and also are the main sources of a traditional Chinese
medicine “Xiebai” for treatment of chest pain, stenocar-
dia, and heart asthma. Xiebai saponin I demonstrates
inhibitory activity on cyclic AMP phosphodiesterase with
an IC50 of 12.3 × 10-5 M and strong cytotoxic activity to
Hela cells at 50 µg/mL dose.9 Its inhibition on the
hypoxia/reoxygenation (H/R)-induced protein tyrosine
kinase activation and therefore protective effect on the
gap junctional intercellular communication injury were
also reported.10 Because saponins exist in plants in a
great heterogeneous manner, as glycoconjugates in mam-
mals, isolation of each component is a formidable task11
that has hampered the detailed biological and pharma-
cological studies of saponins. Chemical synthesis should
provide a realistic way to determine the availability of
homogeneous saponins, thus affording new opportunities
for understanding and applying this important group of
natural products. We have recently synthesized a number
of saponins,12 including dioscin,13 by using conventional
glycosylation methods, mainly with glycosyl trichloro-
acetimidate and thioglycoside donors. Here we focus our
Glycosyl Tr iflu or oa cetim id a tes. 2.
Syn th esis of Dioscin a n d Xieba i Sa p on in I
Biao Yu* and Houchao Tao
State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
byu@pub.sioc.ac.cn
Received J une 26, 2002
Abstr a ct: Two trisaccharide steroidal saponins, dioscin (1)
and Xiebai saponin I (2) with various bioactivities, were effi-
ciently synthesized using the newly developed glycosyl N-
phenyl trifluoroacetimidates (10-13) as glycosylation do-
nors. Thus, dioscin was synthesized in five steps and a 33%
overall yield from diosgenin and glycosyl trifluoroacetimi-
dates (10 and 11). Xiebai saponin I was synthesized in eight
steps and a 32% overall yield from laxogenin and glycosyl
trifluoroacetimidates (10, 12, and 13), whereupon, the rare
steroid laxogenin was prepared from diosgenin in four steps
and an overall 69% yield. All the glycosylation reactions
involved in the present syntheses demonstrated that glycosyl
trifluoroacetimidates were successful donors comparable to
the corresponding glycosyl trichloroacetimidates.
attention on the newly developed glycosyl trifluoroace-
14-16
timidate donors
in the synthesis of dioscin (1) and
Xiebai saponin I (2).
Dioscin, diosgenin-3-yl R-L-rhamnopyranosyl-(1f2)-[R-
L-rhamnopyranosyl-(1f4)]-â-D-glucopyranoside (1), which
has been isolated from a number of oriental vegetables
and traditionally medicinal plants, is one of the most
common saponins occurring in plants. The broad spec-
trum of bioactivities of dioscin, which demonstrates
moderate to good antitumor,1,2 antivirus,3 antifungal,4
and antiinflammatory,5-7 as well as immunostimulant
activities,8 has attracted great attention. In contrast,
Xiebai saponin I, laxogenin-3-yl R-L-arabinopyranosyl-
(1f6)-[â-D-xylopyranosyl-(1f4)]-â-D-glucopyranoside (2),
has been isolated only from the bulbs of Allium chinense,9
which are used as pickles and spices in China and J apan
(1) Inhibition of growth of various tumor cells with IC50 at the µM
level, see: (a) Hu, K.; Dong, A. J .; Yao, X. S.; Kobayashi, H.; Iwasaki,
S. Planta Med. 1996, 62 (6), 573. (b) Nakamura, T.; Komori, C.; Lee,
Y.-y.; Hashimoto, F.; Yahara, S.; Nohara, T.; Ejima, A. Biol. Pharm.
Bull. 1996, 19 (4), 564.
(2) Inhibition of DNA synthesis of C6 glioma cells at 10 mg/mL,
see: Chiang, H. C.; Tseng, T. H.; Wang, C. J .; Chen, C. F.; Kan, W. S.
Anticancer Res. 1991, 11 (5), 1911.
Saponins 1 and 2 have the aglycone of diosgenin and
laxogenin, respectively. While diosgenin is a bulk mate-
rial for manufacturing steroidal hormones and contra-
(3) Anti HSV-1 (herpes simlex virus type 1) activity with EC50
)
(9) (a) Kuroda, M.; Mimaki, Y.; Kameyama, A.; Sashida, Y.; Nikaido,
T. Phytochemistry 1995, 40 (4), 1071. (b) Baba, M.; Ohmura, M.; Kishi,
N.; Okada, Y.; Shibata, S.; Peng, J .; Yao, S.-S.; Nishino, H.; Okuyama,
T. Biol. Pharm. Bull. 2000, 23 (5), 660.
(10) (a) Zhang, Y.-W.; Morita, I.; Shao, G.; Yao, X.-S.; Murota, S.-I.
Planta Med. 2000, 66 (2), 114. (b) Zhang, Y.-W.; Morita, I.; Zhang, L.;
Shao, G.; Yao, X.-S.; Murota, S.-I. Planta Med. 2000, 66 (2), 119.
(11) Hostettmann, K.; Marston, A. Saponins; Cambridge University
Press: Cambridge, UK, 1995.
(12) (a) Yu, B.; Hui, Y. Chemical Synthesis of Bioactive Steroidal
Saponins. In Glycochemistry: Principles, Synthesis, and Application;
Wang, P. G., Bertozzi, C. R., Eds.; Marcel Dekker: New York, 2001; p
163. (b) Yu, B.; Xie, J .; Deng, S.; Hui, Y. J . Am. Chem. Soc. 1999, 121,
12196. (c) Yu, B.; Liao, J .; Zhang, J .; Hui, Y. Tetrahedron Lett. 2001,
42, 77.
(13) (a) Deng, S.; Yu, B.; Hui, Y.; Yu, H.; Han, X. Carbohydr. Res.
1999, 317, 53. (b) Deng, S.; Yu, B.; Hui, Y. Tetrahedron Lett. 1998, 39,
6511.
0.56 µg/mL, which is comparable to that of Acyclovir, see: Ikeda, T.;
Ando, J .; Miyazono, A.; Zhu, X.-H.; Tsumagari, H.; Nohara, T.;
Yokomizo, K.; Uyeda, M. Biol. Pharm. Bull. 2000, 23 (3), 363.
(4) Antifungal activity, see: (a) Takechi, M.; Shimada, S.; Tanaka,
Y. Phytochemistry, 1991, 30 (12), 3943. (b) Hufford, C. D.; Liu, S.; Clark,
A. M. J . Nat. Prod. 1988, 51 (1), 94.
(5) Inhibition of mouse ear edema at an oral dose of 100 mg/kg,
see: Kim, S. Y.; Son, K. H.; Chang, H. W.; Kang, S. S.; Kim, H. P.
Arch. Pharmacal Res. 1999, 22 (3), 313.
(6) Inhibitory effect on cyclic AMP phosphodiesterase, see: Mimaki,
Y.; Nakamura, O.; Sashida, Y.; Nikaido, T.; Ohmoto, T. Phytochemistry
1995, 38 (5), 1279.
(7) Inactivation of human pleural fluid phospholipase A2, see: Baek,
S. H.; Kim, S. H.; Son, K. H.; Chung, K. C.; Chang, H. W. Arch.
Pharmacal Res. 1994, 17 (4), 218.
(8) Increasing of 3H-thymidine incorporation of Con A-stimulated
lymphocytes maximally at 0.01 mg/mL, see: Chiang, H. C.; Wang, J .
J .; Wu, R. T. Anticancer Res. 1992, 12 (5), 1475.
(14) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
10.1021/jo026103c CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002
J . Org. Chem. 2002, 67, 9099-9102
9099