New Olefin Metathesis Catalysts Based on Innocuous and Abundant Metals

描述(由申请人提供)：迫切需要一种新的基于无害和丰富的金属的强大的烯烃歧化催化剂，但很少有人致力于解决这一问题。在这一领域缺乏报道与低价过渡金属亚烷基化合物的制备相对困难有关。这种未得到满足的需求代表着一个重要的问题：在发现此类催化剂之前，金属污染和经济方面的担忧将继续阻碍烯烃歧化药物的开发、生产和商业化。我们的长期目标是为合成化学家群体提供廉价、无毒、高效、坚固和选择性(例如，对映体选择性、E/Z-非对映选择性)的烯烃歧化催化剂。这一应用的总体目标是开发基于二亚胺和双(亚氨基)吡啶配体负载的低价钼和铁金属的烯烃歧化催化剂。本项目的一个次要目标是开发一种制备低价过渡金属亚烷基配合物的新方法。这项研究背后的理论基础是，这种催化剂的发现将为制药业配备一种强大的工具，最终将产生更负担得起、更安全、更清洁的治疗药物生产方法。为了实现总体目标，将实现以下三个具体目标。在具体目标1中，基于金属前体与1，1-二苯基-2-丙基-1-醇衍生物的反应，开发了一种易于制备低价金属亚烷基配合物的新方法，其中一个苯基在其间位上带有给电子基。具体目标1的工作假设是，供电子基团将激活环，并有利于形成烯烃歧化活性的金属亚烷基络合物，而不是非活性的金属亚烯亚基物种。在具体目标2中，这种新方法将被用来制备二亚胺和双(亚氨基)吡啶配体负载的铁和钼的亚烷基配合物。此外，还将在特定目标下研究两种制备目标金属亚烷基配合物的替代方法2。第一种替代方法将基于金属-氯化物-氢化物与丙烯酰氯衍生物的反应，而第二种方法将涉及制备金属环丁烷化合物。特定目标2的工作假设如下：已被证明在Ziegler-Natta烯烃聚合中具有活性的配体-金属体系在烯烃歧化反应中具有很高的活性潜力。最后，具体目标3将重点测试新的金属亚烷基配合物在不同的烯烃歧化反应中的催化活性，并将包括制备真正感兴趣的生物医学相关支架。这项工作的完成将产生基于廉价和无害金属的新型烯烃歧化催化剂和制备低价过渡金属亚烷基络合物的新的通用方法。这项研究具有重要意义，因为它将促进烯烃歧化药物的发现和商业化。 与公共健康相关：烯烃复分解是一种构建碳-碳键的合成方法，它在发现新的药物方面发挥了重要作用。这项拟议的工作旨在开发毒性更低、更环保、更便宜的烯烃歧化催化剂。这些改进将加快和促进药物开发进程，从而最终提高公众健康。

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.