New Olefin Metathesis Catalysts Based on Innocuous and Abundant Metals

描述（由申请人提供）：目前迫切需要基于无害和丰富的金属的新型坚固的烯烃分解催化剂，但在解决这一问题方面的努力很少。在有机金属化学这一领域缺乏报道与制备低价过渡金属的烷基烯配合物相对困难有关。这种未被满足的需求代表了一个重要的问题：在这种催化剂被发现之前，烯烃合成药物的开发、生产和商业化将继续受到金属污染和经济问题的阻碍。我们的长期目标是为合成化学家提供廉价、无毒、高效、稳定和选择性（如对映选择性、E/ z非对映选择性）的烯烃复分解催化剂。本应用程序的总体目标是开发以二亚胺和双（亚）吡啶配体为载体的低价钼和铁金属为基础的烯烃复分解催化剂。本课题的次要目标是开发一种制备低价过渡金属烷基烯配合物的新方法。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种强大的工具，最终将产生更经济、更安全、更清洁的治疗方法。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，基于金属前驱体与1,1-二苯基-2-丙基-1-醇衍生物之间的反应，其中一个苯基在其间位上带有给电子基团，将开发一种易于制备低价金属烷基烯配合物的新方法。具体目标1的工作假设是，给电子基团将激活环，并有利于形成烯烃合成活性金属烷基烯配合物，而不是非活性金属烷基烯配合物。在具体目标2中，将使用这种新方法制备由二亚胺和双（亚胺）吡啶配体负载的铁和钼烷基烯配合物。此外，在特定目的2下，还将研究制备靶向金属烷基烯配合物的两种替代方法。第一种替代方法将基于金属-氯化物-氢化物配合物与丙炔氯衍生物的反应，而第二种方法将涉及制备金属环丁烷化合物。具体目标2的工作假设如下：已被证明在齐格勒-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很高的活性潜力。最后，具体目标3将侧重于测试新的金属烷基烯配合物在不同烯烃复分解反应中的催化活性，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新的基于廉价和无害金属的坚固的烯烃复分解催化剂，并为制备低价过渡金属的烷基烯配合物提供一种新的通用方法。这项研究具有重要意义，因为它将促进烯烃合成药物的发现和商业化。

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.