Dedicated to the memory of Professor Keith Fagnou. His legacy in contributing seminal
advances to C–H functionalization chemistry and in training exceptional scientists
has left a lasting impact on the field.
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
Key words
C–H functionalization - borylation - Minisci reaction - fluorination - late-stage
functionalization - medicinal chemistry