Catalytic Asymmetric Dearomative Spirocyclisations

The design of new methods to synthesize and manipulate complex heterocyclic molecules is extremely important , especially given that such compounds form the basis of a vast array of biologically useful natural products, pharmaceuticals and crop protection products. In particular, procedures which allow complex 3D molecular architectures to be constructed quickly from simple precursors are of great importance, as they facilitate the biological testing of previously unexplored regions of 'chemical space' for potential applications (e.g. in drug discovery). As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically active heterocycles. This proposal centres on the formation and subsequent elaboration of spirocyclic 3D scaffolds from far simpler, readily available 2D aromatic precursors. A series of two-step protocols based of 'dearomatisation' (to form the key 3D building block) and 'functionalisation' (to exploit its high reactivity and further increase molecular complexity) are proposed. Highly promising preliminary studies have been carried out which establish the viability of this novel approach; the key dearomatsation step is performed using a very small quantity of a simple copper or silver catalyst and is easy to perform, employing mild conditions and non-toxic reagents. The discovery of a number of extremely versatile one-pot protocols is anticipated. The methods developed will also be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. The main aims of the proposal are therefore:

(i) to establish electrophilic alkyne activation as versatile method for the dearomatisation of heteroaromatics leading to novel spirocycles;

(ii) to investigate the use of solid supported catalysts and 'flow' variants of the key dearomatisation / spirocyclisation reaction;

(iii) to develop asymmetric variants (building on the 77% ee, 99% yield obtained in preliminary studies);

(iv) to exploit the synthetic potential of the 3D 'building blocks' generated by examining additional functionalisation modes, including reactions with a range of nucleophiles, cross-coupling reactions and redox processes;

(v) to investigate alternative electrophilic activation modes;

(vi) to develop cascade reaction sequences and to apply these methods in target synthesis: Satavaptan, spirobacillene B, plicamine, coerulescine, spirobenzofuran, coixspiroeneones A-E, rychnophylline, mollenine A and cephalotaxine have all been identified as potential natural product/pharmaceutical targets. In addition, medicinal targets suggested by collaborators will also be considered.

It is our aim that the dearomatisation/functionalisation protocols will become indispensable tools for the construction of biologically important 3D scaffolds, with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes.

This ambitious programme will be carried out by a PDRA over a 3 year period.

As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically important heterocycles. This proposal centres on the formation and subsequent elaboration of versatile spirocyclic building blocks from simple aromatic precursors. The methods proposed are expected to expedite the synthesis of a vast array of diverse, highly functionalised 3D scaffolds with high therapeutic potential from simple, readily available aromatic precursors. A straightforward two-step system of 'dearomatisation' and 'functionalisation' is proposed; these methods use mild reagents and conditions and are expected to lead to the development of a range of extremely versatile one-pot protocols. Thus they will be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry.

In view of the operational simplicity and versatility of the proposed methods we believe that its potential is enormous. We plan to optimise the procedure, explore its scope, develop solid supported/flow variants and prepare the products as single enantiomers, as required by the regulatory authorities. We will also seek to further increase molecular complexity by adapting the methods developed for use in cascade reaction sequences. Finally, we will apply this new cyclisation procedure to prepare complex pharmaceuticals and bioactive natural products in order to validate and showcase the novel chemistry and highlight its utility. Given the novelty and efficiency of the chemistry carried out in preliminary studies, and the highly encouraging asymmetric possibilities, high profile publications are likely.

It is our aim that the key dearomatisation process and the resulting spirocyclic building blocks will have 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, and those involved in the development of improved "green" routes to high value synthetic intermediates. In addition, these new procedures, which dramatically increase the ease with which bioactive heterocycles can be prepared, could well lead to the discovery of new drugs or agrochemicals which would 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 and agrochemical candidates. We will also seek to establish collaborations with the discovery arms of UK/EU pharma/agro-chemical companies, and later with scale-up and production chemists in industry.

All potentially valuable IP arising from this research programme will 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 80 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.