The Productive Merger of Transition Metal and Enamine Catalysis for the Enantioselective Functionalization of Aldehydes

Abstract

Enamine catalysis is a branch of organocatalysis that enables the stereoselective construction of carbon-carbon and carbon-heteroatom bonds at the α-position of aldehydes and ketones using an amine catalyst. While this technology has provided dozens of successful organic reactions, several transformations have so far remained elusive. A strategy that is becoming increasingly popular to expand the scope of enamine catalysis is the merger of enamine catalysis with transition metal catalysis. This dual catalytic approach of combining an amine catalyst with an appropriate transition metal catalyst has led to the development of organic reactions that are not possible with either catalyst system individually. This thesis describes our efforts to apply this strategy to transformations that have not been possible through enamine catalysis alone.

The catalytic production of CF3-containing stereogenicity has been the focus of many research efforts due to the importance of organofluorine compounds in the pharmaceutical, medicinal, and materials sciences. Enamine catalysis, however, has been unable to produce α-CF3 carbonyls through mono-catalytic strategies. Chapter 2 details our successful development of an amine and transition metal-catalyzed enantioselective trifluoromethylation of aldehydes using an electrophilic trifluoromethylating reagent.

Another challenge in synthetic organic chemistry has been the enantioselective construction of enolizable α-aryl carbonyls. Neither organocatalysis nor transition metal catalysis has been able to accomplish this transformation, in a general sense, using unfunctionalized carbonyl substrates. In Chapter 3, we describe our development toward this goal using diaryliodonium salts in a copper and amine-catalyzed protocol.