ORGANIC
LETTERS
2
002
Vol. 4, No. 21
671-3673
A Simple and Effective Method for
Phosphoryl Transfer Using TiCl4
Catalysis
3
Simon Jones* and Dimitrios Selitsianos
Department of Chemistry, UniVersity of Newcastle upon Tyne, Bedson Building,
Newcastle upon Tyne, NE1 7RU, UK
Received July 26, 2002
ABSTRACT
A number of Lewis acids have been evaluated as catalysts for the phosphoryl transfer, the most efficient being TiCl
4
. Application of this
methodology to the phosphorylation of a number of representative target alcohols is presented
Many important highly functionalized molecules in Nature
contain phosphate esters, in particular, those based upon
carbohydrate residues. Complex polysaccharides bearing
phosphate esters are now commonly found as the structural
components of cell walls and are implicated in many
biological processes as varied as regulating immune response,
carried out by formation of the alkoxide of the substrate,
usually employing n-BuLi, necessarily limiting its application
to those substrates with compatible functional groups. A
better method is to treat the alcohol with the chlorophosphate
in the presence of a proton scavenger such as triethylamine,
4
with or without a nucleophilic catalyst. This latter route
1
host-pathogen interactions, and tumor metathesis. Structur-
ally related inositol phosphates are also important biological
offers significant advantages over the former and has been
employed in the synthesis of compounds such as inositol
5
6
messengers that act as a second messenger in regulating
monophosphate inhibitors, D-fructose phosphate analogues,
2
transmembrane signaling. As well as serving a critical role
and Lipid A-type pyrancarboxylic acid derivatives, among
others.
in maintaining vital biological processes, phosphate esters
have been incorporated into many important pharmaceutical
agents such as Honvan and Emcyt used in the treatment of
cancer of the prostate. One of the primary roles that such a
group has in these agents is to improve the water solubility
of the agent and hence its bioavailability.
Our interest in the development of methods to accomplish
enantioselective phosphoryl transfer led us to consider
another little explored mode of reactivity for the formation
of phosphates through the use of Lewis acid catalysis. A
number of groups have discussed the use of catalysts
containing species such as Cu(II), La(III), Fe(III), Cr(III),
Ti(IV), Zr(IV), Y(III), and Sn(IV) for the hydrolysis of
fluorophosphates and phosphonate and phosphate esters,7
while others have reported macrocyclic ligand complexes
There are several approaches for the preparation of
3
phosphate esters. One of the more widely used methods in
the synthesis of nucleotides is through the use of phosphor-
amidites, although this necessarily requires the handling of
sensitive phosphorus(III) intermediates and a subsequent
oxidation step. A more direct approach involves reaction of
the alcohol substrate with a chlorophosphate. This can be
8
that catalyze this reaction. However, only one report has
(4) van Boom, H. H.; de Rooy, F. M.; Reese, C. B. J. Chem. Soc., Perkin
Trans. 1 1973, 2513.
(
5) Schulz, J.; Beaton, M. W.; Gani, D. J. Chem. Soc., Perkin Trans. 1
2000, 943.
(6) Mochizuki, T.; Iwano, Y.; Shiozaki, M.; Kurakata, S.-I.; Kanai, S.;
Nishijima, M. Tetrahedron 2000, 56, 7691.
(1) Dwek, R. A. Chem. ReV. 1996, 96, 683.
(2) Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315.
(3) Slotin, L. A. Synthesis 1977, 737.
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0.1021/ol026618q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002