Absolute configuration determination of chiral molecules in the solution state using vibrational circular dichroism

Advances in the measurement, calculation, and application of vibrational circular dichroism (VCD) for the determination of absolute configuration are described. The purpose of the review is to provide an up-to-date perspective on the capability of VCD to solve problems of absolute stereochemistry for chiral molecules primarily in the solution state. The scope of the article covers the experimental methods needed for the accurate measurement of VCD spectra and the theoretical steps required to systematically deduce absolute configuration. Determination of absolute configuration of a molecule by VCD requires knowledge of its conformation or conformational distribution, and hence VCD analysis necessarily provides solution-state conformation information, in many cases available by no other method, as an additional benefit. Comparisons of the advantages and limitations of VCD relative to other available chiroptical methods of analysis are also presented.     

X-ray diffraction studies on the absolute configuration of alpha- and beta-anordrins

The molecular structures and absolute configurations of alpha- and beta-anordrins are reported. Pure alpha- and beta-epimers were obtained with recrystallization and column chromatography combined with high-pressure liquid chromatography methods; they were identified by high-resolution infrared and mass spectra and 1H and 13C nuclear magnetic resonance. By single crystal x-ray diffraction analysis, the crystals of alpha- and beta-epimers were found to belong to the orthorhombic space groups P2(1)2(1)2(1) and P2(1)2(1)2, respectively. The molecular structures of these two epimers were determined. The absolute configurations were deduced by conformation analysis, 1H nuclear magnetic resonance, and comparison with the absolute configuration of the starting material. The absolute configurations of asymmetric centers of alpha- and beta-epimers were observed to be 2R, 5S, 8R, 9S, 10S, 13S, 14S, 17R, and 2S, 5S, 8R, 9S, 10S, 13S, 14S, 17R, respectively. These results were confirmed by the x-ray diffraction determination of the absolute configuration of 2 alpha,17 alpha-diethynyl-A-nor-5 alpha- androstane-2 beta, 17 beta-diol dichloroacetate.     

Direct assignment of the absolute configuration of molecules from crystal morphology

A method for direct assignment of the absolute configuration of molecules and the absolute structures of polar crystals, independent to that of Bijvoet, is described. The method correlates between the two-dimensional packing arrangement of specific faces, that delineate crystals during their growth and dissolution, with molecules present in the environment. The structural information stored in these faces is transferred to "tailor-made" molecules added to the solvent by controlled morphological changes induced to the growing crystals and by the creation of etch pits at specific crystal faces during their dissolution. In addition, the "tailor-made" molecules are occluded enantioselectively as guests within specific sectors of the host crystals. The method is illustrated for a variety of molecules and crystals including the assignment of the absolute configuration of several alpha-amino acids as "tailor-made" additives in centrosymmetric crystals of glycine and serine, for the absolute structure of polar crystals of sugars and alpha-amino acids and consequently the absolute configuration of molecules packed in such crystals.     

Chemical study of the essential oil of Cyperus rotundus.

Minor constituents of the essential oil of Cyperus rotundus have been investigated. The three new sesquiterpene hydrocarbons (-)-isorotundene, (-)-cypera-2,4(15)-diene, (-)-norrotundene and the ketone (+)-cyperadione were isolated and their structures elucidated. The absolute configuration of (-)-rotundene was derived by chemical correlation and enantioselective gas chromatography.     

Marine bis-γ-pyrone polypropionates of onchidione family and their effects on the XBP1 gene expression

Two additional new members of the onchidione family, 16-epi-onchidione (1) and 4-epi-onchidione (2), co-occurring with six previously reported bis-γ-pyrone polypropionates including onchidione (3), were isolated from the marine pulmonate Onchidium sp. Their structures were determined by extensive spectroscopic analysis and by comparison with 3 and onchidione-related derivatives. The absolute configuration of 1 was established by X-ray diffraction analysis employing graphite monochromated Cu K_α radiation (λ?=?0.71073?Å) with small Flack parameter 0.08. In addition, the absolute stereochemistry of previously reported onchidionol (6) was confirmed by the X-ray diffraction analysis. Some of the isolated compounds showed significant activation effects on the splicing of XBP1 mRNA as ER stress modulators to inhibit the growth of tumors.     

Absolute configuration of tropane alkaloids bearing two alpha,beta-unsaturated ester functions using electronic CD spectroscopy: application to (R,R)-trans-3-hydroxysenecioyloxy-6-senecioyloxytropane

The absolute configuration of heterocyclic natural products substituted with two mobile alpha,beta-unsaturated esters was studied using electronic circular dichroism (CD) spectroscopy. The conformational flexibility of the side chains imposed the use of density functional theory calculation to determine the set of the most probable conformations in solution. The electronic CD and UV spectra were calculated by Boltzmann-weighted average of the simulated spectra using the results of the excited states calculation of a set of simplified structures. Comparison with the experimental CD spectrum allowed to determine whether the calculations were made with the right enantiomer. The method was applied to the determination of the absolute configuration of (R,R)-trans-3-hydroxysenecioyloxy-6-senecioyloxytropane.     

Absolute configuration of (-)-2,6-dimethyl-10-(p-tolyl)-2,6(E)-undecadiene from Cistus monspeliensis

(-)-2,6-Dimethyl-10-(p-tolyl)-2,6(E)-undecadiene (1) is a major constituent in the essential oil of Cistus monspeliensis, an aromatic shrub common in Mediterranian countries. 1 was isolated by column chromatography, subjected to ozonolyses, and the absolute configuration was determined by enantioselective gas chromatographic correlation with the ozonolysis product of the sesquiterpene hydrocarbon ar-curcumene with known absolute configuration.     

Conformational,configurational, and supramolecular studies of podocephalol acetate from Lasianthaea aurea

Although podocephalol ( 1 ) and its derived acetate 2 were found in Lasianthaea podocephala four decades ago, and 1 was later detected in the essential oils of several vegetal species, its absolute configuration (AC) and conformational preferences remained to be established. The structures of ar‐himachalene 1 , now isolated from Lasianthaea aurea, and its derived acetate 2 , were herein confirmed by extensive 1D and 2D nuclear magnetic resonance (NMR) studies, while the conformational preferences of the cycloheptene was established by density functional theory (DFT) calculations, which in combination with vibrational circular dichroism measurements provided the (R) absolute configuration of the molecules. The structure and AC were further verified through the Flack and Hooft parameters calculations derived from single crystal X‐ray diffraction data of 2 . In addition, careful evaluation of the crystal data allowed observing supramolecular layers cell package, an uncommon property in natural terpenes that might have potential applications. A transmission electron microscopy analysis of crystal of 2 was also possible, providing its physical characteristics at the micrometric scale.     

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Asymmetric Autocatalysis Induced by Chiral Crystals of Achiral Tetraphenylethylenes

The achiral hydrocarbon tetraphenylethylene crystallizes in enantiomorphous forms (chiral space group: P2₁) to afford right- and left-handed hemihedral crystals, which can be recognized by solid-state circular dichroism spectroscopic analysis. Chiral organic crystals of tetraphenylethylene mediated enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to give, in conjunction with asymmetric autocatalysis with amplification of chirality, almost enantiomerically pure (S)- and (R)-5-pyrimidyl alkanols whose absolute configurations were controlled efficiently by the crystalline chirality of the tetraphenylethylene substrate. Tetrakis(p-chlorophenyl)ethylene and tetrakis(p-bromophenyl)ethylene also show chirality in the crystalline state, which can also act as a chiral substrate and induce enantioselectivity of diisopropylzinc addition to pyrimidine-5-carbaldehyde in asymmetric autocatalysis to give enantiomerically enriched 5-pyrimidyl alkanols with the absolute configuration correlated with that of the chiral crystals. Highly enantioselective synthesis has been achieved using chiral crystals composed of achiral hydrocarbons, tetraphenylethylenes, as chiral inducers. This chemical system enables significant amplification of the amount of chirality using spontaneously formed chiral crystals of achiral organic compounds as the seed for the chirality of asymmetric autocatalysis.     

Revision of the absolute configuration of plumericin and isoplumericin from Plumeria rubra

The absolute configurations of plumericin (1) and isoplumericin (2), isolated from Plumeria rubra, were re-assigned based on a combination of X-ray crystal-structure determination and quantum-mechanical calculations of their circular dichroism (CD) spectra. The experimental CD spectra showed an excellent match with those calculated for the (1S,5R,8R,9R,10R) absolute configuration (corresponding to ent-1 and ent-2, resp.), opposite to that generally accepted and published in the literature. Since the (false) plumericin configuration has been often used to derive the absolute configuration of related iridoids by chemical correlation, their absolute configurations also have to be reconsidered.     

Fast methods of enantiopurity determination for the Soai reaction: Towards a general enantioenrichment detector?

The Soai reaction system possesses a remarkable combination of characteristics (enantioselective autocatalysis, strong positive nonlinearity leading to asymmetric amplification, ability to be triggered by wide variety of exogenous enantioenriched materials) that make it a potential starting point for a generalized detector for enantioenrichment. In this study we apply standard approaches used in pharmaceutical process research to the problem of developing a rapid method for analysis of the enantiopurity of the Soai reaction product. Several methods for rapid analysis (<1 min per sample) are described, including an approach using chiral supercritical fluid chromatography (SFC) and an approach using achiral chromatography with circular dichroism (CD) detection. Some thoughts on incorporation into a device for generalized enantioenrichment detection are presented.     

Structure determination of chiral sulfoxide in diastereomeric bicalutamide derivatives

We report on the synthesis and investigation of two diastereomers (5a and 5b) of a new bicalutamide analog with an asymmetric carbon atom and a chiral sulfoxide group. These bicalutamide analogs are novel androgen receptor antagonists with biological activities that depend significantly on the configuration of their stereogenic centers. We determined the absolute configuration at the SO center by combining X-ray and NMR measurements with quantum chemical calculations. Since 5a and 5b failed to yield satisfactory crystals for X-ray crystal structure determination, analogs 6a and 6b differing in only one remote functional group relative to the chiral sulfoxide were synthesized, which yielded satisfactory crystals. X-ray structure determination of 6a and 6b provided the absolute configuration at the chiral sulfoxide. Since the structural difference between 5 and 6 is remote from the chiral sulfoxide, the structural assignment was extended from the diastereomers of 6 to those of 5 provisionally. These assignments were verified with the help of measured and DFT-calculated proton and carbon NMR chemical shifts.     

Enantioselective semipreparative HPLC separation of PCB metabolites and their absolute structure elucidation using electronic and vibrational circular dichroism

Polychlorinated biphenyls (PCBs) remain one of the most important groups of environmental contaminants. The fate (transformation) as well as the toxicological implications of the different metabolism steps are subject to considerable debate. The aim of this study is to start a comprehensive investigation of atropisomeric PCB metabolites, i.e., hydroxy, methoxy, methylthionyl, and methylsulfonyl PCBs in different biota. For this purpose, enantioselective semipreparative liquid chromatography is used to obtain pure enantiomers of PCB metabolites. Electronic circular dichroism (UV-CD) and vibrational circular dichroism (VCD) in combination with computational techniques were applied to determine their absolute structures. Approximately 18-25 mg of each enantiomer of the following metabolites were obtained using semipreparative HPLC on beta-cyclodextrin-based columns: 4-MeO-CB149, 4-MeS-CB149, 4-MeSO2-CB149, 3-MeS-CB149, and 3-MeSO2-CB149. The enantiomeric purity of the separated enantiomers was in the range of 95.0-99.9%. Rotational angles and absolute configurations were also determined. This study establishes a sound method for future preparation and absolute structure determination of compounds belonging to the same class.     

Sesquiterpenoids and diarylheptanoids from Nidus vespae and their inhibitory effects on nitric oxide production

Two coriamyrtin-type sesquiterpenes, fengfangin A (1) and tutin (2), and six diarylheptanoids, namely alnusone (3), centrolobol (4), muricarpone B (5), 1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)heptan-3-one (6), (3S)-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)heptan-3-ol (7), and (3S)-1-(4-hydroxyphenyl)-7-(3,4-dihydroxyphenyl)heptan-3-ol (8), were isolated from the 95% EtOH extract of nidus vespae, the nest of Polistes species. Their structures were identified by spectroscopic methods. Compounds 1 and 8 are new products. The absolute configuration of 1 was determined by single-crystal X-ray diffraction analysis using Flack parameter. The biological tests showed that compounds 5, 6, and 8 could inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells with IC(50) values in the range of 13-17 μM, whereas the sesquiterpenes were inactive in this assay (>25 μM). In addition, the ecological significance of the presence of neurotoxic sesquiterpene lactones in nidus vespae is briefly discussed.     

Vibrational Circular Dichroism (VCD), VCD Exciton Coupling,and X‐ray Determination of the Absolute Configuration of an α,β‐Unsaturated Germacranolide

The absolute configuration of 1 was deduced by vibrational circular dichroism together with the evaluation of the Flack and Hooft X‐ray parameters. Vibrational circular dichroism exciton coupling, using the carbonyl group signals, confirmed the absolute configuration of 2 . In addition, sodium borohydride reduction of the 11,13‐double bond of 6‐epi‐desacetyllaurenobiolide ( 1 ) yields an almost equimolecular mixture of C11 epimers, while reduction of the same double bond of 6‐epi‐laurenobiolide ( 2 ) provided almost exclusively the (11S) diastereoisomer 4 . Chirality 27:247–252, 2015. © 2015 Wiley Periodicals, Inc.     

Enantioselective analysis of praziquantel in plasma samples

A direct enantioselective high-performance liquid chromatography method is described for the quantitative determination of praziquantel enantiomers in plasma samples. The method involves two-step extraction of plasma with toluene, evaporation of the solvent and chromatography on a Chiralcel OD-H column using hexane-ethanol (85:15, v/v) as the mobile phase and detection at 220 nm. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies.     

Intensity Correlation-Based Calibration of FRET

Dual-laser flow cytometric resonance energy transfer (FCET) is a statistically efficient and accurate way of determining proximity relationships for molecules of cells even under living conditions. In the framework of this algorithm, absolute fluorescence resonance energy transfer (FRET) efficiency is determined by the simultaneous measurement of donor-quenching and sensitized emission. A crucial point is the determination of the scaling factor α responsible for balancing the different sensitivities of the donor and acceptor signal channels. The determination of α is not simple, requiring preparation of special samples that are generally different from a double-labeled FRET sample, or by the use of sophisticated statistical estimation (least-squares) procedures. We present an alternative, free-from-spectral-constants approach for the determination of α and the absolute FRET efficiency, by an extension of the presented framework of the FCET algorithm with an analysis of the second moments (variances and covariances) of the detected intensity distributions. A quadratic equation for α is formulated with the intensity fluctuations, which is proved sufficiently robust to give accurate α-values on a cell-by-cell basis in a wide system of conditions using the same double-labeled sample from which the FRET efficiency itself is determined. This seemingly new approach is illustrated by FRET measurements between epitopes of the MHCI receptor on the cell surface of two cell lines, FT and LS174T. The figures show that whereas the common way of α determination fails at large dye-per-protein labeling ratios of mAbs, this presented-as-new approach has sufficient ability to give accurate results. Although introduced in a flow cytometer, the new approach can also be straightforwardly used with fluorescence microscopes.     

Vibrational and electronic circular dichroism monitoring of copper(II) coordination with a chiral ligand

Novel copper(II) coordination compounds with chiral macrocyclic imine ligands derived from R-/S-camphor were asymmetrically synthesized and characterized with the aid of chiroptical spectroscopies. Crystal structures of both enantiomers were determined by single crystal X-ray diffraction analysis. Circular dichroism (CD) spectra were analyzed using a simplified exciton model as well as quantum chemical computations. The absolute configuration of the copper(II) coordination compounds determined from CD was found consistent with the crystal data. The copper(II) complexes were further investigated by vibrational CD (VCD) measurement combined with density functional theory calculation. The complex formation was evidenced by spectral shifts of the characteristic bands in the CD and VCD spectra.