syn-Benzene dioxides: chemoenzymatic synthesis from 2,3-cis-dihydrodiol derivatives of monosubstituted benzenes and their application in the synthesis of regioisomeric 1,2- and 3,4-cis-dihydrodiols and 1,4-dioxocins

Abstract

cis-2,3-Dihydrodiol metabolites of monosubstituted halobenzenes and toluene have been used as synthetic precursors of the corresponding 3,4-cis-dihydrodiols. Enantiopure syn-benzene dioxide intermediates were reduced to the 3,4-cis-dihydrodiols and thermally racemised via the corresponding 1,4-dioxocins. The syn-benzene dioxide-1,4-dioxocin valence tautomeric equilibrium ratio was found to be dependent on the substituent position. The methodology has also been applied to the synthesis of both enantiomers of the 1,2-(ipso)- and 3,4-cis-dihydrodiols of toluene. This chemoenzymatic approach thus makes available, for the first time, all three possible cis-dihydrodiol regioisomers of a monosubstituted benzene.

Determination of absolute configuration of conformationally flexible cis‐dihydrodiol metabolites: Effect of diene substitution pattern on the circular dichroism spectra and optical rotations

“…The other % ee values were determined by stereochemical correlation during their chemoenzymatic synthesis (3a-3f, method iv). 37 X-ray crystallography of the cycloadduct diMTPA esters (from 1a, 1d, and 5e) and stereochemical correlation (3a-3f, method iv) provided unequivocal AC determination methods. Tentative ACs were determined by method ii (1b, 1c, 2b, 2d, 2f, and 5a-5e) and method iii (1b, 2b, 2g, and 5f ).…”

“…Support for the electron-donating effect of a fluorine atom on an alkene group (trigonal carbon atoms) was evident from the upfield 1 H d values of vinyl fluoride groups in intermediates involved in the synthesis of 3b. 37 The case of trifluoromethyl-substituted cis-dihydrodiols 1c and 2c is exceptional. As found previously for 4c, 26 when X 5 CF 3 conformer M 2 is the most stable one due to the strong intramolecular hydrogen bond OÀ ÀHÁ Á ÁF 3 C.…”

“…The cis-dihydrodiols 3a, 3b, 3d, obtained from 4a, 4b and 4d, respectively, by chemoenzymatic synthesis (and 3c), 37 deserve special mention, since the substituent Y cannot directly interact with the hydroxy groups, as does the X group in other cis-dihydrodiols. This is reflected in the observation that neither M 2 nor P 2 contribute significantly to the pool of low-energy conformers.…”

Arene cis‐Diol Dehydrogenase‐Catalysed Regio‐ and Stereoselective Oxidation of Arene‐, Cycloalkane‐ and Cycloalkene‐cis‐diols to Yield Catechols and Chiral α‐Ketols

“…Although the NCDD enzyme was found to catalyse the preferential dehydrogenation of 2 S enantiomers of 2,3‐ cis ‐dihydrodiols, its ability to accept the isomeric 3,4‐ cis ‐dihydrodiols 3 S , as substrates, had not been investigated in the past, due to their unavailability (Scheme ). Several 3,4‐ cis ‐dihydrodiols 3 S have been reported in recent years, as very minor metabolites,6c,e,f and others have been obtained by a four‐step chemoenzymatic synthesis, from the corresponding 2,3‐ cis ‐dihydrodiols 2 S 8e. A sample of 3,4‐ cis ‐dihydrodiol 3d S , available from the latter study, when used as a substrate for E. coli narB yielded bromocatechol 5d in excellent yield (84%).…”

“…This may account for the regio‐ and stereoselectivity aspects of cis ‐diol dehydrogenase‐catalysed formation of catechols having received relatively little attention 7a–h. The recent development of chemoenzymatic routes to 2,3‐ cis ‐dihydrodiol enantiomers 2 R ,8a,b cis ‐dihydrodiol diastereoisomers 2 S 8c,d and 3,4‐ cis ‐dihydrodiol regioisomers 3 S 8e provided the opportunity for further studies of regio‐ and stereoselectivity of benzene cis ‐diol dehydrogenase (BCDD) and naphthalene cis ‐diol dehydrogenase (NCDD) enzymes, during the formation of catechols 4 or 5 (Scheme ).…”