J. Am. Chem. Soc. 1998, 120, 7137-7138
7137
Scheme 1
Assembly of Oligosaccharide Libraries with a
Designed Building Block and an Efficient Orthogonal
Protection-Deprotection Strategy
Chi-Huey Wong,* Xin-Shan Ye, and Zhiyuan Zhang
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed April 21, 1998
ReVised Manuscript ReceiVed June 9, 1998
The molecular diversity of oligosaccharides has been recog-
nized in their involvement in numerous important biochemical
recognitions.1 The efficient synthesis of oligosaccharides for the
study of their structure and function is, however, still a very
significant challenge for synthetic organic chemists.2 Recent
development in the field includes approaches such as one-pot
synthesis,3 enzymatic glycosylation,4 glycal strategy,5 and com-
binatorial chemistry.6 With regard to combinatorial carbohydrate
synthesis, a major problem is the lack of an efficient orthogonal
protection-deprotection strategy. To tackle this problem, we
describe here an effective library approach to oligosaccharides
using a designed building block with four selectively removable
protecting groups as the core for the source of acceptors and high-
yielding coupling with different donors. As illustrated in Scheme
1, we envisaged that if seven glycosyl donors are used in this
orthogonal strategy, the disaccharide library will have 56 com-
pounds generated after the first glycosylation. These disaccharides
can produce 168 acceptors from the core moiety, which, after
glycosylation with seven donors, will generate 1176 trisaccharides.
Following the same strategy, a library of 38 416 pentasaccharides
will be generated.
Scheme 2a
a Reagents and conditions: (a) NH2NH2/AcOH, THF/MeOH (10:1);
(b) NaHCO3, MeOH/H2O (5:1), 60 °C; (c) HF-pyridine, HOAc/THF
(1:4); (d) trifluoroacetic acid, CH2Cl2, -20 °C.
Scheme 3a
To demonstrate the feasibility of this strategy, the monosac-
charide building block 1 with four selectively removable protect-
ing groups was designed (Scheme 2). The four chosen protecting
groups, chloroacetyl (ClAc), p-methoxybenzyl (PMB), levulinyl
(Lev), and tert-butyldiphenylsilyl (TBDPS), can be selectively
removed in high yields with sodium bicarbonate, trifluoroacetic
acid, hydrazine, and hydrogen fluoride-pyridine, respectively,
a Reagents and conditions: (a) t-BuPh2SiCl, imidazole, DMF, 100%;
(b) i. Bu2SnO, toluene/benzene, reflux; ii. p-CH3OC6H4CH2Cl, Bu4NI,
DMF, 60 °C, 49%; (c) ClCH2COCl, Et3N, CH2Cl2, -20 °C to room
temperature, 52%; (d) levulinic acid, DCC, 4-DMAP, CH2Cl2, 83%; (e)
i. HO(CH2)5CO2Me, NIS, TMSOTf, 4 Å MS, CH3CN, -20 °C to room
temperature; ii. HgBr2, toluene/CH3NO2, 60 °C, 85%. DCC ) 1,3-
dicyclohexylcarbodiimide; 4-DMAP ) 4-(dimethylamino)pyridine; NIS
) N-iodosuccinimide; TMSOTf ) trimethylsilyl trifluoromethane-
sulfonate.
(1) Varki, A. Glycobiology 1993, 3, 97. Sears, P.; Wong, C.-H. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 12086.
(2) For recent reviews, see: Arya, P.; Ben, R. N. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1280. Paulsen, H. Angew. Chem., Int. Ed. Engl. 1995, 34,
1432.
(3) See, for example: (a) Douglas, N. L.; Ley, S. V.; Lu¨cking, U.; Warriner,
S. L. J. Chem. Soc., Perkin Trans. 1 1998, 51. (b) Geurtsen, R.; Holmes, D.
S.; Boons, G.-J. J. Org. Chem. 1997, 62, 8145. (c) Tsukida, T.; Yoshida, M.;
Kurokawa, K.; Nakai, Y.; Achiha, T.; Kiyoi, T.; Kondo, H. J. Org. Chem.
1997, 62, 6876. (d) Chenault, H. K.; Castro, A. Tetrahedron Lett. 1994, 35,
9145. (e) Yamada, H.; Harada, T.; Miyazaki, H.; Takahashi, T. Tetrahedron
Lett. 1994, 35, 3979. (f) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993,
115, 1580. (g) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc.
1994, 116, 7919.
using the conditions reported previously7 with slight modifications
to ensure that deprotection of each group in the presence of the
others is highly selective. The synthesis of 1 is illustrated in
Scheme 3. Starting from the thioglycoside 6, the four hydroxyl
groups were selectively protected to give 7, which was glycosyl-
ated with methyl 6-hydroxyhexanate to give 1.
(4) Takayama, S.; McGarvey, G. J.; Wong, C.-H. Chem. Soc. ReV. 1997,
26, 407.
(5) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380.
(6) Random glycosylation: (a) Kanie, O.; Barresi, F.; Ding, Y.; Labbe, J.;
Otter, A.; Forsberg, L. S.; Ernst, B.; Hindsgaul, O. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2720. (b) Ding, Y.; Kanie, O.; Labbe, J.; Palcic, M. M.; Ernst,
B.; Hindsgaul, O. AdV. Exp. Med. Biol. 1995, 376 (Glycoimmunology), 261.
(c) Ding, Y.; Labbe, J.; Kanie, O.; Hindsgaul, O. Bioorg. Med. Chem. 1996,
4, 683. Latent-active glycosylation: Boons, G.-J.; Heskamp, B.; Hout, F.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2845. Solid-phase method: Liang,
R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.;
Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.; Kahne,
D. Science 1996, 274, 1520.
(7) For previous deprotection of the ClAc group, see: Naruto, M.; Ohno,
K.; Naruse, N.; Takeuchi, H. Tetrahedron Lett. 1979, 251. For deprotection
of the PMB group, see: (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O.
Tetrahedron Lett. 1982, 885. (b) Johansson, R.; Samuelsson, B. J. Chem. Soc.,
Perkin Trans. 1 1984, 2371. For deprotection of the Lev group, see: van
Boom, J. H.; Burgers, P. M. J. Tetrahedron Lett. 1976, 4875. For deprotection
of the TBDPS group, see: Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis,
N. A. J. Org. Chem. 1979, 44, 4011. Nicolaou, K. C.; Seitz, S. P.; Pavia, M.
R. J. Am. Chem. Soc. 1981, 103, 1222.
S0002-7863(98)01361-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/03/1998