Research Themes in the Clayden Group

Theme 1: Rational Conformational Control

Current and recent funding in this area – 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.

b) Desymmetrisation and dynamic methods for the 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:

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. 201420, 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. 201210, 716-719 [doi 10.1039/c1ob06490h]

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171. Biocatalytic desymmetrisation of an atropisomer mediated by both an enantioselective oxidase and ketoreductasesBo Yuan, Abigail Page, Christopher P. Worrall, Franck Escalettes, Simon C. Willies, Joseph J. W. McDouall, Nicholas J. Turner and Jonathan Clayden; Angew. Chemie Int. Ed. 201049, 7010-7013 [doi 10.1002/anie.201002580]

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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. 200948, 6398-6401 [doi 10.1002/anie.200901719]

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158. Atropisomerism at C–S bonds: asymmetric synthesis of diaryl sulfones by dynamic resolution under thermodynamic control; Jonathan Clayden, James Senior and Madeleine Helliwell Angew. Chemie Int. Ed. 200948, 6270-6273 [doi 10.1002/anie.200901718]

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154. Controlling axial conformation in 2-arylpyridines and 1-arylisoquinolines: application to the asymmetric synthesis of QUINAP by dynamic thermodynamic resolution; Jonathan Clayden, Stephen P. Fletcher, Joseph J. W. McDouall and Stephen J. M. Rowbottom J. Am. Chem. Soc. 2009131, 5331-5434 [doi 10.1021/ja900722q]

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140. N,N’-Diarylureas: A New Family of Atropisomers Exhibiting Highly Diastereoselective Reactivity; Jonathan Clayden, Hazel Turner, Madeleine Helliwell and Elizabeth Moir J. Org. Chem. 200873, 4415-4423 [doi 10.1021/jo702706c]

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139. Enantioselective synthesis of an atropisomeric diaryl ether; Jonathan Clayden, Christopher P. Worrall, Wesley J. Moran and Madeleine Helliwell Angew. Chemie Int Ed. 2008, 47, 3234-3237 [doi 10.1002/anie.200705660]

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126. Three groups good, four groups bad? Atropisomerism in ortho-substituted diaryl ethers; Mark S. Betson, Jonathan Clayden, Christopher P. Worrall and Simon Peace; Angew. Chem. Int Ed., 200645, 5803-5807 (Angew. Chemie 2006118, 5935) [doi 10.1002/anie.200601866]

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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

 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. 20156, 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. 201479, 4659-4675 [doi 10.1021/jo500714b]

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216. Thionoglycine as a multifunctional spectroscopic reporter of screw-sense preference in helical foldamers; Matteo De Poli and Jonathan Clayden Org. Biomol. Chem. 201412, 836-843 [doi 10.1039/c3ob42167h]

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212. The N-terminal nonapeptide of cephaibols A and C: a naturally occurring example of mismatched helical screw-sense controlUgo Orcel, Matteo De Poli, Marta De Zotti and Jonathan Clayden Chem. Eur. J. 201319, 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 chainRobert A. Brown, Tommaso Marcelli, Matteo De Poli, Jordi Solà, and Jonathan Clayden Angew. Chemie Int. Ed. 201251, 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. 2011133, 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 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:

239. Screw sense alone can govern enantioselective extension of a helical peptide by kinetic resolution of a racemic amino acidLiam Byrne, Jordi Solà and Jonathan Clayden Chem. Commun. 201551, 10965-10968 [doi 10.1039/c5cc01790d]

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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. 201453, 151-155 [doi 10.1002/anie.201308264]

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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 Nature2004431, 966-971 [doi 10.1038/nature02933]

b) Synthesis of artificial receptors.

We are currently working to make molecules which mimic biology’s ability to encode, manipulate and communicate information.  We have reported an artificial receptor that bonds diol ligands and relays information about their structure and stereochemistry to a spectroscopic reporter lying some nanometer distances away. Our current work in this area is seeking to extend these molecules to 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 are exploring the possibility of building artificial rhodopsin mimics that capture information about incident light and communicate that information to a distance chemical site through a conformational change.

Representative publications in this area:

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. 2015137, 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. 20135, 853-860 [doi 10.1038/nchem.1747]

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c) Conformation in membranes

Several fungal antibiotics function by selectively inserting into bacterial membranes.  We are using various analytical technioques to look at related synthetic, but bio-insipred, helical structures and explore the way in which their conformation is dependent on their environment.  We compare structures in solution and in the membrane phase to try and understand how these antibiotics work and to develop structures specifically designed for function in the membrane (ion channels or receptor mimics for example

Publications in this area are in preparation


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:

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. 201554, 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. 201517, 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. 201349, 9734-9736 [doi 10.1039/c3cc46193a]

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223. Dihydrothiophenes containing quaternary stereogenic centres by sequential stereospecific rearrangements and ring-closing metathesis; Gaëlle Mingat, Joseph J. W. McDouall and Jonathan Clayden Chem. Commun. 201450, 6754-6757 [doi 10.1039/c4cc02596b]

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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. 201012, 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. Soc2007129, 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. 201315, 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 201534, 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. 201315, 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. 201218, 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. 2005127, 2412-2413 [doi 10.1021/ja042415g]

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