Toluene dioxygenase-catalyzed cis-dihydroxylation of benzo[b]thiophenes and benzo[b]furans: synthesis of benzo[b]thiophene 2,3-oxide

Abstract

Enzymatic cis-dihydroxylation of benzo[b]thiophene, benzo[b]furan and several methyl substituted derivatives was found to occur in both the carbocyclic and heterocyclic rings. Relative and absolute configurations and enantiopurities of the resulting dihydrodiols were determined. Hydrogenation of the alkene bond in carbocyclic cis-dihydrodiols and ring-opening epimerization/reduction reactions of heterocyclic cis/trans-dihydrodiols were also studied. The relatively stable heterocyclic dihydrodiols of benzo[b]thiophene and benzo[b]furan showed a strong preference for the trans configuration in aqueous solutions. The 2,3-dihydrodiol metabolite of benzo[b]thiophene was utilized as a precursor in the chemoenzymatic synthesis of the unstable arene oxide, benzo[b]thiophene 2,3-oxide.

A Green and Versatile Route to Highly Functionalized Benzofuran Derivatives Using Biomimetic Oxygenation

“…This was assigned to oxygenation of benzofuran although the structural characterization was not definitive . Oxygenation of benzofuran and methylbenzofurans through other bio‐catalytic processes, using Pseudomonas putida or toluene dioxygenase, afforded dihydrodiols.…”

Enantiopurity and absolute configuration determination of arene cis‐dihydrodiol metabolites and derivatives using chiral boronic acids

“…The enantiomeric mixtures of diols ( 68a cis ‐d cis and 71a cis ‐c cis ), on reaction with (−)‐( S )‐MEPBA 4a S , formed the major boronate diastereomers ( 70a–d and 73a–c ). 1 H–NMR analyses of the boronates showed the upfield OMe signals between ( δ OMe 3.06–3.27) and provided a range of Δ δ OMe values (15–120); the ee values were found in the range 43–63% (Table ) . As recorded earlier for boronates of carbocyclic cis ‐dihydrodiols, from polycyclic arenes, larger Δ δ OMe values were again observed for metabolites ( 71a cis ‐c cis , Δ δ OMe 90–120 Diagram 4) compared with the much smaller Δ δ OMe values from the monocyclic cis diols ( 68a cis ‐d cis , Δ δ OMe 15–25).…”

“…Stereochemical characterization of cis ‐diol metabolites, initially formed by TDO‐catalyzed dihydroxylation of thiophene ( 68a cis ‐d cis , 71a cis , and 71b cis ) and furan ( 71c cis ) rings (Scheme ), proved to be difficult, due to their equilibration (epimerization) with the corresponding trans isomers ( 68a trans ‐d trans and 71a trans ‐c trans ) at ambient temperature …”

“…The epimerization involved a spontaneous ring opening process via acyclic aldehyde intermediates ( 69a–d and 72a–c ), with the equilibrium favoring trans isomers in hydroxylic solvents (80–100% trans in CD 3 OD or D 2 O) and cis isomers in less polar solvents (60–80% cis in CDCl 3 ) . Reaction with (−)‐( S )‐MEPBA 4a S simplified the problem of stereochemical analysis, presented by cis / trans isomerization of the heterocyclic diols, as the corresponding boronates ( 70a–d and 73a–c ) were only formed from cis isomers.…”

“…As separations (Δ δ OMe ) of diagnostic 1 H–NMR signals of the boronates, formed using MEPBA 4a S with (+) and (−)‐catechols ( 82a–e ), were relatively small ( δ OMe 3.15–3.28), it was considered appropriate to test the new boronic acid (+)‐MPPBA 4c R (Table ) . The magnitude of the observed values (Δ δ OMe 20–120), for boronates from enantiomers of catechols ( 82a–e ) with (+)‐MPPBA 4c R , confirmed that the reagent can be successfully applied, to determine the ee values of chiral catechol metabolites derived from benzylic alcohols, and possibly also to catechols derived from alkylaryl sulfoxides …”