Assignment Of Configuration Research Articles

Organocatalytic hydrogen bond donor/Lewis base (HBD/LB) synthesis and chiroptical properties of thiabridged [5]helicenes.

Thiabridged [5]helicenes are obtained from thioaryl-N-phthalimido benzo[a]phenothiazines using a hydrogen bond donor/Lewis base organocatalytic approach. Resolution of [5]helicenes using either (1S)-(-)-camphanic acid as a chiral auxiliary or CSP-HPLC is reported. Thiabridged [5]helicenes show an exceptional configurational stability with racemization energy barriers higher than 40 kcal mol-1. Electronic circular dichroism and TD-DFT calculations permit the assignment of the absolute configuration, demonstrating that the sign of optical rotation is not easily related to the M or P structure. Separated enantiomers show circularly polarized luminescence with high dissymmetry ratio.

First total synthesis of asperilactone B. Revision of absolute stereochemistry of asperilactones B and C.

The first total synthesis and absolute configuration assignment of asperilactone B (I) have been accomplished. Additionally, a revision of the absolute stereochemistry of asperilactone C has been done. The first total synthesis of the opposite enantiomer of asperilactone B (ent-I) has also been achieved, as well as that of C-7 epimers of both asperilactones B (8) and C (9).

Sigma receptor and aquaporin modulators: chiral resolution, configurational assignment, and preliminary biological profile of RC752 enantiomers

The key role of chiral small molecules in drug discovery programs has been deeply investigated throughout last decades. In this context, our previous studies highlighted the influence of the absolute configuration of different stereocenters on the pharmacokinetic, pharmacodynamic and functional properties of promising Sigma receptor (SR) modulators. Thus, starting from the racemic SR ligand RC752, we report herein the isolation of the enantiomers via enantioselective separation with both HPLC and SFC. After optimization of the eco-sustainable chiral SFC method, both enantiomers were obtained in sufficient amount (tens of mg) and purity (ee up to 95%) to allow their characterization and initial biological investigation. Both enantiomers a) displayed a high affinity for the S1R subtype (Ki = 15.0 ± 1.7 and 6.0 ± 1.2 nM for the (S)- and (R)-enantiomer, respectively), but only negligible affinity toward the S2R (> 350 nM), and b) were rapidly metabolized when incubated with mouse and human hepatic microsomes. Furthermore, the activity on AQP-mediated water permeability indicated a different functional profile for the enantiomers in terms of modulatory effect on the peroxiporins gating.

Absolute configuration assignment of highly fluorinated carboxylic acids via VCD and MRR spectroscopy

Chiral analysis has become a crucial step in studying the stereospecific synthesis of Active Pharmaceutical Ingredients (APIs). Both Vibrational Circular Dichroism (VCD) and Molecular Rotational Resonance (MRR) spectroscopy are capable of determining absolute configurations (ACs) via comparison of experimental and calculated data. In this regard, each technique has its own caveats. In VCD analysis, accurate prediction of the normal modes as well as rigorous conformational searches of both the analyte and potential (self-)aggregation products are required to optimally match experimental spectra. In MRR analysis, chiral species are resolved through complexation with a chiral tag to prepare spectrally distinct diastereomeric complexes. Although individual complex isomers can be distinguished, spectral assignments need to be matched to unique isomer geometries for unambiguous AC assignment. In this work, the ACs of two highly fluorinated carboxylic acids were successfully assigned using VCD and MRR spectroscopy. In the VCD analysis, the M06-2X functional was demonstrated to be superior to B3LYP and B3LYP-GD3 in accurately predicting the C–F normal modes and both monomeric and dimeric spectral contributions were observed. In a similar analysis with broadband MRR, most experimentally identified geometries had more than one possible computational match. Nevertheless, careful consideration of the chiral tag, as well as additional isomer assignments, resulted in successful assignment of the AC. This comparative study demonstrates the power of contemporary VCD analysis and the unique contributions of MRR to the analytical toolbox.

Obtaining Pure 1H NMR Spectra of Individual Pyranose and Furanose Anomers of Reducing Deoxyfluorinated Sugars.

Due to tautomeric equilibria, NMR spectra of reducing sugars can be complex with many overlapping resonances. This hampers coupling constant determination, which is required for conformational analysis and configurational assignment of substituents. Given that mixtures of interconverting species are physically inseparable, easy-to-use techniques that enable facile full 1H NMR characterization of sugars are of interest. Here, we show that individual spectra of both pyranoside and furanoside forms of reducing fluorosugars can be obtained using 1D FESTA. We discuss the unique opportunities offered by FESTA over standard sel-TOCSY and show how it allows a more complete characterization. We illustrate the power of FESTA by presenting the first full NMR characterization of many fluorosugars, including of the important fluorosugar 2-deoxy-2-fluoroglucose. We discuss in detail all practical considerations for setting up FESTA experiments for fluorosugars, which can be extended to any mixture of fluorine-containing species interconverting slowly on the NMR frequency-time scale.

Indoloquinazoline alkaloids suppress angiogenesis and inhibit metastasis of melanoma cells

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1–21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.

Hide45: A Method for Optimal Payload Data Hiding in Base45 Encoded Strings

Base45 encodes pairs of octets using 3 characters from an alphabet of 45 printable symbols. Previous works showed the ability to hide payload data into encoded strings by exploiting the unused configurations of the Base45 encoding. In this paper, we present Hide45, an algorithm for hiding data into Base45 encoded strings that optimizes the embedding capacity, according to the frequency distribution of the input data. Experimental tests show that an optimal assignment of bit configurations to the most frequent pairs of octets allows to reach a payload capacity very close to the theoretical capacity of the method, improving over a baseline assignment by up to 53%.

New results on the decay spectroscopy of 254No with GABRIELA@SHELS

The structure of the nucleus has been studied for more than 20 years: the last publications on its decay spectroscopy are from LBNL [1], GSI [2], JYFL [3] and ANL [4]. Four decay schemes featuring two isomers have been published and are interpreted differently in terms of excitation energy and decay scheme of the 2 nd isomer and configuration assignments of both K-isomers. These discrepancies have triggered new experiments including this one, performed with the GABRIELA [5, 6] array, at the focal plane of the SHELS [7] separator at the FLNR, Dubna. The first part of this proceeding will present the experimental setup and the analysis techniques used to reveal the electromagnetic decay of the known isomers in 254No. The second part will focus on the new results obtained with more than 1 million 254No nuclei implanted in the focal plane detector. In particular, the internal conversion electron spectrum observed in the decay of the 8− K-isomer has revealed the presence of a strong transition, most likely E0, suggesting low-lying shape coexistence in this nucleus as predicted in [8, 9]. The γ-ray spectrum obtained from the decay of the short-lived 170 μs isomer has revealed new γ-ray lines putting in doubt the previous interpretations about this isomer decay.

Absolute configuration reassignment of nectamazin A: Implications to related neolignans

The ability of nature to produce structurally complex molecules makes the determination of the absolute configuration of natural products a challenging task. Although extensive NMR analysis generally allows for the reliable assignment of relative configurations, the assignments of absolute stereochemistry are commonly performed by empirical comparisons of optical rotation (OR) and/or electronic circular dichroism (ECD) data obtained for related molecules. Such an approach, however, may lead to misassignments and consequent error propagations. Herein, we present the case of the bicyclo(3.2.1)octane neolignan named (+)-nectamazin A. This compound was first reported in 2009 from Nectandra amazonum Nees. (Lauraceae) and had its absolute configuration determined as 7R,8S,3′S,4′R,5′S by means of experimental ECD spectroscopy. Our chemical studies on Ocotea aciphylla (Lauraceae) led to the isolation of (+)-nectamazin A. The extensive analysis of OR, ECD, and vibrational CD data aided by quantum chemical calculations, however, indicated (+)-nectamazin A to have the 7S,8R,3′R,4′S,5′R absolute configuration, in conflict with the configuration reported in the literature. The cause of the original incorrect assignment of (+)-nectamazin A derives from the direct comparison of experimental OR and ECD data obtained for structurally related molecules with different chromophoric systems. As an alternative, VCD spectroscopy is presented as a more reliable and sensitive technique to stereochemical investigations of bicyclo(3.2.1)octane neolignans.

Revision of the Absolute Configurations of Chelocardin and Amidochelocardin.

Even with the aid of the available methods, the configurational assignment of natural products can be a challenging task that is prone to errors, and it sometimes needs to be corrected after total synthesis or single-crystal X-ray diffraction (XRD) analysis. Herein, the absolute configuration of amidochelocardin is revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and time-dependent density-functional theory (TDDFT)-ECD calculations. As amidochelocardin was obtained via biosynthetic engineering of chelocardin, we propose the same absolute configuration for chelocardin based on the similar biosynthetic origins of the two compounds and result of TDDFT-ECD calculations. The evaluation of spectral data of two closely related analogues, 6-desmethyl-chelocardin and its semisynthetic derivative 1, also supports this conclusion.

Korrektur der absoluten Konfiguration von Chelocardin und Amidochelocardin

AbstractSelbst mit Hilfe modernster Techniken ist die Bestimmung der absoluten Konfiguration von Naturstoffen eine anspruchsvolle und fehleranfällige Herausforderung. Dementsprechend gibt es auch Fälle, in denen die Stereochemie nach einer Totalsynthese oder einer Kristallstrukturanalyse (XRD) korrigiert werden muss. In diesem Artikel korrigieren wir die absolute Konfiguration von Amidochelocardin auf Basis einer Kombination aus XRD, NMR, ECD‐Spektroskopie und time‐dependent density‐functional theory (TDDFT)‐ECD‐Berechnungen. Da Amidochelocardin aus einer genetisch veränderten Chelocardin‐Biosynthese stammt, ist eine identische Stereochemie naheliegend. Die Ergebnisse von TDDFT‐ECD‐Berechnungen unterstützen diese Vermutung. Zusätzlich konnte die Analyse der Spektren von zwei strukturell verwandten Analoga, 6‐Desmethyl‐Chelocardin (6‐DMCHD) und dem semisynthetischen Derivat 1 von 6‐DMCHD diese Hypothese bestätigen.

Insight into the photolytic degradation products of Rosuvastatin: Full chiral and structural elucidation and conversion kinetics by a combined chromatographic, spectroscopic and theoretical approach

Rosuvastatin (RSV) is a well-established lipid-lowering drug. RSV is susceptible to degradation under various stress conditions and forms two cyclic derivatives by a radical-mediated photolytic mechanism. On a structural basis, these epimeric compounds (reported as FP-B in the European Pharmacopeia monograph Rosuvastatin tablets) retain the configuration of the stereogenic carbons of RSV (3R,5S) and have opposite absolute configurations at the third stereogenic center. Herein, we report the kinetics of formation and the complete structural characterization, including the assignment of the absolute configuration, of each epimer collected after HPLC separation on a chiral stationary phase. The stereochemistry of the epimers was determined by comparison of the experimental circular dichroism data with the corresponding theoretical values. Kinetic studies revealed that RSV degrades completely to FP-B within 3 h at room temperature. Furthermore, through a multi-disciplinary approach involving chromatography (HPLC and UHPLC), circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), it was demonstrated that FP-B in turn degrades to the lactones under the mild acidic conditions of the chromatographic mobile phase. The ability of RSV to form multiple degradation products may affect the quantification of RSV-related substances and draw attention to potentially toxic RSV-like species in the environment.

Miliutine A acid, a new cyclofarnesane sesquiterpene from the stems of Miliusa velutina

Six compounds were isolated from the ethyl acetate extract of the stems of Miliusa velutina, including miliutine A acid (1), a new cyclofarnesane sesquiterpenoid; miliutine B methyl ester (2), a cyclofarnesane sesquiterpenoid which was determined the absolute configuration for the first time and four known phenol derivatives (3–6). NMR spectroscopic and mass spectrometry were used for identifying relative configurations. The assignments of the absolute configurations were determined based on Electronic Circular Dichroism (ECD) and NOESY spectra analysis. All six compounds were screened for their in vitro cytotoxic activities against HepG2 cell line using the SRB assay and they showed weak or none activities.

Absolute configuration assignment of marine natural products in Brazil

Brazil is one of the most biodiverse countries in the world, with a coastline that stretches over 7,000 km including various marine ecosystems, such as coral reefs, mangroves, and seagrass beds, among other habitats. These diverse environments provide a rich source of compounds, derived from primary or secondary metabolism, which may have countless biological activities. Research on marine natural products (MNP) in Brazil has been ongoing for several decades and led to the discovery of numerous bioactive compounds with potential applications in medicine, agriculture, and cosmetics. These MNP are structurally complex, both from an architectural and stereochemical point of view. However, even with all the well-established techniques for the absolute configuration (AC) assignment, this stage of structural characterization of natural products is still under-explored and remains a challenge. This review presents an overview of natural product chemistry in Brazil, focusing on the stereochemical assignment of marine chiral compounds. The main goals are to describe the techniques employed in the assignments as well as to highlight the importance of choosing the appropriate methods for chiral natural products AC determinations.

Application of methyl itaconate–anthracene adducts (MIAs) in configuration assignment of chiral primary amines by means of 1H NMR

Methyl itaconate–anthracene adducts (MIAs) were previously introduced as chiral derivatizing agents (CDAs) for the determination of chiral secondary alcohols. In this study, they were further employed with chiral primary amines to assign their absolute configuration. Each chiral amine compound was linked to the (R)- and (S)-MIAs through amidation to obtain diastereomeric amides in moderate yield. The modified Mosher's method was applied, where the difference in chemical shift (ΔδSR = δHS−MIA-amide – δHR−MIA-amide) values of each substituent of the chiral amine adducts was utilized to validate the capability of MIAs as CDAs. Finally, the proposed model was successfully achieved, and the MIAs were proven effective for the determination of the absolute configuration of chiral amines.

High resolution electronic spectroscopy of uranium mononitride, UN.

The isoelectronic molecules UN and UO+ are known to have Ω = 3.5 and Ω = 4.5 ground states, respectively (where Ω is the unsigned projection of the electronic angular momentum along the internuclear axis). A ligand field theory model has been proposed to account for the difference [Matthew and Morse, J. Chem. Phys. 138, 184303 (2013)]. The ground state of UO+ arises from the U3+(5f3(4I4.5))O2- configuration. Owing to the higher nominal charge of the N3- ligand, the U3+ ion in UN is stabilized by promoting one of the 5f electrons to the more polarizable 7s orbital, reducing the repulsive interaction with the ligand and rendering U3+(5f27s(4H3.5))N3- the lowest energy configuration. In the present work, we have advanced the characterization of the UN ground state through studies of two electronic transitions, [18.35]4.5-X(1)3.5 and [18.63]4.5-X(1)3.5, using sub-Doppler laser excitation techniques with fluorescence detection. Spectra were recorded under field-free conditions and in the presence of static electric or magnetic fields. The ground state electric dipole moment [μ = 4.30(2) D] and magnetic ge-factor [2.160(9)] were determined from these data. These values were both consistent with the 5f27s configurational assignment. Dispersed fluorescence measurements were used to determine vibrational constants for the ground and first electronically excited states. Electric dipole moments and magnetic ge-factors are also reported for the higher-energy electronically excited states.

Synthetic Study of Natural Metabolites Containing a Benzo[c]oxepine Skeleton: Heterocornol C and D.

A versatile strategy for the enantioselective synthesis of a benzo[c]oxepine structural core containing natural secondary metabolites was developed. The key steps of the synthetic approach include ring-closing alkene metathesis for seven-member ring construction, the Suzuki-Miyaura cross-coupling reaction for the installation of the double bond and Katsuki-Sharpless asymmetric epoxidation for the introduction of chiral centers. The first total synthesis and absolute configuration assignment of heterocornol D (3a) were achieved. Four stereoisomers, 3a, ent-3a, 3b and ent-3b, of this natural polyketide were prepared, starting with 2,6-dihydroxy benzoic acid and divinyl carbinol. The absolute and relative configuration of heterocornol D was assigned via single-crystal X-ray analysis. The extension of the described synthetic approach is further presented with the synthesis of heterocornol C by applying the ether group reduction method to the lactone.

Assignment of the absolute configuration of molecules that are chiral by virtue of deuterium substitution using chiral tag molecular rotational resonance spectroscopy.

Chiral tag molecular rotational resonance (MRR) spectroscopy is used to assign the absolute configuration of molecules that are chiral by virtue of deuterium substitution. Interest in the improved performance of deuterated active pharmaceutical ingredients has led to the development of precision deuteration reactions. These reactions often generate enantioisotopomer reaction products that pose challenges for chiral analysis. Chiral tag rotational spectroscopy uses noncovalent derivatization of the enantioisotopomer to create the diastereomers of the 1:1 molecular complexes of the analyte and a small, chiral molecule. Assignment of the absolute configuration requires high-confidence determinations of the structures of these weakly bound complexes. A general search method, CREST, is used to identify candidate geometries. Subsequent geometry optimization using dispersion corrected density functional theory gives equilibrium geometries with sufficient accuracy to identify the isomers of the chiral tag complexes produced in the pulsed jet expansion used to introduce the sample into the MRR spectrometer. Rotational constant scaling based on the fact that the diastereomers have the same equilibrium geometry gives accurate predictions allowing identification of the homochiral and heterochiral tag complexes and, therefore, assignment of absolute configuration. The method is successfully applied to three oxygenated substrates from enantioselective Cu-catalyzed alkene transfer hydrodeuteration reaction chemistry.

Learned Progressive Image Compression With Dead-Zone Quantizers

Progressive coding is essential to the practical deployment of learned image compression over heterogeneous networks and clients. Existing methods for learned progressive image compression require complex and empirical design to achieve near-optimal rate-distortion performance over a wide range of bit-rates. However, these methods are limited by the implicit learned mechanism based on neural networks and introduction of uniform quantizers. In this paper, we propose generalized learned progressive image compression with analytic rate-distortion optimization using dead-zone quantizers on the latent representation. Specifically, we reveal that dead-zone quantizers, as a general case of uniform quantizers, are equivalent to uniform quantizers in fixed-rate nonlinear transform coding and can prevent extra redundancy in embedded quantization for progressive coding. Consequently, we propose rate-distortion optimized learned progressive coding by approximating the optimal quantizer in the source spaces using dead-zone quantizers in an analytic manner on the Laplacian source. To our best knowledge, this paper is the first to achieve general learned progressive coding from the perspective of optimal quantizers. The proposed method achieves theoretically sound and practically efficient embedded quantization and learned progressive coding of latent representations with improved rate-distortion performance. It can also enable embedded quantization with diverse assignments of truncation points and support flexible configuration of quality layers of varying numbers and at varying target bit-rates. Furthermore, we successfully incorporate the proposed method into existing pre-trained fixed-rate models to realize progressive learned image compression without re-training. Experimental results demonstrate that the proposed method achieves state-of-the-art rate-distortion performance in learned progressive image compression compared with traditional codecs and recent learned methods.

Targeted Isolation of Dolabellane Diterpenoids from the Soft Coral Clavularia viridis Using Molecular Networking.

LC-MS/MS-based molecular networking annotation coupled 1H NMR detection allowed the depiction of the soft coral Clavularia viridis to produce a profile of dolabellane-type diterpenoids. Chromatographic separation of the EtOAc fraction resulted in the isolation of 12 undescribed dolabellane-type diterpenoids, namely, clavirolides J-U (1-12). Their structures were characterized by the extensive analysis of the spectroscopic data, including the calculated ECD and X-ray diffraction for the configurational assignments. Clavirolides J-K are characterized by a 1,11- and 5,9-fused tricyclic tetradecane scaffold fused with a α,β-unsaturated-δ-lactone, and clavirolide L possesses a 1,11- and 3,5-fused tricyclic tetradecane scaffold, which extend the dolabellane-type scaffolds. Clavirolides L and G showed significant inhibition against HIV-1 without RT enzyme inhibition, providing additional non-nucleosides with different mechanisms from efavirenz.