Alkaloid Synthesis via Asymmetric C-CN Activation

在过去的几年里，我们的实验室发现了药用生物碱中的重要结构基序， 吲哚和哌啶类化合物可以利用极不寻常的反应性非常容易地合成。这个 激活无张力的碳-碳西格马键(C-C键)，长久以来被认为是惰性的，除非在 高温和/或高压，可以快速构建具有综合挑战性的全碳季铵盐 中心的这些框架在温和的条件下由简单的材料制成。此应用程序的目标是 探索可广泛应用于生物活性合成的C-CN活化条件 生物碱。在C-CN活化能够广泛应用之前，还有许多问题需要解决。人们对此知之甚少 从机理观点来看，芳基或季碳取代的烯烃可能发生的反应 以合成有用的方式进行迁移插入，或者其他类似的有机腈是否会经历 C-CN激活。我们将验证我们的中心假设，即C-CN激活将容忍其他 功能，同时从简单的构建块提供密集功能化的生物碱核心。在AIM 1，我们描述了我们将如何构建一个机械模型，该模型将允许在我们解决问题时进行理性优化 挑战C-CN活化反应。在目标2中，我们描述了几个稀有的， 生物活性生物碱将使我们能够推进氰胺化方法，同时提供 合成社区，举例说明如何使用C-CN激活，并提供探索材料 生物医学问题。在目标3中，我们详细介绍了在这两个框架之外的其他生物活性框架 主要基序可能是通过氰甲酸酯的受控激活来构建的。我们还建议 易于制备的1，3-二烯的双氰胺化和顺序氰胺化/氰酯化反应 是含邻位全碳分子的不对称合成的非常有效的方法 第四纪立体中心。完成我们的目标将提供四类自然稀缺， 在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 我们对氰胺化的理解。机械主义模式不仅将创新 探索潜在相关均衡并捕获假定中间体的实验，但也将指导 我们对发展新化学的思考。氰基酯化和C-CN串联活化的研究 将扩大可通过C-CN激活访问的目标的曲目。除了C-CN激活外，还有几个 在目标化合物的合成过程中，还提出了其他未开发的合成方法。 生物碱。然而，我们希望，对C-C激活的更好理解和在 复杂生物碱的合成将为合成界提供高效可靠的 生物碱的制备方法。

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.