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1. An S =1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation

   https://doi.org/10.1002/anie.202309362  

   Paris, Jared C. ; Hu, Sha ; Wen, Aiwen ; Weitz, Andrew C. ; Cheng, Ronghai ; Gee, Leland B. ; Tang, Yijie ; Kim, Hyomin ; Vegas, Arturo ; Chang, Wei‐chen ; et al ( September 2023 , Angewandte Chemie International Edition)

   Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O₂‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competentS=1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA fromMethyloversatilis thermotoleran, which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment.

    

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2. Single-Step Replacement of an Unreactive C–H Bond by a C–S Bond Using Polysulfide as the Direct Sulfur Source in the Anaerobic Ergothioneine Biosynthesis

   https://doi.org/https://doi.org/10.1021/acscatal.0c01809  

   Ronghai Cheng, Lian Wu ( July 2020 , ACS catalysis)

   null (Ed.)

   Ergothioneine, a natural longevity vitamin and antioxidant, is a thiol-histidine derivative. Recently, two types of biosynthetic pathways were reported. In the aerobic ergothioneine biosyntheses, non-heme iron enzymes incorporate a sulfoxide into an sp2 C–H bond from trimethyl-histidine (hercynine) through oxidation reactions. In contrast, in the anaerobic ergothioneine biosynthetic pathway in a green-sulfur bacterium, Chlorobium limicola, a rhodanese domain containing protein (EanB), directly replaces this unreactive hercynine C–H bond with a C–S bond. Herein, we demonstrate that polysulfide (HSSnSR) is the direct sulfur source in EanB catalysis. After identifying EanB’s substrates, X-ray crystallography of several intermediate states along with mass spectrometry results provide additional mechanistic details for this reaction. Further, quantum mechanics/molecular mechanics (QM/MM) calculations reveal that the protonation of Nπ of hercynine by Tyr353 with the assistance of Thr414 is a key activation step for the hercynine sp2 C–H bond in this trans-sulfuration reaction. 

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3. Tuning the H‐Atom Transfer Reactivity of Iron(IV)‐Oxo Complexes as Probed by Infrared Photodissociation Spectroscopy

   https://doi.org/10.1002/ange.202016695  

   Tripodi, Guilherme L. ; Dekker, Magda M. J. ; Roithová, Jana ; Que, Jr., Lawrence ( February 2021 , Angewandte Chemie)

   Reactivities of non‐heme iron(IV)‐oxo complexes are mostly controlled by the ligands. Complexes with tetradentate ligands such as [(TPA)FeO]²⁺(TPA=tris(2‐pyridylmethyl)amine) belong to the most reactive ones. Here, we show a fine‐tuning of the reactivity of [(TPA)FeO]²⁺by an additional ligand X (X=CH₃CN, CF₃SO₃⁻, ArI, and ArIO; ArI=2‐(^tBuSO₂)C₆H₄I) attached in solution and reveal a thus far unknown role of the ArIO oxidant. The HAT reactivity of [(TPA)FeO(X)]^+/2+decreases in the order of X: ArIO > MeCN > ArI ≈ TfO⁻. Hence, ArIO is not just a mere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)‐oxo complex as a labile ligand. The detected HAT reactivities of the [(TPA)FeO(X)]^+/2+complexes correlate with the Fe=O and FeO−H stretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence, the most reactive [(TPA)FeO(ArIO)]²⁺adduct in the series has the weakest Fe=O bond and forms the strongest FeO−H bond in the HAT reaction.

    

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4. Tuning the H‐Atom Transfer Reactivity of Iron(IV)‐Oxo Complexes as Probed by Infrared Photodissociation Spectroscopy

   https://doi.org/10.1002/anie.202016695  

   Tripodi, Guilherme L. ; Dekker, Magda M. J. ; Roithová, Jana ; Que, Jr., Lawrence ( February 2021 , Angewandte Chemie International Edition)

   Reactivities of non‐heme iron(IV)‐oxo complexes are mostly controlled by the ligands. Complexes with tetradentate ligands such as [(TPA)FeO]²⁺(TPA=tris(2‐pyridylmethyl)amine) belong to the most reactive ones. Here, we show a fine‐tuning of the reactivity of [(TPA)FeO]²⁺by an additional ligand X (X=CH₃CN, CF₃SO₃⁻, ArI, and ArIO; ArI=2‐(^tBuSO₂)C₆H₄I) attached in solution and reveal a thus far unknown role of the ArIO oxidant. The HAT reactivity of [(TPA)FeO(X)]^+/2+decreases in the order of X: ArIO > MeCN > ArI ≈ TfO⁻. Hence, ArIO is not just a mere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)‐oxo complex as a labile ligand. The detected HAT reactivities of the [(TPA)FeO(X)]^+/2+complexes correlate with the Fe=O and FeO−H stretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence, the most reactive [(TPA)FeO(ArIO)]²⁺adduct in the series has the weakest Fe=O bond and forms the strongest FeO−H bond in the HAT reaction.

    

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5. Experimental and computational studies of the mechanism of iron-catalysed C–H activation/functionalisation with allyl electrophiles

   https://doi.org/10.1039/d1sc01661j  

   DeMuth, Joshua C. ; Song, Zhihui ; Carpenter, Stephanie H. ; Boddie, Theresa E. ; Radović, Aleksa ; Baker, Tessa M. ; Gutierrez, Osvaldo ; Neidig, Michael L. ( July 2021 , Chemical Science)

   Synthetic methods that utilise iron to facilitate C–H bond activation to yield new C–C and C–heteroatom bonds continue to attract significant interest. However, the development of these systems is still hampered by a limited molecular-level understanding of the key iron intermediates and reaction pathways that enable selective product formation. While recent studies have established the mechanism for iron-catalysed C–H arylation from aryl-nucleophiles, the underlying mechanistic pathway of iron-catalysed C–H activation/functionalisation systems which utilise electrophiles to establish C–C and C–heteroatom bonds has not been determined. The present study focuses on an iron-catalysed C–H allylation system, which utilises allyl chlorides as electrophiles to establish a C–allyl bond. Freeze-trapped inorganic spectroscopic methods ( 57 Fe Mössbauer, EPR, and MCD) are combined with correlated reaction studies and kinetic analyses to reveal a unique and rapid reaction pathway by which the allyl electrophile reacts with a C–H activated iron intermediate. Supporting computational analysis defines this novel reaction coordinate as an inner-sphere radical process which features a partial iron–bisphosphine dissociation. Highlighting the role of the bisphosphine in this reaction pathway, a complementary study performed on the reaction of allyl electrophile with an analogous C–H activated intermediate bearing a more rigid bisphosphine ligand exhibits stifled yield and selectivity towards allylated product. An additional spectroscopic analysis of an iron-catalysed C–H amination system, which incorporates N -chloromorpholine as the C–N bond-forming electrophile, reveals a rapid reaction of electrophile with an analogous C–H activated iron intermediate consistent with the inner-sphere radical process defined for the C–H allylation system, demonstrating the prevalence of this novel reaction coordinate in this sub-class of iron-catalysed C–H functionalisation systems. Overall, these results provide a critical mechanistic foundation for the rational design and development of improved systems that are efficient, selective, and useful across a broad range of C–H functionalisations. 

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