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

Lead Research Organisation: University of Sheffield
Department Name: Chemistry

Abstract

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.

Planned Impact

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.
 
Description This award has allowed the discovery of an efficient resolution of a variety of nitrogen-containing heterocycles. These compounds are of importance to the pharmaceutical industry as potential drug fragments or scaffolds and the methodology has potential for exploitation for related synthetic chemistry and medicinal chemistry. The research has allowed a more in-depth study by calculations (density functional theory) that has led to understanding of the conformations and reactivity of the compounds.

The results of the research have been published in high quality journals and dissemination at conferences and meetings. Significant achievements from the award include the provision of trained scientists (two research associates) and a beneficial collaboration with the industrial sector including product compounds for marketing by the company.
Exploitation Route The methodology developed could be used by other researchers in industry or academia. This will provide novel products with potential use particularly within the pharmaceutical and fine chemical industries. We have published six papers in the primary literature of the results of the research and these are the primary method by which the results have been made available for others.
Sectors Chemicals

Pharmaceuticals and Medical Biotechnology

URL https://sites.google.com/sheffield.ac.uk/coldhamgroup/research/kinetic-resolution-chemistry
 
Description The research led to the production of compounds of interest to the fine chemical and pharmaceutical industries. In particular, the collaborating company Liverpool ChiroChem have used the outcomes of the research and exploited the ability to prepare novel small molecule compounds by incorporating one of these into their catalogue. This enhances the portfolio and standing of the UK company and provides potential economic impact. Their catalogue is available to other researchers particularly those in the pharmaceutical industry, for example as part of compound collections for fragment based drug discovery or building blocks for potential new drugs.
First Year Of Impact 2021
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
 
Description Applying photocatalysis to make nitrogen-containing rings
Amount £103,316 (GBP)
Funding ID NIF\R1\191853 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2021 
End 02/2023
 
Description Preparation of novel substituted small molecules with potential bioactivity: An academic and fine chemicals industry collaboration
Amount £38,899 (GBP)
Funding ID SIF\R2\202031 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2021 
End 02/2022
 
Description Computational chemistry 
Organisation University of Sheffield
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution The PDRA has worked with the partner, Prof Anthony Meijer, to conduct computational chemistry studies. This has resulted in novel results that support the experimental data.
Collaborator Contribution The partner, Prof Anthony Meijer, has provided training and support to the PDRA. This is in the area of Density Functional Theory to perform calculations and has involved the partner's time and expertise to enhance the research.
Impact Publications so far that have arisen from the research: DOI: 10.1002/chem.202101248 DOI: 10.1055/a-1638-2478 The research has been presented at conferences, internal and external.
Start Year 2018
 
Description Liverpool ChiroChem 
Organisation Liverpool ChiroChem
Country United Kingdom 
Sector Private 
PI Contribution We have arranged regular meetings with Liverpool ChiroChem to discuss the research. This has provided an academic link to the company and expanded their access to expertise in a related area of chemistry. The PDRA spent time in the laboratories at Liverpool ChiroChem and contributed to this interaction and understanding.
Collaborator Contribution Liverpool ChiroChem have provided considerable input to the project. In addition to regular meetings to discuss the research, they hosted the PDRA in their laboratories (Jul-Aug 2021). This has led to knowledge exchange and shaped the direction of the research in regard to the types of compounds that have been prepared. Liverpool ChiroChem have contributed chemicals, use of equipment and facilities, and time.
Impact Publications so far that have arisen from the research: DOI: 10.1002/chem.202101248 DOI: 10.1055/a-1638-2478 The research has been presented at conferences, internal and external. An outcome of the research is that one of the compounds has been incorporated into the Liverpool ChiroChem catalogue for marketing.
Start Year 2018
 
Description External lectures overseas 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presentation of the research to academics, postdoctoral fellows, postgraduate students, and undergraduate students at overseas Universities together with discussions of the research with practitioners and interested persons.
Year(s) Of Engagement Activity 2019,2021
 
Description Poster presentation at conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Poster presentation at a conference in the UK. Promoted discussion of the science and interest from external practitioners.
Year(s) Of Engagement Activity 2019,2020,2021
 
Description Presentation to academics in the Department 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Presentation of the research to other academic staff members in the Department. This informed staff of the research to encourage understanding and potential collaboration. For example, in July 2020 a presentation was made as part of a Chemistry Research Showcase Symposium to members of the Department.
Year(s) Of Engagement Activity 2018,2020
 
Description Presentation to postgraduate and undergraduate students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presentation of the research to postdoctoral fellow, postgraduate students, and undergraduate students at the University of Sheffield. This allowed knowledge exchange and greater appreciation of the research.
Year(s) Of Engagement Activity 2019,2020,2021,2022
 
Description Presentations to visitors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The PDRA and PI presented the results of the research to audiences consisting of visiting academics to the Department. This promoted discussion and interest in the work including from international visitors and led to helpful suggestions for further research.
Year(s) Of Engagement Activity 2019,2020,2021
 
Description Web site to promote the research 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A web site has been set up to engage all interested persons across the world. This has encouraged interactions with overseas researchers particularly those who have stated that they have viewed the web pages and would like to carry out research in our group.
Year(s) Of Engagement Activity 2019,2020,2021,2022