Controllable Enhanced Reactivity of Radical Intermediates in Olefin Cyclopropanation via Electron-Withdrawing Substituents in Biomimetic Catalysts

Abstract

Cyclopropane serves as a pivotal structural motif in numerous pharmaceuticals, fuels, and natural products. Iron-containing heme enzymes have recently been extensively explored as biocatalysts for olefin cyclopropanation via electrophilic carbene transfer. However, mechanistic and structural constraints pose significant challenges for transforming electron-deficient olefins and modulating reactivity using these systems. Herein, we report the design of biocompatible biomimetic catalysts inspired by free radical reactivity, integrating heme-active iron porphyrin and axial ligands to study cyclopropanation of challenging electron-deficient olefins and transient radical regulation mechanisms. Owing to their electronic tunability, substituent-induced electronic effects were identified for the first time as dominating the catalytic activity of radical intermediates in cyclopropanation. The electron-withdrawing Fe^III(Cl)-CF₃ catalyst exhibited enhanced activity with a reaction rate of 4.86 x 10^–5 M·s^–1, reaching max 27.2 x 10^–5 M·s^–1 after system optimization. DFT calculations revealed that electron-withdrawing substituents stabilize transition states by generating strong Fe–C bonds through high positive charge localization on the central metal, thereby reducing energy barriers in rate-limiting steps. Additionally, the highly reactive α-C alkyl radicals generated post-reaction contribute substantially to the catalytic efficacy. As anticipated, [Fe^III(Cl)-TFMPP] demonstrated efficient cyclopropanation across diverse olefins (up to 99% yield and 99 : 1 dr).

Keywords

Metalloporphyrin / Biomimetic catalyst / Cycloaddition / Radicals / Cooperative effects / Ligand design / Asymmetric catalysis / Simulated calculation

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