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Staff profile

Overview

Andrew Whiting

Emeritus Professor

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Emeritus Professor in the Department of Chemistry

Biography

PhD (1981-’84): University of Newcastle upon Tyne, working on beta-lactam chemistry. Post-doctoral research (1984-’86): Boston College, MA, USA, working on natural product synthesis and asymmetric synthesis and developing chiral Diels-Alder Lewis-acid catalysts. Industrial experience (1986-’88): Ciba-Geigy plc., Central Research UK, working on varied topics, including developing new methodology for the preparation of novel amino-acid analogues and asymmetric synthesis. Academic experience: Chemistry Department, UMIST (1989-2001), moved to Readership at Durham (2001) and promoted to Professor in 2009.

Current Research Interests

The major activity is increasingly related to innovation, working with two spinout companies setup through research carried in our group, i.e. LightOx Ltd. (lightox.co.uk) and more recently, Nevrargenics Ltd. (nevrargenics.com). These two companies are driving forward novel drugs in the areas of phototherapeutic therapy and neurodegenerative disease treatment, respectively.

Our research themes revolve more around chemical biology more recently, but our background efforts have been in organometallic chemistry, catalysis, asymmetric and stereoselective synthesis, particularly looking a new, cleaner, greener and water tolerant catalytic processes. These areas are exemplified below by some recent published papers:

Bifunctional catalysis: synthesis and applications of aminoboronic acids

We are interested in developing new methods for the synthesis of organoboron compounds for a number of reasons (see below) and
one major ongoing project in this area involves the design, synthesis and
development of new bifunctional catalysts based on amino-boronic acids. For example, homoboroproline is an excellent enamine-based organic/bifunctional catalyst especially when the boron Lewis acidity is tuned in situ by esterification, as shown in the reaction below, and we have reported a detailed study of how this catalyst system works, as well as making both enantiomers available and producing effectively 98% e.e.1

We have also recently developed an efficient highly enantioselective synthesis of the enantiomeric catalyst using an Sn2-like borylation route from natural proline, i.e.:2

Bifunctional catalysts can also be used to generate boronate enolates in situ and in water! In this case, we found that a phenylbenzimidazole boronate 'ate'-complex could catalyse to aldol reaction as follows:3

Direct amide formation

Despite what we are told at undergraduate level, direct amide formation from amines and carboxylic acids works, and without the need to use atom uneconomic methods. We have been working on the development of catalysts to accomplish this reaction under increasingly lower temperature conditions, especially by using organoboron bifunctional catalysts and other activated aryl boronic acids.4 We have even reported the first example an asymmetric process involving a chiral boronic acid catalyst which can achieve kinetic resolution of a racemic amine through direct amide formation, as shown below.5

We have also delved into the heavily misunderstood uncatalysed reaction which is much more facile than many working in the area realise! We have proposed, backed up by theoretical calculations, that hydrogen-bonded dimeric carboxylic acid complexes could well be involved in such reactions, as outlined below.6a

This mechanism contrasts with recent work that has uncovered the hitherto hidden workings of boron-based amidation catalysis.6b In fact, we now understand that amidation catalysis by boron requires two boron atoms, acting cooperatively, particularly through B-X-B bridged systems, where X = O or N, with the two borons acting as bridges to doubly activate carboxylic groups; mechanistic proposals which have been reinforced by extensive DFT calculations.

Nitroso- and imino-dienophile based formal aza-Diels-Alder reactions: novel approaches to nitrogen heterocycles

Our interest in developing novel routes to nitrogen heterocycles using clean catalytic methods goes back many years, particularly involving imino dienophiles, for example, using zinc(II) binol complexes as shown below,7 and has recently been extended to look at a range imine-mediated formal cycloaddition reactions, to access a number of different hydropyridine analogues.7

In addition, we have been developing novel copper-based air oxidative formation of acyl nitroso species from hydroxamic acids, which are then efficiently trapped out as Diels-Alder adducts, such as shown below, and in conjunction with Dr Bertrand Carboni (Rennes University) we have aalso reported the reaction of nitroso compounds with borodienes to access pyrroles, amongst other things.8

Borylation of unsaturated imines

We are interested in developing new, catalytic, asymmetric routes to gamma-amino alcohols and beta-amino acids etc, and together with Prof Elena Fernández' group at the Universitat Rovira i Virgili in Tarragona, a rapid and efficient entry to such systems is being developed using borylation of unsaturated imines, i.e. as summarised below, and has been extended to synthesis of antidepressants, and even applied to highly reactive unsaturated aldehyde analogues.9

Stereocontrolled polyene natural product synthesis

We have pioneered the use of vinylboronate esters which undergo Heck-Mizoroki coupling to derive dienyl and polyenyl-boronates systems. This is a powerful technology when coupled with highly efficient iodo-deboronation methods, which can be carried out with either inversion or retention of stereochemistry. The additional use of Suzuki-Miyaura cross-coupling completes the technology to access highly sensitive polyene systems, particularly with cis-alkene geometries present and we are currently part-way through the total synthesis of the anti-leukemic agent viridenomycin using this technology, i.e. as outlined here:10

Design and synthesis of organic compounds for controlled cellular development

We collaborate widely with research groups in Biology (Dr Carrie Ambler & Dr Paul Chazot), Psychology (Dr Alex easton and Dr David Sanderson) and Physics (Prof John Girkin), here in Chemistry (Dr Ehmke Pohl), the Northern Centre for Cancer Research, Newcastle (Dr Chris Redfern), High Force Research (Dr Roy Valentine), and with the University of
Aberdeen (Dr Iain Greig and Prof Peter McCaffery). Our role has been the design, modelling and synthesis of synthetic retinoids, i.e. analogues of retinoic acids, including all-trans-retinoic acid, ATRA). These types of systems act as molecular triggers causing changes in cellular development processes. For example, we have been developing light and heat stable analogues (such as EC23 and EC1911) of ATRA and its isomers which are still capable of inducing cell differentiation in stem cell systems deriving neural cells in the case of EC23. Recently, this owrk has led to the identification of synthetic retinoids with the potential to treat neurodegenerative diseases, which we are taking forwards through the spinout company Nevrargenics (https://nevrargenics.com/).

In addition, we have been developing novel copper-based air oxidative formation of acyl nitroso species from hydroxamic acids, which are then efficiently trapped out as Diels-Alder adducts, such as shown below, and in conjunction with Dr Bertrand Carboni (Rennes University) we have also reported the reaction of nitroso compounds with borodienes to access
pyrroles, amongst other things.8

In addition, we have now created fluorescent variants, which we are using for bioimaging purposes12 and other medical applications, including cell killing using systems specially designed to be particularly fluorescent. A spinout company, LightOx Ltd. has also been setup to commercialise this work involving the sale of fluorescent imaging probes and the development novel phototherapeutic drugs.

New materials directed synthesis: novel, environmentally benign approaches to crosslinked polymers

We have an ongoing project involving patented technology developed jointly with the Materials Science department at Manchester, which has involved the design and synthesis of bifunctional crosslinking polymer monomers for application in water-borne latex coating systems. For example, HydroxyEthylSulfonylStyrene (HESS)13 is a reactive monomer species which was developed by us to demonstrate the concept in a new entirely-water based crosslinking system. This type of crosslinking system only forms crosslinks upon coating and evaporation of water
from the emulsion system due to the formation of reactive vinylsulfones which under facile addition reactions with, for example, hydroxyl groups, i.e. as schematically shown below. This area is being further developed currently for decorative coatings in collaboration with AkzoNobel.

Acknowledgements

We would like to thank the following for support over the years (not all of which still exist!): EPSRC, BBSRC, MRC, Royal Society, RSC, GSK, Schering-Plough, Syngenta, Pfizer, High Force Research, Merck, AkzoNobel, Knoll Pharmaceuticals, Johnson-Matthey, Holliday Dyes &
Chemicals, ICI Surfactants, Chiroscience, Schlumberger Cambridge Research and Ciba-Geigy.

References

1. a) I. Georgiou, A. Whiting, Org. Biomol. Chem., 2012, 10, 2422-2430, DOI:10.1039/C2OB06872A; b) A. S. Batsanov, I. Georgiou, P. R. Girling, L. Pommier, H. C. Shen and A. Whiting, Asian J. Org. Chem., 2014, 3, 470-479, DOI: 10.1002/ajoc.201300127

2. I. Georgiou, A. Whiting, Eur. J. Org. Chem., 2012, 4110–4113, DOI: 10.1002/ejoc.201200652

3. K. Aelvoet, A. S. Batsanov, A. J. Blatch, L. G. F. Patrick, C. A. Smethurst, A. Whiting, Angew. Chem., 2008, 47, 768-770, DOI: 10.1002/anie.200705643

4. a) K. Arnold, A. S. Batsanov, B. Davies, A. Whiting, Green Chem., 2008, 10, 124-134, DOI: 10.1039/b712008g; b) S. Liu, Y. Yang, X. Liu, A. S. Batsanov and A. Whiting, Eur. J. Org. Chem., 2013, 5692-5700, DOI: 10.1002/ejoc.201300560

5. K. Arnold, B. Davies, D. Hérault, A. Whiting, Angew. Chem., 2008, 47, 2673-2676, DOI: 10.1002/anie.200705643

6. a) H. Charville, D. Jackson, G. Hodges, A. Whiting, M. R. Wilson, Eur. J. Org. Chem., 2011, 5981–5990, DOI: 10.1002/ejoc.201100714; b) S. Arkhipenko, M. T. Sabatini, A. S. Batsanov, V. Karaluka, T. D. Sheppard, H. S. Rzepa and A. Whiting, Chem. Sci., 2018, 9, 1058-1072

7. a) L. Di Bari, S. Guillarme, J. Hanan, A. P. Henderson, J. A. K. Howard, G. Pescitelli, M. R. Probert, P. Salvadori, A. Whiting, Eur. J. Org. Chem., 2007, 5771-5779, DOI: 10.1002/ejoc.200700731; b) P. R. Girling, A. S. Batsanov, A. D. J. Calow, H. C. Shen, A. Whiting, Tetrahedron, 2016, DOI: 10.1016/j.tet.2016.01.006

8. D. Chaiyaveij, A. S. Batsanov, M. A. Fox, T. B. Marder and A. Whiting, J. Org. Chem., 2015, 80, 9518-9543, DOI: 10.1021/acs.joc.5b01470; b) F. Tripoteau, L. Eberlin, M. A. Fox, B. Carboni and A. Whiting, Chem. Commun., 2013, 49, 5414-5416, DOI:10.1039/C3CC42227E

9. a) C. Solé, A. Tatla, J. Mata, A. Whiting, H. Gulyás, E. Fernandez, Chem. Eur. J., 2011, 17, 14248-14257, DOI: 10.1002/chem.201102081; b) A. D. J. Calow, E. Fernández and A. Whiting, Org. Biomol. Chem., 2014, 12, 6121-6127, DOI: 10.1039/C4OB01142B; c) A. Pujol, A. D. J. Calow, A. S. Batsanov and A. Whiting, Org. Biomol. Chem., 2015, 13, 5122-5130, DOI: 10.1039/C4OB02657H

10. A. S. Batsanov, J. P. Knowles, A. Whiting, J. Org. Chem., 2007, 72, 2525-2532, DOI: 10.1021/jo0626010

11. a) J. H. Barnard, C. E. Bridgens, A. Botsanov, E. B. Cartmell, V. B. Christie, J. C. Collings, T. B. Marder, S. Przyborski, C. P. F. Redfern, A. Whiting, Org. Biomol. Chem., 2008, 6, 3497-3507, DOI: 10.1039/b808574a; b) G. Clemens, K. R. Flower, A. P. Henderson, A. Whiting, S. A. Przyborski, M. Jimenez-Hernandez, F. Ball, P. Bassan, G. Cinque and P. Gardner, Mol. BioSyst., 2013, 9, 677-692, DOI: 10.1039/C3MB25505K

12. Patent application: PCT/GB2015/052956

13. D. J. Berrisford, P. A. Lovell, N. R. Suliman, A. Whiting, Chem. Commun, 2005, 5904-5906.

Other recent publications:

Detection and time-tracking activation of a photosensitiser on live single colorectal cancer cells using Raman spectroscopy, J. Gala de Pablo, D. R. Chisholm, C. A. Ambler, S. A. Peyman, A. Whiting and S. D. Evans, Analyst, 2020, DOI: 10.1039/D0AN01023E

Generating skeletal diversity and complexity from boron-substituted 1,3-dienes and enophiles, B. François, L. Eberlin, F. Berrée,A. Whiting and B. Carboni, Eur. J. Org. Chem., 2020, 3282-3293, DOI: 10.1002/ejoc.202000330

Access to fused pyrroles from cyclic 1,3-dienyl boronic esters and arylnitroso compounds, B. François, Benjamin, L. Eberlin, F. Berrée, A. Whiting and B. Carboni, J. Org. Chem., 2020, 85, 5173-5182; DOI: org/10.1021/acs.joc.9b03214

Decay in retinoic acid signalling in varied models of Alzheimer disease and restoration of gene expression with novel receptor acid receptor ligands (RAR-Ms), T. Khatib, D. R. Chisholm, A. Whiting, B. Platt and P. McCaffery, Alzheimers Res. Ther., 2020, 73, 935-954; DOI: 10.3233/JAD-190931 

A low temperature, vinylboronate ester-mediated, iterative cross-coupling approach to xanthomonadin polyenyl pigment analogues, K. S. Madden, J. P. Knowles and A. Whiting, Tet., 2019, 75, 130657; DOI: org/10.1016/j.tet.2019.130657

Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids, T. Khatib, P. Marini, S. Nunna, D. R. Chisholm, A. Whiting, C. Redfern, I. Greig and P. McCaffery, Cell Commun. Signal., 2019, 17:40, DOI: 10.1186/s12964-019-0352-4

CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity, R. Zolfaghari, A. Whiting, C. Ross, C.-H. Wei, D. Chisholm and F. Mattie, Anal. Biochem., 2019, 577, 98-109, DOI: 10.1016/j.ab.2019.04.022

A bioluminescence reporter assay for retinoic acid control of translation of the GluR1 subunit of the AMPA glutamate receptor, T. Khatib, B. Müller, A. Whiting, D. Chisholm, C. Redfern and P. McCaffery, Mol. Neurobiol., 2019, DOI: 10.1007/s12035-019-1571-9

Using Nature’s polyenes as templates: Studies of synthetic xanthomonadin analogues and realising their potential as antioxidants, K. S. Madden, H. R. E. Jokhoo, F. D. Conradi, J. P. Knowles, C. W. Mullineaux and A. Whiting, Org. Biomol. Chem., 2019, 17, 3752-3759, DOI: 10.1039/C9OB00275H

Photoactivated cell-killing involving a low molecular weight, donor-acceptor diphenylacetylene, D. R. Chisholm, R. Lamb, T. Pallett, V. Affleck, C. Holden, J. Marrison, P. O’Toole, P. D. Ashton, K. Newling, A. Steffen, A. K. Nelson, C. Mahler, R. Valentine, T. S. Blacker, A. J. Bain, J. Girkin, T. B. Marder, A. Whiting and C. A. Ambler, Chem. Sci.,2019, 10, 4673-4683, DOI: 10.1039/C9SC00199A

A solid-supported phenylboronic acid-based catalyst for direct amidation, Y. Du, T. Barber, S. E. Lim, I. R. Baxendale and A. Whiting, Chem. Comm., 2019,55, 2916-2919, DOI: 10.1039/C8CC09913H

Fluorescent retinoic acid analogues as probes for biochemical and intracellular characterization of retinoid signalling pathways, D. R. Chisholm, C. Tomlinson, G.-L. Zhou, C. Holden, V. Affleck, R. Lamb, K. Newling, P. Ashton, R. Valentine, C. Redfern, J. Erostyak, G. Makkai, C. A. Ambler, A. Whiting and E. Pohl, ACS Chem. Biol., 2019, 14, 369–377, DOI: 10.1021/acschembio.8b00916

Research interests

  • Biological chemistry
  • Synthetic retinoids
  • Asymmetric Catalysis
  • Bifunctional Catalysis
  • Target and Natural Product Synthesis

Esteem Indicators

  • 2000: FRSC: Admitted as Fellow of the Royal Society of Chemistry

Publications

Journal Article

Supervision students

Abbey Butler

Research Postgraduate

Alejandro Cuello-Rodriguez