Key Research Interests and Expertise

Double and Multi-Kinetic Resolution
Enantioselective synthesis is an important goal and conventional methods rely on asymmetric induction or classical/kinetic resolution, in which a chiral auxiliary is used at a specific step to gain access to non-racemic samples. In our multi-KR approach, the all the steps of a retrosynthetic analysis are assessed for the possibility of chiral intervention and prioritised. As the synthesis proceeds, a series of kinetic resolutions progressively improves the enantiomeric excess (e.e.) until the level is high enough to allow the product crystallise as a single enantiomer. Whereas the conventional approach can sometime require extensive and time-consuming optimisation at a specific step (a potential ‘bottle-neck’), the multi-KR approach allows additional KR steps to be introduced into the synthetic plan to further improve e.e. if the original selection for KRs lack the required levels of stereorecognition. There are two important advantages to multi-KR: no individual step needs full optimisation, and once enantiopurity has been achieved, further work to optimise stereoselectivity improves the chemical yield of the synthesis (e.g. for scale-up), not the enantioselectivity. The double-KR approach has been exemplified in our work on tetrathiahelicines (see selected publications), and research in this area now moves to apply the concept in general to the synthesis of natural products and bioactives.

Asymmetric ‘click’ chemistry
Because the 1,2,3-triazoles lack chirality, until our work in this area, the famous Sharpless/Mendal CuAAC ‘click’ reaction had been performed only once with chiral auxiliaries on the copper. Our aim is to generalise the asymmetric variant of ‘click’ chemistry by studying the desymetrisation of diynes, including, for the first time, conceptually important meso diynes. Compared with the many thousands of papers on ‘click’ chemistry, there are still only a handful on asymmetric ‘click’ chemistry, but this total grows more rapidly as other research groups pick up this topic which is set to become a major and highly competitive research area. Our aim is to develop the method as a general strategy in asymmetric synthesis to take prochiral diyne starting materials on to enantiopure final products which exploit the properties of 1,2,3-triazoles as ligating (including bioligating) sites in novel series of chiral ligands and bioactives, and as part of the fused aromatic ring systems of helicenes (see below).

Enantioselective Synthesis of Helicenes
The twisted pi systems of helicenes provide a unique class of organic structures in which the two ends of a series of ortho-fused aromatic rings can no longer lie in the same plane because they overlap. Such structures are chiral and when there is sufficient overlap, the barrier to epimerisation is high. Our interest in helicenes springs from their potential in nonlinear optics (NLO), and particularly their predicted but as yet unrealised special suitability for use in Two Photon Circular Dichroism (TPCD), a goal which will lead ultimately to a new method of bioimaging which combines the confocality of two-photon absorption with the sensitivity to the stereochemical environment demonstrated in circular dichroism spectroscopy. Current target molecules in the group include tetrathia[7]helicenes addressed by a one-pot double-KR approach, and a new class of hexaazahelicenes than can be accessed by a double asymmetric ‘click’ strategy. Both conventional ‘single-dipole full-turn’ and our novel ‘double-dipole half turn’ designs are targets for the group.

Ubiquitin Ligase Inhibitors
Ubiquitin ligases are enzymes which are implicated in tumour outgrowth and spread and so are attractive targets for new approaches to develop anticancer bioactives (PI: Chantry). As a synthetic chemistry component of a larger collaborative project with Chantry, Hemmings, Page (Schools of Biological Sciences and Chemistry) we are working on the design and synthesis of new and more potent inhibitors for E3 ubiquitin ligases employing a fragment-based strategy which involves the synthesis of small binding motifs and linkers, assisted by modelling studies to aid the molecular design process.

‘Open Lab Africa’
The neglected tropical diseases (NTDs) still cause great human suffering in some of the poorest countries on the planet. The UEA ‘Open Lab Africa’ project is adopting a fresh and novel approach to this global challenge in a collaborative effort with Duvendack, Gallash, Hamilton, McDermott, (Schools of Development Studies, Law, and Pharmacy) at UEA and Frey (University of Southampton) together with institutes in Cameroon, Democratic Republic of the Congo, Ghana, Kenya, Tanzania, and Uganda. The synthetic chemistry part of the project involves the identification and synthesis of new lead structures and their analogues in a fragment-based approach towards new capabilities to address particular NTDs which are of most serious or growing concern in the subSaharan region of Africa. The project combines an Open Lab-Book and Open Med-Chem approach which invites institutes and specialists around the world to follow, advise, and even join in the project.

Research Funding

Big C
Synthesis and evaluation of X-ray structure inspired ubiquitin ligase inhibitors as anticancer lead compounds
Stephenson, GR
1-Oct-20 – 30-Sept-23
£ 89349.

Ceres
Novel Water Resistant Flax Bio-composites
21-Jun-20 – 20 Sept-21
Stephenson, GR
£279792

Leverhulme Trust
Asymmetric 'click'-synthesis of helicenes
Stephenson, GR
27-Mar-17 – 26-Mar-20
£ 166,029

InnovateUK
Towards fully sustainable high-performance biocomposites for lightweight vehicles
Stephenson, GR
01-Apr-16 – 31-Mar-18
£ 285,179

EU Interreg IVA
Academie-Industrie Chemistry Channel (A-I chem channel)
Stephenson, GR
02-Nov-11 – 30-June-2015
€ 988,444

EPSRC
Highly anisotopic helicene-based NLOphores for two photon circular dichroism
Stephenson, GR
01-Oct-09 – 30-Sept-13
£ 270,570

EU Interreg IVA
Innovative Synthesis: Chemistry and Entrepreneurship (IS:CE chem)
Stephenson, GR
01-June-08 – 30-Sept-13
€ 1,597,285

Daphne Jackson Trust
Introducing a new twist to photonics
Fellowship for K. Hamilton
01-July-08 – 30-June-10
£ 38,817
 
EPSRC
Nanoscale and molecular photonics
Meech, SR, Cammidge, AN, Andrews, DL, Reading, M, Stephenson, GR, Mayes, AG and Barker, S
01-Sep-05 - 31-Aug-07
£255,840

EPSRC
EU COST Chemistry D26: European collaboration for calculation inspired synthesis of NLO responsive aryl and helicenyl organometallics Stephenson, GR
01-Jul-06 - 31-Jul-07
£20,414

EPSRC
Enantioselective organoiron / heterocycloaddition approach to hippeastrine
Stephenson, GR
01-Mar-03 - 31-Mar-06
£82,497

EPSRC
European collaboration to synthesise and evaluate NLO compounds with novel photorefractive properties
Stephenson, GR
30-Jul-02 –
29-Jan-06
£21,041

SmithKline Beecham
CASE Award: Custom synthesis and automated evaluation to optimise the asymmetric Heck reaction
Stephenson, GR
01-Oct-01 - 30-Sep-04
£20,550

CEC
Organometallic dipoles with NLO properties
Stephenson, G R
01-Mar-98 – 28-Feb-02
£114,400

CSL
Studentship: Synthesis of stable-isotope-labelled lipids for nutritional studies
Stephenson, G R and Shepherd, MJ (CSL)
01-Oct-98 - 30-Sep-01
£42,747

GlaxoWellcome
CASE Award: Develop catalytic versions of stoichiometric organometallic reactions
Stephenson, G R
01-Oct-98 - 30-Sep-01
£18,000

 

Research Group Membership

PhD students

  • James Tonkin
  • James Sharpe*
  • Jake Rigby*

* indicates collaborative project

Postdoctoral Visiting Fellows

  • Lloyd Sayer
  • Rhoda Beskeni

Senior Technical Officer

  • Adam Wright

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