Stereoselective synthesis of α-glycosyl phosphites and phosphoramidites via o-selective glycosylation of H-phosphonate derivatives

Article abstract of DOI:10.1021/ol802190x

(Chemical Equation Presented) A highly stereo- and chemoselective glycosylation of H-phosphonate derivatives with glycosyl iodides was discovered as a reverse reaction of the formation of a glycosyl iodide from a glycosyl phosphite and I^- under mild acidic conditions. Further study on the unique reaction showed that the reaction provided various α-glycosyl phosphites and phosphoramidites In a highly stereoselective manner with complete O-selectivity.

Full text of DOI:10.1021/ol802190x

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5297-5300
Stereoselective Synthesis of r-Glycosyl
Phosphites and Phosphoramidites via
O-Selective Glycosylation of
H-Phosphonate Derivatives
Fumiko Matsumura, Natsuhisa Oka, and Takeshi Wada*
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The
UniVersity of Tokyo, Bioscience Building 702, 5-1-5 Kashiwanoha, Kashiwa,
Chiba 277-8562, Japan
wada@k.u-tokyo.ac.jp
Received September 18, 2008
ABSTRACT
A highly stereo- and chemoselective glycosylation of H-phosphonate derivatives with glycosyl iodides was discovered as a reverse reaction
of the formation of a glycosyl iodide from a glycosyl phosphite and I- under mild acidic conditions. Further study on the unique reaction
showed that the reaction provided various r-glycosyl phosphites and phosphoramidites in a highly stereoselective manner with complete
O-selectivity.
Glycosyl phosphates are the repeating units of phosphogly-
cans, which are widely distributed in nature as the constitu-
ents of cell-wall or capsule of bacteria and yeasts, glycocalyx
of a protozoan parasite Leishmania, etc.1 Since these
phosphoglycans often work as virulence factors of pathogenic
bacteria, etc., their structures and functions have been
extensively studied. Chemically synthesized fragments of the
phosphoglycans and their analogues are indispensable tools
for these studies and their therapeutic applications have also
been studied continuously.2
Since the glycosyl phosphate units consisting of the
phosphoglycans have the R-anomeric configuration in most
cases, R-glycosyl phosphate derivatives are required as
building blocks to construct R-glycosyl phosphate diester
intersaccharide linkages via condensation reactions.2b Cur-
rently, glycosyl H-phosphonate monoesters are employed as
building blocks because their R-isomers, especially those
having a 2-O- or N-acyl group, can be synthesized with
relative ease,2b,3 though they have some drawbacks, such as
the instability of H-phosphonate diester intermediates.1a,3a,b
Several methods have been reported for the synthesis of
R-glycosyl phosphate triesters, but it is difficult to use them
as the building blocks via partial deprotection of their
phosphate moiety and following condensation due to their
chemical instability. Therefore, their applications are mostly
limited to those as glycosyl donors.2b,4 Only a very limited
number of other building blocks are available (e.g., R-D-
Man, R-D-GlcNAc 1-phosphoramidites), which can be ste-
(1) (a) Hansson, J.; Oscarson, S. Curr. Org. Chem. 2000, 4, 535–564.
(b) Weintraub, A. Carbohydr. Res. 2003, 338, 2539–2547. (c) Naderer, T.;
Vince, J. E.; McConville, M. J. Curr. Mol. Med. 2004, 4, 649–665.
(2) (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–
3092. (b) Nikolaev, A. V.; Botvinko, I. V.; Ross, A. J. Carbohydr. Res.
2007, 342, 297–344.
(3) (a) Westerduin, P.; Veeneman, G. H.; van der Marel, G. A.; van
Boom, J. H. Tetrahedron Lett. 1986, 27, 6271–6274. (b) Berkin, A.; Coxon,
B.; Pozsgay, V. Chem. Eur. J. 2002, 8, 4424–4433. (c) Ruhela, D.;
Vishwakarma, R. A. J. Org. Chem. 2003, 68, 4446–4456. (d) Higson, A. P.;
Ross, A. J.; Tsvetkov, Y. E.; Routier, F. H.; Sizova, O. V.; Ferguson,
M. A. J.; Nikolaev, A. V. Chem. Eur. J. 2005, 11, 2019–2030
.
10.1021/ol802190x CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

reoselectively synthesized by using the stereoelectronic effect
of 2-O- or N-acyl protecting groups.3a,5
Table 1. Synthesis of R-D-Glucosyl Phosphite 3 from
R-D-Glucosyl Iodide 1 and Dimethyl H-Phosphonate 2a,b
On the other hand, while studying the chemistry of
glycosyl iodides,6 we found that an R-D-glucosyl iodide 16b
underwent a unique O-selective glycosylation with dimethyl
H-phosphonate (2) in a highly R-selective manner (Table
1).7 Further investigation showed that the new reaction
provided various R-glycosyl phosphites and phosphoramid-
ites including potential building blocks for phosphoglycans,
which are otherwise difficult to obtain (e.g., R-D-Glc, R-D-
Gal 1-phosphoramidites). The results of this study are
described in this paper.
The reaction was carried out as follows: The R-D-glucosyl
iodide 1 was allowed to react with dimethyl H-phosphonate
2 in the presence of 1,8-bis(dimethylamino)naphthalene
(DMAN) to give the corresponding glucosyl phosphite 3
(Table 1). The reaction was monitored by TLC and quenched
when 1 was completely consumed. Stereoselectivity of the
reaction was determined by 31P NMR analysis of crude 3,8
which was then converted into the corresponding glycosyl
boranophosphate triester 4 by treatment with BH3·THF and
isolated by silica gel column chromatography. As we have
recently reported,9 glycosyl boranophosphate triesters are
superior in chemical stability to the corresponding glycosyl
phosphites and phosphates and can be used as building blocks
to synthesize glycosyl phosphate-containing molecules through
deprotection of the boranophosphate moiety and condensa-
tion, whereas such applications are difficult for the glycosyl
phosphites.
equiv
entry of 2
reaction conditions
R:ꢀc % of yieldd
1
2
3
4
5
6
7
8
9
10
1.1 DMAN, MeCN, 25 °C, 48 h
89:11
91:9
93:7
93:7
92:8
88:12
41
71
93
82
79
34
28
83
71
76
3
3
DMAN, MeCN, 25 °C, 8 h
DMAN, MeCN, 0 °C, 24 h
DMAN, MeCN, 25 °C, 2 h
DIPEA, MeCN, 25 °C, 2 h
K2CO3, MeCN, 25 °C, 30 h
10
10
10
10
10
10
10
DTBMP, MeCN, 25 °C, 48 h 79:21
DMAN, toluene, 25 °C, 65 h 98:2
DMAN, dioxane, 25 °C, 75 h 95:5
DMAN, DMF, 25 °C, 15 min 92:8
a MS 3 A was used for MeCN and MS 4 A was used for the other
solvents. b The glucosyl phosphite 3 was converted into the corresponding
boranophosphate triester 4 by treatment with BH3·THF at rt for 15 min and
c
isolated. Anomeric ratios of 3 (31P NMR). d Isolated yields of 4.
Increasing the amount of 2 accelerated the reaction and
improved the yield of the final product 4. The stereoselec-
tivity of the reaction was also slightly improved (entries 1,
2, and 4). Glycosyl iodide 1 decomposed very slowly into
5;6 this resulted in low yields when the reaction of 1 with 2
was slow (entries 1 and 2). In contrast, decomposition of 1
was suppressed at 0 °C or in less-polar solvents (toluene,
dioxane), though an extended reaction time was required
(entries 3, 8, and 9). N,N-Diisopropylethylamine (DIPEA)
gave similar results to DMAN (entries 4 and 5), whereas
weaker bases resulted in lower yields and stereoselectivity
(entries 6 and 7). This is due to the isomerization of the
resultant 3 and the reverse reaction to regenerate 1 in mild
acidic media, especially in the case of 2,6-di-tert-butyl-4-
methylpyridine (DTBMP).7 It should be noted that the
glycosyl iodide 1 immediately decomposed into 5 when a
strong base such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) was used in the reactions (data not shown). In entries
1, 2, 6, and 7, a P-glycoside 610 was also observed as a major
byproduct, which was not observed under appropriate
conditions (entries 3-5 and 8-10). The reaction was
accelerated as the polarity of the solvent increased, but the
stereoselectivity was slightly reduced (entries 4 and 8-10).
Next, the reaction was applied to other glycosyl iodides 7-96
(Table 2, entries 1-3). When 2,3,4,6-tetra-O-acetyl glycosyl
iodide 7 was used, only ca. 50% of 7 was converted into the
desired glycosyl phosphite with poor stereoselectivity (entry 1).
1H NMR analysis of the reaction revealed that neighboring
group participation of the 2-O-acyl group occurred to generate
some rather stable 1,2-cyclic intermediates, resulting in a lower
reaction rate and stereoselectivity. In contrast, the reaction was
applicable to per-O-benzyl glycosyl iodides 8 and 9, though
the stereoselectivity was modest in the case of the mannosyl
iodide 9 (entries 2 and 3).
(4) (a) Schmidt, R. R.; Gaden, H.; Jatzke, H. Tetrahedron Lett. 1990,
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7758–7760.
It is noteworthy that the O-selective glycosylation occurred
not only with dimethyl H-phosphonate 2 but also with an
H-phosphonamidate derivative 11,11 yielding glycosyl phos-
phoramidites 14-165 from the glycosyl iodides 1, 8, and
106 (Table 2, entries 4-6) with good stereoselectivity and
(7) We found the reaction as a reverse reaction of the generation of 1
from a glycosyl phosphite and I- under mild acidic conditions. Tanaka,
H.; Sakamoto, H.; Sano, A.; Nakamura, S.; Nakajima, M.; Hashimoto, S.
Chem. Commun. 1999, 1259–1260. Details are given in the Supporting
Information.
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1994, 50, 6523–6536.
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Org. Lett., Vol. 10, No. 22, 2008
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Table 2. Synthesis of Glycosyl Phosphites 12 and 13 and Phosphoramidites 14-16a
b
a MS 3 A was used for MeCN. MS 4 A was used for the other solvents. Anomeric ratios of glycosyl phosphites 12-16 (31P NMR). c Isolated yields
and anomeric ratios (R:ꢀ, determined by 31P NMR) of 14-18 are given in parentheses. The glycosyl boranophosphates 17 and 18 were derived from 12 and
13, respectively.
complete O-selectivity. Since the ꢀ-isomers of 14-16 were
more prone to decomposition on silica gel, highly R-enriched
14-16 were obtained after a simple silica gel column
chromatography.
Thus, the study demonstrated that glycosyl iodides un-
derwent an O-selective glycosylation with H-phosphonate
derivatives to give the corresponding R-glycosyl phosphites
and phosphoramidites in a highly stereoselective manner.
Since the resultant R-glycosyl phosphoramidites and bora-
nophosphate triesters derived from the glycosyl phosphites
are potentially useful as building blocks of phosphoglycans
and are otherwise difficult to synthesize, the method devel-
oped in this study should expand the availability of chemi-
cally synthesized phosphoglycans and their analogues.
In addition, it is important to note that it is not only a unique
reaction of glycosyl iodides, but also an unprecedented O-
selective reaction of H-phosphonate derivatives. It is well-known
that the reactions of H-phosphonate diesters with C-electrophiles
are almost exclusively P-selective.12 Therefore, the elucidation
of the reaction mechanism will provide new insights into the
chemistry of H-phosphonate derivatives. Although further
(11) Ahmadibeni, Y.; Parang, K. Org. Lett. 2005, 7, 5589–5592.
Org. Lett., Vol. 10, No. 22, 2008
5299

investigation is necessary for full clarification of the reaction
mechanism, the data obtained in this study indicate that it
proceeds via the nucleophilic attack of the lone pair on the PdO:
function to the highly reactive ꢀ-glycosyl iodides, which are in
equilibrium with the dominating R-isomers.13 Further studies
on the mechanism as well as on the applications of the reaction
are in progress.
Acknowledgment. We thank Professor Kazuhiko Saigo
(University of Tokyo) for helpful suggestions. We also thank
the Futaba Electronics Memorial Foundation for the scholar-
ship to F.M. This work was financially supported by MEXT
Japan.
Supporting Information Available: Experimental details
1
and characterizing data, including H, 13C and 31P spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Soborovskii, L. Z.; Baina, N. F. J. Gen. Chem. USSR 1959, 29,
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OL802190X
(13) See the Supporting information.
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