Cis-dihydrodiols

Benzene dioxygenase is a complex enzyme consisting of three protein components, that catalyse the conversion of benzene to benzene cis-dihydrodiol. Give two reasons why this biotransformation should be carried out using whole cells as opposed to using enzyme preparations. 

Boyd DR, McMordie RAS, Porter HP, Dalton H, Jenkins RO, Howarth OW (1987) Metabolism of bicyclic aza-arenes by Pseudomonas to yield vicinal ci -dihydrodiols and phenols. J Chem Soc Chem Commun 1722-1724. 

FIGURE 8.7 Examples of chemical syntheses based on cyclohexadiene cis dihydrodiols (a) pinitol, (b) condnramine A, (c) (-)-laminitol, and (d) conduritol analogs. (From Neilson, A.H. and Allard, A.-S. The Handbook of Environmental Chemistry, Springer, 1998. With permission.)... 

There is clearly enormous potential using other cis dihydrodiols produced from benzocyclo-alkenes, or from the numerous dihydrodiols produced from polycyclic carbocyclic and heterocyclic substrates. 

Ziffer H, K Kabuta, DT Gibson, VM Kobal, DM Jerina (1977) The absolute stereochemistry of several cis dihydrodiols microbially produced from substituted benzenes. Tetrahedron 33 2491-2496. 

Dimethylaminobenzoates have also been used to establish the absolute configuration of diols in the presence of an aromatic chromophore, including metabolites of benzo[a]pyrene163 and precocene I164, as well as the cis-dihydrodiol derived from 12-methylbenz[a]anthracene165 and diastereomeric 2,2 -spirobiindane-l,l -diols166. 

Zeyer, J., Lehrbach, P. R. Timmis, K. N. (1985). Use of cloned genes of Pseudomonas TOL plasmid to effect biotransformation of benzoates to cis-dihydrodiols and catechols by Escherichia coli cells. Applied and Environmental Microbiology, 50, 1409-13. 

Arthurs CL, Raftery J, Whitby HL, Whitehead RC, Wind NS, Stratford D (2007) Arene cis-Dihydrodiols Useful Precursors for the Preparation of Analogues of the Anti-Tumour Agent, 2-Crotonyloxymethyl-(4/ ,5/ ,6/ )-4,5,6-trihydroxycyclohex-2-enone (COTC). Bioorg Med Chem Lett 17 5974... 

Toluene Dioxygenase Indigo or Prostaglandins from Substituted Benzenes via cis-Dihydrodiols... 

The discovery of an intermediate, benzene-cis-dihydrodiol, from the oxidation of benzene to C02 in a mutant of Pseudomonas putida (Gibson, 1968) led to a big effort to find corresponding new transformations and to utilize the diol products for other syntheses. 

A toluene dioxygenase (TOD) operon was isolated from a Pseudomonas strain which can grow on toluene through expression of the TOD operon, and cloned into E. coli. The TOD complex can convert both toluene and indene to the corresponding cis-dihydrodiols but has to be induced by toluene, which is toxic to the microorganism above a certain concentration. One measure to reduce toxicity is addition of soybean oil to the biotransformation to form a second, hydrophobic solvent phase to partition the toxic toluene from the aqueous biocatalyst solution. Expression of the operon in E. coli and process optimization lead to a titer of 1 g L-1 product with over 99% e.e. after 24 h of fermentation. However, the titer was not high enough for commercially attractive levels. 

Hudlicky T, Reed JW (2009) Celebrating 20 years of SYNLETT - special account on the merits of biocatalysis and the impact of arene cis-dihydrodiols on enantioselective synthesis. Synlett 2009 685-703... 

Isopropylbenzene catabolism is analogous to the degradation of toluene by the tod pathway (Eaton and Timmis, 1986). The initial step involves attack by a dioxygenase to form a cis-dihydrodiol. The ipb operon is regulated at the transcriptional level and the regulator is thought to be a protein of the XylS family (Berendes et al., 1998). 

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

In M. vanbaalenii PYR-1, an aromatic-ring dioxygenase produces cis-dihydrodiols from PAHs they have been identified (Heitkamp et al, 1988b Khan et al, 2001 Moody et al, 2001, 2004) but their toxicity has not yet been determined. The cA-dihydrodiols are further metabolized to other products whose toxicity also has not been examined, such as chrysene 4,5-dicarboxylic acid, 4-formylchrysene-5-carboxylic acid and 10-oxabenzo[fife/]chrysen-9-one (Schneider et al, 1996 Moody et al, 2004). 

Boyd, D.R., McMordie, R.A.S., Porter, H.P., Dalton, H., Jenkins, R.O. and Howarth, O.W. (1987) Metabolism of bicyclic aza-arenes by Pseudomonas putida to yield vicinal cis-dihydrodiols and phenols. Chemical Communications, 22,1722-1724. 

B. and Schmid, A. (2006) Selective hydrolysis of the nitrile group of cis-dihydrodiols. Jourrud of Molecular Catalysis B Enzymatic, 38, 76-83. 

Boyd, D.R. and Bugg, T.D.H. (2006) Arene cis-dihydrodiol formation from biology to application, organic and... 

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. 

Cl6H1402 benz(a)anthracene-5,6-cis-dihydrodiol 32373-17-4 623.15 55.834 2 29291 Cl6H1603 ethyl alpha-hydroxydiphenylacetate 52182-15-7 568.48 50.501 2... 

Humphreys, J. L., Lowes, D. J., Wesson, K. A. and Whitehead, R. C. (2006) Arene cis-dihydrodiols - useful precursors for the preparation of antimetabolites of the shikimic acid pathway application to the synthesis of 6,6-difluoroshikimic acid and (6S)-6-fluoroshikimic acid. Tetrahedron, 62, 5099-5108. 

Although the product from the transformation of toluene by mutants of Pseudomonas putida lacking dehydrogenase activity is the cis-2R,3S dihydrodiol, the cis-2S,3R dihydrodiol has been synthesized from 4-iodotoluene by a combination of microbiological and chemical reactions. P. putida strain UV4 was used to prepare both enantiomers of the ds-dihydrodiol, and iodine chemically removed with H2-Pd/C. Incubation of the mixture of enantiomers with P. putida NCIMB 8859 selectively degraded the 2R,3S compound to produce toluene cis-2S,3R dihydrodiol (Allen et al. 1995). A few illustrative syntheses using benzene and toluene cis-dihydrodiols are given. 

Racemic pinitol from benzene cis-dihydrodiol benzoate by successive epoxidation and osmylation (Figure 6.135a) (Ley at al. 1987) ... 

Laminitol from toluene cis-dihydrodiol by successive epoxida-tions (Figure 6.135c) (Carless et al. 1991) ... 

Allen, C.C.R., D.R. Boyd, F. Hempenstall, M.J. Larkin, and N.D. Sharma. 1999. Contrasting effects of a nonionic surfactant on the biotransformation of polycyclic aromatic hydrocarbons to cis-dihydrodiols by soil bacteria. Appl. Environ. Microbiol. 65 1335-1339. 

The extremely labile bacterial oxidation product of phthalic acid, 4,5-cis-dihydrodiol 167 was synthesized via the base-induced ring opening of oxabicyclo [2.2.1] substrate 166. Selective deprotonation of the less-hindered exo proton was possible, Eq. 108 [162]. 

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