Harnessing Multistep Chalcogen Bonding Activation in the α-Stereoselective Synthesis of Iminoglycosides.

The use of noncovalent interactions (NCIs) has received significant attention as a pivotal synthetic handle. Recently, the exploitation of unconventional NCIs has gained considerable traction in challenging reaction manifolds such as glycosylation due to their capacity to facilitate entry into difficult-to-access sugars and glycomimetics. While investigations involving oxacyclic pyrano- or furanoside scaffolds are relatively common, methods that allow the selective synthesis of biologically important iminosugars are comparatively rare. Here, we report the capacity of a phosphonochalcogenide (PCH) to catalyze the stereoselective α-iminoglycosylation of iminoglycals with a wide array of glycosyl acceptors with remarkable protecting group tolerance. Mechanistic studies have illuminated the counterintuitive role of the catalyst in serially activating both the glycosyl donor and acceptor in the up/downstream stages of the reaction through chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates opens up new mechanistic opportunities based on iterative ChB catalyst engagement and disengagement in multiple elementary steps.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

The accuracy limit of chemical shift predictions for species in aqueous solution.

Interpreting NMR experiments benefits from first-principles predictions of chemical shifts. Reaching the accuracy limit of theory is relevant for unambiguous structural analysis and dissecting theoretical approximations. Since accurate chemical shift measurements are based on using internal reference compounds such as trimethylsilylpropanesulfonate (DSS), a detailed comparison of experimental with theoretical data requires simultaneous consideration of both target and reference species ensembles in the same solvent environment. Here we show that ab initio molecular dynamics simulations to generate liquid-state ensembles of target and reference compounds, including explicitly their short-range solvation environments and combined with quantum-mechanical solvation models, allows for predicting highly accurate 1H (∼0.1-0.5 ppm) and aliphatic 13C (∼1.5 ppm) chemical shifts for aqueous solutions of the model compounds trimethylamine N-oxide (TMAO) and N-methylacetamide (NMA), referenced to DSS without any system-specific adjustments. This encompasses the two peptide bond conformations of NMA identified by NMR. The results are used to derive a general-purpose guideline set for predictive NMR chemical shift calculations of NMA in the liquid state and to identify artifacts of force field models. Accurate predictions are only obtained if a sufficient number of explicit water molecules is included in the quantum-mechanical calculations, disproving a purely electrostatic model of the solvent effect on chemical shifts.

Online coupling of liquid chromatography and two-dimensional diffusion ordered spectroscopy for the analysis of oligostyrenes.

The aim of this study was to introduce a powerful coupling of Liquid Adsorption Chromatography (LAC) and Diffusion-Ordered Spectroscopy (DOSY) for comprehensive structure analysis. This new hyphenation approach facilitated the simultaneous separation of a polymer mixture and the determination of molar masses within a single 3D experiment. The online coupling of High-Performance Liquid Chromatography (HPLC) and two-dimensional DOSY-NMR will be called 3D-LAC-NMR-DOSY experiment. Our methodology enabled the chromatographic separation of analytes based on their chemical heterogeneity, and provided accurate molar masses of the analytes through 2D-DOSY. This new method was demonstrated on a polystyrene oligomer mixture. In this case, the oligostyrenes could be separated with LAC according to their tacticity and chain length in protonated acetonitrile as eluent and DOSY measurements provided the molar masses of each oligomer. In order to show the power of the 3D-LAC-NMR-DOSY method, the comparison to 2D-DOSY, 3D-DOSY and LAC-NMR was separately evaluated. Furthermore, the recently published solvent-independent molar mass calibration of diffusion coefficients was also successfully applied in our LAC-DOSY studies for molar mass predictions of the oligomers in acetonitrile. The predicted molar masses were in good agreement with the LAC-DOSY measurements and were verified by calibrations of diffusion coefficients and mass spectrometry. Finally, this pioneering 3D technique offers a powerful new tool for advancing structure analysis and enhancing our understanding of complex systems such as oligostyrenes.

Exploiting π and Chalcogen Interactions for the ß-Selective Glycosylation of Indoles through Glycal Conformational Distortion.

Harnessing unconventional noncovalent interactions (NCIs) is emerging as a formidable synthetic approach in difficult-to-access glycosidic chemical space. C-Glycosylation, in particular, has gained a flurry of recent attention. However, most reported methods are restricted to the relatively facile access to α-C-glycosides. Herein, we disclose a ß-stereoselective glycosylation of indoles by employing a phosphonoselenide catalyst. The robustness of this protocol is exemplified by its amenability for reaction at both the indolyl C- and N- reactivity sites. In contrast to previous reports, in which the chalcogens were solely involved in Lewis acidic activation, our mechanistic investigation unraveled that the often neglected flanking aromatic substituents of phosphonoselenides can substantially contribute to catalysis by engaging in π-interactions. Computations and NMR spectroscopy indicated that the chalcogenic and aromatic components of the catalyst can be collectively exploited to foster conformational distortion of the glycal away from the usual half-chair to the boat conformation, which liberates the convex ß-face for nucleophilic attack.

Cooperative Bifurcated Chalcogen Bonding and Hydrogen Bonding as Stereocontrolling Elements for Selective Strain-Release Septanosylation.

The exploitation of noncovalent interactions (NCIs) is emerging as a vital handle in tackling broad stereoselectivity challenges in synthesis. In particular, there has been significant recent interest in the harnessing of unconventional NCIs to surmount difficult selectivity challenges in glycosylations. Herein, we disclose the exploitation of an unconventional bifurcated chalcogen bonding and hydrogen bonding (HB) network, which paves the way for a robust catalytic strategy into biologically useful seven-membered ring sugars. Through 13C nuclear magnetic resonance (NMR) in situ monitoring, NMR titration experiments, and density functional theory (DFT) modeling, we propose a remarkable contemporaneous activation of multiple functional groups consisting of a bifurcated chalcogen bonding mechanism working hand-in-hand with HB activation. Significantly, the ester moiety installed on the glycosyl donor is critical in the establishment of the postulated ternary complex for stereocontrol. Through the 13C kinetic isotopic effect and kinetic studies, our data corroborated that a dissociative SNi-type mechanism forms the stereocontrolling basis for the excellent α-selectivity.

The Universal Calibration for Structure- and Solvent-Independent Molar Mass Determinations of Polymers Using Diffusion-Ordered Spectroscopy.

It will be shown how diffusion-ordered spectroscopy (DOSY) can produce a universal calibration of molar mass dependences of polymers compared to size exclusion chromatography (SEC) or recently published DOSY methods. Whereas SEC can deliver only structure-independent universal calibrations for a particular solvent, DOSY was used for creating solvent-independent calibrations for a certain polymer. Now, we can demonstrate a universal calibration method that generates both a structure- and solvent-independent molar mass calibration. Only one mathematical function describes the structure- and solvent-independent calibrations for DOSY by implementing the Mark-Houwink approach. The derived equation is tested on polystyrene (PS), poly(ethylene oxide), and poly(methyl methacrylate) of different molar masses and in different solvents. Altogether, 94 diffusion coefficients representing 16 molar mass calibrations of the diffusion coefficients in 10 different solvents could be perfectly matched to one universal calibration function with an average deviation of just 2.5%. It was also found that the Mark-Houwink parameters calculated by DOSY are very close to the SEC data. In any case, this new approach is a very useful tool for the determination of molar masses and new Mark-Houwink parameters via DOSY.

Gauging the Strength of the Molecular Halogen Bond via Experimental Electron Density and Spectroscopy.

Strong and weak halogen bonds (XBs) in discrete aggregates involving the same acceptor are addressed by experiments in solution and in the solid state. Unsubstituted and perfluorinated iodobenzenes act as halogen donors of tunable strength; in all cases, quinuclidine represents the acceptor. NMR titrations reliably identify the strong intermolecular interactions in solution, with experimental binding energies of approx. 7 kJ/mol. Interaction of the σ hole at the halogen donor iodine leads to a redshift in the symmetric C-I stretching vibration; this shift reflects the interaction energy in the halogen-bonded adducts and may be assessed by Raman spectroscopy in condensed phase even for weak XBs. An experimental picture of the electronic density for the XBs is achieved by high-resolution X-ray diffraction on suitable crystals. Quantum theory of atoms in molecules (QTAIM) analysis affords the electron densities and energy densities in the bond critical points of the halogen bonds and confirms stronger interaction for the shorter contacts. For the first time, the experimental electron density shows a significant effect on the atomic volumes and Bader charges of the quinuclidine N atoms, the halogen-bond acceptor: strong and weak XBs are reflected in the nature of their acceptor atom. Our experimental findings at the acceptor atom match the discussed effects of halogen bonding and thus the proposed concepts in XB activated organocatalysis.

Comprehensive Study of the Enhanced Reactivity of Turbo-Grignard Reagents.

Since its introduction in 2004, Knochel's so called Turbo-Grignard reagents revolutionized the usage of Grignard reagents. Through the simple addition of LiCl to a magnesium alkyl an outstanding increase in reactivity can be achieved. Though the exact composition of the reactive species remained mysterious, the reactive mixture itself is readily used not only in synthesis but also found its way into more distant fields like material science. To unravel this mystery, we combined single-crystal X-ray diffraction with in-solution NMR-spectroscopy and closed our investigations with quantum chemical calculations. Using such a variety of methods, we have gained insight into and an explanation for the extraordinary reactivity of this extremely convenient reagent by determining the structure of the first bimetallic reactive species [t-Bu2 Mg ⋅ LiCl ⋅ 4 thf] with two tert-butyl anions at the magnesium center and incorporated lithium chloride.

Polyurea Thickened Lubricating Grease-The Effect of Degree of Polymerization on Rheological and Tribological Properties.

Lubricating greases based on urea thickeners are frequently used in high-performance applications since their invention in 1954. One property that has so far been neglected in the further development of these systems due to their low solubility and the resulting difficulty of analysis, is to better understand how the degree of polymerization affect such polyurea lubricating systems. In this work, we prepared three different oligo- or polyurea systemswith different degrees of polymerization (DP) and investigated the influence of DP on rheological and tribological properties. The results showed that the DP has an influence on the flow limit in rheology as well as on the extreme pressure (EP) and anti-wear (AW) properties as examined by tribology measurements. By optimizing the DP for a thickener system, comparable EP and AW properties can be achieved through the use of additives. The DP showed an increasing influence on the flow limit. This could reduce damage to rolling bearings due to lateral loading at rest. Therefore, modifying the DP of the polyurea systems shows similar effects as the addition of external additives. Overall, this would reduce the use of additives in industrial applications.

Hidden intermediates in Mango III RNA aptamer folding revealed by pressure perturbation.

Fluorescent RNA aptamers have the potential to enable routine quantitation and localization of RNA molecules and serve as models for understanding biologically active aptamers. In recent years, several fluorescent aptamers have been selected and modified to improve their properties, revealing that small changes to the RNA or the ligands can modify significantly their fluorescent properties. Although structural biology approaches have revealed the bound, ground state of several fluorescent aptamers, characterization of low-abundance, excited states in these systems is crucial to understanding their folding pathways. Here we use pressure as an alternative variable to probe the suboptimal states of the Mango III aptamer with both fluorescence and NMR spectroscopy approaches. At moderate KCl concentrations, increasing pressure disrupted the G-quadruplex structure of the Mango III RNA and led to an intermediate with lower fluorescence. These observations indicate the existence of suboptimal RNA structural states that still bind the TO1-biotin fluorophore and moderately enhance fluorescence. At higher KCl concentration as well, the intermediate fluorescence state was populated at high pressure, but the G-quadruplex remained stable at high pressure, supporting the notion of parallel folding and/or binding pathways. These results demonstrate the usefulness of pressure for characterizing RNA folding intermediates.