Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled.