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

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.

Heterocyclic compounds are the mainstay of the pharmaceutical and agrochemical industries. Oxindoles are of particular importance, as indicated by the recent success of Sutent, Pfizer's blockbuster anti-cancer drug. In 2010, we discovered a high yielding and practically straightforward procedure for the preparation of 3,3'-disubstituted-oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach. This "green" procedure uses cupric acetate monohydrate (< £1/10 g), in catalytic amounts, with toluene as solvent and gives high yields without the need to exclude air and moisture.

We believe that the potential of this new copper-based methodology is enormous, not only for the preparation of oxindoles, but also to prepare other important heterocyclic compounds. In this proposal we will first extend this novel copper-based route to prepare spirocyclic oxindoles, and will then go on to develop procedures which enable the substituted oxindoles to be prepared as single enantiomers, as required by the regulatory authorities. In addition, we will extend the copper-based methodology to prepare related heterocyclic systems. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate this novel chemistry and highlight its utility.

It is our aim to develop this copper-based procedure into a truly powerful synthetic tool with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes. In particular, we believe that this research will impact greatly on academic groups involved with the preparation of biological lead compounds and in natural product synthesis. In addition, these novel copper-catalysed Ar-H / C-H double activation processes will be of direct relevance to the rapidly growing number of research groups involved in C-H activation projects and in the development of improved "green" routes to high value synthetic intermediates. Researchers interested in mechanistic organic chemistry, particularly involving copper-catalysis and radical processes, will also be intrigued by the results of this research, which should inspire new synthetic and mechanistic advances. Collaborations will be established in these areas.

In addition, these new copper-based procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs which would enhance the quality of life and thus make a direct societal impact. In terms of compounds prepared in York on this project, we will make novel synthetic analogues and natural products available for bioassay in the laboratories of our collaborators in order to identify potentially useful drug candidates. We will also seek to establish collaborations with the discovery arms of UK/EU pharmaceutical and agrochemical companies, and later with scale-up and production chemists in industry.

All potentially valuable IP arising from this research programme will then be discussed with the University of York Industrial Liaison Office, and with any industrial collaborator, and patent protection will be investigated. Once IPR is secure, the results will be published in the scientific literature and described in lectures/poster displays and using the www.

This research programme will also have a direct impact in terms of the production of highly trained manpower. Around 75 research personnel from the Taylor group have entered the chemical industry and many have also gone into academic and teaching appointments. The postdoctoral researcher on this grant, together with any associated students (final year project, Erasmus etc.), will be experienced in the development and optimisation of organic methodology, and in heterocyclic and natural product chemistry, at the frontiers of the area, and so will be in great demand for industrial, teaching or academic vacancies.