Organocatalyzed Enantioselective Michael Addition of 2‐Hydroxypyridines and α,β‐Unsaturated 1,4‐Dicarbonyl Compounds

The framework of 2‐pyridones is prevalent in biologically and medicinally important molecules. Here we report that chiral N ‐substituted 2‐pyridones were prepared by enantioselective, organocatalytic aza‐Michael additions of halogenated 2‐hydroxypyridines (pyridin‐2(1 H )‐ones) to α,β‐unsaturated‐1,4‐dketones or 1,4‐ketoesters. The reactions were optimized by the choice of solvents and systematic screening of Cinchona alkaloid‐based bifunctional catalysts to achieve excellent yields and enantioselectivities (up to 98% yield and >99% ee). Density functional theory calculations provided rationales for the observed enantioselectivity. Formal synthesis of a human rhinovirus protease inhibitor was achieved using the chiral Michael adduct generated by this method. magnified image