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FRINATEK-Fri prosj.st. mat.,naturv.,tek

Sustainable and Selective Metathesis: From Fundamental Insights to New Chemicals and Pharmaceuticals

Alternative title: Bærekraftig og selektiv metatese: Fra fundamental innsikt til nye kjemikalier og legemidler

Awarded: NOK 10.2 mill.

Project Number:

262370

Application Type:

Project Period:

2017 - 2022

Partner countries:

Olefin metathesis, a class of chemical reactions sometimes likened to "a dance in which the couples change partners", is the most powerful, versatile methodology known for the assembly of molecular carbon frameworks. Metathesis holds enormous potential as a low-waste, more environmentally benign means of producing new pharmaceuticals and transforming renewable resources. Key to these reactions are molecular catalysts, based on ruthenium. Industrial uptake, however, is limited by the poor stability of these catalysts. A major project goal has been to develop stable, long-lived catalysts that deliver the high productivities essential to expand industrial use. More stable and industrially compatible catalysts will, in turn, make it possible to address another important challenge limiting the application of olefin metathesis: developing catalysts that generate solely the target molecule in each case, rather than product mixtures. Avoiding product mixtures is particularly important for production of pharmaceuticals. The intended biological activity of pharmaceuticals is typically achieved only for one of the potentially many products, that is, only a single molecular structure is responsible for the activity. Achieving such fine control of the product structure and the catalyst stability requires both fundamental insight into the underlying ruthenium chemistry and the means and techniques to convert the fundamental knowledge into new and improved catalysts. To fulfill this requirement, a project team covering a wide range of competences, techniques and infrastructure was assembled, ranging from computational and experimental uncovering of molecular structure and properties, to high-throughput testing of many new catalysts in parallel. Designing more stable catalysts, the first project goal, requires insight into the mechanisms with which they decompose as well as the structural features that determine a catalyst's robustness against each of these decomposition mechanisms. The project has described the key decomposition modes in detail, and, for the first time, uncovered the structural features that accelerate and prevent each of these modes. Remarkably, even if these pathways are different, they all lead to the very similar decomposition products. Even more remarkably, starting from these decomposition products, the active catalyst may be regenerated. The project has thus uncovered that decomposition, in contrast to long-held beliefs, is not irreversible, an insight that may be used to regenerate spent catalyst as well as to design more robust catalysts. The above insights have been, and are being, used to design more stable and long-lived catalysts. The project has been instrumental in showing how emerging catalysts based on a particular class of molecular fragment (cyclic (alkyl)(amino)carbenes, CAAC) are almost immune to a key catalyst decomposition mode that is independent of the catalyst concentration, at the same time as being very vulnerable toward another decomposition mode that depends on the catalyst concentration. The project has thus revealed why these catalysts are excellent, and should only be used, at low concentrations. More importantly, future efforts at designing robust, high-performing catalysts should focus on reconciling the two opposing effects of the CAAC fragments. Attempts at making selective versions, producing narrower product distributions, of the longer-lived CAAC-based catalysts have proven challenging, for two reasons: (i) The new, stable catalysts are less symmetric than their unstable predecessors, and therefore respond less cleanly and predictably to the introduction of molecular fragments intended to achieve selectivity, and (ii) these new, selectivity-inducing fragments have resulted in too bulky and crowded catalyst molecules. In other words, rather than foster chemical reactivity, these catalysts tend to block the starting materials from reacting. Attempts at overcoming these challenges, by making both smaller and more symmetric catalysts, continue beyond the project.

The interdisciplinary approach taken in this project, with one research group (in Bergen) predominantly using computational techniques and the other (in Ottawa) using experimental ones, has proved to be very fruitful. The two groups have continued, and will continue, to use this advantage in other projects, and the approach is also expected to inspire other research groups to adopt similar strategies. The project has offered clear insights into the factors governing catalyst stability and has also pointed at emerging catalysts with superior stability and performance. These catalysts are now rapidly gaining popularity in academia and industry. Long-term, the new, more stable catalysts and the insight gained from the project are expected to help realize the potential of olefin metathesis in challenging transformations of biomass and pharmaceutical manufacturing, thereby contributing to realizing global development goals.

Olefin metathesis, the most versatile methodology known for the assembly of molecular carbon frameworks, has been embraced across chemistry since the 2005 Nobel Prize. This success has been driven by readily-handled ruthenium catalysts, first developed in the 1990s, that tolerate functional group-rich compounds. Surprisingly, however, these catalysts are much less productive than any other leading class of catalyst. They decompose readily, via little-understood pathways, into species that promote competing isomerization of both the 1-alkene reagents and the intended internal-alkene products. Facile isomerization between cis and trans internal alkenes means that low catalyst stability is a particular challenge in stereoselective olefin metathesis. Indeed, this accounts for the inability of any known catalyst to selectively deliver the highly-desired trans-olefin products. To rectify these deficiencies, and unleash the full, vast potential of olefin metathesis in production of specialty chemicals and pharmaceuticals, we will develop new catalysts with much longer lifetimes. From these more stable catalysts, we will, in turn, design productive new catalysts with high cis or trans selectivities. The team consists of computational, structural, organometallic, and organic chemists with globally leading strengths in olefin metathesis, spanning mechanistic studies of activation and deactivation, catalyst design, and synthetic applications. Catalysts will be built via iterative prediction-experiment loops involving rational computational molecular design and experimental implementation. Predictions will benefit from computationally- and experimentally-derived mechanistic insight, and from unique tools for automated molecular design, characterization, and high-throughput catalyst screening. Lead catalysts will be tested in challenging transformations of natural products and pharmaceuticals.

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FRINATEK-Fri prosj.st. mat.,naturv.,tek