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Synthesis of medicinally important macrocycles via Successive ring expansion

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Traditionally, medium sized rings and macrocycles are made by forming a chemical bond between the two ‘ends’ of a long linear molecule (A), but competing side reactions and/or dimerisation reactions usually dominate in such processes, leading to inefficient reaction processes. This research is based on a new system for macrocycle synthesis in which the difficult macrocyclisation step is completely avoided, and instead, macrocycles are ‘grown’ via the iterative expansion of smaller ring systems via Successive Ring Expansion (SuRE, B). In SuRE, a smaller cyclic molecule (or ‘starter unit’) undergoes a simple chemical transformation to attach a linear ‘linker’ molecule onto it. A reactive group attached to this linker can then attach itself to the ‘starter unit’ (to briefly form another smaller ring fused onto its side) and then fragment to form a single, larger ring; overall, this corresponds to the insertion of the ‘linker’ into the original ring of the ‘starter unit’. A crucial factor in the reaction design is the fact that the chemical groups present in the ‘starter unit’ are replicated in the expanded product, therefore the same series of steps can then be repeated with a new linker to form an even larger ring; indeed, the sequence can theoretically be repeated indefinitely, allowing the synthesis of macrocycles of virtually any ring size and composition.

In this work, it is planned to use SuRE for the synthesis of bioactive medium sized rings and macrocycles, to facilitate to discovery of new pharmaceutical lead compounds. Our published ring expansion methods (see Angew. Chem. Int. Ed. 2015, 54, 15794; Chem. Eur. J. 2017, 23, 2225; Chem. Eur. J. 2017 doi: 10.1002/chem.201703316, e.g. illustrated in the Figure below) demstarte the power of these method to construct large ring compounds via the SuRE method. In this project, it is our aim to use and expand our established SuRE method in the preparation of medium-sized rings/macrocycles for bioassay. By varying the size, properties and functionality of both the cyclic starter unit and linear fragment, an enormous range of functionalised macrocycles, and medium sized ring scaffolds should be accessible. To help direct the choice of target molecules, it is planned to employ a combination of physicochemical predictive tools and traditional biological screening results to help to prioritise which compounds to make, in order maximise the chances of identifying new pharmaceutical lead compounds. Further functionalisation/derivatisation of the scaffolds shown will likely be necessary to improve their drug-like properties.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

Training in synthetic organic chemistry will be provided to ensure the student has a strong overall knowledge of organic chemistry as well as the synthesis of other small molecules and the associated practical techniques that all synthetic chemists need to master, i.e. anhydrous techniques, chromatographic purification, compound characterisation etc. This will be supplemented by attendance at the organic section problem classes. The student will also be trained in spectroscopy, especially NMR characterisation of complex compounds and mass spectrometry. Attending group meetings will allow regular opportunities to develop skills in presenting and discussing scientific ideas, and will provide a broader grounding in organic chemistry.

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. Chemistry at York was the first academic department in the UK to receive the Athena SWAN Gold award, first attained in 2007 and then renewed in October 2010 and in April 2015.


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 those from countries outside the UK. Wild Fund Scholarships offer up to full tuition fees for those from countries from outside the European Union. EU students may also be offered £6,000 per year towards living costs. For further information see: View Website

Related Subjects

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

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