Glycosylation reactions with 'disarmed' thioglycoside donors promoted by N-iodosuccinimide and HClO4-silica

Article abstract of DOI:10.1016/j.tetlet.2005.06.119

Glycosylation of 'disarmed' thioglycosides promoted by NIS in the presence of HClO₄ immobilized on silica compares very favourably with the accepted NIS-TfOH procedure.

Full text of DOI:10.1016/j.tetlet.2005.06.119

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5923–5925
Glycosylation reactions with ÔdisarmedÕ thioglycoside
donors promoted by N-iodosuccinimide and HClO4–silica
Balaram Mukhopadhyay, Beatrice Collet and Robert A. Field*
Centre for Carbohydrate Chemistry, School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
Received 8 May 2005; revised 20 June 2005; accepted 22 June 2005
Available online 11 July 2005
Abstract—Glycosylation of ÔdisarmedÕ thioglycosides promoted by NIS in the presence of HClO4 immobilized on silica compares
very favourably with the accepted NIS–TfOH procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
Understanding the role of glycosylation in biology is
highly dependent on the development of new chemical
glycosylation techniques to provide rapid, straightfor-
ward access to synthetic glycoconjugates.1 In the last
few years, remarkable improvements have been made
through orthogonal glycosylation strategies, reactivity
tuning methodologies based on ÔarmedÕ and ÔdisarmedÕ
glycosylation reagents2,3 and instrument-based auto-
mated glycosylation strategies.4 Of the building blocks
in common use, the stability and ease of handling of
thioglycosides makes them particularly attractive glyco-
syl donor agents.5 In the search for simpler, practical
chemistries for preparing oligosaccharides, we have
developed procedures for the efficient synthesis6 and
activation of thioglycosides.7 A key contribution to gly-
cosylation with thioglycosides was made in 1990 by van
Boom and co-workers,8 who first reported the use of N-
iodosuccinimide (NIS) in conjunction with triflic acid as
a promoter to activate ÔdisarmedÕ thioglycosides. The
same reagent combination was also introduced in 1990
by Fraser-Reid and co-workers for the activation of Ôdis-
armedÕ pentenyl glycosides;9 more recently, this work
was extended to explore ytterbium triflate in conjunction
with NIS for the activation of n-pentenyl orthoesters.10
The use of salts of strong acids in conjunction with N-
bromosuccinimide to activate thioglycosides has been
investigated by Kusumoto and co-workers.11 Recent re-
ports of the use of perchloric acid immobilized on silica
(HClO4–silica) as an effective acid catalyst for sugar
acetylation12 and Ferrier rearrangement of glycals13
drew us to investigate the application of this reagent in
combination with NIS for thioglycoside activation.14
Herein, we describe the use of HClO4–silica as a practi-
cal alternative to triflic acid for NIS-promoted glycosyl-
ation reactions with ÔdisarmedÕ thioglycosides.
Initial investigations,15–17 employing 1.1 mol equiv NIS
and ca. 80 mg of HClO4–silica per mmol of donor,
focused on the reaction of p-tolyl 2,3,4,6-tetra-O-ace-
tyl-b-D-thioglucopyranoside 1 with the primary alcohol
of methyl 2,3,4-tri-O-benzyl-a-D-glucopyranoside 5 in
dichloromethane at 0 °C. Reaction was essentially com-
plete within 1 h, affording the expected 1,2-trans-disac-
charide 8a in 82% yield after chromatographic
purification (Scheme 1). Control experiments with silica
replacing HClO4–silica showed no significant reaction
OAc
O
AcO
STol
AcO
OAc
O
OAc
1
+
AcO
AcO
NIS
HClO4-silica
O
OAc
BnO
BnO
O
OH
O
BnO
BnO
OMe
8a
BnO
BnO
OMe
5
Keywords: Glycosylation; Thioglycoside; NIS; Perchloric acid–silica.
*
Scheme 1. Thioglycoside glycosylation promoted by NIS/HClO4–
Corresponding author. Tel.: +44 1603 593983; fax: +44 1603
silica.
592003; e-mail: r.a.field@uea.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.119

5924
B. Mukhopadhyay et al. / Tetrahedron Letters 46 (2005) 5923–5925
Table 1. Results of NIS/HClO4 promoted glycosylation reactions with ÔdisarmedÕ thiglycoside donors
HO
BnO
BnO
BnO
BnO
BnO
HO
Acceptors
Donors
O
O
O
HO
BnO
BnO
BnO
BnO
OMe
OMe
OMe
6
7
5
AcO
O
AcO
STol
8a (82%)
9a (85%)
8b (81%)
9b (79%)
8c (83%)
9c (81%)
AcO
OAc
1
OAc
O
AcO
STol
AcO
OAc
2
AcO
OAc
O
AcO
AcO
10a (74%)
11a (87%)
10b (78%)
11b (80%)
10c (76%)
11c (85%)
STol
STol
3
Me
O
AcO
AcO
OAc
4
Yields in parentheses are those after chromatographic purification.
over 5 h, illustrating that silica is not itself sufficiently
acidic to activate NIS.
HO
BzO
OBz
AcO
AcO
OAc
O
O
Br
+
HO
AcO
O
STol
12
Looking more broadly, a series of NIS/HClO4–silica
promoted reactions were investigated with representa-
tive ÔdisarmedÕ thioglycoside donors 1–4 and a system-
atic series of glycosyl acceptors, 5–7. In all cases,
reactions gave excellent results, providing the expected
1,2-trans-linked disaccharides in 74–87% isolated yields
(Table 1).17 Reactions were typically complete in no
more than 1 h at ice-bath temperature, with reactions
employing the more reactive deoxyhexose (rhamnose)
donor 4 complete in ca. 1/2 h. In the case of the C-2
axial mannoside donor 3, isolated yields of the disaccha-
rides were somewhat lower due to formation of the
hemiacetal by hydrolysis of the orthoester intermediate
formed during the glycosylation reaction. Presumably
the greater inherent reactivity of the corresponding
rhamnoside overcomes this issue.
3
NIS
HClO4-silica
AcO
OAc
O
OAc
O
AcO
AcO
AcO
AcO
AcO
+
O
OBz
O
O
OBz
O
BzO
Br
O
BzO
O
Br
HO
O
AcO
AcO
O
OAc
14 (10%)
13 (72%)
AcO
NaN3
DMF
AcO
OAc
O
Extending to a one-pot double glycosylation, synthesis
of the N-linked glycan trimannoside core [3,6-di-O-(a-
D-mannopyranosyl)-a-D-mannopyranoside] in a form
suitable for conjugation to surfaces was investigated.
Reaction of acceptor 12 with 2.6 equiv of donor 3 affor-
ded trisaccharide 13 in 72% yield, along with 10% of the
1,6-linked disaccharide 14 (Scheme 2). Conversion of the
alkyl halide 13 to known azide 1518 was then effected
with NaN3 in DMF in good yield.
AcO
AcO
O
OBz
O
BzO
N3
O
O
O
AcO
AcO
15 (93%)
OAc
AcO
Scheme 2. Synthesis of a known18 protected derivative of the N-linked
glycan trimannoside core.
In conclusion, HClO4–silica in combination with N-iodo-
succinimide is a very effective promoter for 1,2-trans-
glycosylation reactions with ÔdisarmedÕ thioglycoside
donors. HClO4–silica is much easier to handle and
store than the triflic acid typically used for glycosylation
reactions of this nature.
Acknowledgements
We thank Dr. Alan Haines for valuable discussions dur-
ing the course of this work. This study was supported by

B. Mukhopadhyay et al. / Tetrahedron Letters 46 (2005) 5923–5925
5925
12. Misra, A. K.; Tiwari, P.; Madhusudan, S. K. Carbohydr.
Res. 2005, 340, 325–329.
13. (a) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem.
2004, 69, 6137–6140; (b) Misra, A. K.; Tiwari, P.;
Agnihotri, G. Synthesis 2005, 2, 260–266.
the BBSRC and UEA. We gratefully acknowledge the
EPSRC Mass Spectrometry Service Centre, University
of Wales, Swansea, for invaluable support.
14. For instance, this reagent system can be used for the
sequential, one-pot acetalation–acylation of sugars:
Mukhopadhyay, B.; Russell, D. A.; Field, R. A. Carbo-
hydr. Res. 2005, 340, 1075–1080.
15. HClO4–silica was prepared essentially as described previ-
ously,13a except that it was dried for 2 h at 110 ° C instead
of for 6 h.
References and notes
1. (a) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 2004,
59, 69–134; (b) Best Synthetic Methods: Carbohydrates;
Osborn, H. M. I., Ed.; Academic Press: London, 2003.
2. Reviewed in: Yu, B.; Yang, Z. Y.; Cao, H. Z. Curr. Org.
Chem. 2005, 9, 179–194.
3. (a) Baeschlin, D. K.; Green, L. G.; Hahn, M. G.; Hinzen,
B.; Ince, S. J.; Ley, S. V. Tetrahedron: Asymmetry 2000,
11, 173–197; (b) Kanie, O.; Ito, Y.; Ogawa, T. J. Am.
Chem. Soc. 1994, 116, 12073–12074; (c) Fraser-Reid, B.;
Udodong, U. E.; Wu, Z. F.; Ottosson, H.; Merritt, J. R.;
Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927–
942; (d) Veeneman, G. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 275–278.
4. (a) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Adv.
Carbohydr. Chem. Biochem. 2003, 58, 35–54; (b) Plante, O.
J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291,
1523–1527.
5. Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52,
179–205, and citations therein.
16. Typical glycosylation procedure:
a
mixture of
1
˚
(1.3 mmol), 6 (1 mmol) and 4 A MS in dry CH2Cl2
(20 mL) was cooled to 0 °C. NIS (1.5 mmol) was added
followed by HClO4–silica (100 mg) and stirring was
continued until complete consumption of 6 (TLC). The
mixture was filtered through CeliteÒ and the filtrate was
washed with aq Na2SO3 solution, aq NaHCO3 solution
and H2O. After drying and evaporation of the organic
layer, the crude product was purified by flash chromato-
graphy using n-hexane–EtOAc (2:1).
17. Known compounds gave analytical data consistent with
the literature: 5,19 6,20 7,21 8a,22 b23 and c9 and 9a,b.24 All
new compounds gave analytical data (1H, 13C NMR and
HRMS) consistent with the structures given.
18. Karamanska, R.; Mukhopadhyay, B.; Russell, D. A.;
Field, R. A. Chem. Commun. 2005, 3334–3336.
19. Pasti, C.; Rinaldi, E.; Cervellati, C.; Dallocchio, F.;
Hardre, R.; Salmon, L.; Hanau, S. Bioorg. Med. Chem.
2003, 11, 1207–1214.
6. Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.;
Field, R. A. J. Org. Chem. 2004, 69, 7758–7760.
7. (a) For instance: Cura, P.; Aloui, M.; Kartha, K. P. R.;
Field, R. A. Synlett 2000, 1279–1280; (b) Kartha, K. P. R.;
Aloui, M.; Field, R. A. Tetrahedron Lett. 1996, 37, 8807–
8810.
20. Dasgupta, F.; Anderson, L. Carbohydr. Res. 1990, 202,
239–255.
21. Koto, S.; Morishima, N.; Owa, M.; Zen, S. Carbohydr.
Res. 1984, 130, 73–84.
8. Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331–1334.
22. Schmidt, R. R.; Michel, J. Angew. Chem. 1980, 92, 763–
764.
23. Sakai, J.; Takeda, T.; Ogihara, Y. Carbohydr. Res. 1981,
95, 125–131.
9. Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-
Reid, B. J. Chem. Soc., Chem. Commun. 1990, 270–272.
10. Jayaprakash, K. N.; Radhakrishnan, K. V.; Fraser-Reid,
B. Tetrahedron Lett. 2002, 43, 6953–6955.
24. Poletti, L.; Rencurosi, A.; Lay, L.; Russo, G. Synlett 2003,
15, 2297–2300.
11. Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.;
Kusumoto, S. Tetrahedron 1995, 51, 4923–4932.