Total synthesis of the cylindrospermopsin alkaloids

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.

Research output from this work will be of considerable interest to synthetic chemists in academia and industry alike and will be disseminated via the international literature and at national and international conferences. Whilst this work is focused on the total synthesis of the natural products, it does have the potential to develop, as the preparation and testing of analogues of the natural materials may open other avenues for exploitation with industrial or other academic partners. The direct beneficiaries from the work will be the researcher and my research group, as the presence of a highly motivated synthetic chemist will add considerable expertise and leadership in the laboratory environment, presenting an essential overall learning experience for the scientist once in place. The work will enable the RA to develop the required leadership skills to flourish and progress into an academic or industrial career in chemistry. From a wider perspective, the interest in algal blooms and public health issues continues to grow, and the particular problems associated with cylindrospermopsin producing species are becoming more widespread. Projects addressing this and other concerns will be of interest to a wider public audience and a more comprehensive study of the areas involved offers the potential for wealth creation and improved public health.