A Unified, Practical Synthesis of Five-Membered Aromatic Heterocycles

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


The world's top-selling pharmaceutical of 2000-2012 was the cholesterol-lowering drug Lipitor, an organic molecule containing at its core a five-membered ring called a 'pyrrole', which comprises four carbon atoms and one nitrogen atom. A related five-membered oxygen-containing ring called a 'furan' is another common motif found in many drugs and agrochemicals, such as the pyrethroid insecticide resmethrin. Although these and other structurally similar organic ring systems continue to form a cornerstone of research in the pharmaceutical and agrochemical industry, the most common methods for their synthesis restrict the design of new drug / agrochemical leads, due to the intrinsic structural requirements of the chemical reactions used to build the ring.

In this proposal, we aim to develop a new reaction that can prepare four different classes of these important molecules, using a novel palladium-catalyzed process to form the ring system. The method will be able to access a wide range of products (many previously unattainable), as it allows us to easily 'tune' the positioning of different functional groups around the ring. We plan to use conceptually simple, easily applied methods to assemble the reaction substrates from cheap starting materials (such as alkynes, aldehydes and ketones), thus enabling the research to be readily adopted by end users. These short synthetic routes minimise environmental and economic cost, as does the avoidance of expensive air or moisture sensitive catalysts, and toxic reagents. Taken together, these considerations fit neatly into the EPSRC Grand Challenge theme of 'Dial-a-Molecule', whereby a single reaction type can 'dial up' many different products in a straightforward and rapid fashion.

To maximize the impact of this research, interactions with industrial end-users in the UK pharmaceutical and agrochemical industry form an integral part of this proposal. By directly collaborating with two companies through an interactive knowledge and material exchange programme, we will be able to explore targets of specific and current industrial relevance, and also ensure that the technology we develop can be readily adopted by these industries. This could facilitate the development of new pharmaceuticals and agrochemicals (not least through testing of compounds we will make in the course of the project) - which has consequent benefits not only from an economic perspective, but more importantly in improving human health and in tackling the global challenge of food security.

In summary, a combination of robust synthetic methodology, cheap starting materials, and commonly available catalysts could lead to a new and readily deployed method for the synthesis of four important organic compound classes with a proven track record of application in human health and agriculture. This work will streamline research in these fields, which are major global challenges of the 21st century.

Planned Impact

This project aims to develop a new catalytic technology, widely communicated to beneficiaries, which enables the rapid and 'dialable' construction of five-membered aromatic heterocycles. Drugs and agrochemicals with these cores are proven success stories on the commercial market; improving the synthesis and diversity of these compounds could lead to significant national and global impact.

The main beneficiaries of the research are expected to be workers in the pharmaceutical and agrochemical sectors. By establishing collaborations with two UK pharma/agrochem companies, we take steps to deliver the impact envisaged from this project by directly engaging with end users in a proactive and responsive manner. The benefit to these companies arises from the development of new, flexible technology for heterocycle synthesis, and its direct transfer to workers at UK sites, which facilitates commercial implementation. Our engagement with these companies includes the identification of targets against which we can evaluate and refine the chemistry, and also biological evaluation of appropriate products. There is thus a real possibility that useful bioactive leads could emerge directly from the project, resulting in economic benefit, and improved human healthcare and agriculture (new drug /agrochemical leads). As compound screening is built into the 'in kind' contribution from these collaborators, we hope to accelerate knowledge transfer and adoption of the technology.

Society at large will benefit from the heterocycle products arising from these sectors. Given the proven track record of relevant heterocycles such as atorvastatin (Lipitor) and ranitidine (Zantac) - blockbuster drugs with multi-billion dollar returns - the potential for economic gain through facilitation of lead discovery is clear. This improves scientific and economic UK competitiveness; equally, applications in human health or agriculture result in improved quality of life. The importance of these impacts is emphasised through the EPSRC's own mission / priority funding areas (Healthcare technologies, Catalysis, Sustainable technologies) and also by the recognised need for improved agricultural yields to respond to the health and food demands of the growing global population.

A feasible timescale for the realisation of these benefits sees transfer of reaction technology to commercial beneficiaries in the course of the grant, via meetings and short secondments by the PDRA to the collaborators, facilitating adoption and implementation of the chemistry. Our publication strategy will disclose this work to a wider audience during and beyond the period of the project. Economic / health benefit is a longer term prospect (10 years) due to the timescale of discovery-to-market, but it is clear that the importance of these compound classes supports a realistic anticipation of significant economic return.

The PDRA working on this project will assimilate new research skills, and enhance their professional network through commercial and academic interactions. They will gain a wider appreciation of the interests and needs of the commercial sector, which will be of use in their future employment. Presentation, leadership, and project management skills, which form an essential part of the collaborative feedback loop, will also be developed.

Societal impact also arises from public engagement, where we build on a recent Pathways to Impact grant linked to the Oxford Botanic Garden. The PI will continue to engage with the community by connecting aspects of this chemistry research to plants. Public discussion forums and school activities will be held, centring on the use of chemicals in agriculture as a necessity to meet the demands of the growing global population (see Pathways to Impact). The PI will use this outlet to increase public awareness of the role of chemistry in society, and how advances in methodology translate to new bioactive molecules.


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Description We have discovered that the heterocycle ring systems we were targeting can be prepared using a novel concept in catalysis, namely the use of two catalysts in one reaction pot where each catalyst is the same metal species, but in a different oxidation state. This is a unique finding in catalysis, to the best of our knowledge. We have also discovered an alternative reaction pathway whereby two different metal catalysts act in concert to form the heterocycle product.
Exploitation Route The routes developed to the heterocycle targets are readily applicable and scalable. We have published a manuscript on our work in ACS catalysis, in which we demonstrate a rare case of two oxidation states of the same metal playing discrete roles in a catalytic cascade process. This concept of dual oxidation state catalysis could be used by other catalysis researchers.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology