However, surprisingly no fluorous protecting group for
phosphate has yet been reported. Fluorous groups for
the temporary tagging of the hydroxyls or permanent
tagging of the phosphates of nucleotides have been
reported in the context of nucleic acid synthesis to assist
separation, and some of these fluorous tags have been
commercialized.8 However, since the tags for phos-
phates cannot be removed, they cannot serve a dual
purpose also as a protecting group. We envisioned
fluorous protecting groups for phosphates that could
function as tags, but also could be removed under mild
conditions when necessary, would be useful in the synth-
esis of phosphate-containing molecules (Figure 1), al-
lowing both easy purification and a handle for
microarray formation. Herein we report the design and
synthesis of the first fluorous protecting group for
phosphate and demonstrate its use in carbohydrate
synthesis.
conditions in which the benzyl phosphate was stable, a
haloethyl ester of phosphate caught our attention. These
haloethyl groups can generally be removed under mild
reducing conditions. Fluorous bromo-alcohol 1, first re-
ported in 1984,10 had shown use as a carbamate-type
protecting group for amines associated with carbohydrate
and peptide structures and could be deprotected using Zn/
Ac2O/Et3N to provide an N-acetyl.11 We reasoned that
this fluorous alcohol 1 with a bromide at the β-position
could potentially be suitable for phosphate protection if
conditions for its easy removal could be found. However, a
concern was the extra stereogenic center of the haloalkyl
group, coupled with the stereogenicity of the phosphate
ester with a benzyl and a carbohydrate substituent and the
chirality inherent in sugars; the resulting diastereomers
could make separations and structure elucidation challen-
ging enough to render the fluorous phosphate protecting
group more trouble than it was worth.
Scheme 1. Synthesis of Fluorous Protected Dibenzyl Phosphate
Figure 1. Concept of the fluorous protecting and tagging group
for phosphate.
In the search for a fluorous protecting group for phos-
phate, 3-(perfluorooctyl)propanol;which contains a
C8F17 moiety with a simple three carbon alkyl linker and
is commercially available;was a natural starting point. If
this fluorous alkyl alcohol could be readily added and
removed from a phosphate, it could serve as a protecting
group. To test the reactivity of this fluorous alcohol, a
model study using dibenzyl 3-(perfluorooctyl)propyl phos-
phate was initiated. The benzyl groups on the phosphate
ideally would serve as the same sort of “permanent”
protecting group often used on the hydroxyls of carbohy-
drates that is removed by hydrogenolysis only at the very
end of a synthesis. Generally alkyl protecting groups of
phosphates are removed using small nucleophiles.9 Un-
fortunately, various nucleophiles such as azide or iodide
served only to remove one of the benzyl groups in quanti-
tative yields; the fluorous alcohol largely remained in
position.
To first test the relative stability of the fluorous
haloalkyl group and the benzyl group on phosphate, a
simple dibenzyl phosphate was made using standard
phosphoramidite chemistry (Scheme 1). The fluorous
bromo-alcohol 1 was coupled with dibenzyl phosphor-
amidite 2 in the presence of tetrazole to yield phosphite
3, which was then oxidized to phosphate 4 using m-
chloroperoxybenzoic acid (m-CPBA) in 98% yield in
two steps after FSPE purification. Various conditions
were tested to remove the fluorous protecting group,
including Zn/NH4HCO2/CH3OH, Zn/HOAc/THF,
and Pd/C/CH3OH/NH4HCO2.12 The reaction was mon-
itored by TLC and 31P NMR. All of these conditions
successfully removed the fluorous group on 4, yielding
the desired phosphate 5, without removal of either
benzyl group. The Zn/NH4HCO2 conditions in metha-
nol provided the fastest and cleanest reaction. Further
optimization of the deprotection conditions showed that
by using Zn/NH4HCO2 in CH3CN/THF (4:1) the reac-
tion could go to completion in 1-2 h. The resulting
ammonium salt of phosphoric acid was purified by a
In the continued search for a fluorous protecting
group for phosphate that could be easily removed under
(8) (a) Pearson, W. H.; Berry, D. A.; Stoy, P.; Jung, K.-Y.; Sercel,
A. D. J. Org. Chem. 2005, 70, 7114. (b) Tripathi, S.; Misra, K.; Sanghvi,
Y. S. Org. Prep. Proc. Intl. 2005, 37, 257. (c) Beller, C.; Bannwarth, W.
Helv. Chim. Acta 2005, 88, 171. (d) Gupta, A. P.; Will, S. G. Compounds
and methods for synthesis and purification of oligodeoxyribonucleo-
tides. PCT Int. Appl. WO 2008077600, 2008.
(10) Coudures, C.; Pastor, R.; Cambon, A. J. Fluorine Chem. 1984,
24, 93.
(11) Manzoni, L.; Castelli, R. Org. Lett. 2006, 8, 955.
(12) (a) Liu, Y.; Lien, I. F. F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D.
Org. Lett. 2004, 6, 209. (b) Ingram, L. J.; Taylor, S. D. Angew. Chem.,
Int. Ed. 2006, 45, 3503.
(9) Holy, A. Synthesis 1998, 381.
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