Synthesis of Ribo‐Azanucleosides by Anodic Oxidation: Reactivity Control of Intermediate for Efficient Access to Pharmacophores

Azanucleosides, the sugar‐modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β‐anomers of ribo‐azanucleosides, by means of site‐specific anodic C−H activation by using a nitroalkane–lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2′‐substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β‐anomers of ribo‐azanucleosides with all four nucleobases in a stereoselective manner. Efficient synthesis of ribo‐azanucleosides with all four nucleobases was achieved for the first time by means of anodic oxidation. A mechanistic study of the reaction and the armed/disarmed concept from glycochemistry indicated that the acetoxy group at the 2′‐position can decrease the reactivity of the intermediate. Employing trifluoroacetic acid additive for electrosynthesis increased the reactivity of the intermediate, which significantly improved the reaction efficiency.