Harnessing the Power of C–H Functionalization Chemistry to Accelerate Drug Discovery

Abstract The field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications in organic synthesis. Recognizing the potential of this emerging field to impact drug discovery, a dedicated effort was established in our laboratories more than ten years ago, with the goal of facilitating the application of C–H functionalization chemistries to active medicinal-chemistry programs. Our approach centered around the strategy of late-stage functionalization (LSF) wherein C–H functionalization chemistry is employed in a systematic and targeted manner to generate high-value analogues from advanced drug leads. To successfully realize this approach, we developed broadly useful LSF chemistry platforms and workflows that increased the success rates of the C–H functionalization chemistries and accelerated access to new derivatives. The LSF strategy, when properly applied, enabled a rapid synthesis of molecules designed to address specific medicinal-chemistry issues. Several case studies are presented, along with descriptions of the group’s platforms and workflows. 1 Introduction 2 Building an LSF Chemistry Toolbox 2.1 C–H Borylation 2.2 Minisci Platforms 2.3 Automated Direct-Metalation Platform 3 Building an LSF Workflow 4 LSF Application Case Studies 4.1 BTK Inhibitor Program 4.2 GPR40 Agonist Program 5 Conclusions