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Alkaloid Synthesis via Asymmetric C-CN Activation

通过不对称 C-CN 激活合成生物碱

基本信息

批准号：
8877566
负责人：
CHRISTOPHER J DOUGLAS
金额：
$ 25.38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-12-31
项目状态：
已结题

项目摘要

Within the last few years, our laboratory discovered that important structural motifs in medicinal alkaloids, indoles and piperidines, could be synthesized with extraordinary ease using highly unusual reactivity. The activation of an unstrained carbon-carbon sigma bond (C-C bond), long thought to be 'inert' except under high temperature and/or pressure, can quickly build the synthetically challenging all-carbon quaternary center of these frameworks in mild conditions from simple materials. The objective of this application is to discover C-CN activation conditions that are broadly applicable to the synthesis of biologically active alkaloids. Many questions remain before C-CN activation can widely used. Little is known about the reaction from a mechanistic standpoint, how aryl- or quaternary carbon-substituted alkenes might undergo migratory insertion in a synthetically useful manner, or whether other similar organonitriles will undergo C-CN activation. We will test our central hypothesis that C-CN activation will be tolerant of other functionalities while providing densely functionalized alkaloid cores from simple building blocks. In Aim 1, we describe how we will construct a mechanistic model that will allow rational optimization as we tackle challenging C-CN activation reactions. In Aim 2, we describe how the synthesis of several rare, biologically active alkaloids will allow us to advance cyanoamidation methodology while providing the synthetic community with examples how C-CN activation might be used, and provide materials to probe biomedical questions. In Aim 3, we detail how additional biologically active frameworks outside the two main motifs might be constructed by the controlled activation of cyanoformate esters. We also propose that dual cyanoamidation and sequential cyanoamidation/cyanoesterification of easily prepared 1,3-dienes will be exceptionally powerful approach to the asymmetric synthesis of molecules containing vicinal all-carbon quaternary stereocenters. Completion of our objectives will provide four classes of naturally scarce, structurally challenging, biological active materials for further therapeutic discovery, but will also deepen our understanding of cyanoamidation. A mechanistic model will not only incorporate innovative experiments that probe potentially relevant equilibria and trap putative intermediates, but will also guide our thinking in developing new chemistry. Our studies on cyanoesterification and tandem C-CN activation will expand the repertoire of targets accessible by C-CN activation. In addition to C-CN activation, several additional underdeveloped methods in synthesis are proposed during the syntheses of our targeted alkaloids. We hope, however, that the better understanding of C-C activation and demonstrated use in the synthesis of complex alkaloids will provide the synthetic community with a highly efficient and reliable method for the preparation of alkaloids.

在过去的几年里，我们的实验室发现，药用生物碱中的重要结构基序，吲哚和哌啶，可以非常容易地使用非常不寻常的反应性合成。的非应变碳-碳σ键（C-C键）的活化，长期以来被认为是“惰性”的，除非在高温和/或高压，可以快速构建具有合成挑战性的全碳季铵盐，这些框架的中心在温和的条件下从简单的材料。本申请的目的是发现广泛适用于生物活性化合物合成的C-CN活化条件，生物碱C-CN活化法的广泛应用还存在许多问题。很少有人知道的从机理的角度来看，芳基或季碳取代的烯烃如何进行以合成有用的方式迁移插入，或者其他类似的有机腈是否会经历 C-CN活化。我们将测试我们的中心假设，即C-CN激活将容忍其他同时从简单的结构单元提供密集官能化的生物碱核心。在Aim中 1，我们描述了我们将如何构建一个机械模型，将允许合理的优化，因为我们解决挑战C-CN活化反应。在目标2中，我们描述了如何合成几种罕见的，生物活性生物碱将使我们能够推进氰基酰胺化方法，同时提供合成社区的例子，如何C-CN活化可能使用，并提供材料，以探讨生物医学问题。在目标3中，我们详细介绍了两个框架之外的其他生物活性框架，可以通过氰基甲酸酯的受控活化来构建主要基序。我们亦建议容易制备的1，3-二烯的双氰基酰胺化和顺序氰基酰胺化/氰基酯化将是一种非常有效的不对称合成含邻位全碳分子的方法四元立构中心完成我们的目标将提供四类自然稀缺，结构上具有挑战性的生物活性材料，用于进一步的治疗发现，但也将深化我们对氰酰胺化的理解一个机械化的模型不仅会包含创新实验，探测潜在的相关平衡和陷阱假定的中间体，但也将指导我们在开发新化学方面的想法。我们对氰酯化和串联C-CN活化的研究将扩大C-CN激活可达到的靶标的库。除了C-CN活化之外，在我们的目标合成过程中，提出了其他不发达的合成方法。生物碱然而，我们希望，更好地理解C-C激活和证明在复杂生物碱的合成将为合成界提供一种高效可靠的生物碱的制备方法。