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

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.