48th Scottish Regional Organic Division Meeting University of St Andrews 9th January 2020

Sir William Henry Perkin Image reproduced with permission from RSC Library

48th RSC Scottish Organic Division Perkin Meeting Medical Sciences Building University of St Andrews The organisers acknowledge the valuable support from all our sponsors and exhibitors, who provide the backing to stage this conference.

We also acknowledge all the assistance from the Chemistry Office support staff in the organisation of this event.

For links to our sponsors, please visit chemistry.st-andrews.ac.uk/perkin

48th Scottish Regional Organic Division ‘Perkin’ Meeting University of St Andrews School of Chemistry

0930–1025 Welcome Coffee and Poster Hanging (School of Medicine Café)

1025–1030 Welcome and Opening Remarks (Booth Lecture Theatre)

1030–1240 Session 1 (Booth Lecture Theatre) Chair: Professor Andy Smith

1030–1055 BEING PERSISTENT: EXPLORING CHEMICAL GENOTYPES AND PHENOTYPES USING SYNTHETIC REPLICATORS Professor Doug Philp (University of St Andrews)

1055–1120 THE DEVELOPMENT OF DDD1305143; A PRECLINICAL CANDIDATE FOR THE TREATMENT OF VISCERAL LEISHMANIASIS Dr Michael Thomas (University of Dundee)

1120–1135 A UNIFIED BIOMIMETIC APPROACH TO THE BREVIANAMIDES Dr Robert Godfrey (University of Edinburgh)

1135–1200 DEVELOPMENT OF A MAIN GROUP C-H BOND-BREAKING TOOL: COMPLEMENTARY STRATEGY TO DIRECTED ORTHO-METALLATION Dr Charles O’Hara (University of Strathclyde)

1200–1225 MECHANISM OF THE DIRECT AMIDATION REACTION Dr Laurent Trembleau (University of Aberdeen)

1225–1240 BUCHWALD HARTWIG DIVERSIFICATION OF UNPROTECTED HALOTRYPTOPHANS, HALOTRYPTOPHAN CONTAINING TRIPEPTIDES AND THE NATURAL PRODUCT BARETTIN IN AQUEOUS CONDITIONS Dr Rosemary Lynch (University of St Andrews)

1240–1345 Lunch, Exhibition and Poster Session (School of Medicine Café and Seminar Room)

1345–1530 Session 2 (Booth Lecture Theatre) Chair: Professor Nick Westwood 1345–1410 1-SULFONYL-1,2,3-TRIAZOLES AS CARBENE PRECURSORS: H-INSERTION AND AZAHETEROCYCLE SYNTHESIS Dr Alistair Boyer (University of Glasgow)

1410–1425 NOVEL SOLID-PHASE APPROACH TO THE SYNTHESIS OF PEPTIDES AND SMALL MOLECULES CONTAININIG A PHOSPHOTYROSINE MOIETY Dr Nikolai Makukhin (University of Dundee)

Thursday 9th January 2020

1425–1450 MECHANISTIC INSIGHTS INTO SELECTIVE UV-INDUCED SELF-REPAIR OF DNA LESIONS Dr Rafal Szabla (University of Edinburgh)

1450–1505 RANKING SELECTIVITY IN IRIDIUM-CATALYSED HYDROGEN ISOTOPE EXCHANGE REACTIONS Dr Daria Timofeeva (University of Strathclyde)

1505–1530 LIGAND-BASED DESIGN OF SHORT PEPTIDE ANTAGONISTS OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) Dr Chris Coxon (Heriot-Watt University)

1530–1600 Coffee, Exhibition and Poster Session (School of Medicine Café and Seminar Room)

1600–1700 Session 3 (Booth Lecture Theatre) Chair: Professor David O’Hagan 1600–1605 PRESENTATION OF RSC ORGANIC STEREOCHEMISTRY AWARD Professor Alison Hulme (Past President, RSC Organic Division)

1605–1700 LATE STAGE FLUORINATION WITH METAL ALKALI FLUORIDE Professor Veronique Gouverneur FRS (University of Oxford)

1700–1705 Closing remarks and prizegiving (Booth Lecture Theatre)

1705–1800 Wine Reception (School of Medicine Café and Seminar Room)

1845–2100 Speakers’ Dinner (The Tail End Restaurant, St Andrews)

* Please note there are no scheduled fire alarms today.

Oral Presentations

Oral presentation (Academic) O1

BEING PERSISTENT: EXPLORING CHEMICAL GENOTYPES AND PHENOTYPES USING SYNTHETIC REPLICATORS

Jürgen Huck1, Tamara Kosilkova1,2, Baillie A. DeHaven2, Douglas Philp1,2,*

1. School of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom 2. Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston IL 60201, USA [email protected]

The emergence of collections of simple chemical entities that create self-sustaining reaction networks, embedding replication1 and catalysis, are cited as potential mechanisms for the appearance on the early Earth of systems that satisfy minimal definitions of life. In this presentation, we will examine a functional reaction network2 that creates and maintains a set of privileged replicator structures through auto- and cross-catalysed reaction cycles that is created from the pairwise combinations of four reagents. We will demonstrate that the addition of individual pre-formed templates to this network, representing instructions to synthesize a specific replicator, induces changes in the output composition of the system that represent a network-level response. We will examine the consequences of the catalytic connections that exist between the four replicators in this network and the system-level behaviour that they encode through sets of serial transfer experiments. This encoding imposes limits on the compositional variability that can be induced by repeated exposure of the network to instructional inputs in the form of preformed templates. The origin of this persistence is traced through kinetic simulations to the properties and inter-relationships between the critical ternary complexes formed by the auto- and crosscatalytic templates. These results demonstrate that in an environment where there is no continuous selection pressure, the network connectivity, described by the catalytic relationships and system-level interactions between the replicators, is persistent, thereby limiting the ability of this network to adapt and evolve.

References 1. T. Kosikova, D. Philp Chem. Soc. Rev. 2017, 46, 7274–7305. 2. J. Huck, T. Kosikova, D. Philp J. Am. Chem. Soc. 2019, 141, 13905–13913. Oral presentation (Academic) O2

THE DEVELOPMENT OF DDD1305143; A PRECLINICAL CANDIDATE FOR THE TREATMENT OF VISCERAL LEISHMANIASIS

Michael Thomas On behalf of the University of Dundee / GSK Kinetoplastid Collaboration Wellcome Centre for Anti-Infectives Research, Discovery Centre, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH [email protected]

Visceral leishmaniasis (VL) is a poverty associated parasitic infection responsible for around 50,000 deaths worldwide every year. Currently available treatments are hampered by issues such as toxicity, cost and route of administration. There is therefore an urgent need for new short course oral treatments. The Drug Discovery Unit, University of Dundee, and the GSK Kinetoplastid Discovery Performance Unit, Tres Cantos, formed a partnership to conduct drug discovery for kinetoplastid diseases with an initial focus on VL. Within this collaboration, a novel chemical series was identified with in vitro activity in an intra-cellular Leishmania assay. Early SAR exploration led to compounds with efficacy in a mouse model of VL, and a subsequent focus on scaffold hopping identified DDD1305143 as a preclinical candidate.1

References 1. A preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. Wyllie et al. PNAS, 2019 116 (19) 9318-9323. https://doi.org/10.1073/pnas.1820175116

Oral presentation (Postdoc) O3

A UNIFIED BIOMIMETIC APPROACH TO THE BREVIANAMIDES

Robert C. Godfrey, Nicholas J. Green, Gary S. Nichol, Andrew L. Lawrence* School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ [email protected], [email protected]

The brevianamides are a family of fungal-derived indole alkaloids.1-4 The archetypal member, brevianamide A,1 has been the subject of intense synthetic attention due to its complex polycyclic structure and enigmatic biosynthetic origins. However, despite five decades of research, no chemical synthesis has been reported. Based on the hypothesis that the related natural product dehydrodeoxybrevianamide E was a plausible biosynthetic precursor, we have achieved the first total synthesis of (+)-brevianamide A (7 steps, 8.0% overall yield, 750 mg scale).5 This biomimetic synthesis demonstrates the chemical feasibility of a revised biosynthetic hypothesis, wherein brevianamide A is formed alongside its diastereomer, brevianamide B, via a spontaneous, late-stage Diels–Alder reaction, without direct enzyme participation. Subsequent biosynthetic investigations by Williams, Sherman, Li and co- workers provide further evidence in support of the suggested non-enzyme mediated, biosynthetic Diels–Alder reaction.6 We are currently exploring whether dehydrodeoxybrevianamide E might be a common intermediate in a unified (bio)synthesis of the wider family of brevianamide alkaloids.

References

1. J. Birch, J. J. Wright, J. Chem. Soc. D, Chem. Commun., 1969, 664–645. 2. G. Y. Li, T. Yang, Y. G. Luo, X. Z. Chen, D. M. Fang, G. L. Zhang, Org. Lett., 2009, 11, 3714–3717. 3. F. Song, X. Liu, H. Guo, B. Ren, C. Chen, A. M. Piggot, K. Yu, H. Gao, Q. Wang, M. Liu, X. Liu, H. Dai, L. Zhang, R. J. Capon, Org. Lett., 2012, 14, 4770–4773. 4. X. Xu, X. Zhang, X. Nong, J. Wang, S. Qi, Mar. Drugs, 2017, 15, 43. 5. R. C. Godfrey, N. J. Green, G. S. Nichol, A. L. Lawrence, ChemRxiv, 2019, doi.org/10.26434/chemrxiv.8224148.v1. 6. Y. Ye, L. Du, X. Zhang,S. A. Newmister, W. Zhang, S. Mu, A. Minami, M. McCauley, J. V. Alegre- Requena, A. E. Fraley, M. L. Adrover-Castellano, N. Carney, V. V. Shende,H. Oikawa, H. Kato, S. Tsukamoto, R. S. Paton, R. M. Williams, D. H. Sherman, S. Li, ChemRxiv, 2019, doi.org/10.26434/chemrxiv.9122009.v1. Oral presentation (Academic) O4

DEVELOPMENT OF A MAIN GROUP C-H BOND-BREAKING TOOL: COMPLEMENTARY STRATEGY TO DIRECTED ORTHO-METALLATION

Antonio J. Martínez-Martínez, Sonia Bruña, Michael Fairley, Charles T. O’Hara* Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL [email protected]

The most widely employed metallation strategy in synthesis is Directed ortho-Metallation (DoM), which generally employs an alkylithium or lithium amide reagent to affect the deprotonation. The first example of DoM was reported as long ago as 1938/9,1,2 and this discovery propelled organometallic compounds from being ‘exotic rarities to indispensable tools in modern synthesis’.3 While there have been several reports of metallation at more remote sites, in general these reactions operate in a similar fashion to DoM, namely that the position of metalation is controlled by the substituent attached to the aromatic ring. In our template approach, we replace the lithium metallator with a macrocyclic sodium magnesiate n reagent [Na4Mg2(TMP)6 Bu2] 1 (TMP = 2,2,6,6-tetramethylpiperidide). This reagent can be prepared in a facile manner. It functions as a regioselective base and it is primarily the positions of the metal centres within the template ring that control the positional metallation reactions. In this presentation, our recent results using 1 to perform regioselective metallations of several simple commercially available arenes will be discussed, culminating in Directed ortho–metaʹ- and meta–metaʹ-dimetallations.4 We have also shown that polyarenes can be metallated and after electrophilically quenching with iodine it is possible to generate hitherto unknown iodoarenes (figure), which have potential for use in materials and pharmaceutical applications.5 Finally, recent unpublished work which details a dual metallation/metal-halogen exchange protocol will be discussed, culminating in the facile synthesis of meta-substituted arenes.

I I

I I I I

I I I I I

I I I I I

I I I I References 1. H. Gilman, R. L. Bebb, J. Am. Chem. Soc. 1939, 61, 109-112. 2. G. Wittig, U. Pockels, H. Droge, Ber. Deutsch. Chem. Gesel. 1938, 71, 1903-1912. 3. M. Schlosser, Organometallics in Synthesis Third Manual. (Ed. M. Schlosser), John Wiley & Sons, Inc., Hoboken, New Jersey, 2013. 4. A. J. Martínez-Martínez, A. R. Kennedy, R. E. Mulvey, C. T. O’Hara, Science, 2014, 346, 834-837. 5. A. J. Martínez-Martínez, S. Justice, B. J. Fleming, A. R. Kennedy, I. D. H. Oswald, C. T. O’Hara, Science Adv., 2017, e1700832. Oral presentation (Academic) O5

MECHANISM OF THE DIRECT AMIDATION REACTION

Laurent Trembleau Laboratory of Supramolecular Chemistry, Chemistry Department, University of Aberdeen, Meston Walk, Aberdeen, AB24 3UE [email protected]

Amides are ubiquitous in Nature. They are the key functional groups of proteins, are present in many important pharmaceuticals (e.g. paracetamol, penicillins), and have been at the origin of the discovery of several ground-breaking polymeric materials (e.g. nylon, Kevlar). Although the formation of amides is a straightforward reaction using conventional coupling reagents, it typically produces one equivalent of unwanted by-product (leaving group)1. In order to design potential organocatalysts for this simple reaction, we decided to elucidate the mechanism of amide-bond formation for the direct reaction of a carboxylic acid with an amine, producing the desired amide, and water as only by-product.

In this oral presentation, I will describe the kinetic studies performed for the direct amide-bond formation (lactamization) of 2-aminophenylacetic acid, a simplified system chosen for its solubility in various organic solvents. The kinetics data, along with DFT calculations, validate a mechanism by which the hydrogen- bonded carboxylic acid dimer2 is a key activated intermediate of the reaction in organic solvents.3 The present work represents a significant step towards the development of organocatalysts for the formation of amides in an economical and environmentally-friendly way.

References 1. a) H. Lundberg, F. Tinnis, N. Selander, H. Adolfsson, Chem. Soc. Rev., 2014, 43, 2714-2742; b) R. M. Lanigan, T. D. Sheppard, Eur. J. Org. Chem., 2013, 33, 7453-7465. 2. H. Charville, D. A. Jackson, G. Hodges, A. Whiting, M. R. Wilson, Eur. J. Org. Chem., 2011, 30, 5981–5990.

Oral presentation (Postdoc) O6

BUCHWALD HARTWIG DIVERSIFICATION OF UNPROTECTED HALOTRYPTOPHANS, HALOTRYPTOPHAN CONTAINING TRIPEPTIDES AND THE NATURAL PRODUCT BARETTIN IN AQUEOUS CONDITIONS

R. Lynch, Y. Renault, S.V. Sharma, P. Cárdenas, R.J.M. Goss School of Chemistry, University of St Andrews, St Andrews, KY16 9ST [email protected], [email protected]

Blending synthetic chemistry and biology provides a powerful tool to development of natural product analogues. To further enable this, compatible synthetic tools are needed. Tryptophan is an essential amino acid, abundant within peptides and proteins, and central to their fluorescence, folding and structure.1 Although there has been significant research exploring the cross-coupling chemistry of nucleosides and the aromatic amino acid phenylalanine, both in their free state or as components of larger systems, the cross-coupling of halotryptophan has seemingly received little attention. Methodology now exists for the modification of halotryptophans, by Sonogashira2 and Suzuki- Miyaura3,4 but, to the best of our knowledge, the utilisation of Buchwald Hartwig amination (BHA) of halotryptophans and their derivatives was not explored.

We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans in aqueous systems and demonstrate this methodology applicable to the modification of unprotected halotryptophans, tripeptides and the natural product barettin.5 The general applicability of our protocols to unprotected substrates, densely packed with a variety of functional groups, is pioneering and opens new perspectives in late-stage modification of complex natural products.

References 1. G.D. Rose, A.R. Geselowitz, G.J. Lesser, R.H. Lee, M.H. Zehfus, Science, 1985, 229, 834-838; (b) D.A. Dougherty, Science, 1996, 271, 163-168. 2. M.J. Corr, S.V. Sharma, C. Pubill-Ulldemolins, R.T. Bown, P. Poirot, D.R.M. Smith, C. Cartmell, A. Abou Fayadc and R.J.M. Goss, Chem. Sci., 2017, 8, 2039-2046. 3. A. Deb Roy, R.J.M. Goss, G.K. Wagner and M. Winn, Chem. Commun., 2008, 4831– 4833. 4. (a) A. Deb Roy, S. Grüschow, N. Cairns and R.J.M. Goss, J. Am. Chem. Soc., 2010, 132, 12243–12245; (b) S.V. Sharma, X. Tong, C. Pubill-Ulldemolins, C. Cartmell, E.J.A. Bogosyan, E.J. Rackham, E. Marelli, R.B. Hamed and R.J.M. Goss, Nat. Commun., 2017, 8, 229-238. 5. Y.J.G. Renault, R. Lynch, E. Marelli, S.V. Sharma, C. Pubill-Ulldemolins, J.A. Sharp, C. Cartmell, P. Cárdenas, R.J.M. Goss, Chem. Commun., 2019, 55, 13653-13656. Oral presentation (Academic) O7

1-SULFONYL-1,2,3-TRIAZOLES AS CARBENE PRECURSORS: H-INSERTION AND AZAHETEROCYCLE SYNTHESIS

Alistair Boyer

School of Chemistry, University of Glasgow, Glasgow, G12 8QQ [email protected]

1,2,3-Triazoles are well-established as highly valuable, both as being valuable motifs in themselves, and as a robust method of uniting molecular fragments with 100% atom economy. Generally, 1,2,3-triazoles are very stable despite their high nitrogen content. However, the introduction of an electron-withdrawing N-substituent in 1-sulfonyl-1,2,3- triazoles (1-STs) allows access to Dimroth equilibration and, in the presence of a rhodium(II) carboxylate catalyst, 1-STs can lose nitrogen gas to form the corresponding carbenes. Over recent years, this strategy has been exploited in the design of a vast array of valuable reactions, forming value-added products from simple building blocks.[1] 1-STs are generally synthesised under copper catalysis (CuAAC to give 4-substituted products) or anionic conditions (5-substituted products). We have explored strain[2] and electronic[3] activation in the context of 1-ST synthesis and developed reactions using the resulting products (Scheme 1).

Upon treatment with a Rh(II) catalyst, the cyclooctyne-derived 1-STs undergo denitrogenation and then rapid intramolecular C–H insertion to form [3.3.0]-bicyclic products (Scheme 2).[4] 5-Allyl-1-aza-1STs underwent a complex series of reactions, starting with a Rh(II) carboxylate-promoted 1,2-hydrogen shift to form highly substituted nitrogen heterocycles with high selectivity.

References [1] a) Reviews: H. M. L. Davies, J. S. Alford, Chem. Soc. Rev. 2014, 43, 5151; b) P. Anbarasan, D. Yadagiri, S. Rajasekar, Synthesis 2014, 46, 3004; [2] a) D. H. Ess, G. O. Jones, K. N. Houk, Org. Lett. 2008, 10, 1633; b) F. Schoenebeck, D. H. Ess, G. O. Jones, K. N. Houk, J. Am. Chem. Soc. 2009, 131, 8121; [3] a) R. E. Harmon, F. Stanley, S. K. Gupta, J. Johnson, J. Org. Chem.1970, 35, 3444; b) N. Selander, V. V. Fokin, J. Am. Chem. Soc. 2012, 134, 2477; [4] A. Mordini, F. Russo, M. Valacchi, L. Zani, A. Degl'Innocenti, G. Reginato, Tetrahedron 2002, 58, 7153. Oral presentation (Postdoc) O8

NOVEL SOLID-PHASE APPROACH TO THE SYNTHESIS OF PEPTIDES AND SMALL MOLECULES CONTAININIG A PHOSPHOTYROSINE MOIETY

Nikolai Makukhin, Sarath Ramachandran, Alessio Ciulli* School of Life Sciences, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH [email protected]

Recently we have reported the first co-crystal structures of the E3 ubiquitin ligase complex SOCS2-ElonginB-ElonginC with bound phosphorylated epitope peptides from its physiological substrates erythropoietin receptor (EpoR) and growth hormone receptor (GHR)1. SOCS2, as a SH2-domain protein, binds to phosphotyrosine-modified peptides accommodating them in an extended conformation to capture specific interactions. This work gives a blueprint for a structure-based rational design of SOCS2 small-molecule binders. These binders can be used as SOCS2 inhibitors, and also provide new E3 ligase ligands for the synthesis of proteolysis targeting chimeras (PROTACs) to hijack SOCS2 ubiquitination activity as a strategy to induce the degradation of a desired protein of interest. To rapidly generate phosphotyrosine analogues, we have developed a novel solid-phase synthesis that involves the attachment of tyrosine phosphoramidite to Wang resin followed by oxidation with TBHP. Using the orthogonal protecting groups allows specific modifications of C or N-terminus of phosphotyrosine and makes the approach convenient in both split-mix and parallel synthesis. This strategy provides the advantages of facile isolation of final products as well as a high-throughput generation of large libraries in short period of time. It can also be expanded to the synthesis of peptides. Combining the developed approach and structure-based drug design, the first nanomolar SOCS2 binding ligand has been obtained.

References 1. W.-W. Kung, S. Ramachandran, N. Makukhin, E. Bruno, A. Ciulli. Nat. Commun. 2019, 10, 2534.

Oral presentation (Academic) O9

MECHANISTIC INSIGHTS INTO SELECTIVE UV-INDUCED SELF-REPAIR OF DNA LESIONS

Rafal Szabla

EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK. [email protected]

Cyclobutane pyrimidine dimers (CpDs) are considered as the most common DNA lesions arising during the exposure of the biopolymer to UV light. While these lesions can be repaired in living organisms by e.g. photolyases, such sophisticated repairing factors were absent on Archean Earth. Recent experimental findings suggested that specific DNA sequences exhibit fascinating self-repairing capabilities, which could efficiently protect them from the detrimental effects of pyrimidine dimerization.1 Nevertheless, the exact molecular mechanism of this process remained obscure until recently, owing to considerable challenges associated with synthesis of selectively damaged sequences. In this talk, I will describe the mechanistic details of the self-repair process determined by means of MD simulations and highly accurate quantum-chemical calculations involving the algebraic diagrammatic construction to the second order method, ADC(2).2 In particular, our results demonstrate that the UV-induced self- repair of the GAT=T sequence is triggered by sequential electron transfer operating downhill along the slope of the potential energy surface in the lowest excited singlet state. Assessment of the efficiency and availability of this process in other DNA sequences containing native and alternative nucleobases could enable us to identify the most UV-resistant oligomers which could survive in the harsh environment of early Earth.

References 1. D. B Bucher, C. L. Kufner, A. Schlueter, T. Carell, W. Zinth, J. Am. Chem. Soc. 2016, 138, 186–190. 2. R. Szabla, H. Kruse, P. Stadlbauer, J. Sponer, A.L. Sobolewski, Chem. Sci. 2018, 9, 3131–3140. Oral presentation (Postdoc) O10

RANKING SELECTIVITY IN IRIDIUM-CATALYSED HYDROGEN ISOTOPE EXCHANGE REACTIONS

Daria S. Timofeeva, David M. Lindsay, David J. Nelson*, William J. Kerr* Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK G1 1XL [email protected] / [email protected] / [email protected]

Hydrogen isotope exchange (HIE) is important in drug development and in studies of reaction mechanisms. Iridium chlorocarbene complex Ir-1 and NHC/phosphene complex Ir-2 developed by the Kerr group have proved to be highly effective and selective catalysts in HIE reactions for a broad range of substrate.1 In these reactions, the metal catalyst is directed to a specific C-H bond by a directing group (DG) that coordinates to the iridium centre. Recently the Nelson group has ranked the ‘strength’ of directing groups in ruthenium-catalysed C-H arylation reactions.2 Now we use similar methodology to understand reactivity and selectivity in iridium-catalysed HIE.

We have conducted competition reactions between the substrates bearing different DGs, with

<1 equivalent of D2. For each pair of the substrates, time-independent competition constants κ (eq 1) using both catalysts were quantified. These values formally relate to the relative rates of the reactions of two substrates (eq 2). Linear regression using data from a series of the competition HIE reactions provided relative rate constants krel for each substrate. The resulting directing group power scale can serve to predict the regioselectivity in molecules with multiple competing directing groups, which was proved by intramolecular competition studies.

References 1. a) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson, G. N. Nilsson, Chem. Commun., 2008, 1115-1117. b) A. R. Cochrane, S. Irvine, W. J. Kerr, M. Reid, S. Andersson, G. N. Nilsson, J. Label Compd. Radiopharm., 2013, 56, 451-454. c) W. J. Kerr, G. J. Knox, L. C. Paterson, doi: 10.1002/jlcr.3812. 2. J. McIntyre, I. Mayoral-Soler, P. Salvador, A. Poater, D. J. Nelson, Cat. Sci. Technol., 2018, 8, 3174-3182.

Oral presentation (Academic) O11

LIGAND-BASED DESIGN OF SHORT PEPTIDE ANTAGONISTS OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP)

Christian Steuer, Patrick M. Killoran, Talhat Chaudhry, G. Hutcheon, David A. Kendall and Christopher R. Coxon*

Institute of Chemical Sciences, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS

Migraine is a neurological disorder that presents as a crippling headache often accompanied by nausea, vomiting, photophobia or phonophobia; commonly associated with altered sensory perceptions and can last from 4 to 72 hours in adults.1 It is estimated that 11% of the world’s population suffers from migraine, and over a lifetime 43% of women and 18% of men will experience a migraine.2 The World Health Organisation (WHO) has ranked frequent migraine as a severe disability; in the same category as dementia, quadriplegia and active psychosis.3 Currently, the mainstay of migraine management is the triptan family of serotonin 5-HT1B and 5-HT1D receptor agonists e.g., sumatriptan. However, moderate clinical effectiveness (around 60% of patients benefit) coupled with possible cardiovascular side effects and contraindications, has prompted further recent research into new modalities and pharmacological targets for migraine intervention.

1. Ligand-based design 2. Antagonist synthesis 3. Biological evaluation

Calcitonin gene related peptide (1-37) Calcitonin gene related peptide (1-37)

Hairpin mimetics Hairpin mimetics

Helix mimetics Helix mimetics Truncation Truncation

Activity Affinity I Affinity II Activity Affinity I Affinity II Hairpin-like Helix Hairpin-like Hairpin-like Helix Hairpin-like

The 37 amino acid neuropeptide, calcitonin gene-related peptide (CGRP) is known to play an important role in the pathology of migraine.4 The observation that antagonism of the CGRP-receptor interaction relieves symptoms led to clinical trials of selective antagonists. Structurally, CGRP has 3 main important regions; an amidated C-terminal hairpin-like region, an α-helix linker region and a hairpin-like N-terminus. Removal of the N-terminal activity site afforded a competitive antagonist and, therefore, the affinity site II has generally been the target for CGRP drug developments thus far.5 This presentation will discuss our development of modified, truncated CGRP 27-37 analogues that have shown potent antagonist activity, in vivo efficacy and tolerability in animal trials; as well as second generation antagonists designed using a ligand-based approach through preparing stapled helical analogues of the midsection of CGRP. These represent a new modality for the possible treatment of migraine. This work has revealed the importance of secondary structure stability for achieving mimicry and antagonism of the natural peptide.

References 1. P.J. Goadsby, U. Reuter, Y. Hallström, G. Broessner, J.H. Bonner, F. Zhang, S. Sapra, H. Picard, D.D. Mikol, R.A. Lenz, N. Engl. J. Med., 2017, 377, 1698–1699. 2. P. Irimia, E. Cittadini, K. Paemeleire, A. Cohen and P. Goadsby, Cephalalgia, 2008, 28, 626–630. 3. T.B. Ustün, J. Rehm, S. Chatterji, S. Saxena, R. Trotter, R. Room, J. Bickenbach, Lancet, 1999, 354, 111–5. 4. S.G. Amara, V. Jonas, M.G. Rosenfeld, E.S. Ong and R.M. Evans, Nature, 1982, 298, 240–244. 5. A.F. Russo, Annu. Rev. Pharmacol. Toxicol., 2015, 55, 533–552.

2019 Organic Stereochemistry Award Winner

Professor Véronique Gouverneur University of Oxford

Awarded for creative work in stereoselective fluorine chemistry and asymmetric catalytic fluorination with metal alkali fluorides.

About the Winner Véronique Gouverneur secured a PhD in chemistry at the Université Catholique de Louvain (LLN, Belgium), under the supervision of Professor L Ghosez. In 1992, she moved to a postdoctoral position with Professor R Lerner at the Scripps Research Institute (California, USA). From 1994 until 1998, she was Maître de Conférence at the University Louis Pasteur in Strasbourg (France). She worked with Dr C Mioskowski and was Associate Member of the ISIS Institute directed by Professor J-M Lehn during this period. Véronique started her independent academic career at the University of Oxford in 1998 in the Chemistry Faculty and was promoted to Professor of Chemistry in 2008. Since her appointment in Oxford, she holds a tutorial fellowship at Merton College Oxford where she teaches organic chemistry. Her research aims at developing new approaches to address long-standing problems in the synthesis of fluorinated molecules including pharmaceutical drugs and probes for imaging (Positron Emission Tomography). This work reported in >200 peer-reviewed publications and patents has been rewarded by numerous distinctions, more recently the ACS Award for Creative work in Fluorine Chemistry 2015, the RSC Tilden Prize 2016, the Tetrahedron Chair 2016, and the Prelog Medal 2019. She is currently coordinating the European ITN project FLUDD (H2020-MSCA-ITN-2016), and holder of an ERC Advanced Grant (2019-2023). She is also serving as the Chair of the journal Chemical Communications published by the Royal Society of Chemistry.

Text from: rsc.org/ScienceAndTechnology/Awards/OrganicStereochemistryAward/2019-Winner.asp Plenary Lecture O12

LATE STAGE FLUORINATION WITH METAL ALKALI FLUORIDE

Véronique GOUVERNEUR

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road OX1 3TA Oxford (UK) [email protected]

The invention of chemical reactions to create fluorine-containing molecules is an important aspect of modern medicine. Positron Emission Tomography (PET) with short-lived 18F- radiotracers is an imaging modality that can diagnose diseases, and monitor how patients respond to therapy. Moreover, the stable isotope 19F is commonly used in drug discovery to identify lead molecules and improve their properties. In this lecture, we will provide an overview of the key reactions we have developed to advance fluorine-based medicine, a rewarding process that has enhanced our fundamental understanding of fluorine chemistry, more specifically fluoride reactivity.

Poster Presentations

P1 Kevin Miranda Toward the Discovery of New Antimicrobial Agents from Underexplored Marine-Derived Fungi in Egypt

P2 Stephen Patterson Use of Chemical Proteomics to identify the MOLECULAR target of AN ANti-leishmanial preclinical candidate

P3 Assel Baibek FluorescEnt FUNGAL probes: multiplexed imaging of microorganisms

P4 Arwa Alqahtani Total Synthesis of Complex Polycyclic Natural Products Using a Novel Cascade Reaction Selective Au(I)-Catalysed Hydroarylation of Alkynes: Towards the FAcile synthesis of 3,3’-unsymmetrical Euan McLean P5 BisindolylALKANES P6 Marta Diez-Castellnou An Organic chemistry toolkit for nanoparticle-bound surface monolayers

P7 Jennifer Clark Design, synthesis and evaluation of novel autotaxin inhibitors

P8 Emmanuel Oluwabusola New bromotyrosine metabolites from a Fijian Sponge Aplysinella rhax

P9 Adam Bond Stereoselective synthesis of bumped BET inhibitors

P10 Dan Baillache Development of Kinase Inhibitors for the Treatment of Glioblastoma

P11 Holly McErlain Synthesis of Novel PET Imaging Agents for PARP-1 Based on Olaparib-Derived Inhibitors

P12 David Morgan Development of Small Molecule EPAC1 and EPAC2 Activity Regulators

P13 David Cain Total Synthesis of Aspidosperma Alkaloids Utilizing a Cascade Suzuki–Miyaura/Diels–Alder Reaction

P14 Alasdair Cooper Understanding & Exploiting Selectivity in Nickel-Catalysed Cross Coupling

P15 Daniel Edwards Repurposing protein nanopores as artificial transmembrane enzymes Structural-Activity Relationship of PfCLK3 inhibitor GSK-TCMDC151: Towards the development of a new Kopano Mapesa P16 class of antimalarial P17 Shen Qu Isothiourea-catalysed Acylative Kinetic Resolution of Acyclic Tertiary Alcohols

P18 Emma Campbell Splice-switching small molecules as inducers of apoptosis

P19 Jake Stuart Synthetic Investigations into the Biogenesis of Dievodiamine

P20 Jessica Elwood Centrosymmetric Approach Towards the Synthesis of Fused Polycyclic Ether Natural Products

P21 Charles Ropert-Portejoie Resistance to thyroid hormone αlpha: an emerging genetic disease OF TRα

P22 Ane Valera Adaptation of Enzymes in the Valine Pathway for the Production of Methacrylate Intermediates

P23 Kieran Nicholson Transborylation for asymmetric catalysis Synthesis and Reactivity of 1-Sulfonyl-1,2,3-triazoles: Formation of 6-Membered Nitrogen-Containing Matthew Martin P24 Heterocycles Continuous-Flow Synthesis and Application of Polymer-Supported BODIPY Photosensitisers for the Christopher Thomson P25 Generation of Singlet Oxygen; Process Optimised by In-Line NMR Spectroscopy P26 Ganyuan Xiao Two ways of transforming γ-oxidized lignin via NHC and Cu catalysis

P27 Christopher Rennie Regioselective synthesis of C4h and D2h phthalocyanines

P28 Oluwatofunmilayo Diyaolu Egyptian Fungal Antibiotic Metabolites – from Pharaohs To Modern Textiles

P29 Silvia De Cesare Biocatalytic routes to enantiopure amino acids

P30 Sarah Memarzadeh Small-molecule induced protein degradation for the prevention of metastasis

P31 Jeff Wong Lithiation-substitution of alkyl-1,3,4-oxadiazoles and benzyltetrazoles in batch and flow conditions

P32 Rodrigo R. F. A. Gouy Target Elucidation of Novel Trypanosomatids Inhibitors

P33 Liam Wilson A New class of small molecule intracellular pH sensors for Raman Microscopy

P34 Yael Ben-Tal Shedding light on the mechanism of photoredox cross-electrophile coupling by in-situ illumination NMR

P35 Selma Crecente Garcia β-turn mimics based on ligation chemistry

P36 Xuan Feng Two new fluorometabolites from Streptomyces calvus

P37 Nathan Knight Iridium(i) catalysis for sp3 hydrogen isotope exchange via amide directing groups Poster presentation P1

TOWARD THE DISCOVERY OF NEW ANTIMICROBIAL AGENTS FROM UNDEREXPLORED MARINE-DERIVED FUNGI IN EGYPT

Ahmed A. Hamed1,2 , Sylvia Soldatou2 , M. Mallique Qader3 , Coralie Pavesi2 , Kevin J. Miranda2, Nabil A. Ibrahim4 , Mohamed S. Abdelaziz1 , Basma Eid4 , Mosaad A. Ghareeb5, Mostafa E. Rateb3 and Rainer Ebel*1 1 Microbial Chemistry Department, National Research Centre, 33 El-Buhouth Street, P.O. Box 12622, Dokki, Giza, Egypt. 2 Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK. 3 School of Computing, Engineering & Physical Sciences, University of the West of Scotland, Paisley PA1 2BE, UK. 4 Textile Research Division, National Research Centre, Scopus Affiliation ID 60014618, 33 EL Buhouth St., Dokki, Giza, P.O. 12622, Egypt. 5 Medicinal Chemistry Department, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza 12411, Egypt. [email protected] Historically, natural products have been used for the treatment of many diseases since ancient times. One of the earliest records of medicinal use of natural products dating back to the ancient Egyptian civilization (pharaohs). As an Egyptian pharmaceutical record, the ancient Egyptian medical Ebers Papyrus (2900 B.C.), in which over 700 plant-based drugs were recorded for the treatment of many diseases. In our days, great attention has been given to endophytic fungi due to the chemical diversity of their secondary metabolites. Therefore, this study was undertaken to isolate and identify endophytic and associated fungi from plant and marine organisms collected from two locations in Egypt, Hurghada and Inland saline lakes of Wadi El Natrun1. As a result, 51 pure fungal strains were isolated, cultivated on different media and their extracts were screened biologically as antimicrobial against some pathogenic microorganism and as antioxidant activity using DPPH2. Based on the bioassay data, 15 isolates exhibited interesting antimicrobial and antioxidant activity. Morphological and genetic studies of the selected isolates have shown that they belong to six genera (Aspergillus, Epicoccum, Penicillium, Cladosporium, Paecilomyces, Alternaria). Based on chemical screening and dereliction by analysis of the LC-MS/MS and H-NMR data, the extracts with promising chemical profile were purified using different chromatographic techniques and pure compounds were evaluated as antimicrobial, antibiofilm against some clinical pathogens. Our main target is to use these bioactive compounds to functionalize the textile to improve comfort, performance and protection.

References 1. A. Hamed, M. Abdel-Aziz, Bull. Natl. Res. Cent., 2018,42, 22. 2. A. I. Prihantini, S. Tachibana, Asian Pac. J. Trop. Biomed., 2017, 7, 110-115.

Poster presentation P2

USE OF CHEMICAL PROTEOMICS TO IDENTIFY THE MOLECULAR TARGET OF AN ANTI-LEISHMANIAL PRECLINICAL CANDIDATE

S. Patterson, M. Thomas, M. De Rycker, M.D. Urbaniak, S. Ghidelli-Disse, A.H. Fairlamb, I.H. Gilbert* and S. Wyllie*

Mode of Action Group, Division of Biological Chemistry & Drug Discovery, Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, DD1 5EH [email protected]

Visceral leishmaniasis (VL), resulting from infection with Leishmania donovani and L. infantum, causes 20,000-40,000 deaths annually. There is an urgent need for new, effective treatments for VL.1 However, the development of new VL therapies is hindered by the paucity of validated drug targets in Leishmania spp.2 The anti-leishmanial pyrazolopyrimidine 1 (DDD00853651, GSK3186899) was developed from a phenotypic screening hit against L. donovani. Compound 1 is efficacious in a mouse model of VL and has been declared a preclinical candidate.3

Determining the mode of action (MoA) and/or molecular targets of new chemical series can greatly benefit drug discovery projects.4 Here, a number of complementary methodologies, including chemical proteomics, were used to investigate the MoA of 1. The pyrazolopyrimidine structure-activity relationship from the medicinal chemistry programme3 was used to inform the design of four analogues containing a PEG linker. Subsequent synthesis and assay of these analogues demonstrated that they retained in vitro anti-leishmanial activity. One of these analogues was covalently bound to a resin to give 2. This resin-bound analogue was then used to pull-down specific proteins from L. donovani whole-cell lysates. Leishmania proteins specifically binding to the resin were identified using MS-enabled quantitative proteomics. Several kinases were found to specifically bind to 2, including the cdc-2-related kinase 12 (CRK12). Additional chemical proteomics and biological studies confirmed that the pyrazolopyrimidines act principally by inhibiting L. donovani CRK12. The inhibition of CRK12 is a novel anti-leishmanial MoA, and so these studies have identified CRK12 as a new chemically validated drug target for VL.

References 1. S.L. Croft, S. Sundar & A.H. Fairlamb Clin. Microbiol. Rev. 2006, 19, 111-126. 2. I.H. Gilbert J. Med. Chem. 2013, 56, 7719-7726. 3. M.G. Thomas, M. De Rycker, M. Ajakane, S. Albrecht et al J. Med. Chem. 2019, 62, 1180-1202. 4. G.C. Terstappen, C. Schlüpen, R. Raggiaschi & G. Gaviraghi Nat. Rev. Drug Disc., 2007, 6, 891–903. 5. S. Wyllie, M. Thomas, S. Patterson, S. Crouch et al Nature, 2018, 560, 192–197. Poster presentation P3

FLUORESCENT FUNGAL PROBES: MULTIPLEXED IMAGING OF MICROORGANISMS

A. Baibek,a M. Ucuncu,a B. Short,b G. Ramage,b A. Lilienkampf,a M. Bradleya*

a) EaStCHEM School of Chemistry, Joseph Black Building, University of Edinburgh, EH9 3FJ Edinburgh, UK [email protected]

b) Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G2 3JZ, UK

The current, culture-based detection methods for microorganisms are inherently slow, preventing accurate point-of-care diagnostics and treatment, which is crucial for patients in intensive care as well as those in a rural setting in developing countries. As an alternative, “optical molecular imaging”, using target specific fluorescent probes, can be used for rapid diagnosis of infection,1 ideally allowing the identification of the species.

Here, clinically used antifungal polyene Amphotericin B (AmB) was used as a fungi selective targeting moiety, with various fluorophores (e.g. environmentally sensitive dyes) conjugated to both the amino group of the mycosamine and carboxylic acid site of the aglycon moiety. Far-red emitting probes, with Cy5 conjugated to the carboxylic acid site of AmB, showed efficient labelling of different clinical strains of fungi, including AmB-tolerant strain of Candida auris. Furthermore, the probes showed the labelling of fungal biofilms, where penetration of external molecules is challenged by extracellular matrix.2 Finally, after confirming that the probes showed selective labelling of fungi in the presence of bacteria, Cy5 conjugated AmB probe was used together with specific Gram-positive and Gram-negative1 bacteria probes and used for multiplexed imaging and identification of different microorganisms in a complex mixture.

References 1. A.R. Akram, M. Bradley, K. Dhaliwal, Sci. Transl. Med., 2018, 10 (464). 2. L. Sherryl, G. Ramage, R. Kean, A. Borman, E.M. Johnson, M.D. Richardson, R.R. Richardson, Emerg. Infect. Dis., 2017, 23(2), 328–331.

Poster presentation P4

TOTAL SYNTHESIS OF COMPLEX POLYCYCLIC NATURAL PRODUCTS USING A NOVEL CASCADE REACTION

Arwa Alqahtani

University of Glasgow, School of Chemistry, Joseph Black Building Glasgow G12 8QQ, Email: [email protected].

The guaianolide natural product morrocolide A is a member of a broad family of sesquiterpene natural products (Figure 1). The guaianolides contain a challenging 5,7,5- fused tricyclic system and considerable attention has been given to the development of efficient synthetic routes to members of this family of natural products. With these targets in mind, a synthetic strategy has been developed by the Clark group that enables formation of 5,7,5-fused tricyclic systems. This poster details the strategy and progress toward testing the effectiveness of the strategy on a model system. To date a model vinylcyclopropane has been synthesised from 6-hexyn-1-ol in seven steps and in 15–17% overall yield (Scheme 1). 6-Hexyn-1-ol was converted into an ynenone and subsequent treatment with a Brønsted acid resulted in cyclisation to form the furan and the pendant bicyclo[3.1.0]hexane system in one pot and in reasonable yield. The precursor required for the key Cope rearrangement was obtained by conversion the side chain on the bicyclo[3.1.0]hexane into a vinyl substituent.

Figure 1

Scheme 1

Following construction of the model system, the synthesis of morrocolide A will commence with conversion of a carbohydrate into a substituted oxetane, which will serve as our starting material for the real system (Scheme 2).

Scheme 2

References 1. F. Hilmi, O. Sticher, J. Heilmann, J. Nat. Prod. 2002, 65, 523–526. 2. V. Klaus, S. Wittmann, H. M. Senn, J. S. Clark, Org. Biomol. Chem. 2018, 16, 3970–3982. 3. S. Lucas, H. Iding, A. Alker, H. Wessel, J. Carbohydr. Chem. 2006, 25, 187–196. Poster presentation P5

SELECTIVE AU(I)-CATALYSED HYDROARYLATION OF ALKYNES: TOWARDS THE FACILE SYNTHESIS OF 3,3’-UNSYMMETRICAL BISINDOLYLALKANES

E. B. McLeana, F. Cutoloa, D. J. Burnsb and A.-L. Lee*a. aInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS bSyngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK. [email protected]

The indole ring system is a prevalent motif in a number of natural products and biologically relevant molecules. Of these compounds, one particularly interesting set are the bisindolylalkanes. The most simple of these diindolylmethane 1 has been shown to have the ability to inhibit tumour cell growth in breast cancer cell lines,1 other derivatives have also been shown to have anti-bacterial properties.2

The syntheses of these interesting scaffolds from simple alkyne 2 and indole 3 starting materials via two sequential catalytic hydroarylation reactions at near ambient conditions, would be an attractive proposition. While there are examples of this approach in the literature, the scope of products accessible is often restricted to symmetrical bisindolylalkanes, where both indoles in the molecule are identical. This is due to the intermediate vinylindoles (e.g. 4) being prone to further reaction with another equivalent of indole nucleophile.3 For this reason a simple procedure for the synthesis of unsymmetrical bisindolylalkanes from an alkynes 2 and indoles 3 has proved elusive.

Here, we present our work on the development of a Au(I)-catalysed selective hydroarylation of alkynes using indoles. Through a thorough study of reaction conditions and factors which influence selectivity, we have successfully developed a set of conditions which allow us to control the reaction to stop at the vinyl indole 4. This allows us to isolate a range of substituted vinyl indoles 4 in high yield under mild conditions.

This poster will also highlight our current efforts to incorporate this reaction into a facile one-pot synthesis of unsymmetrical bisindolyalkanes 9 through a second acid-catalysed hydroarylation of vinylindole 7.

References 1. C. Hong, G. L. Firestone, L. F. Bjeldanes, Biochem. Pharmacol., 2002, 63, 1085-1097. 2. S. E. O’Connor and J. J. Maresh, Nat. Prod. Rep., 2006, 23, 532-547. 3. For examples see: C. Ferrer, C. H. M. Amijs and A. M. Echavarren, Chem. Eur. J., 2007, 13, 1358-1373; J. Scheißl, M. Rudolph and A. S. K. Hashmi, Adv. Synth. Catal., 2017, 359, 639-653. Poster presentation P6

AN ORGANIC CHEMISTRY TOOLKIT FOR NANOPARTICLE-BOUND SURFACE MONOLAYERS

M. Diez-Castellnou, R. Suo, N. Marro, E. R. Kay* EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST [email protected]

Fine control over the properties of nanomaterials is essential for their applications in the macroscopic world. In addressing this necessity, monolayer functionalised gold nanoparticles (AuNPs), consisting of an inorganic core (e.g. gold) stabilised by a monolayer of organic molecules, can benefit from lessons learned in the organic molecular world. In recent years, the Kay group has specialised in the translation of organic chemistry tools to control the features of AuNPs. Notably, the development of a new concept, dynamic covalent nanoparticles (DCNPs),1 has been enabled by employing dynamic covalent exchange reactions, based on hydrazones2 or boronic acids,3 to control the macroscopic properties of functionalised AuNPs. Incorporating carbonyl functional groups on the surface of metal nanoparticles is attractive for the rich reversible and irreversible chemical transformations that could then be used for chemoselective divergent modification of AuNP-bound molecules. However, for metal nanoparticles, incorporating aldehydes is particularly challenging, as these are reactive under the reducing conditions required for nanoparticle synthesis. To overcome this problem, we have looked to the organic chemistry toolbox: introducing aldehydes masked as acetals provides a convenient and tuneable route to achieve aldehyde-functionalised AuNPs. We have subsequently exploited the rich reactivity of aldehydes, giving access to diverse nanoparticle-bound monolayer constitutions, including rapidly equilibrating environment- responsive imines, or instantaneous solubility switching via formation of negatively charged bisulfite adducts.

N

O F

O O OH O O H S O- O O O O F F F

H N N O F O F

References 1. E. R. Kay, Chem. - Eur. J. 2016, 22, 10706–10716. 2. a) F. della Sala, E. R. Kay, Angew. Chem. Int. Ed. 2015, 54, 4187–4191. b) W. Edwards, N. Marro, G. Turner, E. R. Kay, Chem. Sci. 2017, 9, 125–133. c) N. Marro, F. della Sala, E. R. Kay, Chem. Sci. 2019, DOI: 10.1039/C9SC04195H 3. S. Borsley, E. R. Kay, Chem. Commun. 2016, 52, 9117–9120.

Poster presentation P7

DESIGN, SYNTHESIS AND EVALUATION OF NOVEL AUTOTAXIN INHIBITORS

Jennifer M. Clark,a Fernando Salgado-Polo,b Anastassis Perrakisb and Craig Jamiesona* a Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL b Division of Biochemistry, Netherlands Cancer Institute, 1066 CX, Amsterdam, Netherlands [email protected]

Fibroproliferative diseases account for 45% of all deaths in the developing world.1 Autotaxin (ATX) is an extracellular secretory enzyme responsible for the hydrolysis of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA). Subsequent delivery of LPA to its G-protein coupled receptors, LPAR1-6, facilitates a variety of downstream signalling effects including cellular migration and proliferation, which are directly associated with a range of debilitating disease types, such as Idiopathic Pulmonary Fibrosis (IPF) and cancer. Utilising the SAR knowledge gained from two focused libraries of novel lead-like compounds (Figure 1),2,3 this project has sought to develop synthetically tractable compounds with the potential to target both the tunnel and active site of ATX, employing bespoke steroidal and warhead motifs respectively, enabling the development of an entirely novel class of ATX inhibitors. Initial investigation of optimal linker length followed by detailed biochemical analysis encouraged exploration of conformationally restrained analogues which has led to the generation of our most advanced compound in the series to date (IC50 = 28 nM). Several in vitro and crystallisation studies have been carried out which serve as an indication that this lead species and emerging analogues have the ability to function as therapeutic tools to further probe the pathophysiological capacity of Autotaxin in diseases such as fibrosis and cancer.

References 1. C. B. Nanthakumar, R. J. D. Hatley et al. Nat. Rev. Drug. Discov. 2015, 14, 693-720. 2. W.-J. Keune, F. Potjewyd, T. Heidebrecht, F. Salgado-Polo et al. J. Med. Chem. 2017, 60, 2006-2017. 3. F. Potjewyd, W.-J. Keune, J. M. Clark, C. Jamieson, Manuscript in Preparation.

Poster presentation P8

NEW BROMOTYROSINE METABOLITES FROM A FIJIAN SPONGE APLYSINELLA RHAX E. Oluwabusolaa, J. Tabudravua, K. Feussnerd, F. Annangb, G. Pérez-Morenoc, L. Ruiz- Pérezc, D. González-Pacanowskac, F. Reyesb, R. Ebela, M. Jaspars*a a Marine Biodiscovery Centre. Department of Chemistry, University of Aberdeen, AB24 3UE. Aberdeen, UK b Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 34.18016- Armilla (Granada), Spain. c Instituto de Parasitología y Biomedicina “López-Neyra”, Consejo Superior de Investigaciones Científicas,Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, s/n, 18016-Armilla (Granada), Spain. d Institute of Applied Sciences, Faculty of Science, Technology and Environment, University of the South Pacific, Private Mail Bag, Fiji Island. [email protected]

Marine sponges are highly diverse and capable of biosynthesizing a greater variety of natural bioactive products than other invertebrate phyla. Those belonging to the family Verongida are known producers of brominated secondary metabolites. The methanolic extract of the Fijian marine sponge Aplysinella rhax collection was fractionated and purified by reversed phase HPLC to yield 9-bromotyrosine derivatives including two that have not been described in the literature before: psammaplin O (5) and 3-bromo-2-hydroxyl-5-(methoxycarbonyl)benzoic acid (7), alongside psammaplins A-D (1-4), bisaprasin, (3-bromo-4-hydroxyphenyl)acetonitrile (8) and 3-bromo-4-hydroxybenzoic acid (9). The structures of the new compounds were elucidated by HRMS, and 1D and 2D NMR spectroscopic analyses. Psammaplin A and D showed moderate activity against both T. cruzi Tulahuen C4 and P. falciparum 3D7 with IC50 values of 30-43 µM and 60-67 µM respectively. Additionally, compounds 3 and 8 displayed weak activity against P. falciparum 3D7.

References 1. D. Faulkner, Nat. Prod. Rep. 1984, 1, 551. 2. C. Jiménez, P. Crews, Tetrahedron 1991, 47, 2097-2102. 3. K. Kunze, H. Niemann, S. Ueberlein, R. Schulze, H. Ehrlich, E. Brunner, P. Proksch, K. Pée, Mar. Drugs 2013, 11, 1271-1287. 4. a) P. Bergquist, New Zealand, J. Zool. 1980, 7, 443-503; b) E. Fattorusso, L. Minale, G. Sodano, Chem. Comm. 1970, 751. Poster presentation P9

STEREOSELECTIVE SYNTHESIS OF BUMPED BET INHIBITORS Adam Bond, Andrea Testa, Alessio Ciulli*

University of Dundee, School of Life Sciences, Dow St, Dundee DD1 5EH, [email protected]

The four Bromo and Extra-Terminal (BET) proteins, Brd2, Brd3, Brd4 and Brdt, play a crucial role in transcriptional regulation and other processes such as cell proliferation and inflammation. Each of the BET proteins contains two tandem bromodomains which are conserved across the family and are responsible for binding to acetylated lysine residues such as those at the N-terminus of histones. They have become an attractive therapeutic target as misregulation of BET proteins have been linked to diseases such as cancer, neurological disorders and inflammation. There are many examples of BET inhibitors, including JQ11 and I-BET7622, however, due to the high homology of BET bromodomains, these inhibitors are pan-selective and cannot discriminate between the bromodomains within the BET family. Our group has previously established a bump-&-hole approach to overcome this by selectively targeting a conserved Leucine residue found in BET bromodomains with alkylated I-BET762 derived probes ET3 and 9-ME-14. A limitation to the current synthetic route of these probes is that they require chiral separation following any alkylation step. Separation can be costly and also lead to low yields due to loss of material. We have achieved a new stereoselective route to obtain a key precursor which can be used in a divergent synthesis to yield a variety of bumped inhibitors containing a benzodiazepine scaffold. We demonstrate application of this new route to create novel bumped JQ1- analogues in >99% ee. Our new synthesis has also provided, for the first time, unambiguous evidence to the absolute stereochemistry of the active mutant-selective bumped ligand.

References 1. P. Filippakopoulos et al., Nature, 2010, 468, 1067. 2. O. Mirguet et al., J. Med. Chem. 2013, 56, 19, 7501-7515 3. M. G. J. Baud et al., Science, 2014, 346, 638-641. 4. A. C. Runcie et al., Chem. Sci., 2018, 9, 2452-2468.

Poster presentation P10

DEVELOPMENT OF KINASE INHIBITORS FOR THE TREATMENT OF GLIOBLASTOMA

D. Baillache, M. Valero-Grinan, A. Unciti-Broceta CRUK Edinburgh Cancer Research Centre Institute of Genetics and Molecular Medicine, University of Edinburgh Crewe Road South, Edinburgh, EH4 2XU [email protected]

Glioblastoma multiforme (GBM) is the most aggressive of all brain tumours. The average survival post diagnosis is 12 months, and with maximum available treatment this is only extended to 14 months. Given the poor clinical outcomes for this cancer, this represents a significant clinical need. Genomic characterisation of this cancer has shown that receptor tyrosine kinases are disrupted, as such a kinase inhibitor could be used to treat glioma.1 The principal aim of research was to design and synthesise a range of novel molecules for the treatment of GBM using a ligand-based phenotypic approach.2 Data collected would be used to drive further iterations of design and synthesis and any resultant lead molecules would undergo target deconvolution to determine their modes-of-action and inhibitory profiles. Using ligand-based phenotypic-drug-discovery, a range of novel inhibitors were designed around an ATP-based core to probe structure-activity-relationships of the scaffold. The novel inhibitors were screened against two glioma cell-lines, T98 and U-87, to determine their phenotypic effect and the data was used to drive three subsequent rounds of drug design and screening. By screening in this iterative manner, several lead molecules with near sub- micromolar potency have been discovered. To date, 90+ novel molecules have been designed, synthesised and screened. Through screening, hit and lead compounds have been found to have EC50’s in the low µM range. Lead molecules have been further screened in two patient-derived cell-lines and a blood- brain-barrier cell model, to determine how they behave in a range of different cancerous and healthy cells. This data has been used to identify two key molecules for further rounds of optimisation and screening prior to target deconvolution studies.

References 1. Bastien, J. I. L.; Mcneill, K. A.; Fine, H. A. Molecular Characterizations of Glioblastoma , Targeted Therapy , and Clinical Results to Date. Cancer 2015, 502–516. 2. Fraser, C.; Dawson, J. C.; Dowling, R.; Houston, D. R.; Weiss, J. T.; Munro, A. F.; Muir, M.; Harrington, L.; Webster, S. P.; Frame, M. C.; Brunton, V. G.; Patton, E. E.; Carragher, N. O.; Unciti-Broceta, A. Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. J. Med. Chem. 2016, 59, 4697–4710.

Poster presentation P11

SYNTHESIS OF NOVEL PET IMAGING AGENTS FOR PARP-1 BASED ON OLAPARIB-DERIVED INHIBITORS

H. McErlain1, M. C. Liuzzi1,2, A. J. Chalmers2 and A. Sutherland1* 1 WestCHEM, School of Chemistry, University of Glasgow, Glasgow, G12 8QQ. 2 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, G61 1QH. [email protected]

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein which performs ADP- ribosylation of damaged DNA to facilitate the repair of single-strand DNA breaks.1 PARP-1 inhibition ultimately leads to double-strand DNA breaks that are repaired by breast cancer susceptibility proteins (BRCAs). In BRCA1/2 defective cell lines double-strand DNA breaks cannot be repaired, leading to cell death.2 As such, there has been great interest in the development of PARP-1 inhibitors for the treatment of BRCA1/2 defective cancers, such as breast and ovarian cancer.2 The most successful PARP-1 inhibitor is olaparib which is used in the treatment of BRCA1/2 mutated ovarian cancer. A key problem in the evaluation of PARP-1 inhibitor cancer treatment efficacy remains the inability to image tumours over- expressing PARP-1 non-invasively in vivo. Consequently, the aim of this project is to discover novel high affinity analogues of olaparib that can be radiofluorinated and used for PET imaging of PARP-1. Using a synthetic route which allowed for late-stage diversification of olaparib, a small library of eight non-radioactive, novel olaparib analogues has been prepared and the physiochemical properties of these compounds assessed via HPLC methodology.3 Four compounds determined as optimal candidates have been assessed by in vitro biological investigation for PARP-1 specificity, inhibition activity and radiosensitisation in clonogenic assays with two glioblastoma cell lines. All four novel olaparib analogues synthesised in this project have displayed comparable potency to olaparib thus far.

O O

NH NH N N O O

N N O F N N F F X O O Olaparib 8 Novel olaparib analogues where X = NH, NHCH2, OCH2, S or N Figure 1: Olaparib and novel olaparib-derived analogues

References 1. P. Bai, Molecular Cell, 2015, 58, 947–958. 2. H. E. Bryant et al., Nature, 2005, 434, 913–917. 3. A. A. S. Tavares et al., Nucl. Med. Biol., 2012, 39, 127–135.

Poster presentation P12

DEVELOPMENT OF SMALL MOLECULE EPAC1 AND EPAC2 ACTIVITY REGULATORS David Morgan, Urszula Luchowska, Padraic Whelan, Graeme Barker* Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS [email protected]

EPAC proteins are important intracellular signalling sensors for cyclic adenosine monophosphate (cAMP). These proteins are known to be involved in the development and progression of a variety of different diseases, including atherosclerosis. Atherosclerosis is the build-up of fatty plaques within arterial walls, which restricts blood flow and can lead to a more serious conditions such as a stroke, heart attack or aneurism.1 As of 2019, cardiovascular disease (CVD) is the largest cause of mortality in the world, responsible for 1 in 3 deaths,1 making the development of new and improved methods of treatment vitally important.

Recently, the Yarwood group has discovered the first non-cyclic nucleotide based EPAC1 selective partial agonist, I942.2, 3 With this, we have developed new small molecules based on I942 to gain an understanding of the structure-activity relationship (SAR). Additionally, we have worked on another structurally distinct compound SY009 and have begun analogous SAR studies.4

References 1. British heart foundation UK factsheet, https://www.bhf.org.uk/-/media/files/research/heart-statistics/bhf-cvd- statistics-uk-factsheet.pdf?la=en (accessed 21th November 2019). 2. E. Parnell, S. P. McElroy, J. Wiejak, G. L. Baillie, A. Porter, D. R. Adams, H. Rehmann, B. O. Smith and S. J. Yarwood, Sci. Rep., 2017, 7. 3. U. Luchowska-Stańska, D. Morgan, S. J. Yarwood and G. Barker, Biochem. Soc. Trans., 2019, 47, 1415– 1427. 4. E. M. Beck, E. Parnell, A. Cowley, A. Porter, J. Gillespie, J. Robinson, L. Robinson, A. D. Pannifer, V. Hamon, P. Jones, A. Morrison, S. Mcelroy, M. Timmerman, H. Rutjes, P. Mahajan, D. Morgan and G. Barker, Cells, 2019, 8, 1425–1443. Poster presentation P13

TOTAL SYNTHESIS OF ASPIDOSPERMA ALKALOIDS UTILIZING A CASCADE SUZUKI–MIYAURA/DIELS–ALDER REACTION David L. Cain, Niall A. Anderson, Allan J. B. Watson*

EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

[email protected]

Cascade reactions present a useful strategy in reaction design due to their ability to streamline chemical synthesis.1-3 The modularity with which complex molecules can be created by embedding downstream reactivity into small, simple precursors is an appealing strategy for chemists. Cascade reactions facilitate the use of reactive, non-isolable intermediates which can reduce step count and therefore lead to an overall increase in reaction efficiency. The Diels–Alder reaction is one of the most widely exploited reactions within cascade sequences in the synthesis of natural products.1-3 To this end, it was envisioned that a cascade reaction sequence could be employed in the total synthesis of Aspidosperma alkaloids. This family of alkaloids has been of significant interest to synthetic chemists, owing to their interesting topological structure and biological properties.4 This work demonstrates the application of a Suzuki–Miyaura/Diels–Alder (SM/DA) cascade reaction in the synthesis of various Aspidosperma alkaloids (Scheme 1). The SM/DA protocol allows the creation of the complex skeletal framework in a single reaction, which can then be subjected to a series of simple chemical manipulations to furnish a natural product library. The optimization of the SM/DA protocol will be presented, alongside showcasing the reaction through the shortest synthetic route to Aspidospermidine to date.5

Scheme 1: Cascade Suzuki–Miyaura/Diels–Alder reaction for Aspidosperma alkaloid synthesis.

References 1. L. F. Tietze, Chem. Rev. 1996, 96, 115–136. 2. K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134–7186. 3. J. D. Winkler, Chem. Rev. 1996, 96, 167–176. 4. J. M. Saya, E. Ruijter, R. V. A. Orru, Chemistry 2019, 25, 8916–8935. 5. S. B. Jones, B. Simmons, A. Mastracchio, D. W. C. MacMillan, Nature 2011, 475, 183–188.

Poster presentation P14

UNDERSTANDING & EXPLOITING SELECTIVITY IN NICKEL-CATALYSED CROSS COUPLING

A. K. Cooper,a D. K. Leonard,a S. Bajo,a P. Burton,b D. J. Nelson*a a WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK; b Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK; [email protected]

Transition metal catalysed cross coupling reactions are amongst the most commonly used in organic synthesis today.1,2 New catalysts and ligands are constantly under development, in an effort to increase the efficiency and applicability of this procedure.3 To complement this, mechanistic studies are essential, particularly towards understanding oxidative addition to Ni, and how this affects catalytic reactions. One aspect of this area is the ability to affect selectivity and/or reactivity in oxidative addition using coordinating groups attached to the substrate.4 Competition experiments between substrates which contain coordinating groups and substrates that do not have been carried out, and selectivity (or lack thereof) in these reactions has been measured. In addition, kinetic experiments reveal the effect of substituents on the rate of oxidative addition of a selection of these substrates.5 Intramolecular competition experiments have been carried out to understand whether coordinating functional groups can enable chemists to achieve selectivity in the cross- coupling reactions of functionalised substrates.

References 1. N. Miyaura, A Suzuki, Chem. Rev., 1995, 95, 2457-2483 2. F.-S. Han, Chem. Soc. Rev., 2013, 42, 5270 3. J. Malineni, R. Jezorek, N. Zhang, V. Percec, Synthesis (Stuttg)., 2016, 48, 2795-2807 4. O. V. Zenkina, A. Karton, D. Freeman, L. J. W. Shimon, J. M. L. Martin, M. E. van der Boom, Inorg. Chem., 2008, 47, 5114-5121 5. S. Bajo, G. Laidlaw, A. R. Kennedy, S. Sproules, D. J. Nelson, Organometallics, 2017, 36, 1662-1672

Poster presentation P15

REPURPOSING PROTEIN NANOPORES AS ARTIFICIAL TRANSMEMBRANE ENZYMES

Daniel C. Edwards, Amanda G. Jarvis and Scott L. Cockroft*

EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK Email: [email protected]

Nanopore sensing has become a well-established tool for the investigation of a wide range of biophysical and chemical phenomena at the single-molecule level. In particular, staphylococcal α-haemolysin (αHL) has emerged as a convenient and robust biological construct for nanopore sensing. The atomically precise dimensions of the pore results in a highly reproducible ion current when a transmembrane voltage is applied across a membrane containing a single nanopore. Thus, the presence of small molecules within the pore partially blocks the ion current flow, allowing the detection of single molecules, and even the sequencing of DNA and organic polymers.1 Recently, such ion currents were shown to resolve mechanistic intermediates of Cu-catalysed click reactions through divergent in situ modification of the wild-type αHL.2,3 Here we propose the manufacture of an artificial transmembrane metalloenzyme for the purpose of alkene metathesis. Hoveyda-Grubbs (HG) 2nd generation catalyst offers an attractive target for bioconjugation to the αHL channel, given the variety of modifiable moieties. Formation of an alkene metathesis transmembrane nano- reactor would provide meticulous analysis of transient coordination intermediates, rapidly exchanging equilibria and quantitative resolution of the metal-catalysed cycle. Looking further ahead, arrays of nanopore-modified membranes might be exploited as preparative-scale flow reactors.

cis Olefin attachment

Lys target CM RCM

ROM A NHS linker Modification of HG

trans

References 1. W. Shi, A. K. Friedman and L. A. Baker, Anal. Chem., 2017, 89, 157-188. 2. S. Borsley and S. L. Cockroft, ACS Nano, 2017, 6, 1109-1113. 3. M. M. Haugland, S. Borsley, D. F. Cairns-Gibson, A. Elmi and S. L. Cockroft, ACS Nano, 2019, 13, 4101- 4110. Poster presentation P16

STRUCTURAL-ACTIVITY RELATIONSHIP OF PFCLK3 INHIBITOR GSK- TCMDC151: TOWARDS THE DEVELOPMENT OF A NEW CLASS OF ANTIMALARIAL

Kopano Mapesa,a,b Amit Mahindra,a Omar Janha,b, Ana Sanchez-Azqueta,b Mahmood M Alam,b Andrew B. Tobin,b Andrew G. Jamiesona* a School of Chemistry, University of Glasgow; b Institute of Cell, Systems and Molecular Biology, University of Glasgow [email protected]

The development of next generation antimalarials which have prophylactic, transmission blocking and curative potential requires the identification of new druggable biochemical pathways. The Plasmodium falciparum protein kinase PfCLK3 has been shown to function within multiple stages of the parasite life cycle, playing a critical role in RNA splicing with inhibition leading to the down-regulation of several essential parasite genes.1,2 Using chemogenetics we previously demonstrated that PfCLK3 is a potential antimalarial drug target.2 Using a high-throughput screen to identify selective inhibitors of PfCLK3, TCMDC- 135051 was identified as one of a series of hit compounds incorporating a 7-azaindole core.2,3 A library of compounds were then synthesised in an effort to establish a SAR around the core scaffold.3 These compounds were tested against the recombinant PfCLK3 protein kinase and assessed for their activity against chloroquine sensitive 3D7 parasites. This poster will include the synthetic route to these TCMDC-135051 analogues and biological activity data.

References 1. Solyakov, L. et al., Global kinomic and phosphoproteomic analyses of the human malaria parasite Plasmodium falciparum. 2011, Nat. Commun., 2, 565. 2. Alam, M. et al. Validation of the protein kinase PfCLK3 as a multi-stage cross species malarial drug target. Science 2019, 365, 6456. 3. DOI: 10.26434/chemrxiv.9817202.v1

Poster presentation P17

ISOTHIOUREA-CATALYSED ACYLATIVE KINETIC RESOLUTION OF ACYCLIC TERTIARY ALCOHOLS

S. Qu, S. M. Smith, V. Laina, M. D. Greenhalgh and A. D. Smith* ADS Group [email protected]

Chiral acyclic tertiary alcohols are commonly present in many bioactive compounds.[1] Although their enantioselective synthesis has attracted much attention, with some progress made in the past decade, it still remains a significant challenge. While direct asymmetric 1,2- addition of nucleophiles into carbonyls has emerged as the most popular synthetic route for obtaining highly enantioenriched acyclic tertiary alcohols,[2] alternative metal-free synthetic methods remain surprisingly underdeveloped. Kinetic resolution (KR) serves as a powerful tool when a racemate can be easily obtained but asymmetric synthesis proves challenging; in this regard there is currently no general method to allow the KR of acyclic tertiary alcohols using small molecule catalysts. This poster describes the development of an operationally simple and highly enantioselective isothiourea (ITU)-catalysed acylative KR of acyclic tertiary alcohols, allowing access to highly enantioenriched compounds (er up to > 99:1) with s factor up to > 500. Investigation of the reaction scope and limitations suggest that both the reactivity and enantioselectivity of the system are sensitive to the steric and electronic environment around the stereogenic carbon centre. While α-aryl-α-methyl esters proved to be the optimal substrate class, this newly developed procedure can also resolve α-alkenyl-α-methyl esters and α-alkyl-α-methyl esters with excellent enantioselectivity. Transition state models are proposed to explain the sense of enantioselectivity observed within this process.

References 1. a) K. Tamura, M. Furutachi, N. Kumagai, M. Shibasaki, J. Org. Chem., 2013, 78, 22, 11396-11403; b) R. F. Majewski, K. N. Campbell, S. Dykstra, R. Covington, J. C. Simms, J. Med. Chem., 1965, 8, 5, 719-720; c) J. P. Carter et. al., J. Med. Chem., 1991, 34, 10, 3065-3074; d) V. Bajaj, J. A. A. Langtry, Br. J. Dermatol., 2007, 157, 1, 118-121; e) R. J. Mier, et. al., Arch. Pediatr. Adolesc. Med., 2000, 154, 12, 1214-1218; 2. a) Y-L. Liu, X-T. Lin, Adv. Synth. Catal., 2019, 361, 876-918; b) M. Shibasaki, M. Kanai, Chem. Rev., 2008, 108, 2853-2873; c) A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard, Angew. Chem. 2012, 124, 3218- 3221; d) B. Bieszczad, D. G. Gilheany, Angew. Chem. Int. Ed., 2017, 56, 4272-4276; e) A. P. Pulis, A. Varela, C. Citti, P. Songara, D. Leonori, V. K. Aggarwal, Angew. Chem. Int. Ed., 2017, 56, 10835-10839; f) Y. Huang, R-Z. Huang, Y. Zhao, J. Am. Chem. Soc., 2016, 138, 6571-6576;

Poster presentation P18

SPLICE-SWITCHING SMALL MOLECULES AS INDUCERS OF APOPTOSIS

Emma Campbell1, Olivia I. Rutherford1, Andrea Taladriz-Sender1, Carika Weldon2, Laurence H. Hurley3, Cyril Dominguez2, Ian C. Eperon2, Glenn A. Burley1*. 1Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK. 2Department of Biochemistry, University of Leicester, Leicester, UK. 3College of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721. [email protected], [email protected]

The Bcl-2 protein family are essential gatekeeper regulators of apoptosis.1 One such protein, Bcl-x is of particular interest as a therapeutic target. It has two splicing isoforms; pro- apoptotic Bcl-xS and the anti-apoptotic Bcl-xL, the latter of which is upregulated in a variety of cancers. Thus, exogenous regulation of Bcl-x splicing, which biases the pathway towards the pro-apoptotic Bcl-xS isoform could provide a new, novel mechanism for cancer therapy (Figure 1). 2,3

Figure 1: Alternative splicing pathways of Bcl-x towards the shorter isoform (Bcl-xS) and the longer isoform (Bcl-xL). Structure of GQC-05 (a known splice-switcher of Bcl-x) shown in the box.4

In this poster, we present a suite of small molecules that induce switching of the splicing 4 pathway of Bcl-x in favour of the production of the pro-apoptotic Bcl-xS isoform. A focused structure-activity-relationship profile revealed key functional requirements for splice-switching activity of this panel of ellipticine compounds. Furthermore, we present a one-pot, modular route for the synthesis of ellipticine analogues. This will allow us to access an extensive library of small molecules, that can be used to probe the mechanism of binding and act as potential therapeutic leads.

References 1. Yip, K. W.; Reed, J. C. Bcl-2 Family Proteins and Cancer. Oncogene, 2008, 27, 6398 – 6406. 2. Naryshkin, N. et al. SMN2 Splicing Modifiers Improve Motor Function and Longevity in Mice with Spinal Muscular Atrophy. Science, 2014, 345, 6197. 3. Sivaramakrishnan, M. et al. Binding To SMN2 Pre-mRNA-Protein Complex Elicits Specificity For Small Molecule Splicing Modifiers. Nat. Commun., 2017, 8. 4. Weldon, C. et al. Identification Of G-Quadruplexes In Long Functional RNAs Using 7 Deazaguanine RNA. Nucleic Acids Res., 2018, 46, 886 – 896.

Poster presentation P19

SYNTHETIC INVESTIGATIONS INTO THE BIOGENESIS OF DIEVODIAMINE

Jake T. Stuart, Andrew L. Lawrence* School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK [email protected]

(+)-Dievodiamine is a bisindole alkaloid isolated by Feng and co-workers in 2010 from the unripe fruits of Evodia rutaecarpe.1 It represents the most complex member of the wider (+)- evodiamine family of alkaloids, but its biosynthetic origins remain unclear.2 Taylor, Unsworth and co-workers reported the first and only total synthesis of racemic dievodiamine in 2013.3

As the name suggests, (+)-dievodiamine formulates as a complex oxidised dimer of (+)- evodiamine.1 We propose that (+)-dievodiamine is produced through a retro-6π electrocyclic ring-opening of our postulated biosynthetic intermediate ‘pre-dievodiamine’. Our studies, however, reveal that selective oxidation and dimerisation of (+)-evodiamine, to give pre- dievodiamine, is difficult to achieve due to facile over-oxidation. We have thus proposed and investigated an alternative linear biosynthetic pathway, which does not involve a dimerisation. This poster will detail our synthetic studies towards pre-dievodiamine, via both linear and convergent biomimetic strategies, and a model study of the key retro-6π electrocyclic ring- opening.

References 1. Q. Z. Wang, J. Y. Liang, X. Feng, Chin. Chem. Lett. 2010, 21, 596–599 2. W. C. Chuang, C. Y. Chu, S. J. Sheu, J. Chromatogr. A, 1996, 2, 317–323 3. C. Kitsiou, W. P. Unsworth, R. J. K. Taylor, Org. Lett. 2013, 15, 3302–3305

Poster presentation P20

CENTROSYMMETRIC APPROACH TOWARDS THE SYNTHESIS OF FUSED POLYCYCLIC ETHER NATURAL PRODUCTS

J. Elwood and J. S. Clark* Joseph Black Building, University of Glasgow, University Pl, Glasgow G12 8QQ [email protected]

Fused polycyclic ether natural products are found in marine dinoflagellates and higher organisms which feed on algae.1 Many of these natural products are potent neurotoxins that are responsible for human poisoning episodes; however, a small selection of these compounds are potential lead compounds for the development of new drugs.2 For example, brevenal can be used to treat the effects that arise due to exposure to the brevetoxins.3 The formation of fused polycyclic ethers has posed many a challenge to researchers, in terms of ring size, stereochemistry and step count.4 We are developing a novel and highly efficient route towards the fused polycyclic ether systems that allows rings to be constructed bidirectionally by exploiting both the apparent and hidden symmetry embedded in the natural products. This approach will allow complex bicyclic systems to be prepared in 4-8 steps, therefore significantly reducing the length of routes towards many natural products.

The strategy involves the synthesis of achiral centrosymmetric bicyclic systems from cyclooctadiene. Desymmetrisation of the centrosymmetric dione affords the key intermediate that can be used to prepare a wide variety of other bicyclic systems. Ring expansion allows access to hemibrevetoxin B and many other natural products.

References 1. T. Yasumoto and M. Murata, Chem. Rev., 1993, 93, 1897–1909. 2. Y. Shimizu, Marine Natural Products, Academic Press, New York, 1st edn., 1978, vol. 1. 3. H. Fuwa, M. Ebine, A. J. Bourdelais, D. G. Baden and M. Sasaki, J. Am. Chem. Soc., 2006, 128, 16989– 16999. 4. K. C. Nicolaou and R. J. Aversa, Isr. J. Chem., 2011, 51, 359–377. Poster presentation P21

RESISTANCE TO THYROID HORMONE ΑLPHA: AN EMERGING GENETIC DISEASE OF TRα

Charles Ropert-Portejoie and Nicholas C. O. Tomkinson*. Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, Scotland, G1 1XL [email protected]

Nuclear receptors (NRs) are a family of proteins that regulate the expression of target genes which are activated by the binding of a specific hormone. Thyroid receptors (TRs) are a member of the NR family/group and play a critical role in developmental processes such as skeletal growth, the central nervous system, cardiac function and homeostasis. Recently, several mutations in the gene encoding for TRα, an isoform of TR, have been reported in the literature. These mutations prevent the normal function of TRα leading to disease. Considered as orphan diseases, affecting a small percentage of the population, they represent a fundamental challenge for the scientific community to develop effective treatments. A recent study identified a de novo heterozygous nonsense mutation in a gene encoding for TRα, which generated a mutant TRα where amino acid 403 (glutamic acid (E)) was substituted for a stop codon (X). 1 This affords a non-complete TRα (E403X) with absent residues (E403 to V410), resulting in a truncated helix 12 (H12). Truncation of H12 in the mutant TRα (E403X) means that it is unable to dislodge the protein Co-Repressor (CoR) and recruit the protein Co-Activator (CoA), preventing transcriptional activation of target genes. Based upon a mechanistic understanding of TRα, a strategy has been designed to restore normal activity of the protein. Using the natural hormone T3 (Scheme 1) as a template, synthetic ligands 1 and 2, have been synthesised, each containing an extended chain with different functional groups present, to mimic the missing amino acids from H12. After ligand binding to the TRα mutant (E403X), we hypothesize this could dislodge CoR and enable recruitment of CoA.

Scheme 1: Thyroid hormone T3 used as a template to build up synthetic ligands 1 and 2, with extended chain, to dislodge CoR and recruit CoA.

Within this poster, we will present our ongoing efforts to prepare a library of compounds to restore normal activity to the TRα mutant (E403X). To date, 5 families of synthetic ligand have been successfully synthesised and submitted for biological examination.

References 1. Bochukova, E. and al., N. Engl. J. Med., 2012, 366, 243–249.

Poster presentation P22

ADAPTATION OF ENZYMES IN THE VALINE PATHWAY FOR THE PRODUCTION OF METHACRYLATE INTERMEDIATES Ane Valera, Laurent Trembleau, Hai Deng* Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen, AB24 3FX. [email protected]

Methacrylic acid (MAA) and methacrylate esters (MAs) are important precursors for the synthesis of many useful products, most notably for the manufacture of polymers1.The world production capacity of MAA has almost doubled in the past 15 years and reached about 2.2 million tons per year2. Currently MAA and derivatives are prepared synthetically by using toxic reagents, such as extremely hazardous acetone cyanohydrin (ACH) and hydrogen cyanide. In addition to this, the ACH process generates significant amounts of ammonium sulphate as by-product3. Consequently, there is a pressing need to discover safer and greener synthetic strategies towards the industrial production of MAA and MAs. In this respect, microbial fermentation and synthetic biology approaches are attractive alternatives. In this poster, we will show how we have engineered an E. coli chassis by assembling key genes into bespoke gene clusters to produce methacrylate precursors.

A

B

Fig. 1. A) Engineered gene chassis for HIBA 2 synthesis. B) Structures of methacrylic acid 1 and HIBA 2.

References 1. B. Matthias, and U.Fritz, Ullmann’s Encyclopedia of Industrial Chemistry, 2003, Vol.23. 2. K. Nagai, New developments in the production of methyl methacrylate. Applied Catalysis A: General, 2001, 221, 367-377. 3. T. Degnan, Advances for a new, greener catalytic process for methyl methacrylate production. Focus on Catalysts, 2018, 1, 1-2.

Poster presentation P23

TRANSBORYLATION FOR ASYMMETRIC CATALYSIS

Kieran Nicholson, Joanne Dunne, Thomas Langer, Stephen Thomas*

Joseph Black Building, EaStChem School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ AstraZeneca, Charter Way, Macclesfield, Cheshire, SK10 2NA [email protected]

Currently, asymmetric reduction is dominated by the use of transition metal catalysts. Recently, interest has grown in the use of main group catalysts as alternatives. Boranes have been used as stoichiometric reductants, and there are several examples of enantiopure boranes for asymmetric hydroboration.1 We have discovered and developed a synthetic methodology where boranes can be used catalytically with the use of transborylation to drive catalytic turnover.2,3 Here we have applied this methodology to an enantiopure borane catalyst, using transborylation as a means for catalyst regeneration. The borane catalyst is readily generated in situ from commercially available starting materials, achieving good yields (up to 90%) and excellent enantiofidelity (up to >99% ef) across a range of functionalised substrates. The use of transborylation for turnover in asymmetric carbonyl reduction provides a promising advance in the broader use of main group catalysts for enantioselective hydroboration.

References 1. M. M. Midland, J. I. McLoughlin, J. Org. Chem., 1984, 49, 1317-1319. 2. N. W. J. Ang, C. S. Buettner, S. Docherty, A. Bismuto, J. R. Carney, J. H. Docherty, M. J. Cowley, S. P. Thomas, Synthesis, 2018, 50, 803-808. 3. E. Nieto-Sepulveda, A. D. Bage, L. A. Evans, T. A. Hunt, A. G. Leach, S. P. Thomas, G. C. Lloyd-Jones, J. Am. Chem. Soc., 2019, 141, 18600-19611.

Poster presentation P24

SYNTHESIS AND REACTIVITY OF 1-SULFONYL-1,2,3-TRIAZOLES: FORMATION OF 6-MEMBERED NITROGEN-CONTAINING HETEROCYCLES

Matthew L. Martin, Alistair Boyer* Joseph Black Building, University of Glasgow, University Ave, Glasgow, G12 8QQ [email protected]

1-Sulfonyl-1,2,3-triazoles (1-STs) are valuable building blocks for organic chemistry. In the presence of a suitable catalyst such as rhodium, the electron withdrawing nature of the 1- sulfonyl group promotes ring opening of the 1-ST, the loss of nitrogen and the formation a metallocarbene (Scheme 1).1-11 Using these metallocarbenes a wide array of valuable transformations have been performed, including the formation of valuable heterocycles.6-10

Scheme 1

A novel rhodium catalysed 1,2-CH migration reaction of 4-allyl-5-dialylamino 1-STs has been developed and achieves a highly efficient and chemoselective synthesis of Z-dienes (Scheme 2). Through careful control of the reaction conditions, further reaction of these Z- dienes allows access to a large range of nitrogen heterocycles including: dihydropyridines, pyridines, dihydoazetes and cyclic amidines.

Scheme 2

References 1) Chem. Soc. Rev., 2014, 43, 5151. 2) Justus Liebig’s Ann. der Chemie, 1909, 364, 183–226. 3) J. Am. Chem. Soc., 2012, 134, 2477–2480. 4) T. Miura and M. Murakami, in Rhodium Catalysis in Organic Synthesis, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2019, pp. 449–470. 5) L. Li, X.-H. Xia, Y. Wang, P. P. Bora and Q. Kang, Adv. Synth. Catal., 2015, 357, 2089–2097. 6) S. Chuprakov, S. W. Kwok, L. Zhang, L. Lercher and V. V. Fokin, J. Am. Chem. Soc., 2009, 131, 18034–18035. 7) T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972–14974. 8) A. Boyer, Org. Lett., 2014, 16, 1660–1663. 9) A. Boyer, Org. Lett., 2014, 16, 5878–5881. 10) A. Boyer, J. Org. Chem., 2015, 80, 4771–4775. 11) N. Selander, B. T. Worrell and V. V. Fokin, Angew. Chemie Int. Ed., 2012, 51, 13054–13057.

Poster presentation P25

CONTINUOUS-FLOW SYNTHESIS AND APPLICATION OF POLYMER- SUPPORTED BODIPY PHOTOSENSITISERS FOR THE GENERATION OF SINGLET OXYGEN; PROCESS OPTIMISED BY IN-LINE NMR

SPECTROSCOPY Christopher G. Thomsona, Callum M. S. Jonesb, Georgina Rosaira, David Ellisa, Jose Marques-Huesob, Ai-Lan Leea and Filipe Vilela*a (a) Institute of Chemical Sciences / (b) Institute of Sensors, Signals and Systems, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, United Kingdom. Email: [email protected] /// [email protected] Development of efficient heterogeneous photocatalysts has been described as one of the biggest challenges in the field of photochemistry.1 Previous reports of immobilised photosensitisers have generally focused on porphyrin sensitisers and have been synthesised under conventional batch conditions.2 We have established a mild protocol for the formation of immobilised BODIPY (BDP) photosensitisers on Merrifield resins (PS-BDP) in continuous-flow and demonstrated the superior quality of materials produced in flow over conventional batch synthesis.3 Utilising a linker strategy through a position of the BDP molecule not in conjugation with the photosensitiser core avoided altering the molecular optoelectronic properties, allowing the PS-BDP to be identified easily by UV/Vis spectroscopy. Despite being non-conjugated, the support and linker was found to significantly enhance photosensitisation efficiency through reducing intramolecular photoinduced electron transfer (PET). An unexpected side-reaction led to the isolation of two novel compounds and demonstrated the ability to easily fine tune the optoelectronic properties of BODIPY cores to enhance photosensitisation efficiency. The polymer-supported photosensitiser was further post-synthetically modified to obtain the immobilised optimal dichlorinated photosensitiser, which displayed a remarkable 9-times enhancement in photosensitisation efficiency. In-line 1H-NMR spectroscopy was used to optimise flow rate and pressure, resulting in an overall 24-fold enhancement of singlet oxygen photosensitisation from the initial material and conditions. The heterogeneous photosensitisers sustained photosensitising ability after 96 hours of irradiation, however leaching of BDP from the polymer-support was evident from photostability studies.

References 1 M. B. Plutschack, B. Pieber, K. Gilmore and P. H. Seeberger, Chem. Rev., 2017, 117, 11796–11893. 2 X. Han, R. A. Bourne, M. Poliakoff and M. W. George, Chem. Sci., 2011, 2, 1059–1067. 3 C. G. Thomson, C. M. S. Jones, G. Rosair, D. Ellis, J. Marques-Hueso, A. Lee, F. Vilela, Accepted in J. Flow Chem. (November 2019).

Poster presentation P26

TWO WAYS OF TRANSFORMING γ-OXIDIZED LIGNIN VIA NHC AND Cu CATALYSIS Ganyuan Xiao, Isabella Panovic, James R. D. Montgomery, Christopher S. Lancefield and Nicholas J. Westwood* NJW Group e-mail address: [email protected]

Current research focuses on the depolymerisation of lignin to deliver aromatic monomers. However, the last processing step often requires high temperatures and/or harsh chemical treatments, leading to a residual lignin that cannot be used further. In this context, we have been inspired by Zip lignin1, in which chemically labile ester bonds were introduced by genetic engineering. The presence of the esters made it prone to depolymerisation under relatively mild conditions. We have therefore been searching for ways to modifying lignin’s β- O-4 unit to give ester-containing chains that can be easily depolymerised.

Initial studies focused on the use of NHC redox esterification2 but were ultimately derailed by the fact that the phenolic rebound reaction proved inefficient. In the end we compromised and used butanol as an alternative rebound reactant leading to the direct depolymerization to give versatile monomers from lignin. In a second attempt, a Cu/TEMPO3 system was used to form the desired aryl ester in high yield. With the optimized reaction conditions achieved in small model compounds, this chemistry was successfully applied to a polymeric β-O-4 model.

References 1. Karlen, Steven D., et al. Science advances. 2016, 2 (10), e1600393. 2. Xiao, G.; Lancefield, C. S.; Westwood, N. J. ChemCatChem 2019, 11 (14), 3182-3186. 3. Xiao, G.; Montgomery, J.; Panovic, I.; Westwood, N. J. Manuscript in preperation. Poster presentation P27

REGIOSELECTIVE SYNTHESIS OF C4h AND D2h PHTHALOCYANINES

Christopher C. Rennie,a Jaime Hillis,a Katie D. Mulholland,c Sang B. Yoon,c Eleanor K. Sitch,c Alasdair I. McKay,c Katharina Edkins,b and Robert M. Edkinsa*

aWestCHEM Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom bSchool of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK cChemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK E-mail: [email protected]

Phthalocyanines (Pc) are 18π-macrocycles that have found themselves in a renaissance period due to their impressive photophysical and photochemical properties. Due to these photophysical and photochemical properties, Pcs are utilized in a variety of applications ranging from their initial use as dyes to organic solar cells, non-linear optics, and light- activated cancer treatment (mainly as photothermal and photodynamic agents). Metalled Pcs are typically synthesized through a templated cyclotetramerization of four substituted phthalonitrile molecules. However, a common problem with this chemistry is that the use of non-C2v phthalonitriles leads to the formation of a statistical regioisomer mixture of C4h, Cs, C2v, and D2h isomers in a 1:4:2:1 ratio that are often not separable. Selective formation of a single regioisomer is sought after, regardless of their application.1

Here we present our approach to synthesizing the single C4h isomer, exploiting Ir-catalysed bis-borylation of phthalonitrile to provide a highly functional intermediate that can be diversified using Suzuki-Miyaura cross-coupling reactions with a variety of aryl halides. These

3,5-disubstituted intermediate phthalonitriles form the C4h Pc isomer regioselectively through steric control. Using this methodology, zinc and magnesium Pcs with a previously unexplored 1,3,8,10,15,17,22,24-substitution pattern were synthesized; the latter yields the free-base Pc upon de-metallation. Adapting previous work reported by Leznoff et al., we also used a neopentyl glycol linker to synthesize a linked bis-phthalonitrile which enforces the synthesis 2 of a D2h symmetry phthalocyanine. In future work, we will further derivatize these linked phthalonitriles using the same borylation chemistry to give multi-functional D2h Pcs.

Previous work R R R R

N N N N N N N N N N N N R R R R R CN Cyclotetramerisation N M N N M N N M N N M N R R R R CN N N N N N N N N N N N N

R R R R

C D C C Our work 4h 2h 2v s

R R

R O CN NC O O N N R CN N N R N S Ar N R N O Cyclotetramerization R CN Cyclotetramerisation N M N N M N CN R NC R R CN N NO2 N R N N N N O CN R C4h D2h O R R

C4h References 1. K. D. Mulholland, S. Yoon, C. C. Rennie, E. K. Sitch, A. I. McKay, K. Edkins, R. M. Edkins. Unpublished 2. C. C. Leznoff, D. M. Drew, Can. J. Chem., 1996, 74, 307-318. Poster presentation P28

EGYPTIAN FUNGAL ANTIBIOTIC METABOLITES – FROM PHARAOHS TO MODERN TEXTILES

Sylvia Soldatou1, Mallique M. Qader2, Coralie Pavesi1, Kevin J. Miranda1, Oluwatofunmilayo A. Diyaolu1, Ahmed A. Hamed3, Mostafa E. Rateb2 and Rainer Ebel1* 1Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK. 2School of Computing, Engineering & Physical Sciences, University of the West of Scotland, Paisley PA1 2BE, UK. 3Microbial Chemistry Department, National Research Center, Giza 12622, Egypt. [email protected]

Since the discovery of penicillin, fungi have been in the spotlight as a prolific source of bioactive agents with many examples in the literature 85orphyrin85i their importance in drug discovery1. In our efforts towards the discovery of new bioactive fungal metabolites from niche ecosystems, several fungal strains were isolated from marine organisms and plants collected from Hurghada (Red Sea) and Wadi El Natrun valley, respectively. Based on the antimicrobial screening against a panel of pathogenic microorganisms, fifteen endophytic or invertebrate-associated fungal isolates were 85orphyrin85i for further analysis. Chemical investigation was carried out for organic extracts obtained from small-scale fermentations. Specifically, analysis of the MS2 data through the GNPS platform revealed several known compounds which clustered with unidentified parent ions, suggesting the presence of new secondary metabolites. Fungal fermentation on rice afforded enough biomass for fractionation and separation which led to the isolation of a suite of new and known compounds belonging to various classes. Itaconic acid and kojic acid derivatives were isolated from a Cladosporium sp., whereas a new cyclo-peptide and a new morpholine-2,5- dione were isolated from an Epicoccum sp. and Alternaria sp., respectively. Moreover, potentially new analogues of emericellamide A were identified in the molecular network of the crude extract of a marine Aspergillus sp. An 85orphyrin85 Aspergillus strain produced a suite of butyrolactone derivatives. The pure metabolites were screened for antibiotic and cytotoxic activity. The goal of this interdisciplinary project is to incorporate the new antimicrobial compounds onto textile substrates to enhance their functionality.

References 1. Tan et al., Singapore Med J. 2015, 56, 366-367. Poster presentation P29

BIOCATALYTIC ROUTES TO ENANTIOPURE AMINO ACIDS

Silvia De Cesare,a Dr. Guiomar Sanchez Carron,a Dr. Nick Mulholland,b Prof. Gideon Grogan and Prof. Dominic J. Campopiano*a

a) The University of Edinburgh, School of Chemistry, Joseph Black Building, David Brewster Rd, Edinburgh, EH9 3JW, UK. b) Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY. c) The University of York, School of Chemistry, Heslington, York, YO10 5DR. Enantiopure natural and unnatural amino acids are highly valuable compounds, given their importance as chiral building blocks for the synthesis of pharmaceuticals, cosmetics and agrochemicals.1 Recently, the emerging use of these compounds, as tools for protein engineering, has also been reported.2 This work describes a biocatalytic route to optically pure amino acids, by optimising the coupling of two enzymes, an engineered N-acetyl-amino acid racemase (NAAAR)3 and an L- or D-acylase. This results in a dynamic kinetic resolution (DKR, Scheme 1) of racemic starting materials into either of the enantiopure targets.4

Scheme 2: Biocatalytic DKR of N-Ac-DL-amino acids to enantiopure L/D-amino acids.

A novel 1H-NMR assay has been developed to monitor the key NAAAR-catalysed de- acetylation step and measure its relative conversion. We also investigated the substrate scope of the coupled enzymes and optimised biotransformation conditions for scaled-up synthesis.

References: 1. D. J. Craik, D. P. Fairlie, S. Liras, D. Price, Chem. Biol. Drug Des., 2013, 81, 136 – 147. 2. F. Agostini, J.-S. Vçller, B. Koksch, C.s G. Acevedo-Rocha, V. Kubyshkin, and N. Budisa, Angew. Chem. Int. Ed., 2017, 56, 9680 – 9703 3. S. Baxter, S. Royer, G. Grogan, F. Brown, K. E. Holt-Tiffin, I. N. Taylor, I. G. Fotheringham, D. J. Campopiano, J. Am. Chem. Soc., 2012, 134, 19310−19313 4. C. Femmer, M. Bechtold, T. M. Roberts, S. Panke, Appl. Microbiol. Biotechnol., 2016, 100, 7423–7436 Poster presentation P30

SMALL-MOLECULE INDUCED PROTEIN DEGRADATION FOR THE PREVENTION OF METASTASIS

Sarah Memarzadeh, Nikki Paul, Laura Machesky, Justin Bower and David France* University of Glasgow, School of Chemistry, WestCHEM, Joseph Black Building, University Avenue, G12 8QQ [email protected]

Metastasis is the major contributor to cancer mortality, however, available therapeutics are limited and identification of an appropriate target is challenging. Fascin, a protein involved in the formation of invasive metastatic structures by bundling actin, has been identified as a potential target. Instead of inhibiting this protein-protein interaction with traditional small molecules, this project seeks to design and synthesise Proteolysis Targeting Chimeras (PROTACs) capable of degrading fascin by leveraging the cellular degradation machinery (ubiquitin-proteasome system). As a proof of concept, a fascin-HaloTag fusion protein was cloned and expressed in cancer cells. Subsequent treatment of the cells with different HaloPROTACs showed degradation of the fusion protein. These results give way to further investigation into degradation the target protein and potential containment of metastatic spread of cancer cells.

References 1. T. N. Seyfried and L. C. Huysentruyt, Crit Rev Oncog, 2013, 18, 43-73. 2. D. Tarin, Semin Cancer Biol, 2011, 21, 72-82. 3. M. Toure and C. M. Crews, Angew Chem Int Ed Engl, 2016, 55, 1966-1973. 4. A. Li, J. C. Dawson, M. Forero-Vargas, H. J. Spence, X. Yu, I. König, K. Anderson and L. M. Machesky, Curr Biol, 2010, 20, 339-345. 5. D. L. Buckley, K. Raina, N. Darricarrere, J. Hines, J. L. Gustafson, I. E. Smith, A. H. Miah, J. D. Harling and C. M. Crews, ACS Chem Biol, 2015, 10, 1831-1837.

Poster presentation P31

LITHIATION-SUBSTITUTION OF ALKYL-1,3,4-OXADIAZOLES AND BENZYLTETRAZOLES IN BATCH AND FLOW CONDITIONS

Jeff Y. F. Wong, Agnieszka Lewandowska, Benjamin R. Trowse and Graeme Barker* Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, U.K. [email protected] and [email protected]

1,3,4-Oxadiazoles and tetrazoles are important in the pharmaceutical industry as bioisosteres of amides and carboxylic acids respectively with similar sizes, clogP and a higher metabolic stability.1,2 Despite this privileged position in medicinal chemistry late-stage modifications are rare, due to perceived fragility. We have developed a new lithiation-substitution protocol for the modification of alkyl-1,3,4-oxadiazoles and benzyltetrazoles. The use of easily accessible organolithium reagents for the α-functionalisation of alkyloxadiazoles and benzyltetrazoles will allow the rapid generation of structural analogue libraries for high-throughput screening. Previously reported conditions for oxadiazole metalations require cryogenic temperatures (–78 °C) and suffer from poor yields and scope.3 Our optimal conditions for the lithiation-substitution of oxadiazoles use LDA, metalating at –30 °C for 1 minute in batch conditions prior to electrophilic trapping. The electrophile and substrate scopes have been fully explored. While temperatures higher than –30 °C lead to complete decomposition of the lithiated oxadiazole in batch, the superior mixing afforded by flow reaction conditions allow us to intercept this unstable intermediate with electrophiles, affording high yields at rt.4

Although alkyltetrazole metalations were known in the literature, previously reported conditions require N-trityl-protection and cryogenic temperatures (–78 °C); the deprotection of N-trityltetrazoles requires gaseous HCl.5 In this context, we have also developed a lithiation-substitution protocol for unprotected benzyltetrazoles. This was achieved using n-BuLi at 0 °C for 3 hours prior to electrophilic trapping. The electrophile and substrate scopes have also been fully explored.6

References 1. J. Bostrom, A. Hogner, A. Llina, E. Wellner and A. T. Plowright, J. Med. Chem., 2012, 55, 1817−1830. 2. R. N. Butler, Adv. Heterocycl. Chem., 1977, 21, 323–435. 3. D. Barrett, V. Boncek, J. Catalano, D. Deaton, A. Hassell, C. Jurgensen, S. Long, R. McFadyen, A. Miller, L. Miller, J. Payne, J. Ray, V. Samano, L. Shewchuk, F. Tavares, K. Wells-Knecht, D. Willard, L. Wright and H. Zhou, Bioorg. Med. Chem. Lett., 2005, 15, 3540–3546. 4. J. Y. F. Wong, J. M. Tobin, F. Vilela and G. Barker, Chem. Eur. J., 2019, 25, 12439–12445 5. B. E. Huff, M. E. LeTourneau, M. A. Staszak and J. A. Ward, Tetrahedron Lett., 1996, 37, 3655–3658. 6. J. Y. F. Wong, A. Lewandowska, B. R. Trowse and G. Barker, Org. Lett., 2019, 21, 7069–7072. Poster presentation P32

TARGET ELUCIDATION OF NOVEL TRYPANOSOMATIDS INHIBITORS

R. P. F. A. Gouy, L. Tulloch, R. E. Woods G. J. Florence*, T. K. Smith GJF Group, School of Chemistry, BSRC, University of St Andrews, St Andrews, KY16 9ST [email protected]

The neglected tropical diseases (NTDs) of the trypanosomatid family, are responsible for a specific class of parasitic diseases, Trypanosoma Cruzi (American Trypanosomiasis) causative of Chagas disease, Trypanosoma Brucei (Human African Trypanosomiasis) causative of Sleeping Sickness and Leishmania Major (Leishmaniasis). The current concern for these diseases is the growing report of cases around the world, the lack of effective treatments and possible targets to be explored.1 The synthesis of natural products and analogues remains an important aspect of medicinal chemistry, developing compounds with potential biological activity and its use for the identification of potential targets.2 Recent studies and further work within our groups on fumagillin (1) have shown a promising activity within the trypanosomatid family, allowing us to explore its structure to identify its target within these parasites.3

This poster will detail the current approach for the identification of potential target of fumagillin and analogues. Our work focusses on the modification of the unsaturated side chain as in 2, which can be readily modified via the carboxylic acid moiety or via the core cyclohexane scaffold. Further modification of the structure is underway to achieve a photoaffinity-labelling probe to identify its possible target.

References 1 F. E. Koehn and G. T. Carter, Nat. Rev. Drug Discov., 2005, 4, 206–220. 2 R. M. Reguera, E. Calvo-Álvarez, R. Álvarez-Velilla and R. Balaña-Fouce, Int. J. Parasitol. Drugs Drug Resist., 2014, 4, 355–357. 3 G. O. Donovan, C. L. Paradise and S. R. Skinner, 2010, 19, 5128–5131.

Poster presentation P33

A NEW CLASS OF SMALL MOLECULE INTRACELLULAR pH SENSORS FOR RAMAN MICROSCOPY

Liam T. Wilson,† William J. Tipping,‡ Lauren E. Jamieson,‡ Corinna Wetherill,‡ Karen Faulds,‡ Duncan Graham,‡ Zoë Henley,§ Simon P. Mackay┴ and Nicholas C. O. Tomkinson†*

†Department of Pure and Applied Chemistry, WestCHEM, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K. ‡ Centre for Molecular Nanometrology, WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, 99 George Street, Glasgow, G1 1RD, U.K. §GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K. ┴Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, U.K.

E-mail: [email protected]; [email protected]

Intracellular pH (pHi) homeostasis is intertwined with several cellular processes such as 1 2 proliferation, and apoptosis. Additionally, many diseases are associated with aberrant pHi profiles. Notably, cancer cells are associated with increased pHi and decreased extracellular 3 pH (pHe). As such, sensors of pHi are essential tools for chemical biology, helping elucidate biochemical information and possible therapeutic pathways. Raman microscopy and nonlinear variants such as Stimulated Raman Spectroscopy (SRS) have emerged as complementary techniques to fluorescence microscopy for cellular imaging.4 Raman probe molecules often utilize bioorthogonal chemical functional groups such as alkynes which reside in the ‘cell-silent’ region (1800–2600 cm-1) of the Raman spectrum and are readily distinguishable from endogenous cell signals.5 In this poster, we will report the design and synthesis of 14 chemical probes which contain ionizable moieties in electronic conjugation with a bisarylbutadiyne Raman reporter. We found that modulation of electron delocalization via protonation/deprotonation events influenced the alkyne stretching frequency (νalkyne), rendering their spectra sensitive to pH. This enabled the determination of the pKa(H) of each compound by Raman spectroscopy. The modular design strategy facilitated rational pKa(H) tuning by substitution of the ionizable moiety. Between the set of 14 compounds, we have achieved continuous pH sensitivity across the range 2–10, providing a foundation for developing Raman pH sensors for any physiological microenvironment. A candidate with optimal properties was selected (1), which was then calibrated and used to quantify a reduction in Prostate Cancer (PC3) cell pHi in response to treatment with the pro-apoptotic drug etoposide.

2224 7.40 2222 7.35 )

-1 7.30 2220 i 7.25 cm (

2218 pH 7.20 7.15 alkyne 2216 ν 7.10 2214 7.05 7.00 3 4 5 6 7 8 9 0 1 2 3 4 5 6 pH Time (h) Figure 1: Small molecule pH sensors for Raman microscopy. A: Design of pH sensitive bisarylbutadiynes; B: Structure of cytoplasmic pHi sensor 1; C: νalkyne of sensor 1 as a function of environmental pH; D: Plot of PC3 -1 cell pHi as a function of time after treatment with Etoposide (80 µg mL , 30 min). pHi was measured by Raman microscopy, following treatment with 1 (25 µM, 30 min). References 1. M. Flinck, S. H. Kramer and S. F. Pedersen, Acta Physiol., 2018, 223, e13068. 2. D. Lagadic-Gossmann, L. Huc and V. Lecureur, Cell Death Differ., 2004, 11, 953–961. 3. M. Schindler, S. Grabski, E. Hoff and S. M. Simon, Biochemistry, 1996, 35, 2811–2817. 4. L. Opilik, T. Schmid and R. Zenobi, Annu. Rev. Anal. Chem., 2013, 6, 379–398. 5. Z. Zhao, Y. Shen, F. Hu and W. Min, The Analyst, 2017, 142, 4018–4029. Poster Presentation P34

SHEDDING LIGHT ON THE MECHANISM OF PHOTOREDOX CROSS- ELECTROPHILE COUPLING BY IN-SITU ILLUMINATION NMR

Y. Ben-Tal and G.C, Lloyd-Jones* School of Chemistry, Joseph Black Building, David Brewster Road, University of Edinburgh, Edinburgh, EH9 3FJ [email protected]

The last few years have seen an explosion in the development of synthetic methodology utilising photoredox catalysis, in particular the class of Ni/photocatalyst dual-catalyst photoredox catalysis pioneered in 2014 by the groups of Molander, MacMillan and Doyle1. However, despite the growing prevalence of this kind of reaction in both industrial and academic chemistry, the mechanisms of this type of transformation remain poorly understood and few mechanistic studies have been conducted. This work takes the silane-mediated bromide-bromide sp2-sp3 cross coupling developed by the MacMillan group in 2016 (figure 1.) as a case study in order to probe the mechanism, both of this particular transformation and as representative of the class of reactions as a whole2. Like many of the reactions of this type this reaction requires the presence of a base to proceed with good yield; however, even minor changes to the substrates used often require dramatic and unpredictable alterations to the nature of the base3. This phenomenon cannot be explained by any currently postulated mechanism.

Figure 1. The general scheme of bromide-bromide photoredox dual-catalyst cross coupling.

Here we present the results of kinetic monitoring via an in-situ illumination NMR spectroscopy apparatus that we have constructed. The effect of each of the reaction components on the kinetics of the system has been observed. Furthermore, a key intermediate has been observed and isolated. From these results a preliminary mechanistic proposal has been postulated.

References 1. Z. Zuo, D. T. Ahneman, L. Chu, J.. Terrett, A. G. Doyle, D. W. C. MacMillan. Science., 2014, 345 (6195), 437-440; J. C. Tellis, D. N. Primer, G. A. Molander. Science., 2014, 345 (6195), 433-436. 2. P. Zhang, C. Le, and D. W. C. MacMillan. J. Am. Chem. Soc., 2016, 138, 8084−8087. 3. From personal communication with collaborators at Bayer. Poster presentation P35

β-TURN MIMICS BASED ON LIGATION CHEMISTRY

Selma Crecente Garcia, Andrew R Thomson* School of Chemistry, University of Glasgow [email protected]

There are many examples of β-turn mimics in the literature1 but most of them involve complex synthetic pathways, which limits their applicability in peptide chemistry. A wide variety of scaffolds have been reported but hydrazide-based linkages have not been particularly explored. Hydrazide linkages are compatible with the use of ligation chemistry to join two peptide fragments whilst making use of the residual functionality that usually serves no purpose beyond enabling the new connection. This project is focused on the synthesis of β-turn mimics based on a hydrazide linkage that results from the reductive amination between a hydrazide component and an aromatic carbonyl fragment. This strategy is based on established ligation chemistry and is compatible with aqueous conditions and unprotected peptide substrates.

The mimics proposed have been implemented in a β-hairpin designed by Cochran et al.,2 TrpZip1, which forms a type II’ β-turn.

References 1. Nair, R. V.; Baravkar, S. B.; Ingole, T. S.; Sanjayan, G. J. Chem. Commun. 2014, 50 (90), 13874–13884. 2. A. G. Cochran, N. J. Skelton and M. A. Starovasnik, Proc. Natl. Acad. Sci., 2001, 98, 5578–5583.

Poster Presentation P36

TWO NEW FLUOROMETABOLITES FROM STREPTOMYCES CALVUS

Xuan Feng, Davide Bello, Phillip T. Lowe, Joshua Clark and David O’Hagan* DOH Group, School of Chemistry, University of St Andrews, St Andrews, KY16 9ST. [email protected]

The antibiotic nucleocidin is a product of the soil bacterium Streptomyces calvus T-3018.1,2 It is distinct from the other fluorometabolites such as fluoroacetate, 4-fluorothreonine, as it is not derived from 5’-fluorodeoxyadenosine (5’-FDA)3 via the classic fluorinase.4 It seems to have its own enzymatic fluorination process.

We disclose here the structures of two 4’-fluoro-3’-O-β-glucosylated metabolites (F-Mets I and II) which appear and then disappear before the generation of nucleocidin in the culture of S. calvus.5 The putative biosynthetic gene cluster for nucleocidin has UDP-glucose dependent glucosyl transferase (nucGT) and glucosidase (nucGS) encoding genes. We demonstrate that these genes express enzymes that have the capacity to attach and remove glucose from the 3’-O-position of adenosine analogues. In the case of F-Met II, deglucosylation with the NucGS (glucosidase) generates nucleocidin suggesting a role in its biosynthesis.

References 1. S. O. Thomas, V. L. Singleton, J. A. Lowery, R. W. Sharpe, L. M. Pruess, J. N. Porter, J. H. Mowat and N. Bohonos, Antibiot. Annu., 1956, 1956–1957. 2. X. M. Zhu, S. Hackl, M. N. Thaker, L. Kalan, C. Weber, D. S. Urgast, E. M. Krupp, A. Brewer, S. Vanner, A. Szawiola, G. Yim, J. Feldmann, A. Bechthold, G. D. Wright and D. L. Zechel, ChemBioChem, 2015, 16, 2498–2506. 3. D. O'Hagan and H. Deng, Chem. Rev., 2015, 115, 634–649. 4. (a) D. O Hagan, C. Schaffrath, S. L Cobb, J. T. G. Hamilton and C. D Murphy, Nature, 2002, 416, 279; (b) C. Dong, F. L. Huang, H. Deng, C. Schaffrath, J. B. Spencer, D. O'Hagan and J. H. Naismith, Nature, 2004, 427, 561–565. 5. X. Feng, D. Bello, P. T. Lowe, J. Clark, D. O’Hagan, Chem. Sci., 2019, 10, 9501-9505.

Poster presentation P37

IRIDIUM(I) CATALYSTS FOR sp3 HYDROGEN ISOTOPE EXCHANGE VIA AMIDE DIRECTING GROUPS

Nathan Knight and William J. Kerr* Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow, G1 1XL, UK [email protected]

Isotopically labelled compounds have become essential tools in the pharmaceutical industry, primarily for use in ADMET studies of potential drug candidates.1 Increasingly, these studies are being conducted earlier in the drug discovery process to determine the best compounds to progress. Metal- catalysed hydrogen isotope exchange (HIE) allows late-stage incorporation of hydrogen isotopes into candidates without the time-consuming re-synthesis of desired analogues using expensive deuterated or tritiated starting materials.2 We have developed a range of iridium catalysts, bearing both bulky phosphine and N-heterocyclic carbene (NHC) ligands, which have proved to be effective HIE catalysts (Scheme 1, Top). Under mild reaction conditions, the catalysts deliver high levels of incorporation via an ortho-directed C—H activation process (Scheme 1, Bottom left).3 Recently, this work has been extended into the much 3 4 rarer, and more challenging, HIE of sp hybridised C—H bonds. Indeed, Kerr group catalysts have now been applied to the HIE of sp3 carbon centres using pharmaceutically ubiquitous amide bond directing groups. Initially, this methodology was applied to N-benzyl lactams considering different aryl substituents and lactam ring sizes; with excellent levels of incorporation observed (Scheme 1, Bottom right). Interesting aryl labelling was observed in many cases allowing the opportunity for either selective benzylic incorporation or a “global” labelling procedure. Expansion of this methodology beyond N-benzyl lactams delivered a broad range of deuterium incorporated substrates.

Scheme 1

References 1. J. Atzrodt, V. Derdau, W. J. Kerr, and M. Reid, Angew. Chem. Int. Ed. 2018, 7, 1758-1784. 2. J. Atzrodt, V. Derdau, W. J. Kerr, and M. Reid, Angew. Chem. Int. Ed. 2018, 12, 3022-3047. 3. J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B. Mondal, J. A. Parkinson, L.C. Paterson, M. Reid, T. Tuttle, S. Andersson, and G. N. Nilsson, Adv. Synth. Catal. 2014, 17, 3551-3562. 4. W. J. Kerr, R. J. Mudd, M. Reid, J. Atzrodt, and V. Derdau, ACS Catal. 2018, 11, 10895-10900.

Previous Meetings

The RSC Scottish Regional Organic Division Meeting was first run in 1972 at the University of Edinburgh and was referred to as the Scottish Perkin Meeting – Perkin, referring to the Organic Division of the RSC named after Sir William Henry Perkin.

Shown below are all the previous meetings, and the plenary lecturers.

Meeting Year Location Plenary Lecturer(s) 1 1972 University of Edinburgh 2 1973 University of Strathclyde 3 1974 University of Stirling 4 1975 University of St Andrews G. Maier 5 1976 Heriot Watt University 6 1977 University of Glasgow 7 1978 University of Aberdeen 8 1979 University of Dundee P. v R. Schleyer 9 1980 University of Edinburgh R. A. Abramovich 10 1981 University of Strathclyde (G. Ourisson) C.W. Rees 11 1982 University of Stirling 12 1983 University of St Andrews E. Vogel 13 1984 Heriot Watt University H. Felkin 14 1985 University of Glasgow P. D. Magnus 15 1986 University of Aberdeen A. Van Leusen 16 1987 University of Dundee W. Oppolzer 17 1988 University of Edinburgh D. Arigoni 18 1989 University of Strathclyde K. U. Ingold 19 1990 University of St Andrews M. Regitz 20 1991 Heriot Watt University A. B. Smith III 21 1992 University of Edinburgh H. Prinzbach 22 1993 University of Aberdeen M. Schlosser 23 1994 University of Dundee R. W. Hoffman 24 1995 University of Glasgow M.H. Zenk 25 1996 University of Edinburgh L. N. Mander 26 1997 University of Strathclyde A. G. Myers Meeting Year Location Plenary Lecturer(s) 27 1998 University of St Andrews A. Hirsch 28 1999 University of Aberdeen D. N. Reinhoudt 29 2000 Heriot Watt University R. Ramage, E. J. Thomas 30 2001 University of Glasgow L. S. Liebeskind, V. Snieckus 31 2002 University of Dundee R. Schmidt 32 2003 University of Edinburgh D. Hilvert 33 2004 University of St Andrews L. F. Tietze 34 2005 University of Strathclyde P. Renaud 35 2006 Heriot Watt University F. Würthner 36 2007 University of Glasgow E. Carreira 37 2008 University of Aberdeen B. Gerwick 38 2009 University of Dundee P. Kocienski 39 2010 University of Edinburgh B. Feringa 40 2011 University of Strathclyde M. Lautens, J. Lacour 41 2012 University of St Andrews C. Hunter, GB Hammond 42 2013 Heriot Watt University J. Bower 43 2015 University of Glasgow M. Willis *Held in Jan 2015 44 2016 University of Aberdeen A. Davis *Held in Jan 2016 45 2017 University of Dundee T. Heightman *Held in Jan 2017 46 2018 University of Edinburgh V. Aggarwal *Held in Jan 2018 47 2018 University of Strathclyde J. Clayden *Held in Dec 2018 48 2020 University of St Andrews V. Gouverneur *Held in Jan 2020

*There was no meeting in 2014 owing to a move from December 2014 to January 2015 for the meeting at Glasgow. This pattern continued until 2018, when there were two meetings; one in January at Edinburgh, and the other in December at Strathclyde. The same situation applies for this meeting, where it was scheduled in January 2020, rather than December 2019. Royal Society of Chemistry 48th Scottish Regional Organic Division ‘Perkin’ Meeting Thursday 9th January 2020

0930–1025 Welcome Coffee and Poster Hanging (School of Medicine Café)

1025–1030 Welcome and Opening Remarks (Booth Lecture Theatre)

1030–1240 Session 1 (Booth Lecture Theatre) Chair: Professor Andy Smith

1030–1055 Professor Doug Philp (University of St Andrews) 1055–1120 Dr Michael Thomas (University of Dundee) 1120–1135 Dr Robert Godfrey (University of Edinburgh) 1135–1200 Dr Charles O’Hara (University of Strathclyde) 1200–1225 Dr Laurent Trembleau (University of Aberdeen) 1225–1240 Dr Rosemary Lynch (University of St Andrews)

1240–1345 Lunch, Exhibition and Poster Session (School of Medicine Café and Seminar Room)

1345–1530 Session 2 (Booth Lecture Theatre) Chair: Professor Nick Westwood

1345–1410 Dr Alistair Boyer (University of Glasgow) 1410–1425 Dr Nikolai Makukhin (University of Dundee) 1425–1450 Dr Rafal Szabla (University of Edinburgh) 1450–1505 Dr Daria Timofeeva (University of Strathclyde) 1505–1530 Dr Chris Coxon (Heriot-Watt University)

1530–1600 Coffee, Exhibition and Poster Session (School of Medicine Café and Seminar Room)

1600–1700 Plenary Session (Booth Lecture Theatre) Chair: Professor David O’Hagan

1600–1605 Presentation of RSC Organic Stereochemistry Award 1605–1700 Professor Veronique Gouverneur FRS (University of Oxford)

1700–1705 Closing Remarks and Prizegiving

1705–1800 Wine Reception

1845–2100 Speakers’ Dinner

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