Total synthesis of the cylindrospermopsin alkaloids

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The proposed research is concerned with the synthesis of a family of naturally occurring marine natural products namely cylindrospermopsin , 7-epi-cylindrospermopsin and 7-deoxy-cylindrospermopsin, which are found in several species of blue-green algae. Cylindrospermopsin was originally isolated from a bloom of Cylindrospermopsis raciborskii after an outbreak of a mystery disease on Palm Island in Queensland, Australia. Its unique structure, consisting of uracil ring and a zwitterionic guanidinium/sulfate combination imparts very high water solubility and it is this property which poses a potential threat to water supplies. The biological activity of cylindrospermopsin centers on its toxicity to liver and kidney tissue, its ability to inhibit protein synthesis as well as being able to covalently modify both DNA and RNA. Synthetic efforts toward the natural product have been reported by other groups using linear and convergent strategies, however overall yields for these are generally low (0.2-2% yield) and require a considerable number of operations (19-36 steps)The goal of this project is to develop our already proven approach to a model of the metabolites into a total synthesis of the three molecules via a synthesis mimicking that found in nature (biomimetic). This methodology is convergent in nature and will be shorter than any other reported previously, thus being flexible enough to enable the rapid preparation of the three metabolites. In addition to this, it is hoped that a flexible and rapid method for the preparation of synthetic analogues will emerge from this methodology, enabling the study of the biological mode of action of these compounds. This in turn will lead to an understanding of the structural requirements for biological action and the potential for preparing less toxic analogues, which retain the required activity.