Molecular docking studies of toluene dioxygenase led to the prediction that angular and lateral cisdihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using Pseudomonas putida UV4 whole cells, expressing toluene dioxygenase, confirmed that both angular and lateral cis-dihydroxylation had occurred in the predicted regioselective and stereoselective manner. The toluene dioxygenase-catalysed (Pseudomonas putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2-dihydrodibenzofuran-1,2-diol as the major metabolite in excellent yield. 2-Hydroxydibenzofuran, resulting from dehydration of 1,2-dihydrodibenzofuran-1,2-diol, was also found to undergo cis-dihydroxylation to give a very minor cis-dihydrodiol metabolite. The enantiopurity (> 98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis -dihydrodiol was rigorously established by catalytic hydrogenation and formation of methoxy(trifluoromethyl)phenylacetate derivatives and by X-ray crystallography of an epoxide derivative. Biotransformation of carbazole yielded anthranilic acid as the major metabolite and was consistent with angular cis-dihydroxylation. Synthesis of a cis-diol epoxide derivative showed that the main cis-dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products.
cis-Dihydrodiols, derived from monocyclic aromatic compounds, are valuable chiral pool intermediates for the synthesis of cyclic natural products. A drawback of this approach to the synthesis of polycyclic secondary metabolites, is that the additional rings must be annulated. To date, relatively few chiral natural products have been synthesized from polycyclic arene cis-dihydrodiols. Fungal metabolites ribisins A and B, have now be obtained by functional group manipulation of a major tricyclic arene metabolite, obtained from toluene dioxygenase-catalyzed regioselective and stereoselective cis-dihydroxylation of dibenzo[b,d]furan. The synthetic sequences were marginally shorter than the alternative routes using monocyclic arene cis-dihydrodiols and required no carbon-carbon bond-forming reaction.
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