Method and Strategy Development for the Synthesis of Physiologically Important Natural Products

项目总结/摘要 在过去的三十年里，FDA批准的所有新药中有28%是天然产品，或来自 天然产品，而27%是完全合成的。因此，寻求新的合成方法 获取复杂分子的方法和策略不仅是一个有价值的追求，而且是生物医学的重要组成部分。 研究和药物开发，也有助于合成策略和方法的新要素， 合成化学词典。本申请中提出的研究描述了六种不同的 天然产物分为三大类（二酮哌嗪、生物碱和萜类化合物）。这些 化合物具有一系列生物活性，包括：杀利什曼原虫、抑制NO产生、抗- 抗炎、抗昆虫、抗真菌、抗病毒、对多种癌细胞系的细胞毒性，以及抗 增殖活性对于二酮哌嗪和生物碱项目，我们的目标是开发扩环 该技术将能够有效地获得嵌入的异羟肟酸中间体。更具体地说：目标 1，需要合成N-羟基-2，5-二酮哌嗪衍生物（NHDKP）天然产物haenamindole， raistrickindole A和14-hydroxyterezine D。这一目标还包括开发一种区域选择性环 扩大特特拉姆酸，这将使得能够直接进入高度官能化的NHDKP。目的2 本发明的重点是叶下珠定（phyllantidine）和Flueggeacosine B的合成， 含有N-O键。在Aim-1中开发的优化扩环化学的范围将在 这旨在提供两种合成中的关键中间体。目标3偏离了目标1和目标2， 通过其在复杂合成环境中的应用，进一步发展酮亚胺鎓化学。在 目前，实现每一个目标的工作都处于不同的发展阶段，这种发展将继续下去， 在补助期内不断发展。与我们所有的合成努力一样，中间体的收集 将提交给NIH进行SAR研究，一旦材料在手，将寻求进一步的合作。 除了后者对生物医学科学的直接贡献外，我们的合成努力（以及 将继续）教育研究生和博士后研究人员在规划和执行 复杂分子合成

PROJECT SUMMARY/ABSTRACT Over the past three decades, 28% of all new FDA approved drugs have been natural products, or derived from natural products, while 27% have been entirely synthetic in origin. Thus, the pursuit of new synthetic methods and strategies to access complex molecules is not only a worthy pursuit, but a critical component of biomedical research and drug development that also contributes novel elements of synthetic strategy and methods to the lexicon of synthetic chemistry. The studies proposed within this application describe the pursuit of six different natural products that fall into three general classes (diketopiperazine, alkaloid, and terpenoid). These compounds possess a range of biological activities including: leishmanicidal, NO production inhibition, anti- inflamatory, antiinsectan, antifungal, antiviral, cytotoxicity against a variety of cancer cell lines, as well as anti- proliferative activity. For the diketopiperazine and alkaloid projects we are aiming to develop ring expansion technology that will enable efficient access to imbedded hydroxamic acid intermediates. More specifically: Aim 1, entails syntheses of the N-hydroxy-2,5-diketopiperazine-derived (NHDKP) natural products haenamindole, raistrickindole A, and 14-hydroxyterezine D. This aim also includes the development of a regioselective ring expansion of tetramic acids that will enable the direct acces of to highly functionalized NHDKP’s. Aim 2 focuses on syntheses of phyllantidine and flueggeacosine B, two members of a securinega alkaloid subset that contain N-O bonds. The scope of the optimized ring-expansion chemistry developed in Aim-1 will be expand in this aim to deliver key intermediates in both syntheses. Aim 3 is a departure from aims 1 and 2 and turns toward further development of keteniminium chemistry by its application in a complex synthetic setting. At present, work toward each aim is at a different stage of development and this development will continue to evolve over the course of the grant period. As with all of our synthetic endeavors, collections of intermediates will be submitted to the NIH for SAR studies and once materials are in hand further collaborations are sought. In addition to direct contributions to biomedical science afforded by the latter, our synthetic efforts have (and will continue to) educate graduate students and postdoctoral researchers in the planning and execution of complex molecule synthesis.