Asymmetric Synthesis of Nitrogen Heterocycles

氮杂环的不对称合成

• 批准号: 10246858
• 负责人: Tomislav Rovis
• 金额: $ 32万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246858
• 关键词: Alkenes; Amines; Biological; Carbon; Catalysis; Chemicals; Chemistry; Complex; Coupling; Docking; Elements; Eye; Goals; Health; Incidence; Methodology; Methods; Molecular; Nitrogen; Pharmacologic Substance; Positioning Attribute; Prevalence; Pyrrolidines; Reaction; Research; Scaffolding Protein; Source; Streptavidin; Structure; Therapeutic Agents; Time; Transition Elements; Work; catalyst; cycloaddition; design; interest; metalloenzyme; novel; piperidine; programs; scaffold; small molecule; stereochemistry

Project Summary/Abstract Nitrogen is the fourth most common element in pharmaceuticals and biologically active molecules, after only C, H and O. Its incidence greatly eclipses that of other important elements such as S and F. Methods to introduce nitrogen moieties into commonly available starting materials would provide practitioners with rapid access to more complex structures. We have had a long-standing interest in assembling nitrogen heterocycles due to their prevalence and importance. Our work began with approaches to construction of bicyclic structures using cycloaddition chemistry. Over time, it evolved to using C–H activation and generating monocyclic structures. With an eye towards increased utility and impact, we have continued to evolve our approach to using increasingly abundant alkene partners with broadly versatile amine derivatives for the continued synthesis of nitrogen heterocycles as well as acyclic scaffolds. Thus, this competitive renewal is focused on several complementary venues: Aim 1: Stereospecific Catalytic Alkene Difunctionalization Reactions. Alkenes are among the most ubiquitous starting materials available. The delivery of two functionalities across the stereochemically defined alkene allows access to complementary diastereomers if the reaction is stereospecific. We will develop a suite of difunctionalization reactions including carboamination, carbocarbation and related transformations. Where possible we will use unfunctionalized precursors in such a way to increase utility and ease of execution. Aim 2: Chemoselective Coupling of Alkenes and Nitrogen Electrophiles. We will extend alkene functionalization chemistry to convert simple -olefins directly into pyrrolidines, piperidines and allylic amine derivatives, functionalizing not just the alkene itself but also the allylic, homoallylic and bis-homoallylic positions. Aim 3: Design of Artificial Metalloenzymes for Enhanced Reactivity and Asymmetric Catalysis. Many of these reactions create chiral products. We will control the absolute stereochemistry of the transformations with novel metalloenzymes derived from transition metal catalysts docked within monomeric streptavidin protein scaffolds.

项目概要/摘要 氮是药物和生物活性分子中第四常见的元素，仅次于 只有 C、H 和 O。它的发生率大大超过了其他重要元素，例如 S 和 F。 将氮部分引入常用的起始材料将为实践者提供快速 我们长期以来对组装氮杂环有着浓厚的兴趣。 由于它们的普遍性和重要性，我们的工作从构建双环结构的方法开始。 随着时间的推移，它演变为使用 C-H 活化并生成单环。 着眼于提高实用性和影响力，我们不断改进我们的方法。 使用日益丰富的烯烃伙伴和广泛用途的胺衍生物来持续 因此，这种竞争性更新的重点是氮杂环和无环支架的合成。 几个互补的地点： 目标 1：立体定向催化烯烃双官能化反应是最普遍的反应之一。 可用的起始材料在立体化学定义的烯烃上提供两种功能。 如果反应是立体特异性的，则可以获得互补的非对映异构体。 双官能化反应包括碳胺化、碳碳化和相关转化。 我们可能会使用未功能化的前体，以提高实用性和易于执行。 目标 2：烯烃和氮亲电子试剂的化学选择性偶联我们将扩展烯烃官能化。 将简单的α-烯烃直接转化为吡咯烷、哌啶和烯丙胺衍生物的化学方法， 不仅对烯烃本身进行官能化，而且对烯丙基、高烯丙基和双同烯丙基位置进行官能化。 目标 3：设计用于增强反应性和不对称催化的人工金属酶。 反应产生手性产物。我们将用新颖的方法控制转化的绝对立体化学。 来自对接在单体链霉亲和素蛋白支架内的过渡金属催化剂的金属酶。