Prof Patrick Bailey

• drug delivery
• peptides
• medicinal chemistry
• heterocyclic synthesis
• cycloaddition reactions
• indole alkaloids
• chemical education

Pat Bailey carried out his undergraduate and DPhil studies in chemistry at the University of Oxford, before taking up a lectureship at York in 1983.  In 1993, he took up the Chair of Organic Chemistry at Heriot-Watt University, Edinburgh, subsequently moving to UMIST in 2001.  He currently holds a Chair of Organic Chemistry at the University of Manchester, and is Associate Dean for Teaching & Learning in the Faculty of Engineering & Physical Sciences.

His research has focused on four main themes: work on protein mechanisms, most recently on peptide transporters; the synthesis of indole alkaloids; developing new methods for preparing medicinally important heterocyclic molecules, especially piperidines via hetero-Diels-Alder chemistry; and studies on the synthesis and properties of peptides, especially constrained and cyclic peptides. His research has been published in around 100 papers, and was recognized by a Yorkshire Cancer Research Campaign career development award (1986-91), the Zeneca Research Award for Organic Chemistry in 1994, and election to the Royal Society of Edinburgh (1999).

His teaching has been recognized by the RSC Higher Education Teaching Award (1998), the RSC Nyholm Lectureship (2000), and the UMIST Teaching Award (2003).  He has also given numerous ‘popular’ chemistry talks to schools and the general public, for which he received the 1999 Lord Kelvin Lecturership by British Association for the Advancement of Science, and he was awarded a National Teaching Fellowship in 2005.

The research being carried out by my group all involves work on biologically important molecules, focusing on the 4 main sub-themes:

            a) studies on protein mechanisms, especially peptide transporters (refs 1-5);
            b) synthesis of indole alkaloids (refs 6-10);
            c) hetercyclic synthesis and hetero-cycloadditions (refs 11-15);
            d) peptide chemistry and cyclic/constrained peptides (refs 16-20).

I have also been enthusiastically involved in the developing new educational methods, and in the public understanding of science in general, and chemistry in particular (see refs 21-25).

a) Studies on protein mechanisms (refs 1-5).  We have been involved in three projects probing protein/enzyme mechanisms:  studying the ras  oncogene protein (YCRC), studies on abzymes (LINK project), and (most recently) work on the PepT1 transporter protein.  This latter project is a major ongoing research programme and we are providing all of the synthetic input into a major collaborative programme with colleagues at York and Oxford (ca £1M total funding from The Wellcome Trust).  We have already made major international contributions to probing the structural and mechanistic features of the PepT1 peptide transporter protein, using a range of carefully designed di- and tri-peptides and peptide analogues, and are now developing ways of using peptidic carriers to improve the oral bioavailability of drugs.

b) Synthesis of indole alkaloids (refs 6-10).  The tetrahydro-b-carboline moiety is a sub-structure common to hundreds of indole alkaloids, but a major synthetic problem has been accessing cis-1,3-disubstituted derivatives.  By a careful study of the mechanism of the Pictet-Spengler reaction, we have developed the only general (and asymmetric) route to cis-1,3-disubstituted tetrahydro-b-carbolines, starting from L-tryptophan (Scheme 1), and we have applied this to the synthesis of several natural products and analogues.

c) Hetercyclic synthesis and hetero-cycloadditions (refs 11-15).  The piperidine moiety is the most commonly occurring heterocyclic system amongst alkaloids, almost always incorporating a 1-substituent, and numerous drugs and drug leads require this sub-structure.  However, there were no general reliable routes to 1-substituted piperidines in 1990, and the obvious entry via Diels-Alder chemistry had proved elusive.  We not only solved the basic problem using imines as dienophiles, but we then discovered and developed asymmetric versions.

            We were the first to discover conditions under which imines of the type PhCH2N=CHCO2R could undergo aza-Diels-Alder reactions with acyclic dienes; this opened up a rapid, simple, and flexible route to a wide range of substituted piperidines, and we demonstrated that replacement of benzyl by the 1-phenylethyl auxiliary gave valuable asymmetric induction.  This chemistry has been further developed to give >95% asymmetric induction using matched N-1-phenylethyl and 8-phenylmenthyl ester auxiliaries (Scheme 2), and is now the best asymmetric route to compounds of this type.

d) Peptide chemistry and cyclic/constrained peptides (refs 16-20).  Polycyclic peptides (PCPs) are a new class of compounds, allowing us to prepare small peptides with well-defined 3D structures.  Several groups have incorporated amino acids into hosts, but we are the only ones to have developed unnatural receptors from a totally peptidic core.

            Crucial to our research was the development of reliable synthetic procedures.  During 1990-1995, having demonstrated that such compounds could be made, and that they would bind guests enantiospecifically (see Figures 1 & 2), we extended the synthetic methodology to allow access to a wide range of PCPs.  Although the synthetic hurdles were substantial, the foundations have been laid for a major research programme in my group;  we are now attempting to prepare enzyme mimics, and initial results would indicate that this should be an important new area of host-guest chemistry with considerable potential.

Studies on PepT1

1) Affinity prediction for substrates of the peptide transporter PepT1
P. D. Bailey, C.A.R. Boyd, I.D. Collier,  J.G. George, G.L. Kellett, D. Meredith, K.M. Morgan, R. Pettecrew and R.A. Price
Chemical Communications, 2006, 323-325

2) Probing dipeptide E/Z-configuration using pH control of thiopeptide analogues, and application to the PepT1 transporter
P.D. Bailey, C.A.R. Boyd, I.D. Collier, G.L. Kellett, D. Meredith, K.M. Morgan, R. Pettecrew and R.A. Price
Organic and Biomolecular Chemistry, 2005, 3, 4038-4039

3) Conformational and spacial preferences for substrates of PepT1
P.D. Bailey, C.A.R Boyd, I.D. Collier,  J.G. George, G.L. Kellett, D. Meredith, K.M. Morgan, R. Pettecrew,  R.G. Pritchard and R.A. Price
Chemical Communications, 2005, 5352-5354

4) Identification of a candidate membrane protein for the basolateral peptide transporter of rat small intestine
E.J. Shepherd, N. Lister, J.A. Affleck, J.R. Bronk, G.L. Kellett, I.D. Collier, P.D. Bailey and C.A.R. Boyd
Biochemical & Biophysical Research Communications, 2002, 296, 918-922

5) A Substrate Template for Peptide Transporter PepT1
P.D. Bailey, C.A.R. Boyd, J.R. Bronk, I.D. Collier, D. Meredith, K.M. Morgan and C.S. Temple
Angewandte Chemie, Int. Ed. Engl., 2000, 39, 506-508

Indole alkaloids

6) Cis-specific Pictet-Spengler reaction
L. Alberch, P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and R. G. Pritchard
European Journal of Organic Chemistry, 2004, 1887-1890

7) Total synthesis of (–)-raumacline
P.D. Bailey, P.D. Clingan, T.J. Mills, R.A. Price and R.G. Pritchard
Chemical Communications, 2003, 2800

8) A concise, efficient route to fumitremorgins
P.D. Bailey, P.J. Cochrane, K. Lorenz, I.D. Collier, D.P.J. Pearson and G.M. Rosair
Tetrahedron Lett., 2001, 42, 113-115

9) The Total Synthesis of (–)-Suaveoline
P.D. Bailey and K.M. Morgan
J. Chem. Soc., Perkin Trans. 1, 2000, 3578-3583

10) New Asymmetric Routes to Ajmaline and Suaveoline Indole Alkaloids
P.D. Bailey, K.M. Morgan, D.I. Smith and J.M. Vernon
J. Chem. Soc., Perkin Trans. 1, 2000, 3566-3577

Heterocyclic compounds and hetero-cycloaddition reactions

11) Spiro cyclisations of N-acyliminium ions involving an aromatic p-nucleophile
P.D. Bailey, K.M. Morgan, D.I. Smith and J.M. Vernon
Tetrahedron, 2003, 59, 3369-3378

12) The use of the aza-Diels-Alder reaction in the synthesis of pinidine and other piperidine alkaloids
P.D. Bailey, P.D. Smith, K.M. Morgan and G.M. Rosair
Tetrahedron Letters, 2002, 43, 1071-1074

13) A high yielding route to substituted piperidines via the aza-Diels-Alder reaction
P.D. Bailey, P.D. Smith, F. Pederson, W. Clegg, G.M. Rosair and S.J. Teat
Tetrahedron Letters, 2002, 43, 1067-1070

14) An Unusual Oxidative Rearrangement of azabicyclo[2.2.1]heptenes, Providing a Stereoselective Route to 2'- and 3'-hydroxycyclopentylglycines
P.D. Bailey, I.M. McDonald, G.M. Rosair and D. Taylor
Chemical Communications, 2000, 2451-2452

15) a-Chloronitroso Compounds derived from Carbohydrate Ketones:  Cycloadditions With Cyclic Dienes, a Synthesis of (-)-Physoperuvine and a Formal Synthesis of (+)-Epibatidine
A. Hall, P.D. Bailey,  D.C. Rees, G.M. Rosair and R.H. Wightman
J. Chem. Soc., Perkin Trans 1, 2000, 329-343

Peptide chemistry and constrained/cyclic peptides

16) Synthesis of conformationally constrained amino acid and peptide derivatives
P.D. Bailey, N. Bannister, M. Bernad, S. Blanchard and A.N. Boa
J. Chem. Soc., Perkin Trans. 1, 2001,  3245-3251

17) The asymmetric synthesis and conformational analysis of new C2-symmetric macrocycles derived from head-to-head linked a-amino acids and benzene or pyridine
P.D. Bailey, S.E.L. Everitt, K.M. Morgan and A.G. Brewster
Tetrahedron, 2001,  57,  1379-1386

18) Piperazine-2,3,5-triones in the Synthesis of Constrained Peptides
P.D. Bailey, A.N. Boa, S.R. Baker, J. Clayson, E.J. Murray and G.M. Rosair
Tetrahedron Letters, 1999, 40, 7557-7560

19) The Design and Synthesis of Cyclic Peptide Chelators
P.D. Bailey, D.J. Bennett, R. Gilfillan, N.J. Hales and J.D. Heffernan
Peptides 96 (R. Ramage and R. Epton, eds.), pp 227-228, Mayflower Sci. Ltd., 1998

20) Synthesis and Structure of a New Type of Polycyclic Peptide
P.D. Bailey, D.G.W. Clarke and G.A. Crofts
Journal of the Chemical Society, Chemical Communications, 1992, 658-660

Education in Chemistry

21) The 'poor Raymond' investigation: a team work exercise to inspire new students P.D. Bailey
Proceedings of The Science Learning and Teaching Conference 2005, pp 53-58, The HE Academy, 2005

22) Fireworks, stink-bombs and magic bullet medicines
P.D. Bailey
Chemistry Review, 2002, 11(3), 18-22.

23) Chemical education: theory and practice
P.D. Bailey and C.J. Garratt
University Chemistry Education, 2002,  6,  39-57

24) Teaching chemists to communicate? Not my job!
P.D. Bailey
University Chemistry Education, 2001,  5,  80-86

25) Getting the Message Across: Key Skills for Scientists (3rd revised edition)
P.D. Bailey and S.E. Shinton (K. MacDonald, ed.)
pp 48, Royal Society of Chemistry, London, 2001