Hyperolactone C: determination of its absolute configuration by comparison of experimental and calculated CD spectra

A detailed conformational analysis of hyperolactone C diastereomers and enantiomers ((5R,9R),(5S,9S) and (5S,9R),(5R,9S)) was done with molecular mechanics and density functional theory methods. Time-dependent density functional theory (B3PW91/TZVP) was used to calculate electronic transition energies (UV/vis spectra) and rotational strengths of the respective conformations. The effect of solvation (acetonitrile solution) on excitation energies and electronic circular dichroism was approximated by the polarizable continuum model. By comparison of the simulated CD spectrum with that measured for hyperolactone C isolated from Hypericum lloydii, its absolute configuration can be assigned as (5S,9S).     

Quantum-chemical calculations on the electronic circular dichroism of (-)-dibromophakellin and (-)-dibromophakell-statin

The CD spectra of the pyrrole-imidazole alkaloids, (-)-dibromophakellin and (-)-dibromophakellstatin, have been calculated employing the quantum-chemical time-dependent density functional theory. Comparison of calculated and measured spectra showed that this well-established method is also a useful tool to elucidate the absolute stereochemistry of this class of compounds. The computational results have further been used to analyze the spectra measured in methanol and to explain the remarkable red shift of one CD band when trifluoroethanol is used as a solvent instead of methanol.     

An attempt to determine the absolute configuration of two ascolactone stereoisomers with time-dependent density functional theory

Two stereoisomers of ascolactone (A, B), natural products with two asymmetric carbon atoms, are isolated from the marine-derived fungus Ascochyta salicorniae. Although these compounds show virtually opposite CD spectra and [alpha]D, 1H- and 13C-NMR data exclude the presence of enantiomers and suggest ascolactone A and B to be epimeric lactones. By comparing the experimental CD spectra with those calculated employing time-dependent density functional theory (TDDFT), we elucidate the configuration at one of the asymmetric carbon atoms.     

Chiral dialkyl ditellurides: Conformation of chiral chromophore by circular dichroism and DFT calculation

The twisted structure of ditellurides, in a similar way as in other dichalcogenes, leads to different absorption of circularly polarized light by quasi‐enantiomeric chiral orbitals. Chiral optically active ditellurides are not common compounds and this phenomenon is not widely reported. As chiral ditellurides found an application in asymmetric synthesis, their molecular structure, understood as their conformation, became an important factor for understanding their reactivity. Until now there are few examples of chiral ditellurides known and their structure was not analyzed in details. This article presents the results of our most recent research on the structure of chiral ditellurides investigated by electronic circular spectroscopy (ECD) supported by quantum‐chemical calculation. This enables us to suggest a relationship between chirality of alkyl substituent and chirality (conformation) of ditelluride.     

A theoretical study on the exciton circular dichroism of propeller‐like metal complexes of bipyridine and tripodal tris(2‐pyridylmethyl)amine derivatives

Time‐dependent density functional theory (TD‐DFT) has been employed to simulate the circular dichroism (CD) spectra of bipyridyl ruthenium(II) complexes as well as zinc(II) and copper(II) complexes containing tris(2‐pyridylmethyl)amine (TPA) derivatives. A qualitative model is used to account for the mechanism by which the bis‐ and tris‐bipyridine complexes (or analogous systems) exhibit exciton CD. The model is further used to predict the sign of the exciton CD bands. The predictions are in agreement with experiment and DFT calculations. A comprehensive analysis is presented of the subtle differences in the CD spectra of this series of related complexes. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Absolute configuration and conformational analysis of a degradation product of inhalation anesthetic Sevoflurane: A vibrational circular dichroism study

1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane, compound B, is a product obtained in the degradation of the anesthetic Sevoflurane. Enantiopure (+)-B was investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-B in CDCl(3) solution in the 2,000-900 cm(-1) region are compared with the ab initio predictions of absorption and VCD spectra obtained from density functional theory using B3LYP/6-31G* basis set for different conformers of (S)-1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane. This comparison indicates that (+)-B is of the (S)-configuration in CDCl(3) solution, in agreement with previous literature results. Our results also indicate that this compound adopts six predominant conformations in CDCl(3) solution.     

Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion,electronic circular dichroism,and vibrational circular dichroism spectra

The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5‐dimethyl‐2‐(naphthalen‐1‐yl)‐6‐(naphthalen‐1‐yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (−)‐(aR , aR ), or conversely (+)‐(aS , aS ).     

Ab initio calculations for the optical rotations of conformationally flexible molecules: a case study on six-, seven-, and eight-membered fluorinated cycloalkanol esters

Based on the time-dependent density functional response theory, an approach for the prediction of optical rotations of enantiomers of conformationally flexible molecules was developed. The method was applied successfully for the determination of the absolute configuration of trans-2-fluorocycloalkanol acetates with different ring sizes. The largest deviations between experimental and theoretical [alpha](D) values are 10 deg x [dm x (g/cc)](-1) (about 20% error). These theoretical results suggest that the optical rotation in these molecules is dominated by the local (1R;2R) configuration of the two substituents and that different ring and even axial/equatorial orientations play a less important role.     

Absolute configuration of 3-hydroxy acids formed by Stenotrophomonas maltophilia: application of multidimensional gas chromatography and circular dichroism spectroscopy.

The soil bacterium Stenotrophomonas maltophilia was found to transform various long-chain fatty acids selectively into 3-hydroxy fatty acids of shorter chain length. Their chiral evaluation was performed by multidimensional gas chromatography (MDGC) on modified cyclodextrin phase comparing the enantiodistribution of 1,3-diol formed without loss of stereochemical information from a representative microbial product with those of synthetic (3RS)- and (3S)-1,3-diols. Enantiomeric excesses of 84-98% (R) were determined for the microbially produced 3-hydroxy acids. In addition, the CD exciton chirality method was applied to determine their absolute configuration. Derivatization with 9-anthryldiazomethane and 2-naphthoylimidazole led to the required bichromophoric structures. Their CD spectra displayed a positive first Cotton effect around 254 nm and a negative second Cotton effect around 237 nm, which confirmed the (R)-configuration of the bacterial products.     

Absolute configuration of the diterpenoids icetexone and conacytone from Salvia ballotaeflora

Detailed literature inspections regarding the diterpenoids icetexone ( 1 ) and conacytone ( 3 ) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single‐crystal X‐ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kα graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate ( 2 ) and conacytone triacetate ( 4 ) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4 , respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3‐hydroxythymoquinone ( 6 ) and its tautomer 4‐hydroxy‐1,2‐quinone 7 , on 6‐hydroxythymoquinone ( 8 ) and its tautomer ortho‐quinone 9 , and on icetexone ( 1 ) and the claimed natural occurring ortho‐quinone tautomer romulogarzone ( 5 ) indicate that 2‐hydroxy‐1,4‐quinones are more stable, by some 11‐14 kcal/mol, than their 4‐hydroxy‐1,2‐quinone tautomers, and therefore, romulogarzone ( 5 ) is inexistent.     

Solvent‐dependent inversion of circular dichroism signal in naproxen: An unusual effect!

The electronic circular dichroism (ECD) spectra of naproxen enantiomers were studied as a function of solvents using experimental (circular dichroism) and theoretical (time‐dependent density functional theory) approaches. The (R)‐ and (S)‐naproxen enantiomers presented an unusual inversion in their ECD signals in the presence of ethanol and water when compared with polar aprotic solvents such as acetonitrile. From a practical point of view, these findings deserve great attention because these solvents are widely used for high‐performance liquid chromatography analysis in quality control of chiral pharmaceutical drugs. This is particularly relevant to naproxen because the (S)‐naproxen has anti‐inflammatory properties, whereas (R)‐naproxen is hepatotoxic. A time‐dependent density functional theory computer simulation was conducted to investigate the signal inversion using the solvation model based on density, a reparameterization of polarized continuum model. Electronic circular dichroism signals of conformers were calculated by computer simulation and their contribution to the combined spectra obtained according to Boltzmann weighting. It was found that the experimentally observed ECD signal inversion can be associated with the minor or major contribution of different conformers of naproxen.     

Study on the Absolute Configurations of 3‐Alkylphthalides using TDDFT Calculations of Chiroptical Properties

Absolute configurations (ACs) of 3‐alkylphthalides including natural products (?)‐3‐n‐butylphthalide ( (S)‐1 ) and fuscinarin have been studied using chiroptical properties and quantum chemical calculation. Electronic circular dichroism and optical rotatory dispersion spectra of (S)‐1 predicted adopting time‐dependent density functional theory and hybrid functionals coincide very well with the experimental and literature data of (S)‐1 , leading unambiguously to AC assignment as S for levorotatory isomer. The relationship between structures and chiroptical properties of 3‐alkylphthalides were also studied using theoretical calculation. It is found that when the alkyl group is adjacent to the single chiral center in the molecule, both the length of the alkyl side chain and the polarity of solvent may exert significant effect on electronic circular dichroism spectra. On the basis of these observations, it is recommended that the long‐chain alkyl group may be replaced by at least propyl instead of methyl group in such compounds. The present work shows that combination of chiroptical properties and ab initio calculations can provide a feasible and reliable way to the AC establishment of novel 3‐alkylphthalide derivatives with a high degree of confidence. Chirality 24:987‐993, 2012. © 2012 Wiley Periodicals, Inc.     

Enantiomers of C(5)-chiral 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives: Analytical and semipreparative HPLC separation, chiroptical properties, absolute configuration, and inhibitory activity against monoamine oxidase

The HPLC enantiomer separation of a novel series of C(5)-chiral 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives, with inhibitory activity against monoamine oxidases (MAO) type A and B, was accomplished using polysaccharide-based chiral stationary phases (CSPs: Chiralpak AD, Chiralcel OD, and Chiralcel OJ). Pure alcohols, such as ethanol and 2-propanol, and typical normal-phase binary mixtures, such as n-hexane and alcohol modifier, were used as mobile phases. Single enantiomers of several analytes examined were isolated on a semipreparative scale, and their chiroptical properties were measured. The assignment of the absolute configuration was established for one compound by single-crystal X-ray diffraction method and for the other three by CD spectroscopy. The inhibitory activity against MAO of racemic samples and single enantiomers were evaluated in vitro.