Oxidative Coupling Of Phenols Research Articles

Bismuthanes as Hemilabile Donors in an O2 -Activating Palladium(0) Complex.

A xanthene-based bismuthane/phosphane chelating ligand has been accessed that has enabled the synthesis of a palladium(0) bismuthane complex. The bismuthane donor proved to be hemilabile as it switched to a dangling position upon addition of O2 that gave a palladium(II) peroxide complex. Unlike the corresponding 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) palladium peroxide, the bismuth analogue could be employed for catalytic phosphane oxidation and oxidative phenol coupling.

On the applicability of nanodiamonds produced by detonation synthesis for phenol testing in aqueous media

It was found that the catalytic effect of modified nanodiamonds (MND) in the H2O2–4-aminoantipyrine–phenol oxidative azo coupling reaction is due to microimpurities of iron and copper ions on the surface of nanoparticles. The efficiency of MND as a catalyst is determined by the amount of surface impurities of these ions and can be doubled by their additional adsorption on nanoparticles. Using MND for phenol indication ensures a linear yield of the colored product of the azo coupling reaction over an analyte concentration range of 0.05–10 μg/mL. The possibility of reusing MND for phenol testing in aqueous samples was demonstrated.

Bio-inspired oxidative phenolic coupling: Total synthesis of the diarylether heptanoid (±)-pterocarine

The diaryletherheptanoid natural product, pterocarine, is expeditiously synthesized using a bioinspired intramolecular oxidative phenolic coupling of acerogenin G. The cyclization precursor is prepared from a simple cinnamic acid derivative in three high yielding synthetic operations. The key oxidative coupling is inspired by biosynthetic hypotheses; however, the oxidative coupling proceeds with concomitant hydroxylation of the diphenyl ether motif.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Visible Light Copper Photoredox-Catalyzed Aerobic Oxidative Coupling of Phenols and Terminal Alkynes: Regioselective Synthesis of Functionalized Ketones via C≡C Triple Bond Cleavage.

Direct oxidative coupling of phenols and terminal alkynes was achieved at room temperature by a visible-light-mediated copper-catalyzed photoredox process. This method allows regioselective synthesis of hydroxyl-functionalized aryl and alkyl ketones from simple phenols and phenylacetylene via C≡C triple bond cleavage. 47 examples were presented. From a synthetic perspective, this protocol offers an efficient synthetic route for the preparation of pharmaceutical drugs, such as pitofenone and fenofibrate.

Solvent-controlled selective synthesis of biphenols and quinones via oxidative coupling of phenols.

A regioselective synthesis of unsymmetrical and symmetrical biphenols and binaphthols via oxidative coupling of phenols or naphthols in the presence of K2S2O8 in CF3COOH under ambient conditions is described. Interestingly, the 1 : 1 ratio of H2O and CH3CN solvent mixtures at 80 °C instead of CF3COOH provided substituted unsymmetrical quinones. A gram-scale synthesis of biphenols and binaphthols was demonstrated.

A concise synthetic approach to parvistemin A and (±)-diperezone

Concise syntheses of parvistemin A and diperezone are achieved using ring expansion of cyclobutenones and oxidative phenolic coupling under basic conditions.

Alternative Oxidase Gene Family in Hypericum perforatum L.: Characterization and Expression at the Post-germinative Phase.

Alternative oxidase (AOX) protein is located in the inner mitochondrial membrane and is encoded in the nuclear genome being involved in plant response upon a diversity of environmental stresses and also in normal plant growth and development. Here we report the characterization of the AOX gene family of Hypericum perforatum L. Two AOX genes were identified, both with a structure of four exons (HpAOX1, acc. KU674355 and HpAOX2, acc. KU674356). High variability was found at the N-terminal region of the protein coincident with the high variability identified at the mitochondrial transit peptide. In silico analysis of regulatory elements located at intronic regions identified putative sequences coding for miRNA precursors and trace elements of a transposon. Simple sequence repeats were also identified. Additionally, the mRNA levels for the HpAOX1 and HpAOX2, along with the ones for the HpGAPA (glyceraldehyde-3-phosphate dehydrogenase A subunit) and the HpCAT1 (catalase 1), were evaluated during the post-germinative development. Gene expression analysis was performed by RT-qPCR with accurate data normalization, pointing out HpHYP1 (chamba phenolic oxidative coupling protein 1) and HpH2A (histone 2A) as the most suitable reference genes (RGs) according to GeNorm algorithm. The HpAOX2 transcript demonstrated larger stability during the process with a slight down-regulation in its expression. Contrarily, HpAOX1 and HpGAPA (the corresponding protein is homolog to the chloroplast isoform involved in the photosynthetic carbon assimilation in other plant species) transcripts showed a marked increase, with a similar expression pattern between them, during the post-germinative development. On the other hand, the HpCAT1 (the corresponding protein is homolog to the major H2O2-scavenging enzyme in other plant species) transcripts showed an opposite behavior with a down-regulation during the process. In summary, our findings, although preliminary, highlight the importance to investigate in more detail the participation of AOX genes during the post-germinative development in H. perforatum, in order to explore their functional role in optimizing photosynthesis and in the control of reactive oxygen species (ROS) levels during the process.

Involucratusins A-H: Unusual Cadinane Dimers from Stahlianthus involucratus with Multidrug Resistance Reversal Activity.

Three novel cadinane dimers, involucratusins A–C (1–3), five unique nor-cadinane-dimers, involucratusins D–H (4–8), together with a known compound (9) were isolated from the rhizomes of Stahlianthus involucratus. Their challenging structures and absolute configurations were determined by spectroscopic data, CD experimentation, chemical conversions and single-crystal X-ray diffraction. Compounds 1–3 are unusual cadinane dimers with new connection and novel cores. Compound 4 is a unique nor-cadinane-dimer, and 5 and 6 are two pairs of hemiketal racemates with novel dinor-cadinane-dimer backbone. Compounds 7 and 8 represent unusual dodecanor-cadinane-dimer and tetradecanor-cadinane-dimer carbon skeletons, respectively. The possible biogenetic pathways of 1–8 were proposed, involving nucleophilic addition, SN2 nucleophilic displacement, [3 + 3] benzannulation, oxidative cleavage, decarboxylation, and oxidative phenol coupling reactions. Multidrug resistance (MDR) reversal activity assay of the isolates were evaluated in doxorubicin-resistant human breast cancer cells (MCF-7/DOX). The combined use of these novel cadinane dimers at a concentration of 10 μM increased the cytotoxicity of doxorubicin by 2.2–5.8-fold. It is the first report about the MDR reversal activity of cadinane dimers.

Comparative Transcriptome Reconstruction of Four Hypericum Species Focused on Hypericin Biosynthesis.

Next generation sequencing technology rapidly developed research applications in the field of plant functional genomics. Several Hypericum spp. with an aim to generate and enhance gene annotations especially for genes coding the enzymes supposedly included in biosynthesis of valuable bioactive compounds were analyzed. The first de novo transcriptome profiling of Hypericum annulatum Moris, H. tomentosum L., H. kalmianum L., and H. androsaemum L. leaves cultivated in vitro was accomplished. All four species with only limited genomic information were selected on the basis of differences in ability to synthesize hypericins and presence of dark nodules accumulating these metabolites with purpose to enrich genomic background of Hypericum spp. H. annulatum was chosen because of high number of the dark nodules and high content of hypericin. H. tomentosum leaves are typical for the presence of only 1–2 dark nodules localized in the apical part. Both H. kalmianum and H. androsaemum lack hypericin and have no dark nodules. Four separated datasets of the pair-end reads were gathered and used for de novo assembly by Trinity program. Assembled transcriptomes were annotated to the public databases Swiss-Prot and non-redundant protein database (NCBI-nr). Gene ontology analysis was performed. Differences of expression levels in the marginal tissues with dark nodules and inner part of leaves lacking these nodules indicate a potential genetic background for hypericin formation as the presumed site of hypericin biosynthesis is in the cells adjacent to these structures. Altogether 165 contigs in H. annulatum and 100 contigs in H. tomentosum were detected as significantly differentially expressed (P < 0.05) and upregulated in the leaf rim tissues containing the dark nodules. The new sequences homologous to octaketide synthase and enzymes catalyzing phenolic oxidative coupling reactions indispensable for hypericin biosynthesis were discovered. The presented transcriptomic sequence data will improve current knowledge about the selected Hypericum spp. with proposed relation to hypericin biosynthesis and will provide a useful resource of genomic information for consequential studies in the field of functional genomics, proteomics and metabolomics.

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64–70μM) for the MDA-MB-231 cell line after 24–48h of treatment, but they were more selective and much more potent (IC50 4–16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1–2μM), probably as the result of slow hydrolysis of their methyl ester functions.

5′-O-Methyldioncophylline D, a 7,8′-coupled naphthylisoquinoline alkaloid from callus cultures of Triphyophyllum peltatum, and its biosynthesis from a late-stage tetrahydroisoquinoline precursor

The natural tetrahydroisoquinoline phylline (4) was synthesized in a specifically [1,1′-13C2]-labeled form, and fed to callus cultures of Triphyophyllum peltatum. Its incorporation into naphthylisoquinoline alkaloids, among them habropetaline A (8) (as evidenced by 1H, 13C NMR, and 2D INADEQUATE experiments), proved 4 to be the authentic coupling substrate for the enzyme-mediated phenol-oxidative coupling with a naphthalene portion. During the feeding experiments, a new alkaloid was discovered, 5′-O-methyldioncophylline D (5). It is the first 7,8′-linked (d-type) naphthylisoquinoline isolated from a Dioncophyllaceae plant. The new alkaloid consists of two closely eluting, slowly interconverting atropo-diastereomers, (P)-5 and (M)-5. Their full absolute stereostructures were assigned, i.e., by spectroscopic and online HPLC-CD investigations.

Product formation from phenolic compounds removal by laccases: A review

Lignolytic enzymes are very promising tools for biotechnological applications in water treatment. Among them, laccases (EC 1.10.3.2: p-diphenol:dioxygen oxidoreductase) are versatile enzymes with the ability to oxidize a wide range of aromatic and non-aromatic compounds (polyphenols, aryl diamines, anilines, methoxy substituted phenols, organic/inorganic metal compounds, etc.). Laccases have confirmed their potential for the degradation of recalcitrant residual phenolic compounds in water. Typically, oxidation of a laccase substrate leads to the formation of free radical with the concomitant loss of one electron and reduction of molecular oxygen into water. The formed radicals can react via non-enzymatic reactions i.e. oxidative condensation, and oxidative phenolic coupling or oxidative coupling, leading to the formation of soluble or non-soluble reaction products, several of them of polymeric nature. As many studies have highlighted the generation of products potentially more toxic than the parent molecules with the use of tertiary treatments such as advanced oxidative processes (AOPs) applied in water treatment plans, the identification of reaction products generated by the degradation of phenolic contaminants in water by laccases, and their potential toxicity, have to be investigated. This review summarizes and discuss progress made this last decades in identification of products and their risk assessment regarding their potential toxicity for a list of the most studied recalcitrant phenolic pollutants in water, such as dyes, bisphenol A, triclosan, nonylphenol, natural and synthetic hormones, etc.

ChemInform Abstract: Bioinspired Syntheses of Dimeric Hydroxycinnamic Acids (Lignans) and Hybrids, Using Phenol Oxidative Coupling as Key Reaction, and Medicinal Significance Thereof

AbstractReview: 106 refs.

ChemInform Abstract: Oxidant‐Controlled Catalytic Transformations of Phenols with Unexpected Cleavage of Aromatic Rings.

AbstractA novel copper‐catalyzed oxidative coupling of electron rich phenols that involves the cleavage of a benzene ring is described to yield 3‐furanyl substituted benzofurans (III) and (V).

ChemInform Abstract: Metal‐Free [3 + 2] Oxidative Coupling of Phenols with Alkenes: Synthesis of Dihydrobenzofurans.

AbstractAn environmentally benign and metal‐free [3+2]‐cycloaddition of phenols and styrenes with sodium persulfate as an oxidant affords dihydrobenzofurans.

Enhanced tissue adhesiveness of injectable gelatin-based hydrogels using thiomer

Event Abstract Back to Event Enhanced tissue adhesiveness of injectable gelatin-based hydrogels using thiomer Thai Thanh Hoang Thi1, Yunki Lee1*, Kyung Min Park2 and Ki Dong Park1 1 Ajou University, Department of Molecular Science and Technology, Korea 2 Incheon National University, Division of Bioengineering, College of Life Sciences and Bioengineering, Korea Introduction: Tissue adhesives have received much attention as alternative materials to medical sutures and staples. Although they have been widely used for the wound closure and management, their adhesive strength and biocompatible properties are still need to be improved for variously clinical applications. Thiomers are promising candidates for adhesive improvement since thiol groups can react with cysteine-rich glycoproteins on tissue to form disulfide cross-linked networks[1]. We thus hypothesized that adhesive strength of 3-(4-hydroxy-phenyl)-propionic acid-gelatin (GH) hydrogels formed by horseradish peroxidase (HRP)-catalyzed oxidation can be improved with the addition of thiolated gelatin (GS). Furthermore, HRP not only catalyzes the oxidative coupling of phenols but also induces the disulfide formation in the presence of H2O2 or under aerobic condition[2]. This combination leads to form synergistic networks of phenol-phenol and disulfide bonds for increasing an intragel crosslink and extra gel-tissue interactions (Fig.1). Materials and Methods: GH was synthesized by coupling primary amine of gelatin with the carboxyl group of 3-(4-hydroxy-phenyl)-propionic acid using EDC/NHS chemistry[3]. To prepare thiolated gelatin, 1,4-dithio-DL-threitol was used to break SS-bond of cystamine-conjugated gelatin. The chemical structure of GH and GS were characterized by 1H NMR and FT-IR. The phenol content of GH and thiol content of GS were determined by UV-Vis spectroscopy and Ellman’s assay. The GH/GS hydrogels were fabricated using HRP/in the presence of H2O2. To explore the effect of thiol degree on hydrogel properties, the gelation time, elastic modulus, swelling behavior, degradation rate and adhesive strength were investigated as a function of GS concentration. In vitro cell studies were carried out using human dermal fibroblasts (hDFBs) on GH/GS hydrogel surfaces to test their cytotoxicity. Fig 1. Schematic representations of in situ forming GH/GS hydrogels with the possible mechanisms. Results and Discussions: GH and GS were synthesized successfully with the phenol content of 140 μmol/g and thiol content of 137 μmol/g. GH/GS gels were formed within 15 seconds to 5 minutes depending on GS and HRP concentration. Their elastic moduli were increased from 6.7 to 10.3 kPa following the increase of added GS concentration. The adhesive force of GH/GS (5/5 wt%) hydrogels (72.6 kPa) was 15.8 times higher than fibrin glue (4.6 kPa) and 6.5 times higher than GH only hydrogels (11.1 kPa) (Fig.2a) due to the disulfide formation between hydrogel and tissue, and the increase of inherently sticky gelatin content. Fluorescent images (Fig.2c) showed that GH/GS bioadhesives were non-cytotoxicity as compared to GH only hydrogels (Fig.2b). In addition, WST-1 results shown the GH/GS 5/2.5 and 5/5 wt% achieved 90 and 81 % cell proliferation as compared to GH only hydrogels that is an acceptable value for cytocompatible consideration. Fig 2. Adhesive force of GH/GS hydrogels as a function of GS concentration (a). Live/dead staining images of hDFBs cultured on GH (b) and GH/GS (c) hydrogels after 3d. Conclusions: In summary, GH/GS hydrogels exhibited fast gelation, tunable adhesion, excellent biocompatibility, showing a promising potential for use in a wide range of biomedical applications. Furthermore, disulfide bonds are the dynamic covalent interactions and sensitive to pH or redox potential that can be developed as a smart glue in our future study. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (2015R1A2A1A14027221)

Injectable Degradation-Resistant Hyaluronic Acid Hydrogels Cross-Linked via the Oxidative Coupling of Green Tea Catechin.

The oxidative coupling of phenols by horseradish peroxidase (HRP) is widely utilized to cross-link polymer-phenol conjugates for hydrogel formation. Phenols containing one aromatic ring are most commonly used, and the addition of hydrogen peroxide (H2O2) is an indispensable step in catalyzing the enzymatic reaction. We describe here a hydrogel composed of polyphenol as the cross-linking moiety. (-)-Epigallocatechin-3-gallate (EGCG), a green tea catechin, was conjugated to hyaluronic acid (HA) to form HA-EGCG conjugates. Addition of HRP to a solution of HA-EGCG conjugates at pH 7.4 induced gelation in 7 min. Notably, the addition of exogenous H2O2 was not required, as H2O2 was generated via EGCG autoxidation. Moreover, cross-linking between HA-EGCG conjugates occurred in situ through EGCG quinone formation, even when no HRP was added. This approach of forming hydrogels circumvented the safety concern associated with HRP due to its plant origin. Furthermore, the EGCG moieties endowed the hydrogels with resistance toward hyaluronidase-mediated degradation in vivo.

ChemInform Abstract: The Quest for an Oxidative Coupling of Phenols and Indoles Towards Benzofuroindolines: A Two‐Stage Approach

AbstractReview: [14 refs.

4′‐O‐Methylnorbelladine feeding enhances galanthamine and lycorine production by Leucojum aestivum L. shoot cultures

Galanthamine and lycorine are Amaryllidaceae alkaloids that exhibit a wide range of pharmacological activities. Organic synthesis and plant extraction are the two main commercial sources of galanthamine. Since total organic synthesis is low yielding and complex, and the harvesting of plant biomass is causing wild plant depletion, in vitro cultures offer an alternative approach. Amaryllidaceae alkaloids can be regarded as derivatives of the common precursor 4′‐O‐methylnorbelladine via intramolecular oxidative phenol coupling. The aim of this work was to enhance the biosynthetic pathway of these alkaloids using in vitro techniques. The precursor 4′‐O‐methylnorbelladine was incorporated into the liquid medium of Leucojum aestivum shoot cultures at different concentrations (0, 0.05, 0.1, or 0.2 g/L). The cultures were conducted for various periods of time (15, 30, and 40 days). After alkaloid extraction and according to LC‐ESI‐MS analysis, the precursor highly stimulated the biosynthesis of both galanthamine (0.5 mg/g dry weight [DW], V/S 0.01 mg/g DW in the control sample, i.e. without precursor) and lycorine (0.2 mg/g DW, V/S 0.04 mg/g DW in the control sample) after its biotransformation by the shoot cultures. The optimal culture conditions for the production of both alkaloids were 0.1 g/L of precursor and 15 days of culture.