New Reactions for Targeting the Akuammiline Alkaloids

本项目由化学合成计划和促进竞争性研究的既定计划共同资助，以支持达特茅斯学院Jimmy Wu教授的研究。吴博士正在开发具有独特化学结构的有机化合物的新化学合成。这项研究导致了具有重要物理和/或生物特性的分子的发现。为了实现这些目标，吴教授发明了新的反应，可以应用于合成一类抗糖尿病化合物，这些化合物是在西非生长的Akuamma树的种子中发现的。吴教授还与达特茅斯大学计算机科学系的Lori Loeb教授合作，制作了一系列动画短片，重点介绍有机化学和其他STEM主题的重要概念。目标受众是初中生、高中生和大学生，以及普通大众。该系列的第四部动画目前正在制作中，讲述了艾塞那肽的故事，艾塞那肽是一种fda批准的治疗2型糖尿病的药物，最初是在吉拉怪物的唾液中发现的。吴教授在吲哚类生物碱akuamma家族复杂天然产物全合成的背景下，积极追求杂环化学的进步。他的策略是利用他的研究小组最近开发的反应作为合成的关键步骤。这些反应包括脱芳香吲哚3+2环化反应和亲核分子拦截的贝克曼断裂等。这些化合物中至少有一个成员具有抗糖尿病特性，并且被认为通过双重抑制钠/葡萄糖共转运体SGLT1和SGLT2起作用。此外，吴教授正在利用从这些合成中收集到的基础知识，作为制备复杂杂环支架的基础，以填充新的化学空间。该奖项的广泛科学影响是多方面的，最明显的是在了解1型和2型糖尿病方面取得了进展。此外，化学领域的其他人将这些新发明的反应用于与阿库胺类无关的合成，也会带来好处。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project is jointly funded by the Chemical Synthesis program and the Established Program to Stimulate Competitive Research to support the research of Professor Jimmy Wu of Dartmouth College. Dr. Wu is developing new chemical synthesis of organic compounds with unique chemical structures. This research is leading to the discovery of molecules with important physical and/or biological properties. To accomplish these goals, Prof. Wu invents new reactions that can be applied to the synthesis of a class of anti-diabetic compounds that are found in the seeds of the Akuamma trees which grow in western Africa. In collaboration with Professor Lori Loeb of the Department of Computer Science at Dartmouth, Professor Wu is also producing a series of short, animated films focused on important concepts in organic chemistry and other STEM topics. The target audience is middle school, high school, and college students, as well as the general public. The fourth animation in this series is currently in production and tells the story of exenatide, an FDA-approved drug for type 2 diabetes that was first discovered in the saliva of the Gila monster. Professor Wu is actively pursuing advances in heterocyclic chemistry within the context of the total synthesis of complex natural products from the akuamma family of indoline alkaloids. His strategy makes use of reactions recently developed in his research group as key steps in the synthesis. These reactions include the dearomative indole 3+2 annulation reaction and nucleophile-intercepted Beckmann fragmentation, among others. At least one member of these compounds possesses anti-diabetic properties and is thought to work by dual inhibition of the sodium/glucose co-transporters SGLT1 and SGLT2. Additionally, Professor Wu is using fundamental knowledge gleaned from these syntheses as the basis for preparing complex heterocyclic scaffolds that populate novel chemical space. The broader scientific impacts of this award are multi-fold, with the most obvious being advances in understanding both type 1 and type 2 diabetes. In addition, benefits arise from the use of these newly invented reactions by others in the chemical community in synthetic endeavors unrelated to the akuammilines.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.