Concise synthesis of two natural triterpenoid saponins, oleanolic acid derivatives isolated from the roots of Pulsatilla chinensis

Article abstract of DOI:10.1016/j.carres.2009.05.011

The first synthesis of two natural triterpenoid saponins, which were isolated from the roots of Pulsatilla chinensis and exhibited excellent in vitro cytotoxic activity against HL-60 cells, was concisely achieved in a convergent approach. We employed an o

Full text of DOI:10.1016/j.carres.2009.05.011

Carbohydrate Research 344 (2009) 1276–1281
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Concise synthesis of two natural triterpenoid saponins, oleanolic acid
derivatives isolated from the roots of Pulsatilla chinensis
*
Qingchao Liu, Peng Wang, Lei Zhang, Tiantian Guo, Guokai Lv, Yingxia Li
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2009
Received in revised form 11 May 2009
Accepted 12 May 2009
Available online 18 May 2009
The first synthesis of two natural triterpenoid saponins, which were isolated from the roots of Pulsatilla
chinensis and exhibited excellent in vitro cytotoxic activity against HL-60 cells, was concisely achieved in
a convergent approach. We employed an odourless 2-methyl-5-tert-butylphenyl (Mbp) thioglycoside and
trichloroacetimidate donors in one-pot reaction as a key step.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Triterpenoid saponins
HL-60 cells
Mbp thioglycoside
Trichloroacetimidates
One-pot reaction
1. Introduction
cially the development of a ‘one-pot sequential glycosylation’
strategy, has greatly facilitated the synthesis of oligosaccharides
Triterpenoid saponins, which are widely distributed in plants
and in some marine organisms,1–4 have been reported to present a
broad spectrum of well-defined biological and pharmacological
activities, including anti-tumour,5–12 anti-inflammatory,13 anti-fun-
gal,14–16 and anti-HIV.17–19 Attracted by these interesting biological
activities, several research groups have reported on the synthesis of
many oleanane-type triterpenoid saponins.20–28 Notably, the syn-
thesis of b-hederin, hederacolchiside A1 and its anologues with
prominent anti-tumour activity were reported by Cheng and co-
workers.29,30 Recently, we were attracted by two naturally occurring
and glycoconjugates bearing complicated sugar moieties.32–41 By
applying the ‘one-pot sequential glycosylation’ procedure, Yu and
co-workers have successfully completed the synthesis of a group
of natural dioscins and a bidesmosidic triterpene saponin.42–44
However, thiols (such as thioethanol, thiophenol and thiocresol)
utilized as precursors all have a repulsive smell, even far below
toxic concentrations. Recently, Mallet and co-workers have
successfully used the novel 2-methyl-5-tert-butylphenyl (Mbp)
thioglycosides as odourless precursors for oligosaccharide synthe-
sis.45 In light of these considerations, we decided to adopt the ‘one-
pot sequential glycosylation’ strategy with the combined use of
Mbp thioglycosides and trichloroacetimidates as donors to com-
plete the synthesis of the target molecules.
oleanane-type triterpenoid saponins: 3-O-[b-
(1?4)-b- -glucopyranosyl-(1?3)- -rhamnopyranosyl-(1?2)-
-arabinopyranosyl]oleanolic acid (1), and, 3-O-{b- -glucopyrano-
syl-(1?4)-b- -glucopyranosyl-(1?3)- -rhamnopyranosyl-(1?2)
-[b- -glucopyranosyl-(1?4)]- -arabinopyranosyl}oleanolic acid
D-glucopyranosyl-
D
a-L
a-L
D
D
a-L
The glycosyl donors involved in the synthesis are shown in
Scheme 1. Glycosyl trichloroacetimidates 346,47 and 448 were read-
ily prepared in good yields from the corresponding 1-OH sugars. In
our strategy, thioglycoside 8, a latent glycosyl donor for the next
D
a-L
(2) (Fig. 1), which were isolated from the roots of Pulsatilla chinensis
by Sashida and co-workers.31 These triterpenoid saponins show
prominent cytotoxic activity against HL-60 cells with an IC50 of
glycosylation, was prepared from 1,2,3,4-tetra-O-acetyl-a,b-L-
2.6 and 2.7
l
g/mL, respectively.31 Herein, we report the synthesis
rhamnopyranoside (5),49 in which the anomeric acetate group
was replaced by the MbpS group in the presence of BF3ꢀOEt2, fol-
lowed by deprotection of the hydroxyl groups to afford 2-
of the two natural saponins.
methyl-5-tert-butylphenyl 1-thio-a-L-rhamnopyranoside (7) in an
2. Results and discussion
excellent yield. Then according to the simple one-pot strategy,50
treatment of 7 with triethylorthoacetate and a catalytic amount
of p-toluenesulfonic acid (p-TsOH) formed the corresponding
orthoesters, which were directly acetylated in situ to protect the
remaining hydroxy group. Then the reaction mixture was diluted
with dichloromethane and shaken with 1 M HCl to effect orthoes-
The development of various glycosylation methods and sophis-
ticated approaches using protecting group manipulations, espe-
* Corresponding author. Tel.: +86 532 82032150; fax: +86 532 82033054.
E-mail address: liyx417@ouc.edu.cn (Y. Li).
0008-6215/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.carres.2009.05.011

Q. Liu et al. / Carbohydrate Research 344 (2009) 1276–1281
1277
Because of the abnormal ring conformation of the arabinose
residue, the 40-OH of 12 was in the equatorial position and
should have a higher reactivity than the 30-OH in the glycosyla-
tion, Cheng and co-workers have proved this point.30 Herein,
saponin 2 was further synthesized from the key intermediate
12
O
OH
28
R
O
3
O
O
HO
O
12, which was coupled with 2,3,4,6-tetra-O-benzoyl-a-D-gluco-
O
pyranosyl trichloroacetimidate (3) in anhydrous CH2Cl2 in the
presence of TMSOTf, regioselectively providing the correspond-
ing product 13 in 89% yield. The chemical shift of the C-40 chan-
ged from 71.8 ppm in 12 to 72.3 ppm in 13, while the chemical
shift of C-30 in both 12 and 13 is 69.5 ppm. Finally removal of
benzyl and benzoyl groups furnished saponin 2, whose analyti-
cal data are identical in all respects to those reported in the lit-
erature (Table 1).31
HO
O
HO
HO
O
OH
O
HO
HO
O
HO
HO
HO
Saponin 1 R = H
HO
O
Saponin 2 R =
HO
HO
HO
Figure 1. Structures of saponins 1 and 2.
In conclusion, an efficient and practical approach has been ap-
plied to the synthesis of triterpenoid saponins 1 and 2 with the
use of Mbp thioglycoside and trichloroacetimidate donors, a pro-
cess that should be of value in the synthesis of this kind of triter-
penoid saponins for further pharmacological research.
3. Experimental
3.1. General methods
Commercial reagents were used without further purification
unless specialized. Solvents were dried and redistilled prior to
use in the usual way. Thin-layer chromatography (TLC) was
performed on precoated E. Merck Silica Gel 60 F254 plates.
Flash column chromatography was performed on silica gel
(200–300 mesh, Qingdao, China). Melting points were deter-
mined on a Fisher–Johns apparatus and are uncorrected. Optical
rotations were determined with a Perkin–Elmer Model 241 MC
polarimeter. UV spectra were recorded on a Beckman DU 640
UV spectrophotometer. 1H NMR and 13C NMR spectra were ta-
ken on a JEOL JNM-ECP 600 spectrometer with tetramethylsil-
ane as the internal standard, and chemical shifts are recorded
in d values. Mass spectra were recorded on a Q-TOF Global
mass spectrometer.
Scheme 1. Synthesis of Mbp thioglycoside
trichloroacetimidates 3 and 4.
8 and the structure of glycosyl
ter rearrangement, affording the desired 2-methyl-5-tert-butyl-
phenyl 2,4-di-O-acetyl-1-thio- -rhamnopyranoside (8) in satis-
factory yield (77%, three steps).51
a
-L
With an efficient synthetic access to the key intermediate 8, we
next turned our attention to a ‘one-pot sequential glycosylation’
strategy for the efficient synthesis of natural saponins 1 and 2 uti-
lizing the Mbp thioglycosides and trichloroacetimidates as donors.
As depicted in Scheme 2, coupling of Mbp thioglycoside 8 with imi-
date 4 was completed within 45 min with the use of catalytic
amount of TMSOTf (0.2 equiv) at ꢁ78 °C, providing the desired tri-
saccharide Mbp thioglycoside donor. Without purification, the
reaction mixture was warmed to ꢁ10 °C, then saponin acceptor
10, which was readily derived from compound 9, was added, fol-
lowed by addition of N-iodosuccinimide (NIS) (2.0 equiv) and
TMSOTf (0.5 equiv), affording the fully protected saponin 11 in a
76% yield for two steps. Removing the isopropylidene of 11 with
the p-TsOH in CH2Cl2 and MeOH, intermediate 12 was achieved
in 97% yield. Interestingly, the arabinopyranosyl residue in 12
adopted a 1C4 conformation instead of the typical 4C1 form. This
conformational assignment was supported by a broad single peak
of the H-10 signal of arabinosyl moiety of 12. This phenomenon
was consistent with that reported in the literature.30 Removal of
the 28-O-benzyl group in 12 by hydrogenolysis in the presence
of Pd/C, followed by removal of the benzoyl groups on the sugar
residues with NaOMe in MeOH and CH2Cl2 afforded the expected
natural saponin 1 in satisfactory yields. The arabinopyranosyl moi-
ety returned to the normal 4C1 conformation, and this was sup-
3.2. 2-Methyl-5-tert-butylphenyl 2,3,4-tri-O-acetyl-1-thio-a-L-
rhamnopyranoside (6)
A mixture of 5 (2.00 g, 6.02 mmol) and 2-methyl-5-tert-butyl-
thiophenol (1.63 g, 9.03 mmol) was dissolved in CH2Cl2 (15 mL)
and the solution was cooled to 0 °C. To the solution was slowly
added BF3ꢀEt2O (6.37 mL, 30.1 mmol) under an N2 atmosphere.
The reaction mixture was warmed to rt and stirred for 1 h until
the starting material was consumed and the product 6 was formed.
The reaction mixture was diluted with CH2Cl2 (60 mL) and sequen-
tially washed with satd aq NaHCO3 (15 mL ꢂ 3), and satd aq NaCl
(15 ꢂ 2 mL). The organic phase was dried over Na2SO4, filtered
and concentrated. The residue was purified by silica-gel flash col-
umn chromatography (5:1–3:1 petroleum ether–EtOAc) to afford
6 as a white solid (2.34 g, 86%).
Rf 0.36 (4:1, petroleum ether–EtOAc); ½a D23
ꢁ79 (c 1.55, CHCl3);
ꢃ
IR (KBr) mmax 2973, 1747, 1365, 1217, 1050, 976, 894, 824,
746 cmꢁ1
.
1H NMR (CDCl3): d 7.53 (s, 1H, Harom), 7.23 (d, 1H, J 6.6 Hz, Har-
om), 7.15 (d, 1H, J 7.7 Hz, Harom), 5.52 (s, 1H, H-1), 5.30–5.35 (m, 2H,
H-2, H-4), 5.15 (t, 1H, J 9.9 Hz, H-3), 4.41 (dq, 1H, J 9.9, 5.5 Hz, H-5),
2.40 (s, 3H, CH3 thio), 2.15, 2.08, 2.02 (s each, 3H each, CH3CO ꢂ 3),
1.29 (s, 9H, t-Bu), 1.25 (d, 3H, J 5.5 Hz, H-6).
13C NMR (CDCl3): d 170.3, 170.2, 170.1, 150.0, 137.0, 132.2,
130.3, 130.1, 125.4, 85.5 (C-1), 71.8, 71.4, 69.7, 68.0, 34.6, 31.5,
21.2, 21.0, 20.9, 20.5, 17.6.
ported by the H-10 signal of arabinopyranosyl moiety of 1 (J1 ,2
0
0
5.9 Hz). The physical data for 1 are well in agreement with those
reported in the literature (Table 1).31

1278
Q. Liu et al. / Carbohydrate Research 344 (2009) 1276–1281
Scheme 2. Synthesis of target compounds 1 and 2 by two sequential glycosylation steps.
HRESIMS: m/z calcd for [M+Na+] C23H32NaO7S: 475.1766;
found: 475.1755.
3.4. 2-Methyl-5-tert-butylphenyl 2,4-di-O-acetyl-1-thio-
rhamnopyranoside (8)
a-L-
3.3. 2-Methyl-5-tert-butylphenyl 1-thio-
de (7)
a
-
L
-rhamnopyranosi-
To a solution of compound 7 (1.35 g, 4.14 mmol) in dry DMF
(15 mL), triethylorthoacetate (1.05 mL, 6.20 mmol) was added, fol-
lowed by a catalytic amount of camphorsulfonic acid (CSA, 191 mg,
0.83 mmol). The mixture was stirred for 4 h. After complete con-
version by thin-layer chromatography (TLC) (1:1 petroleum
ether–EtOAc), Et3N was added to neutralize the solution. Ac2O
(0.77 mL, 8.28 mmol), Et3N (1.76 mL, 12.4 mmol), and DMAP
(50 mg, 0.42 mmol) were added, and the mixture was allowed to
stir for 1 h at room temperature. When TLC (2:1, petroleum
ether–EtOAc) showed complete conversion, MeOH (0.5 mL) was
carefully added to destroy excess Ac2O, and the mixture was di-
luted with CH2Cl2 (80 mL). The organic layer was shaken with
1 M HCl (20 ꢂ 3 mL), followed by washing with satd aq NaHCO3
(20 ꢂ 3 mL) and water (20 ꢂ 3 mL). Finally the organic layer was
separated, dried over Na2SO4, filtered and concentrated. The crude
product was purified by silica gel column chromatography (6:1
petroleum ether–EtOAc) to give 8 (1.31 g, 77% three steps) as a
white solid.
A mixture of compound 6 (2.00 g, 4.42 mmol) and NaOMe
(0.16 g, 4.42 mmol) in MeOH (15 mL) was stirred at rt for 20 min.
The products 7 were detected on TLC (15:1 CH2Cl2–MeOH). After
completion of the reaction, the reaction mixture was treated with
Dowex H+ resin and filtered. After concentration, the residue was
purified by column chromatography on silica gel (20:1 CH2Cl2–
MeOH) to give 7 (1.41 g, 98%) as a white solid; Rf 0.36 (15:1
CH2Cl2–MeOH); ½a D23
ꢁ193 (c 1.50, CHCl3).
ꢃ
1H NMR (CDCl3, 500 MHz): d 7.56 (d, 1H, J 2.0 Hz, Harom), 7.24
(dd, 1H, J 7.6, 2.0 Hz, Harom), 7.14 (d, 1H, J 7.6 Hz, Harom), 5.41 (s,
1H, H-1), 4.27 (br s, 1H, H-2), 4.21 (t, 1H, J 9.6 Hz, H-4), 3.89 (br
s, 1H, H-4), 3.64 (m, 1H, H-5), 2.40 (s, 3H, CH3 thio), 1.30 (d, 3H, J
5.9 Hz, H-6), 1.28 (s, 9H, t-Bu).
13C NMR (CDCl3, 125 MHz): d 149.8, 136.4, 132.7, 129.9, 129.5,
127.2, 124.8, 87.5 (C-1), 73.7, 72.9, 72.4, 69.3, 34.5, 31.3, 31.2, 20.2,
19.5, 17.5.
Rf 0.28 (3:1 petroleum ether–EtOAc); ½a D23
ꢁ106 (c 1.65, CHCl3);
ꢃ
HRESIMS: m/z calcd for [M+Na+] C17H26NaO4S: 349.1450;
found: 349.1457.
IR (KBr) mmax 3498, 2957, 1747, 1377, 1225, 1101, 1050, 840,
778 cmꢁ1
.

Q. Liu et al. / Carbohydrate Research 344 (2009) 1276–1281
1279
Table 1
1H and 13C NMR of glycoside moieties of natural products 1 and 2 compared with synthesized compounds 1 and 2a
Position
1 (lit.)
1H (ppm) J (Hz)
1
J (Hz)
5.9
2 (lit.)
13C (ppm) 1H (ppm) J (Hz)
2
13C (ppm) 1H (ppm)
13C (ppm) 1H (ppm)
J (Hz)
13C (ppm)
105.2
10
4.83 d
6.1
105.2
75.7
74.4
69.2
65.6
4.84 d
105.8
4.70 d
6.6
105.3
76.1
74.3
69.9
65.2
4.70 d
4.44 dd
4.15–4.19 m
4.20–4.36 m
4.40 dd
6.4
8.5, 6.4
20
4.52 dd
4.22 m
4.23 m
4.29 dd
3.79 brd
6.18 d
7.0, 6.1
4.50–4.58 m
4.22–4.33 m
4.22–4.33 m
4.22–4.33 m
3.81 d
4.43 dd
4.16 dd
4.23 m
4.40 dd
3.74 br d
6.14 d
4.92 dd
4.74 dd
4.47 dd
4.63 dq
1.56 d
8.5, 6.6
8.5, 3.5
30
40
50-1
50-2
100
10.2, 3.9
10.2
0.8
11.2, 2.8
11.2
0.7
2.9, 0.7
9.4, 2.9
9.4, 9.4
9.4, 6.1
6.1
11.3, 2.9
11.3
10.6
3.75 br d
6.14 s
4.91 br s
4.74 dd
4.47 t
4.63 dq
1.56 d
5.42 d
4.08 dd
4.20–4.36 m
4.20–4.36 m
3.89–3.91 m
4.49–4.53 m
4.42 dd
101.6
71.7
83.5
73.0
69.7
18.4
106.5
75.5
76.6
81.1
6.19 s
4.97 br s
4.77 dd
4.50-4.58 m
4.62 dq
1.56 d
102.2
83.9
101.5
71.5
83.2
72.9
69.7
18.5
106.4
75.4
76.6
81.2
76.5
61.8
101.4
82.9
200
4.93 dd
4.75 dd
4.48 dd
4.62 dq
1.55 d
3.0, 0.8
9.5, 3.0
9.5, 9.5
9.5, 6.1
6.1
300
10.1, 3.7
9.4, 3.0
9.5
9.5, 6.0
6.0
7.9
9.0, 7.8
400
500
9.2,5.5
5.9
8.0
600
1000
2000
3000
4000
5000
5.43 d
7.9
5.45 d
106.8
105.5
5.42 d
7.9
106.3
104.9
106.5
4.09 dd
4.26 dd
4.36 dd
3.92 ddd
4.55 dd
4.40 dd
5.19 d
9.1, 7.9
9.1, 9.1
9.1, 9.1
4.11 t-like
4.22-4.33 m
4.36 t
8.7, 8.3
4.08 dd
4.25 dd
4.31 dd
3.92 ddd
4.53 dd
4.42 dd
5.15 d
9.1, 7.9
9.1, 9.1
9.1, 9.1
9.1,3.7,2.3
12.1, 3.7
12.1, 2.3
7.9
9.2
9.0,3.5,2.4
9.1, 3.6, 2.5 76.6
3.92 ddd
4.50–4.58 m
4.42 dd
6
6
000-1
000-2
12.0, 3.6
12.0, 2.5
7.9
61.8
12.4, 2.3
7.8
8.7, 8.3
12.0,2.3
7.9
9.0, 7.9
10000
105.0
74.7
78.2
71.5
5.20 d
104.9
74.7
78.2
71.4
5.15 d
4.06 dd
4.15–4.19 m
4.15–4.19 m
3.98 m
20000
4.07 dd
4.20 dd
4.16 dd
3.99 ddd
4.51 dd
4.27 dd
9.0, 7.9
9.0, 9.0
9.0, 9.0
9.0, 5.8, 2.4 78.4
11.8, 2.4
11.8, 5.8
4.07 t-like
4.22–4.33 m
4.17 t
4.05 dd
4.18 dd
4.15 dd
3.98 ddd
4.51 dd
4.26 dd
5.11 d
8.9, 7.9
8.9, 8.9
8.9, 8.9
30000
40000
9.2
9.1, 5.9, 25
50000
4.00 ddd
4.50–4.58 m
4.22–4.33 m
8.9, 5.7, 2.5 78.4
60000-1
62.4
11.7, 2.5
11.7, 5.7
7.8
62.4
4.49–4.53 m
4.20–4.36 m
5.11 d
6
0000-2
100000
106.5
75.4
78.4
71.2
78.7
62.5
7.7
8.7, 8.2
200000
4.02 dd
4.19 dd
4.21 dd
3.89 ddd
4.49 dd
4.35 dd
8.9, 7.8
8.9, 8.9
8.9, 8.9
8.9,5.1,2.5
11.9, 2.5
11.9, 5.1
4.02 dd
300000
4.15–4.19 m
4.15–4.19 m
4.20–4.36 m
4.49–4.53 m
4.20–4.36 m
400000
500000
600000-1
6
00000-2
a
Spectra were measured in pyridine-d5.
1H NMR (CDCl3): d 7.52 (d, 1H, J 2.2 Hz, Harom), 7.24 (dd, 1H, J
to give the fully protected saponin 11 (167 mg, 76% two steps) as
a white solid. The amounts of the reactants and the yields of the
saponin products were calculated based on saponin acceptor 10.
7.7, 2.2 Hz, Harom), 7.14 (d, 1H, J 7.7 Hz, Harom), 5.39 (d, 1H, J
1.4 Hz, H-1), 5.35 (dd, 1H, J 2.4, 1.5 Hz, H-2), 4.93 (t, 1H, J 9.9 Hz,
H-4), 4.36 (dq, 1H, J 9.9, 5.5 Hz, H-5), 4.06 (dd, 1H, J 9.9, 3.3 Hz,
H-3), 2.40 (s, 3H, CH3 thio), 2.17, 2.16 (s each, 3H each, CH3CO ꢂ 3),
1.29 (s, 9H, t-Bu), 1.24 (d, 3H, J 5.5 Hz, H-6).
½
a 2D3
ꢃ
+43.8 (c 2.50, CHCl3); Rf 0.31 (2:1 petroleum ether–EtOAc);
IR (KBr)
m
max 2938, 1735, 1451, 1264, 1089, 1066, 1023, 707 cmꢁ1
.
1H NMR (CDCl3): d 7.20–8.08 (m, 40H, Ph-H), 5.75 (t, 1H, J
9.2 Hz, H-30000), 5.70 (t, 1H, J 9.6 Hz, H-3000), 5.51 (t-like, 1H, J 9.2,
8.7 Hz, H-2000), 5.40 (t-like, 1H, J 9.2, 8.3 Hz, H-20000), 5.36 (t, 1H, J
9.6 Hz, H-4000), 5.32 (t, 1H, J 3.7 Hz, H-12), 5.25 (br s, 1H, H-200),
5.20 (s, 1H, H-100), 5.13 (d, 1H, J 12.4 Hz, PhCHH), 5.09 (d, 1H, J
13.0 Hz, PhCHH), 4.99 (t-like, 1H, J 10.1, 9.7 Hz, H-60000-1), 4.88 (d,
1H, J 7.8 Hz, H-1000), 4.73 (d, 1H, J 7.3 Hz, H-10000), 4.49 (m, 2H, H-
6000-1, H-60000-2), 4.28 (t-like, 1H, J 9.7, 9.2 Hz, H-40000), 4.15 (t, 1H, J
9.2 Hz, H-300), 4.13 (d, 1H, J 7.3 Hz, H-10), 4.07–4.10 (m, 1H, H-30),
4.01 (dd, 1H, J 12.4, 2.7 Hz, H-50-1), 3.95 (dd, 1H, J 11.5, 5.5 Hz,
H-6000-2), 3.91 (m, 1H, H-500), 3.68–3.71 (m, 4H, H-40, H-50-2, H-
5000, H-50000), 3.62–3.66 (m, 2H, H-20, H-400), 3.00 (dd, 1H, J 11.9,
4.6 Hz, H-3), 2.92 (dd, 1H, J 13.7, 3.7 Hz, H-18), 2.05, 1.96 (s each,
3H each, CH3CO ꢂ 2), 1.46, 1.42 (s each, 3H each, O-(CH3)2-O),
1.04 (d, 3H, J 6.0 Hz, H-600), 1.18, 0.94, 0.93, 0.92, 0.86, 0.72, 0.63
(s each, 3H each, CH3 ꢂ 7).
13C NMR (CDCl3): d 171.8, 170.7, 150.0, 137.0, 132.4, 130.3,
125.4, 85.6 (C-1), 75.1, 74.8, 69.5, 67.5, 34.6, 31.5, 31.4, 21.2,
20.5, 17.6;
HRESIMS: m/z calcd for [M+Na+] C21H30NaO6S: 433.1661;
found: 433.1644.
3.5. Benzyl 3-O-[2,3,4,6-tetra-O-benzoyl-b-
4)-2,3,6-tri-O-benzoyl-b- -glucopyranosyl-(1?3)-2,4-di-O-acetyl-
-rhamnopyranosyl-(1?2)-3,4-O-isopropylidene- -arabino-
pyranosyl]oleanolate (11)
D-glucopyranosyl-(1?
D
a
-
L
a-L
A solution of Mbp thioglycoside (8, 45 mg, 0.11 mmol) in CH2Cl2
(5 mL) and 4 Å MS (80 mg) was stirred at room temperature under
argon for 30 min, and then cooled to ꢁ78 °C. At this temperature, a
solution of TMSOTf (0.2 equiv) in dry CH2Cl2 was injected, and after
10 min a trichloroacetimidate 4 (280 mg, 0.23 mmol, 2.1 equiv) in
dry CH2Cl2 was added, respectively. The resulting mixture was stir-
red for additional 30 min and then warmed up to ꢁ10 °C. To the
above-mentioned mixture was added a solution of saponin accep-
tor 10 (79 mg, 0.11 mmol, 1.0 equiv) in CH2Cl2 (2 mL), followed by
NIS (50 mg, 0.11 mmol, 2.0 equiv). After stirring for 1 h, the reac-
tion was quenched with Et3N, and then filtered through a pad of
Celite. The filtrate was concentrated. The residue was purified by
silica gel column chromatography (3:1 petroleum ether–EtOAc)
13C NMR (CDCl3): d 177.6 (C-28), 170.2, 169.6, 165.7, 165.6,
165.5, 164.8, 164.7, 143.8 (C-13), 136.5, 133.5, 133.4, 133.3,
129.8, 128.6, 128.5, 128.4, 128.1, 122.6 (C-12), 110.3 (O–(CH3)2C–
O), 103.4 (C-10), 101.5 (C-10000), 101.2 (C-1000), 94.6 (C-100), 88.9 (C-
3), 78.8, 76.3, 75.9, 74.7, 73.3, 73.1, 72.9, 72.4, 72.0, 71.9, 69.4,
66.3, 66.0, 62.8, 62.6, 62.1, 60.5, 55.9, 47.7, 46.8, 46.0, 41.8, 39.4,
39.2, 38.7, 36.8, 33.9, 33.2, 32.8, 32.5, 30.8, 29.8, 28.1, 27.8, 26.2,
26.0, 23.8, 23.5, 23.2, 21.2, 21.0, 20.1, 18.4, 17.4, 17.0, 16.4, 15.4,
14.3.

1280
Q. Liu et al. / Carbohydrate Research 344 (2009) 1276–1281
HRMALDI-MS: m/z calcd for [M+Na]+ C116H128O30: 2023.8383;
found: 2023.8383.
12.7 Hz, PhCHH), 4.91 (t, 1H, J 9.9 Hz, H-400), 4.89 (d, 1H, J 7.7 Hz,
H-100000), 4.84 (d, 1H, J 1.1 Hz, H-100), 4.75 (d, 1H, J 7.7 Hz, H-1000),
4.68 (dd, 1H, J 12.1, 3.3 Hz, H-60000-1), 4.59 (d, 1H, J 10.4 Hz, H-50-
1), 4.44 (dd, 1H, J 12.1, 4.4 Hz, H-60000-2), 4.40 (d, 1H, J 3.9 Hz, H-
10), 4.37 (dd, 1H, J 12.7, 2.8 Hz, H-50-2), 4.29 (t, 1H, J 9.3 Hz, H-
4000), 4.19 (m, 1H, H-50000), 4.03 (m, 1H, H-40), 3.97–4.00 (m, 2H, H-
300, H-5000), 3.90 (m, 1H, H-500000), 3.70–3.74 (m, 2H, H-6000-1, H-
3.6. Benzyl 3-O-[2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl-(1?
4)-2,3,6-tri-O-benzoyl-b-
-rhamnopyranosyl-(1?2)-
(12)
D
-glucopyranosyl-(1?3)-2,4-di-O-acetyl-
a
-
L
a-L
-arabinopyranosyl]oleanolate
6
00000-1), 3.67–3.69 (m, 3H, H-30, H-50, H-6000-2), 3.62 (dd, 1H, J 5.5,
A mixture of compound 11 (150 mg, 0.075 mmol) and p-TsOH
(13 mg, 0.075 mmol) in 1:2 CH2Cl2–MeOH (6 mL) was stirred at
r.t. When TLC (3:2 petroleum ether–EtOAc) showed that deprotec-
tion had completed, Et3N (0.1 mL) was added, and the mixture was
concentrated and purified through a silica gel column chromatog-
raphy (2:1 petroleum ether–EtOAc) to afford 12 (142 mg, 97%) as a
white solid.
3.8 Hz, H-20), 3.54 (dd, 1H, J 12.1, 3.8 Hz, H-600000-2), 2.96 (dd, 1H,
J 11.5, 4.4 Hz, H-3), 2.90 (dd, 1H, J 15.4, 5.5 Hz, H-18), 2.04, 1.90
(s each, 3H each, CH3CO ꢂ 2), 0.96 (d, 3H, J 6.1 Hz, H-600), 1.11,
0.92, 0.90, 0.84, 0.82, 0.67, 0.58 (s each, 3H each, CH3 ꢂ 7).
13C NMR (CDCl3): d 177.7 (C-28), 170.1, 169.6 (CH3CO), 166.0,
165.9, 165.8, 165.4, 165.0, 143.9 (C-13), 136.6, 133.7, 133.4,
130.0, 128.7, 128.6, 128.5, 128.4, 122.7 (C-12), 102.7 (C-10), 101.6
(C-10000), 101.2 (C-100000), 101.1 (C-1000), 97.2 (C-100), 90.2 (C-3), 75.8,
75.4, 73.0, 72.5, 72.4, 72.3 (C-40), 72.2, 72.1, 72.0, 71.0, 69.9, 69.5
(C-30), 66.7, 66.1, 63.1, 62.7, 61.9, 55.8, 47.8, 46.9, 41.9, 41.6,
39.5, 39.2, 36.8, 33.3, 30.9, 29.9, 28.2, 26.1, 25.9, 23.9, 23.2, 21.0,
17.4, 17.0, 16.5, 15.5, 14.4.
½
a 2D2
ꢃ
+31.1 (c 3.20, CHCl3); Rf 0.18 (2:1 petroleum ether–EtOAc);
IR (KBr) mmax 2933, 1726, 1448, 1255, 1083, 705 cmꢁ1
.
1H NMR (CDCl3): d 7.28–8.04 (m, 40H, Ph-H), 5.74 (t, 1H, J
9.3 Hz, H-30000), 5.70 (t, 1H, J 9.4 Hz, H-3000), 5.50 (dd, 1H, J 9.4,
8.8 Hz, H-2000), 5.33–5.39 (m, 2H, H-20000, H-4000), 5.28 (t, 1H, J
3.8 Hz, H-12), 5.18 (br s, 1H, H-200), 5.10 (d, 1H, J 12.6 Hz, PhCHH),
5.06 (d, 1H, J 12.7 Hz, PhCHH), 4.96 (t, 1H, J 9.9 Hz, H-400), 4.91 (s,
1H, H-100), 4.90 (d, 1H, J 8.8 Hz, H-10000), 4.80 (d, 1H, J 7.7 Hz, H-
1000), 4.62 (br s, 1H, H-10), 4.58 (dd, 1H, J 12.1, 2.3 Hz, H-50-1),
4.42 (dd, 1H, J 12.1, 1.8 Hz, H-50-2), 4.26 (t, 1H, J 9.4 Hz, H-40000),
3.98–4.02 (m, 2H, H-300, H-6000-1), 3.84 (m, 1H, H-5000), 3.69–3.80
(m, 7H, H-20, H-30, H-40, H-500, H-50000, H-60000-1, H-60000-2), 3.55 (dd,
1H, J 12.1, 4.4 Hz, H-6000-2), 3.04 (dd, 1H, J 11.4, 3.7 Hz, H-3), 2.91
(dd, 1H, J 14.4, 4.1 Hz, H-18), 1.91, 1.90 (s each, 3H each,
CH3CO ꢂ 2), 1.02 (d, 3H, J 6.1 Hz, H-600), 1.11, 0.92, 0.89, 0.89,
0.86, 0.75, 0.59 (s each, 3H each, CH3 ꢂ 7).
3.8. 3-O-[b-
-rhamnopyranosyl-(1?2)-
acid (1)
D
-Glucopyranosyl-(1?4)-b-
D-glucopyranosyl-(1?3)-
a-L
a-L
-arabinopyranosyl]oleanolic
A mixture of 12 (60 mg, 0.03 mmol) and 10% Pd–C (30 mg) in
1:1 CH2Cl2–MeOH (8 mL) in the presence of AcOH (two drops)
was stirred under 1 atm of H2 for 4 h. The reaction mixture was
then filtered, and the filtrate was concentrated to dryness to give
a white solid. The solid was dissolved in 2:1 MeOH–CH2Cl2
(8 mL), and then NaOMe (40 mg) was added. After stirring at rt
for 8 h, the solution was neutralized with ion-exchange resin
(H+), then filtered and concentrated. The residue was purified by
column chromatography on silica gel (3:1 CHCl3–MeOH) to give
1 (25 mg, 79% two steps) as a white solid.
13C NMR (CDCl3): d 177.5 (C-28), 170.1, 169.5, 165.9, 165.8,
164.8, 144.0 (C-13), 136.5, 133.3, 129.8, 129.7, 129.5, 129.3,
128.6, 128.5, 128.4, 128.3, 128.1, 122.5 (C-12), 101.9 (C-10), 101.2
(C-1000), 101.0 (C-10000), 98.0 (C-100), 90.4 (C-3), 75.8, 75.7, 72.9,
72.4, 72.0, 71.8 (C-40), 71.5, 69.5 (C-30), 66.9, 66.0, 62.7, 55.5,
47.7, 46.8, 46.0, 41.8, 41.5, 39.4, 39.1, 38.6, 36.8, 33.9, 33.2, 32.6,
32.4, 30.8, 29.8, 28.2, 28.0, 25.9, 25.8, 23.7, 23.4, 23.1, 20.9, 20.2,
18.3, 17.4, 16.9, 16.5, 15.4.
Mp 235–237 °C; ½a D25
ꢁ5.85 (c 0.60, 1:1 CHCl3–MeOH); Rf 0.23
ꢃ
(2:1, CHCl3–MeOH); IR (KBr) mmax 3401, 2941, 1696, 1649, 1381,
1073 cmꢁ1
.
1H NMR (C5D5N): d 6.19 (s, 1H, H-100), 5.49 (t, 1H, J 3.6 Hz, H-12),
5.45 (d, 1H, J 8.0 Hz, H-1000), 5.20 (d, 1H, J 7.8 Hz, H-10000), 4.97 (br s,
1H, H-200), 4.84 (d, 1H, J 5.9 Hz, H-10), 4.77 (dd, 1H, J 10.1, 3.7 Hz, H-
300), 4.62 (dq, 1H, J 9.2, 5.5 Hz, H-500), 4.50–4.58 (m, 4H, H-20, H-400,
H-6000-1, H-60000-1), 4.42 (dd, 1H, J 12.4, 2.3 Hz, H-6000-2), 4.36 (t, 1H, J
9.2 Hz, H-4000), 4.22–4.33 (m, 6H, H-30, H-40, H-50-1, H-3000, H-30000, H-
HRMALDI-MS: m/z calcd for [M+Na]+ C113H124O30: 1983.8065;
found: 1983.8070.
3.7. Benzyl 3-O-{2,3,4,6-tetra-O-benzoyl-b-
4)-2,3,6-tri-O-benzoyl-b- -glucopyranosyl-(1?3)-2,4-di-O-acetyl-
-rhamnopyranosyl-(1?2)-[2,3,4,6-tetra-O-benzoyl-b- -gluco-
pyranosyl-(1?4)]- -arabinopyranosyl}oleanolate (13)
D-glucopyranosyl-(1?
D
a-L
D
6
0000-2), 4.17 (t, 1H, J 9.2 Hz, H-40000), 4.11 (t-like, 1H, J 8.7, 8.3 Hz, H-
a-L
2000), 4.07 (t-like, 1H, J 8.7, 8.3 Hz, H-20000), 4.00 (ddd, 1H, J 9.1, 5.9,
2.5 Hz, H-50000), 3.92 (ddd, 1H, J 9.0, 3.5, 2.4 Hz, H-5000), 3.81 (d, 1H,
J 10.6 Hz, H-50-2), 3.29–3.31 (m, 2H, H-3, H-18), 1.56 (d, 3H, J
5.9 Hz, H-600), 1.33, 1.32, 1.14, 1..03, 0.98, 0.97, 0.85 (s each, 3H
each, CH3 ꢂ 7).
A mixture of compound 12 (100 mg, 0.05 mmol), 4 Å molecular
sieves (150 mg) and compound 3 (40 mg, 0.06 mmol) in dry CH2Cl2
(5 mL) was stirred at rt under argon for 30 min then cooled to
ꢁ30 °C. TMSOTf (5
lL, 0.03 mmol) was added, and the reaction
13C NMR (C5D5N): d 180.4 (C-28), 145.4 (C-13), 123.2 (C-12),
106.8 (C-1000), 105.8 (C-10), 105.5 (C-10000), 102.2 (C-100), 89.2 (C-3),
83.9 (C-300), 81.6, 79.0, 78.8, 77.2, 76.2, 75.9, 75.3, 73.4, 72.2, 72.0,
70.3, 69.7, 66.1, 62.9, 62.3, 56.5, 48.6, 47.3, 42.7, 42.5, 40.3, 40.1,
39.4, 37.6, 34.8, 33.8, 33.7, 31.5, 28.9, 28.7, 27.2, 26.7, 24.3, 19.0,
18.0, 17.7, 16.1.
mixture was stirred for 30 min and then warmed to rt. The product
13 was detected on TLC (3:2 petroleum ether–EtOAc). After com-
pletion of the reaction, the reaction mixture was quenched with
Et3N (0.1 mL), diluted with CH2Cl2 (10 mL) and filtered. After con-
centration, the residue was purified by column chromatography on
silica gel (2:1 petroleum ether–EtOAc) to give 13 (112 mg, 89%) as
a white solid.
HRESIMS: m/z calcd for C53H85O21 [MꢁH+]: 1057.5583; found:
1057.5582.
½
a 2D2
+28.9 (c 1.35, CHCl3); Rf 0.25 (2:1 petroleum ether–EtOAc);
ꢃ
IR (KBr)
m
max 3400, 2930, 1731, 1451, 1264, 1093, 1023, 704 cmꢁ1
.
3.9. 3-O-{b-
-rhamnopyranosyl-(1?2)-[b-
binopyranosyl}oleanolic acid (2)
D
-Glucopyranosyl-(1?4)-b-
D
-glucopyranosyl-(1?3)-
1H NMR (CDCl3): d 7.25–8.04 (m, 60H, Ph-H), 5.94 (t, 1H, J
9.9 Hz, H-30000), 5.74 (t, 1H, J 9.4 Hz, H-3000), 5.68 (t, 1H, J 9.9 Hz,
H-40000), 5.67 (t, 1H, J 9.4 Hz, H-300000), 5.52 (dd, 1H, J 9.9, 8.3 Hz, H-
a-L
D-glucopyranosyl-(1?4)]-a-L
-ara-
2
0000), 5.47 (dd, 1H, J 9.9, 7.7 Hz, H-200000), 5.35 (m, 2H, H-2000, H-400000),
A mixture of 13 (50 mg, 0.02 mmol) and 10% Pd–C (25 mg) in
CH2Cl2–MeOH (V:V/1:1, 8 mL) in the presence of AcOH (2 drops)
was stirred under 1 atm of H2 for 4 h. The reaction mixture was
5.28 (t, 1H, J 3.6 Hz, H-12), 5.13 (dd, 1H, J 3.3, 1.7 Hz, H-200), 5.10 (d,
1H, J 12.6 Hz, PhCHH), 5.08 (d, 1H, J 7.7 Hz, H-10000), 5.06 (d, 1H, J

Q. Liu et al. / Carbohydrate Research 344 (2009) 1276–1281
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then filtered and the filtrate was concentrated to dryness to give a
white solid. The solid was dissolved in MeOH–CH2Cl2 (V:V/2:1,
8 mL), and then NaOMe (40 mg) was added. After stirring at rt
for 8 h, the solution was neutralized with ion-exchange resin
(H+), then filtered and concentrated. The residue was purified by
column chromatography on silica gel (1:1, CHCl3–MeOH) to give
2 (19 mg, 76% two steps) as a white solid.
Mp 246–248 °C; ½a D25
ꢁ7.52 (c 0.60, 1:1 CHCl3–CH3OH); Rf 0.21
ꢃ
(1:1 CHCl3–MeOH); IR (KBr) mmax 3412, 2930, 1692, 1505,
1077 cmꢁ1
.
1H NMR (C5D5N, 500 MHz): d 6.14 (s, 1H, H-100), 5.46 (t, 1H, J
3.0 Hz, H-12), 5.42 (d, 1H, J 7.9 Hz, H-1000), 5.15 (d, 1H, J 7.9 Hz,
H-10000), 5.11 (d, 1H, J 7.7 Hz, H-100000), 4.91 (br s, 1H, H-200), 4.74
(dd, 1H, J 9.4, 3.0 Hz, H-300), 4.70 (d, 1H, J 6.4 Hz, H-10), 4.63 (dq,
1H, J 9.5, 6.0 Hz, H-500), 4.49–4.53 (m, 3H, H-6000-1, H-60000-1, H-
6
00000-1), 4.47 (t, 1H, J 9.5 Hz, H-400), 4.44 (dd, 1H, J 8.5, 6.4 Hz, H-
20), 4.42 (dd, 1H, J 12.0, 2.3 Hz, H-6000-2), 4.40 (dd, 1H, J 11.3,
2.9 Hz, H-50-1), 4.20–4.36 (m, 6H, H-3000, H-40, H-4000, H-500000, H-
6
0000-2, H-600000-2), 4.15–4.19 (m, 4H, H-30, H-30000, H-40000, H-400000),
4.08 (dd, 1H, J 9.0, 7.8 Hz, H-2000), 4.06 (dd, 1H, J 9.0, 7.9 Hz, H-20000),
4.02 (dd, 1H, J 8.7, 8.2 Hz, H-20000), 3.98 (m, 1H, H-50000), 3.89–3.91
(m, 2H, H-5000, H-500000), 3.75 (br d, 1H, J 11.3 Hz, H-50-2), 3.24 (dd,
1H, J 11.5, 4.2 Hz, H-3), 3.20 (dd, 1H, J 13.7, 3.7 Hz, H-18), 1.56
(d, 3H, J 6.0 Hz, H-600), 1.29, 1.29, 1.12, 1.00, 0.97, 0.95, 0.82 (s each,
3H each, CH3 ꢂ 7).
13C NMR (C5D5N, 125 MHz): d 180.1 (C-28), 144.8 (C-13), 122.5
(C-12), 106.5 (C-100000), 106.3 (C-1000), 105.2 (C-10), 104.9 (C-10000),
101.4 (C-100), 88.7 (C-3), 82.9, 78.7, 78.1, 77.7, 76.1, 75.5, 75.2,
74.2, 72.7, 71.7, 71.6, 69.6, 64.7, 64.3, 62.6, 48.0, 46.6, 46.4, 42.1,
41.9, 39.7, 39.5, 37.0, 34.2, 33.2, 33.1, 32.0, 30.9, 30.7, 29.8, 29.5,
28.2, 28.1, 26.5, 26.1, 23.7, 22.8, 18.4, 18.3, 17.3, 17.0, 15.4, 14.1.
HRESIMS: m/z calcd for C59H95O26 [MꢁH+]: 1219.6112; found:
1219.6094.
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Acknowledgement
This work was financially supported by the Natural Science
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Supplementary data
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