Circular dichroism, optical rotation and absolute configuration of 2-cyclohexenone-cis-diol type phenol metabolites: redefining the role of substituents and 2-cyclohexenone conformation in electronic circular dichroism spectra

Abstract

The absolute configurations of 2-cyclohexenone cis-diol metabolites resulting from the biotransformation of the corresponding phenols have been determined by comparison of their experimental and calculated circular dichroism spectra (TDDFT at the PCM/B2LYP/Aug-cc-pVTZ level), optical rotations (calculated at the PCM/B3LYP/Aug-cc-pVTZ level) and by stereochemical correlation. It is found that circular dichroism spectra and optical rotations of 2-cyclohexenone derivatives are strongly dependent on the ring conformation (M or P sofa S(5) or half-chair), enone non-planarity and the nature and positions of the hydroxy and alkyl substituents. The effect of non-planarity of the enone chromophore, including the distortion of the C=C bond, is determined for the model structures by TDDFT calculations at the PCM/B2LYP/6-311++G(2d,2p) level. Non-planarity of the C=C bond in the enone chromophore is commonly encountered in 2-cyclohexenone derivatives and it is a source of significant rotatory strength contribution to the electronic circular dichroism spectra. It is shown that the two lowest-energy transitions in acrolein and 2-cyclohexenone and its derivatives are n(C=O)-π(C=O)* and π(C=C)-π(C=O)*, as expected, while the shorter-wavelength (below 200 nm) transitions are of more complex nature. In 2-cyclohexenone and its alkyl derivatives it is predominantly a mixture of π(C=C)-π(C=C)* and π(C=C)-σ* transitions, whereas the presence of hydroxy substituent results in a dominant contribution due to the n(OH)-π(C=O)* transition. A generalized model for correlation of the CD spectra of 2-cyclohexenones with their structures is presented.

Oxidative biotransformations of phenol substrates catalysed by toluene dioxygenase: A molecular docking study

“…It was noted that, within the TDO active site, the meta-position of bound toluene was very close to the imidazole ring of His-311. This observation led to the proposal, that an attractive interaction between the acidic OH group of meta-phenol substrates and the basic imidazole ring, could explain the observed regio-and stereo-selective dihydroxylation of phenolic substrates, to yield cisdihydrodiols B and H and the preferred ketotautomers F and G [7][8][9][10][11]. Conversely, the TDO-catalysed cisdihydroxylation was inhibited by the presence of an alkyl group at the meta-position of non-phenolic disubstituted benzene substrates, e.g.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Thus, toluene dioxygenase (TDO) [2,3,[7][8][9][10][11], naphthalene dioxygenase (NDO) [9,12], biphenyl dioxygenase (BPDO) [9,12,13] and o-xylene dioxygenase (OXDO) [14] have all been used to catalyse the formation of catechols B, as major metabolites of phenols A. To date, the binding interactions of phenolic substrates with amino acid residues at the active site of RHDs are relatively unexplored.…”

“…TDO-catalysed hydroxylation mechanisms have been postulated to account for: (a) the formation of benzene-1,2-diols (catechols, D) via triol intermediates (C) [3], (b) benzene-1,4-diols (hydroquinones, E) [11,14] and (c) cyclohex-2-en-1-one cis-diols (F and G) via cis-dihydrodiol metabolites (B and H) [7][8][9][10][11]13] (Scheme 1). While the dehydration of cyclohex-2-en-1-onecis-diols F and G, to yield hydroquinones E, was observed in the presence of acid and occurred during biotransformations, neither triol C nor cisdihydrodiol intermediates B and H were detected.…”

“…Recent reports showed that, in many cases, catechols B were accompanied by a new family of cyclohex-2-en-1-one cis-diols, as major metabolites (F and G) [7][8][9][10][11]13]. Biotransformations of phenols, with the TDO-expressing constitutive mutant Pseudomonas putida UV4 and recombinant strain Escherichia coli p-CL-4t, resulted in more than twenty cyclohex-2-en-1-one cis-diols (F and G) being added to this new family of metabolites [7][8][9][10][11].…”

“…Biotransformations of phenols, with the TDO-expressing constitutive mutant Pseudomonas putida UV4 and recombinant strain Escherichia coli p-CL-4t, resulted in more than twenty cyclohex-2-en-1-one cis-diols (F and G) being added to this new family of metabolites [7][8][9][10][11]. Hydroquinones E were also detected as minor phenol derivatives using bacteria expressing TDO [7][8][9][10][11], NDO [12], BPDO [12]and OXDO [14].…”