Catalytic Asymmetric Synthesis of Azaarene-Functionalized Tertiary Amines and α-Amino Acid Derivatives from E/Z-Ketimine Mixtures via Enantioselective Radical Coupling

The ubiquity of imine-containing azaarenes in pharmaceutically important molecules has inspired remarkable developments in facile and precise catalytic synthesis strategies. Nonetheless, the methods to access the valuable α-azaaryl-substituted tertiary amines and α-amino acid derivatives are still extremely scarce. This situation can be ascribed to the weak electron-withdrawing capability and strong basicity of azaarenes, resulting in poor reactivity of substrates and incompatibility of the previous enantiocontrol modes used to yield those non-azaarene-functionalized variants. Herein, we report a modular and efficient synthetic approach that is an enantioselective reductive coupling of azaarene-substituted E/Z-ketimine mixtures with 4-substituted 1,4-dihydropyridines as the radical precursors via cooperative photoredox and chiral Brønsted acid catalysis. The enantioselective radical coupling engaged by α-azaaryl odd-electron species is responsible for the assembly of the aza-quaternary carbon stereocenters α to azaarenes. This work provides a promising strategy for the direct use of E/Z-ketimine mixtures in asymmetric synthesis.