New Reactions for Targeting the Akuammiline Alkaloids

针对 Akuammiline 生物碱的新反应

• 批准号: 1856273
• 负责人: Jimmy Wu
• 金额: $ 45万
• 依托单位: Dartmouth College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856273&HistoricalAwards=false
• 关键词: New; Reactions; Targeting; Akuammiline; Alkaloids

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.

该项目由化学合成项目和促进竞争研究的既定项目共同资助，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。这项研究正在导致发现具有重要物理和/或生物特性的分子。为了实现这些目标，吴教授发明了新的反应，可用于合成一类抗糖尿病化合物，这些化合物存在于非洲西部生长的Akuamma树的种子中。吴教授与达特茅斯计算机科学系的洛里·勒布教授合作，制作了一系列动画短片，重点关注有机化学和其他STEM主题的重要概念。目标受众是初中、高中和大学生，以及普通大众。该系列的第四部动画目前正在制作中，讲述了一种被FDA批准用于治疗2型糖尿病的药物exenobenzene的故事，这种药物最初是在希拉怪物的唾液中发现的。 吴教授积极追求杂环化学的进步，从吲哚生物碱的akuamma家族的复杂天然产物的全合成的背景下。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。这些反应包括脱芳吲哚3 + 2成环反应和亲核试剂拦截的贝克曼片段化等。这些化合物中至少有一种具有抗糖尿病特性，并被认为通过双重抑制钠/葡萄糖共转运蛋白SGLT 1和SGLT 2发挥作用。 此外，吴教授正在使用从这些合成中收集的基础知识作为制备填充新化学空间的复杂杂环支架的基础。该奖项的更广泛的科学影响是多方面的，最明显的是在理解1型和2型糖尿病方面的进步。此外，这些新发明的化学反应在与阿库阿米林无关的合成领域中的应用也带来了好处。该奖项反映了NSF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。

项目成果

Diversification of Nucleophile-Intercepted Beckmann Fragmentation (NuBFr) Products and Related DFT Studies

亲核试剂截获的贝克曼断裂 (NuBFr) 产品的多样化及相关 DFT 研究

• DOI: 10.1021/acs.joc.0c01486
• 发表时间: 2020
• 期刊: The Journal of Organic Chemistry
• 作者: Lowder, Leah;Zhao, Fengyue;Vaughan, Mathes M.;Houk, K. N.;Liu, Fang;Wu, Jimmy
• 通讯作者: Wu, Jimmy