N(3)-protection of thymidine with Boc for an easy synthetic access to sugar-alkylated nucleoside analogs

The use of Boc as a nucleobase-protecting group in the synthesis of sugar-modified thymidine analogs is reported. Boc was easily inserted at N(3) by a simple and high-yielding reaction and found to be stable to standard treatments for the removal of Ac and tBuMe2Si (TBDMS) groups, as well as to ZnBr2-mediated 4,4′-dimethoxytrityl (DMTr) deprotection. Boc Protection proved to be completely resistant to the strong basic conditions required to regioselectively achieve O-alkylation, therefore, providing synthetic access to a variety of sugar-alkylated nucleoside analogs. To demonstrate the feasibility of this approach, two 3′-O-alkylated thymidine analogs have been synthesized in high overall yields and fully characterized.