Coupling Of Phenols Research Articles

Chiral vanadium complex-catalyzed oxidative coupling of arenols

This report describes the recent advances in the development of chiral vanadium complex-catalyzed oxidative couplings of phenols such as polycyclic phenols, hydroxycarbazoles, resorcinol, and sesamol derivatives. Catalysts containing a vanadium metal and multidentate ligand prepared from salicylaldehydes and chiral amino acids provide chemists with a powerful tool for the efficient synthesis of optically active, axially chiral compounds, which can be readily transformed into biologically active compounds and chiral ligands. • Recent advances in the development of chiral vanadium complex-catalyzed oxidative couplings of phenols. • Catalysts containing a vanadium metal and multidentate ligand prepared from salicylaldehydes and chiral amino acids. • Powerful tool for the efficient synthesis of optically active, axially chiral compounds.

Coupling without Coupling Reactions: En Route to Developing Phenols as Sustainable Coupling Partners via Dearomatization-Rearomatization Processes.

Transition-metal-catalyzed cross-coupling reactions represent one of the most straightforward and efficient protocols to assemble two different molecular motifs for the construction of carbon-carbon or carbon-heteroatom bonds. Because of their importance and wide applications in pharmaceuticals, agrochemicals, materials, etc., cross-coupling reactions have been well recognized in the 2010 Nobel Prize in chemistry. However, in the classical transition-metal-catalyzed cross-coupling reactions (e.g., the Suzuki-Miyaura, the Buchwald-Hartwig, and the Ullmann cross-coupling reactions), organohalides, which mainly stem from the nonrenewable fossil resources, are often utilized as coupling partners with halide wastes being generated after the reactions. To make cross-coupling reactions more sustainable, we initiated a general research program by employing phenols and cyclohexa(e)nones (the reduced forms of phenols) as pivotal feedstocks (coupling partners), instead of the commonly used fossil-derived organohalides, for cross-coupling reactions to build C-O, C-N, and C-C bonds. Phenols (cyclohexa(e)nones) are widely available and can be obtained from lignin biomass, highlighting their renewable and sustainable features. Moreover, water is expected to be the only stoichiometric byproduct, thus avoiding halide wastes.Notably, the cross-coupling reactions utilizing phenols/cyclohexa(e)nones are not based on the traditional transition-metal-catalyzed "oxidative-addition and reductive-elimination" mechanism, but via a novel "phenol-cyclohexanone" redox couple. This new working mechanism opens up new horizons of designing cross-coupling reactions via simple nucleophilic addition of cyclohexanones along with aromatization processes, thereby simplifying the design and avoiding laborious optimization of transition-metal precursors (e.g., Pd, Ni, Cu, etc.), as well as ligands in classical transition-metal-catalyzed cross-coupling reactions. Specifically, in this Account, we will summarize and discuss our related research work in the following three categories: "formal oxidative couplings of cyclohexa(e)nones", "formal reductive couplings of phenols", and "formal redox-neutral couplings of phenols". The successes of these research projects clearly demonstrated our initial inspirations and rational designs to develop cross-coupling reactions without the "conventional cross-coupling conditions" by pushing the reaction frontiers from initial cyclohexanones, ultimately, to the sustainable phenol targets.

Synthesis of Pummerer’s ketone and its analogs by iodosobenzene-promoted oxidative phenolic coupling

An intermolecular phenolic coupling promoted by iodosobenzene leading to Pummerer’s ketone and its analogs has been developed. The reaction allows for the preparation of products derived from both phenols and naphthols, bearing various substitution patterns, in excellent diasteroselectivity. The Pummerer’s ketone-type compounds form as sole low molecular weight products, which together with simple experimental conditions, makes the reaction a convenient entry to this important molecular motif.

Overexpression of polygalacturonase-inhibiting protein (PGIP) gene from Hypericum perforatum alters expression of multiple defense-related genes and modulates recalcitrance to Agrobacterium tumefaciens in tobacco

Hypericum perforatum L is a remarkable source of high-value secondary metabolites with increasing applications in pharmaceutical industry. However, improvement in the production of secondary metabolites through genetic engineering is a demanding task, as H. perforatum is not amenable to Agrobacterium tumefaciens-mediated transformation. In this study, we identified a Polygalacturonase-inhibiting protein (PGIP) gene from a subtractive cDNA library of A. tumefaciens-treated H. perforatum suspension cells. The role of HpPGIP in defense against A. tumefaciens was analyzed in transgenic Nicotiana tabacum overexpressing HpPGIP alone or fused at the N-terminus to Phenolic oxidative coupling protein (Hyp-1), a gene that positively modulates resistance to A. tumefaciens. Furthermore, virus-induced gene silencing was employed to knock down the expression of the PGIP homologous in N. benthamiana. Results showed that Agrobacterium-mediated expression efficiency greatly decreased in both HpPGIP and Hyp-1-PGIP transgenic plants, as assessed by GUS staining assays. However, silencing of PGIP in N. benthamiana increased the resistance to A. tumefaciens rather than susceptibility, which correlated with induction of pathogenesis-related proteins (PRs). The expression of core genes involved in several defense pathways was also analyzed in transgenic tobacco plants. Overexpression of HpPGIP led to up-regulation of key genes involved in hormone signaling, microRNA-based gene silencing, homeostasis of reactive oxygen species, and the phenylpropanoid pathway. Overexpression of Hyp-1-PGIP seemed to enhance the effect of PGIP on the expression of most genes analyzed. Moreover, HpPGIP was detected in the cytoplasm, nucleus and the plasma membrane or cell wall by confocal microscopy. Overall, our findings suggest HpPGIP modulates recalcitrance to A. tumefaciens-mediated transformation in H. perforatum.

Insight into multicopper oxidase laccase from Myrothecium verrucaria ITCC-8447: a case study using in silico and experimental analysis

The oxidation activity of multicopper-oxidases overlaps with different substrates of laccases and bilirubin oxidases, thus in the present study an integrated approach of bioinformatics using homology modeling, docking, and experimental validation was used to confirm the type of multicopper-oxidase in Myrothecium verrucaria ITCC-8447. The result of peptide sequence of M. verrucaria ITCC-8447 enabled to predict the 3 D-structure of multicopper-oxidase. It was overlapped with the structure of laccase and root mean square deviation (RMSD) was 1.53 Å for 533 and, 171 residues. The low binding energy with azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (-5.64) as compared to bilirubin (-4.39) suggested that M. verrucaria ITCC-8447 have laccase-like activity. The experimental analysis confirmed high activity with laccase specific substrates, phenol (18.3 U/L), ampyrone (172.4 U/L) and, ampyrone phenol coupling (50 U/L) as compared to bilirubin oxidase substrate bilirubin (16.6 U/L). In addition, lowest binding energy with ABTS (-5.64), syringaldazine SYZ (-4.83), guaiacol GCL (-4.42), and 2,6-dimethoxyphenol DMP (-4.41) confirmed the presence of laccase. Further, complete remediation of two hazardous model pollutants i.e., phenol and resorcinol (1.5 mM) after 12 h of incubation and low binding energy of −4.32 and, −4.85 respectively confirmed its removal by laccase. The results confirmed the presence of laccase in M. verrucaria ITCC-8447 and its effective bioremediation potential.

Solution NMR Studies of CYP121 of Mycobacterium tuberculosis; Evidence that Ligand Binding is Bi‐modal

Mycobacterium tuberculosis (Mtb) is the causative pathogen in the development of tuberculosis (TB). The rise of multi‐drug resistant forms of TB, combined with the fact that one third of the world’s population are carriers of latent TB, underscores the need for the development of novel anti‐TB agents. A current drug target is the cytochrome P450 (CYP) 121 of Mtb; an essential enzyme that mediates an unusual phenol coupling reaction of the dipeptide di‐cyclotyrosine (cYY). Our current understanding of atomic level active site/inhibitor interactions in CYP121 stems primarily from co‐crystallization of drug fragments or cYY with the enzyme. However, these studies result in protein structures that reflect the same unchanging conformation, thus resulting in a gap in our understanding of dynamic active site/ligand interactions that would otherwise help inform specificity in the design of novel CYP121 inhibitors.In this preliminary work, we’ve begun to address this gap by adapting CYP121 for analysis by solution NMR. The enzyme produces a well‐dispersed, resolvable 1H‐15N HSQC spectrum. We have acquired 2D spectra of the enzyme while bound to a variety of azoles representing a range of ligand sizes and chemistry. We report that, while ligands with a similar overall structure (econazole and miconazole) produce similar perturbations of the NMR spectra, other ligands with distinct overall structures (ketoconazole and fluconazole) produce chemical shift perturbations that are unexpectedly similar to each other, yet can be categorized separately from other ligand‐induced changes. These preliminary studies suggest that ligand binding in CYP121 is partially bi‐modal, indicative of a structure that retains a semi‐rigid backbone in solution. This work lays the foundation for understanding CYP121 dynamics that will be a critical component of future drug design of novel anti‐TB agents.Support or Funding InformationResearch supported by start‐up funds at SUNY BuffaloA backbone amide resonance of CYP121 in response to azole bindingFigure 1

A Fasciclin Protein Is Essential for Laccase-Mediated Selective Phenol Coupling in Sporandol Biosynthesis.

The biaryl scaffold, often showing axial chirality, is a common feature of various fungal natural products. Their biosynthesis requires an oxidative phenol-coupling reaction usually catalyzed by laccases, cytochrome P450 enzymes, or peroxidases. The combination of a laccase and a fasciclin domain-containing (fas) protein is encoded in many biosynthetic gene clusters of biaryls from ascomycetes. However, such phenol-coupling systems including their regio- and stereoselectivity have not been characterized so far. Elucidating the biosynthesis of the antiparasitic binaphthalene sporandol from Chrysosporium merdarium, we demonstrate the combination of a laccase and a fas protein to be crucial for the dimerization reaction. Only the heterologous coproduction of the laccase and the fas protein led to a functional phenol-coupling system, whereas the laccase alone showed no coupling activity. Thus, the laccase/fas protein combination forms an independent group of phenol-coupling enzymes that determines the coupling activity and selectivity of the reaction concurrently and applies to the biosynthesis of many fungal natural products with a biaryl scaffold.

Synthesis of a Bcl9 Alpha-Helix Mimetic for Inhibition of PPIs by a Combination of Electrooxidative Phenol Coupling and Pd-Catalyzed Cross Coupling

Teraryl-based alpha-helix mimetics have resulted in efficient inhibitors of protein-protein interactions (PPIs). Extending the concept to even longer oligoarene systems would allow for the mimicking of even larger interaction sites. We present a highly efficient synthetic modular access to quateraryl alpha-helix mimetics, in which, at first, two phenols undergo electrooxidative dehydrogenative cross-coupling. The resulting 4,4′-biphenol is then activated by conversion to nonaflates, which serve as leaving groups for iterative Pd-catalyzed Suzuki-cross-coupling reactions with suitably substituted pyridine boronic acids. This work, for the first time, demonstrates the synthetic efficiency of using both electroorganic as well as transition-metal catalyzed cross-coupling in the assembly of oligoarene structures.

Computational Biotransformation Profile of Emerging Phenolic Pollutants by Cytochromes P450: Phenol-Coupling Mechanism.

Phenols are ubiquitous environmental pollutants, whose biotransformation involving phenol coupling catalyzed by cytochromes P450 may produce more lipophilic and toxic metabolites. Density functional theory (DFT) computations were performed to explore the debated phenol-coupling mechanisms, taking triclosan as a model substrate. We find that a diradical pathway facilitated by compound I and protonated compound II of P450 is favored vs alternative radical addition or electron-transfer mechanisms. The identified diradical coupling resembles a "two-state reactivity" from compound I characterized by significantly high rebound barriers of the phenoxy radicals, which can be formulated into three equations for calculating the ratio [coupling]/[hydroxylation]. A higher barrier for rebound than for H-abstraction in high-spin triclosan can facilitate the phenoxy radical dissociation and thus enable phenol coupling, while H-abstraction/radical rebound causing phenol hydroxylation via minor rebound barriers mostly occurs via the low-spin state. Therefore, oxidation of triclosan by P450 fits the first equation with a ratio [coupling]/[hydroxylation] of 1:4, consistent with experimental data indicating different extents of triclosan coupling (6-40%). The high rebound barrier of phenoxy radicals, as a key for the mechanistic identification of phenol coupling vs hydroxylation, originates from their weak electron donor ability due to spin aromatic delocalization. We envision that the revealed mechanism can be extended to the cross-coupling reactions between different phenolic pollutants, and the coupling reactions of several other aromatic pollutants, to infer unknown metabolites.

Cross dehydrogenative C-O coupling catalysed by a catenane-coordinated copper(i).

Catalytic activity of copper(i) complexes supported by phenanthroline-containing catenane ligands towards a new C(sp3)–O dehydrogenative cross-coupling of phenols and bromodicarbonyls is reported. As the phenanthrolines are interlocked by the strong and flexible mechanical bond in the catenane, the active catalyst with an open copper coordination site can be revealed only transiently and the stable, coordinatively saturated Cu(i) pre-catalyst is quickly regenerated after substrate transformation. Compared with a control Cu(i) complex supported by non-interlocked phenanthrolines, the catenane-supported Cu(i) is highly efficient with a broad substrate scope, and can be applied in gram-scale transformations without a significant loss of the catalytic activity. This work demonstrates the advantages of the catenane ligands that provide a dynamic and responsive copper coordination sphere, highlighting the potential of the mechanical bond as a design element in transition metal catalyst development.

Microwave Irradiated Palladium-Catalyzed Cascade Type Cross Coupling of Phenols and Halides for the Synthesis of Polyphenolic Ethers

A mild, cascade type methodology was developed for the synthesis of polyphenolic ethers by the palladium-catalyzed cross coupling of phenols and halo compounds under microwave heating. In most cases, reactions run in neat conditions and in some cases, IPA/water mixture, and 1,4-dioxane were employed as solvents to furnish the products. By applying this new method, we were able to synthesize and purify a good number of polyether compounds with complete spectral data.

A one-pot protocol for the fluorosulfonation and Suzuki coupling of phenols and bromophenols, streamlined access to biaryls and terphenyls.

A one-pot protocol for the fluorosulfation and Suzuki coupling of phenols is described. The tandem reaction proceeds efficiently at room temperature, and various biaryls and biaryl fluorosulfates were obtained in good to excellent yields. Furthermore, biaryl fluorosulfates were utilized as versatile building blocks for the preparation of terphenyls.

Sulfoxide-mediated oxidative cross-coupling of phenols.

A metal-free, oxidative coupling of phenols with various nucleophiles, including arenes, 1,3-diketones and other phenols, is reported. Cross-coupling is mediated by a sulfoxide which inverts the reactivity of the phenol partner. Crucially, the process shows high selectivity for cross-versus homo-coupling and allows efficient access to a variety of aromatic scaffolds including biaryls, benzofurans and, through an iterative procedure, aromatic oligomers.

Scope and Mechanism of the Ruthenium-Catalyzed Dehydrative C–H Coupling of Phenols with α,β-Unsaturated Carbonyl Compounds: Expedient Synthesis of Chromene and Benzoxacyclic Derivatives

Chromene and benzoxacyclic derivatives were efficiently synthesized from the ruthenium-catalyzed dehydrative C–H coupling reaction of phenols with α,β-unsaturated carbonyl compounds. The cationic r...

Transgenic expression of Hyp-1 gene from Hypericum perforatum L. alters expression of defense-related genes and modulates recalcitrance to Agrobacterium tumefaciens.

Phenolic oxidative coupling protein (Hyp-1) isolated from Hypericum perforatum L. was characterized as a defense gene involved in H. perforatum recalcitrance to Agrobacterium tumefaciens-mediated transformation Hypericum perforatum L. is a reservoir of high-value secondary metabolites of increasing interest to researchers and to the pharmaceutical industry. However, improving their production via genetic manipulation is a challenging task, as H. perforatum is recalcitrant to Agrobacterium tumefaciens-mediated transformation. Here, phenolic oxidative coupling protein (Hyp-1), a pathogenesis-related (PR) class 10 family gene, was selected from a subtractive cDNA library from A. tumefaciens-treated H. perforatum suspension cells. The role of Hyp-1 in defense against A. tumefaciens was analyzed in transgenic Nicotiana tabacum and Lactuca sativa overexpressing Hyp-1, and in Catharanthus roseus silenced for its homologous Hyp-1 gene, CrIPR. Results showed that Agrobacterium-mediated expression efficiency greatly decreased in Hyp-1 transgenic plants. However, silencing of CrIPR induced CrPR-5 expression and decreased expression efficiency of Agrobacterium. The expression of core genes involved in several defense pathways was also analyzed in Hyp-1 transgenic tobacco plants. Overexpression of Hyp-1 led to an ample down-regulation of key genes involved in auxin signaling, microRNA-based gene silencing, detoxification of reactive oxygen species, phenylpropanoid pathway and PRs. Moreover, Hyp-1 was detected in the nucleus, plasma membrane and the cytoplasm of epidermal cells by confocal microscopy. Overall, our findings suggest Hyp-1 modulates recalcitrance to A. tumefaciens-mediated transformation in H. perforatum.

Dehydrogenative Anodic C-C Coupling of Phenols Bearing Electron-Withdrawing Groups.

We herein present a metal‐free, electrosynthetic method that enables the direct dehydrogenative coupling reactions of phenols carrying electron‐withdrawing groups for the first time. The reactions are easy to conduct and scalable, as they are carried out in undivided cells and obviate the necessity for additional supporting electrolyte. As such, this conversion is efficient, practical, and thereby environmentally friendly, as production of waste is minimized. The method features a broad substrate scope, and a variety of functional groups are tolerated, providing easy access to precursors for novel polydentate ligands and even heterocycles such as dibenzofurans.

Single- and multi-component chiral supraparticles as modular enantioselective catalysts

Nanoscale biological assemblies exemplified by exosomes, endosomes and capsids, play crucial roles in all living systems. Supraparticles (SP) from inorganic nanoparticles (NPs) replicate structural characteristics of these bioassemblies, but it is unknown whether they can mimic their biochemical functions. Here, we show that chiral ZnS NPs self-assemble into 70–100 nm SPs that display sub-nanoscale porosity associated with interstitial spaces between constituent NPs. Similarly to photosynthetic bacterial organelles, these SPs can serve as photocatalysts, enantioselectively converting L- or D-tyrosine (Tyr) into dityrosine (diTyr). Experimental data and molecular dynamic simulations indicate that the chiral bias of the photocatalytic reaction is associated with the chiral environment of interstitial spaces and preferential partitioning of enantiomers into SPs, which can be further enhanced by co-assembling ZnS with Au NPs. Besides replicating a specific function of biological nanoassemblies, these findings establish a path to enantioselective oxidative coupling of phenols for biomedical and other needs.

Copper-Catalyzed ortho-Selective Dearomative C–N Coupling of Simple Phenols with O-Benzoylhydroxylamines

A Cu-catalyzed dearomative amination of simple phenols with O-benzoylhydroxylamines (R′RN–OBz) to synthesize α-aminocyclohexa-2,4-dienones is reported. This intermolecular transformation occurs exc...

Diversity in Fungal Intermolecular Phenol Coupling of Polyketides: Regioselective Laccase-Based Systems.

Polyketides form a structurally diverse and pharmaceutically important class of secondary metabolites. Both diversity and biological activity are largely facilitated by post-polyketide synthase tailoring including methylation, oxidation, reduction, glycosylation, and dimerization. Cytochrome P450 enzymes (CYPs), flavin-dependent monooxygenases (FMOs), and laccases are known to catalyze phenol coupling in the biosynthesis of polyketide dimers. Polyketide homodimers resulting from enzyme catalysis are often formed in a highly regio- and stereoselective manner, in contrast to analogous nonenzymatic dimerization. Although it is known that CYPs and FMOs are capable of selectively generating one of several putative isomers, hitherto described laccases depend on auxiliary proteins to achieve similar selectivity. Herein, regioselective phenol coupling catalyzed by a fungal laccase is demonstrated. The heterologously produced Av-VirL from Aspergillus viridinutans selectively generated the 6,6'-homodimer of (R)-semivioxanthin. Genome analysis is used to show that laccase-based phenol-coupling systems are widespread in fungi. Homologues of Av-VirL were identified in the putative biosynthetic gene clusters of vioxanthin, xanthomegnin, and xanthoepocin, and of the perylenequinones hypocrellin A, elsinochrome A, and cercosporin. These findings show that laccases are capable of selective phenol coupling in the absence of auxiliary proteins.

Water Dispersible Red Fluorescent Carbon Nanoparticles via Carbonization of Resorcinol

Although fluorescent carbon nanoparticles have enormous biomedical application potential, the synthesis of high quality red fluorescent carbon nanoparticles is challenging. Here we report water dispersible, red fluorescent carbon nanoparticles of 10–25 nm hydrodynamic size with the fluorescence quantum yield of 25%. The approach involves controlled carbonization of resorcinol in ethylene glycol–Na3PO4 at 190 °C under air exposure. At this condition resorcinol undergoes oxidative phenol coupling associated with dehydration that leads to the nucleation of a π-conjugated 2D graphitic sheet followed by growth into a condensed graphitic core. The method is used to prepare 50–60 mg of particles in one batch and can be easily adapted for gram scale synthesis. The nanoparticles maintain good colloidal stability and fluorescence stability under physiological conditions, display concentration dependent and reversible transition between red to green fluorescence, and can be conjugated with primary amine terminated material by simple incubation. This nanoparticle can be used as a bioimaging probe via conversion into different colloidal nanobioconjugates.