Synthesis of (25R)-ruscogenin-1-yl β-D-xylopyranosyl-(1→3)- [β-D-glucopyranosyl-(1→2)]-β-D-fucopyranoside

Article abstract of DOI:10.1016/S0008-6215(00)00244-5

The synthesis of (25R)-ruscogenin-1-yl β-D-xylopyranosyl-(1→3)- [β-D-glucopyranosyl-(1→2)]-β-D-fucopyranoside, a saponin from the tuber of Liriope muscari (Decne.) Bailey, is described.

Full text of DOI:10.1016/S0008-6215(00)00244-5

www.elsevier.nl/locate/carres
Carbohydrate Research 329 (2000) 745–754
Synthesis of (25R)-ruscogenin-1-yl
b-
D
-xylopyranosyl-(1“3)-[b-
D
-glucopyranosyl-(1“2)]-
b-
D
-fucopyranoside
Meizheng Liua, Biao Yu a,*1, Xiangyang Wu a, Yongzheng Hui a,*2, Kwok-Pui Fung b
aState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
bDepartment of Biochemistry, The Chinese Uni6ersity of Hong Kong, Hong Kong
Received 15 June 2000; accepted 8 August 2000
Abstract
The synthesis of (25R)-ruscogenin-1-yl b-
D
-xylopyranosyl-(1“3)-[b-
D
-glucopyranosyl-(1“2)]-b-D-fucopyran-
oside, a saponin from the tuber of Liriope muscari (Decne.) Bailey, is described. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: (25R)-Ruscogenin-1-yl b-
D
-xylopyranosyl-(1“3)-[b-
D
-glucopyranosyl-(1“2)]-b-D-fucopyranoside; Saponin; Synthesis
1. Introduction
cari (Decne.) Bailey [2]. This saponin was
reported to have strong in vivo anti-inflamma-
tory and immunopharmacological activities
[3]. Herein, we report a total synthesis of this
saponin [4].
Various Ophiopogon and Liriope species
have been commonly used as a traditional
Chinese herbal medicine under the name of
Maidong, which possesses tonic effects [1].
Saponins are believed to be the active princi-
ples in Maidong plants. Thus far, more than
60 steroidal saponins have been isolated from
these species, and most of these saponins are
(25R or 25S)-ruscogenin-1-yl saponins [1]. Sa-
2. Results and discussion
Saponin 1 was retrosynthetically discon-
nected into trisaccharide donor 2 and steroid
acceptor 3 (Scheme 1). Trichloroacetimidate
donor 2, which lacks a functional group for
neighboring-group participation, was envi-
sioned to achieve the formation of the desired
ponin 1, namely (25R)-ruscogenin-1-yl b-
xylopyranosyl - (1“3) - [b - - glucopyranosyl-
-fucopyranoside, with the typical
D
-
D
(1“2)]-b-
D
structure, has been isolated from Liriope mus-
b
D
-glycosidic linkage via an S 2 reaction [5].
N
Steroid 3 would conceivably be derived from
diosgenin by introduction of a 1b-OH. The
3-OH of 3 was believed to be more active than
the 1b-OH and would, therefore, be protected
as a TBS ether.
E-mail address: byu@pub.sioc.ac.cn (B. Yu).
1 *Corresponding author. Tel.: +86-21-64163300; fax: +
86-21-64166128.
2 *Corresponding author.
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00244-5

746
M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
[6]. Oxidation of diosgenin with DDQ gave
the trienone 4, which was further oxidized
with H2O2 in the presence of NaOMe to
provide the epoxide 5. The transformation of
epoxide 5 into diol under Li/NH3 reduction
conditions was found to be capricious. Both
5
6
D -1a,3b-diol 6, D -1a,3b-diol 7 and several
other unidentified products were produced in
varying amounts. Under carefully controlled
anhydrous conditions, 6 was obtained in
ꢀ50% yield, without any isomer 7 being de-
tected. If a proton source was provided during
the reduction by repeatedly charging with
solid NH4Cl [7], 7 turned out to be the major
1
product (42%). The H NMR spectrum of 6
showed one broad doublet at 5.50 ppm (J 5.2
Hz) for H-6, while that of 7 showed two
doublets at 5.39 ppm (J 10.0 Hz) and 5.28
ppm (J 10.0 Hz), respectively, for H-6 and
Scheme 1. Retrosynthesis of saponin 1.
As shown in Scheme 2, the b-OH was read-
ily introduced onto C-1 of the commercially
available diosgenin using a similar strategy to
that employed in the conversion of cholestane-
type steroids into vitamin D and its analogues
H-7. Diol
6
was treated with tert-
butylchlorodimethylsilane and imidazole in
DMF to give 8. Subsequently, attempts to
invert the 1a-OH of 8 into the b configuration
Scheme 2. Reagents and conditions: (a) DDQ, dioxane, reflux, 8 h, 69%; (b) H2O2, NaOMe, MeOH, rt, overnight, 68%; (c)
Li/NH3, THF, then NH4Cl, ꢀ50% (for 6); (d) TBSCl, imidazole, DMF, rt, overnight, 100%; (e) PDC, CH2Cl2, rt, 92%; (f)
NaBH4, THF, 70% (for 3); (g) Ac2O, DMAP, pyridine, 94%; (h) 5 N HCl, acetone, rt, 1 h, 96%.

M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
747
Scheme 3. Reagents and conditions: (a) 3% HCl, AllOH, 80 °C, 93%; (b) (CH3)2C(OCH3)2, TsOH (0.1 equiv), rt, 83%; (c) 14,
,
BF3·Et2O (0.7 equiv), CH2Cl2, 4 A molecular sieves, −20 °C, 73%; (d) 50% HOAc, 60 °C, 93%; (e) CH3C(OCH3)3, TsOH (0.1
equiv), rt, 20 min, then 20% HOAc, rt, overnight, 87%; (f) 18, BF3·Et2O (0.7 equiv), CH2Cl2, 4 A molecular sieves, −20 °C, 90%;
,
(g) ICF2(CF2)4CF2Cl, Na2S2O4, NaHCO3, CH3CN–H2O, rt; (h) Zn, NH4Cl, EtOH, reflux, 76% (2 steps); (i) Cl3CCN, DBU,
CH2Cl2, 81%.
by the Mitsunobu reaction [8] were unsuccess-
ful. It could be explained that the reaction
center at C-1 of 8 was seriously hindered by
the methyl group at C-19 and the TBSO
group at C-3. Therefore, an oxidation–reduc-
tion sequence was utilized to effectively
epimerize the 1a-OH of 8. Thus, 8 was oxi-
dized by PDC to give ketone 9 (92%). Reduc-
tion of 9 with NaBH4 mainly provided the
expected 1b-OH product 3 (70%), with 8 being
obtained in 25% yield. This stereoselectivity
can be attributed to the bulkiness of TBS
substitution on 3b-OH. Because in similar
cases without 3-substitution, the 1a-epimer
was the predominant product [9]. In order to
confirm its structure, 3 was acetylated to give
Trisaccharide trichloroacetimidate 2 was
synthesized as shown in Scheme 3. 1,2:3,4-Di-
O-isopropylidene-a-
D
-fucopyranoside
(11),
readily prepared from galactose in three steps
[10], was treated with 3% HCl in allyl alcohol
to give allyl a- -fucopyranoside 12 in high
D
yield (93%). Treatment of 12 with 2,2-
dimethoxypropane and a catalytic amount of
TsOH provided 13 with the 2-OH free. Glyco-
sylation of 13 with 2,3,4,6-tetra-O-acetyl- -
D
glucopyranosyl trichloroacetimidate (14) with
promotion of BF3·OEt2 led to the disaccharide
15 in good yield (73%). Removal of the O-iso-
propylidene group with 50% HOAc readily
afforded diol 16. Since it has been commonly
found that the equatorial 3-OH is more active
than the axial 4-OH for galactopyranose, ara-
binopyranose and fucopyranose derivatives
[11], a regioselective glycosylation of 16, giv-
ing a 1“3 linked product, was expected.
However, glycosylation of 16 with 2,3,4-tri-O-
1
ester 10. The H NMR signal for H-1 was
moved downfield from 3.50 ppm (in 3) to 4.58
ppm (dd, J 11.9, 4.4 Hz), and an obvious
NOE signal showed up between H-1 and H-3
of 10. Furthermore, desilylation of 3 with 5 N
HCl afforded (25R)-ruscogenin, whose physi-
cal data was identical to that of an authentic
sample.
acetyl-
D
-xylopyranosyl
trichloroacetimidate
(18) with promotion by BF3·OEt2 gave a mix-
ture of the 3-O-, 4-O-, and 3,4-di-O-xylosy-

748
M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
,
Scheme 4. Reagents and conditions: (a) TMSOTf (0.2 equiv), −5ꢀ0 °C, CH2Cl2, 4 A molecular sieves, 2 h, 69% (for 22); (b)
TMSOTf (2.0 equiv), −78 °C, CH2Cl2, 5 min; (c) MeONa–MeOH, rt, 3 h, 85%.
lated products in comparable amounts. There-
fore, diol 16 was acetylated in a regioselective
manner at 4-OH by treatment with triethy-
lorthoacetate and a catalytic amount of
TsOH, followed with 20% HOAc, providing
eliminated under Zn and NH4Cl in EtOH to
afford 20 in 76% yield. Addition of 20 with
CCl3CN afforded
2
in 81% yield.
Trichloroacetimidate 2 was confirmed to be in
1
the a configuration by H NMR analysis: l
1
17 in 87% yield [12]. 2D H NMR analysis of
6.40 (d, 1 H, J 3.5 Hz, H-1).
17 showed that the signal at 5.25 ppm (t, J 3.4
Hz) corresponding to Fuc-H-4 moved
downfield from 4.00 ppm in 16 to 5.25 ppm,
demonstrating that only the 4-OH of 17 was
masked with an acetyl group. Subsequently,
17 was easily xylosylated with 18 to give the
desired trisaccharide 19 in high yield (90%).
1H NMR analysis of 19 showed that the sig-
nals for the anomeric protons were at 4.98
ppm (d, J1,2 3.2 Hz), 4.59 ppm (d, J1%,2% 7.8
Hz), and 4.64 ppm (d, J1%%,2%% 6.3 Hz), respec-
tively, indicating that the desired glycosidic
linkages of 1a, 1%b, and 1%%b were obtained.
Deallylation of trisaccharide 19 using PdCl2
in HOAc [13], followed by treatment with
CCl3CN and DBU, afforded the trisaccharide
trichloroacetimidate 2 in 43% yield. The rela-
tively low yield of the above transformation
resulted from side reactions during deallyl-
ation under PdCl2. For example, Wacker oxi-
dation products were produced in consider-
able amounts, which were inseparable from
the deallylation product 20 [14,15]. Therefore,
we applied our recently developed method for
deallylation [15]. Treatment of 19 with
C6ClF12I and Na2S2O4–NaHCO3 in CH3CN–
H2O provided the corresponding b-iodido-g-
perfluoroalkane derivative, which was then
With donor 2 and acceptor 3 at hand, we
sought to effect the final glycosylation to as-
semble the target saponin 1 (Scheme 4). How-
ever, coupling of 3 with trichloroacetimidate
donors (either trisaccharide donor 2 or simple
monosaccharide donor 21 [16]) under normal
conditions for Schmidt’s glycosylation [5] was
found to be difficult, conceivably due to the
steric hindrance of the 1b-OH of 3. Finally,
employing Schmidt’s ‘inverse procedure’ [17]
in which the acceptor 3 was first activated by
a catalytic amount of TMSOTf before addi-
tion of the glycosyl donors (21 or 2), we
obtained the desired glycosylation products 22
(69%) and 23 (46%, together with 10% of its a
1
anomer), respectively. H NMR analysis of 23
showed the signals for three anomeric protons
at 4.89 ppm (d, J 7.8 Hz), 4.84 ppm (d, J 7.7
Hz), and 4.31 ppm (d, J 7.3 Hz), respectively,
representing that the expected glycosidic 1%b,
1%%b, 1%%%b linkages were obtained. Desilylation
of 23 with 2.0 equivalents of TMSOTf under
low temperature (−78 °C) cleanly afforded
the desired desilylated product (on TLC),[18]
which was directly subjected to NaOMe–
MeOH to furnish saponin 1 in 85% yield. The
physical data for the synthetic sample was in
good agreement with those reported [2].

M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
749
min, and then ammonia (100 mL) was trapped
in the flask. Lithium wire was cut into short
pieces and added. After being stirred for 1 h,
epoxide 5 (100 mg, 0.23 mmol) in THF (10
mL) was added dropwise during 30 min. The
cooling bath was removed, and the mixture
was allowed to warm to −40 °C for 20 min.
The flask was dipped in a cooling bath and
anhydrous NH4Cl was added during 2 h
(note: take care! vigorous reaction). The mix-
ture turned white and pasty. Most of the
ammonia was removed in a stream of argon.
The residue was diluted with ether, washed
with brine and dried. Evaporation left a white
solid that was applied to a silica gel column
(1:1 petroleum ether–EtOAc) to afford 6 (54
mg, 53%) as a white solid: mp\230 °C;
[h]2D0−160.7° (c 0.54, CHCl3); IR (KBr); w
3441, 2954, 920, 900 cm−1 (intensity 900\
3. Experimental
General methods.—See Ref. [19].
(25R)-Spirostan-1,4,6-triene-3-one (4).—A
solution of diosgenin (4.49 g, 10.8 mmol) and
dichlorodicyanobenzoquinone (DDQ) (7.38 g,
30.5 mmol) in dioxane (200 mL) was heated
under reflux for 8 h, and then cooled, filtered
and applied to a short column of silica gel
(CH2Cl2) to gave a crude product, which was
further purified by a silica gel column chro-
matography (3:1 petroleum ether–EtOAc) to
afford 4 (3.04 g, 69%) as a white solid: mp
194–195 °C; [h]D20 −109.5° (c 0.1, CHCl3); IR
(KBr); w 2972 (s), 1668 (s), 1049 (m) cm−1; H
1
NMR (300 MHz, CDCl3): l 7.04 (d, 1 H, J
10.0 Hz), 6.23 (d, 2 H, J 9.8 Hz), 6.02 (d, 1 H,
J 13.3 Hz), 6.00 (s, 1 H), 4.42 (dd, 1 H, J 14.2,
7.5 Hz), 3.47 (m, 1 H), 3.35 (t, 1 H, J 10.9
Hz), 1.21 (s, 3 H), 0.97 (d, 3 H, J 6.9 Hz), 0.90
(s, 3 H), 0.80 (d, 3 H, J 6.2 Hz); EIMS (m/z):
409 [M++1], 408 [M+]; HREIMS (m/z):
Calcd for C27H36O3: 408.2664. Found:
408.2637.
1
920). H NMR (300 MHz, CDCl3): l 5.50
(brd, 1 H, J 5.7 Hz), 4.40 (q, 1 H, J 7.1 Hz),
3.51–3.31 (m, 4 H), 1.00 (s, 3 H), 0.92 (d, 3 H,
13
J 6.8 Hz), 0.78 (m, 6 H); C NMR (75 MHz,
CDCl3): l 137.30, 125.39, 109.27, 80.73, 72.85,
66.83, 66.36, 62.05, 56.34, 41.83, 41.67, 41.36,
40.22, 39.48, 38.22, 31.86, 31.36, 30.27, 29.66,
28.78, 20.07, 19.46, 17.10, 16.23, 14.47; EIMS
(m/z): 431 [M++1], 430 [M+], 412 (M+−
H2O).
1h,2h-Epoxy-(25R)-spirostan-4,6-dien-3-
one (5).—H2O2 (30%, 1 mL) was added to a
solution of trienone 4 (30 mg, 0.073 mmol) in
MeOH (20 mL) containing 0.2% NaOMe. The
mixture was stirred at 15 °C overnight and
then diluted with ether (20 mL). The organic
layer was dried and concentrated. The residue
was purified by a silica gel column chromatog-
raphy (3:1 petroleum ether–EtOAc) to give 5
(21.2 mg, 68%) as a white solid: mp 167–
168 °C; [h]2D0−17.1° (c 0.23, CHCl3); IR
(KBr): w 2981 (s), 1730 (s), 1670 (s), 1620,
(25R)-Spirostan-6-en-1h,3i-diol
(7).—A
solution of epoxide 5 (100 mg, 0.23 mmol) in
dry liquid NH3 (10 mL) and THF (10 mL) at
−78 °C under argon was stirred for 1 h and
warmed up to −30 °C. To the above solu-
tion, NH4Cl (110 mg) was added, followed by
lithium pieces (12 mg). After the blue color
faded, the addition of NH4Cl (80 mg) and
lithium pieces (12 mg) was repeated six times.
After the mixture was kept blue for 2 h, the
reaction was charged with NH4Cl at −78 °C,
then diluted with EtOAc (20 mL). The organic
layer was washed with brine, dried over
Na2SO4 and then concentrated. The residue
was purified by a silica gel column chromatog-
raphy (1:1 petroleum ether–EtOAc) to give 7
(42 mg, 42%) as a white solid: mp\230 °C;
[h]2D0−167.8° (c 0.33, CHCl3); IR (KBr): w
3441, 2954, 920, 900 cm−1 (intensity 900\
1460, 1080 (m) cm−1; H NMR (300 MHz,
1
CDCl3): l 6. 08 (m, 2 H), 5.66 (d, 1 H, J 0.9
Hz), 4.44 (q, 1 H, J 10.0 Hz), 3.59 (d, 1 H, J
4.1 Hz), 3.48–3.45 (m, 2 H), 3.40 (t, 1 H, J
10.8 Hz), 1.20 (s, 3 H), 0.98 (d, 3 H, J 6.9 Hz),
0.90 (s, 3 H), 0.80 (d, 3 H, J 6.3 Hz); EIMS
(m/z): 425 [M++1], 424 [M+]; HREIMS (m/
z): Calcd for C27H36O4 424.2614. Found:
424.2649.
(25R)-Spirostan-5-en-1h, 3i-diol (6).—A
three-necked flask was fitted with a dropping
funnel, a cold-finger condenser filled with
solid CO2, and an inlet tube connected to an
ammonia source, with gas drying by KOH.
Argon was swept through the system for 10
1
920). H NMR (300 MHz, CDCl3): l 5.40
(brd, 1 H, J 12.0 Hz), 5.28 (brd, 1 H, J 12.0

750
M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
(M+−Me), 485 [M+−tBu, 100%]. Anal.
Calcd for C33H54O4Si: C, 73.01; H, 10.03.
Found: C, 73.02; H 10.50.
Hz), 4.35 (m, 1 H), 3.98 (m, 1 H), 3.79 (t, 1
H), 3.41 (m, 1 H), 3.31 (t, 1 H, J 10.8 Hz),
0.90 (d, 3 H, J 6.8 Hz), 0.75 (s, 3 H), 0.74 (s,
3 H), 0.72 (d, 3 H, J 6.3 Hz); 13C NMR (75
MHz, CDCl3): l 130.72, 128.03, 109.25, 80.81,
72.02, 67.21, 66.83, 62.07, 54.14, 46.60, 41.52,
39.80, 38.65, 38.42, 37.77, 36.96, 35.95, 31.58,
31.35, 30.24, 28.75, 20.45, 17.10, 16.48, 14.46,
12.47; EIMS (m/z): 431 [M++1], 430 [M+],
412 [M+−H2O]; HREIMS (m/z): Calcd for
C27H42O4: 430.3083. Found: 430.3095.
3i-O-tert-Butyldimethylsilyl-(25R)-rusco-
genin (3).—To a solution of 9 (110 mg, 0.20
mmol) in dry THF (20 mL) was added NaBH4
(67 mg, 0.20 mmol). After being stirred at rt
for 2 h, the reaction was quenched by addition
of water (0.1 mL). The mixture was then
concentrated in vacuo. The residue was
purified by silica gel column chromatography
(6:1 petroleum ether–EtOAc) to give 8 (27
mg, 25%) and 3 (77 mg, 70%) as white solids.
3: mp\230 °C; [h]D20 −76.3° (c 0.11, CHCl3);
IR (KBr); w 3481, 2953, 2860, 1045, 921, 900
3i-O-tert-Butyldimethylsilyl-(25R)-spiro-
stan-5-en-1h-ol (8).—A solution of 6 (342 mg,
0.80 mmol), tert-butylchlorodimethylsilane
(145 mg, 0.96 mmol), and a catalytic amount
of imidazole in DMF (8 mL) was stirred
overnight. The mixture was poured into water
and extracted with EtOAc. The combined ex-
tracts were washed with aq NaHCO3, brine
and water, respectively, and then dried over
Na2SO4 and concentrated to dryness. The
residue was purified by a silica gel column (6:1
petroleum ether–EtOAc) to afford 8 (218 mg,
100%) as a white solid: mp\230 °C; [h]D20
1
cm−1 (intensity 900\921); H NMR (300
MHz, CDCl3): l 5.51 (brd, 1 H, J 5.6 Hz),
4.40 (q, 1 H, J 6.7 Hz), 3.55–3.39 (m, 4 H),
1.03 (s, 3 H), 0.91 (d, 3 H, J 6.7 Hz), 0.88 (s,
9 H), 0.79 (d, 3 H, J 6.0 Hz), 0.78 (s, 3 H),
0.09 (s, 6 H); EIMS (m/z): 544 [M+], 543
[M+−1], 526 [M+−H2O], 487 [M+−tBu].
Anal. Calcd for C33H56O4Si: C, 72.74; H,
10.37. Found: C, 72.34; H, 10.39.
1
+338.7° (c 0.11, CHCl3); H NMR (CDCl3):
1i-O-Acetyl-3i-O-tert-butyldimethylsilyl-
(25R)-ruscogenin (10).—A solution of 3 (10
mg, 0.018 mmol) in Ac2O and pyridine (1:1, 2
mL) was stirred overnight and then concen-
trated with toluene to dryness. The residue
was purified by a silica gel column chromatog-
raphy (15:1 petroleum ether–EtOAc) to af-
ford 10 (10 mg, 94%) as a white solid: mp.
210–211 °C; [h]D20 −120.7° (c 0.25, CHCl3);
1H NMR (300 MHz, CDCl3): l 5.54 (brd, 1
H, J 5.2 Hz), 4.58 (dd, 1 H, J 11.9, 4.4 Hz),
4.38 (m, 1 H), 3.56–3.46 (m, 3 H), 3.36 (t, 1
H, J 10.7), 0.95 (d, 3 H, J 6.9 Hz), 0.87 (s, 12
H), 0.79 (d, 3 H, J 5.8 Hz), 0.77 (s, 3 H), 0.05
(s, 3 H), 0.04 (s, 3 H); EIMS (m/z): 587
[M++1], 586 [M+], 585 [M+−1], 529 [M+
−tBu].
(25R)-Ruscogenin.—To a solution of 3 (10
mg, 0.018 mmol) in acetone (5 mL) was added
5 N HCl (0.5 mL). After stirring at rt for 1 h,
the solution was diluted with EtOAc (20 mL).
The organic extract was washed with 5%
NaHCO3, dried over anhydrous Na2SO4 and
evaporated to dryness. The residue was
purified by silica gel column chromatogra-
phy (1:1 petroleum ether–EtOAc) to give
l 5.50 (brd, 1 H, J 5.2 Hz), 4.35 (q, 1 H, J 7.1
Hz), 3.87 (m, 1 H), 3.75 (brs, 1 H), 3.41 (m, 1
H), 3.31 (t, 1 H, J 10.8 Hz), 0.98 (s, 3 H), 0.91
(d, 3 H, J 6.7 Hz), 0.82 (s, 9 H), 0.74 (d, 3 H),
0.70 (d, 3 H), 0.01(s, 6 H); EIMS (m/z): 526
[M+−H2O], 487 (M+−tBu). Anal. Calcd for
C33H56O4Si: C 72.74; H 10.37. Found: C
72.62; H 10.67.
3i-O-tert-Butyldimethylsilyl-(25R)-spiro-
stan-5-en-1-one (9).—To a solution of 8 (79
mg, 0.15 mmol) in CH2Cl2 (5 mL) was added
pyridinium dichromate (PDC, 100 mg). The
mixture was stirred at rt for 1 h and then
filtered through a pad of Celite. The filtrates
were concentrated. The residue was purified
by silica gel column chromatography (20:1
petroleum ether–EtOAc) to give 9 (72 mg,
92%) as a white solid: mp 215–216 °C; [h]D20
−25.8° (c 0.06, CHCl3); IR (KBr); w 2955,
2859, 1708 (s), 921, 901 cm−1 (intensity 901\
1
921). H NMR (300 MHz, CDCl3): l 5.59
(brd, 1 H, J 5.3 Hz), 4.41 (m, 1 H), 3.74 (m, 1
H), 3.47 (m, 1 H), 3.37 (t, 1 H, J 10.6 Hz),
0.97 (d, 3 H, J 6.7 Hz), 0.94 (s, 12 H), 0.79 (d,
3 H), 0.78 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H);
EIMS (m/z): 543 [M+ +1], 542 [M+], 527

M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
751
Allyl(2,3,4,6-tetra-O-acetyl-i-
osyl)-(1“2)-3,4-O-isopropylidene-h- -fuco-
D
-glucopyran-
(25R)-ruscogenin (7.6 mg, 96%) as a white
solid: mp\230 °C; [h]2D0 −91.4° (c 0.50,
CHCl3); H NMR (300 MHz, CDCl3): l 5.54
D
1
pyranoside (15).—To a suspension of 13 (0.96
g, 3.94 mmol), trichloroacetimidate 14 (2.13 g,
(brd, 1 H, J 5.6 Hz), 4.40 (m, 1 H), 3. 56 (m,
1 H), 3.48–3.41 (m, 2 H), 3.37 (t, 1 H, J 10.9
Hz), 1.05 (s, 3 H), 0.99 (d, 3 H, J 6.1 Hz), 0.97
(d, 3 H, J 6.6 Hz), 0.80 (s, 3 H). 13C NMR:
138.2, 125.4, 109.3, 80.8, 77.9, 68.1, 66.9, 62.3,
56.5, 50.4, 42.9, 42.4, 42.0, 41.7, 40.1, 39.9,
32.4, 32.04, 32.0, 31.4, 30.3, 28.8, 23.8, 17.1,
16.3, 14.5, 13.0; EIMS (m/z): 430 [M+], 412
[M+−H2O]; HREIMS (m/z): Calcd for
C27H42O4: 430.3083. Found: 430.3047.
,
4.33 mmol), and 4 A molecular sieves (1.0 g)
in dry CH2Cl2 (10 mL) under argon at
−40 °C, was added BF3·Et2O (0.25 mL, 1.87
mmol) dropwise. After stirring for 3 h, the
mixture was treated with satd aq NaHCO3 (1
mL) and then diluted with CH2Cl2 (100 mL).
The organic layer was separated, dried with
sodium sulfate and then concentrated in
vacuo. The residue was purified by silica gel
column chromatography (3:1 petroleum–
EtOAc) to give 15 (1.65 g, 73%) as a white
solid: mp 81–82 °C; [h]2D0 +47.0° (c 0.36,
Allyl h-
O-isopropylidene-a-
D
-fucopyranoside (12).—1,2;3,4-Di-
D-fucopyranoside (11)
(5.93 g, 24.3 mmol) was suspended and heated
in a allyl alcohol solution (100 mL) containing
3% HCl at 80 °C for 2 h until the solution
became clear. The resulting solution was then
concentrated in vacuo to afford a colorless
residue, which was purified by silica gel
column chromatography (15:1 CHCl3–
MeOH) to give 12 (4.99 g, 93%) as a white
1
CHCl3); H NMR (300 MHz, CDCl3): l 5.87
(m, 1 H), 5.29–5.02 (m, 5 H), 4.88 (d, 1 H, J
3.5 Hz), 4.86 (d, 1 H, J 7.9 Hz), 4.26–4.10 (m,
5 H), 4.02–3.98 (m, 2 H), 3.78 (m, 1 H), 3.67
(m, 1 H) 2.07, 2.03, 2.00, 1.95 (s each, 3 H
each), 1.50, 1.33 (s each, 3 H each), 1.32 (d, 3
H, J 6.5 Hz); EIMS (m/z): 559 [M+−CH3].
Anal. Calcd for C26H38O14: C, 54.35; H, 6.62.
Found: C, 53.97; H, 6.84.
1
solid: [h]2D0 +42.9° (c 0.8, CHCl3). H NMR
(300 MHz, CDCl3): l 5.93 (m, 1 H), 5.32 (m,
1 H), 4.88 (d, 1 H, J 3.7 Hz), 4.15 (m, 1 H),
4.08–3.98 (m, 2 H), 3.84–3.68 (m, 3 H);
EIMS (m/z): 205 [M++1], 147 [M+−OAll,
100%]. HREIMS (m/z): Calcd for C9H16O5+
1-H2O: 187.0892. Found: 187.0945.
Allyl(2,3,4,6-tetra-O-acetyl-i-
D
-glucopyran-
osyl)-(1“2)-h- -fucopyranoside (16).—A so-
D
lution of 15 (1.58 g, 0.75 mmol) in 50% AcOH
(26 mL) was heated at 60 °C for 1.5 h and
then concentrated in vacuo. The residue was
purified by silica gel column chromatography
(1:1 petroleum–EtOAc) to afford 16 (1.36 g,
93%) as a white solid: mp 131–132 °C; [h]D20
Allyl 3,4-O-isopropylidene-h- -fucopyran-
D
oside (13).—To a solution of 12 (3.0 g, 0.015
mol) and 2,2-dimethoxypropane (4.7 mL,
0.036 mol) in CH2Cl2 (10 mL) was added a
catalytic amount of p-TsOH·H2O. After stir-
ring overnight, the mixture was neutralized
with triethylamine and then concentrated. The
residue was purified by silica gel column chro-
matography (4:1 petroleum–EtOAc) to give
13 (2.98 g, 83%) as a white solid: mp 47–
1
+89.4° (c 0.1, CHCl3); H NMR (300 MHz,
CDCl3): l 5.92 (m, 1 H), 5.30 (dd, 1 H, J 17.3,
1.5 Hz), 5.21 (t, 1 H, J 9.4 Hz), 5.17 (t, 1 H,
J 10.3 Hz), 5.06 (t, 1 H, J 9.7 Hz), 5.04 (dd, 1
H, J 9.4, 8.0 Hz), 4.98 (d, 1 H, J 3.1 Hz), 4.78
(m, 1 H), 4.20–3.97 (m, 6 H), 3.87 (t, 1 H, J
9.7 Hz), 3.84 (m, 1 H), 3.70 (m, 1 H), 2.08,
2.05, 2.03, 2.00 (s each, 3 H each), 1.28 (d, 3
H, J 6.5 Hz); ESIMS (m/z): 573 [M+K+],
557 [M+Na+], 553 [M++1+H2O]. Anal.
Calcd for C23H34O14: C, 51.66; H, 6.41.
Found: C, 51.38; H 6.24.
1
48 °C; [h]2D0 +19.7° (c 0.5, CHCl3); H NMR
(300 MHz, CDCl3): l 5.91 (m, 1 H), 5.29–5.20
(m, 2 H), 4.86 (d, 1 H, J 3.9 Hz), 4.24 (dd, 1
H, J 12.4, 4.0 Hz), 4.21 (dd, 1 H, J 6.4, 6.0
Hz), 4.13 (ddd, 1 H, J 12.3, 6.9, 1.3 Hz), 4.05
(m, 1 H), 4.04 (m, 1 H), 3.79 (m, 1 H), 1.51 (s,
3 H), 1.34 (s, 3 H), 1.31 (d, 3 H); EIMS (m/z):
245 [M+ +1], 229 [M+−CH3], 187 [M+−
OAll, 100%]; HREIMS (m/z): Calcd for
C12H20O5: 244.1311. Found: 244.1296.
Allyl(2,3,4,6-tetra-O-acetyl-i-
D
-glucopyran-
osyl)-(1“2)-4-O-acetyl-h- -fucopyranoside
D
(17).—To a solution of 16 (1.40 g, 2.62 mmol)
in CH2Cl2 (20 mL) was added triethyl or-
thoacetate (2.2 mL) and p-TsOH·H2O (10

752
M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
mg). After stirring at rt for 20 min, 20%
HOAc (15 mL) was added, and the mixture
was vigorously stirred overnight. CH2Cl2 (40
mL) was added to the mixture, and the solu-
tion was sequentially washed with water, aq
NaHCO3 and water. It was then dried and
concentrated to a residue. The residue was
purified by silica gel column chromatography
(1:1 petroleum–EtOAc) to give (17) (1.32 g,
87%) as a white solid: mp 109–110 °C; [h]D20
H), 3.33 (m, 1 H, J 8.0 Hz), 2.16, 2.15, 2.14,
2.09, 2.03, 2.02, 2.01, 1.99 (s each, 3 H each),
1.09 (d, 3 H, J 6.4 Hz); ESIMS (m/z): 858
[M+1+Na+], 853 [M++1+H2O]. Anal.
Calcd for C36H50O22: C, 51.78; H, 6.00.
Found: C, 51.54; H 6.20.
2,3,4,6-Tetra-O-acetyl-i-
(1“2)-[(2,3,4-tri-O-acetyl-i-
osyl)-(1“3)]-4-O-acetyl-h- -fucopyranosyl
D
-glucopyranosyl-
D
-xylopyran-
D
trichloroacetimidate (2). To a mixture of 19
(200 mg, 0.24 mmol) in CH3CN–H2O (4:1, 15
mL), was added C6ClF12I (135 mg, 0.29
mmol), followed by addition of a mixture of
Na2SO4 (25 mg, 0.14 mmol) and NaHCO3 (12
mg, 0.14 mmol). After stirring at rt for 1 h,
the mixture was extracted with EtOAc. The
organic layer was washed with brine, dried
over anhydrous Na2SO4 and then concen-
trated to give a residue. To a solution of the
above residue in dry EtOH (5 mL) was added
Zn (40 mg, 0.6 mmol) and NH4Cl (16 mg,
0.12 mmol). After refluxing for 10 min, the
mixture was filtered. The filtrates were concen-
trated and then purified by silica gel column
chromatography (1:1 petroleum ether–
EtOAc) to give 20 (148 mg, 76%, a mixture of
1
+63.3° (c 0.39, CHCl3); H NMR (600 MHz,
CDCl3): l 5.92 (m, 1 H), 5.30–5.25 (m, 2 H),
5.21 (t, 1 H, J 9.5 Hz), 5.18 (t, 1 H, J 10.3
Hz), 5.07 (t, 1 H, J 9.7 Hz), 5.04 (dd, 1 H, J
9.6, 9.2 Hz), 5.01 (d, 1 H, J 3.4 Hz), 4.78 (d,
1 H, J 7.9 Hz), 4.20–4.15 (m, 4 H), 4.10 (m, 1
H), 4.05 (t, 1 H, J 12.8 Hz), 3.80 (m, 1 H, J
9.9 Hz), 3.72 (m, 1 H), 2.18, 2.08, 2.04, 2.03,
2.00 (s each, 3 H each), 1.13 (d, 3 H, J 6.7
Hz); ESIMS (m/z): 615 [M+K+], 599 [M+
Na+], 594 (M++H2O). Anal. Calcd for
C25H36O15: C, 52.06; H, 6.30. Found: C, 52.08;
H, 6.37.
Allyl(2,3,4,6-tetra-O-acetyl-i-
osyl)-(1“2)-[(2,3,4-tri-O-acetyl-i-
pyranosyl)-(1“3)]-4-O-acetyl-h- -fucopyran-
D-glucopyran-
D
-xylo-
D
1
a, b anomers) as a white amorphous solid: H
oside (19).—To a suspension of 17 (820 mg,
1.42 mmol), trichloroacetimidate 18 (659 mg,
NMR analysis confirmed the removal of allyl
group. To a solution of 20 (100 mg, 0.12
mmol) and trichloroacetonitrile (0.12 mL, 1.2
mmol) in CH2Cl2 (1 mL) was added DBU
(0.014 mL, 0.09 mmol) dropwise at 0 °C. The
mixture was stirred for 30 min and then di-
rectly purified by silica gel column chromatog-
raphy (2:1 petroleum ether–EtOAc) to afford
,
1.56 mmol), and 4 A molecular sieves (1.0 g)
in dry CH2Cl2 (6 mL) under argon at
−40 °C, was added BF3·Et2O (0.12 mL, 0.11
mmol) dropwise. After stirring for 3 h, the
reaction mixture was treated with satd aq
NaHCO3 (4 mL) and then diluted with
CH2Cl2 (20 mL). The organic layer was sepa-
rated, dried over sodium sulfate and concen-
trated in vacuo. The residue was purified by
silica gel column chromatography (1:1
petroleum–EtOAc) to give 19 (0.74 g, 90%)
and recovered 18 (250 mg) as white solids. 19:
mp 85–86 °C; [h]D20 +130.6° (c 0.13, CHCl3);
1H NMR (600 Hz, CDCl3): l 5.91 (m, 1 H),
5.32–5.23 (m, 2 H), 5.19 (d, 1 H, J 10.4 Hz),
5.13 (t, 1 H, J 9.3 Hz), 5.06 (t, 1 H, J 10.0
Hz), 5.07 (t, 1 H, J 9.1 Hz), 5.02 (dd, 1 H, J
8.8, 8.5 Hz), 4.98 (d, 1 H, J 3.2 Hz), 4.94 (m,
1 H), 4.87 (dd, 1 H, J 8.7, 6.5 Hz), 4.64 (d, 1
H, J 6.3 Hz), 4.59 (d, 1 H, J 7.8 Hz), 4.22 (dd,
1 H, J 12.0 Hz), 4.15 (m, 2 H), 4.11 (m, 1 H),
4.10–4.04 (m, 2 H), 3.84 (m, 1 H), 3.70 (m, 1
1
2 (95 mg, 81%) as a white foam: H NMR
(300 MHz, CDCl3): l 8.50 (s, 1 H), 6.40 (d, 1
H, J 3.5 Hz), 5.31 (d, 1 H, J 3.6 Hz), 5.08 (m,
3 H), 4.90 (m, 3 H), 4.60 (d, 1 H, J 6.4 Hz),
4.47 (d, 1 H, J 9.4 Hz), 4.15 (m, 6 H), 3.72 (m,
1 H), 3.42 (m, 1 H), 2.20–1.90 (m, 24 H), 1.10
(d, 3 H, J 6.3 Hz). Trichloroacetimidate 2 was
not stable and was directly used in the next
glycosylation reaction.
(25R) - 3i - tert - Butyldimethylsilyl - rusco-
genin-1i-yl 2,3,4-tri-O-acetyl-i- -fucopyran-
D
oside (22).—A solution of 2 (38 mg, 0.070
mmol) in dry CH2Cl2 (3 mL) was stirred in the
,
presence of 4 A molecular sieves (5 mg) under
argon at rt for 30 min. A solution of TMSOTf

M. Liu et al. / Carbohydrate Research 329 (2000) 745–754
753
7.3 Hz), 3.68 (m, 1 H), 3.57 (m, 1 H), 3.47–
3.41 (m, 3 H), 3.37 (t, 1 H, J 10.5 Hz), 3.33
(dd, 1 H, J 12.1, 4.4 Hz); FABMS (m/z): 1321
[M++1], 1320 [M+], 1265 [M++1-OAc].
HREIMS: Calcd for C66 H100O25Si: 1321.6350.
Found: 1321.6401.
in CH2Cl2 (0.1 N, 1.4 mL) was then added
dropwise, followed by the addition of
trichloroacetimidate 21 (34 mg, 0.079 mmol).
After stirring for 2 h, the mixture was treated
with satd aq NaHCO3 (4 mL) and then di-
luted with CH2Cl2 (20 mL). The organic layer
was separated, dried over sodium sulfate, and
then concentrated in vacuo. The residue was
purified by silica gel column chromatography
(2:1 petroleum ether–EtOAc) to give 22 (37
mg, 69%, based on 2) as a white solid: mp
(25R)-Ruscogenin-1i-yl
i- -glucopyran-
D
osyl-(1“2)-[i- -xylopyranosyl-(1“3)]-i- -
D
D
fucopyranoside (1).—Compound 23 (5 mg,
0.0038 mmol) was treated with TMSOTf
(0.0095 mmol) in dry CH2Cl2 (3 mL) under
argon for 10 min, followed by addition of
neutral Al2O3 (3 mg), and then filtration. The
filtrates were concentrated and dissolved in
MeOH (2 mL) containing a catalytic amount
of NaOMe. The mixture was stirred for 2 h
and then concentrated to give a residue, which
was purified by silica gel column chromatog-
raphy (2:1 CH2Cl2–MeOH) to afford saponin
1 (2.8 mg, 85%) as a white amorphous solid:
[h]2D0 −87.3° (c 0.11, pyridine, lit. −90.3°, c
1
75–76 °C; [h]2D0 −26.6° (c 1.5, CHCl3); H
NMR (300 MHz, CDCl3): l 5.44 (brd, 1 H, J
5.5 Hz), 5.13 (m, 1 H), 5.02 (dd, 1 H, J 10.5,
7.4 Hz), 4.93 (m, 1 H), 4.35 (d, 1 H, J 7.4 Hz),
4.32 (m, 1 H), 3.66 (m, 1 H), 3.40–3.33 (m, 2
H), 3.29 (t, 1 H, J 10.8 Hz), 2.09, 1.97, 1.92 (s
each, 3 H each), 1.11 (d, 3 H, J 6.3 Hz), 0.93
(s, 3 H), 0.88 (d, 3 H, J 6.9 Hz), 0.82 (s, 9 H),
0.74 (s, 3 H), 0.72 (d, 3 H, J 5.7 Hz); FABMS
(m/z): 819 [M++1], 818 [M+], 817 [M+−1].
(25R)-3-O-i-tert-Butyldimethylsilyl-rusco-
1
0.63 [1]); H NMR (pyridine-d5): l 5.85 (d, 1
H, J 7.0 Hz), 5.78 (brd, 1 H, J 5.9 Hz), 5.47
(d, 1 H, J 7.8 Hz), 5.20 (d, 1 H, J 6.9 Hz), 4.93
(dd, 1 H, J 10.5 Hz), 4.86 (dd, 1 H, J 3.0 Hz),
4.65–4.62 (m, 3 H), 4.58 (dd, 1 H), 4.54 (dd, 1
H, J 11.2, 5.3 Hz), 4.40–4.37 (m, 2 H), 4.31–
4.27 (m, 4 H), 4.17 (t, 1 H, J 8.6 Hz), 4.15 (m,
1 H), 4.06 (dd, 1 H, J 11.8, 4.1 Hz), 3.90 (dd,
1 H, J 10.9 Hz), 3.88 (m, 1 H), 3.71 (m, 1 H),
3.65 (t, 1 H, J 10.6 Hz), 1.64 (d, 3 H, J 6.5
Hz), 1.47 (s, 3 H), 1.25 (d, 3 H, J 6.5 Hz), 1.12
(s, 3 H), 0.85 (d, 1 H, J 5.8 Hz); FABMS
(m/z): 909 [M+K+], 893 [M+Na+], 871
[M++1], 869 [M+−1]. HREIMS (m/z):
Calcd for C44 H70O17: 871.4676. Found:
871.4691.
genin-1i-yl
copyranosyl-(1“2)-[(2,3,4-tri-O-acetyl-i-
xylopyranosyl)-(1“3)]-4-O-acetyl-i- -fuco-
2,3,4,6-tetra-O-acetyl-i- -glu-
D
D-
D
pyranoside (23).—A solution of 2 (24 mg, 0.04
mmol) in dry CH2Cl2 (3 mL) was stirred in the
,
presence of 4 A molecular sieves (50 mg)
under argon at rt for 30 min. Then a solution
of TMSOTf in CH2Cl2 (0.1 N, 8 mL) was
added dropwise. After stirring for 20 min,
trichloroacetimidate 3 (100 mg, 0.11 mmol)
was added. The mixture was stirred for an-
other 2 h and then treated with satd aq
NaHCO3 (4 mL) and diluted with CH2Cl2 (20
mL). The organic layer was separated, dried
over sodium sulfate and concentrated in
vacuo. The residue was purified by silica gel
column chromatography (1:1 petroleum
ether–EtOAc) to give 23 (16 mg, 46%) and its
a anomer (3 mg, 10%) as white amorphous
Acknowledgements
This work was supported by the Ministry of
Science and Technology of China and Hong
Kong Industry Department. B.Yu thanks a
grant from NSFC (29925203).
1
solids. 23: [h]D20 −49.2° (c 0.09 in CHCl3); H
NMR (600 MHz, CDCl3): l 5.55 (brd, 1 H, J
5.7 Hz), 5.18 (t, 1 H, J 9.3 Hz), 5.16 (m, 1 H),
5.12 (m, 1 H, J 9.7 Hz), 5.07 (m, 1 H, J 6.9
Hz), 4.91–4.86 (m, 2 H), 4.89 (d, 1 H, J 7.8
Hz), 4.85 (t, 1 H, J 9.1 Hz), 4.84 (d, 1 H, J 7.7
Hz), 4.39 (m, 1 H), 4.37 (m, 1 H, J 3.9 Hz),
4.31 (d, 1 H, J 7.3 Hz), 4.12 (dd, 1 H, J 12.4,
3.6 Hz), 4.09 (dd, 1 H, J 12.1, 4.0 Hz), 3.81
(dd, 1 H, J 9.7, 3.3 Hz), 3.75 (dd, 1 H, J 9.7,
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