The total synthesis of the potent new antibiotic disciformycin B (2) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH4)2‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.
New biomarkers indicating the abuse of drugs and alcohol are still of major interest for clinical and forensic sciences. The endogenous neurotransmitter and approved drug, gamma-hydroxybutyric acid (GHB), is often illegally used for drug-facilitated crimes by spiking GHB into alcoholic beverages. Analytical detection windows of only 6 h in blood and 12 h in urine are often too short to provide reliable proof of GHB ingestion. Therefore, new biomarkers are needed to prove exogenous GHB administration. Previously, amino acid GHB conjugates were discovered in an untargeted metabolomics screening and fatty acid esters with GHB were recently discussed as promising biomarkers to enlarge the analytical detection time windows. However, the development of analytical methods is still slowed down since reference compounds for targeted screenings are still missing. In this paper, we describe simple procedures for the rapid synthesis and purification of amino acid GHB conjugates as well as fatty acid esters, which can be adopted in analytical and clinical/forensic laboratories. Structural characterization data, together with IR, 1 H-nuclear magnetic resonance (NMR), 13 C-NMR, high-resolution mass spectra (MS), and MS/MS spectra in positive and negative ionization mode are reported for all obtained GHB conjugates and GHB conjugate precursors.
Wir beschreiben die Totalsynthese des potenten neuen Antibiotikums Disciformycin B (2), das eine ausgeprägte Aktivität gegenüber Methicillin‐ und Vancomycin‐resistenten Stämmen von Staphylococcus aureus (MRSA/VRSA) aufweist. Der zentrale Syntheseschritt besteht in der Makrozyklisierung eines Tetraens zum 12‐gliedrigen Makrolactonring des Naturstoffs durch eine ringschließende Olefinmetathese. Zwar wurde neben dem Makrozyklus über einen alternativen Ringschlussmetatheseweg auch ein Cyclopentenderivat gebildet, es konnten jedoch Bedingungen gefunden werden, die das gewünschte Makrolacton als Hauptprodukt lieferten. Die Schlüsselschritte bei der Herstellung des Metathesesubstrats waren eine hocheffiziente Evans‐syn‐Aldolreaktion, die asymmetrische Brown‐Allylierung des Angelikaaldehyds, sowie die stereoselektive 1,2‐Reduktion eines Enons mittels Zn(BH4)2. Die Synthese wurde nach der Makrozyklisierung über eine dehydratative Glykosylierung zur Einführung des d‐Arabinofuranosylrests und schließlich eine chemoselektive Oxidation eines allylischen Alkohols zu Ende geführt.
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