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.