Chemoselective cross-coupling via control of anion metathesis at Pd(II)

Palladium-catalysed cross-coupling has revolutionised the way molecules are made and are essential to the continued production of myriad products from small bioactive molecules to materials and from small scale to manufacture. A number of these processes have become privileged, with their impact demonstrated from tonne-scale application to the Nobel Prize. Increased mechanistic understanding of catalytic reactions underpins improvements of existing processes while driving development of new methods. By interrogating reactivity and selectivity as a function of the palladium species formed from a key anion exchange (metathesis) event, this proposal aims to bring new understanding to the most important classes of cross-coupling reaction while providing methods for the preparation of novel and synthetically powerful architectures.

Our preliminary proof-of-concept experiments in support of this proposal have shown that the anion metathesis event is influenced by different variables specific to catalytic reactions (for example, the substrate, the reaction medium). We have also shown that stoichiometrically prepared palladium complexes with different anions have profoundly different reactivities when assessed using a bifunctional chemical probe. Lastly, we have tentatively shown that this differential reactivity can allow the preparation of highly useful molecules.

This proposal will comprehensively investigate this anion metathesis event to allow predictability and the rational application of this unappreciated event as a method for catalytic control of multi-reactive systems and, in this proposal, allow access useful synthetic scaffolds tailored towards application in Medicinal Chemistry.

Potential Economic Impact of the Research. Catalysis is central to the preparation of molecules for healthcare (pharmaceuticals, imaging), food security (herbicides, pesticides), and devices and energy conversion/harvesting (materials, catalysts). The importance of catalysis and a strong UK presence in this field has been highlighted in major reviews including the International Review of Chemistry, REF, the RSC Chemistry Roadmap, and the Chemistry Innovation Knowledge Transfer Network roadmap. This National Importance is reflected in EPSRC physical sciences strategy: advances in catalysis support the Energy, Manufacturing the Future, and Healthcare Technologies themes and the "Dial-a-Molecule" Grand Challenge.

Underpinning this proposed research programme is the development of new knowledge of Pd catalysis. The new knowledge gained here may be used to facilitate more rapid access to molecules (e.g., in discovery phase) or more efficient access to molecules (e.g., in process chemistry) ultimately leading to economic gain of the company and wider UK in due course. In collaboration with GlaxoSmithKline (GSK) as well as using our own established platform, we will explore the application of this new synthetic methodology in the context of Medicinal Chemistry for the step-efficient construction of bioactive molecules with specific function. The applicant has strong programme of catalytic reaction development and collaborative Medicinal Chemistry projects with well-defined knowledge transfer mechanisms. The applied aspects have been designed in consultation with our project partner to ensure business relevance, therefore promoting impact and fostering further collaboration.

Outputs: Patent protection of intellectual property; exploration of licenses, develop new medicinal agents independently and in collaboration with GSK.

Mechanisms of delivering Economic Impact: Knowledge Exchange partnership and EPSRC Impact Acceleration Account (IAA), Scottish Enterprise Proof of Concept or the Technology Strategy Board's Biomedical Catalyst.


Potential Societal Impact of the Research. The objective of this research is to improve knowledge and control of catalytic processes and show this can be applied. In the context of new knowledge, improved understanding of Pd catalysis may allow the refinement of chemical processes that ultimately benefit the production of materials of products that may have a downstream impact on the consumer while also improving economy (see above). In the context of Medicinal Chemistry, new medicinal chemistry agents for hard to treat diseases (for example, the PI's programme targets Idiopathic Pulmonary Fibrosis, which has just been granted Orphan Status) have a clear impact on society by prolonging or improving life. Thus the potential societal impact of this proposed programme could be very significant.

Outputs: Public discussion of the role of catalysis in the pharmaceutical industry; dissemination of results through the mainstream press, and UoS websites.

Mechanisms of delivering Societal Impact: Delivery of presentations at the Glasgow Science Festival and Glasgow Science Centre events.