A Stereoselective Approach to β-l-Arabino Nucleoside Analogues: Synthesis and Cyclization of Acyclic 1′,2′-synN,O-Acetals

Abstract

Reported herein is a novel and versatile strategy for the stereoselective synthesis of unnatural β-L-arabinofuranosyl nucleoside analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine bases. These unusual acetals undergo a C1' to C4' cyclization where the OTMS of the acetal serves as the nucleophile to generate 2'-oxynucleosides with complete retention of configuration at the C1' acetal center. N,OTMS-acetals are obtained diastereoselectively from additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr(2)·OEt(2). The strategy reported is addressing important synthetic challenges by providing stereoselective access to unnatural L-nucleosides starting from easily accessible pools of D-sugars and, as importantly, by allowing the formation of the sterically challenging 1',2'-cis nucleosides. A wide variety of nucleoside analogues were synthesized in 7-8 steps from easily accessible D-xylose.