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FRIPRO-Fri prosjektstøtte

Water-tolerant catalysis: Boosting chemical biology, medicine, and sustainable chemical manufacturing

Alternative title: Vanntolerant katalyse: Et løft for kjemisk biologi, medisin og bærekraftig kjemisk produksjon

Awarded: NOK 10.0 mill.

Project Number:

288135

Application Type:

Project Period:

2019 - 2024

Funding received from:

Location:

Partner countries:

Catalysts accelerate chemical reactions, reduce energy demands, and produce less waste than non-catalyzed processes. Catalysis is hence a cornerstone of environmentally friendly green chemistry and technology. An exceptionally versatile, Nobel-Prize-winning catalytic technology known as olefin metathesis enables the formation and rearrangement of chemical bonds between carbon atoms. This holds enormous potential as a low-waste, more sustainable means of building carbon-based molecules, for applications in chemical biology, materials, and medicine. To date, however, these potentially transformative opportunities are limited by decomposition of the catalysts that enable reaction. The capacity of water to trigger decomposition is particularly important, both because water is ubiquitous, and because its negative impact has been widely overlooked. Traces of water are invariably present in drug manufacturing, while water is essential as a co-solvent in chemical biology. Water has been generally dismissed, however, as a cause of poor catalyst productivity. Indeed, metathesis catalysts based on the metal ruthenium have been viewed as water-tolerant for decades. Fundamental limitations have begun to be acknowledged in recent years, as attention turned to carrying out challenging metathesis reactions in water. The project aimed at developing high-performing, water-tolerant catalysts capable of realizing the great promise of metathesis. The team of experts unites outstanding experimental and computational strengths in olefin metathesis (including globally leading capabilities in understanding and overcoming catalyst decomposition), in catalyst design, and in the synthesis of challenging molecular targets that represent highly desirable new drug classes. Truly water-tolerant catalysts would be a significant step forward in pharmaceutical manufacturing. More broadly, they would open the door to efficient metathetical transformations of water-soluble biological molecules in their native media. Long-standing goals, including the assembly and modification of carbon-carbon bonds in molecules such as DNA, in cells and water-rich environments, may thus be realized. Given that the problems of water as a co-solvent are only beginning to be widely acknowledged, it is unsurprising that problems arising from lesser amounts of water have gone overlooked. We have now demonstrated that even trace water is severely detrimental to the productivity of leading ruthenium catalysts, and that the combination of water and base (conditions ubiquitous in chemical biology and pharmaceutical manufacturing) is much more deleterious than either water or base alone. This information offers important clues to the pathways by which water triggers decomposition: it points toward direct attack by water on the intact complex, independent of effects arising from the polarity of water as a medium. In parallel work, we have succeeded in identifying catalyst features that maximize water-tolerance. This advance will be key to enabling the initiatives outlined above, and has aided in understanding the fundamental nature of the problem. The relevant decomposition pathways are now largely resolved. We have established that decomposition by water and base is due to formation of metathesis-inactive hydroxide complexes. We have also clarified the basis for the dramatically shorter catalyst lifetimes in the absence of base. These depend on the water concentration. At trace levels, water does not trigger new decomposition pathways: rather, its capacity to hydrogen-bond to groups present on the metal accelerates the classic pathways by which all metathesis catalysts decompose. In bulk water, decomposition occurs via direct binding of water to the metal. The acidity of the bound water molecule enables transformation into hydroxide species even in the absence of base. Building on this understanding, we have now designed reaction conditions and catalysts to suppress these pathways, resulting in breakthrough performance in the presence of water. In collaboration with industrial partners, we are engaged in applying the new catalysts in advanced technologies, including DNA-encoded chemical libraries to accelerate catalyst discovery. We are also exploiting our improved understanding of the mechanisms by which water undermines metathesis activity in work aimed ata the computationally-guided design of water-tolerant catalysts. We will incorporate this understanding into training sets for de novo molecular design, with the goal of automating the systematic, efficient design of water-tolerant catalysts.

The project has offered clear insights into the factors governing catalyst decomposition by water. It has revealed key vulnerabilities in the currently dominant catalysts, including commercial examples, and has established design parameters that have led to new catalysts with superior water-stability and performance. These catalysts are now being applied in important contexts in the pharmaceutical industry. Long-term, the new catalysts and insights gained from the project are expected to help realize the potential of olefin metathesis in challenging transformations in drug discovery and manufacturing, thereby contributing to realizing global development goals.

Water-tolerant metal catalysis holds enormous promise for applications in chemical biology, medicine, and sustainable chemical manufacturing. Olefin metathesis (OM), as the most versatile 'green technology' now known for the catalytic assembly of carbon-carbon bonds, offers tantalizing prospects for the synthesis of new drugs, the utilization of bio-based feedstocks, and the potential to modify biomolecules in their native and/or water-rich environments. To date, however, the profoundly detrimental effect of water on catalyst performance limits these potentially transformative opportunities. The present proposal is aimed at developing high-performing, water-tolerant metathesis technologies capable of realizing this promise. To this end, a diverse team of experts has been assembled, which unites outstanding experimental and computational strengths in olefin metathesis (including globally leading capabilities in understanding and overcoming catalyst decomposition), in catalyst and ligand design, and in the synthesis of challenging molecular targets that represent highly desirable new drug classes. A major strategic asset is the synergy between the team’s superb facilities for high-throughput screening and characterization of molecular catalysts, and unique, innovative computational tools for analysis and catalyst redesign. Leading experimental and computational approaches will be used to delineate the pathways by which water decomposes metathesis catalysts, knowledge that will be used for the informed design of water-compatible, high-performing metathesis catalysts. Catalyst redesign will be accelerated by streamlined synthetic methodologies that expedite production of new catalysts for screening. Outstanding catalysts identified through this program will be tested in challenging transformations of natural products and pharmaceuticals, by the team and their collaborators in pharma.

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FRIPRO-Fri prosjektstøtte

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