New catalytic methods for the rapid synthesis of N-unprotected chiral aziridines and amines

快速合成N-未保护的手性氮丙啶和胺的新催化方法

• 批准号: 10596519
• 负责人: Laszlo Kurti
• 金额: $ 36.86万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596519
• 关键词: Agrochemicals; Alkanes; Alkenes; Amination; Amines; Aniline; Aziridines; Biochemistry; Biological; Biology; Carboxylic Acids; Chemicals; Chemistry; Communities; Complex; Development; Environment; Epoxy Compounds; Friends; Investments; Ketones; Laboratories; Medicine; Metals; Natural Products; Nitrogen; Organic Synthesis; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Production; Reaction; Route; Structure; analog; biological preparation; carbonyl compound; cost; drug candidate; enantiomer; member; novel; oxaziridine; rapid technique; small molecule

Project Summary Amines and their derivatives are ubiquitous substances since they are present in the overwhelming majority of drug molecules, agrochemicals, functional materials as well as many compounds that are produced by living organisms (i.e., natural products). Notably, there are, on average, 2.8 nitrogen atoms in each of the 200 best- selling small molecule drugs and, of these drugs, 80% contain at least one N-heterocyclic fragment. It is also estimated that 45% of drug candidates contain a chiral amine moiety. Among these nitrogen-containing compounds, aromatic and heteroaromatic amines (i.e., anilines) appear as core structures in more than one third of drug candidates while aziridines, the three-membered and equally highly-strained nitrogen analogues of epoxides, are important synthetic intermediates en route to structurally complex molecules due to their versatility in myriad regio- and stereoselective transformations. Not surprisingly, organic chemists invest a considerable amount of effort devising better strategies for synthesis of amines that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. These strategies can also be used for late-stage functionalization of complex molecules that enables the exploration of new chemical space for biological studies. Consequently, new and powerful synthetic strategies and methods for the rapid and direct introduction of nitrogen into readily available and inexpensive precursors such as alkanes, alkenes, arenes, heteroarenes as well as carbonyl compounds are expected to have a far-reaching impact upon how organic synthesis, medicinal chemistry, biochemistry and chemical biology are practiced. In particular, the introduction of unprotected nitrogen and other heteroatoms in a single step and under mild conditions will result in processes that are more efficient and “greener” than currently used multi-step routes and ultimately will lead to the faster development of new medicines. During the course of the proposed project novel metal-catalyzed and organocatalytic amination processes will be developed that will take advantage of both catalytically and stoichiometrically generated electrophilic aminating agents. Thus, the direct synthesis of chiral as well as achiral primary and secondary anilines from aromatic and heteroaromatic compounds, of alpha-aminated carbonyl compounds from ketones and carboxylic acid derivatives, of fully-substituted amines from ketimines, ketoximes and ketiminoesters and of NH- as well as N-alkylaziridines from isolated/unactivated olefins will be achieved. The proposed catalytic amination processes will be thoroughly investigated to uncover and understand their mechanistic underpinnings. Emphasis will be given to the development of reactions that can utilize abundant and inexpensive starting materials and convert these to structurally complex/value added products under operationally simple and mild reaction conditions.

项目概要 胺及其衍生物是普遍存在的物质，因为它们存在于绝大多数物质中 药物分子、农用化学品、功能材料以及许多由生物体产生的化合物 有机体（即天然产物）。值得注意的是，200 个最好的平均每个中都有 2.8 个氮原子。 销售小分子药物，其中 80% 含有至少一个 N-杂环片段。这也是 据估计，45% 的候选药物含有手性胺部分。其中含氮 超过三分之一的化合物中，芳香胺和杂芳香胺（即苯胺）作为核心结构出现 候选药物，而氮丙啶，三元且同样高度紧张的氮类似物 环氧化物由于其多功能性而成为结构复杂分子的重要合成中间体 在无数的区域和立体选择性转变中。毫不奇怪，有机化学家投入了大量资金 付出大量努力设计更好的胺合成策略，作为关键化学构件 生物活性化合物的制备，特别是在药物化学领域。这些策略还可以 用于复杂分子的后期功能化，从而能够探索新的化学空间 用于生物学研究。因此，新的、强大的合成策略和方法可以快速、直接地合成 将氮引入容易获得且廉价的前体中，例如烷烃、烯烃、芳烃、 杂芳烃以及羰基化合物预计将对有机化合物的产生产生深远的影响。 合成、药物化学、生物化学和化学生物学。特别是介绍 在温和条件下一步中未受保护的氮和其他杂原子将导致过程 比目前使用的多步路线更高效、更“环保”，最终将带来更快的速度 新药的开发。 在拟议项目的过程中，新型金属催化和有机催化胺化工艺将 开发将利用催化和化学计量产生的亲电子 胺化剂。因此，从手性和非手性伯苯胺和仲苯胺直接合成 芳香族和杂芳香族化合物，来自酮和羧基的α-胺化羰基化合物 酸衍生物，来自酮亚胺、酮肟和酮亚胺酯的完全取代的胺和 NH- 以及 将从分离的/未活化的烯烃中获得N-烷基氮丙啶。拟议的催化胺化工艺 将进行彻底调查，以揭示和理解其机制基础。重点将是 致力于开发可以利用丰富且廉价的起始材料并将其转化的反应 这些在操作简单和温和的反应条件下生成结构复杂/增值的产品。