Total Synthesis of the Anticancer Agent Haterumalide NA

描述(申请人提供)：Haterumalide NA是最近从冲绳海绵Ircinia sp.中分离出来的一种大环内酯。对P388白血病细胞有较强的细胞毒作用。本研究项目的目标是开发一种简明、模块化、高效的对映体选择性地合成虎杖内酯NA。为了实现这一合成，将开发新的方法学用于三取代和四取代烯烃的立体形成。这一新的过程将是一个两步序列，包括从丙叉醇合成取代的环烯基硅氧烷，然后与有机卤化物进行金属介导的偶联。该合成方法的开发将为进一步研究其生物活性创造足够数量的杂毛豆内酯NA。此外，所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图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.