STEREOCONTROLLED SYNTHESIS OF BIOACTIVE ALKALOIDS

该提案阐述了制定以下方面的总体战略的计划： 立体选择性合成各种生物碱，包括来自 马钱子属、Aspidosperma、Corynantheine、Pleiocarpamine、Akuammiline和 Sarpagine家族 许多结构复杂的天然产物 表现出强大的生物活性，而许多其他的性质， 还没有被调查。 将要开发的合成路线 在这些调查中，预计将导致简明（许多只有5-8 步骤）和许多天然产物的高产合成， 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 第一部分介绍了马钱子及相关化合物的合成新策略 生物碱 这些策略将被扩展到Aspidosperma家族， 天然产品。 特别是，PI将开发有效的合成 vindorosine和vindoline，后者代表 强效且临床上重要的抗癌剂的下半部分 长春碱 第三部分介绍了一些新技术的应用 化学发展到广泛的天然产品， 生物遗传学上来自于Geissoproteinine。 这些合成物被设计成 以最少的步骤完成目标，探索和开发 化学将是一般使用的有机和药物化学家，和 以引入可以适应不对称合成的化学。 的 综合报告将提供机会，探讨 复杂生物碱合成中的Heck型反应。 总的来说，这些调查预计不仅会产生高效率的 合成了多种吲哚类生物碱，也为开发 的方法，特别是钯催化工艺，这应该 证明对其他合成工作有用。

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.