Triggering dissymmetry in achiral dye molecules by chiral solvents: Circular dichroism experiments and DFT calculations

The electronic circular dichroism spectra of achiral product “Lumogen F Red” (ROT‐300) in four different chiral solvents are recorded at different temperatures. DFT calculations allow to identify two enantiomeric conformers for ROT‐300. In vacuo they are equally populated; in chiral solvents one enantiomer prevails. Thermodynamic quantities involved in the chiral preference are derived. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

A theoretical study on the exciton circular dichroism of propeller‐like metal complexes of bipyridine and tripodal tris(2‐pyridylmethyl)amine derivatives

Time‐dependent density functional theory (TD‐DFT) has been employed to simulate the circular dichroism (CD) spectra of bipyridyl ruthenium(II) complexes as well as zinc(II) and copper(II) complexes containing tris(2‐pyridylmethyl)amine (TPA) derivatives. A qualitative model is used to account for the mechanism by which the bis‐ and tris‐bipyridine complexes (or analogous systems) exhibit exciton CD. The model is further used to predict the sign of the exciton CD bands. The predictions are in agreement with experiment and DFT calculations. A comprehensive analysis is presented of the subtle differences in the CD spectra of this series of related complexes. Chirality, 2011. © 2010 Wiley‐Liss, 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.     

Time-resolved circular dichroism in carbonmonoxy-myoglobin: the central role of the proximal histidine

A calculation of the circular dichroism (CD) spectra of carbonmonoxy- and deoxy-myoglobin is carried out in relation to a time-resolved CD experiment. This calculation allows us to assign a dominant role to the proximal histidine in the definition of the electronic normal modes and to interpret the transient CD structure observed in a strain of the proximal histidine. This strain builds up in 10 ps and relaxes in 50 ps as the protein evolves towards its deoxy form.     

Vibrational and electronic circular dichroism monitoring of copper(II) coordination with a chiral ligand

Novel copper(II) coordination compounds with chiral macrocyclic imine ligands derived from R-/S-camphor were asymmetrically synthesized and characterized with the aid of chiroptical spectroscopies. Crystal structures of both enantiomers were determined by single crystal X-ray diffraction analysis. Circular dichroism (CD) spectra were analyzed using a simplified exciton model as well as quantum chemical computations. The absolute configuration of the copper(II) coordination compounds determined from CD was found consistent with the crystal data. The copper(II) complexes were further investigated by vibrational CD (VCD) measurement combined with density functional theory calculation. The complex formation was evidenced by spectral shifts of the characteristic bands in the CD and VCD spectra.     

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.     

Vibrational circular dichroism of 3‐(trifluoroacetyl)‐camphor and its interaction with chiral amines

Vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT) calculations are used to investigate the keto–enol equilibrium of 3‐(trifluoroacetyl)‐camphor (TFC) and to study the interaction of TFC with chiral amines in deuterated Chloroform. It is shown that the VCD spectra of the enol‐ and keto forms of TFC can clearly be distinguished and that the enol form is favored. By deprotonation of the TFC enol with chiral amines, no indication of a mutual diasteriomeric influence on the VCD spectra induced by transfer of stereochemical information between the chiral ionic species is found, neither experimentally nor theoretically. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Study on the Absolute Configurations of 3‐Alkylphthalides using TDDFT Calculations of Chiroptical Properties

Absolute configurations (ACs) of 3‐alkylphthalides including natural products (?)‐3‐n‐butylphthalide ( (S)‐1 ) and fuscinarin have been studied using chiroptical properties and quantum chemical calculation. Electronic circular dichroism and optical rotatory dispersion spectra of (S)‐1 predicted adopting time‐dependent density functional theory and hybrid functionals coincide very well with the experimental and literature data of (S)‐1 , leading unambiguously to AC assignment as S for levorotatory isomer. The relationship between structures and chiroptical properties of 3‐alkylphthalides were also studied using theoretical calculation. It is found that when the alkyl group is adjacent to the single chiral center in the molecule, both the length of the alkyl side chain and the polarity of solvent may exert significant effect on electronic circular dichroism spectra. On the basis of these observations, it is recommended that the long‐chain alkyl group may be replaced by at least propyl instead of methyl group in such compounds. The present work shows that combination of chiroptical properties and ab initio calculations can provide a feasible and reliable way to the AC establishment of novel 3‐alkylphthalide derivatives with a high degree of confidence. Chirality 24:987‐993, 2012. © 2012 Wiley Periodicals, Inc.     

Molecules‐in‐molecules fragment‐based method for the calculation of chiroptical spectra of large molecules: Vibrational circular dichroism and Raman optical activity spectra of alanine polypeptides

The molecules‐in‐molecules (MIM) fragment‐based method has recently been adapted to evaluate the chiroptical (vibrational circular dichroism [VCD] and Raman optical activity [ROA]) spectra of large molecules such as peptides. In the MIM‐VCD and MIM‐ROA methods, the relevant higher energy derivatives of the parent molecule are assembled from the corresponding derivatives of smaller fragment subsystems. In addition, the missing long‐range interfragment interactions are accounted at a computationally less expensive level of theory (MIM2). In this work we employed the MIM‐VCD and MIM‐ROA fragment‐based methods to explore the evolution of the chiroptical spectroscopic characteristics of 3₁₀‐helix, α‐helix, β‐hairpin, γ‐turn, and β‐extended conformers of gas phase polyalanine (chain length n = 6–14). The different conformers of polyalanine show distinctive features in the MIM chiroptical spectra and the associated spectral intensities increase with evolution of system size. For a better understanding the site‐specific effects on the vibrational spectra, isotopic substitutions were also performed employing the MIM method. An increasing redshift with the number of isotopically labeled ¹³C=O functional groups in the peptide molecule was seen. For larger polypeptides, we implemented the two‐step‐MIM model to circumvent the high computational expense associated with the evaluation of chiroptical spectra at a high level of theory using large basis sets. The chiroptical spectra of α‐(alanine)₂₀ polypeptide obtained using the two‐step‐MIM model, including continuum solvation effects, show good agreement with the full calculations and experiment. This benchmark study suggests that the MIM‐fragment approach can assist in predicting and interpreting chiroptical spectra of large polypeptides.     

Circular dichroism spectroscopic study of non‐covalent interactions of poly‐L‐glutamic acid with a porphyrin derivative in aqueous solutions

The interactions of poly‐L ‐glutamic acid and a cationic porphyrin derivative in aqueous solutions were studied by the combination of vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies. It was found that non‐covalent interactions between both agents influence the structure of the polymeric matrix and the guest porphyrins and vice versa, but the physico‐chemical properties of the solutions, especially the pH and the relative permittivity of the solvent, play a key role in the structure of the polypeptide part of the formed complexes. It was shown that the interaction with porphyrins prevents the precipitation of poly‐L ‐glutamic acid in aqueous solution at acidic pH. In special conditions, the porphyrins attached to the polypeptide probably possess face‐to‐face interaction as demonstrated by the enhancement of the characteristic ECD signal and the appearance of sidebands on its short and long wavelength sides. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.     

Vibrational circular dichroism and IR spectral analysis as a test of theoretical conformational modeling for a cyclic hexapeptide

A model cyclohexapeptide, cyclo-(Phe-(D)Pro-Gly-Arg-Gly-Asp) was synthesized and its IR and VCD spectra were used as a test of density functional theory (DFT) level predictions of spectral intensities for a peptide with a nonrepeating but partially constricted conformation. Peptide structure and flexibility was estimated by molecular dynamics (MD) simulations and the spectra were simulated using full quantum mechanical (QM) approaches for the complete peptide and for simplified models with truncated side chains. After simulated annealing, the backbone conformation of the ring structure is relatively stable, consisting of a normal beta-turn and a tight loop (no H-bond) which does not vary over short trajectories. Only in quite long MD runs at high temperatures do other conformations appear. MD simulations were carried out for the cyclic peptide in water and in TFE, which match experimental solvents, as well as with and without protonation of the Asp carboxyl group. DFT spectral simulations were made using the annealed structure and were extended to include basis set variation, to determine an optimal computational approach, and solvent simulation with a polarized continuum model (PCM). Stepwise full DFT simulation of spectra was done for various sequences with the same backbone geometry but based on (1) solely Gly residues, (2) Ala substitution except Gly and Pro, and (3) complete sequences with side chains. Additionally, a selection of structures was used to compute IR and VCD spectra with the optimal method to determine structural variation effects. The side chains, especially the Asp-COOH and Arg-NH(2) transitions, had an impact on the computed amide frequencies, IR intensities and VCD pattern. Since experimentally these groups would have little chirality, due to conformational variation, they do not impact the observed VCD spectra. Correcting for frequency shifts, the Ala model for the cyclopeptide gives the clearest representation of the amide VCD. The experimental sign pattern for the amide I' band in D(2)O and also the sharper, more intense amide I VCD band in TFE was seen to some degree in one conformer with Type II' turns, but the data favor a mix of structures.     

Chiral dialkyl ditellurides: Conformation of chiral chromophore by circular dichroism and DFT calculation

The twisted structure of ditellurides, in a similar way as in other dichalcogenes, leads to different absorption of circularly polarized light by quasi‐enantiomeric chiral orbitals. Chiral optically active ditellurides are not common compounds and this phenomenon is not widely reported. As chiral ditellurides found an application in asymmetric synthesis, their molecular structure, understood as their conformation, became an important factor for understanding their reactivity. Until now there are few examples of chiral ditellurides known and their structure was not analyzed in details. This article presents the results of our most recent research on the structure of chiral ditellurides investigated by electronic circular spectroscopy (ECD) supported by quantum‐chemical calculation. This enables us to suggest a relationship between chirality of alkyl substituent and chirality (conformation) of ditelluride.     

Quantum-chemical calculations on the electronic circular dichroism of (-)-dibromophakellin and (-)-dibromophakell-statin

The CD spectra of the pyrrole-imidazole alkaloids, (-)-dibromophakellin and (-)-dibromophakellstatin, have been calculated employing the quantum-chemical time-dependent density functional theory. Comparison of calculated and measured spectra showed that this well-established method is also a useful tool to elucidate the absolute stereochemistry of this class of compounds. The computational results have further been used to analyze the spectra measured in methanol and to explain the remarkable red shift of one CD band when trifluoroethanol is used as a solvent instead of methanol.     

Circular Dichroism is Sensitive to Monovalent Cation Binding in Monensin Complexes

Monensin is a natural antibiotic that exhibits high affinity to certain metal ions. In order to explore its potential in coordination chemistry, circular dichroism (CD) spectra of monensic acid A (MonH) and its derivatives containing monovalent cations (Li⁺, Na⁺, K⁺, Rb⁺, Ag⁺, and Et₄N⁺) in methanolic solutions were measured and compared to computational models. Whereas the conventional CD spectroscopy allowed recording of the transitions down to 192 nm, synchrotron radiation circular dichroism (SRCD) revealed other bands in the 178–192 nm wavelength range. CD signs and intensities significantly varied in the studied compounds, in spite of their similar crystal structure. Computational modeling based on the Density Functional Theory (DFT) and continuum solvent model suggests that the solid state monensin structure is largely conserved in the solutions as well. Time‐dependent Density Functional Theory (TDDFT) simulations did not allow band‐to‐band comparison with experimental spectra due to their limited precision, but indicated that the spectral changes were caused by a combination of minor conformational changes upon the monovalent cation binding and a direct involvement of the metal electrons in monensin electronic transitions. Both the experiment and simulations thus show that the CD spectra of monensin complexes are very sensitive to the captured ions and can be used for their discrimination. Chirality 28:420–428, 2016. © 2016 Wiley Periodicals, Inc.     

Stereochemical analysis of β‐keto sulfoxides by circular dichroism

Three β‐keto sulfoxides ( 1–3 ) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2 , the X‐ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β‐keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.     

Cis-diastereoselectivity in pictet-spengler reactions of L-tryptophan and electronic circular dichroism studies

The diastereoselective synthesis of optically active 1,3‐disubstituted tetrahydro‐β‐carbolines using polar protic Pictet–Spengler cyclization of (S)‐tryptophan methyl ester with five aldehydes RCHO (R═CH₃, C₂H₅, C₃H₇, C₄H₉, and C₆H₅) was studied. As an alternate route, the cyclization of (S)‐tryptophan with the same aldehydes and subsequent methylation of the resulting tetrahydro‐β‐carboline carboxylic acids were also performed for comparison. ¹³C NMR and electronic circular dichroism (ECD) studies and time‐dependent density functional theory ECD calculations data established the relative 1,3 cis/trans and the absolute configuration (1S,3S/ 1R,3S) of the synthesized compounds. The solid‐state and solution ECD study of the prepared compounds, supported by ECD calculation and X‐ray data, afforded a reliable ECD method for the configurational assignment of 1,3‐disubstituted tetrahydro‐β‐carbolines and revealed the stereochemical factors that determine the characteristic ECD data. Chirality 24:789–795, 2012. © 2012 Wiley Periodicals, Inc.     

Comprehensive secondary‐structure analysis of disulfide variants of lysozyme by synchrotron‐radiation vacuum‐ultraviolet circular dichroism

To elucidate the effects of specific disulfide bridges (Cys6‐Cys127, Cys30‐Cys115, Cys64‐Cys80, and Cys76‐Cys94) on the secondary structure of hen lysozyme, the vacuum‐ultraviolet circular dichroism (VUVCD) spectra of 13 species of disulfide‐deficient variants in which Cys residues were replaced with Ala or Ser residues were measured down to 170 nm at pH 2.9 and 25°C using a synchrotron‐radiation VUVCD spectrophotometer. Each variant exhibited a VUVCD spectrum characteristic of a considerable amount of residual secondary structures depending on the positions and numbers of deleted disulfide bridges. The contents of α‐helices, β‐strands, turns, and unordered structures were estimated with the SELCON3 program using the VUVCD spectra and PDB data of 31 reference proteins. The numbers of α‐helix and β‐strand segments were also estimated from the VUVCD data. In general, the secondary structures were more effectively stabilized through entropic forces as the number of disulfide bridges increased and as they were formed over larger distances in the primary structure. The structures of three‐disulfide variants were similar to that of the wild type, but other variants exhibited diminished α‐helices with a border between the ordered and disordered structures around the two‐disulfide variants. The sequences of the secondary structures were predicted for all the variants by combining VUVCD data with a neural‐network method. These results revealed the characteristic role of each disulfide bridge in the formation of secondary structures. Proteins 2009. © 2009 Wiley‐Liss, Inc.     

VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Three intrinsically unstructured mussel adhesive proteins,mfp‐1, mfp‐2, and mfp‐3: Analysis by circular dichroism

Mussel foot proteins (mfps) mediate fouling by the byssal holdfast and have been extensively investigated as models for versatile polymer‐mediated underwater adhesion and coatings. However, insights into the structural properties of mfps have lagged far behind the nanomechanical advances, owing in part to the inability of these proteins to crystallize as well as their limited solubility. Here, solution secondary structures of mfp‐1, mfp‐2, and mfp‐3, localized in the mussel byssal cuticle, adhesive plaque, and plaque–substratum interface, respectively, were investigated using circular dichroism. All three have significant extended coil solution structure, but two, mfp‐1 and mfp‐2, appear to have punctuated regions of structure separated by unstructured domains. Apart from its punctuated distribution, the structure in mfp‐1 resembles other structural proteins such as collagen and plant cell‐wall proteins with prominent polyproline II helical structure. As in collagen, PP II structure of mfp‐1 is incrementally disrupted by increasing the temperature and by raising pH. However, no recognizable change in mfp‐1's PP II structure was evident with the addition with Ca²⁺ and Fe³⁺. In contrast, mfp‐2 exhibits Ca²⁺‐ and disulfide‐stabilized epidermal growth factor‐like domains separated by unstructured sequence. Mfp‐2 showed calcium‐binding ability. Bound calcium in mfp‐2 was not removed by chelation at pH 5.5, but it was released upon reduction of disulfide bonds. Mfp‐3, in contrast, appears to consist largely of unstructured extended coils.     

Absolute configuration of eremophilane sesquiterpenes from Petasites hybridus: Comparison of experimental and calculated circular dichroism spectra

In‐depth conformational analyses of 10 known eremophilane (= (1S,4aR,7R,8aR)‐decahydro‐1,8a‐dimethyl‐7‐(1‐methylethyl)napththalene) sesquiterpenes, 1 – 10 , from Petasites hybridus were performed with molecular mechanics as well as density functional theory methods. Electronic transition energies and rotational strengths of these eight eremophilane lactones and two petasins were calculated by time‐dependent density functional theory (B3PW91/TZVP). The absolute configurations of the constituents could be assigned by comparison of their simulated and experimental circular dichroism (CD) spectra in methanol as (4S,5R,8S,10R) ( 1 , 2 ), (2R,4S,5R,8S,10R) ( 3 , 4 , 5 ), (2R,4S,5R,8R,9R,10R) ( 6 ), (2R,4S,5R,8R,10R) ( 7 , 8 ), and (3R,4R,5R) ( 9 , 10 ). Single‐crystal X‐ray diffraction data of 8β‐hydroxyeremophilanolide ((8S)‐8‐hydroxyeremophil‐7(11)‐en‐12,8‐olide) ( 1 ) served as starting point for the theoretical conformational calculations of the 8β‐epimers of the eremophilane lactones. Experimental CD spectra as well as ¹H NMR spectra of compound 1 in methanol were considerably dependent on sample concentration. Chirality, 2010. © 2009 Wiley‐Liss, Inc.