A NEW APPROACH TO THE SYNTHESIS OF 4′-CARBON-SUBSTITUTED NUCLEOSIDES: DEVELOPMENT OF A HIGHLY ACTIVE ANTI-HIV AGENT 2′, 3′-DIDEHYDRO-3′-DEOXY-4′-ETHYNYLTHYMIDINE

Oxidation of 3′-O-TBDMS-4′,5′-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the presence of SnCl4, 4 underwent stereoselective ring opening to give 4′-α-allyl (6), 4′-α-(2-bromoallyl) (7), 4′-α-(cyclopenten-3-yl) (8), and 4′-α-cyano (9) derivatives of thymidine. Reactions of the 3′-epimer 12 with organoaluminum reagents gave 4′-α-methyl (13), 4′-α-vinyl (14), and 4′-α-ethynyl (15) analogues. Compounds 13–15 were transformed into corresponding 2′,3′-didehydro-3′-deoxy derivatives. Evaluation of their ability to inhibit the replication of HIV in cell culture showed that 4′-ethynyl-d4T (19) is more potent and less toxic than the parent compound d4T.