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.

项目总结/摘要 氮是药物和生物活性分子中第四常见的元素， 只有C、H和O。它的影响大大超过了其他重要元素，如S和F。方法 将氮部分引入到通常可获得的起始材料中将为从业者提供快速 进入更复杂的结构。我们对组装氮杂环有着长期的兴趣 因为它的重要性和重要性。我们的工作开始于双环结构的构建方法 使用环加成化学。随着时间的推移，它演变为使用C-H激活并产生单环 结构.为了提高效用和影响力，我们继续改进我们的方法， 使用日益丰富的烯烃伙伴与广泛通用的胺衍生物， 氮杂环以及无环骨架的合成。因此，这次竞争性更新的重点是 几个互补的场地： 目的1：立体定向催化烯烃双官能化反应。烯烃是最普遍存在的 可用的起始材料。通过立体化学定义的烯烃传递两个官能团 如果反应是立体特异性的，则允许获得互补的非对映异构体。我们将开发一套 双官能化反应，包括碳胺化、碳二碳酸化和相关的转化。哪里 可能的是，我们将以这样的方式使用未官能化的前体，以增加实用性和易于执行。 目的2：烯烃与氮亲电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、哌啶和烯丙基胺衍生物的化学， 不仅官能化烯烃本身，而且官能化烯丙基、高烯丙基和双高烯丙基位置。 目的3：设计人工金属酶以增强反应活性和不对称催化作用。许多这些 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。 金属酶衍生自停靠在单体链霉亲和素蛋白支架内的过渡金属催化剂。