STEREOCONTROLLED SYNTHESIS OF BIOACTIVE ALKALOIDS

该提案描述了制定以下方面的一般战略的计划 一系列生物碱的立体选择性合成，包括那些来自 马钱子属、无精子科、科林南辛科、苹果科、阿夸米林科和 萨帕吉家族。许多这些结构复杂的天然产品 显示出强大的生物活性，而许多其他的特性 还没有被调查。将开发的合成路线 在这些调查期间，预计将得出简明扼要的结果(许多只有5-8 步骤)和许多天然产物的高产率合成，使得相当大的 可以准备并提交最终目标的数量以供评估 它们的生物活性。 研究计划分为三大部分。第一 介绍了马钱子及其相关化合物的合成新策略。 生物碱。这些策略将扩展到Aspidosperma家族 天然产品。特别是，PI是为了开发有效的合成方法 长春花碱、长春花碱和长春花碱，后者代表 有效的和临床上重要的抗癌药的下部 长春花碱。第三部分介绍了一些新的应用 发展了一系列衍生天然产物的化学 生物遗传来自吉西他嗪。这些合成物的设计目的是 在最少的步骤中完成目标，以探索和开发 有机和药物化学家普遍使用的化学，以及 加入可以适应不对称合成的化学成分。这个 这些综合将提供机会来探索 复杂生物碱合成中的HECK型反应。 总体而言，这些调查预计不仅会导致高效 合成了广泛的吲哚生物碱，也向发展的方向发展 方法学，特别是钯催化的过程，应该 事实证明，这对其他合成努力是有用的。

The proposal describes plans for the development of general strategies for stereoselective synthesis of a wide range of alkaloids, including those from the Strychnos, Aspidosperma, Corynantheine, Pleiocarpamine, Akuammiline, and Sarpagine families. Many of these structurally complex natural products exhibit potent biological activities, while the properties of many others have not been investigated. The synthetic routes that will be developed during these investigations are expected to result in concise (many just 5-8 steps) and high yielding syntheses of many natural products, so that sizable quantities of the final targets can be prepared and submitted for evaluation of their biological activity. The research plan has been divided into three broad sections. The first part describes new strategies for the synthesis of Strychnos and related alkaloids. These strategies will be extend to the Aspidosperma family of natural products. In particular, the PI is to develop efficient syntheses of vincadifformine, vindorosine and vindoline, the latter representing the lower part of the potent and clinically important anticancer agent vinblastine. The third part describes the application of some of the newly developed chemistry to a wide range of natural products that are derived biogenetically from geissoschizine. The syntheses have been designed to complete the target in a minimum number of steps, to explore and develop chemistry that will be of general use to organic and medicinal chemists, and to incorporate chemistry that can be adapted to asymmetric synthesis. The syntheses will offer the opportunity to explore the scope and usefulness of Heck-type reactions in complex alkaloid synthesis. Overall, these investigations are expected to result in not only efficient syntheses of a wide range of indole alkaloids, but also to the development of methodology, particularly palladium catalyzed processes, that should prove useful to other synthetic endeavors.