Enantiodiscrimination of Inherently Chiral Thiacalixarenes by Residual Dipolar Couplings.

Inherently chiral compounds, such as calixarenes, are chiral due to a nonplanar three-dimensional (3D) structure. Determining their conformation is essential to understand their properties, with nuclear magnetic resonance (NMR) spectroscopy being one applicable method. Using alignment media to measure residual dipolar couplings (RDCs) to obtain structural information is advantageous when classical NMR parameters like the nuclear Overhauser effect (NOE) or -couplings fail.

Model free analysis of residual dipolar couplings in small organic compounds.

Residual dipolar couplings (RDCs) contain information on the relative arrangement and dynamics of internuclear spin vectors in chemical compounds. Classically, RDC data is analyzed by fitting to structure models, while model-free approaches (MFA) directly relate RDCs to the corresponding internuclear vectors. The recently introduced software TITANIA implements the MFA and extracts structure and dynamics parameters directly from RDCs to facilitate structure refinement for small organic compounds.

TITANIA: Model-Free Interpretation of Residual Dipolar Couplings in the Context of Organic Compounds.

Residual dipolar couplings (RDCs) become increasingly important as additional NMR parameters in the structure elucidation of organic compounds but are usually used in fitting procedures to discriminate between (computed) structures that are in accordance with RDCs and others that can be ruled out. Thus, the determination of configurations requires prior structural information. The direct use of RDCs as restraints to construct structures based on RDCs has only recently begun also in organic compounds.

Engineering of a Plant Isoprenyl Diphosphate Synthase for Development of Irregular Coupling Activity.

We performed mutagenesis on a regular isoprenyl diphosphate synthase (IDS), neryl diphosphate synthase from Solanum lycopersicum (SlNPPS), that has a structurally related analogue performing non-head-to-tail coupling of two dimethylallyl diphosphate (DMAPP) units, lavandulyl diphosphate synthase from Lavandula x intermedia (LiLPPS). Wild-type SlNPPS catalyses regular coupling of isopentenyl diphosphate (IPP) and DMAPP in cis-orientation resulting in the formation of neryl diphosphate. However, if the enzyme is fed with DMAPP only, it is able to catalyse the coupling of two DMAPP units and synthesizes two irregular monoterpene diphosphates; their structures were elucidated by the NMR analysis of their dephosphorylation products.

Gradient selected pure shift EASY-ROESY techniques facilitate the quantitative measurement of H,H-distance restraints in congested spectral regions.

For elucidating molecular structure and dynamics in solution, NMR experiments such as NOESY, ROESY and EXSY have been used excessively over the past decades, to provide interatomic distance restraints or rates for chemical exchange. The extraction of such information, however, is often prohibited by signal overlap in these spectra. To reduce this problem, pure shift methods for improving the spectral resolution have become popular.

Probing Long-Range Anisotropic Interactions: a General and Sign-Sensitive Strategy to Measure H- H Residual Dipolar Couplings as a Key Advance for Organic Structure Determination.

Residual dipolar couplings (RDCs) are amongst the most powerful NMR parameters for organic structure elucidation. In order to maximize their effectiveness in increasingly complex cases such as flexible compounds, a maximum of RDCs between nuclei sampling a large distribution of orientations is needed, including sign information. For this, the easily accessible one-bond H- C RDCs alone often fall short.

Thermoresponsive Alignment Media in NMR Spectroscopy: Helix Reversal of a Copolyaspartate at Ambient Temperatures.

Poly(aspartic acid esters) are known to form either right-or left-handed α-helices depending on the ester group in the side chain, on solvent and/or on temperature. Polyphenethyl-l-aspartates (PPLA) exhibit a helix reversal from the right- to the left-handed form with increasing temperature. We have recently reported the application of polyphenethylaspartates as helically chiral alignment media.

Engineering of new-to-nature halogenated indigo precursors in plants.

Plants are versatile chemists producing a tremendous variety of specialized compounds. Here, we describe the engineering of entirely novel metabolic pathways in planta enabling generation of halogenated indigo precursors as non-natural plant products. Indican (indolyl-β-D-glucopyranoside) is a secondary metabolite characteristic of a number of dyers plants.

Synthesis of Poly-γ-S-2-methylbutyl-l-glutamate and Poly-γ-S-2-methylbutyl-d-glutamate and Their Use as Enantiodiscriminating Alignment Media in NMR Spectroscopy.

Lyotropic liquid crystalline (LLC) phases of polyglutamic acid derivatives, such as poly-γ-benzyl-l-glutamate, are suitable alignment media for organic structure elucidation by NMR spectroscopy. Their helical structure is responsible for enantiodiscrimination. As part of our ongoing investigations concerning the alignment mechanism(s) of these systems, we considered whether an additional chiral center in the side chain could improve enantiodiscrimination relative to the helical polymer with an achiral side chain.

Uncovering Key Structural Features of an Enantioselective Peptide-Catalyzed Acylation Utilizing Advanced NMR Techniques.

We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers.

Nanoscale Biodegradable Organic-Inorganic Hybrids for Efficient Cell Penetration and Drug Delivery.

We report a comprehensive study on novel, highly efficient, and biodegradable hybrid molecular transporters. To this end, we designed a series of cell-penetrating, cube-octameric silsesquioxanes (COSS), and investigated cellular uptake by confocal microscopy and flow cytometry. A COSS with dense spatial arrangement of guanidinium groups displayed fast uptake kinetics and cell permeation at nanomolar concentrations in living HeLa cells.

Perspectives in the application of residual dipolar couplings in the structure elucidation of weakly aligned small molecules.

This perspective article aims to review the general methodology in the application of residual dipolar couplings (RDCs) in the structure elucidation of small molecules and give the author's view on challenges for future applications. Recent improvements in the availability of alignment media, new pulse sequences for the measurement of couplings and improvements in the analysis software have garnered widespread interest in the technique. However, further generalization is needed in order to make RDC analysis into a truly "routine" method.

Extraction of distance restraints from pure shift NOE experiments.

NMR techniques incorporating pure shift methods to improve signal resolution have recently attracted much attention, owing to their potential use in studies of increasingly complex molecular systems. Extraction of frequencies from these simplified spectra enables easier structure determination, but only a few of the methods presented provide structural parameters derived from signal integral measurements. In particular, for quantification of the nuclear Overhauser effect (NOE) it is highly desirable to utilize pure shift techniques where signal overlap normally prevents accurate signal integration, to enable measurement of a larger number of interatomic distances.

Dynamic behaviour of monohaptoallylpalladium species: internal coordination as a driving force in allylic alkylation chemistry.

Contemporary catalytic procedures involving alkylpalladium(ii) have enriched the arsenal of synthetic organic chemistry. Those transformations usually rely on internal coordination through "directing groups", carefully designed to maximize catalytic efficiency and regioselectivity. Herein, we report structural and reactivity studies of a series of internally coordinated monohaptoallylpalladium complexes.

Exploring the conformational space of bridge-substituted dithienylcyclopentenes.

Stimuli responsive compounds and materials are of high interest in synthetic chemistry and materials science, with light being the most intriguing stimulus due to the possibility to remote control the physicochemical properties of a molecule or a material. There is a constant quest to design photoswitches with improved switching efficiency and especially diarylethene-type switches promise photo cyclization quantum yields up to unity. However, only limited attention has been paid towards the influence of the solution conformation on the switching efficiency.

The influence of electronic modifications on rotational barriers of bis-NHC-complexes as observed by dynamic NMR spectroscopy.

There has been much debate about the σ-donor and π-acceptor properties of N-heterocyclic carbenes (NHCs). While a lot of synthetic modifications have been performed with the goal of optimizing properties of the catalyst to tune reactivity in various transformations (e.g.

RDC-based determination of the relative configuration of the fungicidal cyclopentenone 4,6-diacetylhygrophorone A12.

The hygrophorones, a class of cyclopentenones isolated from fruiting bodies of the genus Hygrophorus (basidiomycetes), show promising antifungal activity. While the constitution of 4,6-diacetylhygrophorone A(12) (3) and the relative configuration of the stereogenic centers in the cyclopentenone ring were elucidated using standard NMR and MS techniques, the relative configuration of the exocyclic stereogenic center could not be assigned. By introducing a sample of 3 into an alignment medium and measuring anisotropic NMR parameters, namely, residual dipolar couplings, we were able to unambiguously determine the relative configuration of all three stereogenic centers in 4,6-diacetylhygrophorone A(12) simultaneously by fitting several structure proposals to the experimental data.

How different are diastereomorphous orientations of enantiomers in the liquid crystalline phases of PBLG and PBDG: a case study.

The orientational properties of the two enantiomers of an example compound, namely isopinocampheol [(+)- and (-)-IPC] in the two enantiomers of a liquid crystalline phase, namely Poly-gamma-benzyl-L/D-glutamate (PBLG/PBDG) with the organic cosolvent CDCl(3), were investigated. The interactions can be either enantiomorphous, leading to equal orientations and residual dipolar couplings (RDCs), or diastereomorphous, leading to different orientations and RDCs. The difference between the two diastereomorphous orientations was determined to be rather small (5 degrees in the Euler angle beta).

pi-Face donor properties of N-heterocyclic carbenes in Grubbs II complexes.

The electron-donating properties of eighteen N-heterocyclic carbenes (N,N'-bis(2,6-dimethylphenyl)imidazol)-2-ylidene and the respective dihydro ligands) with 4,4'-R substituted aryl rings (4,4'-R = NEt2, OMe, Me, H, SMe, F, Cl, Br, I) in the respective Grubbs II complexes were studied using electrochemical techniques. The nature of the 4-R substituent has a strong influence on the RuII/III redox potentials ranging between DeltaE1/2= +0.196 and +0.