Iron-Catalyzed Metathesis and Carbocation Cyclization Reactions

铁催化复分解和碳正离子环化反应

• 批准号: 9765335
• 负责人: Corinna Stefanie Schindler
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765335
• 关键词: Alkaloids; Alkenes; Alkylation; Area; Benign; Biological; Carbon; Chemicals; Chemistry; Complex; Cyclization; Cyclopentenes; Development; Evaluation; Furans; Generations; Genomics; Health; Human; Indenes; Indolizines; Interruption; Investigation; Iron; Ketones; Knowledge; Lead; Libraries; Medicine; Metals; Methodology; Methods; Michigan; Mission; Molecular; Naphthalenes; Natural Products; Periodicity; Pharmacologic Substance; Planet Earth; Procedures; Protocols documentation; Public Health; Pyrans; Pyrroles; Reaction; Reagent; Research; Series; Source; Structure; System; Transition Elements; United States National Institutes of Health; Universities; analog; base; biological research; catalyst; cycloaddition; cyclohexene; drug discovery; functional group; high throughput screening; improved; insight; novel strategies; novel therapeutics; oxetane; pharmacophore; phenanthrene; programs; pyridine; scaffold; tool

Project Summary/Abstract The metathesis reaction between two alkenes represents a powerful tool for the formation of carbon-carbon bonds, which has led to profound synthetic applications in a large variety of biologically active target structures. The corresponding carbonyl-olefin metathesis reaction enables direct carbon-carbon bond construction, however, currently available synthetic methods are severely limited by harsh reaction conditions or require the use of stoichiometric metal alkylidene complexes as reagents. To date, no protocol of general synthetic utility for catalytic carbonyl-olefin metathesis exists. The objective of the proposed research program is to identify a chemical strategy that enables the catalytic carbonyl-olefin metathesis and related carbocyclization reactions based on inexpensive and earth-abundant transition metals. A distinctive feature of this new methodology is that it will provide a general and modular protocol for the synthesis of a large variety of cyclic motifs incorporated in many ubiquitous chemical scaffolds and biologically active complex molecules. Additionally, this new approach enables carbonyl-olefin metathesis reactions under mild reaction conditions with high functional group tolerance. In particular, highly functionalized carbocycles which all constitute core components of pharmacophores with a wide array of biological activities, will be directly accessible in a single transformation. Such carbocycles include cyclopentenes, cyclohexenes, furans, pyrans, pyridines and their analogs, indenes, napthalenes, spirocyclic, polycyclic as well as biaryl building blocks. The utility of these new carbocyclization reactions catalyzed by earth-abundant transition metals will be demonstrated by enabling the synthesis of biologically active target structures from simple, and readily available starting materials. The compounds prepared within this research program will be incorporated into the compound library maintained by the Center for Chemical Genomics (CCG) at the University of Michigan and become part of high-throughput screening (HTS) approaches for biological research and novel drug discovery projects. In summary, the research proposed will establish the first general, catalytic carbonyl-olefin metathesis reaction employing earth-abundant transition metals as a new tool for direct carbon-carbon bond construction which is expected to have wide implications for the area of complex molecule synthesis.

项目摘要/摘要 两个烯烃之间的歧化反应是形成碳-碳的有力工具。 键，这使得它在各种生物活性靶标结构中得到了广泛的合成应用。 相应的羰基-烯烃歧化反应能够直接构建碳-碳键， 然而，目前可用的合成方法受到苛刻反应条件的严重限制或需要 使用化学计量比的金属亚烷基络合物作为试剂。到目前为止，还没有通用的综合效用协议 对于催化的羰基-烯烃歧化反应是存在的。拟议的研究计划的目标是确定一个 使催化羰基-烯烃歧化和相关的碳环化反应成为可能的化学策略 以廉价和富含稀土的过渡金属为基础。 这一新方法的一个显著特点是，它将为 多种无处不在的化学支架和生物材料中多种环状基序的合成 活性复杂分子。此外，这种新方法还可以在以下条件下进行羰基烯烃歧化反应 反应条件温和，官能团耐受性高。特别是，高度官能化的碳环 所有这些都构成了具有广泛生物活性的药效团的核心成分，将是 在单个转换中可直接访问。这种碳环包括环戊烯、环己烯、呋喃、 吡喃、吡啶及其类似物、吲哚、萘、螺环、多环以及联芳基构筑 街区。由富含稀土的过渡金属催化的这些新的碳环化反应的用途将是 通过使生物活性目标结构能够从简单和容易地合成 可用的起始材料。在这项研究计划内制备的化合物将被纳入 密歇根大学化学基因组学中心(CCG)维护的化合物文库 并成为生物研究和新药高通量筛选(HTS)方法的一部分 探索项目。 综上所述，所提出的研究将建立第一个一般的、催化的羰基-烯烃歧化反应。 使用富含地球的过渡金属作为直接构建碳-碳键的新工具，这是 有望在复杂分子合成领域具有广泛的应用前景。