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

项目摘要/摘要 在过去的三十年里，FDA批准的所有新药中有28%是天然产品或从 天然产品，而27%的产品是完全合成的。因此，对新的合成方法的追求 而获取复杂分子的策略不仅是一个有价值的追求，而且是生物医学的关键组成部分 研究和药物开发，也对合成战略和方法的新元素做出贡献 合成化学词典。本申请中提出的研究描述了六种不同的追求 分为三大类的天然产物(二酮基哌嗪、生物碱和萜类)。这些 化合物具有一系列生物活性，包括：杀利什曼，无生产抑制，抗 具有消炎、抗虫、抗真菌、抗病毒、对多种癌细胞的细胞毒性以及抗肿瘤作用。 增殖活性。对于二酮基哌嗪和生物碱项目，我们的目标是开发扩环 能够有效地获取嵌入的异羟肟酸中间体的技术。更具体地说：目标 1，合成了N-羟基-2，5-二酮基哌嗪衍生(NHDKP)天然产物苯氨基吲哚， 该目标还包括开发区域选择性环。 四酸的扩展，使其能够直接进入高度功能化的NHDKP。目标2 重点研究了茶碱和氟乙酸乙酯B的合成，这两种化合物是一种新生生物碱子集的成员 含有N-O键。在AIM-1中开发的优化扩环化学的范围将扩大到 这一目标是为了在这两种合成中提供关键的中间体。目标3与目标1和目标2背道而驰 通过在复杂的合成环境中的应用，促进酮亚胺化学的进一步发展。在… 目前，实现每个目标的工作正处于不同的发展阶段，这一发展将继续 在授权期内不断演变。就像我们所有的合成努力一样，中间体的集合 将提交给美国国立卫生研究院进行搜救研究，一旦材料到位，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(和 将继续)教育研究生和博士后研究人员规划和执行 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.