Total synthesis of the cylindrospermopsin alkaloids

这项拟议的研究涉及合成一类天然存在的海洋天然产物，即圆柱形精蛋白、7-表圆柱型精蛋白和7-脱氧圆柱型精蛋白，它们存在于几种蓝藻中。Cylindropermopsin最初是从澳大利亚昆士兰州棕榈岛爆发一种神秘疾病后的一次开花中分离出来的。其独特的结构，包括尿嘧啶环和两性离子胍/硫酸盐的组合赋予了非常高的水溶解度，正是这种性质对水供应构成了潜在的威胁。柱状精浆蛋白的生物活性主要集中在其对肝和肾组织的毒性、抑制蛋白质合成的能力以及能够对DNA和RNA进行共价修饰。针对天然产物的合成努力已经被其他小组报告使用线性和收敛策略，然而这些的总体产率通常很低(0.2-2%的产率)并且需要相当数量的操作(19-36步)。这个项目的目标是开发我们已经证明的代谢产物模型的方法，通过模仿在自然界中发现的合成(仿生)将三个分子完全合成。这种方法本质上是收敛的，而且比以前报道的任何其他方法都要短，因此足够灵活，能够快速制备这三种代谢物。此外，人们希望从这一方法学中产生一种灵活、快速地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模式。这反过来将导致对生物作用的结构要求的理解，以及制备毒性较低的类似物的可能性，这些类似物保持所需的活性。

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.