NCI-driven regioselectivity and enantioreversal in chiral phosphoric acid-catalyzed arylamine functionalization

Abstract

Non-covalent interactions (NCIs) have emerged as pivotal elements in asymmetric catalysis, enabling precise control over reactivity and selectivity in complex transformations. Despite their central role in designing catalytic systems, mechanistic understanding remains limited for reactions where NCIs concurrently govern regio- and enantioselectivity. The inherent complexity of CPA-catalyzed asymmetric reactions, characterized by diverse NCIs—particularly with arylamine substrates bearing multiple NCI-active motifs—presents formidable challenges for theoretical analysis and data-driven mechanistic modeling. This challenge becomes particularly pronounced when examining the enantioreversal phenomenon, where minute NCI perturbations orchestrate divergent catalytic pathways. Crucially, substrate-controlled enantioreversal operating independently of CPA groups modifications remain conspicuously undercharacterized in multi-selective reactions, particularly at the mechanistic level. In this study, we investigate three representative multi-site CPA-catalyzed asymmetric functionalizations of arylamines, utilizing detailed theoretical calculations to explore the influence of steric effects and NCIs, as well as the interplay between regioselectivity and enantioreversal. Our findings clarify the factors governing regioselectivity and enantioreversal, leading to a detailed elucidation of the mechanistic roles of key variables in existing frameworks. This work provides a robust theoretical foundation for optimizing CPA-catalyzed asymmetric reactions involving arylamines, while paving the way for future machine learning-driven advancements in this domain.