Total synthesis of the cylindrospermopsin alkaloids

本研究旨在合成一类天然存在的海洋天然产物，即柱体精子素、7-外柱体精子素和7-脱氧柱体精子素，它们存在于几种蓝绿藻中。圆筒精子素最初是在澳大利亚昆士兰州棕榈岛爆发一种神秘疾病后从raciborskii圆筒精子花中分离出来的。其独特的结构，由尿嘧啶环和两性离子胍/硫酸盐组合组成，赋予了非常高的水溶性，这一性质对供水构成了潜在的威胁。柱精子素的生物活性主要集中在其对肝脏和肾脏组织的毒性、抑制蛋白质合成的能力以及能够共价修饰DNA和RNA。其他研究小组已经报道了使用线性和收敛策略合成天然产物的努力，但是这些方法的总产率通常很低（0.2-2%产率），并且需要相当多的操作（19-36步）。该项目的目标是将我们已经证明的代谢物模型方法发展为通过合成模拟自然界中发现的三种分子的总合成（仿生）。这种方法本质上是收敛的，比以前报道的任何其他方法都要短，因此足够灵活，可以快速制备三种代谢物。除此之外，希望从这种方法中出现一种灵活而快速的制备合成类似物的方法，从而能够研究这些化合物的生物作用方式。反过来，这将导致对生物作用的结构要求的理解和制备毒性较小的类似物的潜力，这些类似物保留了所需的活性。

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.