Enantioselective Hydroaminations Catalyzed by Yttrium(III)-Bis(sulfoximine) Complexes.

Bis(sulfoximine) yttrium complexes as catalysts for enantioselective intramolecular hydroaminations were prepared for the first time and characterized by a multinuclear NMR study including the nuclei H, C, N and Y. The stoichiometries of the complexes were confirmed by a Job plot. In addition to the experimental results, the Y NMR shifts and the complex structures were elucidated by DFT calculations.

Spatially Resolved Anisotropic Natural Abundance Deuterium 2D-NMR Spectroscopy Using Bimesophasic Lyotropic Chiral Systems.

In this paper, we describe, for the first time, the combined and original use of spatially resolved anisotropic natural abundance deuterium (ANAD) 2D-NMR experiments and bimesophasic lyotropic chiral systems to extract two independent sets of anisotropic parameters such as H-RQCs from a single NMR sample. As a pioneering example, we focus on a mixture of immiscible polypeptides (PBLG) and polyacetylene helical polymers (L-MSP) dissolved in weakly polar organic solvents (chloroform). Nondeuterated (D)-(+)-camphor is used as a model chiral solute.

2,5-[C+C] Ringtransformation of Pyrylium Salts with α-Sulfinylacetaldehydes.

A rapid synthesis of chiral sulfoxide-functionalized -terphenyl derivatives by a 2,5-[C+C] ring transformation reaction of pyrylium salts with in situ generated enantiomerically pure α-sulfinylacetaldehydes is described in this paper. This synthetic method demonstrates, for the first time, the use of α-sulfinylacetaldehydes in a reaction sequence initiated by the nucleophilic attack of pyrylium salts by α-sulfinylcarbanions to generate chiral aromatic systems. The method presented shows a broad applicability starting with various methyl sulfoxides and a number of functionalized pyrylium salts, furnishing -terphenyls with complex substitution patterns from readily accessible starting compounds.

Residual-Chemical-Shift-Anisotropy-Based Enantiodifferentiation in Lyotropic Liquid Crystalline Phases Based on Helically Chiral Polyacetylenes.

Anisotropic NMR spectroscopy, revealing residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) has emerged as a powerful tool to determine the configurations of synthetic and complex natural compounds. The deduction of the absolute in addition to the relative configuration is one of the primary goals in the field. Therefore, the investigation of the enantiodiscriminating capabilities of chiral alignment media becomes essential.

Synthesis and crystal structure of -2-(1,3-dioxo-isoindolin-2-yl)ethyl 4-methyl--phenyl-'-(tri-iso-propyl-sil-yl)benzene-sulfondiimidoate: the first member of a new substance class.

The title compound {systematic name: -2-[7-methyl-4-(4-methylphenyl)-4-(phenylimino)-6,6-bis(propan-2-yl)-3-oxa-4λ-thia-5-aza-6-silaoct-4-en-1-yl]-2,3-dihydro-1-isoindole-1,3-dione}, CHNOSSi, was synthesized by desoxychlorination of 4-methyl--phenyl-'-(triisopropyl-sil-yl)benzene-sul-fon-imid-am-ide and subsequent reaction with 2-(2-hy-droxy-eth-yl)isoindoline-1,3-dione. The racemic compound was crystallized from isopropanol. The structural characterization by single-crystal X-ray diffraction revealed two double-bonded nitro-gen atoms to the central sulfur atom and an overall crystal packing driven by its aromatic inter-actions.

NMR-Based Configurational Assignments of Natural Products: How Floating Chirality Distance Geometry Calculations Simplify Gambling with 2 Diastereomers.

Using NMR data, the assignment of the correct 3D configuration and conformation to unknown natural products is of pivotal importance in pharmaceutical and medicinal chemistry. In this report, we quantify the probability of configurational assignments to judge the quality of structural elucidations using Bayesian inference in combination with floating-chirality distance geometry simulations. Based on reference-free NOE/ROE data, residual dipolar couplings (RDCs), and residual quadrupolar couplings (RQCs) in various combinations, we demonstrate how the relative configurations of three natural compounds, namely, jatrohemiketal (), artemisinin (), and Taxol (), can be unambiguously established without the necessity to carry out time-consuming DFT-based configurational and conformational analyses.

Bayesian Inference Applied to NMR-Based Configurational Assignments by Floating Chirality Distance Geometry Calculations.

Using NMR data, the assignment of the correct 3D configuration and conformation to unknown natural products is of pivotal importance in pharmaceutical and medicinal chemistry. In this report, we quantify the quality and probability of structural elucidations using Bayesian inference in combination with floating chirality distance geometry simulations. Here, we will discuss the configurational analysis of three complex natural products including isopinocampheol (), plakilactone H (), and iodocallophycoic acid A () using NMR restraints of various types and in different combinations (residual dipolar couplings (RDCs) and NOE-derived distances).

Study and quantification of the enantiodiscrimination power of four polymeric chiral LLCs using NAD 2D-NMR.

Identifying and understanding the role of key molecular factors involved in the orientation/discrimination phenomena of analytes in polymer-based chiral liquid crystals (CLCs) are essential tasks for optimizing computational predictions (molecular dynamics simulation) of the existing orienting systems, as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. From this perspective, we propose to quantify and compare the enantiodiscrimination power of four homochiral polymer-based lyotropic liquid crystals (LLCs) toward a given chiral solute using their H residual quadrupolar couplings (H-RQCs) measured by anisotropic natural abundance deuterium 2D-NMR (ANAD 2D-NMR). Two families of chiral polymers are investigated in this study: (i) poly-peptide polymers (PBLG and PCBLL), and (ii) polyacetylene polymers (PDA and L-MSP, a new system never published so far).

A disintegrin derivative as a case study for PHIP labeling of disulfide bridged biomolecules.

A specific labeling strategy for bioactive molecules is presented for eptifibatide (integrilin) an antiplatelet aggregation inhibitor, which derives from the disintegrin protein barbourin in the venom of certain rattlesnakes. By specifically labeling the disulfide bridge this molecule becomes accessible for the nuclear spin hyperpolarization method of parahydrogen induced polarization (PHIP). The PHIP-label was synthesized and inserted into the disulfide bridge of eptifibatide via reduction of the peptide and insertion by a double Michael addition under physiological conditions.

Poly(arylisocyanides) as Versatile, Enantiodiscriminating Alignment Media for Small Molecules.

Lyotropic liquid crystalline (LLC) phases of amino acid derived polyarylisocyanides were employed as chiral alignment media for the measurement of residual dipolar couplings (RDCs) of small chiral organic molecules. Anisotropic samples in CDCl displayed quadrupolar splittings of the deuterium signal in the range of several hundreds of Hertz. The LLC phases showed excellent orienting properties for a broad range of analytes bearing various functional groups.

NMR-Based Configurational Assignments of Natural Products: Gibbs Sampling and Bayesian Inference Using Floating Chirality Distance Geometry Calculations.

Floating chirality restrained distance geometry (fc-rDG) calculations are used to directly evolve structures from NMR data such as NOE-derived intramolecular distances or anisotropic residual dipolar couplings (RDCs). In contrast to evaluating pre-calculated structures against NMR restraints, multiple configurations (diastereomers) and conformations are generated automatically within the experimental limits. In this report, we show that the "unphysical" rDG pseudo energies defined from NMR violations bear statistical significance, which allows assigning probabilities to configurational assignments made that are fully compatible with the method of Bayesian inference.

A novel strategy for site selective spin-labeling to investigate bioactive entities by DNP and EPR spectroscopy.

A novel specific spin-labeling strategy for bioactive molecules is presented for eptifibatide (integrilin) an antiplatelet aggregation inhibitor, which derives from the venom of certain rattlesnakes. By specifically labeling the disulfide bridge this molecule becomes accessible for analytical techniques such as Electron Paramagnetic Resonance (EPR) and solid state Dynamic Nuclear Polarization (DNP). The necessary spin-label was synthesized and inserted into the disulfide bridge of eptifibatide via reductive followed by insertion by a double Michael addition under physiological conditions.

Model-Free Approach for the Configurational Analysis of Marine Natural Products.

The NMR-based configurational analysis of complex marine natural products is still not a routine task. Different NMR parameters are used for the assignment of the relative configuration: NOE/ROE, homo- and heteronuclear couplings as well as anisotropic parameters. The combined distance geometry (DG) and distance bounds driven dynamics (DDD) method allows a model-free approach for the determination of the relative configuration that is invariant to the choice of an initial starting structure and does not rely on comparisons with (DFT) calculated structures.

Configurational Analysis by Residual Dipolar Couplings: Critical Assessment of "Structural Noise" from Thermal Vibrations.

The certainty of configurational assignments of natural products based on anisotropic NMR parameters, such as residual dipolar couplings (RDCs), must be amended by estimates on structural noise emerging from thermal vibrations. We show that vibrational analysis significantly affects the error margins with which RDCs can be back-calculated from molecular models, and the implications of thermal motions on the differentiability of diastereomers are derived.

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.

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.

The Advanced Floating Chirality Distance Geometry Approach-How Anisotropic NMR Parameters Can Support the Determination of the Relative Configuration of Natural Products.

The configurational analysis of complex natural products by NMR spectroscopy is still a challenging task. The assignment of the relative configuration is usually carried out by analysis of interproton distances from NOESY or ROESY spectra (qualitative or quantitative) and scalar () couplings. About 15 years ago, residual dipolar couplings (RDCs) were introduced as a tool for the configurational determination of small organic molecules.

Valine derived poly (acetylenes) as versatile chiral lyotropic liquid crystalline alignment media for RDC-based structure elucidations.

Anisotropic samples of lyotropic liquid crystalline (LLC) phases of valine derived polyaryl acetylenes were employed as chiral alignment media for the measurement of residual dipolar couplings (RDCs) of 12 small, chiral, organic molecules. The quadrupolar splitting of the deuterium signal of CDCl can be adjusted by temperature and concentration changes from 0 to 350 Hz. The LLC phases showed excellent orienting properties for all analytes bearing various functional groups.

H and C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

Invited for this month's cover are the collaborating groups of Dr. Philippe Lesot (DR CNRS) at Université Paris-Sud/Université Paris-Saclay, France, and Professor Michael Reggelin at TU Darmstadt, Germany. The cover shows the proton-decoupled natural abundance deuterium (NAD-{ H}) Q-resolved Fz 2D-NMR spectrum of (±)-3-methylhexane measured in the anisotropic lyotropic chiral liquid-crystalline phase formed by a concentrated solution of a helically chiral polyarylacetylene in chloroform solvent.

H and C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

In this work, the practical/analytical potential of an L-valine-derived polyacetylene (PLA) lyotropic liquid crystal (LLC) is examined to spectrally discriminate enantiomers (racemic mixture) or enantiotopic directions of a large collection (23) of (pro)chiral model compounds (from rigid to flexible and polar to apolar ones), thus covering various important aspects of enantiomorphism. Experimental H-{ H} (deuterated analytes and at natural abundance level) and C-{ H} NMR results are discussed in terms of the difference of H-RQCs or C-RCSAs and compared to those obtained in polypeptide-type LLCs (PBLG). The analysis of the NMR results provides an overview of the enantiodifferentiation capabilities of PLA and gives useful/practical hints for the chemist to select the most appropriate chiral oriented system.

Configurational analysis by residual dipolar couplings: A critical assessment of diastereomeric differentiabilities.

Two independent statistical models for evaluating the certainties of configurational assignments of compounds based on nuclear magnetic resonance (NMR) data are evaluated and compared. Both methods yield weights or probabilities with which two or more structure models (constitutional or configurational isomers or even conformers) could be differentiated based on experimental parameters. Although this paper focusses on the use of residual dipolar couplings (RDCs) for the differentiation of diastereomers, the concept can be expanded to any set of experimental NMR-derived parameters.

Configurational Analysis by Residual Dipolar Coupling Driven Floating Chirality Distance Geometry Calculations.

A new method implemented into a computer program (ConArch ) has been developed and applied to demonstrate the successful implementation of residual dipolar couplings (RDCs) in distance geometry (DG) calculations for the configurational assignment of chiral compounds. Unlike established protocols, the new approach combines floating chirality (fc) in 4D- and 3D-distance bounds driven dynamics (DDD) calculations with structural information from RDCs. Thus, relative configurations of chiral compounds were generated only by observables (e.

Biphasic Liquid Crystal and the Simultaneous Measurement of Isotropic and Anisotropic Parameters by Spatially Resolved NMR Spectroscopy.

Residual dipolar couplings and other anisotropic NMR parameters are powerful tools for molecular structure elucidation when conventional techniques do not suffice. With current liquid crystalline preparations it is necessary to prepare two samples to extract isotropic and anisotropic data from spectra and to derive the residual dipolar couplings. Here, we present the preparation, measurement, and interpretation of a novel biphasic liquid crystalline phase where a single sample can be used to generate both isotropic and anisotropic data.

Direct determination of absolute molecular stereochemistry in gas phase by Coulomb explosion imaging.

Bijvoet's method, which makes use of anomalous x-ray diffraction or dispersion, is the standard means of directly determining the absolute (stereochemical) configuration of molecules, but it requires crystalline samples and often proves challenging in structures exclusively comprising light atoms. Herein, we demonstrate a mass spectrometry approach that directly images the absolute configuration of individual molecules in the gas phase by cold target recoil ion momentum spectroscopy after laser ionization-induced Coulomb explosion. This technique is applied to the prototypical chiral molecule bromochlorofluoromethane and the isotopically chiral methane derivative bromodichloromethane.

Phenylalanine-based polyarylacetylenes as enantiomer-differentiating alignment media.

Lyotropic liquid crystalline phases of a phenylalanine-based polyacetylene are introduced as new enantiodifferentiating alignment media. Based on the unusual temperature dependence of the quadrupolar splitting of the (2)H-signal of the solvent (CDCl(3)), three distinct states of the phase with different orientational properties can be identified. This offers the opportunity to measure multiple alignment data sets without changing the sample.