Origin of enantioselectivity in copper-catalyzed aziridination of enol silyl ethers: a comprehensive DFT study

Chiral 1,2-amino alcohols are indispensable structural motifs in organic synthesis and pharmaceutical development, with the synthesis of chiral aziridine intermediates being a crucial step. Although experimental data indicate that the enantioselectivity (ee) of chiral aziridines is highly sensitive to ligands, anions, and substituents, the underlying stereocontrol mechanism remains elusive due to the challenges of characterizing transient intermediates. In this work, we utilize density functional theory (DFT) calculations to systematically investigate the factors governing stereoselectivity. Our results reveal that anion-induced non-covalent interactions play a pivotal role in stabilizing the R-configuration transition state (the major product) by lowering the activation barrier. Furthermore, we elucidate how the steric and electronic properties of the ligand scaffold orchestrate the copper center's chiral pocket. This study provides fundamental mechanistic insights into copper-catalyzed nitrene transfer, establishing a theoretical blueprint for the rational design of advanced asymmetric catalytic systems.