Reversal of Nucleophilicity of Enamides in Water: Control of Cyclization Pathways by Reaction Media for the Orthogonal Synthesis of Dihydropyridinone and Pyrrolidinone <i>Clausena</i> Alkaloids

A highly efficient, metal-free, and divergent method for the synthesis of 3,4-dihydropyridin-2-one and pyrrolidin-2-one Clausena alkaloids and their analogs is reported. While the oxirane-containing enamides underwent the TFA-mediated 6-endo-enamide-epoxide cyclization reaction in ButOH to produce homoclausenamides, an unprecedented nucleophilic reaction occurred at the α-carbon of enamides in water to yield 5-endo-enamide-epoxide cyclization products in excellent yields. The reversal of nucleophilicity of enamides in intramolecular cyclization is discussed in terms of steric and electronic effects of the oxirane-containing enamides.