New Olefin Metathesis Catalysts Based on Innocuous and Abundant Metals

基于无害且丰富的金属的新型烯烃复分解催化剂

• 批准号: 8150852
• 负责人: Yann Schrodi
• 金额: $ 10.88万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150852
• 关键词: Address; Alkenes; Area; Carbon; Chloride Ion; Chlorides; Communities; Complex; Development; Drug Industry; Economics; Electrons; Family; Goals; Iron; Knowledge; Ligands; Metals; Methodology; Methods; Molybdenum; Nobel Prize; Organometallic Chemistry; Outcomes Research; Pharmaceutical Preparations; Positioning Attribute; Preparation; Process; Production; Public Health; Reaction; Recruitment Activity; Relative (related person); Reporting; Research; Research Activity; Ruthenium; Science; Students; Substance P Receptor; System; Testing; Therapeutic; Training; Transition Elements; Ursidae Family; Work; base; catalyst; commercialization; design; diphenyl; drug candidate; drug development; innovation; interest; meetings; novel; polymerization; propargyl alcohol; pyridine; scaffold; stem; tool

DESCRIPTION (provided by applicant): There exists a critical need for new robust olefin metathesis catalysts based on innocuous and abundant metals, but little effort has been applied toward addressing it. The lack of reports in this area of organometallic chemistry is related to the relative difficulty in preparing alkylidene complexes of low-valent transition metals. This unmet need represents an important problem: until such catalysts are discovered, the development, production, and commercialization of olefin metathesis-enabled drugs will remain hampered by metal-contamination and economic concerns. Our long-term goal is to provide inexpensive, non-toxic, highly efficient, robust and selective (e.g., enantioselective, E/Z-diastereoselective) olefin metathesis catalysts to the community of synthetic chemists. The overall objective of this application is to develop olefin metathesis catalysts based on low-valent molybdenum and iron metals supported by diimine and bis(imino)pyridine ligands. A subordinate objective of this project is to develop a new method for the preparation of low-valent transition metal alkylidene complexes. The rationale behind this research is that the discovery of such catalysts will equip the pharmaceutical industry with a powerful tool that will ultimately yield more affordable, safer, and cleaner methods to produce therapeutics. The following three specific aims will be pursued in order to reach the overall objective. In specific aim 1, a new method for the easy preparation of low-valent metal alkylidene complexes will be developed based on the reaction between metal precursors and derivatives of 1,1-diphenyl-2-propyn-1-ol where one phenyl group bears electron-donating groups in its meta positions. The working hypothesis for specific aim 1 is that the electron-donating groups will activate the ring and favor the formation of olefin metathesis-active metal alkylidene complexes over that of inactive metal allenylidene species. In specific aim 2, this new method will be used to prepare iron and molybdenum alkylidene complexes supported by diimine and bis(imino)pyridine ligands. Additionally, two alternative methods to prepare the targeted metal alkylidene complexes will also be investigated under specific aim 2. The first alternative method will be based on the reaction of metal-chloride-hydride complexes with propargyl chloride derivatives, while the second will involve the preparation of metallacyclobutane compounds. The working hypothesis for specific aim 2 is the following: ligand-metal systems that have proven active in Ziegler-Natta olefin polymerization have a high potential to be active in olefin metathesis. Finally, specific aim 3 will focus on testing the catalytic activity of the new metal alkylidene complexes in different olefin metathesis reactions and will include the preparation of a biomedically relevant scaffold of genuine interest. The completion of this work will yield new robust olefin metathesis catalysts based on inexpensive and innocuous metals and a new general method for preparing alkylidene complexes of low-valent transition metals. This research is significant, because it will facilitate the discovery and the commercialization of olefin metathesis-enabled drugs. PUBLIC HEALTH RELEVANCE: Olefin metathesis is a synthetic method for the construction of carbon- carbon bonds, which has been instrumental in the discovery of novel medicinal agents. The proposed work aims to develop less toxic, "greener", and cheaper olefin metathesis catalysts. These improvements will accelerate and facilitate the drug development process, and therefore ultimately enhance the public health.

描述（由申请人提供）：存在对基于无害和丰富的金属的新的稳健烯烃复分解催化剂的迫切需要，但是几乎没有努力应用于解决它。在有机金属化学的该领域中缺乏报道与制备低价过渡金属的亚烷基络合物的相对困难有关。这种未满足的需求代表了一个重要的问题：在发现这样的催化剂之前，烯烃易位使能药物的开发、生产和商业化将仍然受到金属污染和经济问题的阻碍。我们的长期目标是提供廉价、无毒、高效、稳健和选择性的（例如，对映选择性，E/Z-非对映选择性）烯烃复分解催化剂的合成化学家社区。本申请的总体目标是开发基于由二亚胺和双（亚氨基）吡啶配体负载的低价钼和铁金属的烯烃复分解催化剂。本计画的次要目的是发展一种制备低价过渡金属烷叉配合物的新方法。这项研究背后的基本原理是，这种催化剂的发现将为制药行业提供一个强大的工具，最终将产生更实惠，更安全，更清洁的方法来生产治疗药物。为实现总体目标，将努力实现以下三个具体目标。在具体目标1中，将基于金属前体与其中一个苯基在其Meta位带有给电子基团的1，1-二苯基-2-丙炔-1-醇衍生物之间的反应，开发一种容易制备低价金属烷叉络合物的新方法。具体目标1的工作假设是，供电子基团将活化环，并有利于烯烃复分解活性金属亚烷基络合物的形成，而不是非活性金属亚丙二烯物种的形成。在具体目标2中，该新方法将用于制备由二亚胺和双（亚氨基）吡啶配体支撑的铁和钼亚烷基配合物。此外，还将在具体目标2下研究制备目标金属亚烷基络合物的两种替代方法。第一种替代方法将基于金属-氯化物-氢化物络合物与炔丙基氯衍生物的反应，而第二种方法将涉及金属环丁烷化合物的制备。具体目标2的工作假设如下：已证明在齐格勒-纳塔烯烃聚合中具有活性的配体-金属体系在烯烃复分解中具有高活性潜力。最后，具体目标3将侧重于测试新的金属亚烷基络合物在不同烯烃复分解反应中的催化活性，并将包括真正感兴趣的生物医学相关支架的制备。这项工作的完成将产生新的强大的烯烃复分解催化剂的基础上廉价和无害的金属和一个新的一般方法制备亚烷基配合物的低价过渡金属。这项研究意义重大，因为它将促进烯烃复分解药物的发现和商业化。 公共卫生关系：烯烃复分解是一种用于构建碳-碳键的合成方法，其在发现新的药物制剂中起着重要作用。这项工作的目的是开发毒性更小，“绿色”和更便宜的烯烃复分解催化剂。这些改进将加速和促进药物开发过程，从而最终提高公众健康。