Bicyclo[n.1.1]alkanes (BCAs) have emerged as important building blocks in contemporary drug design. These bridged ring structures are usually prepared from ring-opening reactions of [n.1.1]propellanes, and additions to bicyclo[1.1.0]butanes (BCBs). However, current routes to [n.1.1]propellanes rely on the use of alkyl/aryllithium reagents to effect closure of their three-membered rings, while BCB synthesis is also frequently reliant on strongly basic reaction conditions. This project seeks to address these shortcomings by developing contemporary strategies to improve the sustainability and scalability of propellane and BCB synthesis, and to apply these methods to the functionalisation of BCAs.

Key publications:
Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes. (JACS Au, 2023, 3, 1539)
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)

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

Thiophene S,S-dioxides (TDOs) are convenient but underutilised building blocks in organic chemistry. This project will seek to develop new applications of TDOs in sustainable chemical synthesis. We will exploit their cycloaddition chemistry in the synthesis of carbo- and heterocyclic structures, where the sole byproduct is SO₂; this includes concise syntheses of alkaloid natural products, and other functionality-rich nitrogen containing building blocks. We will also study new aspects of TDO reactivity, such as radical- or photochemical-based transformations, as well as novel analogues of the TDO scaffold.

Key publications:
Collective Synthesis of Illudalane Sesquiterpenes via Cascade Inverse Electron Demand (4 + 2) Cycloadditions of Thiophene S,S-Dioxides. (J. Am. Chem. Soc., 2022, 144, 10017)

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

Polymers in liquid formulations are found in millions of everyday products, from paints to cosmetics. They also play a vital role in agriculture, including as key ingredients to control the delivery of agrochemicals. However, the way these polymers are made, used and disposed of is currently unsustainable. In collaboration with Syngenta, this project will investigate the utilisation of abundant natural carbohydrate feedstocks to produce degradable bio-based polymers, towards more sustainable materials for agricultural applications.

Key publications:
Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from D- and L-Xylose. (Angew. Chem. Int. Ed. 2021, 60, 4524)
Polymers from Sugars and Cyclic Anhydrides: Ring-Opening Copolymerization of a D-Xylose Anhydrosugar Oxetane. (Macromolecules 2021, 54, 5094)
Xylose-derived thionocarbamates as a synthetic handle towards a functional platform of sugar-based polymers. (Polym. Chem., 2024, 15, 3149)

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

For further details please contact Antoine Buchard (antoine.buchard@york.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, 587)
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)

The design of new non-precious metal catalysts and organic catalysts is key to modern reaction innovation and sustainability. This project will involve, the design and synthesis of a new range of chiral organocatalysts bearing chiral heteroatoms. The new library of catalysts will be screened for a range of catalytic enantioselective synthetic organic transformations.

Key publications:
Control of stereogenic oxygen in a helically chiral oxonium ion. (Nature, 2023, 615, 430)
Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings. (J. Am. Chem. Soc. 2022, 144, 14790)

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk) and Martin Smith (martin.smith@chem.ox.ac.uk)

Molecules containing stereogenic phosphorous (V) atoms are commonplace in bioactive medicines and agrochemicals ranging from: antivirals, to cardiovascular treatments, to herbicides, yet their syntheses are often challenging, specific to the target molecule, and use stoichiometric amounts of non-recyclable chiral auxiliaries. This proposal aims to develop sustainable catalytic enantioselective routes to novel chiral phosphorous (V) building blocks and demonstrate their potential downstream broad scope applicability in medicinal and agrochemical research programs.

Key publications:
Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters. (Nat. Chem., 2023, 15, 714)
Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity. (Angew. Chem. Int. Ed. 2024, 63, e202400673)
Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis. (Acc. Chem. Res., 2020, 53, 2235)

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

This project contains exciting opportunities for the production of complex stereochemically defined ‘3D’ heterocycles from simple, easily prepared, ‘2D’ aromatic precursors. This work will allow dearomatisation reactions to become a mainstay of synthetic organic chemistry and will provide outputs that are extremely useful to the pharmaceutical industry.

Key publications:
Evolution of the dearomative functionalization of activated quinolines and isoquinolines: Expansion of the electrophile scope. (Angew. Chem. Int. Ed. 2022, 61, e202204682)
The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation. (Nat. Chem., 2019, 11, 242)

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

Macrocyclic compounds have emerged as a promising alternative to small molecules against difficult-to-treat targets. However, challenges in their synthesis, in particular with regards to cyclisation have hindered further discovery. This project will develop efficient AI-driven approaches to design macrocycle-based inhibitors to tackle the growing threat of microbial drug resistance.

Useful links:
Duarte research group: https://www.duartegroupchem.org
Unsworth research group: https://unsworthlab.weebly.com
Ineos Oxford Institute for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

Out-of-equilibrium chemical processes related to synthetic chemistry are not well understood. We have developed oscillating chemical reactions, which involve both molecular and supramolecular (micelles, vesicles, etc) oscillations, and may serve as the basis for developing new processes. This project will involve learning how to control oscillations using electrochemistry, which is anticipated to provide advantages for future applications.

Key publications:
An autonomously oscillating supramolecular self-replicator. (Nat. Chem., 2022, 14, 805)
A Chemical Reaction Network Drives Complex Population Dynamics in Oscillating Self-Reproducing Vesicles. (J. Am. Chem. Soc., 2024, 146, 18262)
Information transduction via fuel-controlled chemical waves. (Chem, 2024, 10, 1)

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

Asymmetric cross-coupling technologies are powerful techniques that represent the state-of-the-art in the construction of chiral small molecules. Our laboratory has developed a series of Suzuki-type reactions which use commercially available and experimentally convenient boronic acids, but these reactions currently rely on using rhodium-based catalysts. This proposal aims to develop related methods which use non-precious metal as catalysts.

Key publications:
Chelation enables selectivity control in enantioconvergent Suzuki–Miyaura cross-couplings on acyclic allylic systems. (Nat. Chem., 2024, 16, 791)
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)

There is increasing interest in the use of surfactants to tackle key elements of antimicrobial resistance (AMR). It is our hypothesis that the effectiveness of, and opportunities provided by, such agents could be dramatically improved through the incorporation of a “photoswitch” motif into the structure of the surfactant. This work will develop and study such photodynamic surfactants to pioneer a new modality to tackle AMR.

Key publications:
Light Responsiveness and Assembly of Arylazopyrazole-Based Surfactants in Neat and Mixed CTAB Micelles. (JACS Au, 2022, 2, 2670)
Light-Driven Hexagonal-to-Cubic Phase Switching in Arylazopyrazole Lyotropic Liquid Crystals. (J. Am. Chem. Soc., 2024, 146, 12315)

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 pharmaceutical candidates improves medicinal properties and increases the chance to reach the clinic. New chemistry will be developed for the conversion of alkyl chlorides or bromides into alkyl fluorides using safe and cost-effective alkali metal fluorides. More generally, the project will aim at reinventing the iconic Swartz reaction with extension to an enantioconvergent fluorination process applying synergistic asymmetric hydrogen bonding 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)

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)

This project will develop next generation synthetic siderophores - small molecule high affinity iron receptors used by bacteria to accumulate iron. By tethering siderophores to antibiotics, the bacteria’s siderophore uptake mechanism can be exploited to facilitate improved cellular uptake, particularly into antimicrobial resistant Gram-negative bacteria. The student will design and synthesis novel Fe-coordinating ligands, and explore their use as antimicrobial delivery agents.

Useful links:
Langton research group: https://langtonrg.web.ox.ac.uk
Ineos Oxford Institute for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

While hydrogen borrowing (HB) catalysis offers an attractive route for the construction of C-C bonds using alcohols and ketones, current methods rely upon expensive precious metal catalysts. This project will develop sustainable HB methods using earth-abundant metals (iron and cobalt), using a synergistic approach combining pre-catalyst development, reaction screening and mechanistic insight to achieve sustainable HB methods of practical synthetic use in both academia and industry.

Key publications:
Borrowing Hydrogen for Organic Synthesis. (ACS Cent. Sci. 2021, 7, 570)
Functional group tolerant hydrogen borrowing C-alkylation. (Nat. Commun., 2024, 15, 5131)

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

There is significant interest in sp^3-rich heterocyclic scaffolds for medicinal chemistry due to their success in proceeding through the drug development process. In this project, a set of novel 3D bifunctional building blocks will be designed and synthesised; systematic coverage of 3D chemical space and 3D vectors will be achieved by computational analysis. The building blocks will be used in fragment elaboration and evaluated as bioisosteres of arenes/heteroarenes.

Key publications:
Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD). (Angew. Chem. Int. Ed., 2016, 55, 488)
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)

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

There is significant interest in sp³-rich heterocyclic scaffolds for medicinal chemistry due to their success in proceeding through the drug development process. In this project, we will develop the Pd-catalysed sp³-sp² Suzuki-Miyaura cross-coupling of saturated heterocyclic organoborons with aryl/heteroaryl halides. This will provide a step-change in the way that 3D saturated nitrogen and oxygen heterocycles can be constructed, a limitation highlighted by the pharmaceutical industry.

Key publications:
Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization. (Science, 2018, 362, 670)
Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)–C(sp³) Cross-Coupling Methods by Library Synthesis (ACS Med. Chem. Lett., 2020, 11, 597)

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.

Useful links:
Russell research group: http://russell.chem.ox.ac.uk/

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

Resistance to pharmaceuticals, including anti-infectives and cancer drugs, and agrochemicals is a major global health problem. As highlighted by the 2016 O’Neill report, the situation with current antibiotics is perilous. Antibiotics are used on a massive scale in farming and medicine, hence we need sustainable routes for production of new antibiotics not susceptible to current resistance mechanisms. The project will involve the development of enzyme / enzyme inspired reactions for the efficient and sustainable preparation of new antibiotics. Late-stage modification of fermented natural products will be explored 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 for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

Air- and moisture-stable organozinc gels will be prepared using hexatriacontane encapsulation gel technology and used in Pd-catalysed sp³-sp² and sp²-sp² Negishi cross-coupling reactions. Off-the-shelf, stable gel capsules of organozinc reagents could transform the utility of such reagents in synthesis and cross-couplings, especially for reactions on an automated platform. Catalysis using earth-abundant metals (e.g. Co, Ni, Fe) will also be explored.

Key publications:
Organogel delivery vehicles for the stabilization of organolithium reagents. (Nat. Chem., 2023, 15, 319)

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

New reaction manifolds are valuable for the synthesis of complex molecules. This project will focus on the development of radical-polar crossover reactions by employing visible light mediated energy transfer catalysis to generate complex three-dimensional heterocyclic scaffolds. The design of non-precious metal photocatalysts and metal free catalysts will be a key component of this project.

Key publications:
A radical-polar crossover approach to complex nitrogen heterocycles via the triplet state. (ChemRxiv. 2023, Preprint; doi:10.26434/chemrxiv-2023-pcv6m)

For further details please contact Martin Smith (martin.smith@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)

Polymer manufacturing is already responsible for 1.6 Gt CO2 equiv. emissions annually, recent academic study reveals that replacing petrochemical raw materials with biomass, carbon dioxide and waste polymers can help to drive down these emissions enabling net zero targets. This project focusses on a technology of high promise in carbon dioxide utilization – catalytic copolymerization with heterocycles to produce oxygenated polymers.

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)

Functionalised heterocycles remain the cornerstone of medicinal chemistry programmes. This project focuses on developing new metal catalysed coupling reactions for the synthesis of pharmaceutically relevant variants. The combination of mechanistically-guided reaction design, high-throughput experimentation (HTE), and data analysis, will be used to deliver optimal processes, and will be based on the use of heterocyclic sulfinates (and related reagents) as the coupling partners.

Key publications:
Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions. (Angew. Chem. Int. Ed. 2021, 60, 22461)
Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts. (J. Am. Chem. Soc. 2020, 142, 3564)

Useful links:
Willis research group: https://willisgroup.web.ox.ac.uk/
Fairlamb research group: https://fairlamb.group/

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

New (photo)catalytic methods will be developed to convert simple feedstock starting materials, such as carboxylic acids and amines, into valuable, complex, sulfonamide and sulfonimidamide building blocks. The control of stereochemistry will be an important consideration. An emphasis we be place on developing translatable methods, directly relevant for use in discovery chemistry.

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

Useful links:
Willis research group: https://willisgroup.web.ox.ac.uk/

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

Fluorine-containing molecules are essential in a wide range of applications, including in many pharmaceuticals and agrochemicals. This project will develop novel metal-free catalysis for the preparation of functional fluorinated molecules. Perfluoroarenes/heteroarenes will be upcycled and the fluoride liberated by this process will be utilised in tandem, enantioselective C-F bond formation reactions.

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)

The sustainability challenges in oligonucleotide synthesis are well known, with repeated protection, deprotection and washing steps contributing to high PMIs, and typical use of problematic solvents.¹ Further to previous successful studies in our laboratory exploring alternative solvents in solid-phase peptide synthesis² we are interested in the viability and sustainability impact of alternative solvents, protection and deprotection protocols for the growing oligonucleotide sector.

Key publications:
¹Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing. (J. Org. Chem. 2021, 86, 49)
²Greener solvents for solid-phase synthesis. (Green Chem. 2017, 19, 952)

For further details please contact Helen Sneddon (helen.sneddon@york.ac.uk)

We will establish methods for the synthesis of novel, medicinally important bridged bicyclic hydrocarbon (BBH) scaffolds using late-stage oxygenation enabled by unspecific peroxygenase (UPO) enzymes. BBHs will be made using both known and new synthetic approaches, with methods selected that access scaffolds with maximum substituent diversity, and also sustainably. These will then be oxygenated using scalable and sustainable biocatalytic methods to produce novel BBH scaffolds for applications in drug discovery.

Established routes to BBHs will be used to generate suitable substrates to challenge the UPOs to start, and as the project develops, novel BBHs syntheses will also be explored; expertise in the Anderson group (Oxford) will be crucial in supporting these aspects. We will then explore their oxygenation using UPOs. Unsworth and Grogan (York) have a well-established collaboration exploring the selective UPO oxygenation of small organic molecules, and have ready access to large quantities of UPOs with proven efficacy in large scale biocatalysis. Substrate, chemo-, regio- and stereoselectivity of the biotransformations will all be explored; the discovery of highly enantioselective late-stage oxygenation methods is expected. The value of the newly oxygenated BBH scaffolds will be explored for utility in drug discovery with industry partners at MSD.

Key publications:
For background on UPO oxygenation see: Complementary specificity of unspecific peroxygenases enables access to diverse products from terpene oxygenation. (Chem Catalysis, 2024, 4, 100889)

For further details please contact Will Unsworth (william.unsworth@york.ac.uk) and Gideon Grogan (gideon.grogan@york.ac.uk)

Bicyclo[n.1.1]alkanes (BCAs) have emerged as important building blocks in contemporary drug design. These bridged ring structures are usually prepared from ring-opening reactions of [n.1.1]propellanes, and additions to bicyclo[1.1.0]butanes (BCBs). However, current routes to [n.1.1]propellanes rely on the use of alkyl/aryllithium reagents to effect closure of their three-membered rings, while BCB synthesis is also frequently reliant on strongly basic reaction conditions. This project seeks to address these shortcomings by developing contemporary strategies to improve the sustainability and scalability of propellane and BCB synthesis, and to apply these methods to the functionalisation of BCAs.

Key publications:
Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes. (JACS Au, 2023, 3, 1539)
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)

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

Thiophene S,S-dioxides (TDOs) are convenient but underutilised building blocks in organic chemistry. This project will seek to develop new applications of TDOs in sustainable chemical synthesis. We will exploit their cycloaddition chemistry in the synthesis of carbo- and heterocyclic structures, where the sole byproduct is SO₂; this includes concise syntheses of alkaloid natural products, and other functionality-rich nitrogen containing building blocks. We will also study new aspects of TDO reactivity, such as radical- or photochemical-based transformations, as well as novel analogues of the TDO scaffold.

Key publications:
Collective Synthesis of Illudalane Sesquiterpenes via Cascade Inverse Electron Demand (4 + 2) Cycloadditions of Thiophene S,S-Dioxides. (J. Am. Chem. Soc., 2022, 144, 10017)

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

The design of new non-precious metal catalysts and organic catalysts is key to modern reaction innovation and sustainability. This project will involve, the design and synthesis of a new range of chiral organocatalysts bearing chiral heteroatoms. The new library of catalysts will be screened for a range of catalytic enantioselective synthetic organic transformations.

Key publications:
Control of stereogenic oxygen in a helically chiral oxonium ion. (Nature, 2023, 615, 430)
Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings. (J. Am. Chem. Soc. 2022, 144, 14790)

For further details please contact Jonathan Burton (jonathan.burton@chem.ox.ac.uk) and Martin Smith (martin.smith@chem.ox.ac.uk)

Molecules containing stereogenic phosphorous (V) atoms are commonplace in bioactive medicines and agrochemicals ranging from: antivirals, to cardiovascular treatments, to herbicides, yet their syntheses are often challenging, specific to the target molecule, and use stoichiometric amounts of non-recyclable chiral auxiliaries. This proposal aims to develop sustainable catalytic enantioselective routes to novel chiral phosphorous (V) building blocks and demonstrate their potential downstream broad scope applicability in medicinal and agrochemical research programs.

Key publications:
Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters. (Nat. Chem., 2023, 15, 714)
Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity. (Angew. Chem. Int. Ed. 2024, 63, e202400673)
Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis. (Acc. Chem. Res., 2020, 53, 2235)

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

This project contains exciting opportunities for the production of complex stereochemically defined ‘3D’ heterocycles from simple, easily prepared, ‘2D’ aromatic precursors. This work will allow dearomatisation reactions to become a mainstay of synthetic organic chemistry and will provide outputs that are extremely useful to the pharmaceutical industry.

Key publications:
Evolution of the dearomative functionalization of activated quinolines and isoquinolines: Expansion of the electrophile scope. (Angew. Chem. Int. Ed. 2022, 61, e202204682)
The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation. (Nat. Chem., 2019, 11, 242)

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

Macrocyclic compounds have emerged as a promising alternative to small molecules against difficult-to-treat targets. However, challenges in their synthesis, in particular with regards to cyclisation have hindered further discovery. This project will develop efficient AI-driven approaches to design macrocycle-based inhibitors to tackle the growing threat of microbial drug resistance.

Useful links:
Duarte research group: https://www.duartegroupchem.org
Unsworth research group: https://unsworthlab.weebly.com
Ineos Oxford Institute for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

Out-of-equilibrium chemical processes related to synthetic chemistry are not well understood. We have developed oscillating chemical reactions, which involve both molecular and supramolecular (micelles, vesicles, etc) oscillations, and may serve as the basis for developing new processes. This project will involve learning how to control oscillations using electrochemistry, which is anticipated to provide advantages for future applications.

Key publications:
An autonomously oscillating supramolecular self-replicator. (Nat. Chem., 2022, 14, 805)
A Chemical Reaction Network Drives Complex Population Dynamics in Oscillating Self-Reproducing Vesicles. (J. Am. Chem. Soc., 2024, 146, 18262)
Information transduction via fuel-controlled chemical waves. (Chem, 2024, 10, 1)

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

Asymmetric cross-coupling technologies are powerful techniques that represent the state-of-the-art in the construction of chiral small molecules. Our laboratory has developed a series of Suzuki-type reactions which use commercially available and experimentally convenient boronic acids, but these reactions currently rely on using rhodium-based catalysts. This proposal aims to develop related methods which use non-precious metal as catalysts.

Key publications:
Chelation enables selectivity control in enantioconvergent Suzuki–Miyaura cross-couplings on acyclic allylic systems. (Nat. Chem., 2024, 16, 791)
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)

There is increasing interest in the use of surfactants to tackle key elements of antimicrobial resistance (AMR). It is our hypothesis that the effectiveness of, and opportunities provided by, such agents could be dramatically improved through the incorporation of a “photoswitch” motif into the structure of the surfactant. This work will develop and study such photodynamic surfactants to pioneer a new modality to tackle AMR.

Key publications:
Light Responsiveness and Assembly of Arylazopyrazole-Based Surfactants in Neat and Mixed CTAB Micelles. (JACS Au, 2022, 2, 2670)
Light-Driven Hexagonal-to-Cubic Phase Switching in Arylazopyrazole Lyotropic Liquid Crystals. (J. Am. Chem. Soc., 2024, 146, 12315)

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 pharmaceutical candidates improves medicinal properties and increases the chance to reach the clinic. New chemistry will be developed for the conversion of alkyl chlorides or bromides into alkyl fluorides using safe and cost-effective alkali metal fluorides. More generally, the project will aim at reinventing the iconic Swartz reaction with extension to an enantioconvergent fluorination process applying synergistic asymmetric hydrogen bonding 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)

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)

This project will develop next generation synthetic siderophores - small molecule high affinity iron receptors used by bacteria to accumulate iron. By tethering siderophores to antibiotics, the bacteria’s siderophore uptake mechanism can be exploited to facilitate improved cellular uptake, particularly into antimicrobial resistant Gram-negative bacteria. The student will design and synthesis novel Fe-coordinating ligands, and explore their use as antimicrobial delivery agents.

Useful links:
Langton research group: https://langtonrg.web.ox.ac.uk
Ineos Oxford Institute for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

While hydrogen borrowing (HB) catalysis offers an attractive route for the construction of C-C bonds using alcohols and ketones, current methods rely upon expensive precious metal catalysts. This project will develop sustainable HB methods using earth-abundant metals (iron and cobalt), using a synergistic approach combining pre-catalyst development, reaction screening and mechanistic insight to achieve sustainable HB methods of practical synthetic use in both academia and industry.

Key publications:
Borrowing Hydrogen for Organic Synthesis. (ACS Cent. Sci. 2021, 7, 570)
Functional group tolerant hydrogen borrowing C-alkylation. (Nat. Commun., 2024, 15, 5131)

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.

Useful links:
Russell research group: http://russell.chem.ox.ac.uk/

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

Resistance to pharmaceuticals, including anti-infectives and cancer drugs, and agrochemicals is a major global health problem. As highlighted by the 2016 O’Neill report, the situation with current antibiotics is perilous. Antibiotics are used on a massive scale in farming and medicine, hence we need sustainable routes for production of new antibiotics not susceptible to current resistance mechanisms. The project will involve the development of enzyme / enzyme inspired reactions for the efficient and sustainable preparation of new antibiotics. Late-stage modification of fermented natural products will be explored 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 for Antimicrobial Research: https://www.ineosoxford.ox.ac.uk

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

New reaction manifolds are valuable for the synthesis of complex molecules. This project will focus on the development of radical-polar crossover reactions by employing visible light mediated energy transfer catalysis to generate complex three-dimensional heterocyclic scaffolds. The design of non-precious metal photocatalysts and metal free catalysts will be a key component of this project.

Key publications:
A radical-polar crossover approach to complex nitrogen heterocycles via the triplet state. (ChemRxiv. 2023, Preprint; doi:10.26434/chemrxiv-2023-pcv6m)

For further details please contact Martin Smith (martin.smith@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)

Polymer manufacturing is already responsible for 1.6 Gt CO2 equiv. emissions annually, recent academic study reveals that replacing petrochemical raw materials with biomass, carbon dioxide and waste polymers can help to drive down these emissions enabling net zero targets. This project focusses on a technology of high promise in carbon dioxide utilization – catalytic copolymerization with heterocycles to produce oxygenated polymers.

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)

Functionalised heterocycles remain the cornerstone of medicinal chemistry programmes. This project focuses on developing new metal catalysed coupling reactions for the synthesis of pharmaceutically relevant variants. The combination of mechanistically-guided reaction design, high-throughput experimentation (HTE), and data analysis, will be used to deliver optimal processes, and will be based on the use of heterocyclic sulfinates (and related reagents) as the coupling partners.

Key publications:
Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions. (Angew. Chem. Int. Ed. 2021, 60, 22461)
Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts. (J. Am. Chem. Soc. 2020, 142, 3564)

Useful links:
Willis research group: https://willisgroup.web.ox.ac.uk/
Fairlamb research group: https://fairlamb.group/

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

New (photo)catalytic methods will be developed to convert simple feedstock starting materials, such as carboxylic acids and amines, into valuable, complex, sulfonamide and sulfonimidamide building blocks. The control of stereochemistry will be an important consideration. An emphasis we be place on developing translatable methods, directly relevant for use in discovery chemistry.

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

Useful links:
Willis research group: https://willisgroup.web.ox.ac.uk/

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

Polymers in liquid formulations are found in millions of everyday products, from paints to cosmetics. They also play a vital role in agriculture, including as key ingredients to control the delivery of agrochemicals. However, the way these polymers are made, used and disposed of is currently unsustainable. In collaboration with Syngenta, this project will investigate the utilisation of abundant natural carbohydrate feedstocks to produce degradable bio-based polymers, towards more sustainable materials for agricultural applications.

Key publications:
Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from D- and L-Xylose. (Angew. Chem. Int. Ed. 2021, 60, 4524)
Polymers from Sugars and Cyclic Anhydrides: Ring-Opening Copolymerization of a D-Xylose Anhydrosugar Oxetane. (Macromolecules 2021, 54, 5094)
Xylose-derived thionocarbamates as a synthetic handle towards a functional platform of sugar-based polymers. (Polym. Chem., 2024, 15, 3149)

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

For further details please contact Antoine Buchard (antoine.buchard@york.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, 587)
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)

There is significant interest in sp^3-rich heterocyclic scaffolds for medicinal chemistry due to their success in proceeding through the drug development process. In this project, a set of novel 3D bifunctional building blocks will be designed and synthesised; systematic coverage of 3D chemical space and 3D vectors will be achieved by computational analysis. The building blocks will be used in fragment elaboration and evaluated as bioisosteres of arenes/heteroarenes.

Key publications:
Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD). (Angew. Chem. Int. Ed., 2016, 55, 488)
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. (Nature, 2022, 611, 721)

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

There is significant interest in sp³-rich heterocyclic scaffolds for medicinal chemistry due to their success in proceeding through the drug development process. In this project, we will develop the Pd-catalysed sp³-sp² Suzuki-Miyaura cross-coupling of saturated heterocyclic organoborons with aryl/heteroaryl halides. This will provide a step-change in the way that 3D saturated nitrogen and oxygen heterocycles can be constructed, a limitation highlighted by the pharmaceutical industry.

Key publications:
Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization. (Science, 2018, 362, 670)
Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)–C(sp³) Cross-Coupling Methods by Library Synthesis (ACS Med. Chem. Lett., 2020, 11, 597)

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

Air- and moisture-stable organozinc gels will be prepared using hexatriacontane encapsulation gel technology and used in Pd-catalysed sp³-sp² and sp²-sp² Negishi cross-coupling reactions. Off-the-shelf, stable gel capsules of organozinc reagents could transform the utility of such reagents in synthesis and cross-couplings, especially for reactions on an automated platform. Catalysis using earth-abundant metals (e.g. Co, Ni, Fe) will also be explored.

Key publications:
Organogel delivery vehicles for the stabilization of organolithium reagents. (Nat. Chem., 2023, 15, 319)

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

Fluorine-containing molecules are essential in a wide range of applications, including in many pharmaceuticals and agrochemicals. This project will develop novel metal-free catalysis for the preparation of functional fluorinated molecules. Perfluoroarenes/heteroarenes will be upcycled and the fluoride liberated by this process will be utilised in tandem, enantioselective C-F bond formation reactions.

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)

The sustainability challenges in oligonucleotide synthesis are well known, with repeated protection, deprotection and washing steps contributing to high PMIs, and typical use of problematic solvents.¹ Further to previous successful studies in our laboratory exploring alternative solvents in solid-phase peptide synthesis² we are interested in the viability and sustainability impact of alternative solvents, protection and deprotection protocols for the growing oligonucleotide sector.

Key publications:
¹Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing. (J. Org. Chem. 2021, 86, 49)
²Greener solvents for solid-phase synthesis. (Green Chem. 2017, 19, 952)

For further details please contact Helen Sneddon (helen.sneddon@york.ac.uk)

We will establish methods for the synthesis of novel, medicinally important bridged bicyclic hydrocarbon (BBH) scaffolds using late-stage oxygenation enabled by unspecific peroxygenase (UPO) enzymes. BBHs will be made using both known and new synthetic approaches, with methods selected that access scaffolds with maximum substituent diversity, and also sustainably. These will then be oxygenated using scalable and sustainable biocatalytic methods to produce novel BBH scaffolds for applications in drug discovery.

Established routes to BBHs will be used to generate suitable substrates to challenge the UPOs to start, and as the project develops, novel BBHs syntheses will also be explored; expertise in the Anderson group (Oxford) will be crucial in supporting these aspects. We will then explore their oxygenation using UPOs. Unsworth and Grogan (York) have a well-established collaboration exploring the selective UPO oxygenation of small organic molecules, and have ready access to large quantities of UPOs with proven efficacy in large scale biocatalysis. Substrate, chemo-, regio- and stereoselectivity of the biotransformations will all be explored; the discovery of highly enantioselective late-stage oxygenation methods is expected. The value of the newly oxygenated BBH scaffolds will be explored for utility in drug discovery with industry partners at MSD.

Key publications:
For background on UPO oxygenation see: Complementary specificity of unspecific peroxygenases enables access to diverse products from terpene oxygenation. (Chem Catalysis, 2024, 4, 100889)

For further details please contact Will Unsworth (william.unsworth@york.ac.uk) and Gideon Grogan (gideon.grogan@york.ac.uk)