Coupling Of Phenols Research Articles

Regioselective Oxidative Phenol Coupling by a Mushroom Unspecific Peroxygenase.

Bioactive dimeric (pre-)anthraquinones are ubiquitous in nature and are found in bacteria, fungi, insects, and plants. Their biosynthesis via oxidative phenol coupling (OPC) is catalyzed by cytochrome P450 enzymes, peroxidases, or laccases. While the biocatalysis of OPC in molds (Ascomycota) is well-known, the respective enzymes in mushroom-forming fungi (Basidiomycota) are unknown. Here, we report on the biosynthesis of the atropisomers phlegmacin A1 and B1 of the mushroom Cortinarius odorifer. The biosynthesis of these unsymmetrically 7,10'-homo-coupled dihydroanthracenones was heterologously reconstituted in the mold Aspergillus niger. Methylation of the parental monomer atrochrysone to its 6-O-methyl ether torosachrysone by the O-methyltransferase CoOMT1 precedes the regioselective homocoupling to phlegmacin, catalyzed by the enzyme CoUPO1 annotated as an "unspecific peroxygenase" (UPO). Our results reveal an unprecedented UPO reaction, thereby expanding the biocatalytic portfolio of oxidative phenol coupling beyond the commonly reported enzymes. The results show that Basidiomycota use peroxygenases to selectively couple aryls independently of and convergently to any other group of organisms, emphasizing the central role of OPC in natural processes.

Immobilization of laccase on mesoporous metal organic frameworks for efficient cross-coupling of ethyl ferulate.

Laccases act as green catalysts for oxidative cross-coupling of phenolic antioxidnt compounds, but low stability and non-recyclability limit its application. To address that, metal-organic frameworks Cu-BTC and Cr-MOF were synthesized as supports to immobilize the efficient laccase from Cerrena sp. HYB07. The Brunauer-Emmett-Teller surface area of Cu-BTC and Cr-MOF were 1213.2 and 907.1m2/g, respectively. The two carriers respectively presented pore diameters of 1.2-10nm and 1.4-12nm as octahedron, indicating nano-scale mesoporosity. These Cu-BTC and Cr-MOF carriers could adsorb laccase with enzyme loading of 1933.2 and 1564.4U/g carrier, respectively. The stability and organic solvent tolerance of Cu-BTC-laccase and Cr-MOF-laccase were both obviously improved compared to free laccase. Thermal inactivation kinetics showed that both the two immobilized laccases displayed lower thermal inactivation rate constants. Importantly, the Cu-BTC-laccase and Cr-MOF-laccase both showed much higher activity for cross-coupling of ethyl ferulate than free laccase, which had 2.5-fold higher cross-coupling efficiency than that by free laccase. The ethyl ferulate coupling product was also analyzed by mass spectroscopy and the synthesis pathway of ethyl ferulate dimer was proposed. The cross coupling of ethyl ferulate required the formation of radical intermediates of ethyl ferulate generated by laccase mediated oxidation. This work paved the way for MOFs immobilized laccase for cross coupling of antioxidant phenols.

Solvent-dependent reaction mechanisms in the electrooxidative coupling of phenols: insights by operando Raman spectroelectrochemistry.

The electrochemical oxidative phenol coupling reaction is a sustainable method for accessing biphenolic compounds. Using the dimerization of sesamol as a model reaction, insights into the reaction mechanism were gained via operando Raman spectroscopy. By varying the solvent and electrodes, different reaction mechanisms were identified and correlated with the respective product yields.

Advances in Exploring Mechanisms of Oxidative Phenolic Coupling Reactions

Biphenolic compounds serve as important scaffolds for the development of biologically active molecules. Among the methods for the synthesis of biarenols, oxidative coupling, which directly forms a C–C bond, has been extensively explored in various metal‐catalyzed (V, Cr, Co, Fe, Cu, etc.) reactions, electrochemical reactions, and photochemical reactions over the decades. While the exact mechanisms remain elusive in many cases, numerous mechanistic studies have provided valuable insights. This review focuses on the mechanistic details of the oxidative coupling of phenols or naphthols, involving at least one radical at least one radical intermediate. Additionally, the factors governing chemoselectivity (homo‐ and cross‐coupling), regioselectivity (ortho‐, meta‐ and para‐), and enantioselectivity (R and S configuration) are discussed, with a particular emphasis on intermediates and transition states, encompassing various oxidation sites for phenols and potential coupling sites.

Regioselektive Oxidative Phenolkupplung durch eine Unspezifische Peroxygenase aus Ständerpilzen

Regioselektive Oxidative Phenolkupplung durch eine Unspezifische Peroxygenase aus Ständerpilzen

Cell-free hemoglobin and hemin catalyzing triclosan oxidative coupling in plasma: A novel exogenous phenolic pollutants coupling pathway

Previous studies reported that hemoprotein CYP450 catalyzed triclosan coupling is an “uncommon” metabolic pathway that may enhance toxicity, raising concerns about its environmental and health impacts. Hemoglobin, a notable hemoprotein, can catalyze endogenous phenolic amino acid tyrosine coupling reactions. Our study explored the feasibility of these coupling reactions for exogenous phenolic pollutants in plasma. Both hemoglobin and hemin were found to catalyze triclosan coupling in the presence of H₂O₂. This resulted in the formation of five diTCS-2 H, two diTCS-Cl-3 H, and twelve triTCS-4 H in phosphate buffer, with a total of nineteen triclosan coupling products monitored using LC-QTOF. In plasma, five diTCS-2 H, two diTCS-Cl-3 H, and two triTCS-4 H were detected in hemoglobin-catalyzed reactions. Hemin showed a weaker catalytic effect on triclosan transformation compared to hemoglobin, likely due to hemin dimerization and oxidative degradation by H₂O₂, which limits its catalytic efficiency. Triclosan transformation in the human plasma-like medium still occurs with high H₂O₂, despite the presence of antioxidant proteins that typically inhibit such transformations. In plasma, free H₂O₂ was depleted within 40 minutes when 800 µM H₂O₂ was added, suggesting a rapid consumption of H₂O₂ in these reactions. Antioxidative species, or hemoglobin/hemin scavengers such as bovine serum albumin, may inhibit but not completely terminate the triclosan coupling reactions. Previous studies reported that diTCS-2 H showed higher hydrophobicity and greater endocrine-disrupting effects compared to triclosan, which further underscores the potential health risks. This study indicates that hemoglobin and heme in human plasma might significantly contribute to phenolic coupling reactions, potentially increasing health risks.

Synthesis of C2 symmetric hydroxylated biphenyls by microwave-assisted oxidative coupling of natural phenols

Phenolic compounds, abundant in various plants, exhibit a range of biological properties such as anti-inflammatory, antiseptic, and antioxidant activities. C2-symmetric biphenyl structures, present in many pharmacologically active substances, serve as fundamental backbones in many natural products, highlighting the significance of these compounds. This study introduces innovative microwave-assisted oxidative coupling methods for the synthesis of C2 hydroxylated biphenyls starting from thirteen natural phenols, focusing on eco-friendliness and efficiency. This approach aims to minimize environmental impact while emphasizing safety and sustainability by employing microwaves in environmentally sustainable solvents like water. The proposed mechanisms for the oxidative coupling of phenols include various possible reaction pathways, encompassing both homo and hetero radical-radical couplings.

Discovery and Biosynthesis of Cihanmycins Reveal Cytochrome P450-Catalyzed Intramolecular C–O Phenol Coupling Reactions

Discovery and Biosynthesis of Cihanmycins Reveal Cytochrome P450-Catalyzed Intramolecular C–O Phenol Coupling Reactions

Nickel-photoredox-catalyzed E- and Z-stereoconvergent coupling of alkenyl halides and phenols

Abstract Herein, we report a Ni-photoredox-catalyzed stereoconvergent coupling of phenols and alkenyl halides, which affords a Z-coupling product. Moreover, by simply changing the solvent, the reaction also provides access to the E-coupling product with high stereoselectivity. The key factor for changing the stereoisomer of the product was found to be the fluorescence lifetime of photocatalyst.

Solar‐Light‐Driven Photocatalytic Oxidative Coupling of Phenol Derivatives over Bismuth‐Based Porous Metal Halide Perovskites

AbstractThe selective oxidative coupling of phenol derivatives, involving carbon‐carbon (C−C) and carbon‐oxygen (C−O) bond formation, has emerged as a critical approach in the synthesis of natural products. However, achieving precise control over the selectivity in coupling reactions of unsubstituted phenols utilizing solar light as the driving force remains a big challenge. In this study, we report a series of porous Cs3Bi2X9 (X=Cl, Br, I) photocatalysts with tailored band gaps and compositions engineered for efficient solar‐light‐driven oxidative phenol coupling. Notably, p‐Cs3Bi2Br9 exhibited about 73 % selectivity for C−C coupling, displaying a high formation rate of 47.3 μmol gcat−1 h−1 under solar radiation. Furthermore, this approach enables control of the site‐selectivity for phenol derivatives on Cs3Bi2X9, enhancing C−C coupling. The distinctive porous structure and appropriate band‐edge positions of Cs3Bi2Br9 facilitated efficient charge separation, and surface interaction/activation of phenolic hydroxyl groups, resulting in the kinetically preferred formation of C−C over C−O bond. Mechanistic insights into the reaction pathway, supported by comprehensive control experiments, unveiled the crucial role of interfacial charge transfers and Lewis acid Bi sites in stabilizing phenolic intermediates, thereby directing the regioselectivity of diradical couplings and resulting in the formation of unsymmetrical biphenols.

Solar-Light-Driven Photocatalytic Oxidative Coupling of Phenol Derivatives over Bismuth-Based Porous Metal Halide Perovskites.

The selective oxidative coupling of phenol derivatives, involving carbon-carbon (C-C) and carbon-oxygen (C-O) bond formation, has emerged as a critical approach in the synthesis of natural products. However, achieving precise control over the selectivity in coupling reactions of unsubstituted phenols utilizing solar light as the driving force remains a big challenge. In this study, we report a series of porous Cs3Bi2X9 (X=Cl, Br, I) photocatalysts with tailored band gaps and compositions engineered for efficient solar-light-driven oxidative phenol coupling. Notably, p-Cs3Bi2Br9 exhibited about 73 % selectivity for C-C coupling, displaying a high formation rate of 47.3 μmol gcat -1 h-1 under solar radiation. Furthermore, this approach enables control of the site-selectivity for phenol derivatives on Cs3Bi2X9, enhancing C-C coupling. The distinctive porous structure and appropriate band-edge positions of Cs3Bi2Br9 facilitated efficient charge separation, and surface interaction/activation of phenolic hydroxyl groups, resulting in the kinetically preferred formation of C-C over C-O bond. Mechanistic insights into the reaction pathway, supported by comprehensive control experiments, unveiled the crucial role of interfacial charge transfers and Lewis acid Bi sites in stabilizing phenolic intermediates, thereby directing the regioselectivity of diradical couplings and resulting in the formation of unsymmetrical biphenols.

Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots.

Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.

Diazo Quinone: An Effective Phenolic Precursor for Building C(sp2)−C(sp2) Bonds

AbstractPhenolic biaryl and styryl moieties are important structural motifs in natural products, pharmaceuticals, and functional materials. Traditional cross‐coupling often requires pre‐functional substrates and is accompanied by generation of organometallic by‐products. In recent years, diazo quinone has become a new type of high‐efficiency phenolic coupling reagent for the preparation of phenolic biaryl and styryl compounds. This is because it can be used to construct C(sp2)−C(sp2) bonds in an environment‐friendly (transition‐metal‐free) or more direct way. In this review, we focus on recent advances in the field of transition‐metal‐free cross‐coupling reactions of diazo quinones with organoboranes and transition‐metal catalyzed quinoid carbene C(sp2)−H arylation reactions.

Racemic total synthesis of oxomaritidine by iodobenzene-catalyzed oxidative phenolic coupling under mild reaction conditions

A hypervalent iodine-catalyzed phenolic coupling reaction of norbelladine derivatives was examined with a catalytic amount of iodobenzene and meta-chloroperbenzoic acid as the terminal oxidant. The addition of acetic acid dramatically accelerated the reaction rate even at room temperature, and the cyclized products were successfully obtained under mild reaction conditions. The methods were applicable to the racemic total synthesis of oxomaritidine.

β-Cyclodextrin-stabilized Cu nanoparticles catalyzed C–O coupling to access 2-aryloxypyridines

β-Cyclodextrin-stabilized Cu nanoparticles were prepared from CuSO4⋅5H2O using sodium hydroxymethanesulfinate (rongalite) as the reducing agent and β-cyclodextrin as the stabilizing agent. This nanocatalyst showed good catalytic activities in the C–O coupling of phenols with 2-bromopyridine providing 2-aryloxypyridines in moderate to good yields. The catalyst can be recovered and reused five times with slight decrease in its activity.

Characterization of two CYP80 enzymes provides insights into aporphine alkaloid skeleton formation in Aristolochia contorta.

Aporphine alkaloids are a large group of natural compounds with extensive pharmaceutical application prospects. The biosynthesis of aporphine alkaloids has been paid attentions in the past decades. Here, we determined the contents of four 1-benzylisoquinoline alkaloids and five aporphine alkaloids in root, stem, leaf, and flower of Aristolochia contorta Bunge, which belongs to magnoliids. Two CYP80 enzymes were identified and characterized from A. contorta. Both of them catalyze the unusual C-C phenol coupling reactions and directly form the aporphine alkaloid skeleton. AcCYP80G7 catalyzed the formation of hexacyclic aporphine corytuberine. AcCYP80Q8 catalyzed the formation of pentacyclic proaporphine glaziovine. Kingdom-wide phylogenetic analysis of the CYP80 family suggested that CYP80 first appeared in Nymphaeales. The functional divergence of hydroxylation and C-C (or C-O) phenol coupling preceded the divergence of magnoliids and eudicots. Probable crucial residues of AcCYP80Q8 were selected through sequence alignment and molecular docking. Site-directed mutagenesis revealed two crucial residues E284 and Y106 for the catalytic reaction. Identification and characterization of two aporphine skeleton-forming enzymes provide insights into the biosynthesis of aporphine alkaloids.

Recent advances in oxidative phenol coupling for the total synthesis of natural products.

Covering: 2008 to 2023This review will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C-C and C-O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, etc.) will be surveyed. Future directions of this particular area of research will also be assessed.

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Synthetic Studies of Hasubanan Alkaloids Based on Oxidative Phenolic Coupling and Intramolecular Aza-Michael Reaction

Enzyme-mediated and formaldehyde-free formation of phenolic resin coatings

Coatings from phenolic resins are utilized in a wide range of applications and remain a crucial type of thermosetting polymers. Curing at high temperatures and the utilization of formaldehyde, however, are ever more pressing concerns. In this work, a novel approach towards phenolic resin coatings is presented. The rationale follows the concept of Enzyme-Mediated Addressing, a technique for controlled formation of coatings and structures via immobilized enzymes. Employment of Horseradish Peroxidase leads to radical induced coupling of phenol to cross-linked polymers. This well-known polymerization technique is now performed at close proximity to the support surface. Action of the enzyme is shown to lead to formation of nanoparticles from poly phenolic material and their subsequent deposition on the surface. First, important reaction parameters are investigated. From this, largely coalesced films are gained at the ideal reaction conditions. Additionally, some insight into possible process mechanisms is provided. Finally, site-specific coatings are shown to be accessible with this method as well. Due to the applied enzymatic process, formaldehyde-free cross-linking at low temperatures is achieved.

Proposal for the classification of sinomenine alkaloids

The chemical structure of sinoacutine is formed by a phenanthrene nucleus and an ethylamine bridge. Because it has a similar parent structure to morphine, it is subdivided into morphinane. At present, all reports have pointed out that the basic skeleton of morphine alkaloids is salutaridine (the isomer of sinoacutine), which is generated by the phenol coupling reaction of (R)-reticuline. This study shows that the biosynthetic precursors of sinoacutine and salutaridine are different. In this paper, the sinoacutine synthetase (SinSyn) gene was cloned from Sinomenium acutum and expressed SinSyn protein. Sinoacutine was produced by SinSyn catalyzed (S)-reticuline, according to the results of enzyme-catalyzed experiments. The optical activity, nuclear magnetic resonance, and mass spectrum of sinoacutine and salutaridine were analyzed. The classification and pharmacological action of isoquinoline alkaloids were discussed. It was suggested that sinoacutine should be separated from morphinane and classified as sinomenine alkaloids.