WO1994007900A1 - Synthesis of n-glycosylated compounds with the use of a mild, iodine-catalyzed reaction - Google Patents
Synthesis of n-glycosylated compounds with the use of a mild, iodine-catalyzed reaction Download PDFInfo
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- WO1994007900A1 WO1994007900A1 PCT/US1993/009036 US9309036W WO9407900A1 WO 1994007900 A1 WO1994007900 A1 WO 1994007900A1 US 9309036 W US9309036 W US 9309036W WO 9407900 A1 WO9407900 A1 WO 9407900A1
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- the invention concerns N-glycosylated derivatives of non-basic nitrogen nucleophile compounds.
- the invention also concerns a mild, cost-effective, stereoselective, regioselective, and generally applicable method for the preparation of N-glycosides by N- glycosylation of azide and amide nucleophile compounds, more particularly in a preferred aspect, compounds that are useful pharmacological agents (or precursors thereof) such as antibiotics, and antineoplastic and antiviral compounds, e.g., 3' -azido-3' -deoxythymidine (AZT) and 2' , 3'- dideoxyinosine (DDI) .
- the method employs iodine in a catalytic amount that uniquely does not pose an environmental hazard.
- N-nucleosides containing N- glycosidic linkages are currently on the market as medicinally efficacious drugs. Due primarily to the increased importance of certain anti-retroviral nucleosides, most notably AZT and DDI as AIDS drugs (abstracts 10023 and 3092, The Merck Index XI, incorporated by reference herewith) , the list of such N-nucleoside-based drugs continues to grow at an unprecedented rate. For a review, see: Norbeck, D. . Ann Rep . Med. Chem . 1990, 25, 149-158, incorporated herewith by reference.
- N-glycosides of the non-nucleoside type there are numerous N-glycosides of the non-nucleoside type. A number of such N-glycosides show extremely potent biological activities including antibiotic and antitumor activities. In view of the significant medicinal activity of these N-glycoside and N-nucleoside drugs, research efforts are currently directed both at identifying more efficacious drugs with fewer side effects, and at developing improved chemical synthetic methods of making such drugs or their precursors.
- the invention concerns l ⁇ - and l ⁇ -N-glycosylated compounds obtained by reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and six-membered glycals of the formulas I, II and III and la, Ila and Ilia
- RQ is a lower alkyl group (preferably a C ⁇ _4 alkyl group) and R , R2 and R3 are the same or different and represent an aliphatic acyl group (preferably a lower aliphatic acyl group) or an aromatic acyl group such as a benzoyl group, in the presence of a catalytic amount of iodine to provide a reaction mixture of formed l ⁇ - and l ⁇ - N-glycosylated products of the group selected from anomers and epimers, isolating at least one ⁇ - or ⁇ -glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products .
- R , R2 and R3 are the same or different and represent an aliphatic acyl group (preferably a lower aliphatic acyl group) or an aromatic acyl group such as a benzoyl group, in the presence
- nucleophiles examples include propionamide, benzamide, acetanilide, triacetyl cholic acid amide and the like; methyl sulfonamide, phenyl sulfonamide. para-substituted phenyl sulfonamide and the like; ⁇ - caprolactam, azetidine-2-one derivatives and the like; trimethyl stannyl azide, lithium azide and the like.
- the invention concerns a process for preparing N-glycosylated compounds, comprising reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides, as described, and a glycosylating agent selected from acylated, carbonated and thionocarbonated five and six- membered glycals, also as described, of the above formulas I, II and III and la, Ha and Ilia in the presence of a catalytic amount of iodine to provide a reaction mixture of formed l ⁇ - and l ⁇ -N-glycosylated products of the group selected from anomers and epimers, isolating at least one ⁇ - or ⁇ -glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products .
- a non-basic nitrogen nucleophile selected from amides, s
- any of various suitable solvents can be used for the reaction of which THF, acetone, diethyl ether, methylene chloride, chloroform, and benzene are preferred.
- the reaction temperature and time can be varied, e.g., ranging from about 0 to 90°C for about 0.5 to 24 hours.
- the glycals are commonly available or can be prepared by known methods.
- the nitrogen nucleophile is an amide such as acetamide or a similar amide.
- the nitrogen nucleophile is an azide having a counter ion group such as a trimethylsilyl group.
- a preferred glycosylating agent is triacetyl D-glucal.
- pure glycosyl 1-azides and/or 3-azides are produced after workup and isolation by silica gel flash column chromatography; also one or both of the 1-azide ⁇ - anomer and the 3-azide ⁇ -epimer are isolated.
- a particular feature of the present invention resides in the use of a nitrogen nucleophile that includes an azide anion.
- the method includes highly efficient N- glycoside formation between the acyl glucal and the nitrogen nucleophile such as an amide or trimethylsilyl azide, in the presence of a catalytic amount of iodine.
- the iodine catalyst is an extremely mild Lewis acid and yet does not destroy nucleophilic properties at these nitrogen centers.
- the process provides an efficient access to key intermediates for the synthesis of analogs of AZT and DDI and for the synthesis of conventional N-nucleoside antibiotic drugs and their novel N-glycosylated analogs.
- the invention concerns partly and completely deacylated products having enhanced water-solubility, produced by hydrolysis of one or more acyl groups from the acylated product .
- MOH aqueous metal hydroxide
- M Li, K, Na
- Zn (OAc)2'2l_2 ⁇ in methanol
- LiAlI_4 or diisobutylaluminum hydride in benzene, toluene, ether
- Triacetyl D-glucal (3.8 mmol) , acetamide (3.8 mmol) , and iodine (0.76 mmol) were dissolved in 20 mL of THF and the solution was heated to reflux. After refluxing for 18 hours, the reaction mixture was cooled to room temperature and then diluted with 50 L of ethyl acetate. The solution was washed with 15 mL of 10% aqueous Na2S2 ⁇ 3. The aqueous layer was back-extracted with ethyl acetate (4 x 15 mL) . These extracts were combined with the original organic layer. The combined organic layers were dried
- Triacetyl D-glucal (0.275 mmol), trimethylsilyl azide (0.279 mmol), and iodine (0.055 mmol) were dissolved in 1.5 mL of methylene chloride and the solution was stirred at room temperature for 12 hours.
- Example I The procedure of Example I can be used for the stereoselective N-glycosylation of nitrogen nucleophile compounds such as the known compound DDI and its analogs and like pharmacologically useful compounds.
- nitrogen nucleophile compounds such as the known compound DDI and its analogs and like pharmacologically useful compounds.
- the resulting novel N-(acetyl or diacetyl glycosylated) substrate compounds are contemplated to have substantial advantage with respect to greater water solubility and yet have substantially the same useful antiviral activity and posology as DDI and its analogs.
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Abstract
The invention concerns N-glycosylated derivatives of nitrogen nucleophile compounds. The invention also concerns a mild, cost effective, stereoselective, regioselective, and generally applicable method for the preparation of N-glycosides by N-glycosylation of azide and amide nucleophile compounds. The method employs iodine in a catalytic amount that uniquely does not pose an environmental hazard. The invention provides efficient access to key intermediates for the synthesis inter alia of analogs of AZT and DDI and for the synthesis of conventional N-nucleoside antibiotic drugs and their novel N-glycosylated analogs.
Description
SYNTHESISOFN-GLYCOSYLATEDCOMPOUNDSWITHTHE USEOFAMILD,IODINE-CATALYZED REACTION
Field of the Invention
The invention concerns N-glycosylated derivatives of non-basic nitrogen nucleophile compounds. The invention also concerns a mild, cost-effective, stereoselective, regioselective, and generally applicable method for the preparation of N-glycosides by N- glycosylation of azide and amide nucleophile compounds, more particularly in a preferred aspect, compounds that are useful pharmacological agents (or precursors thereof) such as antibiotics, and antineoplastic and antiviral compounds, e.g., 3' -azido-3' -deoxythymidine (AZT) and 2' , 3'- dideoxyinosine (DDI) . The method employs iodine in a catalytic amount that uniquely does not pose an environmental hazard.
Background of the Invention
A vast number of structurally diverse mononucleosides, known as N-nucleosides containing N- glycosidic linkages, are currently on the market as medicinally efficacious drugs. Due primarily to the increased importance of certain anti-retroviral nucleosides, most notably AZT and DDI as AIDS drugs (abstracts 10023 and 3092, The Merck Index XI, incorporated by reference herewith) , the list of such N-nucleoside-based drugs continues to grow at an unprecedented rate. For a review, see: Norbeck, D. . Ann Rep . Med. Chem . 1990, 25, 149-158, incorporated herewith by reference. In addition, there are numerous N-glycosides of the non-nucleoside type.
A number of such N-glycosides show extremely potent biological activities including antibiotic and antitumor activities. In view of the significant medicinal activity of these N-glycoside and N-nucleoside drugs, research efforts are currently directed both at identifying more efficacious drugs with fewer side effects, and at developing improved chemical synthetic methods of making such drugs or their precursors.
Most of the methods currently available for N- glycosylation involve the synthesis of C-l activated, unstable intermediates and thus often have serious drawbacks in terms of yields and/or their practical applicability. In addition, the methods use expensive and/or toxic catalysts for N-glycosylation. Presently, there are only a handful of methods available that effect direct N-glycosylation reactions. The only previously reported chemical means for the introduction of an amide involves the reaction of a glycosyl 1-sulfoxide and N- (trimethylsilyl) acetamide with the use of the potent Lewis acid, triflie anhydride, as a catalyst (Kahne, M. ; Walker, S.; Cheng, Y.; Van Engen, D. J. Am . Chem . Soc . 1989, 111, 6881-6882) . The reaction of glycal with an azide has been reported (Heyns, K.; Lim, M-j . ; Park, J.I. Tet rahedron Let t . 1976, 1477-1480 and Guthrie, R.D.; Irvine, R.W. Carbohydr . Res . 1980, 82, 207-224), but the reaction requires a strong Lewis acid catalyst, boron trifluoride.
Summary and Detailed Description
In one preferred aspect, the invention concerns lα- and lβ-N-glycosylated compounds obtained by reacting a non-basic nitrogen nucleophile selected from amides,
sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and six-membered glycals of the formulas I, II and III and la, Ila and Ilia
where RQ is a lower alkyl group (preferably a Cι_4 alkyl group) and R , R2 and R3 are the same or different and represent an aliphatic acyl group (preferably a lower aliphatic acyl group) or an aromatic acyl group such as a benzoyl group, in the presence of a catalytic amount of iodine to provide a reaction mixture of formed lα- and lβ- N-glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β-glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products .
Examples of suitable nucleophiles include propionamide, benzamide, acetanilide, triacetyl cholic acid amide and the like; methyl sulfonamide, phenyl sulfonamide.
para-substituted phenyl sulfonamide and the like; ε- caprolactam, azetidine-2-one derivatives and the like; trimethyl stannyl azide, lithium azide and the like.
In another preferred aspect, the invention concerns a process for preparing N-glycosylated compounds, comprising reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides, as described, and a glycosylating agent selected from acylated, carbonated and thionocarbonated five and six- membered glycals, also as described, of the above formulas I, II and III and la, Ha and Ilia in the presence of a catalytic amount of iodine to provide a reaction mixture of formed lα- and lβ-N-glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β-glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products . Any of various suitable solvents can be used for the reaction of which THF, acetone, diethyl ether, methylene chloride, chloroform, and benzene are preferred. The reaction temperature and time can be varied, e.g., ranging from about 0 to 90°C for about 0.5 to 24 hours. The glycals are commonly available or can be prepared by known methods. In one preferred embodiment, the nitrogen nucleophile is an amide such as acetamide or a similar amide. In another preferred embodiment, the nitrogen nucleophile is an azide having a counter ion group such as a trimethylsilyl group. A preferred glycosylating agent is triacetyl D-glucal.
In a preferred embodiment employing an azide nucleophile, pure glycosyl 1-azides and/or 3-azides are
produced after workup and isolation by silica gel flash column chromatography; also one or both of the 1-azide α- anomer and the 3-azide α-epimer are isolated.
A particular feature of the present invention resides in the use of a nitrogen nucleophile that includes an azide anion. The method includes highly efficient N- glycoside formation between the acyl glucal and the nitrogen nucleophile such as an amide or trimethylsilyl azide, in the presence of a catalytic amount of iodine. Unlike currently available methods for similar reactions, the iodine catalyst is an extremely mild Lewis acid and yet does not destroy nucleophilic properties at these nitrogen centers. For this purpose, one preferably uses a catalytic amount of iodine (5-50 mol % with 20 mol % being the most representative) . The process provides an efficient access to key intermediates for the synthesis of analogs of AZT and DDI and for the synthesis of conventional N-nucleoside antibiotic drugs and their novel N-glycosylated analogs.
In another preferred aspect, the invention concerns partly and completely deacylated products having enhanced water-solubility, produced by hydrolysis of one or more acyl groups from the acylated product . For hydrolysis, acyl group removal can be achieved for example by selectively deacylating the acylated product, under per se commonly used conditions for hydrolysis and workup, with an aqueous metal hydroxide (MOH; M = Li, K, Na) in methanol or ethanol, or with Zn (OAc)2'2l_2θ in methanol, or (except for amide and azide substrates) with LiAlI_4 or diisobutylaluminum hydride in benzene, toluene, ether or THF.
The invention and the best mode of carrying out
the same are illustrated by the following non-limitative examples .
Example I Reaction of Triacetyl D-Glucal With Acetamide
Triacetyl D-glucal (3.8 mmol) , acetamide (3.8 mmol) , and iodine (0.76 mmol) were dissolved in 20 mL of THF and the solution was heated to reflux. After refluxing for 18 hours, the reaction mixture was cooled to room temperature and then diluted with 50 L of ethyl acetate. The solution was washed with 15 mL of 10% aqueous Na2S2θ3. The aqueous layer was back-extracted with ethyl acetate (4 x 15 mL) . These extracts were combined with the original organic layer. The combined organic layers were dried
(Na2S(_>4) and the solvent was evaporated under reduced pressure. Purification of the crude product (85% yield in a ca 3-5:1 α/β-anomers) by silica gel flash column chromatography with the use of 1:1 THF/hexanes as the eluent provided the two anomerically pure α- and β-N- glycosylated products in 49 and 25% yields, respectively. For α-anomer (fast-eluting anomer) : 1H NMR (360 MHz; CDCI3) δ 2.04 (s,3H) , 2.09 (s,3H) , 2.10 (s,3H) , 3.92
(ddd,lH, J=9.8,5.4,2.5 Hz), 4.17 and 4.25 (AB q, 2H, JAB =
12.1 Hz; the 4.17 ppm peaks are further split into doublets with J = 2.5 Hz, and the 4.25 ppm peaks are further split into doublets with J = 5.4 Hz), 5.30 (dd, 1H, J = 8.9, 1.9 Hz), 5.76 and 5.94 (ABq, 2H, JAB = 10.4 Hz), 6.00-6.06
(m,2H); 13C NMR (90.6 MHz; CDCI3) δ 20.70, 20.96, 23.39, 62.99, 64.45, 74.17, 74.98, 129.45, 129.69, 169.89, 170.37, 170.88. For β-anomer (late-eluting anomer) : 1H NMR (300 MHz; CDCI3) δ 2.05 (s,3H), 2.08 (s,3H), 2.09 (s,3H), 3.91
(ddd,lH,J = 8.5, 5.1, 3.0 Hz), 4.16 and 4.25 (ABq,2H,JAB =
12.1 Hz; the 4.16 ppm peaks are further split into doublets
1 with J = 3.0 Hz, and the 4.25 ppm peaks are further split into d with J = 5.1 Hz), 5.28 (dd, 1H, J = 8.5, 1.8 Hz), 5.84 and 5.99 (ABq,2H,JAB = 10.2 Hz; the 5.84 ppm peaks are split further into doublets of doublets with J = 3.0, 1.5
Hz), 5.92 (d,lH,J = 10.0 Hz), 6.10-6.22 (m, 1H) .
Example II Reaction of Triacetyl D-Glucal With Trimethylsilyl Azide
Triacetyl D-glucal (0.275 mmol), trimethylsilyl azide (0.279 mmol), and iodine (0.055 mmol) were dissolved in 1.5 mL of methylene chloride and the solution was stirred at room temperature for 12 hours. Identical workup as in Example I provided the crude product whose ^H NMR spectrum indicated it to be a mixture of the 1-azide (α:β = 4:1, ca 65% of the mixture) and the 3-azide (α:β = 1.6:1,
ca 35% of the mixture) . Purification of the crude product by silica gel flash column chromatography with 4:1 ethyl acetate/hexanes as the eluent provided pure glycosyl-lα- azide (61%) and 3α-azide (30%) . Upon standing at room temperature, two pure regioisomers provided identical regioisomeric mixtures of 1- and 3-azides (1:2) . These equilibrated 1- and 3-azides were found to be mixtures of 3.5:1 and 2:1 α/β-epimeric mixture, respectively. For 1- azide α-anomer: 1H NMR (300 MHz; CDCI3) δ 2.10 (s,3H), 2.11 (s,3H), 4.05-4.17 (m, 1H) , 4.20-4.41 (m,2H), 5.32 (ddd,lH,J = 9.4, 3.5, 1.9 Hz), 5.57 (s,lH), 5.78 and 5.95 (ABq,2H,JAB = 10.3 Hz); the 5.78 ppm peaks are further split into doublets of doublets with J = 2.9, 2.0 Hz) . For 3-azide α-epimer: 1H NMR (300 MHz; CDCI3) δ 2.08 (s,3H), 2.14 (s,3H), 4.20-4.37 (m, 1H) , 4.89 (dd,lH,J = 5.9, 5.8 Hz), 5.09 (dd,lH,J = 10.4, 4.2 Hz), 6.52 (d, 1H, J = 5.9 Hz); 13ς NMR (75.4 MHz; CDCI3) δ 20.46, 20.58, 53.70, 62.14, 68.50, 71.10, 96.75, 147.14, 169.70, 170.46.
The procedure of Example I can be used for the stereoselective N-glycosylation of nitrogen nucleophile compounds such as the known compound DDI and its analogs and like pharmacologically useful compounds. The resulting novel N-(acetyl or diacetyl glycosylated) substrate compounds are contemplated to have substantial advantage with respect to greater water solubility and yet have substantially the same useful antiviral activity and posology as DDI and its analogs.
Having described the invention, the embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.
Claims
1. lα- and lβ-N-glycosylated compounds obtained by reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and six-membered glycals of the formulas I, II and III and la, Ila and Ilia
where RQ is a lower alkyl group and R^, R2 and R3 are the same or different and represent an aliphatic acyl group or an aromatic acyl group, in the presence of a catalytic amount of iodine to provide a reaction mixture of formed lα- and lβ-N-glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β- glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products.
2. A product according to claim 1 wherein the nitrogen nucleophile is an amide .
3. A product according to claim 1 wherein the nitrogen nucleophile is 2 ' , 3'-dideoxyinosine.
4. A product according to claim 1 wherein the nitrogen nucleophile is a sulfonamide.
5. A product according to claim 1 wherein the nitrogen nucleophile is a lactam.
6. A product according to claim 1 wherein the nitrogen nucleophile is an azide.
7. A product according to claim 1 wherein the nitrogen nucleophile is trimethylsilyl azide.
8. A product according to claim 7 which is the 1-azide α-anomer.
9. A product according to claim 7 which is the 3-azide α-epimer.
10. A process for preparing N-glycosylated compounds, comprising reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and six-membered glycals of the formulas I, II and III and la, Ila and Ilia
where RQ is a lower alkyl group and R]_, R2 and R3 are the same or different and represent an aliphatic acyl group or an aromatic acyl group, in the presence of a catalytic amount of iodine to provide a reaction mixture of formed lα- and lβ-N-glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β- glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products.
11. A process according to claim 10 wherein the nitrogen nucleophile is an amide.
12. A process according to claim 11 wherein the nitrogen nucleophile is 2' , 3'-dideoxyinosine.
13. A process according to claim 10 wherein the nitrogen nucleophile is a sulfonamide.
14. A process according to claim 10 wherein the nitrogen nucleophile is a lactam.
15. A process according to claim 10 wherein the nitrogen nucleophile is an azide.
16. A process according to claim 10 wherein the nucleophile is trimethylsilyl azide.
17. A process according to claim 10 wherein the glycosylating agent is triacetyl D-glucal.
18. A process according to claim 10 wherein one or both anomerically pure α- and β-glycosylated products are isolated by silica gel flash column chromatography.
19. A process according to claim 10 wherein pure glycosyl 1-azides and/or 3-azides are isolated by silica gel flash column chromatography.
20. A process according to claim 10 wherein one or both of the 1-azide α-anomer and 3-azide α-epimer are isolated.
AMENDED CLAIMS
[received by the International Bureau on 21 December 1993 (21.12.93 original claims 1 and 10 amended; other claims unchanged (3 pages)]
1. lα- and lβ-N-glycosylated compounds obtained by reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and si -membered glycals of the formulas I, II and III and la, Ila and IIla
where RQ is a lower alkyl group and R]_, R2 and R3 are the same or different and represent an aliphatic acyl group or an aromatic acyl group, in the presence of a catalytic amount of iodine and in the absence of boron trifluoride to provide a reaction mixture of formed lα- and lβ-N- glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β-glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products .
2. A product according to claim 1 wherein the nitrogen nucleophile is an amide.
3. A product according to claim 1 wherein the nitrogen nucleophile is 2 ' ,3'-dideoxyinosine.
4. A product according to claim 1 wherein the nitrogen nucleophile is a sulfonamide.
5. A product according to claim 1 wherein the nitrogen nucleophile is a lactam.
6. A product according to claim 1 wherein the nitrogen nucleophile is an azide.
7. A product according to claim 1 wherein the nitrogen nucleophile is trimethylsilyl azide.
8. A product according to claim 7 which is the 1-azide α-anomer.
9. A product according to claim 7 which is the 3-azide α-epimer.
10. A process for preparing N-glycosylated compounds, comprising reacting a non-basic nitrogen nucleophile selected from amides, sulfonamides, lactams and azides and a glycosylating agent selected from acylated, carbonated and thionocarbonated five- and six-membered glycals of the formulas I, II and III and la, Ila and Ilia
where RQ is a lower alkyl group and RQ_, R2 and R3 are the same or different and represent an aliphatic acyl group or an aromatic acyl group, in the presence of a catalytic amount of iodine and in the absence of boron trifluoride to provide a reaction mixture of formed lα- and lβ-N- glycosylated products of the group selected from anomers and epimers, isolating at least one α- or β-glycosylated product stereoselectively and/or regioselectively from the mixture, and optionally removing one or more acyl groups from said anomer and epimer products.
11. A process according to claim 10 wherein the nitrogen nucleophile is an amide.
12. A process according to claim 11 wherein the nitrogen nucleophile is 2 ' ,3'-dideoxyinosine.
13. A process according to claim 10 wherein the nitrogen nucleophile is a sulfonamide.
STATEMENT UNDER ARTICLE 19
It is desired to note that the claimed subject matter is novel and can be shown to comprise an inventive step, evidence of which Applicant reserves the right to make of record in due course of the prosecution.
The above amendment does not go beyond the disclosure in tne international application as filed.
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| US95153092A | 1992-09-25 | 1992-09-25 | |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5493731A (en) * | 1993-05-10 | 1996-02-27 | Amnott; James | Necktie accessory |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4604457A (en) * | 1982-09-09 | 1986-08-05 | Otsuka Kagaku Kabushiki Kaisha | 2-substituted cephem derivatives and process for preparing the same |
-
1993
- 1993-09-23 WO PCT/US1993/009036 patent/WO1994007900A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4604457A (en) * | 1982-09-09 | 1986-08-05 | Otsuka Kagaku Kabushiki Kaisha | 2-substituted cephem derivatives and process for preparing the same |
Non-Patent Citations (2)
| Title |
|---|
| CARBOHYDRATE RESEARCH, Volume 82, issued 1980, GUTHRIE et al., "Allylic Substitutions in Tri-O-Acetyl-Glycals and Related Compounds", pages 207-224. * |
| TETRAHEDRON LETTERS, No. 18, issued 1976, HEYNS et al., "Eine Neue Synthese von 3-Amino-Hexopyranosen", pages 1477-1480. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5493731A (en) * | 1993-05-10 | 1996-02-27 | Amnott; James | Necktie accessory |
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