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Non-canonical bio-inspired iron catalysis for aliphatic C–H functionalization
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Xiao-Hua Chena, Yifan Fanb, Zitong Wub, Tao Tub, c, d
Chinese Chemical Letters | 2026, 37(3) : 112132
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Chinese Chemical Letters | 2026, 37(3): 112132
• Editorial •
Non-canonical bio-inspired iron catalysis for aliphatic C–H functionalization
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Xiao-Hua Chena, Yifan Fanb, Zitong Wub, Tao Tub, c, d
Affiliations
  • aCollege of Life Sciences, Hengyang Normal University, Hengyang 421008, China
  • bState Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, College of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021, China
  • cShanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200438, China
  • dZhejiang Key Laboratory of Extreme Environment Functional Materials, Yiwu Research Institute of Fudan University, Yiwu 322000, China
About Author:

CRediT authorship contribution statement

Xiao-Hua Chen: Writing – original draft.

Yifan Fan: Writing – review & editing.

Zitong Wu: Writing – review & editing.

Tao Tu: Writing – review & editing.

Published: 2026-03-15 doi: 10.1016/j.cclet.2025.112132
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Xiao-Hua Chen, Yifan Fan, Zitong Wu, Tao Tu. Non-canonical bio-inspired iron catalysis for aliphatic C–H functionalization[J]. Chinese Chemical Letters, 2026 , 37 (3) : 112132 - . DOI: 10.1016/j.cclet.2025.112132
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Cytochromes P450 (P450s or CYPs) constitute a largesuperfamily of heme-thiolate monooxygenases that are ubiquitous in nature. These remarkable enzymes serve as highly versatile biocatalysts capable of mediating selective oxidations across an exceptionally broad range of organic substrates. In 1979, the pioneering work of Groves and colleagues established the first biomimetic model of P450 enzymes, featuring a synthetic Fe(TPP)Cl catalyst. This landmark system was structurally inspired by the Fe(Ⅲ)-protoporphyrin Ⅸ core that characterizes native P450 enzymes [1]. This seminal work inspired global research efforts and established the foundation of metalloporphyrin chemistry as a biomimetic oxidation catalytical system. Essentially, P450-inspired chemical catalysis aims to construct analogous with active-sites, particularly using porphyrin and porphyrinoid metal complexes, to emulate enzymatic oxidation reactions. However, the classical biomimetic heme iron catalysis involving high-valent iron-oxo species displays inadequate activity toward Csp3−H functionalization and is commonly limited to oxygenation reactions due to ultra-fast oxygen rebound (typical rate constant between 1010 s−1 and 1012 s−1) process [2]. The development of synthetic catalysts that emulate P450-like C(sp3)-H functionalization activity while circumventing competing oxygenation pathways remains a formidable challenge in catalysis, especially in intermolecular carbon–carbon bond formation reactions.
Han and co-workers have subverted the long-held perceptions in P450 biomimetic catalysis, and introduced a transformative P450-mimetic approach utilizing the characteristic axial cysteine-thiolate coordination (Scheme 1a) [3]. On the basis of this new concept, the Han group developed cysteine-inspired thiolate ligands to achieve P450-like catalysis, identifying Boc-Cys-Met-OMe (BCMOM) as the optimal ligand. This system promotes the iron-oxo species' hydrogen-atom abstraction capability from alkanes while suppressing its oxo-transfer reactivity when using H2O2 as the oxidant in CH3CN/H2O mixture (Scheme 1b) [4]. The bioinspired iron/BCMOM catalyst enabled undirected methylene C–H functionalization with 1,4-quinones and azines, allowing direct formation of medicinally relevant C–C bonds while suppressing oxygen rebound. Notably, the reactions proceeded efficiently with only 2 equiv. of diverse alkane substrates, exhibiting site selectivities distinct from conventional approaches. Moreover, these selectivities could be rationally predicted by considering steric constraints, electronic perturbations, and stereoelectronic effects—even in structurally complex molecular frameworks.
Central to the success of the reactions is the use of the bioinspired BCMOM ligand. The thiolate BCMOM ligand plays a dual role in stabilizing the iron center and modulating its redox potential, thereby promoting the generation of high-valent iron-oxo intermediates. High-resolution mass spectrometry identified the formation of a key [(acac)2(BCMOM)2•+FeⅣ(O)] species, confirming the catalytic active state. This highly electrophilic oxidant even selectively activates unactivated secondary C–H bonds without requiring directing or activating groups. Competitive kinetic isotope effect (KIE) studies using cyclohexane/[D12]-cyclohexane mixtures revealed a moderate KIE of 2.05, significantly lower than the that observed for conventional heme iron catalysts (KIE > 3). This contrast highlights the superior efficiency of BCMOM/Fe system in cleaving inert C–H bonds, corroborating prior mechanistic studies on thiolate ligation in cytochrome P450 enzymes [5]. The hydrogen atom transfer (HAT) step generates alkyl radical intermediates, as evidenced by their efficient trapping with the radical scavenger BrCCl3. This observation confirms radical escape dominates over oxygen rebound, enabling subsequent functionalization as illustrated in Scheme 2. The observed preference for secondary C—H bonds likely arises from two key factors: (1) their greater steric accessibility compared to more hindered tertiary C—H bonds, and (2) their higher electron density relative to primary C—H bonds. In cyclic systems, additional stereoelectronic effects may further enhance the site selectivity of secondary C—H bond functionalization.
In summary, Han and coworkers have pioneered an unconventional bioinspired iron/BCMOM catalytic system that achieves undirected functionalization of strong methylene C–H bonds using 1,4-quinones and azines. This remarkable system mimics P450-like hydrogen atom abstraction from alkanes while strategically suppressing the oxygen rebound pathway. The development of this small-molecule catalyst represents a significant breakthrough, as it enables methylene C–H functionalization with three key advantages: (1) exceptional substrate scope, (2) predictable selectivity patterns, and (3) synthetically useful yields. Such capabilities could fundamentally transform modern synthetic methodology by providing a practical solution to longstanding aliphatic C–H functionalization challenges.
References
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1
J.T. Groves, T.E. Nemo, R.S. Myers, J. Am. Chem. Soc. 101 (1979) 1032–1033.
2
M. Newcomb, M.H. Le Tadic, D.A. Putt, P.F. Hollenberg, J. Am. Chem. Soc. 117 (1995) 3312–3313.
3
L. Cheng, H. Wang, H. Cai, et al., Science 374 (2021) 77–81.
4
L. Zhou H. Cai, D. Xie, et al., Nat. Commun. 16 (2025) 4673.
5
T.H. Yosca, A.P. Ledray, J. Ngo, M.T. Green, J. Biol. Inorg. Chem. 22 (2017) 209–220.
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Year 2026 volume 37 Issue 3
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Article Info
doi: 10.1016/j.cclet.2025.112132
  • Receive Date：2025-09-18
  • Online Date：2026-10-29
  • Published：2026-03-15
Article Data
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History
  • Received：2025-09-18
  • Revised：2025-11-13
  • Accepted：2025-11-17
Affiliations
    aCollege of Life Sciences, Hengyang Normal University, Hengyang 421008, China
    bState Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, College of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021, China
    cShanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200438, China
    dZhejiang Key Laboratory of Extreme Environment Functional Materials, Yiwu Research Institute of Fudan University, Yiwu 322000, China

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(T. Tu)
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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