Mechanism-Based Design of Iron-Mediated Carbonyl-Olefin Metathesis Protocols

The activation of carbonyl-containing substrates by Lewis acids is ever present in organic synthesis. However, Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis exhibits reactivity not typically seen in traditional Lewis acid-mediated systems. Building on our detailed understanding of the catalyst behavior in carbonyl-olefin metathesis, this proposal aims to apply that knowledge to the rational design of new metathesis catalysts. To support this, we will employ synthetic, spectroscopic, kinetic, and computational techniques to explore the chemical space influenced by ligand incorporation, assessing their effects on both the catalytic resting state and the turnover-limiting step. Moreover, the substrate itself is currently the most well-characterized ligand for the catalyst in carbonyl-olefin metathesis. We plan to systematically investigate the role of each component of the metathesis substrates to develop a comprehensive model of substrate behavior. Overall, these in-depth synthetic and mechanistic studies will advance the use of carbonyl-olefin metathesis in the synthesis of medicinally valuable compounds. Project Number: 1R15GM164970-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: James Devery | Institution: LOYOLA UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $484,636 | Activity Code: R15 | Study Section: Chemical Synthesis and Biosynthesis Study Section[CSB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11361305