Pitfalls in the Optimization of Conformer Populations to Maximize the Similarity between Predicted and Experimental Chiroptical Spectra.

The conformational populations of pantolactone, epichlorohydrin, and N-acetyl-tryptophan methyl ester were investigated by using similarity analysis between their calculated and experimental chiroptical spectra. By performing the analysis on pantolactone using two different chiroptical methods, namely, vibrational circular dichroism and Raman optical activity, it was found that the optimal sets of conformers do not match between the two methods, indicating that the conformational populations obtained by optimizing the similarity between calculated and experimental spectra are unlikely to be more accurate than energy-based Boltzmann populations. Also, it was found for pantolactone, epichlorohydrin, and N-acetyl-tryptophan methyl ester that the similarity between calculated and experimental spectra would often not vary significantly if each of the populated conformers was discarded, one at a time. This observation indicates that more than one set of conformers can provide acceptable similarity between the predicted and experimental spectra. Therefore, the correct set of conformers cannot be accurately determined by similarity analysis.

Synthesis, characterization and absolute configurations of methyl ladderanoates.

Methyl esters of [5]-ladderanoic acid and [3]-ladderanoic acid were prepared by esterification of the acids isolated from biomass at a wastewater treatment plant. Optical rotations at six different wavelengths (633, 589, 546, 436, 405 and 365 nm) and vibrational circular dichroism (VCD) spectra in the 1800-900 cm-1 region were measured in CDCl3 solvent and compared with quantum chemical (QC) predictions using B3LYP functional and 6-311++G(2d,2p) basis set with polarizing continuum model representing the solvent. QC predictions gave negative optical rotations at all six wavelengths for (R)-methyl [5]-ladderanoate and positive optical rotations for (R)-methyl [3]-ladderanoate, the same signs as previously reported for the corresponding acids. The crystal structure of (-)-methyl [5]-ladderanoate independently confirmed (R) configuration. The QC-predicted VCD spectra using Boltzmann population weighted spectra of individual conformers did not provide satisfactory quantitative agreement with the experimental VCD spectra. An improved quantitative agreement for VCD spectra could be obtained when conformer populations were optimized to maximize the similarity between experimental and predicted VCD spectra, but more improvements in VCD predictions are needed.

Laser-Driven Petahertz Electron Ratchet Nanobubbles.

A laser-driven quantum electron ratchet nanodevice is proposed. The ratchet consists of a series of disconnected bubble-shaped nanodiode structures with a sharp tip to induce a large field enhancement. A laser pulse is used to create a plasmon oscillation in the vertical direction, and the shape of the bubble funnels the electrons toward the sharp tip leading to net electron transport in the horizontal direction. The electron current carries the fingerprint of the driving laser field. The system is modeled by using the time-dependent orbital free density functional theory with nanostructures containing thousands of atoms.

Enhancement of the chiroptical response of α-amino acids via N-substitution for molecular structure determination using vibrational circular dichroism.

The chiroptical response in the form of vibrational circular dichroism (VCD) in the midinfrared region is found to be enhanced when a hydrogen of amino group of l-tryptophan is substituted with acetyl, acryloyl, or maleyl group. The order of preference for VCD enhancement is found to be acryloyl > acetyl > maleyl group. The resulting experimental VCD spectra are also found to be satisfactorily reproduced by the quantum mechanical (QM) predicted spectra. The QM predicted spectra were simulated using the conformer populations, (a) predicted by Gibbs energies and (b) optimized to maximize the similarity between experimental and predicted VCD spectra. It is found that the conformer populations predicted by Gibbs energies do not yield the maximum possible similarity between experimental and the QM predicted spectra. This work identifies the N-substitution of α-amino acids and determining the conformer populations that best reproduce the experimental spectra as two new approaches for molecular structure determination.

Asymmetric Sequential Cu-Catalyzed 1,6/1,4-Conjugate Additions of Hard Nucleophiles to Cyclic Dienones: Determination of Absolute Configurations and Origins of Enantioselectivity.

The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton.

To Avoid Chasing Incorrect Chemical Structures of Chiral Compounds: Raman Optical Activity and Vibrational Circular Dichroism Spectroscopies.

A chemical structure (CS) identifies the connectivities between atoms, and the nature of those connections, for a given elemental composition. For chiral molecules, in addition to the identification of CS, the identification of the correct absolute configuration (AC) is also needed. Several chiral natural products are known whose CSs were initially misidentified and later corrected, and these errors were often discovered during the total synthesis of natural products. In this work, we present a new and convenient approach that can be used with Raman optical activity (ROA) and vibrational circular dichroism (VCD) spectroscopies, to distinguish between the correct and incorrect CSs of chiral compounds. This approach involves analyzing the spectral similarity overlap between experimental spectra and those predicted with advanced quantum chemical theories. Significant labor needed for establishing the correct CSs via chemical syntheses of chiral natural products can thus be avoided.

CDSpecTech: A single software suite for multiple chiroptical spectroscopic analyses.

The program CDSpecTech was developed to facilitate the analysis of chiroptical spectra, which include the following: vibrational circular dichroism (VCD) and corresponding vibrational absorption (VA) spectra; vibrational Raman optical activity (VROA) and corresponding vibrational Raman spectra; electronic circular dichroism (ECD) and corresponding electronic absorption (EA) spectra. In addition, the program allows for generating optical rotatory dispersion (ORD) as the Kramers-Kronig transform of ECD spectra. The simulation of theoretical spectra from transition strengths can be achieved using different bandshape profiles. The experimental and simulated theoretical spectra can be visually compared by displaying them together. A unique feature of CDSpecTech is performing spectral analysis using the ratio spectra; i.e., the dimensionless dissymmetry factor (DF) spectrum, which is the ratio of CD to absorption spectra, and the dimensionless circular intensity difference (CID) spectrum, which is the ratio of VROA to vibrational Raman spectra. The quantitative agreement between experimental and simulated theoretical spectra can also be assessed from the numerical similarity overlap between them. Two different similarity overlap methods are available. The program uses a graphical user interface which allows for ease of use and facilitates the analysis. All these features make CDSpecTech a valuable tool for the analysis of chiroptical spectra. The program is freely available on the World Wide Web.

Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion, electronic circular dichroism, and vibrational circular dichroism spectra.

The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5-dimethyl-2-(naphthalen-1-yl)-6-(naphthalen-1-yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (-)-(aR, aR), or conversely (+)-(aS, aS).

Solvation dependence observed in the electronic dissymmetry factor spectra: how much information are we missing by analyzing the circular dichroism spectra alone?

A study utilizing the newly developed electronic dissymmetry factor (EDF) spectral analysis reveals that for [1,1'-binaphthalene]-2,2'-diol (BN) the experimental EDF spectra show differences due to solvent complexation following the trend in solvent polarity, that are not apparent in the electronic circular dichroism (ECD) or corresponding electronic absorption (EA) spectra. Large experimental EDF spectral magnitudes for BN are seen to peak in regions with no corresponding peaks in the EA spectrum and only a shoulder in the ECD spectrum. This observation indicates that EDF analysis is a new complementary method to conventional ECD analysis of chiral molecules. TD-DFT calculations predict similar EDF peaks as in the experimental EDF spectra, however, the experimentally observed solvation dependent behaviour of the EDF peaks was not reproduced in the calculations. Studies on 6,6'-dibromo-[1,1'-binaphthalene]-2,2'-diol also show similar characteristics in the EDF spectra, though not as pronounced and with different solvent effects. This report thus identifies a new means of chiral molecular structural analysis, hitherto unnoticed, and establishes the use of the dissymmetry factor spectrum as yielding new insight, but at no added cost.

Concentration Dependent Specific Rotations of Chiral Surfactants: Experimental and Computational Studies.

Recent experimental studies have shown unexpected chiroptical response from some chiral surfactant molecules, where the specific rotations changed significantly as a function of concentration. To establish a theoretical understanding of this experimentally observed phenomena, a novel methodology for studying chiral surfactants via combined molecular dynamics (MD) and quantum mechanical (QM) calculations is presented. MD simulations on the +10 000 atom surfactant systems have been performed using MD and QM/molecular mechanics (MM) approaches. QM calculations performed on MD snapshots coupled with extensive analysis on lauryl ester of phenylalanine (LEP) surfactant system indicate that the experimentally observed variation of specific rotation with concentration may be due to the conformational differences of the surfactant monomers in the aggregates. Though traditional MM simulations did not show significant differences in the conformer populations, QM/MM simulations using the forces derived from the PM6 method did predict conformational differences between aggregated and nonaggregated LEP molecules, which is consistent with experimental data. Additionally the electrostatic environment of charged surfactants may also be important, since dramatic changes in the Boltzmann populations of surfactant monomers can be noted in the presence of an electric field generated by the chiral ionic aggregates.

Atropoisomerism in Biflavones: The Absolute Configuration of (-)-Agathisflavone via Chiroptical Spectroscopy.

The first natural occurrence in optically active form of the dimeric flavonoid agathisflavone and definition of its axial chirality using chiroptical spectroscopic methods are described. The experimental electronic circular dichroism, electronic dissymmetry factor, optical rotatory dispersion, vibrational circular dichroism (VCD), and vibrational dissymmetry factor spectra of agathisflavone are presented and analyzed with their corresponding quantum chemical predictions to definitively assign the axial chirality of (-)-agathisflavone as (aS).

Specific Optical Rotations and the Horeau Effect.

The observation of nonequivalence of optical and enantiomeric purities, referred to as the Horeau effect, is thought to arise from molecular aggregation in liquid solutions. Although this effect was first observed in 1969, the conditions under which this effect may, or may not, be observable are not established. Considering the formation of dimers as the simplest form of aggregation, the expressions for specific optical rotations in the presence of homochiral and heterochiral monomer-dimer equilibria are presented. Analysis of these equations indicates that the Horeau effect will not be observable even in the presence of aggregation under either of the following two situations: 1) The specific optical rotation of the monomeric species is equal to that of the dimeric species; 2) The heterochiral equilibrium constant is twice that of the homochiral equilibrium constant.

Determination of the Absolute Configurations Using Exciton Chirality Method for Vibrational Circular Dichroism: Right Answers for the Wrong Reasons?

Quantum chemical (QC) predictions of vibrational circular dichroism (VCD) spectra for the keto form of 3-benzoylcamphor and conformationally flexible diacetates of spiroindicumide A and B are presented. The exciton chirality (EC) model has been briefly reviewed, and a procedure to evaluate the relevance of the EC model has been presented. The QC results are compared with literature experimental VCD spectra as well as with those obtained using the EC model for VCD. These comparisons reveal that the EC contributions to bisignate VCD couplets associated with the C═O stretching vibrations of benzoylcamphor, spiroindicumide A diacetate, and spiroindicumide B diacetate are only ∼30%, ∼3%, and ∼15%, respectively. With such meager EC contributions, the correct absolute configurations (ACs) suggested in the literature for spiroindicumide A diacetate and spiroindicumide B diacetate molecules using the EC concepts can be considered fortuitous. The possibilities for obtaining wrong AC predictions using the EC concepts for VCD are identified, and guidelines for the future use of this model are presented.

Absolute Configuration of (-)-Centratherin, a Sesquiterpenoid Lactone, Defined by Means of Chiroptical Spectroscopy.

(-)-Centratherin is a bioactive sesquiterpenoid lactone, whose absolute configuration (AC) was not established, but has been proposed based on those of germacrane precursors. To verify this proposal, the experimental electronic circular dichroism (ECD), electronic dissymmetry factor (EDF), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD), and vibrational dissymmetry factor (VDF) spectra of (-)-centratherin have been analyzed with the corresponding density functional theoretical predictions. These analyses suggest the AC of naturally occurring (-)-centratherin to be (6R,7R,8S,10R,2'Z).

Structure and Stereochemical Determination of Hypogeamicins from a Cave-Derived Actinomycete.

Culture extracts from the cave-derived actinomycete Nonomuraea specus were investigated, resulting in the discovery of a new S-bridged pyronaphthoquinone dimer and its monomeric progenitors designated hypogeamicins A-D (1-4). The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds. Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners. Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.

Absolute Configuration of a Rare Sesquiterpene: (+)-3-Ishwarone.

To determine the absolute configuration of 3-ishwarone, the experimental electronic circular dichroism (ECD), electronic dissymmetry factor (EDF), optical rotatory dispersion (ORD), vibrational circular dichroism (VCD), and vibrational dissymmetry factor (VDF) spectra of (+)-3-ishwarone are analyzed with the corresponding density functional theoretical predictions for different diastereomers. ECD and ORD spectra by themselves could not facilitate the determination of the absolute configuration of this molecule. However, the magnitude of the experimental EDF of (+)-3-ishwarone is found to match better with that predicted for the (1R,2S,4S,5R,9R,11R) diastereomer. The analyses of similarity measures between experimental and predicted spectra for VCD and VDF clearly suggested that the absolute configuration of (+)-3-ishwarone is (1R,2S,4S,5R,9R,11R).

Comparison of experimental and calculated chiroptical spectra for chiral molecular structure determination.

For three different chiroptical spectroscopic methods, namely, vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and Raman optical activity (ROA), the measures of similarity of the experimental spectra to the corresponding spectra predicted using quantum chemical theories are summarized. In determining the absolute configuration and/or predominant conformations of chiral molecules, these similarity measures provide numerical estimates of agreement between experimental observations and theoretical predictions. Selected applications illustrating the similarity measures for absorption, circular dichroism, and corresponding dissymmetry factor (DF) spectra, in the case of VCD and ECD, and for Raman, ROA, and circular intensity differential (CID) spectra in the case of ROA, are presented. The analysis of similarity in DF or CID spectra is considered to be much more discerning and accurate than that in absorption (or Raman) and circular dichroism (or ROA) spectra, undertaken individually.

Similarity in dissymmetry factor spectra: a quantitative measure of comparison between experimental and predicted vibrational circular dichroism.

To quantitatively determine the agreement between experimental and calculated vibrational circular dichroism (VCD) spectra, a new approach, based on the similarity of dissymmetry factor spectra has been developed and implemented. This method, which places emphasis on robust regions both in the experimental and in the calculated spectra, has been tested with six chiral compounds of known absolute configurations, namely, (R)-(+)-3-chloro-1-butyne, (3R)-(+)-methylcyclopentanone, (3R)-(+)-methylcyclohexanone, (1S)-(-)-α-pinene, (1R)-(+)-camphor, and (S)-(+)-epichlorohydrin. The criterion of maximum overlap among experimental and calculated dissymmetry factor spectra is shown to have definite advantages over those using maximum overlap among VCD or absorption spectra individually. The new method provides a better assessment of the comparison between experimental observations and quantum chemical VCD predictions and improves the confidence in the assignment of absolute configurations.

How important are the intermolecular hydrogen bonding interactions in methanol solvent for interpreting the chiroptical properties?

Two crispine A analogs and tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, endowed with hydroxyl groups that can participate in intramolecular hydrogen bonding, have been synthesized and experimental vibrational circular dichroism (VCD) spectra and optical rotatory dispersion (ORD) data have been measured in CD3OD/CH3OH solvents. The absolute configurations (ACs) of these compounds have been determined using their synthetic schemes, supplemented wherever possible with X-ray diffraction data. The ACs are also analyzed with quantum chemical (QC) calculations of VCD and ORD utilizing implicit solvation as well as explicit solvation models, with the later employing classical molecular dynamics (MD) simulations. It is found that VCD calculations with implicit solvation model are adequate for determining the ACs, despite propensity of studied compounds for intermolecular hydrogen bonding between solute and solvent molecules. This observation is important because time-consuming MD simulations may not be necessary in the type of situations studied here. Additionally, it is found that the QC predicted VCD spectra provided enough diastereomer discrimination for determining the correct AC of studied compounds independently. The same observation did not apply to ORD.