Catalytic Asymmetric Dearomative Spirocyclisations

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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.