Non-symmetrically substituted phenoxazinones from laccase-mediated oxidative cross-coupling of aminophenols: an experimental and theoretical insight

Bruyneel, Frédéric; Dive, Georges; Marchand‐Brynaert, Jacqueline

doi:10.1039/c1ob05795b

Cited by 15 publications

(16 citation statements)

References 76 publications

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“…The proposed molecular pathway (Scheme ),, that led to the formation of asymmetric phenazines in CotA‐laccase mediated reactions, using aromatic amines as substrates, initiates with the abstraction of one electron from the more liable amino group in the substrate molecule, generating the ortho ‐quinonediimine key intermediate ( A ). Under the reaction conditions, this electrophilic species ( A ) suffer rapid nucleophilic addition by other substrate molecule in the para ‐position to an imine group forming the ( B ) intermediate.…”

Section: Resultsmentioning

confidence: 99%

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

et al. 2017

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An efficient and sustainable one-step procedure for the synthesis of new asymmetric phenazines and phenoxazinones from commercially available ortho-substituted diamines and orthosubstituted hydroxyamines is reported. In this study we have expanded the substrate scope of CotAlaccase-catalyzed aerobic oxidations through the use of aromatic amines presenting variable functional groups, including N-substitution, contributing to the rational synthesis of different heterocyclic scaffolds. The transformations proceed smoothly through a cascade of oxidative reactions to the benzoquinonediimine intermediates followed by nucleophilic addition, intramolecular cyclization and aromatization, all performed in mild conditions.

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Section: Resultsmentioning

confidence: 99%

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

et al. 2017

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“…These species suffer rapid nucleophilic addition by other substrate molecules in its most electrophilic carbon atom, followed by a proton shift, yielding the first coupling intermediate (b). The second two-step one electron oxidation is enzymatic and an intramolecular Michael addition of an amino group to the C5 atom, with the displacement of an R group, leading to aminophenazines, which are spontaneously oxidised in air to produce the final asymmetric heterocyclic products [ 65 , 94 ]. For the meta-para -disubstituted aromatic amines, the first step is the in situ generation of a para -benzoquinonediimine intermediate (a’) in a similar way as described above.…”

Section: Application Of Laccases In Bio-oxidative Synthesis Of Heterocyclic Compoundsmentioning

confidence: 99%

“…The oxidative dimerization of 3-HAA and its sulfonated analog 3-hydroxyorthanilic acid (3-HOA), mediated by the fungal laccase from P. cinnabarinus , afforded cinnabarinic acid and the 2-amino-3-oxo-3H-phenoxazin-1,9-disulfonic acid, respectively [ 93 ]. Looking forward to the synthesis of a new class of water-soluble chromophores and potential bioactive molecules through a biocatalytic process, the oxidative homo- and cross-coupling reactions of numerous sulphonamide derivatives of 3-hydroxyorthanilic acid, as well as 3-amino-2-hydroxybenzenesulfonic acid, have been explored using the commercial laccase from T. versicolor leading to symmetrically and non-symmetrically substituted phenoxazinones [ 94 , 95 ]. The 3-amino-4-hydroxybenzene sulfonic acid has also been transformed to corresponding phenoxazinones via laccase-catalysed oxidative dimerization ( Scheme 13 C) [ 96 ].…”

Section: Application Of Laccases In Bio-oxidative Synthesis Of Heterocyclic Compoundsmentioning

confidence: 99%

“…A compound, non-substrate of the enzyme, could still act as a nucleophile to another susceptible o -aminophenol yielding a cross-coupled substituted phenoxazinone. The second two step one-electron enzymatic oxidation and an intramolecular Michael addition of the phenol group to the C5 atom, with the displacement of an R group, leads to a fully reduced aminophenoxazine, which is spontaneously oxidised in air to produce the final heterocycle product [ 65 , 94 ].…”

Section: Application Of Laccases In Bio-oxidative Synthesis Of Heterocyclic Compoundsmentioning

confidence: 99%

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Laccases: Versatile Biocatalysts for the Synthesis of Heterocyclic Cores

2021

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Laccases are multicopper oxidases that have shown a great potential in various biotechnological and green chemistry processes mainly due to their high relative non-specific oxidation of phenols, arylamines and some inorganic metals, and their high redox potentials that can span from 500 to 800 mV vs. SHE. Other advantages of laccases include the use of readily available oxygen as a second substrate, the formation of water as a side-product and no requirement for cofactors. Importantly, addition of low-molecular-weight redox mediators that act as electron shuttles, promoting the oxidation of complex bulky substrates and/or of higher redox potential than the enzymes themselves, can further expand their substrate scope, in the so-called laccase-mediated systems (LMS). Laccase bioprocesses can be designed for efficiency at both acidic and basic conditions since it is known that fungal and bacterial laccases exhibit distinct optimal pH values for the similar phenolic and aromatic amines. This review covers studies on the synthesis of five- and six-membered ring heterocyclic cores, such as benzimidazoles, benzofurans, benzothiazoles, quinazoline and quinazolinone, phenazine, phenoxazine, phenoxazinone and phenothiazine derivatives. The enzymes used and the reaction protocols are briefly outlined, and the mechanistic pathways described.

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“…Similar ndings have been reported on the formation of different unsymmetrical phenoxazinones catalysed by laccase. 28 Apparently, in S. antibioticus the formation of hemi-actinomycins is similarly regiospecic directing the actinomycin half molecule to the b-side of the phenoxazinone nucleus although both 3-HA or 4-MHA -when externally added -are in excess over the concentrations of actinomycin halves in the cells. Nevertheless, during the incubations the symmetrical chromophores cinnabarinic acid or actinocin, respectively, were produced in parallel and in appreciable amounts as revealed by the presence of their bands of R f $ 0.15 and $0.19 both showing a magenta colour on TLC plates (Fig.…”

Section: -Ha and 4-mha Induce Synthesis Of Hemi-actinomycinsmentioning

confidence: 99%

Biosynthetic rivalry of o-aminophenol-carboxylic acids initiates production of hemi-actinomycins in Streptomyces antibioticus

et al. 2014

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Actinomycins consist of two pentapeptide lactone rings attached to 2-amino-4,6-dimethyl-3-oxophenoxazine-1,9-dicarboxylic acid (actinocin). The actinocin moiety is formed through oxidative condensation of two 3-hydroxy-4-methylanthranilic acid (4-MHA) pentapeptide lactones (actinomycin halves) as the last step of actinomycin biosynthesis. We found that feeding of 4-MHA or its putative biogenetic precursor 3-hydroxyanthranilic acid (3-HA) to Streptomyces antibioticus induced formation of different new compounds at the expense of actinomycins. These contain only one pentapeptide lactone ring attached to the b-side of their phenoxazinone ring systems and are formed through premature condensation of the externally added abundant 4-MHA or 3-HA with actinomycin halves. They were termed hemi-actinomycins and C-demethyl-hemi-actinomycins, respectively, which differ from each other in the presence or absence of one or both methyl groups in their phenoxazinone moieties. 3-HA also induces synthesis of various C-demethylactinomycins formed through condensation of actinomycin halves in which 3-HA had been incorporated by the 4-MHA incorporating enzyme in lieu of 4-MHA. 3-HA was not converted to 4-MHA as revealed by its inability to stimulate synthesis of actinomycin or hemi-actinomycin synthesis and thus remained a substrate analogue of 4-MHA rather than its precursor.In contrast to S. antibioticus, actinomycin-producing streptomycetes such as Streptomyces chrysomallus or Streptomyces parvulus do not form hemi-structured actinomycins when fed with 3-HA or 4-MHA.They do not possess the enzyme phenoxazinone synthase (PHS) which in S. antibioticus is present and most probably catalyses premature condensation of abundant 4-MHA or 3-HA with actinomycin halves.Testing hemi-acinomycin IV for drug activity revealed that it intercalates into DNA and inhibits relaxation and supertwisting of DNA by topoisomerase I and DNA-gyrase like actinomycin IV (D). Moreover, it has inhibitory activity on growth of Bacillus subtilis.

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Non-symmetrically substituted phenoxazinones from laccase-mediated oxidative cross-coupling of aminophenols: an experimental and theoretical insight

Cited by 15 publications

References 76 publications

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

Laccases: Versatile Biocatalysts for the Synthesis of Heterocyclic Cores

Biosynthetic rivalry of o-aminophenol-carboxylic acids initiates production of hemi-actinomycins in Streptomyces antibioticus

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