Synthesis and Resolution of 4′-Substituted Nucleosides with Potential Antiviral and Antisense Strategies

Abstract

Nucleoside derivatives having a 4′-substituent show promise as potential antiviral agents as well as nucleoside units for constructing nucleic acid medicines. To develop new nucleosides, it is crucial to achieve feasible access to the intended derivatives, encompassing both enantiomers. Toward this end, we started synthesizing an achiral 4-hydroxymethyldihydrofuran as a sugar precursor, which we subjected to the oxidative glycosylation reaction using hypervalent iodine. The resulting racemate of a 4′-hydroxymethylated thymidine derivative underwent kinetic resolution using lipase, yielding both d- and l-isomers with high optical purity. The d-4′-hydroxymethylstavudine derivative was then converted into the corresponding phosphoramidite derivative, from which an oligonucleotide was synthesized.