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Complementary Synthetic Strategies toward Heterocyclic Boronates

Final Report Summary - COSSHNET (Complementary Synthetic Strategies toward Heterocyclic Boronates)

Abstract

COSSHNET is a dual-partner Industrial Doctorate (EID) offering research training in state-of-the-art chemical synthesis, catalysis, bioactive molecule design and high throughput library synthesis. Through integration of the complementary, interdisciplinary and intersectorial expertise of the partners, this network helped to strengthen Europe’s human resources in the fine chemical and pharmaceutical industries. The researchers were supervised and mentored by internationally recognised experts and had access to state-of-the-art equipment. Hands-on training was supplemented by formal training courses in relevant and related fields, and a wide variety of complementary training courses, summer school and seminars. Researchers benefited from secondments to the industrial partner for a significant period of the project, thereby gaining extensive exposure to a commercially based scientific environment. Overall, the COSSHNET project provided both Early Stage Researchers (ESRs) with an outstanding training experience, through extensive technical and complementary skills development.

Overview and overall objectives:

The dual-partner Industrial Doctorate brought together expertise from the Harrity group at the University of Sheffield and the global healthcare leader Sanofi to make available a selection of technologies for the discovery and chemical synthesis of new small molecule entities. As small bioactive molecules will continue to play an important role in addressing areas relating to health and food security that are of critical concern to the EU, this important action was developed to support and grow the knowledge base in this area.

Traditionally, the Fine Chemicals sectors have favoured the design and development of heteroaromatic compounds. Therefore, one aspect of this activity was to take advantage of classical medicinal chemistry concepts to provide a platform for new advances in these areas based on well-established principles. However, taking inspiration from the biological profile of natural products, the chemistry community has also begun to explore lead compounds bearing multiple sp3-centres and complex stereochemistry. A second and complementary activity therefore focused its small molecule innovation areas towards the synthesis and functionalization of complex heterocyclic compounds. Accordingly, the projects carried significant opportunities to develop areas relating to catalysis and flow chemistry techniques. With respect to the latter, we had significant input from Sanofi who have state-of-the-art expertise and infrastructure in flow chemistry that promised to generate target molecules using faster and cleaner reaction processes with the potential for simple scale-up protocols.

Project website: https://sites.google.com/a/sheffield.ac.uk/cosshnet-eid-itn/home

Progress and results

The 2 recruited ESRs developed new synthetic methods towards heterocycles of value to the pharmaceutical industry. Specifically, an ynone condensation strategy has successfully delivered pyrazole and thiophene boronic acid derivatives, allowing a wide range of hetereoaromatic products to be made available through established cross-coupling chemistry. Moreover, an electrocyclisation method has been discovered that generates highly functionalised pyridines. Both ESR projects progressed well towards the stated objectives. Moreover, and through guidance from our partners at Sanofi, these techniques were refined to allow easy incorporation of sp3-rich heterocyclic motifs. In this way, these complimentary synthetic methods appear to enable the delivery of a wide range of small molecule scaffolds. The potential of both methods to deliver small libraries of lead-like molecules was assessed during the secondment at Sanofi. Intermediates based on the chemistry developed within this programme were exploited in the synthesis of pyrazole, thiophene and pyridine derived compounds. These compounds were analysed for their drug like properties, allowing an assessment of their suitability for further development as pharmaceuticals.
Impact

COSSHNET delivered benefits at the European level in two principal areas; through contributions to the objectives of the European Research Area (ERA) and improving the scientific understanding in support of European policy. The scientific themes and objectives of COSSHNET helped to address research priorities in the Suschem European Technology Platform. COSSHNET contributed to the research needs identified in this Suschem theme by: (i) improving the efficiency of synthetic routes to functionalised heterocyclic compounds through smart synthesis design; (ii) the introduction of new transition metal catalysed cyclisations for the regio- and stereoselective synthesis of drug-like functionalised intermediates; (iii) introducing new reaction platforms and media by the exploitation of high throughput methods.

Overall, the action provided a platform for a new generation of young European scientists to further develop this exciting field through the collaboration of a network with expertise in the design and synthesis of new functionalised heterocycle scaffolds and their employment in drug discovery.