Modular Synthesis of Medicinally Relevant Macrocycles via Cascade Ring Expansion Reactions


   Department of Chemistry

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  Dr W Unsworth  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Background and novelty

Macrocycles (12+ membered rings) and medium-sized rings (8–11 membered) have great potential in medicinal chemistry but are hard to make using current synthetic methods. This project concerns the development of a novel, innovative strategy by which diverse, biologically important macrocycles can be made more easily. In collaboration with AZ, a modular approach will be developed, based on the rapid assembly of simple molecular building blocks into linear precursors, followed by direct conversion into macrocycles using a novel system of Cascade Ring Expansion (CRE) reactions [introduced by the Unsworth group in their previous publication: Angew. Chem., Int. Ed. 2019, 58, 13942]. This practical, versatile and scalable approach is expected to have major implications for the exploration of macrocycles at various stages of pharmaceutical R+D.

Objectives

The main aim of this project is to establish CRE as a major enabling technology for the synthesis of medicinally useful medium-sized rings and macrocycles. Expanding the scope of the CRE concept by varying 3 key reaction components in turn is an important objective – new CRE reactions based on variations to the electrophile, the internal nucleophilic catalyst and the terminal nucleophile will all be explored. By combining the new reactions as an overall package, a practical, versatile and modular system for the synthesis of diversely functionalised medicinally relevant macrocycles will be established. Expanding the CRE concept to longer cascade processes based on substrates containing multiple internal nucleophiles is also a key objective. Finally, translating our methods and molecules made into medicinal chemistry is a major driver in this project and pathways to enable this will be explored through collaboration with project partners at AZ.

Experimental approach

The planned project is extremely open-ended and will suit a PhD candidate who enjoys being in the lab exploring new synthetic organic chemistry methodologies creatively. Candidates who enjoy organic chemistry, curly arrow mechanism, rearrangement reactions and retrosynthetic analysis are especially encouraged to apply. An interest in medicinal chemistry and a desire to work closely with project partners at AZ is also a key attribute we will look for when selecting a candidate.

Training

The Chemistry Department at York offers a wide range of expertise, infrastructure and state-of-the-art equipment to ensure a full, contemporary training for the PhD student. The student will quickly become an expert in synthetic organic chemistry (theory and practice) and associated analytical skills (NMR, MS, HPLC etc.). Training will also include courses from the York Chemistry Innovative Doctoral Training Centre (iDTC) including research skills like Advanced Spectroscopy and Organometallic Chemistry, as well broader skills including science presentation and career planning. In addition to regular meetings with the PI, support is provided through the Chemistry Graduate Office and the TAP (Thesis Advisory Panel) system, which meets every 6 months to monitor progress and provide independent advice. The student will attend regular problem solving sessions, literature groups and group meetings, providing opportunities to present and discuss their work. High level publications are expected to emerge from this project, and the student would be encouraged to actively participate in manuscript preparation. The student would also be strongly encouraged to present the work via talks and posters externally at appropriate points in the project. It is expected that following the PhD, the student would be a prime candidate to enter a career in the pharmaceutical industry, or continue in academia.

You will follow our core cohort-based training programme to support the development of scientific, transferable and employability skills, as well as training on specific techniques and equipment. Training includes employability and professionalism, graduate teaching assistant training and guidance on writing papers. https://www.york.ac.uk/chemistry/postgraduate/training/idtc/idtctraining/  

There will be opportunities for networking and sharing your work both within and beyond the University. Funding is provided to enable you to attend conferences and external training. The department also runs a varied and comprehensive seminar programme.

Equality and Diversity

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/

As part of our commitment to Equality and Diversity, and Widening Participation, we are working with the YCEDE project (https://ycede.ac.uk/) to improve the number of under-represented groups participating in doctoral study.  

Entry requirements 

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a relevant related subject.   Check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

English language requirements: https://www.york.ac.uk/study/postgraduate-research/apply/international/english/

For more information about the project, click on the supervisor's name above to email them. 

For more information about the application process or funding, please click on email institution.

Guidance for applicants: https://www.york.ac.uk/chemistry/postgraduate/apply/

Submit an online PhD in Chemistry application: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3

The closing date is 21 January 2024 but applications may close earlier if a suitable candidate is found.

The start date of the PhD will be 16 September 2024


Chemistry (6)

Funding Notes

This project is fully funded for 4 years by an EPSRC iCASE award with industrial partner, Astra Zeneca.
Includes: (i) a tax-free annual stipend (£18,622 in 2023/24), (ii) tuition fees at the home/overseas rate, (iii) funding for consumables.
Candidates of any nationality are welcome to apply as this funding could potentially be awarded to an exceptional international candidate.

References

Selection process:
You should hold or expect to receive at least an upper second class degree in chemistry or a relevant science subject
Applicants should submit a PhD application to the University of York by 21 January 2024 although applications may close earlier if a suitable candidate is found.
Supervisors may contact candidates either by email, telephone or web-chat to arrange an interview

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