Studies on the mechanism of quaternization of the catharanthine part of vinblastine and vincristine

Abstract

A quaternization reaction was observed at the tertiary nitrogen atom of the catharanthine part of vinblastine instead of the expected cyclopropanation in the Simmons–Smith reaction utilizing diiodomethane and diethylzinc. Investigating the energetic relations, thermodynamic stabilities and the interactions between the molecular orbitals by quantum chemical calculations elucidated the unexpected methylation and confirmed the reaction mechanism. Although the history of the Simmons–Smith reaction goes back more than half a century this represents the first time that the reaction and its possible side-reaction has been studied by DFT level calculations in a complex system.