The objective of this research is the development of olefin metathesis catalysts that function in protic media and the exploration of their biologically relevant applications. Earlier work developed catalysts that function in organic media yielding a metathesis-active family of complexes of the type L2X2Ru=CHR. A large body of work has demonstrated the remarkable utility of these complexes to build carbon-carbon double bonds in organic media. However, due to solubility constraints, the modification of biomolecules such as polypeptides often must be performed in protic media--typically water. Olefin metathesis in water will allow for transformations that proceed under mild conditions and operate on a functional group orthogonal to functionalities normally present in biomolecules.
One aim of the proposed research is to develop L2X2Ru=CHR complexes that demonstrate sufficient stability and activity in protic solvents and which can function in biologically relevant conditions. To this end, the L-type ligands of the L2X2Ru=CHR complexes will be modified to include groups known to increase the solubility of a compound in protic media--e.g, poly(ethylene glycol) and/or quaternary ammonium salts. The use of chelating ligands will also be explored because they have been shown to increase the stability of metathesis catalysts. This catalyst has the potential to be a powerful tool in the exploration and manipulation of structures pertinent to biology. In anticipation of the successful development of this catalyst, the second goal of this research is the demonstration of the power of olefin metathesis as a tool for structural manipulation of biomolecules. Projects exploring the ability of the catalyst to site-specifically post-translationally modify proteins, generate polymerized liposomes, and construct novel reversible hydrogels are proposed. The developed catalysts will be provided to biologically-oriented groups as requested for specific applications. At Caltech alone, the Dervan, Dougherty, and Tirrell groups have projects where the proposed catalysts could be used immediately, and the broad use of the current catalysts in organic media suggests that novel biological applications of metathesis will arise with the availability of the proposed catalyst.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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California Institute of Technology
Schools of Engineering
United States
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Hong, Soon Hyeok; Grubbs, Robert H (2007) Efficient removal of ruthenium byproducts from olefin metathesis products by simple aqueous extraction. Org Lett 9:1955-7
Hong, Soon Hyeok; Grubbs, Robert H (2006) Highly active water-soluble olefin metathesis catalyst. J Am Chem Soc 128:3508-9