NEXT GENERATION RUTHENIUM-CATALYSTS FOR LATE STAGE C-H FUNCTIONALISATION

Catalytic C-H functionalisation is an emerging area of research that has the potential for revolutionising the way chemists make molecules. These new synthetic tools aim at transforming any C-H bond in an organic molecule into any other functionality with complete control, much like one builds models of molecules using plastic balls and sticks. Having a full set of catalysts to perform any desirable modifications in any conceivable molecule is the ultimate aim of the field. This would open a new dawn for molecular sciences, by allowing the straightforward preparation of most molecules, thus accelerating development of pharmaceuticals, sensors, agrochemicals, and organic materials, as well as molecular biology (and chemical biology), contributing to increasing our understanding of biological interactions at the molecular level.

In order to reach this objective, we need to develop novel catalysts and strategies that allow selecting and distinguishing a particular C-H bond from the many others present in a molecule. The selected bond then needs to be broken ('activated') and a different group installed. Furthermore, the catalysts need to be mild and chemoselective, which means that they should not affect any other sections of the molecule as side effects. This is particularly challenging, as C-H bonds are generally much stronger than many common functional groups in molecules.

Our research will investigate the creation of a set of powerful catalysts, based on ruthenium, which can carry out C-H activation with exquisite selectivity, allowing the transformation of one C-H bond in a complex molecule without affecting any other parts of the molecule. While most common catalysts require high temperatures, these catalysts will operate at room temperature, not only facilitating their use on delicate molecules but also providing energy savings. These catalysts will be useful to synthesise new molecules from scratch. Even more importantly, these catalysts will allow the transformation of complex known molecules into new ones in a controlled way (late stage functionalisation), allowing for example the easy modification of current pharmaceuticals in order to modulate their activity, toxicity, side effects...

We will develop a novel set of Ru-catalysts and associated catalytic synthetic methodologies that will provide straightforward access to a variety of direct C-H functionalisations from simple readily available starting materials. Importantly, our catalysts will operate under very mild conditions and will be compatible with heavily functionalised molecules, being suitable for late stage functionalisation of available pharmaceuticals, agrochemicals, natural products and other biologically active molecules. This will greatly enhance our capacity for development in several areas of great impact to society. Furthermore, the novel highly functionalised molecules generated in this project could have potential for applications in a variety of areas that depend on a supply of specialised organic compounds. Thus, this research will deliver both short and long term impact in the following areas:

1) General organic synthetic chemistry: the new catalysts and tools created during the project will be of immediate use for synthetic chemists in all areas, such as natural product synthesis, materials, diversity oriented synthesis and drug discovery.

2) Pharmaceutical companies will benefit from the development of novel C-H functionalization methodologies capable of late stage functionalisation. These techniques have tremendous potential for speeding up drug discovery (by efficiently generating thousands of compounds from a single advanced lead, avoiding lengthy de novo syntheses), provide access to new chemical space and access to new intellectual property space via modification and improvement of current pharmaceuticals. There are currently 6.4 million potentially suitable bioactive (C-H) (hetero)aromatic compounds and, for example, 22 million (hetero)aryl chlorides, bromides iodides and phenols (PubMed data). This means that the chemical space accessible with only one of our new methods (late stage C-H arylation) would be up to ca 140 trillion novel compounds. Our research will have immediate impact on this sector, as the new methodologies will be readily applicable.

3) Novel compounds with new properties: during the course of this project a large library of novel functionalised compounds will be generated. Samples of these compounds can be provided to other academic groups working on a variety of areas (from medicinal chemistry to chemical biology) and are likely to result in further impact in those fields.

4) During the course of this project, two postdoctoral researchers will be trained in state-of-the-art homogeneous catalysis and organometallic chemistry. These skills will make them invaluable for both an academic and an industry environment, as an expert in an expanding area with numerous applications.

5) Dissemination and education: as part of the dissemination of this project, we will produce a video targeted to non-scientists with the aim of introducing the research area, its benefits and its societal impacts to the general public. This engagement will raise the awareness of the importance of our research, and basic research in general, among the public.

6) Long term impacts to society may result from this research: the tools developed in our research will inspire further development of clean, efficient and greener methodologies for C-H functionalisation. Eventually, in a number of decades, the combination of research in the area will lead to chemists being able to rapidly and easily synthesise any molecule of interest with minimal waste, thus providing a major boost to all scientific areas that depend on 'designer molecules', such as medicine, drug discovery, materials and others.