Spiroclip Technology: from Catalogue to Spirocycle in One Step

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.

Our over-riding aim is to develop novel yet practically straightforward chemistry that directly benefits academic, industrial discovery and industrial scale-up chemists.

Rapid access to structurally- and shape-diverse organic compounds is the cornerstone of lead generation in the pharmaceutical and agrochemical industries, essential to meet the burgeoning worldwide healthcare and sustenance requirements. As part of our on-going research programme geared towards the synthesis of diverse organic scaffolds, we have placed great emphasis on designing streamlined and environmentally-friendly cascade and telescoped processes leading to biologically important scaffolds. However, current synthetic approaches to generate complex 3D organic architectures are often time-consuming and labour-intensive.

In this programme, a number of simple and scalable synthetic routes will be designed to convert cheap, commercial starting materials into novel spirocyclic products which will be selectively converted into a range of diverse structural scaffolds, fragments and targets with biological potential. Attention will be given to environmental preparative factors and the sequences will be designed to generate products which occupy 3D space that is under-represented in typical screening libraries; 3D shape will be evaluated computationally. We therefore believe that the potential of this new chemistry is enormous. Rapid dissemination of the new results in meetings, seminars, scientific conferences and high profile publications will ensure its early adoption and hence academic impact.

To maximise the impact in industrial laboratories we will work closely with our existing industrial pharmaceutical partners (Lilly), and with ongoing collaborators in the agrochemical area (Syngenta). These interactions will be invaluable to optimise the design (3D and lead-like properties) of the target products, to organise the optimum biological screening (all synthetic compounds made in York will made available), and to discuss structure-activity relationship (SAR) results. Note that materials transfer agreements have been agreed with both companies and University-approved contracts ave been signed to cover these activities. Taylor is also a member of the EU Innovative Medicines Initiative (IMI): CHEM21: "Chemical Manufacturing Methods for the 21st Century Pharmaceuticals Industries"(Euro26.4M) a consortium involving 6 pharmaceutical companies (GSK, Sanofi, Pfizer, Orion, Bayer Pharma and Janssen), four SMEs and several Universities from across Europe aiming to develop sustainable procedures for the manufacture of medicines. Such interactions will be employed to popularise the new methodology in UK/European research labs. We will also establish specific collaborations with the discovery arms of UK/EU pharma/agro-chemical companies, and later with scale-up and production chemists.

All potentially valuable IP arising from this research programme will be discussed with the University of York Industrial Liaison Office, and with any industrial collaborators, and patent protection will be explored. The results will then be published in the scientific literature, disseminated in lectures/poster displays, and publicised using the university/departmental web resources.

This research programme will also have a direct impact in terms of the production of highly trained manpower. Around 100 research personnel from the Taylor/Unsworth groups have been employed in the chemical industry and many others have gone into academic and teaching appointments. The postdoctoral researcher on this grant, together with any associated students (final year project, Erasmus, PhDs), 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, science communication or academic vacancies.