Methodology towards the synthesis of complex stereochemically dense natural products

复杂立体化学致密天然产物的合成方法

• 批准号: 9257835
• 负责人: Evan Rashied Darzi
• 金额: $ 5.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257835
• 关键词: Address; Alder plant; Alkaloids; Alkynes; Architecture; Chemicals; Complex; Coupling; Diels Alder reaction; FDA approved; Generations; Goals; Hand; Lead; Methodology; Methods; Molecular; Natural Product Drug; Natural Products; Nitrogen; Periodicity; Pharmaceutical Preparations; Phase; Prevalence; Reaction; Research; Route; Therapeutic; Work; cycloaddition; diene; innovation; insight; manzamine A; piperidine; propadiene; scaffold; small molecule; tool

Project Summary/Abstract The piperidine heterocycle is a privileged motif that appears in countless bioactive molecules, including natural products and drugs. As the most prevalent nitrogen-containing heterocycle in chemical therapeutics, the piperidine motif is featured in a plethora of blockbuster drugs. Due to the prevalence of piperidines, new and innovative methodologies to access this motif remain highly sought after. Strained alkyne intermediates such as benzyne and piperidyne have proven to be useful intermediates towards this end, however cycloadditions to these scaffolds typically lead to the introduction of sp2 centers. The use of highly reactive cyclic allenes introduces an added layer of complexity by building an sp3 center and vicinal stereocenters. The proposed research aims to develop the first 3,4-azacyclohexylallne Diels-Alder reaction capable of accessing decorated piperidines that possess quaternary centers. This new strategy will then be employed to complete a concise total synthesis of the manzamine alkaloid Acantholactone.

项目总结/摘要 哌啶杂环是一种特权基序，出现在无数生物活性分子中，包括 天然产品和药物。作为化学治疗中最常用的含氮杂环， 哌啶基序是大量畅销药物的特征。由于哌啶的流行， 人们仍然非常希望采用创新方法来获取这一主题。拉紧的炔中间体，例如 苯炔和哌啶炔已被证明是实现这一目的的有用中间体，然而， 这些支架通常导致sp2中心的引入。高活性环状联烯的使用引入了 通过构建SP3中心和邻近立体中心来增加复杂性层。拟议的研究目标 开发了第一个能够获得修饰的哌啶的3，4-氮杂环己基烯Diels-Alder反应， 具有四元中心。这一新的战略，然后将完成一个简洁的总合成， 曼扎明生物碱异甘草内酯。