A FACILE ROUTE TO PYRIMIDINE-BASED NUCLEOSIDE OLEFINS - APPLICATION TO THE SYNTHESIS OF D4T (STAVUDINE)

An efficient synthetic route to nucleoside olefins in the uridine, cyt idine, and thymidine series is described which utilizes the Garegg-Sam uelsson iodine/triphenylphosphine/imidazole-promoted deoxygenation of the 2',3'-hydroxyl groups as the key step. Cyclopentylidene ketal prot ection was employed for all the nucleoside 2',3'-hydroxyls to facilita te blocking of the 5'-hydroxyl and the pyrimidine nitrogens with the b enzyl or 4-methoxybenzyl (PMB) groups. Deblocking of the cyclopentylid ene group followed by olefination of the resulting diols provided prot ected nucleoside olefins 18-20. Starting with 5-methyluridine 4 and ut ilizing the 4-methoxybenzyl group for 5',N-3 protection, the overall s cheme provided the anti-HIV compound d4T (1) after deprotection of the PMB groups. The dibenzylhypoxanthine nucleoside diol 17 derived from inosine gave either unreacted starting material or decomposition produ cts under several sets of conditions.