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.

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.

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.

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.

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.

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.

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.

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.

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 prioritises 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.

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.

Bicyclo[n.1.1]alkanes (BCAs), and heterocyclic analogues, have emerged as important building blocks in contemporary drug design. 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.
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, 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.

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.

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.

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.

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.