Research themes

Current areas of research in the Clayden group

An overarching theme to our work is stereochemistry, the study of the shape of molecules, and in particular molecular conformation: how to control it and make use of it.

Research Theme 1: Rational Conformational Control (ROCOCO)

Current and recent funding in this area – European Research Council Advanced Grant ROCOCO, BBSRC Grant I007962, JohnsonMatthey Catalysts, BBSRC and EPSRC studentships.

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 still.

  1. 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.

Recent published work in this area:

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. 2009, 48, 6270-6273.

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.

  1. 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. In collaboration with the group of Nick Turner we are investigating 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.

Recent published work in this area:

Biocatalytic desymmetrisation of an atropisomer mediated by both an enantioselective oxidase and ketoreductases

Bo 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. 2010, 49, 7010-7013

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. 2009, 131, 5331-5434

Conformational communication over nanometre distances and through membranes

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.

  1. a) 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 a n 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.

 

Recent published work in this area:

  1. 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. in press (doi 10.1038/nchem.1747)

Nanometre-range communication of stereochemical information by reversible switching of molecular helicity

Jordi Solà, Stephen P. Fletcher, Alejandro Castellanos and Jonathan Clayden, Angew. Chemie Int. Ed. 2010, 49, 6836-6839

  1. b) 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.

 

Recent published work in this area:

Relaying stereochemistry through aromatic ureas: 1,9 and 1,15 remote stereocontrol

Jonathan Clayden, Mark Pickworth and Lyn. H. Jones, Chem. Commun. 2009, 547-549.

Transmitting information along oligoparaphenylenes: 1,12-stereochemical control in a terphenyl tetracarboxamide

Jonathan Clayden, Lluís Vallverdú and Madeleine Helliwell, Chem. Commun. 2007, 2357-2359.

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

Jonathan Clayden, Andrew Lund, Lluís Vallverdú and Madeleine Helliwell, Nature (London), 2004, 431, 966-971.

  1. c) Stereochemistry of helices

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.

Recent published work in this area:

Diastereotopic fluorine substituents as 19F NMR probes of screw-sense preference in helical foldamers

Sarah J. Pike, Matteo De Poli, Wojciech Zawodny, James Raftery, Simon J. Webb and Jonathan Clayden, Org. Biomol. Chem. 2013, 11, 3168-3176.

Left-handed helical preference in an achiral peptide chain is induced by an L-amino acid in an N-terminal Type II b-turn

Matteo De Poli, Marta De Zotti, James Raftery, Juan A. Aguilar, Gareth A. Morris and Jonathan Clayden, J. Org. Chem. 2013, 78, 2248-2255.

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.

Chemical communication: conductors and insulators of screw-sense preference between helical oligo(aminoisobutyric acid) domains

Thomas Boddaert, Jordi Solà, Madeleine Helliwell and Jonathan Clayden Chem. Commun. 2012, 48, 3397-3399.

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.

  1. d) Helices 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)

Recent published work in this area:

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. in press.

 

 

 

Research 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.

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.

 

Recent published work in this area:

Intramolecular arylation of amino acid enolates

Rachel C. Atkinson, Daniel J. Leonard, Julien Maury, Daniele Castagnolo, Nicole Volz, and Jonathan Clayden, Chem. Commun. in press (doi 10.1039/C3CC46193A)

Carbolithiation of S-alkenyl-N-aryl thiocarbamates: carbanion arylation in a connective route to tertiary thiols

Daniele Castagnolo, Daniel J. Foley, Hatice Berber, Renzo Luisi, and Jonathan Clayden, Org. Lett. 2013, 15, 2116-2119.

Reversible aryl migrations in metallated ureas: controlled inversion of configuration at a quaternary carbon atom

Daniel J. Tetlow, Mark A. Vincent, Ian H. Hillier and Jonathan Clayden, Chem. Comm. 2013, 49, 1548-1550.

Amines bearing tertiary substituents by tandem enantioselective carbolithiation–rearrangement of vinyl ureas

Michael Tait, Morgan Donnard, Alberto Minassi, Julien Lefranc, Beatrice Bechi, Giorgio Carbone, Peter O’Brien, and Jonathan Clayden, Org. Lett. 2013, 15, 34-37.

Intramolecular vinylation of secondary and tertiary organolithiums

Julien Lefranc, Anne M. Fournier, Gaëlle Mingat, Simon Herbert, Tommaso Marcelli, and Jonathan Clayden, J. Am. Chem. Soc. 2012, 134, 7286-7289.

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.

Recent published work in this area:

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

Jemma Senczyszyn, Heloise Brice and Jonathan Clayden, Org. Lett. 2013, 15, 1922-1925.

Doubly dearomatising intramolecular coupling of a nucleophilic and an electrophilic heterocycle

Heloise Brice and Jonathan Clayden, Chem. Commun. 2009, 1964-1966.

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.

Recent published work in this area:

Structural influences in lithium pentadienylsilane complexes

Benjamin M. Day, Jonathan Clayden and Richard A. Layfield, Organometallics 2013, 32, 4448-4451.

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

Lithiated tertiary carbanions display variable coordination modes: the evidence from DFT and NMR studies

Mark A. Vincent, Alison Campbell Smith, Morgan Donnard, Philip J. Harford, Joanna Haywood, Ian H. Hillier, Jonathan Clayden, and Andrew E. H. Wheatley, Chem. Eur. J. 2012, 18, 11036-11045.

Research Theme 3: Synthesis of neuroactive and other bioactive compounds

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

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.

Recent published work in this area:

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

Semisynthesis and the galanthamine alkaloid family – Alzheimer’s Treatments from Daffodils.

Galanthamine is a widely used drug for the alleviation of the symptoms of Alzheimer’s disease, and we have been exploring ways to make more efficient the use of daffodils as a source of galanthamine through semi-synthetic transformations of biogenetic Narcissus alkaloids.

 

Reviews of our work and related areas

The Urea Renaissance

Nicole Volz and Jonathan Clayden, Angew. Chemie Int. Ed. 2011, 50, 12148-12155.

Asymmetric synthesis of tertiary thiols and thioethers

Jonathan Clayden and Paul MacLellan, Beilstein J. Org. Chem. 2011, 7, 582-595

Quaternary centres bearing nitrogen (a-tertiary amines) as products of molecular rearrangements

Jonathan Clayden, Morgan Donnard, Julien Lefranc and Daniel J. Tetlow, Chem. Commun. 2011, 4624-4639

Transmission of stereochemical information over nanometre distances in chemical reactions

Jonathan Clayden Chem. Soc. Rev. 2009, 38, 817-829.

Stereochemical relays: communication via conformation

Jonathan Clayden and Neoclis Vassiliou, Org. Biomol. Chem., 2006, 4, 2667-2678.

Atropisomers and near-atropisomers: achieving stereoselectivity by exploiting the conformational preferences of aromatic amides

Jonathan Clayden, Chem. Commun., 2004, 127-135.

Cyclisations of organolithiums onto aromatic rings

Jonathan Clayden and Martin Kenworthy Synthesis 2004, 1721-1726.

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