Research
The central goal of our research program is to develop new catalytic systems that enable stereoselective chemical transformations for the efficient synthesis of biologically and pharmaceutically important molecules. Our approach has been to harness the reactivity of one-electron radical processes through the conceptual development of metalloradical catalysis (MRC), a fundamentally new framework for controlling the reactivity, selectivity, and stereochemistry of homolytic radical reactions. In contrast to traditional closed-shell catalysis, MRC exploits open-shell transition-metal complexes (metalloradicals) as one-electron catalysts. These metalloradicals homolytically activate common substrates without the need for radical initiators, photochemical activation, or applied potential, generating covalently metal-bound organic radicals that remain under the influence of the chiral metal environment. This unique mechanistic paradigm enables precise control of both the radical generation step and the subsequent bond-forming processes, bridging radical chemistry and asymmetric catalysis. Our work has established MRC as a general catalytic platform. Through the design of Co(II)- and Fe(III)-based metalloradical systems supported by聽D2-symmetric chiral amidoporphyrins, we have developed a series of highly stereoselective radical reactions, including olefin cyclopropanation, olefin aziridination, C鈥揌 alkylation, and C鈥揌 amination, that proceed through discrete 伪-metalloalkyl radical (LnM-C鈥�R2) and 伪-metalloaminyl radical (LnM-N鈥�R) intermediates. More recently, our discovery of 伪-Fe(IV)-alkyl and 伪-Fe(IV)-aminyl radicals as reactive yet controllable catalytic intermediates has extended MRC beyond cobalt, opening an entirely new avenue of iron-based metalloradical catalysis (Fe-MRC) for sustainable synthesis. Collectively, these contributions have transformed how chemists view radical reactivity, showing that homolytic one-electron pathways can be rendered predictable, selective, and enantiocontrolled by metalloradical catalysts.
A. Conceptualization and Establishment of Metalloradical Catalysis
While radical reactions have long been recognized for their efficiency and versatility, their synthetic application has been limited by the lack of methods to control selectivity, especially enantioselectivity. Our group addressed this challenge by envisioning open-shell transition-metal complexes as one-electron catalysts capable of mediating controlled radical transformations. We proposed that metalloradicals, defined as metal complexes with a single unpaired electron in a well-defined d orbital, could transfer their radical character to a substrate through homolytic bond activation, generating a metal-bound radical intermediate (e.g., 伪-metalloalkyl, 伪-metalloaminyl, or 伪-metalloxyl radicals) that remains covalently attached to the metal. Because the reactive radical center is not 鈥渇ree,鈥� its subsequent reactivity can be directed by the coordination environment of the metal complex, enabling catalytic control of radical reactivity and selectivity. This concept established a general one-electron catalytic framework, complementary to classical two-electron catalysis, that provides the foundation for MRC as a distinct and broadly applicable paradigm in modern catalysis.
B. D2-Symmetric Chiral Amidoporphyrin Ligand Platform for Metalloradical Catalysts
Our success in developing MRC stems from the rational design of chiral metalloradical catalysts. We created a modular synthetic platform to construct a family of D2-symmetric chiral amidoporphyrins, allowing systematic tuning of the steric, electronic, and chiral environments around the metal center. These porphyrin ligands support low-spin Co(II) and variable-spin Fe(III) complexes that serve as stable metalloradicals. The cobalt(II) complexes, with their (dxy)2(dxz,yz)4(dz2)1 configuration, exhibit persistent radical character localized at the dz2 orbital that can function as metalloradical catalysts to catalyze a wide range of asymmetric radical reactions, while the Fe(III) complexes feature variable-spin d5听configurations that can engage in catalytic one-electron processes involving 伪-Fe(IV)-alkyl and 伪-Fe(IV)-aminyl radical intermediates. Our HuPhyrin family, featuring alkyl-bridged chiral amide units, represents the latest generation of D2-symmetric chiral amidoporphyrins, offering enhanced rigidity and stereochemical definition. These catalysts provide a tunable 鈥渞adical pocket鈥� that controls reactivity through noncovalent interactions, chiral confinement, and radical delocalization, all of which are key features that underpin the selectivity and generality of MRC.
C. Asymmetric Radical Olefin Cyclopropanation via Metalloradical Catalysis
The first successful realization of Co(II)-MRC was the asymmetric olefin cyclopropanation catalyzed by Co(II) complexes of D2-symmetric
chiral amidoporphyrins. This transformation proceeds through stepwise radical addition鈥搑adical substitution, in which the 伪-Co(III)-alkyl radical formed by metalloradical activation of a diazo compound or its hydrazone precursor adds to an alkene to generate a 纬-Co(III)-alkyl radical, which then proceed through 3-exo-tet radical cyclization to form the cyclopropane product while regenerating the Co(II)-metalloradical catalyst. Mechanistic and computational studies confirmed that this radical mechanism is fundamentally distinct from the classical electrophilic metallocarbene pathway of Rh2- and Cu-based catalysts. The Co(II)-MRC system achieves exceptional diastereo- and enantioselectivity across a wide substrate scope, including acceptor-, donor-, and acceptor/acceptor-substituted diazo compounds and challenging heteroaromatic and aliphatic alkenes, thereby establishing MRC as a powerful alternative paradigm in asymmetric carbene chemistry.
D. Enantioselective Radical C鈥揌 Alkylation via Metalloradical Catalysis
Besides radical addition to multiple bonds, we have demonstrated that
伪-Co(III)-alkyl radical intermediates are capable of H-atom abstraction from Csp3鈥揌 bonds followed by radical substitution, furnishing catalytic radical processes for C鈥揌 alkylation. Supported by D2-symmetric chiral amidoporphyrins, the Co(II)-based metalloradical systems can homolytically activate diazo compounds for enantioselective intermolecular C鈥揌 alkylation as well as intramolecular C鈥揌 alkylation, including 1,4-, 1,5-, and 1,6-C鈥揌 alkylation reactions. These metalloradical systems exhibit remarkable chemoselectivity, regioselectivity, and functional-group tolerance, showcasing the versatility of MRC in C鈥揌 functionalization chemistry. For example, we developed a Co(II)-based catalytic system that homolytically activates in situ-generated aliphatic diazo compounds from their hydrazone precursors for stereoselective synthesis of 伪-substituted pyrrolidines via 1,5-C鈥揌 radical alkylation. In addition to chemoselective alkylation of allylic and propargylic C鈥揌 bonds and regioselective 1,5-alkylation, the catalytic radical cyclization is highlighted by its tolerance of various functionalities, including compatibility with a variety of heteroaryl groups.
E. Asymmetric Radical Olefin Aziridination via Metalloradical Catalysis
We have further demonstrated that Co(II)-metalloradicals
can activate organic azides via one-electron radical pathway to generate 伪-Co(III)-aminyl radicals. The Co-stabilized, N-centered radicals undergo radical addition to alkenes to yield 纬-Co(III)-alkyl radical intermediates followed by 3-exo-tet radical cyclization, forming aziridines with regeneration of the Co(II)-metalloradical catalyst. Supported by D2-symmetric chiral amidoporphyrins, the Co(II)-based metalloradical system for radical aziridination accommodates diverse organic azides and alkene substrates, producing aziridines while releasing N鈧� as the only byproduct. For example, we have developed Co(II)-based catalytic systems that homolytically activate trichloroethoxysulfonyl azide, trichloroethoxycarbonyl azide, and fluoroaryl azides for asymmetric olefin aziridination. The Co(II)-based metalloradical systems are operationally simple and capable of aziridinating both aromatic and aliphatic olefins under mild conditions, forming the corresponding aziridines in high yields with excellent enantioselectivities. The operational simplicity, recyclability, and scalability of these systems highlight their synthetic practicality and environmental advantage.
F. Enantioselective Radical C鈥揌 Amination via Metalloradical Catalysis
Building on the chemistry of 伪-Co(III)-aminyl radicals, we have established catalytic C鈥揌 amination with organic azides as another powerful manifestation of Co(II)-based metalloradical catalysis. Supported by D2-symmetric chiral amidoporphyrins, the Co(II)-metalloradical systems can homolytically activate diverse organic azides to enable both intermolecular and intramolecular enantioselective C鈥揌 amination, encompassing 1,5-, 1,6-, and 1,7-C鈥揌 functionalization. For instance, Co(II) complexes of D2-symmetric chiral porphyrins serve as highly effective catalysts for enantioselective C鈥揌 amination of sulfamoyl azides, affording cyclic and acyclic sulfamide derivatives in high yields with excellent enantioselectivities under mild conditions. This catalytic system exhibits broad substrate scope and remarkable versatility, efficiently aminating C鈥揌 bonds of varying electronic and steric character, including the particularly challenging primary and electron-deficient C鈥揌 bonds. Moreover, the Co(II)-based metalloradical catalysts display exceptional chemoselectivity toward allylic and propargylic C鈥揌 bonds, while tolerating a wide range of functional groups. The enantioselectivity of these radical amination processes can be precisely tuned through rational modification of the chiral amidoporphyrin ligand framework, providing an effective handle for asymmetric control. This body of work not only expands the scope of radical amination chemistry but also exemplifies how metalloradical catalysis can transform traditionally uncontrolled radical processes into precisely orchestrated catalytic reactions.
G. Expansion Beyond Cobalt: Iron-Based Metalloradical Catalysis
A major recent advance in our research is the extension of MRC beyond cobalt to iron, an abundant and earth-benign element. We discovered that Fe(III)-based metalloradical systems can activate diazo compounds through a one-electron pathway to form 伪-Fe(IV)-alkyl radicals, which undergo stepwise radical addition鈥搑adical substitution to achieve asymmetric cyclopropanation in high yields with excellent stereocontrol. This finding has introduced a new Fe(III)/Fe(IV) one-electron manifold into MRC and provided the first direct evidence of 伪-Fe(IV)-alkyl radical intermediates by EPR and computational studies. Moreover, Fe(III)-MRC has been extended to radical C鈥揌 amination, where 伪-Fe(IV)-aminyl radicals serve as key intermediates, enabling the enantioselective synthesis of nitrogen heterocycles with high efficiency. These discoveries have broadened the conceptual scope of metalloradical chemistry, demonstrating that the MRC strategy is general across different transition metals and can be tuned to exploit distinct redox and spin configurations.
H. Mechanistic Framework and Future Outlook
The cumulative body of work has established MRC as a distinct catalytic regime where radical reactivity is harnessed through metal鈥搑adical synergy. The mechanistic framework unites radical addition, radical substitution, and H-atom abstraction processes under a coherent model governed by metal-stabilized organic radical intermediates. Ongoing and future efforts are aimed at expanding MRC to 伪-metalloxyl radical intermediates, enabling olefin epoxidation and C鈥揌 hydroxylation, as well as radical cascade and cross-coupling reactions. Emerging work also integrates MRC with photo- and electrochemical catalysis, opening pathways to multi-modal one-electron transformations under sustainable conditions. By bridging the gap between radical chemistry and transition metal catalysis, metalloradical catalysis is redefining how chemists control reactivity, selectivity, and stereochemistry in homolytic radical reactions. The impact of this work extends beyond synthetic methodology. It provides a unifying framework for one-electron catalysis that continues to influence diverse areas of modern chemistry, from sustainable synthesis to bioinspired catalysis and materials design.