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 th 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) olefn 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 metals. 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 central working hypothesis for this proposed work 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. The following three specific aims will be pursued in order to reach the overall objective and test the central hypothesis.
In specific aim 1, Molybdenum(0) dinitrogen complexes and molybdenum(III) trichloride complexes supported by bis(imino)pyridine (or NNN), bis(phosphino)pyridine (PNP), bis(phosphinito)pyridine and bis(phosphito)pyridine (PONOP) ligands will be synthesized and characterized. These molybdenum complexes will serve as precursors for the preparation of molybdenum alkylidene compounds.
In specific aim 2, different methods to turn the molybdenum precursors prepared in specific aim 1 into molybdenum alkylidene compounds LMo=CHR and/or LMo (=CHR) (CH2R) will be investigated. One of these methods is based on work completed during the current SC3 award. Another method will involve the treatment of molybdenum(0) dinitrogen complexes with diazoalkane reagents, while a third method will consist in reacting molybdenum(III) trichloride complexes with different bulky alkyl Grignard reagents. 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 bio medically 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 olefn 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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