Mechanistic Studies in Enantioselective Ion-Pairing Catalysis With Dual Hydrogen-Bond Donors

Abstract

Enantioselective ion-pairing catalysis has emerged as a powerful strategy for controlling the stereochemical outcomes of reactions proceeding through charged intermediates. While ion pairing between chiral ionic catalysts and ionic reactive intermediates enables direct stereochemical communication, a conceptually analogous strategy wherein neutral chiral catalysts bind the counterions of ionic reactive intermediates affords an alternative approach. In principle, ion-binding catalysis offers improved modularity (the chiral catalyst and counterion may be optimized separately) and activity (ion- binding increases the degree of charge separation within the reactive intermediate) relative to chiral ion catalysis. However, the design of systems capable of both efficient ion-binding and stereochemical control remains nontrivial. Dual hydrogen-bond donors, such as ureas and thioureas, have come to define a privileged class of anion-binding catalysts, and the broad utility of these structures motivates study of the features contributing to and limiting their efficiency. In Chapters 2 and 3, we describe contributions to the mechanistic analysis of two amido-thiourea- catalyzed transformations representative of enantioselective anion-abstraction catalysis and enantioselective Brønsted acid co-catalysis, respectively. In the former, mechanistic insights lead to the rational design of a linked, bis-thiourea catalyst with enhanced activity relative to monomeric analogues. Experimental and computational analyses provide insight into the precise mode of substrate activation and suggest opportunities for the design of simplified bis-thioureas that retain the enantioselectivity of the first-generation structure. In the latter, mechanistic insights lead to the development of modified conditions that circumvent product inhibition and non-productive catalyst self-aggregation. In Chapters 4 and 5, we advance a synergistic ion-binding strategy that combines insights from anion-binding and cation-binding catalysis to render two classic sigmatropic rearrangements enantioselective. Catalyst structure–reactivity–selectivity relationship studies and computational analyses provide insight into catalyst–substrate interactions responsible for enantioinduction and reveal that the simultaneous engagement of the prochiral anion and its alkali metal countercation is requisite for both rate-acceleration and enantiocontrol. These transformations have historically been difficult to engage due to the diffuse nature of their transition structures, and the insights gleaned from this work allude to the potential generality of this catalytic strategy for other pericyclic reactions and reactions involving M+ –X ion pairs.