Toward a general mixed quantum/classical method for the calculation of the vibronic ECD of a flexible dye molecule with different stable conformers: Revisiting the case of 2,2,2‐trifluoro‐anthrylethanol

We extend a recently proposed mixed quantum/classical method for computing the vibronic electronic circular dichroism (ECD) spectrum of molecules with different conformers, to cases where more than one hindered rotation is present. The method generalizes the standard procedure, based on the simple Boltzmann average of the vibronic spectra of the stable conformers, and includes the contribution of structures that sample all the accessible conformational space. It is applied to the simulation of the ECD spectrum of (S)‐2,2,2‐trifluoroanthrylethanol, a molecule with easily interconvertible conformers, whose spectrum exhibits a pattern of alternating positive and negative vibronic peaks. Results are in very good agreement with experiment and show that spectra averaged over all the sampled conformational space can deviate significantly from the simple average of the contributions of the stable conformers. The present mixed quantum/classical method is able to capture the effect of the nonlinear dependence of the rotatory strength on the molecular structure and of the anharmonic couplings among the modes responsible for molecular flexibility. Despite its computational cost, the procedure is still affordable and promises to be useful in all cases where the ECD shape arises from a subtle balance between vibronic effects and conformational variety.     

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.     

Spectroscopic Studies on Nicotine and Nornicotine in the UV Region

The UV absorption and electronic circular dichroism (ECD) spectra of (R)‐ and (S)‐nicotine and (S)‐nornicotine in aqueous solution were measured to a significantly lower wavelength range than previously reported, allowing the identification of four previously unobserved electronic transitions. The ECD spectra of the two enantiomers of nicotine were equal in magnitude and opposite in sign, while the UV absorption spectra were coincidental. In line with previous observations, (S)‐nicotine exhibited a negative cotton effect centered on 263 nm with vibronic structure (π–π₁* transition) and a broad, positive ECD signal at around 240 nm associated with the n–π₁* transition. As expected this band disappeared when the pyridyl aromatic moiety was protonated. Four further electronic transitions are reported between 215 and 180 nm; it is proposed the negative maxima around 206 nm is either an n–σ* transition or a charge transfer band resulting from the movement of charge from the pyrrolidyl N lone pair to the pyridyl π* orbital. The pyridyl π–π₂* transition may be contained within the negative ECD signal envelope at around 200 nm. Another negative maximum at 188 nm is thought to be the pyridyl π–π₃* transition, while the lowest wavelength end‐absorption and positive ECD may be associated with the π–π₄* transition. The UV absorption spectra of (S)‐nornicotine was similar to that of (S)‐nicotine in the range 280–220 nm and acidification of the aqueous solution enhanced the absorption. The ECD signals of (S)‐nornicotine were considerably less intense compared to (S)‐nicotine and declined further on acidification; in the far UV region the ECD spectra diverge considerably. Chirality 25:288–293, 2013. © 2013 Wiley Periodicals, Inc.     

Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques

We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC₅₀ of benzimidazole (?)-1 is ～100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (?)/(+)-1 and (?)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (?)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (?) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (?) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy.     

(R)‐Metacycloprodigiosin‐HCl: Chiroptical properties and structure

(R)‐Metacycloprodigiosin can exist in three different tautomeric forms, each with hydrogens at C9′ and C12 in syn or anti orientation. With the addition of HCl, this structural diversity reduces to syn‐(R)‐metacycloprodigiosin‐HCl ( 1a ) and anti‐(R)‐metacycloprodigiosin‐HCl ( 1b ), each with multiple conformers. Energetics and chiroptical properties, namely, electronic circular dichroism (ECD) and specific optical rotation (SOR), of (R)‐metacycloprodigiosin‐HCl have been investigated at B3LYP/6‐311++G(2d,2p) level. The experimental ECD spectra of (R)‐metacycloprodigiosin‐HCl have also been measured. Calculations indicated that the lowest energy conformer of 1b is approximately 2.7 kcal/mol lower in energy than that of 1a , and the energy barrier for anti to syn conversion is approximately 13 kcal/mol. The population weighted calculated SORs of 1a and 1b are, respectively, positive and negative. The respective calculated ECD spectra of these pseudoenantiomers show an almost mirror image relationship between them. The experimental SOR and ECD compare well with those predicted for 1b . Thus, 1b is expected to be predominant, a situation confirmed also by nuclear Overhauser effect (NOE) data, with a similar conclusion reached for prodigiosin R1.     

Chemical Constituents from Tabernaemontana bufalina Lour.

Investigation of the branches and leaves of Tabernaemontana bufalina Lour . led to afford an undescribed monoterpenoid indole alkaloid, namely (3R,7S,14R,19S,20R)‐19‐hydroxypseudovincadifformine ( 1 ), and nine known metabolites ( 2 – 10 ). Their structures were determined by analysis of their NMR and ESI‐MS spectra, and modified Mosher's and calculated electronic circular dichroism (ECD) methods were used for establishing the absolute configuration of compound 1 . Their cytotoxic activities were assayed using two cancer cell lines. As the results, cytotoxic activities on MDA‐MB‐231 and B16 cells showed IC₅₀ values of 8.9 and 0.13 μm for 6 , and of 20.3 and 11.7 μm for 9 , respectively.     

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.     

Assessment of configurational and conformational properties of naringenin by vibrational circular dichroism

The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.     

Tetrathiafulvalene‐[2.2]paracyclophanes: Synthesis,crystal structures,and chiroptical properties

Two racemic tetrathiafulvalene‐[2.2]paracyclophane electron donors EDT‐TTF‐[2.2]paracyclophane 1 and (COOMe)₂‐TTF‐[2.2]paracyclophane 2 have been synthesized via the phosphite mediated cross coupling strategy. Chiral HPLC allowed the optical resolution of the (R_P) and (S_P) enantiomers for both compounds. Solid‐state structures of (R_P)‐ 1 and (rac)‐ 2 have been determined by single crystal X‐ray analysis. Intermolecular π‐π and S???S interactions are disclosed in the packing. Single crystal X‐ray analysis of (R_P)‐ 1 combined with experimental and theoretical circular dichroism spectra allowed the assignment of the absolute configuration of the enantiomers of 1 and 2 .     

Chiroptical properties of 2,2’‐bioxirane

The two enantiomers of 2,2′‐bioxirane were synthesized, and their chiroptical properties were thoroughly investigated in various solvents by polarimetry, vibrational circular dichroism (VCD), and Raman optical activity (ROA). Density functional theory (DFT) calculations at the B3LYP/aug‐cc‐pVTZ level revealed the presence of three conformers (G₊, G_?, and cis) with Gibbs populations of 51, 44, and 5% for the isolated molecule, respectively. The population ratios of the two main conformers were modified for solvents exhibiting higher dielectric constants (G_? form decreases whereas G₊ form increases). The behavior of the specific optical rotation values with the different solvents was correctly reproduced by time‐dependent DFT calculations using the polarizable continuum model (PCM), except for the benzene for which explicit solvent model should be necessary. Finally, VCD and ROA spectra were perfectly reproduced by the DFT/PCM calculations for the Boltzmann‐averaged G₊ and G_? conformers.     

Introduction of axial chirality in a planar aromatic ligand results in chiral recognition with DNA

Dimerization of a hydroxycarbazole produces an axially chiral biaryl, BICOL ( 2 ). One enantiomer (R)‐ 2 , is capable of enantioselective binding to different polymorphs of DNA. The biaryl (R)‐ 2 was shown by fluorescence and circular dichroism to induce a shift of Z‐DNA to B‐DNA. The opposite enantiomer (S)‐ 2 shows no specific binding. The significant difference in behaviour between the two enantiomers (S)‐ 2 and (R)‐ 2 is in line with molecular modelling studies which show two very different binding geometries between the enantiomers with each polymorph of DNA. Copyright © 2010 John Wiley & Sons, Ltd.     

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.     

Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study

So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.     

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.     

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.     

Experimental and Calculated CPL Spectra and Related Spectroscopic Data of Camphor and Other Simple Chiral Bicyclic Ketones

UV, circular dichroism (CD), fluorescence and circularly polarized luminescence (CPL) spectra were recorded for a set of four related [2.2.1] bicyclic compounds ((1S,4S)‐and (1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one, namely (1S)‐ and (1R)‐camphor ( 1 ), (1S,4R)‐4,7,7‐trimethylbicyclo[2.2.1]hept‐5‐en‐2‐one, (1S)‐dehydro‐epicamphor ( 2 ), (1S,4S)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2,5‐dione, (1S)‐5‐oxocamphor ( 3 ), (1S,4R)‐ and (1R,4S)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2,3‐dione, (1S)‐ and (1R)‐camphorquinone ( 4 )) and a set of three related [2.2.2] bicyclic compounds (1S,4S)‐bicyclo[2.2.2]octan‐2,5‐dione (saturated diketone ( 5 )), (1R,4R)‐bicyclo[2.2.2]oct‐7‐en‐2,5‐dione (unsaturated diketone ( 6 )), ((1S,4S)‐bicyclo[2.2.2]oct‐7‐en‐5(S)‐ol‐2‐one (which we refer to as unsaturated hydroxy‐ketone ( 7 )). For the latter three compounds also mid‐IR vibrational circular dichroism (VCD) spectra were recorded and are presented. Time‐Dependent Density Functional (TD‐DFT) calculations provide a satisfactory interpretation of both absorption and emission chiroptical spectra and permit insight into ground and excited state electronic properties. We discuss the applicability of the octant rule or of other approximated models to rationalize the observed sign of the CPL. Chirality 25:589–599, 2013. © 2013 Wiley Periodicals, Inc.     

Four New Chromone Derivatives from Colletotrichum gloeosporioides

Four previously unreported chromones, 5‐hydroxy‐2‐(hydroxymethyl)‐8‐methoxy‐4H‐chromen‐4‐one ( 1 ), (5R,7S)‐5,7‐dihydroxy‐2‐propyl‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 2 ), (5R,7S)‐5,7‐dihydroxy‐2‐methyl‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 3 ), and (5R,7S)‐5,7‐dihydroxy‐2‐[(E)‐prop‐1‐en‐1‐yl]‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 4 ), as well as one known analogue 5‐hydroxy‐2‐methyl‐4H‐chromen‐4‐one ( 5 ) were isolated from the fermentation broth of the endophytic fungus Colletotrichum gloeosporioides derived from the mangrove Ceriops tagal. Their structures were elucidated based on extensive spectroscopic analyses. The absolute configurations of 2 – 4 were determined by comparison the experimental and calculated electronic circular dichroism (ECD) spectra. Compound 2 showed cytotoxic activity against A549 cell line with the IC₅₀ value of 0.094 mm .     

Chiroptical Properties of Streptorubin B: The Synergy Between Theory and Experiment

Analysis of the calculated and measured optical rotation (OR) together with other calculated chiroptical properties such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) of the prodigiosin alkaloid streptorubin B shows that these are dominated by the pseudoenantiomeric atropisomers anti‐(S)‐streptorubin B ( 1A ) and syn‐(S)‐streptorubin ( 1B ). Atropisomerism is a dynamic phenomenon with a potentially nonequilibrium population of isomers, and accordingly the measured chiroptical responses may vary with time, concentration, temperature, and the anion of the salts used. Streptorubin also has the potential to form stacked homodimers for which the optical rotations measured at 589 nm can vary greatly due to the presence of ECD‐active electronic transitions in this region. Chirality 27:745–751, 2015. © 2015 Wiley Periodicals, Inc.     

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

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