Matthias Köck

Oxepinamides A‐C and Fumiquinazolines H‐I: Bioactive Metabolites from a Marine Isolate of a Fungus of the Genus Acremonium

Three new oxepin-containing natural products (1-3) and two new fumiquinazoline metabolites (4-5) have been isolated from organic extracts of the culture broth and mycelia of an Acremonium sp., a fungus obtained from the surface of the Caribbean tunicate Ecteinascidia turbinata. The structures of the five compounds were determined through extensive analysis of 1D- and 2D-NMR data, and mass spectrometry. Compound 1 exhibited good anti-inflammatory activity in a topical RTX-induced mouse ear edema assay. Compounds 4 and 5 exhibited weak antifungal activity toward Candida albicans in a broth microdilution assay.

Differentiation of HMBC two- and three-bond correlations: A method to simplify the structure determination of natural products

Abstract The structure elucidation of natural products, today, relies heavily on the application of proton-detected heteronuclear NMR experiments. Perhaps the most useful of these methods is the HMBC experiment, which provides correlations between protons and carbons over two and three bonds. The application of the HMBC method for the direct translation of H,C correlations to yield bonding information is limited, however, by the fact that it does not distinguish between 2 J CH and 3 J CH correlations. Reported here is an application of the recently described 1,1-ADEQUATE experiment that yields only two bond H,C connectivities in HCC moieties and therefore allows the differentiation of HMBC two- and three-bond correlations. The method is demonstrated on a 14 mg sample of a new marine natural product, 5,6-dihydro lamellarin H ( 1 ). An NMR methodology is presented which allows the differentiation of two- and three-bond correlation in HMBC spectra. The ω 1 -refocused 1,1-ADEQUATE is used to obtain exclusively two-bond correlations which thereby facilitates the assignment of the constitution of complex structures. The method is demonstrated on a new polycyclic marine natural product, 5,6-dihydro lamellarin H.

Improved resolution in proton-detected heteronuclear long-range correlation

Heteronuclear long-range correlations can provide valuable information in many circumstances of spectroscopic work. They can provide correlations to quaternary carbons, which can be useful, e.g., either in the assignment of aromatic resonances or during sequencing of a peptide

Complexation and medium effects on the conformation of cyclosporin A studied by NMR spectroscopy and molecular dynamics calculations.

The conformation of cyclosporin A was investigated in different environments. Whereas there was no distinct difference between the structure of CSA in CDCl3 and THF, the addition of LiCl caused a conformational change. Also, using polar solvents (DMSO, water) induced conformational changes in the backbone as well as the side chains.

Is Enantiomer Assignment Possible by NMR Spectroscopy Using Residual Dipolar Couplings from Chiral Nonracemic Alignment Media?—A Critical Assessment

The discovery of Jean-Baptiste Biot in 1815 that optical activity is not a property bound to a certain aggregation state of matter but a property of the constituting molecules themselves, has had an enormous influence on the structural models that chemists developed at the end of the 19th century, long before the description of the chemical bond was based on quantum mechanics. Pasteur achieved the first separation of enantiomers in 1847, namely by crystallization of a racemic tartrate mixture that separated the two enantiomers into enantiomorphic crystals, solutions of which rotated the plane of linearly polarized light in opposite directions. Not until 1951, when Bijvoet used anomalous X-ray diffraction, it was possible to assign the absolute configuration to a specific enantiomer. However, anomalous X-ray diffraction has not put the problem of assigning absolute configurations to rest, because many chemical compounds cannot be crystallized. Moreover, anomalous X-ray diffraction of molecules that consist exclusively of lightweight atoms commonly lacks the needed accuracy to allow unambiguous assignment of absolute configurations. An alternative method for resolving enantiomers is to convert them to diastereoisomers, either by chemical derivatization with chiral nonracemic moieties or by intermolecular coordination with chiral nonracemic reagents. In this way it is possible to determine absolute configuration from NMR observables, most commonly chemical shifts. The use of chiroptical spectroscopies such as optical rotatory dispersion, and electronic or vibrational circular dichroism is well established, sometimes in combination with ab initio calculations. Further methods are conceivable but impractical momentarily. Yet, there is currently not a simple and universally applicable approach to determine the absolute configuration of molecules with few stereogenic centers. Two recent papers published in 2007 and 2011 have therefore created a lot of excitement in the chemistry and NMR spectroscopy communities. Their titles are: “Stereochemical Identification of (R)and (S)-Ibuprofen Using Residual Dipolar Couplings, NMR, and Modeling”, henceforth called “article 1”, and more recently: “Spin-Selective Correlation Experiment for Measurement of Long-Range J Couplings and for Assignment of (R/S) Enantiomers from the Residual Dipolar Couplings and DFT”, henceforth called “article 2”. Both articles describe the assignment of the absolute configuration of the chiral molecules, ibuprofen 1 (article 1) and 4-methyl-1,3-dioxolan-2-one 2 (article 2), using NMR spectroscopy in chiral nonracemic alignment media (Figure 1). Under chiral nonracemic conditions, the authors measured residual dipolar couplings (RDCs), a NMR parameter only visible in oriented samples, such as in liquid crystals, but not in isotropic solvents. The interaction of the enantiomers with the chiral nonracemic alignment medium gives rise to diastereomorphic associates for which reason the authors indeed found different sets of anisotropic parameters for each enantiomer, in total

Penilumamide, a novel lumazine peptide isolated from the marine-derived fungus, Penicillium sp. CNL-338

A novel lumazine peptide, penilumamide (1), was isolated from the fermentation broth of a marine-derived fungal strain, identified as Penicillium sp. (strain CNL-338) and the structure of the new metabolite was determined by analysis of ESI-TOF MS data combined with 1D and 2D NMR experiments.

NMR studies of phakellins and isophakellins.

Phakellins 3 and 4 and isophakellins 5 and 6 are tetracyclic pyrrole-imidazole alkaloids. Their structure elucidation is herein reviewed using state-of-the-art NMR methods. Special emphasis has been given to the application of ADEQUATE NMR pulse sequences. Furthermore, (15)N NMR chemical shifts, proton T1 relaxation times, and (1)J(CH) coupling constants were determined.

Ageladine A, a pyrrole-imidazole alkaloid from marine sponges, is a pH sensitive membrane permeable dye

The alkaloid ageladine A, a pyrrole-imidazole alkaloid isolated from marine Agelas sponges shows fluorescence in the blue-green range during excitation with UV light with the highest absorption at 370 nm. The fluorescence of this alkaloid is pH dependent. Highest fluorescence is observed at pH 4, lowest at pH 9 with the largest fluorescence changes between pH 6 and 7. Ageladine A is brominated, which facilitates membrane permeation and therefore allows for easy staining of living cells and even whole transparent animal staining. To calculate the exact pH in solutions, cells, and tissues, the actual concentration of the alkaloid has to be known. A ratiometric measurement at the commonly used excitation wavelengths at 340/380 nm allows pH measurements in living tissues with an attenuated influence of the ageladine A concentration on calculated values. The fluorescence changes report small intracellular pH changes induced by extracellular acidification and alkalization as well as intracellular alkalization induced by ammonium chloride.

Validation of structural proposals by substructure analysis and 13C NMR chemical shift prediction.

The 2D NMR-guided computer program COCON can be extremely valuable for the constitutional analysis of unknown compounds, if its results are evaluated by neural network-assisted 13C NMR chemical shift and substructure analyses. As instructive examples, data sets of four differently complex marine natural products were thoroughly investigated. As a significant step towards a true automated structure elucidation, it is shown that the primary COCON output can be safely diminished to less than 1% of its original size without losing the correct structural proposal.

Stylissamides E and F, Cyclic Heptapeptides from the Caribbean Sponge Stylissa caribica

In addition to the four known stylissamides, A (1), B (2), C, and D, two new cyclic heptapeptides, stylissamides E (3) and F (4), were isolated from the Caribbean sponge Stylissa caribica. The structures of 3 and 4 were elucidated from a combination of mass spectrometric and NMR spectroscopic data as cyclo-(cis-Pro(1)-Tyr(2)-trans-Pro(3)-Ala(4)-Ile(5)-Gln(6)-Ile(7)) for stylissamide E (3) and cyclo-(trans-Pro(1)-cis-Pro(2)-Phe(3)-Asp(4)-trans-Pro(5)-Arg(6)-Phe(7)) for stylissamide F (4).