Total Synthesis of the Anticancer Agent Haterumalide NA

描述（由申请人提供）：Haterumalide NA是最近从冲绳海绵Ircinia sp.中分离的大环内酯。发现其对P388白血病细胞表现出强烈的细胞毒性。本研究的目标是开发一种简洁、模块化、高效的对映选择性合成haterumalide NA的方法。为了实现这种合成，将开发新的方法用于立体选择性地形成三取代和四取代烯烃。这种新的方法将是一个两步序列，由炔丙醇合成取代的环烯基硅氧烷，然后金属介导的偶联与有机卤化物。该合成的开发将产生足够量的haterumalide NA用于进一步探索其生物活性。此外，提出的新方法和灵活的合成方案将允许直接获得haterumalide NA的类似物，这可能导致结构活性谱和新的抗癌药物的发现。

DESCRIPTION (provided by applicant): Haterumalide NA is a recently isolated macrolide from an Okinawan sponge Ircinia sp. It was found to exhibit strong cytotoxicity against P388 leukemia cells. The goal of this research project is to develop a concise, modular, and efficient enantioselective synthesis of haterumalide NA. To achieve this synthesis, new methodology will be developed for the stereosetective formation of tri- and tetrasubstituted olefins. This novel process will be a two-step sequence consisting of the synthesis of substituted cycloalkenylsiloxanes from propargyl alcohols followed by metal-mediated coupling with an organohalide. The development of this synthesis will create sufficient quantities of haterumalide NA for further exploration of its biological activity. Furthermore, the novel methodology proposed and the flexible synthetic scheme will permit straightforward access to analogs of haterumalide NA that may lead to a structure activity profile and the discovery of new anticancer drugs.