LongLarf

Catalytic decomposition of H₂O₂ by an iron catalyst is shown to via a Fe(III)OOH intermediate. Surprisingly the expected homolysis of the O−O bound to yield Fe(IV)=O species does not occur significantly and oxidation products are due to radical chain reactions.

Abstract

The catalytic disproportionation of by non-heme Fe(II) complexes of H₂O₂ the ligand N4Py (1,1-bis(pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine) and the formation and reactivity of Fe(III)-OOH and Fe(IV)=O species is studied by UV/Vis absorption, NIR luminescence, (resonance) Raman and headspace Raman spectroscopy, ¹O₂ trapping and DFT methods. Earlier DFT studies indicated that disproportionation of H₂O₂ catalysed by Fe(II)-N4Py complexes produce only ³O₂, however, only the low-spin state pathway was considered. In the present study, DFT calculations predict two pathways for the reaction between Fe(III)-OOH and H₂O₂, both of which yield ³O₂/H₂O₂ and involve either the S=1/2 or the S=3/2 spin state, with the latter being spin forbidden. The driving force for both pathways are similar, however, a minimal energy crossing point (MECP) provides a route for the formally spin forbidden reaction. The energy gap between the reaction intermediate and the MECP is lower than the barrier across the non-adiabatic channel. The formation of ³O₂ only is confirmed experimentally in the present study through ¹O₂ trapping and NIR luminescence spectroscopy. However, attempts to use the ¹O₂ probe ( α ${\alpha }$ -terpinene) resulted in initiation of auto-oxidation rather than formation of the expected endoperoxide, which indicated formation of OH radicals from Fe(III)-OOH, e. g., through O−O bond homolysis together with saturation of methanol with ³O₂. Microkinetic modelling of spectroscopic data using rate constants determined earlier, reveal that there is another pathway for Fe(III)-OOH decomposition in addition to competition between the reaction of Fe(III)-OOH with H₂O₂ and homolysis to form Fe(IV)=O and hydroxyl radical. Notably, after all H₂O₂ is consumed the decay of the Fe(III)-OOH species is predominantly through a second order self reaction (with Fe(III)-OOH). The conclusion reached is that the rate of O−O bond homolysis in the Fe(III)-OOH species to form Fe(IV)=O and an hydroxyl radical is too low to be responsible for the observed oxidation of organic substrates.

Publication date: 14 March 2024

Source: Chem, Volume 10, Issue 3

Author(s): Bethany M. DeMuynck, Lumin Zhang, Emma K. Ralph, David A. Nagib

Nature Chemistry, Published online: 13 February 2024; doi:10.1038/s41557-023-01435-3

The use of biocatalysis to support early-stage drug discovery campaigns remains largely untapped. Here, engineered biocatalysts enable the synthesis of sp3-rich polycyclic compounds through an intramolecular cyclopropanation of benzothiophenes, affording a class of complex scaffolds potentially useful for fragment-based drug discovery campaigns.

The single component flavin-dependent halogenase AetF halogenates a range of 1,1-disubstituted styrenes, often with high stereoselectivity, and AetF and homologues of this enzyme also halogenate terminal alkynes. These findings expand the scope of FDH catalysis, and mutagenesis studies and deuterium kinetic isotope effects provide insight into the unique utility of single component FDHs for biocatalysis.

Abstract

Single component flavin-dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C−H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1′-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.

The ancient art of arranging diatoms (very small algae) under the microscope with a single hair is connected on the Cover picture with the research reported in this Communication (e202318210). The diatoms make up the formula of the disbiradical reported in the study and its characteristic three-line EPR signal. The milky way in the background represents the through-space interaction delivering the explanation for the peculiar EPR signal pattern. (Design and idea: Jan Rosenboom).

A novel promiscuous activity of the phenolic acid decarboxylase from Bacillus subtilis and other CO₂-binding enzymes is described. The enzymes catalyze the photocatalytic CO₂ reduction in the presence of a Ru(bpy)₃ photosensitizer, exhibiting high selectivity for CO₂ reduction over proton reduction (up to 93 %). Remarkably, BsPAD itself does not require an additional metal cofactor for this catalysis.

Abstract

Novel concepts to utilize carbon dioxide are required to reach a circular carbon economy and minimize environmental issues. To achieve these goals, photo-, electro-, thermal-, and biocatalysis are key tools to realize this, preferentially in aqueous solutions. Nevertheless, catalytic systems that operate efficiently in water are scarce. Here, we present a general strategy for the identification of enzymes suitable for CO₂ reduction based on structural analysis for potential carbon dioxide binding sites and subsequent mutations. We discovered that the phenolic acid decarboxylase from Bacillus subtilis (BsPAD) promotes the aqueous photocatalytic CO₂ reduction selectively to carbon monoxide in the presence of a ruthenium photosensitizer and sodium ascorbate. With engineered variants of BsPAD, TONs of up to 978 and selectivities of up to 93 % (favoring the desired CO over H₂ generation) were achieved. Mutating the active site region of BsPAD further improved turnover numbers for CO generation. This also revealed that electron transfer is rate-limiting and occurs via multistep tunneling. The generality of this approach was proven by using eight other enzymes, all showing the desired activity underlining that a range of proteins is capable of photocatalytic CO₂ reduction.

The high potential energy of aryne intermediates can induce reactions that proceed through unorthodox mechanisms. Herein we report the aryne-promoted formation of various helical dibenzochalcophenes from phosphine chalcogenides. Based on DFT computations we propose a mechanism to account for the final C−C bond formation that involves a rare, concerted ligand-coupling event within a hypervalent σ-phosphorane.

Abstract

Arynes are fleeting, high-energy intermediates that undergo myriad trapping reactions by nucleophiles. Their unusual reactivity compared to other electrophiles can spur unexpected mechanistic pathways enroute to the formation of benzenoid products. Herein we explore a particularly unique case of thermally generated arynes reacting with phosphoranes to form helical dibenzothiophenes and -selenophenes. Multiple new helical polycyclic aromatic products are reported. DP4+ and X-ray crystallographic analysis were used in tandem to confirm the structural topologies of selected products and to demonstrate the utility of DP4+ for distinguishing between isomeric polycyclic aromatic compounds. Lastly, we discuss a plausible mechanism consistent with DFT computations that accounts for the product formation; namely, ligand coupling (i.e., reductive elimination) within a hypervalent, pentacarbon-ligated σ-phosphorane furnishes the dibenzothio- or dibenzoselenophene.

The transformation of alkenes into thianthrene-derived cationic electrophiles unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles.

Abstract

Oxidative alkene functionalization reactions are a fundamental class of complexity-building organic transformations. However, the majority of established approaches rely on electrophilic reagents that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene-derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene-derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible.

In this report, we established a method that replicates a hydrophobic environment akin to that of the endoplasmic reticulum, leading to effective suppression in dead-end products and acceleration of reaction rates through high thiolate concentrations for the oxidative folding of cysteine-rich peptides and microproteins.

Abstract

Disulfides in peptides and proteins are essential for maintaining a properly folded structure. Their oxidative folding is invariably performed in an aqueous-buffered solution. However, this process is often slow and can lead to misfolded products. Here, we report a novel concept and strategy that is bio-inspired to mimic protein disulfide isomerase (PDI) by accelerating disulfide exchange rates many thousand-fold. The proposed strategy termed organic oxidative folding is performed under organic solvents to yield correctly folded cysteine-rich microproteins instantaneously without observable misfolded or dead-end products. Compared to conventional aqueous oxidative folding strategies, enormously large rate accelerations up to 113,200-fold were observed. The feasibility and generality of the organic oxidative folding strategy was successfully demonstrated on 15 cysteine-rich microproteins of different hydrophobicity, lengths (14 to 58 residues), and numbers of disulfides (2 to 5 disulfides), producing the native products in a second and in high yield.

The butterfly metamorphosis Within the cocoon's shell (aryl methyl ethers) is encased a secret beauty (phenols), how to liberate it? In their Review (e202317257), Bert U. W. Maes, and Bert F. Sels et al. comprehensively summarize the advancements and perspectives of lignin O-demethylation (metamorphosis). The presence of methoxy groups (cocoon) limits the chemical reactivity and the applicability of lignin-derived compounds. Through O-demethylation (metamorphosis), the reborn product (butterfly) rich in phenolic functionality can start a versatile new life with broader applications.

Antimicrobial resistance is an urgent global public health problem that has made the search for new antibiotics essential. Ribosomally synthesized and post-translationally modified peptides are a promising new class of antibiotics and in this work, we report site-selective modification of their dehydroamino acids by β-amination in order to increase water solubility: the singly modified thiopeptide Thiostrepton showed an increase up to 35-fold and minimum inhibitory concentration tests demonstrated that the antimicrobial activity was still good, albeit lower than the natural peptide.

Abstract

We report the efficient and site selective modification of non-canonical dehydroamino acids in ribosomally synthesized and post-transationally modified peptides (RiPPs) by β-amination. The singly modified thiopeptide Thiostrepton showed an up to 35-fold increase in water solubility, and minimum inhibitory concentration (MIC) assays showed that antimicrobial activity remained good, albeit lower than the unmodified peptide. Also the lanthipeptide nisin could be modified using this method.

The single component flavin-dependent halogenase AetF halogenates a range of 1,1-disubstituted styrenes, often with high stereoselectivity, and AetF and homologues of this enzyme also halogenate terminal alkynes. These findings expand the scope of FDH catalysis, and mutagenesis studies and deuterium kinetic isotope effects provide insight into the unique utility of single component FDHs for biocatalysis.

Abstract

Single component flavin-dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C−H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1′-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.