Iron-Catalyzed Metathesis and Carbocation Cyclization Reactions

铁催化复分解和碳正离子环化反应

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要两种烯烃之间的复分解反应是形成碳-碳的有力工具键，这导致了在多种生物活性靶结构中的深刻合成应用。相应的羰基-烯烃复分解反应能够直接构建碳-碳键，然而，目前可用的合成方法受到恶劣反应条件的严重限制或需要使用化学计量金属亚烷基络合物作为试剂。迄今为止，还没有通用合成实用的方案存在催化羰基-烯烃复分解反应。拟议研究计划的目标是确定实现催化羰基-烯烃复分解和相关碳环化反应的化学策略基于廉价且地球丰富的过渡金属。这种新方法的一个显着特征是，它将为合成多种环状基序，并纳入许多普遍存在的化学支架和生物支架中活性复杂分子。此外，这种新方法使得羰基-烯烃复分解反应能够在反应条件温和，官能团耐受性高。特别是高度功能化的碳环它们都构成具有广泛生物活性的药效基团的核心成分，通过一次转换即可直接访问。此类碳环包括环戊烯、环己烯、呋喃、吡喃、吡啶及其类似物、茚、萘、螺环、多环以及联芳基结构块。这些由地球上丰富的过渡金属催化的新碳环化反应的效用将是通过简单、容易地合成具有生物活性的靶结构来证明可用的起始材料。本研究计划中制备的化合物将被纳入由密歇根大学化学基因组学中心 (CCG) 维护的化合物库并成为生物研究和新药高通量筛选 (HTS) 方法的一部分发现项目。总之，拟议的研究将建立第一个通用的催化羰基-烯烃复分解反应采用地球丰富的过渡金属作为直接碳-碳键构建的新工具预计将对复杂分子合成领域产生广泛影响。