Deciphering the cooperative effect of base and N-substituents on the origin of enantioselectivity switching for Mannich reactions of glycinate by carbonyl catalysts

Abstract

Chiral carbonyl catalysis has developed rapidly in recent years and provided reliable methods for the preparation of chiral molecules, while the effective catalyst model remains unclear, and the size effect of catalyst substituents on the reversal of enantioselectivity needs to be clarified. Herein, the N-quaternized pyridoxals catalyzed asymmetric Mannich reactions of glycinate were studied to obtain fundamental understanding on these issues. The calculations show that the dual activation model aided by base NaHCO3, which contributes additional beneficial OH···N and Na···O/N interactions, is energetically more favorable than the base-free models, and the multiple interactions among the three entities, the base NaHCO3, the catalyst, and the imine substrate, in the enantiocontrolling transition states (TS) are responsible for the high enantioselectivity, rendering the preferred chiral product of (R,R)-4 in reaction I and (S,S)-4 in reaction II. The origin of the reversed enantioselectivity upon the substitution of a methyl for the H on the N-functional group in the catalyst was analyzed, and was attributed to the variation of the preferred orientation of NaHCO3 from facing-up to facing-down owing to the substitution, which created governing interactions to drive the reversal of the enantioselectivity in the such asymmetric Mannich reactions. This understanding of the activation model and the reversed stereoinduction sheds light on the effective chiral N-quaternized pyridoxal catalyst form and role of base on the enantioselectivity, and offers new insights for the future design of related asymmetric catalysts and Mannich reactions.