Mechanism-based design of iron-mediated carbonyl-olefin metathesis protocols

The National Institute of General Medical Sciences awarded Loyola University of Chicago $484,636 on June 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to conduct mechanism-based design of iron-mediated carbonyl-olefin metathesis protocols. The research combines synthetic, spectroscopic, kinetic, and computational techniques to explore catalyst behavior, ligand incorporation effects on the catalytic resting state and turnover-limiting step, and systematic investigation of substrate components. The work aims to advance carbonyl-olefin metathesis for synthesis of medicinally valuable compounds. The performance period runs through May 31, 2029, with work performed at Loyola University of Chicago's Lake Shore Campus in Chicago, Illinois.

Abstract

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.