Computational Insights into the Revised Mechanism of the Gold-Catalyzed Asymmetric Isocyanoacetate Aldol Reaction: Proton Shuttling and Protonative Carbonyl Activation under Ligand–Substrate Interactions

Density functional theory calculations assisted by the artificial force-induced reaction (AFIR) method clarify the mechanism of the gold(I)-catalyzed asymmetric aldol reaction of isocyanoacetates with aldehydes promoted by a chiral ferrocenylbisphosphine ligand bearing an aminoalkyl pendant. The calculations revise the originally proposed mechanism and show that the aminoalkyl group plays pivotal roles in mediating proton shuttling and protonative carbonyl activation. After deprotonation of the gold-bound isocyanoacetate to form an ammonium enolate, the reaction proceeds through proton-assisted enolate addition, ring-closure, and protodeauration, while the gold complex interconverts between two different coordination geometries. The calculations further reveal that stereoselection arises from a concave chiral environment created by the four P -phenyl groups and the protonated amino group, where hydrogen bonding, nonclassical sp 3 -C–H···O interactions, and London dispersion cooperatively differentiate the diastereomeric pathways. This study provides a revised three-dimensional mechanistic picture of a landmark example of asymmetric gold catalysis and highlights general design principles for bifunctional metal/organo cooperative catalysts.