Enantioselective Three-Component Reductive Coupling of Aldehydes, Amines, and Alkynes via Ligand-Enabled Cobalt/Photoredox Dual Catalysis for Modular Synthesis of Allylic Amines

Abstract Here, we disclose a catalytic strategy that merges visible-light photoredox with cobalt catalysis to realize a previously elusive three-component enantioselective reductive coupling of readily available aldehydes, amines, and alkynes. This transformation provides a direct, step-economical route to high-value chiral allylic amines with broad substrate scope and high chemo-, regio-, and enantioselectivity, while overcoming long-standing challenges, including parasitic single-electron over-reduction, competitive aldehyde–alkyne coupling, and the inherent regioselectivity issues of unsymmetrical internal alkynes, and circumventing the moisture sensitivity and limited scope of pre-isolated imines. Central to this breakthrough is the rational design of a chiral phosphoramidite ligand featuring a tricyclic tetrahydrobenzoquinoline core, which avoids coordination saturation at cobalt and establishes a unique electronic “push–pull” synergy with a coordinated iodide anion. Mechanistic studies support an anion-promoted, single-ligand catalytic model wherein a high-spin cobaltacyclopentene intermediate serves as the key stereocontrol element. The monodentate, π-accepting phosphoramidite functions as a flexible electronic buffer, mitigating Pauli repulsion and dramatically lowering the oxidative cyclization barrier. The synthetic utility is demonstrated by late-stage functionalization of complex bioactive molecules and a concise synthesis of the antiplatelet drug prasugrel.