Synthesis of γ-Ketoamides from Nitrones and Ynamides through a Copper-Catalyzed Cascade Reaction

A Cu(II) catalyst has been used to redirect a thermal dipolar cycloaddition and rearrangement reaction of nitrones and ynamides toward the synthesis of γ-keto- and γ-aldoamides. Generation of an iminium intermediate via nucleophilic attack of an activated ynamide is proposed to initiate a diastereoselective rearrangement for C-C bond formation and the combination of catalyst and nitrone protecting group balance reactivity, diastereoselectivity, and sensitivity to hydrolysis. Reaction optimization, scope, and mechanistic studies are described.