Research

Novel methods to synthesise functionalised molecules: macrocycles, spirocycles, heterocycles and natural products

My group is interested in the development of new methods for the synthesis of functionalised, complex molecules with applications.

Current Research Interests: Macrocycle Synthesis, Direct Imine Acylation, spirocyclisation, C–H activation, alkyne activation, copper catalysis, rhodium catalysis, asymmetric synthesis, target synthesis. More deatils on current projects are included below:

Successive Ring Expansion (SuRE)

Important applications across the physical sciences rely on the synthesis of functionalised macrocycles. At present, macrocycles are typically made via the end-to-end cyclisation of a linear precursor, a notoriously difficult and unpredictable transformation; in particular, achieving macrocyclisation (1 → 2, Figure 1a) rather than dimerisation (1 → 3) is a major challenge. The most common strategy used to combat this is to perform the reactions at high-dilution but while successful in many cases, such protocols are generally highly substrate dependent and impractical for large scale synthesis. 

Successive Ring Expansion (SuRE for short) is designed to improve the efficiency of macrocycle synthesis by completely avoiding end-to-end macrocyclisation. It is based on the sequential insertion of linear fragments into existing cyclic systems, by coupling a cyclic compound (4) to a linear fragment 5, which can thenrearrange (6), initiating ring expansion, forming a ring enlarged  product 7. A key design feature is the replication of the functionality in the cyclic starter unit in the ring-expanded product (circled), as this means that the same coupling/ring expansion sequence can be repeated, allowing further iterations to be performed in the same way (7 → 9; 9 → 11). SuRE can incorporate a range of linear fragments and can theoretically be repeated indefinitely, meaning macrocycles of virtually any ring size and composition are potentially accessible.

More deatils on this concept can be found in our first publication arising from this project, see: Angew. Chem. Int. Ed. 2015, 54, 15794 –15798. In this paper, the SuRE concept is validated using a telescoped two-step sequence, to generate macrocyclic lactams and lactones from cyclic β-keto esters (Figure 1c).

See also: Ring expansion approach to medium-sized lactams and analysis of their medicinal lead-like properties

L. G. Baud, M. A. Manning, H. L. Arkless, T. C. Stephens, W. P. Unsworth, Chem. Eur. J. 2017, 23, 2225.

Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams

T. C. Stephens, M. Lodi, A. Steer, Y. Lin, M. Gill, W. P. Unsworth, Chem. Eur. J. 2017 doi: 10.1002/chem.201703316

Catalyst Selective Synthesis

We are interested in the development of new catalytic processes in which multiple products can be generated from a common precursor through catalyst variation. This work has two major benefits: 1) by generating multiple products from a single starting material, the synthesis of potentially valuable compounds can be signifricantly streamlined; 2) we believe that challenging ourselves to uncover new catalyst selective synthetic methods is an effective way to inspire the discovery of new reactions and deliver new insight in catalytic processes.

The best illustration of this can be found in our 2016 publication entitled: Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor. The essence of work is in illustrated in the art work below; much as a single light source can be split into an array of colours with different visible properties, for example in a rainbow, we have been able to apply this concept chemically, to generate an array of 6 products with diverse chemical properties from a single precursor.

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Dearomatising Spirocyclisation

We are interested in the development of new dearomatising spirocyclisation methods, especially those involving alkyne activation with π-acids and metal carbenoid intermedaites.

For selected publications, see:

• Silica-supported silver nitrate as a highly active dearomatising spirocyclisation catalyst: synergistic alkyne activation by silver nanoparticles and silica

A. K. Clarke, M. J. James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2016, 55, 13798–13802

• Catalyst-driven scaffold diversity: selective synthesis of spirocycles, carbazoles and quinolines from indolyl ynones

  J. T. R. Liddon, M. J. James, A. K. Clarke, P. O'Brien, R. J. K. Taylor, W. P. Unsworth, Chem. Eur. J. 2016, 22, 8777–8780.

• Silver(I)-Catalyzed Dearomatization of Alkyne-Tethered Indoles: Divergent Synthesis of Spirocyclic Indolenines and Carbazoles

  M. J. James, R. E. Clubley, K. Y. Palate, T. J. Procter, A. C. Wyton, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Org. Lett. 2015, 17, 4372.

• Silver(I)- or Copper(II)-Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds
  

  M. J. James, J. Cuthbertson, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2015, 54, 7640.

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Publications

Selected publications (for a full list see the York Research database link in the right-hand column)

• Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams

T. C. Stephens, M. Lodi, A. Steer, Y. Lin, M. Gill, W. P. Unsworth, Chem. Eur. J. 2017 doi: 10.1002/chem.201703316

• Ring-Expansion Reactions in the Synthesis of Macrocycles and Medium-Sized Rings

W. P. Unsworth, J. R. Donald, Chem. Eur. J. 2017, 23, 8780

• Ring expansion approach to medium-sized lactams and analysis of their medicinal lead-like properties

  L. G. Baud, M. A. Manning, H. L. Arkless, T. C. Stephens, W. P. Unsworth, Chem. Eur. J. 2017, 23, 2225.

• Catalytic Dearomatization Approach to Quinolizidine Alkaloids:Five Step Total Synthesis of (±)-Lasubine II

  M. J. James, N. D. Grant, Peter O’Brien, R. J. K. Taylor, W. P. Unsworth, Org.Lett. 2016, 18, 6256−6259.

• Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives

  J. T. R. Liddon, A. K. Clarke, R. J. K. Taylor, W. P. Unsworth, Org. Lett. 2016, 18, 6328−6332

• Silica-supported silver nitrate as a highly active dearomatising spirocyclisation catalyst: synergistic alkyne activation by silver nanoparticles and silica

  A. K. Clarke, M. J. James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2016, 55, 13798–13802
  

• Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor

  M. J. James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2016, 54, 9671–9675

• Catalyst-driven scaffold diversity: selective synthesis of spirocycles, carbazoles and quinolines from indolyl ynones

  J. T. R. Liddon, M. J. James, A. K. Clarke, P. O'Brien, R. J. K. Taylor, W. P. Unsworth, Chem. Eur. J. 2016, 22, 8777–8780.

• From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis

  S.J. Chambers, G. Coulthard, W. P. Unsworth, P. O’Brien, R. J. K. Taylor, Chem. Eur. J. 2016, 22, 6496–6500.

• Synthesis of Spirocyclic Indolenines
  

  M. J. James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Chem. Eur. J. 2016 22, 2856–2881.

• The Synthesis of Structurally Diverse Macrocycles By Successive Ring Expansion
  

  C. Kitsiou, J. J. Hindes, P. I’Anson, P. Jackson, T. C. Wilson, E. K. Daly, H. R. Felstead, P. Hearnshaw, W. P. Unsworth, Angew. Chem. Int. Ed. 2015, 54, 15794 –15798.

• Silver(I)-Catalyzed Dearomatization of Alkyne-Tethered Indoles: Divergent Synthesis of Spirocyclic Indolenines and Carbazoles

  M. J. James, R. E. Clubley, K. Y. Palate, T. J. Procter, A. C. Wyton, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Org. Lett. 2015, 17, 4372.

• Silver(I)- or Copper(II)-Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds
  

  M. J. James, J. Cuthbertson, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2015, 54, 7640.

• A One-Pot C–H Insertion/Olefination Sequence for the Formation of α-Alkylidene-γ-butyrolactones.
  

  M G Lloyd, R J K Taylor and W P Unsworth, Org. Lett., 2014, 16, 2772.

• Direct Imine Acylation for Molecular Diversity in Heterocyclic Synthesis.

  W P Unsworth, G Coulthard, C Kitsiou, and R J K Taylor, J. Org. Chem., 2014, 79, 1368.

• ‘Upenamide: trials and tribulations.

  W P Unsworth and R J K Taylor, Org. Biomol. Chem., 2013, 11, 7250.

• Total Synthesis of Spirobacillene A.

  W P Unsworth, J D Cuthbertson and R J K Taylor, Org. Lett., 2013, 15, 3306.

• An Expedient Protecting-Group-Free Total Synthesis of (±)-Dievodiamine.

  W P Unsworth, C Kitsiou and R J K Taylor, Org. Lett., 2013, 15, 3302.

• Direct Imine Acylation: Synthesis of the Proposed Structures of ‘Upenamide.

  W P Unsworth, K A Gallagher, M l Jean, J P Schmidt, L J Diorazio and R J K Taylor, Org. Lett., 2013, 15, 262.

• Direct Imine Acylation: Rapid Access to Diverse Heterocyclic Scaffolds.

  W P Unsworth, C Kitsiou and R J K Taylor, Org. Lett., 2013, 15, 258.

Group

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Current Group Members

Dr. Hon Eong Ho (EPSRC funded PDRA, co-supervised with Richard Taylor and Peter O'Brien)

Dr. Mahendar Lodi (Indian-SERB funded PDRA)

Thomas Stephens (1st year PhD student)

James Rossi-Ashton (1st year PhD, co-supervised with Richard Taylor)

Yun Lin (MRes)

Michelle Yeung (MRes)

Jade Sangha (MChem)

James Pitts (MChem)

Former Group Members

Andrew Steer (Research Associate, co-supervised with Alison Parkin and Gideon Grogan)

Leonard Himmel (Erasmus student 2017)

Laetitia Baud (Erasmus student 2016)

Morgan Manning (MChem 2015-16)

Helen Arkless (MChem 2015-16)

Christiana Kitsiou (PDRA, 2015)

Phil I'Anson (MChem 2014-15)

Jordan Hindes (MChem 2014-15)

Paula Jackson (MChem 2013-14)

Thomas Wilson (MChem 2013-14)

Visitors/placement students

Matthew Gill (2016)

Darius Stankevicius (2016)

Hannah Felstead (2015)

Eleanor Daly (2014)

Peter Hearnshaw (2013)

News

• 04/04/17: Will travels to Germany to give a research talk at the Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll institute, and Freidrich-Schiller Universität Jena, Germany.
• 29/01/17: Welcome to Dr Mahendar Lodi, who is joining us as an Indian-SERB funded PDRA.
• 06/01/17: Will presents on SuRE at RSC hetreocyclic group 1 day meeting at the Institute of Cancer Research.
• 02/01/17: Welcome to 4 month Research Associate Andy Steer, joining us for 4 months from the Clarke group!
• 13/12/16: It's been a very busy month for publictions, with 4 new papers currently out as ASAPs (links to follow when final versions are published). Well done to John (indoleninyl halides), Aimee (spirocyclic dienones), Mickey (pyridine dearomatisation) and Laetitia (SuRE medium rings) and all other co-authors!
• 20/10/16: Will presents on SuRE at AstraZeneca- thanks to Coura Diene for hosting and Darren Stead for organising.
• 17/10/16: Will presents on SuRE at Macrocycles conference at Fidelta in Zagreb.
• 04/10/16: Well done Aimee Clarke, whose recent paper in Angewandte Chemie is faetured as a news article on the York chemistry site.
• 26/09/16: Welcome to new group members Tom, Lin, Michelle, Jade and James!
• 15/09/16: Will presents on SuRE at 2016 Gregynog Synthesis meeting.
• 13/09/16: Congratulations to Michael James, whose catalyst selective synthesis work is featured on the University's new technology webpages
• 15/07/16: Will presents on SuRE at Lilly, Erl Wood. Many thanks to Dr. Peter Lindsay-Scott and Dr. Jen Ciesielski
   for hosting.
• 26/07/16: Will's catalyst selective synthesis work is featured on the York Chemsitry Website.
• 27/06/16: Will and Profs. Richard Taylor and Peter O'Brien are pleased to hear that our EPRSC grant to develop new spirocyclisation and catalyst selective synthesis methods has been chosen for funding. See news article for deatils.
• 23/05/16: Will presents on his SuRE methodlogy at the University of Leeds as part of the the launch event for the EPSRC program grant on 'Integrated computational and synthetic tools to drive the discovery of orthosteric protein-protein interaction inhibitors', led by Prof. Andy Wilson.
• 05/04/16: Welcome to Laetita Baud, who is starting a 4 month placement from the Université Joseph Fourier, Grenoble, France.
• 01/04/16: Welcome to James-Rossi Ashton, who starts as the first Unsworth group PhD student today (co-supervised with Richard Taylor).
• 17/11/15: Will's recent SuRE methodology is featured news on University website: Ringing the changes 'opens road to new medicines'
• 15/11/15: Will presents recent progress on SuRE methodology at the BMOS meeting, Buzios, Rio de Janeiro, Brazil.
• 15/11/15: Will awarded RSC/BMOS young investigator award.

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• 13/11/15: Our SuRE methodology has been published in Angewandte Chemie International edition. Many thanks and congratulatios to Christiana, Jordan, Phil, Paula, Tom, Eleanor, Hannah and Peter for their hard work and important contributions to this work.
• 01/10/15: Welcome to new MChem Students Morgan Manning and Helen Arkless.

About Will

Biography

Will is originally from Coppull, near Chorley in Lancashire (UK). He studied chemistry at the University of Oxford, and remained there to complete his Ph.D. studies in the group of Prof. Jeremy Robertson. He completed his Ph.D. in 2010 and then began work at the University of York, first as a postdoctoral research associate in the group of Prof. Richard J. K. Taylor, before being appointed to a Research and Teaching Fellowship in 2013. He has recently been awarded a Leverhulme Trust Early Career Fellowship to develop new procedures to synthesise functionalised macrocycles. His current research interests include the construction of diverse spirocyclic scaffolds, cascade reactions, macrocylisation and total synthesis. He now lives in York with his wife Hayley and two children Billy and Catherine.

Invited Talks/Seminars

2017

• University of Strathclyde, April 2017
• Institute of Organic and Macromolecular Chemistry of the University of Jena and Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany, April 2017
• Durham University, February 2017
• Institute of Cancer Research, Chelsea. RSC heterocyclic 1 day meeting, January 2017

2016

• University of York, Biological Physics seminar series, November 2016
• Macrocycles Beyond-the-rule-of-5 medicinal chemistry conference, Fidelta, Zagreb, October 2016
• AstraZeneca, October 2016
• Gregynog Synthesis Meeting, September 2016
• Eli Lilly, August 2016
• University of Leeds, May 2016

2015

• Keele University, March 2015
• Bradford University, RSC NE regional meeting, April 2015
• Buzios, Brazil. BMOS meeting, November 2015.
• PUBlic seminar, York Brewery, York. (Public engagement talk)

2014

• May 2014, Zagreb,  Macrocycles - synthesis, medicinal chemistry and biological activity.
• September 2014, Gregynog Synthesis Meeting

Awards

• RSC/BMOS young investigator award, November 2015.
• Dave Kelly cup, Gregynog synthesis meeting, 2014

Vacancies

For current PhD opportunities, see main York Chemistry pages.

Applications from self-funded PhD/PDRA level researchers and Erasmus students are welcomed; contact Will directly for advice and details of current projects (william.unsworth@york.ac.uk)

Photos

Group Christmas meal 2016

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Group Photo 2016 (Left to Right: Lin, Ton, James P, Leo, Will, Jade, James R, Michelle)

Gregynog Synthesis Meeting 2016

Will presenting his SuRE methodlogy at the BMOS meeting, Buzios, Rio de Janeiro, Brazil