1,3-Dipolar cycloaddition of exo-methylenesugars with nitrone: Approach to new amino-C-ketosyl disaccharides

Article abstract of DOI:10.1016/j.tetlet.2004.03.155

Stereoselective 1,3-dipolar cycloadditions of exo-methylenesugars 1a-c to a sugar nitrone 2 were carried out with refluxing a toluene solution and afforded the corresponding cycloadducts, ketosyl spiro-isoxazolidine disaccharides 3a and 4a-c. Followed by reductive cleavage of the N-O bond of the isoxazolidine ring with the treatment of Zn-AcOH-Ac₂O or with catalytic hydrogenation (Pd(OH)₂/C), the cycloadduct 3a could be readily converted into a novel amino-C-disaccharide possessing a ketose form, providing an access to a novel amino-C-ketosyl disaccharides.

Full text of DOI:10.1016/j.tetlet.2004.03.155

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4123–4126
1,3-Dipolar cycloaddition of exo-methylenesugars with nitrone:
approach to new amino-C-ketosyl disaccharidesq
Xiaoliu Li,ꢀ Hideyo Takahashi, Hiro Ohtake and Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo University, Kanagawa, Sagamiko 199-0195, Japan
Received 13 February 2004; revised 21 March 2004; accepted 24 March 2004
Abstract—Stereoselective 1,3-dipolar cycloadditions of exo-methylenesugars 1a–c to a sugar nitrone 2 were carried out with
refluxing a toluene solution and afforded the corresponding cycloadducts, ketosyl spiro-isoxazolidine disaccharides 3a and 4a–c.
Followed by reductive cleavage of the N–O bond of the isoxazolidine ring with the treatment of Zn–AcOH–Ac2O or with catalytic
hydrogenation (Pd(OH)2/C), the cycloadduct 3a could be readily converted into a novel amino-C-disaccharide possessing a ketose
form, providing an access to novel amino-C-ketosyl disaccharides.
Ó 2004 Elsevier Ltd. All rights reserved.
The understanding of the fundamental roles of carbo-
hydrates and glycoconjugates in numerous biological
processes has prompted considerable interest in the
development of potential carbohydrate-based thera-
peutic agents in recent years.1 As one of the most
important carbohydrate mimics, C-glycosides have
attracted great attention due to their stability to chem-
ical and enzymatic hydrolysis of the glycosidic linkage.
Consequently, a number of methodologies for the
preparation of C-glycosides, for instance, using ano-
meric anions, cations, radicals, and carbenes as the
intermediates of the preparation have been extensively
investigated.2;3 Recently, 1,3-dipolar cycloaddition
reactions have also been found application in the syn-
thesis of such compounds.4 Although exo-methyl-
enesugars have been successfully used for the
preparation of C-glycosides,5 very few of examples on
the utilization of 1,3-dipolar cycloaddition of exo-
methylenesugars to the synthesis of C-glycosides, espe-
cially C-disaccharides have been reported.6;7
nitrones under the catalysis of a Lewis acid, and the
conversion of the resulted ketosyl spiro-isoxazolidine to
a novel C-glycosyl amino acid possessing a ketose form.
As a continuation of our research work on the syntheses
of ketosyl C-glycosides using exo-methylenesugars as
the precursor, we wish to report in this letter the 1,3-
dipolar cycloaddition of exo-methylenesugars to a sugar
nitrone affording spiro-isoxazolidine disaccharides, and
followed by a reductive ring opening to give novel
amino-C-ketosyl-disaccharides as shown in Schemes 1–
3.
The 1,3-dipolar cycloadditions of exo-methylenesugars
1a were performed with nitrone 28 by refluxing a toluene
solution to provide the corresponding cycloadducts,
ketosyl spiro-isoxazolidine 3a and 4a in the yields of
17.4% and 52.1%, respectively, (Scheme 1).11;12 It should
be noted that the cycloaddition of 1a and 2 underwent
diastereoselectively and afforded only two anomeric
isomers 3a and 4a possessing R-configuration on C-6,
which is similar to the previous report.7 Under the same
conditions the cycloadditions of the galactose and
mannose derivatives 1b and 1c to nitrone 2 were carried
out, but only O-b-anomeric isomers 4b (53.2%) and 4c
(50.7%) were obtained in these two cases (Scheme 1).12
In the previous study,7 we described a diastereoselective
1,3-dipolar cycloaddition of exo-methylenesugars with
Keywords: Cycloaddition; Nitrone; Disaccharide.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.155
It should be mentioned that Lewis acids, such as ZnCl2,
ZnBr2, AlCl3, BF3ÆOEt2, AlClEt2, were found not to be
efficient to this reaction as catalysts at room tempera-
ture, although it has been recently reported that some
of such Lewis acids could efficiently promote the
1,3-dipolar cycloadditions of some nitrones and
* Corresponding author: Tel.: +81-426-85-3728; fax: +81-426-85-1870;
e-mail: shi-ike@pharm.teikyo-u.ac.jp
ꢀ
Department of Chemistry, Hebei University, Baoding, Hebei 071002,
China.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.155

4124
X. Li et al. / Tetrahedron Letters 45 (2004) 4123–4126
Me
OBn
R3
+N O-
R1
O
O
R4
BnO
BnO
BnO
+
R2
BnO
OMe
1a-c
2
i
OBn
R3
R1
OBn
13
O
11
O
H
O
Me
OMe
BnO
BnO
R4
BnO
OBn
12
10
9
N
O
5
OBn
OBn
OBn
OBn
2
R2
3
7
8
4
BnO
6
1
+
O
O
H
BnO
N
Me
OMe
H
H
3a
4a-c
R1
R2
BnO
R3
H
R4 3: % yield 4: % yield
a (Glc)
b (Gal)
H
H
BnO
H
17.4
-
-
52.1
53.2
50.7
BnO BnO
c (Man) BnO
H
H
BnO
Scheme 1. Reaction conditions: (i) toluene, reflux.
OBn
OBn
O
H
O
H
OMe
OBn
BnO
BnO
i
OMe
OBn
O
BnO
BnO
OBn
OBn
OBn
BnO
BnO
O
OBn
O
HO
H
HN
Me
H
N
Me
5
3a
Scheme 2. Reaction conditions: (i) Zn, AcOH, Ac2O, rt.
OH
OBn
O
H
O
H
OH
O
OMe
HO
HO
i
OMe
OBn
O
BnO
BnO
OH
OH
OBn
OBn
HO
BnO
HO
H
O
HN
Me
H
N
Me
3a
6
Scheme 3. Reaction conditions: (i) Pd(OH)2/C, H2, MeOH.
electron-rich alkene such as, enolic compounds in
9
The relative orientation of the substituents on the isox-
azolidine ring was established from the NOE observa-
tions between H7 and H6, H7 and H9 (Table 1) as
exemplified by the analyses of compounds 3a, 4a–c in
Figure 1. It was found that in the cycloadducts 3a and
4a–c the chiral carbons (C-6) in the isoxazolidine ring
possessed R-configuration. The NOE experiment results
also supported the above assignments on the anomeric
configurations (Fig. 1).
stereoselective way.
This inverse electron-demand
1,3-dipolar cycloaddition carried out thermally would
proceed in the different stereochemical manner as com-
pared with the glycosylation and afforded the b-anomers
stereoselectively.
The structures and configurations of compounds 3a, 4a–
c, 5, and 6 were determined by the analyses of their
1
spectral data of H NMR, 13C NMR, 2D (H–H, C–H)
COSY, and NOESY experiments (See Fig. 1, Table 1
and Ref. 12). It has been reported that in the 13C NMR
spectra of C-glycosides,10 C-ketosides,5h and C-spiro-
ketosides5i;7 the signals of a-anomeric carbons appeared
in upper field than those of b-anomeric carbons. With
comparison of the chemical shifts of the anomeric car-
bons in compounds A and B (Fig. 2) reported previ-
ously,7 the configurations of the anomeric carbons (C-8)
in compounds 3a and 4a–c were assigned.
With the cycloadducts in hands, we turned our attention
to approaching to the synthesis of amino-C-ketosyl
disaccharides by reductively opening the isoxazolidine
ring. As shown in Scheme 2, cycloadduct 3a can be
readily converted into the ring-opened amino-C-ketosyl
disaccharide 5 in yield of 65.1% upon exposure to acti-
vated zinc powder in AcOH–Ac2O solution at room
temperature (Scheme 2). More directly, the cleavage of
the O–N bond, and the debenzylation were accom-

X. Li et al. / Tetrahedron Letters 45 (2004) 4123–4126
4125
OBn
O
O
9
Me
8
7
BnO
BnO
N
O
OBn
OBn
BnO
6
*
Hb
R
Ha
BnO
OMe
H
H
4a
BnO
OBn
OBn
O
O
Hb
Me
O
H
Ha
OBn
O
OMe
BnO
BnO
9
N
O
OBn
OBn
BnO
BnO
Hb
Ha
OBn
OBn
7
8
*
6
BnO
R
H
O
BnO
OMe
H
N
H
Me
4b
3a
BnO
O
BnO
BnO
BnO
O
Me
N
O
OBn
OBn
Hb
Ha
BnO
OMe
H
H
4c
Figure 1. NOE analyses of the compounds 3a, 4a–c.
OBn
OBn
O
O
O
H
BnO
BnO
Bn
N
COOEt
H
β
BnO
BnO
α
BnO
BnO
O
COOEt
N
Bn
B (δβ-C = 107.96 ppm)
A (δα-C = 105.41 ppm)
Figure 2. Chemical shifts of the anomeric carbons in 13C NMR.7
Table 1. Selected NOE data and chemical shifts of the anomeric car-
bons (C-8) in 13C NMR spectra of spiro-isoxazolidines 3a and 4a–c
port for this research from the Ministry of Education,
Science, Sports, and Culture of Japan is gratefully
acknowledged. X.L. thanks the JSPS for a postdoctoral
fellowship.
3a
4a
4b
4c
H7a ! H9
H7a ! H7b
H7a ! H6
H7b ! H9
H7b ! H7a
H7b ! H6
dC-8 (ppm)
0.72%
9.17%
3.38%
0.30%
5.26%
2.02%
0.47%
8.22%
2.11%
0%
0.21%
5.07%
1.80%
0%
1.36%
2.21%
2.18%
0%
References and notes
1.98%
3.71%
1.68%
2.74%
5.41%
3.61%
1. For recent reviews of this topic, please see: Glycoscience:
Chemistry and Chemical Biology; (a) Fraser-Reid, B. O.,
Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; (b)
Carbohydrates in Chemistry and Biology; Ernst, B., Hart,
G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, 2000; (c)
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A., Eds.; Marcel Dekker: New York, 1997; (d) Bertozzi, C.
R.; Kiessling, L. L. Science 2001, 291, 2357; (e) Helenius,
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Science 2001, 291, 2370; (g) Wells, L.; Vosseller, K.; Hart,
G. W. Science 2001, 291, 2376; (h) Compain, P.; Martin,
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Chakraborty, T. K.; Ghosh, S.; Tayaprakash, S. Curr.
Med. Chem. 2002, 9, 421; (k) Ye, X. S.; Zhang, L. H. Curr.
Med. Chem. 2002, 9, 929; (l) Kren, V.; Martinkova, L.
Curr. Med. Chem. 2001, 8, 1303; (m) Wong, A.; Toth, I.
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Curr. Med. Chem. 2000, 7, 73.
104.33
107.60
108.30
108.41
plished in the one step reaction of catalytic hydrogena-
tion (Pd(OH)2/C), and a novel amino-C-ketosyl disac-
charide 6 was afforded in 51.6% yield (Scheme 3). The
spectral data of compounds 5 and 6 were identical with
the proposed structure.12
In summary, we have described a stereoselective syn-
thesis of a new kind of ketosyl spiro-isoxazolidinic di-
saccharides using the 1,3-dipolar cycloaddition of exo-
methylenesugars and a sugar nitrone. The conversion of
the cycloadducts into a novel amino-ketosyl C-disac-
charides was achieved by reductive cleavage of the O–N
bound using the combination of Zn–AcOH–Ac2O or the
catalytic hydrogenation.
Acknowledgements
2. For recent reviews on C-glycosides, please see: (a) Levy,
D. E.; Tang, C. The Chemistry of C-Glycosides; Elsevier:
Oxford, 1995; (b) Somsak, L. Chem. Rev. 2001, 101, 81;
(c) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913;
We are grateful to Misses J. Shimode and M. Kitsukawa
for spectroscopic measurements. Partial financial sup-

4126
X. Li et al. / Tetrahedron Letters 45 (2004) 4123–4126
(d) Jaramillo, C.; Knapp, S. Synthesis 1994, 1; (e)
Dondoni, A.; Marra, A.. Chem. Rev. 2000, 100, 4395.
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(a) RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986,
51, 5458; (b) While this manuscript was in preparation,
another report appeared in the literature on the 1,3-
dipolar cycloaddition of exo-methylenesugars with nitrile
oxide producing spiro-isoxazolines, please see: Colinas, P.
A.; Jager, V.; Lieberknecht, A.; Bravo, R. D. Tetrahedron
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3. For some recent examples on the synthesis of C-glyco-
sides, please see: (a) Abe, H.; Shuto, S.; Matsuda, A.
Tetrahedron Lett. 2000, 41, 2391; (b) Godage, H. Y.;
Fairbanks, A. J. Tetrahedron Lett. 2000, 41, 7489; (c)
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Taylor, R. J. K. Eur. J. Org. Chem. 2002, 23, 1323.
4. (a) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M.
J. Chem. Soc., Perkin. Trans. 1 2002, 2419; (b) Duff, F. J.;
Vivien, V.; Wightman, R. H. Chem. Commun. 2000, 2127;
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Tetrahedron Lett. 2001, 42, 4065; (d) Cardon, F.; Goti, A.;
Brand, A. Org. Lett. 2003, 5, 1475.
5. For some recent examples on the application of exo-
methylenesugars to the synthesis of C-glycosides, please
see: (a) Lin, H.-C.; Yang, W.-B.; Gu, Y.-F.; Chen, C.-Y.;
Wu, C.-Y.; Lin, C.-H. Org. Lett. 2003, 5, 1087; (b) Yang,
W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang, S.-H.; Chang,
C.-C.; Lin, C.-H. J. Org. Chem. 2002, 67, 3773; (c) Griffin,
F. K.; Paterson, D. E.; Murphy, P. V.; Taylor, R. J. R.
Eur. J. Org. Chem. 2002, 1309; (d) Taylor, R. J. R. J.
Chem. Soc., Chem. Commun. 1999, 217; (e) Liu, H.;
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Tetrahedron 2002, 58, 9351; (g) Xie, J.; Molina, A.;
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8. Nitrone 2 was prepared from the corresponding carbohy-
drate aldehyde and methyl hydroxylamine following
Dondoni et al. procedure, please see: Dondoni, A.;
Franco, S.; Junquera, F.; Merchan, F.; Merino, P.; Tejero,
T. Synth. Commun. 1994, 24, 2537.
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11. General procedure for the 1,3-dipolar cycloaddition––A
solution of 1a (210 mg, 0.39 mmol) and 2 (200 mg,
0.41 mmol) in 10 mL of dry toluene was refluxed
under argon for 40 h. The reaction was monitored by
TLC (AcOEt–hexane ¼ 1:3). After the complete of the
reaction, the solvent was removed under reduced
pressure. The residue was applied on silica gel column
chromatography using AcOEt–hexane (1:5) as the
eluent to afford 3a (70 mg, 17.4%) and 4a (210 mg,
52.1%).
6. To the best of our knowledge, only one example of 1,3-
dipolar cycloaddition of exo-methylenesugars with nitrile
12. Physical and spectral data of the new compounds (3a, 4a–
c, 5, 6) are compiled in Supplementary data.