1,3-Dipolar cycloaddition reactions on carbohydrate-based templates: synthesis of spiro-isoxazolines and 1,2,4-oxadiazoles as glycogen phosphorylase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2006.06.058

1,3-Dipolar cycloaddition of aryl nitrile oxides to benzyl/acetyl-protected exo-glucals and to a benzoylated glucosyl cyanide led in high yield to spiro-isoxazolines and to 3-aryl-5-glucosyl-1,2,4-oxadiazoles, respectively. The choice of the protective gr

Full text of DOI:10.1016/j.tetlet.2006.06.058

Tetrahedron Letters 47 (2006) 6143–6147
1,3-Dipolar cycloaddition reactions on
carbohydrate-based templates: synthesis of spiro-isoxazolines
and 1,2,4-oxadiazoles as glycogen phosphorylase inhibitors
a
a
Mahmoud Benltifa,a,b Sebastien Vidal, David Gueyrard,
´
Peter G. Goekjian,a Moncef Msaddekb and Jean-Pierre Pralya,*
aLaboratoire de Chimie Organique 2 – Glycochimie, Universite´ Claude Bernard Lyon 1, UMR-CNRS 5181, CPE-Lyon,
ˆ
Batiment 308, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
b
`
´ ´ ´
Laboratoire de Synthese Heterocyclique, Photochimie et Complexation, Faculte des Sciences de Monastir,
Avenue de l’Environnement, 5000 Monastir, Tunisia
Received 9 April 2006; revised 7 June 2006; accepted 9 June 2006
Available online 7 July 2006
Abstract—1,3-Dipolar cycloaddition of aryl nitrile oxides to benzyl/acetyl-protected exo-glucals and to a benzoylated glucosyl cya-
nide led in high yield to spiro-isoxazolines and to 3-aryl-5-glucosyl-1,2,4-oxadiazoles, respectively. The choice of the protective
groups was important to the outcome of the cycloaddition and for the deprotection of the adducts. Cleavage of the ester protecting
groups (acetyl, benzoyl) provided water-soluble spiro-isoxazolines and 3-aryl-5-glucosyl-1,2,4-oxadiazoles, evaluated as glycogen
phosphorylase inhibitors. Preliminary tests showed IC50 values in the lM range.
Ó 2006 Elsevier Ltd. All rights reserved.
Glycogen phosphorylase1 (GP) is responsible for the
conversion of glycogen to glucose (glycogenolysis). It
contributes to glucose production, for the glycolysis
pathway in muscles, and for delivery of glucose into
the bloodstream in the liver. Hepatic glucose produc-
tion, normally under tight hormonal control, is disregul-
Inhibition2 of GP is emerging as a viable approach3
for the treatment of hyperglycaemia.4,5 The largest fam-
ily of GP inhibitors consists of glucose derivatives,2,6–9
such as glucopyranosyl-spiro-oxathiazoles A,10 -spiro-
(thio)hydantoins B,7 -benzothiazole11 or -benzimidazole
C,11 -1,2,4-oxadiazoles D12 and -1,3,4-oxadiazoles E11
(Fig. 1). 1,3-Dipolar cycloadditions of nitrile oxides to
ated in patients suffering from type
2
diabetes.
OH
OH
OH
O
O
O
N
HO
HO
HO
HO
HO
HO
H
N
S
N
X
OH
OH
OH
Ar
X
O
N
H
O
A
B X = O, S
C X = S, NH
OH
OH
O
N
O
O
N N
HO
HO
HO
HO
Ar
R
N
O
OH
OH
D
R = alkyl, aryl, hetaryl
E R = CH3, CF3
Figure 1. Some known glucose-based inhibitors of GP.
Keywords: 1,3-Dipolar cycloadditions; Glycals; Spiro-isoxazolines; 1,2,4-Oxadiazoles.
*
Corresponding author. Tel.: +33 472 43 11 61; fax: +33 472 44 83 49; e-mail: jean-pierre.praly@univ-lyon1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.058

6144
M. Benltifa et al. / Tetrahedron Letters 47 (2006) 6143–6147
OR
OR
As part of our projects concerning glucose analogs as
GP inhibitors,9,10,12 we have been interested in spiro-
cyclic sugars and C-glycosyl heterocyles. We have pre-
pared differently protected methylene exo-glucals 1–322
using our recently established procedure23,24 from sugar
O
O
Ar
2
C
N O
RO
RO
RO
RO
[3+2]
OR
OR
OBz
Ar
Ar
CH
O
N
lactones while the glucosyl cyanide 8 was prepared
OBz
25
´
Ar
C
N
O
according to Somsak’s method. As reported below,
O
O
N
BzO
BzO
BzO
BzO
cycloadditions between these dipolarophiles and aryl
nitrile oxides and deprotections of the expected cyclo-
adducts were carried out to afford potential GP inhibitors
(Scheme 1).
CN
N
[3+2]
-PhOMe, p-O2NPh
O
OBz
OBz
Ar = Ph,
R = Bn, Et3Si, Ac
p
Figure 2. Cycloaddition approaches towards glucose-based hetero-
cycles as potential GP inhibitors.
The benzylated exo-glucal 123,26 underwent a cycloaddi-
tion reaction with p-anisonitrile oxide at room tempera-
ture to afford the desired spiro-isoxazoline 427 in high
yield with complete regio- and stereoselectivity (Table
1). The regiochemistry of the cycloaddition reaction
methylene exo-glucals and C-glucosyl cyanides (Fig. 2)
could lead, respectively, to spiro-isoxazolines and
1,2,4-oxadiazoles, analogous to the aforementioned
inhibitors.
1
was established from data provided by H NMR, 13C
NMR and 2D NMR experiments (COSY, HSQC,
HMBC). The (R) configuration at the spiro-carbon
atom of cycloadduct 4 was determined by NOE experi-
ments showing a contact between the methylene protons
of the isoxazoline ring and either the H-2 proton of the
sugar ring or a benzylic proton (superimposed signals at
d = 3.70–3.82), (H-4 and H-10, following the systematic
numbering used in the NMR data), but no enhancement
of the H-3 and H-5 signals (H-9 and H-7).
1,3-Dipolar cycloaddition reactions involving carbo-
hydrate derivatives as a dipole or a dipolarophile have been
studied extensively.13 In particular, Gallos et al.14,15
recently reported the cycloaddition of 3,4- and 5,6-unsat-
urated sugars with nitrile oxides. Another study by
Ikegami and co-workers16 described the synthesis of an
amino-C-ketosyl disaccharide by cycloaddition of a
nitrone to a methylene exo-glycal. Electron-deficient
exo-glycals were used by Chapleur and co-workers17,18
for cycloadditions with nitrones and nitrile oxides.
Cycloadditions of nitrile oxides to electron-rich exo-gly-
cals have been studied only briefly by Rajanbabu
and Reddy19 and more recently by Lieberknecht and
co-workers20 and Ikegami and co-workers21 using
substituted and unsubstituted methylene exo-glycals,
respectively. These studies focused primarily on the
cycloaddition regio- and stereoselectivities without con-
sidering the deprotection of the spiro-compounds.
Table 1. 1,3-Dipolar cycloaddition of aromatic nitrile oxides with
methylene exo-glucals 1 and 3
exo-Glucals
Ar
Products (%)
1
3
3
3
p-MeOPh
p-MeOPh
Ph
4 (83)
5a (83)
5b (99)
5c (94)
p-O2NPh
OBn
O
OTES
O
OAc
O
(i)
BnO
BnO
TESO
TESO
AcO
AcO
OBn
(ii)
TESO
OAc
CH
CH
2
CH
2
2
1
4
2
3
(ii)
(ii)
OBn
OAc
No reaction
O
O
BnO
BnO
AcO
AcO
BnO
(iii)
OAc
PhOMe
Ar
O
O
5a-c
N
N
(iv)
OH
OH
O
O
HO
HO
HO
HO
PhOMe
OH
OH
Ar
OH
O
6
7a-c
N
NH
2
Scheme 1. Reagents and conditions: (i) TBAF, THF, rt, 4 h then Ac2O, pyridine, rt, 24 h, 97%; (ii) ArC(Cl)@NOH, Et3N, CH2Cl2, rt, 16 h; (iii) H2,
Pd(OH)2–C 20%, EtOH, rt, 16 h; (iv) NaOMe, MeOH, rt, 2 h.

M. Benltifa et al. / Tetrahedron Letters 47 (2006) 6143–6147
6145
OBz
OBz
Ar
(i)
(ii)
O
O
N
BzO
BzO
BzO
BzO
CN
N
O
OBz
O
OBz
9a-c
8
OH
OH
Ar
O
N
HO
HO
N
+
HO
HO
Ar
N
O
OH
O
N
11a-c
10a-c
Scheme 2. Reagents and conditions: (i) ArC(Cl)@NOH, Et3N, toluene, 110 °C, 16 h; (ii) NaOMe, MeOH/CHCl3 (2/3), rt, 2 h.
However, subsequent hydrogenolysis of the benzyl
ethers of 4 occurred with concomitant reductive cleav-
age of the N–O bond and reduction of the C@N double
bond,16 as evidenced by mass spectroscopy showing a
molecular ion m/z = 329.9 [M+H]+, supporting struc-
ture 6.28
(Table 2).33 Deprotection of the benzoyl esters under
´
Zemplen conditions provided the deprotected 5-C-b-D-
glucosyl-1,2,4-oxadiazoles 10a–c34 (75–92% isolated
yield) together with a small amount of the endo-glucals
11a–c (4–7% isolated yield).
In summary, we developed short and convenient routes
to glucose-derived spiro-isoxazolines and 3-aryl-5-C-
glucosyl-1,2,4-oxadiazoles, based on [3+2] cycloaddition
reactions to acetyl- and benzyl-protected exo-glucals
or a benzoylated b-D-glucopyranosyl cyanide. Use of
ester protective groups gave access to the corresponding
deprotected water-soluble motifs, analogous to
known inhibitors of glycogen phosphorylase. Indeed,
preliminary tests showed that 5-b-D-glucopyranosyl-3-
phenyl-1,2,4-oxadiazole 10b inhibited significantly
(IC50 = 64 lM) rabbit muscle GPb (unphosphorylated
isoform). In contrast, 3-b-D-glucopyranosyl-5-phenyl-
1,2,4-oxadiazole, an isomer of 10b, had a low inhibitory
activity towards GP (IC50 = 1.49 mM).12 Therefore,
the 3-aryl-5-b-D-glucopyranosyl-1,2,4-oxadiazole series
appears to be more promising for GP inhibition. Such
glucose-based analogues are currently investigated and
their syntheses, inhibitory activities as well as data
obtained from crystallographic studies will be reported
in due course.
The triethylsilyl (TES) groups appeared to be a suitable
alternative to benzyl groups, since their cleavage occurs
under mild conditions with fluoride ion. However,
attempted cycloadditions of aromatic nitrile oxides to
the silylated exo-glucal 2 failed to furnish the expected
spiro-derivatives. Complete recovery of unreacted 2
was observed even in refluxing toluene. The lack of reac-
tivity could be attributed to the bulkiness of silyl groups
in 2 hindering the approach of the nitrile oxide.
The acetyl protective group, characterized by limited
steric hindrance and cleavage under mild conditions, ap-
peared as a viable alternative to benzyl and silyl groups.
The acetylated methylene exo-glucal 329 was obtained
from 2 in nearly quantitative yield via a one-pot proce-
dure combining cleavage of silyl ethers and subsequent
acetylation. Finally, cycloaddition at room temperature
afforded the desired spiro-isoxazolines 5a–c in high
yields (Table 1). The regio- and stereochemistries at
the anomeric spiro-centre were determined as before
by 13C NMR and NOE experiments, which showed
unambiguously a contact between the methylene pro-
tons of the isoxazoline ring and the H-2 proton of the
sugar ring. As expected, methanolysis of the acetates
delivered the deprotected spiro-isoxazolines 7a–c in
quantitative yields.30
Acknowledgements
´
ˆ
Financial support by the Region Rhone-Alpes (funds
from MIRA Recherche 2001 and stipends to M.B.)
and the European Union (FP6-IP 503467) is gratefully
acknowledged. Support provided by the French Minis-
try of Foreign Affairs (PAI Balaton No. 11 061PE with
Next, we considered the corresponding [3+2] cycloaddi-
tions to nitriles31,32 as an access to 3-aryl-5-C-glucosyl-
1,2,4-oxadiazoles from the benzoylated b-D-glucosyl
cyanide 825 (Scheme 2). Nitrile 8 reacted in refluxing
toluene with various aryl nitrile oxides to afford the
expected heterocyclic compounds 9a–c in high yields
´
Professor L. Somsak, University of Debrecen, Hungary)
is also acknowledged. The authors are indebted to
Dr. N. G. Oikonomakos (National Hellenic Research
Foundation, Athens, Greece), P. Gergely (Medical
and Health Science Centre, University of Debrecen,
Hungary) and co-workers for IC50 measurements.
Table 2. 1,3-Dipolar cycloaddition of aromatic nitrile oxides with
b-D-glucosyl cyanide 8
References and notes
Cycloadducts
Ar
Yields (%)
1. Johnson, L. N. FASEB J. 1992, 6, 2274–2282.
2. Oikonomakos, N. G. Curr. Protein Pept. Sci. 2002, 3, 561–
586.
9a
9b
9c
p-MeOPh
Ph
p-O2NPh
90
94
99
3. Moller, D. E. Nature 2001, 414, 821–827.

6146
M. Benltifa et al. / Tetrahedron Letters 47 (2006) 6143–6147
4. Zimmet, P.; Alberti, K. G. M. M.; Shaw, J. Nature 2001,
CDCl3): d = 3.05 (s, 2H, H-4), 3.59 (dd, 1H, J = 1.7,
10.9 Hz, CH2OBn), 3.70–3.82 (m, 2H, H-10, CH2OBn),
3.82 (s, 3H, OMe), 3.84 (t, 1H, J = 9.6 Hz, H-8), 4.08 (m,
1H, H-7), 4.15 (t, 1H, J = 9.4 Hz, H-9), 4.43 (d, 1H,
J = 12.2 Hz, OCH2Ph), 4.57 (d, 1H, J = 10.8 Hz,
OCH2Ph), 4.59 (d, 1H, J = 12.2 Hz, OCH2Ph), 4.71 (d,
1H, J = 12.0 Hz, OCH2Ph), 4.86 (d, 1H, J = 10.8 Hz,
OCH2Ph), 4.94 (s, 2H, OCH2Ph), 4.99 (d, 1H,
J = 12.0 Hz, OCH2Ph), 6.89 (d, 2H, J = 8.9 Hz, H-ar),
7.17–7.40 (m, 20H, OCH2Ph), 7.49 (d, 2H, J = 8.9 Hz, H-
ar). 13C NMR (75 MHz, CDCl3): d = 43.2 (C-4), 55.3
(OCH3), 68.0 (CH2OBn), 72.4 (C-7), 73.4, 74.7, 74.9, 75.7
(CH2Ph), 77.7 (C-8), 78.3 (C-10), 84.0 (C-9), 108.6 (C-5),
114.0 (2C, C-ar), 121.6 (C-ar), 127.6, 127.8, 127.9, 128.0,
128.3, 128.4, 128.5, (C-ar), 137.8, 138.1, 138.3 (C-ar),
157.2 (C-3), 161.6 (C-ar). MS (ESI) m/z = 686.1 [M+H]+,
1371.0 [2M+H]+. HRMS (ESI) m/z = C43H44NO7
[M+H]+ calcd 686.3118, found 686.3116.
414, 782–861.
5. Treadway, J. L.; Mendys, P.; Hoover, D. J. Exp. Opin.
Invest. Drugs 2001, 10, 439–454.
´
6. Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P.
Curr. Pharm. Des. 2003, 9, 1177–1189.
´
7. Somsak, L.; Nagy, V.; Hadady, Z.; Felfo¨ldi, N.; Docsa,
T.; Gergely, P. In Frontiers in Medicinal Chemistry; Reitz,
A. B., Kordik, C. P., Choudhary, M. I., Atta ur Rahman,
Eds.; Bentham Science, 2005; Vol. 2, pp 253–272.
8. Chrysina, E. D.; Kosmopoulou, M. N.; Tiraidis, C.;
Kardakaris, R.; Bischler, N.; Leonidas, D. D.; Hadady,
´
Z.; Somsak, L.; Docsa, T.; Gergely, P.; Oikonomakos, N.
G. Protein Sci. 2005, 14, 873–888.
9. Oikonomakos, N. G.; Kosmopoulou, M.; Zographos, S.
´
E.; Leonidas, D. D.; Chrysina, E. D.; Somsak, L.; Nagy,
´
V.; Praly, J.-P.; Docsa, T.; Toth, B.; Gergely, P. Eur. J.
Biochem. 2002, 269, 1684–1696.
´
10. Praly, J.-P.; Boye, S.; Joseph, B.; Rollin, P. Tetrahedron
Selected data for (5R,7R,8R,9S,10R)-8,9,10-tris(acetoxy)-
7-[(acetoxy)methyl]-3-(4-methoxyphenyl)-1,6-dioxa-2-aza-
spiro[4,5]dec-2-ene (5a): 1H NMR (300 MHz, CDCl3):
d = 2.00 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 2.06 (s, 3H, CH3), 3.29 (d, 1H, J = 17.7 Hz, H-4a),
3.38 (d, 1H, J = 17.7 Hz, H-4b), 3.83 (s, 3H, OCH3), 4.03
(dd, 1H, J = 2.0, 12.6 Hz, CH2OAc), 4.27 (dd, 1H,
J = 3.7, 12.6 Hz, CH2OAc), 4.34 (ddd, 1H, J = 2.0, 3.7,
10.1 Hz, H-7), 5.19 (dd, 1H, J = 9.5, 10.1 Hz, H-8), 5.41
(d, 1H, J = 10.0 Hz, H-10), 5.53 (dd, 1H, J = 10.0, 9.5 Hz,
H-9), 6.91 (d, 2H, J = 8.9 Hz, H-ar), 7.58 (d, 2H,
J = 8.9 Hz, H-ar). 13C NMR (75 MHz, CDCl3): d = 20.6
(CH3), 20.6 (CH3), 20.6 (CH3), 20.7 (CH3), 43.5 (C-4),
55.4 (OCH3), 61.4 (CH2OAc), 67.8 (C-8), 69.1 (C-10), 69.2
(C-7), 71.6 (C-9), 106.7 (C-5), 114.2 (2C, C-ar), 120.6 (C-
ar), 128.5 (2C, C-ar), 157.3 (C-3), 161.6 (C-ar), 169.6,
169.8, 170.3, 170.6 (4COCH3). MS (ESI) m/z = 493.9
[M+H]+, 516.0 [M+Na]+, 986.6 [2M+H]+, 1008.7
Lett. 1993, 34, 3419–3420.
11. Hadady, Z.; Toth, M.; Somsak, L. Arkivoc 2004, vii, 140–
´
´
149.
12. Benltifa, M.; Vidal, S.; Fenet, B.; Msaddek, M.; Goekjian,
´
P. G.; Praly, J.-P.; Brunyanszki, A.; Docsa, T.; Gergely, P.
Eur. J. Org. Chem., in press.
13. Osborn, H. M. I.; Gemmel, N.; Harwood, L. M. J. Chem.
Soc., Perkin Trans. 1 2002, 2419–2438.
14. Gallos, J. K.; Koftis, T. V.; Koumbis, A. E.; Moutsos, V.
I. Synlett 1999, 8, 1289–1291.
15. Gallos, J. K.; Koftis, T. V. J. Chem. Soc., Perkin Trans. 1
2001, 415–423.
16. Li, X.; Takahashi, H.; Ohtake, H.; Ikegami, S. Tetra-
hedron Lett. 2004, 45, 4123–4126.
17. Taillefumier, C.; Enderlin, G.; Chapleur, Y. Lett. Org.
Chem. 2005, 2, 226–230.
18. Enderlin, G.; Taillefumier, C.; Didierjean, C.; Chapleur,
Y. Tetrahedron: Asymmetry 2005, 16, 2459–2474.
19. Rajanbabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51,
5458–5461.
[2M+Na]+.
HRMS
(ESI)
m/z = C23H27NO11Na
[M+Na]+ calcd 516.1481, found 516.1488.
28. The NMR spectra of the hydrogenation product suggested
that the reduction of the C@N double bond might be
stereoselective. However, neither the selectivity of the
reduction nor the stereochemistry of the major product
have been established at this time. For stereoselective
reduction of isoxazolines with LiAlH4, see De Blas, J.;
20. Colinas, P. A.; Ja¨ger, V.; Lieberknecht, A.; Bravo, R. D.
Tetrahedron Lett. 2003, 44, 1071–1074.
21. Li, X.; Takahashi, H.; Ohtake, H.; Ikegami, S. Hetero-
cycles 2003, 59, 547–571.
22. (a) Lancelin, J.-M.; Pougny, J.-R.; Sinay, P. Carbohydr.
¨
´
Res. 1985, 136, 369–374; for a recent review on exo-
glycals, see: (b) Taillefumier, C.; Chapleur, Y. Chem. Rev.
2004, 104, 263–292.
Carretero, J. C.; Domınguez, E. Tetrahedron Lett. 1995, 6,
1035–1038.
29. Acetylated exo-glucal 3 has been previously reported:
´
´
´
23. Gueyrard, D.; Haddoub, R.; Said Bacar, N.; Salem, A.;
Goekjian, P. G. Synlett 2005, 520–523.
Toth, M.; Ko¨ver, K. E.; Benyei, A.; Somsak, L. Org.
Biomol. Chem. 2003, 1, 4039–4046.
24. Gueyrard, D.; Fontaine, P.; Goekjian, P. G. Synthesis
2006, 1499–1503.
30. Selected data for (5R,7R,8R,9S,10R)-7-(hydroxymethyl)-
3-(p-methoxyphenyl)-1,6-dioxa-2-azaspiro[4,5]dec-2-ene-
8,9,10-triol (7a): 1H NMR (500 MHz, CD3OD, 55 °C):
d = 3.31 (m, 1H, H-4a), 3.44 (dd, 1H, J = 8.9, 9.2 Hz, H-
8), 3.58 (d, 1H, J = 9.8 Hz, H-10), 3.68–3.83 (m, 5H, H-
4b, CH2OH, H-7, H-9), 3.84 (s, 3H, OCH3), 6.97 (d, 2H,
J = 8.1 Hz, H-ar), 7.62 (d, 2H, J = 8.1 Hz, H-ar). 13C
NMR (125 MHz, CD3OD, 55 °C): d = 44.6 (C-4), 56.0
(OCH3), 62.6 (CH2OH), 71.7 (C-8), 73.3 (C-10), 75.9 (C-
9), 76.4 (C-7), 110.7 (C-5), 115.4 (2C, C-ar), 123.1 (C-ar),
129.5 (2C, C-ar), 159.5 (C-3), 163.2 (C-ar). MS (ESI)
m/z = 326.0 [M+H]+, 348.0 [M+Na]+, 672.9 [2M+Na]+,
997.6 [3M+Na]+. HRMS (ESI) m/z = C15H20N1O7
[M+H]+ calcd 326.1240, found 326.1243.
31. Huisgen, R.; Mack, W.; Anneser, E. Tetrahedron Lett.
1961, 2, 587–589.
32. Hemming, K. J. Chem. Res. (S) 2001, 209–216.
33. Typical procedure for 1,3-dipolar cycloaddition on b-D-
glucosyl cyanide 8: To a solution of compound 8
(0.5 mmol) and hydroximoyl chloride (5 equiv) in distilled
´
25. Somsak, L.; Nagy, V. Tetrahedron: Asymmetry 2000, 11,
1719–1727.
26. Benzylated exo-glucal 1 has been previously reported: see
Ref. 22a and Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang,
S.-H.; Chang, C.-C.; Lin, C.-H. J. Org. Chem. 2002, 67,
3773–3782.
27. Typical procedure for 1,3-dipolar cycloaddition on meth-
ylene exo-glucals: To a solution of the methylene exo-
glucal (0.3 mmol) and hydroximoyl chloride (5 equiv) in
anhydrous dichloromethane (5 mL), a solution of trieth-
ylamine (7.5 equiv) in dry dichloromethane (2 mL) was
added dropwise (syringe pump, 8 h). The mixture was
stirred overnight at room temperature. After concentra-
tion, the crude material was purified by flash chromato-
graphy to afford the desired spiro-isoxazolines 4 and 5a–c.
Selected data for (5R,7R,8R,9S,10R)-8,9,10-tris(benzyl-
oxy)-7-[(benzyloxy)methyl]-3-(4-methoxyphenyl)-1,6-
dioxa-2-azaspiro[4,5]dec-2-ene (4): 1H NMR (300 MHz,

M. Benltifa et al. / Tetrahedron Letters 47 (2006) 6143–6147
6147
toluene (10 mL), a solution of triethylamine (7.5 equiv) in
dry toluene (2 mL) was added dropwise (syringe pump,
8 h) at 110 °C. The mixture was stirred overnight at
110 °C. After evaporation, the crude material was purified
by flash chromatography to afford the desired spiro-
isoxazolines 9a–c.
(C-ar), 130.2, 130.3, 133.6, 133.8, 133.9, 134.0, 162.5, 165.2
(C-ar), 165.6, 166.2, 166.6 (4C, COPh), 168.6 (C-3), 173.5
(C-5). MS (LSIMS, NBA) m/z = 755 [M+H]+. HRMS
(LSIMS, NBA) m/z = C43H35N2O11 [M+H]+ calcd
755.2241, found 755.2242.
34. Selected data for 5-C-(b-D-glucopyranosyl)-3-(p-methoxy-
phenyl)-1,2,4-oxadiazole (10a): 1H NMR (300 MHz,
CD3OD): d = 3.43–3.50 (m, 3H, H-30, H-40, H-50), 3.72
(dd, 1H, J = 4.8, 12.3 Hz, H-60a), 3.79 (t, 1H, J = 9.6 Hz,
H-20), 3.86 (s, 3H, OCH3), 3.91 (d, 1H, J = 12.3 Hz, H-
60b), 4.63 (d, 1H, J = 9.6 Hz, H-10), 7.05 (d, 2H,
J = 8.9 Hz, H-ar), 8.00 (d, 2H, J= 8.9 Hz, H-ar). 13C
NMR (75 MHz, CD3OD): d = 56.0 (OCH3), 62.8 (C-60),
71.2 (C-40), 74.0 (C-20), 75.2 (C-10), 79.2 (C-30), 83.0 (C-
50), 115.2 (2C, C-ar), 120.0 (C-ar), 130.1 (2C, C-ar), 163.8
(C-ar), 169.3 (C-3), 177.9 (C-5). MS (LSIMS, glycerol)
m/z = 339 [M+H]+. HRMS (LSIMS, glycerol) m/z =
C15H19N2O7 [M+H]+ calcd 339.1192, found 339.1191.
Selected data for 5-C-(20,30,40,60-tetra-O-benzoyl-b-D-
glucopyranosyl)-3-(p-methoxyphenyl)-1,2,4-oxadiazole
(9a): 1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3H,
OCH3), 4.38 (m, 1H, H-50), 4.56 (dd, 1H, J = 4.8,
12.3 Hz, H-60a), 4.70 (dd, 1H, J = 1.9, 12.3 Hz, H-60b),
5.23 (d, 1H, J = 9.0 Hz, H-10), 5.86 (t, 1H, J = 9.3 Hz, H-
40), 6.06 (m, 2H, H-20, H-30), 6.89 (d, 2H, J = 8.7 Hz, H-
ar), 7.28–7.55 (m, 12H, H-ar), 7.85–8.05 (m, 10H, H-ar).
13C NMR (75 MHz, CDCl3): d = 55.8 (OCH3), 63.4 (C-
60), 69.5 (C-40), 71.1 (C-20 or 30), 72.9 (C-10), 74.2 (C-20 or
30), 77.6 (C-50), 114.6 (C-ar), 119.0 (C-ar), 128.8, 128.8,
128.9, 129.0 (C-ar), 129.1 (C-ar), 129.1 (C-ar), 129.6, 129.9