Mechanism and Stereocontrol in Chiral Phosphoric Acid-Catalyzed Ynamide-Mediated Atroposelective Couplings of Carboxylic Acids with Amines and Alcohols

Abstract Direct atroposelective coupling of carboxylic acids with amines and alcohols remains challenging. Although recent ynamide-mediated reactions under chiral phosphoric acid (CPA) catalysis have provided efficient access to axial-chiral amides and planar-chiral esters, the activation mode and origin of stereocontrol remain unclear. Here, density functional theory (DFT) calculations were performed on two representative CPA-catalyzed ynamide-mediated transformations, namely atroposelective amidation and atroposelective esterification of carboxylic acids. The results reveal a common hydrogen-bond-bridged dual-substrate activation mode, followed by the formation of a tightly associated chiral phosphate-paired keteniminium-like intermediate in which hydrogen-bonding and ion-pairing interactions coexist, trapped by the carboxylic acid to generate an α-acyloxy enamide, and subsequent coupling with the external nucleophile. Interestingly, the two reactions do not share the same atropo-determining step. In the amidation reaction, reversible amine addition is followed by atropo-determining concerted C–O bond cleavage and protonation, whereas in the esterification reaction the initial alcohol addition is atropo-determining. This divergence likely originates from differences in nucleophile reactivity and in the relative stability of the addition intermediates. Despite the kinetic difference, both reactions follow a common stereocontrol mode: the observed atroposelectivity arises from free energy differences between matched and mismatched substrate accommodation within the chiral CPA pocket. These findings provide a mechanistic foundation for CPA-catalyzed ynamide-mediated atroposelective coupling and may provide insight for the rational design of related asymmetric catalysts.