NEW SYNTHESIS OF 2',3'-DIDEOXY-2',3'-DIDEHYDRO-3'-C-SUBSTITUTED THYMIDINES

The Michael addition reaction of phenylthiolate anion with 2',3'-dideoxy-2',3'-didehydro-3'-nitro-thymidine 1 and subsequent Henry reaction at C-3' with various electron deficient reagents as formaldehyde, methylvinyl ketone and acrylonitrile has produced various diastereomeric mixtures of 1-(2,3-dideoxy-3-C-substituted-2-thiophenyl-3-nitro-beta-D-pentofuranosyl)thymines 4 - 12 [alpha-substitution (major); beta-substitution (minor)] in 29-82% yield. The stereochemistry of products formed in this reaction clearly indicates that the carbanion generated at C3' of diastereomeric 213 (1.3:1 ratio, H-1-NMR) preferentially attacks the electron-deficient reagent from the alpha-face of the pentofuranose ring. Subsequently, the 3'-nitro and 2'-phenylthio groups from 4, 5, 8 and 11 were eliminated upon treatment with Bu3SnH and AIBN to afford 2',3'-dideoxy-2'-3'-didehydro-3'-C-substituted thymidines 13 - 18 in 79-85% yield. The results detailed in this paper represent the first examples of a facile synthesis of 2',3'-dideoxy-2',3'-didehydro-3'-C-branched thymidines using a three-step procedure: (1) Michael addition of the phenylthiolate to nitro-olefin, (2) Henry reaction with electron-deficient reagents, and (3) subsequently,free-radical induced elimination of phenylthio and nitro groups.