A
10A(a) 10B(a) RZ=Ph 11 B
To a stirred solution of diethylaminosulfur trifluoride (16.5 mL, 126.0 mmol) in trichloroethylene (140 mL) was added a solution of benzoic acid (2R,3S,5R,7S)-(tert-butyldimethyl)silanyloxy)-5-hydroxy-4-methylene-l-oxa-spiro [2.5]oct-2-yl methyl ester (l0a) (18.7 g, 46.2 mmol) in trichloroethylene (100 mL at -75 C.
After stirring for 20 min. at -75 C methanol (40 mL) was added, followed by NaHCO3ay (50 mL) and the resulting mixture was diluted with hexane (700 mL) and washed with saturated NaHCO3 solution (600 mL), dried over Na2SO4 and concentrated on rotary evaporator. The residue (25.6 g) was purified by flash chromatography (500g, DCM:hexane:AcOEt 10:20:0.2) to give 11 (13.9 g, 34.2 mmol, 74%); [a]29D +38.9 (c 0.8, CHC13);'H NMR: 8 8.07 (2H, m), 7.57 (1H, m), 7.44 (2H, m), 5.33 (2H, m), 5.20 (1 H, dt, J=2.9, 48Hz), 4.55 (1 H, dd, J=3.2, 12.3 Hz), 4.29 (1 H, m), 4.02 (1 H, dd, J=7.9, 12.3 Hz), 3.37 (1 H, dd, J=3.2, 7.7 Hz), 2.45 (1 H, m), 2.05 (1 H, t, J=11.9 Hz), 1.73 (1H, dm), 1.62 (1H, m), 0.88 (9H, s), 0.08 (3H, s), 0.06 (3H, s); 13C NMR
:
166.25(0), 139.95(0, d, J=17Hz), 132.97(1), 129.75(0), 129.62(1), 128.24(1), 116.32(2, d, J=9Hz), 92.11 (1, d, J=162Hz), 65.23(1), 63.78(2), 62.29(1), 60.35(0), 44.38(2), 41.26(2, d, J=23Hz), 25.81(3), 18.13(0), -4.66(3); MS HR-ES: Calcd.
For C22H31O4SiF: M+H 407.2049 Found: 407.2046.
(1 E,3S,5R)- 2-[5-(tert-Butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13a) OH
Rz ~
WCI6/nBuLi TBSO' ~~ F RZ=H 11 THF TBSO'~F 13a RZ=1 11A
RZ=Ph 11 B
Tungsten hexachloride (36.4 g, 91 mmol) was added at -75 C to THF (800 mL).
The temperature was adjusted to -65 C and nBuLi (73 mL, 182.5 mmol, 2.5M solution in hexane) was added maintaining temperature below -20 C. After the addition was completed the reaction mixture was allowed to come to room temperature and it was stirred for 30 min., cooled down to 0 C, when a solution of benzoic acid (2R,3 S,5 S,7R)-7-(tert-butyldimethyl)silanyloxy)-5-fluoro-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (11) (18.5 g, 45.5 mmol) in THF (50 mL) was added.
Thus formed mixture was allowed to come to room temperature (2h) and stirred for 16h. Methanol (400 mL) was added followed by sodium methoxide (250 mL, 15% in methanol), the resulting mixture was stirred for 30 min then diluted with AcOEt (1 L) and washed with water (1 L) and brine (500 mL). The residue (21.6 g) after evaporation of the dried (NaZSO4) solvent was used for the next step without further purification.
1H-NMR (CDC13); 8 0.09 (s, 6H), 0.81 (s, 9H), 1.80-2.22 (m, 3H), 2.44 (m, 1H), 4.10 (m, 1H), 4.14 (d, 2H, J=6.9 Hz), 4.98 (br s, 1H), 5.10 (d, 1H, J = 50.0 Hz), 5.11 (s, 1H), 5.79 (t, 1 H, J = 6.8 Hz).
(1Z,3S,5R)- 2-[5-(tert-Butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13) OH OH
hv ~ 9-fluorenone TBSO"" F 13a t-BuOMe TBSO',%\ F 13 A solution of (lE,3S,5R)- 2-[5-(tert-butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13a) (21.6 g, crude containing ca 10% of the Z
isomer) and 9-fluorenone (1.8 g, 10 mmol) in tert-Butyl-methyl ether (650 mL) was irradiated with 450W hanovia lamp with uranium core filter for 8 h. The residue after evaporation of solvent (23.95g) was purified by flash chromatography (750g, 5%,20%, AcOEt in hexane) to give the title compound 13 (10.4 g, 36.3 mmol, 80%
from 11). [a]30p +40.1 (c 0.89, EtOH).
' H-NMR : S 5.65 (1 H, t, J=6.8Hz), 5.31(1 H, dd, J=1. 5, 1.7Hz), 5.10 (1 H, ddd, J=3.2, 6.0, 49.9Hz), 4.95(1H, d, J=1.7Hz), 4.28(1H, dd, J=7.3, 12.6Hz), 4.19 (111, ddd, J=1.7, 6.4, 12.7Hz), 4.15(1H, m), 2.48 (1H, dd, J=3.8, 13.0Hz), 2.27-2.13 (2H, m), 1.88 (1H, m), 0.87 (9H, s), 0.07 (6H,s). 13C-NMR: 142.54(0,d, J=17Hz), 137.12(0, d, J=2.3Hz), 128.54(1), 115.30(2, d, J=10Hz), 92.11 (1, d, J=168Hz), 66.82(1, d, J=4.5Hz), 59.45(2), 45.15(2), 41.44(2, d, J=2lHz), 25.76(3), 18.06(0), -4.75(3), -4.85(3).
(1 R,3Z,5S)-t-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy]-dimethylsilane (23) OH CI
Triphosgene ~ Pyridine Hexane TBSO' F
TBSO" F 13 23 To a solution of 13 (8.07 g, 28.2 mmol) and triphosgene (4.18 g, 14.1 mmol) in hexane (150 mL) at 0 C was added over 30 min a solution of pyridine (4.5 mL, 55.6 mmol) in hexane (20 mL) and the reaction mixture was stirred at this temperature for 30 min and at room temperature for another 30 min. The reaction mixture was washed with CuSO4 aq (3 x 200 mL). The combined aqueous layers were back-extracted with hexane (2 x 100 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to give the title compound (9.0 g, overweight). This material was used immediately in the next step without further purification. [a]25D +
73.0 (c 0.28, CHC13); IR (CHC13) 1643, 838 cm"'; 'H-NMR S 0.08 (s, 6H), 0.88 (s, 9H), 1.84-2.03 (m, 1 H), 2.12 (br s, 1H), 2.24 (m, 1H), 2.48 (br d, J = 13 Hz, 1 H), 4.06-4.26 (m, 3H), 5.10 (br d, J = 48 Hz), 5.16 (s, 1 H), 5.35 (s, 1 H), 5.63 (br t, J = 6 Hz, 1 H).
(1 S,3Z,5R)-1-fluoro-5-(t-butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane (6) Ci P(O)Ph2 Ph2P(O)H
~ NaH
DMF TBSO',\\ F
TBSO' ~~ F 23 6 Diphenylphosphine oxide (6.70 g, 33.1 mmol) was added portionwise, over 15 min to a suspension of NaH (1.33 g, 33.1 mmol, 60% dispersion in mineral oil) in DMF
(50 mL) at 10 C. The resulting solution was stirred at room temperature for 30 min and cooled to - 60 C. The solution of crude 23 (9.0 g) in DMF (20 mL)was then added dropwise. The reaction mixture was stirred at -60 C for 2h and at room temperature for lh, diluted with diethyl ether (600 mL) and washed with water (3x200 mL).
The aqueous layers were extracted with diethyl ether (200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give white solid. The crude product was recrystallized from diisopropyl ether (25 mL).
The resulting solid was collected by filtration, washed with cold diisopropyl ether (5 mL) and dried under high vacuum to give the title compound (7.93 g). The mother liquor was concentrated and the residue was subjected to chromatography on silca gel (50 g, 30%-50% AcOEt in hexane) to give title compound (2.22 g). Thus the total yield of the of 6 was (10.1 g, 21.5 mmol, 76% overall from 13. [a]ZSD + 50.2 (c 0.84, CHC13); IR (CHC13) 835, 692 cm"1; UVa. a,, (ethanol) 223 (s 22770), 258 (1950), 265 (1750), 272 nm (1280); MS, m/e 470 (M), 455 (4), 450 (8), 413 (98), 338 (9), (100); 'H-NMR: S 0.02 (s, 6 H), 0.84 (s, 9H), 1.76-1.93 (m, 1 H), 2.16 (m, 2 H), 2.42 (br d, 1 H), 3.28 (m, 2 H), 4.01 (m, 1 H), 5.02 (dm, J = 44 Hz, 1 H), 5.14 (s, 1 H), 5.30 (s, 1 H), 5.5 (m, 1 H), 7.5 (m, 6 H), 7.73 (m, 4 H). Analysis Calcd for C27H36OZFPSi:
C 68.91, H 7.71; F 4.04; Found: C 68.69, H 7.80, F 3.88.
Applying the same procedure by using 4-iodobenzoyl chloride and 4-biphenylcarbonyl chloride respetively, provided compounds 9A, 10A, 11A, 12A
and 9B, lOB, 11B and 12B in similar yields.
Synthesis of C,D-ring/side chain precursor Acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-octahydro-lH-inden-4-yl ester (3a) 1. Ac20/CH2CI2 OH
-H OH 2. Na2CO3/MeOH H
OH H 3 OAc 3a A 11 round bottom flask equipped with stirring bar and Claisen adapter with rubber septum was charged with Lythgoee dio13 (38.41 g, 180.9 mmol), dichloromethane (400 mL), pyridine (130 mL) and DMAP (5.OOg, 40.9 mmol). Acetic anhydride (150 mL) was added slowly and the mixture was stirred at room temperature for 14.5 h.
Methanol (70 mL) was added dropwise (exothermic reaction) to the reaction mixture and the solution was stirred for 30 min. Water (1 L) was added and the aqueous layer was extracted with dichloromethane (2x250 mL). The extracts were washed with HCl (200 mL) and solution of NaHCO3 (200 mL), dried (Na2SO4) and evaporated to dryness with toluene (150 mL). The residue was dissolved in methanol (300 mL) and sodium carbonate (40.0 g) was added. The suspension was stirred for 24 h.
Additional portion of sodium carbonate (10.0 g) was added and the reaction mixture was stirred for 18 h. Methanol was removed on a rotary evaporator. Water (500 mL) was added and the mixture was extracted with ethyl acetate (3x250 mL), dried (NaZSO4) and concentrated in vacuo. The residue was purified by FC (0.4 kg of silica gel, 20%, 30%
hexane - ethyl acetate) to give the title compound 3a (45 g, 98%). 'H NMR
(DMSO-D6) 5.03(1H, br s), 4.26(1H, dd, J=5.9, 5.1 Hz), 3.42-3.36(1H, m), 3.10-3.02(1H, m), 1.99(3H, s), 1.96-1.91(1H, m), 1.77-1.58(3H, m), 1.50-1.08(9H, m), 0.93(3H, d, J=6.6 Hz), 0.85(3H, s).
Acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl-l-((S)-oxopropan-2-yl)-octahydro-lH-inden-4-yl ester (15) (COCI)2, DMSO
H OH CH2CI2, -65 C "-H O
(J:
OAc 3a OAc 15 To a cooled solution (-65 C ) of oxalyl chloride (17 mL, 195 mmol) in dichloromethane (150 mL) was added within 35 min. a solution of DMSO (27 mL, 380 mmol) in dichloromethane (200 mL), keeping the temperature below -65 C.
After complete addition stirring at -65 C was continued for 15 min. Subsequently a solution of acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-octahydro-1H-inden-4-yl ester 3a (41 g, 161 mmol) in dichloromethane (300 mL) was added dropwise within 80 min., keeping the temperature below -65 C. During addition a solid precipitated. After complete addition stirring at -65 C was continued for 1 h.
Subsequently a solution of triethylamine (110 mL) in dichloromethane (200 mL) was added dropwise within 30 min. After complete addition stirring at -65 C was continued for 45 min. The cooling bath was removed and the reaction mixture was allowed to warm to 5 C within 1 h. Dichloromethane (ca. 600 mL) was removed by distillation under reduced pressure and to the residue was added water (600 mL) and tert-Butyl-methyl ether (500 mL). The organic layer was separated and the aqueous layer was extracted with tert-Butyl-methyl ether (2x200 mL). The combined organic layers were dried (NaZSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (800 g of silica gel, 15% ethyl acetate in heptane) affording 38 g (94 %) of the title compound 15 as a slightly yellow oil. 'H
NMR
(CDC13): 8 9.56 (1H, d, J=2.0 Hz), 5.20 (1H, br s), 2.44-2.16 (1H, m), 2.03 (3H, s), 2.00-1.15 (12H, m), 1.11 (3H, d, J=7.0 Hz), 0.92 (3H, s).
The temperature was adjusted to -65 C and nBuLi (73 mL, 182.5 mmol, 2.5M solution in hexane) was added maintaining temperature below -20 C. After the addition was completed the reaction mixture was allowed to come to room temperature and it was stirred for 30 min., cooled down to 0 C, when a solution of benzoic acid (2R,3 S,5 S,7R)-7-(tert-butyldimethyl)silanyloxy)-5-fluoro-4-methylene-l-oxa-spiro[2.5]oct-2-yl methyl ester (11) (18.5 g, 45.5 mmol) in THF (50 mL) was added.
Thus formed mixture was allowed to come to room temperature (2h) and stirred for 16h. Methanol (400 mL) was added followed by sodium methoxide (250 mL, 15% in methanol), the resulting mixture was stirred for 30 min then diluted with AcOEt (1 L) and washed with water (1 L) and brine (500 mL). The residue (21.6 g) after evaporation of the dried (NaZSO4) solvent was used for the next step without further purification.
1H-NMR (CDC13); 8 0.09 (s, 6H), 0.81 (s, 9H), 1.80-2.22 (m, 3H), 2.44 (m, 1H), 4.10 (m, 1H), 4.14 (d, 2H, J=6.9 Hz), 4.98 (br s, 1H), 5.10 (d, 1H, J = 50.0 Hz), 5.11 (s, 1H), 5.79 (t, 1 H, J = 6.8 Hz).
(1Z,3S,5R)- 2-[5-(tert-Butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13) OH OH
hv ~ 9-fluorenone TBSO"" F 13a t-BuOMe TBSO',%\ F 13 A solution of (lE,3S,5R)- 2-[5-(tert-butyldimethyl)silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethanol (13a) (21.6 g, crude containing ca 10% of the Z
isomer) and 9-fluorenone (1.8 g, 10 mmol) in tert-Butyl-methyl ether (650 mL) was irradiated with 450W hanovia lamp with uranium core filter for 8 h. The residue after evaporation of solvent (23.95g) was purified by flash chromatography (750g, 5%,20%, AcOEt in hexane) to give the title compound 13 (10.4 g, 36.3 mmol, 80%
from 11). [a]30p +40.1 (c 0.89, EtOH).
' H-NMR : S 5.65 (1 H, t, J=6.8Hz), 5.31(1 H, dd, J=1. 5, 1.7Hz), 5.10 (1 H, ddd, J=3.2, 6.0, 49.9Hz), 4.95(1H, d, J=1.7Hz), 4.28(1H, dd, J=7.3, 12.6Hz), 4.19 (111, ddd, J=1.7, 6.4, 12.7Hz), 4.15(1H, m), 2.48 (1H, dd, J=3.8, 13.0Hz), 2.27-2.13 (2H, m), 1.88 (1H, m), 0.87 (9H, s), 0.07 (6H,s). 13C-NMR: 142.54(0,d, J=17Hz), 137.12(0, d, J=2.3Hz), 128.54(1), 115.30(2, d, J=10Hz), 92.11 (1, d, J=168Hz), 66.82(1, d, J=4.5Hz), 59.45(2), 45.15(2), 41.44(2, d, J=2lHz), 25.76(3), 18.06(0), -4.75(3), -4.85(3).
(1 R,3Z,5S)-t-butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy]-dimethylsilane (23) OH CI
Triphosgene ~ Pyridine Hexane TBSO' F
TBSO" F 13 23 To a solution of 13 (8.07 g, 28.2 mmol) and triphosgene (4.18 g, 14.1 mmol) in hexane (150 mL) at 0 C was added over 30 min a solution of pyridine (4.5 mL, 55.6 mmol) in hexane (20 mL) and the reaction mixture was stirred at this temperature for 30 min and at room temperature for another 30 min. The reaction mixture was washed with CuSO4 aq (3 x 200 mL). The combined aqueous layers were back-extracted with hexane (2 x 100 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to give the title compound (9.0 g, overweight). This material was used immediately in the next step without further purification. [a]25D +
73.0 (c 0.28, CHC13); IR (CHC13) 1643, 838 cm"'; 'H-NMR S 0.08 (s, 6H), 0.88 (s, 9H), 1.84-2.03 (m, 1 H), 2.12 (br s, 1H), 2.24 (m, 1H), 2.48 (br d, J = 13 Hz, 1 H), 4.06-4.26 (m, 3H), 5.10 (br d, J = 48 Hz), 5.16 (s, 1 H), 5.35 (s, 1 H), 5.63 (br t, J = 6 Hz, 1 H).
(1 S,3Z,5R)-1-fluoro-5-(t-butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane (6) Ci P(O)Ph2 Ph2P(O)H
~ NaH
DMF TBSO',\\ F
TBSO' ~~ F 23 6 Diphenylphosphine oxide (6.70 g, 33.1 mmol) was added portionwise, over 15 min to a suspension of NaH (1.33 g, 33.1 mmol, 60% dispersion in mineral oil) in DMF
(50 mL) at 10 C. The resulting solution was stirred at room temperature for 30 min and cooled to - 60 C. The solution of crude 23 (9.0 g) in DMF (20 mL)was then added dropwise. The reaction mixture was stirred at -60 C for 2h and at room temperature for lh, diluted with diethyl ether (600 mL) and washed with water (3x200 mL).
The aqueous layers were extracted with diethyl ether (200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give white solid. The crude product was recrystallized from diisopropyl ether (25 mL).
The resulting solid was collected by filtration, washed with cold diisopropyl ether (5 mL) and dried under high vacuum to give the title compound (7.93 g). The mother liquor was concentrated and the residue was subjected to chromatography on silca gel (50 g, 30%-50% AcOEt in hexane) to give title compound (2.22 g). Thus the total yield of the of 6 was (10.1 g, 21.5 mmol, 76% overall from 13. [a]ZSD + 50.2 (c 0.84, CHC13); IR (CHC13) 835, 692 cm"1; UVa. a,, (ethanol) 223 (s 22770), 258 (1950), 265 (1750), 272 nm (1280); MS, m/e 470 (M), 455 (4), 450 (8), 413 (98), 338 (9), (100); 'H-NMR: S 0.02 (s, 6 H), 0.84 (s, 9H), 1.76-1.93 (m, 1 H), 2.16 (m, 2 H), 2.42 (br d, 1 H), 3.28 (m, 2 H), 4.01 (m, 1 H), 5.02 (dm, J = 44 Hz, 1 H), 5.14 (s, 1 H), 5.30 (s, 1 H), 5.5 (m, 1 H), 7.5 (m, 6 H), 7.73 (m, 4 H). Analysis Calcd for C27H36OZFPSi:
C 68.91, H 7.71; F 4.04; Found: C 68.69, H 7.80, F 3.88.
Applying the same procedure by using 4-iodobenzoyl chloride and 4-biphenylcarbonyl chloride respetively, provided compounds 9A, 10A, 11A, 12A
and 9B, lOB, 11B and 12B in similar yields.
Synthesis of C,D-ring/side chain precursor Acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-octahydro-lH-inden-4-yl ester (3a) 1. Ac20/CH2CI2 OH
-H OH 2. Na2CO3/MeOH H
OH H 3 OAc 3a A 11 round bottom flask equipped with stirring bar and Claisen adapter with rubber septum was charged with Lythgoee dio13 (38.41 g, 180.9 mmol), dichloromethane (400 mL), pyridine (130 mL) and DMAP (5.OOg, 40.9 mmol). Acetic anhydride (150 mL) was added slowly and the mixture was stirred at room temperature for 14.5 h.
Methanol (70 mL) was added dropwise (exothermic reaction) to the reaction mixture and the solution was stirred for 30 min. Water (1 L) was added and the aqueous layer was extracted with dichloromethane (2x250 mL). The extracts were washed with HCl (200 mL) and solution of NaHCO3 (200 mL), dried (Na2SO4) and evaporated to dryness with toluene (150 mL). The residue was dissolved in methanol (300 mL) and sodium carbonate (40.0 g) was added. The suspension was stirred for 24 h.
Additional portion of sodium carbonate (10.0 g) was added and the reaction mixture was stirred for 18 h. Methanol was removed on a rotary evaporator. Water (500 mL) was added and the mixture was extracted with ethyl acetate (3x250 mL), dried (NaZSO4) and concentrated in vacuo. The residue was purified by FC (0.4 kg of silica gel, 20%, 30%
hexane - ethyl acetate) to give the title compound 3a (45 g, 98%). 'H NMR
(DMSO-D6) 5.03(1H, br s), 4.26(1H, dd, J=5.9, 5.1 Hz), 3.42-3.36(1H, m), 3.10-3.02(1H, m), 1.99(3H, s), 1.96-1.91(1H, m), 1.77-1.58(3H, m), 1.50-1.08(9H, m), 0.93(3H, d, J=6.6 Hz), 0.85(3H, s).
Acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl-l-((S)-oxopropan-2-yl)-octahydro-lH-inden-4-yl ester (15) (COCI)2, DMSO
H OH CH2CI2, -65 C "-H O
(J:
OAc 3a OAc 15 To a cooled solution (-65 C ) of oxalyl chloride (17 mL, 195 mmol) in dichloromethane (150 mL) was added within 35 min. a solution of DMSO (27 mL, 380 mmol) in dichloromethane (200 mL), keeping the temperature below -65 C.
After complete addition stirring at -65 C was continued for 15 min. Subsequently a solution of acetic acid (1R, 3aR, 4S, 7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-octahydro-1H-inden-4-yl ester 3a (41 g, 161 mmol) in dichloromethane (300 mL) was added dropwise within 80 min., keeping the temperature below -65 C. During addition a solid precipitated. After complete addition stirring at -65 C was continued for 1 h.
Subsequently a solution of triethylamine (110 mL) in dichloromethane (200 mL) was added dropwise within 30 min. After complete addition stirring at -65 C was continued for 45 min. The cooling bath was removed and the reaction mixture was allowed to warm to 5 C within 1 h. Dichloromethane (ca. 600 mL) was removed by distillation under reduced pressure and to the residue was added water (600 mL) and tert-Butyl-methyl ether (500 mL). The organic layer was separated and the aqueous layer was extracted with tert-Butyl-methyl ether (2x200 mL). The combined organic layers were dried (NaZSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (800 g of silica gel, 15% ethyl acetate in heptane) affording 38 g (94 %) of the title compound 15 as a slightly yellow oil. 'H
NMR
(CDC13): 8 9.56 (1H, d, J=2.0 Hz), 5.20 (1H, br s), 2.44-2.16 (1H, m), 2.03 (3H, s), 2.00-1.15 (12H, m), 1.11 (3H, d, J=7.0 Hz), 0.92 (3H, s).
Acetic acid (3aR,4S,7aR )-1-E-ethylidene-7a-methyl-octahydroinden-4-yl ester (16) CFiO sc ~
+
benzalacetone_ + +
Pd/C, 230 C
OAc OAc OAc OAc OAc 15 16 54% 4% 27% 5%
Benzalacetone was purified by bulb to bulb distillation (130 C, 10-2 mbar) before use.
To a solution of acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl-l-((S)-oxopropan-2-yl)-octahydro-lH-inden-4-yl ester 15 (38.3 g, 0.15 mol) in diethyl ether (240 mL) was added 10% palladium on charcoal (1.8 g). The suspension was stirred at room temperature for 45 min., filtered through a path of Celite and the filtrate was concentrated in vacuo. To the residue was added benzalacetone (28.3 g, 0.19 mol) and 10% palladium on charcoal (1.8 g). The suspension was degassed by evacuating the flask and refilling with nitrogen. Then the flask was partially immersed in a 230 C oil bath for 40 min. After cooling at room temperature the suspension was diluted with ethyl acetate, filtered through a path of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (1800 g of Si02, 5-10%
ethyl acetate in heptane) affording 21.6 g (65%) of a mixture of ~17E' Di7z~ Di6 and O20 indene olefins, which are present in 51%, 4%, 25%, and 1%, respectively (GC analysis). The mixture of isomers was used in the next step without further purification.
+ + +
AcO H A17E AcO HA16 AcO H 017Z AcO H A20 51% 25% 4% 1%
'H NMR (CDC13, signals of the desired 017E isomer): 5.21 (m, 1H), 4.98-5.07 (m, 1H), 2.15-2.35 (m, 2H), 2.05 (s, 3H), 1.53 (d, 3H, J=7 Hz), S 0.96 (s, 3H).
In a different experiment the desired product was isolated from the mixture of olefins (A 17E: Di7z: 016: 020= 65:4:27:4) by silver nitrate impregnated silica gel medium pressure chromatography in a 55% yield (U.S. Pat. 5,939,408).
+
benzalacetone_ + +
Pd/C, 230 C
OAc OAc OAc OAc OAc 15 16 54% 4% 27% 5%
Benzalacetone was purified by bulb to bulb distillation (130 C, 10-2 mbar) before use.
To a solution of acetic acid (1R, 3aR, 4S, 7aR)-7a-methyl-l-((S)-oxopropan-2-yl)-octahydro-lH-inden-4-yl ester 15 (38.3 g, 0.15 mol) in diethyl ether (240 mL) was added 10% palladium on charcoal (1.8 g). The suspension was stirred at room temperature for 45 min., filtered through a path of Celite and the filtrate was concentrated in vacuo. To the residue was added benzalacetone (28.3 g, 0.19 mol) and 10% palladium on charcoal (1.8 g). The suspension was degassed by evacuating the flask and refilling with nitrogen. Then the flask was partially immersed in a 230 C oil bath for 40 min. After cooling at room temperature the suspension was diluted with ethyl acetate, filtered through a path of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (1800 g of Si02, 5-10%
ethyl acetate in heptane) affording 21.6 g (65%) of a mixture of ~17E' Di7z~ Di6 and O20 indene olefins, which are present in 51%, 4%, 25%, and 1%, respectively (GC analysis). The mixture of isomers was used in the next step without further purification.
+ + +
AcO H A17E AcO HA16 AcO H 017Z AcO H A20 51% 25% 4% 1%
'H NMR (CDC13, signals of the desired 017E isomer): 5.21 (m, 1H), 4.98-5.07 (m, 1H), 2.15-2.35 (m, 2H), 2.05 (s, 3H), 1.53 (d, 3H, J=7 Hz), S 0.96 (s, 3H).
In a different experiment the desired product was isolated from the mixture of olefins (A 17E: Di7z: 016: 020= 65:4:27:4) by silver nitrate impregnated silica gel medium pressure chromatography in a 55% yield (U.S. Pat. 5,939,408).
Acetic acid (3 aR,4S,7aS)-1-((R)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17a) and Acetic acid (3aR,4S,7aS)-1-((S)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17b) H H
::: OH
AcO AcO AcO AcO AcO AcO
16 16a 16b 16c 17a 17b A.250-mL round bottom flask was charged with of the crude alkene mixture containing 16, 16a, 16b, and 16c (4.90 g), of which 16 is the major component, paraformaldehyde (0.84 g, 28 mmol) and dichloromethane (65 mL). The stirred suspension was cooled to -20 C and a 1 M solution of dimethylaluminum chloride in hexane (56 mL) was added at an internal temperature of -10 to -15 C. The mixture was allowed to reach within 1 h and was then immersed into an ice bath where it was held for 2.5 h.
The reaction mixture was diluted with 1:1 dichloromethane - hexane (50 mL) and added in a slow stream to a stirred mixture of ice (112 g) and 1M sulfuric acid (56 mL). An additional portion of 1:1 dichloromethane - hexane (50 mL) was used to complete the transfer. The mixture was stirred vigorously for 8 min, the lower, aqueous portion was re-extracted with dichloromethane (2x50 mL), all organic layers were combined, washed with 1:1 brine - water (30 mL), brine (30 ml) then dried (magnesium sulfate), and evaporated to give the crude alcohol mixture as an oil, (5.78 g). This material was flash-chromatographed on a silica gel column, 35x135 mm, using hexane, 1:19 and 1:9 ethyl acetate - hexane as mobile phases. Unreacted 16c was eluted first (Rf 0.85, TLC
1:4 ethyl acetate - hexane), followed by the mixture of the title compounds 17a and 17b (2.96 g), Rf 0.30, and then by more polar components.
::: OH
AcO AcO AcO AcO AcO AcO
16 16a 16b 16c 17a 17b A.250-mL round bottom flask was charged with of the crude alkene mixture containing 16, 16a, 16b, and 16c (4.90 g), of which 16 is the major component, paraformaldehyde (0.84 g, 28 mmol) and dichloromethane (65 mL). The stirred suspension was cooled to -20 C and a 1 M solution of dimethylaluminum chloride in hexane (56 mL) was added at an internal temperature of -10 to -15 C. The mixture was allowed to reach within 1 h and was then immersed into an ice bath where it was held for 2.5 h.
The reaction mixture was diluted with 1:1 dichloromethane - hexane (50 mL) and added in a slow stream to a stirred mixture of ice (112 g) and 1M sulfuric acid (56 mL). An additional portion of 1:1 dichloromethane - hexane (50 mL) was used to complete the transfer. The mixture was stirred vigorously for 8 min, the lower, aqueous portion was re-extracted with dichloromethane (2x50 mL), all organic layers were combined, washed with 1:1 brine - water (30 mL), brine (30 ml) then dried (magnesium sulfate), and evaporated to give the crude alcohol mixture as an oil, (5.78 g). This material was flash-chromatographed on a silica gel column, 35x135 mm, using hexane, 1:19 and 1:9 ethyl acetate - hexane as mobile phases. Unreacted 16c was eluted first (Rf 0.85, TLC
1:4 ethyl acetate - hexane), followed by the mixture of the title compounds 17a and 17b (2.96 g), Rf 0.30, and then by more polar components.
Acetic acid (3aR,4S,7aS)-1-((S)-2-cyano-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (19a) H H H
OH T AI [\TsJ CN
NaCN
--H
DMAP DMI
ACO ACO H ACO
17a 18a 19a A 100-mL round-bottom flask was charged with a mixture of acetic acid (3 aR,4S,7aS)-1-((R)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3 a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17a) and (3aR,4S,7aS)-1-((S)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17b) (1.02 g, 4 mmol) and dichloromethane (10 mL), DMAP (0.21 g, 0.17 mmol) and 0.71 g (7 mmol) of triethylamine. To this solution was added tosyl chloride (1.14 g, 6 mmol) and the mixture was stirred overnight. The resulting suspension was stirred and diluted with saturated sodium hydrogen carbonate solution (15 mL), stirred for 1 h and transferred to a separatory funnel with the aid of water (5 mL) and ethyl acetate (25 mL).
The aqueous layer was extracted with ethyl acetate (25 mL). The combined extracts were washed with water (10 mL), 1:1 brine -1 M sulfuric acid (10 mL), 1:1 of brine-water 2X 10 mL, and 5:1 brine - pH 7 buffer (10 mL), then dried to a thin oil representing the mixture of acetic acid (3aR,4S,7aS)-7a-methyl-l-[(R)-1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester 18a and the S-isomer 18b; Rf 0.43 (TLC 1:4) for both isomers.
'HNMR (18a) S 0.93 (3H, s), 1.08 (3H, d, J = 6.8 Hz), 1.17 (1H, m), 1.4-2.1 (11H, m), 2.4 (1H, m), 2.45 (3H, s), 3.66 (1H, dd, J,,ic = 9.4, J = 8.3 Hz), 3.97 (1H, dd, J,,;c=
9.4, J = 4.7 Hz), 5.15 (1H, bs), 5.38 (1H, bs), 7.34 (2H, d, J = 8.1 Hz), 7.77 (2H, d, J
8.1 Hz).
This material was taken up in toluene (10 mL), evaporated and the residue was dissolved in 1,3-dimethylimidazolidinone (6 mL). Powdered sodium cyanide (0.30 g) was added and the stirred mixture was immersed into a 55 C bath for 14.5 h and then allowed to cool and distributed between 1:1 ethyl acetate - hexane (25 mL) and water (15 mL). The aqueous phase was extracted with 1:1 ethyl acetate - hexane (2x20 mL). The combined extracts were washed with water (3x15 mL), once with brine (10 mL) then dried and concentrated. These water washes were insufficient to remove all of the residual 1,3-dimethylimidazolidinone. This material was diluted with little MeOH and then diluted with water and seeded to create a crystalline suspension upon shaking. The suspension was further diluted with water until an additional drop did no longer generate turbidity. The suspension was refrigerated for several h; the crystals were filtered off, washed with water and dried (1.03 g), and then recrystallized from hexane. The crystallization from hexane was repeated to give the title compound 19a (0.72 g). Rechromatography of the mother liquors on a silica gel column and using hexane, 1:19 and 1:9 ethyl acetate - hexane as mobile phases, followed by crystallization gave an additional quantity of 19a (0.16 g); total yield 0.88 g, 84 %
from the alcohols 17a and 17b; mp 68-70 C, Rf 0.47 (TLC, 1:4, ethyl acetate -hexane).
'HNMR (19a) S 1.01 (3H, s), 1.26 (3H, d, J = 6.8), 1.39 (1H, m), 1.5-1.6 (211, m), 1.74-1.9 (4H, m), 2.04 (3H, s), 2.07-2.12 (2H, m), 2.33 (1 H, m), 2.4-2.6 (2H, m), 5,19 (1H, bs), 5.55 (1H, bs).
(S)-3-((3 aR,4S,7aS)-4-Hydroxy-7a-methyl-3 a,4,5,6,7,7a-hexahydro-3H-in den-1-yl)-butyraldehyde (20) H H
CN DIBAL-H CHO
\ \
li Fi AcO HO
19a 20 A 25-mL flask, equipped with a magnetic stirrer and a Claisen adapter with nitrogen sweep and septum, was charged with acetic acid (3aR,4S,7aS)-1-((S)-2-cyano-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (19a, 0.26 g, 1 mmol) and toluene (2 mL). The solution was cooled in an ice bath and a 1.5 M
diisobutylaluminum hydride solution in toluene (2 mL) was added dropwise. The mixture was stirred in the ice bath for 1 h and a 1 M sulfuric acid solution (6 mL) was added dropwise. The milky suspension was stirred vigorous for 30 min and then diluted with saturated ammonium chloride solution (4.5 mL). The mixture was stirred for 10 min without removing the flask from the ice-bath and equilibrated with ethyl acetate (20 mL). The aqueous phase was diluted with saturated ammonium chloride solution (4 mL) and re-extracted with ethyl acetate (5 x 10 mL). The combined extracts were washed with 1:1 water - saturated ammonium chloride (2x5 mL) followed by brine (5 mL). The organic layer was dried with sodium sulfate, evaporated to an oil and co-evaporated from hexane to leave 19a as an oily residue. This material was dissolved in 1:1 ethyl acetate - hexane and the solution passed through a Pasteur-pipette, filled with silica gel (bed height 3 cm) then evaporated, together with several mL of the same solvent mixture, to give the title compound 20 as an oily residue, 0.24 g; Rf 0.30 (TLC, 1:4, ethyl acetate - hexane).
'HNMR (20) S 1.10 (3H, s), 1.15 (3H, d, J = 7 Hz), 1.25-1.40 (2H, m), 1.45-1.60 (4H, m), 1.70 (1H, m), 1.75-1.86 (2H, m), 1.90 (1H, m), 1.99 (1H, m), 2.22-2.49 (2H, m), 2.54 (1H, m), 2.72 (1H, m), 4.18 (1H, s), 5.43 (1H, s), 9.68 (1H, m).
(E)-(S)-5-((3 aR,4S,7 aS)-4-Hydroxy-7a-methyl-3 a,4,5,6,7,7a-h exahydro-3H-in den-1-yl)-hex-2-enoic acid ethyl ester (21) H H
CHO (EtO)ZPOCH2COOEt COOEt HO H HO
A 25-mL 2-neck flask was charged with (S)-3-((3aR,4S,7aS)-4-Hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-butyraldehyde (20, 0.2297 g, 1 mmol), triethyl phosphonoacetate (0.78 g, 3.5 mmol) and tetrahydrofuran (4 mL). The stirred 20 solution was cooled to ether / dry-ice temperature and a 1.06 M solution of lithium hexamethyl disilylamide in tetrahydrofuran (3.0 mL) was added dropwise at a bath temperature of -75 C and an intemal temperature of -70 Cover a 40 min period. The temperature was allowed to rise to -45 C after 4.5 h, the cooling bath was removed and saturated ammonium chloride solution (10 mL) was added dropwise. The mixture was equilibrated with ethyl acetate (30 mL), and the organic layer was washed with brine, dried (sodium sulfate) and evaporated, 0.23 g. This mixture contained the ester as a mixture of E/Z in a ratio of 16/84 and less than 5% of residual aldehyde 20. This material was chromatographed on a 25x160 mm silica gel column, 25-40 m, using 1:19 and 1:9 ethyl acetate - hexane to elute the Z-isomer of 21 (0.0343 g) followed by (E)-(S)-5 -((3 aR,4S, 7aS)-4-hydroxy-7a-methyl-3 a,4, 5,6,7, 7a-hexahydro-3H-inden- l-yl)-hex-2-enoic acid ethyl ester (21, 0.196 g), 67% from nitrile 19a. TLC (1:4 ethyl acetate - hexane): Rf 0.23 (20), 0.41 (21) and 0.48 (Z-isomer of 21).
'HNMR (21) S 0.99 (3H, s), 1.06 (3H, d, J = 6.8 Hz), 1.27 (t, J = 7.2 Hz), 1.36 (1H, m), 1.48-1.61 (2H, m), 1.72-1.89 (4H, m), 2.09 (2H, m), 1.95-2.16 (2H, m), 2.22-2.35 (2H, m), 4.17 (2H, q, J = 7.2 Hz), 5.19 (1 H, s), 5.3 6(1 H, s), 5.77 (1 H, d, J = 15.8 Hz), 6.87 (1H, m).
(3aR,4S,7aS)-1-((E)-(S)-5-ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (22) H
COOEt CeC13 OH
EtMgBr H H
HO HO
A 15-mL round bottom flask with a 3-way stopcock, connected to a nitrogen source and a vacuum line, was charged with anhydrous cerium(III) chloride (0.4743 g, 1.924 mmol) and then heated under vacuum in a 210 C bath for 1 h. The flask was allowed to cool, flushed with nitrogen, tetrahydrofuran (3 mL) was added, the resulting suspension was stirred overnight at ambient temperature then cooled in an ice bath and a 1M solution of EtMgBr in tetrahydrofuran (1.85 mL) was added dropwise within 20 min. The mixture was stirred in the ice-bath for 2 h and a solution of (E)-(S)-5-((3aR,4S,7aS)-4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-l-yl)-hex-2-enoic acid ethyl ester (21, 0.157 g, 0.537 mmol), dissolved in tetrahydrofuran (2 mL) was added dropwise within 30 min. The flask that contained 21 was rinsed with tetrahydrofuran (1 mL) and this solution was also added to the reactor after 1 h.
The reaction was quenched 2 h later by the addition of 1:1 ethyl acetate -hexane (3 mL) and brine (1 mL). The mixture was stirred for 5 min in the ice bath, the supernatant was decanted from the white paste, the paste was washed with ethyl acetate (3x3 mL) and the combined organic phases were washed with brine (2 mL), dried (sodium sulfate) and evaporated to give an oily residue (0.19 g) which was flash chromatographed on a 18x 120 mm column using 1:9 and 1:4 ethyl acetate -hexane as mobile phase to furnish (3aR,4S,7aS)-1-((E)-(S)-5-Ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (22, 0.1234 g, 75 %);
Rf 0.18 (TLC, 1: 4, ethyl acetate - hexane).
'HNMR (22) 8 0.83 (6H, 2t, J = 7.3 Hz each), 1.02 (3H, s), 1.03 (3H, d, J =
7.2Hz), 1.37 (1H, m), 1.42-1.58 (8H, m), 1.65-2.00 (6H, m), 2.1-2.3 (3H, m), 4.14 (1H, bs), 5.32 (1H, d, J = 15.8 Hz), 5.33 (1H, d, J = 15.8 Hz), 5.49 (1H, m).
(3aR,4S,7aR )-1-((S,E)-5-ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (5) OH PDC,DCM H
OH H 22 69% O H 5 A solution of (3aR,4S,7aS)-1-((S,E)-6-ethyl-6-hydroxyoct-4-en-2-yl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-o122 (4.70 g, 15.3 mmol, purity according HPLC: 96.5% (k = 212 nm) in dichloromethane (200 mL) was cooled in an ice-bath and treated portionwise with pyridinium dichromate (13.1 g, 34.9 mmol, 2.2 eq.). The reaction mixture was allowed to warm at room temperature overnight, filtered through a path of Celite and the filtercake was washed with dichloromethane. The combined filtrates were washed with a 2 M KHCO3 solution, washed with brine, dried (Na2SO4) and concentrated in vacuo. the residue was purified by column chromatography (Si02, 25% ethyl acetate in heptane) affording the title compound 5 (4.0 g, 85%) as a colorless oil.
'H NMR (CDC13): S 5.54 (ddd, J= 15.6, 7.1, 6.0 Hz, 1 H), 5.38 (dm, J= 15.6 Hz, H), 5.30 (m, 1 H), 2.82 (dd, J= 10.4, 6.0 Hz, 1 H), 2.42 (ddt, J= 15.4, 10.4, 1.6 Hz, 1 H), 2.16-2.33 (m, 4 H), 1.93-2.16 (m, 4 H), 1.84-1.93 (m, 1 H), 1.65 (td, J=
12.1, 5.6 Hz, 1 H), 1.52 (br. q, J= 6.9 Hz, 4 H), 1.34 (br. s, 1 H), 1.05 (d, J= 6.9 Hz, 3 H), 0.85 (br. t, J= 7.2 Hz, 6 H), 0.82 (s, 3 H).
OH T AI [\TsJ CN
NaCN
--H
DMAP DMI
ACO ACO H ACO
17a 18a 19a A 100-mL round-bottom flask was charged with a mixture of acetic acid (3 aR,4S,7aS)-1-((R)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3 a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17a) and (3aR,4S,7aS)-1-((S)-2-hydroxy-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (17b) (1.02 g, 4 mmol) and dichloromethane (10 mL), DMAP (0.21 g, 0.17 mmol) and 0.71 g (7 mmol) of triethylamine. To this solution was added tosyl chloride (1.14 g, 6 mmol) and the mixture was stirred overnight. The resulting suspension was stirred and diluted with saturated sodium hydrogen carbonate solution (15 mL), stirred for 1 h and transferred to a separatory funnel with the aid of water (5 mL) and ethyl acetate (25 mL).
The aqueous layer was extracted with ethyl acetate (25 mL). The combined extracts were washed with water (10 mL), 1:1 brine -1 M sulfuric acid (10 mL), 1:1 of brine-water 2X 10 mL, and 5:1 brine - pH 7 buffer (10 mL), then dried to a thin oil representing the mixture of acetic acid (3aR,4S,7aS)-7a-methyl-l-[(R)-1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester 18a and the S-isomer 18b; Rf 0.43 (TLC 1:4) for both isomers.
'HNMR (18a) S 0.93 (3H, s), 1.08 (3H, d, J = 6.8 Hz), 1.17 (1H, m), 1.4-2.1 (11H, m), 2.4 (1H, m), 2.45 (3H, s), 3.66 (1H, dd, J,,ic = 9.4, J = 8.3 Hz), 3.97 (1H, dd, J,,;c=
9.4, J = 4.7 Hz), 5.15 (1H, bs), 5.38 (1H, bs), 7.34 (2H, d, J = 8.1 Hz), 7.77 (2H, d, J
8.1 Hz).
This material was taken up in toluene (10 mL), evaporated and the residue was dissolved in 1,3-dimethylimidazolidinone (6 mL). Powdered sodium cyanide (0.30 g) was added and the stirred mixture was immersed into a 55 C bath for 14.5 h and then allowed to cool and distributed between 1:1 ethyl acetate - hexane (25 mL) and water (15 mL). The aqueous phase was extracted with 1:1 ethyl acetate - hexane (2x20 mL). The combined extracts were washed with water (3x15 mL), once with brine (10 mL) then dried and concentrated. These water washes were insufficient to remove all of the residual 1,3-dimethylimidazolidinone. This material was diluted with little MeOH and then diluted with water and seeded to create a crystalline suspension upon shaking. The suspension was further diluted with water until an additional drop did no longer generate turbidity. The suspension was refrigerated for several h; the crystals were filtered off, washed with water and dried (1.03 g), and then recrystallized from hexane. The crystallization from hexane was repeated to give the title compound 19a (0.72 g). Rechromatography of the mother liquors on a silica gel column and using hexane, 1:19 and 1:9 ethyl acetate - hexane as mobile phases, followed by crystallization gave an additional quantity of 19a (0.16 g); total yield 0.88 g, 84 %
from the alcohols 17a and 17b; mp 68-70 C, Rf 0.47 (TLC, 1:4, ethyl acetate -hexane).
'HNMR (19a) S 1.01 (3H, s), 1.26 (3H, d, J = 6.8), 1.39 (1H, m), 1.5-1.6 (211, m), 1.74-1.9 (4H, m), 2.04 (3H, s), 2.07-2.12 (2H, m), 2.33 (1 H, m), 2.4-2.6 (2H, m), 5,19 (1H, bs), 5.55 (1H, bs).
(S)-3-((3 aR,4S,7aS)-4-Hydroxy-7a-methyl-3 a,4,5,6,7,7a-hexahydro-3H-in den-1-yl)-butyraldehyde (20) H H
CN DIBAL-H CHO
\ \
li Fi AcO HO
19a 20 A 25-mL flask, equipped with a magnetic stirrer and a Claisen adapter with nitrogen sweep and septum, was charged with acetic acid (3aR,4S,7aS)-1-((S)-2-cyano-l-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (19a, 0.26 g, 1 mmol) and toluene (2 mL). The solution was cooled in an ice bath and a 1.5 M
diisobutylaluminum hydride solution in toluene (2 mL) was added dropwise. The mixture was stirred in the ice bath for 1 h and a 1 M sulfuric acid solution (6 mL) was added dropwise. The milky suspension was stirred vigorous for 30 min and then diluted with saturated ammonium chloride solution (4.5 mL). The mixture was stirred for 10 min without removing the flask from the ice-bath and equilibrated with ethyl acetate (20 mL). The aqueous phase was diluted with saturated ammonium chloride solution (4 mL) and re-extracted with ethyl acetate (5 x 10 mL). The combined extracts were washed with 1:1 water - saturated ammonium chloride (2x5 mL) followed by brine (5 mL). The organic layer was dried with sodium sulfate, evaporated to an oil and co-evaporated from hexane to leave 19a as an oily residue. This material was dissolved in 1:1 ethyl acetate - hexane and the solution passed through a Pasteur-pipette, filled with silica gel (bed height 3 cm) then evaporated, together with several mL of the same solvent mixture, to give the title compound 20 as an oily residue, 0.24 g; Rf 0.30 (TLC, 1:4, ethyl acetate - hexane).
'HNMR (20) S 1.10 (3H, s), 1.15 (3H, d, J = 7 Hz), 1.25-1.40 (2H, m), 1.45-1.60 (4H, m), 1.70 (1H, m), 1.75-1.86 (2H, m), 1.90 (1H, m), 1.99 (1H, m), 2.22-2.49 (2H, m), 2.54 (1H, m), 2.72 (1H, m), 4.18 (1H, s), 5.43 (1H, s), 9.68 (1H, m).
(E)-(S)-5-((3 aR,4S,7 aS)-4-Hydroxy-7a-methyl-3 a,4,5,6,7,7a-h exahydro-3H-in den-1-yl)-hex-2-enoic acid ethyl ester (21) H H
CHO (EtO)ZPOCH2COOEt COOEt HO H HO
A 25-mL 2-neck flask was charged with (S)-3-((3aR,4S,7aS)-4-Hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-butyraldehyde (20, 0.2297 g, 1 mmol), triethyl phosphonoacetate (0.78 g, 3.5 mmol) and tetrahydrofuran (4 mL). The stirred 20 solution was cooled to ether / dry-ice temperature and a 1.06 M solution of lithium hexamethyl disilylamide in tetrahydrofuran (3.0 mL) was added dropwise at a bath temperature of -75 C and an intemal temperature of -70 Cover a 40 min period. The temperature was allowed to rise to -45 C after 4.5 h, the cooling bath was removed and saturated ammonium chloride solution (10 mL) was added dropwise. The mixture was equilibrated with ethyl acetate (30 mL), and the organic layer was washed with brine, dried (sodium sulfate) and evaporated, 0.23 g. This mixture contained the ester as a mixture of E/Z in a ratio of 16/84 and less than 5% of residual aldehyde 20. This material was chromatographed on a 25x160 mm silica gel column, 25-40 m, using 1:19 and 1:9 ethyl acetate - hexane to elute the Z-isomer of 21 (0.0343 g) followed by (E)-(S)-5 -((3 aR,4S, 7aS)-4-hydroxy-7a-methyl-3 a,4, 5,6,7, 7a-hexahydro-3H-inden- l-yl)-hex-2-enoic acid ethyl ester (21, 0.196 g), 67% from nitrile 19a. TLC (1:4 ethyl acetate - hexane): Rf 0.23 (20), 0.41 (21) and 0.48 (Z-isomer of 21).
'HNMR (21) S 0.99 (3H, s), 1.06 (3H, d, J = 6.8 Hz), 1.27 (t, J = 7.2 Hz), 1.36 (1H, m), 1.48-1.61 (2H, m), 1.72-1.89 (4H, m), 2.09 (2H, m), 1.95-2.16 (2H, m), 2.22-2.35 (2H, m), 4.17 (2H, q, J = 7.2 Hz), 5.19 (1 H, s), 5.3 6(1 H, s), 5.77 (1 H, d, J = 15.8 Hz), 6.87 (1H, m).
(3aR,4S,7aS)-1-((E)-(S)-5-ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (22) H
COOEt CeC13 OH
EtMgBr H H
HO HO
A 15-mL round bottom flask with a 3-way stopcock, connected to a nitrogen source and a vacuum line, was charged with anhydrous cerium(III) chloride (0.4743 g, 1.924 mmol) and then heated under vacuum in a 210 C bath for 1 h. The flask was allowed to cool, flushed with nitrogen, tetrahydrofuran (3 mL) was added, the resulting suspension was stirred overnight at ambient temperature then cooled in an ice bath and a 1M solution of EtMgBr in tetrahydrofuran (1.85 mL) was added dropwise within 20 min. The mixture was stirred in the ice-bath for 2 h and a solution of (E)-(S)-5-((3aR,4S,7aS)-4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-l-yl)-hex-2-enoic acid ethyl ester (21, 0.157 g, 0.537 mmol), dissolved in tetrahydrofuran (2 mL) was added dropwise within 30 min. The flask that contained 21 was rinsed with tetrahydrofuran (1 mL) and this solution was also added to the reactor after 1 h.
The reaction was quenched 2 h later by the addition of 1:1 ethyl acetate -hexane (3 mL) and brine (1 mL). The mixture was stirred for 5 min in the ice bath, the supernatant was decanted from the white paste, the paste was washed with ethyl acetate (3x3 mL) and the combined organic phases were washed with brine (2 mL), dried (sodium sulfate) and evaporated to give an oily residue (0.19 g) which was flash chromatographed on a 18x 120 mm column using 1:9 and 1:4 ethyl acetate -hexane as mobile phase to furnish (3aR,4S,7aS)-1-((E)-(S)-5-Ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (22, 0.1234 g, 75 %);
Rf 0.18 (TLC, 1: 4, ethyl acetate - hexane).
'HNMR (22) 8 0.83 (6H, 2t, J = 7.3 Hz each), 1.02 (3H, s), 1.03 (3H, d, J =
7.2Hz), 1.37 (1H, m), 1.42-1.58 (8H, m), 1.65-2.00 (6H, m), 2.1-2.3 (3H, m), 4.14 (1H, bs), 5.32 (1H, d, J = 15.8 Hz), 5.33 (1H, d, J = 15.8 Hz), 5.49 (1H, m).
(3aR,4S,7aR )-1-((S,E)-5-ethyl-5-hydroxy-l-methyl-hept-3-enyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (5) OH PDC,DCM H
OH H 22 69% O H 5 A solution of (3aR,4S,7aS)-1-((S,E)-6-ethyl-6-hydroxyoct-4-en-2-yl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-o122 (4.70 g, 15.3 mmol, purity according HPLC: 96.5% (k = 212 nm) in dichloromethane (200 mL) was cooled in an ice-bath and treated portionwise with pyridinium dichromate (13.1 g, 34.9 mmol, 2.2 eq.). The reaction mixture was allowed to warm at room temperature overnight, filtered through a path of Celite and the filtercake was washed with dichloromethane. The combined filtrates were washed with a 2 M KHCO3 solution, washed with brine, dried (Na2SO4) and concentrated in vacuo. the residue was purified by column chromatography (Si02, 25% ethyl acetate in heptane) affording the title compound 5 (4.0 g, 85%) as a colorless oil.
'H NMR (CDC13): S 5.54 (ddd, J= 15.6, 7.1, 6.0 Hz, 1 H), 5.38 (dm, J= 15.6 Hz, H), 5.30 (m, 1 H), 2.82 (dd, J= 10.4, 6.0 Hz, 1 H), 2.42 (ddt, J= 15.4, 10.4, 1.6 Hz, 1 H), 2.16-2.33 (m, 4 H), 1.93-2.16 (m, 4 H), 1.84-1.93 (m, 1 H), 1.65 (td, J=
12.1, 5.6 Hz, 1 H), 1.52 (br. q, J= 6.9 Hz, 4 H), 1.34 (br. s, 1 H), 1.05 (d, J= 6.9 Hz, 3 H), 0.85 (br. t, J= 7.2 Hz, 6 H), 0.82 (s, 3 H).
Coupling and Synthesis of 1 1-(5-Ethyl-l-methyl-5-trimethylsilanyloxy-hept-3-enyl)-7a-methyl-3,3a,5,6,7,7a-hexahydro-inden-4-one (24) ~ ~OH TMS-Imidazole ~ OTMS
O H O H
To a solution of compound 5 (320 mg, 1.05 mmol) in dichloromethane (20 mL) was added 1-(trimethylsilyl)imidazole (0.2 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 4 d. Reaction control (tlc) showed complete conversion. The mixture was concentrated in vacuo and the residue was purified by column chromatography (Si02, 10% ethyl acetate in heptane) affording compound (377 mg, 95%) as a colorless oil.
1a-Fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) o Ph-P-Ph OH
~ ~OTMS +
O H
TBSO"'~ F
24 ~
g HOF
To a stirred solution of 240 mg (0.51 mmol) of 6 in 5 ml of anhydrous tetrahydrofuran at -78 C was added 0.319 ml (0.51 mmol) of 1.6M n-butyllithium in hexane, dropwise under argon. After stirring for 5 min, to thus obtained red solution was added a solution of 103 mg (0.273 mmol) of 24 in 4 ml of anhydrous tetrahydrofuran, dropwise over a 10 min period. The reaction mixture was stirred at -78 C for 2 hrs, then placed in freezer (-20 C) for one hour, quenched by addition of 10 ml of a 1:1 mixture of 2N Rochelle salt and 2N potassium bicarbonate and warmed up to room temperature. After dilution with additiona125 ml of the same salts mixture, it was extracted with 3 x 90 ml of ethyl acetate. The combined organic layers were washed three times with water and brine, dried over sodium sulfate and evaporated to dryness.
The residue was purified by FLASH chromatography on a 30 mm x 7" silica gel column with hexane-ethyl acetate (1:4), to give 145 mg of disilylated title compound.
O H O H
To a solution of compound 5 (320 mg, 1.05 mmol) in dichloromethane (20 mL) was added 1-(trimethylsilyl)imidazole (0.2 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 4 d. Reaction control (tlc) showed complete conversion. The mixture was concentrated in vacuo and the residue was purified by column chromatography (Si02, 10% ethyl acetate in heptane) affording compound (377 mg, 95%) as a colorless oil.
1a-Fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) o Ph-P-Ph OH
~ ~OTMS +
O H
TBSO"'~ F
24 ~
g HOF
To a stirred solution of 240 mg (0.51 mmol) of 6 in 5 ml of anhydrous tetrahydrofuran at -78 C was added 0.319 ml (0.51 mmol) of 1.6M n-butyllithium in hexane, dropwise under argon. After stirring for 5 min, to thus obtained red solution was added a solution of 103 mg (0.273 mmol) of 24 in 4 ml of anhydrous tetrahydrofuran, dropwise over a 10 min period. The reaction mixture was stirred at -78 C for 2 hrs, then placed in freezer (-20 C) for one hour, quenched by addition of 10 ml of a 1:1 mixture of 2N Rochelle salt and 2N potassium bicarbonate and warmed up to room temperature. After dilution with additiona125 ml of the same salts mixture, it was extracted with 3 x 90 ml of ethyl acetate. The combined organic layers were washed three times with water and brine, dried over sodium sulfate and evaporated to dryness.
The residue was purified by FLASH chromatography on a 30 mm x 7" silica gel column with hexane-ethyl acetate (1:4), to give 145 mg of disilylated title compound.
To a solution of 145 mg of disilyl intermediate in 3 ml anhydrous tetrahydrofuran was added 1.7 ml (1.7 mmol) of 1M tetrabutyl-ammonium fluoride in tetrahydrofuran under argon. The reaction mixture was stirred at room temperature for 18 hrs, and then quenched by addition of 10 ml water and stirring for 15 min. It was diluted with 20 ml of water and brine and extracted with 3 x 80 ml ethyl acetate. The organic layers were washed four times with water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH chromatography on a 30 mm x 5" silica gel column with hexane-ethyl acetate (3:2), and by HPLC on a YMC 50 mm x 50 cm silica gel column with hexane-ethyl acetate (1:1). It gave 90 mg (74%) of the title compound, crystallization from methyl acetate-hexane.
Larger Scale Coupling and Synthesis of 1 1-(5-Ethyl-l-methyl-5-trimethylsilanyloxy-hept-3-enyl)-7a-methyl-3,3a,5,6,7,7a-hexahydro-inden-4-one (24) \ O TMS-Imidazole $HH
OTMS
H O O
To a solution of of (3aR,7aS)-1-((S,E)-6-ethyl-6-hydroxyoct-4-en-2-yl)-7a-methyl-3,3a,5,6,7,7a-hexahydro-3H-inden-4-one (5) (4.0 g, 13.1 mmol) in dichloromethane (200 mL) was added 1-(trimethylsilyl)imidazole (2.2 mL, 14.9 mmol). The reaction mixture was stirred at room temperature for 18 h. According tlc conversion was not complete and additional 1-(trimethylsilyl)imidazole (4.3 mL, 29.1 mmol) was added and stirring was continued for 5 h. The mixture was concentrated in vacuo at and the residue was purified by column chromatography (200 g Si02, 10% ethyl acetate in heptane) affording the title compound 24 (4.6 g, 93%) as a colorless oil.
Purity according HPLC: 100% (,% = 265 nm); 'H NMR (CDC13): S 5.28-5.52 (m, 3 H), 2.83 (dd, J= 10.4, 6.1 Hz, 1 H), 2.43 (ddm, J= 15.4, 10.4 Hz, 1 H), 2.18-2.32 (m, 4 H), 1.94-2.18 (m, 4 H), 1.85-1.93 (m, 1 H), 1.76 (td, J= 12.4, 5.6 Hz, 1 H), 1.53 (br.
q, J= 7.3 Hz, 4 H), 1.16 (d, J= 6.9 Hz, 3 H), 0.83 (s, 3 H), 0.81 (br. t, J=
7.1 Hz, 6 H), 0.47 (s, 9 H); MS: m/e 376 (M), 361 (M - 15), 347 (M - 29).
Larger Scale Coupling and Synthesis of 1 1-(5-Ethyl-l-methyl-5-trimethylsilanyloxy-hept-3-enyl)-7a-methyl-3,3a,5,6,7,7a-hexahydro-inden-4-one (24) \ O TMS-Imidazole $HH
OTMS
H O O
To a solution of of (3aR,7aS)-1-((S,E)-6-ethyl-6-hydroxyoct-4-en-2-yl)-7a-methyl-3,3a,5,6,7,7a-hexahydro-3H-inden-4-one (5) (4.0 g, 13.1 mmol) in dichloromethane (200 mL) was added 1-(trimethylsilyl)imidazole (2.2 mL, 14.9 mmol). The reaction mixture was stirred at room temperature for 18 h. According tlc conversion was not complete and additional 1-(trimethylsilyl)imidazole (4.3 mL, 29.1 mmol) was added and stirring was continued for 5 h. The mixture was concentrated in vacuo at and the residue was purified by column chromatography (200 g Si02, 10% ethyl acetate in heptane) affording the title compound 24 (4.6 g, 93%) as a colorless oil.
Purity according HPLC: 100% (,% = 265 nm); 'H NMR (CDC13): S 5.28-5.52 (m, 3 H), 2.83 (dd, J= 10.4, 6.1 Hz, 1 H), 2.43 (ddm, J= 15.4, 10.4 Hz, 1 H), 2.18-2.32 (m, 4 H), 1.94-2.18 (m, 4 H), 1.85-1.93 (m, 1 H), 1.76 (td, J= 12.4, 5.6 Hz, 1 H), 1.53 (br.
q, J= 7.3 Hz, 4 H), 1.16 (d, J= 6.9 Hz, 3 H), 0.83 (s, 3 H), 0.81 (br. t, J=
7.1 Hz, 6 H), 0.47 (s, 9 H); MS: m/e 376 (M), 361 (M - 15), 347 (M - 29).
1 a-Fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) O
Ph-P-Ph OH
\ OTMS +
Fi O TBSO"~ F
g HO'"% F
A 25 ml flask was charged with (1S,3Z,5R)-1-Fluoro-5-(tert-Butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane 6 (748 mg,1.59 mmol, 1.2 eq) and (3aR,7aS)-1-((S,E)-6-ethyl-6-(trimethylsilyloxy)oct-4-en-2-yl)-7a-methyl-3,3 a,5,6,7,7a-hexahydro-3H-inden-4-one 24 (499 mg, 1.32 mmol). The mixture was co-evaporated with toluene (3x 5 mL), dissolved in THF (10 mL, freshly distilled over Na/benzophenone) and cooled to C. LiHMDS (1.65 mL, 1 M solution in THF, 1.2 eq.) was added dropwise within 5 min. The deep red solution was allowed to warm to -25 C within 1.5 h. TBAF (9 mL, 1 M solution in THF) was added (color turns to orange) and the mixture was allowed to warm to room temperature overnight. The reaction was quenched by pouring slowly into an ice-cold 1 M aqueous solution of KHCO3. Thus formed mixture was extracted with ethyl acetate (3x 25 mL). The combined organic layers were washed with water, brine (3x), dried (Na2SO4) and concentrated in vacuo at 30 C. The residue was purified by colunm chromatography (25% ethyl acetate in heptane), affording: Fraction A: 35 mg (7%) of epimerized CD-block epi-24. Fraction B:
traces of Vitamin D -related byproducts. Fraction C: 27 mg (5%) of 1 as a white solid;
purity according HPLC: 96.8% (k = 265 nm). Fraction D: 450 mg (75%) of 1 as a white solid; purity according HPLC: 93.7% (?, = 265 nm). Fraction E: 30 mg (5%) of 1 as a white solid; purity according HPLC: 92.9% Q, = 265 nm). Fraction D was dissolved in methyl formate (3-4 mL). Heptane (15 mL) was added and the flask was flushed with nitrogen gas until the solution became cloudy. The product started to crystallize and for complete crystallization the flask was stored at 4 C for 1 h. The solvent was decanted and the remaining solid was washed with cold heptane (3 x mL). After flushing with nitrogen gas the solid was dried in vacuo affording:
Fraction F: 331 mg (56% yield) of 1 as a white solid; purity according HPLC: 100% (k =
nm); 'H NMR (CD3CN): S 6.42 (br d, 1 H), 6.10 (br d, 1 H), 5.51 (ddd, 1 H), 5.39 (br d, 1 H), 5.36 (br s, 1 H), 5.35 (br d, 1 H), 5.13 (ddd, 1 H), 5.07 (br s, 1 H), 3.97-4.05 (m, 1 H), 2.92 (d, 1 H), 2.85 (dd, 1 H), 2.57 (dd, 1 H), 2.38 (dd, 1 H), 2.14-2.29 (m, 5 H), 1.96-2.04 (m, 2 H), 1.84-1.89 (m, 1 H), 1.73-1.82 (m, 3 H), 1.64-1.72 (m, 1 H), 1.53 (ddd, 1 H), 1.45 (br. q, 4 H), 1.04 (d, 3 H), 0.81 (t, 6 H), 0.69 (s, 3 H); 13C NMR
(CD3CN): 160.12, 143.37 (d, J=17Hz), 142.83, 137.33, 133.21 (d, J=2Hz), 126.96, 124.84, 120.83, 117.33 (d, J=32Hz), 115.40 (d, J=10Hz), 93.74, 91.51, 74.83, 65.72 (d, J=5Hz), 58.19, 50.31, 45.14, 40.94 (d, J=2lHz), 39.78, 35.21, 33.34, 33.33, 32.46, 29.33, 28.63, 23.56, 20.33, 16.74, 1.41. 19F NMR (CD3CN): 8-177.55; MS: m/e (M + 39), 465 (M + 23), 425 (M - 17). UV kmax: 244 nm (E 13747), 270 nm (c 13756) (CH3OH). [a] 25+101 (c 1.92, CH3OH).
Alternate Coupling and Synthesis of 1 1a-Fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) O
Ph-P-Ph OH
~OH + I ~ ~ H
H
O TBSO' 'N F
g HO'"% F
A solution of 6 (278 mg, 0.59 mmol, 3.6 eq.) in THF (10 mL, distilled over Na-benzophenone) was cooled at -75 C and n-BuLi (0.23 mL, 2.5 M solution in hexanes, 0.57 mmol) was added dropwise. The red solution was stirred for 20 min.
during which the temperature was allowed to rise to -50 C. A solution of 5 (50 mg, 0.164 mmol) in THF (2 mL, distilled over Na-benzophenone) was added dropwise at -50 C within 5 min. Stirring was continued for 2 h during which the temperature was allowed to rise to -10 C. Tlc showed ca. 20% conversion. To the yellow solution was added dropwise TBAF (1.8 mL, 1 M solution in THF, containing ca. 5% water) upon which the solution turned red-brown. The reaction mixture was allowed to reach room temperature overnight. The reaction mixture was quenched by addition of an ice-cold aqueous 1 M KHCO3 solution (3 g in 30 mL of water) and the mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with water and brine, dried (NaZSO4), filtered and the filtrate was concentrated in vacuo at 30 C.
The residue was purified by column chromatography (Si02, 25% ethyl acetate in heptane) affording 1 (13 mg, 18%) as a white foam.
Incorporation by Reference The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference.
Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
Ph-P-Ph OH
\ OTMS +
Fi O TBSO"~ F
g HO'"% F
A 25 ml flask was charged with (1S,3Z,5R)-1-Fluoro-5-(tert-Butyldimethyl)silanyloxy)-2-methenyl-3-(diphenylphosphinoyl)ethylidene cyclohexane 6 (748 mg,1.59 mmol, 1.2 eq) and (3aR,7aS)-1-((S,E)-6-ethyl-6-(trimethylsilyloxy)oct-4-en-2-yl)-7a-methyl-3,3 a,5,6,7,7a-hexahydro-3H-inden-4-one 24 (499 mg, 1.32 mmol). The mixture was co-evaporated with toluene (3x 5 mL), dissolved in THF (10 mL, freshly distilled over Na/benzophenone) and cooled to C. LiHMDS (1.65 mL, 1 M solution in THF, 1.2 eq.) was added dropwise within 5 min. The deep red solution was allowed to warm to -25 C within 1.5 h. TBAF (9 mL, 1 M solution in THF) was added (color turns to orange) and the mixture was allowed to warm to room temperature overnight. The reaction was quenched by pouring slowly into an ice-cold 1 M aqueous solution of KHCO3. Thus formed mixture was extracted with ethyl acetate (3x 25 mL). The combined organic layers were washed with water, brine (3x), dried (Na2SO4) and concentrated in vacuo at 30 C. The residue was purified by colunm chromatography (25% ethyl acetate in heptane), affording: Fraction A: 35 mg (7%) of epimerized CD-block epi-24. Fraction B:
traces of Vitamin D -related byproducts. Fraction C: 27 mg (5%) of 1 as a white solid;
purity according HPLC: 96.8% (k = 265 nm). Fraction D: 450 mg (75%) of 1 as a white solid; purity according HPLC: 93.7% (?, = 265 nm). Fraction E: 30 mg (5%) of 1 as a white solid; purity according HPLC: 92.9% Q, = 265 nm). Fraction D was dissolved in methyl formate (3-4 mL). Heptane (15 mL) was added and the flask was flushed with nitrogen gas until the solution became cloudy. The product started to crystallize and for complete crystallization the flask was stored at 4 C for 1 h. The solvent was decanted and the remaining solid was washed with cold heptane (3 x mL). After flushing with nitrogen gas the solid was dried in vacuo affording:
Fraction F: 331 mg (56% yield) of 1 as a white solid; purity according HPLC: 100% (k =
nm); 'H NMR (CD3CN): S 6.42 (br d, 1 H), 6.10 (br d, 1 H), 5.51 (ddd, 1 H), 5.39 (br d, 1 H), 5.36 (br s, 1 H), 5.35 (br d, 1 H), 5.13 (ddd, 1 H), 5.07 (br s, 1 H), 3.97-4.05 (m, 1 H), 2.92 (d, 1 H), 2.85 (dd, 1 H), 2.57 (dd, 1 H), 2.38 (dd, 1 H), 2.14-2.29 (m, 5 H), 1.96-2.04 (m, 2 H), 1.84-1.89 (m, 1 H), 1.73-1.82 (m, 3 H), 1.64-1.72 (m, 1 H), 1.53 (ddd, 1 H), 1.45 (br. q, 4 H), 1.04 (d, 3 H), 0.81 (t, 6 H), 0.69 (s, 3 H); 13C NMR
(CD3CN): 160.12, 143.37 (d, J=17Hz), 142.83, 137.33, 133.21 (d, J=2Hz), 126.96, 124.84, 120.83, 117.33 (d, J=32Hz), 115.40 (d, J=10Hz), 93.74, 91.51, 74.83, 65.72 (d, J=5Hz), 58.19, 50.31, 45.14, 40.94 (d, J=2lHz), 39.78, 35.21, 33.34, 33.33, 32.46, 29.33, 28.63, 23.56, 20.33, 16.74, 1.41. 19F NMR (CD3CN): 8-177.55; MS: m/e (M + 39), 465 (M + 23), 425 (M - 17). UV kmax: 244 nm (E 13747), 270 nm (c 13756) (CH3OH). [a] 25+101 (c 1.92, CH3OH).
Alternate Coupling and Synthesis of 1 1a-Fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol (1) O
Ph-P-Ph OH
~OH + I ~ ~ H
H
O TBSO' 'N F
g HO'"% F
A solution of 6 (278 mg, 0.59 mmol, 3.6 eq.) in THF (10 mL, distilled over Na-benzophenone) was cooled at -75 C and n-BuLi (0.23 mL, 2.5 M solution in hexanes, 0.57 mmol) was added dropwise. The red solution was stirred for 20 min.
during which the temperature was allowed to rise to -50 C. A solution of 5 (50 mg, 0.164 mmol) in THF (2 mL, distilled over Na-benzophenone) was added dropwise at -50 C within 5 min. Stirring was continued for 2 h during which the temperature was allowed to rise to -10 C. Tlc showed ca. 20% conversion. To the yellow solution was added dropwise TBAF (1.8 mL, 1 M solution in THF, containing ca. 5% water) upon which the solution turned red-brown. The reaction mixture was allowed to reach room temperature overnight. The reaction mixture was quenched by addition of an ice-cold aqueous 1 M KHCO3 solution (3 g in 30 mL of water) and the mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with water and brine, dried (NaZSO4), filtered and the filtrate was concentrated in vacuo at 30 C.
The residue was purified by column chromatography (Si02, 25% ethyl acetate in heptane) affording 1 (13 mg, 18%) as a white foam.
Incorporation by Reference The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference.
Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
Claims (71)
1. A method of producing a vitamin D3 compound of formula I
wherein:
each R1 is independently alkyl;
and pharmaceutically acceptable esters, salts, and prodrugs thereof;
which comprises:
converting a compound of formula VI
wherein R a is a hydroxy protecting group, to a compound of formula VII
wherein R a a hydroxy protecting group and R e is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
converting the compound of formula X to a compound of formula II
reacting the compound of formula II with a compound of formula III
wherein R a is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
wherein:
each R1 is independently alkyl;
and pharmaceutically acceptable esters, salts, and prodrugs thereof;
which comprises:
converting a compound of formula VI
wherein R a is a hydroxy protecting group, to a compound of formula VII
wherein R a a hydroxy protecting group and R e is H or a hydroxyl protecting group;
converting a compound of formula VII to a compound of formula X
converting the compound of formula X to a compound of formula II
reacting the compound of formula II with a compound of formula III
wherein R a is defined as above and Q is a phosphorus-containing group;
to thereby produce a compound of formula I.
2. A method of producing a compound of formula X
wherein:
each R1 is independently alkyl;
which comprises:
converting a compound of formula VI
wherein R a is a hydroxy protecting group, to a compound of formula VII
wherein R a is a hydroxyl protecting group and R e is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X, to thereby produce a compound of formula X.
wherein:
each R1 is independently alkyl;
which comprises:
converting a compound of formula VI
wherein R a is a hydroxy protecting group, to a compound of formula VII
wherein R a is a hydroxyl protecting group and R e is H or a hydroxyl protecting group;
and converting the compound of formula VII to a compound of formula X, to thereby produce a compound of formula X.
3. The method of claims 1 or 2, further comprising:
reacting the compound of formula VI
wherein R a is a hydroxy protecting group, with a hydroxylating reagent to form a compound of formula VII
reacting the compound of formula VI
wherein R a is a hydroxy protecting group, with a hydroxylating reagent to form a compound of formula VII
4. The method of claim 3, further comprising:
subjecting the compound of formula VII
to nucleophilic displacement conditions to form a compound of formula VIII
wherein R a is a hydroxy protecting group;
A is a double or triple bond;
Z is O, S, or NR x; and R x is H or absent.
subjecting the compound of formula VII
to nucleophilic displacement conditions to form a compound of formula VIII
wherein R a is a hydroxy protecting group;
A is a double or triple bond;
Z is O, S, or NR x; and R x is H or absent.
5. The method of claim 4, wherein the compound of formula VIII is a compound of formula VIII-a or a compound of formula VIII-b
6. The method of claim 5, further comprising:
reacting the compound of formula VIII-b with a phosphorous-containing reagent of formula VIII-c wherein Y is OR b, NR b R b, or S(O)n R b; each R d is independently alkyl, aryl, or alkoxy;
each R b is independently H, alkyl, or aryl; and n is 0-2; in the presence of a base to form a compound of formula IX
wherein: R a and Y are as defined above.
reacting the compound of formula VIII-b with a phosphorous-containing reagent of formula VIII-c wherein Y is OR b, NR b R b, or S(O)n R b; each R d is independently alkyl, aryl, or alkoxy;
each R b is independently H, alkyl, or aryl; and n is 0-2; in the presence of a base to form a compound of formula IX
wherein: R a and Y are as defined above.
7. The method of claim 6, further comprising:
reacting the compound of formula IX
with an organometallic reagent to form a compound of formula X
wherein each R1 is independently alkyl.
reacting the compound of formula IX
with an organometallic reagent to form a compound of formula X
wherein each R1 is independently alkyl.
8. The method of claim 3, wherein the hydroxylating reagent comprises paraformaldehyde and a Lewis Acid.
9. The method of claim 8, wherein the Lewis Acid is selected from dimethyl aluminum chloride, diethylaluminum chloride and ethylaluminim dichloride.
10. The method of claim 4, wherein the nucleophilic displacement compound is sodium cyanide (NaCN).
11. The method of claim 5, wherein the compound of formula VIII-a is converted to a compound of formula VIII-b by a reducing agent.
12. The method of claim 11, wherein the reducing agent is selected from diisobutyl aluminum hydride (DIBAL-H).
13. The method of claim 6, wherein the phosphorus-containing compound of formula VIII-a is triethyl phosphonoacetate and the base is lithium hexamethyldisalazide (LiHMDS).
14. The method of claim 7, wherein the organometallic reagent is ethyl magnesium bromide (EtMgBr) .
15. The method of claim 14, further comprising the addition of cerium trichloride (CeCl3).
16. The method of claim 3, wherein the compound of formula VI is Acetic acid 1-ethylidene-7a-methyl-octahydro-inden-4-yl ester:
17. The method of claim 3, wherein the compound of formula VII is Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester or Acetic acid 7a-methyl-1-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester :
18. The method claim 4, wherein the compound of formula VIII is Acetic acid 1-(2-cyano-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-a) or Acetic acid 7a-methyl-1-(1-methyl-3-oxo-propyl)-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester (VIII-b):
19. The method of claim 6, wherein the compound of formula IX is 5-(4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-1-yl)-hex-2-enoic acid ethyl ester:
20. The method of claim 7, wherein the compound of formula X is 1-(5-Ethyl-5-hydroxy-1-methyl-hept-3-enyl)-7a-methyl-3 a,4,5,6,7,7a-hexahydro-3H-inden-4-ol:
21. The method of claim 1, further comprising obtaining the compound of formula VI.
22. The method of claim 21, wherein the compound of formula VI is obtained by:
converting compound 3 to a compound of formula XXI
wherein R a is a hydroxy protecting group;
converting a compound of formula XXI to a compound of formula XX
wherein R a is a hydroxy protecting group;
and convering the compound of formula XX to the compound of formula VI.
converting compound 3 to a compound of formula XXI
wherein R a is a hydroxy protecting group;
converting a compound of formula XXI to a compound of formula XX
wherein R a is a hydroxy protecting group;
and convering the compound of formula XX to the compound of formula VI.
23. The method of claim 22, wherein the oxidation reagent for the conversion of XXI to XX comprises oxalyl chloride.
24. The method of claim 22, wherein the compound of formula XXI is Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-octahydro-inden-4-yl ester:
25. The method of claim 1, further comprising:
converting a compound of formula XII
wherein R a is a hydroxy protecting group, to a compound of formula XII-a wherein R z is H, I, or Ph;
converting the compound of formula XII-a to a compound of formula XV
wherein R, is H or benzoyl;
converting the compound of formula XV to a compound of formula III
wherein, Q is a phosphorus-containing group.
converting a compound of formula XII
wherein R a is a hydroxy protecting group, to a compound of formula XII-a wherein R z is H, I, or Ph;
converting the compound of formula XII-a to a compound of formula XV
wherein R, is H or benzoyl;
converting the compound of formula XV to a compound of formula III
wherein, Q is a phosphorus-containing group.
26. The method of claim 25, wherein the conversion of the compound of formula XII to the compound of formula XII-a is carried out in the presence of an aroyl chloride and base.
27. The method of claim 26, further comprising:
reacting the compound of formula XII-a with an oxidizing agent, to provide a compound of formula XIII
reacting the compound of formula XII-a with an oxidizing agent, to provide a compound of formula XIII
28. The method of claim 27, further comprising:
reacting the compound of formula XIII
with a fluorinating agent, to provide a compound of formula XIV
reacting the compound of formula XIII
with a fluorinating agent, to provide a compound of formula XIV
29. The method of claim 28, further comprising:
reacting the compound of formula XIV
with a deoxygenation agent, to provide a compound of formula XV
reacting the compound of formula XIV
with a deoxygenation agent, to provide a compound of formula XV
30. The method of claim 29, further comprising:
reacting the compound of formula XV
with a deprotection agent, to provide a compound of formula XV
reacting the compound of formula XV
with a deprotection agent, to provide a compound of formula XV
31. The method of claim 28, further comprising:
reacting the compound of formula XIV
with a deoxygenation agent, to provide a compound of formula XVa
reacting the compound of formula XIV
with a deoxygenation agent, to provide a compound of formula XVa
32. The method of claim 31, further comprising:
reacting the compound of formula XVa with an epimerizaing agent, to provide a compound of formula XV
reacting the compound of formula XVa with an epimerizaing agent, to provide a compound of formula XV
33. The method of claim 25, further comprising:
reacting the compound of formula XV
with a chlorinating agent, to provide a compound of formula XVI
reacting the compound of formula XV
with a chlorinating agent, to provide a compound of formula XVI
34. The method of claim 33, further comprising:
reacting the compound of formula XVI
with a phosphorous containing agent in the presence of a base, to provide a compound of formula III
reacting the compound of formula XVI
with a phosphorous containing agent in the presence of a base, to provide a compound of formula III
35. The method of claim 26, wherein the base is pyridine.
36. The method of claim 27, wherein the oxidizing reagent comprises selenium dioxide and t-butyl hydrogen peroxide.
37. The method of claim 28, wherein the fluorinating agent is diethylaminosulfur trifluoride (DAST).
38. The method of claim 29 or 30, wherein the deoxygenation reagent is tris(3,5-dimethylpyrazoyl)hydridoborate rhenium trioxide or tungsten hexachloride/nBuLi.
39. The method of claim 30, wherein the deprotection agent is sodium methoxide.
40. The method of claim 32, wherein the epimerization agent comprises hv and 9-fluorenone.
41. The method of claim 33, wherein the chlorinating agent comprises triphosgene and pyridine.
42. The method of claim 34, wherein the phosphorous containing agent is diphenyl phosphine oxide.
43. The method of claim 35, wherein the base is sodium hydride.
44. The method of claim 26, wherein the compound of formula XII-a is Benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-4-methylene-1-oxa-spiro[2.5]oct-2-ylmethyl ester:
45. The method of claim 27, wherein the compound of formula XIII is Benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-4-methylene-1-oxa-spiro[2.5]oct-2-ylmethyl ester:
46. The method of claim 28, wherein the compound of formula XIV is Benzoic acid 7-(tert-butyl-dimethyl-silanyloxy)-5-fluoro-4-methylene-1-oxa-spiro[2.5]oct-2-ylmethyl ester:
47. The method of claim 29, wherein the compound of formula XV is Benzoic acid 2-[5-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-2-methylene-cyclohexylidene]-ethyl ester:
48. The method of claim 31, wherein the compound of formula XVa is 2-[5-(tert-Butyl-dimethyl-silanyloxy)-3 -fluoro-2-methylene-cyclohexylidene] -ethanol:
49. The method of claim 30 or 32, wherein the compound of formula XV is 2-[5-(tert-Butyl-dimethyl-silanyloxy)-3 -fluoro-2-methylene-cyclohexylidene] -ethanol:
50. The method of claim 33, wherein the compound of formula XVI is tert-Butyl-[3-(2-chloro-ethylidene)-5-fluoro-4-methylene-cyclohexyloxy] -dimethyl-silane:
51. The method of claim 34, wherein the compound of formula III is tert-Butyl-{3-[2-(diphenyl-phosphinoyl)-ethylidene]-5-fluoro-4-methylene-cyclohexyloxy} -dimethyl-silane:
52. The method of claim 1, wherein the coupling reaction of the compound of formula II and the compound of formula III to form the compound of formula I
comprises:
converting the compound of formula II
to a compound of formula XVII
wherein R a is hydroxy protecting group;
reacting the compound of formula XVII with a compound of formula III in the presence of base wherein Q is a phosphorus-containing group, to form a compound of formula XVIII
converting the compound of formula XVIII to the compound of formula I.
comprises:
converting the compound of formula II
to a compound of formula XVII
wherein R a is hydroxy protecting group;
reacting the compound of formula XVII with a compound of formula III in the presence of base wherein Q is a phosphorus-containing group, to form a compound of formula XVIII
converting the compound of formula XVIII to the compound of formula I.
53. The method of claim 1, wherein the reaction of the compound of formula II
and the compound of formula III to produce the compound of formula I is carried out in a single process step.
and the compound of formula III to produce the compound of formula I is carried out in a single process step.
54. The method of claim 52, wherein the compound of formula I is produced in process steps.
55. The method of claim 53, wherein the compound of formula I is produced in process steps.
56. The method of claim 1, wherein each R1 is ethyl.
57. The method of claim 1, wherein the compound of formula I is
58. The method of claim 1 wherein:
reacting a compound of formula II
with a compound of formula III
wherein R a is defined as above and Q is a phosphorus-containing group;
takes place in the presence of a strong base; to thereby produce a compound of formula I.
reacting a compound of formula II
with a compound of formula III
wherein R a is defined as above and Q is a phosphorus-containing group;
takes place in the presence of a strong base; to thereby produce a compound of formula I.
59. The method of claim 58, wherein the strong base is n-butyl lithium.
60. The method of claim 22, further comprising obtaining compound 3.
61. The method of claim 60, wherein compound 3 is obtained by:
converting compound 2 to compound 7 and converting compound 7 to compound 3.
converting compound 2 to compound 7 and converting compound 7 to compound 3.
62. The method of claim 25, further comprising obtaining the compound of formula XII.
63. The method of claim 62, wherein the compound of formula XII is obtained by:
converting compound 2 to compound 4a converting compound 4a to compound 4 and converting compound 4 to the compound of formula XII.
converting compound 2 to compound 4a converting compound 4a to compound 4 and converting compound 4 to the compound of formula XII.
64. The method of claim 63, wherein the epoxidation reagent comprises m-chloroperoxybenzoic acid (m-CPBA).
65. The compound Acetic acid 1-(2-hydroxy-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
66. The compound Acetic acid 7a-methyl-1-[1-methyl-2-(toluene-4-sulfonyloxy)-ethyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester:
67. The compound Acetic acid 1-(2-cyano-1-methyl-ethyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester
68. The compound Acetic acid 7a-methyl-1-(1-methyl-3-oxo-propyl)-3 a,4,5,6,7,7a-hexahydro-3H-inden-4-yl ester
69. The compound 5-(4-hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden-l-yl)-hex-2-enoic acid ethyl ester:
70. The method of claim 9, wherein the Lewis Acid is dimethyl aluminum chloride.
71. The method of any one of claims 1-64 and 70, further comprising obtaining any one of the compounds.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89760907P | 2007-01-25 | 2007-01-25 | |
| US60/897,609 | 2007-01-25 | ||
| PCT/US2008/000970 WO2008091686A2 (en) | 2007-01-25 | 2008-01-25 | SYNTHESIS OF 1α-FLUORO-25-HYDROXY-16-23E-DIENE-26,27-BISHOMO-20-EPI-CHOLECALCIFEROL |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2676512A1 true CA2676512A1 (en) | 2008-07-31 |
Family
ID=39645084
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002676512A Abandoned CA2676512A1 (en) | 2007-01-25 | 2008-01-25 | Synthesis of 1.alpha.-fluoro-25-hydroxy-16-23e-diene-26,27-bishomo-20-epi-cholecalciferol |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA2676512A1 (en) |
| TW (1) | TW200838544A (en) |
| WO (1) | WO2008091686A2 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG70009A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Vitamin d3 analogs |
| EP0998455B1 (en) * | 1997-07-17 | 2003-10-01 | F.Hoffmann-La Roche Ag | Dihomo-seco-cholestanes with two unsaturated bonds in the side chain |
| EP0957098A1 (en) * | 1998-05-14 | 1999-11-17 | F. Hoffmann-La Roche Ag | Intermediates for the synthesis of 3-epi vitamin D3 metabolites and analogs |
| EP1828114B1 (en) * | 2004-11-22 | 2010-04-21 | Wisconsin Alumni Research Foundation | 17,20(e)-dehydro vitamin d analogs and their uses |
-
2008
- 2008-01-25 CA CA002676512A patent/CA2676512A1/en not_active Abandoned
- 2008-01-25 TW TW097102791A patent/TW200838544A/en unknown
- 2008-01-25 WO PCT/US2008/000970 patent/WO2008091686A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008091686A2 (en) | 2008-07-31 |
| WO2008091686A3 (en) | 2008-10-09 |
| TW200838544A (en) | 2008-10-01 |
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