Biological Chemistry - School of Physics and Astronomy - The ...

MAJOR
GRANTS
High-Resolution Mass Spectrometer for
The University of Manchester
Department of Chemistry, EPSRC, £449k.
Potentially Prebiotic Synthesis and
Replication of RNA, EPSRC, £418k.
Completion of a Synthesis of Bryostatins,
EPSRC, £260k.
Stereochemical Communication: Relaying
Information by Conformational
Interactions, EPSRC, £247k.
Biochemical and kinetic analysis of wildtype
mutant acyltransferase variants,
DSM Anti-Infectives, £207k.
Preclinical Development of [IdoA(2S)-
GlcNS]4; an Anti-Tumour and Anti-
Angiogenic Antagonist of FGF-2, Cancer
Research UK, £180k.
Directed evolution in the production of
Cephalosporin antibiotics, BBSRC, £166k.
Chemical predisposition: Divergent
synthesis of an array of natural and
unnatural fatty acid derivatives, EPSRC,
£116k.
10
Organic Chemistry
P.D. Bailey, J.P. Clayden, J.M. Gardiner, P. Quayle, A.C. Regan, J.D. Sutherland,
E.J. Thomas, T.W. Wallace, C.I.F. Watt, and R.C. Whitehead.
The powerful tools of synthesis and mechanistic analysis,
assisted by an ever expanding analytical arsenal, make 21st
century Organic Chemistry an intellectually stimulating and
practically useful subject in its own right, and endow organic
chemists with the ideal skills for the exploration of biology and
materials science. Substantial grant income, outstanding
publications, new appointments and a strong demand for our
graduates and postdoctorals in industry all show that organic
chemistry in Manchester is thriving. What follows is a
'snapshot' of research in this grouping designed to highlight
the excitement of working at the forefront of Organic
Chemistry and at its boundaries with other subjects.
Stereoselectivity and stereospecificity are
crucial to synthesis. Short-range stereocontrol
has arguably been mastered in many cases,
but long-range stereocontrol had been more
elusive until the development of methodology
using allyl stannanes here in Manchester.
Recently, indium (III) and bismuth (III)
promoters have been found to reverse
stereoselectivity 1 and tin-free methods using
bismuth (0) have been developed. 2 In
complementary work, the synthesis was
achieved of a class of molecules –
oligo(xanthenedicarboxamides) – whose
reactions exhibit remote stereocontrol even
though the controlling centre may be
separated from the reaction site by over 20
bond lengths and by a linear distance of over
2.5 nm (Figure 1). Transmission of information
from the controlling centre to the reaction
site has been achieved by relayed
conformational changes, and provides the
basis for a chemical model of allostery with
potential for future elaboration as a molecular
mechanism for communicating and
processing information. 3
In related work, complementary kinetic and
thermodynamic resolution of a chiral biaryl
axis was demonstrated. 4 Still in a chiral vein
but in a biochemical context, insight into
chiral discrimination of the Class II Aldolases
was afforded by examination of the structure
of tagatose-1,6-bisphoshate aldolase. 5 In
chemistry pursued for its possible etiological
relevance, the aldolisation of glyceraldehyde-
2-phosphoglycolaldehyde was shown to be
intra- rather than inter-molecular and, of the
four possible aldopentose-2,4-cyclic
phosphate products, the ribo- and xylo-
stereochemistries were, as predicted,
dominant. 6 In subsequent work, it has been
shown that the same products can be
obtained from the reaction of bisgylcolaldehyde
phosphate diester and
formaldehyde.
Manchester has long been a powerhouse of
organic synthesis and the arrival of Darren
Dixon, from Cambridge, and David Procter,
from Glasgow, in autumn 2004 will add
further to our strength in this area. Over the
period of the report, much has been achieved
synthetically. In the natural product arena
approaches to, and total syntheses of
bryostatins and phomactins, 7 manzamenones
(Figure 2), 8 raumacline, 9 podophyllotoxin, 10
kainoids, 11 PTX-B 12 and Mycalamide A, 13 and
aflatoxins (Figure 3) were described. These
targets have served to validate and showcase
a wide variety of new strategies and
methodologies developed in the grouping
including: novel tin chemistry; predisposed
synthesis; surfactant catalysis; lithiationdearomatizing
cyclization; photochemical ring
expansion of lithiated benzamides; 14
controlled chemoselective lithiation; 15 Dötz
benzannulation; atom transfer radical
cyclisation; 16 green oxidation reactions; 17 aza-
Diels-Alder cycloadditions; 18 cis-specific Pictet-
Spengler reaction; 19 and new enantioselective
catalysis. 20, 21 Chemists' unique ability to
synthesise unnatural substances finds its
widest employment in organic chemistry and
members of the grouping have prepared and
evaluated glycolaldehyde di- and
triphosphate 22 and a variety of fluorinated
shikimates, 24 most notably 6,6difluoroshikimic
acid. 25
At the interface of chemistry and biology,
organic chemistry flourishes and the grouping
has made many contributions. An exit
transporter for the PepT1 mediated transport
of peptides across the small intestine has
been discovered. 26 The crystal stucture for a
cleavage mutant of acyl coenzyme
A:isopenicillin N acyltransferase from
Penicillium chrysogenum has been
determined in collaboration with a Dutch
group. 27 The kinetics and thermodynamics of
transcription factor NF-kB homodimerization
have been analysed. 28 Finally, the first results
of exploratory studies to investigate a linked
prebiotic origin of RNA and coded peptides
have been published. 29,30
Figure 1
Remote stereocontrol: a single conformation of the
starting material is favoured, as the shape at A governs
the orientation of u, u governs v etc., through to z,
which controls the local environment at B. Addition of
the Grignard reagent then occurs with remote
stereocontrol operating through more than 20 bonds.
Figure 2
Manzamenone A, isolated from a marine sponge,
has been synthesised using ideas of predisposed
synthesis.
Figure 3
Aflatoxin B2, a potent mycotoxin produced by
Aspergillus flavus, and which is found to
contaminate many cereal crops, has been
synthesised using organochromium chemistry.
1 S. Donnelly, E. J. Thomas, E. A. Arnott, J. Chem.
Soc., Chem. Commun. 2003, 1460.
2 S. Donnelly, M. Fielding, E. J. Thomas,
Tetrahedron Lett., 2004, 45, 6779.
3 J. Clayden, A. Lund, L. Vallverdú, M. Helliwell,
Nature 2004, in press.
4 D. J. Edwards, R. G. Pritchard, T. W. Wallace,
Tetrahedron Lett. 2003, 44, 4665.
5 D. R. Hall, C. R. Bond, G. Leonard, C. I. F. Watt,
A. Berry, and W. N. Hunter, J. Biol. Chem. 2002,
277, 22018.
6 J. M. Smith, V. Borsenberger, J. Raftery, J. D.
Sutherland, accepted for publication in Chem.
Biodiv. 2004.
7 A. S. Balnaves, G. McGowan, P. D. P. Shapland,
E. J. Thomas, Tetrahedron Lett. 2003, 44, 2713.
8 J. R. Doncaster, H. Ryan, R. C. Whitehead,
Synlett, 2003, 651.
9 P. D. Bailey, P. D. Clingan, R. A. Price, R. G.
Pritchard, Chem. Commun. 2003, 2800.
10 J. P. Clayden, M. N. Kenworthy, M. Helliwell,
Org. Lett. 2003, 6, 831.
11 J. P. Clayden, Strategies and Tactics in Organic
Synthesis, vol. 4, ed Michael Harmata, Academic
Press, 2004.
12 J. M. Gardiner, P. E. Giles, M. M. L. Martin,
Tetrahedron Lett. 2002, 43, 5415.
13 J. M.Gardiner, R.Mills, T. Fessard, Tetrahedron
Lett. 2004, 45, 1215.
14 J. P. Clayden, F. E. Knowles, C. J. Menet, J. Am.
Chem. Soc. 2003, 110, 9278.
15 D. R. Armstrong, S. R. Boss, J. P. Clayden, R.
Haigh, B. A. Kirmani, D. J. Linton, P. Schooler, A.
E. H. Wheatley, Angew. Chem. Int. Ed. 2004,
43, 2135.
16 P. Quayle, D. Fengas, S. Richards, Synlett, 2003,
1797.
17 E. C. Boyd, R. V. H. Jones, P. Quayle, A. J.
Waring, Green Chemistry, 2003, 5, 679.
18 P.D. Bailey, P.D. Smith, F. Pederson, W. Clegg,
G.M. Rosair, S.J. Teat, Tetrahedron Lett. 2002,
43, 1067.
19 L. Alberch, P. D. Bailey, P. D. Clingan, T. J. Mills,
R. A. Price, R. G. Pritchard, Eur. J. Org. Chem.
2004, 1887.
20 J. M. Gardiner, P. D. Crewe, G. E. Smith, K. T.
Veal, R. G. Pritchard, J. E. Warren, Organic Lett.
2003, 5, 467.
21 J. M. Gardiner, P. D. Crewe, G. E. Smith, K. T.
Veal, Chem. Commun. 2003, 618.
22 A. J. Lawrence, J. D. Sutherland, Synlett 2002,
170.
23 J. M.Box, L. M.Harwood, J. L. Humphreys, G. A.
Morris, P. M. Redon, R. C. Whitehead, Synlett
2002, 358.
24 L. Begum, J. M. Box, M. G. B. Drew, L. M.
Harwood, J. L. Humphreys, D. J. Lowes, G. A.
Morris, P. M. Redon, F. M. Walker, R. C.
Whitehead, Tetrahedron 2003, 59, 4827.
25 J. L. Humphreys, D. J. Lowes, K. A. Wesson, R. C.
Whitehead, Tetrahedron Lett. 2004, 45, 3429.
26 E. J. Shepherd, N. Lister, J. A. Affleck, J. R.
Bronk, G. L. Kellett, I. D. Collier, P. D. Bailey,
C.A.R. Boyd, Biochem. Biophys. Res. Commun.
2002, 918.
27 C. M. H. Hensgens, E. A. Kroezinga, B. A. van
Montfort, J. M. van der Laan, J. D. Sutherland,
B. W. Dijkstra, Acta Crystallogr., Sect. D: Biol.
Crystallogr., 2002, D58, 4, 716.
28 Y. S. N. Day, S. L. Bacon, Z. Hughes-Thomas, J.
M. Blackburn, J. D. Sutherland, ChemBioChem
2002, 3, 1192.
29 A.-A. Ingar, R. W. A. Luke, B. R. Hayter, J. D.
Sutherland, ChemBioChem, 2003, 4, 504.
30 V. Borsenberger, M. A. Crowe, J. Lehbauer, J.
Raftery, M. Helliwell, K. Bhutia, T. A. Cox, J. D.
Sutherland, Chemistry & Biodiversity 2004 1, 203.
11