Stopped‐Flow Enantioselective HPLC‐CD Analysis and TD‐DFT Stereochemical Characterization of Methyl Trans‐3‐(3,4‐Dimethoxyphenyl)Glycidate

Caffeic acid‐derived polyethers are a class of natural products isolated from the root extracts of comfrey and bugloss, which are endowed with intriguing pharmacological properties as anticancer agents. The synthesis of new polyether derivatives is achieved through ring‐opening polymerization of chiral 2,3‐disubstituted oxiranes, whose absolute configurations define the overall stereochemistry of the produced polymer. The absolute stereochemistry of one of these building blocks, methyl trans‐3‐(3,4‐dimethoxy‐phenyl)glycidate ( 3 ), was therefore characterized by the combination of enantioselective high‐performance liquid chromatography (HPLC), electronic circular dichroism (ECD) spectroscopy, and time‐dependent density functional theory (TD‐DFT) calculations. Initial efforts aiming at the isolation of enantiomers by means of a standard preparative HPLC protocol followed by offline ECD analysis failed due to unexpected degradation of the samples after collection. The stopped‐flow HPLC‐CD approach, by which the ECD spectra of enantiomers are measured online with the HPLC system, was applied to overcome this issue and allowed a fast, reliable, and chemical‐saving analysis, while avoiding the risks of sample degradation during the collection and processing of enantiomeric fractions. Subsequent TD‐DFT calculations identified ( (2S,3R)-3 as the first eluted enantiomeric fraction on the Lux Cellulose‐2 column, therefore achieving a full stereochemical characterization of the chiral oxirane under investigation. Chirality 27:914–918, 2015. © 2015 Wiley Periodicals, Inc.     

Solvent‐dependent inversion of circular dichroism signal in naproxen: An unusual effect!

The electronic circular dichroism (ECD) spectra of naproxen enantiomers were studied as a function of solvents using experimental (circular dichroism) and theoretical (time‐dependent density functional theory) approaches. The (R)‐ and (S)‐naproxen enantiomers presented an unusual inversion in their ECD signals in the presence of ethanol and water when compared with polar aprotic solvents such as acetonitrile. From a practical point of view, these findings deserve great attention because these solvents are widely used for high‐performance liquid chromatography analysis in quality control of chiral pharmaceutical drugs. This is particularly relevant to naproxen because the (S)‐naproxen has anti‐inflammatory properties, whereas (R)‐naproxen is hepatotoxic. A time‐dependent density functional theory computer simulation was conducted to investigate the signal inversion using the solvation model based on density, a reparameterization of polarized continuum model. Electronic circular dichroism signals of conformers were calculated by computer simulation and their contribution to the combined spectra obtained according to Boltzmann weighting. It was found that the experimentally observed ECD signal inversion can be associated with the minor or major contribution of different conformers of naproxen.     

Absolute Configuration of Oplopanone Derivatives From Serphidium stenocephalum: ECD Spectra of Acyclic Ketones With Front‐Octant Contributions

The electronic circular dichroism (ECD) spectra of two sesquiterpenoids ( 1 and 2 ) related to oplopanone, obtained from a methanolic extract of the plant Serphidium stenocephalum (Artemisia stenocephala), were measured and reproduced by means of time‐dependent density functional theory (TDDFT) calculations, establishing their absolute configuration. The application of ketone octant rule for carbonyl n‐π* ECD band to compounds 1 and 2 , which include an acyclic carbonyl group, was critically assessed. The peculiar oplopanone skeleton makes a straightforward application of the octant rule impossible, because of the uncertainty related to the shape of the so‐called third nodal surface separating front and back octants. The various group contributions to the carbonyl n‐π* ECD band were estimated with TDDFT calculations on selected molecular models obtained by consecutive dissections from 1 . Chirality 26:39–43, 2013. © 2013 Wiley Periodicals, Inc.     

Electronic Circular Dichroism of Chiral Alkenes: B3LYP and CAM‐B3LYP Calculations

Time‐dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) are widely used to determine absolute configurations (ACs) of chiral molecules. Two very popular DFT exchange‐correlation functionals, one hybrid (B3LYP) and one long‐range corrected (CAM‐B3LYP), along with a hierarchical sequence of basis sets were investigated, and the ECD spectra predicted for eight alkenes and compared to gas‐phase experimental spectra. Little variation in predicted ECD spectra was found with the basis set size enlargement, but the sensitivity to the functional is greater. Good agreement was obtained only with the CAM‐B3LYP functional, leading to the conclusion that TDDFT calculations of ECD spectra can routinely provide reliable ACs if and only if an appropriate functional is used. For camphene, twistene, syn‐(E)‐bisfenchylidene, and phyllocladene, solvent effects were estimated. Chirality 27:23–31, 2015. © 2014 Wiley Periodicals, Inc.     

Electronic Circular Dichroism of [16]Helicene With Simplified TD‐DFT: Beyond the Single Structure Approach

The electronic circular dichroism (ECD) spectrum of the recently synthesized [16]helicene and a derivative comprising two triisopropylsilyloxy protection groups was computed by means of the very efficient simplified time‐dependent density functional theory (sTD‐DFT) approach. Different from many previous ECD studies of helicenes, nonequilibrium structure effects were accounted for by computing ECD spectra on "snapshots" obtained from a molecular dynamics (MD) simulation including solvent molecules. The trajectories are based on a molecule specific classical potential as obtained from the recently developed quantum chemically derived force field (QMDFF) scheme. The reduced computational cost in the MD simulation due to the use of the QMDFF (compared to ab‐initio MD) as well as the sTD‐DFT approach make realistic spectral simulations feasible for these compounds that comprise more than 100 atoms. While the ECD spectra of [16]helicene and its derivative computed vertically on the respective gas phase, equilibrium geometries show noticeable differences, these are “washed” out when nonequilibrium structures are taken into account. The computed spectra with two recommended density functionals (ωB97X and BHLYP) and extended basis sets compare very well with the experimental one. In addition we provide an estimate for the missing absolute intensities of the latter. The approach presented here could also be used in future studies to capture nonequilibrium effects, but also to systematically average ECD spectra over different conformations in more flexible molecules. Chirality 28:365–369, 2016. © 2016 Wiley Periodicals, Inc.     

Isolation,Stereochemical Study,and Antioxidant Activity of Benzofuranone Derivatives from a Mangrove‐derived Fungus Eurotium rubrum MA‐150

Enantiomers of a 2‐benzofuran‐1(3H)‐one derivative [(–)‐ 1 and (+)‐ 1 ] and four known analogs ( 2 , 3 , 4 , 5 ) were isolated and identified from the culture extract of Eurotium rubrum MA–150, a fungus obtained from the mangrove‐derived rizospheric soil. Their structures were established by detailed interpretation of nuclear magnetic resonance (NMR) data and the structure of (±)‐ 1 was confirmed by single‐crystal X‐ray diffraction analysis. The absolute configuration of the enantiomers (–)‐ 1 and (+)‐ 1 was determined by means of online high‐performance liquid chromatography – electronic circular dichroism (HPLC‐ECD) measurements and time‐dependent Density Functional Theory – electronic circular dichroism (TDDFT‐ECD) calculations. Compounds (±)‐ 1 as well as 2 and 3 exhibited potent DPPH radical scavenging activities with IC₅₀ values of 1.23, 2.26, and 3.99 μg/mL, respectively. Chirality 28:581–584, 2016. © 2016 Wiley Periodicals, Inc.     

Organocatalytic alkylation of carbohydrate‐containing aldehydes with dihydroquinoline N,O‐acetals: Absolute configuration of 1,2‐dihydroquinolines

The direct catalytic α‐amidoalkylation of dihydroquinolines with aldehydes bearing oxygen functionalities at different positions in a Mannich‐type reaction has been studied. β‐Alkoxy‐aldehyde 1d gave high enantioselectivity, albeit with an inherently poor diastereoselectivity, while the use of α‐alkoxy aldehydes 1c was detrimental also to enantioselectivity. Mannich‐type reactions have been studied for the first time using new chiral carbohydrate‐derived aldehydes 1a,b showing a reactivity markedly influenced by the presence of water. The chiral glycidic backbone showed a slight but significant influence on the overall stereochemical outcome only when present in α‐position of the aldehyde. The absolute stereochemistry of the products was studied by electronic circular dichroism (ECD) spectra and compared with theoretical calculations. ECD analysis easily provides the absolute configuration of 1,2‐dihydroquinoline derivatives such as quinoline‐1(2H)‐carboxylates.     

Chemoenzymatic Approach to Optically Active 4‐Hydroxy‐5‐alkylcyclopent‐2‐en‐1‐one Derivatives: An Application of a Combined Circular Dichroism Spectroscopy and DFT Calculations to Assignment of Absolute Configuration

A series of representative optically active derivatives of 4‐hydroxy‐5‐alkylcyclopent‐2‐en‐1‐one were prepared from the respective 2‐furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4‐hydroxy‐5‐methylcyclopent‐2‐en‐1‐one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers. Chirality 26:300–306, 2014. © 2014 Wiley Periodicals, Inc.     

Enantioselective ene‐reduction of E‐2‐cyano‐3‐(furan‐2‐yl) acrylamide by marine and terrestrial fungi and absolute configuration of (R)‐2‐cyano‐3‐(furan‐2‐yl) propanamide determined by calculations of electronic circular dichroism (ECD) spectra

This work reports the green organic chemistry synthesis of E‐2‐cyano‐3(furan‐2‐yl) acrylamide under microwave radiation (55 W), as well as the use of filamentous marine and terrestrial‐derived fungi, in the first ene‐reduction of 2‐cyano‐3‐(furan‐2‐yl) acrylamide to (R)‐2‐cyano‐3‐(furan‐2‐yl)propanamide. The fungal strains screened included Penicillium citrinum CBMAI 1186, Trichoderma sp. CBMAI 932 and Aspergillus sydowii CBMAI 935, and the filamentous terrestrial fungi Aspergillus sp. FPZSP 146 and Aspergillus sp. FPZSP 152. A compound with an uncommon CN‐bearing stereogenic center at the α‐C position was obtained by enantioselective reactions mediated in the presence of the microorganisms yielding the (R)‐2‐cyano‐3‐(furan‐2‐yl) propanamide 3a . Its isolated yield and e.e. ranged from 86% to 98% and 39% to 99%, respectively. The absolute configuration of the biotransformation products was determined by time‐dependent density functional theory (TD‐DFT) calculations of electronic circular dichroism (ECD) spectra. Finally, the tautomerization of 2‐cyano‐3‐(furan‐2‐yl) propanamide 3a to form an achiral ketenimine was observed and investigated in presence of protic solvents.     

On the aggregation of bilirubinoids in solution as evidenced by VCD and ECD spectroscopy and DFT calculations

Vibrational and electronic circular dichroism (VCD and ECD) spectra of 3 optically active bilirubin analogs with propionic acid groups replaced by (1) 1‐(S)‐methylpropyl groups, (2) 3‐acetoxy‐1‐(S)‐methylpropyl groups, and (3) 1‐(S)‐2‐(R)‐dimethyl‐2‐(methoxycarbonyl)ethyl groups have been recorded at different concentrations in chloroform. The aliphatic chains attached to C‐8 and C‐12 of the 3 chosen mesobilirubins were modified so as to possess no OH group. The variation of the VCD spectra with concentration is consistent with the formation of dimers at high concentration. Density functional theory and time‐dependent density functional theory calculations on monomeric and dimeric forms support such a conclusion. Comparing with previous VCD (ECD) and IR (UV) studies of other mesobilirubin molecules, it is concluded that here, the key feature for aggregation is the missing OH groups on the propionic acid chains. The latter, in synergy with the polar groups of lactam moieties, appear to be involved in intramolecular phenomena and thus favor monomeric forms. Investigation of ECD and UV spectra of the same compounds in mixed DMSO/chloroform solutions provide further clues to the proposed picture.     

ECD cotton effect approximated by the Gaussian curve and other methods

To determine the absolute configuration of chiral compounds, theoretical calculations of ECD spectra have been extensively carried out, where the shape of component CD Cotton effects was approximated by the Gaussian distribution curve. However, in some articles, errors are found in the equations of Gaussian curve expressing CD Cotton effects. In this short review, the correct and general forms of the Gaussian equation and the approximation of the CD curve by other methods are described. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Central-to-axial chirality transfer revealed by liquid crystals: a combined experimental and computational approach for the determination of absolute configuration of carboxylic acids with an α chirality centre

The conversion into 6,7-dihydro-5H-dibenz[c,e]azepine (DAZ) N-protected amides is a viable route for the determination of the absolute configuration of chiral 2-substituted carboxylic acids. The biphenyl moiety of DAZ, besides being a probe of chirality for the electronic circular dichroism (ECD) spectroscopy, makes these systems suitable for configuration assignment by exploiting the chirality amplification which occurs in nematic liquid crystals. To assess the reliability of the liquid crystal method in detecting the absolute stereochemistry of chiral amides bound to a biphenyl group, we measured the helical twisting power of a series of DAZ-N-protected amides and compared these data with the results obtained from ECD measurements. We will show that the liquid crystal method, corroborated by HTP predictions, is trustworthy with our biphenyl derivatives, even when ECD spectra are ambiguous for the presence of aryl moieties displaying strong UV absorptions in the same range of the biphenyl chromophore.     

Synthesis,resolution, and chiroptical properties of hemicryptophane cage controlling the chirality of propeller arrangement of a C3 triamide unit

The five‐steps synthesis of a hemicryptophane cage combining a benzene‐1,3,5‐tricarboxamide unit and a cyclotriveratrylene (CTV) moiety is described. Chiral high‐performance liquid chromatography (HPLC) was used to resolve the racemic mixture. The absolute configuration of the isolated enantiomers was assigned by comparison of the experimental electronic circular dichroism (ECD) spectra with the calculated ones. X‐ray molecular structures reveal that the capped benzene‐1,3,5‐tricarboxamide unit adopts a structurally chiral conformation in solid state: the chirality of CTV moiety controls the Λ or Δ orientation of the three amides.     

Conformational studies on chiral rhodium complexes by ECD and VCD spectroscopy

This article reports vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopic studies in acetonitrile on the chiral Rh(2)(O-Phe-Cbz)(1)(OAc)(3) and Rh(2)(O-Phe-Ac)(1)(OAc)(3) complexes (abbreviated Rh(2)Z(1) and Rh(2)Ac(1) , respectively; Phe, L-phenylalanine; Cbz, benzyloxycarbonyl; Ac, acetyl) supported by theoretical calculations. The ECD spectra of the complexes depend on temperature that indicates the conformational mobility of the chiral ligands. Calculations of the VCD spectra were performed at ab initio (DFT) level of theory using Gaussian 03 [B3LYP functional combined with the LANL2DZ basis set for the dirhodium core and the 6-31G(d) basis set for other atoms]. The population-weighted sums of the computed VCD spectra of the conformers are in excellent agreement with the experimental VCD spectra. The combination of the VCD and ECD spectroscopic methods led us to the structural characterization of the complexes.     

Circular Dichroism Spectroscopy Study of Crystalline‐to‐Amorphous Transformation in Chiral Platinum(II) Complexes

Two couples of enantiomeric platinum(II) complexes: Pt(L_1a)Cl ( 1a ), Pt(L_1b)Cl ( 1b ) and Pt(L_1a)(C ≡ C ? Ph) ( 2a ), Pt(L_1b)(C ≡ C ? Ph) ( 2b ) (L_1a = (+)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene, L_1b = (?)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene) were synthesized and characterized. Their absolute configurations were determined by single crystal X‐ray diffraction and further verified by circular dichroism (CD) spectra (including electronic circular dichroism [ECD] and vibrational circular dichroism [VCD]). These complexes show interesting mechanoluminescence and/or vapoluminescence due to crystalline‐to‐amorphous transformation. The crystalline solids, grinding‐induced amorphous powders, and vapor‐induced amorphous powders of complexes 2a and 2b were comparatively investigated by solid‐state ECD and VCD spectra. The transformation from crystalline solids to amorphous powders was accompanied by significant variances of the spectral feature in both ECD and VCD spectra. Chirality 25:384–392, 2013. © 2013 Wiley Periodicals, Inc.     

Enantiomeric 4‐Acylamino‐6‐alkyloxy‐2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy

The chiral separation of enantiomeric couples of three potential A₃ adenosine receptor antagonists: (R/S)‐N‐(6‐(1‐phenylethoxy)‐2‐(propylthio)pyrimidin‐4‐yl)acetamide ( 1 ), (R/S)‐N‐(2‐(1‐phenylethylthio)‐6‐propoxypyrimidin‐4‐yl)acetamide ( 2 ), and (R/S)‐N‐(2‐(benzylthio)‐6‐sec‐butoxypyrimidin‐4‐yl)acetamide ( 3 ) was achieved by high‐performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434–440, 2016. © 2016 Wiley Periodicals, Inc.     

Preparative Enantioseparation of (RS)‐Baclofen: Determination of Molecular Dissymmetry

The present work reports preparative enantioseparation of (RS)‐baclofen using thin‐layer chromatography (TLC) and high‐performance liquid chromatography (HPLC). Diastereomers were synthesized using a new monochloro‐s‐triazine‐based chiral derivatizing reagent (CDR), namely, N‐(4‐chloro‐6‐piperidinyl‐[1,3,5]‐triazine‐2‐yl)‐L‐phenylalanine, under microwave irradiation. Acetonitrile‐0.1% aq. triflouroacetic acid in gradient elution mode and CH₃OH‐CH₂Cl₂ (4:5; v/v) were successful as mobile phase in HPLC and TLC, respectively. The two diastereomers were isolated by preparative TLC. Molecular dissymmetry was established by developing the lowest energy optimized structures of the diastereomers based on Density Functional Theory and with the help of ¹H NMR showing anisotropic effect associated with aromatic ring of s‐triazine (in the CDR). The configuration of diastereomers was established as [L‐Phe‐(R)‐Bac] and [L‐Phe‐(S)‐Bac], where the first notation refers to the configuration of chiral auxiliary (of the CDR) and the second to that of the analyte Bac. Limits of detection were found to be 0.056 and 0.061 ng mL^?1, respectively, for the two diastereomers. Determination of absolute configuration of the two diastereomers lent support to the elution order and separation mechanism.Chirality 27:299–305, 2015. © 2015 Wiley Periodicals, Inc.     

"Marking" the nitrogen atoms of phenyl-(2-pyridyl)-(3-pyridyl)-(4-pyridyl)-methane. Synthesis and absolute configuration of the corresponding tris(pyridine N-oxide)

To "mark" the nitrogen atoms in phenyl-(2-pyridyl)-(3-pyridyl)-(4-pyridyl)methane (1), we have synthesized the corresponding tris(pyridine N-oxide) 2 by oxidation of 1 with m-chloroperbenzoic acid. The nitrogen atoms of 2 are unequivocally determined by the X-ray crystal analysis of a single crystal of rac-2 whereas the nitrogen atoms cannot be assigned at all in the case of rac-1. N-Oxide 2 can be resolved by chiral high-performance liquid chromatography under similar conditions to those used for the resolution of 1. The calculated circular dichroism (CD) curve for (R)-2 on the basis of time-dependent density functional theory reproduces the experimental spectra very well to suggest that the second-eluted fraction ([CD(+)283]-2) is the R isomer, namely (R)-[CD(+)283]-2. The independent absolute configuration determinations for 1 and 2 are in keeping with the chemical correlation between the two compounds by oxidation of (R)-1 into (R)-2.     

VCD studies on cyclic peptides assembled from L‐α‐amino acids and a trans‐2‐aminocyclopentane‐ or trans‐2‐aminocyclohexane carboxylic acid

The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans‐2‐aminocyclohexane carboxylic acid (Achc) or trans‐2‐aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three‐dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6‐31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR‐based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.