SYNTHESIS OF 3'-DIDEOXY-3'-C-(HYDROXYMETHYL)-4'-THIONUCLEOSIDES AS POTENTIAL INHIBITORS OF HIV

The synthesis of 3'-dideoxy-3'-C-(hydroxymethyl)-4'-thionucleosides is described. For the synthesis of the carbohydrate part, the configurat ion of the secondary hydroxyl group in (2S,3R)-1-O-(p-bromobenzyl)-3- (2'-propenyl)-1,2,4-butanetriol (1) was inverted using Mitsunobu react ion conditions, after which the primary hydroxyl group in product 2 wa s regioselectively benzoylated using phase-transfer catalysis. Oxidati ve cleavage of the allylic double bond, followed by ring closure and e xchange of the p-bromobenzyl protecting group gave the methyl furanosi de derivative 5, which was further converted to the corresponding dibe nzyl dithioacetal 6. Ring closure of 6 involving an intramolecular nuc leophilic substitution by sulfur with inversion of configuration at C- 4 was effected using chlorodiphenylphosphine (CDP), iodine, and imidaz ole to give thiofuranoside 9, which was subsequently condensed with si lylated thymine, cytosine, and 6-chloropurine. The latter was converte d to adenine after the coupling. Deblocking and separation of the anom ers gave the a and P-nucleoside analogues. Compounds 14, 15, and 18-21 were found to be inactive when tested for anti HIV-I activity in vitr o.