Chiroptical Data Research Articles

Chemometric sensing of stereoisomeric compound mixtures with a redox-responsive optical probe.

The analysis of mixtures of chiral compounds is a common task in academic and industrial laboratories typically achieved by laborious and time-consuming physical separation of the individual stereoisomers to allow interference-free quantification, for example using chiral chromatography coupled with UV detection. Current practice thus impedes high-throughput and slows down progress in countless chiral compound development projects. Here we describe a chemometric solution to this problem using a redox-responsive naphthoquinone that enables chromatography-free click chemistry sensing of challenging mixtures. The achiral probe covalently binds amino alcohols within a few minutes at room temperature and generates characteristic UVA and CDA spectra that are intentionally altered via sodium borohydride reduction to provide a second, strikingly different chiroptical data set (UVB and CDB). Chemometric partial least squares processing of the chiroptical outputs then enables spectral deconvolution and accurate determination of individual analyte concentrations. The success of this approach is demonstrated with 35 samples covering considerably varied total analyte amounts and stereoisomeric ratios. All chemicals and machine learning algorithms are readily available and can be immediately adapted by any laboratory.

Chemical constituents isolated from Actinidia polygama and their α-glucosidase inhibitory activity and insulin secretion effect

Actinidia polygama has been used as a traditional medicine for treating various diseases. In the present study, 13 compounds, including three new monoterpenoids (1–3), were isolated from the leaves of A. polygama to investigate the bioactive constituents of the plant. The structures were characterized by analyzing spectroscopic and chiroptical data. These compounds were preliminarily screened for their ability to increase insulin secretion levels after glucose stimulation. Of these, 3-O-coumaroylmaslinic acid (4) and jacoumaric acid (5) showed activity. In further biological studies, these compounds exhibited increased glucose‐stimulated insulin secretion (GSIS) activity without cytotoxicity in rat INS-1 pancreatic β-cells as well as α-glucosidase inhibitory activity. Furthermore, both compounds increased insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), pancreatic and duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression. Hence, these compounds may be developed as potential antidiabetic agents.

Simulation workflows to predict the circular dichroism and circularly polarized luminescence of chiral materials.

Chiral materials are attracting considerable interest in various fields in view of their unique properties and optical activity. Indeed, the peculiar features of chiral materials to absorb and emit circularly polarized light enable their use in an extensive range of applications. Motivated by the interest in boosting the development of chiral materials characterized by enhanced chiroptical properties such as circular dichroism (CD) and circular polarized luminescence (CPL), we herein illustrate in this tutorial how theoretical simulations can be used for the predictions and interpretations of chiroptical data and for the identification of chiral geometries. We are focusing on computational frameworks that can be used to investigate the theoretical aspects of chiral materials' photophysical and conformational characteristics. We will then illustrate ab initio methods based on density functional theory (DFT) and its time-dependent extension (TD-DFT) to simulate CD and CPL signals, and we will exemplify a variety of enhanced sampling techniques useful for an adequate sampling of the configurational space for chiral systems.

Circularly polarized luminescence of helicenes: A data-informed insight.

Helicenes are an interesting scaffold for chiroptical properties and in particular circularly polarized luminescence (CPL). In this short review, we collect the luminescence (glum ) and absorption (gabs ) dissymmetry factors associated to the first Cotton effect of the electronic circular dichroism (ECD) spectrum. Considering the data for 170 [n]-helicenes (n= 4-11), overall we found reasonable correlations between glum and gabs . Despite a few notable exceptions, this would confirm a similarity in the stereochemistry of the ground and emitting excited states for most helicenes. These results may be useful in rationalizing chiroptical data and help chemists in designing new helicene structures with the desired CPL properties.

Computational Approaches and Use of Chiroptical Probes in the Absolute Configuration Assignment to Natural Products by ECD Spectroscopy: A 1,2,3-Trihydroxy-p-menthane as a Case Study.

In this study, the computational analysis of electronic circular dichroism (ECD) spectra and the employment of biphenyl chiroptical probes were compared in the absolute configuration assignment of (-)-1α,2α,3β-trihydroxy-p-menthane (1), taken as a representative example of a UV-transparent chiral natural product. The usefulness of chiroptical probes in the configurational assignments of natural products and their complementarity to the computational protocols is herein highlighted. The biphenyl probe approach proves to be straightforward, reliable, and suitable for conformationally mobile and ECD silent compounds, not treatable by computational analysis of chiroptical data.

Spectroscopic investigation on 1,2-substituted ferrocenes with only planar chirality: How chiroptical data are related to absolute configuration and to substituents

Single enantiomers of three 1,2-substituted ferrocene derivatives, i.e. 1-methoxymethyl-2-hydroxymethylferrocene (1), 1-formyl-2-hydroxymethylferrocene (2) and 1-iodo-2-hydroxymethylferrocene (3), sharing the common hydroxymethyl substituent and the presence of planar chirality only, were investigated for their spectroscopic (IR and UV) and chiroptical (VCD and ECD) properties. Both enantiomers of 1 were obtained for the first time in optically pure form by lipase-catalyzed kinetic resolution of the corresponding racemate (±)-1 and separately converted into formyl derivatives (+)-2 and (–)-2.The experimental spectroscopic and chiroptical data were compared with DFT calculated spectra and excellent correspondence was found for all compounds, allowing one to confirm the previously assigned absolute configurations. The common features in the VCD spectra of a doublet between 940 and 965 cm−1 and the short-wavelength (about 200 nm) doublet and the longest wavelength band in the ECD spectra were analyzed to test whether they may be taken as markers of the absolute configuration (AC). The predominance of conformers with intramolecular hydrogen bond for the first two investigated compounds is predicted by conformational analysis and also confirmed by NMR.

Cannabichromene Racemization and Absolute Stereochemistry Based on a Cannabicyclol Analog.

Cannabichromene (CBC) is unusual among cannabinoids in having been described as both a racemic and a scalemic compound from natural Cannabis sources. Several explanations are available for this circumstance, including facile racemization. Cannabichromene was resolved chromatographically, and the enantiomer matching CBC from local Cannabis was identified. To preclude racemization, CBC was converted to cannabicyclol for further stereochemical analysis. This permitted the (R) absolute stereochemistry to be assigned to natural CBC based on chiroptical data for related natural products and the absolute configuration of a cannabicyclol analog determined by X-ray crystallography. The racemization of CBC was found to be rather slow in the laboratory, but handling practices for natural cannabis products can be inferred to promote the process.

Helicity Control in the Aggregation of Achiral Squaraine Dyes in Solution and Thin Films.

Squaraine dyes are well known for their strong absorption in the visible regime. Reports on chiral squaraine dyes are, however, scarce. To address this gap, we here report two novel chiral squaraine dyes and their achiral counterparts. The presented dyes are aggregated in solution and in thin films. A detailed chiroptical study shows that thin films formed by co‐assembling the chiral dye with its achiral counterpart exhibit exceptional photophysical properties. The circular dichroism (CD) of the co‐assembled structures reaches a maximum when just 25 % of the chiral dye are present in the mixture. The solid structures with the highest relative CD effect are achieved when the chiral dye is used solely as a director, rather than the structural component. The chiroptical data are further supported by selected spin‐filtering measurements using mc‐AFM. These findings provide a promising platform for investigating the relationship between the dissymmetry of a supramolecular structure and emerging material properties rather than a comparison between a chiral molecular structure and an achiral counterpart.

Chiroptical Properties and Conformation of Four Lasiocepsin-Related Antimicrobial Peptides: Structural Role of Disulfide Bridges

We report an investigation of the role of disulfide bridges in the 27-residue antimicrobial peptide lasiocepsin (I) containing two disulfide groups (Cys8–Cys25, Cys17–Cys27) and three its analogs lacking one (II, III) or both (IV) native disulfides. Selective alternate incorporation of one or both disulfide bridges influences symmetry, conformation and biological properties of these peptides as demonstrated in their chiroptical (particularly Raman) properties. The effect of modifying the disulfide bridge pattern on the peptide secondary structure is investigated in water and in the presence of 2,2,2-trifluoroethanol and sodium dodecyl sulphate. A combination of experimental electronic and vibrational chiroptical data shows that both disulfide groups are necessary for stabilizing lasiocepsin secondary structure. While the Cys8–Cys25 disulfide group is important for sustaining lasiocepsin tertiary structure and maintaining its biological activity, the Cys17–Cys27 disulfide bridge has a supporting function consisting in reducing peptide flexibility.

Absolute Configuration Assignment to Chiral Natural Products by Biphenyl Chiroptical Probes: The Case of the Phytotoxins Colletochlorin A and Agropyrenol

The application of flexible biphenyls as chiroptical probes for the absolute configuration assignment to chiral natural products is described. The method is straightforward and reliable and can be applied to conformationally mobile and ECD silent compounds, not treatable by computational analysis of chiroptical data. By this approach, the (6′R) absolute configuration of the phytotoxin colletochlorin A (1) was confirmed, while the absolute configuration of the phytotoxin agropyrenol (2), previously assigned by the NMR Mosher method, was revised and assigned as (3′S,4′S). Moreover, with the biphenyl method the configurational assignment can be obtained simply by the sign of a diagnostic Cotton effect at 250 nm in the ECD spectrum, thus allowing application without the need of advanced knowledge of chiroptical spectroscopy and computational protocols.

Boshramycinones A-C: New anthracyclinones produced by a marine-derived Streptomyces sp.: isolation, structure elucidation and biological activities

Boshramycinones A-C (1–3), three new anthracyclinones, were isolated from the culture broth of the marine-derived Streptomyces sp. Mei 16-1,2 together with 2-acetyl-1,8-dihydroxy-3-methyl-anthraquinone (4) and bafilomycins B1, B2, and C1-amide. The isolated compounds were identified by NMR spectroscopy and mass spectrometry, the absolute configuration of 3 was determined by comparison of experimental and ab initio-calculated chiroptical data. The antimicrobial activity of the bacterial extract and the isolated compounds were assayed using a set of microorganisms, and cytotoxic activities were determined against 36 human cancer cell lines.

Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp. teitensis.

A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 μM, respectively.

Calculating Natural Optical Activity of Molecules from First Principles.

Computations of natural optical activity (OA) from first principles (ab initio) have become indispensable in chiroptical studies of molecular systems. Calculations are used to assign absolute configurations and to analyze chiroptical data, providing a basis for understanding their origin as well as for assigning and predicting experimental results. In this article, methodology for OA computations is outlined and accompanied by a review of selected, mainly recent (ca. 2010-2016) achievements in optical rotation, electronic and vibrational circular dichroism, and Raman OA calculations. We discuss some important aspects of the computational models and methodological developments, along with recently proposed approaches to analyze and interpret OA parameters. We highlight applications of chiroptical computational methods in studies of helicenes and chiral nanoparticles.

Rotenoids, Flavonoids, and Chalcones from the Root Bark of Millettia usaramensis.

Five new compounds, 4-O-geranylisoliquiritigenin (1), 12-dihydrousararotenoid B (2), 12-dihydrousararotenoid C (3), 4'-O-geranyl-7-hydroxyflavanone (4), and 4'-O-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the CH2Cl2/MeOH (1:1) extract of the root bark of Millettia usaramensis ssp. usaramensis by chromatographic separation. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas their absolute configurations were established on the basis of chiroptical data and in some cases also by X-ray crystallography. The crude extract was moderately active (IC50 = 11.63 μg/mL) against the ER-negative MDB-MB-231 human breast cancer cell line, and accordingly compounds 6, 8, 9, 10, 12, and 16 also showed moderate to low cytotoxic activities (IC50 25.7-207.2 μM). The new natural product 1 exhibited antiplasmodial activity with IC50 values of 3.7 and 5.3 μM against the chloroquine-sensitive 3D7 and the chloroquine-resistant Dd2 Plasmodium falciparum strains, respectively, and was also cytotoxic to the HEK293 cell line.

Stereochemical analysis of (+)-limonene using theoretical and experimental NMR and chiroptical data

Using limonene as test molecule, the success and the limitations of three chiroptical methods (optical rotatory dispersion (ORD), electronic and vibrational circular dichroism, ECD and VCD) could be demonstrated. At quite low levels of theory (mpw1pw91/cc-pvdz, IEFPCM (integral equation formalism polarizable continuum model)) the experimental ORD values differ by less than 10 units from the calculated values. The modelling in the condensed phase still represents a challenge so that experimental NMR data were used to test for aggregation and solvent–solute interactions. After establishing a reasonable structural model, only the ECD spectra prediction showed a decisive dependence on the basis set: only augmented (in the case of Dunning's basis sets) or diffuse (in the case of Pople's basis sets) basis sets predicted the position and shape of the ECD bands correctly. Based on these result we propose a procedure to assign the absolute configuration (AC) of an unknown compound using the comparison between experimental and calculated chiroptical data.

Stereochemical Communication within a Chiral Ion Pair Catalyst.

Ionic interactions are increasingly appreciated as a key, asymmetry-inducing factor in enantioselective catalytic transformations, including those involving Brønsted acid or base catalysis, phase-transfer catalysis, and related processes. However, a detailed understanding of these interactions is often lacking. Herein, we show how an enantiopure anion enforces a chiral conformation onto a catalytically relevant achiral cation. Specifically, we use vibrational circular dichroism (VCD) spectroscopy to monitor the transmission of stereochemical information from a chiral phosphate anion to a flexible manganese(III)-salen cation. We show that VCD can be used to study solvent effects and that the obtained chiroptical data directly and quantitatively correlate with the experimentally observed enantioselectivity in an asymmetric olefin epoxidation reaction.

Absolute Configuration of Resveratrol Oligomers Isolated from Hopea utilis

AbstractPhytochemical studies on a stem of Hopea utilis (Dipterocarpaceae) resulted in the isolation of two new resveratrol derivatives, namely hopeaside E (1; resveratrol trimer) and hopeaside F (2; resveratrol pentamer), together with ten known resveratrol derivatives, 3–12. The structures of the new compounds were elucidated by spectroscopic analyses, including NMR experiments, and their absolute configurations were determined on the basis of a comparative configurational analysis using the β‐D‐glucopyranosyl group and chiroptical data. The absolute configuration of (+)‐balanocarpol (3) was also determined by acid‐catalyzed skeletal conversion.

Chiroptical Studies of Flavanone

Chiral HPLC coupled to electronic circular dichroism and laser optical rotation detection (HPLC-ECD-OR) permitted the on-line chiroptical characterization of both enantiomers of racemic flavanone (1) as ECD(-)310-OR(-)670-flavanone and ECD(+) 310-OR(+)670-flavanone for the first and second eluted peaks, respectively. Calculation of the ECD spectrum of one enantiomer at the TD-DFT/DGTZVP level of theory yielded the (S)-ECD(-)310-OR(-)670 and (R)-ECD(+)310-OR(+)670-1 absolute configuration, in agreement with the use of empirical rules for stereochemical assignment. Vibrational circular dichroism spectra of enantiopure compounds, obtained through fraction collection during repeated HPLC runs, were recorded and compared with theoretical traces produced from DFT calculations at the B3LYP/DGDZVP and B3PW91/DGDZVP levels of theory, which further confirmed the absolute configuration obtained from the on-line chiroptical data.

Synthesis, Chiroptical Properties and Density Functional Theory Calculations of 3,3’‐Biphenyl‐2,2’‐BiTropone

The synthesis of new bitropone derivatives, namely, 3,3'-biphenyl-2,2'-bitropone and 7,7'-biphenyl-2,2'-bitropone, are reported. Isolation of enantiomers arising from restricted rotation around the C-C bond connecting the tropone moieties was attempted by means of chiral high performance liquid chromatography (HPLC). No separation was obtained for 7,7'-biphenyl-2,2'-bitropone. For 3,3'-biphenyl-2,2'-bitropone, difficulties were encountered because of the low separation factor of the peaks and the presence of a rapid racemization process. However, quantitative chiroptical data on the antipodes were obtained by linking a circular dichroism (CD) spectrometer and a UV-vis spectrophotometric detector in series to the HPLC instrument. The analysis of the CD and UV-vis spectra in terms of absolute conformations was done with the help of theoretical calculations performed at the Density Functional Theory (DFT) level. The most stable conformations of the 3,3'-biphenyl-2,2'-bitropone in its ground state were obtained. Starting from these minimum energy conformations, it was possible to compute theoretical CD and UV absorption spectra that fit well with the experimental ones. From this comparison the absolute configuration to the antipodes was assigned. Finally, the effect of the presence of the two lateral phenyl substituents on the structure of the bitropone and hence on the CD spectrum is discussed.

The reliability and utility of high reported specific rotations: reports and predictions of molecules with extremely high specific rotations, and high specific rotations suggest revision of the structures of huperzines E′ and F′

A search of the literature for all compounds with [α]D>1000 found 13 molecules with reliably determined specific rotations in excess of 6500, as judged by comparison with DFT-calculated values of [α]D for the same compounds, with a maximum [α]D −11,560 for a decacyclic helicene quinone. Several reports of [α]Ds ranging from 10,000 to 44,000 were judged to be spurious. On the basis of similar computational studies, several molecules are proposed that should have very high [α]Ds but relatively modest visible absorptions, unlike the current record holders, which have strong absorption near the sodium D line. In addition, the search found two natural products, huperzines E′ and F′, that have large reported [α]Ds (−4750 and −3182, respectively), that are inconsistent with their structures. However, computational studies found epimers of the reported structures that possess [α]Ds consistent with the reported chiroptical data.