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

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AbstractThe 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(1H)‐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