A Mechanistic Rationale for the 9-Amino(9-deoxy)epi Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones

Abstract

The 9-amino(9-deoxy)epi cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona-based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones catalyzed by 9-amino(9-deoxy)epi quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the π-facial discrimination of the iminium ion intermediate.