Bicyclo[n.1.1]alkanes, and their heterocyclic analogues, have emerged as highly important 'next generation' scaffolds in contemporary drug design, exhibiting superior physicochemical and pharmacokinetic profiles compared to traditional motifs such as benzene rings. However, access to these structures mainly relies on 1-, 2- or 3-atom insertions into bicyclo[1.1.0]butanes, compounds that are limited in stability, synthetic accessibility, and substituent diversity. Our group has developed alternative approaches based on propellanes – molecules featuring a (strained) C–C bond to which three rings are fused. This project seeks to develop new types of propellanes that can be formed using more sustainable and scalable reaction conditions than 'traditional' propellane syntheses, which rely on polyhalogenated precursors and organolithium reagents; and also to develop new modes of reactivity of both the propellanes, and their valuable ring-opened bridged bicyclic products.

Key publications:
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature 2022, 611, 721)
Hetero[3.1.1]propellanes. (Nat. Chem. 2026, 18, 502)

Useful links:
Anderson research group

For further details please contact Ed Anderson (edward.anderson@chem.ox.ac.uk).

After decades of promise, peptide drugs are now considered a viable therapeutic modality for challenging protein targets. Constrained peptides occupy a unique region of chemical space that bridges biologics and small molecules, accessing therapeutic targets that neither modality addresses well such as protein-protein interfaces. Polycyclic scaffolds, in which a peptide is locked by a single polyfunctional linker into multiple interconnected macrocycles, confer the conformational rigidity required for high affinity and the proteolytic stability required for drug-like exposure. Combined recombinant expression and synthetic cyclisation is more sustainable than traditional solid-phase peptide synthesis by conferring druglike properties to peptides composed of canonical amino acids.
This project will develop a suite of tri- and tetravalent reactive linkers that enable one-step generation of highly diverse polycyclic peptide libraries on a scale compatible with affinity-based screening against challenging therapeutic targets. All linkers will be amenable to linearisation to enable characterisation of hit peptides using well established peptide characterisation techniques.
A student undertaking this project will learn synthetic organic chemistry, peptide synthesis and characterisation, medicinal chemistry with a focus on peptides, and basic biochemistry screening techniques.

Useful links:
Brennan research group

For further details please contact Paul Brennan (paul.brennan@cmd.ox.ac.uk).

The aim of this project is to harness the power of organic chemistry to develop innovative synthetic methodologies, including new photochemical strategies for the late-stage functionalisation of biologically relevant molecules. We have recently demonstrated the unique advantages of employing oxonium ions in organic synthesis, owing to the exceptional leaving-group ability of the oxonium moiety. Building on these findings, we will develop a range of new photochemical and ionic transformations that exploit this distinctive reactivity to enable efficient and selective bond-forming processes. Once established, these methodologies will be applied to the late-stage functionalisation of complex biological molecules facilitating their application in medicinal chemistry and related fields. The synthesis of the required oxonium ions will utilise new sustainable methodologies currently under development. The development of shorter, more efficient, and environmentally sustainable routes to oxonium ions will not only improve the practicality of these transformations but also encourage their broader adoption by the synthetic chemistry community.

Key publications:
Harnessing triaryloxonium ions for aryne generation. (Nat. Synth. 2023, 3, 58)
Synthesis, Characterization, and Reactivity of Complex Tricyclic Oxonium Ions, Proposed Intermediates in Natural Product Biosynthesis. (J. Am. Chem. Soc. 2019, 141, 15951)

Useful links:
Burton research group

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk).

At the heart of this project is the development of sustainable methods for the total synthesis of complex, densely functionalised, natural product-like molecules containing multiple stereocentres for antimicrobial evaluation. The continuing rise of antimicrobial resistance highlights the urgent need for new antibiotics, which forms the central motivation for this proposal. A key component of the project will be the development of novel, sustainable synthetic methods for the preparation of complex intermediates en route to the target molecules. Particular emphasis will be placed on achieving high levels of stereochemical control while improving the efficiency, scalability, and sustainability of the synthetic routes through the application of modern synthetic methods with focus on reducing/eliminating super-stoichiometric transition metal reagents through the use of organic electrochemistry. These advances will not only facilitate access to the target compounds but also establish broadly applicable sustainable synthetic strategies that can be adapted to related classes of biologically active molecules. Antimicrobial evaluation and lead optimisation will be carried out in collaboration with our industrial partner, ensuring that promising compounds are rapidly assessed and advanced towards future therapeutic development. Overall, this project will develop sustainable methodologies and apply them to the synthesis of stereochemically rich natural-product-like molecules for antimicrobial evaluation.

Key publications:
Synthesis of the Spirotetracyclic Core of the Ginkgolides via a Malonyl Radical Cascade. (Org. Lett. 2025, 27, 7927)
Total Synthesis of Salinosporamide A. (Chem. Eur. J. 2018, 24, 6747)

Useful links:
Burton research group

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk).

Cyclic chiral multifunctional building blocks are essential intermediates in the discovery and manufacture of many APIs for medicinal chemistry and agrochemical applications. However, their efficient preparation in single-enantiomer form remains a significant synthetic challenge. This proposal aims to develop new BIMP-catalysed enantioselective desymmetrisation reactions that transform a range of readily accessible symmetric precursors into valuable (known and new) chiral building blocks and demonstrate their downstream applicability in medicinal, agrochemical and antimicrobial research programs.

Key publications:
Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis. (Acc. Chem. Res. 2020, 53, 2235)
Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters. (Nat. Chem. 2023, 15, 714)

Useful links:
Dixon research group

For further details please contact Darren Dixon (darren.dixon@chem.ox.ac.uk).

Macrocyclic compounds are an emerging class of therapeutics that offer a promising alternative to conventional small molecules, combining enhanced selectivity and the ability to target previously undruggable biological targets. Despite their significant therapeutic potential, however, their design has been limited by synthetic challenges, particularly the final cyclisation step. This project aims to accelerate the discovery of bioactive macrocycles through the development of artificial intelligence (AI)-guided strategies for sustainable and efficient macrocycle synthesis. By integrating automated mechanistic analysis, high-throughput experimentation, and machine learning, we will develop a framework to design and prioritise compounds with desirable biological properties and feasible synthetic routes. Building on our group's longstanding expertise in mechanistic exploration and software development, and our long-standing collaboration with industry and academic partners, the resulting methodology and chemical insights will be deployed into industrially relevant applications, supporting a more sustainable and informed drug-discovery pipeline that reduces the need for extensive trial-and-error experimentation.

Useful links:
Duarte research group

For further details please contact Fernanda Duarte (fernanda.duartegonzalez@chem.ox.ac.uk).

The project will explore the potential of earth abundant metal (EAM) catalysts for arylative carbonylation reactions employing suitable aromatic and heteroaromatic halide / pseudohalide and organoboron coupling parters in the presence of a safe carbon monoxide-releasing surrogate and activator. A successful project will provide a complementary tool to the well-known thermal Pd-catalysed reaction variant. In appropriate cases we will explore the dual use of an EAM along with Pd to open-up the activation and functionalisation of more complex organic substrates. Reaction optimisations will be conducted using both an in-house built flow system (with in situ IR characterisation) and batch screening using Chemspeed ISYNTH / powderdose systems (with in line LC-MS characterisation). Bayesian optimisation routines will be deployed to accelerate optimal working reaction conditions, with a focus placed on substrates that are typically bioderived (e.g. oxygen-containing furans and pyrones) and solvents with excellent sustainable and green metrics (e.g. 2,2,5,5-tetramethyloxolane (TMO), cyrene and ethyl acetate). The green metrics of our new processes will be fully evaluated using the York-developed Chem21 green chemistry tool kit.

Useful links:
Green chemistry metrics toolkit
Fairlamb research group
Lynam research group

For further details please contact Ian Fairlamb (ian.fairlamb@york.ac.uk) and/or Jason Lynam (jason.lynam@york.ac.uk).

Cyclobutanes are strained ring systems found in many medicines and natural products. Their unique geometry offers access to new shapes and vectors in drug discovery, yet their potential remains underexplored due to a lack of efficient methods for their stereoselective synthesis.
This project aims to develop new inherently efficient catalytic asymmetric cross-coupling methods to access a variety of functionalised, chiral cyclobutanes. We discovered that diverse C–C bond-forming reactions can be initiated by rhodium-catalysed and complementary transition-metal-catalysed carbometallation of strained prochiral alkenes. Here, we will uncover new catalytic asymmetric carbometallations of cyclobutenes to enable access to valuable, previously inaccessible chiral cyclobutanes and reveal new reactivity in these strained systems.
Mechanistic and computational studies will support the development and understanding of these reactions, as well as the rational design of new transformations. Studying these substrates offers an exciting opportunity to access novel structures relevant to drug discovery, uncover new chemical reactivity, and address challenges in the synthesis of these medicinally important molecules. This work will significantly reduce the number of steps currently needed to access these molecules, while minimising the associated energy consumption, time, and waste.

Key publications:
A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes. (Nat. Chem., 2021, 13, 880)
Rhodium-Catalyzed Asymmetric Arylation of Cyclobutenone Ketals. (Angew. Chem. 2023, 135, e202217381)
Catalytic Enantioselective Synthesis of 3‑Piperidines from Arylboronic Acids and Pyridine. (J. Am. Chem. Soc. 2023, 145, 14221)

Useful links:
Fletcher research group

For further details please contact Stephen Fletcher (stephen.fletcher@chem.ox.ac.uk).

Macrocycles are increasingly important in drug discovery because their constrained three-dimensional structures can access challenging biological targets that are often beyond the reach of conventional small molecules. Despite their importance, the synthesis of chiral macrocycles remains a significant challenge and typically relies on a limited number of ring-closing reactions.
This project aims to develop a fundamentally new approach to macrocycle synthesis using catalytic asymmetric Suzuki-type macrocyclization reactions. We have recently discovered highly selective asymmetric allylic arylation reactions that form carbon–carbon bonds with excellent regio and stereocontrol and here, we propose to harness this chemistry for the construction of macrocyclic rings which would enable simultaneous ring closure and stereogenic centre generation in a single catalytic transformation.
Mechanistic, computational, and synthetic studies will be used to understand and optimise these challenging reactions, establish the factors governing ring size, regioselectivity, and stereoselectivity, and expand the scope of accessible macrocyclic architectures. This work offers an exciting opportunity to create novel chiral macrocycles of relevance to pharmaceutical discovery while uncovering new principles for catalytic macrocyclization. In collaboration with Vertex Pharmaceuticals, we will explore a sustainable and modular strategy for accessing valuable macrocyclic chemical space that is currently difficult to reach using existing synthetic methods.

Key publications:
A Modular Strategy for the Synthesis of Macrocycles and MediumSized Rings via Cyclization/Ring Expansion Cascade Reactions. (J. Am. Chem. Soc. 2024, 146, 5702)
Ligand-enabled override of the memory effect in Rh-catalyzed asymmetric Suzuki reactions. (Chem, 2025, 11, 102550)

Useful links:
Fletcher research group
Unsworth research group

For further details please contact Stephen Fletcher (stephen.fletcher@chem.ox.ac.uk).

Antibiotics make modern medicine possible. From routine surgery to cancer treatment, many hospital interventions rely on effective antibiotics to prevent deadly infections. Antimicrobial resistance (AMR), however, is rising, and bacterial infections are becoming increasingly difficult to treat. Many of the antibiotics that have recently been approved belong to existing antibacterial classes with pre-existing resistance mechanisms. This project will explore a different source of antibacterial molecules: transition metal complexes. These compounds offer shapes, structures and modes of action that are difficult to achieve with conventional organic molecules, making them an exciting but still underexplored route to new antibiotics.
The student will use miniaturised, automated high-throughput synthesis at the University of York to prepare diverse libraries of metal complexes while reducing material use, solvent consumption and waste. These designed and curated libraries will be screened against bacterial target proteins of interest (transpeptidases and other related cell wall enzymes) in functional assays at the INEOS Oxford Institute (IOI) to identify new inhibitors. The resulting data will feed into a human-in-the-loop machine learning workflow that guides the design of focused second-generation libraries with improved target engagement. Promising hits will then be resynthesised, characterised and tested against isolated proteins and subsequently against whole bacterial cells, including clinical isolates and panels of isogenic strains (efflux, porin, siderophore transport knock-outs).
Delivered with the INEOS Oxford Institute, the project combines sustainable synthesis, antimicrobial drug discovery, automation and AI to train a student at the interface of chemistry, microbiology and data-driven molecular design.

Key publications:
Metals to combat antimicrobial resistance. (Nat Rev Chem, 2023, 7, 202)
High-throughput triazole-based combinatorial click chemistry for the synthesis and identification of functional metal complexes. (Nat Commun, 2025, 16, 11195)
Using Machine Learning to Predict the Antibacterial Activity of Ruthenium Complexes. (Angew. Chem. Int. Ed., 2024, 63, e202317901)

Useful links:
Frei research group

For further details please contact Angelo Frei (angelo.frei@york.ac.uk).

Over the past decade, azo photoswitches have become powerful tools in photopharmacology, with focus placed on differential binding affinity of photoswitchable isomers to their biological targets. However, the potential to dynamically regulate other key physicochemical properties of relevance to medicinal chemistry with photoswitches—such as polarity, solubility, and hydrogen-bonding capability—remains poorly unexplored. Building on extensive expertise in heteroaromatic photoswitch design in the Fuchter group, this project will develop new photoswitchable motifs that enable light-controlled modulation of such physiochemical properties. By comparing the physicochemical characteristics of the E and Z isomers, the project will establish new structure–property relationships that can be exploited in bioactive molecular design. Ultimately, these insights will be applied to biologically active ligands, creating photopharmacological agents whose physicochemical properties—and therefore biological performance—can be reversibly controlled with light. The simple light-addressable reagents developed through this project will be very cheap and simple to produce, thus ensuring built in sustainability. Furthermore, the use of light provides an environmentally benign method to control bioactivity in a sustainable way.

Key publications:
Aryl azopyrroles as visible light photoswitchable TRPA1 ligands. (Chem. Sci. 2025, 16, 19777)
Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable Z-isomer stability. (Chem. Sci. 2024, 15, 5360)
Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs). (Chem. Commun. 2022, 58, 10933)

Useful links:
Fuchter research group

For further details please contact Matthew Fuchter (matthew.fuchter@chem.ox.ac.uk).

Waste fluorochemicals including gases present a critical bottleneck to global sustainability. Gases in particular possess high Global Warming Potential (GWP). Synthetic fluorinated gases including hydrofluorocarbons (HFCs), perfluorocarbons (PFCs), and sulfur hexafluoride (SF₆)—can trap heat up to 23,000 times more effectively than CO₂, and persist in the atmosphere for up to 50,000 years.
Historically, end-of-life fluorinated gases (like refrigerants from HVAC and cooling equipment) were incinerated or vented. In this project, novel low-energy technologies will be developed that couple destruction with upcycling towards the synthesis of essential medicines or materials.

Key publications:
Phosphate-enabled mechanochemical PFAS destruction for fluoride reuse. (Nature 2025, 640, 100)
Silicate-Enabled Mechanochemical Mineralization of Polymeric and Nonpolymeric PFAS into Sodium Fluoride. (J. Am. Chem. Soc. 2026, 148, 17977)

Useful links:
Gouverneur research group

For further details please contact Véronique Gouverneur (veronique.gouverneur@chem.ox.ac.uk).

The deoxyfluorination represents an important class of reactions for the conversion of alcohols, aldehydes or carboxylic acids into mono-, di- or trifluorinated products. Such chemistry is typically carried out with hazardous diethylaminosulfur trifluoride (DAST) or other reagents that are toxic, expensive or of poor atom economy. The use of safe and inexpensive alkali metal fluoride for deoxyfluorination chemistry could be transformational for the synthesis of fluorochemicals for medicine and other applications. This project sits within this general context.

Key publications:
Asymmetric Nucleophilic Fluorination Under Hydrogen Bonding Phase-Transfer Catalysis. (Science 2018, 360, 638)
Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond. (J. Am. Chem. Soc. 2022, 144, 5200)
Impact of Multiple Hydrogen Bonds with Fluoride on Catalysis: Insight from NMR Spectroscopy. (J. Am. Chem. Soc. 2020, 142, 19731)
Enantioconvergent nucleophilic substitution via synergistic phase-transfer catalysis. (Nature Catalysis 2025, 8, 107)

Useful links:
Gouverneur research group

For further details please contact Véronique Gouverneur (veronique.gouverneur@chem.ox.ac.uk).

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.

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 research group
Duarte research group

For further details please contact Peter O’Brien (peter.obrien@york.ac.uk).

The Ineos Oxford Institute (IOI) spearheads sustainable drug discovery against devastating mycobacterial diseases, primarily tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization, TB remains a leading global infectious killer, claiming nearly 4,500 lives daily. Mtb evades antibiotic treatment through respiratory flexibility, enabling it to remain dormant within the host. This PhD project aims to exploit this evolutionary advantage by targeting unique components of the Mtb respiratory pathway for novel antibiotic development, addressing the challenge of identifying molecular combinations that cooperatively shut down all energy transduction pathways.
Based at the University of York, you will be trained to solve this challenge using a specialized biophysical toolkit developed by Professors Alison Parkin and Jamie Blaza. Through this collaboration, you will gain advanced expertise in probing the mode of action of respiratory-targeting drugs via a complementary combination of bioelectrochemistry, whole-cell spectroscopy, and cryo-EM. Ultimately, this project will map how IOI-developed chemical compounds eradicate Mtb, teaching us how organic chemical structure maps on to enzyme inhibition to enable the optimization of combinatorial therapies to ensure the sustainable, efficient and responsible deployment of next-generation antibiotics.

Useful links:
Parkin research group
Blaza research group
IOI grand challenges

For further details please contact Alison Parkin (alison.parkin@york.ac.uk).

Clozapine remains the most effective treatment for treatment-resistant schizophrenia, yet the molecular basis of its unique clinical efficacy remains one of the major unanswered questions in neuropsychopharmacology. This project will develop next-generation chemical biology tools to identify the molecular targets, signalling networks and cellular microenvironments that underpin clozapine's distinctive pharmacology. Building on expertise in medicinal chemistry, chemical proteomics and systems pharmacology, the student will develop modular “click-and-play” clozapine probes for quantitative target engagement, chemoproteomic target deconvolution and live-cell signalling studies. Sustainability will be embedded through modular probe design, allowing multiple biological readouts to be generated from common chemical intermediates. In collaboration with Johnson & Johnson Innovative Medicine, this work aims to reveal new therapeutic mechanisms while establishing broadly applicable and resource-efficient chemical biology technologies for drug discovery.

Key publications:
A tubulin binding molecule drives differentiation of acute myeloid leukemia cells. (iScience 2022, 25, 104787)
Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid. (Angew. Chem. Int. Ed. 2020, 59, 2420)

Useful links:
Russell research group

For further details please contact Angela Russell (angela.russell@chem.ox.ac.uk).

Resistance to pharmaceuticals, including anti-infectives is a major and growing global health problem. As highlighted by the 2016 O’Neill report, the current situation with antibiotics is perilous. Antibiotics are used on a massive scale in farming and medicine; hence we need sustainable routes for production of new anti-infectives not susceptible to current resistance mechanisms. Resistance to other classes of drugs, including anti-fungals and cancer drugs as well as agrochemicals is also a major problem. The project will involve the development of enzyme / enzyme inspired and novel reactions for the efficient and sustainable preparation of new anti-infective classes that address the problem of resistance. Approaches will include late-stage modification of fermented natural products to efficiently generate structure activity relationship results, complementing efficient total synthesis approaches.

Useful links:
Schofield research group
Ineos Oxford Institute

For further details please contact Chris Schofield (christopher.schofield@chem.ox.ac.uk).

Structured liquids play a vital role in a wide range of industrial applications, particularly in consumer and personal care products, where gel-like materials have an important role in providing products with appropriate physical performance. Historically, such materials have relied on the use of polymeric materials, which are powerful and tunable viscosification agents that can cope with high-complexity mixtures, including surfactants and emulsions. However, such materials typically have poor sustainability credentials, being derived from crude oil, and suffering from very poor breakdown profiles in
environmental waste.
There have therefore been attempts to replace oil-based polymers as structuring agents with naturally occurring biopolymers, but these have not been wholly successful, owing to limited tunability and/or poor performance. This proposal therefore takes a sustainable supramolecular approach to fluid modification, targeting liquid modifiers that can self-assemble from low-molecular-weight building blocks. In principle, such systems can be synthesised from wholly sustainable resources and the non-covalent interactions responsible for their assembly can easily be reversed, leading to effective degradation into non-persistent, non-toxic fragments after use.

Key publications:
Supramolecular gels – a panorama of low-molecular-weight gelators from ancient origins to next-generation technologies. (Soft Matter, 2024, 20,10)

Useful links:
Smith research group

For further details please contact David Smith (david.smith@york.ac.uk).

Many medium-ring heterocycles are chiral by virtue of restricted rotation about C–C/C–N bonds or their inherent topology. This project will develop efficient enantioselective routes to these molecules using counterion-mediated N-functionalisation. Catalytic dynamic stereocontrol will be used to convert rapidly equilibrating precursors directly into stereochemically defined products, avoiding wasteful resolution strategies. Alongside yield and selectivity, reaction development will address catalyst loading, reagent and solvent choice, and material efficiency, with the objective of establishing practical routes to complex chiral heterocycles that minimise the use of scarce elements and reduce waste.

For further details please contact Martin Smith (martin.smith@chem.ox.ac.uk).

In this collaborative project, bio-based feedstocks will be utilized for the synthesis of a range of unsaturated and saturated nitrogen heterocyclic building blocks. These building blocks will then be decorated to give agrochemical lead-like compounds. Focus will be in two distinct areas: (i) synthesis of heteroaromatics such as pyridines, pyrazines, pyrimidines and quinolines, from a range of bio-based feedstocks; (ii) use of terpene feedstocks for the generation of sp³-rich azepane derivatives, a significantly under-studied scaffold in chemical space, which are proposed as useful 3D building blocks for further chemistry. The project draws on the GCCE’s rich history of the synthesis of bio-based platform molecules using green and sustainable chemistry, and quantifying the environmental impact of the synthetic routes, and the O’Brien group’s recent cutting edge work elaborating Nitrogen heterocycles using organolithiation.

Useful links:
Sneddon research group
O'Brien research group

For further details please contact Helen Sneddon (helen.sneddon@york.ac.uk) and/or Peter O’Brien (peter.obrien@york.ac.uk).

In this project we will develop new chemical strategies to modify peptides via late-stage, transition metal catalysed reactions. Peptides are an important modality in modern drug discovery, bridging the gap between traditional small molecule drugs and larger biologics. Strategies for late-stage diversification, where robust transformations are applied to fully synthesised, deprotected peptides, are particularly impactful on drug discovery – they allow large libraries of peptides to be generated in a single step, while greatly reducing the use of hazardous and environmentally damaging solvents.
This interdisciplinary project will build on our group’s expertise in peptide and protein chemistry to develop conceptually unique approaches to address this challenge. With our industrial partner, Johnson & Johnson, we will target new strategies for both side-chain modification and peptide ‘stapling’ of therapeutic sequences. It is well suited to students with a strong background in synthetic chemistry or chemical biology, and an interest in developing new interdisciplinary skills.

Key publications:
Peptide modification via a mild carbonylative Suzuki–Miyaura reaction gives late-stage access to diaryl-ketones. (Chem. Sci. 2026, 17, 11858)
Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N‑Terminal Protein Modification. (JACS Au 2025, 5, 1983)
Palladium-Mediated Cell-Surface Labeling. (J. Am. Chem. Soc. 2012, 134, 800)

Useful links:
Spicer research group

For further details please contact Chris Spicer (chris.spicer@york.ac.uk).

Protein bioconjugation is a vital tool in modern biomedical and biotechnological research. Our groups recently established a ‘Conjugate Addition/Ring Expansion’ (CARE) approach able to selectively and irreversibly modify the N-terminus of untagged native proteins, including nanobodies for cancer cell and tissue imaging, and human chemokines, with altered downstream activation and processing following modification. Our irreversible bioconjugations are performed in water, operate under mild conditions, and in contrast to more established methods, require few equivalents of probe. In this multidisciplinary project, we will develop new, sustainable tools for bioconjugation using novel rearrangement reactions. The project spans pure organic synthesis, chemical biology, antibiotics and bacterial PROTACS. We will develop new probes designed to promote CARE-like bioconjugation, via conjugate addition with amine groups, followed by in situ rearrangement to reveal reactive functional groups for downstream modification. This will enable the late-stage installation of dual-functional probes that can be used to study and target pathogenic bacteria, bearing: i) novel macrocycles that can modulate target/host binding; and ii) handles for diversification and protein ‘tagging’ to explore cellular delivery of antibiotics and bacterial PROTACS.

Key publications:
N-terminal protein-macrocycles enabled by conjugate addition/ring expansion cascade reactions. (Chem. Sci. 2026, 17, 3320)
Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions. (RSC Chem. Biol. 2022, 3, 334)

Useful links:
Unsworth research group
Spicer research group
Fascione research group

For further details please contact Will Unsworth (william.unsworth@york.ac.uk).

Recycling waste oxygenated polymers to true monomers, including epoxides and cyclic esters, is a low-energy route to more sustainable plastics and elastomers. Understanding how to design catalysts for these depolymerizations is vital to improving efficiency and selectivity.

Key publications:
Chemical Recycling of Polyesters and Polycarbonates: Why Is Zinc(II) Such an Effective Depolymerization Catalyst? (J. Am. Chem. Soc. 2025, 147, 43077)
The Science of Polymer Chemical Recycling Catalysis: Uncovering Kinetic and Thermodynamic Linear Free Energy Relationships. (J. Am. Chem. Soc. 2025, 147, 22734)

Useful links:
Williams research group

For further details please contact Charlotte Williams (charlotte.williams@chem.ox.ac.uk).

Macrocyclic peptides have emerged as an important class of biologically active molecules, as they often display high target specificity and low toxicity. Many hit compounds in these series are now generated using automated microscale biological synthesis methods, such as mRNA displays. However, the molecules delivered by these approaches often feature redundant functional groups that are not suitable to advance along the medicinal chemistry pathway. This project is about developing ‘editing’ methods that can selectivity remove, or modify these redundant functional groups, allowing the initial leads to continue as viable molecules. The project will involve method development, catalysis, multi-stage synthesis, and application of the developed methods to complex molecules. The project is a collaboration between the Willis group at Oxford and Johnson & Johnson pharmaceuticals.

Key publications:
Chapter 1: Peptide Drug Discovery Raison d’Etre: Engineering Mindset, Design Rules and Screening Tools. (ACS Symposium Series, 2022)
Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges. (J. Am. Chem. Soc. 2019, 141, 4167)

Useful links:
Willis research group

For further details please contact Michael Willis (michael.willis@chem.ox.ac.uk).

Peptides are enjoying a renaissance in drug discovery, with the success of GLP-1 agonists such as semaglutide (Wegovy) and tirzepatide (Zepbound) providing a clear demonstration of their biological potential. Modified peptide(like) structures, such as stapled peptides and macrocyclic peptides more generally, are also of considerable current interest. Of relevance to this proposal is that the synthesis of peptides is notorious for having poor sustainability profiles, such as the use of large excesses of reagents, and the need for complex activating/coupling reagents, and the extensive use of protecting groups. This proposal is focused on developing a series of bifunctional reagents that allows for the direct and controllable functionalization of peptide chains, thus providing efficient access to macrocyclic (stapled) targets; this will avoid long synthetic sequences and complex protecting group campaigns. We will develop reagents that have reactivity matched to specific amino acids, allowing selective and efficient reactions. The project will involve reagent design and synthesis, catalysis, and application of the developed methods to complex molecules. The project is a collaboration between the Willis group at Oxford, the Spicer group at York, and the Ineos Institute Oxford.

Key publications:
Synthesis and functionalization of vinyl sulfonimidamides and their potential as electrophilic warheads. (Chem. Sci. 2025, 16, 12860)
Synthesis, Functionalization, and Reactivity of Vinyl Sulfondiimidamides. (Angew. Chem. Int. Ed. 2026, 65, e9885717)

Useful links:
Willis research group

For further details please contact Michael Willis (michael.willis@chem.ox.ac.uk).

Bicyclo[n.1.1]alkanes, and their heterocyclic analogues, have emerged as highly important 'next generation' scaffolds in contemporary drug design, exhibiting superior physicochemical and pharmacokinetic profiles compared to traditional motifs such as benzene rings. However, access to these structures mainly relies on 1-, 2- or 3-atom insertions into bicyclo[1.1.0]butanes, compounds that are limited in stability, synthetic accessibility, and substituent diversity. Our group has developed alternative approaches based on propellanes – molecules featuring a (strained) C–C bond to which three rings are fused. This project seeks to develop new types of propellanes that can be formed using more sustainable and scalable reaction conditions than 'traditional' propellane syntheses, which rely on polyhalogenated precursors and organolithium reagents; and also to develop new modes of reactivity of both the propellanes, and their valuable ring-opened bridged bicyclic products.

Key publications:
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature 2022, 611, 721)
Hetero[3.1.1]propellanes. (Nat. Chem. 2026, 18, 502)

Useful links:
Anderson research group

For further details please contact Ed Anderson (edward.anderson@chem.ox.ac.uk).

After decades of promise, peptide drugs are now considered a viable therapeutic modality for challenging protein targets. Constrained peptides occupy a unique region of chemical space that bridges biologics and small molecules, accessing therapeutic targets that neither modality addresses well such as protein-protein interfaces. Polycyclic scaffolds, in which a peptide is locked by a single polyfunctional linker into multiple interconnected macrocycles, confer the conformational rigidity required for high affinity and the proteolytic stability required for drug-like exposure. Combined recombinant expression and synthetic cyclisation is more sustainable than traditional solid-phase peptide synthesis by conferring druglike properties to peptides composed of canonical amino acids.
This project will develop a suite of tri- and tetravalent reactive linkers that enable one-step generation of highly diverse polycyclic peptide libraries on a scale compatible with affinity-based screening against challenging therapeutic targets. All linkers will be amenable to linearisation to enable characterisation of hit peptides using well established peptide characterisation techniques.
A student undertaking this project will learn synthetic organic chemistry, peptide synthesis and characterisation, medicinal chemistry with a focus on peptides, and basic biochemistry screening techniques.

Useful links:
Brennan research group

For further details please contact Paul Brennan (paul.brennan@cmd.ox.ac.uk).

The aim of this project is to harness the power of organic chemistry to develop innovative synthetic methodologies, including new photochemical strategies for the late-stage functionalisation of biologically relevant molecules. We have recently demonstrated the unique advantages of employing oxonium ions in organic synthesis, owing to the exceptional leaving-group ability of the oxonium moiety. Building on these findings, we will develop a range of new photochemical and ionic transformations that exploit this distinctive reactivity to enable efficient and selective bond-forming processes. Once established, these methodologies will be applied to the late-stage functionalisation of complex biological molecules facilitating their application in medicinal chemistry and related fields. The synthesis of the required oxonium ions will utilise new sustainable methodologies currently under development. The development of shorter, more efficient, and environmentally sustainable routes to oxonium ions will not only improve the practicality of these transformations but also encourage their broader adoption by the synthetic chemistry community.

Key publications:
Harnessing triaryloxonium ions for aryne generation. (Nat. Synth. 2023, 3, 58)
Synthesis, Characterization, and Reactivity of Complex Tricyclic Oxonium Ions, Proposed Intermediates in Natural Product Biosynthesis. (J. Am. Chem. Soc. 2019, 141, 15951)

Useful links:
Burton research group

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk).

At the heart of this project is the development of sustainable methods for the total synthesis of complex, densely functionalised, natural product-like molecules containing multiple stereocentres for antimicrobial evaluation. The continuing rise of antimicrobial resistance highlights the urgent need for new antibiotics, which forms the central motivation for this proposal. A key component of the project will be the development of novel, sustainable synthetic methods for the preparation of complex intermediates en route to the target molecules. Particular emphasis will be placed on achieving high levels of stereochemical control while improving the efficiency, scalability, and sustainability of the synthetic routes through the application of modern synthetic methods with focus on reducing/eliminating super-stoichiometric transition metal reagents through the use of organic electrochemistry. These advances will not only facilitate access to the target compounds but also establish broadly applicable sustainable synthetic strategies that can be adapted to related classes of biologically active molecules. Antimicrobial evaluation and lead optimisation will be carried out in collaboration with our industrial partner, ensuring that promising compounds are rapidly assessed and advanced towards future therapeutic development. Overall, this project will develop sustainable methodologies and apply them to the synthesis of stereochemically rich natural-product-like molecules for antimicrobial evaluation.

Key publications:
Synthesis of the Spirotetracyclic Core of the Ginkgolides via a Malonyl Radical Cascade. (Org. Lett. 2025, 27, 7927)
Total Synthesis of Salinosporamide A. (Chem. Eur. J. 2018, 24, 6747)

Useful links:
Burton research group

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk).

Cyclic chiral multifunctional building blocks are essential intermediates in the discovery and manufacture of many APIs for medicinal chemistry and agrochemical applications. However, their efficient preparation in single-enantiomer form remains a significant synthetic challenge. This proposal aims to develop new BIMP-catalysed enantioselective desymmetrisation reactions that transform a range of readily accessible symmetric precursors into valuable (known and new) chiral building blocks and demonstrate their downstream applicability in medicinal, agrochemical and antimicrobial research programs.

Key publications:
Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis. (Acc. Chem. Res. 2020, 53, 2235)
Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters. (Nat. Chem. 2023, 15, 714)

Useful links:
Dixon research group

For further details please contact Darren Dixon (darren.dixon@chem.ox.ac.uk).

Macrocyclic compounds are an emerging class of therapeutics that offer a promising alternative to conventional small molecules, combining enhanced selectivity and the ability to target previously undruggable biological targets. Despite their significant therapeutic potential, however, their design has been limited by synthetic challenges, particularly the final cyclisation step. This project aims to accelerate the discovery of bioactive macrocycles through the development of artificial intelligence (AI)-guided strategies for sustainable and efficient macrocycle synthesis. By integrating automated mechanistic analysis, high-throughput experimentation, and machine learning, we will develop a framework to design and prioritise compounds with desirable biological properties and feasible synthetic routes. Building on our group's longstanding expertise in mechanistic exploration and software development, and our long-standing collaboration with industry and academic partners, the resulting methodology and chemical insights will be deployed into industrially relevant applications, supporting a more sustainable and informed drug-discovery pipeline that reduces the need for extensive trial-and-error experimentation.

Useful links:
Duarte research group

For further details please contact Fernanda Duarte (fernanda.duartegonzalez@chem.ox.ac.uk).

Cyclobutanes are strained ring systems found in many medicines and natural products. Their unique geometry offers access to new shapes and vectors in drug discovery, yet their potential remains underexplored due to a lack of efficient methods for their stereoselective synthesis.
This project aims to develop new inherently efficient catalytic asymmetric cross-coupling methods to access a variety of functionalised, chiral cyclobutanes. We discovered that diverse C–C bond-forming reactions can be initiated by rhodium-catalysed and complementary transition-metal-catalysed carbometallation of strained prochiral alkenes. Here, we will uncover new catalytic asymmetric carbometallations of cyclobutenes to enable access to valuable, previously inaccessible chiral cyclobutanes and reveal new reactivity in these strained systems.
Mechanistic and computational studies will support the development and understanding of these reactions, as well as the rational design of new transformations. Studying these substrates offers an exciting opportunity to access novel structures relevant to drug discovery, uncover new chemical reactivity, and address challenges in the synthesis of these medicinally important molecules. This work will significantly reduce the number of steps currently needed to access these molecules, while minimising the associated energy consumption, time, and waste.

Key publications:
A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes. (Nat. Chem., 2021, 13, 880)
Rhodium-Catalyzed Asymmetric Arylation of Cyclobutenone Ketals. (Angew. Chem. 2023, 135, e202217381)
Catalytic Enantioselective Synthesis of 3‑Piperidines from Arylboronic Acids and Pyridine. (J. Am. Chem. Soc. 2023, 145, 14221)

Useful links:
Fletcher research group

For further details please contact Stephen Fletcher (stephen.fletcher@chem.ox.ac.uk).

Macrocycles are increasingly important in drug discovery because their constrained three-dimensional structures can access challenging biological targets that are often beyond the reach of conventional small molecules. Despite their importance, the synthesis of chiral macrocycles remains a significant challenge and typically relies on a limited number of ring-closing reactions.
This project aims to develop a fundamentally new approach to macrocycle synthesis using catalytic asymmetric Suzuki-type macrocyclization reactions. We have recently discovered highly selective asymmetric allylic arylation reactions that form carbon–carbon bonds with excellent regio and stereocontrol and here, we propose to harness this chemistry for the construction of macrocyclic rings which would enable simultaneous ring closure and stereogenic centre generation in a single catalytic transformation.
Mechanistic, computational, and synthetic studies will be used to understand and optimise these challenging reactions, establish the factors governing ring size, regioselectivity, and stereoselectivity, and expand the scope of accessible macrocyclic architectures. This work offers an exciting opportunity to create novel chiral macrocycles of relevance to pharmaceutical discovery while uncovering new principles for catalytic macrocyclization. In collaboration with Vertex Pharmaceuticals, we will explore a sustainable and modular strategy for accessing valuable macrocyclic chemical space that is currently difficult to reach using existing synthetic methods.

Key publications:
A Modular Strategy for the Synthesis of Macrocycles and MediumSized Rings via Cyclization/Ring Expansion Cascade Reactions. (J. Am. Chem. Soc. 2024, 146, 5702)
Ligand-enabled override of the memory effect in Rh-catalyzed asymmetric Suzuki reactions. (Chem, 2025, 11, 102550)

Useful links:
Fletcher research group
Unsworth research group

For further details please contact Stephen Fletcher (stephen.fletcher@chem.ox.ac.uk).

Over the past decade, azo photoswitches have become powerful tools in photopharmacology, with focus placed on differential binding affinity of photoswitchable isomers to their biological targets. However, the potential to dynamically regulate other key physicochemical properties of relevance to medicinal chemistry with photoswitches—such as polarity, solubility, and hydrogen-bonding capability—remains poorly unexplored. Building on extensive expertise in heteroaromatic photoswitch design in the Fuchter group, this project will develop new photoswitchable motifs that enable light-controlled modulation of such physiochemical properties. By comparing the physicochemical characteristics of the E and Z isomers, the project will establish new structure–property relationships that can be exploited in bioactive molecular design. Ultimately, these insights will be applied to biologically active ligands, creating photopharmacological agents whose physicochemical properties—and therefore biological performance—can be reversibly controlled with light. The simple light-addressable reagents developed through this project will be very cheap and simple to produce, thus ensuring built in sustainability. Furthermore, the use of light provides an environmentally benign method to control bioactivity in a sustainable way.

Key publications:
Aryl azopyrroles as visible light photoswitchable TRPA1 ligands. (Chem. Sci. 2025, 16, 19777)
Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable Z-isomer stability. (Chem. Sci. 2024, 15, 5360)
Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs). (Chem. Commun. 2022, 58, 10933)

Useful links:
Fuchter research group

For further details please contact Matthew Fuchter (matthew.fuchter@chem.ox.ac.uk).

Waste fluorochemicals including gases present a critical bottleneck to global sustainability. Gases in particular possess high Global Warming Potential (GWP). Synthetic fluorinated gases including hydrofluorocarbons (HFCs), perfluorocarbons (PFCs), and sulfur hexafluoride (SF₆)—can trap heat up to 23,000 times more effectively than CO₂, and persist in the atmosphere for up to 50,000 years.
Historically, end-of-life fluorinated gases (like refrigerants from HVAC and cooling equipment) were incinerated or vented. In this project, novel low-energy technologies will be developed that couple destruction with upcycling towards the synthesis of essential medicines or materials.

Key publications:
Phosphate-enabled mechanochemical PFAS destruction for fluoride reuse. (Nature 2025, 640, 100)
Silicate-Enabled Mechanochemical Mineralization of Polymeric and Nonpolymeric PFAS into Sodium Fluoride. (J. Am. Chem. Soc. 2026, 148, 17977)

Useful links:
Gouverneur research group

For further details please contact Véronique Gouverneur (veronique.gouverneur@chem.ox.ac.uk).

The deoxyfluorination represents an important class of reactions for the conversion of alcohols, aldehydes or carboxylic acids into mono-, di- or trifluorinated products. Such chemistry is typically carried out with hazardous diethylaminosulfur trifluoride (DAST) or other reagents that are toxic, expensive or of poor atom economy. The use of safe and inexpensive alkali metal fluoride for deoxyfluorination chemistry could be transformational for the synthesis of fluorochemicals for medicine and other applications. This project sits within this general context.

Key publications:
Asymmetric Nucleophilic Fluorination Under Hydrogen Bonding Phase-Transfer Catalysis. (Science 2018, 360, 638)
Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond. (J. Am. Chem. Soc. 2022, 144, 5200)
Impact of Multiple Hydrogen Bonds with Fluoride on Catalysis: Insight from NMR Spectroscopy. (J. Am. Chem. Soc. 2020, 142, 19731)
Enantioconvergent nucleophilic substitution via synergistic phase-transfer catalysis. (Nature Catalysis 2025, 8, 107)

Useful links:
Gouverneur research group

For further details please contact Véronique Gouverneur (veronique.gouverneur@chem.ox.ac.uk).

Clozapine remains the most effective treatment for treatment-resistant schizophrenia, yet the molecular basis of its unique clinical efficacy remains one of the major unanswered questions in neuropsychopharmacology. This project will develop next-generation chemical biology tools to identify the molecular targets, signalling networks and cellular microenvironments that underpin clozapine's distinctive pharmacology. Building on expertise in medicinal chemistry, chemical proteomics and systems pharmacology, the student will develop modular “click-and-play” clozapine probes for quantitative target engagement, chemoproteomic target deconvolution and live-cell signalling studies. Sustainability will be embedded through modular probe design, allowing multiple biological readouts to be generated from common chemical intermediates. In collaboration with Johnson & Johnson Innovative Medicine, this work aims to reveal new therapeutic mechanisms while establishing broadly applicable and resource-efficient chemical biology technologies for drug discovery.

Key publications:
A tubulin binding molecule drives differentiation of acute myeloid leukemia cells. (iScience 2022, 25, 104787)
Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid. (Angew. Chem. Int. Ed. 2020, 59, 2420)

Useful links:
Russell research group

For further details please contact Angela Russell (angela.russell@chem.ox.ac.uk).

Resistance to pharmaceuticals, including anti-infectives is a major and growing global health problem. As highlighted by the 2016 O’Neill report, the current situation with antibiotics is perilous. Antibiotics are used on a massive scale in farming and medicine; hence we need sustainable routes for production of new anti-infectives not susceptible to current resistance mechanisms. Resistance to other classes of drugs, including anti-fungals and cancer drugs as well as agrochemicals is also a major problem. The project will involve the development of enzyme / enzyme inspired and novel reactions for the efficient and sustainable preparation of new anti-infective classes that address the problem of resistance. Approaches will include late-stage modification of fermented natural products to efficiently generate structure activity relationship results, complementing efficient total synthesis approaches.

Useful links:
Schofield research group
Ineos Oxford Institute

For further details please contact Chris Schofield (christopher.schofield@chem.ox.ac.uk).

Many medium-ring heterocycles are chiral by virtue of restricted rotation about C–C/C–N bonds or their inherent topology. This project will develop efficient enantioselective routes to these molecules using counterion-mediated N-functionalisation. Catalytic dynamic stereocontrol will be used to convert rapidly equilibrating precursors directly into stereochemically defined products, avoiding wasteful resolution strategies. Alongside yield and selectivity, reaction development will address catalyst loading, reagent and solvent choice, and material efficiency, with the objective of establishing practical routes to complex chiral heterocycles that minimise the use of scarce elements and reduce waste.

For further details please contact Martin Smith (martin.smith@chem.ox.ac.uk).

Recycling waste oxygenated polymers to true monomers, including epoxides and cyclic esters, is a low-energy route to more sustainable plastics and elastomers. Understanding how to design catalysts for these depolymerizations is vital to improving efficiency and selectivity.

Key publications:
Chemical Recycling of Polyesters and Polycarbonates: Why Is Zinc(II) Such an Effective Depolymerization Catalyst? (J. Am. Chem. Soc. 2025, 147, 43077)
The Science of Polymer Chemical Recycling Catalysis: Uncovering Kinetic and Thermodynamic Linear Free Energy Relationships. (J. Am. Chem. Soc. 2025, 147, 22734)

Useful links:
Williams research group

For further details please contact Charlotte Williams (charlotte.williams@chem.ox.ac.uk).

Macrocyclic peptides have emerged as an important class of biologically active molecules, as they often display high target specificity and low toxicity. Many hit compounds in these series are now generated using automated microscale biological synthesis methods, such as mRNA displays. However, the molecules delivered by these approaches often feature redundant functional groups that are not suitable to advance along the medicinal chemistry pathway. This project is about developing ‘editing’ methods that can selectivity remove, or modify these redundant functional groups, allowing the initial leads to continue as viable molecules. The project will involve method development, catalysis, multi-stage synthesis, and application of the developed methods to complex molecules. The project is a collaboration between the Willis group at Oxford and Johnson & Johnson pharmaceuticals.

Key publications:
Chapter 1: Peptide Drug Discovery Raison d’Etre: Engineering Mindset, Design Rules and Screening Tools. (ACS Symposium Series, 2022)
Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges. (J. Am. Chem. Soc. 2019, 141, 4167)

Useful links:
Willis research group

For further details please contact Michael Willis (michael.willis@chem.ox.ac.uk).

Peptides are enjoying a renaissance in drug discovery, with the success of GLP-1 agonists such as semaglutide (Wegovy) and tirzepatide (Zepbound) providing a clear demonstration of their biological potential. Modified peptide(like) structures, such as stapled peptides and macrocyclic peptides more generally, are also of considerable current interest. Of relevance to this proposal is that the synthesis of peptides is notorious for having poor sustainability profiles, such as the use of large excesses of reagents, and the need for complex activating/coupling reagents, and the extensive use of protecting groups. This proposal is focused on developing a series of bifunctional reagents that allows for the direct and controllable functionalization of peptide chains, thus providing efficient access to macrocyclic (stapled) targets; this will avoid long synthetic sequences and complex protecting group campaigns. We will develop reagents that have reactivity matched to specific amino acids, allowing selective and efficient reactions. The project will involve reagent design and synthesis, catalysis, and application of the developed methods to complex molecules. The project is a collaboration between the Willis group at Oxford, the Spicer group at York, and the Ineos Institute Oxford.

Key publications:
Synthesis and functionalization of vinyl sulfonimidamides and their potential as electrophilic warheads. (Chem. Sci. 2025, 16, 12860)
Synthesis, Functionalization, and Reactivity of Vinyl Sulfondiimidamides. (Angew. Chem. Int. Ed. 2026, 65, e9885717)

Useful links:
Willis research group

For further details please contact Michael Willis (michael.willis@chem.ox.ac.uk).

The project will explore the potential of earth abundant metal (EAM) catalysts for arylative carbonylation reactions employing suitable aromatic and heteroaromatic halide / pseudohalide and organoboron coupling parters in the presence of a safe carbon monoxide-releasing surrogate and activator. A successful project will provide a complementary tool to the well-known thermal Pd-catalysed reaction variant. In appropriate cases we will explore the dual use of an EAM along with Pd to open-up the activation and functionalisation of more complex organic substrates. Reaction optimisations will be conducted using both an in-house built flow system (with in situ IR characterisation) and batch screening using Chemspeed ISYNTH / powderdose systems (with in line LC-MS characterisation). Bayesian optimisation routines will be deployed to accelerate optimal working reaction conditions, with a focus placed on substrates that are typically bioderived (e.g. oxygen-containing furans and pyrones) and solvents with excellent sustainable and green metrics (e.g. 2,2,5,5-tetramethyloxolane (TMO), cyrene and ethyl acetate). The green metrics of our new processes will be fully evaluated using the York-developed Chem21 green chemistry tool kit.

Useful links:
Green chemistry metrics toolkit
Fairlamb research group
Lynam research group

For further details please contact Ian Fairlamb (ian.fairlamb@york.ac.uk) and/or Jason Lynam (jason.lynam@york.ac.uk).

Antibiotics make modern medicine possible. From routine surgery to cancer treatment, many hospital interventions rely on effective antibiotics to prevent deadly infections. Antimicrobial resistance (AMR), however, is rising, and bacterial infections are becoming increasingly difficult to treat. Many of the antibiotics that have recently been approved belong to existing antibacterial classes with pre-existing resistance mechanisms. This project will explore a different source of antibacterial molecules: transition metal complexes. These compounds offer shapes, structures and modes of action that are difficult to achieve with conventional organic molecules, making them an exciting but still underexplored route to new antibiotics.
The student will use miniaturised, automated high-throughput synthesis at the University of York to prepare diverse libraries of metal complexes while reducing material use, solvent consumption and waste. These designed and curated libraries will be screened against bacterial target proteins of interest (transpeptidases and other related cell wall enzymes) in functional assays at the INEOS Oxford Institute (IOI) to identify new inhibitors. The resulting data will feed into a human-in-the-loop machine learning workflow that guides the design of focused second-generation libraries with improved target engagement. Promising hits will then be resynthesised, characterised and tested against isolated proteins and subsequently against whole bacterial cells, including clinical isolates and panels of isogenic strains (efflux, porin, siderophore transport knock-outs).
Delivered with the INEOS Oxford Institute, the project combines sustainable synthesis, antimicrobial drug discovery, automation and AI to train a student at the interface of chemistry, microbiology and data-driven molecular design.

Key publications:
Metals to combat antimicrobial resistance. (Nat Rev Chem, 2023, 7, 202)
High-throughput triazole-based combinatorial click chemistry for the synthesis and identification of functional metal complexes. (Nat Commun, 2025, 16, 11195)
Using Machine Learning to Predict the Antibacterial Activity of Ruthenium Complexes. (Angew. Chem. Int. Ed., 2024, 63, e202317901)

Useful links:
Frei research group

For further details please contact Angelo Frei (angelo.frei@york.ac.uk).

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.

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 research group
Duarte research group

For further details please contact Peter O’Brien (peter.obrien@york.ac.uk).

The Ineos Oxford Institute (IOI) spearheads sustainable drug discovery against devastating mycobacterial diseases, primarily tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization, TB remains a leading global infectious killer, claiming nearly 4,500 lives daily. Mtb evades antibiotic treatment through respiratory flexibility, enabling it to remain dormant within the host. This PhD project aims to exploit this evolutionary advantage by targeting unique components of the Mtb respiratory pathway for novel antibiotic development, addressing the challenge of identifying molecular combinations that cooperatively shut down all energy transduction pathways.
Based at the University of York, you will be trained to solve this challenge using a specialized biophysical toolkit developed by Professors Alison Parkin and Jamie Blaza. Through this collaboration, you will gain advanced expertise in probing the mode of action of respiratory-targeting drugs via a complementary combination of bioelectrochemistry, whole-cell spectroscopy, and cryo-EM. Ultimately, this project will map how IOI-developed chemical compounds eradicate Mtb, teaching us how organic chemical structure maps on to enzyme inhibition to enable the optimization of combinatorial therapies to ensure the sustainable, efficient and responsible deployment of next-generation antibiotics.

Useful links:
Parkin research group
Blaza research group
IOI grand challenges

For further details please contact Alison Parkin (alison.parkin@york.ac.uk).

Structured liquids play a vital role in a wide range of industrial applications, particularly in consumer and personal care products, where gel-like materials have an important role in providing products with appropriate physical performance. Historically, such materials have relied on the use of polymeric materials, which are powerful and tunable viscosification agents that can cope with high-complexity mixtures, including surfactants and emulsions. However, such materials typically have poor sustainability credentials, being derived from crude oil, and suffering from very poor breakdown profiles in
environmental waste.
There have therefore been attempts to replace oil-based polymers as structuring agents with naturally occurring biopolymers, but these have not been wholly successful, owing to limited tunability and/or poor performance. This proposal therefore takes a sustainable supramolecular approach to fluid modification, targeting liquid modifiers that can self-assemble from low-molecular-weight building blocks. In principle, such systems can be synthesised from wholly sustainable resources and the non-covalent interactions responsible for their assembly can easily be reversed, leading to effective degradation into non-persistent, non-toxic fragments after use.

Key publications:
Supramolecular gels – a panorama of low-molecular-weight gelators from ancient origins to next-generation technologies. (Soft Matter, 2024, 20,10)

Useful links:
Smith research group

For further details please contact David Smith (david.smith@york.ac.uk).

In this collaborative project, bio-based feedstocks will be utilized for the synthesis of a range of unsaturated and saturated nitrogen heterocyclic building blocks. These building blocks will then be decorated to give agrochemical lead-like compounds. Focus will be in two distinct areas: (i) synthesis of heteroaromatics such as pyridines, pyrazines, pyrimidines and quinolines, from a range of bio-based feedstocks; (ii) use of terpene feedstocks for the generation of sp³-rich azepane derivatives, a significantly under-studied scaffold in chemical space, which are proposed as useful 3D building blocks for further chemistry. The project draws on the GCCE’s rich history of the synthesis of bio-based platform molecules using green and sustainable chemistry, and quantifying the environmental impact of the synthetic routes, and the O’Brien group’s recent cutting edge work elaborating Nitrogen heterocycles using organolithiation.

Useful links:
Sneddon research group
O'Brien research group

For further details please contact Helen Sneddon (helen.sneddon@york.ac.uk) and/or Peter O’Brien (peter.obrien@york.ac.uk).

In this project we will develop new chemical strategies to modify peptides via late-stage, transition metal catalysed reactions. Peptides are an important modality in modern drug discovery, bridging the gap between traditional small molecule drugs and larger biologics. Strategies for late-stage diversification, where robust transformations are applied to fully synthesised, deprotected peptides, are particularly impactful on drug discovery – they allow large libraries of peptides to be generated in a single step, while greatly reducing the use of hazardous and environmentally damaging solvents.
This interdisciplinary project will build on our group’s expertise in peptide and protein chemistry to develop conceptually unique approaches to address this challenge. With our industrial partner, Johnson & Johnson, we will target new strategies for both side-chain modification and peptide ‘stapling’ of therapeutic sequences. It is well suited to students with a strong background in synthetic chemistry or chemical biology, and an interest in developing new interdisciplinary skills.

Key publications:
Peptide modification via a mild carbonylative Suzuki–Miyaura reaction gives late-stage access to diaryl-ketones. (Chem. Sci. 2026, 17, 11858)
Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N‑Terminal Protein Modification. (JACS Au 2025, 5, 1983)
Palladium-Mediated Cell-Surface Labeling. (J. Am. Chem. Soc. 2012, 134, 800)

Useful links:
Spicer research group

For further details please contact Chris Spicer (chris.spicer@york.ac.uk).

Protein bioconjugation is a vital tool in modern biomedical and biotechnological research. Our groups recently established a ‘Conjugate Addition/Ring Expansion’ (CARE) approach able to selectively and irreversibly modify the N-terminus of untagged native proteins, including nanobodies for cancer cell and tissue imaging, and human chemokines, with altered downstream activation and processing following modification. Our irreversible bioconjugations are performed in water, operate under mild conditions, and in contrast to more established methods, require few equivalents of probe. In this multidisciplinary project, we will develop new, sustainable tools for bioconjugation using novel rearrangement reactions. The project spans pure organic synthesis, chemical biology, antibiotics and bacterial PROTACS. We will develop new probes designed to promote CARE-like bioconjugation, via conjugate addition with amine groups, followed by in situ rearrangement to reveal reactive functional groups for downstream modification. This will enable the late-stage installation of dual-functional probes that can be used to study and target pathogenic bacteria, bearing: i) novel macrocycles that can modulate target/host binding; and ii) handles for diversification and protein ‘tagging’ to explore cellular delivery of antibiotics and bacterial PROTACS.

Key publications:
N-terminal protein-macrocycles enabled by conjugate addition/ring expansion cascade reactions. (Chem. Sci. 2026, 17, 3320)
Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions. (RSC Chem. Biol. 2022, 3, 334)

Useful links:
Unsworth research group
Spicer research group
Fascione research group

For further details please contact Will Unsworth (william.unsworth@york.ac.uk).