Synthesis of bidesmosidic dihydrodiosgenin saponins bearing a 3-O-β-chacotriosyl moiety

Article abstract of DOI:10.1016/j.carres.2004.04.014

3-O-β-Chacotriosyl-26-O-β-D-glucopyranosyl-(25R)-furost-5-en (1), a mimic of the antitumor active proto-dioscin, was concisely synthesized from diosgenin in a linear nine steps and in 17% overall yield. Its congeners with a α-L-rhamnopyranosyl, β-lactosyl, or without a substituent at the 26-OH (13-15) were also prepared. Compound 1, as well as 13-15, did not show any inhibition against tumor cells, implying that proto-dioscin might be also inactive, but readily converted into the antitumor active dioscin.

Full text of DOI:10.1016/j.carres.2004.04.014

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1753–1759
Synthesis of bidesmosidic dihydrodiosgenin saponins
bearing a 3-O-b-chacotriosyl moiety
Yichun Zhang,a Yingxia Li,a,* Shilei Zhu,a Huashi Guan,a Feng Linb and Biao Yub,*
aMarine Drugs and Food Institute, Ocean University of China, Qingdao 266003, China
bState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 17 February 2004; accepted 22 April 2004
Available online 10 June 2004
Abstract—3-O-b-Chacotriosyl-26-O-b-
concisely synthesized from diosgenin in a linear nine steps and in 17% overall yield. Its congeners with a a-
D
-glucopyranosyl-(25R)-furost-5-en (1), a mimic of the antitumor active proto-dioscin, was
-rhamnopyranosyl, b-
lactosyl, or without a substituent at the 26-OH (13–15) were also prepared. Compound 1, as well as 13–15, did not show any
L
inhibition against tumor cells, implying that proto-dioscin might be also inactive, but readily converted into the antitumor active
dioscin.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: 3-O-b-Chacotriosyl-26-O-b-D-glucopyranosyl-(25R)-furost-5-en; Proto-dioscin; Furostan saponin; Synthesis
1. Introduction
was found unique against the 60 tumor cell lines in the
NCI’s anticancer screening.3a Furostan saponins are
difficult to obtain from natural sources; enzymatic or
acidic cleavage of the 26-O-glucopyranosyl residue,
followed by an intramolecular acetalization, converts
furostan saponins readily into the corresponding spiro-
stan saponins. In fact, furostan saponins are regarded as
A quite common feature of spirostan saponins is their
inhibitory activities against the growth of tumor cells,
with the potency being highly dependent of the 3-O-
sugar residue. Those bearing a chacotriosyl residue at
the 3-OH are among the most active examples.1 Dioscin
(diosgenin 3-O-b-chacotrioside), one of the most abun-
dant spirostan saponins occurring in plants, represents a
well-studied example, showing promising antitumor
activities both in vitro and in vivo.1;2 The furostan
O
Me
Me
Me
O
proto-dioscin, 3-O-b-chacotriosyl-26-O-b-D-glucopyr-
Me
α-L-Rha-(1-4)
anosyl-22-hydroxyl-(25R)-furost-5-en, and its 22-meth-
oxyl derivative are as potent as dioscin in inhibition of
the growth of tumor cells (IC50s at the lM level).1;3
Interestingly, the cytotoxicity pattern of proto-dioscin
β-D-Glc
α-L-Rha-(1-2)
O
Dioscin
Me
R
O
Me
Me
26
O
Me
Abbreviations: TBDMS, tert-butyldimethylsilyl-; TBDPS, tert-butyl-
diphenylsilyl-; 1-BBTZ, 1-(benzoyloxy)benzotriazole; TBAF, tetra-
butylammonium fluoride; DMAP, 4-(dimethylamino)pyridine; SRB,
sulforhodamine B
α-L-Rha-(1-4)
β-D-Glc
α-L-Rha-(1-2)
β-D-Glc
3
O
Proto-dioscin: R = OH
* Corresponding authors. Tel.: +86-21-6416-3300; fax: +86-21-6416-
6128; e-mail addresses: liyx417@ouc.edu.cn; byu@mail.sioc.ac.cn
Methyl proto-dioscin: R = OMe
1: R = H
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.04.014

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Y. Zhang et al. / Carbohydrate Research 339 (2004) 1753–1759
the biosynthetic precursors of the spirostan saponins.4
Recently, a synthetic approach toward proto-dioscin
has been reported,5 but a practical access still awaits
elaboration. Thus, compound 1, namely 3-O-b-chaco-
Me
H
O
Me
Me
a
Diosgenin
OR
Me
triosyl-26-O-b-
D
-glucopyranosyl-(25R)-furost-5-en,
a
2 R = H
HO
b
3 R = TBDPS
4, c
synthetically easily accessible mimic of proto-dioscin
attracts attention.6 Here we report a facile synthesis of 1
as well as its congeners with different substituents at the
26-OH (13–15) for antitumor evaluation.
OBz
O
BzO
BzO
O
CCl3
OBz
NH
4
Me
H
O
Me
Me
OTBDPS
Me
2. Results and discussion
OBz
O
5
BzO
BzO
In the recent synthesis of compound 1,6 Oscarson and
co-workers subjected the 3-O-TBDMS protected dios-
genin to a mild reductive procedure (BH3ÆMe3N/AlCl3)
to provide the 3-O-TBDMS-dihydrodiosgenin. Sub-
sequent glucosylation of the 26-OH, deprotection of the
3-OTBDMS, assembly of the 3-O-chacotriosyl moiety,
and final removal of the benzyl protecting groups on the
sugar residues afforded the target compound 1. We in-
tended to assemble the 3-O-chacotriosyl linkage before
the attachment of the 26-O-glucosyl residue; thus the
synthetic route would be applicable to the preparation
of the 3-O-chacotrioside congeners with different sugar
residues at the 26-OH. For assembly of the 3-O-chaco-
trioside, we planed to adopt the procedure we developed
for the synthesis of dioscin, where acyl-protected glu-
cosyl and rhamnosyl imidates were employed to ensure
formation of the 1,2-trans glycosidic bonds and a facile
final deprotection.7
O
d
OBz
Me
H
O
Me
Me
OTBDPS
Me
OR
O
1O
R
O
6 R = R1 = H
RO
e
1
7 R = Bz, R1 = H
O
R
NH
CCl3
Me
f
O
O
AcO
AcO
8
AcO
Me
H
Me
Me
O
OR
Me
OBz
O
O
O
BzO
9 R = TBDPS
10 R = H
g
O
Me
O
AcO
AcO
4, h
O
AcO
The synthetic route toward 1 is depicted in Scheme 1.
Reductive opening of the spiroketal of diosgenin with
LiAlH4/AlCl3 gave dihydrodiosgenin 2 in 95% yield.8
Selective protection of the primary 26-OH was achieved
with a TBDPS group to provide 3 (82%). Compound 3
Me
OAc
Me
AcO
AcO
H
O
Me
Me
O
Me
OBz
O
O
OBz
O
O
11
1
was treated with 2,3,4,6-tetra-O-benzoyl-D-glucopyr-
BzO
BzO
O
O
Me
O
BzO
anosyl trichloroacetimidate (4) in the presence of
TMSOTf (0.1 equiv) in CH2Cl2, affording the 3-O-b-
glucopyranoside 5 in an excellent yield (97%).9 Removal
of the benzoyl groups with NaOMe in MeOH readily
gave 6, which was subjected to 1-BBTZ (1-(benzoyl-
oxy)benzotriazole) in the presence of Et3N in CH2Cl2 to
selectively protect the 3,6-OHs of the glucopyranosyl
residue, affording 2,4-diol 7 in a satisfactory 61%
i
AcO
BzO
AcO
AcO
Me
OAc
AcO
AcO
Scheme 1. Reagents and conditions: (a) LiAlH4, AlCl3, Et2O–CH2Cl2,
0 ꢁC fi rt, 1 h, 95%; (b) TBDPSCl, imidazole, DMAP, CH2Cl2, rt, 1 h,
82%; (c) TMSOTf (0.1 equiv), CH2Cl2, 4 A MS, 0 ꢁC fi rt, 97%; (d)
NaOMe, MeOH, rt, 2 h, 97%; (e) 1-BBTZ, CH2Cl2, Et3N, rt, 48 h,
ꢀ
ꢀ
61%; (f) TMSOTf (0.2 equiv), CH2Cl2, 4 A MS, )30 ꢁC fi rt; (g)
TBAF, HOAc, THF, rt, 16 h, 72% (two steps); (h) TMSOTf
yield.7;10 Glycosylation of 7 with 2,3,4-tri-O-acetyl-
L-
ꢀ
rhamnopyranosyl trichloroacetimidate (8) under ‘inverse
addition’ conditions11 provided a crude 9. After cleavage
of the 26-OTBDPS with TBAF in the presence of HOAc
in THF, the desired key intermediate 10 was then con-
veniently purified in 72% yield (two steps). Similar con-
ditions as those used for the glucosylation of the 3-OH of
4 were applied to the coupling of the 26-OH of 10, but led
to only moderate yield of the desired 11 (62%). Finally,
ready removal of the acetyl and benzoyl groups (Na-
OMe, MeOH) furnished the target 1 in 86% yield.
(0.1 equiv), CH2Cl2, 4 A MS, 0 ꢁC fi rt, 62%; (i) NaOMe, MeOH, rt,
overnight, 86%.
Starting from the readily available 3-O-peracylchaco-
triosyl-26-OH derivative 10, the desired congeners with
a different substituent at 26-OH were easily prepared
(Scheme 2). Glycosylation of the 26-OH of 10 with per-
O-acetyl-L-rhamnopyranosyl and per-O-benzoyllactosyl
trichloroacetimidate (8 and 1212) under common con-
ditions (0.1 equiv of TMSOTf, CH2Cl2), followed by

Y. Zhang et al. / Carbohydrate Research 339 (2004) 1753–1759
1755
Me
2.5 mmol) in anhydrous Et2O (40 mL) was added with
stirring over a period of 15 min. Stirring was continued
for 15 min at 0 ꢁC and then 1 h at rt. The mixture was
treated cautiously with water and 10% H2SO4. The
resulting mixture was extracted with Et2O, and the
combined extracts were washed with dilute NaHCO3
solution, dried over Na2SO4, and then concentrated.
The residue was purified by column chromatography
(1:2:1 EtOAc–petroleum ether–CHCl3) to give 2 as a
white solid (0.99 g, 95%): Rf 0.25 (1:1:1 EtOAc–petro-
leum ether–CHCl3); mp 164–166 ꢁC (lit.8c 166–169 ꢁC);
10
H
O
Me
Me
a, b
or b
OR
Me
α-L-Rha-(1-4)
β-D-Glc
α-L-Rha-(1-2)
O
13: R = α-L-Rha
14: R = β-D-Gal-(1-4)-β-D-Glc
15: R = H
BzO
OBz
OBz
O
O
O
CCl3
O
BzO
BzO
OBz
OBz
NH
½aŠ20 )48.8 (c 0.65, CHCl3); 1H NMR (DMSO-d6): d 5.26
D
12
(d, 1H, J ¼ 5.5 Hz, H-6), 4.60 (d, 1H, J 4.7 Hz, 3-OH),
4.36 (t, 1H, J 5.5 Hz, 26-OH), 4.20 (m, 1H, H-16), 3.25–
3.16 (m, 4H, H-3, H-26, H-22), 2.16–2.06 (m, 2H), 1.93–
1.88 (m, 2H), 1.76 (m, 1H), 1.68 (m, 3H), 1.56–1.31 (m,
10H), 1.19–1.03 (m, 4H), 0.99 (m, 1H), 0.96 (m, 6H, H-
19, H-21), 0.87 (m, 1H), 0.81 (d, 3H, J 6.6 Hz, H-27),
0.75 (s, 3H, H-18); ESIMS (m=z): 439.318 [M+Naþ];
calcd 439.318.
Scheme 2. Reagents and conditions: (a) 8 or 12, TMSOTf (0.1 equiv),
ꢀ
CH2Cl2, 4 A MS, )30 ꢁC fi rt; (b) MeONa, MeOH, rt, 18% (for 13,
two steps); 62% (for 14, two steps); 76% (for 15).
removal of the acetyl and benzoyl groups with NaOMe
in MeOH, readily provided the bidesmosidic saponins
13 and 14, after silica gel column chromatography, in
18% and 64% yield, respectively. Direct cleavage of the
acetyl and benzoyl groups on 10 provided the 26-OH
derivative 14.
Compounds 1 and 13–15 were examined for their
inhibitory activity against the human lung adenocarci-
noma A-549, a proto-dioscin-sensitive cell line (IC50
1.64 lM), following the standard SRB(sulforhodamine
B) assay procedure.3c Unfortunately, little inhibition
was observed at and below the concentration of 10 lM.
These results imply that proto-dioscin (generally furo-
stan saponins) might be also inactive, but could be
readily convert into the antitumor active dioscin (gen-
erally spirostan saponins).
3.1.2. 26-O-tert-Butyldiphenylsilyl-3b-hydroxy-(25R)-fu-
rost-5-en (3). TBDPSCl (0.2 mL, 0.79 mmol) was added
dropwise to a stirred mixture of 2 (0.3 g, 0.72 mmol),
imidazole (0.12 g, 1.8 mmol), and DMAP (catalytic
amount) in CH2Cl2 (25 mL) at 10 ꢁC. The mixture was
stirred for 20 min at rt. Removal of solvent afforded a
residue that was subjected to column chromatography
(1:6:1 EtOAc–petroleum ether–CHCl3) to give 3 as a
¼
buff solid (0.39 g, 82%): Rf 0.20 (1:6:1 EtOAc–petroleum
20
ether–CHCl3); mp 47.5–49.0 ꢁC; ½aŠ )34.2 (c 0.61,
D
CHCl3); 1H NMR (DMSO-d6): d 7.61–7.60 (m, 4H,
ArH), 7.47–7.41 (m, 6H, ArH), 5.26 (d, 1H, J 5.2 Hz, H-
6), 4.61 (d, 1H, J 4.7 Hz, 3-OH), 4.20 (m, 1H, H-16),
3.48 (m, 2H), 3.26–3.19 (m, 2H), 2.16–2.06 (m, 2H),
1.92–1.88 (m, 2H), 1.75 (m, 1H), 1.67–1.61 (m, 4H),
1.56–1.45 (m, 7H), 1.38–1.02 (m, 6H), 1.00 (s, 9H), 0.96
(m, 1H), 0.95 (m, 6H, H-19, H-21), 0.90 (m, 1H), 0.88 (d,
3H, J 6.6 Hz, H-27), 0.73 (s, 3H, H-18). 13C NMR
(DMSO-d6): d 141.3, 135.0, 133.2, 129.8, 127.8, 120.3,
89.3, 82.3, 79.2, 69.9, 68.1, 64.6, 56.2, 49.6, 42.2, 40.1,
39.1, 37.3, 36.9, 36.2, 35.1, 31.9, 31.3 (2C), 31.2, 30.3,
29.5, 26.6, 20.2, 19.1, 18.9, 18.8, 16.7, 16.1; ESIMS
(m=z): 677.437 [M+Naþ]; calcd 677.436.
3. Experimental
3.1. General methods
Solvents were purified in the usual way. TLCs were
performed on precoated E. Merck Silica Gel 60 F254
plates. Flash column chromatography was performed
on silica gel (100–200 mesh, Qingdao, China). Optical
rotations were determined with a Perkin–Elmer Model
241 MC polarimeter. Melting points were determined
1
with a ‘Yanaco’ apparatus and were uncorrected. H
3.1.3. 26-O-tert-Butyldiphenylsilyl-3b-O-(2,3,4,6-tetra-O-
NMR and 13C NMR spectra were taken on a JEOL
JNM-ECP 600 MHz spectrometer with tetramethyl-
silane (TMS) as an internal standard, and chemical shifts
are recorded in d values. Mass spectra were obtained on
a HP5989A or a VG Quatro mass spectrometer.
benzoyl-b- -glucopyranosyl)-(25R)-furost-5-en (5). To a
D
mixture of compound 3 (2.88 g, 4.4 mmol), 4 (4.0 g,
ꢀ
5.4 mmol), and powdered 4 A molecular sieves in dried
CH2Cl2 (70 mL) at 0 ꢁC was added TMSOTf (78 lL,
0.44 mmol). After stirring at 0 ꢁC for 0.5 h and then at rt
for 1 h, the reaction was quenched with Et3N. The solid
was then filtered off. The filtrate was concentrated under
vacuum to give a yellow oil that was purified by column
chromatography (1:10:1 EtOAc–petroleum ether–
CHCl3) to give compound 5 as a buff solid (5.23 g, 96%):
3.1.1. 3b,26-Dihydroxy-(25R)-furost-5-en (2). To a stir-
red ice-cold solution of AlCl3 (14.0 g, 0.10 mol) in
anhydrous Et2O (40 mL) was carefully added LiAlH4
(0.95 g, 0.025 mol). Then a solution of diosgenin (1.04 g,

1756
Y. Zhang et al. / Carbohydrate Research 339 (2004) 1753–1759
Rf 0.15 (1:10:1 EtOAc–petroleum ether–CHCl3); mp
7.7, 13.2 Hz, H-16), 3.77–3.74 (m, 2H, H-40, H-50), 3.68
(dd, 1H, J 8.0, 9.5 Hz, H-20), 3.58 (m, 1H, H-3), 3.52 (dd,
1H, J 5.5, 9.8 Hz, H-26), 3.45 (dd, 1H, J 6.2, 9.9 Hz, H-
26), 3.34 (br s, 1H, 40-OH), 3.30 (td, 1H, J 4.0, 7.7 Hz,
H-22), 2.49 (br s, 20-OH), 2.37–1.28 (m, 22H), 1.10 (m,
1H), 0.88 (m, 1H), 1.04 (s, 9H), 1.00 (s, 3H, H-19), 0.99
(d, 3H, J 6.2 Hz, H-21), 0.93 (d, 3H, J 6.6 Hz, H-27),
0.79 (s, 3H, H-18). 13C NMR (CDCl3): d 167.9, 166.9,
140.3, 135.7, 134.2, 133.6, 133.3, 130.1, 130.0, 129.9,
129.6, 129.5, 128.6, 128.5, 127.7, 122.1, 101.6, 90.5, 83.2,
79.9, 78.7, 77.3, 77.1, 76.9, 74.4, 72.2, 69.9, 68.8, 65.4,
63.9, 57.1, 50.2, 40.8, 39.6, 38.9, 38.0, 37.2, 36.9, 36.1,
32.3, 32.1, 32.0, 31.7, 31.2, 30.2, 29.8, 29.5, 27.0, 22.8,
20.8, 19.4, 19.2, 17.0, 16.5, 14.2. ESIMS (m=z): 1047.540
[M+Naþ]; calcd 1047.541.
20
D
127.5–129 ꢁC. ½aŠ +7.3 (c 0.81, CHCl3); 1H NMR
(DMSO-d6): d 7.96–7.42 (m, 30H, ArH), 5.98–5.95 (m,
1H, H-30), 5.56 (t, 1H, J 9.5 Hz, H-40), 5.32 (m, 2H, H-20,
H-10), 5.19 (d, 1H, J 4.0 Hz, H-6), 4.53–4.46 (m, 3H, H-
60, H-50), 4.20 (m, 1H, H-16), 3.49–3.44 (m, 3H), 3.20
(m, 1H), 2.26–1.03 (m, 23H), 0.99 (s, 9H), 0.94 (d, 3H, J
6.6 Hz, H-21), 0.87 (d, 3H, J 6.6 Hz, H-27), 0.85 (m,
1H), 0.84 (s, 3H, H-19), 0.70 (s, 3H, H-18). 13C NMR
(DMSO-d6): d 165.3, 165.1, 164.7, 164.6, 139.8, 135.0,
133.8, 133.7, 133.4, 133.3, 133.2, 129.8, 129.2, 129.1,
129.0, 128.8, 128.7 (2C), 128.4, 127.8, 121.4, 98.4, 89.3,
82.3, 79.0, 73.2, 71.9, 70.8, 69.6, 68.1, 64.5, 62.7, 56.2,
49.4, 40.1, 38.8, 38.4, 37.3, 36.5, 36.1, 35.1, 31.9, 31.4,
31.0, 30.3, 29.4, 29.1, 26.6, 20.1, 18.9, 18.8, 16.7, 16.1.
ESIMS (m=z): 1256.3 [M+1+Naþ].
3.1.6. 26-O-tert-Butyldiphenylsilyl-3b-O-[2,4-di-O-(2,3,4-
3.1.4. 26-O-tert-Butyldiphenylsilyl-3b-O-(b-
D
-glucopyr-
tri-O-acetyl-a-
L
-rhamnopyranosyl)-3,6-di-O-benzoyl-b-D-
glucopyranosyl]-(25R)-furost-5-en (9). To a mixture of 7
anosyl)-(25R)-furost-5-en (6). Compound 5 (200 mg)
was dissolved in 1:1 CH3OH–CHCl3 (15 mL), and then
NaOMe (100 mg) was added. After stirring at rt for 2 h,
the solution was neutralized with ion-exchange resin
(Hþ) and then filtered and concentrated. The residue
was purified by column chromatography (8:1 CHCl3–
MeOH) to afford 6 as a white solid (128 mg, 97%): Rf
0.41 (5:1 CHCl3–MeOH); mp 157–158 ꢁC. ½aŠ )39.1 (c
ꢀ
(1.10 g, 1.07 mmol) and powdered 4 A molecular sieves
in dried CH2Cl2 (20 mL) at )30 ꢁC, TMSOTf (43 lL,
0.25 mmol) was added, followed by dropwise addition
of a solution of 8 (2.33 g, 5.35 mmol) in CH2Cl2 (15 mL).
After stirring at )30 ꢁC for 0.5 h and then at 0 ꢁC for 1 h,
the reaction was quenched with Et3N. The solid was
then filtered off, and the filtrate was concentrated under
vacuum to give a yellow oil. The oil was subjected to
column chromatography (1:3 EtOAc–petroleum ether to
1:2 EtOAc–petroleum ether) to give crude 9 that was
directly subjected to the next reaction. Part of the crude
product (50 mg) was purified with precoated plates of
Silica Gel GF254 (0.25 mm, Qingdao) to afford pure 9 for
20
D
0.77, CHCl3); 1H NMR (DMSO-d6): d 7.61 (m, 4H,
ArH), 7.47–7.41 (m, 6H, ArH), 5.33 (d, 1H, J 5.2 Hz, H-
6), 4.90 (d, 1H, J 4.7 Hz, 30-OH), 4.87 (t, 2H, J 5.5 Hz,
20-OH, 40-OH), 4.43 (t, 1H, J 5.8 Hz, 60-OH), 4.22 (d,
1H, J 7.7 Hz, H-10), 4.19 (m, 1H, H-16), 3.65 (dd, 1H, J
5.5, 9.9 Hz, H-60), 3.20 (m, 1H, H-22), 3.12 (td, 1H, J
4.7, 8.4 Hz, H-30), 3.07 (m, 1H, H-50), 3.02 (td, 1H, J 5.2,
9.2 Hz, H-40), 2.89 (td, 1H, J 4.7, 8.0 Hz, H-20), 2.37 (dd,
1H, J 2.9, 13.6 Hz), 2.14–1.05 (m, 23H), 1.00 (s, 9H),
0.97 (s, 3H, H-19), 0.94 (d, 3H, J 6.6 Hz, H-21), 0.88 (d,
3H, J 6.6 Hz, H-27), 0.74 (s, 3H, H-18). 13C NMR
(DMSO-d6): d 140.5, 135.0, 133.3, 129.8, 127.8, 121.1,
100.7, 89.3, 82.3, 76.8 (2C), 73.5, 70.1, 68.1, 64.6, 61.1,
56.2, 49.6, 40.2, 38.8, 37.3, 36.8, 36.4, 35.1, 31.9, 31.5,
31.2, 30.3, 29.5, 29.3, 20.2, 19.1, 18.9, 18.8, 16.8, 16.1.
ESIMS (m=z): 839.473 [M+Naþ]; calcd 839.470.
analysis: Rf 0.15 (EtOAc–petroleum ether–CHCl3,
20
D
1:10:1) mp 69–70 ꢁC. ½aŠ )33.6 (c 0.22, CHCl3); 1H
NMR (CDCl3): d 8.06–7.36 (m, 20H, ArH), 5.62 (t, 1H,
J 9.1 Hz, H-30), 5.35 (d, 1H, J 5.0 Hz, H-6), 5.16 (d, 1H,
J 3.7 Hz, H-3(rha)), 5.15 (d, 1H, J 3.7 Hz, H-3(rha)),
5.12 (m, 1H, H-2(rha)), 4.98 (dd, 1H, J 1.9, 3.7 Hz, H-
2(rha)), 4.91 (t, 1H, J 10.1 Hz, H-4(rha)), 4.88 (t, 1H, J
10.1 Hz, H-4(rha)), 4.85 (d, 1H, J 1.9 Hz, H-1(rha)), 4.79
(dd, 1H, J 10.1 Hz, H-60), 4.76 (d, 1H, H-1(rha)), 4.67 (d,
1H, J 7.8 Hz, H-1(rha)), 4.51 (dd, 1H, J 5.5, 12.4 Hz, H-
60), 4.36–4.34 (m, H-5(rha)), 4.32–4.29 (m, H-16), 3.97
(t, 1H, J 9.2 Hz, H-40), 3.86 (ddd, 1H, J 1.8, 5.0, 7.3 Hz,
H-50), 3.79 (t, 1H, J 9.2 Hz, H-20), 3.72 (m, 1H, H-
5(rha)), 3.58 (m, 1H, H-3), 3.52 (dd, 1H, J 5.5, 9.7 Hz,
H-26), 3.45 (dd, 1H, J 6.4, 9.6 Hz, H-26), 3.30 (td, 1H, J
4.1, 7.8 Hz, H-22), 2.41–0.82 (m, 24H), 1.99, 1.95, 1.92,
1.89, 1.74 (s each, 3H each, OAcꢀ6), 1.16 (d, 3H, J
6.4 Hz, CH3(rha)), 1.05 (s, 9H), 0.99 (d, 3H, J 6.4 Hz, H-
21), 0.96 (s, 3H, H-19), 0.93 (d, 3H, J 6.8 Hz, H-27), 0.79
(s, 3H, H-18), 0.68 (d, 3H, J 6.4 Hz, CH3(rha)). 13C
NMR (CDCl3): d 170.0 (2C), 169.9, 169.7, 168.9, 165.8,
165.0, 140.0, 135.6, 134.1, 133.3, 133.0, 130.1, 129.9,
129.8, 129.5, 129.1 (2C), 128.4 (2C), 127.6, 122.1, 99.6,
99.0, 98.0, 90.4, 83.1, 79.5, 76.2, 76.0, 73.0, 71.0, 70.5,
3.1.5. 26-O-tert-Butyldiphenylsilyl-3b-O-(3,6-di-O-ben-
zoyl-b- -glucopyranosyl)-(25R)-furost-5-en (7). To a
D
stirred solution of compound 6 (1.49 g, 1.83 mmol) and
1-BBTZ (1.09 g, 4.53 mmol) in CH2Cl2 (30 mL) at rt was
added Et3N (0.63 mL, 4.55 mmol). The reaction mixture
was stirred at rt for 48 h. Removal of the solvent affor-
ded a residue that was subjected to column chroma-
tography (1:3 EtOAc–petroleum ether) to give 7 as a
buff solid (1.15 g, 61%): Rf 0.14 (1:3 EtOAc–petroleum
20
D
ether); mp 82–83 ꢁC. ½aŠ )17.9 (c 0.62, CHCl3); 1H
NMR (CDCl3): d 8.10–7.37 (m, 20H, ArH), 5.35 (d, 1H,
J 5.1 Hz, H-6), 5.21 (t, 1H, J 9.2 Hz, H-30), 4.70–4.63 (m,
2H, H-60), 4.55 (d, 1H, J 7.7 Hz, H-10), 4.30 (q, 1H, J

Y. Zhang et al. / Carbohydrate Research 339 (2004) 1753–1759
1757
70.0, 69.1, 68.8, 68.7, 68.5, 67.5, 66.5, 65.2, 62.8, 56.9,
50.2, 40.7, 39.4, 38.4, 37.9, 37.0, 36.8, 36.0, 32.2, 32.0,
31.5, 31.1, 30.1, 29.7, 26.9, 22.7, 20.8, 20.7, 20.6, 20.3,
19.3, 19.2, 19.1, 17.2, 16.9 (2C), 16.4, 14.1. ESIMS
(m=z): 1591.722 [M+Naþ]; calcd 1591.721.
trated under vacuum to give a yellow oil that was
purified by column chromatography (2:3 EtOAc–
petroleum ether to 4:5 EtOAc–petroleum ether) to give
11 as a white solid (89 mg, 62%): Rf 0.37 (1:1 EtOAc–
20
petroleum ether); mp 121.0–121.5 ꢁC. ½aŠ )30.1 (c 0.77,
D
CHCl3); 1H NMR (CDCl3): d 8.06–7.27 (m, 30H, ArH),
5.89 (t, 1H, J 9.8 Hz, H-300), 5.68 (t, 1H, J 9.5 Hz, H-400),
5.62 (t, 1H, J 9.2 Hz, H-30), 5.54 (dd, 1H, J 8.0, 9.8 Hz,
H-200), 5.35 (d, 1H, J 5.1 Hz, H-6), 5.16 (d, 1H, J 3.3 Hz,
H-3(rha)), 5.15 (d, 1H, J 3.7 Hz, H-3(rha)), 5.12 (m, 1H,
H-2(rha)), 4.98 (dd, 1H, J 1.8, 3.7 Hz, H-2(rha)), 4.92 (t,
1H, J 9.9 Hz, H-4(rha)), 4.88 (t, 1H, J 9.9 Hz, H-4(rha)),
4.86 (d, 1H, J 1.8 Hz, H-1(rha)), 4.86–4.79 (m, 2H, H-60,
H-100), 4.76 (d, 1H, H-1(rha)), 4.68 (d, 1H, J 7.7 Hz, H-
10), 4.62 (dd, 1H, J 3.3, 12.1 Hz, H-600), 4.51 (m, 2H, H-
60, H-600), 4.35 (m, 1H, H-5(rha)), 4.21 (m, 1H, H-16),
4.14 (m, 1H, H-500), 3.97 (t, 1H, J 9.2 Hz, H-40), 3.86
(ddd, 1H, J 1.9, 5.1, 7.3 Hz, H-50), 3.80 (t, 1H, J 8.8 Hz,
H-20), 3.74–3.70 (m, 2H, H-5(rha), H-26), 3.57 (m, 1H,
H-3), 3.36 (dd, 1H, J 6.2, 9.5 Hz, H-26), 3.05 (td, 1H, J
3.7, 8.4 Hz, H-22), 2.41–0.80 (m, 24H), 1.98, 1.95, 1.92,
1.89, 1.74 (s each, 3H each, OAcꢀ6), 1.16 (d, 3H, J
6.2 Hz, CH3(rha)), 0.95 (s, 3H, H-19), 0.87 (d, 3H, J
6.6 Hz, H-21), 0.78 (d, 3H, J 6.6 Hz, H-27), 0.74 (s, 3H,
H-18), 0.68 (d, 3H, J 6.2 Hz, CH3(rha)). 13C NMR
(CDCl3): d 170.0 (2C), 169.9, 169.6, 168.9, 166.1, 165.8,
165.2, 165.0 (2C), 140.0, 133.4, 133.3, 133.2, 133.1 (2C),
133.0, 130.0–128.2, 122.0, 101.4, 99.5, 99.0, 98.0, 90.1,
83.0, 79.5, 77.4, 76.2, 75.3, 72.9, 72.9, 72.0, 71.9, 71.0,
70.4, 70.0, 69.8, 69.1, 68.7, 68.5, 67.5, 66.4, 65.1, 63.2,
62.8, 56.9, 50.0, 40.6, 39.3, 38.4, 37.8, 36.9, 36.7, 33.4,
32.2, 32.0, 31.5, 30.7, 30.3, 29.6, 20.8, 20.7 (2C), 20.6,
20.3, 17.1, 16.8, 16.4, 16.3; ESIMS (m=z): 1931.761
[M+Naþ]; calcd 1931.760.
3.1.7. 26-Hydroxy-3b-O-[2,4-di-O-(2,3,4-tri-O-acetyl-a-
L
-rhamnopyranosyl)-3,6-di-O-benzoyl-b-D-glucopyranosyl]-
25(R)-furost-5-en (10). A solution of the above crude
compound 9 (1.44 g) in anhyd THF (10 mL) was treated
with 1:1 TBAF–HOAc (1.0 M in THF, 10 mL). After
stirring for 12 h at rt, the solution was diluted with
EtOAc and washed with water. The organic layer was
dried and concentrated. The residue was purified by
column chromatography (4:5 EtOAc–petroleum ether to
1:1 EtOAc–petroleum ether) to afford 10 as a buff foam
solid (0.87 g, 72% yield for two steps): Rf 0.27 (1:1
20
D
EtOAc–petroleum ether); mp 116–117 ꢁC. ½aŠ )44.2 (c
1
0.64, CHCl3); H NMR (CDCl3): d 8.05 (m, 4H, ArH),
7.59–7.55 (m, 2H, ArH), 7.47–7.42 (m, 4H, ArH), 5.62
(t, 1H, J 9.1 Hz, H-30), 5.35 (d, 1H, J 5.1 Hz, H-6), 5.16
(d, 1H, J 3.7 Hz, H-3(rha)), 5.15 (d, 1H, J 3.7 Hz, H-
3(rha)), 5.12 (m, 1H, H-2(rha)), 4.98 (dd, 1H, J 1.9,
3.7 Hz, H-2(rha)), 4.91 (t, 1H, J 9.9 Hz, H-4(rha)), 4.88
(t, 1H, J 9.9 Hz, H-4(rha)), 4.85 (d, 1H, J 1.5 Hz, H-
1(rha)), 4.80 (dd, 1H, J 1.8, 12.1 Hz, H-60), 4.76 (d, 1H,
H-1(rha)), 4.67 (d, 1H, J 7.7 Hz, H-10), 4.51 (dd, 1H, J
5.5, 12.4 Hz, H-60), 4.37–4.30 (m, 2H, H-5(rha), H-16),
3.97 (t, 1H, J 9.2 Hz, H-40), 3.86 (ddd, 1H, J 2.2, 5.5,
9.5 Hz, H-50), 3.80 (t, 1H, J 7.7 Hz, H-20), 3.74–3.69 (m,
1H, H-5(rha)), 3.58 (m, 1H, H-3), 3.51 (dd, 1H, J 6.2,
10.6 Hz, H-26), 3.45 (dd, 1H, J 5.9, 10.6 Hz, H-26), 3.34
(td, 1H, J 4.4, 8.1 Hz, H-22), 2.67 (br s, 1H, 26-OH),
2.41–0.86 (m, 24H), 1.99, 1.99, 1.95, 1.92, 1.89, 1.74 (s
each, 3H each, OAcꢀ6), 1.16 (d, 3H, J 6.2 Hz,
CH3(rha)), 1.01 (d, 3H, J 7.0 Hz, H-21), 0.95 (s, 3H, H-
19), 0.92 (d, 3H, J 6.5 Hz, H-27), 0.80 (s, 3H, H-18), 0.68
(d, 3H, J 6.2 Hz, CH3(rha)). 13C NMR (CDCl3): d 170.0,
169.9, 169.7, 168.9, 165.8, 165.0, 140.0, 133.3, 133.0,
130.1, 129.9, 129.8, 129.1, 128.4 (2C), 122.1, 99.5, 99.0,
98.0, 90.4, 83.2, 79.5, 76.2, 73.0, 71.0, 70.5, 70.0, 69.1,
68.8, 68.5, 68.1, 67.5, 66.5, 65.1, 62.8, 56.9, 52.6, 50.0,
40.7, 39.4, 38.4, 37.9, 37.0, 36.7, 35.7, 32.2, 32.0, 31.5,
30.4, 30.2, 29.7, 20.8, 20.7, 20.6, 20.3, 19.2, 18.9, 17.2,
16.9, 16.6, 16.5, 13.9. ESIMS (m=z): 1353.597 [M+Naþ];
calcd 1353.603.
3.1.9.
rhamnopyranosyl)-b-
26-O-b-
D
-Glucopyranosyl-3b-O-[2,4-di-O-(a-
D
L-
-glucopyranosyl]-(25R)-furost-5-en
(1). Compound 11 (89 mg) was dissolved in 1:1 CH3OH–
CHCl3 (15 mL), and then NaOMe (100 mg) was added.
After stirring at rt for 12 h, the solution was neutralized
with ion-exchange resin (Hþ), filtered, and concentrated.
The residue was purified by column chromatography
(60:20:1 CHCl3–MeOH–H2O) to afford 1 as a white
solid (41 mg, 86%): Rf 0.25 (60:20:1 CHCl3–MeOH–
20
D
1
H2O), mp 209–211 ꢁC. ½aŠ )67.3 (c 0.63, CH3OH); H
NMR (CD3OD): d 5.38 (d, 1H, J 5.2 Hz, H-6), 5.19 (d,
1H, J 1.4 Hz, H-1(rha)), 4.83 (d, 1H, J 1.5 Hz, H-
1(rha)), 4.49 (d, 1H, J 8.1 Hz, H-1(glc)), 4.31 (m, 1H, H-
16), 4.22 (d, 1H, J 7.7, H-1(glc)), 4.12 (m, 1H), 3.92 (m,
2H), 3.85 (dd, 1H, J 1.9, 11.7 Hz), 3.82 (dd, 1H, J 1.4,
2.9 Hz), 3.78 (dd, 1H, J 2.2, 12.5 Hz), 3.72 (dd, 1H, J
6.6, 9.5 Hz), 3.67–3.56 (m, 6H), 3.51 (t, 1H, J 9.5 Hz),
3.41–3.22 (m, 9H), 3.17 (dd, 1H, J 7.7, 9.2 Hz), 2.45–
0.95 (m, 24H), 1.25 (d, 3H, J 6.2 Hz, CH3(rha)), 1.23 (d,
3H, J 6.2 Hz, CH3(rha)), 1.04 (s, 3H, H-19), 1.01 (d, 3H,
J 6.5 Hz, H-21), 0.93 (d, 3H, J 6.6 Hz, H-27), 0.83 (s,
3.1.8. 26-O-(2,3,4,6-Tetra-O-benzoyl-b-
syl)-3b-O-[2,4-di-O-(2,3,4-tri-O-acetyl-a- -rhamnopyrano-
syl)-3,6-di-O-benzoyl-b- -glucopyranosyl]-(25R)-furost-5-
D-glucopyrano-
L
D
en (11). To a mixture of 10 (100 mg, 0.075 mmol), 4
ꢀ
(100 mg, 0.135 mmol), and powdered 4 A molecular
sieves in dried CH2Cl2 (10 mL) at 0 ꢁC was added
TMSOTf (2.5 lL). After stirring for 0.5 h at 0 ꢁC and
then 1 h at rt, the reaction was quenched with Et3N. The
solid was then filtered off, and the filtrate was concen-

1758
Y. Zhang et al. / Carbohydrate Research 339 (2004) 1753–1759
3H, H-18). 13C NMR (CD3OD): d 141.9, 122.6, 104.6,
103.0, 102.3, 100.4, 91.7, 84.6, 80.0, 79.3, 79.2, 78.1,
78.0, 77.9, 76.6, 76.1, 75.2, 73.9, 73.7, 72.5, 72.4, 72.2,
71.7, 70.7, 69.8, 66.5, 62.8, 61.9, 58.2, 51.7, 41.8, 40.6,
39.5, 39.1, 38.6, 38.0, 34.7, 33.2, 33.1, 32.9, 31.7, 31.4,
30.7, 21.8, 19.8, 19.2, 18.0, 17.9, 17.2, 17.0. ESIMS
(m=z): 1055.539 [M+Naþ]; calcd 1055.540.
19.8, 19.2, 18.0, 17.9, 17.2, 17.0. ESIMS (m=z): 1217.590
[M+Naþ]; calcd 1217.593.
3.1.12. 3b-O-[2,4-Di-O-(a-
L
-rhamnopyranosyl)-b-D-gluco-
pyranosyl]-26-hydroxy-(25R)-furost-5-en (15). Com-
pound15 was synthesized from 10 by the same
procedure as that used for 1. Compound 15 was purified
by column chromatography (5:1 CHCl3–MeOH to 1:1
CHCl3–MeOH) to give a white solid (76%): Rf 0.32 (2:1
20
D
3.1.10. 26-O-a-
rhamnopyranosyl)-b-
(13). Compound 13 was synthesized from 10 by the same
procedure as that used for compound 1. Compound 13
was purified by column chromatography (2:1 CHCl3–
L
-Rhamnopyranosyl-3b-O-[2,4-di-O-(a-
L-
-glucopyranosyl]-(25R)-furost-5-en
CHCl3–MeOH); mp 211–213.5 ꢁC. ½aŠ )71.1 (c 0.63,
D
1
CH3OH); H NMR (CD3OD): d 5.37 (d, 1H, J 5.2 Hz,
H-6), 5.19 (d, 1H, J 1.4 Hz, H-1(rha)), 4.83 (d, 1H, J
1.5 Hz, H-1(rha)), 4.49 (d, 1H, J 8.1 Hz, H-1(glc)), 4.33–
4.29 (m, 1H, H-16), 4.15–4.10 (m, 1H), 3.93–3.91 (m,
2H), 3.81 (dd, 1H, J 1.8, 3.3 Hz), 3.78 (dd, 1H, J 2.2,
12.5 Hz), 3.66–3.56 (m, 5H), 3.51 (t, 1H, J 9.5 Hz), 3.42–
3.30 (m, 7H), 2.45–0.92 (m, 24H), 1.25 (d, 3H, J 6.2 Hz,
CH3(rha)), 1.23 (d, 3H, J 6.2 Hz, CH3(rha)), 1.04 (s, 3H,
H-19), 1.01 (d, 3H, J 6.5 Hz, H-21), 0.91 (d, 3H, J
6.6 Hz, H-27), 0.83 (s, 3H, H-18). 13C NMR (CD3OD): d
142.0, 122.6, 103.0, 102.3, 100.4, 91.7, 84.6, 80.0, 79.3,
79.2, 78.0, 76.6, 73.9, 73.7, 72.5, 72.4, 72.2, 70.7, 69.8,
68.3, 66.5, 61.9, 58.2, 51.7, 41.8, 40.6, 39.5, 39.1, 38.6,
38.0, 37.0, 33.2, 33.1, 32.9, 31.9, 31.2, 30.7, 21.8, 19.8,
19.2, 18.0, 17.9, 17.0. ESIMS (m=z): 893.490 [M+Naþ];
calcd 893.487.
MeOH to 1:1 CHCl3–MeOH) to give a white solid
(18%): Rf 0.42 (1:2 CHCl3–MeOH); mp 184–187 ꢁC. ½aŠ
20
D
1
)69.6 (c 0.68, CH3OH); H NMR (CD3OD): d 5.37 (d,
1H, J 5.2 Hz, H-6), 5.19 (d, 1H, J 1.1 Hz, H-1(rha)), 4.83
(d, 1H, J 1.5 Hz, H-1(rha)), 4.76 (d, 1H, J 1.4 Hz, H-
1(rha)), 4.49 (d, 1H, J 8.1 Hz, H-1(glc)), 4.31 (m, 1H, H-
16), 4.13 (m, 1H), 3.96 (dd, 1H, J 1.8, 3.3 Hz), 3.93–3.32
(m, 19H), 3.25 (dd, 1H, J 5.9, 9.5 Hz), 2.44 (dd, 1H, J
10.6 Hz), 2.29 (t, 1H, J 10.6 Hz), 2.03–1.26 (m, 19H),
1.25–1.23 (m, 9H, CH3·3(rha)), 1.18–1.06 (m, 2H), 1.04
(s, 3H, H-19), 1.01 (d, 3H, J 6.6 Hz, H-21), 0.97 (m, 1H),
0.94 (d, 3H, J 6.6 Hz, H-27), 0.83 (s, 3H, H-18). 13C
NMR (CD3OD): d 141.9, 122.6, 103.0, 102.3, 100.5,
100.4, 91.6, 84.6, 80.4, 80.0, 79.3, 79.2, 78.0, 76.6, 74.3,
73.9, 73.7, 72.5, 72.4, 72.3, 72.2, 72.0, 70.7, 70.2, 69.9,
69.8, 66.5, 61.9, 58.2, 51.7, 41.8, 40.6, 39.5, 39.1, 38.6,
38.0, 34.7, 33.2, 33.1, 32.9, 32.0, 31.6, 30.7, 21.8, 19.8,
19.3, 18.2, 19.0, 17.9, 17.5, 17.0.
Acknowledgements
This work is supported by the National Basic Research
Program of China (2003CB716400) and the Chinese
Academy of Sciences.
3.1.11. 26-O-(4-O-b-
anosyl-3b-O-[2,4-di-O-(a-
D
-Galactopyranosyl)-b-
D
-glucopyr-
-gluco-
L
-rhamnopyranosyl)-b-
D
References
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synthesized from 10 by the same procedure as that used
for compound 1. Compound 14 was purified by column
chromatography (2:1 CHCl3–MeOH to 1:1 CHCl3–
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20
MeOH); mp 230–232 ꢁC. ½aŠ )44.7 (c 0.52, CH3OH);
D
1H NMR (CD3OD): d 5.37 (d, 1H, J 5.2 Hz, H-6), 5.19
(d, 1H, J 1.4 Hz, H-1(rha)), 4.82 (d, 1H, J 1.5 Hz, H-
1(rha)), 4.49 (d, 1H, J 7.7 Hz, H-1(glc)), 4.35 (d, 1H, J
7.7 Hz, H-1(glc)), 4.31 (m, 1H, H-16), 4.26 (d, 1H, J
7.7 Hz, H-1(gal)), 3.94–3.31 (m, 29H), 3.24 (dd, 1H, J
7.7, 9.2 Hz), 2.44 (dd, 1H, J 2.6, 13.2 Hz), 2.29 (t, 1H, J
11.3 Hz), 2.03–0.95 (m, 22H), 1.25 (d, 3H, J 6.2 Hz,
CH3(rha)), 1.23 (d, 3H, J 6.2 Hz, CH3(rha)), 1.04 (s, 3H,
H-19), 1.01 (d, 3H, J 6.5 Hz, H-21), 0.93 (d, 3H, J
6.6 Hz, H-27), 0.83 (s, 3H, H-18). 13C NMR (CD3OD): d
141.9, 122.6, 105.1, 104.5, 103.0, 102.3, 100.4, 91.6, 84.6,
80.7, 80.0, 79.3, 79.2, 78.0, 77.1, 76.6, 76.5, 76.4, 76.2,
74.8, 73.9, 73.7, 72.6 (2C), 72.5, 72.4, 72.2, 70.7, 70.3,
69.8, 66.5, 62.5, 61.9, 58.2, 51.7, 41.8, 40.6, 39.5, 39.1,
38.6, 38.0, 34.7, 33.2, 33.1, 32.9, 31.7, 31.4, 30.7, 21.8,
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