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: 10374006
• 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/10374006
• 关键词: Agrochemicals; Alkanes; Alkenes; Amination; Amines; Aniline; Aziridines; Biochemistry; Biological; Biology; Carboxylic Acids; Chemicals; Chemistry; Communities; Complex; Development; Epoxy Compounds; Ketones; Laboratories; Medicine; Metals; Natural Products; Nitrogen; Organic Synthesis; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prize; Process; Production; Reaction; Route; Structure; analog; biological preparation; carbonyl compound; cost; drug candidate; 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.

项目摘要 胺及其衍生物是无处不在的物质，因为它们存在于绝大多数 药物分子，农产品，功能材料以及许多通过生物产生的化合物 生物（即天然产物）。值得注意的是，平均有200个最佳的氮原子2.8 出售小分子药物，其中80％的药物至少包含一个N-杂环片段。也是 估计有45％的候选药物含有手性胺部分。在这些含氮 化合物，芳香族和异源胺（即苯胺）在超过三分之一的核心结构中出现 候选药物的同时，三位元素的氮类似物 环氧化物是重要的合成中间体，由于其多功能性而通往结构复杂的分子 在无数的区域和立体选择性转换中。毫不奇怪，有机化学家投资考虑 精力为合成胺的策略设计更好，这些胺作为关键的化学基础 生物活性化合物的制备，尤其是在医学化学方面。这些策略也可以 用于用于探索新化学空间的复杂分子的晚期功能化 用于生物学研究。因此，快速，直接的新的和强大的合成策略和方法 将氮的引入到易于获得和廉价的前体中，例如烷烃，烷烃，竞技场， 杂烯烯和羰基化合物预计将对有机方式产生深远的影响 实践合成，药物化学，生物化学和化学生物学。特别是引言 在一个步骤中，在轻度条件下，未受保护的氮和其他杂原子会导致过程 比当前使用的多步路线更高效，更“绿色”，最终将导致更快的速度 开发新药物。 在拟议的项目过程中，新颖的金属催化和有机催化分析过程将 可以开发将利用催化和石化的亲电的利用 修改代理商。这是手性的直接合成以及次生原发性和次级苯胺的直接合成。 来自酮和羧基的芳香族化合物，芳香族化合物的化合物 来自酮胺，酮症和酮氨基植物以及NH-以及NH-的酸衍生物，来自酮胺的完全取代胺。 将实现来自孤立/未激活烯烃的N-烷基核苷。提出的催化分析过程 将进行彻底研究以发现和了解其机械基础。重点将是 给出了可以利用丰富且廉价的起始材料并转换的反应的发展 在操作简单且温和的反应条件下，它们具有结构复杂/增值的产品。