Determination of the absolute configuration of a chiral oxadiazol-3-one calcium channel blocker, resolved using chiral chromatography, via concerted density functional theory calculations of its vibrational circular dichroism, electronic circular dichroism, and optical rotation

The chiral oxadiazol-3-one 2 has recently been shown to exhibit myocardial calcium entry channel blocking activity, substantially higher than that of diltiazem. To determine the enantioselectivity of this activity, the enantiomers of 2 have been resolved using chiral chromatography. The absolute configuration (AC) of 2 has been determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) spectrum, electronic circular dichroism (ECD) spectrum, and optical rotation (OR) to experimental VCD, ECD, and OR data. All three chiroptical properties yield identical ACs; the AC of 2 is unambiguously determined to be S(+)/R(-).     

Investigating cyclic sotolon,maple furanone and their dimers in solution using optical rotation,electronic circular dichroism and vibrational circular dichroism

The experimental optical rotation (OR), electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of (R)-3-hydroxy-4,5-dimethylfuran-2(5H)-one (sotolon, 1) and (R)-5-ethyl-3-hydroxy-4-methylfuran-2(5H)-one (maple furanone, 2) taken in chloroform were compared to their spectra calculated with time-dependent density functional theory (TDDFT). Sotolon was shown to exist as a dimer in chloroform while maple furanone remains a monomer. Transition state barriers for the enol/keto tautomerization of sotolon were calculated and found to be high. The VCD method offers promise to ultimately distinguish between the presence of monomers or dimers.     

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.     

Ruthenium‐Grafted Vinylhelicenes: Chiroptical Properties and Redox Switching

The properties of mono‐ and bis‐Ru–vinyl[6]helicene complexes ( 2 a and 2 b , respectively), recently synthesized by using molecular engineering of helicenes based on the grafting of lateral organometallic substituents on the π‐helical backbone through a vinyl bridge, are presented. These helicene derivatives are thoroughly characterized, with special attention given to their chiroptical properties and redox switching activity. The UV/Vis and electronic circular dichroism (ECD) spectra of P and M enantiopure species, both in the neutral and oxidized states ([ 2 a ] ^{. +}, [ 2 b ] ^{. +}, and [ 2 b ]²⁺), are analyzed with the aid of quantum‐chemical calculations. The extended π‐conjugation facilitated by the vinyl moiety, clearly visible in the electronic structures of 2 a , b , introduces new active bands in the ECD spectra that consequently lead to a significant increase in optical rotation of Ru–vinylhelicenes compared with the organic precursors. The vibrational circular dichroism (VCD) spectra were measured and calculated for both the organic and organometallic species and constitute the first examples of VCD for metal‐based helicene derivatives. Finally, the redox‐triggered chiroptical switching activity of 2 a , b is examined in detail by using ECD spectroscopy. The modifications of the ECD spectra in the UV/Vis and NIR region are well reproduced and rationalized by calculations.     

振动圆二色谱在轴手性β-双咔啉N—O衍生物立体化学研究中的应用

采用振动圆二色谱(VCD)方法研究了一个具有高度催化活性的轴手性结构的双咔啉N—O化合物的立体化学结构. 在B3LYP/6-311+G(d)水平上得到的计算结果表明, 对于具有负旋光值的双咔啉N—O化合物化合物, 其绝对构型是aS. 同时, 分别计算了双咔啉N—O化合物的电子圆二色谱(ECD)和旋光值, 并与实验结果进行了比较. 在化合物结构完全正确条件下, VCD, ECD和旋光数据均表明, 具有负旋光值的该化合物的绝对构型是aS.     

手性化合物立体结构鉴定中的若干关键共性科学问题探讨

对于手性化合物立体化学理论与实验相结合的研究中容易出现的相关共性科学问题进行了讨论, 包括计算化学中软件、 简化模型的使用及计算过程中相关方法的应用范围和前提条件. 针对性地提出了在能量分析、 旋光光谱(OR)、 电子圆二色光谱(ECD)、 振动圆二色光谱(VCD)和核磁共振碳谱(¹³C NMR)等计算中可能出现的陷阱以及规避方法, 并考察了相关的计算实例.     

Theoretical investigation of differences of optical rotation,electronic circular dichroism and vibrational circular dichroism of α-hydroxyl cyclic ketones and esters as monomers or dimers in solution

To understand or identify whether a dimer forms or not derived from a chiral compound via H-bonds in solution is critically important. In our previous study, sotolon 1 has two methyl groups, it can form dimers in solution, but maple furanone 2, derived from 1, has one ethyl group and one methyl group, it cannot form dimer. This could be checked by using chiroptical spectroscopies of optical rotation (OR), electronic circular dichroism (ECD) and vibrational circular dichroism (VCD). In this study, four methods was used for the chiral α-hydroxyl ketones and esters (3–8). B3LYP and MPW1PM91 methods with four sets were used to calculate OR, ECD and VCD. The theoretical results exhibited that VCD method could provide more details and promises to ultimately distinguish between the presence of monomer or dimer in solution.     

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.     

Comparison of the Electronic and Vibrational Optical Activity of a Europium(III) Complex

The geometry and the electronic structure of chiral lanthanide(III) complexes are traditionally probed by electronic methods, such as circularly polarised luminescence (CPL) and electronic circular dichroism (ECD) spectroscopy. The vibrational phenomena are much weaker. In the present study, however, significant enhancements of vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectral intensities were observed during the formation of a chiral bipyridine–Eu^III complex. The ten‐fold enhancement of the vibrational absorption and VCD intensities was explained by a charge‐transfer process and the dominant effect of the nitrate ion on the spectra. A much larger enhancement of the ROA and Raman intensities and a hundred‐fold increase of the circular intensity difference (CID) ratio were explained by the resonance of the λ=532 nm laser light with the ⁷F₀ → ⁵D₀ transitions. This phenomenon is combined with a chirality transfer, and mixing of the Raman and luminescence effects involving low‐energy ⁷F states of europium. The results thus indicate that the vibrational optical activity (VOA) may be a very sensitive tool for chirality detection and probing of the electronic structure of Eu^III and other coordination compounds.     

Influence of the chemical structure of water-soluble cryptophanes on their overall chiroptical and binding properties

The synthesis and the chiroptical properties of the two enantiomers of the hexacarboxylic acid cryptophane-A derivative, 1, are described in this article. The chiroptical and binding properties of 1 toward achiral and chiral guests have been investigated in water under basic conditions by polarimetry, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and (1)H NMR spectroscopy. These experiments reveal that the (1)H NMR spectra of 1 are very sensitive to the nature of the guest trapped in its cavity whereas ECD and VCD spectra remain unchanged. We also show that the two enantiomers of 1 are able to distinguish between the two enantiomers of a series of small chiral epoxides. The enantiodiscrimination increases with the size of the chiral guest whereas the corresponding binding constants decrease. In contrast to what was observed for other water-soluble cryptophanes, the molecular recognition process is found independent of the nature of the counterions surrounding host 1, shedding light on the importance of the chemical structure of cryptophanes on their binding and chiroptical properties.     

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。     

A single chiroptical spectroscopic method may not be able to establish the absolute configurations of diastereomers: dimethylesters of hibiscus and garcinia acids

Electronic circular dichroism (ECD), optical rotatory dispersion (ORD), and vibrational circular dichroism (VCD) spectra of hibiscus acid dimethyl ester have been measured and analyzed in combination with quantum chemical calculations of corresponding spectra. These results, along with those reported previously for garcinia acid dimethyl ester, reveal that none of these three (ECD, ORD, or VCD) spectroscopic methods, in isolation, can unequivocally establish the absolute configurations of diastereomers. This deficiency is eliminated when a combined spectral analysis of either ECD and VCD or ORD and VCD methods is used. It is also found that the ambiguities in the assignment of absolute configurations of diastereomers may also be overcome when unpolarized vibrational absorption is included in the spectral analysis.     

Chiroptical spectroscopy of surfactants

Three different chiroptical spectroscopic methods, namely, optical rotation, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) have been evaluated for studying the aggregation of sodium dodecylsulfate (SDS), an achiral surfactant, using garcinia acid disodium salt (GADNa) as a chiral probe. The specific rotation and ECD of GADNa are found to be altered by the aggregation of SDS, suggesting for the first time that achiral surfactants can be characterized with chiroptical spectroscopy using appropriate chiral probes. In addition, a chiral compound, fluorenyl methyloxy carbonyl l-leucine sodium salt (FLNa) is found for the first time to behave as a surfactant in water, with 205 ?(2) surface area per molecule at the air-water interface, critical micelle concentration (CMC) of 0.18 M, and Gibbs energy of micellization of -14 kJ/mol. The specific rotation of FLNa in water is found to increase with concentration beyond CMC, suggesting the formation of chiral aggregates. Different conformations of FLNa amenable to micellization have been identified using quantum chemical conformational analysis and their specific rotations calculated. The formation of lamellar aggregates of FLNa in water is suggested to be the cause for increase in specific rotation with concentration beyond CMC.     

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.     

Three Types of Induced Tryptophan Optical Activity Compared in Model Dipeptides: Theory and Experiment

The tryptophan (Trp) aromatic residue in chiral matrices often exhibits a large optical activity and thus provides valuable structural information. However, it can also obscure spectral contributions from other peptide parts. To better understand the induced chirality, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) spectra of Trp‐containing cyclic dipeptides c‐(Trp‐X) (where X=Gly, Ala, Trp, Leu, nLeu, and Pro) are analyzed on the basis of experimental spectra and density functional theory (DFT) computations. The results provide valuable insight into the molecular conformational and spectroscopic behavior of Trp. Whereas the ECD is dominated by Trp π–π* transitions, VCD is dominated by the amide modes, well separated from minor Trp contributions. The ROA signal is the most complex. However, an ROA marker band at 1554 cm^?1 indicates the local χ₂ angle value in this residue, in accordance with previous theoretical predictions. The spectra and computations also indicate that the peptide ring is nonplanar, with a shallow potential so that the nonplanarity is primarily induced by the side chains. Dispersion‐corrected DFT calculations provide better results than plain DFT, but comparison with experiment suggests that they overestimate the stability of the folded conformers. Molecular dynamics simulations and NMR results also confirm a limited accuracy of the dispersion‐DFT model in nonaqueous solvents. Combination of chiral spectroscopies with theoretical analysis thus significantly enhances the information that can be obtained from the induced chirality of the Trp aromatic residue.     

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 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.     

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.     

Analysis of human blood plasma and hen egg white by chiroptical spectroscopic methods (ECD, VCD, ROA)

Chiroptical methods are widely used in structural and conformational analyses of biopolymers. The application of these methods to investigations of biofluids would provide new avenues for the molecular diagnosis of protein-misfolding diseases. In this work, samples of human blood plasma and hen egg white were analyzed using a combination of conventional and chiroptical methods: ultraviolet absorption/electronic circular dichroism (UV/ECD), Fourier transform infrared absorption/vibrational circular dichroism (FTIR/VCD), and Raman scattering/Raman optical activity (Raman/ROA). For comparison, the main components of these substances—human serum albumin (HSA) and ovalbumin (Ova)—were also analyzed by these methods. The ultraviolet region of the ECD spectrum was analyzed using the CDNN CD software package to evaluate the secondary structures of the proteins. The UV/ECD, FTIR/VCD, and Raman/ROA spectra of the substances were quite similar to those of the corresponding major proteins, while some differences were also detected and explained. The conclusions drawn from the FTIR/VCD and Raman/ROA data were in good agreement with the secondary structures calculated from ECD. The results obtained in this work demonstrate that the chiroptical methods used here can be applied to analyze not only pure protein solutions but also more complex systems, such as biological fluids.

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.