A Process Chemistry Benchmark for sp2-sp3 Cross Couplings

As sp(2)-sp(3) disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp(2)-sp(3) cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp(2)-sp(3) bond-forming methods and suggests a path forward for further refinements.

Automated summary

This paper discusses the efforts made to apply and optimize a variety of standard, photo-, and electrochemical sp(2)-sp(3) cross-coupling methods in pharmaceutical development. Evaluation of the performance, benefits, and limitations of these novel methods reveals trends and similarities, suggesting a path forward for further refinement.