Facile sythesis of dioscin and its analogues

Article abstract of DOI:10.1246/cl.2005.1220

Three representative spirostanol saponins that have typical structure of the sugar moiety, diosgenyl 2,3-di-O-α-L-rhamnopyranosyl-β-D- glucopyranoside, diosgenyl 2,4-di-O-α-L-rhamnopyranosyl-β-D- glucopyranoside (dioscin), and diosgenyl 2,6-di-O-α-L-rhamnopyranosyl- β-D-glucopyranoside, were synthesized in a facile way. An approach to selectively mask the C₃-hydroxyl of diosgenyl 4,6-O-benzylidene β-D-glucopyranoside was described. A procedure using cerium(IV) ammonium nitrate for selective removal of tert-butyldimethylsilyl group while retaining levulinyl group is afforded. Copyright

Full text of DOI:10.1246/cl.2005.1220

1220
Chemistry Letters Vol.34, No.9 (2005)
Facile Sythesis of Dioscin and Its Analogues
Shujie Hou, Chuanchun Zou, Liang Zhou, Pingsheng Lei,ꢀ and Dequan Yu
Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences,
Beijing 100050, P. R. China
(Received June 1, 2005; CL-050706)
Three representative spirostanol saponins that have typical
tal and a catalytic amount of p-toluenesulfonic monohydrate in
DMF gave diosgenyl 4,6-O-benzylidene ꢁ-D-glucopyranoside.
The Lev group was introduced by reaction of diosgenyl 4,6-O-
benzylidene ꢁ-D-glucopyranoside with levulinic acid and DCC
in the presence of a catalytic amount of DMAP. The desired
compound 3-O-Lev 6 was afforded in a yield of 73%, although
it was quite difficult to selectively mask one of the hydroxyl
groups of the 2,3-diol of D-glucopyranose, especially when it
was in the ꢁ-form.7 NIS/TMSOTf mediate coupling of ethyl
2,3,4-tri-O-acetyl-1-thio-ꢀ-L-rhamnopyranose (7)8 with 6, gave
8 in a yield of 87%. It was anticipated that treatment with hydra-
zine acetate in CH2Cl2/MeOH would cleave the Lev without the
effect to other acetyl groups. Indeed, compound 8 was converted
into 9 within 2 h in a yield of 90%. Sugar receptor 9 was glyco-
sylated by 2,3,4-tri-O-acety-L-rhamnopyranosyl trichloroimi-
date (10)9 to give the protected diosgenyl trisaccharides 11 in
a yield of 92%. Treatment of 11 with 80% HOAc at 70 ꢁC for
5 h, then removal of all of the acetyl groups with MeONa
furnished 1 in a yield of 85%.
structure of the sugar moiety, diosgenyl 2,3-di-O-ꢀ-L-rhamno-
pyranosyl-ꢁ-D-glucopyranoside, diosgenyl 2,4-di-O-ꢀ-L-rham-
nopyranosyl-ꢁ-D-glucopyranoside (dioscin), and diosgenyl 2,6-
di-O-ꢀ-L-rhamnopyranosyl-ꢁ-D-glucopyranoside, were synthe-
sized in a facile way. An approach to selectively mask the C3-hy-
droxyl of diosgenyl 4,6-O-benzylidene ꢁ-D-glucopyranoside
was described. A procedure using cerium(IV) ammonium nitrate
for selective removal of tert-butyldimethylsilyl group while re-
taining levulinyl group is afforded.
Saponins, a structurally and biologically diverse class of
glycosides, are major component in traditional Chinese medi-
cines.1 The structure diversity of saponins lies mainly in their
sugar moieties.1 Many studies have disclosed that some biolog-
ical functions of saponins can be ascribed to the sapogenin and
some to the carbohydrate residue,2 for example diosgenyl gluco-
sides. Dioscin (2) displays cardiovascular and antitumor activi-
ties.3 Moreover, recent study had found that diosgenyl 2,3-di-
O-ꢀ-L-rhamnopyranosyl-ꢁ-D-glucopyranoside (1) also showed
stronger anticancer activity.4 In contrast to the difficulty in iso-
lation of homogeneous saponins from plants, chemical synthesis
would provide a realistic route to the availability of saponins.
Herein we report a facile way to synthesis dioscin, diosgenyl
2,3-di-O-ꢀ-L-rhamnopyranosyl-ꢁ-D-glucopyranoside and one
of their analogue (diosgenyl 2,6-di-O-ꢀ-L-rhamnopyranosyl-ꢁ-
D-glucopyranoside) (3).
With compound 8 in hand, dioscin (2) and diosgenyl 2,6-di-
O
O
O
O
O
O
O
O
BzO
BzO
b, c, d
O
a
4
Diosgenin
Ph
O
OH
OBz
O
SEt
OLev
OBz
5
6
e
AcO
OAc
OAc
7
In previous work, it was found that protected ethyl 1-thio-
glycosides under the promotion of NIS/TMSOTf could be cou-
pled with spirostanol sapogenins in excellent yields.5 Using this
method, diosgenin was glycosylated by ethyl 2,3,4,6-tetra-O-
benzoyl-1-thio-ꢁ-D-glucopyranoside (4)6 to give a protected di-
osgenyl glycosides 5 (Scheme 1). The hydrolysis of 5 gave dio-
sgenyl ꢁ-D-glucopyranoside2b in a yield of 92%. Treatment of
the diosgenyl monosaccharide with benzaldehyde dimethyl ace-
O
O
O
O
O
O
O
O
f
O
O
OAc
Ph
O
O
OAc
Ph
O
O
OLev
OH
OAc
O
OAc
OAc
O
OAc
8
9
O
O
OC(NH)CCl3
g
O
AcO
O
OAc
O
OAc
10
O
O
O
HO
HO
O
O
O
O
h
OH
O
O
O
OAc
Ph
O
O
O
OH
O
O
OH
OH
OAc
OAc
O
O
O
OH
R3O
R2O
OAc
OAc
HO
OH
OH
1
O
AcO
11
OR1
OH
O
Scheme 1. Reagents and conditions: (a) NIS-TMSOTf,
CH2Cl2, ꢂ15 ꢁC ! rt, 94%; (b) 1 mol/L NaOMe in MeOH, re-
flux, 92%; (c) PhCH(OMe)2, DMF, p-TsOH, (d) levulinic acid,
DCC, DMAP, CH2Cl2, rt, 73%; (e) NIS-TMSOTf, CH2Cl2,
1. R1 = α-L-rhamnopyranosyl, R2 = R3 = H;
2. R2 = α-L-rhamnopyranosyl, R1 = R3 = H;
3. R3 = α-L-rhamnopyranosyl, R1 = R2 = H;
ꢂ30 ꢁC ! rt, 87%; (f) H2NNH2–HOAc, CH2Cl2–MeOH, rt,
ꢁ
.
90%; (g) BF3 Et2O, CH2Cl2, ꢂ40 C ! rt, 92%; (h) 80%
HOAc, 5 h, 70 ꢁC and then MeONa, CH2Cl2–MeOH, rt, 85%.
Figure 1. The structure of dioscin and its analogues.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.9 (2005)
1221
O
O
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 20372085) is gratefully
acknowledged by the authors.
O
O
O
OC(NH)CCl3
OAc
+
O
O
AcO
O
O
b
a
HO
HO
TBDMSO
8
OAc
10
OAc
O
OAc
HO
O
References and Notes
1
OLev
OLev
OAc
O
O
OAc
OAc
c
O
K. Hostettmann and A. Marston, ‘‘Saponins,’’ Cambridge
University Press, New York (1995).
O
OAc
O
12
13
O
2
a) I. Khanna, R. Seshadri, and T. R. Seshadri, Indian J. Chem.,
13, 781 (1975). b) O. Espejo, J. C. Llavot, H. Jung, and F. Giral,
Phytochemistry, 21, 413 (1982). c) M. Miyamura, K. Nakanao,
T. Nohara, T. Tomimatsu, and T. Kawasaki, Chem. Pharm.
Bull., 30, 712 (1982). d) J. C. N. Ma and F. W. Lau, Phytochem-
istry, 24, 1561 (1985).
O
O
TBDMSO
O
d, e
O
O
OAc
O
O
HO
OLev
OH
OH
O
OAc
O
O
AcO
O
OAc
OH
OAc
OH
HO
O
OAc
OH
OH
14
2
O
O
3
4
Z. Wang, J. Zhou, and Y. Ju, Biol. Pharm. Bull., 24, 159 (2001).
Y. Mimaki, A. Yokosuka, M. Kuroda, and Y. Sashida, Biol.
Pharm. Bull., 24, 1286 (2001).
S. J. Hou, C. C. Zhou, P. S. Lei, and D. Q. Yu, Chin. Chem. Lett.,
16, 593 (2005).
Z. Pakulski, D. Pieroyski, and A. Zamojski, Tetrahedron, 50,
2975 (1994).
C. Li, B. Yu, M. Z. Liu, and Y. Z. Hui, Carbohydr. Res., 306,
189 (1998).
T. Fujiwara and K. Aria, Carbohydr. Res., 69, 305 (1979).
I. Kitagawa, N. I. Back, K. Ohashi, M. Sakagami, M.
Yoshikawa, and H. Shibuya, Chem. Pharm. Bull., 37, 1131
(1989).
O
O
O
OC(NH)CCl3
OAc
+
O
O
AcO
HO
AcO
f
O
O
5
6
7
TBDMSO
HO
OAc
10
OAc
O
OAc
O
OLev
OAc
OAc
O
O
OLev
c
OAc
O
O
O
15
OAc
13
O
O
O
O
O
e
O
O
OAc
AcO
OAc
O
O
O
AcO
8
9
OLev
OH
OAc
OAc
OAc
HO
OH
O
O
HO
OH
OH
OH
O
16
OH
3
10 T. W. Greene and P. G. M. Wuts, ‘‘Protective Groups in Organic
Synthiese,’’ 3rd ed., John Wiley & Sons, New York (1999).
11 a) S. V. Ankala and G. Fenteany, Tetrahedron Lett., 43, 4729
(2002). b) G. Bartoli, G. Cupone, R. Dalpozzo, A. De Nino,
L. Maiuolo, A. Procopio, L. Sambri, and A. Tagarelli, Tetrahe-
dron Lett., 43, 5945 (2002).
Scheme 2. Reagents and conditions: (a) 80% HOAc, 3 h, 80 ꢁC,
92%; (b) imidazole, DMAP, TBDMSiCl, DMF, rt, 93%; (c)
ꢁ
.
BF3 Et2O, CH2Cl2, ꢂ40 C ! rt, 58% for 14, 80% for 17;
(d) CAN, CH2Cl2–MeOH, rt, 95%; (e) 1 mol/L NaOMe in
MeOH, rt, 81% for 2, 89% for 3; (f) Ac2O, pyridine, rt, 5 h
and then 80% HOAc, 1 h, 70 ꢁC, 78%.
1
12 The spectral data of 1: H NMR (500 MHz, pyridine-d5): 5.86
(brs, 1H, H-1000), 5.79 (brs, 1H, H-100), 5.29 (d, J ¼ 4:5 Hz,
1H, H-6), 4.90–4.83 (m, 3H), 4.80–4.76 (m, 2H), 4.55–4.20
(m, 4H), 4.34–4.27 (m, 3H), 4.16 (t, J ¼ 8:5 Hz, 1H), 4.07–
4.03 (m, 2H), 3.91–3.87 (m, 1H), 3.79–3.77 (m, 1H), 3.58–
3.46 (m, 2H), 2.74–2.64 (m, 2H), 2.08–1.99 (m, 2H), 1.93 (m,
1H), 1.73 (d, J ¼ 6:0 Hz, 3H), 1.64 (d, J ¼ 5:5 Hz, 3H), 1.13
(d, J ¼ 7:0 Hz, 3H), 1.02 (s, 3H), 0.81 (s, 3H), 0.67 (d,
J ¼ 5:0 Hz, 3H). 13C NMR (75 MHz, pyridine-d5): 140.73,
121.81, 109.23, 103.84, 102.61, 99.86, 87.41, 81.09, 78.40,
78.08, 77.75, 73.80, 73.57, 72.81, 72.62, 72.51(2C), 70.58,
69.87, 66.84, 62.87, 62.24, 56.61, 50.24, 41.95, 40.44, 39.83,
38.64, 37.46, 37.10, 32.29, 32.20, 31.81, 31.66, 30.58, 30.04,
29.25, 21.08, 19.37, 18.66, 18.41, 17.31, 16.32, 15.02. ESI-
MS: 891.6 ðM þ NaÞþ. HRMS (FAB-MS): calcd for
C45H72O16Na ðM þ NaÞþ: 891.4718, found: 891.4725.
13 The spectral data of 2 as reported before: C.-C. Zou, S.-J. Hou,
Y. Shi, P.-S. Lei, and X.-T. Liang, Carbohydr. Res., 338, 721
(2003).
O-ꢀ-L-rhamnopyranosyl-ꢁ-D-glucopyranoside (3) were synthe-
sized as shown in Scheme 2. Treatment of 8 with 80% HOAc
at 80 ꢁC for 3 h provided compound 12 in a yield of 92%. In
0
the presence of imidazole, DMAP and TBDMSiCl, the C6 -OH
of 12 was selectively protected and gave compound 13 in a yield
of 93%. Though 2.0 equiv. TBDMSiCl of 12 had been used, the
0
product of silylation on C4 -OH was not found. Using compound
13 as sugar acceptor to couple with sugar donor 10, protected di-
osgenyl trisaccharide 14 was afforded in a yield of 58%. The low
yield of this glycosylation could be caused by the steric hin-
0
drance of the C4 -OH in 13. During the process of cleavage
TBDMS from 14 in the presence of TBAF in THF, the Lev group
was also removed off. The reason was probably contributed to
the unstability of Lev to Fꢂ caused by TBAF.10 Alternatively,
treatment with CAN11 in MeOH/CH2Cl2, TBDMS of 14 was
cleanly cleaved within 1 h and no loss of the Lev group was ob-
served. The hydrolysis of the intermediate using MeONa/
MeOH, dioscin (2) was produced in 76% yield of two steps. Ace-
tylation of 13 and then treatment with 80% HOAc at 80 ꢁC for
1 h, furnished 15 in a yield of 78% overall two steps. Glycosyla-
tion with sugar donor 10 provided compound 16. Deprotection
of acyl groups with MeONa, afforded target saponin 3 in a yield
of 89%.
In conclusion, regioselective protection C3-hydroxyl of
diosgenyl 4,6-O-benzylidene ꢁ-D-glucopyranoside by levulinyl
group enables compound 8 to be produced in a better yield.
Taken 8 as the synthon, three sugar acceptors 9, 13, and 15 were
gotten respectively in high yields. Therefore, dioscin and its
analogues were facilely prepared in satisfactory overall yields.
1
14 The spectral data of 3: H NMR (500 MHz, pyridine-d5): 6.35
(brs, 1H, H-1000), 5.48 (brs, 1H, H-100), 5.30 (d, J ¼ 4:5 Hz,
1H, H-6), 4.98–4.95 (m, 2H), 4.81 (d, J ¼ 3:5 Hz, 1H), 4.63–
4.61 (dd, J ¼ 3:5, 9.0 Hz, 1H), 4.59–4.48 (m, 4H), 4.37–4.32
(m, 2H), 4.24–4.16 (m, 2H), 4.06 (m, 1H), 3.97–3.92 (m, 2H),
3.59–3.48 (m, 3H), 2.80–2.70 (m, 2H), 2.22 (m, 1H), 1.77 (d,
J ¼ 6:5 Hz, 3H), 1.63 (d, J ¼ 6:0 Hz, 3H), 1.13 (d, J ¼ 7:0
Hz, 3H), 1.00 (s, 3H), 0.80 (s, 3H), 0.68 (d, J ¼ 5:0 Hz,
3H).13C NMR (75 MHz, pyridine-d5): 140.84, 121.63, 109.21,
102.41, 102.17, 100.83, 81.07, 79.53, 78.69, 78.01, 76.55,
74.06, 73.98, 72.79, 72.68, 72.51, 72.22, 71.80, 69.77, 69.51,
67.91, 66.81, 62.84, 56.52, 50.12, 41.91, 40.39, 39.79, 39.16,
37.45, 37.04, 32.17, 31.77, 31.61, 30.55, 30.33, 29.95, 29.57,
29.21, 21.02, 19.35, 18.64, 17.30, 16.29, 15.02. ESI-MS:
891.6 ðM þ NaÞþ, HRMS (FAB-MS): calcd for C45H72O16Na
ðM þ NaÞþ: 891.4718, found: 891.4697.
Published on the web (Advance View) July 30, 2005; DOI 10.1246/cl.2005.1220