Regioselective Oxidative Coupling Research Articles

Regioselective Oxidative Phenol Coupling by a Mushroom Unspecific Peroxygenase

Regioselective Oxidative Phenol Coupling by a Mushroom Unspecific Peroxygenase

Regioselective Oxidative Phenol Coupling by a Mushroom Unspecific Peroxygenase.

Bioactive dimeric (pre-)anthraquinones are ubiquitous in nature. Their biosynthesis via an oxidative phenol coupling (OPC) step is catalyzed by either cytochrome P450 enzymes, peroxidases, or laccases. While the biocatalysis of OPC in molds (Ascomycota) is well-known, the respective enzymes of mushroom-forming fungi (Basidiomycota) are still unknown. Here, we report on the biosynthesis of the atropisomers phlegmacin A1 and B1, unsymmetrical 7,10'-homo-coupled dihydroanthracenones of the mushroom Cortinariusodorifer. The biosynthesis was heterologously reconstituted in the mold Aspergillusniger. We show that methylation of the dimeric (pre-)anthraquinone building block atrochrysone to its 6-O-methyl ether torosachrysone by the O-methyltransferase (CoOMT1) precedes the regioselective homo-coupling to phlegmacin, catalyzed by an unspecific peroxygenase (CoUPO1). Our results revealed an unprecedented UPO-mediated unsymmetric OPC reaction, thereby expanding the biocatalytic portfolio of OPC-type reactions beyond the commonly reported enzymes. The findings highlight the pivotal role of OPC in natural processes, demonstrating that Basidiomycota employed peroxygenases to develop the ability to selectively couple aryls, distinct and convergent to any other group of organisms.

Mechanochemical aerobic oxidative Heck coupling by polymer-assisted grinding: cyclodextrin additive facilitating regioselectivity control

A novel approach utilizing the polymer-assisted grinding (POLAG) technique to facilitate the regioselective oxidative Heck coupling of aryl boronic acids with electronically unbiased olefins under solvent-free conditions was presented.

Visible-Light-Induced Regio-selective Oxidative Coupling of Quinoxalinones with Pyrrole Derivatives

Visible-Light-Induced Regio-selective Oxidative Coupling of Quinoxalinones with Pyrrole Derivatives

Elucidation of the Complete Biosynthetic Pathway of Phomoxanthone A and Identification of a Para-Para Selective Phenol Coupling Dimerase.

Fungal cytochrome P450 enzymes have been shown to catalyze regio- and stereoselective oxidative intermolecular phenol coupling. However, an enzyme capable of catalyzing undirected para-para (C4-4') coupling has not been reported. Here, we revealed the biosynthetic gene cluster (BGC) of phomoxanthone A from the marine fungus Diaporthe sp. SYSU-MS4722. We heterologously expressed 14 biosynthetic genes in Aspergillus oryzae NSAR1 and found that PhoCDEFGHK is involved in the early stage of phomoxanthone A biosynthesis to give chrysophanol and that chrysophanol is then processed by PhoBJKLMNP to yield penexanthone B. A feeding experiment suggested that PhoO, a cytochrome P450 enzyme, catalyzed the regioselective oxidative para-para coupling of penexanthone B to give phomoxanthone A. The mechanism of PhoO represents a novel enzymatic 4,4'-linkage dimerization method for tetrahydroxanthone formations, which would facilitate biosynthetic engineering of structurally diverse 4,4'-linked dimeric tetrahydroxanthones.

Unsymmetrically Regioselective Homodimerization Depends on the Subcellular Colocalization of Laccase/Fasciclin Protein in the Biosynthesis of Phlegmacins.

Phlegmacins are homodimeric dihydroanthracenone natural products featuring two torosachrysone monomers unsymmetrically conjugated by 7,10'-coupling. Herein, we report the identification and characterization of the biosynthetic gene cluster of phlegmacins in ascomycete Talaromyces sp. F08Z-0631. On the basis of the heterologous reconstitution of the phlegmacin pathway in Aspergillus oryzae, we demonstrated an unprecedented laccase-involved unsymmetrically regioselective oxidative coupling reaction. The association of laccase PhlC and the fasciclin partner protein PhlB was verified to be indispensable for the coupling activity. Intriguingly, both proteins can be transferred and located independently at the mitochondrial membrane. Notably, only their subcellular colocalization led to the occurrence of oxidative dimerization. These observations add new insights into the poorly understood catalytic mechanisms of various laccases involved in the biosynthesis of secondary metabolites, particularly those functioning with variable partners.

Nucleophilic C-H Etherification of Heteroarenes Enabled by Base-Catalyzed Halogen Transfer.

We report a general protocol for the direct C-H etherification of N-heteroarenes. Potassium tert-butoxide catalyzes halogen transfer from 2-halothiophenes to N-heteroarenes to form N-heteroaryl halide intermediates that undergo tandem base-promoted alcohol substitution. Thus, the simple inclusion of inexpensive 2-halothiophenes enables regioselective oxidative coupling of alcohols with 1,3-azoles, pyridines, diazines, and polyazines under basic reaction conditions.

Efficient Synthesis of Several Natural Oligostilbenes from the ­Biomimetic Oxidation of Brominated Isorhapontigenin

This study extensively investigated the regioselective oxidative coupling reactions of 5-bromoisorhapontigenin catalyzed by ­FeCl3·6H2O or HRP/H2O2 in different solvent systems and the distinct reductive debromination of the isolated dimeric coupling intermediates. Natural (±)-bisisorhapontigenin A and (±)-lehmbachol A and B were efficiently prepared. (±)-Gnetuhainin I, (±)-gnemontanin E, (±)-7-O-ethylgnetuhainin I, and (±)-gnemontanin F were synthesized for the first time.

Metal-Free Regioselective Cross Dehydrogenative Coupling of Cyclic Ethers and Aryl Carbonyls.

A highly regioselective, efficient, and metal-free oxidative cross dehydrogenative coupling (CDC) of aryl carbonyls with cyclic ethers has been developed. This method offers easy access to substituted α-arylated cyclic ethers with a high functional group tolerance in good to excellent yields. The regioselectivity of this CDC reaction was confirmed by density functional theory (DFT)-based calculations.

Regioselective Copper-Catalyzed Oxidative Coupling of α-Alkylated Styrenes with Tertiary Alkyl Radicals.

A radical-mediated oxidative cross-coupling of readily accessible α-alkylated styrenes with 1,3-dicarbonyl compounds utilizing a combination of Cu(OAc)2 and air as a catalytic system is described. Rather than requiring α-halocarbonyl compounds, this efficient approach enables direct installation of tertiary functionalized alkyl motifs to olefins with simple carbonyl derivatives. The novel protocol is characterized with high allylic selectivities via a competing β-H elimination. Both radical-clock and -trapping experiments provided clear-cut evidence for the intermediacy of an α-keto carbon-centered radical.

Update on Phytochemistry and Pharmacology of Naturally Occurring Resveratrol Oligomers.

Resveratrol oligomers (REVs), a major class of stilbenoids, are biosynthesized by regioselective oxidative coupling of two to eight units of resveratrol monomer. Due to their unique structures and pleiotropic biological activities, natural product chemists are increasingly focusing on REVs in the last few decades. This study presents a detailed and thorough examination of REVs, including chemical structures, natural resources, and biological activities, during the period of 2010–2017. Ninety-two new REVs compounds, including 39 dimers, 23 trimers, 13 tetramers, six resveratrol monomers, six hexamers, four pentamers, and one octamer, have been reported from the families of Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae, and Poaceae. Amongst these families, Dipterocarpaceae, with 50 REVs, accounts for the majority, and seven genera of Dipterocarpaceae are involved, including Vatica, Vateria, Shorea, Hopea, Neobalanocarpus, Dipterocarpus, and Dryobalanops. These REVs have shown a wide range of bioactivities. Pharmacological studies have mainly focused on potential efficacy on tumors, bacteria, Alzheimer’s disease, cardiovascular diseases, and others. The information updated in this review might assist further research and development of novel REVs as potential therapeutic agents.

Bay- and Ortho-Octasubstituted Perylenes.

A key intermediate compound, 2,5,8,11-tetrabromo-1,6,7,12-tetrabutoxyperylene (Per-4Br), was synthesized from 3,6-dibromo-2,7-dioxylnaphthalene via simple regioselective oxidative radical-radical coupling, followed by reduction and nucleophilic substitution. Various bay- and ortho-octasubstituted perylenes containing cyano, methoxy and aryl groups were then obtained by nucleophilic substitution or Pd-catalyzed coupling reactions. X-ray crystallographic analyses reveal that these new perylene molecules process a twisted structure due to steric congestion at the bay-regions and there is no obvious intermolecular π-π interaction. As a result, they exhibit moderate fluorescence quantum yields even in solid state. Therefore, Per-4Br can serve as a versatile building block for various functional perylene dyes with tunable optoelectronic property.

Concise synthesis of several oligostilbenes from the enzyme-promoted oxidation of brominated resveratrol

The simple synthesis of (±)-parthenostilbenins A and B and (±)-quadrangularins A and B, as well as several unnatural resveratrol dimers, was successfully accomplished for the first time. Moreover, (±)-restrytisols B, (±)-leachianols F and G were efficiently prepared with higher yields compared with those in the literatures. The regioselective oxidative coupling reactions of 3,5-dibromo-resveratrol catalyzed by different enzymes in various solvent systems were used as key steps. The coupling mechanisms for the formation of distinct dimeric skeletons were also proposed.

ChemInform Abstract: Synthesis of 3‐Trifluoromethylindoles via Rh‐Catalyzed Regioselective Oxidative Coupling of Acetanilides with Trifluoromethylated Alkynes.

Abstract A practical and efficient synthesis of 3-trifluoromethyl functionalized indoles was successfully developed via Rh-catalyzed oxidative cross-coupling/annulations of readily available acetanilides with trifluoromethylated internal alkynes. Good yields and functional group tolerance as well as excellent regioselectivities were achieved under mild reaction conditions.

Synthesis of 3-trifluoromethylindoles via Rh-catalyzed regioselective oxidative coupling of acetanilides with trifluoromethylated alkynes

A practical and efficient synthesis of 3-trifluoromethyl functionalized indoles was successfully developed via Rh-catalyzed oxidative cross-coupling/annulations of readily available acetanilides with trifluoromethylated internal alkynes. Good yields and functional group tolerance as well as excellent regioselectivities were achieved under mild reaction conditions.

ChemInform Abstract: Palladium‐Catalyzed Tandem Regioselective Oxidative Coupling from Indoles and Maleimides: One‐Pot Synthesis of Indolopyrrolocarbazoles and Related Indolylmaleimides.

An efficient Pd(II)-catalyzed approach for the direct synthesis of indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-diones has been developed from both free and protected (NH) indoles and maleimides via a regioselective tandem oxidative coupling reaction. The yields are moderate to excellent. In addition, 2-substituted indoles are suitable substrates in this protocol, leading to the formation of indolylmaleimides. The present methodology provides a concise route to highly functionalized indolopyrrolocarbazole derivatives.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/α‐Bromoacetophenones with Aldehydes: A Facile Entry to α,β‐Epoxy Ketones.

AbstractNBS/DBU/DMSO is used as oxidative system for the regioselective oxidative coupling reactions.

Rational syntheses of helical π-conjugated oligopyrrins with a bipyrrole linkage: geometry control of bis-copper(II) coordination.

A rational and effective approach for synthesizing linear π-conjugated hexa-, hepta- and octapyrrins through the regioselective oxidative coupling of monoacylated tripyrrane and bilane is described. Depending upon the numbers of pyrrolic units, the geometry and properties of bis-copper(II) complexes could be systematically modulated.

ChemInform Abstract: Weak Coordination Promoted Regioselective Oxidative Coupling Reaction for 2,2′‐Difunctional Biaryl Synthesis in Hexafluoro‐2‐propanol.

AbstractThis method gives access to biaryls from aryl ketones, esters, and carbamates.

Palladium-Catalyzed Tandem Regioselective Oxidative Coupling from Indoles and Maleimides: One-Pot Synthesis of Indolopyrrolocarbazoles and Related Indolylmaleimides.

An efficient Pd(II)-catalyzed approach for the direct synthesis of indolo[3,2-a]pyrrolo[3,4-c]carbazole-6,8-diones has been developed from both free and protected (NH) indoles and maleimides via a regioselective tandem oxidative coupling reaction. The yields are moderate to excellent. In addition, 2-substituted indoles are suitable substrates in this protocol, leading to the formation of indolylmaleimides. The present methodology provides a concise route to highly functionalized indolopyrrolocarbazole derivatives.