Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

Abstract

Nucleoside analogues bearing a fluorine in the C2′-position have been synthesized by SN2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1′,2′-cis-thiofuranosides and d-1′,2′-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2–F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3′ all-carbon quaternary center along with a C2′–F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.