Research Themes in the Clayden Group

Theme 1: Rational Conformational Control

Current and recent funding in this area – EPSRC Programme Grant ‘Molecular Robotics’; European Research Council Advanced Grant ROCOCO, BBSRC Grant I007962, JohnsonMatthey Catalysts, BBSRC and EPSRC studentships.

1.1 Atropisomers and their asymmetric synthesis

Atropisomers—compounds which are chiral by virtue of restricted rotation about a single bond—have provided chemists with some of the most successful ever ligands for asymmetric catalysis.  Our research in this area addresses two areas where there are major opportunities for development.

a) Discovery and application of new atropisomer classes

The vast majority of atropisomeric structures fall into a single class: biaryls, and almost all involve rotational restriction about a C–C bond.  Over the last 15 years we have been exploring atropisomers based on unconventional structures involving amides, ethers, sulfur compounds and ureas.  We have discovered some mechanistically intriguing ways of making them as single enantiomers using dynamic resolution techniques, and we have explored their application as new classes of chiral ligands.  Atropisomers are in effect ‘frozen conformers’, and our work has made extensive use of the connections between conformational control  and atropisomerism.  We’re now looking to use the methods and systems we have pioneered to build new classes of atropisomeric ligands for use in asymmetric catalysis.

Representative publications in this area:

264. Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides

Romain Costil, Harvey J. A. Dale, Natalie Fey, George Whitcombe, Johnathan V. Matlock, Jonathan Clayden

Angewandte Chem. Int. Ed. 2017, in press [doi 10.1002/anie.201706341]

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159. The challenge of atropisomerism in drug discovery

Jonathan Clayden, Wesley J. Moran, Paul J. Edwards and Steven R. LaPlante

Angew. Chemie Int. Ed. 2009, 48, 6398-6401 [doi 10.1002/anie.200901719]

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b) Dynamic methods for the asymmetric synthesis of atropisomers

Even well established atropisomer classes are not typically made by asymmetric synthesis: for some, tedious resolution methods are required. We are investigating alternative methods involving dynamic kinetic resolution or dynamic thermodynamic resolution for achieving atroposelective synthesis.  Recently for example we have explored the application of artificially evolved enzymes catalyzing redox processes to the asymmetric synthesis of atropisomers of potential value in the synthesis of chiral ligands for asymmetric synthesis.

Representative publications in this area:

256. Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N-Oxide Lewis Base Catalysts

Samantha Staniland, Ralph W. Adams, Joseph J. W. McDouall, Irene Maffucci, Alessandro Contini, Damian Grainger, Nicholas J. Turner, Jonathan Clayden

Angew. Chemie. Int. Ed., 2016, 55, 10755-10759 [doi 10.1002/anie.201605486]

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227. Enzymatic desymmetrising redox reactions for the asymmetric synthesis of biaryl atropisomers

Samantha Staniland, Bo Yuan, Nelson Giménez-Agulló, Tommaso Marcelli, Simon Willies, Damian Grainger, Nicholas J. Turner and Jonathan Clayden

Chem. Eur. J. 2014, 20, 13084-13088 [doi 10.1002/chem.201404509]

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188. Is nevirapine atropisomeric? Experimental and computational evidence for rapid conformational inversion

Edmund W. D. Burke, Gareth A. Morris, Mark A. Vincent, Ian H. Hillier and Jonathan Clayden

Org. Biomol. Chem. 2012, 10, 716-719 [doi 10.1039/c1ob06490h]

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1.2 Dynamic Foldamer Chemistry

Helical structures are ubiquitous in Nature, and synthetic structures with well-defined helical conformations are termed ‘foldamers’. We have explored separately the concepts of helical preference (a thermodynamic preference for a global helical structure, as opposed to a random coil) and screw-sense preference (the thermodynamic preference for that helix to adopt a specific left- or right-handedness), by building synthetic helices made from achiral monomers. In biomolecular helices, these concepts are entangled because the chiral monomers (for example amino acids or nucleosides) making up the helix enforce a preference for both helicity and screw-sense.  Using some simple (but previously overlooked) spectroscopic and stereochemical principles, we have developed NMR (1H, 13C and 19F) methods, probes and markers for exploring the kinetics and thermodynamics of helical interconversions on a range of timescales.  We are now extending these probes to include more sensitive fluorescent and coloured reporters.  We are also interested in stressed helices – helices with faults, bends and breaks.  These have rarely been explored, but throw light on mechanisms of helical interconversion in foldamer structures.  By forcing a helix to contain a fault structure, we hope to characterize in detail unusual conformational features such as the elusive peptide gamma turn.

Representative publications in this area

260. A tendril perversion in a helical oligomer: trapping and characterizing a mobile screw-sense reversal

Michael Tomsett, Irene Maffucci, Bryden A. F. Le Bailly, Liam Byrne, Stefan M. Bijvoets,
M. Giovanna Lizio, James Raftery, Craig P. Butts, Simon J. Webb, Alessandro Contini, Jonathan Clayden

Chem. Sci., 2017, 8, 3007-3018 [doi 10.1039/C6SC05474A]

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 253. The meso helix: symmetry and symmetry-breaking in dynamic oligourea foldamers with reversible hydrogen-bond polarity

Romina Wechsel, James Raftery, Dominique Cavagnat, Gilles Guichard, Jonathan Clayden

Angew. Chemie. Int. Ed., 2016, 55, 9657-9661 [doi 10.1002/anie.201604496] (‘Hot Paper’)

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 251. Dynamic foldamer chemistry (review)

Bryden A. F. Le Bailly and Jonathan Clayden

Chem. Commun., 2016, 52, 4852-4863 [review] [doi 10.1039/C6CC00788K]

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247. Refoldable foldamers: global conformational switching by deletion or insertion of a single hydrogen bond

Bryden A. F. Le Bailly, Liam Byrne and Jonathan Clayden

Angew. Chemie Int. Ed. 2016, 55, 2312-2316 [doi 10.1002/anie.201510605]

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236. Flaws in foldamers: conformational uniformity and signal decay in achiral helical peptide oligomers

Bryden A. F. Le Bailly, Liam Byrne, Vincent Diemer, Mohammadali Foroozandeh, Gareth A. Morris, and Jonathan Clayden

Chem. Sci. 2015, 6, 2313-2322 [doi 10.1039/C4SC03944K]

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222. Engineering the structure of an N-terminal beta-turn to maximize screw-sense preference in achiral helical peptide chains

Matteo De Poli, Liam Byrne, Robert A. Brown, Jordi Solà, Alejandro Castellanos, Thomas Boddaert, Romina Wechsel, Jonathan D. Beadle, and Jonathan Clayden

J. Org. Chem. 2014, 79, 4659-4675 [doi 10.1021/jo500714b]

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212. The N-terminal nonapeptide of cephaibols A and C: a naturally occurring example of mismatched helical screw-sense control

Ugo Orcel, Matteo De Poli, Marta De Zotti and Jonathan Clayden

Chem. Eur. J. 2013, 19, 16357-16365 [doi 10.1002/chem.201302648]

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192. Induction of unexpected left-handed helicity by an N-terminal L-amino acid in an otherwise achiral peptide chain

Robert A. Brown, Tommaso Marcelli, Matteo De Poli, Jordi Solà, and Jonathan Clayden

Angew. Chemie Int. Ed. 2012, 51, 1395-1399 [doi 10.1002/anie.201107583]

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179. Measuring screw-sense preference in a helical oligomer by comparison of 13C NMR signal separation at slow and fast exchange

Jordi Solà, Gareth A. Morris and Jonathan Clayden

J. Am. Chem. Soc. 2011, 133, 3712-3715 [doi 10.1021/ja1097034]

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1.3 Molecular Communication Devices

Nature uses molecular conformation in subtle and sometimes elaborate ways to control function and to communicate information—allosteric effects in enzymes, or switching in receptors, for example.

a) Ultra-remote stereocontrol

We have constructed extended molecules in which conformational preferences are relayed over unprecedentedly long distances, and have for the last 10 years been the world record holders for remote stereocontrol (1,23-asymmetric induction published in 2004; 1, 31-, 1,46- and 1,61-asymmetric induction published in 2013). Current work is seeking to extend the ability to control reactions at a distance to catalytic systems, which would allow us to make even more biomimetic receptor mimics with chemical, rather than spectroscopic, outputs. We are also looking to achieve remote stereocontrol through polymers – in other words extend the distances over which information is communicated beyond the nanoscale towards the 0.01-1 micrometre scale.

Representative publications in this area:

215. Foldamer-mediated remote stereocontrol: >1,60 asymmetric induction

Liam Byrne, Jordi Solà, Thomas Boddaert, Tommaso Marcelli, Ralph W. Adams, Gareth A. Morris and Jonathan Clayden

Angew. Chemie. Int. Ed. 2014, 53, 151-155 [doi 10.1002/anie.201308264] (‘VIP paper’)

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See also Highlights summary article: C. P. Johnston and M. D. Smith Angew. Chem. Int. Ed. 2014, 53, 3315-3317 [doi 10.1002/anie.201400154]


239. Screw sense alone can govern enantioselective extension of a helical peptide by kinetic resolution of a racemic amino acid

Liam Byrne, Jordi Solà and Jonathan Clayden

Chem. Commun. 2015, 51, 10965-10968 [doi 10.1039/c5cc01790d]

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100. Ultra-remote stereocontrol by conformational communication of information along a carbon chain

Jonathan Clayden, Andrew Lund, Lluís Vallverdú and Madeleine Helliwell

Nature, 2004431, 966-971 [doi 10.1038/nature02933]

 

b) Synthesis of membrane-bound artificial receptors.

We are currently working to make molecules which mimic biology’s ability to encode, manipulate and communicate information.  We have reported artificial receptors that bind ligands and relay information about their structure and stereochemistry to a spectroscopic reporter lying some nanometre distances away. We have recently used these molecules in systems that function in the membrane environment, potentially allowing us to communicate information across lipid bilayers, in a manner reminiscent of the G-protein coupled receptor.  The protein rhodopsin, central to the function of human vision, is a modified receptor, and we have reported an artificial rhodopsin mimics that captures information about incident light and communicate that information to a distance chemical site through a conformational change.

Representative publications in this area:

259. Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

Francis G. A. Lister, Bryden A. F. Le Bailly, Simon J. Webb and Jonathan Clayden

Nature Chem., 2017, 9, 420-425 [doi 10.1038/nchem.2736]. See also the Nature Chemistry editorial ‘Sending a message to the other side’ (Nature Chem., 2017, 9, 403 [doi 10.1038/nchem.2776]) and Highlight article ‘Membrane messengers’ (Nature Chem., 2017, 9, 403 [doi 10.1038/nchem.2775]) covering this work.

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250. Conformational photoswitching of a synthetic peptide foldamer bound within a phospholipid bilayer

Matteo De Poli, Wojciech Zawodny, Ophélie Quinonero, Mark Lorch, Simon J. Webb and Jonathan Clayden

Science 2016, 352, 575-580 [doi 10.1126/science.aad8352]

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240. Conformational switching of a foldamer in a multi-component system by pH-filtered selection between competing non-covalent interactions

Julien Brioche, Sarah J. Pike, Sofja Tshepelevitsh, Ivo Leito, Gareth A. Morris, Simon J. Webb, and Jonathan Clayden

J. Am. Chem. Soc. 2015, 137, 6680-6691 [doi 10.1021/jacs.5b03284]

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213. End-to-end conformational communication through a synthetic purinergic receptor by ligand-induced helicity switching

Robert A. Brown, Vincent Diemer, Simon J. Webb and Jonathan Clayden

Nature Chem. 2013, 5, 853-860 [doi 10.1038/nchem.1747]

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Theme 2: New Molecular Reactivity

Current and recent funding in this area – EPSRC Grant E0123456, Syngenta, AstraZeneca, GlaxoSmithKline, EPSRC studentships

Over the last 20 years we have discovered ways in which the restricted conformation of planar functional groups such as amides and ureas endue them, and their anionic derivatives, with remarkable new reactivity. Many of these reactions fly in the face of well-established principles of polar reactivity: for example, we discovered how to force anions to attack electron-rich aromatic rings and alkenes, as well as new ways to destroy aromaticity.  We have used the resulting partially saturated products as starting materials in a variety of synthetic strategies.

2.1 Carbolithiation of electron-rich π systems: stereoselective arylation, vinylation and alkylation methods

We are currently exploring ways in which the geometry of te urea linkage and its congeners allows the formation of C–C bonds by unusual, often stereospecific, reactions.  One target group of interest at present are quaternary amino acids arylated at their a-position, which we make by an N to C aryl migration.  We are exploring similar chemistry involving vinylation, which opens up the possibility of making spirocyclic compounds by metathesis chemistry. The methods we develop are then applied to the synthesis of valuable, biologically active targets.

Representative publications in this area:

264. Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides

Romain Costil, Harvey J. A. Dale, Natalie Fey, George Whitcombe, Johnathan V. Matlock, Jonathan Clayden

Angewandte Chem. Int. Ed. 2017, in press [doi 10.1002/anie.201706341]

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263. Geometry-selective C-alkenylation of lithiated α-aminonitriles: quaternary α-alkenyl amino acids and hydantoins

Josep Mas-Roselló, Shuji Hachisu and Jonathan Clayden

Angewandte Chem. Int. Ed. 2017, in press [doi 10.1002/anie.201704908]

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255. Medium Ring Nitrogen Heterocycles by Migratory Ring Expansion of Metallated Ureas

Jessica E. Hall, Johnathan V. Matlock, John W. Ward, Katharine V. Gray, Jonathan Clayden

Angew. Chemie. Int. Ed., 2016, 55, 11153-11157  [doi 10.1002/anie.201605714] (‘VIP paper’ with ChemistryViews highlight feature and Synfacts report)

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241. Pseudoephedrine-directed asymmetric alpha-arylation of alpha-amino acid derivatives

Rachel C. Atkinson, Fernando Fernández-Nieto, Josep Mas Roselló and Jonathan Clayden

Angew. Chem. Int. Ed. 2015, 54, 8961-8965 [doi 10.1002/anie.201502569]

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237. 2,2- And 2,6-diarylpiperidines by aryl migration within lithiated urea derivatives of tetrahydropyridines

Michael B. Tait, Sam Butterworth, and Jonathan Clayden

Org. Lett. 2015, 17, 1236-1239 [doi 10.1021/acs.orglett.5b00199]

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214. Intramolecular arylation of amino acid enolates

Rachel C. Atkinson, Daniel J. Leonard, Julien Maury, Daniele Castagnolo, Nicole Volz, and Jonathan Clayden

Chem. Commun. 2013, 49, 9734-9736 [doi 10.1039/c3cc46193a]

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165. Synthesis of (–)-(S,S)-clemastine by invertive N to C aryl migration in a lithiated carbamate

Anne M. Fournier, Robert A. Brown, William Farnaby, Hideki Miyatake-Ondozabal, and Jonathan Clayden

Org. Lett. 2010, 12, 2222-2225 [doi 10.1021/ol100627c]

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135. Substituted Diarylmethylamines by Stereospecific Intramolecular Electrophilic Arylation of Lithiated Ureas

Jonathan Clayden, Jérémy Dufour, Damian M. Grainger and Madeleine Helliwell

J. Am. Chem. Soc. 2007, 129, 7488-7489 [doi 10.1021/ja071523a]

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2.2 Nucleophilic dearomatisation

We have reported several new methods for nucleophilic attack on aromatic rings that lead to non-aromatic products.  Often, the remaining unsaturation provides a valuable handle for introducing further functionality, and we have used this as a strategy for the synthesis of bioactive targets including kainic acid, an acromelic acid analogue, and several members of the isodomoic acid family. Currently we are seeking to extend our methods to the dearomatising cyclisations and spirocyclisations of heterocyclic substrates.

Representative publications in this area

204. Spirocyclic dihydropyridines by electrophile-induced dearomatizing cyclization of N-alkenyl pyridinecarboxamides

Jemma Senczyszyn, Heloise Brice and Jonathan Clayden

Org. Lett. 2013, 15, 1922-1925 [doi 10.1021/ol400571j]

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152. Doubly dearomatising intramolecular coupling of a nucleophilic and an electrophilic heterocycle

Heloise Brice and Jonathan Clayden

Chem. Commun. 2009, 1964-1966 [doi 10.1039/b901558b]

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2.3 Organolithium structure and reactivity

Organolithiums are the bedrock of many synthetic methods, combining predictable selectivity with broad reactivity.  Many of our synthetic methods are based on organolithium chemistry, and we are exploring the links between conformation, configuration, reactivity and selectivity in these structures.

Representative publications in this area:

235. Directed lithiation of pentadienylsilanes

Benjamin M. Day, Joseph J. W. McDouall, Jonathan Clayden, and Richard A. Layfield

Organometallics 2015, 34, 2348-2355 [doi 10.1021/om501144f]

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232. Lithium choreography determines contrasting stereochemical outcomes of aryl migrations in benzylic carbamates, ureas and thiocarbamates

Mark A. Vincent, Julien Maury, Ian H. Hillier and Jonathan Clayden

Eur. J. Org. Chem. 2015, 953-959 [doi 10.1002/ejoc.201403572]

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209. Manipulating the diastereoselectivity of ortholithiation in planar chiral ferrocenes

Simon A. Herbert, Dominic C. Castell, Jonathan Clayden and Gareth E. Arnott

Org. Lett. 2013, 15, 3334-3337 [doi 10.1021/ol4013734]

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199. Lithium choreography: intramolecular arylations of carbamate-stabilised carbanions and their mechanisms probed by in-situ IR and DFT

Anne M. Fournier, Christopher J. Nichols, Mark A. Vincent, Ian H. Hillier and Jonathan Clayden

Chem. Eur. J. 2012, 18, 16478-16490 [doi 10.1002/chem.201201761]

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Theme 3: Synthesis of Bioactive Compounds

Current and recent funding in this area – Alzeim Ltd., AstraZeneca, EPSRC studentships.

3.1 Isodomoic acids and their analogues – the Amnesic Shellfish Toxins

These toxins have important biological activity that reveals the details of nerve function and provides a tool for the study of Alzheimer’s and Huntington’s diseases.  We have published syntheses of the pharmacologically interesting isodomoic acids, and we are seeking to extend this work to other nitrogen-containing bioactive targets.

Representative publications in this area:

177. A general synthetic approach to the amnesic shellfish toxins: total synthesis of (–)-isodomoic acid B, (–)-isodomoic acid E and (–)-isodomoic acid F

Gilles Lemière, Simon Sedehizadeh, Julie Toueg, Nadia Fleary-Roberts and Jonathan Clayden

Chem. Commun. 2011, 3745-3747 [doi 10.1039/C1CC00048A]

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108. The synthesis of (–)-isodomoic acid C

Jonathan Clayden, Faye. E. Knowles and Ian R. Baldwin

J. Am. Chem. Soc. 2005, 127, 2412-2413 [doi 10.1021/ja042415g]

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