VCD configuration of enantiopure/-enriched tetrasubstituted alpha-fluoro cyclohexanones and their use for epoxidation of trans-olefins.

The configurations of three enantiopure tetrasubstituted alpha-fluoro cyclohexanones (-)-5Ia, (-)-5IIa and (-)-6a were determined by VCD and proved to be (-)-(2S,5R)-5Ia, (-)-(2R,5R)-5IIa, and (-)-(2R,5R)-6a. The VCD study also identified the conformers populated in CDCl3 solution, including higher-energy gas-phase conformers with equatorial fluorine for 5Ia and 5IIa that are stabilized in CDCl3 solution. Used as catalysts for epoxidation of trans olefins (beta-methylstyrene, stilbene, methyl p-methoxy cinnamate) by oxone, it was found that (-)-5Ia is the most efficient for all trans olefins (providing, respectively, 62%, 90% and 66% ee) but that all three ketones provide high ee% with stilbene (78-90% ee). Moreover, the configurations predicted from the stereo outcome of the epoxidation reaction are identical to those determined by VCD.

erythro-1-Naphthyl-1-(2-piperidyl)methanol: synthesis, resolution, NMR relative configuration, and VCD absolute configuration.

The erythro isomer of 1-naphthyl-1-(2-piperidyl)methanol 4, an efficient chiral modifier for asymmetric heterogeneous hydrogenation, was obtained as the major isomer (95%) in two steps while the threo isomer can be obtained as the major isomer (67%) in three steps. erythro-4 and threo-4 were resolved on a CHIRALCEL OD-RH column. It has been shown by VCD that the diastereomer determined as the erythro by NMR was indeed the erythro and that the first eluted (-)-enantiomer on CHIRALCEL OD-R or -RH columns has the (1R,2S) configuration. The VCD studies identify the presence of at least five conformers in CDCl(3) solution. Moreover, this (-)-(1R,2S) absolute configuration found by VCD is consistent with the expected stereo-outcome of catalytic hydrogenation of pyruvate into lactate, which supported the (+)-(1S,2R) assignment.

Hydrogen-stretching vibrational circular dichroism spectroscopy: absolute configuration and solution conformation of selected pharmaceutical molecules.

The vibrational circular dichroism (VCD) spectra of several chiral antiarrhythmic drugs (quinidine, flecainide, RAC 109, and propranolol) and chiral anti-inflammatory drugs (ibuprofen and naproxen) in the OH-, NH- and CH-stretching regions are reported. The absolute configurations of some of these drugs are identified by comparison to VCD spectra of similar molecules and by VCD intensity calculations on fragments of the drugs, utilizing either the locally distributed origin gauge (LDO) model or a priori vibronic coupling theory (VCT) methods. The most abundant conformations of propranolol, flecainide and RAC 109 in non-aqueous solution are also identified from the VCD spectra. This study demonstrates the utility of VCD in this spectral region for identification of solution conformation and absolute configuration for pharmaceuticals of moderate size. The conformations deduced from the VCD spectra provide insight into the stereospecific binding of the antiarrhythmic drugs.

Vibrational circular dichroism: an incisive tool for stereochemical applications.

Vibrational circular dichroism (VCD) is the extension of circular dichroism (CD) from electronic to vibrational transitions in molecules. In this review, we present the basic concepts of VCD and focus on its growing strength for stereochemical applications. There are three principal areas of application of VCD. These are the determination of optical purity, the determination of absolute configuration and the determination of conformational properties of chiral molecules in solution. Until recently, the application of VCD was restricted to the use of instruments that had been custom assembled in academic research laboratories. This situation has now changed. It is possible to purchase a dedicated Fourier transform infrared (FTIR) VCD spectrometer complete with user friendly software. Combined with rapid advances in the ab initio theoretical prediction of infrared (IR) and VCD spectra, the availability of such technology opens the way for the widespread use of VCD spectroscopy for research and industrial applications.

Vibrational optical activity of oligopeptides.

Vibrational optical activity (VOA) is a relatively new spectroscopic technique, which has two principal manifestations, ir vibrational CD and vibrational Raman optical activity. Progress in the study of oligopeptides using both of these forms of VOA is reviewed from the perspective of theoretical and instrumental techniques, spectral results, and structural interpretations.

Comparison of IR and Raman forms of vibrational optical activity.

Natural vibrational optical activity consists of two principal forms. The IR form is known as vibrational circular dichroism (VCD) and is simply the extension of electronic circular dichroism into the IR vibrational region of the spectrum. The Raman form, known as Raman optical activity (ROA), is a new form of optical activity that has no counterpart in the classical forms of optical activity. In this paper, the similarities and differences of the IR and Raman forms of vibrational optical activity will be examined. Although both VCD and ROA were discovered and confirmed in the period from 1973 to 1975, each field has evolved independently with key advances in theoretical description, instrumentation and application coming at different times over the past 20 years. The current relative strengths and weaknesses of VCD and ROA will be discussed, and specific examples of VOA spectra of (-)-alpha-pinene and the amino acid L-alanine, for which overlapping VCD and ROA data are available, will be presented.

Vibrational circular dichroism in ephedra molecules. Experimental measurement and ab initio calculation.

Vibrational circular dichroism (VCD) spectra in the OH- and NH-stretching regions have been measured for six pharmaceutical molecules in the ephedra class, (1S,2R)-norephedrine, (1), (1S,2S)-norpseudoephedrine (2), (1S,2R)-ephedrine (3), (1S,2S)-pseudoephedrine (4), (1S,2R)-N-methylephedrine (5) and (1S,2S)-N-methylpseudoephedrine (6), all in dilute C2Cl4 solution. Ab initio calculations of geometries and vibrational frequencies for a number of conformers of 1 to 6 have been carried out. The recently developed locally distributed origin gauge model for VCD was used to calculate VCD spectra of the conformers for each drug. This ground-state ab initio model, which does not require sum-over-states, magnetic field perturbation or localized molecular orbitals, has been found to give good agreement with experiment in this frequency region. Composite spectra obtained from weighted averages of the calculated conformer spectra agree within a factor of two with observed IR and VCD intensities for five of the ephedra drugs. For (1S,2S)-pseudoephedrine, the discrepancy between experiment and calculation has been interpreted in terms of a coupled-oscillator effect absent in the other molecules.

Vibrational CD studies of interchain hydrogen-bonded tripodal peptides.

The solution conformations of three trispeptides--L,L,L-1,3,5-C6H3[CH2NHCOCH(X)-NHBoc++ +]3, X = CH3 (Ala) or CH2CH(CH3)2 (Leu), and L,L,L-N(CH2CH2NHCOCH[CH2-CH(CH3)2]NHBoc)3--have been determined from their ir and vibrational CD (VCD) spectra in the NH stretching and carbonyl stretching regions in apolar solution. The compounds containing L-Leu are shown to occur primarily in a propeller conformation with C3 symmetry that is stabilized by interchain hydrogen bonds. Through application of the coupled oscillator model of VCD, a right-handed sense for the hydrogen-bonded chains in the propeller is deduced, in agreement with previous empirical force field calculations. The spectra also provide evidence for interchain association between two chains, resulting in a C10-ring. For chains not involved in interchain association, the spectra reveal the presence of C7-rings within a chain. The trispeptide containing L-Ala is found to occur primarily in a random form.

Vibrational CD studies of the solution conformation of simple alanyl peptides as a function of pH.

The CH-stretching vibrational CD (VCD) spectra of glycyl-L-alanine, L-alanylglycine, and L-alanyl-L-alanine have been studied at neutral, high, and low pH in D2O solution. The intense positive VCD band attributed to the C alpha H stretch of the alanyl residue in glycyl-L-alanine at neutral pH is absent in L-alanylglycine. In contrast to the VCD spectra of L-alanine, the positive methine-stretching VCD band in glycyl-L-alanine and L-alanyl-L-alanine is still present at pH 2. Based on the ring current mechanism, the VCD spectra are consistent with the presence of a five-membered CO...HN intramolecular hydrogen-bonded ring between the C-terminal carboxylate and peptide NH groups at neutral and high pH; and a seven-membered COH...O = C hydrogen-bonded ring between the C-terminal carboxyl OH and peptide C = O groups at low pH. In the N-terminal alanyl residue, the peptide C = O group is hydrogen bonded to the NH trans to the methine bond. The CH-stretching VCD spectra of L-alanyl-L-alanyl-L-alanine at neutral pH are consistent with two intramolecularly hydrogen-bonded conformations for the central alanyl residue.