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Cascade Ring Expansion reactions for macrocycle and medium-sized ring synthesis

   Department of Chemistry

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project


Macrocycles (12+ membered rings) and medium-sized rings (8-11-membered) are molecules with great potential in several applied fields, especially medicinal chemistry, but are hard to make using current synthetic methods. This project concerns the development of a new synthetic strategy by which biologically important macrocycles can be made more easily using a novel system of Cascade Ring Expansion (CRE) reactions.[1]. A modular approach will be used, based on the rapid assembly of simple molecular building blocks into linear precursors, followed by their direct conversion into medium-sized rings and macrocycles using CRE.


Making macrocycles using ring expansion reactions while avoiding inefficient end-to-end macrocyclisation is central to this project this project.[1-8]. In CRE, nucleophiles carefully installed within linear starting material are used to mediate cyclisation/ring expansion reaction cascade sequences, that take advantage of internal nucleophilic catalysis to drive the reactions forward.[1] This approach means that the cascades operate solely via comparatively low-energy ‘normal’-sized cyclic transition states, thus enabling a more favourable reaction course to be followed compared to end-to-end macrocyclisation. Our group has published one proof-of-concept study in this area to date[1] and this project is about taking the CRE concept much further, both in terms of the synthetic methods (e.g. by varying all three major reaction components and the lengths of the cascades) and applications. The preparation of diverse compound libraries for bioassay, the development of versatile divergent synthetical protocols, and scale up of the methods are all major goals.

The project will suit candidates interested in the development of new synthetic methodology and target synthesis. Candidates who enjoy retrosynthetic analysis and applying their organic synthesis knowledge with creativity and imagination are especially encouraged to apply.


Training in synthetic chemistry will be provided to ensure the student has a strong overall knowledge of organic chemistry and associated practical techniques e.g. anhydrous methods, purification, characterisation, spectroscopy etc. This will be supplemented by regular mechanistic and retrosynthetic problem classes and group meetings. The student will also attend courses to help develop skills to support their professional development more generally, provided by the iDTC and the award-winning researcher development unit in York. This skill set will ensure the student is in high demand for industrial/academic vacancies after the PhD. By combining utility with high conceptual novelty, several impactful publications are expected to result from this PhD project and the student will be expected to take an active part in their preparation. They will also be encouraged to help disseminate the work where possible through conference presentations, posters and online/social media.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills:

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: .

Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to new students who will pay tuition fees at the overseas rate. Scholarships are competitive and awarded based on academic ability and financial need. For further information see: View Website


All Unsworth et al: (1) Angew. Chem., Int. Ed. 2019, 58, 13942; Angew. Chem. Int. Ed., 2015, 54, 15794; (3) Chem. Eur. J., 2017, 23, 2225; (4) Chem. Eur. J., 2017, 23, 13314; (5) Chem. Eur. J. 2018, 24, 13947–13953; (6) Chem. Sci., 2020, 11, 2876; (7) Chem. Eur. J. 2020, 26, 12674–12683; (8) Org. Biomol. Chem., 2021, 1404–1411.

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