cis‐Dihydroxylation of Tricyclic Arenes and Heteroarenes Catalyzed by Toluene Dioxygenase: A Molecular Docking Study and Experimental Validation

Derek Boyd, Narain D. Sharma, Ian Brannigan, Christopher McGivern, Peter Nockemann, Paul Stevenson, Colin McRoberts, Patrick Hoering, Christopher C.R. Allen

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Molecular docking studies of toluene dioxygenase (TDO) led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using P. putida UV4 whole cells expressing TDO, confirmed that both angular and lateral cis‐dihydroxylation occurred in the predicted regioselective and stereoselective manner. The TDO‐catalysed (P. putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite (> 80% 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 (< 2% yield). The enantiopurity (>98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by formation of diMTPA ester derivatives and X‐ray crystallography of a diol epoxide derivative. The cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products. dioxygenase‐catalysed cis‐dihydroxylation of substituted phenol and aniline substrates with Pseudomonas putida UV4, yielded arene cis‐dihydrodiol metabolites which tautomerised to the preferred cyclohex‐2‐en‐1‐one cis‐diols, as predicted by molecular docking studies. Further metabolism of cyclohex‐2‐en‐1‐one cis‐diols, under similar conditions, formed 4‐hydroxycyclohex‐2‐en‐1‐ones, as a new type of phenol metabolite
Original languageEnglish
JournalAdvanced Synthesis & Catalysis
Early online date18 Mar 2019
Publication statusEarly online date - 18 Mar 2019


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