The introduction of stable and selective catalysts for olefin metathesis (OM) has considerably simplified the construction of double bonds. Herein we propose to tackle two areas of the OM reaction that have received little attention. First, we will address selectivity problems in an important type of OM reaction: metathesis cross-coupling or simply cross metathesis (CM). Second, we will examine the potential applications of OM in chemical biology. OM has no biological counterpart and therefore it may be possible to do metathesis chemistry in the biological milieu without affecting endogenous cellular processes. Although seemingly incongruent goals, both are attainable within the framework of this proposal because of the special nature of the metathesis catalysts we propose to develop: artificial metathesis enzymes. We propose to endow a protein with an OM active-site. A highly modular proteinaceous secondary ligand sphere will allow the use of recombinant molecular biology techniques to generate new ligands for the metathesis catalyst; in this way a large number of catalyst structures can be generated in a short time. The family of catalysts can then be tested in metathesis reactions that are difficult to perform selectively, such as cross metathesis. A hallmark of enzymes is the exquisite selectivity they often display for their substrate, and we believe this can be harnessed in the context of OM to solve many of the current selectivity problems. A second focus of the research will be the application of the metathesis enzyme as a tool for chemical biology. Since there is no biological analogue of OM, it may be possible to use metathesis to tag biomolecules in vivo. Moreover, a protein derived ligand would allow for selective localization in vivo through the selection of an appropriate protein tag.
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