Dioxygenases arene dihydroxylation

Figure 18.12. Benzene dioxygenase, toluene dioxygenase and naphthalene dioxygenase catalyzed dihydroxylation arenes to arene cis-dihydrodiols.

T., Malone, J.F., McGregor, S. and Allen, C.C.R. (2005) Dioxygenase-catalyzed dihydroxylation of arene cis-dihydrodiols and acetonide derivatives a new approach to the synthesis of enantio-pure tetraoxygenated bioproducts from arenes. Chemical Communications, 4934-4936. 

Catechol dioxygenase - intradiol cleavage Arene dihydroxylation 175)... 

SCHEME 32.2 Regio- and stereoselectivity of arene dihydroxylation by arene dioxygenases, (a) For TDO (toluene dioxygenase) and BPDO (biphenyl dioxygenase), (b) For BZDO (benzoate dioxygenase). 

For alkene dihydroxylations, heavy metal oxides such as 0s04 and Ru04 can be applied. They are efficient catalysts but their toxitity makes their use less desirable and there is a dear need for non-toxic metal catalysts. Nevertheless, only a few reports have focused on the use of iron catalysts for alkene dihydroxylations. All systems described so far try to model the naturally occurring Rieske dioxygenase, an enzyme responsible for the biodegradation of arenes via cis-dihydroxylation by soil baderia [66]. 

In the area of mononuclear nonheme iron enzymes, x-ray crystal structures are now also available for the catalytic domain of human phenylalanine hydroxylase [18] and naphthalene 1,2-dioxygenase [19]. The mononuclear iron site of phenylalanine hydroxylase resembles the 2-His-l-Asp site of tyrosine hydroxylase, a result anticipated by sequence homology. More interestingly, naphthalene 1,2-dioxygenase, which catalyzes the c/ s-dihydroxylation of arene double bonds in the biodegradation of aromatics, also has a Fe(His)2(Asp) iron site. These two enzymes augment the increasing number of mononuclear nonheme iron enzymes with a common Fe(His)2(carboxylate) facial triad motif [20],... 

The Rieske dioxygenases (so-called because they contain a Rieske [2Fe—2S] cluster in addition to the mononuclear iron centre) catalyse cw-dihydroxylation of arene double bonds using NADH as the source of two electrons again, both dioxygen atoms are incorporated into the cA-diol product. 

Figure 29 Proposed mechanism for the cis-dihydroxylation reaction of arene dioxygenases.

A number of instances can be cited from the literature wherein the isosteres had similar transformations. Bacterial dioxygenase-catalyzed ci5-dihydroxylation of the tetracyclic arene benzo[c]phenanthrene was found to occur exclusively at fjord region (cavity region) bonds. The isosteric compounds benzo[b]naphthol [l,2-d]furan and benzo[b]naphthol[l,2-d]thiophene were also similarly ci5-dihydroxylated at the fjord region bonds by bacterial dioxygenases (Boyd et al., 2001) (see Fig. 4.3). The isosteres 1,2-dihydronaphthalene, 2,3-dihydrobenzothiophene, and 2,3-dihydro-benzofuran gave similar corresponding diol products on incubation with Pseudomonas putida UV4. Microbes that possess the metabolic pathways to metabolize benzene, when substituted by... 

The enzymatic hydroxylations play a crucial role in detoxification and excretion of toxic arenes and in drug metabolism. The enzymatic degradation of aromatics occurs via two different pathways (i) monooxygenase-mediated formation of arene oxide followed by enzymatic hydrolysis to yield tram-l,2-dio and its further metabolism and (ii) dioxygenase-catalyzed arene cis-dihydroxylation... 

Among bacteria that are capable of metabolizing arenes, certain strains express arene dioxygenase enzymes capable of effecting the dearomatizing dihydroxylation of an arene 1 to give a cis-cyclohexa-3,5-diene-l,2-diol 2 (Scheme 32.1). Ordinarily, such diene diols are merely fleeting... 

Arene dioxygenases catalyze the first step in the metabolism of unactivated aromatic compounds, yielding cw-dihydrodiol of aromatics. As shown in eq. (22), the reaction requires nicotinamide adenine nucleotide (NADH) and molecular oxygen. Substrate specificity of enzymes is high, and products shown in Fig. 27 are produced by benzene-[351, 352], toluene- [353-356], naphthalene- [357-361], biphenyl- [362-364], benzoate-[365-370], and phthalate-dioxygenases [371-378]. In the cases of benzoate [379], 4-sulphobenzoate [380], and 6>-nitrotoluene [381], catechols are formed via unstable dihydroxylated intermediates as shown in eq. (23)... 

Figure 27. Dihydroxylated products formed by arene dioxygenases.

Mechanism for oxygen activation and dihydroxylation by these enzymes is far from established. A mechanism in Scheme 23 [387] which is proposed for putidamonooxin is suggestive for arene dioxygenases. 

Arene.. dioxygenases catalyze reactions other than dihydroxylation of aromatics. For example, toluene dioxygenase catalyzes monooxygenation of indene and indan to 1-indenol and 1-indanol, respectively [382], oxidation of polyhalogenated compounds such as trichloroethylene [eq. (24)] [363, 388-390], and stereoselective sulfoxidation of sulfides [391, 392]. 

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