Designing Olefin Metathesis Catalysts for Frontier Opportunities in Chemical Biology and Beyond

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A major goal of our research is the design of robust, selective catalysts that promote the formation of carbon-carbon bonds via the olefin metathesis reaction. Olefin metathesis is one of the most versatile, powerful tools now in use for the catalytic formation of C-C bonds. Its scope, and its potential to improve the sustainable production of molecules essential to human health and well-being, were recognized with the 2005 Nobel Prize. To date, however, these transformative opportunities are limited by decomposition of the catalysts that enable reaction. While easily-handled catalysts played a major role in expanding the uptake of olefin metathesis in organic synthesis, their limitations have begun to be acknowledged in recent years, as attention turned to carrying out metathesis reactions in challenging contexts. In fact, short lifetimes makes these catalysts insufficiently productive for use in manufacturing processes. In other demanding contexts, such as chemical biology, their performance is unpredictable despite use in excess (that is, as reactants instead of catalysts). Essential to overcome these challenges is an understanding of the underlying inorganic chemistry: the unintended behaviour of the catalyst under the conditions of reaction. We have made unique, world-leading contributions to this area by systematically uncovering the underlying decomposition pathways, and tying these to specific design weaknesses. in the short term, knowledge of the underlying inorganic chemistry provides guidelines for how best to implement metathesis processes. In the longer term, it enables design of new, longer-lived, more productive catalysts. This proposal is aimed at developing high-performing catalysts capable of realizing the great promise of metathesis. We will build on our present understanding to eliminate a key weakness in the catalysts that represent the current state of the art. We will also pursue new capabilities. At present, there are no metathesis catalysts that retain high activity in water, again because water triggers decomposition. This is important, because water is ubiquitous, and because its negative impact has been widely overlooked. We have identified key structural features associated with maximum water-tolerance, which we will use to develop catalysts for use in chemical biology, including in the presence of DNA. These would open the door to efficient transformations of biological molecules in their native media. Long-standing goals for the facile tagging of molecules water-rich environments, and perhaps living cells, may thus be realized. We will also explore new design paradigms, including metathesis catalysts based on the earth-abundant metal nickel. The latter is an ambitous but enticing goal. Cheap Ni catalysts could improve the economic feasibility of metathesis processes, while the much smaller environmental footprint of nickel relative to ruthenium (a byproduct of platinum mining) is also immensely attractive.