Computational NMR Structural Revision of Marinoaziridines A and B.

The putative structures of alkaloids marinoaziridine A and B, the last a recent target of total synthesis, are here revised, on the basis of NMR computer-assisted structural elucidation and DFT prediction of H and C chemical shifts, as pyrroloquinoline alkaloids structurally very similar to the marinoquinolines isolated from the same source.

Reversibly Compressible Cross-Linked Polystyrene Gels, Compatible With Toluene-d and Pyridine-d, for Measurement of Residual Dipolar Couplings and Residual Chemical Shift Anisotropies.

A chemically cross-linked version of polystyrene is presented here that allows the preparation of reversibly mechanically compressible gels as NMR weakly aligning media. The gels can be successfully swollen in aromatic solvents such as toluene-d and pyridine-d, as well as in CDCl, and provided accurate measurements of D RDCs and C-RCSAs.

Anisotropic NMR data acquisition with a prototype 400 MHz cryogen-free NMR spectrometer.

High-temperature superconducting (HTS) materials have recently been incorporated into the construction of HTS cryogen-free magnets for nuclear magnetic resonance (NMR) spectroscopy. These HTS NMR spectrometers do not require liquid cryogens, thereby providing significant cost savings and facilitating easy integration into chemistry laboratories. However, the optimal performance of these HTS magnets against standard cryogen NMR magnets must be evaluated, especially with demanding modern NMR applications such as NMR in anisotropic media.

Phomactinine, the First Nitrogen-Bearing Phomactin, Produced by sp. CBMAI 1333.

Metabolomics analyses and improvement of growth conditions were applied toward diversification of phomactin terpenoids by the fungus sp. CBMAI 1333. Visualization of molecular networking results on Gephi assisted the observation of phomactin diversification and guided the isolation of new phomactin variants by applying a modified version of chemometrics based on a fractional factorial design.

Residual dipolar couplings as a tool for structural analysis of ionic liquids.

An acrylonitrile/dimethylacrylamide cross-linked polymer could be swollen in different imidazolium ionic liquids. Mechanical compression of the obtained polymer gels inside an NMR tube allowed the measurement of residual dipolar couplings. Conformational analysis of the 1-methyl-3-butyl-imidazolium (BMIM) cation could be performed by including the measured RDCs as restraints in time-averaged molecular dynamics.

An Acrylonitrile-Based Copolymer Gel as an NMR Alignment Medium for Extraction of Residual Dipolar Couplings of Small Molecules in Aqueous Solution.

An NMR weakly-aligning polymer gel has been prepared by copolymerization of acrylonitrile and 2-acrylamide-2-methyl-1-propanesulfonic acid in the presence of 1,4-butanediol diacrylate as a cross-linker. The polymer readily swells in water in a large range of temperatures, although the swelling ratio is decreased in saline solutions. The swollen gel can be mechanically compressed, in a reversible way, generating anisotropy, as easily shown in H NMR experiments, and allowing measurement of D residual dipolar couplings (RDCs) through F1-coupled HSQC experiments.

Connection of Isolated Stereoclusters by Combining C-RCSA, RDC, and -Based Configurational Analyses and Structural Revision of a Tetraprenyltoluquinol Chromane Meroterpenoid from .

The seaweed , collected on the southern coast of Galicia, yielded a tetraprenyltoluquinol chromane meroditerpene compound known as , whose structure is revised. The relative configuration of was determined by -based configurational methodology combined with an i/DP4 statistical analysis and further confirmed by measuring two anisotropic properties: carbon residual chemical shift anisotropies (C-RCSAs) and one-bond H-C residual dipolar couplings (-RDCs). The absolute configuration of was deduced by ECD/OR/TD-DFT methods and established as ,,.

Weizhouochrones: Gorgonian-Derived Symmetric Dimers and Their Structure Elucidation Using Anisotropic NMR Combined with DP4+ Probability and CASE-3D.

Natural product dimers have intriguing structural features and often have remarkable pharmacological activities. We report here two uncommon marine gorgonian-derived symmetric dimers, weizhouochrones A () and B (), with indenone-derived monomers, that were isolated from the coral collected from the South China Sea. These dimers are difficult targets for structure elucidation that solely relies upon conventional NMR data such as NOEs and -couplings.

Programmable alignment media from self-assembled oligopeptide amphiphiles for the measurement of independent sets of residual dipolar couplings in organic solvents.

NMR spectroscopy in anisotropic media has emerged as a powerful technique for the structural elucidation of organic molecules. Its application requires weak alignment of analytes by means of suitable alignment media. Although a number of alignment media, that are compatible with organic solvents, have been introduced in the last 20 years, acquiring a number of independent, non-linearly related sets of anisotropic NMR data from the same organic solvent system remains a formidable challenge, which is however crucial for the alignment simulations and deriving dynamic and structural information of organic molecules unambiguously.

Computational Structural Revision of a 4-Hydroxy-3-(1'-angeloyloxy-2',3'-epoxy-3'-methyl)butylacetophenone Compound from .

The structure of the reported compound 4-hydroxy-3-(()-1'-angeloyloxy-()-2',3'-epoxy-3'-methyl)butylacetophenone (), isolated from , has been revised through the use of DFT computational predictions. Re-examination of the reported experimental and DFT computed chemical shifts has led to the proposal of a chromane skeleton rather than the original epoxide derivative. Empirical predictions of the C and H NMR shifts showed a much better fit for the chromane structure than for the epoxide.

NMR spectral fingerprint patterns as diagnostics for the unambiguous configurational analysis of the classic organo-gelator 1,3:2,4-dibenzylidene-d-sorbitol (DBS) and its derivatives.

On the basis of experimental data and density functional theory (DFT) chemical shift and scalar coupling predictions, simple spectral nuclear magnetic resonance (NMR) fingerprint patterns have been established for the determination of the configuration in 1,3:2,4-dibenzylidene-d-sorbitol (DBS), a classic low molecular weight gelator, and its derivatives. The results rigorously prove the orientation of the phenyl rings in DBS that had been previously assumed in the literature on the basis of thermodynamic arguments.

Single experiment measurement of residual dipolar couplings in aqueous solution using a biphasic bisperylene imide chromonic liquid crystal.

The use of the biphasic isotropic/nematic region in a bisperylene imide-based lyotropic liquid crystal system allows the extraction of proton-carbon D residual dipolar couplings in aqueous solution from a single F1-coupled HSQC experiment. The method was successfully applied to the RDC-based conformational analysis of sucrose.

Author Correction: Relative configuration of micrograms of natural compounds using proton residual chemical shift anisotropy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Deuterium Residual Quadrupolar Couplings: Crossing the Current Frontiers in the Relative Configuration Analysis of Natural Products.

The determination of the 3D structure (configuration and preferred conformation) of complex natural and synthetic organic molecules is a long-standing but still challenging task for chemists, with various implications in pharmaceutical sciences whether or not these substances have specific bioactivities. Nuclear magnetic resonance (NMR) in aligning media, either lyotropic liquid crystals (LLCs) or polymer gels, in combination with molecular modeling is a unique framework for solving complex structural problems whose analytical wealth lies in the establishment of nonlocal structural correlations. As an alternative to the already well-established anisotropic NMR parameters, such as RDCs (residual dipolar couplings) and RCSAs (residual chemical shift anisotropies), it is shown here that deuterium residual quadrupolar couplings (H-RQCs) can be extracted from H 2D-NMR spectra recorded at the natural abundance level in samples oriented in a homopolypeptide LLCs (poly-γ-benzyl-l-glutamate (PBLG)).

Karplus relationships of the J and J couplings in organic azides.

Density functional theory (DFT) and second-order polarization propagator approximation (SOPPA) computations in model organic azides revealed a Karplus-like dependence not only of the vicinal J coupling but also of the geminal J one, with the H-C-N N dihedral angle. Karplus equations were derived from the DFT computations on the isopropylazide model system. In light of these stablished relationships, natural abundance H- N couplings obtained for the azide group of the zidovudine antiviral helped to probe its conformation around the C-N bond as being of the synclinal type.

Relative configuration of micrograms of natural compounds using proton residual chemical shift anisotropy.

3D molecular structure determination is a challenge for organic compounds or natural products available in minute amounts. Proton/proton and proton/carbon correlations yield the constitution. J couplings and NOEs oftentimes supported by one-bond H,C residual dipolar couplings (RDCs) or by C residual chemical shift anisotropies (RCSAs) provide the relative configuration.

A DFT/machine-learning hybrid method for the prediction of J couplings.

A machine learning model for the prediction of vicinal proton-proton couplings has been developed based on a hybrid representation that includes geometrical and electronic parameters derived from natural bond orbital (NBO) analysis of low-level BLYP/STO-3G computations. The model can predict J couplings with accuracy comparable or better than the well-known Altona equation, and it can provide sensible J predictions in systems not well handled by the Altona equation such as epoxide or cyclopropane rings.

How large a J coupling can be? Prediction of giant vicinal couplings in quinonoid systems.

Second-order polarization propagator approximation (SOPPA) and density functional theory (DFT) B3LYP computations revealed the presence of giant J couplings, up to more than 60 Hz, in conjugated quinonoid systems, very far above the typical limit of ~15 Hz. Strong hyperconjugative interactions of the C-H σ orbitals with the quinonoid 8-e π system, which allows effective propagation of the spin polarization, seem to be responsible for those extraordinarily large couplings. Computation on several model systems showed the additive nature of the contributions from the available coupling paths to the total coupling.

Computer-Assisted 3D Structure Elucidation (CASE-3D): The Structural Value of J in Addition to J Coupling Constants.

We present a method to use long-range CH coupling constants to derive the correct diastereoisomer from the molecular constitution of small molecules. A set of 79 J and J values collected from a single HSQMBC experiment on a sample of strychnine were used in the CASE-3D (computer-assisted 3D structure elucidation) protocol. In addition to the most commonly used J coupling constants, the subset of 32 J values alone showed an excellent degree of configuration selection.

Stereochemical Elucidation of Natural Products from Residual Chemical Shift Anisotropies in a Liquid Crystalline Phase.

Determination of the stereochemistry of organic molecules still represents one of the major obstacles in the structure elucidation procedure in drug discovery. Although the application of residual dipolar couplings (RDCs) has revolutionized this field, residual chemical shift anisotropies (RCSAs) which contain valuable structural information for nonprotonated carbons have only been scarcely employed so far. In this study, we present a simple but highly effective solution to extract RCSAs of the analytes in a liquid crystalline phase formed by AAKLVFF oligopeptides.

Herpotrichones A and B, Two Intermolecular [4 + 2] Adducts with Anti-Neuroinflammatory Activity from a Species.

Herpotrichones A and B ( and ), two intermolecular [4 + 2] adducts with an unprecedented pentacyclic 6/6/6/6/3 skeleton, were isolated from sp. SF09, an isopod-associated fungus, along with a new shunt product protrichone (). Their structures were elucidated by the analysis of spectroscopic data, residual dipolar coupling (RDC)-based computer-assisted 3D structure elucidation (CASE-3D), and single-crystal X-ray diffraction in combination with electronic circular dichroism (ECD) calculations.

Configuration determination by residual dipolar couplings: accessing the full conformational space by molecular dynamics with tensorial constraints.

Residual dipolar couplings (RDCs) and other residual anisotropic NMR parameters provide valuable structural information of high quality and quantity, bringing detailed structural models of flexible molecules in solution in reach. The corresponding data interpretation so far is directly or indirectly based on the concept of a molecular alignment tensor, which, however, is ill-defined for flexible molecules. The concept is typically applied to a single or a small set of lowest energy structures, ignoring the effect of vibrational averaging.

Effect of the solvent on the conformation of monocrotaline as determined by isotropic and anisotropic NMR parameters.

The conformation in solution of monocrotaline, a pyrrolizidine alkaloid presenting an eleven-membered macrocyclic diester ring, has been investigated using a combination of isotropic and anisotropic nuclear magnetic resonance parameters measured in four solvents of different polarity (D O, DMSO-d , CDCl , and C D ). Anisotropic nuclear magnetic resonance parameters were measured in different alignment media, based on their compatibility with the solvent of interest: cromoglycate liquid crystal solution was used for D O, whereas a poly (methyl methacrylate) polymer gel was chosen for CDCl and C D , and a poly (hydroxyethyl methacrylate) gel for DMSO-d . Whereas the pyrrolizidine ring shows an E exo-puckered conformation in all of the solvents, the macrocyclic eleven-membered ring adopts different populations of syn-parallel and anti-parallel relative orientation of the carbonyl groups according to the polarity of the solvent.

When not to rely on Boltzmann populations. Automated CASE-3D structure elucidation of hyacinthacines through chemical shift differences.

An Akaike Information Criterion (AIC) procedure (CASE-3D) has been successfully applied to the NMR based configurational assignment of reported hyacinthacines (1-3,5-8), recently target of configurational analysis using the popular DP4+ methodology. The present analysis makes use of reported H and C shifts and, in some particular cases, a few J couplings. The difficulty in proper computational prediction of relative energies, in molecules capable of inter-molecular hydrogen bonding, introduces large errors in the prediction of conformationally averaged NMR properties in methods based on Boltzmann averaging such as DP4 or DP4+.

Unexpected behavior of the J coupling constant in unsaturated compounds.

The experimental and theoretical behavior of the (OC)CCH J coupling constant is investigated for a series of α,β-unsaturated compounds (1 to 8), and for some of them, the well-known relationship ( J  <  J ) was observed. However, for some compounds, close values for J and J couplings were observed, and for aldehydes group containing compounds (7 and 8E), an inversion order is observed ( J  >  J ). In all cases where the J  <  J relationship it is not followed, a polar group or electronegative atom oriented in opposite direction (s-trans) to the HCC hydrogen is present, suggesting that conformational preference of such polar group or atoms are important factor on the behavior of J couplings.