J. Liao et al. / Tetrahedron Letters 52 (2011) 3075–3078
3077
unambiguously confirmed by X-ray diffraction analysis of a single
crystal. This also confirmed the -configuration of the 12-OH
a
resulting from the reduction of the 12-carbonyl group in 11. In
contrast, similar reduction of the 12-carbonyl group in 3b-
hydroxy-20S-dammar-24-en-12-one, which has the 20-OH non-
glycosylated, was reported to provide mainly the corresponding
12-b-OH derivative.14(Fig. 1)
In the absence of a sugar residue on the 20-OH, the 3-O-acetyl
group in 9 could be removed easily (10% KOH, MeOH, rt) to provide
3,20-diol 14 in an excellent 90% yield (cf., 10?11; Schemes 2 and
3. Expectedly (cf., 4+5?6 and 9+5?10), glycosidic coupling of diol
14 with glucopyranosyl ortho-hexynylbenzoate 5 (4.0 equiv) under
the promotion of Ph3PAuNTf2 (0.4 equiv) afforded the desired 3,20-
O-bisglycoside 15 (H-10: 4.83 ppm, J = 8.01 Hz; H-100: 5.04 ppm,
J = 8.40 Hz)15 in a good 70% yield. Removal of the benzoyl groups
on 15 (10% KOH, MeOH, rt) furnished the target chikusetsusapo-
nin-LT8 (2) in 80% yield. The 1H and 13C NMR data of the synthetic
compound are identical to those reported for the natural product.12
In summary, ginsenoside Rh2 and chikusetsusaponin-LT8, two
minor components of the dammarane type ginsenosides, were
concisely synthesized, in that efficient glycosylation of the damma-
rane derivatives was achieve with glycosyl ortho-alkynylbenzoate
as donor and Ph3PAuNTf2 as catalyst. The present synthetic ap-
proach shall provide an effective access to the relevant ginsenoside
congeners which are of great pharmacological interest.
12
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (20902097 and 20932009) and the
National Basic Research Program of China (2010CB833202).
References and notes
13
1. Sticher, O. CHEMTECH 1998, 4, 26.
Figure 1. ORTEP drawings of protopanaxadiol 20-O-b-
D-glucoside derivatives 12
2. (a) Gillis, C. N. Biochem. Pharmacol. 1997, 54, 1; (b) Tang, W.; Eisenbrand, G. In
Chinese Drugs of Plant Origins; Springer: London, 1992. pp 711-737.
3. (a) Christensen, L. P. Adv. Food Nutr. Res. 2009, 55, 1; (b) Qi, L.-W.; Wang, C.-Z.;
Yuan, C.-S. Nat. Prod. Rep. 2011, 28, 467.
and 13.16
4. (a) Atopkina, L. N.; Denisenko, V. A.; Uvarova, N. I.; Elyakov, G. B. Carbohydr. Res.
1988, 177, 101; (b) Atopkina, L. N.; Uvarova, N. I.; Elyakov, G. B. Carbohydr. Res.
1997, 303, 449; (c) Anufriev, V. P.; Malinovskaya, G. V.; Denisenko, V. A.;
Uvarova, N. I.; Elyakov, G. B.; Kim, S.-I. I.; Beak, N.-I. Carbohydr. Res. 1997, 304,
179; (d) Hui, Y. -Z.; Yang, Z. -Q.; Liu, J. -Y.; Teng, J. -J.; Xie, H. -Q.; Zhang, J.
Chinese Patent, CN 1587273 A.
5. (a) Danieli, B.; Falcone, L.; Monti, D.; Riva, S.; Gebhardt, S.; Schubert-Zsilavecz,
M. J. Org. Chem. 2001, 66, 262; (b) Ko, S.-R.; Choi, K.-J.; Suzuki, K.; Suzuki, Y.
Chem. Pharm. Bull. 2003, 51, 404.
HO
O
10% KOH, MeOH,
rt, 90%
5
(4.0 eq)
9
PPh3AuNTf2 (0.4 eq),
CH2Cl2, -40oC-rt, 70%
HO
14
6. (a) Yu, B.; Sun, J. Chem. Aisa J. 2009, 4, 642; (b) Yu, B.; Zhang, Y.; Tang, P. Eur. J.
Org. Chem. 2007, 5145.
BzO
BzO
OBz
O
7. (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604; (b) Yang, Y.; Li, Y.; Yu,
B. J. Am. Chem. Soc. 2009, 131, 12076; (c) Yang, Y.; Li, Y.; Yu, B. Tetrahedron Lett.
2010, 51, 1504; (d) Li, Y.; Yang, X. Y.; Liu, Y. P.; Zhu, C. S.; Yang, Y.; Yu, B. Chem.
Eur. J. 2010, 16, 1871; (e) Yang, W.; Sun, J.; Lu, W.; Li, Y.; Shan, L.; Han, W.;
Zhang, W.-D.; Yu, B. J. Org. Chem. 2010, 75, 6879; (f) Li, Y.; Yu, B. Chem. Commun.
2010, 46, 6060.
8. (a) Beak, N. I.; Kim, D. S.; Lee, Y. H.; Park, J. D.; Lee, C. B.; Kim, S. I. Arch. Pharm.
Res. 1995, 18, 164; (b) Ota, T.; Fujikawa-Yamamoto, K.; Zong, Z.-P.; Yamazaki,
M.; Odashima, S. Cancer Res. 1987, 47, 3863; (c) Ota, T.; Meada, M.; Odashima,
S. J. Pharm. Sci. 1991, 80, 1141.
O
BzO
O
2
OBz
O
10% KOH, MeOH,
rt, 80%
BzO
BzO
O
BzO
15
9. (a) Cui, J.-F.; Byström, S.; Eneroth, P.; Björkhem, I. J. Org. Chem. 1994, 59, 8251;
(b) Hui, Y.-Z.; Liu, J.-Y.; Yang, Z.-Q.; Teng, J.-J. Chinese patent, CN 1569882A.
10. Yahara, S.; Tanaka, O.; Nishioka, I. Chem. Pharm. Bull. 1978, 26, 3010.
11. Atopkina, L. N.; Malinovskya, G. V.; Elyakov, G. B.; Uvarova, N. I.; Woerdenbag,
H. J.; Koulman, A.; Pras, N.; Potier, P. Planta Med. 1999, 65, 30.
12. (a) Atopkina, L. N.; Denisenko, V. A. Chem. Nat. Compd. 2006, 42, 55; (b)
Atopkina, L. N.; Denisenko, V. A. Chem. Nat. Compd. 2006, 42, 452.
13. Karikura, M.; Tanizawa, H.; Hirata, T.; Miyase, T.; Takino, Y. Chem. Pharm. Bull.
1992, 40, 2458.
Scheme 3. Synthesis of chikusetsusaponin-LT8 (2).
the 20-OH, this might account for the increased accessibility of the
20-OH in the 12-keto-protopanaxadiol derivatives (e.g., 9). The 12-
carbonyl group in 10 was found to be resistant to reduction with
NaBH4. Nevertheless, when the benzoyl groups on the sugar
residue were removed (i.e., in 11), the 12-carbonyl group was re-
duced smoothly to hydroxyl group under similar conditions
(NaBH4, MeOH, rt), leading to the corresponding 12-OH derivative
in 98% yield; subsequent acetylation (Ac2O, pyridine, rt) provided
13 with the 12-OH remaining intact.13 The structure of 13 was
14. Meng, J.; Zhao, L.; Hu, Y.; Chen, X.; Zhong, D. J. Label. Compd. Radiopharm. 2009,
52, 482.
15. Analytic data for compounds 6 and 15. Compound 6: ½a D25
ꢁ
16.5 (c 1.0, CHCl3), 1
H
NMR (400 MHz, CDCl3) d 8.04–7.82 (m, 8H), 7.68 (t, J = 7.6 Hz, 1H), 7.53–7.26
(m, 11H), 5.94 (t, J = 10.0 Hz, 1H), 5.59 (m, 2H), 5.15 (t, J = 7.2 Hz, 1H), 4.85–
4.80 (m, 2H), 4.62 (dd, J = 3.6, 12.0 Hz, 1H), 4.54 (dd, J = 8.0, 12.0 Hz, 1H), 4.18–
4.13 (m, 1H), 3.10 (dd, J = 4.0, 12.0 Hz, 1H), 2.90 (br, 1H), 2.23–0.60 (m, 55H);