Daniel Whelligan

Dr Daniel Whelligan


Lecturer in Organic/Medicinal Chemistry

Biography

Biography

Daniel Whelligan gained his first degree (1st class) in Natural Sciences from the University of Cambridge (Churchill College) in 2000. After graduation, he spent the summer at Université Bordeaux I, France carrying out organic synthesis in the group of Professor Stephane Quideau. He then moved to the University of Durham for his PhD with Dr Patrick Steel on the use of silenes (Si=C) in novel organic synthetic methods. In 2004, he secured an Alexander von Humboldt Postdoctoral Research Fellowship to work on the use of paracyclophanes in asymmetric catalysis with Professor Carsten Bolm at RWTH Aachen University, Germany. From 2006-7, he took time to travel around the world including a 3 month postdoctoral research placement with Professor Mark von Itzstein at the Institute for Glycomics, Griffith University, Australia. On return to the UK, Daniel worked from 2007-10 at the Institute of Cancer Research (ICR) as a Postdoctoral Training Fellow in Medicinal Chemistry in the group of Dr Swen Hoelder on the discovery of inhibitors of cancer targets. In 2011 he was appointed as Lecturer of Organic/Medicinal Chemistry at the University of Surrey.

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Research interests

The Whelligan group uses organic synthesis to answer questions and solve problems in biology and alkaline fuel cell research. For biology, this includes drug discovery and the design of inhibitors and probes, using medicinal chemistry expertise, for use as investigational tools. During this research, opportunities to develop novel synthetic methods are also exploited. Major projects are described below:

Design and Discovery of Inhibitors of the DNA Repair Enzyme Aag

Collaborators: Ruan Elliott, Brendan Howlin, Lisiane Meira

Aag_video2

The DNA repair enzyme Aag (Alkyladenine glycosylase) locates and excises alkylated or oxidatively damaged DNA bases (orange in the video, right) and thus initiates the base excision repair (BER) pathway. However, through mouse Aag knockout and overexpression studies, it has been shown that in photoreceptor, spleen, thymus, bone marrow, pancreatic β and cerebellum cells, the action of Aag in response to DNA alkylation (by MMS) leads to cell death.1,2 A small molecule inhibitor of Aag is required for use as a tool in further investigations of the biological mechanisms which mediate this cell death. Furthermore, since humans show varying levels of Aag activity and may encounter alkylating agents naturally, from the diet, pollution or as part of chemotherapy, an inhibitor may form a drug discovery lead for diseases or situations where the action of Aag may be leading to tissue degeneration.

We are engaged in Aag inhibitor discovery via two routes, both of which now follow the discovery cycle shown in Fig. 2:

  • Target-based design: Using computational virtual screening, purchase and bioassay of the top 49 predicted inhibitors we have identified a 'hit' on which we are basing more effective inhibitors.
  • Ligand-based design: DNA oligomers containing modified nucleotides have been shown to inhibit Aag. Based on these and their published crystal structures (Fig. 1),3 we have designed potential small molecule inhibitors and are engaged in their synthesis and bioassay.

For a talk to a multidisciplinary audience on this project, see the MILES Showcase Presentation.

This work is supported by a Royal Society Research Grant [RG140689].

This work was supported by the Engineering and Physical Sciences Research Council [grant number EP/I000992/1].

 

References

  • Meira, L. B.; Moroski-Erkul, C. A.; Green, S. L.; Calvo, J. A.; Bronson, R. T.; Shah, D.; Samson, L. D. Proc. Natl. Acad. Sci. 2009, 106, 888.
  • Calvo, J. A.; Moroski-Erkul, C. A.; Lake, A.; Eichinger, L. W.; Shah, D.; Jhun, I.; Limsirichai, P.; Bronson, R. T.; Christiani, D. C.; Meira, L. B.; Samson, L. D. PLoS Genet. 2013, 9, e1003413.
  • Setser, J. W.; Lingaraju, G. M.; Davis, C. A.; Samson, L. D.; Drennan, C. L. Biochemistry 2012, 51, 382.

Ethoxyvinylarenes as Versatile Intermediates for Heterocycle Synthesis

Azaindoles (4) find widespread use in drug discovery yet methods which permit access to all possible regioisomers are limited and their purchase is costly.1,2 Whelligan et al previously published a two-step synthesis of all regioisomers from chloro- or bromo-aminoarenes which involves Suzuki coupling with ethoxyvinylborolane 2, to give an ethoxyvinylarene 3, followed by acid-mediated cyclisation.3 We are now investigating the versatility of the ethoxyvinylarenes 3 in terms of producing substituted azaindoles or tricycles in one step.

References

The Mechanism of Action of Mycolactone, Causative Agent of Buruli Ulcer

Collaborator: Rachel Simmonds

Buruli ulcer is a slow-growing, necrotising skin disease found predominantly in patients in rural areas of developing countries, particularly in Western Africa. It can cover >15% of a patient's body and cause permanent disability. It is caused by the microbial pathogen Mycobacterium ulcerans which secretes mycolactone A/B, the sole cytopathic toxin known to date.1 Importantly, no acute inflammatory response is mediated to the infection and this has been found to be partly due to the immunosuppressive activity of mycolactone A/B.2 As part of ongoing mechanistic studies in the Simmonds group,3 we intend to attach synthetic tags to mycolactone A/B to facilitate 'pull-down' of its protein targets from human cell lines and visualisation of its in-cell localisation using fluorescence.

We are also investigating improved methods for the isolation and purification of mycolactone A/B and mycolactone F (a fatty acid chain analogue) from cultures of M. ulcerans and M. marinum (a fish pathogen), respectively.

References

Alkaline Fuel Cells and Electrolysers: Design and Synthesis of Novel Membrane Head Groups

Collaborator: John Varcoe

Hydrogen fuel cells that use proton exchange membranes as their 'salt bridge' are well established but the alternative, alkaline anion exchange membranes (AAEMs), offer advantages including the use of cheaper, non-platinum metals as the electrocatalysts (anode and cathode).1 The same is true for electrolysers (figure right) which can be used to generate hydrogen from water. We aim to overcome the two main disadvantages of AAEMs compared to proton exchange membranes: 1. the lower conductivity of hydroxide ions and, 2. chemical instabilities of the membranes in the presence of hydroxide.2 To this end, we design and synthesise small organic molecules for radiation grafting into membranes and conversion into cationic head groups. This provides novel AAEMs with improved properties.3,4

References

This work is supported by the Engineering and Physical Sciences Research Council [grant number EP/M005933/1].

 

 

Teaching

Lecture notes, coursework, supplementary videos and documents are available on SurreyLearn.

  • Level 4 (Year 1) CHE1031 Transferable and Quantitative Skills
  • Level 5 (Year 2) CHE2029 Medicinal Chemistry I
  • Level 6 (Year 3) CHE3043 Topics in Organic Chemistry
  • Level 6 (Year 3) CHE3049 Medicinal Chemistry II
  • Level 7 (Year 4) CHEM025 Advanced Topics in Organic Chemistry
  • Level 7 (Year 4) CHEM032 Advanced Medicinal Chemistry

 

 

Departmental duties

Programme Director of Postgraduate Taught courses:

MRes in Chemistry

 

 

Research Group and Facilities

PhD Students

Balqees Al Yahyaei

(4th year)

Aag inhibitors

Eduard Mas

(3rd year)

Aag inhibitors

Adam Bromley

(3rd year)

Drug-polymer conjugates

(Original supervisor:

Dr Gabriel Cavalli)

Cuc Thu Mai

(3rd year)

Polymer tissue scaffolds

(Original supervisor:

Dr Gabriel Cavalli)

Applications for PhD Studentships

Any funded PhD studentships that become available will be advertised on the University of Surrey Chemistry PhD website. Applications from self-funded or overseas government-funded students are welcome. Please email Daniel Whelligan in the first instance.

 

Undergraduate Students

Sarah Cunningham, Mycolactone project.

Rhys Griffiths, Mycolactone project.

Ben Webster, Ethoxyvinylarenes project.

 

Facilities

All organic synthesis is carried out in the recently refurbished Joseph Kenyon laboratory containing 24 state-of-the-art double fume cupboards, spectroscopy suite and cold room. The lab has been shortlisted for a 'Safe, Successful and Sustainable Laboratory Award 2014' and is equipped with all necessary equipment for normal and air-sensitive organic chemistry.

The Department possesses 500 and 300 MHz NMR spectrometers, a triple-quad LCMS and several GCMS, IR and UV-Vis instruments.

News

Media Contacts

Contact the press team

Email:

mediarelations@surrey.ac.uk

Phone: +44 (0)1483 684380 / 688914 / 684378
Out-of-hours: +44 (0)7773 479911
Senate House, University of Surrey
Guildford, Surrey GU2 7XH

My publications

Publications

Alkaline anion-exchange membranes (AAEMs) containing cationic head-groups (e.g. involving quaternary ammonium and imidazolium groups) are of interest with regard to application in alkaline polymer electrolyte fuel cells (APEFCs). This initial ex situ study evaluated the effect of 1 mmol dm concentrations of model molecules containing (AAEM-relevant) cationic groups on the oxygen reduction reaction on a polycrystalline platinum disk (Pt) electrode in aqueous KOH (1 mol dm(-3)). The cationic molecules studied were tetramethylammonium (TMA), benzyltrimethylammonium (BTMA), 1-benzyl-3-methylimidazolium (BMI), 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane (BAABCO) and 6-(benzyloxy)-N,N,N-trimethylhexan-1-aminium (BOTMHA). Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms, derived estimates of apparent electrochemically active surface areas, Tafel slopes, apparent exchange-current densities and the number of electrons transferred (per O molecule) were compared. The results strongly suggest that 1 mmol dm(-3) concentrations of BTMA, BAABCO, and (especially) BMI seriously inhibit the catalytic activities of Pt in an aqueous KOH electrolyte at 25 °C. The negative influence of (benzene-ring-free) TMA and Cl anions (KCl control experiment) appeared to be less severe. The separation of the trimethylammonium group from the benzene ring via a hexyloxy spacer chain (in BOTMHA) also produced a milder negative effect.
Sanganee MJ, Steel PG, Whelligan DK (2004) Stereochemistry of the reaction of Si-phenyl silenes with butadienes: elaboration of the silacycloadducts to provide a novel route to substituted lactones., Org Biomol Chem 2 (16) pp. 2393-2402
Silenes generated through a silyl-modified Peterson olefination procedure can be trapped with a range of alkyl butadienes via a [4 + 2] cycloaddition pathway to afford silacycles accompanied by variable amounts of competing ene, [2 + 2] and silene dimer by-products. The silacycles are formed with good chemo- and stereo-selectivity and provide access to diols and lactones via a phenyl-triggered Fleming-Tamao oxidation.
Syntheses of three regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes, pseudo-geminal, pseudo-ortho, and ortho, have been carried out or, in the latter two cases, newly developed. It has, therefore, been demonstrated that all aromatic-substituted isomers relevant for use as chelating ligands for asymmetric catalysis are accessible. These P,N-ligands, along with their diastereoisomers, were shown to exhibit widely differing activity and enantioselectivity (up to 89% ee) in the Pd-catalyzed asymmetric allylic alkylation reaction.
Quideau S, Pouysegu L, Avellan AV, Whelligan DK, Looney MA (2001) Hypervalent iodine(III)-mediated oxidative acetoxylation of 2-methoxyphenols for regiocontrolled nitrogen benzannulation, Tetrahedron Lett 42 (42) pp. 7393-7396
Nitrogen-tethered 2-methoxyphenols are conveniently dearomatized into synthetically useful orthoquinol acetates by treatment with phenyliodine(III) diacetate in methylene chloride at low temperature. Subsequent fluoride- or base-induce intramolecular nucleophilic addition reactions furnish indole and quinoline derivatives. The potential of this methodology for the synthesis or a functionalized lycorine-type alkaloid skeleton is introduced here. (C) 2001 Elsevier Science Ltd. All rights reserved.
Whelligan DK (2009) Benzotriazole Linker Units, In: Scott PJH (eds.), Linker Strategies in Solid-Phase Organic Synthesis 11 Wiley
Syntheses of polymer-supported benzotriazoles
Polymer-supported benzotriazole linked reactions
Bolm C, Whelligan DK (2006) The synthesis of pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl[2.2]paracyclophanes for use as ligands in asymmetric catalysis, Adv Synth Catal 348 (15) pp. 2093-2100
Synthetic routes to pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl-[2.2]paracyclophanes (and the diastereoisomers of each) for use as N,O ligands in asymmetric catalysis have been devised. The substitution pattern was found to have a strong effect on the rate and enantioselectivity of the formed catalyst in the addition of diethylzinc to benzaldehyde.
Steel PG, Whelligan DK (2002) Silenes: Novel reagents for alkene functionalisation., ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 224 pp. U161-U161 AMER CHEMICAL SOC
Whelligan DK, Thomson DW, Taylor D, Hoelder S (2010) Two-Step Synthesis of Aza- and Diazaindoles from Chloroamino-N-heterocycles Using Ethoxyvinylborolane, J Org Chem 75 (1) pp. 11-15
An efficient two-step route to a broad range of aza- and diazaindoles was established, starting from chloroamino-N-heterocycles, without the need for protecting groups. The method involves an optimized Suzuki-Miyaura coupling with (2-ethoxyvinyl)borolane followed by acetic acid-catalyzed cyclization.
Whelligan DK, Solanki S, Taylor D, Thomson DW, Cheung KMJ, Boxall K, Mas-Droux C, Barillari C, Burns S, Grummitt CG, Collins I, van Montfort RLM, Aherne GW, Bayliss R, Hoelder S (2010) Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization, J Med Chem 53 (21) pp. 7682-7698
We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.
Wang L, Magliocca E, Cunningham E, Mustain W, Poynton S, Escudero-Cid R, Nasef M, Ponce-Gonzalez J, Bance-Souahli R, Slade R, Whelligan D, Varcoe J (2016) An optimised synthesis of high performance radiation-grafted anion-exchange membranes, Green Chemistry 19 pp. 831-843 Royal Society of Cemistry
High performance benzyltrimethylammonium-type alkaline anion-exchange membranes (AEM), for application in electrochemical devices such as anion-exchange membrane fuel cells (AEMFC), were prepared by the radiation grafting (RG) of vinylbenzyl chloride (VBC) onto 25 ¼m thick poly(ethylene-co-tetrafluoroethylene) (ETFE) films followed by amination with trimethylamine. Reductions in electron-beam absorbed dose and amount of expensive, potentially hazardous VBC were achieved by using water as a diluent (reduced to 30 ? 40 kGy absorbed dose and 5%vol VBC) instead of the prior-art method that used organic propan-2-ol diluent (required 70 kGy dose and 20%vol VBC monomer). Furthermore, the water from the aqueous grafting mixture was easily separated from residual monomer (after cooling) and was reused for a further grafting reaction: the resulting AEM exhibited an ion-exchange capacity of 2.1 mmol g-1 (cf. 2.1 mmol g-1 for the AEM made using fresh grafting mixture). The lower irradiation doses resulted in mechanically stronger RG-AEMs compared to the reference RG-AEM synthesised using the prior-art method. A further positive off-shoot of the optimisation process was the discovery that using water as a diluent resulted in an enhanced (i.e. more uniform) distribution of VBC grafts as proven by Raman microscopy and corroborated using EDX analysis: this led to enhancement in the Cl- anion-conductivities (up to 68 mS cm-1 at 80°C for the optimised fully hydrated RG-AEMs vs. 48 mS cm-1 for the prior-art RG-AEM reference). A down-selected RG-AEM of ion-exchange capacity = 2.0 mmol g-1, that was synthesised using the new greener protocol with 30 kGy electron-beam absorbed dose, led to an exceptional beginning-of-life H2/O2 AEMFC peak power density of 1.16 W cm?2 at 60°C in a benchmark test using industrial standard Pt-based electrocatalysts and unpressurised gas supplies: this was higher than the 0.91 W cm-1 obtained with the reference RG-AEM (IEC = 1.8 mmol g-1) synthesised using the prior-art protocol.
Berry MB, Griffiths RJ, Sanganee MJ, Steel PG, Whelligan DK (2004) Silenes as novel synthetic reagents: identification of a practical method for silene generation and trapping., Org Biomol Chem 2 (16) pp. 2381-2392
The elucidation of a robust and reliable sequence for the generation of highly reactive transient silenes from simple aldehydes is described. The key step involves a silyl-modified Peterson olefination which critically depends on the presence of a sub-stoichiometric amount of soluble lithium salts (LiBr).
Sanganee MJ, Steel PG, Whelligan DK (2003) Novel one-pot synthesis of aryltris(trimethylsilyl)silanes., J Org Chem 68 (8) pp. 3337-3339
The simple combination of tris(trimethylsilyl)potassium, ArMgBr, and ArBr provides a novel "one-pot" synthesis of aryl(tristrimethylsilyl)silanes. A mechanistic rationale for this conversion is proposed.
Wylie L, Innocenti P, Whelligan DK, Hoelder S (2012) Synthesis of amino-substituted indoles using the Bartoli reaction, Org Biomol Chem 10 (22) pp. 4441-4447
We report herein the concise preparation of a range of functionalised aminoindoles via a new application of the Bartoli reaction. Scope and limitations of the methodology have been extensively studied to reveal the importance of protecting groups and substitution patterns. The use of amino substituted nitroanilines for the Bartoli reaction is to our knowledge unprecedented. Our work thus represents a novel entry into substituted aminoindoles which are relevant building blocks for both the fine chemical and pharmaceutical industry.
Beemelmanns C, Husmann R, Whelligan DK, Özçubukçu S, Bolm C (2012) Planar-Chiral Bis-silanols and Diols as H-Bonding Asymmetric Organocatalysts, Eur J Org Chem pp. 3373-3376
Ponce-González J, Whelligan DK, Wang L, Bance-Soualhi R, Wang Y, Peng Y, Peng H, Apperley DC, Sarode HN, Pandey TP, Divekar AG, Seifert S, Herring AM, Zhuang L, Varcoe J (2016) High performance aliphatic-heterocyclic benzyl-quaternary ammonium radiation-grafted anion-exchange membranes, Energy and Environmental Science 9 (12) pp. 3724-3735
Anion-exchange membranes (AEM) containing saturated-heterocyclic benzyl-quaternary ammonium (QA) groups
synthesised by radiation-grafting onto poly(ethylene-co-tetrafluoroethylene) (ETFE) films are reported. The relative
properties of these AEMs are compared with the benchmark radiation-grafted ETFE-g-poly(vinylbenzyltrimethylammonium)
AEM. Two AEMs containing heterocyclic-QA head groups were down-selected with higher relative stabilities in aqueous KOH
(1 mol dm-3) at 80°C (compared to the benchmark): these 100 ¼m thick (fully hydrated) ETFE-g-poly(vinylbenzyl-Nmethylpiperidinium)-
and ETFE-g-poly(vinylbenzyl-N-methylpyrrolidinium)-based AEMs had as-synthesised ion-exchange
capacities (IEC) of 1.64 and 1.66 mmol g-1, respectively, which reduced to 1.36 mmol dm-3 (ca. 17 ? 18% loss of IEC) after
alkali ageing (the benchmark AEM showed 30% loss of IEC under the same conditions). These down-selected AEMs exhibited
as-synthesised Cl- ion conductivities of 49 and 52 mS cm-1, respectively, at 90°C in a 95% relative humidity atmosphere, while
the OH- forms exhibited conductivities of 138 and 159 mS cm-1, respectively, at 80°C in a 95% relative humidity atmosphere.
The ETFE-g-poly(vinylbenzyl-N-methylpyrrolidinium)-based AEM produced the highest performances when tested as
catalyst coated membranes in H2/O2 alkaline polymer electrolyte fuel cells at 60°C with PtRu/C anodes, Pt/C cathodes, and
a polysulfone ionomer: the 100 ¼m thick variant (synthesised from 50 ¼m thick ETFE) yielded peak power densities of 800
and 630 mW cm-2 (with and without 0.1 MPa back pressurisation, respectively), while a 52 ¼m thick variant (synthesised
from 25 ¼m thick ETFE) yielded 980 and 800 mW cm-2 under the same conditions. From these results, we make the
recommendation that developers of AEMs, especially pendent benzyl-QA types, should consider the benzyl-Nmethylpyrrolidinium
head-group as an improvement to the current de facto benchmark benzyltrimethylammonium headgroup.
Ong AL, Whelligan DK, Fox ML, Varcoe JR (2013) Impact of 1 mmol dm(-3) concentrations of small molecules containing nitrogen-based cationic groups on the oxygen reduction reaction on polycrystalline platinum in aqueous KOH (1 mol dm(-3)), Physical Chemistry Chemical Physics 15 (43) pp. 18827-18834
Alkaline anion-exchange membranes (AAEMs) containing cationic head-groups (e.g. involving quaternary ammonium and imidazolium groups) are of interest with regard to application in alkaline polymer electrolyte fuel cells (APEFCs). This initial ex situ study evaluated the effect of 1 mmol dm concentrations of model molecules containing (AAEM-relevant) cationic groups on the oxygen reduction reaction on a polycrystalline platinum disk (Pt) electrode in aqueous KOH (1 mol dm(-3)). The cationic molecules studied were tetramethylammonium (TMA), benzyltrimethylammonium (BTMA), 1-benzyl-3-methylimidazolium (BMI), 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane (BAABCO) and 6-(benzyloxy)-N,N,N-trimethylhexan-1-aminium (BOTMHA). Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms, derived estimates of apparent electrochemically active surface areas, Tafel slopes, apparent exchange-current densities and the number of electrons transferred (per O molecule) were compared. The results strongly suggest that 1 mmol dm(-3) concentrations of BTMA, BAABCO, and (especially) BMI seriously inhibit the catalytic activities of Pt in an aqueous KOH electrolyte at 25 °C. The negative influence of (benzene-ring-free) TMA and Cl anions (KCl control experiment) appeared to be less severe. The separation of the trimethylammonium group from the benzene ring via a hexyloxy spacer chain (in BOTMHA) also produced a milder negative effect. © the Owner Societies 2013.
Ong AL, Inglis KK, Whelligan DK, Murphy S, Varcoe JR (2015) Effect of cationic molecules on the oxygen reduction reaction on fuel cell grade Pt/C (20 wt%) catalyst in potassium hydroxide (aq, 1 mol dm(-3))., Phys Chem Chem Phys 17 (18) pp. 12135-12145
This study investigates the effect of 1 mmol dm(-3) concentrations of a selection of small cationic molecules on the performance of a fuel cell grade oxygen reduction reaction (ORR) catalyst (Johnson Matthey HiSPEC 3000, 20 mass% Pt/C) in aqueous KOH (1 mol dm(-3)). The cationic molecules studied include quaternary ammonium (including those based on bicyclic systems) and imidazolium types as well as a phosphonium example: these serve as fully solubilised models for the commonly encountered head-groups in alkaline anion-exchange membranes (AAEM) and anion-exchange ionomers (AEI) that are being developed for application in alkaline polymer electrolyte fuel cells (APEFCs), batteries and electrolysers. Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms and subsequently derived data (e.g. apparent electrochemical active surface areas, Tafel plots, and number of [reduction] electrons transferred per O2) were compared. The results show that the imidazolium examples produced the highest level of interference towards the ORR on the Pt/C catalyst under the experimental conditions used.
Berry MB, Griffiths RJ, Sanganee MJ, Steel PG, Whelligan DK (2003) Silenes as novel synthetic reagents: synthesis of diols and lactones from simple alkyldienes, Tetrahedron Lett 44 (51) pp. 9135-9138
Aryl substituted silenes can be generated by a modified Peterson olefination reaction and trapped in situ to afford silacycles with high diastereoselectivity. These silacycles can be elaborated by 'Fleming-Tamao' type oxidation to provide access to functionalized diols and lactones. (C) 2003 Elsevier Ltd. All rights reserved.
Quideau S, Pouysegu L, Avellan AV, Whelligan DK (2001) Synthetic studies on Amaryllidaceae lycorine-type alkaloids., ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 221 pp. U199-U199 AMER CHEMICAL SOC
In the field of drug discovery, pyrrolopyridine moieties are often incorporated into bioactive molecules. This is due to their ability to form both pi-stacking and hydrogen bonding interactions when binding to target proteins. This project aimed to provide a robust and rapid method of synthesis that will provide access to substituted pyrrolopyridines. The work is based on a previously published method involving the synthesis of ethoxyvinyl(amino)arenes, by Suzuki reaction of halo-aminoarenes, followed by cyclisation. It was hoped this method would be advanced by applying alternative cyclisation reactions to the ethoxyvinyl(amino)arenes to give 3-substituted products in one step. In comparison with previous methods, this route would be inexpensive, robust and applicable to a wide range of substrates. It was also envisaged that alternative starting materials could be used to make it a more generalised method for the synthesis of bicyclic arenes.
Work began with testing the reproducibility of the previously published method of synthesising the ethoxyvinyl(amino)arenes. This was done successfully, although a change in ligand (SPhos to RuPhos) proved beneficial, with seven different analogues being synthesised in yields ranging from 36% to 98%. This same reaction was attempted with halo-hydroxypyridines, with a novel route to furopyridines in mind, but with no success. The synthesis of non-commercially available halo-hydroxypyridines themselves also proved to be challenging with no material being isolated.
Various methods were tested for the bromo-cyclisation of ethoxyvinyl(amino)arenes to 3-bromopyrrolopyridines. A two-step method using acid cyclisation followed by bromination was entirely successful. Two-step, one-pot and one-step methods both appeared to promote polymerisation/oligermisation. Success was achieved with a one-step method employing an acid additive but only on selected ethoxyvinyl(amino)arene isomers and with varying yields.
The work was extended to the attempted synthesis of anti-malarial precursors using the bromo-pyrrolopyridine isomers as building blocks and converting them to alkyl-linked glutarimides. This led to the successful and novel synthesis of the reactants vinyl glutarimide and glutarimylethylborolane. However, successful conditions for their palladium catalysed cross coupling with the bromides were not found.
Wang L, Brink J, Liu Y, Herring A, Ponce-González J, Whelligan DK, Varcoe J (2017) Non-fluorinated pre-irradiation-grafted (peroxidated) LDPE-based
anion-exchange membranes with high performance and stability,
Energy & Environmental Science 10 pp. 2154-2167 Royal Society of Chemistry
Radiation-grafted anion-exchange membrane (RG-AEM) research has predominantly focused on the chemical stability of
the polymer-bound positively-charged head-groups that enable anion conduction. The effect of the backbone polymer
chemistry, of the precursor film, on RG-AEM stability has been studied to a lesser extent and not for RG-AEMs made from
pre-irradiation grafting of polymer films in air (peroxidation). The mechanical strength of polymer films is generally
weakened by exposure to high radiation doses (e.g. from a high-energy e?-beam) and this is mediated by chemical
degradation of the main chains: fluorinated films mechanically weaken at lower absorbed doses compared to nonfluorinated
films. This study systematically compares the performance difference between RG-AEMs synthesised from a
non-fluorinated polymer film (low-density polyethylene ? LDPE) and a partially-fluorinated polymer film (poly(ethylene-cotetrafluoroethylene)
? ETFE) using the peroxidation method (pre-irradiation in air using an e?-beam). Both the LDPE and
ETFE precursor films used were 25 ¼m in thickness, which led to RG-AEMs of hydrated thicknesses in the range 52 ? 60 ¼m.
The RG-AEMs (designated LDPE-AEM and ETFE-AEM, respectively) all contained identical covalently-bound
benzyltrimethylammonium (BTMA) cationic head-groups. An LDPE-AEM achieved a OH? anion conductivity of 145 mS cm-1
at 80 °C in a 95% relative humidity environment and a chloride Cl? anion conductivity of 76 mS cm-1 at 80 °C when fully
hydrated. Alkali stability testing showed that the LDPE-AEM mechanically weakened to a much lower extent when treated
in aqueous alkaline solution compared to the ETFE-AEM. This LDPE-AEM outperformed the ETFE-AEM in H2/O2 anionexchange
membrane fuel cell (AEMFC) tests due to high anion conductivity and enhanced in situ water transport (due to the
lower density of the LDPE precursor): a maximum power density of 1.45 W cm-2 at 80 °C was achieved with an LDPE-AEM
alongside a Pt-based anode and cathode (cf. 1.21 mW cm-2 for the benchmark ETFE-AEM). The development of more
mechanically robust RG-AEMs has, for the first time, led to the ability to routinely test them in fuel cells at 80 °C (cf. 60 °C
was the prior maximum temperature that could be routinely used with ETFE-based RG-AEMs). This development facilitates
the application of non-Pt catalysts: 931 mW cm-2 was obtained with the use of a Ag/C cathode at 80 °C and a Ag loading of
0.8 mg cm-2 (only 711 mW cm-2 was obtained at 60 °C).
Ponce-González J, Ouachan I, Varcoe J, Whelligan D (2017) Radiation-induced grafting of a butyl-spacer styrenic monomer
onto ETFE: the synthesis of the most alkali stable radiationgrafted
anion-exchange membrane to date,
JOURNAL OF MATERIALS CHEMISTRY A 6 (3) pp. 823-827 The Royal Society of Chemistry
An ETFE-(poly(ethylene-co-tetrafluoroethylene))-based radiationgrafted
anion-exchange membrane (AEM) containing a butylspacer
between the benzene and the methylpyrrolidinium groups
(C4-AEM) had double the ex-situ alkali stability at 80 °C compared
to a methylene benchmark (C1-AEM). H2/O2 fuel cells containing
the C4-AEM still achieved a peak power density of > 1 W cm-2.
A major disadvantage of fossil fuels being the primary source of global energy is the negative effect that the burning of such fuels has on the planet. This is evident in factors including climate change. Reverse electrodialysis (RED) is an emerging membrane-based process for clean energy conversion. The technique works by utilising the transport of cations and anions through ion-exchange membranes (IEMs) to create an electrical current, via differences in chemical potential, when mixing salt solutions of different concentrations. The core components of a RED cell, and the largest factor affecting the performance and economic viability, are the IEMs.
Recently, increased efforts have been made with regard to the preparation of IEMs and understanding the relationships between membrane properties and RED cell power performance. The work in this thesis has focused on the development of RED-focused IEMs by radiation induced grafting polymerisation (RIG). The RIG technique has been used to chemically modify commercially available polymer films to produce a large sample of IEMs targeted for application in RED. The IEM properties were experimentally determined and used as part of a literature recognised mathematical model to estimate the gross power densities that can theoretically be obtained by each IEM in a working RED cell.
The results obtained for RIG IEMs contradicts the earlier notion that IEM permselectivity is of less significance than area resistance and indicate that a minimum permselectivity (H 90%) is required for RED IEMs. A trade-off relationship between the two properties is observed, rationalised by Donnan exclusion factors surrounding IEM water content. Chemical crosslinking was implemented into RIG methods to control excessive gravimetric water uptake (WU%). Linear tertiary diamine head-groups were used to produce crosslinked anion-exchange membranes (AEMs), with tetramethylhexanediamine (TMHDA) head-group yielding theoretical gross power densities of 3.42 W m-2 for single IEM RED model calculations and 1.89 W m-2 for AEM/CEM pair calculations (paired with literature SPEEK 65 CEM). Crosslinked CEMs were produced via chemical crosslinking by divinylbenzene (DVB) and bis(vinylphenyl)ethane (BVPE) was implemented into the RIG method, which resulted in cation-exchange membranes (CEMs) yielding theoretical gross power densities of 5.55 and 5.99 W m-2 respectively, for single IEM RED model calculations and 2.81 and 2.71 W m-2 for AEM/CEM pair calculations (paired with commercial Neospeta® AFN AEM).
Ponce-González J, Varcoe J, Whelligan D (2018) Commercial monomer availability leading to missed opportunities?
Anion-exchange membranes made from meta-vinylbenzyl chloride
exhibit an alkali stability enhancement,
ACS Applied Energy Materials 1 (5) pp. 1883-1887 American Chemical Society
Benzyltrimethylammonium-type anion-exchange polymers are
common in alkali membrane fuel cells and water electrolysers but
they suffer from degradation under alkaline conditions. Radiationgrafted
anion-exchange membranes exhibit an alkali stability enhancement
when made using non-commercial meta-only vinylbenzyl
chloride (VBC) monomer, compared to the use of commercially
available para-only or meta/para-mixed VBC isomers. We hypothesize
a mechanism on why the use of meta-VBC eliminates AEM
degradation via chain scission.
The base excision DNA repair (BER) enzyme alkyladenine glycosylase (AAG) can drive DNA damage-induced cell death in specific cell types in mice and can induce frameshift mutagenesis and microsatellite instability in yeast and in human cells. It was hypothesised that humans with overactive AAG, or who encounter higher levels of alkylating agents in the form of pollution, diet or chemotherapy, or suffer an ischaemic reperfusion event such as a stroke, may incur increased tissue damage through this mechanism. An inhibitor of AAG is required to further study this mechanism and form a potential lead for future drug discovery.
In previous work, to discover an inhibitor, a published X-ray co-crystal structure of AAG was used in a virtual screen of two million compounds for potential binding activity. Of the top 49 virtual hits, one real hit triazole-thione-based inhibitor (UNIS00021) with an IC50 of ~60 µM was identified in a biochemical assay. In this thesis, efforts to design and synthesise analogues of UNIS00021 with improved potency against AAG are described.
Successful divergent syntheses were developed which provided access to: 1. analogues varying at the alkyl group of the amide (six different amides); 2. analogues with a free amine in place of the amide and with variation of the length of the alkyl linkage group (five different amines); and 3. analogues bearing a C5-methyl group instead of thiol/thione at the core (one cyclohexylamide triazole). Work was also begun on the synthesis of analogues varying the N4-CH2-aryl group but was not completed due to time constraints.
Two main types of microplate biochemical assay were investigated for assessment of the candidate inhibitors? potencies against AAG using: 1. a surface-bound fluorescein-conjugated substrate DNA-oligomer; and 2. a free substrate oligomer and LCMS. Despite much experimentation, these assays continued to show inconsistent and irreproducible inhibition curves so it was not possible to make conclusions about the candidate inhibitors? potencies.