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: 10782916
• 负责人: Laszlo Kurti
• 金额: $ 9.83万
• 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/10782916
• 关键词: Agrochemicals; Alkanes; Alkenes; Amination; Amines; Award; Aziridines; Biochemistry; Biological; Biology; Chemicals; Chemistry; Communities; Complex; Development; Environment; Friends; Funding; Hydroxylamine; Investments; Medicine; Metals; Methods; Natural Products; Nitrogen; Organic Synthesis; Organism; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Process; Production; Reaction; Reagent; Research; Research Personnel; Route; biological preparation; cost; cycloaddition; drug candidate; halogenation; novel; rapid technique; response; small molecule; tertiary amine

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. 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 may be used for both the early-stage functionalization of simple feedstock chemicals and the late- stage functionalization of complex molecules. Together these approaches enable 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 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 and/or functionalized nitrogen atoms 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 we will focus on the development of novel direct (i.e., non-catalytic) olefin difunctionalization methods. In particular, we are evaluating the native reactivity of N-acyl-N-halo-O- sulfonyl as well as N-acyl-N-halo-O-alkyl/silyl hydroxylamines with feedstock olefins to obtain structurally diverse and multifunctional hydroxylamine derivatives in a single pot (i.e., halo-aminohydroxylation of alkenes). The resulting compounds can serve as structurally complex and versatile electrophilic aminating agents that readily form C-N bonds with a variety of substrates. For example, non-catalytic as well as metal-catalyzed intra- and intermolecular processes will be explored that take advantage of both stoichiometrically and catalytically generated electrophilic aminating agents (i.e., complexity-building transformations, such as in intramolecular and/or intermolecular aliphatic and aromatic C-H amination reactions, olefin aziridinations as well 1,3-dipolar cycloadditions). Thus, the direct synthesis of chiral secondary and tertiary amines from structurally simple precursors will be achieved. The proposed regio- and stereoselective 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。毫不奇怪，有机化学家投资 付出相当大的努力来设计更好的策略来合成作为关键化学品的胺 用于制备生物活性化合物的构建模块，特别是在药物化学领域。这些 策略可用于简单原料化学品的早期功能化和后期功能化。 复杂分子的阶段功能化。这些方法共同推动了新的探索 用于生物学研究的化学空间。因此，新的、强大的合成策略和方法 快速、直接地将氮引入容易获得且廉价的前体中，例如烷烃、 烯烃、芳烃、杂芳烃预计将对有机合成、 实践药物化学、生物化学和化学生物学。特别是，引入 在温和条件下未受保护和/或官能化的氮原子将导致更有效的过程 比目前使用的多步路线更高效、更“绿色”，最终将导致更快的发展 新药。 在拟议项目的过程中，我们将重点开发新型直接（即非催化） 烯烃双官能化方法。特别是，我们正在评估 N-酰基-N-卤代-O- 的天然反应性 磺酰基以及N-酰基-N-卤代-O-烷基/甲硅烷基羟胺与原料烯烃反应以获得结构多样化 和多功能羟胺衍生物在一个锅中（即烯烃的卤代氨基羟基化）。这 所得化合物可以作为结构复杂且通用的亲电胺化剂，很容易 与多种基材形成C-N键。例如，非催化以及金属催化的内部和 将探索利用化学计量和催化的分子间过程 产生亲电胺化剂（即复杂性构建转化，例如分子内 和/或分子间脂肪族和芳香族C-H胺化反应、烯烃氮丙啶化以及1,3-偶极反应 环加成）。因此，从结构简单的化合物直接合成手性仲胺和叔胺 将会取得先兆。拟议的区域选择性和立体选择性胺化工艺将彻底 进行调查以揭示并理解其机制基础。重点将放在 开发可以利用丰富且廉价的起始材料并将其转化为 在操作简单且反应条件温和的情况下生产结构复杂/增值的产品。