Spirocycles, Carbocycles and Heterocycles: Unified Routes via Catalyst Selection

Rapid access to structurally 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. There is a growing realisation that traditional lead identification programmes have been limited in terms of their treatment of 3D structures and there is much current research based on the investigation of molecules which cover much wider regions of chemical space. However, such synthetic approaches to generate complex 3D organic architectures are often time-consuming and labour-intensive - and separate routes are normally required to access different types of structure.

In this programme, a number of simple synthetic routes will be designed to convert cheap, readily available starting materials into high energy reactive intermediates which will be selectively converted into a range of diverse structural types by careful choice of catalysts. Attention will be given to environmental factors (low catalyst loading, telescoped procedures, scale-up potential). This part of the study will uncover fundamental principles in catalysis, mechanism and reactive intermediate chemistry. The sequences will be designed to produce products which occupy 3D space that is under-represented in typical screening libraries and which possess good 'lead-like' properties; 3D shape will be evaluated computationally using a process called principal moments of inertia (PMI). Extensions to give asymmetric variants, solid-supported options, and further diversification will be explored as will validation the novel methodology in target synthesis.

In collaboration with our industrial partners, some targets will be chosen with the aim of generating 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 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 a great deal of 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 - and separate routes are normally required to access different types of structure.

In this programme, a number of simple synthetic routes will be designed to convert cheap, readily-available starting materials into high energy reactive intermediates which will be selectively converted into a range of diverse structural types by careful choice of catalysts. 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 using a process called principal moments of inertia (PMI). 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 (Astex, AstraZeneca, Lilly, Pfizer and Vernalis) in the "York 3D Fragment Library" project, and with ongoing collaborators in the agrochemical area (Bayer and 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. Taylor is also a member of the EU Innovative Medicines Initiative (IMI): CHEM21: "Chemical Manufacturing Methods for the 21st Century Pharmaceuticals Industries"(2012-16; 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 serve to popularise the new methodology in UK/European industrial 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 collaborator, and patent protection will be investigated. 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 100 research personnel from the Taylor/O'Brien groups have entered the chemical industry and many more have also 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 or academic vacancies.