Organic compounds -- part of the class 532-570 series – Organic compounds – Pteroyl per se or having -c- – wherein x is chalcogen – bonded...
Patent
1997-06-26
1999-07-13
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Pteroyl per se or having -c-, wherein x is chalcogen, bonded...
544262, 544265, 544267, 544276, 544277, 544280, 544312, 544317, 5482642, 5482668, 5482676, 5482682, 5482622, C07D47318, C07D47340, C07D47334, C07D47332
Patent
active
059228679
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods and compositions for preparing nucleoside analogues containing dioxolane sugar rings. In particular, the invention relates to the stereoselective synthesis 1,3-dioxolane nucleosides having .beta. or cis configuration.
BACKGROUND OF THE INVENTION
Nucleosides and their analogues represent an important class of chemotherapeutic agents with antiviral, anticancer, immunomodulatory and antibiotic activities. Nucleoside analogues such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), 3'-deoxy-2',3'-didehydrothymidine (d.sub.4 T) and (-)-2'-deoxy-3'-thiacytidine (3TC.TM.) are clinically approved for the treatment of infections caused by the human immunodeficiency viruses. 2'-Deoxy-2'-methylidenecytidine (DMDC, Yamagami et al. Cancer Research 1991, 51, 2319) and 2'-deoxy-2',2'-difluorocytidine (gemcytidine, Hertel et al. J. Org. Chem. 1988, 53, 2406) are nucleoside analogues with antitumor activity. A number of C-8 substituted guanosines such as 7-thia-8-oxoguanosine (Smee et al. J. Biol. Response Mod. 1990, 9, 24) 8-bromoguanosine and 8-mercaptoguanosine (Wicker et al. Cell Immunol. 1987, 106, 318) stimulate the immune system and induce the production of interferon. All of the above biologically active nucleosides are single enantiomers.
Recently, several members of the 3'-heterosubstituted class of 2',3'-dideoxynucleoside analogues such as 3TC.TM.(Coates et al. Antimicrob. Agents Chemother. 1992, 36, 202), (-)-FTC (Chang et al. J. Bio. Chem. 1992, 267, 13938-13942) (-)-dioxolane C (Kim et al. Tetrahedron Lett. 1992, 33, 6899) have been reported to possess potent activity against HIV and HBV replication and possess the .beta.-L absolute configuration. (-)-Dioxolane C has been reported to possess antitumor activity (Grove et al. Cancer Res. 1995, 55, 3008-3011). The dideoxynucleoside analogues (-)-dOTC and (-)-dOTFC (Mansour et al. J. Med. Chem. 1995, 38, 1-4) were selective in activity against HIV-1.
For a stereoselective synthesis of nucleoside analogues, it is essential that the nucleobase be introduced predominately with the desired relative stereochemistry without causing anomerization in the carbohydrate portion. One approach to achieve this is to modify the carbohydrate portion of a preassembled nucleoside by a variety of deoxygenation reactions (Chu et al. J. Org. Chem. 1989, 54, 2217-2225; Marcuccio et al. Nucleosides Nucleotides 1992, 11, 1695-1701; Starrett et al. Nucleosides Nucleotides 1990, 9, 885-897, Bhat et al. Nucleosides Nucleotides 1990, 9, 1061-1065). This approach however is limited to the synthesis of those analogues whose absolute configuration resembles that of the starting nucleoside and would not be practical if lengthy procedures are required to prepare the starting nucleoside prior to deoxygenation as would be the case for .beta.-L dideoxynucleosides. An alternative approach to achieve stereoselectivity has been reported which requires assembling the nucleoside analogue by a reaction of a base or its synthetic precursor with the carbohydrate portion under Lewis acid coupling procedures or SN-2 like conditions.
It is well known in the art that glycosylation of bases to dideoxysugars proceed in low stereoselectivity in the absence of a 2'-substituent on the carbohydrate rings capable of neighboring group participation. Okabe et al. (J. Org. Chem. 1988, 53, 4780-4786) reported the highest ratio of .beta.:.alpha. isomers of ddC of 60:40 with ethylaluminium dichloride as the Lewis acid. However, with a phenylselenenyl substituent at the C-2 position of the carbohydrate (Chu et al. J. Org. Chem. 1980, 55, 1418-1420; Beach et al. J. Org. Chem. 1992, 57, 3887-3894) or a phenylsulfenyl moiety (Wilson et al. Tetrahedron Lett. 1990, 31, 1815-1818) the .beta.:.alpha. ratio increases to 99:1. To overcome problems of introducing such substituents with the desired .alpha.-stereochemistry, Kawakami et al. (Nucleosides Nucleotides 1992, 11, 1673-1682) reported that disubstitution at C-2 of the
REFERENCES:
Tetrahedron Letters, vol. 29, No. 11, 1988, pp. 1239-1242, "A New Synthesis of 2',3'-dideoxynucleosides for Aids Chemotherapy".
Tetrahedron Letters, vol. 33, No. 46, pp. 6949-6952, Oxidative Degradation of L-Ascorbic Acid Acetals to 2',3'-Dideoxy-3'-Oxariboufuranosides . . . .
Journal of the American Chemical Society, vol. 113, 1991, pp. 9377-9379, In Situ Complexation Directs the Stereochemistry of
Tetrahedron Letters, vol. 33, No. 46, 1992, "Oxidative Degradation of L-Ascorbic Acid Acetals to 2',3'-dideoxy-3'-Oxacytidine Stereoisomers . . . ".
Bednarski Krzysztof
Cimpoia Alex
Mansour Tarek
Berch Mark L.
Biochem Pharma Inc.
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