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 configurations of brominated sesquiterpenes determined by vibrational circular dichroism

Two brominated sesquiterpenes, majapolene B (1) and acetylmajapolene B (2), isolated from the red algal genus Laurencia were investigated using vibrational circular dichroism (VCD). The ab initio theoretical VCD and IR calculations of 1 and 2 were performed by density functional theory (DFT) using the B3PW91/6-31G(d,p) basis set. The experimental VCD spectra and corresponding population-weighted theoretical VCD spectra were found to be in excellent agreement in CCl(4) solution in the 1800-850 cm(-1) region, which allowed unambiguous determination of the absolute configurations of (-)-1 and (-)-2 as 7S,10S and 7S,10S, respectively.     

Chiral cruciferous phytoalexins: preparation, absolute configuration, and biological activity

Synthesized by an efficient one-pot spirocyclization method, two chiral cruciferous phytoalexins, 1-methoxyspirobrassinin (2) and 1-methoxyspirobrassinol methyl ether (4a), were prepared through optical resolution using the chiral HPLC method of corresponding racemates. The absolute configuration of natural (+)-2 was elucidated as R by using the direct comparison of ECD and VCD spectra with those of known (S)-(-)-spirobrassinin (1). Another chiral phytoalexin, (-)-4a, had its absolute configuration 2R,3R elucidated through the comparison of observed and calculated VCD. Interestingly, the absolute configurations of natural (S)-(-)-spirobrassinin (1) and (R)-(+)-1-methoxyspirobrassinin (2) were opposite of each other, even though their structures are almost similar, with the exception of an N-methoxy group. A significant difference in the antiproliferative activity between (2R,3R)-(-) and (2S,3S)-(+)-4a was observed.     

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.     

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.     

Determination of the structure of chiral molecules using ab initio vibrational circular dichroism spectroscopy

We discuss the theoretical prediction of vibrational circular dichroism (VCD) spectra using ab initio density functional theory (DFT) and the application of this methodology to the determination of the absolute configurations and conformations of chiral molecules.     

Stereoselective synthesis of 2,3,7-trimethylcyclooctanone and related compounds and determination of their relative and absolute configurations by the MalphaNP acid method

The copper/chiral phosphoramidite (L(1))-catalyzed conjugate addition of dimethylzinc to cycloocta-2,7-dienone 4, followed by the methylation of the intermediate enolate, yielded a single isomer of 7,8-dimethylcyclooct-2-enone (+)-5. Compound (+)-5 was subjected to the second conjugate addition with ent-L(1) giving only one stereoisomer of 2,3,7-trimethylcyclooctanone (+)-6, which was converted to 2,3,7-trimethylcyclooctanol 7. To determine the relative and absolute configurations of these compounds, the (1)H NMR anisotropy method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid {(S)-(+)-MalphaNP acid} 1 was applied. Racemic alcohol (+/-)-7 was esterified with (S)-(+)-MalphaNP acid 1 yielding diastereomeric esters, which were efficiently separated by HPLC on silica gel affording the first-eluted MalphaNP ester (-)-10a and the second-eluted one (-)-10b. The relative and absolute configurations of ester (-)-10a were determined to be (S;1R,2S,3R,7S) by analyzing the (1)H and (13)C NMR spectra of (-)-10a and (-)-10b, especially their HSQC-TOCSY and NOESY spectra, and by applying the MalphaNP anisotropy method. The alcohol 7 formed from (+)-6 was similarly esterified with (S)-(+)-MalphaNP acid 1 yielding an MalphaNP ester, which was identical with (-)-10a, and the relative and absolute configurations of 2,3,7-trimethylcyclooctanone (+)-6 were determined to be (2S,3R,7S).     

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(+).     

Absolute configuration determination of isoflavan-4-ol stereoisomers

Elucidation of the correct stereochemistry of the metabolite is essential for the mechanistic study of bioactive compounds. Isoflavan-4-ol has the same chiropical chromophore as THD, the biosynthetic precursor of the potent phytoestrogen S-equol. Interested in the correct absolute configuration of isoflavan-4-ol stereoisomers and to compare the available practical approaches for the absolute configuration determination, complete absolute configuration analysis of isoflavan-4-ol stereoisomers has been carried out with by means of ECD and VCD spectroscopy as well as modified Mosher method. Theoretical TD-DFT computations resulted in a poor simulation of the observed experimental ECD spectra, and thus inconclusive absolute configuration assignments of isoflavan-4-ol stereoisomers were obtained. However, DFT-assisted VCD spectroscopic analyses successfully determined correct absolute configurations, and further confirmed by modified Mosher method.     

Vibrational circular dichroism spectroscopy study of paroxetine and femoxetine precursors

The solution structures of (3R,4S)- and (3S,4R)- 4-(4-fluorophenyl)-3-hydroxylmethyl- 1-methylpiperidine, which are intermediates in the synthesis of the two pharmaceuticals paroxetine and femoxetine, were studied by vibrational circular dichroism (VCD) spectroscopy. In addition, six derivatives with different substituents attached to the C3 atom were prepared and their VCD and absorption spectra discussed with the aid of ab initio simulations. The VCD spectra were found to be sensitive to the geometry changes. In addition, a subtle variation caused by intermolecular aggregation was apparent in the spectra. The VCD technique can be applied for structural analysis of chiral pharmaceuticals in solutions.     

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 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.     

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.     

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

Phenylglycidols substituted in the 2-, 3-, and 4- positions with fluorine, chlorine, and trifluoromethyl, and with methoxy in the 3- position, were synthesized from the corresponding E-cinnamic acids and separated into their (R,R)- and (S,S)- enantiomers using subcritical fluid chromatography with mixtures of MeOH in CO(2), on either a Chiralpak AD or AS chiral stationary phase. These compounds and commercially-available (R,R)- and (S,S)-phenylglycidol were analyzed for their vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotation (OR) properties to exemplify a strategy whereby the absolute stereochemistry of common and key chiral intermediates is established early in the structure-activity and structure-property relationship phase of a drug discovery program in a pharmaceutical company. From this study, substituents in the phenyl group of the synthesized molecules were found not to grossly alter spectroscopic features, and therefore, diagnostic absorption bands in the respective VCD spectra, and the sign and shape of the measured ECD curves could be used to determine and track the absolute stereochemistry of analogs without necessarily requiring time-consuming ab initio calculations of all low energy conformers for all compounds. VCD, OR, and ECD calculations for the determination of absolute configuration carried out at the DFT level with the hybrid B3PW91 functional and the TZVP basis set were found to be especially useful in this study.     

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.     

Absolute configuration and conformational analysis of a degradation product of inhalation anesthetic Sevoflurane: A vibrational circular dichroism study

1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane, compound B, is a product obtained in the degradation of the anesthetic Sevoflurane. Enantiopure (+)-B was investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-B in CDCl(3) solution in the 2,000-900 cm(-1) region are compared with the ab initio predictions of absorption and VCD spectra obtained from density functional theory using B3LYP/6-31G* basis set for different conformers of (S)-1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane. This comparison indicates that (+)-B is of the (S)-configuration in CDCl(3) solution, in agreement with previous literature results. Our results also indicate that this compound adopts six predominant conformations in CDCl(3) solution.     

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.     

Assessment of configurational and conformational properties of naringenin by vibrational circular dichroism

The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.     

X-ray diffraction studies on the absolute configuration of alpha- and beta-anordrins

The molecular structures and absolute configurations of alpha- and beta-anordrins are reported. Pure alpha- and beta-epimers were obtained with recrystallization and column chromatography combined with high-pressure liquid chromatography methods; they were identified by high-resolution infrared and mass spectra and 1H and 13C nuclear magnetic resonance. By single crystal x-ray diffraction analysis, the crystals of alpha- and beta-epimers were found to belong to the orthorhombic space groups P2(1)2(1)2(1) and P2(1)2(1)2, respectively. The molecular structures of these two epimers were determined. The absolute configurations were deduced by conformation analysis, 1H nuclear magnetic resonance, and comparison with the absolute configuration of the starting material. The absolute configurations of asymmetric centers of alpha- and beta-epimers were observed to be 2R, 5S, 8R, 9S, 10S, 13S, 14S, 17R, and 2S, 5S, 8R, 9S, 10S, 13S, 14S, 17R, respectively. These results were confirmed by the x-ray diffraction determination of the absolute configuration of 2 alpha,17 alpha-diethynyl-A-nor-5 alpha- androstane-2 beta, 17 beta-diol dichloroacetate.