Spirodionic acid, a novel metabolite from Streptomyces sp., part 1: structure elucidation and Diels-Alder-type biosynthesis

Spirodionic acid (1), a novel microbial metabolite with a spiro[4.5]decene skeleton, the 6-ethyl-2H-pyrone 5, dihydrosarkomycin (6), and other metabolites were isolated from the strain Streptomyces sp. Tü 6077. Structural elucidation was accomplished by NMR spectroscopic and mass-spectrometric studies, and the biosyntheses of compounds 1, 5, and 6 were investigated by feeding experiments with (13)C-labeled precursors. All results indicate a biogenetic sequence with metabolite 5 and sarkomycin (7) as precursors in the formation of spirocyclus 1 through an intermolecular Diels-Alder-type reaction.     

Determination of the absolute configuration of the diterpene tonantzitlolone B

In this work synthetic and semi-synthetic studies toward the antitumor active natural product tonantzitlolone B are described, starting with an advanced intermediate obtained from the total synthesis of tonantzitlolone and a natural sample of this compound, respectively. The unknown absolute configuration of the stereogenic center in the side chain was elucidated to be (R).     

Structure elucidation of highly condensed stilbenoids: chiroptical properties and absolute configuration

We investigated the potential roles of the skeleton-based comparative study of electronic circular dichroism (ECD) spectra for an application of absolute configuration (AC) determination of oligostilbenoids (OS). This approach was ultimately achieved followed by the isolation and elucidation of relative configuration (RC) of upunaphenol Q (1) (new compound) and vateriaphenol A (2), namely two octamers are dimeric tetramers of resveratrol (Res). The common building blocks (BB) provide further insight into how smaller OS are apparently conserved during downstream metabolites, as well as providing additional impetus to resolve AC of highly condensed stilbenoids (HCS). They also underline the importance of studies on determination of AC of common BB in the chemical library and to provide chiroptical properties.     

Recent advances in the structure elucidation of small organic molecules by the LSD software

The LSD software proposes the structures of small organic molecules that fit with structural constraints from 1D and 2D NMR spectroscopy. Its initial design introduced limits that needed to be eliminated to extend its scope and help its users choose the most likely structure among those proposed. The LSD software code has been improved, so that it recognizes a wider set of atom types to build molecules. More flexibility has been given in the interpretation of 2D NMR data, including the automatic detection of very long‐range correlations. A program named pyLSD was written to deal with problems in which atom types are ambiguously defined. It also provides a ¹³C NMR chemical shift‐based solution ranking algorithm. PyLSD was able to propose the correct structure of hexacyclinol, a natural product whose structure determination has been highly controversal. The solution was ranked first within a list of ten structures that were produced by pyLSD from the literature NMR data. The structure of an aporphin natural product was determined by pyLSD, taking advantage of the possibility of handling electrically charged atoms. The structure generation of the insect antifeedant azadirachtin by LSD was reinvestigated by pyLSD, considering that three ¹³C resonances did not lead to univocal hybridization states. Copyright © 2013 John Wiley & Sons, Ltd.     

Absolute configuration of new cytotoxic and other bioactive trichothecene macrolides

Three new cytotoxic 10,13-cyclotrichothecane-derived macrolides, myrothecines A-C (1-3), were characterized from the extracts of two Myrothecium roridum strains, IFB-E009 and IFB-E012, isolated as endophytic fungi found on the traditional Chinese medicinal plants Trachelospermum jasminoides and Artemisia annua, respectively. The absolute configuration of myrothecines A-C was elucidated by a combination of spectral techniques (UV, IR, MS, circular dichroism (CD), (1)H and (13)C NMR, DEPT, (1)H-(1)H COSY, NOESY, HMQC, and HMBC spectrascopic analyses), Mosher's ester analysis, and single-crystal X-ray diffraction. The absolute configuration of the reported bioactive analogue, mytoxin B was established by correlating its spectral data with that of known absolute configurational structures. Furthermore, the significance in endophytism (or symbiosis) and biocatabolism, highlighted by production of those macrolides by the endophytic strains, is discussed in brief.     

The absolute configuration of the pyrrolosesquiterpenoid glaciapyrrol A

The total syntheses of the structurally unique and moderately cytotoxic pyrrolosesquiterpenoid glaciapyrrol A that has been isolated from a marine streptomycete by Macherla et al. and of seven of its stereoisomers have been performed from geraniol or nerol, respectively, using a known diastereoselective Ru-catalysed approach for the synthesis of tetrahydrofurans previously reported by Stark and co-workers. Comparison of (1)H and (13)C NMR data unambiguously clarified the relative configuration of natural glaciapyrrol A that was previously only partly solved from the available NMR data. An enantioselective synthesis was carried out resulting in the unnatural enantiomer (11S,12R,15R)-(-)-glaciapyrrol A. These data establish the absolute configuration of the natural product as (11R,12S,15S)-(+)-glaciapyrrol A.     

Enhancing computer-assisted structure elucidation with DFT analysis of J-couplings

Computer-assisted structure elucidation (CASE) is the class of expert systems that derives molecular structures primarily from one-dimensional and two-dimensional nuclear magnetic resonance data. Contemporary CASE systems, including Advanced Chemistry Development/Structure Elucidator (ACD/SE), consider cross-peaks in heteronuclear multiple bond coherence (HMBC) and correlation spectroscopy (COSY) spectra as two- or three-bond correlations by default. However, four and more bond correlations (nonstandard correlations [NSCs]) could be present in these spectra too. The indiscriminate addition of NSCs to the CASE computations is prohibitively expensive. To address this problem, the ACD/SE program performs a logical analysis of observed correlations and determines the minimum number of NSCs. Guided by this information, a more efficient fuzzy structure generation (FSG) algorithm is subsequently applied. Until now, the FSG algorithm was utilized without any verification of the reliability of found NSCs. Here, we report a verification method for NSCs based on the relationship between NSCs and J-couplings computed with high accuracy density functional theory (DFT) methods. We used the example of strychnine to show that 41 (32%) of 8-Hz HMBC cross-peaks were NSCs and were consistent with ^4–6J_CH couplings greater than 0.3 Hz. This cutoff value was largely confirmed by the analysis of NSCs in 11 real-world natural products elucidated by ACD/SE. Additionally, utilizing the example of the CASE study of cleospinol A, we showed that the DFT-computed J-couplings of NSCs can distinctively differentiate the correct structure among six proposed isomers. The proposed approach of NSC verification should further improve the robustness of CASE analysis and can help reveal potential problems with reported experimental data.     

Structural Revision and Elucidation of the Biosynthesis of Hypodoratoxide by 13C,13C COSY NMR Spectroscopy

Feeding of (2,3,4,5,6‐¹³C₅)mevalonolactone to the fungus Hypomyces odoratus resulted in a completely labeled sesquiterpene ether. The connectivity of the carbon atoms was easily deduced from a ¹³C,¹³C COSY spectrum, revealing a structure that was different from the previously reported structure of hypodoratoxide, even though the reported ¹³C NMR data matched. A structural revision of hypodoratoxide is thus presented. Its absolute configuration was tentatively assigned from its co‐metabolite cis‐dihydroagarofuran. Its biosynthesis was investigated by feeding of (3‐¹³C)‐ and (4,6‐¹³C₂)mevalonolactone, which gave insights into the complex rearrangement of the carbon skeleton during terpene cyclization by analysis of the ¹³C,¹³C couplings.     

The structure of hormaomycin and one of its all-peptide aza-analogues in solution: syntheses and biological activities of new hormaomycin analogues

Four new aza-analogues of hormaomycin 1, a secondary metabolite with interesting biological activities produced by Streptomyces griseoflavus, were synthesized and subjected to preliminary tests of their antibiotic activity to provide new insights into the structure-activity relationship studies of this class of compounds. The solution structures of hormaomycin 1 and its aza-analogue 2 a were determined by NMR spectroscopy. The data exhibited a reasonably rigid conformation for both molecules, stabilized by stacking interactions between the aromatic moieties attached to the ring and the side chain. According to NMR-spectral data the aza-analogue epi-2 a has a rather different conformation and indeed shows no antibacterial activity whatsoever.