Organic chemistry poster symposium

Organic chemistry poster symposium 04 December 2023, London

04 December 2023, London Organic chemistry poster symposium

Book of abstracts

Registered charity number: 207890

Welcome Message

Dear Colleagues, Welcome to the 2023 RSC Organic chemistry poster symposium, the Organic Chemistry Community’s flagship event for PhD students. We are delighted to have such a wide range of delegates here today from across the organic chemistry community in both industry and academia. Thank you for taking the time to come along to meet the very best of the next generation of scientists. We are also very grateful for the financial support we have received from industry. The support from today’s headline sponsor Syngenta, alongside all our sponsors listed on page 5, is invaluable in allowing this event to continue running. Today would not be taking place at all, of course, without the enthusiastic support of a large number of academic supervisors and their research groups. This year we were delighted to receive a great response from PhD researchers to take part in the symposium, and the pre-selection committee felt privileged to be given this insight into the range and depth of high-quality, innovative organic chemistry taking place across the UK and Ireland. Finally, we would like to extend a very warm welcome to the 40 poster presenters taking part in the competition today: your chemistry has already triumphed, so please relax and tell us all about it. Indeed, we encourage everyone to engage fully with the chemistry on display, and to enjoy a day of what we hope you will agree is organic chemistry at its very best.

Professor David O’Hagan Organic Chemistry Community

Professor Stephen Clark

Scientific Organising Committee Chair

Council President

Edward Emmett Head of Weed Control Chemistry edward.emmett@syngenta.com

Jealott's Hill International Research Centre Bracknell Berks, RG42 6EY www.syngenta.com

Dear Participants, On behalf of Syngenta may I first congratulate you all on being selected to participate in the Royal Society of Chemistry’s 202 3 Organic Division Poster Symposium. It is a great achievement to have made this stage from an exceptional set of applicants across the breadth of the organic chemistry discipline and we very much look forward to meeting with you and learning more about your research. We at Syngenta are very pleased to continue our relationship with the RSC as headline sponsor for this symposium which celebrates the outstanding chemical research occurring throughout the UK and Ireland. Our innovation is driven by the quality of work of our scientists, many of whom were educated through the universities and research groups you represent and presented their own research at this very meeting in the past. We are proud to support the academic chemistry community not only through this event but also by funding many collaborations, doctoral training centres and partnerships throughout the world. Syngenta Group are one of the world’s leading agriculture companies. Through our mission statement of “bring ing plant potential to life” , our ambition is to help safely feed the world while taking care of the planet. We aim to improve the sustainability, quality, and safety of agriculture with world class science and innovative crop solutions, creating technologies which enable millions of farmers around the world to make better use of limited agricultural resources. At our world class R&D campus in Jealott’s Hill, Berkshire, we work together across many chemical disciplines such as discovery, process synthesis, physical, analytical, formulation, automated and computational chemistries to deliver new crop protection products to market. We champion a diverse and inclusive workplace, put sustainable green chemistry at the heart of what we do, and the quality of our chemists is regularly recognised externally (for example as a winner of the RSC/SCI retrosynthesis competition). We are a proud and innovative community of over 100 chemists who connect into Syngenta’s global scientific research network across the world. Please do come and visit us at our stand to hear more about Syngenta, meet with our chemists and review the opportunities we have for you to join us on our mission. I wish you an enjoyable and productive day and continued success in your career. Edward Emmett, Head of Weed Control Chemistry, Syngenta

Page 1 of 1

Organic Chemistry at the Royal Society of Chemistry The Organic Chemistry Community is one of seven Subject Communities of the Royal Society of Chemistry which its members can join. Each Subject Community encourages, assists and extends the knowledge and study of their discipline. The Organic Chemistry Community has around 8,000 members from across industry and academia across all career stages and is led by a Council elected by the membership to represent the organic chemistry community. The aims of the Organic Chemistry Community are to: • Promote excellence, sustainability, and the exchange of knowledge in the areas of organic chemistry, including a focus on the next generation • Support scientists across all sectors and career stages working in the field of organic chemistry in its broadest interpretation • Foster and strengthen collaborations between organic chemistry and the wider scientific research community • Support and promote all areas of inclusion and diversity across organic chemistry • Influence policymakers on issues related to organic chemistry Organic Chemistry Community activities include: • Providing a forum for organic chemists to connect and exchange information and ideas by hosting our own events, including this annual poster symposium, and regional meetings. • Advocating for and providing expertise on organic chemistry. • Recognising excellence within organic chemistry through our prizes programme. Find out more: rsc.li/organic-community

2024 prizes open for nomination Organic Chemistry Research & Innovation Prizes: • Organic Chemistry early career prize: Hickinbottom Prize • Organic Chemistry mid-career prize: MSD Prize • Organic Chemistry open prize: Pedler Prize • Bader Prize • Sir Derek Barton Gold Medal

Our Research & Innovation Prizes recognise brilliant chemical scientists carrying out amazing work in academia and industry. They include prizes for those at different career stages in general chemistry and for those working in specific fields, as well as interdisciplinary prizes and prizes for those in specific roles.

Organic Division Horizon Prizes: • Bioorganic Chemistry Prize • Perkin Prize in Physical Organic Chemistry • Robert Robinson Prize in Synthetic Organic Chemistry

Our Horizon Prizes highlight the most exciting, contemporary science at the cutting edge of research and innovation. These prizes are for teams or collaborations who are opening up new directions and possibilities in their field, through ground-breaking scientific developments. Any form of discovery or advance in the field of organic chemistry can be nominated. It can be fundamental or applied work, or be multidisciplinary and involve other disciplines. Nominate someone today

Other upcoming events of interest Organic Chemistry Community Regional Meetings: South-West regional meeting 17 January 2024, University of Southampton North-East regional meeting 26 March 2024, University of Hull North-West regional meeting 27 March 2024, University of Manchester South-East regional meeting 8 May 2024, Queen Mary University of London Ireland regional meeting TBC May 2024, University of Galway Scotland regional meeting 13 June 2024, University of Dundee Midlands regional meeting TBC Chemical biology symposium

13 May 2024, London, UK Directing Biosynthesis VII 1 - 3 July 2024, Birmingham, UK For other upcoming organic chemistry meetings please see the events webpage. You can explore the latest organic chemistry research at the Royal Society of Chemistry via our journals, books and databases:

Organising Committee

Judging panel

Paul Davies Birmingham University, UK Tony Davis University of Bristol, UK Liz Jones Syngenta, UK Ai-Lan Lee Heriot-Watt University, UK Kiri North Vertex, UK Tilly Bingham Cumulus Oncology, UK

Stephen Clark (Chair) University of Glasgow, UK Sarah Barry Kings College London, UK Anita Maguire University College Cork, Ireland Angus Morrison

BioAscent, UK Darren Stead

Astrazeneca, UK Will Whittingham Syngenta, UK

Sponsors - Headline

Syngenta Crop Protection and Syngenta Seeds are part of Syngenta Group, one of the world’s leading agriculture companies. Our ambition is to help safely feed the world while taking care of the planet. We aim to improve the sustainability, quality and safety of agriculture with world class science and innovative crop solutions. Our technologies enable millions of farmers around the world to make better use of limited agricultural resources.

Sponsors - Gold

AZ is a global pharmaceutical company with a major UK presence. Our purpose is to push the boundaries of science to deliver life-changing medicines. The best way we can help patients is to be science-led and share this passion with the scientific, healthcare and business communities of the UK

Pharmaron is a premier R&D service provider for the life sciences industry. Founded in 2004, Pharmaron has invested in its people and facilities, and established a broad spectrum of research, development and manufacturing service capabilities throughout the entire drug discovery, preclinical and clinical development process across multiple therapeutic modalities.

Sponsors - Gold

Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people’s lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare – a strategy that aims to fit the right treatment to each patient in the best way possible. Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.

Sygnature Discovery is a world-leading integrated drug discovery Contract Research Organisation. With over 1,000 staff, including more than 700 scientists, delivering over 40 pre-clinical and 22 clinical compounds, with scientists named on over 170 patents. Partnering with global pharma, biotech, and NFP organisations, focussing on oncology, inflammation and immunology, neuroscience, metabolic diseases, infectious diseases, and fibrotic diseases.

Sponsors - Silver

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has a number of partnered products being developed under collaborations with leading pharmaceutical companies. Astex is a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan. For more information about Astex Pharmaceuticals please visit: https://www.astx.com Follow us on LinkedIn For more information about Otsuka Pharmaceutical, please visit: https://www.otsuka.co.jp/en/

BioAscent is a leading provider of science-led integrated drug discovery services, which include de novo assay development, target analysis and bespoke screening strategies, compound screening, medicinal and synthetic chemistry, computational chemistry and compound management, all with access to in-house diversity and fragment libraries.

Posters

Posters have been numbered consecutively: P01 – P40 The 40 abstracts in this book have been produced directly from typescripts supplied by authors. Copyright reserved. Poster prizes There will be a £500 prize for the winning poster, a £500 industry prize and £250 prizes for the two runners-up. There will also be a delegates’ choice prize which is judged by the poster presenters themselves. The first prize winner will also have the opportunity to have work featured on a front cover of Organic & Biomolecular Chemistry, subject to having a paper accepted for publication and the presenter as an author. The industry prize winner will also receive a 1-year personal subscription to Organic & Biomolecular Chemistry in addition to the £500 A summary of the prizes can be seen below. First prize • £500 • The opportunity to have work featured on a front cover of Organic & Biomolecular Chemistry. Industry prize • £500 • A 1-year personal subscription to Organic & Biomolecular Chemistry Runners-up • £250 each Delegates’ choice prize • £200

Poster presentations

P01

A general iridium-catalyzed reductive dienamine synthesis allows a five- step synthesis of catharanthine via the elusive dehydrosecodine Yaseen Almehmadi University of Oxford, UK Kinetics and stability of n-terminal protein modification strategies Lydia Barber University of York, UK Diversity-oriented libraries from benzylic boronic esters via a Pd- catalyzed Matteson reaction of arylboronic acids Kane Bastick University of St Andrews, UK Tailoring halogen-atom transfer (xat) methods for overcoming challenging transformations at unactivated c(sp³)-centers Lewis Caiger University of Manchester, UK A general strategy for the amination of electron-rich and electron-poor heteroaromatics by desaturative catalysis Henry Caldora University of Manchester / RWTH Aachen, UK A reaction with potential: an electrosynthesis of 1,3,4-oxadiazoles from n-acyl hydrazones Luke Chen University of Strathclyde/GSK, UK Borane assisted highly secondary selective deoxyfluorination of isoureas Nojus Cironis The University of Edinburgh, UK

P02

P03

P04

P05

P06

P07

P08

Stereoselective synthesis of α-galactosides Kate Donaghy University College Dublin, Ireland

P09

A novel copper-catalysed c(sp³) -c(sp³) cross-coupling reaction using readily available starting materials David Fernandez Aguado University of Strathclyde / GSK, UK

P10

The hitchhiker’s guide to mechanical isomerism: fundamental motifs and their stereoselective synthesis Peter Gallagher University of Southampton, UK Photocaged zinc (II) cationophores for inter-vesicle signal transduction Shaun Gartland University of Oxford, UK Assessment of the bioorthogonality of the nitrile imine 1,3-dipole Mhairi Gibson University of Strathclyde, UK

P11

P12

P13

3-D building blocks: a modular synthetic platform for elaborating fragments to 3-D lead compounds

Andres R Gomez-Angel University of York, UK

P14

Exploring oxonium ion chemistry in natural product synthesis Harry Hicks University of Oxford, UK Enantioselective carbon-nitrogen bond formation directed by a chiral cation Nicholas Hodson University of Cambridge, UK Non-mechanically interlocked processive catalysis using directionally sequential c–h functionalisation Emma Hollis University of Bristol, UK

P15

P16

P17

Photocatalytic α-C–H heteroarylation of primary amines George Johnson Bath University, UK

P18

eFluorination of activated alcohols using collidinium tetrafluoroborate Cyrille Kiaku University of Greenwich, UK Scalable and sustainable synthetic study towards the rubriflordilactones Pavle Kravljanac University of Oxford, UK

P19

P20

Direct minisci-type C−H Amidation of purine bases David Mooney Heriot Watt University, UK

P21

Application of P,N ligands in the asymmetric alkynylation of quinolone Dairine Morgan University College Dublin, Ireland

P22

Exploring the photochemistry of lithiated enolates James Mortimer University of Bristol, UK

P23

Organocatalytic asymmetric synthesis of α-aminophosphinates Caoimhe Niland University College Dublin, Ireland Turning hydrogen bonding catalysts into enantioenriched iminothiazina- none heterocycles using isothiourea catalysis Alastair Nimmo University of St Andrews, UK Enhancing triethylborane initiation through mechanistic understanding using a novel radical trapping technique Ivan Ocaña University of York, UK Harnessing hydroxylating enzymes for the synthesis of natural products and their analogues with relevance to dementia Yi Ni Ong University of Oxford, UK Palladium-catalysed synthesis of diaryl ethers promoted by a soluble organic base Martyna Ostrowska University of Nottingham, UK Practical difluoroethylation reactions of amines using difluoroacetic acid Oska Pugh University of Nottingham, UK Studies towards the total synthesis of mycapolyol e using iterative ho- mologation of boronic esters Dylan Rigby University of Bristol, UK

P24

P25

P26

P27

P28

P29

P30

Development of novel bifunctional organic superbases for enantioselective synthesis Daniel Rozsar University of Oxford, UK Novel synthetic methods using photoexcited nitroarenes Raquel Sanchez University of Manchester, UK

P31

P32

Synthesis of functionalised pyrrolidinone scaffolds via Smiles-Truce cascade Thomas Sephton University of Manchester, UK Stereospecific alkene 1,2-aminofunctionalisation as a strategy towards complex heterocycles Matthew Smith University of Liverpool, UK Fused porphyrins constrained within rigid rings: towards fully conjugated nanobelts Wojciech Stawski University of Oxford, UK Exploiting oxetane sulfonyl fluorides to access new chemical space for medicinal chemistry Ollie Symes Imperial College London, UK A general arene C–H functionalization strategy via electron donor- acceptor complex photoactivation Leendert van Dalsen University of Manchester, UK Cp*Rh(III)-catalyzed enantioselective C(sp³)–H amidation of cyclobutanes Xing Xu University of Oxford, UK Novel low-bandgap organic semiconductors for near-infrared (NIR)- based applications Adibah Zamhuri University College London, UK

P33

P34

P35

P36

P39

P40

A general iridium-catalyzed reductive dienamine synthesis allows a five-step synthesis of catharanthine via the elusive dehydrosecodine Yaseen A. Almehmadi 1,2 , Darren J. Dixon 1 * 1 Department of Chemistry, University of Oxford, UK, 2 Department of Chemistry, Rabigh College of Science and Arts, Saudi Arabia We developed a new catalytic, highly stereo- and regioselective approach towards the rapid construction of highly functionalized isoquinuclidines (ISQs). These bridged bicycles are abundant in active principle ingredients and natural products, 1 such as catharanthine, 18-methoxycoronaridine, cononusine, and caldaphinidine D (figure 1, a). Our new methodology relies on the use of an iridium (I) complex to hydrosilylate β,γ-unsaturated δ-lactams, which can lead to the downstream formation of a reactive dienamine intermediate, before undergoing a concerted [4+2] cycloaddition reaction with a wide range of dienophiles (figure 1, b). This remarkable transformation proceeds with high stereocontrol, low catalyst loading, and from readily available starting materials, resulting in the formation of complex isoquinuclidine polycyclic products. This robust synthetic approach was also extended to acyclic, aliphatic starting materials, enabling the formation of cyclohexene-substituted amine products and has enables the shortest (five-step) synthetic route to access catharanthine (figure 1, c) to date, an alkaloid that also happens to be a building block for vinblastine 2 (a widely used anticancer drug approved by the World Health Organization for several aggressive cancers such as brain, lung, testicular, bladder, and melanoma cancer).

Figure 1. (a) The prevalence of isoquinuclidines; (b) our work; (c) 5-step biomimetic total synthesis of catharanthine. References 1. Silva, E. M.; Rocha, D. H.; Silva, A. M. Diels−Alder Reactions of 1,2-Dihydropyridines: An Efficient Tool for the Synthesis of Isoquinuclidines. Synthesis 2018 , 50 , 1773−1782. 2. Caputi, L.; Franke, J.; Farrow, S. C.; Chung, K.; Payne, R. M. E.; Nguyen, T.-D.; Dang, T.-T. T.; Soares Teto Carqueijeiro, I.; Koudounas, K.; Dugé de Bernonville, T.; Ameyaw, B.; Jones, D. M.; Vieira, I. J. C.; Courdavault, V.; O’Connor, S. E. Missing Enzymes in the Biosynthesis of the Anticancer Drug Vinblastine in Madagascar Periwinkle. Science 2018 , 360 , 1235−1239.

P01

Kinetics and stability of N-Terminal Protein modification strategies L. J. Barber* 1,2,3 , P. Genever 2,3 , C. D. Spicer 1,3 1 Department of Chemistry, University of York, UK, 2 York Biomedical Research Institute, University of York, UK, 3 Department of Biology, University of York, UK N-terminal targeting has emerged as a powerful means to functionalise proteins, for example in the synthesis of protein-polymer conjugates for tissue engineering or antibody drug conjugates. 1 However, selectivity is often poor or the conjugates formed suffer from instability; 2 identifying the most suitable N-terminal modification strategy for an intended application is therefore critical. We have undertaken a detailed comparative study of the conversion, selectivity, and stability of leading N-terminal modification strategies to provide key insight into the formation and utility of the resultant protein-conjugates. 3 Critically, all N-terminal modification strategies were found to exhibit slow kinetics and some extent of reversibility, with reaction efficiency and selectivity found to be highly protein dependent: there is no “one size fits all” approach to N-terminal protein modification. This work highlights the need for the screening of a toolbox of complementary N-terminal modification strategies to ensure optimal properties are achieved for a given target protein and application. We are now using this work as a platform to develop new modification strategies that address current limitations, including the use of proximity-driven chemistries, and intramolecular cyclisation/hydrogen bonding.

References 1. M. B. Francis et al. Nat. Chem. Biol. 13: 697-705, 2017. 2. M. B. Francis et al. Nat. Chem. Biol. 11: 326-331, 2015. 3. C. D. Spicer et al. RSC Chem. Biol. 4: 56-64, 2023.

P02

Diversity-oriented libraries from benzylic boronic esters via a Pd-catalyzed matteson reaction of arylboronic acids

Kane A. C. Bastick, Allan. J. B. Watson EaStCHEM, University of St Andrews, UK

The rapid construction of small molecule libraries under mild conditions is a core facet of pharmaceutical research in both academic and industrial settings. 1 Approaches to the construction of classical organoboron linchpins, widely utilized in Suzuki–Miyaura and Chan–Lam couplings, typically require the use of stoichiometric organometallic reagents. 2 We have recently disclosed an alternative conceptual approach to the Matteson homologation by using a halomethyl boronic ester as a highly reactive surrogate carbenoid. 3 Under Pd catalysis, this reagent undergoes facile oxidative addition to generate bench stable benzylic Bpin esters that are commercially limited due to the instability of the requisite boronic acid intermediate generated during conventional methodologies. With over 40 examples in hand, we demonstrate the synthetic utility of these C(sp 3 )–B products in a variety of Pd and Cu– mediated protocols to assemble a diverse library of compounds bearing pharmaceutically desirable functional groups. Current limitations of the catalytic homologation are discussed.

References 1. W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring, Nat . Commun . 2010, 1 , 1–13. 2. A. J. J. Lennox, G. C. Lloyd-Jones, Chem . Soc . Rev . 2014, 43 , 412–443.3. 3. K. A. C. Bastick, A. J. B. Watson, ACS Catal. 2023, 13 , 7013−7018.

P03

Tailoring halogen-atom transfer (XAT) methods for overcoming challenging transformations at unactivated c(sp³)-centers Lewis Caiger 1 , Timothée Constantin 1 , James J. Douglas 2 , Daniele Leonori* 3 1 Department of Chemistry, University of Manchester, UK, 2 Early Chemical Development, Pharmaceutical Sciences RD, AstraZeneca, UK, 3 Institute of Organic Chemistry, RWTH Aachen University, Germany Organic halides are integral synthetic intermediates, routinely used both in academia and industry for the preparation of high-value materials. While aryl halides are unparalleled substrates for transition metal catalysed cross-coupling reactions, [1] alkyl halides are still a remarkable challenge. These derivatives suffer from comparatively slower rates of oxidative addition and are susceptible to deleterious β-H elimination from the corresponding alkyl-[M] species (M = metal), leading to a lack of general and effective methods for their functionalisation. Activating alkyl halides by single-electron transfer (SET) is far from facile due to their highly negative reduction potentials ( E red <lt; -2.0 V vs SCE), and thus require strong reductants. Halogen-atom transfer (XAT) however, offers an alternative route for alkyl radical generation without the need of SET. Current XAT strategies are based on tin and silicon reagents that are toxic and expensive. [2] In this poster I will present the applications of α-aminoalkyl and aryl radicals as effective, yet mild and selective XAT agents. [3] The approaches discussed here will highlight the versatile nature of these XAT agents and the orthogonal reactivity offered by the resulting open- shell chemistry.

References 1. (a) A. Suzuki, Angew. Chem., Int. Ed., 2011, 50 , 6723-6737. (b) E.-i. Negishi, Angew. Chem., Int. Ed. , 2011, 50 , 6738-6764. F. Juliá, T. Constantin and D. Leonori, Chem. Rev. , 2022, 122 , 2292-2352. 2. (a) L. Caiger, C. Sinton, T. Constantin, J. J. Douglas, N. S. Sheikh, F. Juliá and D. Leonori, Chem. Sci. , 2021, 12 , 10448- 10454. (b) L. Caiger, H. Zhao, T. Constantin, J. J. Douglas and D. Leonori, ACS Catal. , 2023, 13 , 4985-4991.

P04

A general strategy for the amination of electron-rich and electron- poor heteroaromatics by desaturative catalysis Javier Corpas a , Henry Caldora b , Ester Maria Di Tommaso a , Augusto Hernandez c , Oliver Turner d , Luis Miguel Azofra e , Alessandro Ruffoni* a , Daniele Leonori* a a Institute of Organic Chemistry, RWTH Aachen University, Germany, b Department of Chemistry, University of Manchester, UK, c XChem Inc., Montreal, QC Canada, d Oncology RD Medicinal Chemistry, AstraZeneca, Cambridge, UK, e Instituto de Estudios Ambientales y Recursos Naturales (i-UNAT), Campus Universitario de Tafira, Las Palmas de Gran Canaria, Spain Aminated heterocycles are high value targets in industrial sectors (pharmaceutical and fine chemicals), but their preparation still represents a remarkable synthetic challenge. [1] Disclosed in this poster is a general platform for the synthesis of aminated heterocycles whereby a single catalytic manifold can be used to selectively aminate pyridines, pyrroles, furans, thiophenes and pyrazoles at their most deactivated positions. The mechanistic blueprint for this transformation unveils a brand-new and distinct approach to the preparation of aminated heterocycles that nitration and/or cross-coupling strategies cannot access. Here, our approach harnesses the same amine building blocks that are used in cross-couplings but exploits piperidones, pyrrolidinones etc. as heteroaryl halide surrogates. This addresses simultaneously two key challenges in the formation of heteroaryl C-N bonds: As the carbonyl group acts as formal handle for C–N cross-coupling, we by-pass completely electrophilic aromatic chemistry for either nitration or halogenation and then cross-coupling. Instead, we use carbonyl chemistry, possibly the most generalised and robust reactivities known, to introduce functionalities across the “future” aromatic ring.With this approach we replace the challenging reductive elimination from heteroaryl-organometallic intermediates with a simple condensation between an amine and a carbonyl group, which operates under mild conditions. [2] It is widely known that cross-coupling aminations fail on “real-world” substrates and reaction conditions cannot be translated from one class of heteroaromatics to another, especially going from electron-poor to electron-rich systems. [3] This novel desaturative methodology provides an unprecedented and unified approach to the synthesis of C4 and C3-aminated pyridines (electron-poor) as well as C3-aminated pyrroles, furans, thiophenes and pyrazoles (electron-rich) with over 30 complex primary and secondary amines showcased. Key to the success of this process is the catalytic activity of our cobaloxime which has a dual sequential role, acting first as a H-atom abstractor and then as an oxidant. Evidence for this novel mechanistic interplay will be discussed in detail. [4] References 1. Vitaku, E., Smith, D. T. Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 57, 10257-10274, (2014). 2. Reichert, E. C., Feng, K., Sather, A. C. Buchwald, S. L. Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines. J. Am. Chem. Soc. 145, 3323-3329, (2023). 3. Ruiz-Castillo, P. Buchwald, S. L. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chem. Rev. 116, 12564-12649, (2016). 4. U. Dighe, S., Juliá, F., Luridiana, A., Douglas, J. J. Leonori, D. A photochemical dehydrogenative strategy for aniline synthesis. Nature 584, 75-81, (2020).

P05

A reaction with potential: an electrosynthesis of 1,3,4-oxadiazoles from n-acyl hydrazones Luke Chen 1,2 , James Thompson 1 , Craig Jamieson 2 1 GSK Medicines Research Centre, Stevenage, UK, 2 Department of Pure Applied Chemistry, Glasgow, UK This work has established the electrochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from N -acyl hydrazones. The 1,3,4-oxadiazole is a valuable heterocycle with useful medicinal properties. As a stable bioisostere of esters and amides, ubiquitous functional groups in many drugs and bioactive molecules, incorporating the underutilised oxadiazole enables the expansion and exploration of greater chemical space. [1] To highlight this, it is an important component of raltegravir, a top selling anti-HIV drug in 2020. [2] Consequently, more efficient methods to access these heterocycles are required. Common syntheses of 1,3,4-oxadiazole analogues in the literature involve oxidative or dehydrative cyclisation reactions. [3,4] These methods are, however, often limited by poor atom economy and the need for highly reactive, toxic, or corrosive reagents. Herein is described an electrochemical oxidation which offers a green and attractive alternative. Stoichiometric use of conventional chemical oxidants, and their associated hazards, have been avoided to convert inexpensive and readily available starting materials into valuable products.

Taking an indirect electrolysis approach, this strategy offers advantages to established protocols in that milder conditions can be employed to improve functional group compatibility. Extensive screening efforts have identified hydrogen atom transfer (HAT) mediators, such as DABCO, as the optimum redox catalysts for the reaction. The rapid reaction optimisation was accomplished using the IKA ElectraSyn 2.0, enabling greater accessibility of electrochemistry for synthetic, organic chemists. The operationally simple methodology is also amenable to a one- pot procedure from hydrazone precursors, further simplifying the process. Tolerance for a broad range of relevant functional groups has been demonstrated, with moderate to good yields obtained. This has enabled access to a wide array of medicinally privileged structures which would be valuable additions to a screening collection or as a tool for medicinal chemists, such as for determining structure-activity relationships. Work is ongoing to further explore the substrate scope, harnessing the reactivity to functionalise a wider range of hydrazones. References 1. J. Boström, A. Hogner, A. Llinàs, E. Wellner, and A. T. Plowright, J. Med. Chem. , 2012, 55 , 1817–1830. 2. F. Caputo, S. Corbetta, O. Piccolo, and D. Vigo, Org. Process Res. Dev. , 2020, 24 , 1149–1156. 3. K. D. Patel, S. M. Prajapati, S. N. Panchal, and H. D. Patel, Synth. Commun. , 2014, 44 , 1859– 1875. 4. L. Green, K. Livingstone, S. Bertrand, S. Peace, and C. Jamieson, Chem. Eur. J. , 2020, 26 , 14866–14870.

P06

Borane assisted highly secondary selective deoxyfluorination of isoureas Nojus Cironis, Dr. Dominic Willcox, Dr. Sven Kirschner, Prof. Stephen P. Thomas, Prof. Michael J. Ingleson EaStCHEM School of Chemistry, University of Edinburgh, UK The introduction of fluorine into organic molecules is key in tuning physicochemical properties including acidity/ basicity, lipophilicity/solubility and metabolic stability. As a result fluorinated compounds have found wide applications in the pharmaceutical and agrochemical industries. 1 One of the most utilised fluorination methods is deoxyfluorination which involves replacement of an activated “oxo” group by nucleophilic fluoride. 2 A plethora of highly reactive deoxyfluorination reagents have been developed which sequentially activate the “oxo” group and provide the source of fluoride in situ . 2 A major challenge remains the selective and controlled fluorination of polyol compounds using these, and other, reagents. 3 Here we present a new method for the deoxyfluorination of alcohols, via the intermediate isourea, with a unique mode of action using fluoroboranes (F- B -9-BBN). Good yields were achieved across a series of electronically and sterically differentiated alcohols. Mechanistic studies revealed highly selective deoxyfluorination with a hidden mode of action that was unexpected at the outset of this project. Significantly, the reaction was found to offer orthogonal selectivity to all current deoxyfluorination methods and reagents towards secondary substrates. 3

References 1. E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnely, N. A. Meanwell, J. Med. Chem . 2015, 58 , 8315 – 8359. 2. T. Aggarwal, Sushmita; A. K. Verma, Org. Chem. Front . 2021, 8 , 6452 – 6468. 3. L. Li, C. Ni, F. Wang, J. Hu, Nat. Comm. 2016, 7 , 13320.

P07

Stereoselective synthesis of α-Galactosides Kate E. Donaghy, Dionissia A. Pepe, Joseph J. Ruddy, Eoghan M. McGarrigle Centre for Synthesis and Chemical Biology, University College Dublin, Ireland Nature employs carbohydrates as an integral source of structural biodiversity across all organisms. It is understood that the biological properties of these natural products can be fine-tuned via alteration of glycosidic patterns, particularly with respect to stereochemistry. Consequently, stereochemical control in glycosylation reactions is a significant objective within the field of carbohydrate chemistry. [1] This work is concerned with stereochemical control in α-galactosidation reactions. α-Galactoside units are found in many biologically important compounds, for example in cancer-associated mucin-type glycans. [2] However, existing methods for the α-selective synthesis of galactosides that are broadly applicable to a range of galactosyl substrates are limited. [3-6] Thus, further understanding around the stereochemistry of α-galactosidations is required. This poster will describe a highly α-selective methodology for galactosidation that employs an orthogonal para -substituted benzoate protecting group at position four of the galactosyl donor. Seven galactosyl donors were prepared in yields up to 17% over 6 steps. It was found that donors bearing para -electron-withdrawing substituents, for example a para -nitro substituent, afforded the highest α-selectivities. Interestingly, this was contradictory to existing mechanistic proposals described in the literature that suggest reaction via a dioxolenium ion intermediate. [6-8] Computational investigations, a Hammett study on the effect of this benzoyl para -substituent and investigation into the influence of acceptor nucleophilicity on glycosylation stereoselectivity have allowed for the proposal of a rationale for the excellent α-stereoselectivity described herein. This has contributed significantly to our understanding of these α-galactosylation reactions and has allowed for further development of the methodology in terms of scope and application. [9] The scope of glycosylation has been expanded to accommodate galactosyl-α-1,2-, α-1,3-, α-1,4-, and α-1,6- linkages with exclusive α-selectivities and isolated yields up to 74%. The protecting group tolerance of the methodology is under investigation and includes benzyl, benzylidene and benzoyl groups thus far. This glycosylation has also been applied to the synthesis of a trisaccharide as well as a derivative of the mucin-type core-8 structure. [9] Work towards the application of this methodology to the synthesis of biologically relevant α-fucoside compounds will also be reported.

References 1. R. Laine in Glycosciences (Eds: H. Gabius, S. Gabius), Wiley-VCH, Weinheim, 1996 , 1-14. 2. M. R. Pratt and C. R. Bertozzi, Chem. Soc. Rev. , 2005 , 34 , 58-68. 3. A. V. Demchenko, E. Rousson and G. Boons, Tet. Lett. , 1999 , 40 , 36, 6523. 4. M. Shadrick, Y. Singh and A. V. Demchenko, J. Org. Chem. , 2020 , 85 , 24, 15936. 5. J. D. C. Codée, J. Sun et al , Org. Lett. , 2019 , 21 , 21, 8713. 6. K. Greis, P. H. Seeberger, K. Pagel et al , J. Am. Chem. Soc. , 2022 , 144 , 44, 20258. 7. M. Marianski, K. Pagel et al , Angew. Chem. Int. Ed. , 2020 , 59 , 15, 6166-6171. 8. J. D. C. Codée, T. Boltje et al , Nat. Commun . 2020 , 11 , 2664. 9. K. E. Donaghy, D. A. Pepe, J. J. Ruddy and E. M. McGarrigle, manuscript in preparation .

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A novel copper-catalysed C(sp³) -C(sp³) cross-coupling reaction using readily available starting materials David Fernandez Aguado 1,2 , David M. Lindsay 2 , Tim N. Barrett 1 1 GSK Medicines Research Centre, Stevenage, UK, 2 Department of Pure Applied Chemistry, University of Strathclyde, UK Transition metal-catalysed cross-coupling reactions between sp 2 carbon centres have transformed the synthesis of complex organic molecules over the past three decades. In contrast, advances in the development of general methods that form bonds between sp 3 -hybridised carbons (alkyl-alkyl bonds) remain one of the main challenges in the field of cross-coupling chemistry. 1 These drawbacks are mainly due to the slow oxidative addition of alkyl electrophiles and the propensity of metal-alkyl species to undergo β -hydride elimination. In recent times, nickel-catalysed cross-couplings have emerged as efficient methods to activate primary and secondary alkyl electrophiles for coupling with a variety of nucleophilic partners. However, there has been relatively little exploration of copper catalysis as related to sp 3 -sp 3 coupling. Indeed, this area has seen limited applications in the alkylation of electronically unbiased electrophiles. Thereby, the development of novel platforms that allow the synthesis of alkyl-alkyl bonds through the use of copper, and the expansion to more general and readily accessible cross-coupling partners that are bench-stable, inexpensive, and easily procured, comprises a key challenge in synthetic chemistry. Herein, we have established a copper-catalysed hydroalkylation of olefins with radicals generated from alkyl “Katritzky”-type pyridinium salts, selectively prepared from aliphatic amines ( Figure 1 ). 2 In contrast to other electrophile-nucleophile methods described to date, which employ photoredox techniques and a copper catalyst to effect radical- and bond formation, 3 this copper-catalysed hydroalkylation of olefins represents a unique approach where copper underpins both the radical-generating single-electron transfer and the C-C bond construction. To achieve this goal, the design and modulation of the alkyl pyridinium salt structure, to enhance the single electron transfer process, was a key component of our studies ( Figure 1A ). Our developed method is operationally simple and uses mild reaction conditions, and has been applied to the preparation of a range of alkyl-alkyl bonds (>gt;30 examples) from a diverse array of alkyl amines and olefins, including the late-stage functionalization of drug-like compounds ( Figure 1B ). Given the current focus on pharmaceutically relevant molecules enriched in sp 3 character, this method will allow rapid access to novel regions of 3D chemical space, providing a diverse collection of molecules for compound libraries and leading optimization in drug discovery.

Figure 1 References 1. Choi, J.; Fu, G. C. Science 2017 , 356 , 152–160.

2. Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. J.Am. Chem. Soc . 2017 , 139 , 5313–5316. 3. Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016 , 536 , 322-325.

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The hitchhiker’s guide to mechanical isomerism: fundamental motifs and their stereoselective synthesis Peter Gallagher a,b , Andrea Savoini a,b , Abed Saady a,b , John R. J. Maynard a , Patrick Butler a , Graham J. Tizzard a , Stephen M. Goldup b a Chemistry, University of Southampton, UK, b School of Chemistry, University of Birmingham, UK Upon mechanical bond formation, achiral sub-components can be desymmetrised to yield chiral and geometric isomers. 1 When considering the catenation of oriented and/or facially dissymmetric macrocycles ( I and II ) and rotaxane formation using the same with bilaterally symmetric axles ( III and IV ), seven distinct isomeric motifs can be formed ( V - XI ). 2 Of these, only mechanically planar chiral systems ( V and VIII ) have been studied significantly and axially chiral rotaxanes XI were only discovered in 2022. 3 Here we report a study of the factors controlling the selective synthesis of both of geometric and chiral mechanical isomers and the first direct enantioselective synthesis of a mechanically axially chiral rotaxane. All of the fundamental mechanical stereoisomers can now be synthesised stereoselectively. 4,5

Figure 1: Mechanical isomers of [2]catenanes and [2]rotaxanes through combination of oriented or facially dissymmetric macrocycles I and II and bilaterally symmetric axles III and IV . References 1. H. L. Frisch and E. Wasserman, J. Am. Chem. Soc. , 1961, 83 , 3789–3795. 2. E. M. G. Jamieson, F. Modicom, S. M. Goldup, Chem. Soc. Rev. , 2018, 47 , 5266-5311. 3. J. R. J. Maynard, P. Gallagher, D. Lozano, P. Butler S. M. Goldup, Nat. Chem. , 14 , 1038–1044 (2022).

4. P. Gallagher, A. Savoini, J. R. J Maynard, P. Butler S. M. Goldup, manuscript in preparation 5. A. Savoini, P. Gallagher, A. Saady, G. J. Tizzard S. M. Goldup, manuscript in preparation

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Photocaged zinc (II) cationophores for inter-vesicle signal transduction Shaun Gartland, Toby G. Johnson, Euan Walkley, Matthew J. Langton University of Oxford, UK Generating and maintaining an electrochemical gradient over cell membranes is vital for life. Nature controls membrane potentials with ion selective, membrane spanning protein channels which can facilitate the transport of hydrophilic charge carriers over the hydrophobic interior of a phospholipid bilayer, in some cases upon application of an external stimulus. If the ion transport process is mis-regulated, channelopathies occur which can lead to disease in the nervous, cardiovascular or immune systems. Synthetic species capable of transporting across the membrane have recently emerged as potential therapeutics for channelopathies. [1] Of the transporters demonstrated in the literature, those whose activity can be modulated by the application of external stimuli are particularly attractive. In this context, light shows immense promise as a non-invasive stimulus with high spaciotemporal control. Indeed, photo-switchable and photocaged transporters have been demonstrated in the literature. [2] Whilst there are many examples of anion transport across artificial lipid bilayers, there remain few examples of the transport of biologically relevant cations into artificial cells. In addition, the vast majority of transmembrane transport research carried out thus far has been conducted by considering only one family of vesicles. This is despite intercellular communication being vital in facilitating the survival of complex organisms. The few examples of inter-vesicular communication in the literature require biological components to achieve signal transduction. In this poster, I will present my recent work to develop the first artificial inter-vesicle communication network by anchoring a Zn(II) mobile ionophore to the membrane with a hydrophobic, photolabile group which inhibits the Lewis acidity of the chelating quinoline. [3]

Figure 1 (a) The light triggered intervesicle communication process demonstrated (b) The structure of clioquinol (1), photocaged clioquinol (2a) and magnesium green (MgG). References

1. Yang, G. Yu, J. L. Sessler, I. Shin, P. A. Gale and F. Huang, Chem , 2021, 7 , 3256-3291 2. Ahmad, S. A. Gartland, M. J. Langton, Angew. Chem. Int. Ed. , 22023, e202308842 3. A. Gartland, T. G. Johnson, E. Walkley, M. J. Langton, Angew. Chem. Int. Ed. , 2023, e20230980

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Assessment of the bioorthogonality of the nitrile imine 1,3-Dipole Mhairi Gibson 1 , Craig Jamieson 1 , Jonathan Pettinger 2 1 University of Strathclyde, Glasgow, UK, 2 GlaxoSmithKline, Stevenage, UK

The nitrile imine (NI) 1,3-dipole is a highly reactive and readily accessible synthetic intermediate generated via the photolysis of 2,5-disubstituted tetrazoles. [1] Its ability to participate in 1,3-dipolar cycloadditions has enabled its application in a variety of synthetic methods. [2] Of note, NIs have found application in medicinal chemistry, [3] materials chemistry, [4] and more recently, bioorthogonal chemistry. [5] NI-mediated photoclick reactions have recently found traction in bioorthogonal labelling techniques due to the light-activated, traceless nature of the system and the formation of stable, fluorescent adducts with biomolecules modified with an appropriate dipolarophile. While NIs are renowned for their proclivity towards cycloadditions, this species exhibits broad reactivity with a range of nucleophilic functionalities. [6-8] Such functionalities are ubiquitous in biomolecules and therefore their promiscuous reactivity with the NI dipole may hinder its application as a true bioorthogonal labelling tool. Previous work in our group has sought to explore the reactivity profile of the NI species through a series of competition experiments utilising a library of nucleophilic model substrates and dipolarophiles. Interestingly, the quantification of NI dipole reactivity with a range of carboxylic acid moieties revealed an enhancement in reactivity with decreasing pK a of the acidic coupling partner. These findings have been expanded to assess the biorthogonality of the dipole through the competitive reaction of an electronically activated dipolarophile versus a highly acidic fluorinated carboxylic acid. A range of NI species were generated through photolysis of a 2,5-disubstituted tetrazole and their reactivity with a model substrate was quantified. The selectivity observed demonstrated that NI reactivity can be tuned via modulation of the pK a of an acidic coupling partner. The next phase of this work sought to exploit this observation by exemplifying the application of highly acidic carboxylic acid moieties as novel bioorthogonal handles for NI-mediated photoclick reactions. A suitable NI precursor has been identified which enhances chemoselectivity for the bioorthogonal handle, suppressing the reactivity of endogenous competing nucleophiles. Current work is ongoing to incorporate a selection of highly acidic bioorthogonal handles into model peptide sequences containing multiple nucleophilic amino acid residues, allowing the chemoselectivity of the NI with these novel bioorthogonal handles to be assessed. References 1. R. Huisgen et al ., J. Org. Chem ., 1959, 24 , 892-893. 2. R. Huisgen et al ., Tetrahedron , 1962, 17 , 3-29. 3. P. Conti et al ., Chemistry and Biodiversity , 2008, 5 , 657-663. 4. Y. Iwakura et al ., Die Makromolekulare Chemie , 1966, 97 , 278-281.

5. Z. Li et al ., Angew. Chem. Int. Ed. , 2006, 55 , 2002-2006. 6. R. Huisgen et al ., Chem. Ber. , 1961, 94 , 2503-2509. 7. A. Herner et al ., J. Am. Chem. Soc. , 2016, 138 , 14609-14615. 8. L. Bruché et al ., J. Chem. Soc. Perkin Trans. 1 , 1981, 2245-2249.

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3-D building blocks: a modular synthetic platform for elaborating fragments to 3-D lead compounds Andres R. Gomez-Angel 1 , William T. Butler 1 , James R. Donald 1 , Hanna F. Klein 1 , Stephen Y. Yao 1 ,James D. Firth 1 , Lucia Fusani 2 , Simon C. C. Lucas 2 and Peter O’Brien 1 . 1 Department of Chemistry, University of York, UK, 2 Hit Discovery, The Discovery Centre, Cambridge, UK With the advent of Fragment Based Drug Discovery (FBDD) for the efficient sampling of chemical space, the overall rate of discovery of potential drug candidates starting from fragments has increased. 1 However, this increase has highlighted the need to further develop synthetic chemistry to support FBDD. 2 One of these needs is increasing the 3-D shape of potential drug candidates 3 and interest in 3-D shaped fragments has emerged. 4 Nonetheless, as current libraries possess many compounds with low 3-D shapes 5 and elaborating such compounds is challenging, we now present a new, modular approach for the conversion of 2-D fragments into 3-D lead-like compounds with potential for automation. Our technology platform enables the rapid elaboration of 2-D fragments in three-dimensions. A series of bifunctional 3-D building blocks with defined elaboration vectors has been designed and synthesised ( A , available from Key Organics). Utilising the cyclopropyl MIDA boronate handle, elaboration with medicinally relevant aryl bromides via Suzuki-Miyaura cross-coupling can be achieved. Additionally, a variety of N -functionalisation reactions are demonstrated to give access to a series of lead-like compounds by the use of precedented pharmacophores ( B ) 6,7 – this provides access to a wide range of 3-D vector space ( B ). The utility of our modular synthetic platform is further highlighted by the design and synthesis of selective JAK3 inhibitors utilising two of the designed 3-D building blocks ( C ). Finally, a new generation of 3-D building blocks comprising a cyclobutyl alcohol or BF 3 K is showcased. Using Pd-catalysed sp 3 -sp 2 Suzuki-Miyaura cross-coupling or a novel application of MacMillan’s Ir/Ni-catalysed deoxygenative photoredox cross-coupling 8 allows access to new areas of chemical space not covered by the cyclopropyl building blocks ( D ). Full details will be presented.

References 1. D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke, H. Jhoti, Nat. Rev. Drug Discov . 2016 , 15, 605–619. 2. C. W. Murray, D. C. Rees, Angew. Chemie - Int. Ed. 2016 , 55, 488–492. 3. Lovering, F.; Bikker, J.; Humblet, C., J. Med. Chem . 2009 , 52, 6752-6756. 4. Kidd, S. L.; Osberger, T. J.; Mateu, N.; Sore, H. F.; Spring, D. R., Front. Chem . 2018 , 6, 460. 5. Fuller, N.; Spadola, L.; Cowen, S.; Patel, J.; Schönherr, H.; et al ., Drug. Discov. Today . 2016 , 21, 1272-1283. 6. M. R. Harris, Q. Li, Y. Lian, J. Xiao, A. T. Londregan, Org. Lett . 2017 , 19, 2450–2453. 7. M. R. Harris, H. M. Wisniewska, W. Jiao, X. Wang, J. N. Bradow, Org. Lett . 2018 , 20, 2867–2871. 8. Dong, Z., MacMillan, D.W.C., Nature 2021 ,598, 451–456.

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