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.

Epimeric Mixture Analysis and Absolute Configuration Determination Using an Integrated Spectroscopic and Computational Approach-A Case Study of Two Epimers of 6-Hydroxyhippeastidine.

Structural elucidation has always been challenging, and misassignment remains a stringent issue in the field of natural products. The growing interest in discovering unknown, complex natural structures accompanies the increasing awareness concerning misassignments in the community. The combination of various spectroscopic methods with molecular modeling has gained popularity in recent years. In this work, we demonstrated, for the first time, its power to fully elucidate the 2-dimensional and 3-dimensional structures of two epimers in an epimeric mixture of 6-hydroxyhippeastidine. DFT calculation of chemical shifts was first performed to assist the assignment of planar structures. Furthermore, relative and absolute configurations were established by three different ways of computer-assisted structure elucidation (CASE) coupled with ORD/ECD/VCD spectroscopies. In addition, the significant added value of OR/ORD computations to relative and absolute configuration determination was also revealed. Remarkably, the differentiation of two enantiomeric scaffolds (crinine and haemanthamine) was accomplished via OR/ORD calculations with cross-validation by ECD and VCD.

Silicon-nitride microring resonators for nonlinear optical and biosensing applications.

We discuss the design, fabrication, and characterization of silicon-nitride microring resonators for nonlinear-photonic and biosensing device applications. The first part presents new theoretical and experimental results that overcome highly normal dispersion of silicon-nitride microresonators by adding a dispersive coupler. The latter parts review our work on highly efficient second-order nonlinear interaction in a hybrid silicon-nitride slot waveguide with nonlinear polymer cladding and silicon-nitride microring application as a biosensor for human stress indicator neuropeptide Y at the nanomolar level.

Method for Determining Average Iron Content of Ferritin by Measuring its Optical Dispersion.

We report a method where the refractive index increments of an iron storage protein, ferritin, and apoferritin (ferritin minus iron) were measured over the wavelength range of 450-678 nm to determine the average iron content of the protein. The protein used in this study had ∼3375 iron atoms per molecule. The measurement of optical dispersion over the broad wavelength range was enabled by the use of mesoporous leaky waveguides (LWs) made of chitosan. We present a facile approach for fabricating mesoporous chitosan waveguides for improving the measurement sensitivity of macromolecules such as ferritin. Mesoporous materials allow macromolecules to diffuse into the waveguide, maximizing their interaction with the optical mode and thus increasing sensitivity by a factor of ∼9 in comparison to nonporous waveguides. The sensitivity was further improved and selectivity toward ferritin was achieved by the incorporation of antibodies in the waveguide. The method presented in this work is a significant advance over the state of the art method, the enzyme linked immunosorbent assay (ELISA) used in clinics, because it allows determining the average content of ferritin in a single step. The average iron content of ferritin is an important marker for conditions such as injury, inflammation, and infection. Thus, the approach presented here of measuring optical dispersion to determine the average iron content of ferritin has a significant potential to improve the point of care analysis of the protein for disease diagnosis and screening.

Assignment Through Chiroptical Methods of The Absolute Configuration of Fungal Dihydropyranpyran-4-5-Diones Phytotoxins, Potential Herbicides for Buffelgrass (Cenchrus ciliaris) Biocontrol.

Radicinin and cochliotoxin (1 and 2) two phytotoxic pyranpyran-4,5-diones were isolated together with their close metabolites 3-epi-radicinin, radicinol, and its 3-epimer (3-5), from the culture filtrates of Cochliobolus australiensis, a fungus proposed as mycoherbcide for biocontrol of buffelgrass, a very noxious and dangerous weed. The absolute configuration of cochliotoxin was determined by chiroptical Optical Rotatory Dispersion (ORD), Electronic Circular Dichroism (ECD), and Vibrational Circular Dichroism (VCD)) and computational methods. The same methods were used to confirm that of radicinin, radicinol and their 3-epimers, previously determined with chemical, spectroscopic and ECD methods.

Importance and Difficulties in the Use of Chiroptical Methods to Assign the Absolute Configuration of Natural Products: The Case of Phytotoxic Pyrones and Furanones Produced by Diplodia corticola.

α-Pyrones and furanones are metabolites produced by Diplodia corticola, a pathogen of cork oak. Previously, the absolute configuration (AC) of diplopyrone was defined by chiroptical methods and Mosher's method. Using X-ray and chiroptical methods, the AC of sapinofuranone C was assigned, while that of the (4S,5S)-enantiomer of sapinofuranone B was established by enantioselective total synthesis. Diplofuranone A and diplobifuranylones A-C ACs are still unassigned. Here electronic and vibrational circular dichroism (ECD and VCD) and optical rotatory dispersion (ORD) spectra are reported and compared with density functional theory computations. The AC of the (4S,5S)-enantiomer of sapinofuranone B and sapinofuranone C is checked for completeness. The AC of diplobifuranylones A-C is assigned as (2S,2'S,5'S,6'S), (2S,2'R,5'S,6'R), and (2S,2'S,5'R,6'R), respectively, with the Mosher's method applied to define the absolute configuration of the carbinol stereogenic carbon. The AC assignment of sapinofuranones is problematic: while diplofuranone A is (4S,9R), sapinofuranones B and C are (4S,5S) according to ORD and VCD, but not to ECD. To eliminate these ambiguities, ECD and VCD spectra of a di-p-bromobenzoate derivative of sapinofuranone C are measured and calculated. For phytotoxicity studies, it is relevant that all six compounds share the S configuration for the stereogenic carbon atom of the lactone moiety.

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).

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).

Enantiomeric 4-Acylamino-6-alkyloxy-2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy.

The chiral separation of enantiomeric couples of three potential A3 adenosine receptor antagonists: (R/S)-N-(6-(1-phenylethoxy)-2-(propylthio)pyrimidin-4-yl)acetamide (), (R/S)-N-(2-(1-phenylethylthio)-6-propoxypyrimidin-4-yl)acetamide (), and (R/S)-N-(2-(benzylthio)-6-sec-butoxypyrimidin-4-yl)acetamide () was achieved by high-performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434-440, 2016. © 2016 Wiley Periodicals, Inc.

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).

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).

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.

Agarsenone, a Cadinane Sesquiterpenoid from Commiphora erythraea.

Agarsenone (1), a new cadinane sesquiterpenoid, was isolated from the resin of Commiphora erythraea. The structures of 1 and its decomposition products agarsenolides (2a and 2b) and myrrhone (3) were established by extensive NMR spectroscopic analysis. The absolute configuration of 3 and the relative and absolute configurations of 1 were assigned by comparison of experimental and calculated optical rotatory dispersion and electronic circular dichroism spectra.

Absolute configurations of fungal and plant metabolites by chiroptical methods. ORD, ECD, and VCD studies on phyllostin, scytolide, and oxysporone.

The absolute configuration (AC) of the bioactive metabolites phyllostin (1) and scytolide (2), two hexahydro-1,4-benzodioxines produced by Phyllosticta cirsii, and oxysporone (3), a dihydrofuropyranone recently isolated from a strain of Diplodia africana, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra. Computational prediction of ORD, ECD, and VCD allowed us to assign (3S,4aR,8S,8aR) AC to naturally occurring (-)-1, while (4aR,8S,8aR) AC was assigned to (-)-2 employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment. Theoretical prediction of both ORD and ECD spectra of 3 led to assignment of (4S,5R,6R) AC to (+)-3. In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects. This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration.

Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.

Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (-) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived (3)J(HH) scalar couplings, (15)N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (-)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (-)-erythro-mefloquine HCl is correct.

Andhraxylocarpins†A-E: structurally intriguing limonoids from the true mangroves Xylocarpus granatum and Xylocarpus moluccensis.

Five new limonoids, including andhraxylocarpins A and B (1 and 2) which contain a 9-oxa-tricyclo[3.3.2.1(7, 10)]undecane-2-ene motif, andhraxylocarpins C and D (3 and 4), which contain a (Z)-bicyclo[5.2.1]dec-3-en-8-one substructure, and andhraxylocarpin E (5), which contains a tricyclo[3.3.1.1(3, 6)]decane-9-one scaffold, were isolated from the seeds of two true mangroves, Xylocarpus granatum and Xylocarpus moluccensis, that were collected in the estuaries of Andhra Pradesh, India. The absolute configurations of these compounds were determined by extensive NMR investigations, single-crystal X-ray diffraction analysis, and by circular dichroism and optical rotatory dispersion spectroscopy, in combination with quantum-chemical calculations. The pronounced structural diversity of limonoids from these mangroves might originate from environmental factors.

Probing kinetic mechanisms of protein function and folding with time-resolved natural and magnetic chiroptical spectroscopies.

Recent and ongoing developments in time-resolved spectroscopy have made it possible to monitor circular dichroism, magnetic circular dichroism, optical rotatory dispersion, and magnetic optical rotatory dispersion with nanosecond time resolution. These techniques have been applied to determine structural changes associated with the function of several proteins as well as to determine the nature of early events in protein folding. These studies have required new approaches in triggering protein reactions as well as the development of time-resolved techniques for polarization spectroscopies with sufficient time resolution and sensitivity to probe protein structural changes.

Time-dependent density functional response theory for electronic chiroptical properties of chiral molecules.

Methodology to calculate electronic chiroptical properties from time-dependent density functional theory (TDDFT) is outlined. Applications of TDDFT to computations of electronic circular dichroism, optical rotation, and optical rotatory dispersion are reviewed. Emphasis is put on publications from 2005 to 2010, but much of the older literature is also cited and discussed. The determination of the absolute configuration of chiral molecules by combined measurements and computations is an important application of TDDFT chiroptical methods and discussed in some detail. Raman optical activity (ROA) spectra are obtained from normal-mode derivatives of the optical rotation tensor and other linear response tensors. A few selected (ROA) benchmarks are reviewed.

Bijvoet in solution reveals unexpected stereoselectivity in a Michael addition.

The absolute configuration of small crystallizable molecules can be determined with anomalous X-ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration. In this contribution, a new fundamental methodology for resolving the absolute configuration will be presented that does not require crystallization. With residual dipolar coupling enhanced NMR spectroscopy, ensembles of a limited number of structures are created reflecting the correct conformations and relative configuration. Subsequently, from these ensembles, optical rotation dispersion (ORD) spectra are predicted by DFT calculations and compared to experimental results. The combination of these two steps reveals the absolute configuration of a flexible molecule in solution, which is a big challenge to chiroptical methods and DFT in the absence of NMR spectroscopy. Here the absolute stereochemistry of the product of a new Michael addition, synthesized via a niobium(V) chiral enolate, will be elucidated by using the new methodology.

Importance of solvation in understanding the chiroptical spectra of natural products in solution phase: garcinia acid dimethyl ester.

The optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra of (+)-garcinia acid dimethyl ester have been measured and analyzed by comparison with the corresponding spectra predicted by quantum chemical methods for (2S,3S)-garcinia acid dimethyl ester. For solution-phase calculations the recently developed continuous surface charge polarizable continuum model (PCM) has been used. It is found that gas-phase predictions and PCM predictions at the B3LYP/aug-cc-pVDZ level yield nearly mirror-image ECD spectra in the 190-250 nm region for the same absolute configuration and that gas-phase ECD predictions lead to incorrect absolute configuration. At the CAM-B3LYP/aug-cc-pVDZ level, however, gas-phase predictions and PCM predictions of ECD in the 190-250 nm region are not so different, but PCM predictions provide better agreement with the experimental observations. For carbonyl stretching vibrations, the vibrational band positions predicted at the B3LYP/aug-cc-pVDZ level in gas-phase calculations differ significantly from the corresponding experimentally observed band positions, and this discrepancy has also been corrected by the use of PCM. In addition, the solution-phase VCD predictions provided better agreement (with experimental VCD observations) than gas-phase VCD predictions. These observations underscore the importance of including solvent effects in quantum chemical calculations of chiroptical spectroscopic properties.