Total Synthesis of Bioactive Complex Molecules

项目摘要/摘要 该项目的目标是开发一条统一的、不对称的路线， 阿夸米林生物碱。Akuammiline生物碱是一类吲哚生物碱 因其复杂的结构而引起了合成社区的注意 以及它们耐人寻味的生物活动。家庭成员已经被证明持有 治疗癌症、疼痛、炎症、糖尿病、抑郁症和疱疹的潜力 单纯疱疹病毒。 建议的路线应允许进入各种核心结构的 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 使用统一路线可同时获得(-)-苦皮碱和(-)-11-甲氧基长春花碱。这个 前者应该使用具有挑战性的后期氧化来接近。 在合成(-)-苦参碱之后，我将探索和优化一个不寻常的结构 从(-)-苦皮碱重排得到(-)-11-甲氧基长春花碱。使用 为了更灵活地获得这两种天然产品，我建议扩大 Fischer吲哚化法及其在近邻化合物中的应用 第四纪中心。引入邻近的四级立体中心仍然是一个 化学合成中的巨大挑战。有了这种方法，我将使用它 完成(-)-苦皮碱的首次全合成，这是一种具有衍生物的化合物 这显示了治疗2型糖尿病的希望。最后，我建议使用这个 获得(-)-(Ψ)-阿夸米林的方法学，可以说是最复杂的阿夸米林 到目前为止分离出来的生物碱。此外，在我的研究过程中生成的所有化合物 研究将提交进行生物测试。

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.