Stereoselective Oxidative Coupling of Amino Acids or Oligopeptides with Aldehydes: A Mechanism Study

The stereoselective oxidative coupling of amino acids with aldehydes, catalyzed by chiral primary amines, plays a crucial role in the stereoselective modification of carboxyl groups. However, the underlying mechanisms, particularly whether the reaction proceeds via an SN1 or SN2 pathway, remain unknown. To address this gap, we employed density functional theory (DFT) calculations at the M06–2X (or ωB97-XD) level to investigate the reaction mechanism. Our results reveal that the nucleophilic attack serves as both the rate-determining step and the stereoselectivity-determining step. Noncovalent interactions (NCI) and distortion/interaction-activation strain (D/I-AS) analyses indicate that stereoselectivity is predominantly governed by the configuration of the imine and the noncovalent interactions between the heterocyclic and naphthalene moieties. These results provide mechanistic insights into the stereochemical control of oxidative coupling reactions, improving our understanding of stereoselective transformations in organic synthesis.