Microbial arene oxidation

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Microbial arene oxidation (MAO) refers to the process by which microbial enzymes convert aromatic compounds into more oxidized products. The initial intermediates are arene oxides. A number of oxidized products are possible, the most commonly employed for organic synthesis are cis-1,2-dihydroxy-cyclohexa-3,5-dienes ("dihydrodiols"). [1]

Contents

The oxidation of aromatic compounds to dearomatized products is a step in the processing of arenes. Since seminal study by Gibson on enzymes inPseudomonas putida, four classes of enzymes have been identified that accomplish arene oxidation to dihydrodiols: [2]

The substrate specificity of these enzymes is low. Enantiomeric purities in excess of 90% are routine but varies with substrate. For instance, 1,4-substituted benzenes often render diols of lower enantiomeric purity. However, accessing the "unnatural" enantiomer of product is often difficult without tailored enzymes.

(1)

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Mechanism and stereochemistry

Oxidations by bacterial dioxygenases give cis-dihydrodiols. This outcome sets the mechanism of bacterial oxidation apart from mammalian and fungal versions of the process, which yield trans-dihydrodiols. [3] The cis configuration of the product together with isotopic labeling studies implicate a dioxetane intermediate. [4] This intermediate has not been observed, however.

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A reliable model has been developed that accounts for the stereo- and site selectivity of the reaction. [5] With the large substituent of the arene pointing up and other substituents pointed leftward, approach of dioxygen occurs to the top face of the arene, on the right-hand side. This model breaks down for some highly substituted substrates, such as phenanthrene and 2-naphthalenes, and does not apply to BZDs.

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Scope

Toluene dioxygenase oxidizes toluene to 1,2-dihydroxyl-6-methylcyclohexa-3,5-diene. [6] Aromatic esters are also good substrates for these enzymes, giving dihydrodiols in moderate yields along with some other oxidation products (see equation (8) below).

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Naphthalene dioxygenase is found in a variety of Pseudomonas organisms. It catalyzes the oxidation of other polyclic aromatic compounds as well, although yields tend to be low for substrates other than naphthalene. [4]

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Biphenyl dioxygenase oxidizes a relatively wide array of aromatic substrates and exhibits low substrate specificity. [7] Biphenyl oxidation can also be accomplished using TDOs or NDOs.

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The site selectivity of BZDs differs from that of the other three classes. Oxidation takes place in an ipso-cis fashion, independent of the substitution pattern of the arene. [8]

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Undesirable oxidized side products are often observed during microbial arene oxidations, particularly for "unnatural" substrates. Benzylic oxidation has been noted in a number of cases. Sulfides are always oxidized to sulfoxides. [9]

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An important limitation of the reaction is that only a single enantiomer of product is available when the wild type enzyme is used. Enzymes that generate "unnatural" enantiomers must be engineered via site-directed mutagenesis or other biochemical techniques. The development of organisms and enzymes that exhibit "unnatural" stereoselectivity is an ongoing research activity. [10]

Applications in organic synthesis

Because of concerns about the efficiency and selectivity of oxidation of more complex substrates, MAO is usually carried out early in synthetic sequences. However, simple dihydrodiols may be manipulated to give complex products through a variety of methods. In addition, the microbial oxidation process is compatible with a number of functional groups.

For instance, thioether-containing dihydrodiols may be accessed by the oxidation of iodobenzene followed by cross-coupling in the presence of tin sulfides. [11]

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Dihydrodiols have been elaborated to a variety of alkaloid natural products. Two examples are shown below. [12] [13]

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Conditions of MAO reactions require handling microbes in an aseptic environment. Often, specialized bacterial strains are needed to effect particular transformations. Dihydrodiols themselves must be stored under basic conditions (pH > 9) to prevent acid-catalyzed dehydration. [14]

Related Research Articles

Aromatic compounds are those chemical compounds that contain one or more rings with pi electrons delocalized all the way around them. In contrast to compounds that exhibit aromaticity, aliphatic compounds lack this delocalization. The term "aromatic" was assigned before the physical mechanism determining aromaticity was discovered, and referred simply to the fact that many such compounds have a sweet or pleasant odour; however, not all aromatic compounds have a sweet odour, and not all compounds with a sweet odour are aromatic compounds. Aromatic hydrocarbons, or arenes, are aromatic organic compounds containing solely carbon and hydrogen atoms. The configuration of six carbon atoms in aromatic compounds is called a "benzene ring", after the simple aromatic compound benzene, or a phenyl group when part of a larger compound.

Rieske protein

Rieske proteins are iron–sulfur protein (ISP) components of cytochrome bc1 complexes and cytochrome b6f complexes and are responsible for electron transfer in some biological systems. John S. Rieske and co-workers first discovered the protein and in 1964 isolated an acetylated form of the bovine mitochondrial protein. In 1979 Trumpower's lab isolated the "oxidation factor" from bovine mitochondria and showed it was a reconstitutively-active form of the Rieske iron-sulfur protein
It is a unique [2Fe-2S] cluster in that one of the two Fe atoms is coordinated by two histidine residues rather than two cysteine residues. They have since been found in plants, animals, and bacteria with widely ranging electron reduction potentials from -150 to +400 mV.

Aromatic-ring-hydroxylating dioxygenases (ARHD) incorporate two atoms of dioxygen (O2) into their substrates in the dihydroxylation reaction. The product is (substituted) cis-1,2-dihydroxycyclohexadiene, which is subsequently converted to (substituted) benzene glycol by a cis-diol dehydrogenase.

Cometabolism is defined as the simultaneous degradation of two compounds, in which the degradation of the second compound depends on the presence of the first compound. This is in contrast to simultaneous catabolism, where each substrate is catabolized concomitantly by different enzymes. Cometabolism occurs when an enzyme produced by an organism to catalyze the degradation of its growth-substrate to derive energy and carbon from it is also capable of degrading additional compounds. The fortuitous degradation of these additional compounds does not support the growth of the bacteria, and some of these compounds can even be toxic in certain concentrations to the bacteria.

An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14.

Catechol 1,2-dioxygenase

Catechol 1,2- dioxygenase is an enzyme that catalyzes the oxidative ring cleavage of catechol to form cis,cis-muconic acid:

In enzymology, a cis-1,2-dihydro-1,2-dihydroxynaphthalene dehydrogenase (EC 1.3.1.29) is an enzyme that catalyzes the chemical reaction

In enzymology, a cis-1,2-dihydrobenzene-1,2-diol dehydrogenase (EC 1.3.1.19) is an enzyme that catalyzes the chemical reaction

Benzene 1,2-dioxygenase Class of enzymes

In enzymology, a benzene 1,2-dioxygenase is an enzyme that catalyzes the chemical reaction

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Dioxygenase

Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand.

Mallory reaction

In organic chemistry, the Mallory reaction is a photochemical-cyclization–elimination reaction of diaryl-ethylene structures to form phenanthrenes and other polycyclic form polycyclic aromatic hydrocarbons and heteroaromatics. This name reaction is named for Frank Mallory, who discovered it while a graduate student.

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(+)-Benzo(<i>a</i>)pyrene-7,8-dihydrodiol-9,10-epoxide Cancer-causing agent derived from tobacco smoke

(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer.

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References

  1. ↑ Johnson, R. A. Org. React. 2004, 63, 117. doi : 10.1002/0471264180.or063.02
  2. ↑ Gibson, D. T.; Koch, J. R.; Kallio, R. E. Biochemistry1968, 7, 2653
  3. ↑ Walker, N.; Wiltshire, G. H. J. Gen. Microbiol.1953, 8, 273.
  4. 1 2 Jeffrey, A. M.; Yeh, H. J. C.; Jerina, D. M.; Patel, T. R.; Davey, J. F.; Gibson, D. T. Biochemistry1975, 14, 575.
  5. ↑ Boyd, D. R.; Sharma, N. D.; Hand, M. V.; Groocock, M. R.; Kerley, N. A.; Dalton, H.; Chima, J.; Sheldrake, G. N. J. Chem. Soc., Chem. Commun.1993, 974.
  6. ↑ Gibson, D. T.; Hensley, M.; Yoshioka, H.; Mabry, T. J. Biochemistry1970, 9, 1626.
  7. ↑ Gibson, D. T.; Roberts, R. L.; Wells, M. C.; Kobal, V. M. Biochem. Biophys. Res. Commun.1973, 50, 211.
  8. ↑ Knackmuss, H.-J.; Beckmann, W.; Otting, W. Angew. Chem. Int. Ed. Engl.1976, 15, 549.
  9. ↑ Boyd, D. R.; McMordie, R. A. S.; Sharma, N. D.; Dalton, H.; Williams, P.; Jenkins, R. O. J. Chem. Soc., Chem. Commun.1989, 339.
  10. ↑ Yu, C.-L.; Parales, R. E.; Gibson, D. T. J. Indust. Microbiol. Biotech.2001, 27, 94.
  11. ↑ Boyd, D. R.; Hand, M. V.; Sharma, N. D.; Chima, J.; Dalton, H.; Sheldrake, G. N. J. Chem. Soc., Chem. Commun.1991, 1630.
  12. ↑ Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R.; Abboud, K. Tetrahedron Lett.1996, 37, 8155.
  13. ↑ Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett.1999, 40, 3077.
  14. ↑ Hudlicky, T.; Stabile, M. R.; Gibson, D. T.; Whited, G. M. Org. Synth. 1999, 76, 77.
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