A Unified, Practical Synthesis of Five-Membered Aromatic Heterocycles

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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.