We have determined the absolute configurations of conformationally flexible cis-dihydrodiol metabolites (cis-1,2-dihydroxy-3,5-cyclohexadienes), bearing different substituents (e.g., Br, F, CF3, CN, Me) in 3- and 5-positions, by the method of confrontation of experimental and calculated electronic CD spectra and optical rotations. Convergent results were obtained by both methods in eight out of ten cases. For the difficult cases, where either conformer population and/or chiroptical properties (calculated rotational strengths of the long-wavelength Cotton effect or optical rotations) of contributing conformers remain inconclusive, the absolute configuration could still be correctly assigned based on one of the biased properties (either ECD or optical rotation). This approach appears well-suited for a broad spectrum of conformationally flexible chiral molecules.
A combination method of ozonolysis and chiral stationary phase (CSP)-GC–MS analysis has been developed to determine the enantiopurity values and absolute configurations of a range of alkaloid and coumarin hemiterpenoids derived from C- and O-prenyl epoxides.
Abstract Toluene dioxygenase‐catalysed cis ‐dihydroxylations of substituted aniline and phenol substrates, with a Pseudomonas putida UV4 mutant strain and an Escherichia coli pCL‐4t recombinant strain, yielded identical arene cis ‐dihydrodiols, which were isolated as the preferred cyclohex‐2‐en‐1‐one cis ‐diol tautomers. These cis ‐diol metabolites were predicted by preliminary molecular docking studies, of anilines and phenols, at the active site of toluene dioxygenase. Further biotransformations of cyclohex‐2‐en‐1‐one cis ‐diol and hydroquinone metabolites, using Pseudomonas putida UV4 whole cells, were found to yield 4‐hydroxycyclohex‐2‐en‐1‐ones as a new type of phenol bioproduct. Multistep pathways, involving ene reductase‐ and carbonyl reductase‐catalysed reactions, were proposed to account for the production of 4‐hydroxycyclohex‐2‐en‐1‐one metabolites. Evidence for the phenol hydrate tautomers of 4‐hydroxycyclohex‐2‐en‐1‐one metabolites was shown by formation of the corresponding trimethylsilyl ether derivatives. magnified image
The cis-dihydrodiol enantiomer preferentially formed, by dioxygenase-catalysed oxidation of 1,4-disubstituted benzene substrates in growing cultures of Pseudomonas putida UV4, is found to be largely controlled by the relative size of the substituents.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Evidence that a 1,2-dihydroxycyclohexadienide anion is stabilized by aromatic "negative hyperconjugation" is described. It complements an earlier inference of "positive" hyperconjugative aromaticity for the cyclohexadienyl cation. The anion is a reactive intermediate in the dehydration of benzene cis-1,2-dihydrodiol to phenol. Rate constants for 3-substituted benzene cis-dihydrodiols are correlated by σ(-) values with ρ = 3.2. Solvent isotope effects for the reactions are k(H(2)O)/k(D(2)O) = 1.2-1.8. These measurements are consistent with reaction via a carbanion intermediate or a concerted reaction with a "carbanion-like" transition state. These and other experimental results confirm that the reaction proceeds by a stepwise mechanism, with a change in rate-determining step from proton transfer to the loss of hydroxide ion from the intermediate. Hydrogen isotope exchange accompanying dehydration of the parent benzene cis-1,2-dihydrodiol was not found, and thus, the proton transfer step is subject to internal return. A rate constant of ~10(11) s(-1), corresponding to rotational relaxation of the aqueous solvent, is assigned to loss of hydroxide ion from the intermediate. The rate constant for internal return therefore falls in the range 10(11)-10(12) s(-1). From these limiting values and the measured rate constant for hydroxide-catalyzed dehydration, a pK(a) of 30.8 ± 0.5 was determined for formation of the anion. Although loss of hydroxide ion is hugely exothermic, a concerted reaction is not enforced by the instability of the intermediate. Stabilization by negative hyperconjugation is proposed for 1,2-dihydroxycyclohexadienide and similar anions, and this proposal is supported by additional experimental evidence and by computational results, including evidence for a diatropic ("aromatic") ring current in 3,3-difluorocyclohexadienyl anion.
Toluene dioxygenase-catalysed oxidation of mono-substituted benzene substrates (R = F, Cl, Br, I, Me, Et, CH2OAc, CHCH2, CCH, CF3, CN, OMe, OEt, SMe) in growing cultures of Pseudomonas putida UV4 yielded the corresponding cis-dihydrodiol metabolites. Palladium-catalysed cross-coupling of cis-(1S,2S)-1,2-dihydroxy-3-iodocyclohexa-3,5-diene with a range of tributyltin compounds provided a chemoenzymatic route to a further series of cis-dihydrodiol derivatives of monosubstituted benzenes (R = D, CH2CHCH2, Bun, SEt, SPri, SBut, SPh, SC6H4Me-4). The enantiopurities and absolute configurations of the cis-dihydrodiols, obtained by both enzymatic and chemoenzymatic routes, were determined by several new methods including 1H NMR spectroscopic analysis of the bis-MTPA esters of the 4-phenyl-1,2,4-triazoline-3,5-dione cycloadducts, X-ray crystallography, circular dichroism spectroscopy and stereochemical correlation.
Procaryotic (bacterial) dioxygenase-catalysed asymmetric dihydroxylation of chromene and 2,2-dimethylchromene to yield the (4S)-enantiomers of the corresponding cis-diols exclusively is reported. The epoxide, and derived cis- and trans-diol products from the previously reported eucaryotic (mammalian) metabolism of precocene-1 (7-methoxy-2,2-dimethylchromene), and the corresponding epoxide and diol derivatives of chromene and 2,2-dimethylchromene, have now been obtained in enantiopure form by chemical resolution of the corresponding bromohydrins using methoxy-(trifluoromethyl)phenylacetic acid (MTPA) or camphanate esters. The absolute configurations of the epoxides, cis- and trans-diols have been determined by chemical synthesis from, and stereochemical correlation with, the corresponding camphanate and MTPA esters. X-Ray crystal structure analysis has provided an unequivocal method for assignment of the absolute stereochemistry in each case.
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