Synthesis of 2,3-dideoxy-2,2-difluoro-L-glycero-pentofuranosyl nucleosides.
Various 2,3-dideoxy-2,2-difluoro-L-glycero-pentofuranosyl nucleosides were synthesized via the key intermediate, 5-O-benzoyl-2,3-dideoxy-2,2-difluoro-L-glycero-pentofuranose (6). 2,3-O-Isopropylidene-L-glyceraldehyde was coupled with ethyl bromodifluoroacetate under Reformatsky conditions to obtain the diastereomeric mixture of ethyl (4S)-3-hydroxy-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-difluoro propionate (1). Treatment of compound 1 with carbon disulfide, sodium hydride and methyl iodide followed by reduction afforded ethyl (4S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-difluoro propionate (3). Compound 3 was treated with 5% HCl in ethanol, followed by refluxing in benzene under Dean-Stark conditions, to afford the lactone 4. The compound 4 was protected and reduced to afford the key intermediate 6. For the synthesis of pyrimidine derivatives 8-21, compound 6 was converted to the mesylate 7 and condensed with various silyl protected pyrimidine bases. The inosine and adenine derivatives 38-41 were obtained from compound 6 and 6-chloropurine using standard procedures. Compounds 22-35 and 38-41 were evaluated for their antiviral activity against HIV-1, HBV, HSV-1 and HSV-2, and for cellular toxicity. None of the synthesized compounds showed any significant activity or toxicity. Single-crystal X-ray structure of 1-(2,3-dideoxy-2,2-difluoro-beta-L-glycero-pentofuranosyl)-5-iodocytosin e (34) suggested a 2'-exo/3'-endo conformation for the carbohydrate moiety.
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602-2352, USA.
L P
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M G
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C K
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D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002236:Carbohydrate Conformation; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology; D013696:Temperature; D014709:Vero Cells / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D015224:Dideoxynucleosides