Determination of the absolute configurations of flexible molecules: synthesis and theoretical simulation of electronic circular dichroism/optical rotation of some pyrrolo[2,3-b]indoline alkaloids--a case study

The paper describes the synthesis and chiroptical properties of (-)-1,2,3,3a,8,8a,-hexahydro-1,3a-dimethyl-pyrrolo[2,3-b]indole, (-)-1, one of the monomeric units of many flexible polypyrroloindoline alkaloids and (-)-chimonanthine, (-)-2. The aim of this investigation is to show that, under certain circumstances, namely, with molecules for which the sign and order of magnitude of [alpha](D) are determined by the lowest-energy valence-shell transitions (referred to as class (a) molecules), a small basis set calculation of chiroptical properties provides reliable results, and that such a treatment can be employed for absolute configurational assignment of larger oligomers, for which the increased flexibility renders the analysis as formidable task. Actually, as the aforementioned two molecules belong to class (a) systems, a TDDFT/B3LYP/6-31G* calculation of the ECD and ORD spectra gives rise to a more than satisfactory simulation of these data, assuming the reported absolute configurations. In other words, the use of the TDDFT/B3LYP method with the small 6-31G* basis set enables one to treat large and flexible molecules such as (-)-2 (52 atoms and 6 conformers) by usage of a simple PC in about 2 weeks. This protocol demonstrates that an ab initio prediction of ECD/ORD spectra results in reliable assignments of absolute configuration of even relatively large natural products, thus economizing computation time.     

Assignment of the absolute configuration of [n]-ladderanes by TD-DFT optical rotation calculations

In this study, we report theoretical specific rotation values for a series of cis-/trans-alkylated-[5]-ladderanes and cis-/trans-methylated-[n]-ladderanes. Using time-dependent density functional response theory optical rotation calculations, we can assign (+) and (-) optical rotation signs to trans-(S)-alkyl-[5]-ladderane and trans-(R)-alkyl-[5]-ladderane configurations, respectively. In order to qualitatively validate our absolute configuration predictions, we computed optical rotation values at three different levels of theory--B3LYP, RI-BP86, and Hartree-Fock--using the aug-cc-pVDZ basis set. We observe a novel rung-parity-controlled oscillatory optical rotatory phenomenon in our computations, which, to the best of our knowledge, has never been reported or observed before. Furthermore, this preliminary analysis of optical rotation properties in this class of compounds should facilitate the correct absolute stereochemical assignment of natural and synthetic ladderanes, such as the trans-isomer of pentacyclic C(20)-fatty acid methyl ester (pentacycloanammoxic methyl ester), without the need for derivatization, in particular for cases where NMR or X-ray crystal structures are not readily available.     

Carbohydrate analysis of bacterial polysaccharides by high-pH anion-exchange chromatography and online polarimetric determination of absolute configuration

A significant problem in structure determination of complex carbohydrates, especially for bacterial polysaccharides, is determination of the absolute configuration of the component monosaccharides. A number of analytical methods have been used for this purpose but, as a result of the wide variety of chemical properties of sugars found in complex polysaccharides, no single method is universally applicable. High-resolution gas chromatography of volatile derivatives with chiral reagents is the most widely used method. Optical activity, although direct and simple, lacks sensitivity generally requiring a large quantity of pure monosaccharide. We report a combination of high-performance anion-exchange chromatography (HPAEC) with combined electrochemical pulsed amperometric detection and in-line detection of optical rotation with an in-line laser polarimeter for analysis of a number of sugars found in complex polysaccharides. We show that application of the method for analysis of capsular polysaccharides of several gram-positive and gram-negative pathogenic bacteria provides useful information simultaneously on carbohydrate composition and the enantiomeric configuration of component sugars.     

Reliable HPLC separation,vibrational circular dichroism spectra,and absolute configurations of isoborneol enantiomers

Resolution of chiral compounds has played an important role in the pharmaceutical field, involving detailed studies of pharmacokinetics, physiological, toxicological, and metabolic activities of enantiomers. Herein, a reliable method by high‐performance liquid chromatography (HPLC) coupled with an optical rotation detector was developed to separate isoborneol enantiomers. A cellulose tris(3, 5‐dimethylphenylcarbamate)‐coated chiral stationary phase showed the best separation performance for isoborneol enantiomers in the normal phase among four polysaccharide chiral packings. The effects of alcoholic modifiers and column temperature were studied in detail. Resolution of the isoborneol racemate displayed a downward trend along with an increase in the content of ethanol and column temperature, indicating that less ethanol in the mobile phase and lower temperature were favorable to this process. Moreover, two isoborneol enantiomers were obtained via a semipreparative chiral HPLC technique under optimum conditions, and further characterized by analytical HPLC, and experimental and calculated vibrational circular dichroism (VCD) spectroscopy, respectively. The solution VCD spectrum of the first‐eluted component was consistent with the Density Functional Theory (DFT) calculated pattern based on the SSS configuration, indicating that this enantiomer should be (1S , 2S , 4S )‐(+)‐isoborneol. Briefly, these results have provided reliable information to establish a method for analysis, preparative separation, and absolute configuration of chiral compounds without typical chromophoric groups.     

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(+).     

Synthesis,characterization and absolute configurations of methyl ladderanoates

Methyl esters of [5]-ladderanoic acid and [3]-ladderanoic acid were prepared by esterification of the acids isolated from biomass at a wastewater treatment plant. Optical rotations at six different wavelengths (633, 589, 546, 436, 405 and 365 nm) and vibrational circular dichroism (VCD) spectra in the 1800–900 cm⁻¹ region were measured in CDCl₃ solvent and compared with quantum chemical (QC) predictions using B3LYP functional and 6-311++G(2d,2p) basis set with polarizing continuum model representing the solvent. QC predictions gave negative optical rotations at all six wavelengths for (R)-methyl [5]-ladderanoate and positive optical rotations for (R)-methyl [3]-ladderanoate, the same signs as previously reported for the corresponding acids. The crystal structure of (−)-methyl [5]-ladderanoate independently confirmed (R) configuration. The QC-predicted VCD spectra using Boltzmann population weighted spectra of individual conformers did not provide satisfactory quantitative agreement with the experimental VCD spectra. An improved quantitative agreement for VCD spectra could be obtained when conformer populations were optimized to maximize the similarity between experimental and predicted VCD spectra, but more improvements in VCD predictions are needed.     

Specific Optical Rotations and the Horeau Effect

The observation of nonequivalence of optical and enantiomeric purities, referred to as the Horeau effect, is thought to arise from molecular aggregation in liquid solutions. Although this effect was first observed in 1969, the conditions under which this effect may, or may not, be observable are not established. Considering the formation of dimers as the simplest form of aggregation, the expressions for specific optical rotations in the presence of homochiral and heterochiral monomer–dimer equilibria are presented. Analysis of these equations indicates that the Horeau effect will not be observable even in the presence of aggregation under either of the following two situations: 1) The specific optical rotation of the monomeric species is equal to that of the dimeric species; 2) The heterochiral equilibrium constant is twice that of the homochiral equilibrium constant. Chirality 28:181–185, 2016. © 2015 Wiley Periodicals, Inc.     

Circular dichroism spectroscopy and DFT calculations in determining absolute configuration and E/Z isomers of conjugated oximes

The primary purpose of this work was to demonstrate the suitability of circular dichroism (CD) spectroscopy in stereochemical studies of α,β ‐unsaturated oximes, with particular emphasis on determination of E and Z geometry of the oxime double bond. As models for this study, O‐phenyl and O‐triphenylmethyl (trityl) oximes of 4‐hydroxy‐2‐methylcyclopent‐2‐en‐1‐one were selected. These model compounds differ in both absolute configuration at C4 carbon atom and E ‐Z configuration of the oxime double bond. The basic dichroic technique applied was electronic circular dichroism (ECD) assisted by quantum‐chemical calculations and vibrational circular dichroism (VCD) for selected cases. Such an approach enabled effective implementation of both goals. Thus, we were able to associate the signs of Cotton effects in the range of 190–240 nm with the absolute configuration at C4 and within 240–300 nm with the E ‐ or Z ‐geometry of the oxime double bond. Within this work, optical activity of the protecting trityl group was also studied towards formation of the propeller‐shaped conformations by using the same combined CD/DFT methodology. As shown, the helical structure of the trityl group has a considerable influence on the ECD spectra. However, the MPM and PMP conformers of the trityl group are in fact almost equally populated in the conformational equilibrium, making it impossible to distinguish them. On the other hand, rotamers of the hydroxyl group at C4 show a decisive impact on the VCD spectra in both phenoxy and trityl oximes.     

Enantioselective preparative HPLC separation of the HBCD-Stereoisomers from the technical product and their absolute structure elucidation using X-ray crystallography

1,2,5,6,9,10-Hexabromocyclododecane (HBCD) is a widely used flame retardant, which tends to persist in the environment and accumulates in biota. The six stereoisomers (three racemates named alpha-, beta-, and gamma-HBCD) of the technical mixture were isolated with high-performance liquid chromatography (HPLC). Direct separations were performed on a chiral stationary phase containing permethylated beta-cyclodextrin (NUCLEODEX beta-PM column) and the pure enantiomers of alpha-, beta-, and gamma-HBCD were physically characterized for the first time. The absolute configurations of all six isomers were determined by anomalous dispersion using single crystal X-ray crystallography. Optical rotations alphaD in tetrahydrofuran were +4.2/-4.0 (alpha-HBCD), +26.1/-27.5 (beta-HBCD), and +68.0/-66.3 (gamma-HBCD). The sense of rotation could be correlated with the absolute configurations of alpha-, beta-, and gamma-HBCD enantiomers and their order of elution on a chiral permethylated beta-cyclodextrin-bonded stationary phase. The diastereomersalpha-, beta-, and gamma-HBCD displayed distinctly different melting points as well as (1)H-, (13)C NMR, and IR spectra.     

The absolute configuration of the new amino acid 2-amino-4-methyl-hex-5-enoic acid from a new guinea Boletus

The absolute configuration of the 2-amino-4-methyl-hex-5-enoic acid isolated from Boletus was shown to be 2S, 4S, by an unambiguous synthesis of its dihydro derivative from 2S-(?)-2-methylbutan-1-ol.     

Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate,a muscarinic antagonist

The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding affinities to the five cloned m₁–m₅ muscarinic receptors of the stereoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared through the synthesis of their racemates followed by chemical resolution as (+) and (−) tartrate or (+) and (−) dibenzoyltartrate salts. The isomers with cis-configuration of OH and COOH substituents of the cyclohexane are also obtained by coupling optically active (1S, 2S) or (1R,2R)-1-hydroxy-[1,1′-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-diethylamino-2-propanol. Chiral GC and HPLC methods are used to determine their optical purity. The absolute configurations of the four cis- and four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. Chirality 9:713–721, 1997. © 1997 Wiley-Liss, 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.     

An attempt to determine the absolute configuration of two ascolactone stereoisomers with time-dependent density functional theory

Two stereoisomers of ascolactone (A, B), natural products with two asymmetric carbon atoms, are isolated from the marine-derived fungus Ascochyta salicorniae. Although these compounds show virtually opposite CD spectra and [alpha]D, 1H- and 13C-NMR data exclude the presence of enantiomers and suggest ascolactone A and B to be epimeric lactones. By comparing the experimental CD spectra with those calculated employing time-dependent density functional theory (TDDFT), we elucidate the configuration at one of the asymmetric carbon atoms.     

Determination of the absolute configuration of 6-alkylated alpha-pyrones from Ravensara crassifolia by LC-NMR

The absolute configuration of asymmetric centres of two alpha-pyrones isolated from Ravensara crassifolia was determined using the Mosher method. The conventional analysis of the purified ester derivatives by 1H-NMR was replaced by a rapid and sensitive method in which the alpha-pyrones were analysed under isocratic reversed-phase LC-NMR conditions prior to and after derivatisation reactions. Comparison of the LC-1H-NMR spectra of the actual alpha-pyrones with those of the corresponding Mosher's esters recorded in the acetonitrile:deuterated water solvent system exhibited shifts comparable with those obtained using conventional deuterated solvents. Based on the shifts recorded, determination of the absolute configuration was possible by application of Mosher rules. The use of LC-NMR has permitted a direct analysis of crude reaction mixtures containing less than 50 microg of the starting material. Completion of the reaction was checked by LC-MS and the crude reaction mixture was analysed by stop-flow LC-NMR. This methodology seems very promising for the determination at the micro-scale level of the absolute configuration of natural products which are available only in very small amounts.     

Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy

Recent advances in the development of chiral derivatizing and solvating agents that facilitate the determination of enantiomeric excess and absolute configuration are reviewed. These include metal-containing species, host-guest systems, donor-acceptor compounds, and liquid crystal discriminating agents. In the aggregate, these reagents can be used to analyze a wide range of compound classes.     

Assignment of absolute configuration of 3-hydroxy beta-lactams by the NMR "mix and shake" method

The absolute configurations of several 3-hydroxy beta-lactams were assigned by the NMR "mix and shake" methodology developed by Riguera and co-workers. The results from the NMR study correlated perfectly with the absolute configurations obtained from X-ray crystallographic structure analyses and chiral-phase HPLC data.     

Hyperolactone C: determination of its absolute configuration by comparison of experimental and calculated CD spectra

A detailed conformational analysis of hyperolactone C diastereomers and enantiomers ((5R,9R),(5S,9S) and (5S,9R),(5R,9S)) was done with molecular mechanics and density functional theory methods. Time-dependent density functional theory (B3PW91/TZVP) was used to calculate electronic transition energies (UV/vis spectra) and rotational strengths of the respective conformations. The effect of solvation (acetonitrile solution) on excitation energies and electronic circular dichroism was approximated by the polarizable continuum model. By comparison of the simulated CD spectrum with that measured for hyperolactone C isolated from Hypericum lloydii, its absolute configuration can be assigned as (5S,9S).     

Crystal structure and absolute configuration of (+)546-[copy4Cl2]HDBT: An example of torsional isomerism

The crystal structure and absolute configuration of the (?)₅₈₉-dibenzoylmonohydrogentartrate salt of the cation [Co(pyridine)₄Cl₂]⁺ have been determined from a three-dimensional X-ray analysis. Single crystals were grown from dimethylsulfoxide: space group P2₁2₁2₁, Z = 4, and cell dimensions a = 21.463(4), b = 23.112(3), and c = 7.490(1) Å. Full-matrix least-squares refinement on F converged at R = 0.075, 196 variables and 2029 observations. The cation has pseudotetragonal coordinate geometry, with axial Cl and equatorial N atoms. The dihedral angles between the pyridine ligands and the equatorial plane are 47(1), 39(1), 50(1), and 45(1)° and torsional isomerism is responsible for the solid-state chiroptical properties of the cation. The preferential crystallization of the P atropisomer of the cation is attributed to a general electrostatic attraction between cation and anion.     

Determination of absolute configuration of 1,3-diols by the modified Mosher's method using their di-MTPA esters.

1,3-Diols are frequently involved in biologically important compounds and, therefore, determination of the stereochemistry of these structural elements, in particular those in acyclic systems, has been one of the focuses of attention in natural products chemistry. The modified Mosher's method, commonly used for the determination of the absolute configuration of secondary alcohols, was applied to determine the absolute configuration of 1,3-diols with their di-MTPA esters. Several epimeric pairs of syn- and anti-1,3-diols with known absolute configurations were converted to the corresponding di-MTPA esters and the iDelta;delta values were then calculated. For the acyclic syn-1,3-diols, the iDelta;delta values were systematically arranged as predicted from the basic concept of the modified Mosher's method, demonstrating that the method is valid for these compounds. In contrast, the iDelta;delta values were irregularly arranged for the acyclic anti-1,3-diols and, accordingly, this method is not valid for these cases. These results are complementary to those of the previously reported CD exciton chirality method and, hence, the combined use of the modified Mosher's method and the CD exciton chirality method can determine the absolute configuration of the acyclic 1,3-diols. Also, this method is successfully applicable to cyclic 1,3-diols irrespective of their relative stereochemistry.