Absolute Configuration, Conformation, and Circular Dichroism of Monocyclic Arene Dihydrodiol Metabolites:  It is All Due to the Heteroatom Substituents

Abstract

Absolute configurations and conformations of selected cis-1,2-dihydrodiols, isolated from bacterial enzyme-catalyzed arene dihydroxylation, have been examined by comparison of experimental and DFT-calculated CD spectra and confrontation with the results of X-ray diffraction studies in the crystalline phase. The equilibrium between the diene P and M conformers in cis-dihydrodiols is strongly dependent on the intramolecular OH-OH, OH-pi, and OH-F hydrogen bonding pattern and is crucial in determining the sign and magnitude of the long-wavelength diene pi-pi transition Cotton effect. The differences originate from a dominant contribution of either P-helical (1b, X=Me) or M-helical conformers (1d, X=F), or are due to M and P low-energy conformers, both contributing a positive rotational strength (1c, X=Br). Computations show that cis-dihydrodiol 1e (X=CF3) has only one M conformer stabilized by an intramolecular O-H...F hydrogen bond. cis-Dihydrodiol 1f (X=CN) shows a Cotton effect of the sign opposite to the sense of helicity of the dominating conformer. The results of the computations highlight the inadequacy of the Diene Helicity Rule and the Allylic Chirality Rule to correlate observed Cotton effects with dihydrodiol absolute configuration. A reliable model is presented to predict the absolute configuration of substituted benzene dihydrodiol derivatives from CD spectra, based on the confrontation of DFT-computed and experimental CD spectra. For 3-alkyl derivatives, a simple noncomputational model is offered, which is based on the contributions of the allylic hydroxy groups and the diene core in P and M conformers.

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

“…In cases where full agreement (ECD and OR) is not achieved, analysis of conformer population and/or chiroptical properties of contributing conformers allows identification of one of the two properties (ECD or OR) with which the assignment of AC is considered conclusive. 26 Experimental and calculated ECD and OR measurements have been successfully applied to a series of chiral cis-dihydrodiol metabolites (B/B 0 Y 5 H or X = Y = H) obtained from the corresponding substituted benzene substrates (A, Y 5 H or X = Y = H; Scheme 1). [26][27][28] Thus, using whole cells of the bacterium Pseudomonas putida UV4 (a source of toluene dioxygenase, TDO), asymmetric dihydroxylation of monosubstituted benzene substrates A (Y 5 H) yielded mainly enantiopure (>98% ee) cis-dihydrodiols B (Y 5 H).…”

“…26 Experimental and calculated ECD and OR measurements have been successfully applied to a series of chiral cis-dihydrodiol metabolites (B/B 0 Y 5 H or X = Y = H) obtained from the corresponding substituted benzene substrates (A, Y 5 H or X = Y = H; Scheme 1). [26][27][28] Thus, using whole cells of the bacterium Pseudomonas putida UV4 (a source of toluene dioxygenase, TDO), asymmetric dihydroxylation of monosubstituted benzene substrates A (Y 5 H) yielded mainly enantiopure (>98% ee) cis-dihydrodiols B (Y 5 H). 26,29 Only the cis-dihydrodiol from fluorobenzene (A, X 5 F, Y 5 H) showed evidence of the other enantiomer B 0 (Y 5H, X 5F, 60-70% ee).…”

“…[26][27][28] Thus, using whole cells of the bacterium Pseudomonas putida UV4 (a source of toluene dioxygenase, TDO), asymmetric dihydroxylation of monosubstituted benzene substrates A (Y 5 H) yielded mainly enantiopure (>98% ee) cis-dihydrodiols B (Y 5 H). 26,29 Only the cis-dihydrodiol from fluorobenzene (A, X 5 F, Y 5 H) showed evidence of the other enantiomer B 0 (Y 5H, X 5F, 60-70% ee). By contrast, biotransformation of 1,4-disubstituted benzene cis-dihydrodiols (A, X = Y = H) often yielded both enantiomers (B/ B 0 , X = Y = H), particularly when substituents X and Y were of similar size.…”

44 Absolute Configuration

“…Although a similar approach was applied to the monocyclic arene dihydrodiol by Gawronski and coworkers [32], isoflavone dihydrodiol provides more challenges due to the rigid and resonance-stabilized chromen-4-one ring substituent. In the details of the CD spectrum simulation, the ground state geometry of four possible conformers of 2 0 ,3'-dihydro-(2 0 R,3 0 S)-cis-dihydroxyisoflavone was optimized at the restricted Hartree-Fock level using a standard semiempirical AM1 method of the HyperChem program (Fig.…”

“…Analytical Biochemistry 397 (2010) [29][30][31][32][33][34][35][36] Contents lists available at ScienceDirect…”