Analysis of the major chiral compounds of Artemisia herba-alba essential oils (EOs) using reconstructed vibrational circular dichroism (VCD) spectra: En route to a VCD chiral signature of EOs

An unprecedented methodology was developed to simultaneously assign the relative percentages of the major chiral compounds and their prevailing enantiomeric form in crude essential oils (EOs). In a first step the infrared (IR) and vibrational circular dichroism (VCD) spectra of the crude essential oils were recorded and in a second step they were modelized as a linear weighted combination of the IR and VCD spectra of the individual spectra of pure enantiomer of the major chiral compounds present in the EOs. The VCD spectra of enantiomer of known enantiomeric excess shall be recorded if they are not yet available in a library of VCD spectra. For IR, the spectra of pure enantiomer or racemic mixture can be used. The full spectra modelizations were performed using a well known and powerful mathematical model (least square estimation: LSE) which resulted in a weighting of each contributing compound. For VCD modelization, the absolute value of each weighting represented the percentage of the associate compound while the attached sign addressed the correctness of the enantiomeric form used to build the model. As an example, a model built with the non-prevailing enantiomer will show a negative sign of the weighting value. For IR spectra modelization, the absolute value of each weighting represented the percentage of the compounds without of course accounting for the chirality of the prevailing enantiomers. Comparison of the weighting values issuing from IR and VCD spectra modelizations is a valuable source of information: if they are identical, the EOs are composed of nearly pure enantiomers, if they are different the chiral compounds of the EOs are not in an optically pure form. The method was applied on four samples of essential oil of Artemisia herba-alba in which the three major compounds namely (−)-α-thujone, (+)-β-thujone and (−)-camphor were found in different proportions as determined by GC–MS and chiral HPLC using polarimetric detector. In order to validate the methodology, the modelization of the VCD spectra was performed on purpose using the individual VCD spectra of (−)-α-thujone, (+)-β-thujone and (+)-camphor instead of (−)-camphor. During this work, the absolute configurations of (−)-α-thujone and (+)-β-thujone were confirmed by comparison of experimental and calculated VCD spectra as being (1S,4R,5R) and (1S,4S,5R) respectively.     

Assignment of absolute configurations of permethrin and its synthon 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic circular dichroism,optical rotation,and X-ray crystallography

The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute configurations are of central importance for the detailed investigation and correct assignment of stereoselective effects. In this context, single stereoisomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), a precursor, metabolite, and environmental degradation product of PM, were isolated from a mixture of all four stereoisomers in enantiomeric excesses of >99% via a two-step chromatographic process combining a diastereoselective reversed-phase separation in the first step with a direct enantiomer separation in the second step. Esterification of DCCA stereoisomers with 3-phenoxybenzyl alcohol yielded PM. Electronic circular dichroism (ECD) spectra of DCCA and PM stereoisomers were measured in non-polar (cyclohexane containing 5% v/v 1,2-dichloroethane) and non-protic polar (acetonitrile) solvents. Cotton effects suitable to distinguish the four stereoisomers of each DCCA and PM were obtained. Absolute configurations of DCCA were determined by confrontation of calculated (time-dependent density-functional theory using B3LYP hybrid functional) and experimental ECD and optical rotation (OR) data. Fully convergent results between ECD and X-ray diffractometry (analysis of DCCA isomers co-crystallized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine), which was employed as a reference method, were obtained. The importance of considering dimer formation of DCCA in solution for the computational delineation of absolute configurations was demonstrated by (1R,3R)-cis-DCCA for which the ΔG Boltzmann averaged calculated monomeric form delivered the opposite sign of OR compared to the dimeric form and the value determined experimentally in dichloromethane. For (1S,3R)-trans-DCCA both monomer and dimer delivered the identical sign of OR and this was in agreement with the experimental measurement. In contrast to OR, the calculated ECD spectra of these two DCCA stereoisomers were less sensitive toward intermolecular association.     

Isochromanes from Aspergillus fumigatus,an endophytic fungus from Cordyceps sinensis

Four previously undescribed isochromanes were isolated from the fermentation broth of an endophytic fungus Aspergillus fumigatus, which was obtained from the fruiting body of Cordyceps sinensis. Their structures were elucidated through extensive spectroscopic analyses. One racemic isochromane was further purified by chiral HPLC to yield a pair of enantiomers and their absolute configurations were determined by quantum chemical ECD calculations. These isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-ME-231) and the result showed that compounds 1a and 2 exhibited moderate growth inhibition against MV4-11 cell line.     

Phthalide-derived oxaspiroangelioic acids A–C with an unprecedented carbon skeleton from an aqueous extract of the Angelica sinensis root head

Three phthalide-derived analogues, oxaspiroangelioic acids A–C (1–3), were isolated as minor components of an aqueous extract of the Angelica sinensis root heads (guitou). Oxaspiroangelioic acids A and B were racemates separated into enantiomers by chiral HPLC. Their structures including absolute configurations were determined by spectroscopic data analysis, single crystal X-ray diffraction, exciton chirality method and electronic circular dichroism (ECD) calculation. These compounds share an undescribed carbon skeleton, for which biosynthetic pathways are proposed. Compound 1 and its enantiomers showed almost identical activity inhibiting Tandem of P domains in a weak inwardly rectifying K⁺ channel 1 (TREK-1).     

Absolute configuration of bioactive furanogermacrenones from Commiphora erythraea (Ehrenb) Engl. by computational analysis of their chiroptical properties

Absolute configurations (+)-(4S), (+)-(3S,4R), (−)-(2S,4S), and (−)-(1R,2R,4S) were assigned, for the first time, to bioactive furanogermacranes extracted from Commiphora erythraea resin by DFT computational analysis of their ORD curves and ECD spectra. This analysis established that all of these compounds share the same absolute configuration at the methyl-substituted carbon thus allowing us to hypothesize a biosynthetic relationship among these structurally related metabolites.     

Chiral resolution and bioactivity of enantiomeric furofuran lignans from Juglans mandshurica Maxim

Abstract

Enantiomers have generally been reported mostly for racemic mixtures with a 1:1 ratio, as in that case there were weak Cotton effects in the ECD spectrum and negligible optical rotations. A furofuran lignan (sesamin), with a remarkable rotation and significant Cotton effects, was isolated from Juglans mandshurica Maxim. Subsequently, sesamin was resolved by chiral HPLC to afford a pair of enantiomers, (+)-sesamin (a) and (?)-sesamin (b), in a ratio of approximately 1:3. Their absolute configurations were determined by computational analysis of their electronic circular dichroism (ECD) spectrum. In addition, the pair of enantiomers were evaluated for the inhibition of self-induced Aβ aggregation. Interestingly, (+)-sesamin (a) (67.7%) and (?)-sesamin (b) (80.6%) exhibited different degrees of anti-Aβ aggregation activity. The different inhibition profiles were further explained by molecular dynamics and docking simulation study.     

Synthesis and chiral discrimination of cyclic aromatic amides and the determination of their absolute configuration by TD-DFT calculations

Novel chiral cyclic molecules composed of aromatic triamides were constructed in modest yield from 4-N-(4′-methoxybenzyl)amino-3-decyloxybenzoic acid using dichlorotriphenylphosphorane, because of the preorganized component of the tertiary benzanilide moieties. A racemic mixture of two diastereomers, syn and anti conformers of cyclic aromatic triamides, was resolved into enantiomers by HPLC using a preparative chiral column. The absolute configuration of each enantiomer in both diastereomers was determined by comparison of the time-dependent density functional theory (TD-DFT) calculated circular dichroic (CD) spectra with the experimentally derived CD spectra recorded on each sample.     

Optical Resolution and Structure Determination of New Indolizidine Alkaloids from Elaeocarpus sphaericus

Two new indolizidine alkaloids, (±)‐3‐oxoisoelaeocarpine ( 1 ) and (±)‐elaeocarpine N‐oxide ( 2 ), along with three known alkaloids, (±)‐isoelaeocarpine ( 3 ), (±)‐elaeocarpine ( 4 ), and (?)‐isoelaeocarpiline ( 5 ), were isolated from an EtOH extract of the branches and leaves of Elaeocarpus sphaericus. The structures of these compounds were determined by spectroscopic and chemical methods. Furthermore, enantiomers of compounds 1 and 3 were separated on a chiral CD‐Ph column, and their absolute configurations were determined by TD‐DFT (=time‐dependent density‐functional theory) quantum‐chemical calculations of their electronic circular dichroism (ECD) spectra.     

Determination of the absolute configuration of a chiral oxadiazol-3-one calcium channel blocker, resolved using chiral chromatography, via concerted density functional theory calculations of its vibrational circular dichroism, electronic circular dichroism, and optical rotation

The chiral oxadiazol-3-one 2 has recently been shown to exhibit myocardial calcium entry channel blocking activity, substantially higher than that of diltiazem. To determine the enantioselectivity of this activity, the enantiomers of 2 have been resolved using chiral chromatography. The absolute configuration (AC) of 2 has been determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) spectrum, electronic circular dichroism (ECD) spectrum, and optical rotation (OR) to experimental VCD, ECD, and OR data. All three chiroptical properties yield identical ACs; the AC of 2 is unambiguously determined to be S(+)/R(-).     

Resolution of P-Sterogenic 1-Phenylphosphin-2-en-4-one 1-Oxide into Two Enantiomers by (R,R)-TADDOL and Conformational Diversity of the Phosphinenone Ring and TADDOL in the Crystal State

The resolution of racemic 1-phenylphosphin-2-en-4-one 1-oxide (2), was achieved through the fractional crystallization of its diastereomeric complexes with (4R,5R)-(−)-2,2-dimethyl -α,α,α′,α′-tetraphenyl-dioxolan-4,5-dimethanol (R,R-TADDOL) followed by the liberation of the individual enantiomers of 2 by flash chromatography on silica gel columns. The resolution process furnished the two enantiomers of 2 of 99.1 and 99.9% e.e. at isolated yields of 62 and 59% (counted for the single enantiomer), respectively. The absolute configurations of the two enantiomers were established by means of X-ray crystallography of their diastereomerically pure complexes, i.e., (R)-2•R,R)-TADDOL and (S)-2•(R,R)-TADDOL. The structural analysis revealed that in the (R)-2•(R,R)-TADDOL complex, the P-phenyl substituent occupied a pseudoequatorial position, whereas in (S)-2•(R,R)-TADDOL, it appeared in both the pseudoequatorial and the pseudoaxial positions in four symmetrically independent molecules. Concurrent conformational changes of the TADDOL molecules were best described by the observed changes of a pseudo-torsional CO...OC angle that could be considered as a possible measure of TADDOL conformation in its receptor–ligand complexes. The structural analysis of the (R,R)-TADDOL molecule revealed that efficiency of this compound for use as an effective resolving factor comes from its ability to flexibly fit its structure to both enantiomers of a ligand molecule, producing a rare case of resolution for both pure enantiomers with one chiral separating agent. The resolved (R)-2 was used to assign the absolute configuration of a recently described (−)-1-phenylphosphin-2-en-4-one 1-sulfide by chemical correlation. In addition, an attempted stereoretentive reduction of (R)-2 by PhSiH₃ at 60 °C revealed an unexpectedly low barrier for P-inversion in 1-phenylphosphin-2-en-4-one.     

Chromatographic resolution, solution and crystal phase conformations, and absolute configuration of tert-butyl(dimethylamino)phenylphosphine-borane complex

The enantiomers of tert-butyl(dimethylamino)phenylphosphine-borane complex 2 have been separated by HPLC using cellulose tris-p-methylbenzoate as chiral stationary phase. The borane protection could be removed without racemization and the P-configuration of the free aminophosphine 1 has shown to be stable in solution. Infrared (IR) and vibrational circular dichroism (VCD) spectra have been measured in CD2Cl2 solution for both enantiomers. B3LYP/6-31+G(d) DFT calculations allowed a prediction that complex (S)-2 exists as three conformers in equilibrium and computed population-weighted IR and VCD spectra. Predicted and experimental IR and VCD spectra compared very well and indicate that enantiomer (+)-2 has the S absolute configuration. This assignment has been confirmed by an X-ray diffraction study on a single crystal of (+)-2. The crystal structure of enantiomerically pure 2 appears to be very close to the most stable computed conformer which proved to be predominant in solution.     

Total synthesis of (±) maculalactone A, maculalactone B and maculalactone C and the determination of the absolute configuration of natural (+) maculalactone A by asymmetric synthesis

Maculalactones A, B and C from the marine cyanobacterium Kyrtuthrix maculans are amongst the only compounds based on the tribenzylbutyrolactone skeleton known in nature and (+) maculalactone A from the natural source possesses significant biological activity against various marine herbivores and marine settlers. We now report a concise synthesis of racemic maculalactone A in five steps from inexpensive starting materials. Maculalactones B and C were synthesized by a minor modification to this procedure, and the synthetic design also permitted an asymmetric synthesis of maculalactone A to be achieved in around 85% ee. The (+) and (−) enantiomers of maculalactone A were assigned, respectively, to the S and R configurations on the basis of the chiral selectivity expected for catecholborane reduction of an unsymmetrical ketone in the presence of Corey's oxazoborolidine catalyst. Surprisingly, it appeared that natural (+) maculalactone A was biosynthesized in K. maculans in a partially racemic form, comprising ca. 90-95% of the (S) enantiomer and 5-10% of its (R) enantiomer. Coincidentally therefore, the percentage enantiomeric excess of the product obtained from asymmetric synthesis almost exactly matched that found in nature.     

Synthesis,crystal structure,and absolute configuration of the enantiomers of chiral drug xibenolol hydrochloride

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2, the synthetic precursor of the chiral drug xibenolol 1, was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes (S)- and (R)-3, and then into the xibenolol enantiomers. Single crystals of (+)- and (?)-1·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute (R)- and (S)-configurations were assigned to these compounds and to the other intermediate chiral substances.     

Enantioselective Extraction System Containing Binary Chiral Selectors and Chromatographic Enantioseparation Method for Determination of the Absolute Configuration of Enantiomers of Cyclopentolate

The distribution coefficients and enantioseparation of cyclopentolate were studied in an extraction system containing d-tartaric acid ditertbutyl ester in organic phase and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase. Various parameters involved in the enantioseparation such as the type and the concentration of chiral selectors, pH value and a wide range of organic solvents were investigated. The maximum enantioselectivity (α = 2.13) and optimum distribution coefficients (K _R = 0.85, K _S = 0.40) were obtained under the following conditions: 0.10 mol/L HP-β-CD in aqueous phase and 0.20 mol/L d-tartaric acid ditertbutyl ester in decanol as organic phase. Cyclopentolate is present as a racemic mixture to the aqueous phase. The potentially different biological activities of cyclopentolate enantiomers have not been examined yet. Two chiral liquid chromatography methods have been developed for the direct separation of the enantiomers of cyclopentolate. First method was used for the quantification analysis of cyclopentolate enantiomers in aqueous phase. Second method used two chiroptical detectors: electronic circular dichroism (ECD) and optical rotation (OR) for the identification of individual cyclopentolate enantiomers from the organic phase enriched with (R)-enantiomer. The absolute stereochemistry was determined by means of the comparison of the experimental and computed ECD spectra and signs of OR. The ECD spectra of chiral analytes were measured on-line using HPLC-ECD technique.     

Synthesis and resolution of 4,4,6,6-tetramethyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-1,10-dicarboxylic acid

Optimized consecutive regioselective dimetallation and carboxylation of 4,4,6,6-tetramethyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine provided the corresponding dicarboxylic acid as a new, structurally rigid member of the atropisomeric 1-arylpyrrole family. Resolution of the new racemate was accomplished with several chiral bases and the absolute configurations of the pure enantiomers were determined by the combined application of ECD spectroscopy and quantum chemical calculations.     

Comparison of Coated and Immobilized Chiral Stationary Phases Based on Amylose tris-[(S)-α-Methylbenzylcarbamate] for the HPLC Enantiomer Separation of α-Lipoic Acid and Its Reduced Form

The couple of chiral sulfur compounds α-lipoic acid (ALA)/α-dihydrolipoic acid (DHALA) has attracted considerable attention in recent years owing to its remarkable anti-inflammatory and antioxidant properties. It is well known that the chirality of the C6 plays a key role in determining the biological activity of ALA. The natural occurring (R)-ALA enantiomer is an essential cofactor for key oxidative metabolism enzyme complexes and, after oral administration of the racemic mixture, it shows higher plasma concentration than (S)-ALA. Differently, the in vivo enantioselective action difference between the enantiomers of DHALA has not yet been studied. This lacking is perhaps due to the unavailability of analytical methods capable of determining the enantiomeric composition of biological samples during pharmacokinetic and pharmacodynamic events. In the present work, the direct and baseline enantioresolution of both chiral acids by HPLC on two amylose-derived chiral stationary phases is presented. The proposed chiral enantioselective protocol, therefore, does not require pre- or on-column derivatization. The performance of the coated Chiralpak AS-H CSP and the new immobilized Chiralpak IH-3 CSP, which have the same chiral selector amylose tris-[(S)-α-methylbenzylcarbamate], were compared using conventional normal-phase mobile phases containing ethanol or 2-propanol as alcoholic solvents and a fixed percentage of trifluoroacetic acid. Nonconventional eluents containing dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran as organic cosolvents were applied in the separation of the enantiomers of two carboxylic acids on the immobilized Chiralpak IH-3 CSP. The effect of the column temperature was carefully evaluated in order to improve enantioselectivity. Adequate amounts of enantiomers were isolated by an analytical-size Chiralpak IH-3 column and submitted to chiroptical measurements. The absolute configuration assignment of the isolated enantiomers was determined by a multidisciplinary procedure based on the comparison of the experimental and calculated chiroptical properties.     

Antiviral enantiomers of a bisindole alkaloid with a new carbon skeleton from the roots of Isatis indigotica

A pair of indole alkaloid enantiomers with a novel bisindolylacetamide skeleton, insatindibisindolamides A and B (1a and 1b), was isolated from an aqueous extract of Isatis indigotica roots. The enantiomers were separated by chiral HPLC. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, including 2D NMR, X-ray crystallography, and electronic CD (ECD) calculation. The proposed biosynthetic pathway and preliminary investigations of the biological activity of compounds 1a and 1b are also discussed.     

Stereochemical assignments of rubiaquinones A–C,naphthoquinone derivatives from Rubia yunnanensis

Three new naphthoquinone derivatives, rubiaquinones A–C (1–3), were isolated from the roots of Rubia yunnanensis. Rubiaquinone A (1) was a racemic naphthoquinone dimer consisting of a 1,4-dihydroxynaphthalene and a 4-hydroxy-1,2-naphthoquinone moieties with a 2-oxo-propyl group. Rubiaquinones B (2) and C (3) were structurally unique trimeric naphthoquinones with a racemic nature possessing one chiral axis and one chiral carbon in common. The planar structures of 1–3 were assigned by detailed spectroscopic analyses, and enantiomers of 1–3 were obtained by optical resolutions. The absolute configurations of (+)-1 and (?)-1 were elucidated by interpretation of the ECD spectra with the aid of TDDFT ECD calculation, while those of enantiomers obtained from 2 and 3 were assigned by analyses of the composite ECD spectra generated by summing appropriate ECD spectra of enantiomers. Rubiaquinone A (1) exhibited antimicrobial activity against Bacillus subtilis.     

Dioxacyclophanes as a Scaffold for Silicon-based Circularly Polarized Luminescent Materials

Planar chiral dioxacyclophanes were designed and synthesized as a key scaffold for materials with circularly polarized luminescence (CPL). Representative planar chiral 1,12-dioxa[12](1,4)naphthaleneophane-derived organosilane compounds (?)-(R)-1, (+)-(R)-2, and (?)-(R)-3 were prepared by (+)-sparteine-mediated aryl metalation and an electrophilic reaction with chlorosilanes. The absolute configurations of the planar chirality were determined in the R form by single-crystal X-ray analysis. Optically active compound (+)-(R)-2 exhibited blue fluorescence and a CPL signal with a dissymmetry factor (g_lum value) of 0.001 in solution. The electronic structure was corroborated by DFT and TD-DFT calculations rationalizing the observed spectroscopic properties.     

Theoretical and experimental study of the absolute configuration of helical structure of (2R,3S)-Rubiginone A2 analog

A novel analogue of (2R,3S)-Rubiginone A₂ was synthesized as a chiral helical model compound via an eight-step procedure (2.7% overall yield). Quantum methods, such as density functional theory (DFT) at different basis sets of 6-311+(d), 6-311++G(2d,p), were used to compute its optical rotation and electronic circular dichroism at the B3LYP/6-311++G(2d,p) level in the gas phase and in solution using PCM model, respectively. UV corrections were performed in electronic circular dichroism (ECD) simulations to match the experimental ECD well. The suitable computational methods, e.g., B3LYP/6-311++G(2d,p)//B3LYP/6-311++G(2d,p) in the gas phase using zero-point energy in Boltzmann statistics, were found and suggested for optical rotation and circular dichroism computations that can be used for absolute configuration determination of chiral helical compounds.