Efficient synthesis of flaccidoside II, a bioactive component of Chinese folk medicine di Wu

Article abstract of DOI:10.1080/07328300903260192

A bidesmosidic triterpene saponin, flaccidoside II, which was isolated from Di Wu, a Chinese folk medicine from dry rhizome of Anemone flaccida Fr. Schmidt, was efficiently synthesized in a convergent approach. We employed two glycosyl trichloroacetimidate donors in a one-pot reaction as a key step. [Supplementary materials are available for this article. Go to the publisher's online edition of the Journal of Carbohydrate Chemistry for the following free supplemental resource(s): ¹H NMR, ¹³C NMR and HR mass spectra for all synthesized compounds, 2, 6, 9-11, and Flaccidoside II (1).

Full text of DOI:10.1080/07328300903260192

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Efficient Synthesis of Flaccidoside II, a
Bioactive Component of Chinese Folk
Medicine Di Wu
Qingchao Liu a , Lei Zhang a , Xiangpeng Li a , Tiantian Guo a , Peng
Wang a & Yingxia Li b
a School of Medicine and Pharmacy , Ocean University of China ,
Qingdao, 266003, China
b School of Pharmacy , Fudan University , Shanghai, 201203, China
Published online: 17 Nov 2009.
To cite this article: Qingchao Liu , Lei Zhang , Xiangpeng Li , Tiantian Guo , Peng Wang & Yingxia Li
(2009) Efficient Synthesis of Flaccidoside II, a Bioactive Component of Chinese Folk Medicine Di Wu,
Journal of Carbohydrate Chemistry, 28:9, 506-519
To link to this article: http://dx.doi.org/10.1080/07328300903260192
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Journal of Carbohydrate Chemistry, 28:506–519, 2009
ꢀ
C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300903260192
Efficient Synthesis of
Flaccidoside II, a Bioactive
Component of Chinese Folk
Medicine Di Wu
Qingchao Liu,1 Lei Zhang,1 Xiangpeng Li,1 Tiantian Guo,1
Peng Wang,1 and Yingxia Li2
1School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
2School of Pharmacy, Fudan University, Shanghai 201203, China
A bidesmosidic triterpene saponin, flaccidoside II, which was isolated from Di Wu, a
Chinese folk medicine from dry rhizome of Anemone flaccida Fr. Schmidt, was efficiently
synthesized in a convergent approach. We employed two glycosyl trichloroacetimidate
donors in a one-pot reaction as a key step.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of the Journal of Carbohydrate Chemistry for the following free supplemental
resource(s): 1H NMR, 13C NMR and HR mass spectra for all synthesized compounds, 2,
6, 9-11, and Flaccidoside II (1)
Keywords Bidesmosidic triterpene saponins; Flaccidoside II; Di Wu; Glycosyl
trichloroacetimidates; One-pot reaction
INTRODUCTION
Saponins, glycosides of steroids and triterpenes, are widely distributed in
plants and in some marine organisms.[1,2] It is noteworthy that more than
half of the triterpene saponins are glycosides of oleanolic acid or its deriva-
tives, with one sugar chain attached through an ether linkage at C-3 and
another through an ester linkage at C-28,[3] which have been reported to
present a broad spectrum of well-defined biological and pharmacological
activities, including antitumor,[4–11] anti-inflammatory,[12] antifungal,[13–15]
and anti-HIV.[16–18] Attracted by these interesting biological activities, several
Received June 13, 2009; accepted August 14, 2009.
Address correspondence to Yingxia Li, School of Pharmacy, Fudan University, Shanghai
201203, China. E-mail: liyx417@fudan.edu.cn
506

Efficient Synthesis of Flaccidoside II
507
Figure 1: Structure of target compound flaccidoside II (1).
research groups reported on the synthesis of many oleanane-type triterpenoid
saponins.[19–28] Notably, flaccidoside II, 3-O-(α-L-rhamnopyranosyl-(1→2)-
β-D-xylopyranosyl)
oleanolic
acid
α-L-rhamnopyranosyl-(1→4)-β-D-
glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (Fig. 1), a bioactive component
of Di Wu, which is a Chinese folk medicine from dry rhizome of Anemone flac-
cida Fr. Schmidt,[29–31] and 3,28-di-O-rhamnosylated oleanolic acid saponins
mimicking components of Chinese folk medicine Di Wu have been synthesized
by Du et al.[32,33] Based on the structural complexity and bioactivity study of
flaccidoside II, we are interested in preparing this bidesmosidic triterpene
saponin via a more convenient way. Herein, we report a full account on the
synthesis of flaccidoside II.
RESULTS AND DISCUSSION
A few facile synthetic strategies for construction of the bidesmosidic oleanane-
type saponins bearing the distinctive disaccharide, the α-L-rhamnopyranosyl-
(1→2)-β-D-xylopyranosyl moiety, have been reported.[32] Fortunately, the de-
velopment of glycosylation procedures by one-pot protocols has made the
synthesis of oligosaccharides and glycoconjugates bearing complicated sugar
moiety available or even easier.[34–46] Recently, by applying the “one-pot se-
quential glycosylation” procedure, we have successfully completed the synthe-
sis of three bidesmosidic oleanolic acid saponins (Scabiosaponins E-G).[21] En-
couraged by these accomplishments, we decided to adopt this strategy with
two trichloroacetimidates as donors to complete the synthesis of the target
molecule.[47] Such an approach would allow us to rapidly access a variety of
structural analogs of flaccidoside II.
As shown in Scheme 1, saponin 1 can be retrosynthetically disconnected
into two distinct fragments 2 and 3.[48] The former could be assembled from
three building blocks 4,[21] 5,[46] and 6 through two successive glycosylation

Q. Liu et al.
508
Scheme 1: Retrosynthesis of flaccidoside II (1).
steps in the one-pot reaction. The trisaccharide moiety 6 may also be gen-
erated from the corresponding α-L-rhamnopyranosyl trichloroacetimidate 3,
4-O-β-glucopyranoside 7,[42] and 6-O-β-glucopyranoside 8[49] via a one-pot gly-
cosylation strategy.
With three building blocks 3, 7, and 8 in hand, we first constructed the
trisaccharide moiety 6 by utilizing the thioglycoside and trichloroacetimidate
as donors in a one-pot sequential glycosylation. As depicted in Scheme 2, cou-
pling of p-tolyl 2,3,6-tri-O-benzoyl-1-thio-β-D-glucopyranoside 7 and 2,3,4-tri-
O-benzoyl-α-L-rhamnopyranosyl trichloroacetimidate 2 was completed within
45 min with the use of a catalytic amount of trimethylsilyl trifluoromethane-
sulfonate (TMSOTf, 0.2 equiv.) at –78◦C, providing the desired disaccharide
thioglycoside donor. Without purification, the reaction mixture was warmed
to –10◦C, and then the acceptor 1,2,3,4-tetra-O-benzoyl-α-D-glucopyranose(8)
was added, followed by addition of N-iodosuccinimide (NIS, 2.0 equiv.) and
TMSOTf (0.5 equiv.), affording the desired product 9 in a 75% yield for
two steps. Selective debenzoylation on 9 with NH2NH2·HOAc in DMF, fol-
lowed by C-1 Schmidt activation with trichloroacetonitrile (Cl3CCN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in dry CH2Cl2, afforded the correspond-
ing imidate 6 in a yield of 87% over two steps.
With an efficient synthetic access to the key trisaccharide moiety 6, we
then set about our final assembly of the target natural product flaccidoside
II (1), which we thought could be prepared in an efficient way by one-pot
sequential glycosylation employing two glycosyl trichloroacetimidates donors
(Scheme 3). Herein, condensation of oleanolic ester 5 with 3,4-di-O-benzoyl-2-

Efficient Synthesis of Flaccidoside II
509
Scheme 2: Synthesis of trisaccharide donor 6. Reagents and conditions: (a) TMSOTf (0.2
equiv), CH2Cl2, 4 Å MS, –78◦C; (b) NIS (2.0 equiv), TMSOTf (0.5 equiv), –10◦C, 75% for two
steps; (c) NH2NH2·HOAc, DMF; then Cl3CCN, DBU, CH2Cl2, r.t., 87% for two steps.
Scheme 3: Synthesis of flaccidoside II (1). Reagents and conditions: (a) TMSOTf (0.3 equiv),
CH2Cl2, 4 Å MS, –78◦C → rt; (b) 6 (1.6 equiv), CH2Cl2, 4 Å MS, 0◦C, 65% for two steps; (c)
NH2NH2·HOAc, CH2Cl2-CH3OH (1:1), 88%; (d) 3 (1.2 equiv), CH2Cl2, 4 Å MS, rt, 86%; (e)
NaOMe, CH2Cl2-CH3OH (1:2), 85%.

Q. Liu et al.
510
O-levulinoyl-β-D-xylopyranosyl trichloroacetimidate (4) under the promotion
of TMSOTf (0.3 equiv) at –78◦C for 30 min provided the desired product,
which was then transformed into the key intermediate 5ꢁ by warming to am-
bient temperature for 30 min. Following addition of a CH2Cl2 solution of the
trisaccharide trichloroacetimidate donor 6 to the above mixture at 0◦C, the
desired glycoside 2 was obtained. Removing the Lev protecting group by
treatment with NH2NH2·HOAc in CH2Cl2-CH3OH finished the synthesis of
10 in 88% yield.21 Glycosylation of saponin acceptor 10 with 2,3,4-tri-O-
benzoyl-α-L-rhamnopyranosyl trichloroacetimidate (3) catalyzed by TMSOTf
gave the fully protected saponin derivative 11 in 86% yield. Finally, re-
moval of the benzoyl groups with NaOMe in MeOH-CH2Cl2 afforded the
target compound flaccidoside II (1) in 85% yield, whose analytical data
are identical in all respects to those reported in the literature[31] (Table
1).
In conclusion, a highly efficient and practical method has been developed
for the synthesis of flaccidoside II (1). The key to this approach is the use of one-
pot sequential glycosylation, resulting in a significantly simplified synthetic
procedure and isolation of intermediates. Further investigation on prepara-
tion and bioactive evaluation of its derivatives is currently under way in our
research group.
EXPERIMENTAL
General methods
CH2Cl2 was distilled from CaH2 under a N2 atmosphere. DMF and CH3OH
were distilled from 4 MS under a N2 atmosphere prior to use. TLC was per-
formed on precoated Merck silica gel 60 F254 plates. Flash column chromatog-
raphy was performed on silica gel (200–300 mesh, Qingdao, China). Optical
rotations were determined with a JASCO P-1020 polarimeter. Melting points
were determined with a Yanaco apparatus and are uncorrected. NMR spectra
were recorded on a Jeol JNM-ECP 600-MHz spectrometer with Me4Si as the
internal standard, and chemical shifts recorded in δ value. Mass spectra were
obtained on a Q-TOF GIOBAL mass spectrometer.
2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-(1→4)-2,3,6-tri-O-
benzoyl-β-D-glucopyranosyl-(1→6)-1,2,3,4-tetra-O-benzoyl-
α-D-glucopyranoside (9)
A mixture of thioglycoside 7 (66 mg, 0.11 mmol) and 4 MS (100 mg) in
CH2Cl2 (5 mL) was stirred at rt under argon for 30 min, and then cooled to

Efficient Synthesis of Flaccidoside II
511
Table 1: 1H and 13C NMR of glycoside moieties of natural product flaccidoside II (1)
compared with synthesized compound 1a
1 (lit.)
J (Hz)
7.7
1
Position
1H (ppm)
4.96 d
13C (ppm)
1H (ppm)
J (Hz)
13C (ppm)
95.5
1ꢁ
95.6
73.9
78.0
70.7
77.1
69.1
4.97 d
3.92 t-like
4.08–4.15 m
4.65–4.68 m
4.16–4.19 m
4.30–4.36 m
4.20–4.24 m
6.23 d
7.7
8.7, 8.2
2ꢁ
3ꢁ
4ꢁ
5ꢁ
6ꢁꢁ-1
6ꢁꢁ-2
1ꢁꢁ
6.21 d
8.0
104.8
75.3
76.4
78.6
78.0
61.1
8.2
9.2
104.7
83.9
2ꢁꢁ
4.08–4.15 m
4.40 t
3ꢁꢁ
4ꢁꢁ
4.16–4.19 m
4.08–4.15 m
4.08–4.15 m
3.64 m
5ꢁꢁ
6ꢁꢁ-1
6ꢁꢁꢁ-2
1ꢁꢁꢁ
2ꢁꢁꢁ
3
5.83 br s
102.6
72.5
72.7
73.9
70.2
18.5
106.1
79.5
77.8
71.4
66.9
5.85 br s
102.6
106.0
101.8
4.65–4.68 m
4.54 dd
9.1, 3.2
4ꢁꢁꢁ
5ꢁꢁꢁ
6ꢁꢁꢁ
1ꢁꢁꢁꢁ
2ꢁꢁꢁꢁ
3ꢁꢁꢁꢁ
4ꢁꢁꢁꢁ
4.30–4.36 m
4.95 qd
9.1, 5.9
6.0
7.3
1.69 d
4.79 d
6.0
6.9
1.69 d
4.81 d
4.20–4.24 m
4.30–4.36 m
4.08–4.15 m
4.30–4.36 m
3.69 t
5
ꢁꢁꢁꢁ-1
5ꢁꢁꢁꢁꢁꢁꢁꢁꢁ-2
1ꢁꢁꢁꢁꢁ
2ꢁꢁꢁꢁꢁ
3
11.0
1.0
3.2, 1.4
9.6, 3.2
6.51 br s
1.68 d
101.8
72.3
72.5
73.9
69.7
18.5
6.53 d
4.87 dd
4.69 dd
4ꢁꢁꢁꢁꢁ
5ꢁꢁꢁꢁꢁ
6ꢁꢁꢁꢁꢁ
4.30–4.36 m
4.76 qd
9.2, 6.0
5.9
5.9
1.70 d
aSpectra were measured in pyridine-d5.
–78◦C. At this temperature, a solution of TMSOTf (0.2 equiv.) in dry CH2Cl2
was injected, and after 10 min trichloroacetimidate 3 (142 mg, 0.23 mmol, 2.1
equiv.) in dry CH2Cl2 was added. The resulting mixture was stirred for addi-
tional 30 min and then warmed up to –10◦C. To the above mixture was added a
solution of acceptor 8 (66 mg, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), followed
by NIS (50 mg, 0.11 mmol, 2.0 equiv.). After being stirred for 1 h, the reaction
mixture 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 (4:1, petroleum ether–EtOAc) to give the trisaccharide moi-
ety 9 (127 mg, 75% two steps) as a white solid. The amounts of the reactants

Q. Liu et al.
512
and the yield of product 9 were calculated based on acceptor 8. Rf 0.41 (3:1,
25
petroleum ether-EtOAc); [α]D +37.3 (c 1.2, CHCl3); IR (KBr) ν: 2947, 1729,
1
1607, 1465, 1259, 1089, 1068, 709 cm-1; H NMR (CDCl3): δ 7.21–8.07 (m, 50
H, Ph-H), 6.69 (d, J = 3.7 Hz, 1 H, H-1), 6.18 (t, J = 9.9 Hz, 1 H, H-3), 5.86
(t, J = 10.0 Hz, 1 H, H-3ꢁ), 5.68 (dd, J = 9.9, 3.3 Hz, 1 H, H-3ꢁꢁ), 5.55 (dd, J
= 3.3, 1.5 Hz, 1 H, H-2ꢁꢁ), 5.50–5.54 (m, 2 H, H-4, H-4ꢁꢁ), 5.46 (dd, J = 9.9, 3.6
Hz, 1 H, H-2), 5.43 (dd, J = 10.0, 7.7 Hz, 1 H, H-2ꢁ), 5.20 (d, J = 1.5 Hz, 1 H,
H-1ꢁꢁ), 5.00 (dd, J = 12.5, 1.8 Hz, 1 H, H-6ꢁ-1), 4.93 (d, J = 7.7 Hz, 1 H, H-1ꢁ),
4.64 (dd, J = 12.5, 3.9 Hz, 1 H, H-6ꢁ-2), 4.45 (m, 1 H, H-5), 4.29 (t, J = 9.3
Hz, 1 H, H-4ꢁ), 4.05 (m, 1 H, H-6–1), 4.03 (m, 1 H, H-5ꢁ), 4.00 (dq, J = 9.9, 6.2
Hz, 1 H, H-5ꢁꢁ), 3.79 (dd, J = 11.8, 5.6 Hz, 1 H, H-6–2), 0.76 (d, J = 6.2 Hz, 3
H, H-6ꢁꢁ); 13C NMR (CDCl3): δ 171.1, 165.8, 165.6, 165.4, 165.0, 133.6, 133.4,
133.3, 133.2, 133.0, 132.9, 132.8, 130.0, 129.9, 129.8, 129.7, 129.4, 129.3, 129.1,
129.0, 128.8, 128.7, 128.6, 128.4, 128.3, 128.1, 100.8 (C-1), 98.8 (C-1ꢁꢁ), 90.0 (C-
1ꢁ), 73.8, 73.6, 72.3, 71.9, 71.4, 71.1, 70.5, 70.4, 69.5, 68.9, 67.8, 67.2, 62.5, 60.3,
17.0; HR-MALDI-MS: m/z calcd for C88H72O25Na [M+Na+] 1551.4264; found:
1551.4255.
2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-(1→4)-2,3,6-tri-O-
benzoyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-O-benzoyl-α-D-
glucopyranosyl Trichloroacetimidate (6)
To a solution of 9 (120 mg, 0.08 mmol) in DMF was added NH2NH2·HOAc
(9 mg, 0.1 mmol), and the mixture was stirred at rt overnight. After TLC (1:1,
petroleum ether-EtOAc) indicated that the reaction was complete, the reac-
tion mixture was concentrated under reduced pressure. The solid residue was
purified by silica gel column chromatography (1:2, petroleum ether-EtOAc) to
afford a white solid. To a mixture of the solid in CH2Cl2 (2 mL) were added
trichloroacetonitrile (0.1 mL) and DBU (0.01 mL). The reaction mixture was
stirred at rt for 2 h and then concentrated in vacuo. The solid residue was
purified by silica gel column chromatography (1:3, petroleum ether-EtOAc) to
25
1
afford 6 (109 mg, 87%) as a white solid. [α]D +117 (c 1.05, CHCl3); H NMR
(CDCl3): δ 8.40 (s, 1 H, N-H), 7.25–8.13 (m, 45 H, Ph-H), 6.68 (d, J = 3.4 Hz,
1 H, H-1), 6.18 (t, J = 9.9 Hz, 1 H, H-3), 5.86 (t, J = 9.2 Hz, 1 H, H-3ꢁ), 5.69
(dd, J = 10.1, 2.4 Hz, 1 H, H-3ꢁꢁ), 5.56 (br s, 1 H, H-2ꢁꢁ), 5.53 (t, J = 9.9 Hz, 1
H, H-4), 5.49 (t, J = 10.0 Hz, 1 H, H-4ꢁꢁ), 5.40 (dd, J = 9.9, 3.4 Hz, 1 H, H-2),
5.36 (dd, J = 9.9, 7.7 Hz, 1 H, H-2ꢁ), 5.22 (s, 1 H, H-1ꢁꢁ), 5.01 (dd, J = 12.1,
2.0 Hz, 1 H, H-6ꢁ-1), 4.96 (d, J = 7.7 Hz, 1 H, H-1ꢁ), 4.65 (dd, J = 12.4, 3.3 Hz,
1 H, H-6ꢁ-2), 4.43 (m, 1 H, H-5), 4.31 (t, J = 9.2 Hz, 1 H, H-4ꢁ), 4.10 (m, 1 H,
H-6–1), 3.98–4.04 (m, 1 H, H-5ꢁ, H-5ꢁꢁ), 3.82 (dd, J = 11.7, 5.8 Hz, 1 H, H-6–2),
0.77 (d, J = 5.7 Hz, 3 H, H-6ꢁꢁ); 13C NMR (CDCl3): δ 165.9, 165.6, 165.4, 165.2,
160.3 (C = NH), 133.3, 133.2, 133.0, 132.9, 129.9, 129.8, 129.7, 129.4, 129.2,

Efficient Synthesis of Flaccidoside II
513
129.0, 128.7, 128.4, 128.3, 128.2, 100.6 (C-1ꢁ), 98.7 (C-1ꢁꢁ), 93.0 (C-1), 90.7, 73.9,
73.6, 72.3, 72.1, 71.4, 71.1, 70.7, 70.2, 69.5, 68.6, 67.8, 67.2, 62.5, 17.0; HR-
MALDI-MS: m/z calcd for C83H68NO24Cl3Na [M+Na+] 1590.3094; found: 1590.
3089.
3-O-(3,4-Di-O-benzoyl-2-O-levulinoyl-β-D-xylopyranosyl)
Oleanolic Acid 2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-
(1→4)-2,3,6-tri-O-benzoyl-β-D-glucopyranosyl-(1→6)-2,3,
4-tri-O-benzoyl-β-D-glucopyranosyl Ester (2)
A mixture of 5 (200 mg, 0.29 mmol), 4 (206 mg, 0.34 mmol, 1.2 equiv.),
and 4 MS (400 mg) in dry CH2Cl2 (5 mL) was stirred at rt for 30 min and
then cooled to –78◦C. TMSOTf (15 µL, 0.09 mmol, 0.3 equiv.) was added slowly.
After being stirred at –78◦C for 30 min, the reaction mixture was warmed up
to rt for 30 min, and then cooled to 0◦C. A solution of 6 (674 mg, 0.43 mmol,
1.5 equiv.) in dry CH2Cl2 (5 mL) was injected slowly. The reaction mixture was
stirred at 0◦C for 30 min, and then warmed up to rt for another 30 min. The
reaction was quenched by addition of Et3N (0.3 mL) and then filtered. The
filtrate was concentrated and purified by silica gel column chromatography
(2:1, petroleum ether–EtOAc) to afford 2 (434 mg, 65% based on acceptor 5)
25
as a white solid, Rf = 0.27 (2:1, petroleum ether-EtOAc); [α]D 20.7 (c 2.23,
1
CHCl3); IR (KBr) ν: 3069, 2945, 1735, 1596, 1451, 1265, 1062, 707 cm-1; H
NMR (CDCl3): δ 7.25–8.11 (m, 55 H, Ph-H), 5.86 (t, J = 9.7 Hz, 1 H, H-3ꢁ),
5.84 (d, J = 8.3 Hz, 1 H, H-1ꢁ), 5.82 (t, J = 9.6 Hz, 1 H, H-3ꢁꢁ), 5.68 (dd, J =
10.2, 3.1 Hz, 1 H, H-3ꢁꢁꢁ), 5.65 (t, J = 7.3 Hz, 1 H, H-3ꢁꢁꢁꢁ), 5.60 (dd, J = 9.6,
8.3 Hz, 1 H, H-2ꢁ), 5.57 (br s, 1 H, H-2ꢁꢁꢁ), 5.52 (t, J = 9.6 Hz, 1 H, H-4ꢁ), 5.47
(t, J = 9.6 Hz, 1 H, H-4ꢁꢁꢁ), 5.43 (dd, J = 9.7, 7.7 Hz, 1 H, H-2ꢁꢁ), 5.41 (br s, 1
H, H-12), 5.29 (m, 1 H, H-4ꢁꢁꢁꢁ), 5.22 (m, 1 H, H-6ꢁ-1), 5.21 (s, 1 H, H-1ꢁꢁꢁ), 4.99
(m, 2 H, H-1ꢁꢁ, H-6ꢁꢁ-1), 4.67 (d, J = 6.8 Hz, 1H, H-1ꢁꢁꢁꢁ), 4.64 (dd, J = 12.4,
3.6 Hz, 1 H, H-6ꢁꢁ-2), 4.35 (dd, J = 12.1, 4.5 Hz, 1H, H-5ꢁꢁꢁꢁ-1), 4.25 (t, J = 9.3
Hz, 1H, H-4ꢁꢁ), 4.11 (m, 1 H, H-5ꢁꢁꢁ), 3.89–3.99 (m, 4 H, H-5ꢁ, H-5ꢁꢁ, H-5ꢁꢁꢁꢁ-2,
H-6ꢁ-2), 3.51 (dd, J = 8.8, 7.0 Hz, 1 H, H-2ꢁꢁꢁꢁ), 3.18 (dd, J = 11.9, 4.6 Hz, 1
H, H-3), 2.95 (dd, J = 13.7, 3.7 Hz, 1 H, H-18), 0.76 (d, J = 5.9 Hz, 3 H, H-
6ꢁꢁꢁ), 0.98, 0.96, 0.87, 0.85, 0.85, 0.71, 0.48 (s each, 3 H each, CH3 × 7); 13C
NMR (CDCl3): δ 205.1, 203.5 (CH3COCH2CH2CO), 175.5 (C-28), 171.2, 165.9,
165.6, 165.4, 165.3, 165.2, 165.1, 164.6, 143.0 (C-13), 133.3, 133.2, 133.0, 130.1,
130.0, 129.9, 129.8, 129.7, 129.5, 129.3, 128.9, 128.4, 128.3, 128.2, 122.6 (C-
12), 103.3 (C-1ꢁꢁꢁꢁ), 100.3 (C-1ꢁꢁ), 98.9 (C-1ꢁꢁꢁ), 91.9 (C-1ꢁ), 89.3 (C-3), 75.1, 74.0,
73.9, 73.6, 73.5, 73.4, 73.3, 73.2, 73.0, 72.6, 72.4, 71.4, 71.1, 70.5, 69.8, 69.5,
67.7, 55.3, 46.8, 41.6, 39.0, 38.9, 37.9, 33.0, 30.6, 29.6, 27.9, 25.4, 23.6, 17.0,
16.4, 15.3; HR-MALDI-MS: m/z calcd for C135H136O34Na [M+Na+] 2323.8842;
found: 2323.8805.

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3-O-(3,4-Di-O-benzoyl-β-D-xylopyranosyl) Oleanolic Acid
2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-(1→4)-2,3,6-tri-O-
benzoyl-β-D-glucopyranosyl-(1→6)-2,3,
4-tri-O-benzoyl-β-D-glucopyranosyl Ester (10)
To a stirred solution of 2 (368 mg, 0.16 mmol) in CH2Cl2 (50 mL) and
CH3OH (50 mL) was added NH2NH2·HOAc (50 mg, 0.5 mmol). After 2 h,
the solution was concentrated. The residue was purified by silica gel column
chromatography (2:1, petroleum ether–EtOAc) to afford 10 (308 mg, 88%) as a
white solid. Rf = 0.20 (2:1, petroleum ether-EtOAc); [α]D25 19.5 (c 2.01, CHCl3);
IR (KBr) ν: 3067, 2941, 1731, 1605, 1450, 1267, 1090, 706 cm-1; 1H NMR
(CDCl3): δ 7.24–8.11 (m, 55 H, Ph-H), 5.86 (t, J = 9.6 Hz, 1 H, H-3ꢁ), 5.82
(d, J = 8.2 Hz, 1 H, H-1ꢁ), 5.80 (t, J = 9.6 Hz, 1 H, H-3ꢁꢁ), 5.65 (dd, J = 10.2,
3.2 Hz, 1 H, H-3ꢁꢁꢁ), 5.48–5.59 (m, 3 H, H-2ꢁ, H-2ꢁꢁꢁ, H-3ꢁꢁꢁꢁ), 5.41 (t, J = 9.6 Hz,
1 H, H-4ꢁ), 5.36 (t, J = 9.7 Hz, 1 H, H-4ꢁꢁꢁ), 5.36 (m, 2 H, H-12, H-2ꢁꢁ), 5.30 (m,
1 H, H-4ꢁꢁꢁꢁ), 5.19 (s, 1 H, H-1ꢁꢁꢁ), 4.99 (m, 2 H, H-1ꢁꢁ, H-6ꢁꢁ-1), 4.64 (dd, J = 12.4,
3.5 Hz, 1 H, H-6ꢁꢁ-2), 4.55 (d, J = 6.9 Hz, 1H, H-1ꢁꢁꢁꢁ), 4.31 (dd, J = 12.7, 6.0 Hz,
1H, H-5ꢁꢁꢁꢁ-1), 4.25 (t, J = 9.6 Hz, 1 H, H-4ꢁꢁ), 4.09 (m, 1 H, H-5ꢁꢁꢁ), 3.89–4.07 (m,
4 H, H-5ꢁ, H-5ꢁꢁ, H-5ꢁꢁꢁꢁ-2, H-6ꢁ-2), 3.80 (dd, J = 8.8, 7.1 Hz, 1 H, H-2ꢁꢁꢁꢁ), 3.20
(dd, J = 11.5, 3.8 Hz, 1 H, H-3), 2.90 (dd, J = 14.1, 3.7 Hz, 1 H, H-18), 0.76 (d,
J = 6.0 Hz, 3 H, H-6ꢁꢁꢁ), 0.99, 0.99, 0.96, 0.88, 0.87, 0.81, 0.47 (s each, 3 H each,
CH3 × 7); 13C NMR (CDCl3): δ 175.7 (C-28), 165.9, 165.6, 165.4, 165.2, 164.6,
143.0 (C-13), 133.3, 133.2, 133.0, 130.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.5,
129.3, 128.9, 128.4, 128.3, 128.2, 122.7 (C-12), 105.2 (C-1ꢁꢁꢁꢁ), 100.4 (C-1ꢁꢁ), 98.9
(C-1ꢁꢁꢁ), 92.0 (C-1ꢁ), 89.8 (C-3), 75.2, 73.9, 73.6, 73.5, 73.4, 73.1, 73.0, 72.6, 72.5,
72.4, 71.5, 71.3, 71.1, 71.0, 69.8, 69.5, 67.8, 62.4, 60.3, 55.5, 41.6, 39.0, 36.7,
32.9, 30.6, 28.3, 25.4, 23.6, 22.7, 21.0, 17.0, 16.7, 16.6, 15.4, 14.2; HR-MALDI-
MS: m/z calcd for C130H130O32Na [M+Na+] 2225.8419; found: 2225.8438.
3-O-(2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-(1→2)-3,4-di-O-
benzoyl-β-D-xylopyranosyl) Oleanolic Acid
2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl-(1→4)-2,3,6-tri-O-
benzoyl-β-D-glucopyranosyl-(1→6)-2,3,
4-tri-O-benzoyl-β-D-glucopyranosyl Ester (11)
Compound 10 (220 mg, 0.1 mmol), trichloroacetimidate 3 (74 mg, 0.12
mmol), and powdered 4 molecular sieves (0.20 g) in dry CH2Cl2 (8 mL) were
stirred for 40 min at rt, and then TMSOTf (0.005 mL, 0.01 mmol) was added
dropwise. The mixture was stirred for 10 min followed by addition of Et3N
and filtration. The filtrate was concentrated and purified by silica gel column
chromatography (3:2, petroleum ether-EtOAc) to afford 11 (228 mg, 86%) as a
white solid, Rf = 0.28 (3:2, petroleum ether-EtOAc); mp 152–154◦C; [α]D25 53.6

Efficient Synthesis of Flaccidoside II
515
(c 1.12, CHCl3); IR (KBr) ν: 3089, 2945, 1726, 1614, 1451, 1272, 1097, 1085,
1
1027, 709 cm-1; H NMR (CDCl3): δ 7.26–8.10 (m, 73 H, Ph-H), 5.86 (t-like,
J = 9.7, 9.6 Hz, 1 H, H-3ꢁ), 5.78–5.84 (m, 3 H, H-1ꢁ, H-3ꢁꢁ, H-3ꢁꢁꢁ), 5.71 (t-like,
J = 7.3, 6.9 Hz, 1 H, H-3ꢁꢁꢁꢁ), 5.66 (dd, J = 10.1, 3.2 Hz, 1 H, H-3ꢁꢁꢁꢁꢁ), 5.61
(t-like, J = 10.1, 9.7 Hz, 1 H, H-4ꢁꢁꢁ), 5.56–5.58 (m, 2 H, H-2ꢁ, H-2ꢁꢁꢁ), 5.53 (m,
1H, H-2ꢁꢁꢁꢁꢁ), 5.49 (t, J = 10.1 Hz, 1 H, H-4ꢁꢁꢁꢁꢁ), 5.42 (t-like, J = 10.1, 9.6 Hz,
1H, H-4ꢁ), 5.35–5.38 (m, 3H, H-12, H-2ꢁꢁ, H-1ꢁꢁꢁ), 5.21–5.24 (m, 1 H, H-4ꢁꢁꢁꢁ), 5.19
(s, 1 H, H-1ꢁꢁꢁꢁꢁ), 5.00 (d, J = 8.2 Hz, 1 H, H-1ꢁꢁ), 4.86 (d, J = 5.0 Hz, 1 H, H-
1
ꢁꢁꢁꢁ), 4.63 (dd, J = 12.4, 3.7 Hz, 1 H, H-5ꢁ), 4.50–4.53 (m, 1 H, H-5ꢁꢁꢁ), 4.39 (dd,
J = 12.4, 4.6 Hz, 1 H, H-5ꢁꢁꢁꢁ-1), 4.25 (t, J = 9.2 Hz, 1 H, H-4ꢁꢁ), 4.08–4.13 (m, 2
H, H-2ꢁꢁꢁꢁ, H-6ꢁ-2), 4.06–4.08 (m, 1 H, H-6ꢁꢁ-1), 3.95–3.98 (m, 2 H, H-5ꢁꢁꢁꢁꢁ, H-6ꢁꢁ-
2), 3.89–3.92 (m, 2 H, H-5ꢁꢁ, H-6ꢁ-1), 3.65 (dd, J = 11.9, 6.9 Hz, 1 H, H-5ꢁꢁꢁꢁ-2),
3.21 (dd, J = 11.9, 4.6 Hz, 1 H, H-3), 1.33 (d, J = 5.9 Hz, 3 H, H-6ꢁꢁꢁꢁꢁ), 0.76
(d, J = 5.9 Hz, 3 H, H-6ꢁꢁꢁ), 1.08, 0.96, 0.95, 0.87, 0.87, 0.82, 0.47 (s each, 3
H each, CH3×7); 13C NMR (CDCl3): δ 175.4, 165.7, 165.6, 165.5, 165.4, 165.2,
165.0, 143.0 (C-13), 133.4, 133.3, 133.2, 133.1, 133.0, 132.9, 129.9, 129.8, 129.7,
129.7, 129.6, 129.5, 129.2, 129.1, 128.5, 129.4, 128.3, 128.2, 128.2, 122.6 (C-12),
103.3 (C-1ꢁꢁꢁꢁ), 100.3 (C-1ꢁꢁ), 98.8 (C-1ꢁꢁꢁꢁꢁ), 97.5 (C-1ꢁꢁꢁ), 91.9 (C-1ꢁ), 89.3 (C-3),
75.1, 73.8, 73.5, 72.8, 72.3, 72.2, 71.8, 71.3, 71.0, 70.5, 70.3, 69.6, 69.4, 69.3,
67.6, 67.2, 66.6, 62.4, 61.2, 60.3, 55.6, 47.5, 46.7, 45.7, 41.5, 41.0, 39.1, 38.8,
38.7, 36.7, 33.7, 32.9, 31.8, 31.7, 30.9, 30.5, 29.6, 28.0, 27.9, 25.9, 25.3, 23.6,
23.3, 22.6, 18.1, 17.4, 16.9, 16.6, 16.4, 15.5, 14.2; HR-MALDI-MS: m/z calcd for
C157H152O39Na [M+Na+] 2683.9845; found: 2683.9803.
3-O-(α-L-Rhamnopyranosyl-(1→2)-β-D-xylopyranosyl) Oleanolic
Acid α-L-Rhamnopyranosyl-(1→4)-β-D-
glucopyranosyl-(1→6)-β-D-glucopyranosyl Ester (1)
To a solution of 11 (200 mg, 0.08 mmol) in dry CH2Cl2–MeOH (1:2, 20 mL)
was added a newly prepared NaOMe in MeOH solution (1.0 mol/L, 0.20 mL).
The mixture was stirred at rt for 5 h and neutralized with Dowex H+ resin to
pH 7 and then filtered. The filtrate was concentrated and the resulting residue
was purified by silica gel column chromatography (1:20:0.1, MeOH-CHCl3-
H2O) to give 1 (76 mg, 85%) as white amorphous solids. Rf = 0.26 (1:20:0.1,
MeOH-CHCl3-H2O); mp 191–193◦C; [α]D –29.6 (c 0.25, C5H5N); IR (KBr) ν:
25
3506, 2941, 1729, 1646, 1451, 1272, 1086, 1051 cm-1; 1H NMR (C5D5N): δ 6.53
(d, J = 1.0 Hz, 1 H, H-1ꢁꢁꢁꢁꢁ), 6.23 (d, J = 8.2 Hz, 1 H, H-1ꢁꢁ), 5.85 (br s, 1 H,
H-1ꢁꢁꢁ), 5.38 (t, J = 3.6 Hz, 1 H, H-12), 4.97 (d, J = 7.7 Hz, 1 H, H-1ꢁ), 4.95
(dq, J = 9.1, 5.9 Hz, 1 H, H-5ꢁꢁꢁ), 4.87 (dd, J = 3.2, 1.4 Hz, 1 H, H-2ꢁꢁꢁꢁꢁ), 4.81
(d, J = 7.3 Hz, 1 H, H-1ꢁꢁꢁꢁ), 4.76 (dq, J = 9.2, 6.0 Hz, 1 H, H-5ꢁꢁꢁꢁꢁ), 4.69 (dd,
J = 9.6, 3.2 Hz, 1 H, H-3ꢁꢁꢁꢁꢁ), 4.65–4.68 (m, 2 H, H-2ꢁꢁꢁ, H-4ꢁ), 4.54 (dd, J =
9.1, 3.2 Hz, 1 H, H-3ꢁꢁꢁ), 4.40 (t, J = 9.2 Hz, 1 H, H-3ꢁꢁ), 4.20–4.24 (m, 2 H,

Q. Liu et al.
516
H-2ꢁꢁꢁꢁ, H-6ꢁ-2), 4.16–4.19 (m, 2 H, H-4ꢁꢁ, H-5ꢁ), 4.08–4.15 (m, 5 H, H-2ꢁꢁ, H-3ꢁ,
H-4ꢁꢁꢁꢁ, H-5ꢁꢁ, H-6ꢁꢁ-1), 3.92 (t-like, J = 8.7, 8.2 Hz, 1 H, H-2ꢁ), 3.69 (t, J = 11.0
Hz, 1 H, H-5ꢁꢁꢁꢁ-2), 3.64 (m, 1 H, H-6ꢁꢁ-2), 3.28 (dd, J = 11.9, 4.1 Hz, 1 H, H-3),
3.14 (dd, J = 13.8, 4.1 Hz, 1 H, H-18), 1.70 (d, J = 5.9 Hz, 3 H, H-6ꢁꢁꢁꢁꢁ), 1.69
(d, J = 6.0 Hz, 3 H, H-6ꢁꢁꢁ), 1.23, 1.22, 1.18, 1.08, 0.87, 0.87, 0.86 (s each, 3 H
each, CH3 × 7); 13C NMR (C5D5N): δ 176.4 (C-28), 144.0 (C-13), 122.7 (C-12),
106.0 (C-1ꢁꢁꢁꢁ), 104.7 (C-1ꢁꢁ), 102.6 (C-1ꢁꢁꢁ), 101.8 (C-1ꢁꢁꢁꢁꢁ), 95.5 (C-1ꢁ), 88.4 (C-3),
79.5, 78.6, 78.1, 77.9, 77.8, 77.0, 76.4, 75.2, 74.0, 73.9, 73.7, 72.6, 72.5, 72.3,
71.4, 70.7, 70.2, 69.6, 69.0, 66.8, 61.1, 56.0, 47.9, 46.9, 46.1, 42.0, 41.5, 39.8,
39.4, 38.9, 36.9, 33.9, 33.0, 32.4, 30.6, 29.9, 28.1, 27.9, 26.7, 25.9, 23.7, 23.6,
23.2, 18.6, 18.4, 17.4, 17.0, 15.6; ESIHR-MS: m/z calcd for C59H97O25 [M+H+]:
1205.6319; found: 1205.6345.
ACKNOWLEDGMENT
This work is supported by the National Basic Research Program of China
(30701046).
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