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Total Synthesis of Isotopically-Labeled Cylindrospermopsin Cyanotoxins

  • Author(s): Chen, Joanna
  • Advisor(s): Zakarian, Armen
  • et al.
Abstract

Cyanobacteria, also known as blue-green algae, are prokaryotic organisms that inhabit freshwater and brackish lakes. They produce toxic secondary metabolites known as cyanotoxins, the increased occurrence of which is believed to be a result of eutrophication. Among them, cylindrospermopsin and its derivatives have become the subject of intense interest from food safety agencies and the scientific community due to their rapidly expanding global presence. Toxins produced by cyanobacterial blooms pose a threat to the aquatic ecosystem and its biodiversity. For these reasons, various analytical methods have been developed for the quantitative monitoring of cylindrospermopsin levels in fresh water and fish. However, in all cases, sufficient accuracy, reproducibility, and standard curve linearity have only been demonstrated for narrow concentration ranges or for relatively high limits of quantification. Isotopically-labeled compounds serve as primary analytical standards in isotope-dilution mass spectrometry (IDSM) - an analytical method of highest metrological quality. A common limiting factor in application of these compounds is access to pure samples with isotope placement at non-exchangeable positions to avoid a loss of label. Here, we demonstrate this concept by a concise and scalable total synthesis of the complex cyanobacterial alkaloids cylindrospermopsin, 7-epi-cylindrospermopsin, and 7-deoxycylindrospermopsin from [15N]-ammonium chloride, in which all nitrogen atoms are in the form of 15N isotope with greater than 99.5% isotope incorporation.

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