C-H functionalisation of saturated nitrogen heterocycles, building blocks for drug discovery

The ability to prepare novel heterocyclic compounds efficiently is critical to the success of the pharmaceutical, agrochemical, and fine chemical industries. With the growing healthcare burden and the increasing market for single mirror image drugs, it is essential that new ways to access such compounds are found that meet this need. Current methods to prepare even fairly simple multi-substituted, saturated nitrogen-containing ring systems that are of medicinal relevance are often long-winded and complex, particularly for quaternary substituted compounds where more than one substituent is located on the same carbon atom.

This project will use simple chemistry with readily available reagents and a diverse selection of easily accessed starting materials to prepare novel substituted heterocycles, including quaternary substituted compounds. The chemistry uses a simple deprotonation, yet this provides a powerful way to provide a range of different products. In addition it allows the ability to control the absolute configuration to prepare heterocycles that are enriched as a single mirror image.

The project will be carried out in collaboration with industry to help steer the choice of targets. The aim will be to generate compounds of pharmaceutical interest that will be made available as scaffolds for drug synthesis. In addition, we aim to uncover principles of mechanism and molecular interaction through collaboration by carrying out calculations and spectroscopy.

The research is aligned with the EPSRC Dial-a-Molecule grand challenge and with the priority areas of novel and efficient chemical synthesis, sustainable chemistry, and potentially new physical sciences for biology and healthcare. It also fits with the EPSRC strategy to champion excellence in research, training, and impact as described in the Strategic Plan. This project has particular application to the UK fine chemical industry and hence the pharmaceutical industry and will enhance the EPSRC world-leading investment in partnership with industry.

Who might benefit from this research?

This proposal describes research to benefit academic and industrial researchers particularly in the field of chemistry. The focus is on developing new ways to make substituted saturated and partially saturated heterocyclic compounds especially with control of stereochemistry. The research makes use of relatively simple chemistry to allow substitution of heterocycles and will allow access to new substituted heterocycles of relevance to the pharmaceutical, agrochemical, and fine chemical industries. This will benefit academic groups who want methods to prepare novel structures or test properties of compounds. It will also benefit industrial groups who want to access biologically relevant heterocycles for tests in their programmes. The research will benefit the PDRA, who will gain knowledge and skills in research at the forefront of the discipline and being part of helping a research group. It will improve the standing of the UK and the reputation of the UK as it engages in research of the highest quality.

How might they benefit?

The research will lead to an increase in knowledge and understanding in the area of preparing substituted saturated heterocycles. These are of particular importance to industry but also are very relevant to academia as the majority of all known compounds are heterocyclic. Hence researchers in chemistry are likely to benefit from the methods discovered to prepare their own heterocycles. The research could impact on society and lead to economic benefits if the methodology or the compounds are used in industry.

To maximise the impact and ensure that other researchers will be able to benefit and know about the results we will publish the work in internationally acclaimed chemistry journals and through talks at conferences and on-site visits to companies and Universities. The Workplan describes milestones and publications will be written as soon as possible after sufficient data have been gathered for each of the Tasks 1-3 in the programme, as outlined in the Pathways to Impact statement.

The PDRA will benefit from the research experience and the training provided. He or she will develop new skills in synthetic, organometallic, physical organic, theoretical, and spectroscopic chemistry. In addition, interaction with Liverpool ChiroChem will give an industrial and medicinal chemistry perspective that will be invaluable for their future employability. All these aspects will enhance the impact of the project and the standing of the UK.