Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1 degrees amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the alpha,beta-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.