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.
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.
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