Chiral diketopyrrolo[3,4-c]pyrrole-based oligothiophenes: Synthesis and characterization of aggregated states in solution and thin films.

In this work, we synthesized a family of three structurally related chiral oligothiophenes containing a 1,4-diketo-3,6-diarylpyrrolo[3,4-c]pyrrole (DPP) unit as the central core; functionalized with the same (S)-3,7-dimethyl-1-octyl chains on the nitrogen atoms of lactam moieties, they only differ in the number of lateral thiophene units. The aggregation modes of these π-conjugated chiral systems were evaluated by means of UV-Vis absorption and ECD spectroscopies in conditions of solution aggregation (CHCl3 /MeOH mixtures) and as thin films, describing in particular the impact of the π-conjugation length on the chiroptical properties. Interestingly, we found that the variable number of thiophene units attached to the DPP core affects not only the propensity to aggregation but also the aggregates' helicity. ECD revealed information about the supramolecular arrangement of these molecules, that one would not obtain by using conventional optical spectroscopy and microscopy techniques. Thin film samples revealed very different aggregation modes with respect to solution aggregates, casting doubts on the common assumption that these latter may serve as simple models of the former ones.

Enantioselective high-performance liquid chromatography combined with spectroscopic methods and theoretical calculations: A valid strategy to determine the absolute configuration of eugenol derivatives.

The absolute configuration of three chiral eugenol derivatives was assigned by a multi-step methodology based on enantioselective HPLC combined with spectroscopic and theoretical calculations. Milligram amounts of enantiopure forms used for stereochemical characterization were isolated by HPLC on the immobilized amylose-based chiral stationary phase Chiralpak IG using normal phase elution conditions. The absolute configuration was indirectly determined for one of the three compounds by 1H NMR via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (Mosher's acid). Comparison of the experimental and predicted electronic circular dichroism spectra confirmed the stereochemical assignment by Mosher's method and extended the absolute configuration assignment to two other chiral compounds.

Sesquiterpenoids and Cytochalasins with Immunosuppressive Activity from Sonchus wightianus.

The plant species, Sonchus wightianus DC., was historically used in China for both medicinal and dietary uses. In present study, seven new guaiane sesquiterpenoids (1-7) and one cytochalasin (8), along with five known guaianes (9-13) and two known cytochalasins (14 and 15), were isolated from the whole plants of S. wightianus. These guaianes showed structural variations in the substituents at C-8 and/or C-15, and compounds 6 and 7 are two sesquiterpenoid glycoside derivatives. Their structures were determined by extensive analysis of spectroscopic, electronic circular dichroism, and X-ray diffraction data, and chemical method. Biological tests revealed that compounds 5 and 8 are potent and selective immunosuppressive reagents.

Testing the Simplified Molecular Dynamics Approach to Improve the Reproduction of ECD Spectra and Monitor Aggregation.

A simplified molecular-dynamics-based electronic circular dichroism (ECD) approach was tested on three condensed derivatives with limited conformational flexibility and an isochroman-2H-chromene hybrid, the ECD spectra of which could not be precisely reproduced by the conventional ECD calculation protocol. Application of explicit solvent molecules at the molecular mechanics (MD) level in the dynamics simulations and subsequent TDDFT-ECD calculation for the unoptimized MD structures was able to improve the agreements between experimental and computed spectra. Since enhancements were achieved even for molecules with limited conformational flexibility, deformations caused by the solvent molecules and multitudes of conformers produced with unoptimized geometries seem to be key factors for better agreement. The MD approach could confirm that aggregation of the phenanthrene natural product luzulin A had a significant contribution to a specific wavelength range of the experimental ECD. The MD approach has proved that dimer formation occurred in solution and this was responsible for the anomalous ECD spectrum. The scope and limitations of the method have also been discussed.

FCclasses3: Vibrationally-resolved spectra simulated at the edge of the harmonic approximation.

We introduce FCclasses3, a code to carry out vibronic simulations of electronic spectra and nonradiative rates, based on the harmonic approximation. Key new features are: implementation of the full family of vertical and adiabatic harmonic models, vibrational analysis in curvilinear coordinates, extension to several electronic spectroscopies and implementation of time-dependent approaches. The use of curvilinear valence internal coordinates allows the adoption of quadratic model potential energy surfaces (PES) of the initial and final states expanded at arbitrary configurations. Moreover, the implementation of suitable projectors provides a robust framework for defining reduced-dimensionality models by sorting flexible coordinates out of the harmonic subset, so that they can then be treated at anharmonic level, or with mixed quantum classical approaches. A set of tools to facilitate input preparation and output analysis is also provided. We show the program at work in the simulation of different spectra (one and two-photon absorption, emission and resonance Raman) and internal conversion rate of a typical rigid molecule, anthracene. Then, we focus on absorption and emission spectra of a series of flexible polyphenyl molecules, highlighting the relevance of some of the newly implemented features. The code is freely available at http://www.iccom.cnr.it/en/fcclasses/.

Spatially Resolved Chiroptical Spectroscopies Emphasizing Recent Applications to Thin Films of Chiral Organic Dyes.

Instrumental techniques able to identify and structurally characterize the aggregation states in thin films of chiral organic π-conjugated materials, from the first-order supramolecular arrangement up to the microscopic and mesoscopic scale, are very helpful for clarifying structure-property relationships. Chiroptical imaging is currently gaining a central role, for its ability of mapping local supramolecular structures in thin films. The present review gives an overview of electronic circular dichroism imaging (ECDi), circularly polarized luminescence imaging (CPLi), and vibrational circular dichroism imaging (VCDi), with a focus on their applications on thin films of chiral organic dyes as case studies.

Chiral perturbation on single benzene-based fluorophores: A structure/(chir)optical activity relationship study.

In this paper, we describe the synthesis and the (chir)optical properties of a novel series of circularly polarized luminescent emitters. These molecules involve a compact single benzene-based donor-acceptor fluorophore composed of two cyclic alkylamines as electron donors and a phthalonitrile moiety as electron acceptor linked to a configurationally stable BINOL acting as a chiral perturbation unit. These new compounds display fair quantum yields (up to 66%) with emission maxima around 500 nm in toluene solutions, and the study of their chiroptical properties has shown that the cyclic alkylamine's ring size affects significantly the luminescence dissymmetry factors, reaching 2.2 × 10-3 for the larger cyclic alkylamine moieties.

A New Carvotacetone Derivative from the Aerial Part of Sphaeranthus africanus.

Sphaeranthus africanus L. is native in Vietnam. Little is known about α-glucosidase inhibition of Sphaeranthus africanus and its isolated compounds. A bioactive-guided isolation was applied to the Vietnamese Sphaeranthus africanus to find α-glucosidase inhibitory components. Eight compounds were detected and structurally elucidated. They are 3-angeloyloxy-5-[2'',3''-epoxy-2''-methylbutanoyloxy]-7-hydroxycarvotacetone, 3-angeloyloxy-5-[3''-chloro-2''-hydroxy-2''-methylbutanoyloxy]-7-hydroxycarvotacetone, 3-angeloyloxy-5-[2''R,3''R-dihydroxy-2''-methyl-butanoyloxy]-7-hydroxycarvotacetone, 3-angeloyloxy-5-[2''S,3''R-dihydroxy-2''-methylbutanoyloxy]-7-hydroxycarvotacetone, 3-angeloyloxy-5-[2''S,3''S-dihydroxy-2''-methylbutanoyloxy]-7-hydroxycarvotacetone, 5-angeloyloxy-7-hydroxy-3-tigloyloxycarvotacetone, 3-O-methylquercetin, and chrysosplenol D. Their chemical structures were elucidated by extensive 1D and 2D NMR analysis and high-resolution mass spectroscopy as well as comparisons in literature. 3-Angeloyloxy-5-[2''S,3''S-dihydroxy-2''-methylbutanoyloxy]-7-hydroxycarvotacetone is a new compound. Isolated compounds were evaluated for the α-glucosidase inhibition. Isolated compounds showed moderate activity with IC50 values ranging from 128.9-274.3 µM while others are weak. A molecular docking study was conducted, indicating that isolated compounds are potent α-glucosidase inhibitory compounds.

Stereochemical Properties of Two Schiff-Base Transition Metal Complexes and Their Ligand by Using Multiple Chiroptical Spectroscopic Tools and DFT Calculations.

Two transition metal complexes were synthesized with Ni(II) and Cu(II) using a tetradentate Schiff-base ligand, (R,R) and (S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. The stereochemical properties of the ligand and the metal complexes were investigated using a combined experimental and theoretical approach. Multiple spectroscopic techniques, which include IR, vibrational circular dichroism (VCD), UV-Vis and electronic circular dichroism (ECD), as well as Raman and the newly discovered ECD-circularly polarized Raman (i.e., eCP-Raman) spectroscopies were utilized. The good agreement achieved between the experimental and simulated IR, VCD, UV-Vis and ECD spectra of the ligand allowed one to identify the presence of three main ligand conformers in solution, thanks, especially to the high VCD sensitivity to the conformations associated with the tertbutyl groups. The helicity of the metal complexes was identified to be M and P for those with the (R,R) and (S,S) ligands, respectively. Furthermore, eCP-Raman measurements were carried out for the two metal complexes under (near) resonance. Their induced solvent chiral Raman features were explained, and the potential application of eCP-Raman was discussed.

Theoretical-Computational Modeling of CD Spectra of Aqueous Monosaccharides by Means of Molecular Dynamics Simulations and Perturbed Matrix Method.

The electronic circular dichroism (ECD) spectra of aqueous d-glucose and d-galactose were modeled using a theoretical-computational approach combining molecular dynamics (MD) simulations and perturbed matrix method (PMM) calculations, hereafter termed MD-PMM. The experimental spectra were reproduced with a satisfactory accuracy, confirming the good performances of MD-PMM in modeling different spectral features in complex atomic-molecular systems, as already reported in previous studies. The underlying strategy of the method was to perform a preliminary long timescale MD simulation of the chromophore followed by the extraction of the relevant conformations through essential dynamics analysis. On this (limited) number of relevant conformations, the ECD spectrum was calculated via the PMM approach. This study showed that MD-PMM was able to reproduce the essential features of the ECD spectrum (i.e., the position, the intensity, and the shape of the bands) of d-glucose and d-galactose while avoiding the rather computationally expensive aspects, which were demonstrated to be important for the final outcome, such as (i) the use of a large number of chromophore conformations; (ii) the inclusion of quantum vibronic coupling; and (iii) the inclusion of explicit solvent molecules interacting with the chromophore atoms within the chromophore itself (e.g., via hydrogen bonds).

Semi-Preparative Separation, Absolute Configuration, Stereochemical Stability and Effects on Human Neuronal Cells of MDPV Enantiomers.

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.

Multistate Aggregation-Induced Chiroptical Properties of Enantiopure Disulfide-Mediated Bispyrene Macrocycles.

A chiral bispyrene macrocycle designed for exclusive intermolecular excimer fluorescence upon aggregation was synthesized by a double hydrothiolation of a bis-enol ether macrocycle followed by intramolecular oxidation of free thiols. Unusually high stereoselectivity was achieved for the thiol-ene additions under templated conditions and Et3 B/O2 radical initiation. After enantiomer separation (chiral stationary phase HPLC), aqueous conditions provoked aggregation. Detailed structural evolution was afforded by ECD/CPL monitoring. Three regimes can be observed and characterized by strong modifications in chiroptical patterns under, at, or above a 70 % H2 O : THF threshold. In luminescence, high glum dissymmetry factors values were obtained, up to 0.022, as well as a double sign inversion of CPL signals during the aggregation, a behavior rationalized by time-dependent density functional theory (TDDFT) calculations. Langmuir layers of enantiopure disulfide macrocycles were formed at the air-water interface and transferred onto solid substrates to afford Langmuir-Blodgett films, which were then studied by AFM and UV/ECD/fluorescence/CPL.

Aggregation Modes of Chiral Diketopyrrolo[3,4-c]pyrrole Dyes in Solution and Thin Films.

The chiroptical features of chiral diketopyrrolo[3,4-c]pyrrole (DPP) derivatives have been only marginally investigated to date. In this regard, we have synthesized ad hoc four chiral DPP dyes, functionalized with enantiopure alkyl groups from natural sources either on the lactam moieties or on the terminal positions of the π-conjugated backbone, to promote an efficient self-assembly into chiral supramolecular structures. For each of them, the aggregation modes has been investigated by absorbance and ECD spectroscopies in conditions of solution aggregation and on thin films, considering the effects of deposition technique (drop casting vs. spin coating) and post-deposition operations (solvent and thermal annealing). The effect of the structure of lateral π-conjugated units attached to the central DPP scaffold, as well as that of the position of the alkyl chiral group, has been assessed. ECD revealed superior capability, compared to absorbance spectroscopy, to provide information on the aggregation modes and to detect the possible co-existence of multiple aggregation pathways.

Electronic Circular Dichroism-Circularly Polarized Raman (eCP-Raman): A New Form of Chiral Raman Spectroscopy.

This Concept article summarizes recent work on the development of a new form of chiral Raman spectroscopy, eCP-Raman, which combines two spectroscopies: electronic circular dichroism (ECD) and circularly polarized Raman (CP-Raman). First, some puzzling observations while carrying out Raman optical activity (ROA) measurements of several transition metal complexes under resonance are described, as well as the search for the mechanisms responsible. Then an equation for quantifying the eCP-Raman contribution is presented, followed by several examples of how eCP-Raman influences the IR -IL spectra of achiral and chiral solvent molecules and of a number of chiral solutes under resonance. The conditions to extract resonance ROA, when the eCP-Raman contribution is minimized, are also discussed. Finally, we comment on the potential applications of eCP-Raman.

Smart IM-MS and NMR study of natural diastereomers: the study case of the essential oil from Senecio transiens.

Unambiguous identification of the components of a natural mixture remains a challenging and meticulous issue. Usually, different analytical techniques and laborious separation protocols are employed; nevertheless, in some cases, delicate and equivocal problems are hardly addressed by traditional methods. In this context, an original methodology for the analysis of natural samples consisting of recent mass spectrometry methods based on ion mobility (MS-IM) is proposed. As an example, a polar fraction obtained by the essential oil prepared from Senecio transiens, an endemic plant harvested on the Corsica Island, was selected for this study to show how IM-MS-based methods easily provide very useful insights suggesting the presence of two diastereomers. To unambiguously confirm this hypothesis and verify reliability of the IM-MS results, the purified compounds were further analysed by means of nuclear magnetic resonance (NMR) methodologies, allowing the structural elucidation and the identification of two new natural compounds, diastereomers of 4-acetoxy-5,9-dimethyl-3-(2-methylpropenyl)-2-oxabicyclo[4.4.0] dec-9-ene, reported here for the first time.

Menisperdaurines A-W, structurally diverse isoquinoline alkaloids from Menispermum dauricum and their dopamine D1 receptor activities.

A total of 33 structurally diverse isoquinoline alkaloids were isolated from the rhizomes of Menispermum dauricum, including seventeen benzylisoquinoline analogues (menisperdaurines A-Q, 1-17), five protoberberine analogues (menisperdaurines R-V, 18-22), a quaternary phenanthrene alkaloid (menisperdaurine W, 23) and ten known compounds (24-33). Compound structures, including absolute configurations, were determined by extensive spectroscopic methods, quantum chemical calculations of chemical shifts, and calculated and experimental electronic circular dichroism (ECD) data. Compounds 1-5 were glycosidic benzylisoquinolines with glucose moieties attached at the C-12 position. Compound 8 was the first example that was isolated from the rhizomes of Menispermum dauricum, benzylisoquinoline and an aromatic unit connected by a sugar bridge. Compounds were evaluated for their inhibitory effects on the dopamine D1 receptor. Compounds 1, 8, 21, 24 and 29 showed potent D1 antagonistic activities, with IC50 values ranging from 1.0 to 4.5 µM. Compound 1 exhibited the highest antagonistic activity with an IC50 value of 1.0 ± 0.2 µM.

Chiroptical spectroscopic studies for the absolute configuration determination of hexahydrocurcumin and octahydrocurcumin.

Hexahydrocurcumin (HHC) and octahydrocurcumin (OHC) were synthesized, and their enantiomers were separated using supercritical fluid chromatography. The absolute configurations (ACs) of HHC and OHC were independently determined using experimental measurements and quantum theoretical predictions of vibrational circular dichroism, electronic circular dichroism, and optical rotatory dispersion. These studies lead to AC assignments of (-)-(R)-HHC and (+)-(R,R)-OHC. The AC of OHC is further confirmed by its structure determined from single crystal x-ray diffraction.

ECD exciton chirality method today: a modern tool for determining absolute configurations.

The application of the exciton chirality method (ECM) to interpret electronic circular dichroism (ECD) spectra is a well-established and still popular approach to assign the absolute configuration (AC) of natural products, chiral organic compounds, and organometallic species. The method applies to compounds containing at least two chromophores with electric dipole allowed transitions (e.g., π-π* transitions). The exciton chirality rule correlates the sign of an exciton couplet (two ECD bands with opposite sign and similar intensity) with the overall molecular stereochemistry, including the AC. A correct application of the ECM requires three main prerequisites: (a) the knowledge of the molecular conformation, (b) the knowledge of the directions of the electric transition moments (TDMs), and (c) the assumption that the exciton coupling mechanism must be the major source of the observed ECD signals. All these prerequisites can be easily verified by means of quantum-mechanical (QM) calculations. In the present review, we shortly introduce the general principles that underpin the use of the ECM for configurational assignments and survey its applications, both classic ones and some reported in the recent literature. Based on these examples, we will stress the advantages of the ECM but also the key requisites for its correct application. Additionally, we will discuss the dependence of the couplet sign on geometrical parameters (angles α,ß,γ between TDMs), which can be helpful for discerning the sign of exciton chirality in ambiguous situations. Finally, we will present a molecular orbital (MO) description of the exciton coupling phenomenon.

Secondary Metabolites from the Fresh Leaves of Pinus yunnanensis Franch.

Fifteen metabolites, including two flavonols (1-2), three lignans (3-5), and ten diterpenoids (6-15), were isolated from the leaves of Pinus yunnanensis. Among them, flavanonol (1) were identified as undescribed flavonol derivative with natural rarely B-ring fission lactone. Massive spectroscopic methods, the DP4+ probabilities and CD/ECD calculations were applied to establish the structure of component 1. Among these compounds, taxifolin (2) showed potent cytotoxicity, having IC50 values from 21.33 to 45.48 µg/mL, it also showed broad antibacterial activity against human pathogens with MIC values from 32 to 64 µg/mL.

Synthesis and Vibrational Circular Dichroism Analysis of N-Heterocyclic Carbene Precursors Containing Remote Chirality Centers.

VCD analysis of 16 diastereomeric pairs of NHC precursors containing two isolated chirality centers and different substitution patterns identified VCD transitions characteristic of the chirality center in the imidazolium ring or in the side chain, which, in contrast to ECD and OR, could be utilized to assign the two chirality centers separately by simple comparison, regardless of the type and position of achiral aromatic substituents. While the ECD and OR data showed great dependence on the position of an achiral substituent such as a methoxy group, characteristic experimental VCD transitions remained consistent and they could be used to determine the absolute configuration of all the regio- and stereoisomers and substituted analogues. VCD, ECD and OR approaches were evaluated, and several carbene precursors were found, for which only the VCD method could distinguish the four stereoisomers. With t-butyl, phenyl or 2-naphthyl substituents at the C-1' chirality center, the ECD spectra of the C-1' epimers were near-identical, and hence it was only the VCD approach that showed distinct differences suitable for the configurational assignment. The chiroptical characterization of our diastereomeric pairs of NHC precursors enables the future application of related derivatives having different substitution patterns in stereoselective transformations.