Novel Strategies for Addressing Classical Challenges in C-C Bond Formation

Abstract

The societal mission of improving human health is directly impacted by the field of synthetic organic chemistry via its ability to enable rapid construction of therapeutic small molecules. The development of new synthetic strategies offers a scalable alternative to nature for access to molecular scaffolds and gives pharmaceutical companies the ability to meet the high demand for medicines. Perhaps the most important contributor towards this goal in modern chemical techniques is that of catalysis. Particularly, this thesis focuses on the use of transition metal catalysis to forge previously difficult carbon-carbon bonds.

The direct and enantioselective α-arylation of carbonyls has long been a classical problem in synthesis. In the past decades, strategies achieving this goal have utilized transition metals Pd and Ni as catalysts for the formation of stable α-quaternary centers. A method is discussed herein that uses a novel ligand design for a Cu catalyst to achieve mild conditions for the building of enantio-enriched α-aryl esters that possess an enolizable α-C–H bond. A proposed penta-coordinate Cu species is thought to be critical for furnishing the high enantioselectivity between the cross coupling of a silyl ketene acetal and a diaryliodonium salt to forge the α-Csp3–Csp2 bond.

The MacMillan research program has played a pivotal role in the recent renaissance of photoredox catalysis in synthetic organic chemistry. The potential of visible light-excited complexes to furnish valuable bonds through nontraditional mechanisms has recently been explored by several synthetic organic groups. The merger of photoredox catalysis with transition metal catalysis has led to the advent of metallaphotoredox catalysis, a dual catalytic system, and a novel approach to traditional cross coupling mechanisms and transformations. Specifically, this thesis outlines the application of metallaphotoredox catalysis to develop robust C-C cross coupling methodologies, both Csp3–Csp2 and Csp3–Csp3. A unique strategy towards cross-electrophile coupling using silyl radicals for halogen atom abstraction is described herein. Additionally, the development of a robust radiochemical method for installing methyl isotopes in medicinal scaffolds is discussed using the same silyl-mediated cross-electrophiles strategy.