Spiroclip Technology: from Catalogue to Spirocycle in One Step

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In order to meet burgeoning worldwide healthcare and food-security demands, rapid access to diverse organic structures is the key to continued progress in the pharmaceutical and agrochemical industries. There is a growing acknowledgment that traditional synthetic approaches have been limited in terms of the range of complex 3D-structures and there is much current research based on the investigation of more 3D molecules to address this shortfall. However, such synthetic approaches to non-planar organic architectures are often time-consuming and labour-intensive.The problems of poor synthetic accessibility are particularly acute for the synthesis of a class of molecules called spirocycles, systems that have been recently identified as important but under-exploited scaffolds. The main aim of this proposal is to design and develop novel chemistry to make a diverse range of spirocyclic structural types via one-step or one-pot procedures, from catalogue starting materials, using robust and scalable protocols which will be readily adopted by industrial partners to generate building blocks, biological probes and, particularly, fragments for drug discovery. Extensions to give 'single-handed' (enantiomerically pure) variants, solid-supported options, and further diversification will be explored. Validation of the new methods in the synthesis of real drugs/biologically active materials will also be attempted. Collaborators will be consulted to ensure that the molecules made are appropriate for real-life industrial applications; e.g. they possess good 'drug-like' properties, with capacity for further elaboration, and where possible, that they occupy 3D-space that is under-represented in typical drug screening libraries. Potential pharmaceutical and agrochemical lead compounds which will be made available for biological screening. The proposal is underpinned by significant and promising preliminary studies and we anticipate that the study will also lead to advances in our knowledge of fundamental principles in catalysis, mechanism and synthetic chemistry. We also expect that the sequences will be adopted by synthetic chemists in both industrial and academic arenas. The new chemistry and technology described fits full square in the EPSRC Dial-a-Molecule grand challenge area, and in several current Priority Areas (Catalysis, Novel and Efficient Chemical Synthesis, Sustainable Chemistry and eventually New Physical Sciences for Biology and Healthcare, and Innovative Production Processes). The new science is also relevant to the areas of catalysis and training highlighted in the EPSRC Strategic Plan 2015, with great potential in the manufacturing and healthcare sectors, also highlighted in the 2015 plan. In addition, the novel chemistry should be useful to prepare new structures relevant to the 2014 EPSRC initiative in anti-microbial resistance (AMR). Of particular importance are the potential applications of the new methodology in the UK pharmaceutical and agrochemical industries.This ambitious programme will be carried out by a PDRA over a 3 year period.