Synthesis and Diversification of Csp3-rich Scaffolds

Abstract

The incorporation of pharmaceutically-relevant complexity into organic molecules in a reliable and modular fashion has long been a guiding principle of synthetic methods development. Recently, as studies have emphasized the importance of three-dimensionality in drug discovery, there has been revitalized interest in the installation of sp3-hybridized fragments. Transition metal catalysis, distinguished in its capacity to seamlessly forge bonds between otherwise unreactive reactants, has been somewhat lackluster in the context of constructing three-dimensional frameworks between sp3-hybridized centers. The early focus of transition metal catalysis on arene and alkene functionalization, coupled with problematic B-hydride elimination from palladium, have caused a disparity in the chemical space accessible by cross-coupling. The merger of photoredox catalysis with metal catalysis has been largely successful in incorporating novel sp3-hybridized scaffolds into the realm of cross coupling over the last decade. Metal catalysts can sequester organic radicals from solution, generating transient organometallic intermediates from readily available functional groups such as carboxylic acids, alcohols, and activated C–H bonds. This has served to both expand the pool of available sp3-rich precursors as well as advance novel disconnections not possible by thermal activation modes. Herein are described applications of this platform toward the synthesis and diversification of sp3 fragments. Chapter 2 details the direct cross-coupling of strong C–H bond-bearing aliphatic frameworks with aryl electrophiles via nickel catalysis. Chapter 3 discloses the synthesis of a novel cubane carboxylic acids, and their subsequent engagement in a variety of decarboxylative coupling protocols catalyzed by copper.