Iminosugar thioglycosides as glycosyl donors: a route to disaccharides with an iminosugar moiety

Article abstract of DOI:10.1016/j.tetlet.2007.11.160

The iminosugar thioglycosides are used as glycosyl donors in glycosidation reactions. Thereby, iminosugar glycosides and disaccharide analogues with an iminosugar moiety are prepared. The yields are high and the method is stereoselective.

Full text of DOI:10.1016/j.tetlet.2007.11.160

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 910–913
Iminosugar thioglycosides as glycosyl donors:
a route to disaccharides with an iminosugar moiety
*
´
´
Jose Fuentes , Nader R. Al Bujuq, Manuel Angulo, Consolacion Gasch
Departamento de Quı´mica Orga´nica y Servicio de RMN, Universidad de Sevilla, Apartado 120, Seville E-41071, Spain
Received 27 September 2007; revised 14 November 2007; accepted 26 November 2007
Available online 3 December 2007
´
Dedicated to Professor M. Angeles Pradera on the occasion of her retirement
Abstract
The iminosugar thioglycosides are used as glycosyl donors in glycosidation reactions. Thereby, iminosugar glycosides and disaccha-
ride analogues with an iminosugar moiety are prepared. The yields are high and the method is stereoselective.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Iminosugars; Thioglycosides; Glycosidations; Iminosugar–disaccharides
The iminocyclitols, also known as iminosugars, are a
type of natural and synthetic sugar analog in which the
endocyclic oxygen atom has been substituted by a nitrogen
atom. These compounds are glycosidase and glycosyltrans-
ferase inhibitors, and consequently they can be useful in the
treatment of metabolic disorders and inflammatory pro-
cesses.1 In the last 15 years, much effort has been directed
at the synthesis of five-, six- and seven-membered imino-
cyclitols, that is, ‘monosaccharide–iminosugars’.2,3 How-
ever, data on disaccharide derivatives containing one or
two iminosugar moieties are scarce. Several C-linked
imino-disaccharide derivatives with an iminosugar moiety
have been prepared,4 and related compounds with an
amino group5,6 or sulfur atom as inter-glycosidic group
have also been described.5 The synthesis of 1,6-imino-di-
and imino-tri-saccharide derivatives, through glycosidation
of nojirimycin derivatives with catalytic amounts of
TMSOTf, has also been reported.7
have been widely used as glycosyl donors in glycosidation
reactions, to prepare oligosaccharides.8 The thioglycosides
have also been used as chiral inductors in enzymatic syn-
thesis9 and have been tested as antithrombotic agents.10
Recently, we have reported the stereoselective preparation
of iminosugar thioglycosides11 starting from anhydro-
iminosugar derivatives.
In this Letter, we report on the use of the iminosugar
ethyl thioglycoside 3 (Scheme 1) as glycosyl donor in
glycosidation reactions. The glycosyl acceptors were simple
alcohols and partially protected sugar derivatives with a
free hydroxyl group at position 6 or position 3.
In an earlier paper,12 we have reported the glycosidation
of methanol using an imino-anhydroglucose derivative,
related to 1, as glycosyl donor, but the yield was low and
no other alcohol was used. We have also carried out the
reaction of the anhydroiminoribose11 derivative 1 with dif-
ferent alcohols to obtain compounds 2; however, the reac-
tion was not possible when benzyl and cyclohexyl alcohols
were used as glycosyl acceptors.13
The thioglycosides, a type of glycoside in which the ano-
meric carbon atom has been substituted by a sulfur atom,
Compound 1 was transformed11 into the ethyl thioglyco-
side 3, which by reaction with benzyl bromide produced the
5-O-benzyl derivative 4, suitable for use as glycosyl donor
in glycosidation reactions.
*
Corresponding author. Tel.: +34 954551518; fax: +34 954624960.
E-mail address: jfuentes@us.es (J. Fuentes).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.160

J. Fuentes et al. / Tetrahedron Letters 49 (2008) 910–913
911
CO2Et
CO2Et
CO2Et
CO2Et
iminosugar glycosides 5 and 614 in 88% and 87% yield,
respectively, and as a single diastereoisomer each. The
pseudoanomeric configuration (configuration of C-2, using
the number of piperidine ring) was established through
NOE experiments and molecular modelling calculations.
Thus, a NOESY experiment performed on 6 showed the
results indicated in Figure 1. The molecular model of 6
obtained by energy minimization using a force field based
N
OR
N
O
i
ii
BnO
O
O
O
O
1
2
iii
CO2Et
CO2Et
SEt
CO2Et
CO2Et
CO2Et
CO2Et
SEt
3
approach15 yielded theoretical JH,H couplings (J2,3 = 1.2,
J3,4 = 8.5, J4,5 = 2.7, J5,6a = 4.9, J5,6b = 10.1) in very good
agreement with the experimental data,14 and proton–pro-
ton distances that were in very good agreement with the
whole set of NOE experimental observations. Particularly
important was the detection of a weak NOE between H-2
and the endo methyl group (Mea) (4.5 A) and between
H-5 and a CH2 of the cyclohexyl group (3.7 A) which are
exclusive NOEs crucial to demonstrate the proposed S con-
figuration for C-2.
To study the use of 4 as glycosyl donor, the acceptor
being a sugar derivative, the partially protected monosac-
charide derivatives with the CH2OH group free, 10 and
11, and the derivative with the 3-OH group free, 12, were
chosen.16
N
OR
N
N
iv
v
BnO
O
HO
O
BnO
O
O
O
O
5-9
3
4
5
7
6
8
9
O
OMe
OBn
O
O
O
O
O
OMe
OBn
R
Bn
Ph
O
O
BnO
O
OBn
Scheme 1. Reagents and conditions: (i) BF3ꢁOEt2; (ii) ROH, 0 °C, 45 min;
(iii) PTSA/DMF, EtSH, 0 °C, 45 min; (iv) DMF/NaH, BnBr; (v)
DMTST, MeCN, ROH, ꢀ20 °C.
OH
OH
The reaction of 4 with benzyl and cyclohexyl alcohol in
acetonitrile using dimethyl(methylthio)sulfonium triflate
(DMTST) as promoter, at ꢀ20 °C for 2 h, produced the
O
O
O
OMe
OBn
O
O
O
OMe
OBn
O
Ph
O
BnO
O
OBn
OH
CO2Et
10
11
12
The glycosidation reactions between the iminoglycosyl
donor 4 and acceptors 10–12 were carried out (Table 1)
in different solvents, under different conditions, and using
methyl triflate,17 DMTST18 and methyl benzene selenyl tri-
flate19 (PhSeTfOMe) as promoter. In every case, the corre-
sponding disaccharide derivative with iminosugar moieties
7–9 (Scheme 1) was obtained only as the b-anomer.20 The
yields were higher for the glycosidations on primary posi-
tions (10, 11) than for the glycosidation on a secondary
CO2Et
H6a
N
O
H6b
H5
H2
H3
O
BnO
H4
O
Meb
Mea
Fig. 1. NOE experiments on 6.
Table 1
Glycosidations of 10–12 with 4
Acceptor
Product
Solvent
Promotor (equiv)
Temperature (°C)
Reaction time (h)
Yield (%)
10
7
DMF
Ether
Ether
Dichloromethane
Acetonitrile
Acetonitrile
TFOMe (5.0)
TfOMe (5.0)
DMTST (3.0)
DMTST (3.0)
DMTST (2.0)
PhSeTfOMe (2.0)
rt
rt
ꢀ40
ꢀ40
ꢀ20
ꢀ10
48.0
24.0
3.0
3.0
2.0
23
30
65
30
80
45
2.0
11
12
8
9
Acetonitrile
Dichloromethane
Acetonitrile
Toluene
DMTST (2.0)
DMTST (3.0)
PhSeTfOMe (1.5)
PhSeTfOMe (1.5)
ꢀ20
ꢀ20
ꢀ30
0
2.0
1.0
24.0
2.0
60
50
32
42
Acetonitrile
1,2-Dichloroethane
Acetonitrile
DMTST (2.0)
PhSeTfOMe (2.0)
PhSeTfOMe (2.0)
0
0
0
2.0
3.0
2.0
45
Decompose
44

912
J. Fuentes et al. / Tetrahedron Letters 49 (2008) 910–913
7. Sawada, D.; Takahashi, H.; Shiro, M.; Ikegami, S. Tetrahedron Lett.
2005, 46, 2399–2403.
8. For a review, see: (a) Garegg, P. J. Adv. Carbohydr. Chem. Biochem.
1997, 52, 179–205. See also:(b) Demchenko, A. V.; Pornsuriyasak, P.;
De Meo, C.; Malysheva, N. N. Angew. Chem., Int. Ed. 2004, 43,
3069–3072; (c) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435–
position (12). The best yields were obtained using aceto-
nitrile as solvent, DMTST as promoter, reaction time of
2 h and a temperature of ꢀ20 °C (0 °C for 12).
The vicinal coupling constants for the iminosugar ring
of the iminodisaccharides 7–9 had similar values to that
for 6, which is indicative of b-configuration for the pseudo-
anomeric carbon (C-2 in the piperidine numbering).
In conclusion, glycosidation using iminosugar thio-
glycosides as glycosyl donors is a highly stereoselective
method to prepare disaccharide analogs with an iminosugar
moiety. The method has been used with partially protected
sugars with one free hydroxyl group at position 6 or 3, and
with simple alcohols as glycosyl acceptors. The scope and
limitations of this method are currently under study in
our laboratory.
´
´
436; (d) Lopez, J. C.; Gomez, A. M.; Uriel, C.; Fraser-Reid, B.
Tetrahedron Lett. 2003, 44, 1417–1420.
9. Defaye, J.; Gelas, J. In Studies Natural Products Chemistry; Altaur-
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11. (a) Fuentes, J.; Sayago, F. J.; Illangua, J. M.; Gasch, C.; Angulo, M.;
Pradera, M. A. Tetrahedron: Asymmetry 2004, 15, 603–615. and 2004,
15, 3783–3789; (b) Pradera, M. A.; Sayago, F. J.; Illangua, J. M.;
Gasch, C.; Fuentes, J. Tetrahedron Lett. 2003, 44, 6605–6608.
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8, 3443–3456.
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results communicated to the ‘Eighth Tetrahedron Symposium’ Berlin,
Germany, June 2007, Communication P343.
Acknowledgements
´
´
We thank the Direccion General de Investigacion of
Spain and the Junta de Andalucıa (grant numbers CTQ
14. Selected structural data for (2S,3R,4R,5R)-5-benzyloxy-2-cyclohexyl-
oxy-1-diethoxycarbonylvinyl-3,4-O-isopropylidenepiperidine (6). Yield:
´
25
87%; ½aꢂD ꢀ94.2 (c 1.3, CH2Cl2). 1H NMR (500 MHz, CDCl3) d 7.43
2005-01830/BQU and FQM 134) and the AECI of the
Ministerio de Asuntos Exteriores of Spain for the award
of a fellowship to NRAB. We also thank Dr. M. A. Prader-
a for some starting materials and Dr. J. Angulo for the help
in the molecular modelling study.
(s, 1H, @CHN), 7.35–7.28 (m, 5H, Ar), 4.61 (s, 2H, PhCH2), 4.54 (dd,
1H, J4,3 = 7.7, J4,5 = 2.3, H-4), 4.47 (d, 1H, J2,3 = 1.6, H-2), 4.33
(ddd, 1H, J5,6a = 6.1, J5,6b = 10.3, H-5), 4.24 (m, 3H, COOCH2CH3
and H-3), 4.15 (q, 2H, COOCH2CH3), 3.36 (dd, 1H, J6a,6b = 11.4, H-
6a), 3.33 (m, 1H, C6H11), 3.18 (t, 1H, H-6b), 1.73–1.44 (m, 6H,
C6H11), 1.41, 1.32 (each s, each 3H, C(CH3)2), 1.32, 1.24 (each t, each
3H, 2COOCH2CH3), 1.20–1.10 (m, 4H, C6H11); 13C NMR
(125.7 MHz, CDCl3) d 167.6, 167.1 (2C@O), 149.9 (@CHN), 137.6,
128.6, 128.2, 128.1 (Ph), 110.8 (C(CH3)2), 95.9 (@C), 90.7 (C-2), 75.8
(C-3), 72.2 (C-4), 71.9 (PhCH2), 68.9 (C-5), 61.1, 60.2
(2COOCH2CH3), 43.6 (C-6), 74.5, 32.8, 31.0, 25.5, 23.7, 23.4
(C6H11), 26.3, 24.5 [C(CH3)2], 14.4, 14.2 (2COOCH2CH3). HRCIMS
m/z obsd 532.2887; calcd for C24H42NO8, 532.2910.
References and notes
1. See as examples: (a) Afarinkia, K.; Bahar, A. Tetrahedron: Asymme-
try 2005, 12, 1239–1287; (b) Lillelund, V. H.; Jensen, H.; Liang, X.;
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as Glycosidase Inhibitors; Wiley-VCH: Weinheim, 1999; (d) Sinnot,
M. L. Chem. Rev. 1990, 90, 1171–1202; (e) Winchester, B.; Fleet, G.
W. G. Glycobiology 1992, 2, 199–210; (f) Giannis, A. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 178–180.
15. For the molecular modelling calculations the force field TRIPOS was
used as implemented in Sybyl 7.3 (Tripos Inc.). The starting structure
was built with a ring puckering corresponding to a skewed boat
conformation, as it was the only ring conformation in qualitative
agreement with the experimental J-couplings, and, at the same time,
showing the largest number of bulky exocyclic groups in the most
stable equatorial or isoclinal orientations. The exocyclic torsions were
optimized by determining the energy minimum in torsional energy
maps with 60° increments (gridsearch module in Sybyl). Gasteiger–
2. For a review, see: Casiragui, G.; Zanardi, F.; Rassu, G.; Spann, P.
Chem. Rev. 1995, 95, 1677–1716.
3. See as examples: (a) Blanco, M. J.; Sardina, F. J. J. Org. Chem. 1998,
63, 3411–3416; (b) Sayago, F. J.; Fuentes, J.; Angulo, M.; Gasch, C.;
Pradera, M. A. Tetrahedron 2007, 63, 4695–4702; (c) Fuentes, J.;
Gasch, C.; Olano, D.; Pradera, M. A.; Repetto, G.; Sayago, F. J.
Tetrahedron: Asymmetry 2002, 13, 1743–1753; (d) Chabeand, L.;
Landais, Y.; Reneaud, P. Org. Lett. 2005, 7, 2587–2590; (e) Li, H.;
Bleriot, Y.; Chantereau, C.; Mallet, J. M.; Sollogoub, M.; Zhang, Y.;
Huckel atomic partial charges were used and the energy minimization
¨
steps in all the calculations consisted in 1000 conjugated-gradients
maximum iterations, an energy gradient limit of 0.01 Kcal/mol A,
using a distance-dependent dielectric constant of 1ꢁr, and a non-
bonded cutoff of 8 A. Energy minimization led to significantly
improved agreement between experimental and theoretical J-cou-
plings. Theoretical distances were measured on the energy minimum,
and the J-couplings were obtained using the Haasnoot–Altona
empirical equation (Haasnoot, C. A. G.; De Leeuw, F. A. A. M.;
Altona, C. Tetrahedron 1980, 36, 2783–2792). Any molecular model
with an inverted configuration at C-2 was unable to predict the set of
exclusive NOEs described in the discussion of results.
´
´
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Rodrıguez-Garcıa, E.; Vogel, P.; Jimenez-Barbero, J.; Sinay, P. Org.
Biomol. Chem. 2004, 2, 1492–1499.
´
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4. See as examples: (a) Garcıa-Aparicio, V.; Fernandez-Alonso, M. C.;
Angulo, J.; Asencio, J. L.; Canada, F. J.; Jime´nez-Barbero, J.;
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Mootoo, D. R.; Cheng, X. Tetrahedron: Asymmetry 2005, 16, 519–
527; (b) Aslam, T.; Fuchs, M. G. G.; Le Formal, A.; Wightman, R. H.
Tetrahedron Lett. 2005, 46, 3249–3252; (c) Sharma, G. V. M.;
Pendem, N.; Reddy, K. R.; Krishna, P. R.; Narsimulo, K.; Kunwar,
A. C. Tetrahedron Lett. 2004, 45, 8807–8810; (d) Agryropoulos, N.
G.; Sarli, V. C. Tetrahedron Lett. 2004, 45, 4237–4240; (e)
Dondoni, A.; Giovanni, P. P.; Marra, A. Tetrahedron Lett. 2000,
41, 6195–6199.
16. Compound 10 was a commercial product. For the preparation of 11,
see: Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res.
1987, 167, 305–311; and for the preparation of 12, see: Roe¨n, A.;
´
5. (a) Campanini, L.; Dureault, A.; Depezay, J.-C. Tetrahedron Lett.
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Padron, J. I.; Vazquez, J. T. J. Org. Chem. 2003, 68, 4615–4630.
1996, 37, 5095–5098; (b) Barbaud, C.; Bols, M.; Lundt, I.; Sierks, M.
R. Tetrahedron 1995, 51, 9063–9078.
6. (a) Gravier-Pelletier, C.; Maton, W.; Le Merrer, Y. Tetrahedron Lett.
2002, 43, 8285–8288; (b) Gravier-Pelletier, C.; Maton, W.; Lecourt,
T.; Le Merrer, Y. Tetrahedron Lett. 2001, 42, 4475–4478.
17. Lo¨nn, H. J. Carbohydr. Chem. 1987, 6, 301–306.
18. Krog-Jensen, C.; Oscarson, S. J. Org. Chem. 1996, 61, 1234–1238.
19. Ito, Y.; Ogawa, T. Carbohydr. Res. 1990, 202, 165–175.
25
20. Selected structural data for the iminodisaccharide 7. Yield: 77%; ½aꢂD
ꢀ65.5 (c 1.9, CH2Cl2). 1H NMR (500 MHz, CDCl3) d 7.45 (s, 1H,

J. Fuentes et al. / Tetrahedron Letters 49 (2008) 910–913
913
@CHN), 7.34-7.25 (m, 5H, Ph), 5.50 (d, 1H, J1 ;2 ¼ 5:1, H-10), 4.60 (s,
2H, PhCH2), 4.58–4.54 (m, 2H, H-4, H-30), 4.49 (d, 1H, J2,3 = 1.3,
2COOCH2CH3), 1.23 (s, 6H, C(CH3)2). 13C NMR (125.7 MHz,
CDCl3) d 167.6, 167.0 (2C@O), 149.6 (@CHN), 137.0, 128.6, 128.0,
127.8 (Ph), 110.9, 109.9, 108,7 (3 C(CH3)2), 96.5 (@C), 96.3 (C-10),
93.0 (C-2), 75.1 (C-3), 71.9, 71.8 (C-4 and CH2Ph), 71.2 (C-40), 70.8,
70.5 (C-5 and C-30), 70.0 (C-20), 67.1 (C-50), 66.2 (C-60), 61.1, 60.2
(2COOCH2CH3), 43.1 (C-6), 26.3, 26.2, 26.1, 25.0, 24.9, 24.6 (3
C(CH3)2), 14.5, 14.3 (2COOCH2CH3). HRFABMS m/z obsd
714.3107; calcd for C35H49NO13Na, 714.3102.
0
0
H-2), 4.34 (dd, 1H, J3,4 = 7.7, H-3), 4.31 (dd, 1H, J2 ;3 ¼ 2:5, H-20),
0
0
4.28 (m, 1H, H-5), 4.25, 4.15 (each q, each 2H, 2COOCH2CH3), 4.04
(dd, 1H, J3 ;4 ¼ 2:0, J4 ;5 ¼ 7:8, H-40), 3.84 (m, 1H, H-50), 3.64 (dd,
0
0
0
0
1H, J5 ;6 a ¼ 5:6, J6 a;6 b ¼ 10:0, H-60a), 3.49 (m, 2H, H-60b, H-6a),
3.25 (t, 1H, J5,6b = 10.7, J6a,6b = 10.7, H-6b), 1.56, 1.49, 1.44, 1.43
(each s, each 3H, 2C(CH3)2), 1.32, 1.23 (each t, each 3H,
0
0
0
0