A facile approach to phosphonic acid diesters

Article abstract of DOI:10.1002/hc.10130

A effective method to prepare symmetric H-phosphonate diesters of carbohydrates was presented. The phosphoramidate method, H-phosphonate method and condendation of phosphonic acid and hydroxy compounds by dicyclohexycarbodiimide were reported for the synthesis of symmetric H-phosphonates. It was found that after the pyridine was removed under pressure, the products were obtained in purity of >95%.

Full text of DOI:10.1002/hc.10130

Heteroatom Chemistry
Volume 14, Number 3, 2003
A
Facile Approach to Phosphonic
Acid Diesters
1
1,2
1
Qiang Xiao, Yong Ju, and Yufen Zhao
1
The Key Laboratory of Bioorganic Phosphorus Chemistry, Ministry of Education,
Department of Chemistry, School of Life Sciences and Engineering, Tsinghua University,
Beijing 100084, P.R. China
2
National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P.R. China
Received 21 May 2002; revised 12 September 2002
which are versatile intermediates in the synthesis of
ABSTRACT: The symmetric H-phosphonates of car-
phosphonate derivatives of carbohydrate. It can be
further conjugated with amino acid using Todd re-
action [5] and can also be oxidized by iodine, sul-
fur, or selenium to obtain phosphonate, phospho-
bohydrate and other compounds were conveniently
prepared by direct transesterification of the corre-
sponding monohydroxylic compounds with diphenyl
phosphite. The approach has the merits of mild reac-
tion conditions and high yields. ꢀC 2003 Wiley Periodi-
rothioate, and phosphoroselenoate of carbohydrate
respectively [6].
cals, Inc. Heteroatom Chem 14:208–210, 2003; Published
There were three methods reported in the litera-
online in Wiley InterScience (www.interscience.wiley.
ture for the synthesis of symmetric H-phosphonates.
com). DOI 10.1002/hc.10130
The first is the phosphoramidate method, which has
been greatly developed in the synthesis of oligonu-
cleotides [7]. Using this method, phosphoramidate
diesters are synthesized and hydrolyzed under the
activation of 1H-tetrazole. The second is the H-
phosphonate method [8], which was first described
by Todd in 1952 [9] and later developed by Stawinski
INTRODUCTION
Recently, there is an increasing interest in phospho-
diesters with respect to their particular biological
and chemical properties. The phosphodiester struc-
tures, such as nucleic acids [1] and phospholipids [2],
are fully studied. On the contrary, there is little in-
formation about the significance and the properties
of phosphodiesters that link saccharides exclusively
[10]. It has become a powerful method for the in-
troduction of phosphodiesters in natural products.
It is necessary to prepare H-monophosphonates and
then couple with another alcohol. The third is the
condensation of phosphonic acid and hydroxy com-
pounds by dicyclohexycarbodiimide [11]. Although
this method has the advantage to start from commer-
cially available compounds, its yield is moderate and
the by-product dicyclohexylurea is hard to remove.
Therefore, it is necessary to set up a facile way.
[3,4]. For the study of the biological significance
of carbohydrate phosphonates, we primarily syn-
thesized symmetric H-phosphonates of saccharides,
Correspondence to: Yong Ju; e-mail: juyong@tsinghua.edu.cn.
Contract grant sponsor: NSFC.
Contract grant numbers: 20132020, 20175026, 29672022, and
0172033.
2
RESULTS AND DISCUSSION
Contract grant sponsor: Ministry of Science and Technology.
Contract grant sponsor: Chinese Ministry of Education.
Contract grant sponsor: Tsinghua University.
ꢀ
c 2003 Wiley Periodicals, Inc.
Diphenyl phosphite (2; DPP) is a commercially avail-
able, inexpensive phosphorylation reagent. It can
2
08

A Facile Approach to Phosphonic Acid Diesters 209
FIGURE 1 The 31P NMR spectra of the reaction of DPP (2)
with 1c in pyridine.
appeared immediately. Those at δ = 5.3 and 6.0 ppm
are the signals of H-phosphonate 4, which is a pair
of diastereoisomers. The peak at δ = 9.0 ppm is 3c.
The H-phosphonate 4 was gradually converted to
SCHEME 1 Symmetric H-phosphonate prepared via trans-
esterification with DPP (2).
3c in almost quantitative yield after 1.5 h. Other
monohydroxylic carbohydrate derivatives were
investigated and the results are listed in Table 1.
In the same way, symmetric H-phosphonate of zi-
dovudine 3h was synthesized in almost quantitative
yield. Compound 3h is an important intermediate
in the synthesis of phosphoramidate prodrugs of
zidovudine and has been previously synthesized in
moderate yield using the third method [14].
undergo fast transesterification with alcohols in pyri-
dine to afford mixtures of the corresponding di-
alkyl and alkyl phenyl H-phosphonate [12]. Inspired
by this observation, a new approach to symmetri-
cal disaccharide H-phosphonate diesters was inves-
tigated (Scheme 1). Tetradecanol 1a was selected
to explore the possibility. DPP was treated with
In conclusion, an effective method was set up
to prepare symmetric H-phosphonate diesters of
carbohydrates. After the pyridine was removed un-
der reduced pressure, the products were obtained
in purity of >95% and could be used directly
2
equiv. of tetradecanol in anhydrous pyridine at
room temperature. The reaction was monitored by
3
1
P NMR spectroscopy. After 1.5 h, all the DPP (sig-
nal δ
= 1.7 ppm) was quantitatively converted into
a new peak (δ
p
p
= 8.5 ppm), which was assigned to
the H-phosphonate 3a by an authentic sample [13].
Hexadecanol 1b was also tested and the result was
excellent.
TABLE 1 The Spectral Data of Symmetric H-Phosphonatesa
The reaction of 1,2:5,6-diisopropylidene-D-
glucose (1c) with DPP (Scheme 2) was monitored
by the P NMR spectrum (Fig. 1). Three new peaks
31P NMRb
ESI-MS
3
1
1
3
(Hz) (M + H)+ (M + Na)+
P-H
δ
J
(Hz)
J
P-H
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
8.4
8.7
9.0
10.3
9.9
10.2
10.1
9.7
677
8.4
475
531
567
599
567
695
743
567
581
497
553
589
621
589
717
765
589
603
686
717
717
717
716
714
718
717
8.5
10.4
10.4
10.6
10.5
10.4
10.3
10.4
10.6
a
All reactions were performed in 1 mmol scale.
b
SCHEME 2 Reaction of 1,2:5,6-diisopropylidene-D-glucose
The values were determined in pyridine using a Bruker AMP 200 at
81 Hz (85% H PO as internal standard).
(1c) with DPP (2).
3
4

2
10 Xiao, Ju, and Zhao
without further purification [15]. The mild condi-
tions are compatible with the presence of sensitive
protecting groups and they make the method use-
ful for synthetic purposes. Efforts to employ this
approach in the synthesis of the conjugates carbohy-
drate with amino acid, some oligosaccharides hav-
ing phosphonate units and phosphoramidate pro-
drugs of zidovudine are currently under way in our
laboratory.
[6] Lindh, I.; Stawinski, J. J Org Chem 1989, 54, 1338–
342.
7] Beaucage, S. L.; Iyer, R. P. Tetrahedron 1993, 49,
925–1963.
8] Engel, R. (Ed.). Handbook of Organophosphorus
Chemistry; Marcel Dekker: New York, 1992.
1
[
[
1
[9] Corby, N. S.; Kenner, G. W.; Todd, A. R. J Chem Soc
952, 3669–3672.
1
[
10] (a) Garegg, P. J.; Regberg, T.; Stawinski, J.;
Stromberg, R. Chem Scr 1985, 25, 280–282;
(b) Garegg, P. J.; Regberg, T.; Stawinski, J.;
Stromberg, R. Chem Scr 1986, 26, 59–62.
11] Munoz, A.; Hubert, C.; Luche, J. L. J Org Chem 1996,
[
[
[
[
6
1, 6015–6017.
EXPERIMENTAL
12] Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.;
Kraszewski, A. Synthesis 1995, 427–430.
13] Deng, C. H.; Li, Y. M.; Xu, N.; Zhao, Y. F. J Chem Res
General Experimental Procedure: 1 mmol 1a–j was
co-distilled twice with 2 ml anhydrous pyridine, and
then dissolved in 3 ml pyridine. DPP (2) (0.5 mmol) in
(S) 1999, 589–589.
14] (a) Kers, I.; Stawinski, J.; Girardet, J. L.; Imbach, J.
L.; Perigaud, C.; Gosselin, G.; Aubertin, A. M. Nucleo-
sides Nucleotides 1999, 18, 2317–2325; (b) Perigaud,
C.; Lefebvre, I.; Pompon, A.; Aubertin, A. M.; Kirn,
A.; Szabo, T.; Stawinski, J.; Imbach, J. L. Antivir Res
2
ml pyridine was added in one portion. The mixture
3
1
was stirred for 2 h. After P NMR showed that all the
DPP had converted, pyridine was evaporated under
vacuum at 40 C. Compounds 3a–j were obtained in
◦
1
993, 22, 143–153.
15] For example, compound 3c has been oxidized to
phosphonate directly by I2 in pridine/H O (49:1) in
3
1
>
95% purity judged by P NMR.
[
2
9
0% overall yield. Spectroscopic data of the phospho-
3
1
nate (triethylammonium salt): P NMR: (81 MHz,
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1