P14) Sustainable Synthesis for Medicinal Chemistry in 3-Dimensions: Bioisosteres, PROTAC Linkers, Scaffold Hopping and Unnatural Amino Acids

About the project

About the Project The O’Brien group has an ongoing interest in exploring sp3-rich scaffolds for use in medicinal chemistry. In this work, a key design feature was the use of bifunctional 3-D building blocks with rigid scaffolds and two defined vectors, achieved using cyclopropane and cyclobutane cores with different cross-coupling handles. However, the cross-coupling handles required the use of the precious metals Pd and Ir. In this project, a new collaborative effort between the O’Brien and Duarte groups, we will systematically explore small-molecule 3-D bifunctional chemical space. The computational enumeration of 3-D chemical space will enable us to identify a specific set of building blocks to access. Concise, sustainable routes to the selected building blocks will be implemented (minimising solvent use and waste) and routes will be critiqued in terms of the 12 principles of green chemistry. Where building blocks with similar vectors are identified, we will only synthesise the one with the most efficient synthesis from a green chemistry perspective. Exit vector control will allow optimization of the physiochemical/pharmacokinetic properties of lead-like molecules (small-molecules and PROTACS). New 3-D building blocks will be equipped with sulfonyl hydrazide (NHNHTs) cross-coupling handles, allowing simple and sustainable Ni-mediated cross-coupling to be used (to replace the previously used Pd and Ir). We will target applications such as bioisosteres, PROTAC linkers, scaffold hopping, fragment elaboration and unnatural amino acids. Supervisory Team: Prof Peter O’Brien (Chemistry York), Prof Fernanda Duarte Gonzalez (Chemistry Oxford), Key publications: Modular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery, J. Am. Chem. Soc. 2025, 147, 29292 Design, modular synthesis and screening of 58 shape-diverse 3-D fragments, Chem. Sci. 2025, 16, 20030 The Heterocycle Isostere Explorer: A Computational Tool for the Discovery of Novel Aromatic Heterocyclic Isosteres, J. Med. Chem. 2026, 69, 4408 Useful links: O’Brien group information Duarte group information Further information The EPSRC Centre for Doctoral Training in Chemical Synthesis for a Healthy Planet (CSHP CDT) is a EPSRC-funded centre focused on training the next generation of synthetic chemists, developing a sustainable, innovative chemistry culture that equips students to address major emerging and future global challenges in Human Health, Energy & Materials, and Food Security. We offer a fully-funded four year PhD programme, delivered jointly by the Universities of Oxford and York, comprised of taught courses and a substantive research project. Student cohorts will work together in a 4-month training period at both Oxford and York, before embarking on their main PhD projects. These substantive projects will be industry co-supervised, and based at either the Department of Chemistry in Oxford, or the Green Chemistry Centre of Excellence at York and the associated Department of Chemistry. This PhD project will primarily be based at the University of York. The first application deadline is 12 noon on the 13th November 2026 . We will continue to receive applications following this deadline, however some of the projects may be filled following the assessment of the first round of applications. We therefore encourage you to submit your application early to ensure that your first choice project is available. All project partners recognise the importance of equal participation, progression and success for all. We strive to provide a working, learning, social and living environment that will enable all our staff and students to contribute fully, to flourish and to excel - a place where we can ALL be ourselves. The Department of Chemistry in York holds an Athena SWAN Gold Award, while the Department of Chemistry in Oxford holds a Silver Award. Both are committed to supporting equality and diversity for all staff and students. The Departments strive to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel; for more details, see: Equality and Diversity at York and Equality and Diversity at Oxford . In particular, we recognise the importance of the equal participation of women at all levels in a subject that has traditionally been male-dominated. We also particularly encourage applications from people who identify as Black, Asian or from a Minority Ethnic background, who are underrepresented across the partnership. Eligibility Criteria You must have, or expect to gain, a minimum 2:1 Honours degree or international equivalent in a subject relevant to the proposed PhD project (usually chemistry or chemical engineering, but please get in touch if you think your qualification may be relevant). Enthusiasm for research, the ability to think and work independently, excellent analytical skills and strong verbal and written communication skills are also essential requirements. Check the entry requirements for your country. English language requirements. How to apply Submit an online PhD in Chemistry application . You will need to prepare the following information: 1000-word personal statement, focusing on your interest and experience in your proposed field of research Clearly state your 1-2-3 choice of substantive research projects chosen from our list at the end of your personal statement Transcripts detailing your university-level qualifications and marks to date Two Academic/Professional References: you will be required to submit contact details for 2 referees Complete the CSHP CDT Studentship: Equality, Diversity and Inclusion (EDI) Data Form (for York applicants only). For more details on the application and selection processes, and for answers to general questions (i.e. funding eligibility, project allocation, etc.) please visit our how to apply and FAQs section or join us for our online open event . Contact Details Project-specific Prof Peter O’Brien, peter.obrien@york.ac.uk General CDT enquiries: cshp-cdt@chem.ox.ac.uk or chem-env-pgr@york.ac.uk

Research areas