Organic chemistry poster symposium

5 December 2022, London, UK Organic chemistry poster symposium

5 December 2022, London, UK Organic chemistry poster symposium #organic-poster

Book of abstracts

Registered charity number: 207890

Welcome Message

Dear Colleagues, Welcome to the 2022 Organic chemistry poster symposium, the Organic Chemistry Community’s, formerly Organic Division, 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. It is particularly nice to be back to an in-person event again in Burlington House after two years of hosting the event online only. 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. We are indebted to today’s headline sponsor Syngenta, alongside all our sponsors listed on page 5). Today wouldn’t 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’d 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 Council President

Professor AnnMarie O’Donoghue Scientific Organising Committee Chair

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 2 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 chem istry discipline and we very much look forward to meeting with you and learning more about your research. We at Syngenta are very p leased 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 a nd 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 , doc toral 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” , o ur 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 and process synthesis , physical, analytical, formulation, automated and computational c hemistries 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 c hemists who connect into Syngenta’s global scientific research network across the world. Please do come and visit us at our stand to he ar more about Syngenta, meet with our scientists 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

Organising committee

Judging panel

AnnMarie C. O’Donoghue (Chair) Durham University, UK

Ross Denton, University of Nottingham, UK 2022 Bader Award winner

Stephen Clark University of Glasgow, UK

Louis Morrill, Cardiff University, UK 2022 Organic Division early career award: Hickinbottom Award winner

Martin Eastgate Bristol Myers Squibb, United States

Amelie Joffrin GSK, UK

Katherine Wheelhouse GlaxoSmithKline, UK

2022 Organic Division mid-career Award: Merck, Sharp and Dohme Award winner

Eoghan McGarrigle University College Dublin, Ireland

Kenneth Ling Syngenta, UK

Darren Stead AstraZeneca, UK

Rebecca Harvey Concept Life Sciences, UK

Damien Valette MSD, UK

Meeting information

The programme for the Organic chemistry poster symposium is available to download from the website https://rsc.li/organic-poster2022.

This e-book contains abstracts of the 40 posters presented at symposium. All abstracts are 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, as selected by the judging panel. 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 Delegates will also have the opportunity to vote for their favourite poster of the day, sponsored by Organic & Biomolecular Chemistry, and RSC Chemical Biology. 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

Delegate prize • £200

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 6,000 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, regional meetings as well as supporting other events. • Advocating and providing expertise for organic chemistry. • Recognising excellence within organic chemistry through our prizes programme.

Find out more: https://rsc.li/organic-division

2022 prizes open for nomination Organic Community Research & Innovation Prizes: • Organic Chemistry early career prize: Hickinbottom Prize • Organic Chemistry mid-career prize: Merck, Sharp & Dohme Prize • Organic Chemistry open prize: Pedler Prize • Bader Prize

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 Community Horizon Prizes: • Bioorganic Chemistry Prize • Perkin Prize in Physical Organic Chemistry • Robert Robinson Prize in Synthetic Organic Chemistry Nominate someone today

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.

Other upcoming events of interest

Chemical biology symposium 15 May, London, UK Poster abstract deadline: 6 March 2023

Electrosynthesis 12-14 July 2023, Edinburgh, UK and online Poster abstract deadline: 2 May 2023

27th International symposium: Synthesis in organic chemistry 24-27 July 2023, Oxford, UK Poster abstract deadline: 15 May 2023

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:

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.

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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

Evotec’s mission is to discover and develop highly effective therapeutics and make them globally available to patients. Evotec has established itself as a global platform company, leveraging its data-driven multimodality platform for both proprietary and partnered research. We seek talented individuals to join our UK Discovery and Development chemistry departments.

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Charnwood Molecular is an award-winning, UK-based CRO, providing expert synthetic chemistry support to the fine chemical, pharmaceutical and biotechnology industries for over 20 years.

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UCB is a global biopharmaceutical company dedicated to discovering and developing treatments that aim to transform the lives of people living with neurological and immunological conditions. We work with patients and others to address unmet need and support patients to achieve their goals and live the lives they want.

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Poster presentations

P01

Development of an asymmetric alkene hydroheteroarylation methodology Timothy Aldhous University of Bristol, UK Point-to-helical chirality transfer in the diastereoselective synthesis of boron dipyrromethenes (BODIPYs) Aminah Almarshad Newcastle University, UK A ‘clip-cycle’ approach towards enantioselective synthesis of substituted tetrahydropyrans Khadra Alomari University of York, UK The enantioselective total synthesis of sealutomicin C Stuart Astle University of Oxford, UK Electrochemical nucleophilic benzylic C(sp³)-H functionalization Alexander Atkins University of Bristol, UK Enantioselective Giese additions of prochiral α-amino radicals via chiral phosphoric acid catalysis Paul David Bacoș University of Cambridge, UK

P02

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Transamidation-driven molecular pumps Lorna Binks University of Manchester, UK

P08

Mechanism driven, divergent iron-catalysed C-H functionalisation Luke Britton University of Edinburgh, UK

P09

Asymmetric synthesis of aromatic lipoxin A 4 analogues with biological evaluation Lucy Byrne University College Dublin, Ireland The design and synthesis of inhibitors for the essential Leishmania bromodomain LdBDF5 Jennifer Carter University of Oxford, UK The development of oxaziridine-based methionine spin-labels for EPR Siyao Chen University of St Andrews, UK New approaches in iridium catalysis for sp 3 hydrogen isotope exchange (HIE) of amino acids and peptides Megan Cuthbert University of Strathclyde, UK Short electrochemical asymmetric synthesis of (+)- N -acetylcolchinol Yi Du Loughborough University, UK Diastereodivergent synthesis of cyclopentyl boronic esters bearing contiguous fully substituted stereocentres Molly Fairchild University of Bristol, UK Overcoming the internal alkyne problem in [2+2+2] cycloadditions John Halford-McGuff University of St Andrews, UK Light-controllable nucleic acids for control of in vitro gene expression Denis Hartmann University of Oxford, UK

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Using variable field NMR to understand dynamic exchange Jean-Paul Heeb University of Bristol, UK

P18

Enecarbamates as platforms for the synthesis of diverse polycyclic scaffolds Alexandra Hindle University of Leeds, UK Encoding information and transporting cargo with a supramolecular oscillator Michael Howlett University of Oxford, UK Pre-catalyst activation and speciation in topical cross-couplings – why it matters? David Husbands University of York, UK One trillion photoswitchable cyclic peptides: shining light on questions in chemical biology Thomas Jackson Imperial College London and The Francis Crick Institute, UK Exploring the conformational bias of amides to unlock reactivity Mehul Jesani University of Bristol, UK Optimising continuous flow chemoenzymatic processes for fine chemical manufacturing Harrison Johnson-Evans University of Leeds, UK Biocompatible 1,2-carbonyl rearrangements in living E. coli Nick Johnson University of Edinburgh, UK Exploiting molecular length as a means of enhancing control and selectivity of anion relay transporters Toby Johnson University of Oxford, UK One-carbon ring expansion of pyrroles and indoles to 3-arylazinium salts Ben Joynson University of Nottingham, UK

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Exploring the design of copper artificial metalloenzymes Eva Klemencic University of Edinburgh, UK Next generation bioisosteres - photocatalytic construction of azabicycles Nicoleta Lazar University of Oxford, UK Small-molecule mimicry of the formylglycine-generating enzyme Guillermo Palop NUIG, Ireland Thiophene S,S-dioxides as a versatile building block for efficient complex total synthesis Kun Ho (Kenny) Park University of Oxford, UK A dynamic thermodynamic resolution strategy for the stereocontrolled synthesis of streptonigrin Luis Fernando Valdez Pérez The University of Sheffield, UK

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Asymmetric total synthesis of (–)-phaeocaulisin A Aron Peter The University of Manchester, UK

P33

A chemoenzymatic total synthesis of 13-deoxytetrodecamycin – Identification and application of TedJ, a new Diels-Alderase, in the synthesis of an antibiotic. Joe Russell University of Bristol, UK

P34

Rupturing aromaticity by periphery overcrowding Promeet Saha University of Durham, UK

P35

Controlling mechanical geometrical isomerism in rotaxanes Andrea Savoini University of Southampton, UK

P36

From bench-stable carbenes to blatter-type radicals Matthew Smith Durham University, UK

P37

Metal-free reductive amination of carboxylic acids by brønsted acid activation Milly Stoneley University of Nottingham, UK B(C 2 F 5 ) 3 -catalysed C3 alkylation of indoles and oxindoles Laura Winfrey University of Leicester, UK A bi-directional centrosymmetric strategy towards the synthesis of marine polyether natural products Sophie Woolford University of Glasgow, UK Nucleophile Inducing Cyclisation/ring Expansion reactions (NICE) for synthesis of medium-sized rings and macrocycles Illya Zalessky University of York, UK

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Development of an asymmetric alkene hydroheteroarylation methodology

Timothy P Aldhous 1 , Paul Kemmitt 2 , Natalie Fey 1 , John F. Bower 3 1 University of Bristol, UK 2 AstraZeneca, UK 3 University of Liverpool, UK

The Suzuki reaction has become a mainstay of the pharmaceutical industry for the formation of planar “2D” biaryl structures. While chiral alkyl nucleophiles (e.g. 2 ) can be used to access “3D” benzylic stereocentres (e.g. 3 ), this approach can often lead to isomeric side-products. 1 An “ideal” alternate approach is to form benzylic stereocentres directly via the enantioselective addition of aryl C-H bonds ( 4 ) across alkenes ( 5 ). 2 To develop this, the Bower group recently reported enantioselective Ir-catalysed hydroarylations of alkenes with acetanilides to provide tertiary benzylic stereocenters. 3 The focus of my work has been to broaden the scope of this methodology by designing new chiral catalyst systems ( Scheme 1B ). I have developed enantioselective protocols that provide tertiary benzylic stereocentres via the hydroarylation of mono-substituted alkenes 7 with a wide range of benzenoid and heterocyclic ( 6 ) arenes ( Scheme 1C ). By employing 1,1-disubstituted alkenes in this protocol, a broad range of products bearing challenging quaternary benzylic centres can be accessed in an atom and step economical manner. 4 In a recent advancement, I have achieved exciting preliminary results which show that enantioenriched quaternary stereocentres can be accessed through this reaction manifold.

References 1. D. Leonori, V. K. Aggarwal, Angew. Chem. Int. Ed. 2015 , 54 , 1082.

2. T. P. Aldhous, R. W. M. Chung, A. G. Dalling, J. F. Bower, Synthesis , 2021 , 53 , 2961–2975. 3. S. Grélaud, P. Cooper, L. J. Feron, J. F. Bower, J. Am. Chem. Soc., 2018 , 140 , 9351. 4. P. Cooper, A. G. Dalling, E. H. E. Farrar, T. P. Aldhous, S. Grélaud, E. Lester, L. J. Feron, P. D. Kemmitt, M. N. Grayson, J. F. Bower, Chem. Sci. , 2022 , Advance Article .

P01

Point-to-helical chirality transfer in the diastereoselective synthesis of boron dipyrromethenes (BODIPYs) Aminah Almarshad 1,2 , Felicity Frank 1 , Julian Knight 1 and Michael Hall* 1 1 Newcastle University, UK, 2 Imam Abdulrahman Bin Faisal University, Saudi Arabia The boron dipyrromethenes (BODIPYs) are a class of fluorescent organic dyes that have found use in numerous applications such as biological imaging, solar cells, and photodynamic therapy. 1 Our research group is concerned with the design and investigation of new synthetic routes to produce helically chiral BODIPYs, which have the ability to emit circularly polarized luminescence (CPL), for future application in CPL imaging. The synthesis of helically chiral BODIPYs is challenging, and previous routes often rely on resolution of racemic mixtures by chiral HPLC. 2 Here we demonstrate the first use of enantiopure amino acid and amino alcohol substituents as chiral auxiliaries, capable of controlling the formation of helical chirality in the BODIPYs through a point-to-helical chirality transfer mechanism. Our synthetic strategy involves the introduction of enantiopure amino acid or amino alcohol chiral auxiliaries via S N Ar chemistry, followed by helicity creation through a boron chelation reaction. 3 Point-to-helical chirality transfer has been achieved with high diastereomeric excess (up to 84%), and with the relative stereochemistry of the products confirmed by single crystal X-ray diffraction (SCXRD). This novel synthetic strategy has allowed us to access a range of helically chiral BODIPYs for future chiroptical analysis.

References 1. Treibs and F. H. Kreuzer, Justus Liebigs Ann. Chem ., 1968, 718 , 208–223. 2. R. B. Alnoman, S. Rihn, D. C. O’Connor, F. A. Black, B. Costello, P. G. Waddell, W. Clegg, R. D. Peacock, W. Herrebout, J. G. Knight and M. J. Hall, Chem. Eur. J ., 2016, 22 , 93–96. 3. F. J. Frank, P. G. Waddell, M. J. Hall and J. G. Knight, Org. Lett ., 2021, 23 , 8595-8599.

P02

A ‘clip-cycle’ approach towards enantioselective synthesis of substituted tetrahydropyrans Khadra Alomari 1,2 and Paul Clarke 2 1 Jazan University, Saudi Arabia, 2 University of York, UK Tetrahydropyrans are the fifth most prevalent heterocycle in pharmaceutical molecules 1 , therefore, the development of new methodologies for their asymmetric synthesis can provide access to novel biologically relevant molecules. 2 Despite the popularity of the intramolecular oxa-Michael reaction for the synthesis of substituted THPs, the control of enantioselectivity usually focus on intermolecular reactions, with only a few intramolecular variations reported. 3,4 An asymmetric ‘clip-cycle’ reaction has been developed toward the synthesis of 2,2- and 3,3-spirocyclic THPs with high enantioselectivity (up to 99%). The cyclisation precursors were initially prepared by ‘clipping’ together the alcohol fragment and an aryl thioacrylate ( via catalytic olefin metathesis), which was then followed by intramolecular oxa-Michael cyclization catalysed by chiral phosphoric acids (CPA) to yield the tetrahydropyran products. α, β-Unsaturated thioesters sit in the ‘Goldilocks zone’ of the reactivity 5 and enantioselectivity. They can be easily converted into a wide variety of different functional groups. 6 The absolute stereochemistry of cyclization was determined experimentally as ( S ).

References 1. R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem. , 2014, 57 , 5845–5859. 2. I. Paterson and C. A. Luckhurst, Tetrahedron Lett. , 2003, 44 , 3749–3754. 3. Y. Lu, G. Zou and G. Zhao, ACS Catal. , 2013, 3 , 1356–1359. 4. L. Becerra-Figueroa, S. Movilla, J. Prunet, G. P. Miscione and D. Gamba-Sánchez, Org. Biomol. Chem. , 2018, 16 , 1277– 1286.

5. C. J. Maddocks, K. Ermanis and P. A. Clarke, Org. Lett. , 2020, 22 , 8116–8121. 6. H. Fuwa, N. Ichinokawa, K. Noto and M. Sasaki, J. Org. Chem. , 2012, 77 , 2588–2607.

P03

The enantioselective total synthesis of Sealutomicin C Stuart Astle, Sean Guggiari and Jonathan Burton University of Oxford, UK

The sealutomicins are a family of anthraquinone-fused natural products isolated from the actinomycete Nonomuraea sp. MM565M-173N2. 1 Sealutomicins B – D all display in vitro antibacterial activity against a range of gram-positive bacteria; however, due to the scarcity of material isolated, no investigations have yet been made into the mechanism by which this occurs. Furthermore, sealutomicins B – D all bear strong structural similarities to the natural product unciaphenol, which inhibits replication of antiretroviral-resistant HIV strains without concomitant cytotoxicity to host T-cells, raising the possibility of similar antiviral effects being observed for sealutomicins B – D. 2 As such, these natural products are synthetic targets of promising medicinal and therapeutic use.

We have successfully completed the first total synthesis of sealutomicin C in an 18-step route via intermediate A (Figure 2 ). Compound A is prepared in 98% ee from commercially available 2-bromobenzaldehyde and 5-methoxyisatin in a 10-step sequence, which features an enantioselective dihydroquinoline synthesis using a proline-derived catalyst, and an organolithium cyclisation to form a key arene-ketone bond. Subsequent manipulation of the aldehyde handle of A enables installation of the α,β-unsaturated ester side chain, while a Hauser-Kraus annulation is used to access the anthraquinone unit to give the target natural product as a single enantiomer.

Attention has now shifted to the conversion of intermediate A to sealutomicins B and D. We envisage that the aldehyde moiety of A may be used as a handle to access the α-hydroxybutenolide side chain of both natural products, and that the same Hauser-Kraus annulation may be used to install the required anthraquinone units. This presentation will discuss both the synthesis of sealutomicin C and subsequent efforts towards sealutomicins B and D. References 1. J. Antibiot. (Tokyo) , 2021 , 74 , 291 - 299 2. Org. Lett. , 2015 , 17 , 5304 - 5307

P04

Electrochemical nucleophilic benzylic C(sp³)-H functionalization Alexander P. Atkins 1 , Joseph A. Tate 2 and Alastair J. J. Lennox 1 * 1 University of Bristol, UK, 2 Syngenta, UK The development of selective C(sp 3 )—H functionalization reactions is necessary for improved step-, time- and waste-efficiency in synthetic chemistry. Unfunctionalized benzylic C(sp 3 )—H bonds are found in pharmaceutical and agrochemical active ingredients but are also prone to enzymatic oxidation. 1 Recently, electrochemistry has been demonstrated as a means to selectively functionalize benzylic C(sp 3 )—H bonds to produce new carbon— carbon and carbon—heteroatom bonds. 2 Anodic oxidation negates the need for traditional chemical oxidants and facilitates the coupling of electrochemically generated intermediates with inexpensive feedstock nucleophiles that can be used to increase molecular complexity or resistance to enzymatic oxidation. This work describes the use of electrochemical C(sp 3 )—H oxidation to generate benzylic cations that can be captured by a series of nucleophiles to afford higher value products. For the first time, carboxylic acids are demonstrated as an inexpensive source of nucleophile for C—O carboxylation and a means to access functionalized benzylic esters. 3 This method is applicable to a range of benzylic coupling partners, produces hydrogen gas as the sole by-product, and can be scaled up to gram-scale using flow electrochemistry. Fluoride sources can also be employed as the nucleophile to afford the corresponding benzyl fluorides. Stability studies indicate that primary benzyl fluorides are a more stable and therefore suitable target than secondary and tertiary benzyl fluorides. Precise control of the electrolysis waveform facilitates access to the more difficult primary benzyl fluorides which is demonstrated on a selection of primary benzylic substrates.

Abstract Graphic

References 1. Xie, L.; Chen, K.; Cui, H.; Wan, N.; Cui, B.; Han, W.; Chen, Y. ChemBioChem., 2020, 21 (13), 1820−1825. 2. Selected examples: Hou, Z.; Liu, D.; Xiong, P.; Lai, X.; Song, J.; Xu, H., Angew. Chem., Int. Ed., 2021, 60 (6), 2943−2947., Wang, H.; Liang, K.; Xiong, W.; Samanta, S.; Li, W.; Lei, A., Sci. Adv. 2020, 6 (20), 1-7., H. Gao, X. Chen, P.-L. Wang, M.-M. Shi, L.-L. Shang, H.-Y. Guo, H. Li and P. Li, Org. Chem. Front., 2022, 9, 1911–1916. 3. A. P. Atkins, A. C. Rowett, D. M. Heard, J. A. Tate, A. J. J. Lennox, Organic Letters, 2022, 24(28), 5105 5108.

P05

Enantioselective Giese additions of prochiral α-amino radicals via chiral phosphoric acid catalysis Bacoș, P. David, Lahdenperӓ, Antti S. K. and Phipps, Robert J. * University of Cambridge, UK

Amines that feature an adjacent stereocentre are important chemical building blocks in a range of applications. 1 Recent years have seen a dramatic increase in methods that form these via α-amino radical intermediates, but very few can exert control over the newly formed stereocentre. 2,3 Because stereochemistry can have profound impact on the interactions of small molecules with biological systems, this represents a huge barrier to the wider adoption of these methodologies. We have designed a strategy to overcome this challenge in the context of one of the most important radical carbon-carbon bond forming reactions, the Giese reaction. 4 Incorporation of a removable basic heteroarene motif into the amine partner enables a network of attractive non-covalent interactions between a phosphoric acid catalyst, the subsequently formed α-amino radical, and the Giese acceptor, allowing the catalyst to exert very high levels of control during the C−C bond forming step. 5 Furthermore, the chiral catalyst is also able to control the facial selectivity of attack on the Giese acceptor, allowing control of chirality originating from the acceptor β-position. The reaction products are of particular importance as they are analogues of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system, and we further demonstrate the concise synthesis of a leading pharmaceutical and a natural product. We anticipate that our strategy of using a heteroaryl motif to enable hydrogen bonding with a chiral catalyst will not only to be applicable to other α-amino radical functionalisation processes but could also be expanded more broadly to other asymmetric radical transformations. References 1. Q. Yin, Y. Shi, J. Wang, and X. Zhang, Chem. Soc. Rev , 2020, 49 , 6141-6153. 2. S. Mondal, F. Dumur, D. Gigmes, M. P. Sibi, M. P. Bertrand, and M. Nechab, Chem. Rev. , 2022, 122 , 5842-5976.

3. M. H. Shaw, J. Twilton, and D. W. C. MacMillan, J. Org. Chem. , 2016, 81 , 6898-6926. 4. A. L. Gant Kanegusuku and J. L. Roizen, Angew. Chem. Int. Ed. , 2021, 60 , 21116-21149. 5. R. S. J. Proctor, A. C. Colgan, and R. J. Phipps, Nat. Chem. , 2020, 12 , 990-1004.

P06

Transamidation-driven molecular pumps Lorna Binks 1 , Chong Tian 1 , Stephen D. P. Fielden 1 , Iñigo J. Vitorica-Yrezabal 1 and David A. Leigh 1,2 1 University of Manchester, UK, 2 East China Normal University, China Protein pumps actively transport substrates away from equilibrium. 1 These biomolecular machines are generally extremely structurally complex, assembled from multiple protein subunits and having molecular masses in excess of 500 kDa. A number of much smaller artificial molecular pumps have been designed. 2 These minimalist systems can provide insights into the basic mechanisms required to drive chemical systems away from equilibrium 3 .Here we report a new class of synthetic molecular pumps that use a stepwise information ratchet mechanism to achieve the kinetic gating required to sequester their macrocyclic substrates from bulk solution. 1 Threading occurs as a result of active template reactions between the pump terminus amine and an acyl electrophile, whereby the bond-forming reaction is accelerated through the cavity of a crown ether. 2 Carboxylation of the resulting amide results in displacement of the ring to the collection region of the thread. Conversion of the carbamate to a phenolic ester provides an intermediate rotaxane suitable for further pumping cycles. In this way rings can be ratcheted onto a thread from one or both ends of appropriately designed molecular pumps. Each pumping cycle results in one additional ring being added to the thread per terminus acyl group. The absence of pseudorotaxane states ensures that no dethreading of intermediates occurs during the pump operation. This facilitates the loading of different macrocycles in any chosen sequence, illustrated by the pump-mediated synthesis of a [4]rotaxane containing three different macrocycles as a single sequence isomer. A [5]rotaxane synthesized using a dual- opening transamidation pump was structurally characterized by single-crystal X-ray diffraction, revealing a series of stabilizing CH···O interactions between the crown ethers and the polyethylene glycol catchment region of the thread.The ability to drive molecular systems directionally away from equilibrium with ratchet mechanisms has ramifications not only for synthesis but for many other aspects of molecular nanotechnology. 6

References 1. J. C. Skou, Angew. Chem., Int. Ed. ,1998, 37 , 2320−2328. 2. S. Erbas-Cakmak, D. A. Leigh, C. T. McTernan, A. L. Nussbaumer, Chem. Rev. , 2015, 115 ,10081−10206. 3. E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem., Int. Ed. , 2007, 46 , 72−191. 4. L.Binks, C. Tian, S. D. P. Fielden, I. J. Vitorica-Yrezabal and D. A. Leigh, J. Am. Chem. Soc. , 2022, 144 , 15838-15844. 5. S.D. P. Fielden, D. A. Leigh, C. T. Mcternan, B. Perez-Saavedra, I. J. Vitorica-Yrezabal, J. Am. Chem. Soc. ,2018, 140 , 6049−6052. 6. I. Aprahamian, ACS Cent.Sci. , 2020, 6 , 347−358.

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Mechanism driven, divergent iron-catalysed C-H functionalisation Luke Britton a , Gary S. Nichol a , Andrew P. Dominey b and Stephen P. Thomas* a a University of Edinburgh, UK, b GSK Medicines Research Centre, UK

Direct C–H functionalisation reactions offer a sustainable method for molecular construction and diversification, 1,2 however, these reactions remain dominated by the use of precious metal catalysts. Due to their high abundance, inexpensiveness, and low toxicities, Earth-abundant metal alternatives have gained significant interest. 3 This poster will present our mechanistic studies on the iron-catalysed C-H functionalisation of carboarenes, heteroarenes, and alkenes. We have isolated and characterised (solution- and solid state) the key iron-aryl, and for the first time, iron-alkenyl C-H metallation products. These species have been shown to be on-cycle and enabled divergent C-H functionalisation to be achieved for C-H borylation, 4,5 or hydrogen isotope exchange (HIE) reactions. 6 Alongside this, a novel activation method was revealed whereby the catalytically active iron dihydride was generated in the absence of a hydride source. 6 Using pinacolborane (HBpin), we were able to catalyse the C-H borylation reaction of carboarenes and heteroarenes with the largest functional group tolerance of any Earth-abundant metal catalysed C-H borylation reaction (including amines, alcohols, silanes, phosphonates, esters, and amides). Reactivity was demonstrated across 50 examples and orthogonal selectivity was observed to precious metal catalysed C-H borylation. Further fundamental studies gave insight into observed side reactivity. 4,5 Chemo- and regioselective HIE reactions were enabled by simply swapping HBpin for CD 3 OD. HIE exchange reactions of heteroarenes and, for the first time, alkenes, gave up to 97% “D” incorporation across 38 examples including complex natural products and pharmaceuticals (including caffeine, cimetidine, ketoconazole, and quinine). 6 Most significantly, mechanistic investigations led to the first and only example of an iron-alkenyl complex isolated and characterised in the solid-state. Additionally, we have identified a new mechanism for the formation of the catalytically active iron-dihydride using alcohols as the hydride source. The broad reactivity, mechanistic understanding, and operational simplicity of these catalytic protocols provides a platform for the wider adoption of sustainable, Earth-abundant metal catalysts. References 1. Seregin, I. V.; Gevorgyan, V., Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 2007, 36 , 1173-1193. 2. Díaz-Requejo, M. M.; Pérez, P. J., Coinage Metal Catalyzed C−H Bond Functionalization of Hydrocarbons. Chem. Rev. 2008, 108 , 3379-3394. 3. Egorova, K. S.; Ananikov, V. P., Which Metals are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts. Angew. Chem. Int. Ed. 2016, 55 , 12150-12162. 4. Britton, L .; Docherty, J. H.; Dominey, A. P.; Thomas, S. P., Iron-Catalysed C(sp 2 )-H Borylation Enabled by Carboxylate Activation. Molecules 2020, 25 , 905. 5. Britton, L .; Docherty, J. H.; Nichol, G. S.; Dominey, A. P.; Thomas, S. P., Iron-catalysed C(sp 2 )-H Borylation with Expanded Functional Group Tolerance. Chin. J. Chem . 2022 . 6. Britton, L .; Docherty, J. H.; Sklyaruk, J.; Cooney, J.; Nichol, G. S.; Dominey, A. P.; Thomas, S. P., Iron-catalysed Alkene and Heteroarene H/D Exchange by Reversible Protonation of Iron-hydride Intermediates. Chem. Sci. 2022, 13 , 10291-10298.

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Asymmetric synthesis of aromatic lipoxin A 4 analogues with biological evaluation Lucy Byrne , Olivia Bracken, Derek Gilroy and Patrick J. Guiry University College Dublin, Ireland email: lucy.byrne3@ucdconnect.ie, p.guiry@ucd.ie Lipoxins are a class of bioactive compounds which play a vital role in the process and resolution of inflammation in the human body. They were first isolated in human leukocytes by Serhan and Samuelsson in 1984. 1 Lipoxins are enzymatically derived from arachidonic acid by a family of lipoxygenase enzymes and regulate components of both the innate and the adaptive immune systems. Their primary role is to initiate the resolution of inflammation by activating the FPR2/ALX receptor. 2 Lipoxins’ ability to resolve inflammation is essential to the restoration of heathy immune function.

This work focuses on the synthesis of a library of LXA 4 analogues, specifically designed to overcome the rapid metabolic deactivation that arises in the natural Lipoxin mimetic. The series of molecules were designed through the molecular hybridisation of aromatic LXA 4 analogues and Resolvin (RvD1), another important endogenous mediator in the resolution of inflammation. 3 This work also explores the modification of the aromatic core of the RvD1-LXA 4 molecule to include imidazole/ triazole moieties, which are prevalent in many pharmaceutically relevant compounds. The asymmetric synthesis of these heteroaromatic-LXA 4 analogues will be presented, along with preliminary results of their biological evaluation.

Biological evaluation of these compounds was carried out in collaboration with Prof. Derek Gilroy of University College London and shows the success of these LXA 4 mimetics in the inhibition of key inflammatory cytokines. References 1. Serhan, C. N.; Hamberg, M.; Samuelsson, B. Proc. Natl. Acad. Sci. U. S. A. 1984 , 81 (17 I), 5335–5339. 2. O’Sullivan, T. P.; Vallin, K. S. A.; Shah, S. T. A.; Fakhry, J.; Maderna, P.; Scannell, M.; Sampaio, A. L. F.; Perretti, M.; Godson, C.; Guiry, P. J. J. Med. Chem. 2007 , 50 (24), 5894–5902. 3. Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.; Devchand, P. R.; Mirick, G.; Moussignac, R. L.. J. Exp. Med. 2002 , 196 (8), 1025–1037.

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The design and synthesis of inhibitors for the essential Leishmania bromodomain LdBDF5 Jennifer Carter 1 , Nathaniel Jones 2 , Catherine Russell 2 , Jeremy Mottram 2 , Anthony Wilkinson 2 , Jacob Bush 3 , Stuart Conway 1 1 University of Oxford, UK, 2 University of York, UK, 3 GlaxoSmithKline, UK

Leishmaniasis is a disease caused by the parasite Leishmania that is epidemic across Africa, Asia, and Latin America. 1 Leishmania have complex lifecycles, adopting a range of phenotypes to survive in multiple hosts. 2 Epigenetic processes link genotype to phenotypic diversity in a population and so must play a role in regulation of the Leishmania lifecycle. Bromodomain-containing proteins (BCPs) are epigenetic proteins which recognise acetylated lysine (KAc) residues in histones and regulate transcription. Therefore, it might be possible to develop Leishmania specific bromodomain inhibitors that impair epigenetic functions in the parasite. Ld BDF5 is a BCP that contains two bromodomains ( Ld BDF5.1 and Ld BDF5.2) and interprets histone acetylation marks in Leishmania to maintain normal levels of gene expression. 3 Inducible gene deletion has shown that Ld BDF5 is essential for parasite survival in its two main life stages; the promastigote and the amastigote. 3 The aim of this project is to design, synthesise, and evaluate high affinity bromodomain ligands that are selective for Ld BDF5 to help validate this protein as a therapeutic target to treat leishmaniasis. We adopted a fragment-based screening approach to identify ligands for Ld BDF5. A total of 32 KAc-mimicking fragments were synthesised and evaluated using biophysical assays. We identified 10 compounds that interact with Ld BDF5.1, but none binding to Ld BDF5.2. Compound 1 ( K d = 1410 nM, microscale thermophoresis) was selected to probe the SAR of Ld BDF5.1 (Figure 1). A concise synthetic route was developed to synthesise 35 analogues of 1 with modifications at two positions, R 1 and R 2 . The introduction of an aromatic ring at R 2 led to substantial increases in compound affinity. Addition of a 3-nitro or 3-nitrile group on the aromatic ring generated compounds 2 , 3 and 4 which show a >10-fold increase in affinity for LdBDF5.1We hypothesise that the nitro and nitrile groups on the benzene ring are forming H-bonds with T-99. A range of amines and water solubilising groups were introduced at R 1 . The combination of a morpholine ring at R 1 , and a 3-nitro benzene ring at R 2 gives compound 3 , with K d = 68 nM. Optimised compounds are being tested in parasite viability assays and demonstrate promising activity in the parasite, with compound 3 having EC 50 = 5.5µM in promastigotes. References 1. Alvar, J., Yactayo, S. and Bern, C., Leishmaniasis and poverty. Trends Parasitol 22 , 552-557 (2006) 2. Field, M., Horn, D., Fairlamb, A. et al. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat Rev Microbiol 15 , 217–231 (2017) 3. Jones, N.G., Geoghegan, V., Moore, G. et al. Bromodomain factor 5 is an essential regulator of transcription in Leishmania . Nat Commun 13 , 4071 (2022)

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The development of oxaziridine-based methionine spin-labels for EPR Siyao Chen, Gordon J. Florence and Bela E. Bode University of St Andrews, UK Methionine (Met) is a sulfur-containing proteinogenic amino acid playing various biophysical and biochemical functions. Due to its rare occurrence on the protein surface, Met has become a potentially greater protein modification target without modifying and compromising other surface-accessible amino acid residues. Therefore, the physiological function of modified proteins will not be interfered with. Recently, redox-activated chemical tagging (ReACT) has become the first method to modify Met residues specifically over other nucleophilic amino acids at physiological conditions ( Scheme 1 ). 1 A novel application of ReACT has been proposed in the Florence group: combining site-directed spin-label (SDSL) with Met-specific ReACT. Due to Met’s rareness on the protein surface, ReACT will only modify Met residues introduced by site-directed mutagenesis of proteins with a low risk of affecting the protein’s normal function. This offers potential advantages over the use of SDSL probes to modify cysteine (Cys) residues. This poster details synthetic access to a range of nitroxide radical-containing oxaziridine probes and assessment of their selectivity towards Met over Cys and other amino acid residues. Currently, pyrroline nitroxide radical oxaziridine has been found with a 100-fold selectivity on Met over Cys, and further chemical modifications will be carried out to improve the selectivity.

Scheme 1. Schematic presentation of methionine selective ReACT References 1. S. Lin, X. Yang, S. Jia, A. M. Weeks, M. Hornsby, P. S. Lee, R. V. Nichiporuk, A. T. Iavarone, J. A. Wells, F. D. Toste and C. J. Chang, Science , 2017, 355 , 597–602.

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New approaches in iridium catalysis for sp 3 hydrogen isotope exchange (HIE) of amino acids and peptides Megan Cuthbert 1 , Sumei Ren 2 , Neil Strotman 2 , David M. Lindsay 1 and William J. Kerr 1 * 1 University of Strathclyde, UK, 2 Department of Process Research & Development, Merck Research Laboratories (MRL),USA Hydrogen isotope exchange (HIE) has received considerable attention in recent years due to the requirement for isotopically labelled compounds for use in pharmaceutical ADMET assays and in the study of organic reaction mechanisms. 1 In particular, Lewis base-directed, iridium catalysed HIE is of particular importance in drug discovery, given the ability of this process for late-stage introduction of deuterium or tritium directly into drug candidates. Efficient, direct replacement of C-H bonds with deuterium and tritium in potential drug candidates are critical processes for the development of new drug candidates. The Kerr group has carried out extensive studies on iridium(I) pre-catalysts bearing bulky N-heterocyclic carbene (NHC) and phosphine ligands to facilitate directed labelling processes within aromatic systems (Scheme 1). 1,2 A range of directing groups (DG), such as amides, heterocycles, ketones and sulfonamides, could be successfully employed under mild conditions to selectively activate the ortho- position, yielding the desired labelled products in high isotopic incorporations. Although these highly effective catalysts have been developed for a range of sp 2 -hybridised systems, the directed HIE of sp 3 -hybridised C–H bonds still remains challenging. 2 With the pharmaceutical industry’s increased focus on drug candidates with increased sp 3 character, we sought to explore the HIE of biologically relevant amino acids and peptides.

Our group have recently demonstrated a successful labelling methodology for sp 3 -hybridised C–H bonds of α -amino acids, giving excellent isotopic incorporations. 3 We have since expanded this work to β-amino acids due to their increased resistance to proteolytic cleavage and improved pharmacokinetic profiles. This area remains underexplored and, therefore, a mild approach for the deuteration of β -amino acid motifs is highly desirable and could aid the successful development of novel peptide therapeutics. Through extensive screening of various iridium(I) pre-catalysts and conditions, we have achieved excellent deuterium incorporations across a range of protected β -amino acids under mild conditions (Scheme 2). By exploiting common amino acid protecting groups, selective labelling was attained via a proposed 5-membered metallocyclic intermediate, achievingup to 97% incorporation even at challenging tertiary centres.Additionally, we also labelled a selection of cyclic amino acid residues including the antifungal antibiotic cispentacin.Furthermore, the labelling process is stereoretentive, as confirmed by chiral HPLC studies.

Additionally, preliminary studies have demonstrated impressive incorporations in β-amino acid containing dipeptides (Scheme 3). High incorporationswere obtained for all examples even at tertiary centres within the peptides.Moreover, computational density functional theory (DFT) studies have been carried out alongside experimental investigations to rationalise our findings.

References 1. J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem., Int. Ed ., 2018, 57 , 1758–1784. 2. J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem., Int. Ed. , 2018, 57 , 3022–3047. 3. A. E. Queen, PhD Thesis , The University of Strathclyde, 2020.

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Short electrochemical asymmetric synthesis of (+)- N -acetylcolchinol Yi Du, Adelaide Lunga and Andrei V. Malkov Loughborough University, UK

A short synthesis of N -acetylcolchinol using a greener and step-economical pathway is reported where all the redox reactions, except for the asymmetric reduction, were carried out electrochemically, replacing protocols that employ transition metals or stoichiometric hazardous reagents. In a 4-step racemic sequence, chemoselective reduction of chalcone and intramolecular oxidative arene–arene coupling were performed in an electrochemical cell giving the target N -acetylcolchinol with an overall 41% yield. In a 7-step asymmetric variant, electrochemistry was also employed for the deprotection of p -methoxyphenyl amine. The target compound was obtained with a 33% overall yield and 99.5 : 0.5 er.

References 1. Y. DU, A. Lunga, A.E. Rubtsova and A.V. Malkov, Green Chemistry , 2022 , DOI: 10.1039/D2GC02321K.

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