Mg(II)/H-Bonding Catalyst Design for Asymmetric Amination–Protonation Reaction

Abstract Given the strong interaction between amine and ketone groups, which often act as catalyst–substrate partners via iminium ion catalysis, the catalytic asymmetric aza-conjugate addition of common cyclic amines to unsaturated enones has never been successfully achieved. This model reaction is inherently challenging due to both the self-racemization of the amino–ketone products and the autocatalysis arising from the amine–ketone interaction. Consequently, this most straightforward and efficient route to chiral γ-amino alcohols remains unrealized to date. Herein, through the rational design of a novel Mg(II)/H-bonding catalytic strategy based on newly developed trihydroxyl chiral ligands, we have successfully suppressed the self-activation pathway between amines and conjugated enones, thereby achieving the desired amination–protonation reaction with high enantioselectivities. This new catalytic system proves highly effective for the one-pot synthesis of diverse chiral γ-amino alcohols bearing tertiary or quaternary stereocenters. Mechanistic investigations, including the identification of the formed metal complex and the true catalytically active species, the study of key transition states, and the elucidation of the coordination details of the Mg(II)/H-bonding catalyst through DFT-optimized processes, support a plausible mechanism for the asymmetric amination–protonation process.