VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Absolute Configuration and Predominant Conformations of a Chiral Crown Ether‐Based Colorimetric Sensor: A Vibrational Circular Dichroism Spectroscopy and DFT Study of Chiral Recognition

In the present work, we report a comprehensive vibrational circular dichroism (VCD) spectroscopic study of a chiral crown ether which features an axial chiral 3.3'‐diphenyl‐1,1'‐binaphthyl group as chiral moiety. By comparing the experimental and calculated VCD spectra, we show that the presumably very flexible crown ether preferably adopts only one ring conformation. Conformational flexibility is observed in the 2,4‐dinitrophenyl‐diazophenol group, which was previously introduced for colorimetric detection of primary amines and amino alcohols (Cho et al., Chirality 2011;23:349–353). The VCD spectra of the host–guest complexes with phenyl glycinol (PG) and phenyl alaninol have been studied as well. Based on the spectra calculated, it is shown that the diastereomeric complexes in general can be differentiated using VCD spectroscopy. Furthermore, the experimental VCD spectra of the complexes of the host molecule with PG support the above finding. Chirality 25:294–300, 2013. © 2013 Wiley Periodicals, Inc.     

VCD studies on cyclic peptides assembled from L‐α‐amino acids and a trans‐2‐aminocyclopentane‐ or trans‐2‐aminocyclohexane carboxylic acid

The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans‐2‐aminocyclohexane carboxylic acid (Achc) or trans‐2‐aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three‐dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6‐31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR‐based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Vibrational and chiroptical spectroscopic characterization of γ‐turn model cyclic tetrapeptides containing two β‐Ala residues

The optical spectroscopic characterization of γ‐turns in solution is uncertain and their distinction from β‐turns is often difficult. This work reports systematic ECD and vibrational circular dichroism (VCD) spectroscopic studies on γ‐turn model cyclic tetrapeptides cyclo(Ala‐β‐Ala‐Pro‐β‐Ala) ( 1 ), cyclo(Pro‐β‐Ala‐Pro‐β‐Ala) ( 2 ) and cyclo(Ala‐β‐Ala‐Ala‐β‐Ala) ( 3 ). Conformational analysis performed at the 6‐31G(d)/B3LYP level of theory using an adequate PCM solvent model predicted one predominant conformer for 1‐3 , featuring two inverse γ‐turns. The ECD spectra in ACN of 1 and 2 are characterized by a negative n→π* band near 230 nm and a positive π→π* band below 200 nm with a long wavelength shoulder. The ECD spectra in TFE of 1‐3 show similar spectra with blue‐shifted bands. The VCD spectra in ACN‐d₃ of 1 and 2 show a +/?/+/? amide I sign pattern resulting from four uncoupled vibrations in the case of 1 and a sequence of two positive couplets in the case of 2 . A ?/+/+/? amide I VCD pattern was measured for 3 in TFE‐d₂. All three peptides give a positive couplet or couplet‐like feature (+/?) in the amide II region. VCD spectroscopy, in agreement with theoretical calculations revealed that low frequency amide I vibrations (at ～1630 cm^?1 or below) are indicative of a C₇ H‐bonded inverse γ‐turns with Pro in position 2, while γ‐turns encompassing Ala absorb at higher frequency (above 1645 cm^?1). Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Absolute configuration determination and conformational analysis of (−)‐(3S,6S)‐3α,6β‐diacetoxytropane using vibrational circular dichroism and DFT techniques

The absolute configuration of semisynthetic (?)‐3α,6β‐acetoxytropane 1 , prepared from (?)‐6β‐hydroxyhyoscyamine 2 , has been determined using vibrational circular dichroism (VCD) spectroscopy. The vibrational spectra (IR and VCD) were calculated using DFT at the B3LYP/DGDZVP level of theory for the eight more stable conformers which account for 99.97% of the total relative abundance in the first 10 kcal/mol range. The calculated VCD spectra of all considered conformations showed two distinctive spectral ranges, one between 1300 and 1200 cm^?1, and the other one in the 1150–950 cm^?1 region. When compared with the experimental VCD spectrum, the first spectral region confirmed the calculated conformational preferences, whereas the second region showed little change with conformation, thus allowing the determination of the absolute configuration of 1 as (3S,6S)‐3α,6β‐diacetoxytropane. Also, the bands in the second region showed similarities between 1 and 2 in both the experimental and calculated VCD spectra, suggesting that these bands are mainly related to the absolute configuration of the rigid tropane ring system, since they show conformational independency, no variations with the nature of the substituent, and are composed by closely related vibrational modes. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Stereochemical analysis of β‐keto sulfoxides by circular dichroism

Three β‐keto sulfoxides ( 1–3 ) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2 , the X‐ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β‐keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.     

Axially chiral N‐(o‐aryl)‐4‐hydroxy‐2‐oxazolidinone derivatives from diastereoselective reduction of N‐(o‐aryl)‐2,4‐oxazolidinediones: Thermally interconvertible atropisomers via ring‐chain‐ring tautomerization

The reduction of the axially chiral N‐(o‐aryl)‐5,5‐dimethyl‐2,4‐oxazolidinediones by NaBH₄ yielded axially chiral N‐(o‐aryl)‐4‐hydroxy‐5,5‐dimethyl‐2‐oxazolidinone enantiomers having a chiral center at C‐4, with 100% diastereoselectivity as has been shown by their ¹H and ¹³C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring‐chain‐ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Chiral Amine Enantiomeric Excess Determination Using Self‐Assembled Octahedral Fe(II)‐Imine Complexes

A receptor assembly composed of iron(II) triflate and pyridine‐2,6‐dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha‐chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha‐chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay. Chirality 27:294–298, 2015. 2015 Wiley Periodicals, Inc.     

Chemoenzymatic Approach to Optically Active 4‐Hydroxy‐5‐alkylcyclopent‐2‐en‐1‐one Derivatives: An Application of a Combined Circular Dichroism Spectroscopy and DFT Calculations to Assignment of Absolute Configuration

A series of representative optically active derivatives of 4‐hydroxy‐5‐alkylcyclopent‐2‐en‐1‐one were prepared from the respective 2‐furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4‐hydroxy‐5‐methylcyclopent‐2‐en‐1‐one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers. Chirality 26:300–306, 2014. © 2014 Wiley Periodicals, Inc.     

Enantioselective separation of (±)‐β‐hydroxy‐1,2,3‐triazoles by supercritical fluid chromatography and high‐performance liquid chromatography

This paper reports the enantioseparation of β‐hydroxy‐1,2,3‐triazole derivatives, which present a broad range of biological properties, by supercritical fluid chromatography (SFC) and high‐performance liquid chromatography techniques (HPLC). Polysaccharide‐based chiral columns (cellulose and amylose) were used to evaluate the separation in SFC and HPLC. Time of analyses, consumption of solvent, and parameter optimization were reduced using SFC technique. The columns based on cellulose chiral stationary phase using 2‐propanol and ethanol as modifiers showed the best results for the enantioresolution of the (±)‐β‐hydroxy‐1,2,3‐triazoles by SFC analyses. These techniques were applied to evaluate the selectivity of biocatalytic reduction of β‐keto‐1,2,3‐triazoles by marine‐derived fungus Penicillium citrinum CBMAI 1186 to obtain the (±)‐β‐hydroxy‐1,2,3‐triazoles.     

Discrimination of Axial and Central Stereogenic Elements in Chiral Bis(oxazolines) Based on Atropisomeric 3,3′‐Bithiophene Scaffolds Through Chiroptical Spectroscopies

Two diastereoisomeric pairs of bis‐oxazolines, provided with a stereogenic center at carbon 4 and based on the 3,3′‐bithiophene atropisomeric scaffold, were synthesized and structurally characterized. They differ in the substituents at positions 2 and 5 of the thiophene rings, which are functionalized with methyl (1) or phenyl (2) groups, respectively. In vibrational circular dichroism (VCD) spectra, recorded in CCl₄ solutions, it is possible to distinctly recognize the characteristic features of axial and central stereogenic elements. In tandem with Density Functional Theory (DFT) calculations, the absolute configuration (AC) of the diastereoisomers was safely established. In this case, VCD was shown to be superior to ECD (electronic circular dichroism) in the assignment of AC. The normal modes, evaluated from DFT calculations, show that the VCD signals in correspondence with the stereogenic axis of the bithiophene unit are different for 1 and 2. The VCD spectra of a molecular analog of 1, the (S)‐2,2′,5,5′‐tetramethyl‐4,4′‐bis‐(diphenylphosphino)‐3,3′‐bithiophene oxide (3), characterized by the same 3,3′‐bithiophene scaffold, but devoid of stereogenic centers, exhibits signals similar to those observed in the case of diastereoisomer (aS,R,R)‐1a, associated with almost identical normal modes. Chirality 28:686–695, 2016. © 2016 Wiley Periodicals, Inc.     

Absolute configuration assignment of (+)‐fluralaner using vibrational circular dichroism

The absolute configurations of the separated enantiomers of fluralaner, a racemic animal health product used to prevent fleas and ticks, have been assigned using vibrational circular dichroism (VCD). The crystallographic structure of the active enantiomer (+)‐fluralaner has previously been shown to have the (S ) configuration using small molecule crystallography. We sought a faster analytical method to determine the absolute configuration of the separated enantiomers. When comparing the measured IR (infrared) and VCD spectra, it is apparent that the amide carbonyl groups appear in the IR but are nearly absent in the VCD. Computational work to calculate the VCD and IR using in vacuo models, implicit solvation, and explicitly solvated complexes has implicated conformational averaging of the carbonyl VCD intensities.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Structure and absolute configuration of ginkgolide B characterized by IR‐ and VCD spectroscopy

Experimental and calculated (B3LYP/6‐31G(d)) vibrational circular dichroism (VCD) and IR spectra are compared, illustrating that the structure and absolute configuration of ginkgolide B (GB) may be characterized directly in solution. A conformational search for GB using MacroModel and subsequent DFT optimizations (B3LYP/6‐31G(d)) provides a structure for the lowest energy conformer which agrees well with the structure determined by X‐ray diffraction. In addition, a conformer at an energy of 7 kJ mol^?1 (B3LYP/6‐311+G(2d,2p)) with respect to the lowest energy conformer is predicted, displaying different intramolecular hydrogen bonding. Differences between measured and calculated IR and VCD spectra for GB at certain wavenumbers are rationalized in terms of interactions with solvent, intermolecular GB‐GB interactions, and the potential presence of more than one conformer. This is the first detailed investigation of the spectroscopic fingerprint region (850?1300 cm^?1) of the natural product GB employing infrared absorption and VCD spectroscopy. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Vibrational circular dichroism as a probe of solid‐state organisation of derivatives of cyclic β‐amino acids: Cis‐ and trans‐2‐aminocyclobutane‐1‐carboxylic acid

Peptide models built from cis‐ and trans‐2‐aminocyclobutane‐1‐carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier‐transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N‐tert‐butyloxycarbonyl (Boc) derivatives of 2‐aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc?(cis‐ACBC)?NH?Bn and Boc?(trans‐ACBC)?NH?Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans‐ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis‐ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid‐state geometry of related ACBC derivatives, which shows that no long‐range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6‐ or 8‐membered cyclic NH?O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans‐ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H‐bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long‐range organisation in the crystal.     

The determination of the absolute configurations of chiral molecules using vibrational circular dichroism (VCD) spectroscopy

The vibrational circular dichroism (VCD) spectra of the two enantiomers of a chiral molecule are of equal magnitude and opposite sign: i.e. mirror-image enantiomers give mirror-image VCD spectra. In principle, the absolute configuration (AC) of a chiral molecule can therefore be determined from its VCD spectrum. In practice, the determination of the AC of a chiral molecule from its experimental VCD spectrum requires a methodology which reliably predicts the VCD spectra of its enantiomers. The only reliable methodology developed to date uses the Stephens quantum-mechanical theory of the rotational strengths of fundamental vibrational transitions, developed in the early 1980s, implemented using ab initio density functional theory in the GAUSSIAN program in the mid 1990s. This methodology has by now been widely used in determining ACs from experimental VCD spectra. In this article we discuss the protocol for determining the ACs of chiral molecules with optimum reliability and its implementation for a variety of molecules, including the D3 symmetry perhydrotriphenylene, a thiazino-oxadiazolone recently shown to be a highly active calcium entry channel blocker, the alkaloid natural products schizozygine, iso-schizogaline, and iso-schizogamine, and the iridoid natural products plumericin, iso-plumericin, and prismatomerin. The power of VCD spectroscopy in determining ACs, even for large organic molecules and for substantially conformationally-flexible organic molecules is clearly documented.     

Lanthanide Tris(β‐diketonates) as Useful Probes for Chirality Determination of Biological Amino Alcohols in Vibrational Circular Dichroism: Ligand to Ligand Chirality Transfer in Lanthanide Coordination Sphere

A series of lanthanide tris(β‐diketonates) functioned as useful chirality probes in the vibrational circular dichroism (VCD) characterization of biological amino alcohols. Various chiral amino alcohols induced intense VCD signals upon ternary complexation with racemic lanthanide tris(β‐diketonates). The VCD signals observed around 1500 cm^?1 (β‐diketonate IR absorption region) correlated well with the stereochemistry and enantiomeric purity of the targeted amino alcohol, while the corresponding monoalcohol, monoamine, and diol substrates induced very weak VCD signals. The high‐coordination number and dynamic property of the lanthanide complex offer an effective chirality VCD probing of biological substrates. Chirality 26:293–299, 2014. © 2014 Wiley Periodicals, Inc.     

Substituent effects on chiral resolutions of derivatized 1‐phenylalkylamines by heptakis(2,3‐di‐O‐methyl‐6‐O‐tert‐butyldimethylsilyl)‐β‐cyclodextrin GC stationary phase

Chiral resolutions of trifluoroacetyl‐derivatized 1‐phenylalkylamines with different type and position of substituent were investigated by capillary gas chromatography by using heptakis(2,3‐di‐O‐methyl‐6‐O‐tert‐butyldimethylsilyl)‐β‐cyclodextrin diluted in OV‐1701 as a chiral stationary phase. The influence of column temperature on retention and enantioselectivity was examined. All enantiomers of meta‐substituted analytes as well as fluoro‐substituted analytes could be resolved. Temperature had a favorable influence on enantioselectivity for small amines with substituents at the ortho‐position. The type of substituent at the stereogenic center of amines also had a crucial effect as the ethyl group led to poor enantioseparation. Among all analytes studied, trifluoroacetyl‐derivatized 1‐(2′‐fluorophenyl)ethylamine exhibited baseline resolution with the shortest analysis time.     

Chirality of camphor derivatives by density functional theory

Infrared (IR) and vibrational circular dichroism (VCD) spectra of chiral camphor, camphorquinone and camphor-10-sulfonic acid (CSA), known as standard compounds for electronic circular dichroism (ECD) spectroscopy, are measured and their vibrational frequencies, infrared intensities, and rotational strengths are calculated using density functional theory (DFT). The observed IR and VCD spectra of chiral camphor and camphorquinone in carbon tetrachloride solution are reproduced by the DFT calculations, but those of CSA are not. DFT calculations of hydration models, where an anionic CSA specifically binds a few water molecules, are carried out. The average of the simulated VCD spectra in the hydration models is more consistent with the observed spectra. In addition, the wavelengths and dipole and rotational strengths for chiral camphor, camphorquinone, anionic CSA, and the hydration models were calculated by time-dependent DFT. In the region of 280-300 nm, the calculated wavelengths of the ECD bands for chiral camphor and camphorquinone coincide with the observed wavelengths that have been reported, and the calculated wavelengths for the hydration models are closer to the observed wavelengths reported than are those calculated for chiral anionic CSA. Consequently, the analysis combined with VCD and ECD spectroscopy using DFT calculations can elucidate the chirality of optically active molecules, even in an aqueous solution.     

Stereochemistry of the Brivaracetam Diastereoisomers

The stereochemistry of all four stereoisomers of brivaracetam was determined using vibrational circular dichroism (VCD) spectroscopy. By comparing experimentally obtained VCD spectra and computationally simulated ones, the absolute configurations can be confidently assigned without prior knowledge of their relative stereochemistry. Neither the corrected mean absolute errors analysis of the nuclear magnetic resonance (NMR) data, nor the matching of experimental and calculated infrared spectra allowed the diastereoisomers to be distinguished. VCD spectroscopy itself suffices to establish the absolute configurations of all diastereoisomers. The relative stereochemistry could also be statistically confirmed by matching experimental and computed NMR spectra using the CP3 algorithm. The combination of VCD and NMR is recommended for molecules bearing more than one chiral center, as the relative configurations obtained from NMR serve as an independent check for those established with VCD. Analysis of the calculated VCD spectra reveals that the localized NH₂ scissoring mode at around 1600 cm^‐1 is characteristic for intramolecular hydrogen bonding, while the orientation of the ethyl group is reflected by the delocalized modes between 1150 and 1050 cm^‐1. Chirality 28:215–225, 2016. © 2016 Wiley Periodicals, Inc.