Summary
Macrocycles (12+ membered rings) are molecules with great potential in medicinal chemistry, but they are hard to make using current methods. This project, in collaboration with GlaxoSmithKline (GSK), concerns the development of an innovative new synthetic strategy by which biologically important macrocycles can be made more easily. 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 macrocycles using a novel system of Cascade Ring Expansion (CRE) reactions.[1] The CRE methods we hope to develop during this PhD will be practical, versatile and scalable, and have important implications for the construction of medicinally relevant macrocycles in pharmaceutical Research and Development.
Project
Making macrocycles using ring expansion reactions (as opposed to inefficient end-to-end macrocyclisation) is at the heart of this project, as it is in all of the macrocycle syntheses developed in our groups in York.[1-8] In CRE, nucleophiles strategically built into linear starting material are used to mediate cyclisation/ring expansion reaction cascade sequences.[1] This ensures that the cascade operates solely via cyclisation reactions which proceed through comparatively low-energy ‘normal’-sized cyclic transition states. This enables a more favourable reaction course to be followed, compared to traditional end-to-end macrocyclisation. Our groups have published one proof-of-concept study in this area to date,[1] but this project is all about taking the promising findings to the next level, both in terms of the synthetic methods (e.g. by varying all three major reaction components and the lengths of the cascades) and applications in medicinal chemistry (with support from project partners at GSK). 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. Opportunities to improve the synthesis using automation technologies will also be explored, and reaction selectivity (including atroposelectivity) and mechanism will be studies using a combined synthetic and computational (DFT) approach. No prior experience of automation/DFT is needed – full training will be provided.
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
Training in synthetic chemistry (led by Unsworth) 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 be trained in the computational chemistry (DFT) aspects of the project (led by Lynam) and 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 multidisciplinary 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. There will also be regular opportunities to interact with GSK scientists and undertake an optional ca. three-month placement working on the PhD project on site at GSK (Stevenage).
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: https://www.york.ac.uk/chemistry/postgraduate/idtc/
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: https://www.york.ac.uk/chemistry/ed/.
For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution
This PhD will formally start on 1 October 2021. Induction activities will start on 27 September.
To apply for this project, submit an online PhD in Chemistry application: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3
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