A new, iterative strategy of oligosaccharide synthesis based on highly reactive β-bromoglycosides derived from selenoglycosides

Article abstract of DOI:10.1021/ol016713j

equation presented Stereoselective conversion of a selenoglycoside to a β-bromoglycoside in the absence of a glycosyl acceptor followed by the coupling with another selenoglycoside affords the corresponding glycosylated selenoglycoside, which could be dir

Full text of DOI:10.1021/ol016713j

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3867-3870
A New, Iterative Strategy of
Oligosaccharide Synthesis Based on
Highly Reactive â-Bromoglycosides
Derived from Selenoglycosides
Shigeru Yamago,* Takeshi Yamada, Osamu Hara, Hiroki Ito, Yosuke Mino, and
Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan
yamago@sbchem.kyoto-u.ac.jp
Received September 7, 2001
ABSTRACT
Stereoselective conversion of a selenoglycoside to a â-bromoglycoside in the absence of a glycosyl acceptor followed by the coupling with
another selenoglycoside affords the corresponding glycosylated selenoglycoside, which could be directly used for the next glycosylation. The
iteration of this sequence allows the synthesis of a variety of oligosaccharides including an elicitor active heptasaccharide.
Despite recent advances in synthetic carbohydrate chemistry,
efficient and high throughput synthesis of oligosaccharides
still remains a major challenge.1,2 Since the reactivity control
of anomeric substituents in glycosyl donors and acceptors
is difficult, conventional synthetic methodologies require
laborious protection-deprotection procedures that diminish
overall synthetic efficiency. To overcome this problem,
several glycosylation strategies, including the two-stage
activation method,3 armed-disarmed glycosylation,4 one-pot
synthesis,5 the orthogonal method,6 enzymatic glycosylation,7
the programmable one-pot strategy,8 and solid-phase syn-
thesis,9 have been recently developed.10,11
(3) Nicolaou, K. C.; Ueno, H. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Kekker, Inc.: New York, 1997; pp 313-338.
Nicolaou, K. C.; Bockovich, N. J.; Carcanague, D. R. J. Am. Chem. Soc.
1993, 115, 8843.
(4) (a) Mootoo, D. R.; Koradsson, P.; Udodong, U.; Fraser-Reid, B. J.
Am. Chem. Soc. 1988, 110, 5583. (b) Zuurmond, H. M.; van der Meer, P.
H.; van der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. J.
Carbohydr. Chem. 1993, 12, 1091. (c) Hashimoto, S.; Sakamoto, H.; Honda,
T.; Abe, H.; Nakamura, S.; Ikegami, S. Tetrahedron Lett. 1997, 38, 8969.
(5) (a) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580. (b)
Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc. 1994, 116, 7917.
Takahashi, T.; Adachi, M.; Matsuda, A.; Doi, T. Tetrahedron Lett. 2000,
41, 2599. (c) Douglas, N. L.; Ley, S. V.; Lu¨cking, U.; Warriner, S. J. Chem.
Soc., Perkin Trans. 1 1998, 51. (d) Tsukida, T.; Yoshida, M.; Kurokawa,
K.; Nakai, T.; Achiha, T.; Kiyoi, T.; Kondo, H. J. Org. Chem. 1997, 62,
6876.
* Email
for
second
corresponding
author:
yoshida@
sbchem.kyoto-u.ac.jp.
(1) For recent review articles on oligosaccharide synthesis, see: (a)
PreparatiVe Carbohydrate Chemistry; Hanessian, S.; Ed.; Marcel Kekker,
Inc.: New York, 1997. (b) Sears, P.; Wong, C.-H. Science 2001, 291, 2344.
(c) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349. (d) Koeller,
K. M.; Wong, C.-H. Chem. ReV. 2000, 100, 4465. (e) Herzner, H.; Reipen,
T.; Schltz, M.; Kunz, H. Chem. ReV. 2000, 100, 4495.
(2) (a) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239. (b) Zhang,
Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J.
Am. Chem. Soc. 1999, 121, 734.
(6) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073.
(7) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 521. Takayama, S.; McGarvey, G. J.; Wong,
C.-H. Chem. Soc. ReV. 1997, 26, 407.
10.1021/ol016713j CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

While the use of a single anomeric substituent both for
donors and acceptors is obviously desirable for ideal oli-
gosaccharide synthesis, only a few examples have been
reported so far, namely, the glycal assembly method.12,13 We
report here a new approach toward such strategy. 2-Acyl-
protected selenoglycopyranoside 1 was found to be converted
stereoselectively to the corresponding 1-â-bromoglycoside
2 upon treatment with Br2.14 While the reaction of halogly-
cosides with glycosyl acceptors usually requires activators,
e.g., heavy metal salts,15 we found that â-bromoglycoside 2
reacts smoothly with various glycosyl acceptors in the
absence of such activators.16 When a selenoglycoside is used
as an acceptor, the anomeric seleno group is retained in the
product. Therefore, the repetition of the reaction sequence
provides rapid construction of oligosaccharides. Thus, the
present approach provides a new, powerful strategy for
oligosaccharide synthesis.
Table 1. Glycosidation of Selenoglycosides
Figure 1. â-Bromoglycoside-mediated glycosylation.
The â-bromoglycoside 2a was found to be formed
quantitatively upon reaction of benzoyl-protected 1a (Ar )
Ph or Tol)17 in CH2Cl2 with Br2 (0.5 equiv) at -20 to 0 °C
for 30 min, and the arylselenyl moiety was converted to the
a Yield was based on the donor for entries 1, 2, 4, and 5, wherein a
slight excess of the acceptor was used (1.1 equiv for entries 1 and 2, and
1.5 equiv for entries 3 and 4) and on the acceptor for the rest, wherein a
slight excess of the donor was used (1.1 equiv for entry 6, and 1.5 equiv
for entries 3 and 7).
(8) Ye, X. S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410.
(9) Danishefsky, S. J.; McClure, K. F.; Randolph, J. T.; Ruggeri, R. R.
B. Science 1993, 260, 1307. 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. Seeberger,
P.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685. Plante, O. J.; Palmacci,
E. R.; Seeberger, P. H. Science 2001, 291, 1523.
(10) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1432. (b)
Boons, G.-J.; Tetrahedron 1996, 52, 1095.
(11) Steric and/or electronic tuning: (a) Mehta, S.; Pinto, M. Tetrahedron
Lett. 1991, 32, 4435. (b) Udodong, U. E.; Madsen, R.; Roberts, C.; Fraser-
Reid, B. J. Am. Chem. Soc. 1993, 115, 7886. (c) Geurtsen, R.; Coˆte´, F.;
Hahn, M. G.; Boons, J. J. Org. Chem. 1999, 64, 7828.
(12) Kim, H. M.; Kim, I. J.; Danishefsky, S. J. S. J. Am. Chem. Soc.
2001, 123, 35 and references therein.
(13) A new iterative glycosylation using 1-hydroxyl glycosides has been
reported very recently; see, Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew.
Chem., Int. Ed. 2001, 40, 414.
(14) While the synthesis and the reaction of acyl-protected â-bromogly-
cosides have been reported, little is known about their synthetic potential;
see, Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2199. Lemieux,
R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2214. See also: Paulsen, H.
Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(15) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(16) (a) Yamago, S.; Kokubo, K.; Yoshida, J. Chem. Lett. 1997, 111.
(b) Yamago, S.; Kokubo, K.; Murakami, H.; Mino, Y.; Hara, O.; Yoshida,
J. Tetrahedron Lett. 1998, 39, 7905.
corresponding diselenide as judged by the 77Se NMR of the
reaction mixture. The diselenide was also isolated and
identified after reaction with a glycosyl acceptor. The H
1
NMR experiments in CD2Cl2 revealed that the reaction was
extremely stereoselective (95-98% â-selective). Treatment
of 1a with 1 equiv of ArSeBr also afforded â-2a in
quantitative yield with high â-selectivity. Therefore, the
reaction of 1a with Br2 seems to involve initial formation of
2a and ArSeBr, which subsequently reacts with the remaining
1a to give 2a and the diselenide.18 Because of the mild
reaction conditions, isomerization of â-2a to the thermody-
namically more stable R-isomer was very slow (less than
10% of â-2a isomerized after 1 day at room temperature).
(17) Benhaddou, R.; Czernecki, S.; Randriamandimby, D. Synlett 1992,
967. Zuurmond, P. H.; van der Meer, P. H.; van der Klein, P. A. M.; van
der Marel, G. A.; van Boon, J. H. J. Carbohydr. Chem. 1993, 12, 1091.
(18) Krief, A.; Dumont, W.; Denis, J. N. J. Chem. Soc., Chem. Commun.
1980, 656.
3868
Org. Lett., Vol. 3, No. 24, 2001

The acetyl-protected selenoglycoside 1b also gave the
corresponding â-bromoglycoside 2b, whereas the benzyl-
protected 1c gave the R-isomer as the sole product (>97%
R-selectivity). Thioglycoside 5, however, gave the bromogly-
coside in 65% yield with 76% â-selectivity after 3 days at
room temperature.19 The â-bromoglycosides 2a and 2b
reacted with various glycosyl acceptors. Thus, treatment of
2a with MeOH (1.0 equiv) and 2,6-lutidine (1.0 equiv) in
CH2Cl2 afforded the ortho ester 3a (P ) Bz, R ) Me, R′ )
Ph) in quantitative yield. Tributylstannyl methyl ether20 also
reacted with 2a to give the ortho ester in quantitative yield.
It should be noted that â-fluoro- (8d), â-chloro- (8e), and
R-bromoglycosides were far less reactive than 2 under
identical conditions or even in the presence of Bu4NI.21
Treatment of the ortho ester with a catalytic amount of Me3-
SiOTf gave quantitatively the corresponding O-glycoside
(Table 1, entry 1).22
Scheme 1. Synthesis of Elicitor Active Heptasaccharidea
We next examined the use of the selenoglycoside as the
glycosyl acceptor, since the coupling of 2 with glycosyl
acceptors does not require any chemical activators that might
destroy the anomeric seleno group. The coupling of 1a with
C-6 hydroxyl or C-6 tributylstannyloxyl selenoglycoside (9ii
or 9iii23) proceeded smoothly, and the desired disaccharide
10 was obtained in good yield after in situ isomerization of
the initially formed ortho ester (entry 3). By repeating the
same reaction sequence, we synthesized tri- and tetrasac-
charides in good yields (entries 4 and 5). Because C-2 alkyl-
protected glycosides are more reactive than C-2 acyl-
protected glycosides, the former always acts as a donor and
the latter acts as an acceptor in the armed and disarmed
glycosylation strategy.4 The present strategy, however,
enables the use of a C-2 acyl-protected glycoside as a donor
and a C-2 alkyl-protected glycoside as an acceptor (entry
6). It is also noteworthy that galactose derivatives could be
used as glycosyl donors (entry 7).
a Reaction conditions: (a) 1b (1.5 equiv)/Br2 (0.75 equiv),
CH2Cl2, 0 °C, 0.5 h, then 7 (1.0 equiv), rt, 5 h; Ac2O (1.5 equiv),
Et3N (1.5 equiv), DMAP (0.1 equiv), rt, 0.5 h. (b) Me3SiOTf (0.1
equiv), CH2Cl2, 0 °C, 0.5 h, then H2O (10 equiv), rt, 0.5 h. (c)
C3H5SnBu3 (1.3 equiv), TfOH (0.3 equiv), CH2Cl2, rt, 2 h. (d) 6i
(1.2 equiv)/Br2 (0.6 equiv), CH2Cl2, 0 °C, 0.5 h, then 13ii rt, 10
min, and then Me3SiOTf (0.1 equiv), 0 °C, 0.5 h. (e) 5% aqueous
HF/MeCN/CH2Cl2, rt, 12 h. (f) 14i (1.0 equiv)/Br2 (0.5 equiv),
CH2Cl2, 0 °C, 0.5 h, then 6iii (1.2 equiv), rt, 10 min, and then
Me3SiOTf (0.1 equiv), 0 °C, 0.5 h. (g) 14i (2.0 equiv)/Br2 (1.0
equiv), CH2Cl2, 0 °C, 0.5 h, then 15iii (1.0 equiv), rt, 1 h, then
Me3SiOTf (0.1 equiv), 0 °C, 0.5 h. (h) Br2 (0.5 equiv), CH2Cl2, 0
°C, 0.5 h, then H2O (20 equiv), rt, 0.5 h. (i) H2 (50 atm), Pd(OH)2/
C, EtOH, 50 °C, 16 h then Ac2O (14 equiv), DMAP (2 equiv),
Et3N (20 equiv), CH2Cl2, rt, 16 h. (j) MeONa (25 equiv), MeOH,
rt, 0.5 h.
Figure 2. Substrates examined for the glycosylation.
7, acetylation of the C2 hydroxyl group, isomerization of
the ortho ester, and in situ hydrolysis of the benzylidene
acetal afforded 13ii in good combined yield. Stannyl ether
The utility of the current strategy has been demonstrated
in the synthesis of elicitor active heptasaccharide 16C24
(Scheme 1). Thus, activation of 1b with Br2, coupling with
(20) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworth: London, 1987; Chapter 11.
(21) Kartha, K. P. R.; Cura, P.; Aloui, M.; Readman, S. K.; Rutherford,
T. J.; Field, R. A. Tetrahedron: Asymmetry 2000, 11, 581. Horne, G.;
Mackie, W.; Tetrahedron Lett. 1999, 40, 8697. Allen, J. G.; Fraser-Reid,
B. J. Am. Chem. Soc. 1999, 121, 468.
(19) (a) Weygand, F.; Ziemann, H.; Bestmann, H. J. Chem. Ber. 1958,
91, 2534. (b) Kihlberg, J. O.; Leigh, D.; Bundle, D. R. J. Org. Chem. 1990,
55, 2860.
Org. Lett., Vol. 3, No. 24, 2001
3869

13iii derived from 13ii was coupled with the bromoglycoside
prepared from 6i to afford the trisaccharide 14i, which was
coupled with 6ii to give the tetrasaccharide 15i. Activation
of 14i by Br2 and subsequent coupling with 15iii derived
from 15i afforded the heptasaccharide 16A in good yield.
Treatment of 16A with Br2 followed by reaction with water,
deprotection of the silyl and benzyl groups, and subsequent
acetylation afforded per-acetylated glycoside 16B, which
easily hydrolyzed to 16C upon treatment with MeONa. Since
16A also possesses a selenoglycoside moiety, it can be used
for further elongation of oligosaccharides.
substituent both for glycosyl donors and acceptors. The
success of the present strategy is ascribed to the activation
of selenoglycosides to highly reactive â-bromoglycosides in
the absence of glycosyl acceptors. Further development of
this strategy is now under investigation.
Acknowledgment. This work was partly supported by
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan. We thank
Mr. H. Fujita and Ms. H. Ushitora of our department for the
measurement of NMR and MS spectra, respectively, and Dr.
H. Watanabe of Varian Japan Ltd. for the measurement of
NMR spectra.
In summary, we have developed a new iterative strategy
for the synthesis of oligosaccharides using a single anomeric
Supporting Information Available: Spectral data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) Wang, W.; Kong, F. J. Org. Chem. 1998, 63, 5744.
(23) Yamago, S.; Yamada, T.; Nishimura, J.; Ito, Y.; Mino, Y.; Yoshida,
J. Unpublished results.
(24) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F; J. Am.
Chem. Soc. 1997, 119, 449 and references therein.
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