Structure and absolute configuration of a visamminol derivative using IR and vibrational circular dichroism

The aerial parts of Arracacia tolucensis (Kunth) Hemsl. (Apiaceae) provided the new visamminol derivative (S)-(+)-4′-O-angeloylvisamminol (1), along with the known angular pyranocoumarin 2. Analysis of HMBC NMR correlations did not allow distinction of the linear dihydrofurochromone 1 from pyranochromone 5. The structure and S absolute configuration of (+)-1 was therefore established by comparison of the IR and vibrational circular dichroism spectra of the natural product with the DFT B3LYP/DGDZVP calculated spectra for (S)-1 and (S)-5. Structural verification followed by single crystal X-ray diffraction of (+)-1 and chemical correlation.     

Determination of the absolute configuration of a key tricyclic component of a novel vasopressin receptor antagonist by use of vibrational circular dichroism

We present the results of a study using vibrational circular dichroism (VCD) for (+)-1, which furnished an unambiguous determination of its absolute configuration as S. The most abundant conformation of (+)-1 in CDCl(3) solution was also established.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochromanone S-oxide

We reexamined the absolute configuration (AC) of the chiral sulfoxide 1-thiochromanone S-oxide (1) using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of 1 was analyzed using density functional theory (DFT). DFT predicts two stable conformations of 1, separated by <1 kcal/mole. Their VCD spectra were calculated using the DFT/GIAO methodology. The VCD spectrum predicted for the equilibrium mixture of the two conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The AC of 1 is therefore definitively R(-)/S(+).     

Elucidation of the absolute configuration of JNJ-27553292, a CCR2 receptor antagonist, by vibrational circular dichroism analysis of two precursors

The absolute configurations of two precursors, that is, 1-(3',4'-dichlorophenyl)-propanol and 1-(3',4'-dichlorophenyl)-propanamine, of a potent 2-mercapto-imidazole CCR-2 receptor antagonist, JNJ-27553292, were determined using vibrational circular dichroism. As a consequence, the absolute configuration of the antagonist itself was also determined. The two precursor compounds were subjected to a thorough conformational analysis and rotational strengths were calculated at the B3LYP/cc-pVTZ level of theory. Based on these data, vibrational circular dichroism spectra were simulated, which in turn were compared with experimental spectra. Agreement between the spectra allowed the assignment of the absolute configuration, which is in agreement with the proposed configuration based on stereospecific reactions on similar compounds.     

Determination of the absolute configuration and solution conformation of gossypol by vibrational circular dichroism

Vibrational circular dichroism (VCD) measurements and density functional theory (DFT) calculations were used to obtain the first definitive assignment of the absolute configuration for the polyphenolic binaphpthyl dialdehyde gossypol and a determination of the solution conformation in CDCl(3). VCD spectra recorded for the two resolved enantiomers are near mirror images and excellent agreement between the observed IR and VCD spectra and intensity calculations carried out at the DFT (B3LYP/6-31G*) level establish the absolute configurations of (+)-gossypol as P and (-)-gossypol as M, with two conformations in CDCl(3) solution that differ in isopropyl group orientation.     

Absolute configuration of eremophilanoids by vibrational circular dichroism

The absolute configurations (AC) of natural occurring 6-hydroxyeuryopsin (1), of its acetyl derivative 2, and of eremophilanolide 8 were confirmed by comparison of the experimental vibrational circular dichroism (VCD) spectra with theoretical curves generated from density functional theory (DFT) calculations. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field. All MMFF94 conformers were further optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by calculations of their vibrational frequencies at the B3LYP/6-31G(d,p); the VCD spectra of 2 and 8 were also calculated at the B3PW91/DGDZVP level of theory. Good agreement between theoretical and experimental VCD curves unambiguously verified the 4S,5R,6S absolute configuration for 1 and 2, and the 1S,4S,5R,6S,8S,10S configuration for 8.     

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.     

Absolute configuration determination of chiral molecules in the solution state using vibrational circular dichroism

Advances in the measurement, calculation, and application of vibrational circular dichroism (VCD) for the determination of absolute configuration are described. The purpose of the review is to provide an up-to-date perspective on the capability of VCD to solve problems of absolute stereochemistry for chiral molecules primarily in the solution state. The scope of the article covers the experimental methods needed for the accurate measurement of VCD spectra and the theoretical steps required to systematically deduce absolute configuration. Determination of absolute configuration of a molecule by VCD requires knowledge of its conformation or conformational distribution, and hence VCD analysis necessarily provides solution-state conformation information, in many cases available by no other method, as an additional benefit. Comparisons of the advantages and limitations of VCD relative to other available chiroptical methods of analysis are also presented.     

Absolute configuration of podophyllotoxin related lignans from Bursera fagaroides using vibrational circular dichroism

The ethanol extract from the dried exudate of Bursera fagaroides (Burseraceae) showed significant cytotoxic activity in the HT-29 (human colon adenocarcinoma) test system. The extract provided four podophyllotoxin related lignans, identified as (7′R,8R,8′R)-(−)-deoxypodophyllotoxin (3), (7′R,8R,8′R)-(−)-morelensin (4), (8R,8′R)-(−)-yatein (5), and (8R,8′R)-(−)-5′-desmethoxyyatein (6), whose spectroscopic and chiroptical properties were compared with those of (7R,7′R,8R,8′R)-(−)-podophyllotoxin (1) and its acetyl derivative (2). Their absolute configurations were assigned by comparison of the vibrational circular dichroism spectra of 1 and 3 with those obtained by density functional theory calculations.     

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.     

Determination of absolute configuration of salvic acid,an ent-labdane from Eupatorium salvia,by vibrational circular dichroism

The relative stereochemistry at C13 and the absolute configuration of salvic acid, a constituent of the leaves of Eupatorium salvia, were established as the 13-(R)-ent-labdane 1. The results follow from vibrational circular dichroism measurements of the derived O-methyl ether methyl ester 3 which were compared to DFT B3LYP/DGDZVP calculated spectra. The relative stereochemistry of salvic acid at C13 was independently verified by single crystal X-ray diffraction measurements of 1, and of its derived diol 4.     

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.     

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.     

Absolute configuration of (−)-myrtenal by vibrational circular dichroism

The VCD spectrum of the monoterpene (−)-myrtenal (1) was compared with theoretical spectra using ab initio density functional theory (DFT) calculations at the B3LYP/6-31G(d,p), B3LYP/6-31G+(d,p), B3LYP/6-311G+(d,p), B3LYP/DGDZVP, and B3PW91/DGTZVP levels of theory. Conformational analysis of 1 indicated that the lowest energy conformer was s-trans-C2-C10, which contributes more than 98.5% to the total conformational population regardless of the employed level of theory. The use of a recently developed confidence level algorithm demonstrated that VCD spectra calculated for the main conformer, using the indicated hybrid functionals and basis set, gave no significant changes, from where it follows that B3LYP/DGDZVP calculations provide a superior balance between computer cost and VCD spectral accuracy. The DGDZVP basis set demanded around a quarter the time than the 6-311G+(d,p) basis set while providing similar results. The spectral comparison also provided evidence that the levorotatory enantiomer of myrtenal has the 1R absolute configuration.     

Determination of the absolute configurations of synthetic daunorubicin analogues using vibrational circular dichroism spectroscopy and density functional theory

The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl₃ solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6‐311G** and 6‐311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Absolute configuration of labdanes and ent-clerodanes from Chromolaena pulchella by vibrational circular dichroism

The aerial parts of Chromolaena pulchella biosynthesize two groups of diterpenes belonging to opposite enantiomeric series, specifically, the furanoid ent-clerodanes (5R,8R,9S,10R)-(-)-hardwikiic acid (1), methyl (5R,8R,9S,10R)-(-)-hardwikiate (2), (5S,8R,9S,10R)-(-)-hautriwaic acid lactone (3), methyl (5R,8R,9S,10R)-(-)-nidoresedate (4) and methyl (8R,9R)-(-)-strictate (5), as well as the labdanes (5S,8R,9R,10S)-(+)-(13E)-labd-13-ene-8,15-diol (6) and (5S,8R,9R,10S)-(+)-isoabienol (7). The absolute configuration of the two groups of diterpenes was unambiguously assigned by comparison of the vibrational circular dichroism spectra of 3 for ent-clerodanes, and of 7 for labdanes with their theoretical spectra obtained by density functional theory calculations. The results support a biogenetic proposal to diterpenes found in the studied botanical species.     

The absolute configuration of 1-carboxyethyl substituents on common hexoses by circular dichroism

Determination of the absolute configuration of the 1-carboxyethyl substituent on a monosaccharide by circular dichroism measurements was found to be a sensitive and simple method. It relies on comparison of the spectrum of a 1-carboxyethyl substituted sugar or sugar derivative with the spectra of (R)- and (S)-lactic acid in the region 200-260 nm in which the (R)- and (S)-configuration give negative and positive deltaepsilon, respectively. The oligo- or poly-saccharide containing a 1-carboxyethyl substituted sugar is hydrolyzed to monomers and the 1-carboxyethyl substituted sugar isolated by chromatography. The CD spectrum obtained for the 1-carboxyethyl substituted sugar in water solution at pH 2 is then compared with spectra of (R)- and (S)-lactic acid. The sign for the absorption and a maximum of comparable intensity and appearance around 210 nm, identify the stereochemistry.     

Enantioselective semipreparative HPLC separation of PCB metabolites and their absolute structure elucidation using electronic and vibrational circular dichroism

Polychlorinated biphenyls (PCBs) remain one of the most important groups of environmental contaminants. The fate (transformation) as well as the toxicological implications of the different metabolism steps are subject to considerable debate. The aim of this study is to start a comprehensive investigation of atropisomeric PCB metabolites, i.e., hydroxy, methoxy, methylthionyl, and methylsulfonyl PCBs in different biota. For this purpose, enantioselective semipreparative liquid chromatography is used to obtain pure enantiomers of PCB metabolites. Electronic circular dichroism (UV-CD) and vibrational circular dichroism (VCD) in combination with computational techniques were applied to determine their absolute structures. Approximately 18-25 mg of each enantiomer of the following metabolites were obtained using semipreparative HPLC on beta-cyclodextrin-based columns: 4-MeO-CB149, 4-MeS-CB149, 4-MeSO2-CB149, 3-MeS-CB149, and 3-MeSO2-CB149. The enantiomeric purity of the separated enantiomers was in the range of 95.0-99.9%. Rotational angles and absolute configurations were also determined. This study establishes a sound method for future preparation and absolute structure determination of compounds belonging to the same class.     

Conformational analysis of perezone and dihydroperezone using vibrational circular dichroism

The vibrational circular dichroism (VCD) spectra of perezone and dihydroperezone measured from CDCl₃ solutions were quite similar, suggesting analogous conformations for both molecules. Their absolute configurations were confirmed by comparison of the experimental VCD spectrum of each compound with curves generated from theoretical calculations using density functional theory (DFT) at the B3LYP/DGDZVP level of theory taking into account their conformational mobility. Conformational analysis of the 8-(R) enantiomer showed 19 low energy conformers in a 2.4 kcal/mol energy range, while for 8-(R), with the saturated side alkyl chain, 34 conformers were considered in the first 2 kcal/mol. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field, all MMFF94 conformers were geometrically optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by reoptimization and calculations of their vibrational frequencies at the B3LYP/DGDZVP level. Good agreement between the theoretical 8-(R) enantiomers and experimental VCD curves were observed for both.     

An investigation of the thermal unfolding of swine pepsinogen using circular dichroism.

The thermal unfolding of swine pepsinogen is investigated using circular dichroism (CD) in the pH range 6-9. CD spectra and single wavelength melting curves are analyzed to show the presence of two resolvable transitions. Analysis of difference CD spectra by the method of singular value decomposition indicates that the changes in conformation are distinct in the two transitions. Single wavelength melting curves show that only one of the transitions has a strong pH dependence. The results are discussed in terms of earlier kinetic and calorimetric data to suggest the presence of one or more intermediates in the reaction.