Enantioselective Chemical Synthesis Methods Using Lewis Base and Transition Metal Catalysis

The straightforward laboratory preparation of structural motifs commonly found in therapeutic agents is a critical driver for the design and development of new and more efficient chemical reactions. This is especially true in the pharmaceutical industry where efforts to increase the 3-dimensional complexity of pharmaceutical lead candidates has resulted in substantial challenges related to their efficient and cost-effective preparation. While our capacity to make complex molecules has become greatly developed, the preparation of stereochemically complex targets in useful quantities remains very difficult. Accordingly, there is a critical need for the design and development of new and efficient stereoselective reactions with which to address this challenge. The long-term objective of our research laboratory is to introduce a general, modular, and operationally trivial toolbox of effective stereoselective reactions. Within this remit, we have leveraged both Lewis base and transition metal catalysis as sources of unique and enabling reactivity but have also embraced cooperative catalysis as a general blueprint for reaction design. Cooperativity emulates mechanisms commonly encountered in enzymes, exploiting synergy between simultaneous yet complementary catalysis control bond formation. Our rationale is that, by making two catalysts work together, greater control over reactivity and stereoselectivity could be possible than when using either catalyst in isolation. This will allow us to design entirely new chemical reactions that work by entirely new reaction mechanisms. This promises much for the design of new, efficient, and operationally trivial catalytic stereoselective reactions with which to expedite the design, development, and manufacture of medicines to manage and treat diseases. Based on exciting preliminary data we have obtained in enantioselective Lewis base catalysis and Lewis base/transition metal cooperativity — the research described in this proposal will provide the scientific community with straightforward, reliable and flexible methods for chemical synthesis. This work will significantly impact human health and medicine by establishing routine synthetic protocols for the preparation of valuable fluorinated molecular scaffolds, which will contribute to the design and development of new clinical agents. Project Number: 1R01GM157347-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Thomas Snaddon | Institution: TRUSTEES OF INDIANA UNIVERSITY, BLOOMINGTON, IN | Award Amount: $631,989 | Activity Code: R01 | Study Section: Chemical Synthesis and Biosynthesis Study Section[CSB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11225902