Stereoselective synthesis of 1′-α-cyano carbocyclic pyrimidine nucleoside analogs via a chelation-controlled 1′-α-hydroxymethylation strategy

Abstract

1′-α-Cyano nucleoside analogs have emerged as key structural motifs as antiviral agents. Due to their importance, we developed a novel stereoselective synthetic route to access 1′-α-cyano carbocyclic nucleoside analogs. The strategy relies on LDA-promoted chelation-controlled enolization, which favors a highly selective Si-face six-membered transition state with paraformaldehyde, delivering the exclusive 1′-α-hydroxymethylation product. This straightforward approach proceeds without the need for metal catalysts or additional promoters, highlighting its practicality and efficiency. The resulting 1′-α-hydroxymethylation intermediate enabled the synthesis of the desired 1′-α-cyano carbocyclic pyrimidine nucleoside analogs in a stereo controlled manner. This work represents the first example of such a selective and catalyst free access to these carbocyclic scaffolds.