Tuning the Reactivity of Ketones through Unsaturation: Construction of Cyclic and Acyclic Quaternary Stereocenters via Zn-ProPhenol Catalyzed Mannich Reactions

Abstract

Introduction of unsaturation adjacent to the carbonyl drastically improves the reactivity of the Zn-ProPhenol catalyzed Mannich reactions between N-carbamoyl imines and a-branched ketones. Despite only a small change in the substrate acidity, the bimetallic catalyst can preferentially recognize and activate unsaturated ketones over their fully saturated counterparts, providing a chemo-, diastereo-, and enantioselective route to valuable β-aminoketones bearing both cyclic and acyclic quaternary stereocenters, which are common motifs in numerous biologically active alkaloids. Unsaturated ketones and imines with various substitution patterns are viable substrates, and the reaction can be performed on multi-millimole scale at low catalyst loading without impacting its efficiency. More importantly, the unsaturation introduced via the nucleophile provides a useful platform for structural diversification.