Development of Robust, Scaleable Catalytic Processes through Fundamental Understanding of Reaction Mechanisms

Homogenous transition metal-catalyzed reactions have become a mainstay in organic synthesis and are frequently employed in the discovery and manufacture of modern pharmaceutical compounds. Due to the complex, multi-variant nature of these transformations, the pharmaceutical industry primarily relies on parallel experimentation, such as high-throughput (HTP) screening and design of experiments approaches, to identify and optimize conditions for metal-mediated reactions. Although useful for rapid reaction development, these methods have limitations and may fail to provide critical data for the successful scale-up and implementation of these complex multi-step processes. Due to these limitations, it may be necessary to also evaluate a fundamental mechanism-focused approach towards reaction development. In this article, we review several important lessons from our laboratories at Bristol-Myers Squibb where a combination of HTP screening and mechanistic understanding revealed new insights into known catalytic transformations and facilitated the development of robust, reliable catalytic processes to support the bulk production of pharmaceutical targets.