Recent efforts to develop improved approaches include
the use of 50-cyclosaligenyl phosphates7b,10 and 50-imida-
zolium salts as donors.7a,11 The cyclosaligenyl phosphates
have been used to prepare nucleotides, NDP-sugars, and
DNPs; however, prior protection of reactive groups, such
as hydroxyl or amino groups, on the donor or acceptor,
isolation of the donor, and deprotection of the product are
usually required, and yields can be highly variable.7b The
50-imidazolium salts have been used for the synthesis of
nucleotides, nonhydrolyzable nucleotide analogs, NDP-
sugars, and DNPs. These donors are prepared using the
procedure of Bogachev which involves the in situ protec-
tion of the hydroxyl and amino groups and formation of a
50-mixed anhydride by reacting an unprotected nucleoside
monophosphate with an excess of trifluoroacetic anhy-
dride (TFAA).11a After removal of unreacted TFAA, the
mixed anhydride is reacted with N-methylimidazole which
results in the formation of a highly activated 50-imidazo-
lium donor. This species is then reacted with a phosphory-
lated acceptor to givea partially protectedproduct which is
then treated with aq. ammonium acetate to remove the
protecting groups and give the desired product. Although
this procedure is rapid and gave DNPs, NTPs, and NTP
analogs in respectable yields, NDP-sugars were obtained
in modest to low yields11d and we have found that this
approach cannot be used to activate nucleoside di- or
triphosphates.
Our general approach to nucleoside polyphosphates
involves reacting a nucleoside mono-, di-, or triphosphate
with a sulfonylimidazolium salt of type 1 (Scheme 1). This
would initially produce mixed anhydride 2. This could
potentially act as a donor and react with a phosphorylated
acceptor togivethe desired nucleosidepolyphosphates and
their conjugates. Alternatively, the released N-methylimi-
dazole could react with 2 to produce a highly reactive
imidazolium salt of type 3 which could also act as a donor
and react with acceptors to give the desired products.
Scheme 1. General Procedure for Preparing Nucleoside Poly-
phosphates and Their Conjugates
Enzymatic methods have also been developed; however,
this approach is limited by scale and the substrate specifi-
city and availability of the enzymes.12 Recently, a solid
phase approach has been reported.13 However, this meth-
od requires the multistep synthesis of a polymer with a
unique linker and multistep syntheses of polyphosphites
prior to the solid phase chemistry.
A procedure that can be performed on a wide variety of
substrates, requiring no protecting groups on the acceptor
or donor, providing the products rapidly, cleanly, and in
high yields, would represent a significant advance in the
preparation of these compounds. However, such a proce-
dure has yet to be reported. Here we report, using un-
protected acceptors and donors, a rapid and high yielding
procedure for the synthesis of nucleoside polyphosphates
and their conjugates using sulfonylimidazolium salts as
key reagents.
Sulfonyl imidazolium salts, like sulfonyl chlorides, have
been used as reagents for the sulfonation of hydroxyl and
amino groups.14 Sulfonyl chlorides readily sulfonate the
hydroxyl groups of carbohydrates and the hydroxyl and
amino groups of nucleosides and nucleotides.15 This sug-
gests that sulfonyl imidazolium salts might be problematic
for the synthesis of nucleoside polyphosphates using un-
protected substrates. However, we reasoned that the reac-
tion between the negatively charged phosphate moiety and
the positively charged sulfonyl imidazolium salt would be
much faster than the reaction between the salt and neutral
hydroxyl and amino groups as would the subsequent
reaction between the charged donor and phosphate group
of the acceptor. To investigate this sulfonylimidazolium
salts 6 and 7 were prepared by reacting phenylsulfonyli-
midazolides 4 and 516 with methyl triflate in ether at rt
(Scheme 2). Compounds 6 and 7 precipitated out of
solution during the reaction. Filtration of the mixtures
gave6 and 7 aswhite powdersinalmostquantitativeyields,
and no further purification was necessary. Compounds
6 and 7 can be stored under Ar or N2 at ꢀ20 °C for months
without any detectable decomposition. Compound 7 ex-
hibited slightly better solubility properties in organic
(9) For some examples, see: (a) Baisch, G.; Ohrlein, R. Bioorg. Med.
Chem. 1997, 5, 383. (b) Ko, H.; Das, A.; Carter, R. L.; Fricks, L. P.;
Zhou, Y.; Ivanov, A. A.; Melman, A.; Joshi, B. V.; Kovac, P.; Hajduch,
J.; Kirk, K. L.; Harden, T. K.; Jacobson, K. A. Bioorg. Med. Chem.
2009, 17, 5298.
(10) (a) Warnecke, S.; Meier, C. J. Org. Chem. 2009, 74, 3024. (b)
Wendicke, S.; Warnecke, S.; Meier, C. Angew. Chem., Int. Ed. 2008, 47,
1500. (c) Wolf, S.; Zismann, T.; Lunau, N.; Meier, C. Chem.;Eur. J.
2009, 15, 7656.
(11) (a) Bogachev, V. S. Russ. J. Bioorg. Chem. 1996, 22, 599. (b)
Mohamady, S.; Jakeman, D. J. Org. Chem. 2005, 70, 10588. (c) Marlow,
A. L.; Kiessling, L. L. Org. Lett. 2001, 3, 2517. (d) Timmons, S. C.;
Jakeman, D. Carbohydr. Res. 2008, 343, 865.
(14) (a) O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57, 4775.
(b) Robinson, J. K.; Lee, V.; Claridge, T. D. W.; Baldwin, J. E.;
Schofield, C. J. Tetrahedron 1998, 54, 98l.
(12) (a) Theoclitou, M. E.; El-Thaher, T. S. H.; Miller, A. D. J.
J. Chem. Soc., Chem. Commun. 1994, 5, 659. (b) Theoclitou, M. E.;
Wittung, E. P. L; Hindley, A. D.; El-Thaher, T. S. H.; Miller, A. D. J. J.
Chem. Soc., Perkin Trans. 1 1996, 16, 2009. (c) Huang, K.; Frey, P. A. J.
Am. Chem. Soc. 2004, 126, 9548.
(15) For examples see: (a) Neumann, J.; Weingarten, S.; Thiem, J.
Eur. J. Org. Chem. 2007, 7, 1130. (b) Tang, X.; Dmochowski, I. J. Org.
Lett. 2005, 7, 279.
(16) Compounds 4 and 5 were prepared in 96% and 99% yields
respectively from the corresponding sulfonyl chlorides and imidazole or
2-methylimidazole. See the Supporting Information.
(13) Ahmadibeni, Y.; Parang, K. Org. Lett. 2007, 9, 4483.
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