SYNTHESIS OF Csp3-RICH SCAFFOLDS VIA METALLAPHOTOREDOX CATALYSIS

Abstract

The synthesis of Csp3-rich scaffolds in organic chemistry is essential to obtain molecules of three-dimensional complexity. While many methods exist to introduce aliphatic groups via nucleophilic substitution, such as heteroatom or enolate alkylation, these methods have inherent limitations with regard to substrate scope. In particular, the formation of bonds between unactivated sp3-hybridized carbon centers has long remained a challenge, especially between sterically congested centers. This stands in contrast to bonds between sp2-hybridized centers, which have become facile to prepare due to the advent of transition metal-catalyzed cross-coupling. Because of their importance in the pharmaceutical industry, methods that enable the modular synthesis of complex aliphatic frameworks are still in demand, and the field has advanced rapidly in previous decades.

By merging photoredox catalysis with transition metal catalysis, the MacMillan lab has shown over the last five years that numerous organic functional groups can be activated to generate alkyl radicals which can subsequently be leveraged for cross-coupling with various electrophiles. Herein are described applications of this platform for the synthesis of medicinally relevant Csp3-rich scaffolds. Chapter 2 describes the cross-coupling of aliphatic carboxylic acids with alkyl halides to generate challenging alkyl–alkyl bonds via nickel catalysis. Chapter 3 discloses the decarboxylative hydroalkylation of alkynes to selectively generate structurally complex alkene products. Chapter 4 focuses on the cross-electrophile coupling of alkyl bromides to enable the installation of valuable small alkyl groups onto more complex frameworks. Finally, Chapter 5 details the three-component coupling reaction of [1.1.1]propellane to generate drug-like bicyclo[1.1.1]pentane compounds via copper catalysis.