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1. Intra- and intermolecular Fe-catalyzed dicarbofunctionalization of vinyl cyclopropanes

   https://doi.org/10.1039/D0SC00467G  

   Liu, Lei; Lee, Wes; Yuan, Mingbin; Acha, Chris; Geherty, Michael B.; Williams, Brandon; Gutierrez, Osvaldo (March 2020, Chemical Science)

   null (Ed.)

   Design and implementation of the first (asymmetric) Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes (VCPs) with alkyl halides and aryl Grignard reagents has been realized via a mechanistically driven approach. Mechanistic studies support the diffusion of alkyl radical intermediates out of the solvent cage to participate in an intra- or intermolecular radical cascade with a range of VCPs followed by re-entering the Fe radical cross-coupling cycle to undergo (stereo)selective C(sp 2 )–C(sp 3 ) bond formation. This work provides a proof-of-concept of the use of vinyl cyclopropanes as synthetically useful 1,5-synthons in Fe-catalyzed conjunctive cross-couplings with alkyl halides and aryl/vinyl Grignard reagents. Overall, we provide new design principles for Fe-mediated radical processes and underscore the potential of using combined computations and experiments to accelerate the development of challenging transformations. 

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2. Cooperative Photometallobiocatalysis: Nonheme Fe Enzyme‐Catalyzed Enantioconvergent Radical Decarboxylative Azidation, Thiocyanation, and Isocyanation of Redox‐Active Esters

   https://doi.org/10.1002/anie.202506361  

   Zhao, Liu‐Peng; Lin, Ken; Xie, Pei‐Pei; Liu, Huichong; Xiang, Hengye; Liu, Xin; Zhao, Yunlong; Liu, Peng; Yang, Yang (July 2025, Angewandte Chemie International Edition)

   Abstract Cooperative catalysis with an enzyme and a small‐molecule photocatalyst has recently emerged as a potentially general activation mode to advance novel biocatalytic reactions with synthetic utility. Herein, we report cooperative photobiocatalysis involving an engineered nonheme Fe enzyme and a tailored photoredox catalyst to achieve enantioconvergent decarboxylative azidation, thiocyanation, and isocyanation of redox‐active esters via a radical mechanism. We repurposed and further evolved metapyrocatechase (MPC), a nonheme Fe extradiol dioxygenase not previously studied in new‐to‐nature biocatalysis, for the enantioselective C─N₃, C─SCN, and C─NCO bond formation via an enzymatic Fe─X intermediate (X═N₃, NCS, and NCO). A range of primary, secondary, and tertiary alkyl radical precursors were effectively converted by our engineered MPC, allowing the syntheses of organic azides, thiocyanates, and isocyanates with good to excellent enantiocontrol. Further derivatization of these products furnished valuable compounds including enantioenriched amines, triazoles, ureas, and SCF₃‐containing products. DFT and MD simulations shed light on the mechanism as well as the binding poses of the alkyl radical intermediate in the enzyme active site and the π‐facial selectivity in the enantiodetermining radical rebound. Overall, cooperative photometallobiocatalysis with nonheme Fe enzymes provides a means to develop challenging asymmetric radical transformations eluding small‐molecule catalysis. 

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3. General method for iron-catalyzed multicomponent radical cascades–cross-couplings

   https://doi.org/10.1126/science.abj6005  

   Liu, Lei; Aguilera, Maria Camila; Lee, Wes; Youshaw, Cassandra R.; Neidig, Michael L.; Gutierrez, Osvaldo (October 2021, Science)

   Transition metal–catalyzed cross-coupling reactions are some of the most widely used methods in chemical synthesis. However, despite notable advantages of iron (Fe) as a potentially cheaper, more abundant, and less toxic transition metal catalyst, its practical application in multicomponent cross-couplings remains largely unsuccessful. We demonstrate 1,2-bis(dicyclohexylphosphino)ethane Fe–catalyzed coupling of α-boryl radicals (generated from selective radical addition to vinyl boronates) with Grignard reagents. Then, we extended the scope of these radical cascades by developing a general and broadly applicable Fe-catalyzed multicomponent annulation–cross-coupling protocol that engages a wide range of π-systems and permits the practical synthesis of cyclic fluorous compounds. Mechanistic studies are consistent with a bisarylated Fe(II) species being responsible for alkyl radical generation to initiate catalysis, while carbon-carbon bond formation proceeds between a monoarylated Fe(II) center and a transient alkyl radical. 

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4. Transition-metal-free C(sp ³ )–H/C(sp ³ )–H dehydrogenative coupling of saturated heterocycles with N -benzyl imines

   https://doi.org/10.1039/D0SC00031K  

   Liu, Zhengfen; Li, Minyan; Deng, Guogang; Wei, Wanshi; Feng, Ping; Zi, Quanxing; Li, Tiantian; Zhang, Hongbin; Yang, Xiaodong; Walsh, Patrick J. (January 2020, Chemical Science)

   A unique C(sp 3 )–H/C(sp 3 )–H dehydrocoupling of N -benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C–C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical–radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals. 

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5. Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals

   https://doi.org/10.1038/s41467-020-18658-4  

   Zhu, Chuan; Liu, Ze-Yao; Tang, Luning; Zhang, Heng; Zhang, Yu-Feng; Walsh, Patrick J.; Feng, Chao (December 2020, Nature Communications)

   null (Ed.)

   Abstract Despite remarkable recent advances in transition-metal-catalyzed C(sp 3 )−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary -C(sp 3 )−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp 3 ) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert -alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials. 

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