Asymmetric Alkylation of Aldehydes via New Strategies in Organic Catalysis

Abstract

The construction of carbonyl α-alkyl stereocenters is an important and long- standing challenge in organic synthesis. The chiral α-alkyl carbonyl is a common motif found in natural products and medicinal targets. However, general technologies do not exist for a direct asymmetric carbonyl α-alkylation protocol.

The synergistic catalysis strategy, wherein the nucleophile and electrophile are simultaneously activated by separate catalysts, allows access to difficult transformations that are impossible to access via mono-catalysis strategies. The intersection of a chiral amine catalyzed nucleophile activation (enamine catalysis) and a metal-catalyzed electrophile activation has been applied to the development of direct methods for carbonyl α-(sp3)-carbon functionalization. This thesis describes our efforts to develop

novel asymmetric aldehyde α-alkylation technologies via the merger of enamine and metal catalysis.

Electron-deficient arenes and heteroarenes are incorporated in pharmaceutical compounds, yet a direct carbonyl α-benzylation employing electron-deficient benzyl electrophiles has not been achieved. The enantioselective α-benzylation of aldehydes employing electron-poor arenes and heteroarenes has been achieved via a synergistic enamine/photoredox catalysis strategy (chapter 2).

Methyl stereogenicity is the most common chiral alkyl motif, yet no direct methods exist for asymmetric electrophilic methylation. A synergistic enamine/copper catalysis strategy has been applied towards the development of an asymmetric aldehyde α-methylation via the coupling of a chiral enamine with an electrophilic alkylcopper(III). Progress regarding the development of this novel transformation is detailed in chapter 3.