Photocatalytic Methods for Fluorination, Cyanation, and Proximity Labeling

Abstract

The development of innovative catalytic methods has given rise to unprecedented synthetic organic transformations, which facilitate the assembly of complex molecular architectures. Over the past decade, photoredox catalysis has emerged as a powerful catalytic strategy for the activation of abundant organic molecules. By harnessing visible light, photocatalysts drive single-electron and energy transfer events to organic and organometallic substrates, generating reactive open-shell intermediates under mild conditions. In recent years, the MacMillan lab has focused its research efforts on the development of novel photocatalytic platforms that enable previously elusive chemical transformations.The unique effects imparted by fluorine atoms in organic scaffolds have been exploited in pharmaceutical agents, agrochemicals, and materials. Broadly applicable synthetic methods for C–F bond formation are, then, required to access fluorinated motifs. Chapter 2 describes a photocatalytic radical chain reaction enabling the fluorination of alkyl bromides with complementary reactivity to established closed-shell nucleophilic substitution methods. In collaboration with the Houk group, the origin of the observed kinetic selectivity for C–F over thermodynamically favored Si–F bond formation is explored computationally. The merger of photoredox catalysis with transition-metal catalysis, termed metallaphotoredox, has been a key area of focus in our laboratory since our initial publication in 2014. Chapter 3 details the copper metallaphotoredox-catalyzed cyanation of a range of (hetero)aryl bromides. This reaction proceeds via the intermediacy of aryl radicals generated using silyl radical-mediated halogen atom abstraction, thus bypassing a challenging copper oxidative addition step. Chapter 4 discloses ongoing research efforts towards the application of photoredox catalysis to chemical biology. Specifically, in collaboration with the Milone lab, our laboratory’s newly developed photocatalytic proximity labeling platform, termed μMap, enables high-resolution elucidation of chimeric antigen receptor (CAR) T cell protein microenvironments.