Selective Functionalization of Aliphatic Amines - Supplement to Support Mariah Ramos

脂肪胺的选择性官能化 - 支持 Mariah Ramos 的补充

• 批准号: 10798989
• 负责人: Tomislav Rovis
• 金额: $ 6.97万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798989
• 关键词: Amines; Biological; Derivation procedure; Drug Compounding; FDA approved; Light; Methods; Nitrogen; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Principal Investigator; Procedures; Property; Route; Structure-Activity Relationship; Testing; Therapeutic; Time; Variant; Work; design; irradiation; nitrene; novel; pyridine; scaffold; ylide; Amines; Biological; Derivation procedure; Drug Compounding; FDA approved; Light; Methods; Nitrogen; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Principal Investigator; Procedures; Property; Route; Structure-Activity Relationship; Testing; Therapeutic; Time; Variant; Work; design; irradiation; nitrene; novel; pyridine; scaffold; ylide

Principal Investigator: Rovis, Tomislav Abstract Recent years have brought about a greatly enhanced understanding of structure-activity relationships (SARs) of biologically relevant compounds. Accordingly, there is a greater need for streamlined, complementary syntheses to access practical drug scaffolds. Current methods focus on editing the periphery of drug compounds to install versatile functional handles. Alternatively, altering the core of target molecules would provide access to diverse drug scaffolds while leaving peripheral handles untouched. Direct core editing would significantly decrease the design-synthesis-test time, as most drug core alterations require an entirely new synthesis. This proposal describes an efficient synthetic route to access 1,2-diazepines from readily available pyridines through dearomative ring expansion. Aim 1 outlines using previously established methods to obtain the pyridinium ylide intermediate on multi-gram scale, the diazepine can be obtained through a 6π electrocyclic ring opening upon irradiation with 370nm light. 1,2-Diazepines are among the least common nitrogen heterocycles present in FDA approved drugs, likely due to the lack of synthetic pathways that enable access to these scaffolds rather than their biological properties. While pyridine expansions are generally multistep procedures, our work has shown promise for a one-pot route to this expansion product. Additionally, Aims 2 and 3 propose novel, alternate methods of obtaining these valuable products. A one-pot catalytic nitrene transfer with simultaneous irradiation could afford the 1,2 diazepine and variants. Taken together, this proposal provides access to synthetically difficult drug cores, while also introducing synthetic handles for further derivatization. 5

首席研究员：罗维斯，托米斯拉夫 抽象的 近年来，人们对结构活性关系（SARS）的理解非常大大增强 生物学相关的化合物。彼此之间，更需要简化，完整 合成以获取实用药物脚手架。当前的方法着重于编辑药物的外围 化合物以安装多功能功能手柄。或者，改变目标分子的核心将 在离开外围手柄的同时，提供潜水员毒品脚手架的访问权限。直接核心编辑 由于大多数药物核心的变化都需要完全减少设计合成测试时间 新合成。该提案描述了一种有效的合成途径 可通过亲爱的环扩展可用的吡啶。使用先前建立的AIM 1大纲 获得多克级中间的吡啶属的方法，可以获得地西平 通过370nm的光照射后，通过6π电环环开口。 1,2-二氮杂志是 FDA批准的药物中存在的最不常见的氮杂环，可能是由于缺乏合成的 能够进入这些脚手架而不是其生物学特性的途径。而吡啶 扩展通常是多步骤程序，我们的工作显示了对此一台途径的承诺 扩展产品。此外，目标2和3提案小说，获得这些有价值的替代方法 用简单辐射的一锅催化硝酸转移可以负担1,2地白氮平 和变体。综上 引入合成手柄以进一步推导。 5