Synthesis and antiviral activities of 1′-carbon-substituted 4′-thiothymidines Original Research Article

4-Thiofuranoid glycals substituted at the 1-position with methyl (5), (t-butyldimethylsilyloxy)methyl (7), and acetoxymethyl (8) groups were prepared from the 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPDS)-4-thiofuranoid glycal (3) by way of LDA-lithiation. N-Iodosuccimide-initiated electrophilic glycosidation between silylated thymine and these 1-carbon-substituted 4-thioglycals gave the respective β-anomers (9, 10, and 13) stereoselectively. Tin radical-mediated removal of the 2′-iodine atom from these products provided the corresponding 1′-branched 4′-thiothymidine derivatives (11, 12, and 14) in good yields. The 1′-hydroxymethyl derivative (15) served as a precursor for the preparation of the formyl (16), cyanoethenyl (17), and cyano (19) derivatives. Among the deprotected 1′-branched 4′-thiothymidines (20–25), the 1′-methyl analogue 20 showed the most potent anti-HSV-1 activity, but it was much less active than the parent compound 4′-thiothymidine.