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Department of Chemistry

Prof. Andrew Whiting, BSc Hns, PhD, FRSC CChem

Personal web page

Professor in the Department of Chemistry
Telephone: +44 (0) 191 33 42081
Director, Centre for Sustainable Chemical Processes

(email at andy.whiting@durham.ac.uk)

Director of the Center for Sustainable Chemistry and Catalysis (CSCP)

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 research themes ongoing in our group revolve around 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

Recently, 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.6

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 anaogues.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, Prof John Girkin), here in Chemistry (Dr Ehmke Pohl), the Northern Centre for Cancer Research, Newcastle (Dr Chris Redfern), University of Würzburg (Prof Todd Marder), High Force Research (Dr Roy Valentine), and recently with the Universities of Aberdeen (Prof Peter McCaffery) and Manchester (Prof Peter Gardiner). Our role has been the design, modelling and synthesis of synthetic retinoids, i.e. analogues of 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.

In addition, we have now created fluorescent variants, which we are using for bioimaging purposes.12 Some of these compounds are available for evaluation for free, as outlined in the flyer shown below, and we hope will find new applications in a range of novel cell biology applications.

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.

Recent relevant 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. H. Charville, D. Jackson, G. Hodges, A. Whiting, M. R. Wilson, Eur. J. Org. Chem., 2011, 5981–5990, DOI: 10.1002/ejoc.201100714

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. Cinqueand 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.

Selected Publications

Journal Article

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