Prof. Andrew Whiting, BSc Hns, PhD, FRSC CChem
(email at firstname.lastname@example.org)
Director of the Center for Sustainable Chemistry and Catalysis (CSCP)
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
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) 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 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 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.
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.
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.
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.
Department of Chemistry
- Bioactive Chemistry and Synthesis
- Catalysis and Sustainable Chemical Processes
- Biological chemistry
- Synthetic retinoids
- Asymmetric Catalysis
- Bifunctional Catalysis
- Target and Natural Product Synthesis
- Eberlin, L., Macé, A., Batsanov, A. S., Carboni, B. & Whiting, A. (2018). A Dienyl Boronate‐Aryl Nitroso Ene Reaction Entry to C‐Pyrrolyl Nitrones and Subsequent Conversion to Isoxazolidines. ChemistrySelect 3(16): 4557-4561.
- Rzepa, H.S., Arkhipenko, S., Wang, E., Batsanov, A.S., Sabatini, M.T., Karaluka, V., Whiting, A. & Sheppard, T.D. (2018). An accessible method for DFT calculation of 11B NMR shifts of organoboron compounds. Journal of Organic Chemistry 83(15): 8020-8025.
- Arkhipenko, Sergey, Batsanov, Andrei, Sabatini, Marco, Karaluka, Valerija, Sheppard, Tom, Rzepa, Henry & Whiting, Andrew (2018). Mechanistic insights into boron-catalysed direct amidation reactions. Chemical Science 9(4): 1058-1072.
- Haffez, H., Khatib, T., McCaffery, P., Przyborski, S., Redfern, C. & Whiting, A. (2018). Neurogenesis in Response to Synthetic Retinoids at Different Temporal Scales. Molecular Neurobiology 55(3): 1942-1950.
- Haffez, H., Chisholm, D. R., Tatum, N. J., Valentine, R., Redfern, C., Pohl, E., Whiting, A. & Przyborski, S. (2018). Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids. Bioorganic & Medicinal Chemistry 26(8): 1560-1572.
- Pujol, Alba & Whiting, Andrew (2017). Double Diastereoselective Approach to Chiral syn- and anti-1,3-Diol Analogues through Consecutive Catalytic Asymmetric Borylations. The Journal of Organic Chemistry 82(14): 7265-7279.
- Haffez, H., Chisholm, D. R., Valentine, R., Pohl, E., Redfern, C. & Whiting, A. (2017). The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors. MedChemComm 8(3): 578-592.
- Girling, P.R., Batsanov, A.S., Calow, A.D.J., Shen, H.C. & Whiting, A. (2016). Alternative tandem cyclisation pathways in the reaction between imines and enones. Tetrahedron 72(8): 1105-1113.
- Chisholm, David R., Valentine, Roy, Pohl, Ehmke & Whiting, Andrew (2016). Conjugate Addition of 3-Buytn-2-one to Anilines in Ethanol: Alkene Geometric Insights through In Situ FTIR Monitoring. The Journal of Organic Chemistry 81(17): 7557-7565.
- Chisholm, D. R., Zhou, G.-L., Pohl, E., Valentine, R. & Whiting, A. (2016). Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines. Beilstein Journal of Organic Chemistry 12: 1851-1862.
- Liu, S., Zhang, Q., Li, H., Yang, Y., Tiana, X. & Whiting, A. (2015). A visible light induced α-H chlorination of alkylarenes with inorganic chloride under nanoAg@AgCl. Chemistry: A European Journal 21(27): 9671-9675.
- Chaiyaveij, D., Batsanov, A.S., Fox, M.A., Marder, T.B. & Whiting, A. (2015). An experimental and computational approach to understanding the reactions of acyl nitroso compounds in [4+2]-cycloadditions. The Journal of Organic Chemistry 80(19): 9518-9534.
- Whiting, Andrew, Madden, Katrina S., David, Sylvain & Knowles, Jonathan P. (2015). Heck-Mizoroki Coupling of Vinyliodide and Applications in The Synthesis of Dienes and Trienes. Chemical Communications 51(57): 11409-11412.
- Pujol, A., Calow, A. D. J., Batsanov, A. S. & Whiting, A. (2015). One-pot catalytic asymmetric borylation of unsaturated aldehyde-derived imines; functionalisation to homoallylic boronate carboxylate ester derivatives. Organic & Biomolecular Chemistry 13(18): 5122-5130.
- Eberlin, Ludovic, Carboni, Bertrand & Whiting, Andrew (2015). Regioisomeric and substituent effects upon the outcome of the reaction of 1-borodienes with nitrosoarene compounds. The Journal of Organic Chemistry 80(13): 6574-6583.
- La Cascia, E., Sanz, X., Bo, C., Whiting, A. & Fernandez, E. (2014). Asymmetric metal free β-boration of α,β-unsaturated imines assisted by (S)-MeBoPhoz. Organic and Biomolecular Chemistry 13(5): 1328-1332.
- Batsanov, A. S., Georgiou, I., Girling, P. R., Pommier, L., Shen, H. C. & Whiting, A. (2014). Asymmetric synthesis and application of homologous pyrroline-2-alkylboronic acids: Identification of the B-N distance for eliciting bifunctional catalysis of an asymmetric aldol reaction. Asian Journal of Organic Chemistry 3(4): 470-479.
- Madden, K. S., Mosa, F. A. & Whiting, A. (2014). Non-isoprenoid polyene natural products - structures and synthetic strategies. Org. Biomol. Chem 12: 7877-7899.
- Calow, A. D. J., Carbó, J. J., Cid, J., Fernández, E. & Whiting, A. (2014). Understanding α,β-unsaturated imine formation from amine additions to α,β-unsaturated aldehydes and ketones: an analytical and theoretical investigation. The Journal of Organic Chemistry 79(11): 5163-5172.
- Tripoteau, F., Eberlin, L., Fox, M. A., Carboni, B. & Whiting, A. (2013). A novel, efficient synthesis of N-aryl pyrroles via reaction of 1-boronodienes with arylnitroso compounds. Chemical Communications 49(47): 5414-5416.
- Calow, A. D. J., Batsanov, A. S., Pujol, A., Solé, C., Fernández, E. & Whiting, A. (2013). A selective transformation of enals into chiral γ-amino alcohols. Organic Letters 15(18): 4810-4813.
- Calow, A. D. J., Solé, C., Whiting. A. & Fernández, E. (2013). Base-free β-boration of α,β-unsaturated imines catalysed by Cu2O with concurrent enhancement of asymmetric induction. ChemCatChem 5(8): 2233-2239.
- Clemens, G., Flower, K.R., Gardner, P., Henderson, A. P., Knowles, J. P., Marder, T. B., Whiting, A. & Przyborski, S. A. (2013). Design and biological evaluation of synthetic retinoids: Probing length vs. stability vs. activity. Molecular BioSystems 9(12): 3124-3134.
- Liu, S., Yang, Y., Liu, X., Ferdousi, F. K., Batsanov, A. S. & Whiting, A. (2013). Direct Amidation of Amino Acid Derivatives Catalyzed by Arylboronic Acids: Applications in Dipeptide Synthesis. European Journal of Organic Chemistry 2013(25): 5692-5700.
- Ilyashenko, G., Al-Safadi, R., Donnan, R., Dubrovka, R., Pancholi, J., Watkinson, M. & Whiting, A. (2013). Facile synthesis of a 1,1’-desymmetrised ferrocene backbone and its one-pot double-“click” functionalisation. RSC Advances 3(38): 17081-17087.
- Zhou, G.-L., Tams, D. M., Marder, T. B., Valentine, R., Whiting, A. & Przyborski, S. A. (2013). Synthesis and applications of 2,4-disubstituted thiazoles derivatives as small molecule modulators of cellular development. Organic & Biomolecular Chemistry 11(14): 2323-2334.
- Clemens, G., Flower, K. R., Henderson, A. P., Whiting, A., Przyborski, S. A., Jimenez-Hernandez, M., Ball, F., Bassan, P., Cinque, G. & Gardner, P. (2013). The action of all-trans-retinoic acid (ATRA) and synthetic retinoid analogues (EC19 and EC23) on human pluripotent stem cells differentiation investigated using single cell infrared microspectroscopy. Molecular BioSystems 9(4): 677-692.
- Girling, P.R., Batsanov, A.S., Shen, H.C. & Whiting, A. (2012). A multicomponent formal [1+2+2+1]-cycloaddition for the synthesis of dihydropyridines. Chemical Communications 48(40): 4893-4895.
- I. Georgiou; & A. Whiting; (2012). An efficient enantioselective (R)-homoboroproline from (S)-proline using borylation approach. European Journal of Organic Chemistry 2012(22): 4110-4113.
- A. D. J. Calow;, C. Solé;, E. Fernandez; & A. Whiting; (2012). Novel transformation of α,β-unsaturated aldehydes and ketones to γ-amino alcohols or 1,3-oxazines via a 4 or 5 step, one-pot sequence. Chemical Communications 48(93): 11401.
- W. Na;, A. Messinis;, A. S. Batsanov;, Y. Zhen;, A. Whiting; & T. B. Marder; (2012). Palladium(II)-catalysed tandem cyclisation of electron-deficient aromatic enynes. Chemical Communications 48(80): 9986-9988.
- S. Liu;, Y. Yang;, X. Zhen;, J. Li;, H. He; J. Feng; & A. Whiting; (2012). Stereoselective synthesis and rearrangement-fragmentation of arylidene N-alkoxydiketopiperazines. Organic & Biomolecular Chemistry 10(3): 663-670.
- C. Solé;, A. Tatla;, J. Mata;, A. Whiting;, H. Gulyás; & E. Fernandez; (2011). Catalytic 1,3-difunctionalization of organic backbones via a highly stereoselective, one-pot, boron conjugate-addition/reduction/oxidation process. Chemistry - A European Journal 17(50): 14248.
- J. P. Knowles;, V. E. O’Connor; & A. Whiting; (2011). Studies towards the synthesis of the northern polyene of viridenomycin and synthesis of Z-double bond analogues. Organic & Biomolecular Chemistry 9(6): 1876-1886.
- Mears, R.J., Sailes, H.E., Watts, J.P. & Whiting, A. (2006). A stereoselective remote homochiral boronate ester-mediated aldol reaction. Arkivoc 2006(1): 95-103.
- Batsanov, A.S., Lightfoot, A.P., Twiddle, S.J.R. & Whiting, A. (2006). Bis(2,6-dimethylpyridyl)iodonium dibromoiodate. Acta crystallographica section E structure reports online E62: o901-o902.
- Greenwell, H.C., Bowden, A.A., Chen, B.Q., Boulet, P., Evans, J.R.G., Coveney, P.V. & Whiting, A. (2006). Intercalation and in situ polymerization of poly(alkylene oxide) derivatives within M+-montmorillonite (M = Li, Na, K). Journal of Materials Chemistry 16(11): 1082-1094.
- Blatch, A.J., Howard, J.A.K., Probert, M.R. & Whiting, A. (2006). N-(diphenylphosphinoyl)hydroxylamine. Acta crystallographica section E structure reports online 62(11): o5343-o5345.
- Blatch, A.J., Howard, J.A.K., Probert, M.R., Smethurst, C.A. & Whiting, A. (2006). Potassium 4-nitrophenylsulfonate monohydrate. Acta crystallographica section E structure reports online 62(4): m741-m743.
- A.J. Blatch, O.V. Chetina, J.A.K. Howard, L.G.F. Patrick, C.A. Smethurst & A. Whiting (2006). Synthesis and structure of bifunctional N-alkylbenzimidazole phenylboronate derivatives. Organic & Biomolecular Chemistry 4(17): 3297-3302.
- Blatch, A.J., Howard, J.A.K., Probert, M.R., Smethurst, C.A. & Whiting, A. (2006). tert-Butyl N-(phosphinoyloxy)carbamate. Acta crystallographica section E structure reports online 62(11): o5346-o5348.
- Whiting, A. & Walton, S. (2006). Unexpected exothermic reaction between thioacetic acid and DMSO. Organic Process Research & Development 10(4): 846-846.
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