Biomimetic asymmetric transamination reactions catalyzed by axial pyroxamine organocatalysts: Mechanism and origin of stereoselectivity

Abstract

Biomimetic asymmetric transamination reactions have emerged as a focal point within the organocatalysis domain, generating substantial interest. However, the detailed mechanism and origin of stereoselectivity are remains elusive. Within this context, we present an exhaustive theoretical investigation into the detailed mechanism and origin of stereoselectivity governing such reactions between α-keto acids and amines catalyzed by axial pyroxamine. The fundamental reaction pathway can be divided into two stages, i.e. amino transfer stage to form chiral amine product and imine hydration stage for the generation of ketone product. To uncover the mystery of the chiral center produced by protonation in the amino transfer stage, five possible pathways were investigated and compared. This thorough examination unequivocally identifies the HOAc-assisted [1,3]-proton transfer as the pivotal step dictating stereoselectivity within the most energetically advantageous route. Further atoms-in-molecules (AIM) analysis was carried out to predict the origin of stereoselectivity. Notably, the N–H⋯O hydrogen bond interaction occurring between the pyridoxamine catalyst and α-keto acid of substrate has been pinointed as the driving force responsible for the energetical favorability of S-configurational pathway. These insights will be of great value for understanding and rational design of biomimetic organocatalysts for transamination reactions.