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.