Renaissance in chiroptical spectroscopic methods for molecular structure determination

Two of the chiroptical spectroscopic methods, namely optical rotatory dispersion (ORD) and electronic circular dichroism (ECD), have been around for several decades. But their use in determining the absolute configuration and predominant conformation is gaining renewed interest with the availability of quantum mechanical methods for predicting ORD and ECD. Two other methods, namely vibrational circular dichroism (VCD) and vibrational Raman optical activity (VROA), are relatively new and offer convenient approaches for deducing the structural information in chiral molecules. With the availability of quantum mechanical programs for predicting VCD and VROA, these methods have attracted numerous new researchers to this area. This review summarizes the latest developments in these four areas and provides examples where more than one method has been used to confirm the information obtained from individual methods.     

Chiroptical spectroscopic determination of molecular structures of chiral sulfinamides: t-butanesulfinamide

The absolute configuration of t-butanesulfinamide has been determined as (-)-(S) using three different chiroptical spectroscopic methods, namely, vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD). Furthermore, the predominant conformation of this molecule is determined to have S=O and NH2 groups staggered with respect to the three methyl groups and to have amine hydrogens in gauche orientation with respect to S=O. The quality of predictions obtained for vibrational properties, namely, vibrational absorption and VCD, is found to be satisfactory with the B3LYP functional and 6-31G* basis set. However, this basis set is found to be inadequate for obtaining reliable predictions of electronic properties, namely, electronic absorption and ECD, but a larger aug-cc-pVDZ basis set is found to provide satisfactory prediction of electronic properties. t-Butanesulfinamide serves as an example which invalidates the recommendation of using the 6-31G* basis set for molecules that exhibit the same sign for the long-wavelength ECD band and ORD. This molecule also emphasizes the importance of simultaneous investigation of ECD and ORD, and the use of multiple chiroptical spectroscopic methods, for reliable determination of molecular stereochemistry.     

Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism, and optical rotation: the iridoids plumericin and isoplumericin

The absolute configurations (ACs) of the iridoid natural products, plumericin (1) and isoplumericin (2), have been re-investigated using vibrational circular dichroism (VCD) spectroscopy, electronic circular dichroism (ECD) spectroscopy, and optical rotatory dispersion (ORD). Comparison of DFT calculations of the VCD spectra of 1 and 2 to the experimental VCD spectra of the natural products, (+)-1 and (+)-2, leads unambiguously to the AC (1R,5S,8S,9S,10S)-(+) for both 1 and 2. In contrast, comparison of time-dependent DFT (TDDFT) calculations of the ECD spectra of 1 and 2 to the experimental spectra of (+)-1 and (+)-2 does not permit definitive assignment of their ACs. On the other hand, TDDFT calculations of the ORD of (1R,5S,8S,9S,10S)-1 and -2 over the range of 365-589 nm are in excellent agreement with the experimental data of (+)-1 and (+)-2, confirming the ACs derived from the VCD spectra. Thus, the ACs initially proposed by Albers-Sch?nberg and Schmid are shown to be correct, and the opposite ACs recently derived from the ECD spectra of 1 and 2 by Els?sser et al. are shown to be incorrect. As a result, the ACs of other iridoid natural products obtained by chemical correlation with 1 and 2 are not in need of revision.     

Chiroptical spectroscopy and the validation of crystal structure stereochemical assignments

The absolute stereochemistry of chiral molecules is ideally established to atomic resolution by X-ray crystallographic analysis. However, chiroptical spectroscopies, namely electronic circular dichroism (ECD), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD) and Raman optical activity (ROA), play important complementary roles in establishing relative and absolute sterochemistries as well as allowing determinations of optical purity. A brief summary of chiroptical spectroscopies is presented, along with guidance to their advantages and disadvantages. The application of ECD to verifying that single crystals selected for crystallographic analysis are indeed representative of bulk material is described.     

Absolute configuration assignment of caffeic acid ester derivatives from Tithonia diversifolia by vibrational circular dichroism: the pitfalls of deuteration

Recently, it was observed that infrared (IR) and vibrational circular dichroism (VCD) calculations including deuterated hydroxyl groups in phenolic and saccharide moieties improved significantly the agreement with experimental data obtained in methanol-d₄. In the present study, the relative and absolute configurations of three methanol-soluble caffeic acid ester derivatives 1–3, isolated from Tithonia diversifolia, were established by a combined use of experimental and calculated ¹³C NMR chemical shifts, as well as electronic circular dichroism (ECD) and VCD spectroscopies. Interestingly, the attempt to reproduce the deuteration pattern arising from possible isotopic exchange in methanol-d₄ solution led to nearly mirror image calculated VCD spectra for 1 when compared to the non-deuterated molecule with the same absolute configuration. This latter fact can potentially lead to absolute configuration misassignments. A closer inspection of the vibrational chiroptical properties of 1 revealed that the deuteration status of the tertiary hydroxyl group at C-2 is critical for the correct reproduction of experimental VCD data in protic solvents. Therefore, in the case of stereochemical analysis of polar chiral natural product molecules, a combination of VCD and ECD is recommended.     

Determining the absolute configuration of two marine compounds using vibrational chiroptical spectroscopy

Chiroptical techniques are increasingly employed for assigning the absolute configuration of chiral molecules through comparison of experimental spectra with theoretical predictions. For assignment of natural products, electronic chiroptical spectroscopies such as electronic circular dichroism (ECD) are routinely applied. However, the sensitivity of electronic spectral parameters to experimental conditions and the theoretical methods employed can lead to incorrect assignments. Vibrational chiroptical methods (vibrational circular dichroism, VCD, and Raman optical activity, ROA) provide more reliable assignments, although they, in particular ROA, have been little explored for assignments of natural products. In this study, the ECD, VCD, and ROA chiroptical spectroscopies are evaluated for the assignment of the absolute configuration of a highly flexible natural compound with two stereocenters and an asymmetrically substituted double bond, the marine antibiotic Synoxazolidinone A (SynOxA), recently isolated from the sub-Arctic ascidian Synoicum pulmonaria. Conformationally averaged nuclear magnetic resonance (NMR), ECD, Raman, ROA, infrared (IR) and VCD spectral parameters are computed for the eight possible stereoisomers of SynOxA and compared to experimental results. In contrast to previously reported results, the stereochemical assignment of SynOxA based on ECD spectral bands is found to be unreliable. On the other hand, ROA spectra allow for a reliable determination of the configuration at the double bond and the ring stereocenter. However, ROA is not able to resolve the chlorine-substituted stereogenic center on the guanidinium side chain of SynOxA. Application of the third chiroptical method, VCD, indicates unique spectral features for all eight SynOxA isomers in the theoretical spectra. Although the experimental VCD is weak and restricted by the limited amount of sample, it allows for a tentative assignment of the elusive chlorine-substituted stereocenter. VCD chiroptical analysis of a SynOxA derivative with three stereocenters, SynOxC, results in the same absolute configuration as for SynOxA. Despite the experimental challenges, the results convincingly prove that the assignment of absolute configuration based on vibrational chiroptical methods is more reliable than for ECD.     

Absolute configuration of C2-symmetric spiroselenurane: 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole

The enantiomers of 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole have been separated on a chiral preparative chromatographic column. The experimental vibrational circular dichroism (VCD) spectra have been obtained for both enantiomers in CH(2)Cl(2). The theoretical VCD spectra have been obtained by means of density functional theoretical calculations with the B3 LYP density functional. From a comparison of experimental and theoretical VCD spectra, the absolute configuration of an enantiomer with positive specific rotation in CH(2)Cl(2) at 589 nm is determined to be R. This conclusion has been verified by comparing results of experimental optical rotatory dispersion (ORD) and electronic circular dichroism (ECD) to predictions of the same properties using the B3 LYP functional for the title compound.     

Electronic Structure and Circular Dichroism of Natural Alboatisins Isolated from Aerial Parts of Isodon Albopilosus: DFT and TDDFT Study

The stable conformations of a series of bioactive molecules, (?)-alboatisins A?C, are identified via Monte Carlo searching with the MMFF94 molecular mechanics force field. Then, the optical rotation (OR) values, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectra were calculated using the gradient-corrected density functional theory method. The vibrational and transition modes of molecular chirality were explored in terms of their microscopic origin. The calculated specific rotations are in agreement with the experimental values. From the OR analysis, it was concluded that optical rotation values areregulated by hydroxyl substitution. Vibrations occurring on the chiral skeleton may cause strong absorption in VCD spectra; VCD spectra are thus the spectral response to deformation vibrations on the chiral carbon skeleton. The lowest-energy negative Cotton effect is caused by σ→π^* transition. Frontier molecular orbital analysis showed that strong ECD absorptions are produced when the dominant transition on the chiral skeleton is asymmetric; ECD spectra show the result of transitions lacking asymmetry on the chiral skeleton.     

Configurational and conformational analysis of chiral molecules using IR and VCD spectroscopies: spiropentylcarboxylic acid methyl ester and spiropentyl acetate

The chiral monosubstituted derivatives of spiropentane, spiropentylcarboxylic acid methyl ester, 1, and spiropentyl acetate, 2, have been synthesized in optically active form. Configurational and conformational analysis of 1 and 2 has been carried out using infrared (IR) and vibrational circular dichroism (VCD) spectroscopies. Analysis of the experimental IR and VCD spectra has been carried out using ab initio density functional theory (DFT). For both 1 and 2, DFT predicts two populated conformations. Comparison to experiment of the conformationally averaged IR and VCD spectra of 1 and 2, predicted using DFT, provides unequivocal evidence of the predicted conformations and yields the absolute configurations R(-)/S(+) for 1 and R(+)/S(-) for 2. These absolute configurations are consistent with the R(-)/S(+) absolute configuration of spiropentylcarboxylic acid, assigned previously via X-ray crystallography of its alpha-phenylethylammonium salt.     

Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism and optical rotation: the schizozygane alkaloid schizozygine

The development of density functional theory (DFT) methods for the calculation of vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and transparent spectral region optical rotation (OR) has revolutionized the determination of the absolute configurations (ACs) of chiral molecules using these chiroptical properties. We report the first concerted application of DFT calculations of VCD, ECD, and OR to the determination of the AC of a natural product whose AC was previously undetermined. The natural product is the alkaloid schizozygine, isolated from Schizozygia caffaeoides. Comparison of DFT calculations of the VCD, ECD, and OR of schizozygine to experimental data leads, for each chiroptical technique, to the AC 2R,7S,20S,21S for the naturally occurring (+)-schizozygine. Three other alkaloids, schizogaline, schizogamine, and 6,7-dehydro-19beta-hydroxyschizozygine, have also been isolated from S. caffaeoides and shown to have structures closely related to schizozygine. Assuming a common biosynthetic pathway, their ACs are defined by that of schizozygine.     

Synthesis of the Natural Product Building Block 5‐(3‐Bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one and its Chiral Characterization by Using Chiroptical Spectroscopy

The absolute configuration of 5‐(3‐bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one, an intermediate in the synthesis of various natural products, is assigned by using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD). Experimental spectra were compared to density functional theory (DFT) calculations of the molecule with known configuration. These three techniques independently confirm that the absolute configuration is (S)‐5‐(3‐bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one, thus enabling us to assign the absolute configuration with high reliability. The reliability of the VCD analysis was assessed quantitatively by using the CompareVOA program. We found that, in cases in which the agreement between theory and experiment was very good, a value of 10 cm^?1 for the triangular weighting function gave a more‐realistic discriminative power between enantiomers than the default value of 20 cm^?1.     

Synthesis and chiroptical properties of cryptophanes having C1-symmetry

New enantiopure cryptophanes 3-7 having C(1)-symmetry have been synthesized. Electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) have been used to investigate their chiroptical properties, and the results are compared to those obtained for cryptophane-A (1) having D(3)-symmetry. The ECD spectra of compounds 3-7 show Cotton effects that differ from those of cryptophane-A. However, our results suggest that a confident determination of the absolute configuration of the monofunctionalized cryptophanes can be made using ECD spectroscopy. Interestingly, we have found that the ECD spectra of cryptophanes, especially the (1)L(b) transition, are very sensitive to the nature of the solvent. These spectral modifications are essentially due to bulk solvent properties rather than the ability of a particular solvent to insert into the cavity of cryptophanes. On the other hand, VCD spectra of the monofunctionalized cryptophanes have not revealed significant spectral modifications with respect to the VCD spectrum of the CHCl(3) at cryptophane-A complex, except for CHCl(3) at 7 and to a smaller extent for CHCl(3) at 6. These spectral modifications, which essentially consist in lower intensities of VCD bands associated with the cryptophane backbone, were perfectly reproduced by ab initio calculations performed at DFT (B3PW91/6-31G*) level. These results clearly demonstrate that VCD measurements associated with DFT calculations allow an easy determination of the absolute configuration of cryptophane-A derivatives.     

Combined use of three forms of chiroptical spectroscopies in the study of the absolute configuration and conformational properties of 3-phenylcyclopentanone, 3-phenylcyclohexanone,and 3-phenylcycloheptanone

Three forms of chiroptical spectroscopies, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and optical rotatory dispersion (ORD) have been employed to study the configuration and conformational properties of the three molecules: (S)-3-phenylcyclopentanone, (S)-3-phenylcyclohexanone, and (S)-3-phenylcycloheptanone (including (S)-3-phenylcyclopentanone-2,2,5,5-d₄ and (S)-3-phenylcyclohexanone-2,2,6,6-d₄). ECD and VCD spectra in the mid-IR for the three molecular systems are marginally dependent on fine conformational details, as interpreted in terms of standard DFT computational methods, with common spectroscopic features to the three systems clearly identified. Accounting for vibronic coupling mechanisms reproduces the structuring of ECD n→π^∗ band. The ORD curves are quite similar for the three types of molecules, but their interpretation highlights a crucial role played by conformations of the cycloalkanone ring in the case of (S)-3-phenylcycloheptanone. The same conclusions are reached by considering the VCD spectra in the CH-stretching region.     

Absolute configuration of diterpenoids from Jatropha dioica by vibrational circular dichroism

The absolute configuration of jatropholone A 1 and B 2, including the possibility to observe the vibrational circular dichroism (VCD) capacity to differentiate between two epimeric compounds in the presence of an inherently dissymmetric chromophore, which normally dominates VCD and electronic circular dichroism (ECD) spectra, followed after comparison of their experimental and DFT calculated VCD spectra, allowed us to conclude that although non-local (M/P) chirality generated by atropisomerism dominates over local chirality generated by an (R/S) change, the stereogenic center can confidently be assigned by VCD after DFT calculations. In addition, the absolute configurations of jatrophatrione 3 and citlalitrione 4, a compound proposed as a taxonomic marker for the genus Jatropha, were assigned by contrasting their respective calculated and experimental IR and VCD spectra. The evaluation of Flack and Hooft parameters obtained from the single-crystal X-ray diffraction data of jatropholone B acetate 6, and of 4 independently confirmed the absolute configurations of these molecules.     

Vibrational circular dichroism and absolute configuration of chiral sulfoxides: tert-butyl methyl sulfoxide

Mid-infrared vibrational unpolarised absorption and vibrational circular dichroism (VCD) spectra of CCl4 solutions of tert-butyl methyl sulfoxide (1) are reported. The spectra are compared to ab initio density functional theory (DFT) calculations carried out using two functionals, B3PW91 and B3LYP, and two basis sets, 6-31G* and TZ2P. The VCD spectra are calculated using Gauge-invariant atomic orbitals (GIAOs). The analysis of the VCD spectrum confirms the R(-)/S(+) absolute configuration of 1. The advantages and disadvantages of VCD spectroscopy in determining the absolute configurations of chiral sulfoxides are discussed.     

光学活性和手性光谱的溯源和发展

概述了19世纪以来光学活性和手性光谱的发现和发展,着重对旋光色散(ORD)、电子圆二色(ECD)和振动圆二色(VCD)光谱的发展背景和基本原理作出介绍。其中特别提及华人科学家徐光宪和徐云洁在手性光谱发展历程中的杰出贡献。     

应用电子圆二色光谱方法确定手性金属配合物的绝对构型

与电子能级跃迁相关的电子圆二色(ECD)光谱因其研究对象宽泛,与涉及振动能级的振动圆二色(VCD)光谱互补,已成为应用于手性立体化学研究的集成手性光谱的主流表征手段。本文概述了确定手性金属配合物绝对构型的三种主要方法,详细介绍了ECD光谱法在确定手性金属配合物绝对构型中的应用,其中着重强调了激子手性方法,并对集成手性光谱学未来的发展趋势做出了展望。     

Enantiopure, monodisperse alleno-acetylenic cyclooligomers: effect of symmetry and conformational flexibility on the chiroptical properties of carbon-rich compounds

A series of enantiopure, monodisperse alleno-acetylenic cyclooligomers were synthesized. The single-crystal X-ray structures of the cyclic trimer and hexamer were resolved, providing insights into the symmetry of these molecules. Electronic circular dichroism (ECD), optical rotatory dispersion (ORD), Raman spectroscopy, and vibrational circular dichroism (VCD) data were analyzed with the aid of theoretical calculations. This multidimensional approach ultimately provided general guidelines that are useful for designing carbon-rich compounds with intense chiroptical properties.     

Determination of the Absolute Configuration of Pentacoordinate Chiral Phosphorus Compounds in Solution by Using Vibrational Circular Dichroism Spectroscopy and Density Functional Theory

Vibrational circular dichroism (VCD) spectroscopic measurements and density functional theory (DFT) calculations have been used to obtain the absolute structural information about four sets of diastereomers of pentacoordinate spirophosphoranes derived separately from l‐ (or d‐ ) valine and l‐ (or d‐ ) leucine for the first time. Each compound contains three stereogenic centers: one at the phosphorus center and two at the amino acid ligands. Extensive conformational searches for the compounds have been carried out and their vibrational absorption (VA) and VCD spectra have been simulated at the B3LYP/6‐311++G** level. Although both VA and VCD spectra are highly sensitive to the structural variation of the apical axis, that is, the O? P? O or N? P? O arrangement, the rotamers generated by the aliphatic amino side chains show little effect on both. The dominant experimental VCD features in the 1100–1500 cm^?1 region were found to be controlled by the chirality at the phosphorus center, whereas those at the C?O stretching region are determined by the chirality of the amino acid ligands. The good agreement between the experimental VA and VCD spectra in CDCl₃ solution and the simulated ones allows us to assign the absolute configurations of these pentacoordinate phosphorus compounds with high confidence. This study shows that the VCD spectroscopy complemented with DFT calculations is a powerful and reliable method for determining the absolute configurations and dominating conformers of synthetic phosphorus coordination complexes in solution.     

Vibrational circular dichroism DFT study on bicyclo[3.3.0]octane derivatives

The absolute configurations of four bicylco[3.3.0]octane derivatives: endo-bicyclo[3.3.0]octane-2,6-diol, endo-2,6-diacetoxybicyclo[3.3.0]octane, endo-bicyclo[3.3.0]octane-2,6-dione and bicyclo[3.3.0]octa-2,6-dien-2,6-bistriflate were studied by vibrational circular dichroism (VCD). These chiral derivates are of interest as intermediates in the asymmetric synthesis of enantiomerically pure natural products and chiral ligands for asymmetric catalysis. VCD has been used to determine the absolute configuration of each compound, proving the capability of VCD for molecules with several stereogenic centres. IR and VCD spectra have been simulated at the B3LYP/6-31G¹ level for all possible diastereomers. Based on the agreement between the experimental and the calculated spectrum, the stereochemistry of each compound could be assigned. The predicted absolute configurations are found to agree with literature data.