PHOSPHO-TRANSFER CHEMISTRY
Dr Terence P. Kee
Phospho-transfer catalysis refers to the transfer of a phospho function, [(RO) 2P(O)] or derivative, from one chemical
site to another mediated by a distinct catalytic species (Scheme 1).1
Phosphorylation
of
proteins
CAT
involves
[P-O]
bond
formation
Scheme 1
O
CAT
CAT
P
and cleavage catalysed by kinase
X
P
P
P
P
=
OR
and phosphatase enzymes.
RO
B
A
A
B
A
B
[X = O, C, S, N, H...]
A less well investigated variant is phosphonylation, where a phosphorus-carbon [P-C] bond is formed. Phosphorylation
results in phosphate esters whilst phosphonylation results in phosphonate esters. Whilst phosphate esters form the
backbone of the genetic materials DNA and RNA and are key elements in cellular signalling, phosphonate esters,
especially -hydroxy and -amino phosphonates find widespread application as phosphate ester mimics, enzyme
inhibitors, transition state analogues, antibiotics, antiviral agents, and in nucleotide technology.2 Within each application
stereochemistry of the functionalised phosphonate is crucial in eliciting the required properties. 3 Since initiation in 1992,
we have in this laboratory explored several problems within phospho-transfer chemistry. Indicators of the international
standing of our laboratory within the field of phosphorus chemistry include; increasing invitations to present aspects of
our work at international meetings,4 specially commissioned articles in peer review journals and monographs,4 a Visiting
Professorship at the Universite de Cergy-Pontoise, France (April-May 1999) and invitation to serve as a member of the
National Scientific Committee for the 16th International Conference on Phosphorus Chemistry, UK (July 2004). A
selection of our most recent research themes in phosphorus chemistry are outlined below.
OSiMe3
Ph
Ph
Me
P
SiMe3
P
N
N
R
SiMe3
Ar
Me
ArCHO
(R = Me, iPr)
Scheme 2
Ar = n-X-C6H4 (n = 2,3,4)
X = Me, MeO, Br, Cl, NO2 etc
N
N
R
SiMe3
d.s. < 24:1
(SP;SC):(SP:RC)
Asymmetric Catalysis: The principal [P-C]
bond formation project in our laboratory at
present, focuses on the development of catalytic
enantioselective, aerobic variants of the
phospho-Aldol reaction (Scheme 3).6 To date
we have achieved enantioselectivities (e.e.’s)
<60% through the use of a class of aluminium
complex.7
Asymmetric Synthesis: In 1992 we published a new
development to one of the most versatile asymmetric [P-C]
bond-forming processes, the asymmetric phospho-Mukaiyama
aldol reaction (Scheme 2). Subsequent work in our laboratory has
revealed diastereoselectivities <96% (24:1) with substituted
benzaldehyde substrates (Scheme 2) and new phosphodiamidite
reagents.5 A combination of structure-activity, isotopic labelling
and NMR studies has allowed us to rationalise stereocontrol in
these systems.5
CAT
HO
X
RO
RO
OH
CAT
O
P
H
RO
RO
RO
P
P
+
X-
RO
R'
R'
H
Scheme 3. R = Alkyl, aryl etc. CAT = catalyst.
X = O (phospho-Aldol); X = NR
(phospho-Mannich)
H-transfer
O
RO
P
XH
RO
R'
Conformational Dynamics of Triphenylphosphines:
We are exploring the use of conformational
diastereoisomerism in helically chiral tris-orthofunctionalised triphenylphosphines such as [1-[2-(bis-{2[1phenylethylimino)methyl]phenyl}phosphinoyl)phenyl]met
Mechanism and Inhibition of Vacuolar Proton-Pumping
ATPase Enzymes (left with space-filling
h-[E]-ylidene]-(1-phenylethyl)amine
view emphasising helical chirality).8
CN
H
a
a
H
b
N P Cl
N
b
CN
Dynamic [P-X] Exchange in Phosphorus(III) Systems:
We have developed the first examples of chiral two-coordinate phosphenium salts.9 In addition
to a quantitative examination of Lewis acidity of these compounds9b, we have examined the
mechanisms of degenerate halogen exchange in phosphorus(III) halides (left) such as (8R,9R)1,3-bis-(4-cyanobenzyl)-2-chloro-octahydro-benzo[1,3,2]diazaphosphole
using
variable
temperature and concentration 13C{1H}-NMR and gNMR full line-shape simulations.10
Pre-Biotic Phosphorus Chemistry in Origin-of-Life Studies11 – The PHOSMETIC Project
This is a relatively new venture for us and one that is set to become perhaps the major theme of research within our
group. We have been looking to explore possible pre-biotic phosphorus feed-stocks other than inorganic phosphate.
Initial work has been supported through the auspices of the EU Leonardo Program and the Nuffield Foundation whilst
the more recent and substantial PHOSMETIC (Phosphorus Modelling on ExtraTerrestrial ICes) Project, funded by the
Leverhulme Trust has produced some remarkable recent results. We have provided experimental evidence for the
hypothesis that exoitic phosphorus chemicals, phosphonate esters, found on the Murchsion carbonaceous chondrite
meteorite might have resulted from hydrolytic modification of [PC]-containing species.12 A more recent follow up to
this work has identified, for the first time, direct evidence that chemically reactive, water soluble sources of phosphorus
were available to pre-biotic chemistry on the early Earth as a result of hydrolytic modification under photolytic
conditions, of certain meteorites such as the Nantan meteorite whose Earth-fall was observed and documented in
China in 1516.13 This and other features are currently under more detailed investigation.
References
1. T. P. Kee, Chemistry in Britain, 1996, 32(1), 41 and references therein.
2. R. L. Hilderbrand (Ed.), The Role of Phosphonates in Living Systems, RCRC Press, Boca Raton, Fl., 1983; R. Engel, Chem. Rev., 1977,
77, 349; G. M. Blackburn, Chem. Ind., 1981, 134.
3. See for example, V. A. Solodenko, M. Y. Belik, S. V. Galushko, V. P. Kukhar, E. V. Kozlova, D. A. Mironenko and V. K. Svedas,
Tetrahedron: Asymmetry, 1993, 4, 1965 and references therein.
4. Including GECOM-CONCOORD 97, Val d’Oise, France (May 1997); Agichem97, Marburg, Germany (Sept. 1997); XIV
International Conference on Phosphorus Chemistry, Cincinnati USA (July 1998); CERC3, Rostock, Germany (1999) and XV
International Conference on Phosphorus Chemistry, Sendai, Japan (July 2001). Recently commissioned international pieces include
book chapters in; Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain, Ed; F. Mathey, Pergamon, Oxford, 2001 (Ch. 4);
New Aspects of Phosphorus Chemistry II, Ed; J-P. Majoral, Springer, Berlin, 2003 (Ch. 2).
5. V. Sum, A. J. Davies and T. P. Kee, J. Chem. Soc., Chem. Commun., 1992, 1771; P. G. Devitt and T. P. Kee, ibid, 1994, 3169; V. Sum,
C. A. Baird, T. P. Kee and M. Thornton-Pett, ibid, 1994, 3183; M. J. Cain, C. A. Baird and T. P. Kee, Tetrahedron Letts., 1994, 35,
8671; M. J. Cain, A. Cawley, V. Sum, D. Brown, M. Thornton-Pett and T. P. Kee, Inorg. Chim. Acta., in the press.
6. M. C. Mitchell, A. Cawley and T. P. Kee, Tetrahedron Letts., 1995, 36, 287; P. G. Devitt, et. al., Tetrahedron: Asymmetry, 1995, 6, 2039;
S. R. Davies et. al., J. Organomet. Chem., 1998, 550, 29.
7. J. P. Duxbury, A. Cawley, M. Thornton-Pett, L. Wantz, J. N. D. Warne, R. Greatrex, Dearg Brown and T. P. Kee, Tetrahedron
Letts., 1999, 40, 4403; J. P. Duxbury, J. N. D. Warne, R. Mushtaq, C. V. Ward, M. Thornton-Pett, M. Jiang, R. Greatrex and T. P.
Kee, Organometallics, 2000, 19, 4445; M. Jiang, S. Dalgarno, C. A. Kilner, M. A. Halcrow and T. P. Kee, Polyhedron, 2001, 20, 2151; C.
V. Ward, M. Jiang and T. P. Kee, Tetrahedron Letts., 2000, 41, 6181; T. D. Nixon and T. P. Kee, Topics Curr. Chem., 2003, 223, 45; A.
Davis, C. A. Kilner and T. P. Kee, Inorg. Chim. Acta., in the press (#0140); T. D. Nixon, S. Dalgarno, C. V. ward, M. Jiang, M. A.
Halcrow, C. A. Kilner, M. Thornton-Pett and T. P. Kee, Comptes Rendus Chimie, in the press (#MGC4).
8. M. R. Whitnall, K. K. Hii, M. Thornton-Pett and T. P. Kee, J. Organomet. Chem., 1997, 529, 35; M. R. Whitnall, M. Thornton-Pett
and T. P. Kee, Inorg. Chim. Acta., 2003, 355, 95.
9. (a) V. A. Jones, M. Thornton-Pett and T. P. Kee, J. Chem. Soc., Chem. Commun., 1997, 1317; (b) V. A. Jones, S. Sriprang, H. G.
Butler, M. Thornton-Pett, and T. P. Kee, J. Organomet. Chem., 1998, 567, 199; (c) S. L. Renard and T. P. Kee, J. Organomet. Chem.,
2002, 643-644, 516.
10. S. L. Renard, J. Fisher, C. A. Kilner, M. Thornton-Pett and T. P. Kee, J. Chem. Soc., Dalton Trans., 2002, 2921.
11. A. J. Marks, I. B. Gorrell, F. Bouillot and T. P. Kee, Educ. Chem., 2005, 42, 68.
12. I. B. Gorrell, L. Wang, A. J. Marks, D. E. Bryant, F. Bouillot, A. Goddard, D. E. Heard and T. P. Kee, Chem. Commun., in press.
See press release; The Reporter http://reporter.leeds.ac.uk/504/s2.htm.
13. D. E. Bryant and T. P. Kee, manuscript in preparation.