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

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Project Summary Lewis acid-activation of carbonyl-containing substrates is broadly utilized in organic synthesis. However, iron(III)- catalyzed carbonyl-olefin ring-closing metathesis employs reactivity not typically observed in Lewis acid- facilitated reactions. Using our detailed understanding of the mechanistic behavior of the iron catalyst in carbonyl- olefin metathesis, this proposal intends to apply this knowledge in the rational design of new metathesis catalysts. It is our hypothesis that, via appropriate ligand support, the reaction can be performed in solvents preferred in the production of pharmaceuticals, the natural, inhibitory mechanism can be prevented, and chemists will be able to select for a specific transition state in the turnover-limiting step. To facilitate catalyst design, synthetic, spectroscopic, kinetic, and computational techniques will be employed to observe the chemical space created by the incorporation of ligands, measuring their impact on the resting state of the catalytic cycle, as well as the turnover-limiting step. Further, substrate itself acts as a reactivity-directing ligand. Therefore, simple modifications to the carbonyl and olefin metathesis partners can not only change the operating mechanism, but dramatically alter reaction outcomes. Overall, these rigorous synthetic and mechanistic studies will employ the factors we have enumerated thus far to provide improved reaction outcomes, enhancing the use of carbonyl- olefin metathesis in the construction of medicinally important molecules.