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Biomedical subjects

L A Nafie

Publications and source records attributed to L A Nafie.

At least 19 recordsLinked to original sources
PubMed2004

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.

Journal Article↗
PubMed2003

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.

Amino Alcohols↗
PubMed2001

Spectroscopic methods for determining enantiomeric purity and absolute configuration in chiral pharmaceutical molecules.

Analytical support, such as methods development, along with identification and characterization of intermediates and impurities, are critical in the development of a chemical process. The preparation of a drug substance requires the development of analytical methods for monitoring reactions and identifying impurities. Methods development for a chiral drug molecule is more difficult as the method must be capable of monitoring the overall reaction as well as possible racemization of starting materials and products. Chiral methods are often required to monitor the reaction steps of a synthesis, however, the development of enantiomeric purity methods are time-consuming and expensive. The use of chiroptical detectors, such as circular dichroism (CD), optical rotation (OR) and vibrational circular dichroism (VCD), can help to reduce or eliminate the need to develop chiral monitoring methods and also to predict absolute configuration. Recently, VCD has shown remarkable success with the latter and currently holds the most promise as a general, direct method that can be used as an alternative to X-ray crystallography. Each of the mentioned techniques can help analytical chemists to reduce the time associated with traditional enantiomeric purity methods development and to determine absolute configuration. This review will discuss the scope and limitations of these techniques for the rapid and routine determination of both enantiomeric excess and absolute configuration.

Chromatography, High Pressure Liquid↗
PubMed1999

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.

Anti-Arrhythmia Agents↗
PubMed1998

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.

Camphor↗
PubMed1997

Infrared and Raman vibrational optical activity: theoretical and experimental aspects.

Advances in the field of vibrational optical activity (VOA) are reviewed over the past decade. Topics are surveyed with an emphasis on the theoretical and instrumental progress in both vibrational circular dichroism (VCD) and Raman optical activity (ROA). Applications of VOA to stereochemical and biological problems are reviewed, with a bias toward new kinds of experiments made possible by theoretical and instrumental advances. In the field of VCD, the most notable advances have taken place in the quality and size of ab initio calculations of VOA intensities and in the quality of step-scan Fourier transform instrumentation. For ROA, the most dramatic progress has occurred in the areas of theoretical formulation and high-throughput instrumentation. Applications of VOA now include all major classes of biological and pharmaceutical molecules. VOA's importance as a diagnostic tool will likely grow as the control of molecular chirality increases in research and industrial areas.

Circular Dichroism↗
PubMed1995

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.

Amides↗
PubMed1994

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.

Circular Dichroism↗
PubMed1992

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.

Amino Acid Sequence↗
PubMed1989

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.

Alanine↗
PubMed1977

Near-infrared magnetic circular dichroism of cytochrome c'.

The near-infrared magnetic circular dichroism (MCD) of Rhodospirillum rubrum, Chromatium vinosum, and Rhodopseudomonas palustris cytochromes c' are reported. The spectra of the reduced protein are very similar to those of deoxymyoglobin. The spectra of the oxidized proteins in the pD range 1-13 can be analyzed on the basis of four species A, B, C, and D. The existence of nine species, reported in a recent electron paramagnetic resonance study, is not substantiated. The MCD spectra support the assignment of B as high spin and C and D as low spin. The MCD of species A is close to that of high-spin proteins and does not support the recently proposed assignment of a mixed high- and intermediate-spin ground state for this species. The energies of the near-IR electronic transitions of all four oxidized species point to axial ligation via oxygen, assuming histidine to be the opposite axial ligand. Unfortunately, insufficient model compounds with ligation by carboxyl or hydroxyl moieties exist to enable more precise assignments.

Chromatium↗