The chiral pyridoxal-catalyzed biomimetic Mannich reaction: the mechanism and origin of stereoselectivity

A biomimetic organocatalyst with a pyridoxal-like structure is one of the most successful examples of catalyzing organic reactions under mild conditions in an asymmetric synthesis field. However, the origin of stereoselectivity for these kinds of reactions remains less studied in theory. Herein, we performed density functional theory (DFT) calculations to explore the detailed mechanism of the biomimetic chiral pyridoxal-catalyzed Mannich reaction between glycine and aryl N-diphenylphosphinyl imine to obtain a chiral amine product. The calculated results indicate that the reaction occurs through two stages, including condensation and asymmetric addition, and asymmetric addition has been identified as the stereoselectivity-determining process. Furthermore, atoms-in-molecules (AIM) analysis demonstrated that the N-HMIDLINE HORIZONTAL ELLIPSISO and O-HMIDLINE HORIZONTAL ELLIPSISN hydrogen bond interactions between the axially chiral biaryl pyridoxal catalyst and the imine were responsible for the energetic favorability of the RR-configurational pathway, which was in agreement with the experimental observations. By constructing and comparing the transition states with different groups on the substitute, 2D contour maps indicated that steric hindrance should be another key factor for switchable stereoselectivity. Furthermore, we have additionally investigated the possible structural models of the different catalyst species to explore their actual roles.