Bicyclo[n.1.1]alkanes (BCAs), and heterocyclic analogues, have emerged as important building blocks in contemporary drug design.^1,2 These bridged ring structures are conveniently prepared from ring-opening reactions of [n.1.1]propellanes. However, current routes to [n.1.1]propellanes rely on the use of alkyl/aryllithium reagents to effect closure of at least one three-membered ring.^2,3
This project seeks to address this shortcoming by developing alternative, contemporary strategies to improve the sustainability and scalability of propellane and heteropropellane synthesis, and to extend these methods to the functionalisation of BCAs. A key focus will be the use of electrosynthetic methods, including both batch and automated flow technology,⁴ as well as new precursors to propellane frameworks that avoid polyhalogenated starting materials. The project will further explore novel methods for propellane isolation and handling that avoid reliance on the typical cryogenic storage of ethereal solutions, which limits scale, transport, and also applications of propellanes (and the resulting BCA derivatives) in medicinally-relevant settings.

Key publications:
1. Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes. (JACS Au, 2023, 3, 1539)
2. Hetero[3.1.1]propellanes. (ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-tnx0l)
3. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)
4. Development of a multistep, electrochemical flow platform for automated catalyst screening. (Catal. Sci. Technol., 2022, 12, 4266)

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

Difluoromethyl-1,2,4-triazoles can act as bioisosteric replacements for acidic tetrazole rings. The applicability of substituted derivatives of this scaffold, however, is limited by lengthy syntheses and the availability of suitable starting materials. In this proposal, we want to develop tools to assemble substituted difluoromethyl-1,2,4-triazoles in a highly modular and resource-efficient fashion. This will give us a more sustainable access to the scaffold by shortening multistep synthetic procedures to essentially one single step, thereby significantly reducing waste and the consumption of solvents as well as energy. The candidate will then apply the developed methods to a medicinal chemistry project and optimise small molecule inhibitors for a hard-to-drug protein target.

Key publications:
Acidic triazoles as soluble guanylate cyclase stimulators. (Bioorg. Med. Chem. Lett., 2011, 21, 6515)

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

Modern life is impossible to imagine without polymers. However, the environmental persistence and reliance on fossil resources of most used polymers make them unsustainable. In collaboration with SCG Chemicals, this project will investigate the utilisation of abundant natural carbohydrate feedstocks to produce recyclable and degradable bio- based plastics, whose properties can compete with or complement those of polyolefins such as polyethylene, towards a circular economy of plastics with a low carbon footprint.

Key publications:
Polymers from sugars and unsaturated fatty acids: ADMET polymerisation of monomers derived from D-xylose, D-mannose and castor oil. (Polym. Chem., 2020, 11, 2681)
Xylose-Based Polyethers and Polyesters Via ADMET Polymerization toward Polyethylene-Like Materials. (ACS Appl. Polym. Mater. 2021, 3, 5870)
Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products. (ACS Catal. 2020, 10, 8880)

Useful links:
Buchard research group: www.buchardgroup.org

For further details please contact Antoine Buchard (antoine.buchard@york.ac.uk).

We have recently reported an exceedingly mild method for aryne generation by treatment of triaryloxonium ions with solid potassium phosphate in acetonitrile at room temperature. The aims of this proposal are twofold: i) to develop new, sustainable and efficient methods for the synthesis of triaryloxonium ions, and ii) to further explore and develop the chemistry of the underexplored triaryloxonium ion functional group. The three proposed methods of oxonium ion synthesis should allow the current 3/4 step linear synthesis to be reduced to a "one-pot, plug-and-play" method allowing oxonium ion synthesis from a variety of differentially functionalised starting materials and will result in synthetic procedures with reduced Process Mass Intensity (PMI). These new, more sustainable methods will enable the chemistry of this underexplored functional group to be readily developed, and as well as allowing recycling and reuse of biaryloxonium building blocks. Shorter, more efficient and sustainable methods of oxonium ion synthesis will serve to facilitate up-take of the developed methodology by the chemistry community.

Key publications:
Harnessing triaryloxonium ions for aryne generation (Nat. Synth. 2023, 3, 58)

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

Configurationally defined, partially and fully substituted vicinal amino alcohols are indispensable motifs in natural products, pharmaceuticals, and agrochemicals, and serve as critical building blocks across a range of synthetic applications. Traditional synthetic approaches predominantly rely on polar bond retrosynthetic logic and protecting group strategies, often resulting in lengthy and inefficient routes to these valuable structures. As medicinal chemistry increasingly prioritizes sp³-rich architectures, there is a pressing need for novel and efficient methodologies to access these complex motifs.
This proposal outlines a two-stage, three-component strategy that addresses this challenge by integrating cutting-edge enantioselective catalysis with stereoselective electrocatalytic decarboxylative transformations. In the first stage, chiral vicinal amino alcohol building blocks bearing redox-active ester functionalities are constructed with high stereocontrol. In the second stage, these intermediates will undergo modular and selective electrocatalytic decarboxylation, affording a broad array of enantiopure, partially and fully substituted amino alcohols.
Distinct from conventional methods, this build-and-modify approach is both general and modular, leveraging readily available starting materials such as aldehydes, ketones, and organohalides. The proposed platform enables unprecedented stereoselective and chemoselective access to structurally diverse amino alcohols, offering transformative potential for both high-throughput library generation and the synthesis of complex molecular targets.

Key publications:
Direct Catalytic Enantio- and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates. (Angew. Chem. Int. Ed., 2015, 54, 4895)
A New Family of Cinchona-Derived Amino Phosphine Precatalysts: Application to the Highly Enantio- and Diastereoselective Silver-Catalyzed Isocyanoacetate Aldol Reaction. (J. Am. Chem. Soc., 2011, 133, 1710)
Bespoke and Accessible Electrochemical Reactors. (ACS Cent. Sci. 2024, 10, 2000)
Stereoselective amino alcohol synthesis via chemoselective electrocatalytic radical cross-couplings. (Nat. Chem., 2025, 17, 44)

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

Tertiary and fully substituted carbon centres bearing a heteroatom (e.g. oxygen or nitrogen) are increasingly prevalent in pharmaceuticals, agrochemicals, and natural products due to their beneficial physicochemical and pharmacokinetic properties. As drug discovery shifts toward sp³-rich scaffolds, there is a growing demand for new, efficient methods to construct these challenging motifs. To address this, we propose a general, redox-neutral photocatalytic coupling strategy that enables broad-in-scope carbon–carbon bond formation between abundant radical precursors and diverse and abundant partners. This new technology has the potential to offer broad applicability and mechanistic innovation for both high throughput library generation and complex target molecule synthesis.

Key publications:
Photocatalytic reverse polarity Povarov reaction. (Chem. Sci., 2018, 9, 6653)
Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines. (Org. Lett. 2018, 20, 6794)
Primary α-tertiary amine synthesis via α-C–H functionalization. (Chem. Sci., 2019,10, 3401)
Photocatalytic Reductive Formation of α-Tertiary Ethers from Ketals. (Org. Lett. 2019, 21, 6668)
α-Tertiary Dialkyl Ether Synthesis via Reductive Photocatalytic α-Functionalization of Alkyl Enol Ethers. (ACS Catal. 2020, 10, 11430)

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

This project will develop new catalytic methods for making C-C bonds and expand the scope of hydrogen borrowing catalysis; and is a collaboration with a major pharmaceutical company. The sustainability aspect lies in the utilisation of earth abundant metal catalysts (eg Mn, Fe) to reduce our reliance on rare transition metals and is increased by the use of common feedstock alcohols as efficient alkylating agents. Note that these reactions produce water as the stoichiometric by-product.
At the heart of a hydrogen borrowing (HB) alkylation is an aldol process, forming a C=C bond. Typically, this reaction requires high temperatures and stoichiometric strong bases, which limits the functionality within the products. This project will design new reactions where the problematic aldol is replaced by more efficient C=C bond formation requiring much milder conditions and will lead to fundamentally new products. Importantly, we have designed a new role for the metal hydride formed after alcohol oxidation: in addition to reducing the alkene product, we aim to use the [MH] species to reduce, and recycle, an oxygenated by-product from the olefination. This will allow the alkene forming reaction to use catalytic reagents and greatly improve efficiency and reduce the amount of waste produced.

Key publications:
Dynamic Kinetic Resolution Allows Control of Remote Stereochemistry in Asymmetric Hydrogen Borrowing Alkylation. (Angew. Chem. Int. Ed. 2025, 64, e202424959)
Hydrogen-Borrowing-Based Methods for the Construction of Quaternary Stereocentres. (Angew Chem. Int. Ed. 2025, 64, e202423179)
Functional group tolerant hydrogen borrowing C-alkylation. (Nature: Communications 2024, 15, 5131)

For further details please contact Tim Donohoe (timothy.donohoe@chem.ox.ac.uk).

Macrocyclic compounds are a promising alternative to small molecules for targeting difficult-to-treat diseases. However, challenges in their synthesis have hindered their application. This project aims to develop efficient computational methods to support sustainable and effective macrocycle synthesis. It will incorporate automated tools, high-throughput experimentation (HTE), and machine learning to design and identify novel macrocycles for biological applications.

Useful links:
Duarte research group: https://www.duartegroupchem.org

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

Whole-cell biocatalysis is emerging as a sustainable and environmentally-compatible alternative to chemical catalysis. This approach takes advantage of the metabolism of a bacterial cell for the production of valuable target molecules, with highly (enantio)selective transformations being enabled in water-containing media, under ambient conditions and by using renewable feedstocks. Despite these clear advantages, limitations associated with the transport of substrates and catalysts through cell membranes are often reducing the overall catalytic effectiveness of whole-cell setups. The aim of this project is therefore to develop suitable delivery vectors to transport the respective active components into cells. Target reactions include the production of active pharmaceutical ingredients and the selective activation of masked antimicrobial prodrugs using Ru and Pd catalysis. The work will use bio-derived components, degradable linkers, and enzymatic synthesis where possible and experiments will be performed on small scales to minimise the usage of chemicals. Catalytic performance will be assessed though product analysis by chiral HPLC, electronic absorption and fluorescence spectroscopy and via the release of antimicrobial products, as appropriate.

Key publications:
Redox-switchable siderophore anchor enables reversible artificial metalloenzyme assembly. (Nat Catal. 2018, 1, 680)
Siderophore-Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells. (Chem. Eur. J. 2023, 29, e202202536)
Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis. (J. Am. Chem. Soc. 2024, 146, 4351)

For further details please contact Anne Duhme-Klair (anne.duhme-klair@york.ac.uk).

Cyclobutanes are strained ring systems found in many medicines and natural products. Their unusual geometry offers access to new shapes and vectors in drug discovery — but they remain underused due to inefficient, non-sustainable routes for their synthesis. This project develops a greener, catalytic asymmetric cross-coupling platform that transforms simple cyclobutenes into richly functionalised, chiral cyclobutanes.
Our approach emphasises sustainability at every stage: starting from cyclobutenes that are readily accessible in 1–2 steps from feedstocks, avoiding protecting groups, and eliminating stoichiometric reagents. As well as being atom-economical, modular, and convergent, it enables rapid access to diverse products and the opportunity to discover, understand, and harness new reactivity patterns. These methods represent a step-change over current multistep approaches and align with the goals of circular chemistry.
In collaboration with J&J Innovative Medicine, we will use their High Throughput Experimentation (HTE) Centre of Excellence to accelerate catalyst development and explore the potential of these scaffolds in real-world drug discovery. Students will also investigate new reactivity patterns, such as 1,2-difunctionalisation or hydroalkylation, guided by J&J’s interest and expertise.
This project offers training in asymmetric catalysis, reaction design, and industry collaboration — while contributing to more sustainable ways of making high-value molecules for pharmaceutical applications.

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)
Rhodium-Catalyzed Asymmetric Suzuki and Related Cross-Coupling Reactions. (Aldrichimica Acta, 2024, 57, 1)

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

Cost effective and sustainable ways to tackle the growing AMR crisis are a critical and global need. The coupling of light to therapeutic action has high potential in new approaches to AMR management, through improved selectivity, decreased selection pressures, etc. We aim to develop photoswitchable agents that can selectively label the N-termini of proteins with light-dependent reversibility. The combination of such agents with antimicrobial peptides and proteins would allow for spatiotemporal control of antimicrobial action. By ensuring the use of sustainable feedstocks and a low number of synthetic steps in the generation of the target agents, we will ensure sustainability is built into the approach from the start. Overall, this work will pioneer a new modality to tackle AMR and new light-addressable reagents in chemical biology.

Key publications:
Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable Z-isomer stability. (Chem. Sci., 2024,15, 5360)
Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N-Terminal Protein Modification. (JACS Au, 2025, 5, 1983)
Light Responsiveness and Assembly of Arylazopyrazole-Based Surfactants in Neat and Mixed CTAB Micelles. (JACS Au, 2022, 2, 2670)

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

The introduction of saturation in the form of C_sp3-F into agrochemical candidates improves biological properties and increase the chance to reach the market. New chemistry will be developed for the synthesis of di- and trifluorinated molecules using safe and cost-effective fluorinating reagents. Our goal is to invent a process to replace the Swarts reaction that relies on corrosive and dangerous antimony trifluoride more often combined with chlorine gas or hydrogen fluoride.

Key publications:
Phosphate-Enabled Mechanochemical PFAS Destruction for Fluoride Reuse. (Nature 2025, 640, 100)
One-Step HF-Free Synthesis of Alkali Metal Fluorides from Fluorspar. (J. Am. Chem. Soc. 2025, 147, 6338)
Fluorspar to Fluorochemicals upon Low-Temperature Activation in Water. (Nature, 2024, 635, 359)
Fluorochemicals from Fluorspar via a phosphate-enabled mechanochemical process that bypasses HF. (Science 2023, 381, 302)

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

The introduction of saturation in the form of C_sp3-F into pharmaceutical candidates improves medicinal properties and increase the chance to reach the clinic. New chemistry will be developed for the conversion of alcohols into alkyl fluorides using safe and cost-effective alkali metal fluorides. Our goal is to invent a deoxyfluorination process under asymmetric phase transfer catalysis.

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)

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

This project will explore methods to use earth abundant, Lewis acidic main group catalysts to catalyse organic transformations in water by exploiting micellar confinement. The student will prepare novel micellar catalysts that leverage solvent insensitive halogen and chalcogen bonding interactions, and designer functionalized (chiral) surfactants to mediate a wide range of organic transformations relevant to pharmaceutical and fine chemical synthesis in water.

Useful links:
Langton research group: https://langtonrg.web.ox.ac.uk
Shimizu research group: https://www.york.ac.uk/chemistry/people/sshimizu/
Centre for Transformation of Chemistry: https://transforming-chemistry.org/en/

For further details please contact Matthew Langton (matthew.langton@chem.ox.ac.uk).

Quaternary carbon stereocenters, particularly all carbon ones, are key structural moieties in pharmaceuticals yet remain challenging to synthetically construct as there is no general catalytic asymmetric solution. The discovery and development of efficient synthetic methods for quaternary carbon stereocenters would expand a discovery chemists’ toolbox as well as provide the basis for sustainable commercial manufacturing. Towards this goal, this proposal aims to develop new base metal-catalysed methods for the selective functionalization of C-H bonds to desymmetrize prochiral molecules. In particular, we intend to introduce quaternary carbon stereochemistry by functionalisation of one of two enantiotopic substituents of a prochiral quaternary carbon center. Base metal catalysts, including iron and cobalt, will be the focus of catalyst development in this work due to their improved sustainability and reduced toxicity compared to traditional precious metal catalysts, representing a key development towards a more sustainable synthetic future.

Key publications:
Iron-catalyzed stereoselective C–H alkylation for simultaneous construction of C–N axial and C-central chirality. (Nat. Commun. 2024, 15, 3503)

For further details please contact Michael Neidig (michael.neidig@chem.ox.ac.uk)

There is interest in 3-D heterocyclic scaffolds for medicinal chemistry. The O'Brien group has recently disclosed a modular synthetic platform for the elaboration of 2-D fragments into 3-D lead-like compounds that utilised 3-D cyclopropyl organoboron building blocks (with distinct vectors in 3-D). In terms of sustainable synthesis, there are significant limitations with the 1^st generation building blocks, namely multi-step synthesis using stoichiometric reagents and Pd-catalysed cross-coupling for aryl group attachment. To address, in a new collaborative project with Sneddon, 2^nd generation cyclopropyl N-hydroxyphthalimide (NHP) ester building blocks will be explored. This will include: (i) a one-step synthesis of the building blocks using diazo-NHP esters under Cu(I) catalysis and (ii) a reductive decarboxylative Ni-catalysed cross-electrophile coupling. The scope of the Ar-Br in the cross-coupling step will be explored as it will be necessary to demonstrate broad scope with medicinally-relevant motifs for use in the modular fragment elaboration platform. Finally, a range of cyclopropyl NHP-ester 3-D building blocks will be synthesised and cross-coupled – the building blocks will contain different 3-D vectors between the N–Boc and cyclopropane ester bonds (assessed using of the computed lowest energy conformation). In this way, a more sustainable modular synthetic platform for fragment elaboration will be developed.

Key publications:
Modular Synthetic Platform for Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery. (J. Am. Chem. Soc. 2025, 147, 29292)
Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings. (Angew. Chem. Int. Ed. 2022, 61, e202205673)

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

While naphthalene and equivalent heterobiaryl rings are often encountered in drugs, candidates and lead molecules, they can be susceptible to cytochrome P450-mediated metabolism and exhibit flat, sp²-rich structures and are almost invariably derived from fossil fuel sources, limiting their current and future utility. Yet, few viable alternatives have been described. In this project we propose to build on our preliminary findings that aryl-fused bicyclo[3.1.1]heptanes (aryl BCHeps) can serve as effective bioisosteric replacements for naphthalene or (iso) quinolines, and can be accessed via an unusual photosensitiser-induced mechanism and extend into other unexplored problematic heterobiaryl bioisosteres.

Key publications:
Synthesis of Aryl-fused Bicyclo[3.1.1]heptanes (BCHeps) and Validation as Naphthyl Bioisosteres. (ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-t0t94)

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: https://schofield.web.ox.ac.uk
Ineos Oxford Institute: https://www.ineosoxford.ox.ac.uk

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

luorine-containing molecules are essential in a range of applications, including many pharmaceuticals and crop-protection products. This collaborative project will develop novel metal-free catalysis for the preparation of functional fluorinated molecules. Non-metal catalysts, based on earth-abundant elements, will avoid the need for expensive, toxic precious-metals. Readily available fluorinated building blocks will be upcycled through highly atom economical reactions. Overall, this will allow the preparation of functional fluorinated molecules in more sustainable ways.
The project will build on recent work in our groups to develop novel, non-metal catalysts, for the sustainable manipulation of fluorine atoms. We will take perfluoroarenes/heteroarenes as starting materials, which are readily available, but in the current push to eliminate perfluorinated molecules will benefit from partial defluorination. These will be upcycled to more valuable building blocks by C-F bond functionalisation, developing catalysis based on simple phosphines reported by Slattery and Lynam.
C-F activation liberates fluoride, which will be captured and utilised in tandem, enantioselective C-F bond formation processes. This will make use of recent advances by Gouverneur, using chiral ureas as hydrogen bonding phase-transfer catalysts. The project will involve synthesis, catalyst development and mechanistic studies and will leverage the complementary expertise in York and Oxford to provide broad training.

Key publications:
Metallomimetic C–F Activation Catalysis by Simple Phosphines. (J. Am. Chem. Soc. 2024, 146, 2005)
Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis. (Science 2018, 360, 638)

For further details please contact John Slattery (john.slattery@york.ac.uk).

This project will focus on efficient approaches to the synthesis of complex heterocyclic molecules through the development of a photochemical cycloaddition/fragmentation process. These reactions will be enabled through the design and application of sustainable photosensitizers based upon earth abundant metals and metal-free scaffolds.

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

In this project we will establish novel chemical biology tools to explore post translational modification (PTM) of lysine residues, centred on the use of conjugation addition/ring expansion (CARE) cascade reactions for selective peptide/protein bioconjugation. This project in underpinned by the ‘CARE’ method, developed by Unsworth and coworkers for use on small molecule systems¹. More recently, Unsworth, Spicer, Fascione and coworkers extended the CARE method for application in protein modification, exploiting water as a solvent for sustainable production of potent bioconjugates². Post-translational modifications of lysines are pivotal regulators of many important biological processes, including regulation of expression. Lysines modification is important in peptide drugs, e.g. the anti-obesity medicine semaglutide, and are potential value in modifying antibodies with drugs, including antibiotics. In this CSHP CDT project, we will: (i) develop and screen CARE reagents for pH controlled selective modification of lysine residues within proteins; ii) develop CARE reagents for selective modification and reactivity profiling of lysine residues including in antibiotic targets, such as beta-lactamases that enable resistance to carbapenems and other beta-lactam antibiotics³, and iii) use the CARE bioconjugation to construct macrocycle-modified lysine containing peptides, with potential application as novel therapeutics.

Key publications:
1. Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions. (RSC Chem. Biol., 2022, 3, 334)
2. N-terminal protein-macrocycles enabled by conjugate addition/ring expansion cascade reactions. (ChemRxiv. 2025; doi:10.26434/chemrxiv-2025-06817)
3. Biochemical and structural investigations clarify the substrate selectivity of the 2-oxoglutarate oxygenase JMJD6. (J. Biol. Chem. 2019, 294,11637)

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

Aligning with Green Chemistry Principle 7, this project will focus on using renewable feedstocks to replace petroleum-based chemicals in the production of valuable compounds such as furoic acid, furan dicarboxylic acid, and (S)-γ-hydroxymethyl-α,β-butenolide, which have applications in food preservation, pharmaceuticals, and polymer synthesis. Current challenges in this field include limited mechanistic understanding, selectivity issues, and undesirable side-reactions. To address this, we will employ an automated flow platform to develop homogeneous Fe-catalysed oxidation of biomass derivatives. This high-throughput approach will generate substantial data, providing a deeper understanding of reaction pathways, side-reactions, and mechanisms, ultimately leading to a more informed and effective approach to catalyst design.

Key publications:
Development of a multistep, electrochemical flow platform for automated catalyst screening. (Catal. Sci. Technol. 2022, 12, 4266)

For further details please contact Charlotte Willans (charlotte.willans@york.ac.uk).

Polymer manufacturing is already responsible for 1.6 Gt CO₂ equiv. emissions annually, our recent research reveals that replacing petrochemical raw materials with biomass, carbon dioxide and waste polymers can help to drive down these emissions, and provide other sustainability benefits, to reach net zero targets. This project focusses on a technology of high promise in carbon dioxide utilization: catalytic copolymerization with heterocycles to produce recyclable plastics for use in high-value areas, including electronics, transport and construction.

Key publications:
Quantifying CO₂ Insertion Equilibria for Low-Pressure Propene Oxide and Carbon Dioxide Ring Opening Copolymerization Catalysts. (J. Am. Chem. Soc. 2024, 146, 10451)
Insights into the Mechanism of Carbon Dioxide and Propylene Oxide Ring-Opening Copolymerization Using a Co(III)/K(I) Heterodinuclear Catalysts. (J. Am. Chem. Soc. 2022, 144, 17929)

Useful links:
Williams research group: https://cwilliamsresearch.web.ox.ac.uk/

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

Adhesives play a critical role in many technologies from construction, transportation, electronics to consumer goods. There are growing environmental concerns, legislation and customer pressure to deliver more sustainable adhesives and to ensure they maximise recycling of other components. Adhesives which can bond/de-bond on demand and which are degradable after use are particularly important. Here, we will develop new lower carbon footprint sustainable polymers, sourced from biomass and waste carbon dioxide, as debondable, recyclable and degradable adhesives.

Key publications:
Bio-based and Degradable Block Polyester Pressure-Sensitive Adhesives. (Angew. Chem. Int. Ed. 2020, 59, 23450)
Switchable Catalysis Improves the Properties of CO₂-Derived Polymers: Poly(cyclohexene carbonate-b-ε-decalactone-b-cyclohexene carbonate) Adhesives, Elastomers, and Toughened Plastics. (J. Am. Chem. Soc. 2020, 142, 4367)

Useful links:
Williams research group: https://cwilliamsresearch.web.ox.ac.uk/

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

Amino acids and peptides are essential components of modern medicines; however, native systems still present challenges. This project will use modern catalytic methods to achieve the sustainable synthesis of amino acid mimetics based on sulfur functional groups. These new mimetics have been designed to address the limitations present in the naturally occurring systems. Control of stereochemistry will be key, and exploring how these new mimetics, and their associated structural features, effect the gross conformation of peptide chains will be explored. We will prepare mimetics that allow compatibility with automated peptide synthesis, and will also explore applications of the developed chemistry to the late-stage functionalisation of peptide chains. Developing new synthetic methods is at the core of this proposal, and key to achieving this will be delivering a sustainable catalytic synthesis based on abundant substrates, and non-precious metal catalysts.

Key publications:
Exploiting trans-Sulfinylation for the Synthesis of Diverse N-Alkyl Sulfinamides via Decarboxylative Sulfinamidation. (Angew. Chem. Int. Ed. 2024, 63, e202407970)
Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides. (J. Am. Chem. Soc. 2023, 145, 21623)
The Catalytic Synthesis of Aza-Sulfur Functional Groups. (Synthesis 2025, 57, 1429)

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

Bicyclo[n.1.1]alkanes (BCAs), and heterocyclic analogues, have emerged as important building blocks in contemporary drug design.^1,2 These bridged ring structures are conveniently prepared from ring-opening reactions of [n.1.1]propellanes. However, current routes to [n.1.1]propellanes rely on the use of alkyl/aryllithium reagents to effect closure of at least one three-membered ring.^2,3
This project seeks to address this shortcoming by developing alternative, contemporary strategies to improve the sustainability and scalability of propellane and heteropropellane synthesis, and to extend these methods to the functionalisation of BCAs. A key focus will be the use of electrosynthetic methods, including both batch and automated flow technology,⁴ as well as new precursors to propellane frameworks that avoid polyhalogenated starting materials. The project will further explore novel methods for propellane isolation and handling that avoid reliance on the typical cryogenic storage of ethereal solutions, which limits scale, transport, and also applications of propellanes (and the resulting BCA derivatives) in medicinally-relevant settings.

Key publications:
1. Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes. (JACS Au, 2023, 3, 1539)
2. Hetero[3.1.1]propellanes. (ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-tnx0l)
3. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)
4. Development of a multistep, electrochemical flow platform for automated catalyst screening. (Catal. Sci. Technol., 2022, 12, 4266)

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

Difluoromethyl-1,2,4-triazoles can act as bioisosteric replacements for acidic tetrazole rings. The applicability of substituted derivatives of this scaffold, however, is limited by lengthy syntheses and the availability of suitable starting materials. In this proposal, we want to develop tools to assemble substituted difluoromethyl-1,2,4-triazoles in a highly modular and resource-efficient fashion. This will give us a more sustainable access to the scaffold by shortening multistep synthetic procedures to essentially one single step, thereby significantly reducing waste and the consumption of solvents as well as energy. The candidate will then apply the developed methods to a medicinal chemistry project and optimise small molecule inhibitors for a hard-to-drug protein target.

Key publications:
Acidic triazoles as soluble guanylate cyclase stimulators. (Bioorg. Med. Chem. Lett., 2011, 21, 6515)

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

We have recently reported an exceedingly mild method for aryne generation by treatment of triaryloxonium ions with solid potassium phosphate in acetonitrile at room temperature. The aims of this proposal are twofold: i) to develop new, sustainable and efficient methods for the synthesis of triaryloxonium ions, and ii) to further explore and develop the chemistry of the underexplored triaryloxonium ion functional group. The three proposed methods of oxonium ion synthesis should allow the current 3/4 step linear synthesis to be reduced to a "one-pot, plug-and-play" method allowing oxonium ion synthesis from a variety of differentially functionalised starting materials and will result in synthetic procedures with reduced Process Mass Intensity (PMI). These new, more sustainable methods will enable the chemistry of this underexplored functional group to be readily developed, and as well as allowing recycling and reuse of biaryloxonium building blocks. Shorter, more efficient and sustainable methods of oxonium ion synthesis will serve to facilitate up-take of the developed methodology by the chemistry community.

Key publications:
Harnessing triaryloxonium ions for aryne generation (Nat. Synth. 2023, 3, 58)

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

Configurationally defined, partially and fully substituted vicinal amino alcohols are indispensable motifs in natural products, pharmaceuticals, and agrochemicals, and serve as critical building blocks across a range of synthetic applications. Traditional synthetic approaches predominantly rely on polar bond retrosynthetic logic and protecting group strategies, often resulting in lengthy and inefficient routes to these valuable structures. As medicinal chemistry increasingly prioritizes sp³-rich architectures, there is a pressing need for novel and efficient methodologies to access these complex motifs.
This proposal outlines a two-stage, three-component strategy that addresses this challenge by integrating cutting-edge enantioselective catalysis with stereoselective electrocatalytic decarboxylative transformations. In the first stage, chiral vicinal amino alcohol building blocks bearing redox-active ester functionalities are constructed with high stereocontrol. In the second stage, these intermediates will undergo modular and selective electrocatalytic decarboxylation, affording a broad array of enantiopure, partially and fully substituted amino alcohols.
Distinct from conventional methods, this build-and-modify approach is both general and modular, leveraging readily available starting materials such as aldehydes, ketones, and organohalides. The proposed platform enables unprecedented stereoselective and chemoselective access to structurally diverse amino alcohols, offering transformative potential for both high-throughput library generation and the synthesis of complex molecular targets.

Key publications:
Direct Catalytic Enantio- and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates. (Angew. Chem. Int. Ed., 2015, 54, 4895)
A New Family of Cinchona-Derived Amino Phosphine Precatalysts: Application to the Highly Enantio- and Diastereoselective Silver-Catalyzed Isocyanoacetate Aldol Reaction. (J. Am. Chem. Soc., 2011, 133, 1710)
Bespoke and Accessible Electrochemical Reactors. (ACS Cent. Sci. 2024, 10, 2000)
Stereoselective amino alcohol synthesis via chemoselective electrocatalytic radical cross-couplings. (Nat. Chem., 2025, 17, 44)

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

Tertiary and fully substituted carbon centres bearing a heteroatom (e.g. oxygen or nitrogen) are increasingly prevalent in pharmaceuticals, agrochemicals, and natural products due to their beneficial physicochemical and pharmacokinetic properties. As drug discovery shifts toward sp³-rich scaffolds, there is a growing demand for new, efficient methods to construct these challenging motifs. To address this, we propose a general, redox-neutral photocatalytic coupling strategy that enables broad-in-scope carbon–carbon bond formation between abundant radical precursors and diverse and abundant partners. This new technology has the potential to offer broad applicability and mechanistic innovation for both high throughput library generation and complex target molecule synthesis.

Key publications:
Photocatalytic reverse polarity Povarov reaction. (Chem. Sci., 2018, 9, 6653)
Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines. (Org. Lett. 2018, 20, 6794)
Primary α-tertiary amine synthesis via α-C–H functionalization. (Chem. Sci., 2019,10, 3401)
Photocatalytic Reductive Formation of α-Tertiary Ethers from Ketals. (Org. Lett. 2019, 21, 6668)
α-Tertiary Dialkyl Ether Synthesis via Reductive Photocatalytic α-Functionalization of Alkyl Enol Ethers. (ACS Catal. 2020, 10, 11430)

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

This project will develop new catalytic methods for making C-C bonds and expand the scope of hydrogen borrowing catalysis; and is a collaboration with a major pharmaceutical company. The sustainability aspect lies in the utilisation of earth abundant metal catalysts (eg Mn, Fe) to reduce our reliance on rare transition metals and is increased by the use of common feedstock alcohols as efficient alkylating agents. Note that these reactions produce water as the stoichiometric by-product.
At the heart of a hydrogen borrowing (HB) alkylation is an aldol process, forming a C=C bond. Typically, this reaction requires high temperatures and stoichiometric strong bases, which limits the functionality within the products. This project will design new reactions where the problematic aldol is replaced by more efficient C=C bond formation requiring much milder conditions and will lead to fundamentally new products. Importantly, we have designed a new role for the metal hydride formed after alcohol oxidation: in addition to reducing the alkene product, we aim to use the [MH] species to reduce, and recycle, an oxygenated by-product from the olefination. This will allow the alkene forming reaction to use catalytic reagents and greatly improve efficiency and reduce the amount of waste produced.

Key publications:
Dynamic Kinetic Resolution Allows Control of Remote Stereochemistry in Asymmetric Hydrogen Borrowing Alkylation. (Angew. Chem. Int. Ed. 2025, 64, e202424959)
Hydrogen-Borrowing-Based Methods for the Construction of Quaternary Stereocentres. (Angew Chem. Int. Ed. 2025, 64, e202423179)
Functional group tolerant hydrogen borrowing C-alkylation. (Nature: Communications 2024, 15, 5131)

For further details please contact Tim Donohoe (timothy.donohoe@chem.ox.ac.uk).

Macrocyclic compounds are a promising alternative to small molecules for targeting difficult-to-treat diseases. However, challenges in their synthesis have hindered their application. This project aims to develop efficient computational methods to support sustainable and effective macrocycle synthesis. It will incorporate automated tools, high-throughput experimentation (HTE), and machine learning to design and identify novel macrocycles for biological applications.

Useful links:
Duarte research group: https://www.duartegroupchem.org

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 unusual geometry offers access to new shapes and vectors in drug discovery — but they remain underused due to inefficient, non-sustainable routes for their synthesis. This project develops a greener, catalytic asymmetric cross-coupling platform that transforms simple cyclobutenes into richly functionalised, chiral cyclobutanes.
Our approach emphasises sustainability at every stage: starting from cyclobutenes that are readily accessible in 1–2 steps from feedstocks, avoiding protecting groups, and eliminating stoichiometric reagents. As well as being atom-economical, modular, and convergent, it enables rapid access to diverse products and the opportunity to discover, understand, and harness new reactivity patterns. These methods represent a step-change over current multistep approaches and align with the goals of circular chemistry.
In collaboration with J&J Innovative Medicine, we will use their High Throughput Experimentation (HTE) Centre of Excellence to accelerate catalyst development and explore the potential of these scaffolds in real-world drug discovery. Students will also investigate new reactivity patterns, such as 1,2-difunctionalisation or hydroalkylation, guided by J&J’s interest and expertise.
This project offers training in asymmetric catalysis, reaction design, and industry collaboration — while contributing to more sustainable ways of making high-value molecules for pharmaceutical applications.

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)
Rhodium-Catalyzed Asymmetric Suzuki and Related Cross-Coupling Reactions. (Aldrichimica Acta, 2024, 57, 1)

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

Cost effective and sustainable ways to tackle the growing AMR crisis are a critical and global need. The coupling of light to therapeutic action has high potential in new approaches to AMR management, through improved selectivity, decreased selection pressures, etc. We aim to develop photoswitchable agents that can selectively label the N-termini of proteins with light-dependent reversibility. The combination of such agents with antimicrobial peptides and proteins would allow for spatiotemporal control of antimicrobial action. By ensuring the use of sustainable feedstocks and a low number of synthetic steps in the generation of the target agents, we will ensure sustainability is built into the approach from the start. Overall, this work will pioneer a new modality to tackle AMR and new light-addressable reagents in chemical biology.

Key publications:
Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable Z-isomer stability. (Chem. Sci., 2024,15, 5360)
Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N-Terminal Protein Modification. (JACS Au, 2025, 5, 1983)
Light Responsiveness and Assembly of Arylazopyrazole-Based Surfactants in Neat and Mixed CTAB Micelles. (JACS Au, 2022, 2, 2670)

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

The introduction of saturation in the form of C_sp3-F into agrochemical candidates improves biological properties and increase the chance to reach the market. New chemistry will be developed for the synthesis of di- and trifluorinated molecules using safe and cost-effective fluorinating reagents. Our goal is to invent a process to replace the Swarts reaction that relies on corrosive and dangerous antimony trifluoride more often combined with chlorine gas or hydrogen fluoride.

Key publications:
Phosphate-Enabled Mechanochemical PFAS Destruction for Fluoride Reuse. (Nature 2025, 640, 100)
One-Step HF-Free Synthesis of Alkali Metal Fluorides from Fluorspar. (J. Am. Chem. Soc. 2025, 147, 6338)
Fluorspar to Fluorochemicals upon Low-Temperature Activation in Water. (Nature, 2024, 635, 359)
Fluorochemicals from Fluorspar via a phosphate-enabled mechanochemical process that bypasses HF. (Science 2023, 381, 302)

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

The introduction of saturation in the form of C_sp3-F into pharmaceutical candidates improves medicinal properties and increase the chance to reach the clinic. New chemistry will be developed for the conversion of alcohols into alkyl fluorides using safe and cost-effective alkali metal fluorides. Our goal is to invent a deoxyfluorination process under asymmetric phase transfer catalysis.

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)

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

This project will explore methods to use earth abundant, Lewis acidic main group catalysts to catalyse organic transformations in water by exploiting micellar confinement. The student will prepare novel micellar catalysts that leverage solvent insensitive halogen and chalcogen bonding interactions, and designer functionalized (chiral) surfactants to mediate a wide range of organic transformations relevant to pharmaceutical and fine chemical synthesis in water.

Useful links:
Langton research group: https://langtonrg.web.ox.ac.uk
Shimizu research group: https://www.york.ac.uk/chemistry/people/sshimizu/
Centre for Transformation of Chemistry: https://transforming-chemistry.org/en/

For further details please contact Matthew Langton (matthew.langton@chem.ox.ac.uk).

Quaternary carbon stereocenters, particularly all carbon ones, are key structural moieties in pharmaceuticals yet remain challenging to synthetically construct as there is no general catalytic asymmetric solution. The discovery and development of efficient synthetic methods for quaternary carbon stereocenters would expand a discovery chemists’ toolbox as well as provide the basis for sustainable commercial manufacturing. Towards this goal, this proposal aims to develop new base metal-catalysed methods for the selective functionalization of C-H bonds to desymmetrize prochiral molecules. In particular, we intend to introduce quaternary carbon stereochemistry by functionalisation of one of two enantiotopic substituents of a prochiral quaternary carbon center. Base metal catalysts, including iron and cobalt, will be the focus of catalyst development in this work due to their improved sustainability and reduced toxicity compared to traditional precious metal catalysts, representing a key development towards a more sustainable synthetic future.

Key publications:
Iron-catalyzed stereoselective C–H alkylation for simultaneous construction of C–N axial and C-central chirality. (Nat. Commun. 2024, 15, 3503)

For further details please contact Michael Neidig (michael.neidig@chem.ox.ac.uk)

While naphthalene and equivalent heterobiaryl rings are often encountered in drugs, candidates and lead molecules, they can be susceptible to cytochrome P450-mediated metabolism and exhibit flat, sp²-rich structures and are almost invariably derived from fossil fuel sources, limiting their current and future utility. Yet, few viable alternatives have been described. In this project we propose to build on our preliminary findings that aryl-fused bicyclo[3.1.1]heptanes (aryl BCHeps) can serve as effective bioisosteric replacements for naphthalene or (iso) quinolines, and can be accessed via an unusual photosensitiser-induced mechanism and extend into other unexplored problematic heterobiaryl bioisosteres.

Key publications:
Synthesis of Aryl-fused Bicyclo[3.1.1]heptanes (BCHeps) and Validation as Naphthyl Bioisosteres. (ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-t0t94)

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: https://schofield.web.ox.ac.uk
Ineos Oxford Institute: https://www.ineosoxford.ox.ac.uk

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

This project will focus on efficient approaches to the synthesis of complex heterocyclic molecules through the development of a photochemical cycloaddition/fragmentation process. These reactions will be enabled through the design and application of sustainable photosensitizers based upon earth abundant metals and metal-free scaffolds.

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

Polymer manufacturing is already responsible for 1.6 Gt CO₂ equiv. emissions annually, our recent research reveals that replacing petrochemical raw materials with biomass, carbon dioxide and waste polymers can help to drive down these emissions, and provide other sustainability benefits, to reach net zero targets. This project focusses on a technology of high promise in carbon dioxide utilization: catalytic copolymerization with heterocycles to produce recyclable plastics for use in high-value areas, including electronics, transport and construction.

Key publications:
Quantifying CO₂ Insertion Equilibria for Low-Pressure Propene Oxide and Carbon Dioxide Ring Opening Copolymerization Catalysts. (J. Am. Chem. Soc. 2024, 146, 10451)
Insights into the Mechanism of Carbon Dioxide and Propylene Oxide Ring-Opening Copolymerization Using a Co(III)/K(I) Heterodinuclear Catalysts. (J. Am. Chem. Soc. 2022, 144, 17929)

Useful links:
Williams research group: https://cwilliamsresearch.web.ox.ac.uk/

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

Adhesives play a critical role in many technologies from construction, transportation, electronics to consumer goods. There are growing environmental concerns, legislation and customer pressure to deliver more sustainable adhesives and to ensure they maximise recycling of other components. Adhesives which can bond/de-bond on demand and which are degradable after use are particularly important. Here, we will develop new lower carbon footprint sustainable polymers, sourced from biomass and waste carbon dioxide, as debondable, recyclable and degradable adhesives.

Key publications:
Bio-based and Degradable Block Polyester Pressure-Sensitive Adhesives. (Angew. Chem. Int. Ed. 2020, 59, 23450)
Switchable Catalysis Improves the Properties of CO₂-Derived Polymers: Poly(cyclohexene carbonate-b-ε-decalactone-b-cyclohexene carbonate) Adhesives, Elastomers, and Toughened Plastics. (J. Am. Chem. Soc. 2020, 142, 4367)

Useful links:
Williams research group: https://cwilliamsresearch.web.ox.ac.uk/

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

Amino acids and peptides are essential components of modern medicines; however, native systems still present challenges. This project will use modern catalytic methods to achieve the sustainable synthesis of amino acid mimetics based on sulfur functional groups. These new mimetics have been designed to address the limitations present in the naturally occurring systems. Control of stereochemistry will be key, and exploring how these new mimetics, and their associated structural features, effect the gross conformation of peptide chains will be explored. We will prepare mimetics that allow compatibility with automated peptide synthesis, and will also explore applications of the developed chemistry to the late-stage functionalisation of peptide chains. Developing new synthetic methods is at the core of this proposal, and key to achieving this will be delivering a sustainable catalytic synthesis based on abundant substrates, and non-precious metal catalysts.

Key publications:
Exploiting trans-Sulfinylation for the Synthesis of Diverse N-Alkyl Sulfinamides via Decarboxylative Sulfinamidation. (Angew. Chem. Int. Ed. 2024, 63, e202407970)
Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides. (J. Am. Chem. Soc. 2023, 145, 21623)
The Catalytic Synthesis of Aza-Sulfur Functional Groups. (Synthesis 2025, 57, 1429)

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

Modern life is impossible to imagine without polymers. However, the environmental persistence and reliance on fossil resources of most used polymers make them unsustainable. In collaboration with SCG Chemicals, this project will investigate the utilisation of abundant natural carbohydrate feedstocks to produce recyclable and degradable bio- based plastics, whose properties can compete with or complement those of polyolefins such as polyethylene, towards a circular economy of plastics with a low carbon footprint.

Key publications:
Polymers from sugars and unsaturated fatty acids: ADMET polymerisation of monomers derived from D-xylose, D-mannose and castor oil. (Polym. Chem., 2020, 11, 2681)
Xylose-Based Polyethers and Polyesters Via ADMET Polymerization toward Polyethylene-Like Materials. (ACS Appl. Polym. Mater. 2021, 3, 5870)
Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products. (ACS Catal. 2020, 10, 8880)

Useful links:
Buchard research group: www.buchardgroup.org

For further details please contact Antoine Buchard (antoine.buchard@york.ac.uk).

Whole-cell biocatalysis is emerging as a sustainable and environmentally-compatible alternative to chemical catalysis. This approach takes advantage of the metabolism of a bacterial cell for the production of valuable target molecules, with highly (enantio)selective transformations being enabled in water-containing media, under ambient conditions and by using renewable feedstocks. Despite these clear advantages, limitations associated with the transport of substrates and catalysts through cell membranes are often reducing the overall catalytic effectiveness of whole-cell setups. The aim of this project is therefore to develop suitable delivery vectors to transport the respective active components into cells. Target reactions include the production of active pharmaceutical ingredients and the selective activation of masked antimicrobial prodrugs using Ru and Pd catalysis. The work will use bio-derived components, degradable linkers, and enzymatic synthesis where possible and experiments will be performed on small scales to minimise the usage of chemicals. Catalytic performance will be assessed though product analysis by chiral HPLC, electronic absorption and fluorescence spectroscopy and via the release of antimicrobial products, as appropriate.

Key publications:
Redox-switchable siderophore anchor enables reversible artificial metalloenzyme assembly. (Nat Catal. 2018, 1, 680)
Siderophore-Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells. (Chem. Eur. J. 2023, 29, e202202536)
Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis. (J. Am. Chem. Soc. 2024, 146, 4351)

For further details please contact Anne Duhme-Klair (anne.duhme-klair@york.ac.uk).

There is interest in 3-D heterocyclic scaffolds for medicinal chemistry. The O'Brien group has recently disclosed a modular synthetic platform for the elaboration of 2-D fragments into 3-D lead-like compounds that utilised 3-D cyclopropyl organoboron building blocks (with distinct vectors in 3-D). In terms of sustainable synthesis, there are significant limitations with the 1^st generation building blocks, namely multi-step synthesis using stoichiometric reagents and Pd-catalysed cross-coupling for aryl group attachment. To address, in a new collaborative project with Sneddon, 2^nd generation cyclopropyl N-hydroxyphthalimide (NHP) ester building blocks will be explored. This will include: (i) a one-step synthesis of the building blocks using diazo-NHP esters under Cu(I) catalysis and (ii) a reductive decarboxylative Ni-catalysed cross-electrophile coupling. The scope of the Ar-Br in the cross-coupling step will be explored as it will be necessary to demonstrate broad scope with medicinally-relevant motifs for use in the modular fragment elaboration platform. Finally, a range of cyclopropyl NHP-ester 3-D building blocks will be synthesised and cross-coupled – the building blocks will contain different 3-D vectors between the N–Boc and cyclopropane ester bonds (assessed using of the computed lowest energy conformation). In this way, a more sustainable modular synthetic platform for fragment elaboration will be developed.

Key publications:
Modular Synthetic Platform for Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery. (J. Am. Chem. Soc. 2025, 147, 29292)
Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings. (Angew. Chem. Int. Ed. 2022, 61, e202205673)

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

luorine-containing molecules are essential in a range of applications, including many pharmaceuticals and crop-protection products. This collaborative project will develop novel metal-free catalysis for the preparation of functional fluorinated molecules. Non-metal catalysts, based on earth-abundant elements, will avoid the need for expensive, toxic precious-metals. Readily available fluorinated building blocks will be upcycled through highly atom economical reactions. Overall, this will allow the preparation of functional fluorinated molecules in more sustainable ways.
The project will build on recent work in our groups to develop novel, non-metal catalysts, for the sustainable manipulation of fluorine atoms. We will take perfluoroarenes/heteroarenes as starting materials, which are readily available, but in the current push to eliminate perfluorinated molecules will benefit from partial defluorination. These will be upcycled to more valuable building blocks by C-F bond functionalisation, developing catalysis based on simple phosphines reported by Slattery and Lynam.
C-F activation liberates fluoride, which will be captured and utilised in tandem, enantioselective C-F bond formation processes. This will make use of recent advances by Gouverneur, using chiral ureas as hydrogen bonding phase-transfer catalysts. The project will involve synthesis, catalyst development and mechanistic studies and will leverage the complementary expertise in York and Oxford to provide broad training.

Key publications:
Metallomimetic C–F Activation Catalysis by Simple Phosphines. (J. Am. Chem. Soc. 2024, 146, 2005)
Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis. (Science 2018, 360, 638)

For further details please contact John Slattery (john.slattery@york.ac.uk).

In this project we will establish novel chemical biology tools to explore post translational modification (PTM) of lysine residues, centred on the use of conjugation addition/ring expansion (CARE) cascade reactions for selective peptide/protein bioconjugation. This project in underpinned by the ‘CARE’ method, developed by Unsworth and coworkers for use on small molecule systems¹. More recently, Unsworth, Spicer, Fascione and coworkers extended the CARE method for application in protein modification, exploiting water as a solvent for sustainable production of potent bioconjugates². Post-translational modifications of lysines are pivotal regulators of many important biological processes, including regulation of expression. Lysines modification is important in peptide drugs, e.g. the anti-obesity medicine semaglutide, and are potential value in modifying antibodies with drugs, including antibiotics. In this CSHP CDT project, we will: (i) develop and screen CARE reagents for pH controlled selective modification of lysine residues within proteins; ii) develop CARE reagents for selective modification and reactivity profiling of lysine residues including in antibiotic targets, such as beta-lactamases that enable resistance to carbapenems and other beta-lactam antibiotics³, and iii) use the CARE bioconjugation to construct macrocycle-modified lysine containing peptides, with potential application as novel therapeutics.

Key publications:
1. Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions. (RSC Chem. Biol., 2022, 3, 334)
2. N-terminal protein-macrocycles enabled by conjugate addition/ring expansion cascade reactions. (ChemRxiv. 2025; doi:10.26434/chemrxiv-2025-06817)
3. Biochemical and structural investigations clarify the substrate selectivity of the 2-oxoglutarate oxygenase JMJD6. (J. Biol. Chem. 2019, 294,11637)

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

Aligning with Green Chemistry Principle 7, this project will focus on using renewable feedstocks to replace petroleum-based chemicals in the production of valuable compounds such as furoic acid, furan dicarboxylic acid, and (S)-γ-hydroxymethyl-α,β-butenolide, which have applications in food preservation, pharmaceuticals, and polymer synthesis. Current challenges in this field include limited mechanistic understanding, selectivity issues, and undesirable side-reactions. To address this, we will employ an automated flow platform to develop homogeneous Fe-catalysed oxidation of biomass derivatives. This high-throughput approach will generate substantial data, providing a deeper understanding of reaction pathways, side-reactions, and mechanisms, ultimately leading to a more informed and effective approach to catalyst design.

Key publications:
Development of a multistep, electrochemical flow platform for automated catalyst screening. (Catal. Sci. Technol. 2022, 12, 4266)

For further details please contact Charlotte Willans (charlotte.willans@york.ac.uk).