Application of Solid-Phase Chemistry for the Synthesis of 3′-Fluoro-3′-Deoxythymidine

Abstract

Reported solution-phase methods for the synthesis of 3′-fluoro-3′-deoxythymidine (FLT) are cumbersome, require purification of intermediates, and include several protecting/deprotecting steps. To circumvent these problems, a solid-phase strategy was designed for the synthesis of FLT. Thymidine was immobilized on trityl resin via the 5′-hydroxyl group. The subsequent mesylation of the free 3′-hydroxyl group in the presence of methanesulfonyl chloride afforded the polymer-bound 3′-O-mesylthymidine. Nucleophilic substitution of the mesyl moiety by hydroxyl group in the presence of sodium hydroxide produced the polymer-bound threothymidine. Fluorination with diethylaminosulfur trifluoride followed by acidic cleavage of the polymer-bound FLT in the presence of trifluoroacetic acid afforded FLT.

Keywords:

• FLT
• Solid-phase synthesis
• Trityl resin