The importance of skeletal mutation synthetic methodologies, which insert or delete atoms or functionality in the ‘core’ of molecules, is disrupting how chemists make complex molecules. In particular, the ability to rapidly ‘hop’ between different molecular scaffolds (e.g. a quinoline to an indole) impacts lead optimization stages of drug design. It allows a streamlined access to target derivatives from a common starting point instead of bespoke synthetic routes to each target, thus accelerating discovery programmes and minimizing chemical waste from synthesis. However, the stoichiometric reactants and intermediates used for skeletal editing strategies thusfar (atom insertion or atom deletion) are high in energy, posing hazards of safety (explosivity) and storage (degradation). Visible light photochemistry allows generation of high energy intermediates in situ from abundant, safe visible photons. Flow reactors allow to i) increase the scalability of chemical processes while minimizing the quantities of hazardous reactants/intermediates ii) maximize light penetration for photochemical reactions. Taken together, flow photochemistry represents an ideal platform to achieve skeletal mutations, yet has been underexplored to date. 

Using their expertise in photo- and flow chemistry,[1-5] Dr Joshua Philip Barham’s group at the University of Strathclyde is pursuing this goal. With preliminary results in hand, we are now recruiting for a PhD position.

Applications are welcome for motivated candidates for a PhD student interested in using photochemistry and continuous flow technology for a novel, skeletal mutation of complex heterocyclic molecules, including drug scaffolds. You will form part of a 4-person team (two PhD students and one postdoctoral researcher), working with a postdoctoral researcher with expertise in skeletal editing. You will interact with an expanding team of PhD students and postdoctoral researchers researching synthetic photoelectrochemistry, in the context of Dr. Barham’s UKRI EPSRC Grant (formerly European Research Council Starting Grant, title: Hybrid Electrochemically-mediated Light Irradiated Organic Synthesis (HELIOS)).

Aims of the project

• to develop flow photochemical reaction conditions for a novel skeletal mutation of a commonplace heterocyclic structure in medicinal chemistry, building upon preliminary results
• to apply the methodology to a broad substrate scope of simple scaffolds and generate various ring sizes of products
• to examine the feasibility of the methodology to existing top-200 selling drug molecules, with potential to generate new (patentable) analogues that access new chemical spaces

The project will be co-supervised by Prof. Craig Jamieson and a member of staff at a leading UK pharmaceutical company. Supervision will include regular (bi-weekly) 1-1 physical meetings with Dr. Barham, and bi-monthly virtual meetings including the other supervisors.

You will join an international and dynamic team of researchers at the University of Strathclyde. Opportunities will exist to interact with researchers at the University of Regensburg in Germany, and participate in short-term research exchanges and conferences, via Dr Barham’s connections there as an Adjunct Professor.

References

1. Klöpfer, V., Eckl, R, Floß, J., Roth, P. M. C., Reiser, O., Barham, J. P. Green Chem. 2021, 23, 6366-6372. (Outside Front Cover, 2021 Green Chemistry ‘HOT Article’)
2. Mandigma, M. J. P., Zurauskas, J., MacGregor, C. I., Edwards, L. J., Shahin, A., d’Heureuse, L., Yip, P., Birch, D. J. S., Gruber, T., Heilmann, J., John, M. P., Barham, J. P. Chem. Sci. 2022, 13, 1912-1924. (Outside Back Cover, ‘Most popular 2021 catalysis articles’)
3. Domański, M., Marcou, G., Barham, J. P. J. Flow Chem. 2024, 14, 349-355.
4. Shütte, J., Corsi, D., Haumer, W., Schmid, S., Žurauskas, J., Barham, J. P. Green Chem. 2024, 26, 6446-6453.
5. Kaur, J., Mandigma, M. J. P., Bapat, N., Barham, J. P. ChemRxiv 2024, DOI: 10.26434/chemrxiv-2024016879.

Further information

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