Chirality and diastereoselection of Δ/Λ-configured tetrahedral zinc complexes through enantiopure Schiff base complexes: combined vibrational circular dichroism, density functional theory, 1H NMR, and X-ray structural studies.

The metal-centered Δ/Λ-chirality of four-coordinated, nonplanar Zn(A(^)B)(2) complexes is correlated to the chirality of the bidentate enantiopure (R)-A(^)B or (S)-A(^)B Schiff base building blocks [A(^)B = (R)- or (S)-N-(1-(4-X-phenyl)ethyl)salicylaldiminato-κ(2)N,O with X = OCH(3), Cl, Br]. In the solid-state the (R) ligand chirality induces a Λ-M configuration and the (S) ligand chirality quantitatively gives the Δ-M configuration upon crystallization as deduced from X-ray single crystal studies. The diastereoselections of the pseudotetrahedral zinc-Schiff base complexes in CDCl(3) solution were investigated by (1)H NMR and by vibrational circular dichroism (VCD) spectroscopy. The appearance of two signals for the Schiff-base -CH═N- imine proton in (1)H NMR indicates an equilibrium of both Δ- and Λ-diastereomers with a diastereomeric ratio of roughly 20:80% for all three ligands. VCD proved to be very sensitive to the metal-centered Δ/Λ-chirality because of a characteristic band representing coupled vibrations of the two ligand's C═N stretch modes. The absolute configuration was assigned on the basis of agreement in sign with theoretical VCD spectra from Density Functional Theory calculations.

Structure elucidation and absolute stereochemistry of isomeric monoterpene chromane esters.

Six novel monoterpene chromane esters were isolated from the aerial parts of Peperomia obtusifolia (Piperaceae) using chiral chromatography. This is the first time that chiral chromane esters of this kind, ones with a tethered chiral terpene, have been isolated in nature. Due to their structural features, it is not currently possible to assess directly their absolute stereochemistry using any of the standard classical approaches, such as X-ray crystallography, NMR, optical rotation, or electronic circular dichroism (ECD). Herein we report the absolute configuration of these molecules, involving four chiral centers, using vibrational circular dichroism (VCD) and density functional theory (DFT) (B3LYP/6-31G*) calculations. This work further reinforces the capability of VCD to determine unambiguously the absolute configuration of structurally complex molecules in solution, without crystallization or derivatization, and demonstrates the sensitivity of VCD to specify the absolute configuration for just one among a number of chiral centers. We also demonstrate the sufficiency of using the so-called inexpensive basis set 6-31G* compared to the triple-ζ basis set TZVP for absolute configuration analysis of larger molecules using VCD. Overall, this work extends our knowledge of secondary metabolites in plants and provides a straightforward way to determine the absolute configuration of complex natural products involving a chiral parent moiety combined with a chiral terpene adduct.

Near-infrared and mid-infrared Fourier transform vibrational circular dichroism of proteins in aqueous solution.

Vibrational circular dichroism (VCD) of a series of proteins in H(2)O solution with differing secondary structure are reported for the first time in the near-infrared (NIR) region as well as the NH-stretching region. The Fourier transform (FT) near-infrared (NIR) measurements were carried out between 6000 to 4000 cm(-1). FT-VCD measurements were simultaneously carried out for the mid-infrared (mid-IR) region from 2000 to 800 cm(-1) for direct comparison to VCD in the NIR region. The NIR VCD spectra of proteins show distinct spectral features for different protein structural motifs, indicating a valuable new method to study protein conformations. The principal VCD transitions in the NIR region are two combination bands, the amide A-II and B-II bands, of the amide A and B fundamentals with the amide II fundamental, and the second overtone of the amide II, referred to as the amide 3 x II band. VCD in the amide A and B band region consisting primarily of NH stretching motions were successfully obtained in H(2)O for the first time for an insulin fibril sample. Similar to the enhanced VCD signal observed in amide I and II regions, the amide A and B VCD of insulin fibril shows strong intensity enhancements, providing an additional valuable probe of protein fibril growth and development in solution. The relative sensitivities of the mid-IR, N-H stretching, and NIR regions are discussed.

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.

Induced folding by chiral nonplanar aromatics.

We report a structural motif based on a C(3)-symmetric bowl-shaped core, on which three substituted amino acids on the periphery adopt either a folded or a spread-out conformation. This class of chiral folded structures is achieved by controlling the reactivity of the stereogenic protons on the nonplanar aromatic rings of trioxatricornan to afford predominantly C(3)-symmetric isomers. Bromination of trioxatricornan afforded a C(1)-symmetric and a C(3)-symmetric trisubstituted isomer, with the former being the major product as a statistical consequence during the reaction cascade. To obtain the C(3) symmetric isomer as the major product, C-H activation by means of ortho-lithiation with the bulky tert-butyl lithium and tetramethylethylenediamine was followed by a nucleophilic substitution that successfully reversed the statistically controlled regioselectivity. Further derivatization of the trioxatricornan with amino acids or menthol afforded diastereomers that were resolved by preparative chromatography. The absolute configurations of the diastereomers were determined by vibrational circular dichroism (VCD) in combination with density functional theory (DFT) and electronic circular dichroism (ECD). The folding structure of cysteine-derivatized trioxatricornan diastereomers was determined by two-dimensional NMR spectroscopy and molecular dynamics calculation, which revealed that one diastereomer has the amino acids folded toward the cavity of trioxatricornan and the other has a "spread-out" structure.

Subtle chirality in oxo- and sulfidorhenium(v) complexes.

Enantioenriched square-pyramidal oxo- and sulfidorhenium(v) complexes have been prepared and their stereochemistry studied by vibrational circular dichroism (VCD) spectroscopy.

Isotopic difference spectra as an aide in determining absolute configuration using vibrational optical activity: vibrational circular dichroism of 13C- and 2H-labelled nonamethoxy cyclotriveratrylene.

The use of isotopic difference spectra in vibrational optical activity is demonstrated as a supplemental aide in determining the absolute configuration of chiral molecules. It is shown that IR and VCD difference spectra associated with isotopic substitution observed in experimental spectra can be accurately reproduced by density functional theory calculations when the IR and VCD spectra of the original isotopomer are calculated to reasonable accuracy. Results for isotopically substituted nonamethoxy cyclotriveratrylene are presented to illustrate the degree of agreement between measured and calculated IR and VCD difference spectra for several isotopomers of this molecule. These findings highlight the utility of isotoptic substitution as an aide to verifying the determination of absolute configuration using vibrational optical activity.

Structural and optical isomers of nonamethoxy cyclotriveratrylene: separation and physical characterization.

The paper concerns the structural and optical isomers of nonamethoxy-tribenzocyclononene (compound 1). In the first part of the paper it is shown that 1 exists in two structural isomers: a rigid crown (c-1) with C3 symmetry and a flexible saddle (s-1) with C1 symmetry. The latter, not previously known, can be prepared from the as-synthesized c-1 by quenching a hot solution (or the melt) followed by HPLC separation. The crown/saddle equilibrium, isomerization kinetics, and associated thermodynamic parameters in various organic solvents are reported. Carbon-13 MAS NMR, X-ray diffraction, and differential scanning calorimetry (DSC) of polycrystalline c-1 and s-1 racemates are also reported. The different melting points of the isomers and their rapid isomerization in the melt result in unconventional DSC thermograms involving multiple endothermic and exothermic transitions. The second part of the paper concerns the chiral properties of 1. Both the saddle and crown isomers are structurally chiral, but due to the fast pseudorotation of s-1 in solution, it cannot be separated into its enantiomers. Those of c-1 were separated by HPLC using a chiral column. Their X-ray structure and melting points differ considerably from those of the racemate. This and their fast racemization in the melt lead to complex DSC thermograms with multiple transitions. Solutions of the neat enantiomers exhibit a relatively small specific optical rotation. In the UV they show circular dichroism for the B1u and B2u transitions, with the latter exhibiting a clear couplet structure. Infrared and vibrational circular dichroism spectra of the enantiomers in solution are reported. Comparison of these spectra with quantum mechanical simulations provides unambiguous identification of the enantiomers.

Synthesis and vibrational circular dichroism of enantiopure chiral oxorhenium(V) complexes containing the hydrotris(1-pyrazolyl)borate ligand.

The infrared and vibrational circular dichroism (VCD) spectra of six chiral oxorhenium(V) complexes, bearing a hydrotris(1-pyrazolyl)borate (Tp) ligand, have been investigated. These complexes are promising candidates for observation of parity violation (symmetry breaking due to the weak nuclear force). New chiral oxorhenium complexes have been synthesized, namely, [TpReO(eta2-O(CH3)CH2CH2O-O,O)] (4a and 4b) diastereomers and [TpReO(eta2-N(CH3)CH2CH2O-N,O)] (5) and [TpReO(eta2-N(tBu)CH2CH2O-N,O)] (6) enantiomers. All compounds could be obtained in enantiomerically pure form by using either column chromatography or HPLC over chiral columns. VCD spectroscopy of these compounds and of [TpReO(eta2-N(CH3)CH(CH3)CH(Ph)O-N,O)] (2) and [TpReO(eta2-N(CH2)3CHCO2-N,O)] (3) (with chiral bidentate ligands derived, respectively, from ephedrine and proline) were studied. This allowed the absolute configuration determination of all compounds together with their conformational analysis, by comparing calculated and experimental spectra. This is the first VCD study of rhenium complexes which further demonstrates the applicability of VCD spectroscopy in determining the chirality of inorganic complexes.

Fourier transform near-infrared vibrational circular dichroism used for on-line monitoring the epimerization of 2,2-dimethyl-1,3-dioxolane-4-methanol: A pseudo racemization reaction.

Near-infrared (near-IR) Fourier transform vibrational circular dichroism (FT-VCD) spectroscopy has been used to monitor the epimerization of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (S-DDM). The near-IR-VCD spectra display clear isolated VCD bands at the range of 4700-5050 cm(-1) resulting from the OH stretch-bend combination bands of S-DDM, which were found to decrease in intensity with increasing reaction time. The near-IR-VCD spectra of 10 reference samples obtained were subjected to partial least-squares (PLS) regression analysis, and the results were used to build predictive models for enantiomeric excess (EE) determination. Multivariate regression was carried out on three different sets of spectra, corresponding to the epimerization of S-DDM in three different solvents: methylcyclohexane, carbon tetrachloride and tetrahydrofuran. The effects of solvent in DDM epimerization are discussed in terms of the relative stabilization of the reaction intermediate of the DDM epimerization reaction. The results of these near-IR-VCD studies for the determination of EE highlights the potential of VCD for in situ real-time process monitoring of the reaction kinetics of chiral molecules in solution.

Determination of the absolute configuration and solution conformation of a novel disubstituted pyrrolidine acid A by vibrational circular dichroism.

Compound A, a novel disubstituted pyrrolidine acid, is a member of a new class of agents that are potentially useful for the treatment of diabetes and dyslipidemia. The absolute configuration of this compound was determined by using vibrational circular dichroism (VCD). The results are in agreement with the assignments based on both X-ray analysis and the stereo-selective chemical synthesis. During VCD analysis, the solution conformation for a portion of compound A in CDCl(3) was also established. The compound is found to associate as an H-bonded carboxylic acid "dimer" in CDCl(3) solution, and VCD calculations on a model dimer fragment were required to establish the absolute configuration.

Chlorofluoroiodomethane as a potential candidate for parity violation measurements.

CHFClI is among the more favorable molecules for parity violation (PV) measurements in molecules. Despite the fact that calculated PV effects are two orders of magnitude smaller than in some organometallic compounds, CHFClI displays interesting features which could make possible a new experimental PV test on this molecule. Indeed, ultrahigh resolution spectroscopy using an ultrastable CO(2) laser is favored by several intrinsic properties of this molecule. For example, the high vapor pressure of CHFClI allows investigation by supersonic beam spectroscopy. Indeed, the spectroscopic constants have been accurately determined by microwave and millimetre wave spectroscopy. This is important for the subsequent selection of an appropriate absorption band of CHFClI that could be brought to coïncide with the absorption of CO(2). Partially resolved (+)- and (-)-CHFClI enantiomers with respectively 63.3 and 20.5% ee's have been recently prepared and analyzed by molecular recognition using chiral hosts called cryptophanes. Finally, the S-(+)/R-(-) absolute configuration was ascertained by vibrational circular dichroïsm (VCD) in the gas phase.

Structure and absolute configuration of nyasol and hinokiresinol via synthesis and vibrational circular dichroism spectroscopy.

The absolute configuration of the norlignan (+)-nyasol was determined to be S by comparison of the experimental vibrational circular dichroism data with first-principle calculations taking into account the eight lowest energy conformations. The established absolute configuration of (+)-nyasol enables establishment of the absolute configuration of (-)-hinokiresinol, which is concluded to be S. A total synthesis and resolution of hinokiresinol has been performed to resolve the conflicting reports of the coupling constant of the vinylic protons of the disubstituted double bond in this molecule. Racemic hinokiresinol was resolved. Both enantiomers possess the same antiplasmodial activity.

Enantiomeric excess determination by fourier transform near-infrared vibrational circular dichroism spectroscopy: simulation of real-time process monitoring.

The first use of near-infrared (NIR) Fourier transform vibrational circular dichroism (FT-VCD) to follow changes in the enantiomeric excess (EE) of chiral sample molecules in time using a flow-cell sampling apparatus is reported. Simultaneous changes in the fractional composition and the EE of a mixture of two different chiral molecules were monitored as a function of time. This simulates the progress of the chemical reaction from a chiral reactant to a chiral product where the mole fractions and EE values of both species may change with time. For the molecules studied, alpha-pinene, camphor, and borneol, the accuracy of following EE changes for one species alone is approximately 2%, while for simultaneously following EE changes in two species it is approximately 3% for 30 min sampling periods at 16 cm(-1) spectral resolution. These findings demonstrate the potential for VCD to be used in the NIR region for real-time monitoring of the composition and %EE of chemical reactions involving the synthesis of chiral molecules.

Stereochemical determination and bioactivity assessment of (S)-(+)-curcuphenol dimers isolated from the marine sponge Didiscus aceratus and synthesized through laccase biocatalysis.

Electrospray ionization mass spectrometry-guided isolation of extracts from Didiscus aceratus led to the discovery of several new derivatives of the bioactive bisabolene-type sponge metabolite (S)-(+)-curcuphenol (1). The compounds obtained by this method included a mixture of known (2) and new (3) dihydroxylated analogs as well as a novel family of dimeric derivatives, dicurcuphenols A-E (4-8), and dicurcuphenol ether F (9). Dimers 4-9 were also subsequently obtained through a hemisynthetic method in which 1 was incubated with the enzyme laccase. Atropisomeric dimers 5 and 6 were subjected to vibrational circular dichroism analysis thereby establishing their absolute biaryl axial chirality as P and M, respectively. In contrast to 1, metabolites 2-9 exhibited weak or no cytotoxic or lipoxygenase inhibitory effects.

Phase equilibrium in poly(rA).poly(rU) complexes with Cd2+ and Mg2+ ions, studied by ultraviolet, infrared, and vibrational circular dichroism spectroscopy.

Ultraviolet (UV) and infrared (IR) absorption and vibrational circular dichroism (VCD) spectroscopy were used to study conformational transitions in the double-stranded poly(rA). poly(rU) and its components-single-stranded poly(rA) and poly(rU) in buffer solution (pH 6.5) with 0.1M Na+ and different Mg2+ and Cd2+ (10(-6) to 10(-2) M) concentrations. Transitions were induced by elevated temperature that changed from 10 up to 96 degrees C. IR absorption and VCD spectra in the base-stretching region were obtained for duplex, triplex, and single-stranded forms of poly(rA) . poly(rU) at [Mg2+],[Cd2+]/[P] = 0.3. For single-stranded polynucleotides, the kind of conformational transition (ordering --> disordering --> compaction, aggregation) is conditioned by the dominating type of Me2+-polymer complex that in turn depends on the ion concentration range. The phase diagram obtained for poly(rA) . poly(rU) has a triple point ([Cd2+] approximately 10(-4)M) at which the helix-coil (2 --> 1) transition is replaced with a disproportion transition 2AU --> A2U + poly(rA) (2 --> 3) and the subsequent destruction of the triple helix (3 --> 1). The 2 --> 1 transitions occur in the narrow temperature interval of 2 degrees -5 degrees . Unlike 2 --> 1 and 3 --> 1 melting, the disproportion 2 --> 3 transition is a slightly cooperative one and observed over a wide temperature range. At [Me2+] approximately 10(-3) M, the temperature interval of A2U stability is not less than 20 degrees C. In the case of Cd2+, it increases with the rise of ion concentration due to the decrease of T(m) (2-->3). The T(m) (3-->1) value is practically unchanged up to [Cd2+] approximately 10(-3)M. Differences between diagrams for Mg(2+) and Cd2+ result from the various kinds of ion binding to poly(rA).poly-(rU) and poly(rA).

Determination of the absolute configuration and solution conformation of the antifungal agents ketoconazole, itraconazole, and miconazole with vibrational circular dichroism.

The absolute configuration assignments of three antifungal agents, (+)-(2R,4S)-ketoconazole, (+)-(2R,4S)-itraconazole (with (S)-configuration at the sec-butyl group) and (+)-(S)-miconazole nitrate have been confirmed by using vibrational circular dichroism (VCD). For these three antifungal drugs, this study also provides evidence for the most abundant conformations of miconazole and for the relative conformations of the azole, dichlorophenyl, and methoxyphenyl groups in ketoconazole and itraconazole, in chloroform solution.

Determination of enantiomeric excess in samples of chiral molecules using fourier transform vibrational circular dichroism spectroscopy: simulation of real-time reaction monitoring.

The first use of Fourier transform vibrational circular dichroism (FT-VCD) to follow changes in the percent enantiomeric excess (% EE) of chiral molecules in time using a flow cell sampling apparatus is reported. FT-VCD, as opposed to dispersive scanning VCD, eliminates the need to scan the VCD spectrum in time to monitor the % EE at more than one spectral location. The first use of partial least-squares chemometric analysis to determine % EE values from kinetic sets of VCD spectral data is also reported. These two advances have been used to monitor simultaneously changes in the fractional composition and the % EE of a mixture of two different chiral molecules. This simulates the progress of the chemical reaction from a chiral reactant to a chiral product where the % EE of both molecules can change with time. For the molecules studied, alpha-pinene, camphor, and borneol, the accuracy of following % EE changes for one species alone is approximately 1%, while for simultaneously following % EE changes in two species is approximately 2% for 10-20-min sampling periods at 4 cm(-)(1) spectral resolution. This accuracy can be increased for the same collection times or maintained for shorter periods of collection by lowering the spectral resolution. These findings demonstrate the potential for VCD to be used for real-time monitoring of the composition and % EE of chemical reactions involving the synthesis chiral molecules.

Extension of fourier transform vibrational circular dichroism into the near-infrared region: continuous spectral coverage from 800 to 10 000 cm(-1).

We report the first vibrational circular dichroism (VCD) spectra with continuous coverage from 800 cm(-1) in the mid-infrared (MIR) region to 10 000 cm(-1) in the near-infrared (NIR) region. This coverage is illustrated with MIR and NIR absorbance and VCD spectra of 2,2-dimethyl-dioxolane-4-methanol (DDM), alpha-pinene, and camphor that serve as calibration samples over this entire region. Commercially available, dual-source Fourier transform (FT) MIR and NIR VCD spectrometers were equipped with appropriate light sources, optics, and detectors, and were modified for dual-polarization-modulation (DPM) operation. The combination of liquid-nitrogen- and thermoelectric-cooled HgCdTe (MCT) detectors, as well as InGaAs and Germanium (Ge) detectors operating at room temperature, permitted collection of the desired absorbance and VCD spectra across the range of vibrational fundamental, combination band, and overtone frequencies. The spectra of DDM and alpha-pinene were measured as neat liquids and recorded for both enantiomers in the various spectral regions. Spectra for camphor were all measured in CCl(4) solution at a concentration of 0.6 M, except for the carbonyl-stretching region, where a more dilute concentration was used. The typical anisotropy ratios (g) of the three molecules were estimated with respect to their strongest VCD bands in each spectral region. It was found that for all three molecules in the spectral regions above 2000 cm(-1), anisotropy ratios are approximately the same order (10(-5)) of magnitude. However, in the MIR region, the typical anisotropy ratios are significantly different for the three molecules. This study demonstrates that with modern FT-VCD spectrometers modified for DPM operation, VCD spectra can be measured continuously across a wide spectral range from the MIR to nearly the visible region with an unsurpassed combination of signal-to-noise ratio and spectral resolution.