Enantioselective alpha-Functionalization of Aldehydes: New Strategies in Enamine Catalysis

Abstract

Chiral enamine catalysis is a sub-field of organocatalysis that has enabled the stereoselective assembly of C–C and C–heteroatom bonds at the α-position of aldehydes and ketones over the past fifteen years. While this mode of catalysis has provided access to numerous organic transformations, there remain a number of challenging transforms that are inaccessible. Our group has recently introduced the concept of synergistic catalysis, or the merger of two discrete catalytic cycles to enable challenging reactions to occur. In particular, the merger of enamine catalysis with transition metal-, photoredox-, and Lewis acid-catalysis has bore out a number of new strategies to this end, and these transformations would not be possible with either catalytic cycle individually. This thesis will describe our efforts to utilize synergistic catalysis to access reactions that were previously challenging via enamine catalysis alone.

The installation of nitrogen-bearing functionality at the α-position of carbonyls has been a pervasive challenge in organic synthesis due to its prevalence in pharmaceuticals and natural products. The key challenge in the synthesis of these molecules is that they require an electrophilic source of nitrogen to react with the inherently electron-rich carbonyl α-position. Our group, as well as others, has been interested in developing enantioselective, catalytic methods for generating these important bonds. Enamine catalysis has been used previously for the production of α-amino carbonyls but is limited in that it requires a commercially available azodicarboxylate. Chapter two of this thesis will describe an enantioselective α-amination of aldehydes which relies on both enamine catalysis as well as a photoredox process to generate electrophilic nitrogen-centered radicals which rapidly couple with chiral enamines to generate the desired a-amino carbonyl.

Another prevalent challenge within the synthetic community has been the enantioselective α-arylation of aldehydes. Chapter 3 of this thesis will address this challenge and detail an enantioselective α-arylation of aldehydes via the merger of Cu(II) and amine catalysis. Inspired by the Chan-Evans-Lam cross coupling, we were able to develop a cross-coupling between aldehydes and commercially available boronic acids.