Conformational Analysis of an Antibacterial Cyclodepsipeptide Active against Mycobacterium tuberculosis by a Combined ROE and RDC Analysis.

Griselimycin (GM) and methylgriselimycin (MGM), naturally produced by microorganisms of the genus Streptomyces, are cyclic depsipeptides composed of ten amino acids. They exhibit antibacterial activity against Mycobacterium species by inhibiting the sliding clamp of prokaryotic DNA polymerase III and are therefore considered as potential anti-tuberculosis drugs. The difference between the peptides is the presence of l-(R)-4-methyl-proline in MGM instead of l-proline in GM at position 8 of the amino acid sequence. Methylation increases both metabolic stability and activity of MGM compared to GM. To get deeper insight into the structure-activity relationship, the solution structure of the cyclic part of MGM was determined using rotating-frame nuclear Overhauser effect (ROE) distance restraints and residual dipolar couplings (RDC). The structure of MGM in solution is compared to the structure of GM in a co-crystal with DNA polymerase III subunit beta. As a result, a highly defined structural model of MGM is obtained, which shows related characteristics to the bound GM.

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. To corroborate the proposed mechanism, we also investigated the catalyst in mixtures with both trans-cyclohexane-1,2-diol enantiomers separately, using advanced NMR methods such as T1 relaxation time and diffusion-ordered spectroscopy (DOSY) measurements to probe molecular aggregation. We determined intramolecular distance changes within the catalyst after diol addition from quantitative NOE data. Finally, we developed a pure shift EASY ROESY experiment using PSYCHE homodecoupling to directly observe intermolecular NOE contacts between the trans-1,2-diol and the cyclohexyl moiety of the catalyst hidden by spectral overlap in conventional spectra. All experimental NMR data support the results proposed by earlier computations including the proposed key role of dispersion interaction.

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. Here, we describe a detailed NMR spectroscopic investigation on the conformational distribution of bridge-substituted dithienylcyclopentenes in solution. We could discriminate between several photoactive and photoinactive as well as two diastereomorphous conformations and show that the trends observed in the switching efficiency match the conformer populations obtained from state of the art NMR parameters in solution.

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.