Cu(II)-Catalysed C-H Activation Routes to Heterocycles; Applications in Target Synthesis

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Heterocyclic compounds are the mainstay of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of medicinal interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly synthetic procedures. Thus, we have successfully developed a number of improved routes to heterocyclic building blocks utilising cascade and telescoped processes. As part of this programme, we recently developed a high yielding moisture- and air-insensitive procedure for the preparation of 3,3'-disubstituted oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach using an extremely cheap and readily available reagent, cupric acetate monohydrate (ACS grade, < £1/10 g), in DMF as solvent. Such a straightforward method of generating quaternary stereogenic centres is noteworthy. In 2010, we discovered a much improved procedure which uses catalytic amounts of cupric acetate monohydrate in toluene or mesitylene as solvent and gives equally high yields of oxindole products without the need to exclude air and moisture.We are now fully focused on demonstrating the broad utility of the improved cupric acetate monohydrate procedure and we believe that the potential of this methodology is enormous, particularly, given that many of today's drugs are based on oxindoles (e.g. the blockbuster anti-cancer drug, Sutent). The main aims of this proposal are therefore: (i) to further exploit the novel copper-based C-H activation chemistry to develop a route to spirocyclic oxindoles, (ii) to explore the development of asymmetric variants for all substrate classes, (iii) to extend the methodology to the synthesis of related heterocyclic systems, and, very importantly, (iv) to apply, and therefore validate, the new copper-catalysed cyclisation procedure in complex pharmaceutical and natural product target synthesis. It is our aim to develop this new procedure into a truly powerful synthetic tool with far-reaching applications in both academic research and industrial medicinal chemistry and scale-up processes. This ambitious programme will be carried out by a PDRA over a 3 year period.