Total Synthesis of Bioactive Complex Molecules

项目总结/摘要 该项目的目标是开发一个统一的，不对称的路线，以几个 紫堇碱生物碱阿库阿米林生物碱是吲哚生物碱家族， 由于其复杂的结构， 以及它们有趣的生物学活动。该家族的成员被证明 治疗癌症、疼痛、炎症、糖尿病、抑郁症和疱疹的潜力 单纯病毒 拟议的路线应允许进入各种核心结构， akuammilines，通过探索具有挑战性的合成转化。我 期望通过两个目标的完成来完成综合研究。首先我会 使用统一的路线获得（-）-picrinine和（-）-11-methoxyvincorine。的 其中的前一种应该可以使用具有挑战性的后期氧化来获得。 在（-）-picrinine的合成之后，我将探索和优化一个不寻常的结构， 从（-）-Picrinine重排以允许获得（-）-11-甲氧基长春新碱。与 为了灵活地获得这两种天然产品，我建议扩大范围 Fischer吲哚化方法，通过使用它来获得具有邻位的化合物 四元中心邻位四级立构中心的引入仍然是一个重要的问题。 化学合成中的巨大挑战。有了这种方法，我将使用它 完成了首次全合成（-）-苦味酸， 有望用于治疗2型糖尿病。最后，我建议用这个 获取（-）-（N）-阿库阿米林的方法，可以说是最复杂的阿库阿米林 迄今为止分离的生物碱。此外，在我的研究过程中产生的所有化合物 将提交研究进行生物测试。

Project Summary/Abstract The goal of this project is to develop a unified, asymmetric route to several akuammiline alkaloids. The akuammiline alkaloids are a family of indole alkaloids that have garnered attention from the synthetic community for both their complex structures and their intriguing biological activities. Members of the family have been shown to hold potential for treating cancer, pain, inflammation, diabetes, depression, and herpes simplex virus. The proposed routes should allow access to a variety of the core structures of the akuammilines, through the exploration of challenging synthetic transformations. I expect to accomplish the synthetic studies via the completion of two aims. First, I will use the unified route to access both (–)-picrinine and (–)-11-methoxyvincorine. The former of these should be accessible using a challenging, late stage oxidation. Following the synthesis of (–)-picrinine, I will explore and optimize an unusual structural rearrangement from (–)-picrinine to allow access to (–)-11-methoxyvincorine. With flexible access to those two natural products, I then propose to broaden the scope of the Fischer indolization methodology by using it to access compounds with vicinal quaternary centers. The introduction of vicinal quaternary stereocenters remains a formidable challenge in chemical synthesis. With that methodology in hand, I will use it to complete the first total synthesis of (–)-picraline, a compound which has derivatives that show promise for the treatment of type 2 diabetes. Finally, I propose to use this methodology to access (–)-(Ψ)-akuammigine, arguably the most complex akuammiline alkaloid isolated to date. Additionally, all compounds made during the course of my research will be submitted for biological testing.