Synergistic Interplay of a Non‐Heme Iron Catalyst and Amino Acid Coligands in H2O2 Activation for Asymmetric Epoxidation of α‐Alkyl‐Substituted Styrenes

Highly enantioselective epoxidation of α‐substituted styrenes with aqueous H₂O₂ is described by using a chiral iron complex as the catalyst and N‐protected amino acids (AAs) as coligands. The amino acids synergistically cooperate with the iron center in promoting an efficient activation of H₂O₂ to catalyze epoxidation of this challenging class of substrates with good yields and stereoselectivities (up to 97 % ee) in short reaction times.     

Engineering Rieske Non‐Heme Iron Oxygenases for the Asymmetric Dihydroxylation of Alkenes

The asymmetric dihydroxylation of olefins is of special interest due to the facile transformation of the chiral diol products into valuable derivatives. Rieske non‐heme iron oxygenases (ROs) represent promising biocatalysts for this reaction as they can be engineered to efficiently catalyze the selective mono‐ and dihydroxylation of various olefins. The introduction of a single point mutation improved selectivities (≥95 %) and conversions (>99 %) towards selected alkenes. By modifying the size of one active site amino acid side chain, we were able to modulate the regio‐ and stereoselectivity of these enzymes. For distinct substrates, mutants displayed altered regioselectivities or even favored opposite enantiomers compared to the wild‐type ROs, offering a sustainable approach for the oxyfunctionalization of a wide variety of structurally different olefins.     

Isonitrile Formation by a Non‐Heme Iron(II)‐Dependent Oxidase/Decarboxylase

The electron‐rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We herein provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non‐heme iron(II)‐dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)‐3‐((carboxymethyl)amino)butanoic acid to (R)‐3‐isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, of which several members are critical for the virulence of pathogenic mycobacteria.     

Aromatic Hydroxylation at a Non‐Heme Iron Center: Observed Intermediates and Insights into the Nature of the Active Species

Mechanism of substrate oxidations with hydrogen peroxide in the presence of a highly reactive, biomimetic, iron aminopyridine complex, [Fe^II(bpmen)(CH₃CN)₂][ClO₄]₂ ( 1 ; bpmen=N,N'‐dimethyl‐N,N'‐bis(2‐pyridylmethyl)ethane‐1,2‐diamine), is elucidated. Complex 1 has been shown to be an excellent catalyst for epoxidation and functional‐group‐directed aromatic hydroxylation using H₂O₂, although its mechanism of action remains largely unknown. 1 , 2 Efficient intermolecular hydroxylation of unfunctionalized benzene and substituted benzenes with H₂O₂ in the presence of 1 is found in the present work. Detailed mechanistic studies of the formation of iron(III)–phenolate products are reported. We have identified, generated in high yield, and experimentally characterized the key Fe^III(OOH) intermediate (λ_max=560 nm, rhombic EPR signal with g=2.21, 2.14, 1.96) formed by 1 and H₂O₂. Stopped‐flow kinetic studies showed that Fe^III(OOH) does not directly hydroxylate the aromatic rings, but undergoes rate‐limiting self‐decomposition producing transient reactive oxidant. The formation of the reactive species is facilitated by acid‐assisted cleavage of the O? O bond in the iron–hydroperoxide intermediate. Acid‐assisted benzene hydroxylation with 1 and a mechanistic probe, 2‐Methyl‐1‐phenyl‐2‐propyl hydroperoxide (MPPH), correlates with O? O bond heterolysis. Independently generated Fe^IV?O species, which may originate from O? O bond homolysis in Fe^III(OOH), proved to be inactive toward aromatic substrates. The reactive oxidant derived from 1 exchanges its oxygen atom with water and electrophilically attacks the aromatic ring (giving rise to an inverse H/D kinetic isotope effect of 0.8). These results have revealed a detailed experimental mechanistic picture of the oxidation reactions catalyzed by 1 , based on direct characterization of the intermediates and products, and kinetic analysis of the individual reaction steps. Our detailed understanding of the mechanism of this reaction revealed both similarities and differences between synthetic and enzymatic aromatic hydroxylation reactions.     

A 2‐Tyr‐1‐carboxylate Mononuclear Iron Center Forms the Active Site of a Paracoccus Dimethylformamidase

N,N‐dimethyl formamide (DMF) is an extensively used organic solvent but is also a potent pollutant. Certain bacterial species from genera such as Paracoccus, Pseudomonas, and Alcaligenes have evolved to use DMF as a sole carbon and nitrogen source for growth via degradation by a dimethylformamidase (DMFase). We show that DMFase from Paracoccus sp. strain DMF is a halophilic and thermostable enzyme comprising a multimeric complex of the α₂β₂ or (α₂β₂)₂ type. One of the three domains of the large subunit and the small subunit are hitherto undescribed protein folds of unknown evolutionary origin. The active site consists of a mononuclear iron coordinated by two Tyr side‐chain phenolates and one carboxylate from Glu. The Fe³⁺ ion in the active site catalyzes the hydrolytic cleavage of the amide bond in DMF. Kinetic characterization reveals that the enzyme shows cooperativity between subunits, and mutagenesis and structural data provide clues to the catalytic mechanism.     

Electronic Structure Modulation in an Exceptionally Stable Non‐Heme Nitrosyl Iron(II) Spin‐Crossover Complex

The highly stable nitrosyl iron(II) mononuclear complex [Fe(bztpen)(NO)](PF₆)₂ (bztpen=N‐benzyl‐N,N′,N′‐tris(2‐pyridylmethyl)ethylenediamine) displays an S=1/2?S=3/2 spin crossover (SCO) behavior (T_1/2=370 K, ΔH=12.48 kJ mol^?1, ΔS=33 J K^?1 mol^?1) stemming from strong magnetic coupling between the NO radical (S=1/2) and thermally interconverted (S=0?S=2) ferrous spin states. The crystal structure of this robust complex has been investigated in the temperature range 120–420 K affording a detailed picture of how the electronic distribution of the t_2g–e_g orbitals modulates the structure of the {FeNO}⁷ bond, providing valuable magneto–structural and spectroscopic correlations and DFT analysis.     

Chemical Synthesis of the 20 kDa Heme Protein Nitrophorin 4 by α‐Ketoacid‐Hydroxylamine (KAHA) Ligation

The chemical synthesis of the 184‐residue ferric heme‐binding protein nitrophorin 4 was accomplished by sequential couplings of five unprotected peptide segments using α‐ketoacid‐hydroxylamine (KAHA) ligation reactions. The fully assembled protein was folded to its native structure and coordinated to the ferric heme b cofactor. The synthetic holoprotein, despite four homoserine residues at the ligation sites, showed identical properties to the wild‐type protein in nitric oxide binding and nitrite dismutase reactivity. This work establishes the KAHA ligation as a valuable and viable approach for the chemical synthesis of proteins up to 20 kDa and demonstrates that it is well‐suited for the preparation of hydrophobic protein targets.     

Synthesis and structure of a µ‐oxo diiron(III) complex with an N‐pyridylmethyl‐N,N‐bis(4‐methylbenzimidazol‐2‐yl)amine ligand and its catalytic property for hydrocarbon oxidation

A µ‐oxo diiron(III) complex [{Fe(pbba)Cl}₂(µ‐O)]Cl₂ (1, pbba = N‐pyridylmethyl‐N,N‐bis(4‐methylbenzimidazol‐2‐yl)amine) bearing multi‐imidazolyl motifs was synthesized and characterized by X‐ray crystallography to closely mimic the structural features of methane monooxygenase. As shown by its X‐ray crystal structure, complex 1 is a centrosymmetric dimer with an Fe? O? Fe angle of 180° , and pseudo‐octahedral around each iron(III) center. The catalytic ability of title compound in the oxidation of alkane and alkene is investigated by employing tert‐butylhydroperoxide and m‐chloroperbenzoic acid as oxidants under mild conditions. The catalytic oxidation results showed that radical intermediate dominates the oxidation process. Copyright © 2008 John Wiley & Sons, Ltd.     

Characterization of Mononuclear Non‐heme Iron(III)‐Superoxo Complex with a Five‐Azole Ligand Set

Reaction of O₂ with a high‐spin mononuclear iron(II) complex supported by a five‐azole donor set yields the corresponding mononuclear non‐heme iron(III)–superoxo species, which was characterized by UV/Vis spectroscopy and resonance Raman spectroscopy. ¹H NMR analysis reveals diamagnetic nature of the superoxo complex arising from antiferromagnetic coupling between the spins on the low‐spin iron(III) and superoxide. This superoxo species reacts with H‐atom donating reagents to give a low‐spin iron(III)–hydroperoxo species showing characteristic UV/Vis, resonance Raman, and EPR spectra.     

Mononuclear Nonheme High‐Spin (S=2) versus Intermediate‐Spin (S=1) Iron(IV)–Oxo Complexes in Oxidation Reactions

Mononuclear nonheme high‐spin (S=2) iron(IV)–oxo species have been identified as the key intermediates responsible for the C?H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C?H bond activation of hydrocarbons by a synthetic mononuclear nonheme high‐spin (S=2) iron(IV)–oxo complex occurs through an oxygen non‐rebound mechanism, as previously demonstrated in the C?H bond activation by nonheme intermediate (S=1) iron(IV)–oxo complexes. We also report that C?H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high‐spin (HS) and intermediate‐spin (IS) iron(IV)–oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)–oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.     

Iron(II)‐Catalyzed Biomimetic Aerobic Oxidation of Alcohols

We report the first Fe^II‐catalyzed biomimetic aerobic oxidation of alcohols. The principle of this oxidation, which involves several electron‐transfer steps, is reminiscent of biological oxidation in the respiratory chain. The electron transfer from the alcohol to molecular oxygen occurs with the aid of three coupled catalytic redox systems, leading to a low‐energy pathway. An iron transfer‐hydrogenation complex was utilized as a substrate‐selective dehydrogenation catalyst, along with an electron‐rich quinone and an oxygen‐activating Co(salen)‐type complex as electron‐transfer mediators. Various primary and secondary alcohols were oxidized in air to the corresponding aldehydes or ketones with this method in good to excellent yields.     

Direct Catalytic Synthesis of Unprotected 2‐Amino‐1‐Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine

Aryl‐substituted amino alcohols are privileged scaffolds in medicinal chemistry and natural products. Herein, we report that an exceptionally simple and inexpensive Fe^II complex efficiently catalyzes the direct transformation of simple alkenes into unprotected amino alcohols in good yield and perfect regioselectivity. This new catalytic method was applied in the expedient synthesis of bioactive molecules and could be extended to aminoetherification.     

Pathway from N‐Alkylglycine to Alkylisonitrile Catalyzed by Iron(II) and 2‐Oxoglutarate‐Dependent Oxygenases

N‐alkylisonitrile, a precursor to isonitrile‐containing lipopeptides, is biosynthesized by decarboxylation‐assisted ‐N≡C group (isonitrile) formation by using N‐alkylglycine as the substrate. This reaction is catalyzed by iron(II) and 2‐oxoglutarate (Fe/2OG) dependent enzymes. Distinct from typical oxygenation or halogenation reactions catalyzed by this class of enzymes, installation of the isonitrile group represents a novel reaction type for Fe/2OG enzymes that involves a four‐electron oxidative process. Reported here is a plausible mechanism of three Fe/2OG enzymes, Sav607, ScoE and SfaA, which catalyze isonitrile formation. The X‐ray structures of iron‐loaded ScoE in complex with its substrate and the intermediate, along with biochemical and biophysical data reveal that ‐N≡C bond formation involves two cycles of Fe/2OG enzyme catalysis. The reaction starts with an Fe^IV‐oxo‐catalyzed hydroxylation. It is likely followed by decarboxylation‐assisted desaturation to complete isonitrile installation.     

TMEDA in Iron‐Catalyzed Hydromagnesiation: Formation of Iron(II)‐Alkyl Species for Controlled Reduction to Alkene‐Stabilized Iron(0)

N,N,N′,N′‐Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron catalysis, finding application in reactions as diverse as cross‐coupling, C?H activation, and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron‐catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular‐level insight into the role of TMEDA in achieving effective catalysis. The key is the initial formation of TMEDA–iron(II)–alkyl species which undergo a controlled reduction to selectively form catalytically active styrene‐stabilized iron(0)–alkyl complexes. While TMEDA is not bound to the catalytically active species, these active iron(0) complexes cannot be accessed in the absence of TMEDA. This mode of action, allowing for controlled reduction and access to iron(0) species, represents a new paradigm for the role of this important reaction additive in iron catalysis.     

Enantioselective Addition of a 2‐Alkoxycarbonyl‐1,3‐dithiane to Imines Catalyzed by a Bis(guanidino)iminophosphorane Organosuperbase

A chiral bis(guanidino)iminophosphorane catalyzes enantioselective addition reactions of a 1,3‐dithiane derivative as a pronucleophile. The chiral uncharged organosuperbase facilitates the addition of benzyloxycarbonyl‐1,3‐dithiane to aromatic N‐Boc‐protected imines to provide optically active α‐amino‐1,3‐dithiane derivatives, which are valuable versatile building blocks in organic synthesis.