Synthesis of halogenated derivatives of thymol and their antimicrobial activities

The vanadium-dependent chloroperoxidase from Curvularia inaequalis is an efficient biocatalystf or the in situ generation of hypohalous acids and subsequent electrophilic oxidation/ halogenation reactions. Especially,i ts superb activity andstability under operational conditions make it an attractive catalyst for organic synthesis. Herein,t he efficient bromination of thymolw as investigated, and turnover numbers of the enzyme were found to exceed 2000 000. The major noveltyo ft he work is that vanadium chloroperoxidase is more useful as ab rominating enzymet han vanadiumb romoperoxidase in terms of operational stability,b esides being far more stable than hemecontaining peroxidases.The halogenation of phenols by using elementary hypervalent halogen species is aw ell-known and well-established reaction in organic synthesis. Hypochlorites and hypobromites are frequently used as reagents, but following an in situ generation strategyt og eneratet he reactive hypohalogenites may be more advantageous. To attain this goal, vanadium-basedc atalysts [1] can be used to catalyze the formation of OBr À or OCl À ions from the corresponding halides by using H 2 O 2 as the oxidant. However,o wing to the relatively poor activity of these catalysts, high molar ratios of substrate to catalyst( S/C) are necessaryt oa ttain full conversion within ar easonable time frame.A lternatively,h aloperoxidases enable significantly lower catalystl oadings owing to the intrinsically higher activity of these catalysts.[2] Particularly,s o-called vanadium haloperoxidases are of interest here, as their stability towards the oxidant (H 2 O 2 )i ss ignificantly highert han that of the corresponding heme-dependent haloperoxidases, which suggests simpler and more robust reactionschemes.[3]In the present study,w ee valuated the vanadium-dependent chloroperoxidase from Curvulariai naequalis (CiVCPO)a sacatalyst for the chemoenzymatic halogenation of phenols. [3c, 4] In addition to its halogenatinga ctivity,t he vanadiumc hloroperoxidasea lso catalyzes the sulfoxidation of sulfides to sulfoxides [4d] andi sa ble to oxidize2 ,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), ac lassical chromogenich eme peroxidases ubstrate, and the industrial sulfonated azo dye Chicago Sky Blue 6B.[4d]As am odel substrate for our studies we chose thymol (Scheme 1) because of the interesting antimicrobiala ctivity of its halogenated derivatives.[5] Production of CiVCPOCiVCPO was obtained from heterologous expression in recombinant Escherichia coli by following ap reviously reported procedure.[4c] From a2Ls cale fermentation, 30 mg of essentially pure CiVCPO was obtained by using at wo-step purification procedure. The specific activity (A spec )[ monochlordimedon (MCD)a ssay] of the enzyme was22.5 AE 0.1 Umg À1. Characterization of CiVCPOIn af irst set of experiments,w ee valuated the basic biochemical properties of CiVCPO.A ss hown in Figure 1, the pH range of CiVCPO is fairly broad with an optimum at approximately pH 5.Acidic pH values were rather detrimen...

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“…As a model substrate for our studies we chose thymol (Scheme ) because of the interesting antimicrobial activity of its halogenated derivatives …”

Section: Methodsmentioning

confidence: 99%

Chemoenzymatic Halogenation of Phenols by using the Haloperoxidase from Curvularia inaequalis

Fernández‐Fueyo

Wingerden

Renirie³

et al. 2015

ChemCatChem

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“…Application of our chemoenzymatic bromination was likewise possible using the monoterpene thymol ( 12 ). Halogenated thymol derivatives possess antibacterial and antifungal properties, making their synthesis valuable for a number of applications in the pharmaceutical industry . With Am VHPO as a catalyst, p ‐bromothymol ( 13 a ) was predominantly formed (88 % yield), with the o ‐isomer ( 13 b ) being only a minor product.…”

Section: Figurementioning

confidence: 99%

“…Halogenated thymol derivatives possess antibac-terial and antifungal properties, makingt heir synthesis valuable for an umber of applicationsi nt he pharmaceutical industry. [23] With AmVHPO as ac atalyst, p-bromothymol (13 a)w as predominantly formed (88 %y ield), with the o-isomer (13 b) being only am inor product. This result is in clear contrast to the conversion obtained by applying the VBPO from A. nodosum, [4b] and, in this case, rather resembles the unusualp roduct selectivity of fungal VCPOs.…”

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confidence: 99%

Characterization of a Cyanobacterial Haloperoxidase and Evaluation of its Biocatalytic Halogenation Potential

et al. 2016

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Vanadium-dependent haloperoxidases (VHPOs) are a class of halogenating enzymes found in fungi, lichen, algae, and bacteria. We report the cloning, purification, and characterization of a functional VHPO from the cyanobacterium Acaryochloris marina (AmVHPO), including its structure determination by X-ray crystallography. Compared to other VHPOs, the AmVHPO features a unique set of disulfide bonds that stabilize the dodecameric assembly of the protein. Easy access by high-yield recombinant expression, as well as resistance towards organic solvents and temperature, together with a distinct halogenation reactivity, make this enzyme a promising starting point for the development of biocatalytic transformations.

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“…The respective O-benzyl derivative 20 was prepared through the selective ortho-bromination of thymol 19 in 65% yield, 44 and after the respective benzylation reaction, 20 was subjected to the optimised reaction conditions to give the desired product in 87% yield (Scheme 4). Although the yield of 9e, starting from 20 (87%), was slightly higher than the one obtained from 8e (85%), the broad scope of the developed reaction conditions was demonstrated since the electronic nature of the aromatic rings and the possible steric effects were not determinant during the transformation.…”

Section: Palladium-catalysed Direct Arylation Through C-h Activationmentioning

confidence: 99%

The study of metal-free and palladium-catalysed synthesis of benzochromenes via direct C–H arylation using unactivated aryl benzyl ethers derived from essential oils as raw materials

et al. 2017

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Synthesis of halogenated derivatives of thymol and their antimicrobial activities

Cited by 26 publications

References 7 publications

Chemoenzymatic Halogenation of Phenols by using the Haloperoxidase from Curvularia inaequalis

Chemoenzymatic Halogenation of Phenols by using the Haloperoxidase from Curvularia inaequalis

Characterization of a Cyanobacterial Haloperoxidase and Evaluation of its Biocatalytic Halogenation Potential

The study of metal-free and palladium-catalysed synthesis of benzochromenes via direct C–H arylation using unactivated aryl benzyl ethers derived from essential oils as raw materials

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