One-electron radical chemistry has attracted rising consideration in natural synthesis resulting from its distinct reactivity in comparison with conventional two-electron polar chemistry. Controlling the stereoselectivity, particularly enantioselectivity, of radical reactions has lengthy been a formidable problem. Amongst latest advances, metalloradical catalysis (MRC) affords a conceptually completely different strategy, attaining management over reactivity and stereoselectivity via the catalytic era of metal-stabilized natural radicals as key intermediates governing subsequent homolytic radical reactions. Co(II) complexes of porphyrins ([Co(Por)])—steady 15e-metalloradicals—have been demonstrated as efficient MRC catalysts, involving basically distinct α-Co(III)-alkyl and α-Co(III)-aminyl radical intermediates. Introducing D₂-symmetric chiral amidoporphyrins as supporting ligands, Co(II)-based MRC has efficiently enabled numerous uneven radical reactions, together with C=C bond cyclopropanation and aziridination, and C–H bond alkylation and amination, with exact management over reactivity and stereoselectivity. Increasing past Co(II)-based programs, we’ve got explored different open-shell transition-metal complexes, particularly five-coordinate Fe(III) complexes of porphyrins ([Fe(Por)X]), as potential metalloradical catalysts for MRC. The low toxicity, abundance and cost-effectiveness of iron make Fe(III)-based metalloradical catalysts engaging, providing alternatives to discover numerous catalytic processes for stereoselective radical transformations.

Though the air-sensitive Fe(II) complexes of porphyrins have been studied extensively, steady Fe(III) complexes of porphyrins haven’t been unambiguously established as real catalysts for catalytic transformations in metallocarbene programs, particularly in radical pathways. Though MRC has been primarily demonstrated utilizing low-spin d⁷ [Co(Por)] (Fig. 1a), we questioned whether or not [Fe(Por)X], with the well-known spin-crossover of the d⁵ configuration, may additionally function as potential metalloradical catalysts. Our focus was on investigating [Fe(Por)X] for olefin cyclopropanation with diazo compounds, a catalytic course of beforehand presumed to proceed by way of in situ-reduced Fe(II) complexes and a concerted mechanism (Fig. 1b). We envisioned a stepwise radical mechanism for Fe(III)-catalysed cyclopropanation (Fig. 1c), producing trifluoromethyl-substituted cyclopropanes of nice medicinal-chemistry curiosity (Supplementary Fig. 1). Nonetheless, the power of [Fe(Por)X] to homolytically activate diazo reagent 1’ and generate α-Fe(IV)-alkyl radical intermediate I remained unknown, together with essential mechanistic concerns. Might α-Fe(IV)-alkyl radicals I function a catalytic intermediate for radical addition to substrate alkenes 2, and would the ensuing γ-Fe(IV)-alkyl radicals II bear intramolecular radical substitution by way of 3-exo-tet radical cyclization to ship the cyclopropane merchandise? Furthermore, the diastereoselectivity and enantioselectivity controls of the novel transformation by Fe(III)-MRC have remained open questions. Drawing inspiration from Co(II)-MRC improvement, we anticipated D₂-symmetric chiral amidoporphyrins to perform as an efficient ligand platform to help an Fe(III)-based metalloradical system and govern the stereochemical course of the proposed radical cyclopropanation.

Fig. 1. Proposed stepwise radical mechanism for cyclopropanation of alkenes with in situ-generated α-trifluoromethyldiazomethane by way of Fe(III)-based metalloradical catalysis

Below optimized situations, we evaluated the scope of [Fe(P3)Cl]-catalysed uneven cyclopropanation with in situ-generated trifluoromethyldiazomethane (1’) from hydrazone 1 within the presence of Cs₂CO₃, using completely different alkenes as substrates (Desk 1).

Desk 1. Uneven cyclopropanation of alkenes by [Fe(P3)Cl] with in situ-generated α-trifluoromethyldiazomethane and numerous diazo compounds

To elucidate the underlying mechanism of the Fe(III)-based metalloradical system for olefin cyclopropanation, we carried out experimental research and density useful idea (DFT) computations.

Fig. 2. DFT examine on the origin of the enantioselectivity of the uneven cyclopropanation of styrene with trifluoromethyldiazomethane (1’) by [Fe(P3)Cl]

Fig. 3. Experimental research on the catalytic mechanism of olefin cyclopropanation by the Fe(III)-based metalloradical system

In abstract, we’ve got explicitly demonstrated the operation of Fe(III)-based MRC within the context of its software for uneven olefinm cyclopropanation. Supported by the D₂-symmetric chiral amidoporphyrin 3,5-Di^tBu-QingPhyrin because the optimum ligand, the Fe(III)-based metalloradical system, which operates underneath delicate situations in a one-pot vogue with in situ-generated α-trifluoromethyldiazomethane, is extremely efficient for radical cyclopropanation of a variety of alkenes, affording trifluoromethyl-substituted cyclopropanes in excessive yields with each excessive diastereoselectivity and enantioselectivity. Moreover, we’ve got proven that the Fe(III)-based metalloradical system is broadly efficient in activating completely different lessons of diazo compounds for uneven radical cyclopropanation, providing a doubtlessly normal and virtually sustainable strategy for stereoselective synthesis of priceless three-membered carbocycles. Our systematic experimental research, together with detailed DFT computations, present a number of traces of convincing proof supporting the real motion of Fe(III)-based metalloradical catalysis and make clear the underlying stepwise radical mechanism. Particularly, we’ve got established that the five-coordinate Fe(III) complexes of porphyrins ([Fe(Por)X]), a category of steady 15e-metalloradical complexes, can perform as potent metalloradical catalysts which have the power to homolytically activate diazo compounds and generate α-Fe(IV)-alkyl and γ-Fe(IV)-alkyl radicals as catalytic intermediates. Past cyclopropanation, our ongoing analysis goals to discover the reactivity of α-Fe(IV)-alkyl radicals, in H-atom and X-atom abstraction reactions. We imagine that the outcomes introduced right here will lay a strong basis for Fe(III)-based metalloradical catalysis and pave the way in which for the event of novel stereoselective radical transformations. This work represents an necessary step in the direction of advancing the sector of metalloradical catalysis and holds promise for the design of environment friendly radical strategies for stereoselective natural synthesis.