Engaging Chiral Cationic Intermediates by Anion-Binding in Asymmetric Catalysis

Abstract

Anion-binding catalysis by dual hydrogen-bond donors such as ureas and squaramides has been demonstrated as a powerful strategy for the development of highly enantioselective transformations involving prochiral cationic intermediates, such as iminium ions, oxocarbenium ions, carbenium ions, and episulfonium ions. The research described in this dissertation explores the ability of dual H-bond donor catalysts to engage chiral cationic intermediates and to induce enantioselectivity in transformations involving such intermediates. In Chapters 1, we provide an overview of the progress and challenges in the development of enantioselective halo- and seleno-functionalization reactions, which proceed via three-membered ring cationic halonium or seleniranium ions. In Chapter 2, we report a highly enantioselective selenocyclization reaction that is promoted by the combination of a chiral squaramide catalyst, a mineral acid, and an achiral Lewis base. Mechanistic studies reveal that the enantioselectivity originates from the dynamic kinetic resolution of seleniranium ions through anion-binding catalysis. Chapter 3 details our discovery of a squaramide-catalyzed enantioselective iodoisocyanation reaction, which represents a rare example in asymmetric intermolecular halofunctionalization of simple olefins. Kinetic studies reveal that [I(NCO)2]–1 anion is the counterion of iodonium intermediate and the dual H-bond donor catalyst aggregates in the resting state. Hammett analysis indicates that the degree of stabilization by catalyst to the iodonium intermediate accounts for both catalysis and enantioselectivity. The reactions developed in Chapter 2 and 3 have therefore extended anion-binding catalysis to reactions involving chiral and stereochemically labile halonium and seleniranium cations. Knowledge learned in these studies will provide valuable guidance to the development of asymmetric transformations involving other chiral cationic intermediates.