C–H Functionalization Reactions for Bioisostere Synthesis and Isotopic Labeling

Abstract

The development of new C–H functionalization reactions is critical to expediate synthesis and access unexplored chemical space. Among various approaches, hydrogen atom transfer (HAT) has emerged as a particularly powerful strategy to cleave C–H bonds through radical abstraction. While these protocols have diversified C–H bonds of various bond strengths, they often require harsh conditions and are low yielding. To address these limitations, photoredox catalysis has revolutionized radical HAT pathways by enabling the discovery of more effective HAT reagents, and their mild generation.This thesis presents the use of novel radical-mediated C–H activation processes for isotopic labeling and bioisostere synthesis. Chapter 2 details the deuteration and tritiation of the strong C(sp3)–H bonds in pharmaceuticals for applications in ADME studies. Chapter 3 presents a strategy to synthesize complex 2-substituted bicyclo[1.1.1]pentanes (BCPs) through bromination of the BCP bridge C–H bonds, followed by their derivatization. Finally, Chapter 4 covers the construction of cubane isomers with underexplored exit vectors in drug discovery via HAT, pericyclic and metallaphotoredox methodologies.