Diaryl Ether Bonds Research Articles

Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids

The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5‐7 steps. The gram‐scale synthesis of various well‐designed enantiopure benzylisoquinoline monomers was accomplished via an enzymatic stereoselective Pictet–Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalizations in a sequential one‐pot process. A modified intermolecular copper‐mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head‐to‐tail or tail‐to‐tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron‐rich diaryl ether bond, and subsequent intramolecular Suzuki–Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent‐isogranjine, tetrandrine and O‐methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.

Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids.

The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5-7 steps. The gram-scale synthesis of various well-designed enantiopure benzylisoquinoline monomers was accomplished through an enzymatic stereoselective Pictet-Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalization in a sequential one-pot process. A modified intermolecular copper-mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head-to-tail or tail-to-tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron-rich diaryl ether bond, and subsequent intramolecular Suzuki-Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent-isogranjine, tetrandrine and O-methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.

Herringbone Helical Foldamers from Aromatic Ether Derived ϵ-Amino Acid Peptides.

Oligomers based on an aromatic ether derived ϵ-amino acid peptides folded into herringbone helical structures, induced by successive NH-O-NH & O-NH-O bifurcated hydrogen bonding interactions and reinforced by π-π stacking between aryls from adjacent layers. The diaryl ether bonds -O- worked both as structural units to provide turn motifs for changing the amplitude of the slope along the axis of helix for herringbone formation, and also as acceptors for hydrogen bonding. Attachment of a single chiral carbon to the C-termini of the peptides induced excess of single-handed screw sense and amplification through the chain propagation as exemplified by chain length dependent circular dichroism (CD) investigations.

Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin biodegradation by extracellular lignin-modifying enzymes from ligninolytic fungus

Ligninolytic fungi secrete extracellular lignin-modifying enzymes (LME) that degrade plant polymers for fungal nutrition but that are, because of their broad substrate specificity, also applicable for the degradation of many hazardous pollutants. Laccase is one of the most well characterized LME and is involved in the removal and degradation of recalcitrant aromatic compounds with or without the assistance of laccase-mediators. The Ligninolytic fungus Rigidoporus sp. FMD21 can degrade 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) with a half-life of 6.2 days. Using Rigidoporus sp. FMD21 crude extracellular enzyme extract (ExE) that mainly consisted of laccase, 77.4% of 2,3,7,8-TCDD was degraded within 36 days. The degradation rate did not depend on the 2,3,7,8-TCDD concentration in the tested range between 0.005 and 0.5 pgTEQ/μL. 2,3,7,8-TCDD was analysed by DR-CALUX® bioassay and the degradation was confirmed by GC-HRMS. In this study, we found evidence for cleavage of the diaryl ether bond in the 2,3,7,8-TCDD molecule and here we propose a new degradation mechanism in which 3,4-dichlorophenol is the main metabolite of 2,3,7,8-TCDD degradation by FMD21’s ExE. Six laccase-mediators were tested. Three of them 1-hydroxybenzotriazole (HBT), syringaldehyde (Syr) and violuric acid (Vio) showed an equipotent added effect on 2,3,7,8-TCDD degradation by ExE, however only in case of Vio a level of significance was reached. The others showed no effect or negatively impacted degradation. In conclusion, we have shown that Rigidoporus sp. FMD21 produces extracellular enzymes, mainly laccases that apparently are able to degrade the highly recalcitrant and most toxic 2,3,7,8-congener of TCDD via diaryl bond cleavage into 3,4-dichlorophenol.

Synthesis of an Ellagitannin Component, the Macaranoyl Group with a Tetra-ortho-Substituted Diaryl Ether Structure.

Herein, a practical synthesis of the macaranoyl group contained in ellagitannins, i.e., a C-O digallate structure with a tetra-ortho-substituted diaryl ether bond, is described. The methodology involved an oxa-Michael addition/elimination reaction between a brominated ortho-quinone monoketal and a phenol with a hexahydroxydiphenoyl moiety in the presence of 18-crown-6 under dark conditions, followed by reductive aromatization. The existence of rotamers originating from the constructed ether moiety is discussed as well.

Cover Feature: Mechanistic Study of Diaryl Ether Bond Cleavage during Palladium‐Catalyzed Lignin Hydrogenolysis (ChemSusChem 17/2020)

Cover Feature: Mechanistic Study of Diaryl Ether Bond Cleavage during Palladium‐Catalyzed Lignin Hydrogenolysis (ChemSusChem 17/2020)

Mechanistic Study of Diaryl Ether Bond Cleavage during Palladium-Catalyzed Lignin Hydrogenolysis.

Hydrogenolysis has emerged as one of the most effective means of converting polymeric lignin into monoaromatic fragments of value. Reported yields may be higher than for other methods and can exceed the theoretical yields estimated from measures of the content of lignin's most readily cleaved alkyl-aryl ether bonds in β-ether units. The high yields suggest that other units in lignin are being cleaved. Diaryl ether units are important units in lignin, and their cleavage has been examined previously using simple model compounds, such as diphenyl ether. Herein, the hydrogenolysis of model compounds that closely resemble the native lignin 4-O-5 diaryl ether units was analyzed. The results provided unexpected insights into the reactivity and partial cleavage of these compounds. The models and lignin polymer produced not only monomers, but also unusual 1,3,5-meta-substituted aromatics that appear to be diagnostic for the presence and the cleavage of the 4-O-5 diaryl ether unit in lignin.

Formal Cross-Coupling of Diaryl Ethers with Ammonia by Dual C(Ar)–O Bond Cleavages

The conversion of renewable resources and inexpensive inorganic chemicals directly into higher value-added organic chemicals is becoming more and more important for our society’s future sustainable development. Lignin, being the second most abundant organic carbon renewable resource on Earth, has been treated as waste in the pulp and paper industry. The 4-O-5 linkage diaryl ether bond is the strongest among the three types of ether linkages in lignins. Selective cleavage of this linkage can potentially generate smaller processable bio-based aromatic polymeric materials and compounds. Furthermore, there has been a long synthetic interest in coupling reactions with aryl ethers via C(Ar)–O bond cleavage, for example, for polyphenylene oxide (PPO) waste recycling. On the other hand, ammonia is a very inexpensive industrial inorganic chemical. Herein, we report a direct conversion of diaryl ethers and ammonia into aniline derivatives and arenes, providing a model for selective lignin 4-O-5 linkage modification...

Cloning and sequencing of the gene encoding the enzyme for the reductive cleavage of diaryl ether bonds of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Geobacillus thermodenitrificans UZO 3

We have previously reported that a cell-free extract prepared from Geobacillus thermodenitrificans UZO 3 reductively cleaves diaryl ether bonds of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), a dioxin with the highest toxicity, in a sequential fashion producing 3',4',4,5-tetrachloro-2-hydroxydiphenyl ether (TCDE) as the intermediate, and 3,4-dichlorophenol (DCP) as the final reaction product. The detection of TCDE implicated the discovery of an unprecedented dioxin-degrading enzyme that reductively cleaves the diaryl ether bonds. In this study, we report the cloning and sequencing of the dioxin reductive etherase gene dreE which codes for the 2,3,7,8-TCDD-degrading enzyme. We showed that dreE was expressed in Escherichia coli and that the product of the expression could reductively cleave diaryl ether bonds of 2,3,7,8-TCDD to produce TCDE. Furthermore, we established that the amino acid sequence encoded by dreE was homologous to an enzyme with yet unknown function that is encoded by a gene located in the riboflavin (vitamin B2) biosynthesis operon in Bacillus subtilis. We also showed that the amino acid sequence possesses a coenzyme A (CoA) binding site that is conserved in the N-acyltransferase superfamily. For the first time, the degradation of 2,3,7,8-TCDD at the molecular level using a enzyme of bacterial origin has been demonstrated. A novel mechanism model for the reductive cleavage of diaryl ether bond of 2,3,7,8-TCDD was also proposed.

In situ determination of potential-driven structural changes in a redox-active plumbagin polymer film on a glassy carbon electrode using PM IRRAS under electrochemical control

Complex redox reactions occurring in the poly(plumbagin) involve reversible reduction and oxidation of the quinone moiety accompanied by parallel oxidation reactions taking place both, in the polymer backbone and in side chains. In acidic medium the methyl side chain undergoes oxidation to a carboxylic acid. In neutral solution the diaryl ether bond is oxidized to unstable hemiacetals, leading to the breakdown of the ether bond and finally to the degradation of the polymer film. Understanding of potential-dependent changes in the composition and structure of redox-active polymers adsorbed on an electrode surface requires a concerted use of spectroscopic and electrochemical techniques. Infrared reflection-absorption spectroscopy techniques are often used in in situ electrochemical experiments, but require surfaces strongly reflecting IR radiation (e.g. gold). Here a glassy carbon electrode (GCE) is used for in situ polarization modulation infrared reflection-absorption spectroscopy (PM IRRAS) experiments with electrochemical control. Due to a weak reflection of the IR light from the GCE surface, the sensitivity of the PM IRRAS decreases compared to metallic surfaces but was sufficient for the analysis of a redox-active polymer film. Electrochemical studies show that the mechanism of the redox reaction of the quinone/hydroquinone couple depends on the used solvent (D2O, H2O) and on the pD (pH) of the electrolyte solution. In H2O a two electron transfer reactions are accompanied by two protonation reactions. The first protonation reaction takes place after the first electron transfer and is the rate-determining step. The dependence of the redox potential on pD shows that the transfer of two electrons is accompanied by one deuteration reaction. Deuterium ions produced during the parallel oxidation reactions of the polymer backbone serve as the substrate for the chemical step of the quinone reduction reaction. In D2O, similarly to H2O, the rate-determining step is a chemical reaction. The rate-determining reaction depends on pD of the electrolyte solution. This work shows clearly that the isotopic substitution, often used in spectroscopic experiments, may have a large impact on the electrochemical behavior of redox-active compounds.

Effects of maturity on the pyrolytic fingerprint of coals from North Borneo

Pyrolysis-gas chromatography-mass spectrometry (Py-GC–MS) and thermally assisted hydrolysis and methylation (THM-GC–MS) were applied to 27 coal samples of lignite to high volatile bituminous rank (vitrinite reflectance %Ro=0.28–0.66) from the Malaysian states of Sabah and Sarawak on Borneo, to investigate rank effects on molecular properties. The molecular fingerprints of these coals appeared to be controlled by diagenetic and, to a smaller extent, early catagenetic transformations (%Ro 0.28–0.50). The molecular assemblages from immature coals consist mainly of lignin-derived material and long-chain (≥C24) ester-bound polymethylene chains, whereas mature coals are enriched in short (C10–C25) free and/or trapped (isoprenoid) hydrocarbons, alkylated phenols and resinite aromatic derivatives. By comparing a large suite of potential molecular proxies of maturation (indices of pristane formation, resin aromatization, lignin alteration stages, etc.) and other maturity proxies (%Ro, Tmax), rank effects on different coal constituents are illustrated, as well as the suitability of the proxies for specific rank ranges. The results highlight the importance of decarboxylation of long-chain fatty acids (%Ro 0.35–0.40) and the progressive accumulation of resistant aryl-O (probably diaryl ether) bonds at advanced stages of maturity. The coals from Pinangah in Sabah were more mature than those from Sarawak (Mukah and Balingian coalfields), whereas the molecular signature of other coals from northeastern Sabah (Sandakan area) and southeastern Sabah (Silimpopon and Maliau areas) varied across the rank range studied.

Polyphenolic ellagitannins and gallotannins: Structures, synthesis and biological activity - from folk medicine to chemical biology via wine sciences

Hydrolyzable tannins constitute a class of plant bioactive polyphenols primarily composed of ellagitannins and gallotannins derived from the metabolism of gallic acid. Ellagitannins feature galloyl units esterified to a sugar core, usually glucose, and characterized by the presence of biaryl and diaryl ether bonds between some or all of their galloyl units.[1] Among ellagitannins, there exists a subclass of structurally unique nonahydroxyterphenoyl (NHTP)-bearing C-glucosidic molecules featuring an open-chain glucose core and exemplified by vescalagin. The fact that some of these C-glucosidic ellagitannins are found in wine as a result of aging of this beverage in oak-made barrels provided us with the impetus to examine their chemical reactivity and biological activity. Indeed, during aging in oak barrels, the hydroalcoholic and slightly acidic (i.e., pH 3–4) wine solution enables the solid-liquid extraction of these ellagitannins. Once in the wine solution, some of these natural products such as vescalagin can capture grape-derived nucleophilic entities such as the flavanols catechin and epicatechin and the anthocyanin oenin to furnish condensation products, some of them having been postulated as active principles in Asian herbal medicines.[2] Of pharmacological importance is the fact that several of these found-in-wine ellagitannin hybrids are much more potent than etoposide (VP-16) at inhibiting in vitro the anti-cancer target DNA topoisomerase IIa.[2a,b] Furthermore, we recently discovered that vescalagin is capable of drastically perturbing the actin cytoskeleton by interacting selectively with the actin filaments, both in vitro and in cellulo.[3] Moreover, gallotannins, in which galloyl units and/or depsidically-linked chains of galloyl units are usually esterified to a glucopyranose core, and some of their simpler precursors exhibit some interesting properties with possible applications as antifibrillogenic agents. Thus, the various biophysico-chemical properties we unveiled for these hydrolysable tannins will be presented and their exploitation in the development of therapeutic agents discussed during this lecture.

Development of a highly sensitive assay for enzyme‐mediated reductive degradation of polychlorinated dibenzo‐p‐dioxin

The degradation of 2-chloro-4,5-O-(4'-methyl-7', 8'-diphenyl)ether (CMDPE), an analog of 2,7-dichlorodibenzo-p-dioxin (2,7-DCDD), mediated by Geobacillus sp. UZO 3 cell-free extract was monitored. Ethyl acetate extracts of a complete reaction mixture incubated at 65°C for 18 h were analyzed either by thin layer chromatography (TLC) fractionation coupled with spectrometric detection or by gas chromatography-mass spectrometry (GC-MS). The reaction product 4-methylumbelliferone (4MU) was successfully isolated by TLC and visualized by a transilluminator at 450 nm. The 4MU, 4-chlorophenol, and reaction intermediate 6-chlorophenoxy-4-methylumbelliferone were all successfully detected by GC-MS. The presence of these compounds suggest that Geobacillus sp. UZO 3 cell-free extract also catalyzes the reductive cleavage of the diaryl ether bonds of CMDPE in a similar mechanism previously reported in 2,7-DCDD. In the present study, the authors describe a simple and highly sensitive fluorescent assay for a new dioxin degrading enzyme(s).

Novel enzymatic activity of cell free extract from thermophilic Geobacillus sp. UZO 3 catalyzes reductive cleavage of diaryl ether bonds of 2,7-dichlorodibenzo- p-dioxin

We characterized the ability of the cell free extract from polychlorinated dibenzo- p-dioxins degrading bacterium Geobacillus sp. UZO 3 to reduce even highly chlorinated dibenzo- p-dioxins such as octachlorodibenzo- p-dioxins in incineration fly ash. The degradation of 2,7-dichlorodibenzo- p-dioxin (2,7-DCDD) as a model dioxin catalyzed by the cell free extract from this strain implicates that the ether bonds of 2,7-DCDD molecule undergo reductive cleavage, since 4′,5-dichloro-2-hydroxydiphenyl ether and 4-chlorophenol were detected as intermediate products of 2,7-DCDD degradation.

Novel enzymatic activity of cell-free extract from Thermophilic geobacillus sp SH2B-J2 catalyzes reductive cleavage of diaryl ether bonds of 2,7-Dichlorodibenzo-p-dioxin

Novel enzymatic activity of cell-free extract from Thermophilic geobacillus sp SH2B-J2 catalyzes reductive cleavage of diaryl ether bonds of 2,7-Dichlorodibenzo-p-dioxin

Structural Characterization of the Lignin from Jute (Corchorus capsularis) Fibers

The structural characteristics of the lignin from jute (Corchorus capsularis ) fibers, which are used for high-quality paper pulp production, were studied. The lignin content (13.3% Klason lignin) was high compared to other nonwoody bast fibers used for pulp production. The lignin structure was characterized by pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), 2D-NMR, and thioacidolysis. Upon Py-GC/MS, jute fibers released predominantly products from syringylpropanoid units with the S/G ratio being 2.1 and a H/G/S composition of 2:33:65. 2D-NMR of the milled wood lignin (MWL) isolated from jute fibers showed a predominance of beta-O-4' aryl ether linkages (72% of total side chains), followed by beta-beta' resinol-type linkages (16% of total side chains) and lower amounts of beta-5' phenylcoumaran (4%) and beta-1' spirodienone-type (4%) linkages and cinnamyl end groups (4%). The high predominance of the S-lignin units, together with the high proportion of beta-O-4' aryl ether linkages, which are easily cleaved during alkaline cooking, are advantageous for pulping. On the other hand, a small percentage (ca. 4%) of the lignin side chain was found to be acetylated at the gamma-carbon, predominantly over syringyl units. The analysis of desulphurated thioacidolysis dimers provided additional information on the relative abundances of the various carbon-carbon and diaryl ether bonds and the type of units (syringyl or guaiacyl) involved in each of the above linkage types. Interestingly, the major part of the beta-beta' dimers included two syringyl units, indicating that most of the beta-beta' substructures identified in the HSQC spectra were of the syringaresinol type (pinoresinol being absent), as already observed in the lignin of other angiosperms.

Structural characterization of milled wood lignins from different eucalypt species

AbstractThe chemical structure of milled-wood lignins fromEucalyptus globulus,E. nitens,E. maidenii,E. grandis, andE. dunniiwas investigated. The lignins were characterized by analytical pyrolysis, thioacidolysis, and 2D-NMR that confirmed the predominance of syringyl over guaiacyl units and only showed traces ofp-hydroxyphenyl units.E. globuluslignin had the highest syringyl content. The heteronuclear single quantum correlation (HSQC) NMR spectra yielded information about relative abundances of inter-unit linkages in the whole polymer. All the lignins showed a predominance of β-O-4′ ether linkages (66–72% of total side-chains), followed by β-β′ resinol-type linkages (16–19%) and lower amounts of β-5′ phenylcoumaran-type (3–7%) and β-1′ spirodienone-type linkages (1–4%). The analysis of desulfurated thioacidolysis dimers provided additional information on the relative abundances of the various carbon-carbon and diaryl ether bonds, and the type of units (syringyl or guaiacyl) involved in each of the above linkage types. Interestingly, 93–94% of the total β-β′ dimers included two syringyl units indicating that most of the β-β′ substructures identified in the HSQC spectra were of the syringaresinol type. Moreover, three isomers of a major trimeric compound were found which were tentatively identified as arising from a β-β′ syringaresinol substructure attached to a guaiacyl unit through a 4-O-5′ linkage.

Chemical Synthesis of Six Novel 17β-Estradiol and Estrone Dimers and Study of Their Formation Catalyzed by Human Cytochrome P450 Isoforms

Our earlier studies have shown that over 20 nonpolar 17beta-estradiol metabolite peaks were detected following incubations of radioactive 17beta-estradiol with human liver microsomes or recombinant human cytochrome P450 isoforms in the presence of NADPH as a cofactor. The structures of two representative nonpolar metabolites were identified earlier as dimers of 17beta-estradiol linked through a diaryl ether bond between the C-3 phenolic oxygen of one molecule and the C-2 or C-4 aromatic carbon of another. Six additional putative dimers between estrone and 17beta-estradiol with structures similar to the two identified ones were synthesized in this study. Using these newly synthesized estrogen dimers as reference standards, we demonstrated that incubations of human liver microsomes or various human cytochrome P450 isoforms with estrone or 17beta-estradiol alone or two estrogens in combination in the presence of NADPH as a cofactor resulted in the formation of all eight estrogen dimers in varying quantities.

Chemical synthesis of two novel diaryl ether dimers of estradiol-17β

We recently detected the formation of estradiol-17β (estradiol) dimers, linked together through a diaryl ether bond between the C-3 phenolic oxygen of one estradiol molecule and the 2- or 4-position aromatic carbon of another estradiol, following incubations of [ 3 H ]estradiol with human liver microsomes or cytochrome P450 enzymes in the presence of NADPH. Using estradiol as the starting material, we designed a four-step method for the chemical synthesis of these two estrogen dimers with the Ullmann condensation reaction as a key step. Step 1: Synthesis of 2- or 4-bromoestradiol from estradiol. Step 2 : Protection of the C-3 phenolic hydroxyl group of the 2- or 4-bromoestradiol. Step 3 : The Ullmann condensation reaction between the phenol-protected bromoestradiol and the estradiol potassium salt under our modified reaction conditions (with a 41% product yield). Step 4 : Removal of the C-3 benzyl group by catalytic hydrogenation. The chromatographic and various spectrometric properties of the two synthesized compounds were identical to those metabolically formed by human cytochrome P450 3A4.

Synthesis of Ruthenium‐Labelled Tripeptoids with Alternating Amide and Diaryl Ether Bonds

AbstractFree‐amino forms of 4‐O‐methyldopamine and 4‐O‐methyltyramine react as nucleophiles in a chemoselective manner with [RuCp]+‐complexed p‐substituted chloroarenes. As a consequence, it is not necessary to use protecting groups for the synthesis of peptoids with alternating amide and diaryl ether bonds. [RuCp]+‐labelled diaryl ether tripeptoids containing DOPA‐ and tyrosine‐derived subunits have been assembled as model compounds. The purification of the charged complexes was conveniently achieved employing aminopropyl‐functionalised silica as a stationary phase. The free‐amino form of tripeptoid 2 resembles the ABB′ partial structure of the macrocyclic bastadins, biologically active natural products from the marine sponge Ianthella. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)