Synthesis,Structural Characterization,and Chiroptical Studies of Bidentate Salen‐Type Lanthanide (III) Complexes

The salen‐type ligand prepared with (R,R) diphenylethan‐1,2‐diamine and salicylaldehyde provides stable and inert complexes KLnL₂ upon simple reaction with lanthanide halides or pseudohalides LnX₃ (Ln = Tb³⁺‐Lu³⁺; X = Cl^? or TfO^?) of its potassium salt. All the complexes were completely characterized through nuclear magnetic resonance (NMR), electronic circular dichroism (ECD) in the UV and some (Er³⁺, Tm³⁺, Yb³⁺) also with Near‐IR ECD (NIR‐ECD) and luminescence (Tb³⁺, Tm³⁺). Careful analysis of the NMR shifts demonstrated that the complexes are isostructural in solution and afforded an accurate geometry. This was further confirmed by means of Density Functional Theory (DFT) optimization of the Lu³⁺ complex, and by comparing the ligand‐centered experimental and time‐dependent TD‐DFT computed UV‐ECD spectra. As final validation, we used the NIR‐ECD spectrum of the Yb³⁺ derivative calculated by means of Richardson's equations. The excellent match between calculated and experimental ECD spectra confirm the quality of the NMR structure.  Chirality 27:857–863, 2015. © 2015 Wiley Periodicals, Inc.     

Isolation,Stereochemical Study,and Cytotoxic Activity of Isobenzofuran Derivatives From a Marine Streptomyces sp.

A new 1,3‐dihydroisobenzofuran derivative ( 1 ), together with its epimer ( 2 ), was isolated from marine Streptomyces sp. W007. The structure of the two compounds was established by extensive spectroscopic analysis and comparison with reported data. The absolute configurations of 1 and 2 were determined by a combination of experimental and computational means, including J‐coupling analysis and nuclear Overhauser effect spectroscopy (NOESY) spectra, nuclear magnetic resonance (NMR) calculations, electronic circular dichroism (ECD), and optical rotation (OR) calculations. Compound 1 had no cytotoxicity against human lung adenocarcinoma cell line A549, while compound 2 exhibited weak activity, suggesting that the biological activity depends on the configuration of a single chirality center. Chirality 27:82–87, 2015. © 2014 Wiley Periodicals, Inc.     

Eight new biflavonoids with lavandulyl units from the roots of Sophora flavescens and their inhibitory effect on PTP1B

In the course of studying the components from the roots of Sophora flavescens, eight new unusual biflavonoids consisting of a flavanone fused with a dihydrochalcone skeleton were isolated. These new chemical structures were elucidated by means of UV, IR, HRESIMS, NMR and ECD spectroscopic data and a comparison of experimental ECD spectra with calculated ECD spectra. Some compounds were subjected to an antidiabetic bioassay on human recombinant PTP1B inhibition, and showed strong inhibitory activity.     

Experimental and theoretical studies of vacuum-ultraviolet electronic circular dichroism of hydroxy acids in aqueous solution

The electronic circular dichroism (ECD) spectra of three L-hydroxy acids (L-lactic acid, (+)-(S)-2-hydroxy-3-methylbutyric acid, and (-)-(S)-2-hydroxyisocaproic acid) were measured down to 160 nm in aqueous solution using a vacuum-ultraviolet ECD spectrophotometer. To assign the two positive peaks around 210 and 175 nm and the one negative peak around 190 nm in the observed spectra, the ECD spectrum of L-lactic acid was calculated using time-dependent density functional theory (DFT) for the optimized structures by DFT and a continuum model. The observed ECD spectrum was successfully reproduced as the average spectrum for four optimized structures with seven water molecules that localized around the COO(-) and OH groups of L-lactic acid. The positive peak around 210 nm and the negative peak around 185 nm in the calculated spectrum were attributable to the nπ* transition of the carboxyl group, with the latter peak also being influenced by the ππ* transition of the carboxyl group; however, the positive peak around 165 nm involved unassignable higher energy transitions. The comparison of the calculated ECD spectra for L-lactic acid and L-alanine revealed that the network with loose hydrogen bonding around the COO(-) and OH groups is responsible for the flexible conformation of hydroxy acids and complicated side-chain dependence of ECD spectra relative to amino acids.     

Transmission vs. Diffuse Transmission in Circular Dichroism: What to Choose for Probing Solid‐State Samples?

Recent advances in equipment enabled the collection of solid‐state electronic circular dichroism (ECD) spectra using the commercially available integrating sphere attachment for a regular ECD spectrometer. This accessory was designed to reduce negative factors occurring in solid‐state ECD measurements, and is, thereby, very useful for recording diffuse transmittance CD (DTCD) spectra using the pellet technique. In the present article, the operating principle of the integrating sphere and utility of the DTCD method in recording solid‐state ECD spectra is demonstrated. Based on illustrative examples, i.e., 10‐camphorsulfonic acid ammonium, cholest‐4‐en‐3‐one, (3R,4R,5S)‐oseltamivir, and (S)‐linezolid, ECD solid‐state measurements were performed by means of both transmission and diffusion methods and later compared. Selection of these compounds as models for comparative studies was made in view of their different chromophoric systems and the profound importance in the pharmaceutical industry. During the course of this work the benefits and limitations of the use of integrating sphere are presented. The final conclusion is that more relevant solid‐state spectra can be obtained by means of the DTCD method. Chirality 27:441–448, 2015. © 2015 Wiley Periodicals, Inc.     

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.     

Unusual CD couplet pattern observed for the pi*<--n transition of enantiopure (Z)-8-methoxy-4-cyclooctenone: an experimental and theoretical study by electronic and vibrational circular dichroism spectroscopy and density functional theory calculation

Ultraviolet absorption (UV) and electronic circular dichroism (ECD) spectra of enantiopure (Z)-8-methoxy-4-cyclooctenone (MCO) were measured in hexane to give a normal single UV absorption band at 298 nm, which is assigned to the carbonyl's pi*<--n transition. Unexpectedly, the ECD spectrum exhibited an apparent couplet pattern with vibrational fine structures. Obviously, the conventional CD exciton coupling mechanism cannot be applied to this bisignate CD signal observed for single-chromophoric MCO. Variable temperature-ECD and vibrational circular dichroism (VCD) spectral measurements, simultaneous UV and ECD spectral band resolution, and density functional theory (DFT) calculations of energy and structure revealed that this apparent CD couplet originates from a rather complicated spectral overlap of more than three conformers of MCO, two of which exhibit mirror-imaged ECD spectra at appreciably deviated wavelengths. In the simultaneous band-resolution analysis, the observed UV and ECD spectra were best fitted to four overlapping bands. Two major conformers were identified by comparing the experimental IR and VCD spectra with the simulated ones, and the other two by comparing the observed UV and ECD spectra with the theoretical ones obtained by time-dependent DFT calculations. It was shown that the combined use of experimental ECD and VCD spectra and theoretical DFT calculations can give a reasonable interpretation for the Cotton effects of the conformationally flexible molecule MCO.     

Electronic and vibrational circular dichroism of aromatic amino acids by density functional theory

Structures of model compounds mimicking aromatic amino acid residues in proteins are optimized by density functional theory (DFT), assuming that the main-chain conformation was a random coil. Excitation energies and dipole and rotational strengths for the optimized structures were calculated based on time-dependent DFT (TD-DFT). The electronic circular dichroism (ECD) bands of the models were significantly affected by side-chain conformations. Hydration models of the aromatic residues were also subjected to TD-DFT calculations, and the ECD bands of these models were found to be highly perturbed by the hydration of the main-chain amide groups. In addition to calculating the random-coil conformation, we also performed TD-DFT calculations of the aromatic residue models, assuming that the main-chain conformation was an alpha-helix or beta-strand. As expected, the overall feature of the ECD bands was also perturbed by the main-chain conformations. Moreover, vibrational circular dichroism (VCD) spectra of the hydration models in a random-coil structure were simulated by DFT, which showed that the VCD spectra are more sensitive to the side-chain conformations than the ECD spectra. The present results show that analyses combining ECD and VCD spectroscopy and using DFT calculations can elucidate the main- and side-chain conformations of aromatic residues in proteins.     

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.     

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.     

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.     

Improving protein identification using complementary fragmentation techniques in fourier transform mass spectrometry

Identification of proteins by MS/MS is performed by matching experimental mass spectra against calculated spectra of all possible peptides in a protein data base. The search engine assigns each spectrum a score indicating how well the experimental data complies with the expected one; a higher score means increased confidence in the identification. One problem is the false-positive identifications, which arise from incomplete data as well as from the presence of misleading ions in experimental mass spectra due to gas-phase reactions, stray ions, contaminants, and electronic noise. We employed a novel technique of reduction of false positives that is based on a combined use of orthogonal fragmentation techniques electron capture dissociation (ECD) and collisionally activated dissociation (CAD). Since ECD and CAD exhibit many complementary properties, their combined use greatly increased the analysis specificity, which was further strengthened by the high mass accuracy (approximately 1 ppm) afforded by Fourier transform mass spectrometry. The utility of this approach is demonstrated on a whole cell lysate from Escherichia coli. Analysis was made using the data-dependent acquisition mode. Extraction of complementary sequence information was performed prior to data base search using in-house written software. Only masses involved in complementary pairs in the MS/MS spectrum from the same or orthogonal fragmentation techniques were submitted to the data base search. ECD/CAD identified twice as many proteins at a fixed statistically significant confidence level with on average a 64% higher Mascot score. The confidence in protein identification was hereby increased by more than 1 order of magnitude. The combined ECD/CAD searches were on average 20% faster than CAD-only searches. A specially developed test with scrambled MS/MS data revealed that the amount of false-positive identifications was dramatically reduced by the combined use of CAD and ECD.     

A New Fusicoccane-Type Norditerpene and a New Indone from the Marine-Derived Fungus Aspergillus aculeatinus WHUF0198

A new norditerpene named aculeaterpene A ( 1 ) and a new indone named aculeaindone A ( 2 ), along with eight known compounds 3 – 10 were isolated from the culture extract of Aspergillus aculeatinus WHUF0198. The structural characterization of compounds 1 and 2 were performed by spectroscopic analysis, including 1D and 2D NMR and HR-ESI-MS experiments, whereas the absolute configurations were determined by comparing their experimental or calculated ECD spectra. Compound 1 was the first report of fusicoccane-based norditerpene, in which the C-20 was degraded and tured into a hydroxy group.     

Twisted paddlewheel rhodium complexes: Contribution of central and axial chirality to ECD,VCD, and NMR spectra

Dirhodium complexes bearing N-substituted chiral amino acid ligands are investigated. These complexes have an unusual twisted paddlewheel structure, showing inherent chirality. We would like to demonstrate that parallel application of chiroptical spectroscopic methods (ECD and VCD) and NMR spectroscopy combined with quantum chemical calculations constitutes a powerful tool to determine the configuration of the complexes unequivocally. Two chiroptical methods are needed to determine the absolute configuration: ECD for the coordinated nitrogen atom and VCD for the rhodium core. A quick to use NMR method is also presented: Upon the coordination of small molecules in the axial position, the relative configuration of both the rhodium core and the nitrogen atom can be determined simultaneously by studying spatial proximities provided by 1D NOE spectra.     

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.     

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.     

Determination of sulfinpyrazone and two of its metabolites in human plasma and urine by gas chromatography and selective detection

A selective and sensitive gas chromatographic method for simultaneous determination of sulfinpyrazone and two of its metabolites (the para-hydroxylated metabolite and the sulfone metabolite) in biological fluids using alkali flame ionization detection (AFID), electron capture detection (ECD) and mass fragmentographic detection is described. The compounds are extracted from the samples, methylated and separated on 2% OV-17 or 8% OV-225 columns. Phenylbutazone is used as internal standard. Standard curves are linear. The coefficient of variation at 10 μg/ml of sulfinpyrazone in plasma was shown to be 1.8% (AFID), and the detection limits were 0.1 μg/ml (AIFD) and 10 ng/ml (ECD). Mass spectra of the methylated compounds are shown and serum concentration curves after oral administration of 100 mg sulfinpyrazone to two persons are determined together with the excreted amounts of drug and metabolites.     

Optical spectroscopic elucidation of beta-turns in disulfide bridged cyclic tetrapeptides

Vibrational circular dichroism (VCD) spectroscopic features of type II beta-turns were characterized previously, but, criteria for differentiation between beta-turn types had not been established yet. Model tetrapeptides, cyclized through a disulfide bridge, were designed on the basis of previous experimental results and the observed incidence of amino acid residues in the i + 1 and i + 2 positions in beta-turns, to determine the features of VCD spectra of type I and II beta-turns. The results were correlated with electronic circular dichroism (ECD) spectra and VCD spectra calculated from conformational data obtained by molecular dynamics (MD) simulations. All cyclic tetrapeptides yielded VCD signals with a higher frequency negative and a lower frequency positive couplet with negative lobes overlapping. MD simulations confirmed the conformational homogeneity of these peptides in solution. Comparison with ECD spectroscopy, MD, and quantum chemical calculation results suggested that the low frequency component of VCD spectra originating from the tertiary amide vibrations could be used to distinguish between types of beta-turn structures. On the basis of this observation, VCD spectroscopic features of type II and VIII beta-turns and ECD spectroscopic properties of a type VIII beta-turn were suggested. The need for independent experimental as well as theoretical investigations to obtain decisive conformational information was recognized.     

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.     

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.