Asymmetric, Organocatalytic 1,4-Addition of Pyridinyl Acetates with Crystallization-Enabled Diastereoconvergency

Azaarenyl acetates represent promising building blocks for the synthesis of stereochemically complex scaffolds containing pharmaceutically relevant heterocycles. Current methods that employ azaarenyl acetates as nucleophiles in enantioselective transformations generally rely on metal catalysts and are only compatible with 2-azaarenyl acetates, limiting the diversity of electron-deficient heterocycles that can be installed. We have developed the first enantioselective, organocatalytic method for the 1,4-addition of 4-azaarenyl acetates into trisubstituted electrophilic alkenes. The resulting products – possessing three contiguous stereocenters – are obtained in modest to high diastereo- and enantioselectivites. Mechanistic studies suggest a scenario in which two of the stereocenters are under kinetic control, while the β-keto amide stereocenter undergoes a thermodynamically-controlled crystallization-induced diastereomer transformation.