First total synthesis of an exceptionally potent antitumor saponin, OSW- 1

Article abstract of DOI:10.1021/jo981685c

OSW-1 (1), an acylated disaccharide cholestane saponin from Ornithogalum saudersiae with exceptionally potent antitumor activity, was first synthesized from commercially available dehydroisoandrosterone, L-arabinose, and D-xylose in total 27 steps with the longest linear sequence of 14 steps and in 6% yield.

Full text of DOI:10.1021/jo981685c

202
J . Org. Chem. 1999, 64, 202-208
F ir st Tota l Syn th esis of a n Excep tion a lly P oten t An titu m or
Sa p on in , OSW-1
Shaojiang Deng, Biao Yu,* Yun Lou, and Yongzheng Hui*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received August 19, 1998
OSW-1 (1), an acylated disaccharide cholestane saponin from Ornithogalum saudersiae with
exceptionally potent antitumor activity, was first synthesized from commercially available
dehydroisoandrosterone, L-arabinose, and D-xylose in total 27 steps with the longest linear sequence
of 14 steps and in 6% yield.
Sch em e 1. Retr osyn th esis of OSW-1 (1)
In tr od u ction
Saponins, a large family of glycoconjugates with for-
midably enormous structural diversity, have recently
been attracting a surge of interest due to the increased
understanding of their wide spectrum of biological and
pharmacological activities.1,2 Saponin OSW-1 (1),3,4 namely
3â,16â,17R-trihydroxycholest-5-en-22-one 16-O-{O-(2-O-
(4-methoxybenzoyl)-â-D-xylopyranosyl)-(1f3)-2-O-acetyl-
R-arabinopyranoside}, is the major component of a small
group of cholestane saponins isolated recently by Sashida
et al. from the bulbs of Ornithogalum saudersiae,3-5
a
species of the lily family without any medicinal folkloric
background. Tremendous attention has been given to this
molecule since the report of its extraordinarily potent
antitumor activities at the 210th National Meeting of the
American Chemical Society (1995, Chicago, IL).2 In vitro
assays showed that OSW-1 was extremely toxic against
a broad spectrum of malignant tumor cells, such as
leukemia HL-60, mouse mastrocarcinoma, human pul-
monary adenocarcinoma, human pulmonary large cell
carcinoma, and human pulmonary squamous cell carci-
noma including adriamycin-resistant P388 leukemia and
camptothecin-resistant P388, with IC50 between 0.1 and
0.7 nM, which is about 10-100 times more potent than
those of the clinically applied anticancer agents, such as
mitomycin C, adriamycin, cisplatin, camptothecin, and
taxol.4 The cytotoxicity profile of OSW-1 is strikingly
similar to that of cephalostatins, a group of dimeric
steroid-pyrazines from marine organisms,6 with Pearson
correlation coefficients between 0.60 and 0.83,4 while
structurally, the aglycon of OSW-1 is reminiscent of half
of the cephalostatins. Fuchs therefore hypothesized that
they might have the same mechanism of action.7 More-
over, OSW-1 exhibited little toxicity to normal cells in
vitro and prolonged the life span of P388 leukemia
infected mice by 59% via a single administration at 10
µg/kg.4 Thus, synthesis of this saponin was an attractive
goal, and herein we report the first total synthesis of this
molecule. It is worth noting that, very recently, Fuchs et
al. have reported the first synthesis of the aglycone part
of this molecule;7 coincidentally, we adopted an es-
sentially similar strategy for this part.
* Corresponding author. Fax: (86)21-64166128, email: byu@
pub.sioc.ac.cn
(1) Hostettmann, K., Marston, A. Saponins; Cambridge University
Press: Cambridge, UK, 1995.
(2) (a) Rouhi, A. M. Chem. Eng. News 1995, September 11, 28. (b)
Waller, G. R.; Yamasaki, K. Ed., In Advances in Experimental Medicine
and Biology; Saponins Used in Traditional and Modern Medicine.
Plenum Press: New York, 1996; Vol. 404.
(3) Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaido, T.;
Ohmoto, T. Phytochemistry 1992, 31, 3969.
(4) Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano,
T.; Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J . A. Bioorg.,
Med. Chem. Lett. 1997, 7, 633.
(5) Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano,
T.; Oka, K.; Dobashi, A.; Koike, K.; Nikaido, T. Bioorg., Med. Chem.
Lett. 1996, 6, 2635. (b) Kuroda, M.; Mimaki, Y.; Sashida, Y.; Nikaido,
T.; Ohmoto, T. Tetrahedron Lett. 1993, 34, 6073.
Resu lts a n d Discu ssion
Saponin OSW-1(1) was logically disconnected into two
quite distinct parts, i.e., cholestane aglycone 2 and
disaccharide moiety 3 (Scheme 1), which could be further
envisioned to be derived from dehydroisoandrosterone,
L-arabinose, and D-xylose. J udicious choice of protecting
groups is of great importance for the syntheses of
polyhydroxyl glycoconjugates; therefore, protecting groups
(silyl groups for hydroxyls and ethylene glycol ketal for
(6) (a) Ganesan, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 611. (b)
Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.; Dufresne,
C.; Christie, N. D.; Schmidt, J . M.; Doubek, D. L.; Krupa, T. S. J . Am.
Chem. Soc. 1988, 110, 2006.
(7) Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 1099.
10.1021/jo981685c CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/15/1998

Total Synthesis of Anticancer Saponin, OSW-1
J . Org. Chem., Vol. 64, No. 1, 1999 203
Sch em e 2. In sta lla tion of th e C17 Sid e Ch a in a
Sch em e 3. Syn th esis of th e Aglycon e 2a
a
Reagents and conditions: (a) HOCH2CH2OH, CH(OEt)3,
TsOH‚H2O (cat.), CH2Cl2, rt, 4 days, 96%; (b) TBAF, THF, rt, 10
h, 95%; (c) TBSCl, imidazole, DMF, rt, overnight, 96%; (d) OsO4
(1.2 equiv), Py, ether, -20 °C, 3 h, 41%; (e) ClCOCOCl, DMSO,
Et3N, CH2Cl2, -78 °C, 1 h, 78%; (f) NaBH4, CeCl3‚7H2O, THF, 0
°C, 3 h, 93%.
a
precedented.10b,13 Finally, the installation of the C17 side
chain was completed by oxidation of alcohol 9 with PDC,
providing C22-keto 10 in 83% yield.
Reagents and conditions: (a) Ph3PEtBr, tert-BuOK, THF,
reflux, 4 h, 78%; (b) TBDPSCl, imidazole, DMF, rt, overnight,
100%; (c) (CH2O)n, BF3-OEt2 (0.05 equiv), CH2Cl2, rt, 10 min, 75%;
(d) Dess-Martin periodinane, CH2Cl2, rt, 3 h, 86%; (e) (3-
methylbutyl)magnesium bromide, ether, rt, 1 h, 96%; (f) PDC,
CH2Cl2, DMF, rt, overnight, 83%.
With cholestane 10 at hand, the elaboration of the
16â,17R-diol proceeded successfully (Scheme 3). First, the
C22 carbonyl of 10 was masked as an ethylene glycol
ketal under very mild conditions (catalytic TsOH, HC(O-
Et)3, and room temperature),14 giving 11 slowly (4 days)
and in high yield (96%). Then the 3-TBDPS ether of 11
was converted to the 3-TBS ether in two steps giving 13,
to avoid the possible problems associated with acyl group
migration and cleavage in the final removal of the robust
TBDPS ether under TBAF or HF/Py. At this stage, a
model reaction was carried out by treatment of disac-
charide moiety 29 with TBAF, which led to very complex
mixtures of products. Finally, diene 13 was subjected to
OsO4 (1.2 equiv),15 affording the corresponding 16R,17R-
diol 14 in moderate yield (41%), accompanied by some
more polar byproducts and starting material. In this step,
the resulting osmates were highly inert to sodium
bisulfite, a common agent used for cleavage of the
osmates; therefore, hydrogen sulfide was used instead
to quench the reaction.15b Treatment of 14 with DMSO/
ClCOCOCl12 conveniently afforded the desired C16 keto
15 in 78% yield, which was then reduced under NaBH4/
CeCl3 to provide the required 16â-OH aglycone 2 exclu-
sively.7 Thus, we achieved the preparation of 2 in overall
12 steps and 10% yield from dehydroisoandrosterone (4).
The construction of the other part of the target,
disaccharide moiety 3, was carried out in a very concise
and straightforward manner (Scheme 4, 5). The xylosyl
keto) were selected to allow complete removal under
neutral or near neutral conditions.
Cholestane aglycone 2 was synthesized starting from
the industrial material dehydroisoandrosterone (4). On
the basis of well-established vitamin D chemistry,8 the
installation of the C17 side chain was proven to be of little
problem (Scheme 2). Wittig olefination of ketone 4 gave
diene 5 stereoselectively,9 and then the 3-OH of 5 was
masked as its TBDPS (tert-butyldiphenylsilyl) ether to
provide 6, which underwent an ene reaction with
paraformaldehyde in the presence of catalytic BF3‚OEt2
to generate the desired homoallylic alcohol 7 stereose-
lectively and in satisfactory yield (75%).10 With the use
of BF3-OEt2, the corresponding ene reaction did not
happen between isoamyl-CHO and 6, and a 3-OTBS (tert-
butyldimethylsilyl) ether could not survive. Oxidation of
alcohol 7 with Dess-Martin periodinane11 provided al-
dehyde 8 smoothly and in good yield (86%), while under
Swern conditions,12 8 was obtained in a mixture with
another inseparable product, conceivably its C20 epimer.
Grignard addition of aldehyde 8 with (3-methylbutyl)-
magnesium bromide afforded the expected adduct in high
1
yield (96%), based on its H NMR spectrum, containing
only one isomer (9). Grignard additions to the cholestane
C22 aldehyde, where the formation of the Cram product,
i.e., the 22R-epimer, predominates, have been well-
(13) Yamada, H.; Nishizawa, M. J . Org. Chem. 1995, 60, 386. (b)
Tsubuki, M.; Kanai, K.; Keino, K.; Kakinuma, N.; Honda, T. Ibid. 1992,
57, 2930. (c) Poyser, J . P.; Ourisson, G. J . Chem. Soc., Perkin Trans.
1 1974, 2061.
(14) Caserio, F. F.; Roberts, J . D. J . Am. Chem. Soc. 1958, 80, 5837.
(15) For previous introduction of 16R,17R-cis dihydroxy groups onto
steroids, see (a) Bernstein, S.; Lenhard, R. H.; Allen, W. S.; Heller,
M.; Littell, R.; Stolar, S. M.; Feldman, L. I.; Blank, R. H. J . Am. Chem.
Soc. 1959, 81, 1689. (b) Wendler, N. L.; Taub, D. Ibid. 1960, 82, 2836.
(c) Bernstein, S.; Littell, R. J . Org. Chem. 1959, 24, 429. (d) Brown, J .
J .; Bernstein, S. Ibid. 1961, 26, 5033.
(8) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
(9) Batcho, A. D.; Berger, D. E.; Davoust, S. G.; Wovkulich, P. M.;
Uskokovic, M. R. Helv. Chim. Acta 1981, 64, 1682.
(10) Drefahl, G.; Ponsold, K.; Schick, H. Chem. Ber. 1965, 98, 604.
(b) Houston, T. A.; Tanaka, Y.; Koreeda, M. J . Org. Chem. 1993, 58,
4287.
(11) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(12) Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979,
44, 4148.

204 J . Org. Chem., Vol. 64, No. 1, 1999
Deng et al.
Sch em e 4. Syn th esis of Tw o Mon osa cch a r id e
Bu ild in g Block sa
Sch em e 5. Syn th esis of th e Disa cch a r id e Moiety
3a
a
Reagents and conditions: (a) BnOH, HCl (gas), rt, overnight;
(b) MBzCl, Py, -35 °C to room temperature, overnight, 65%; (c)
TESCl, imidazole, DMF, rt, 93%; (d) 10% Pd-C, H2 (40 atm),
EtOAc, 40 °C, 24 h, 76%; (e) CCl3CN, DBU, CH2Cl2, rt, 3 h, 79%;
(f) BnOH, HCl (gas), rt, overnight; (g) Me2C(OMe)2, TsOH‚H2O
(cat.), DMF, rt, 5 h; (h) Ac2O, Py, rt, overnight, 72% (three steps);
(i) 70% HOAc in H2O, 70 oC, 1 h, 94%.
a
Reagents and conditions: (a) BF3-OEt2 (0.05 equiv), 4 Å MS,
CH2Cl2, -60 °C to -40 °C, 30 min, 100% (two isomers); (b) Ac2O,
o
Py, overnight; (c) TESOTf, lutidine, CH2Cl2, -20 C, 1 h, 70% (for
29), 21% (for 30); (d) 10% Pd-C, H2 (50 atm), EtOAc, 50 oC, 3
days, 50%; (e) CCl3CN, DBU, CH2Cl2, rt, 6 h, 65%.
for 26 was 3.92 ppm, while that of 28 was 5.05-4.98 ppm.
The mixture of 25 and 26, without separation, was
further subjected to TESOTf, 21 affording disaccharides
29 (70%) and 30 (21%), which were readily separable on
a silica gel column (Scheme 5). In this step of transfor-
mation, the conditions previously used for converting diol
17 to its corresponding TES ether 18; (TESCl, imidazole,
DMF) led to no reaction. The following removal of the
anomeric benzyl group of 29 was found to be even more
difficult than in the case of 18, under forcing conditions
(10% Pd-C, 50 atm H2, 50 °C, 3 days), the corresponding
hemiacetal 31 was generated in 50% yield and 36% of
29 was recovered. Finally, treatment of 31 with CCl3CN/
DBU18 provided the expected disaccharide donor 3 (65%),
which was found to be very unstable and should be
directly used in the next step.
Although the research in our group and others have
shown that the glycosylation of a steroid acceptor,
especially those with a stereo-hindered hydroxyl group,
with a sugar donor which has a neighboring acetyl group
was rather difficult,22 glycosylation of the 16â,17R-diol 2
with disaccharide imidate 3 proceeded smoothly under
the promotion of TMSOTf 23 to provide the fully protected
OSW-1 (32) in satisfactory yield (69%). Whereas this
reaction has not happened under the promotion of BF3‚
Et2O. It was interestingly noted that both the xylosyl and
arabinosyl moiety comformationally preferred the 1C4
form, which was deduced from the small coupling con-
stants between trans H-1 and H-2 of both sugars, i.e.,
J 1,2 (ara) < 1 Hz, and J 1,2 (xyl) ≈ 0.9 Hz.24 The C22
ethylene glycol ketal of 32 was found to be easily cleaved
during the course of NMR analysis under the action of
the trace acid containing in CDCl3. Finally, all of the
donor 20 was readily prepared from D-xylose in five steps
as shown in Scheme 4. Therein, the 2-O-MBz (4-meth-
oxybenzoyl) group was regioselectively introduced by
treatment of triol 16 under MBzCl/Py, affording 17 in
65% yield.16 The chemical shift for H-2 of 16 was 3.23
ppm, which was downshifted to 5.11 ppm for 17.17 Then,
the diol of 17 was masked as the bis-TES ether to afford
18 in excellent yield (93%). The anomeric benzyl group
of 18 was found to be rather resistant to hydrogenolysis;
therefore, stronger conditions (10% Pd-C, 40 atm H2, 40
°C, 24 h) were employed to generate the hemiacetal 19
(76% yield, 20% of 18 recovered), which was then
converted18 to the corresponding trichloroacetimidate 20.
Meanwhile, the arabinosyl acceptor 24 was readily
prepared from L-arabinose in four steps and in 67% yield,
i.e., benzylation of 1-OH, isopropylidenation of 3,4-OH,
acetylation of 2-OH, and final removal of isopropylidene.
Although the arabinosyl acceptor 24 has two hydroxyl
groups, a regioselective glycosylation with the xylosyl
donor 20 was expected because it is well-known that the
equatorial 3-OH is much more active than the axial 4-OH
for a pyranoside.19 Consequently, glycosylation of diol 24
with 20 under BF3‚Et2O20 catalysis gave the desired 1f3
linked disaccharide 25 as the major product, which could
not be separated from its 1f4 linked isomer 26 through
silica gel column chromatography on a large scale. The
classification of the glycosylation position was readily
confirmed by comparison of the “acylation shift”17 of 25
with its acetylation product 27, or 26 with its acetylation
product 28, i.e., the chemical shift of ara-H-4 for 25 was
4.02-4.06 ppm, which was found to be downshifted to
5.25 ppm after acetylation; the chemical shift of ara-3-H
(16) The procedure was based on the preparation of methyl 2-O-
benzoyl-R-D-xylopyranoside: Tsuda, Y.; Haque, M. E.; Yoshimoto, K.
Chem. Pharm. Bull. 1983, 31, 1612.
(17) For “acylation shift”, see: Agrawal, P. K. Phytochemistry 1992,
31, 3307.
(18) Numata, M.; Sugimoto, M.; Koike, K.; Ogawa, T. Carbohydr.
Res. 1987, 163, 209.
(19) Baer, H. H.; Abbas, S. A. Carbohydr. Res. 1980, 84, 53. (b)
Paulsen, H.; Paal, M. Ibid. 1985, 137, 39. (c) Ogawa, T. Chem. Soc.
Rev. 1994, 397. (d) Windmuller, R.; Schmidt, R. R. Tetrahedron Lett.
1994, 35, 7927.
(21) Seebach, D.; Chow, H.-F.; J ackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmermann, J . Libigs Ann. Chem. 1986, 1281. (b)
Heathcock, C. H.; Young, S. D.; Hagen, J . P.; Pilli, R.; Badertscher, U.
J . Org. Chem. 1985, 50, 2095.
(22) Liu, M.; Yu, B.; Hui, Y. Tetrahedron Lett. 1998, 39, 415. (b) Li,
C.; Yu, B.; Liu, M.; Hui, Y. Carbohydr. Res. 1998, 306, 187. (c) Urban,
F. J .; Moore, B. S.; Breitenbach, R. Tetrahedron Lett. 1998, 31, 4421.
(d) Wulff, G.; Rohle, G. Angew. Chem., Int. Ed. Engl. 1974, 13, 157.
(23) Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 32, 3353.
(24) Collins, P.; Ferrier, R. Monosaccharides, J ohn Wiley & Sons:
New York, 1995; pp 22-32.
(20) Schmidt, R. R.; Michel. J . Angew. Chem., Int. Ed. Engl. 1980,
19, 731.

Total Synthesis of Anticancer Saponin, OSW-1
J . Org. Chem., Vol. 64, No. 1, 1999 205
Sch em e 6. Assem bly of th e Ta r get OSW-1 (1)a
filtered. The filtrates were concentrated in vacuo to give a
residue, which was purified by flash column chromatography
(petroleum ether-EtOAc, 50:1 to 20:1 and then 10:1) to afford
7 (6.51 g, 75%) as a white foam, and recovered starting
1
material 6 (1.61 g, 20%). 7: [R]20 -55.99 (c 1.15 CHCl3); H
D
NMR (300 MHz, CDCl3) 7.70-7.30 (10H, m), 5.41 (1H, brs),
5.13 (1H, brd, J ) 5.0), 3.60-3.45 (3H, m), 1.05 (9H, s), 1.01
(3H, s), 1.00 (3H, d), 0.78 (3H, s); 13C NMR (75 MHz, CDCl3)
157.56, 141.57, 135.77, 134.82, 129.44, 127.45, 122.96, 120.91,
73.19, 66.53, 57.34, 50.65, 46.98, 42.52, 37.15, 36.73, 35.35,
34.85, 31.87, 31.56, 31.21, 30.53, 27.01, 20.74, 19.35, 19.15,
18.07, 16.21; EIMS m/z 567, 511. Anal. Calcd for C38H52O2Si‚
0.5H2O: C, 78.98; H, 9.24. Found: C, 78.93; H, 9.38.
a
Reagents and conditions: (a) TMSOTf (0.05 equiv), 4 Å MS,
C22 Ald eh yd e (8). A suspension of 7 (6.51 g, 11.44 mmol)
and Dess-Martin periodinane (6.32 g, 14.9 mmol) in CH2Cl2
(70 mL) was stirred at room temperature for 3 h and then
quenched by addition of Na2S2O3 and NaHCO3 solution and
extracted with CH2Cl2. The organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (petro-
leum ether-EtOAc, 50:1) to afford 8 (5.57 g, 86%) as a white
solid, and recovered the starting material 7 (411 mg, 6%). 8:
CH2Cl2, -20 oC, 45 min, 69%; (b) Pd(MeCN)2Cl2, acetone-water
(v:v, 20:1), rt, overnight, 79%.
protecting groups (one TBS, three TES, and one ethylene
glycol ketal) were removed smoothly and cleanly in a
single step by employing Pd(MeCN)2Cl2 as a catalyst25
to furnish the final target OSW-1 (1) in satisfactory yield
(79%) (Scheme 6). The physical data obtained were
absolutely identical to those reported by Sashida.3
In summary, the extraordinarily potent antitumor
saponin OSW-1 (1) was constructed from commercially
available dehydroisoandrosterone, L-arabinose, and D-
xylose in total 27 steps, with the longest linear sequence
being 14 steps, and in 6% yield.
[R]29 -32.30 (c 1.35 CHCl3); 1H NMR (300 MHz, CDCl3) 9.44
D
(1H, d, J ) 2.2), 7.70-7.30 (10H, m), 5.46 (1H, br), 5.13 (1H,
d, J ) 5.2 Hz), 3.53 (1H, m), 3.01 (1H, dq, J ) 6.9), 1.17 (3H,
d, J ) 6.9), 1.05 (9H, s), 1.01 (3H, s), 0.78 (3H, s); 13C NMR
(75 MHz, CDCl3) 201.07, 152.00, 141.63, 135.78, 134.83,
129.44, 127.46, 127.01, 120.80, 73.19, 57.04, 50.60, 47.07,
46.07, 42.52, 37.16, 36.75, 34.58, 31.87, 31.50, 30.54, 27.02,
20.65, 19.34, 19.15, 15.98, 14.31; EIMS m/z 509, 199. Anal.
Calcd for C38H50O2Si: C, 80.51; H, 8.89. Found: C, 80.31; H,
8.48.
Exp er im en ta l Section 26
22-Alcoh ol (9). To a solution of 8 (5.57 g, 9.83 mmol) in
dry ether (100 mL) was slowly added a solution of (3-
methylbutyl)magnesium bromide (14.7 mmol, 1 M) in ether,
which was prepared from 3-methylbutyl bromide and magne-
sium. After being stirred at room temperature for 1 h, the
mixture was quenched with saturated NH4Cl solution and
extracted with ether. The ether layer was then washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (petro-
leum ether-EtOAc, 20:1 to 10:1) to provide 9 (6.04 g, 96%) as
a pale yellow foam: [R]18D -46.84 (c 2.36 CHCl3); 1H NMR (300
MHz, CDCl3) 7.70-7.30 (10H, m), 5.47 (1H, brd, J ) 3.0), 5.13
(1H, brd, J ) 5.0), 3.64-3.48 (2H, m), 1.05 (9H, s), 1.01 (3H,
s), 0.99 (3H, d, J ) 6.9), 0.88 (3H, d, J ) 6.6), 0.87 (3H, d, J )
6.6), 0.84 (3H, s); EIMS m/z 581, 199. Anal. Calcd for C43H62O2-
Si: C, 80.82; H, 9.78. Found: C, 81.07; H, 9.82.
(Z)-3â-(t er t -Bu t yld ip h e n ylsiloxy)-5,17(20)-p r e gn a -
d ien e (6). To a suspension of Ph3PEtBr (35.65 g, 96.0 mmol)
in THF (150 mL) was added a solution of t-BuOK (10.77 g,
96.0 mmol) in THF (80 mL) at room temperature. After the
resulting orange suspension was stirred for 1 h, a solution of
dehydroisoandrosterone (7.0 g, 24.3 mmol) was added, and the
mixture was then refluxed for another 4 h. After being cooled
to room temperature, the reaction was quenched with satu-
rated NH4Cl solution and then extracted with EtOAc. The
combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (petroleum ether-
EtOAc, 6:1 to 4:1) to afford 5 (5.62 g, 78%) as a white solid:
[R]29 -68.83 (c 2.19 CHCl3); 1H NMR (300 MHz, CDCl3) 5.34
D
(1H, brd, J ) 5.2), 5.12 (1H, tq, J ) 2.1, 7.2), 3.51 (1H, m),
1.65 (3H, dt), 1.01 (3H, s), 0.88 (3H, s); EIMS m/z 301, 300.
A mixture of 5 (2.26 g, 7.51 mmol), TBDPSCl (2.5 mL, 9.77
mmol), and imidazole (1.28 g, 18.8 mmol) in dry DMF (20 mL)
was stirred overnight at room temperature. The suspension
was then diluted with petroleum ether, the organic layer was
washed with saturated NaHCO3 and brine, respectively, dried
over MgSO4, and filtered. The filtrate was concentrated in
vacuo to give a residue, which was purified by a flash column
22-Keton e (10). A suspension of 9 (6.0 g, 9.39 mmol),
pyridinium dichromate (5.3 g, 14.1 mmol), and crushed 4 Å
MS (5 g) in dry CH2Cl2 (50 mL) and DMF (10 mL) was stirred
at room temperature for 2 h and then filtered through a short
silica gel column. The filtrates were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (petroleum ether-
EtOAc, 100:1 to 50:1) to afford 10 (4.97 g, 83%) as a pale yellow
chromatography (petroleum ether) to afford 6 (4.08 g, 100%)
syrup: [R]18 +3.60 (c 1.1 CHCl3); 1H NMR (300 MHz, CDCl3)
1
as a white solid: [R]18 -56.26 (c 1.85 CHCl3); H NMR (300
D
D
7.70-7.30 (10H, m), 5.34 (1H, br), 5.12 (1H, d), 3.52 (1H, m),
3.16 (1H, q, J ) 6.9), 1.13 (3H, d), 1.05 (9H, s), 1.01 (3H, s),
0.85 (3H, d, J ) 6.0), 0.84 (3H, d, J ) 6.0), 0.81 (3H, s); 13C
NMR (75 MHz, CDCl3) 211.54, 154.36, 141.59, 135.79, 134.85,
129.46, 127.47, 125.19, 120.89, 73.22, 57.18, 50.60, 47.36,
45.74, 42.54, 38.30, 37.18, 36.76, 34.70, 33.10, 31.90, 31.53,
31.25, 30.62, 27.65, 27.05, 22.50, 22.27, 20.73, 19.36, 19.17,
16.86, 16.29; EIMS m/z: 636, 579, 199. Anal. Calcd for
MHz, CDCl3) 7.70-7.30 (10H, m), 5.18-5.08 (2H, m), 3.60-
3.48 (1H, m), 1.64 (3H, dt, J ) 2.0, 7.1), 1.06 (9H, s), 1.00 (3H,
s), 0.87 (3H, s); 13C NMR (75 MHz, CDCl3) 150.29, 141.32,
135.77, 134.84, 129.42, 127.45, 121.00, 113.43, 73.23, 56.53,
50.08, 44.04, 42.49, 37.17, 36.98, 36.56, 31.89, 31.70, 31.44,
31.39, 27.02, 24.46, 21.18, 19.39, 19.15, 16.60, 13.12; EIMS
m/z 537, 481. Anal. Calcd for C37H50OSi: C, 82.47; H, 9.35.
Found: C, 82.46; H, 9.20.
22-Hom oa llylic Alcoh ol (7). To a suspension of 6 (8.20 g,
15.2 mmol) and paraformaldehyde (2.28 g, 75.9 mmol) in dry
CH2Cl2 (80 mL) was added a solution of BF3-OEt2 in CH2Cl2
(10 mL, 0.07 M). After being stirred at room temperature for
10 min, the mixture was quenched with Et3N (1 mL) and
C
43H60O2Si: C, 81.06; H, 9.51. Found: C, 81.41; H, 9.88.
Eth ylen e Glycol Keta l (11). A solution of ketone 10 (4.79
g, 7.80 mmol), ethylene glycol (4.5 mL, 82 mmol), triethyl-
orthoformate (6.5 mL, 39 mmol) and TsOH‚H2O (80 mg) in
CH2Cl2 (50 mL) was stirred at room temperature for 4 d and
then quenched with Et3N (0.5 mL). The mixture was extracted
with CH2Cl2, and the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography to afford ketal 11
(25) Lipshutz, B. H.; Pollart, D.; Monforte, J .; Kotsuki, H. Tetrahe-
dron Lett. 1985, 26, 705.
(26) For “General Methods”, see: Lu, S.-F.; O′yang, Q.-Q.; Guo, Z.-
W.; Yu, B.; Hui, Y.-Z. J . Org. Chem. 1997, 62, 8400.
(5.12 g, 96%) as a pale yellow foam: [R]22 -40.56 (c 1.92
D

206 J . Org. Chem., Vol. 64, No. 1, 1999
Deng et al.
CHCl3); 1H NMR (300 MHz, CDCl3) 7.90-7.30 (10 H, m), 5.65
(1H, br), 5.14 (1H, br), 3.95 (4H, s), 3.54 (1H, m), 1.06 (9H, s),
1.02 (3H, s), 1.01 (3H, d, J ) 6.1), 0.86 (3H, d, J ) 6.6), 0.84
(3H, d, J ) 6.6), 0.79 (3H, s); 13C NMR (75 MHz, CDCl3) 156.59,
141.56, 135.79, 134.88, 129.45, 127.48, 124.05, 121.10, 113.86,
73.28, 65.86, 65.27, 57.36, 50.73, 47.53, 42.58, 39.21, 37.21,
36.78, 34.94, 33.99, 32.47, 31.94, 31.67, 31.43, 30.60, 28.41,
27.06, 22.68, 20.81, 19.26, 19.17, 17.38, 15.69; EIMS m/z: 680,
199, 143. Anal. Calcd for C45H64O3Si: C, 79.36; H, 9.47.
Found: C, 79.42; H, 9.82.
s); 13C NMR (75 MHz, CDCl3) 215.45, 141.56, 120.66, 115.40,
85.36, 72.45, 63.43, 63.28, 49.48, 46.91, 45.38, 42.74, 41.16,
37.18, 37.08, 36.66, 32.73, 32.20, 32.01, 30.75, 30.20, 28.29,
25.92, 22.69, 22.44, 20.12, 19.42, 18.22, 14.99, 14.25, -4.58;
EIMS m/z: 588, 143. Anal. Calcd for C35H60O5Si: C, 71.38; H,
10.27. Found: C, 71.61; 10.61.
16r,17â-Tr a n s Diol (2). A suspension of 15 (98 mg, 0.166
mmol), CeCl3‚7H2O (80 mg, 0.22 mmol) and NaBH4 (40 mg,
1.1 mmol) in THF (5 mL) was stirred at 0 °C for 3 h and then
quenched with methanol and diluted with ether. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column
chromatography to afford 2 (91 mg, 93%) as a while solid:
3-Alcoh ol (12). A solution of the TBDPS ether 11 (290 mg,
0.426 mmol) and tetrabutylammonium fluoride (0.85 mL, 1
M solution in THF) in dry THF (1 mL) was stirred at room
temperature for 10 h and then diluted with ether. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column
chromatography (petroleum ether-EtOAc, 4:1) to afford 12
[R]25 -35.00 (c 1.48 CHCl3); 1H NMR (300 MHz, CDCl3) 5.30
D
(1H, d, J ) 4.8), 4.15-3.85 (5H, m), 3.48 (1H, m), 2.59 (1H, q,
J ) 7.4), 1.18 (3H, s), 0.99 (3H, s), 0.87 (9H, s), 0.03 (6H, s);
13C NMR (75 MHz, CDCl3) 141.42, 121.11, 116.49, 86.81, 81.55,
72.57, 64.09, 62.86, 49.66, 47.89, 47.82, 42.77, 37.29, 36.51,
35.97, 33.91, 33.16, 32.81, 32.75, 32.06, 31.92, 29.67, 28.28,
25.93, 22.70, 22.26, 20.69, 19.41, 18.23, 12.55, 11.95, -4.85;
EIMS m/z: 575, 510, 143. Anal. Calcd for C35H62O5Si: C, 71.13;
H, 10.57. Found: C, 71.02; H, 10.93.
(179 mg, 95%) as a white solid: [R]25 -46.01 (c 2.08 CHCl3);
D
1H NMR (300 MHz, CDCl3) 5.65 (1H, brs), 5.34 (1H, d, J )
4.9), 3.94 (4H, brs), 3.50 (1H, m); 13C NMR (75 MHz, CDCl3)
156.53, 141.04, 124.01, 121.57, 113.84, 71.72, 65.83, 65.23,
57.31, 50.76, 47.50, 42.32, 39.17, 37.21, 36.74, 34.90, 33.95,
32.42, 31.63, 31.38, 30.68, 28.36, 22.77, 22.62, 20.82, 19.30,
17.34, 15.67; EIMS m/z 441, 143. Anal. Calcd for C29H46O3‚
0.25H2O: C, 77.89; H, 10.48. Found: C, 77.99; H, 10.78.
3-TBS Eth er (13). A solution of alcohol 12 (179 mg, 0.404
mmol), TBDMSCl (91 mg, 0.603 mmol), and imidazole (69 mg,
1.01 mmol) in DMF (1.5 mL) was stirred at room temperature
overnight and then diluted with ether. The organic layer was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatog-
Ben zyl 2-O-(4-m et h oxylb en zoyl)-r-D-xylop yr a n osid e
(17). A solution of D-xylose (5.0 g) in HCl-saturated BnOH (25
mL) was stirred at room temperature overnight and then
poured into ether (250 mL), and placed overnight. The result-
ing crystal was filtered to obtain benzyl R-D-xylopyranoside
1627 (2.5 g, 31%) as a white solid: 1H NMR (300 MHz,
CD3SOCD3) 7.40-7.20 (5H, m), 4.72 (1H, d, J ) 3.6), 4.66 and
4.44 (2H, AB peak, J ) 11.2), 3.50-3.30 (4H, m), 3.23 (1H,
dd, J ) 3.6, 9.3); EIMS m/z: 241, 223, 91.
raphy (petroleum ether-EtOAc, 100:1) to afford 13 (216 mg,
To a cooled solution (-35 °C) of 16 (14.68 g, 61.1 mmol) in
dry Py (100 mL) was slowly added 4-methoxybenzoyl chloride
(12.5 g, 73.3 mmol), and then the reaction temperature was
gradually elevated to room temperature. After being stirred
overnight, the reaction was quenched with MeOH and con-
centrated in vacuo. The residue was dissolved in EtOAc, which
was washed with diluted HCl, saturated NaHCO3 solution and
brine, respectively, and then dried over MgSO4 and concen-
trated in vacuo. The residue was purified by flash column
chromatography to afford 17 (14.94 g, 65%) as a white foam:
[R]29D +188.8 (c 1.35 CHCl3); 1H NMR (300 MHz, CDCl3) 8.10-
6.80 (9H, m), 5.11 (1H, d, J ) 3.3), 4.89 (1H, dd, J ) 3.3, 9.6),
4.76 and 4.50 (2H, AB, J ) 12.1), 4.13 (1H, m), 3.88 (3H, s),
3.95-3.70 (3H, m); EIMS m/z: 375, 357, 135. Anal. Calcd for
1
96%) as a white solid: [R]25 -37.96 (c 2.24 CHCl3); H NMR
D
(300 MHz, CDCl3) 5.66 (1H, brs), 5.32 (1H, d, J ) 4.9), 3.96
(4H, brs), 3.47 (1H, m), 0.88 (9H, s), 0.05 (6H, s); 13C NMR (75
MHz, CDCl3) 156.59, 141.83, 124.01, 121.06, 113.84, 72.60,
65.83, 65.24, 57.37, 50.86, 47.52, 42.87, 39.19, 37.34, 36.84,
34.95, 33.96, 32.43, 32.10, 31.68, 31.40, 30.71, 28.37, 25.93,
22.62, 20.82, 19.33, 18.23, 17.34, 15.65, -4.58; EIMS m/z: 556,
485, 143. Anal. Calcd for C35H60O3Si: C, 75.48; H, 10.86.
Found: C, 75.68; H, 11.26.
16r,17r-Cis Diol (14). To a cooled solution (-20 °C) of 13
(849 mg, 1.52 mmol) in ether (20 mL) and Py (1 mL) was added
OsO4 (480 mg, 1.89 mmol), and the resulting black solution
was stirred at -20 °C to room temperature for 3 h and then
quenched by bubbling H2S through the solution and filtered.
The filtrates were concentrated in vacuo to afford a residue,
which was purified by flash column chromatography (petro-
leum ether-EtOAc, 50:1 to 20:1) to afford 14 (367 mg, 41%)
C
20H22O7: C, 64.16; H, 5.92. Found: C, 64.43; H, 5.94.
Ben zyl 3,4-Bis-O-(tr ieth ylsilyl)-2-O-(4-m eth oxylben zoyl)-
r-D-xylop yr a n osid e (18). To a solution of 17 (11.45 g, 30.58
mmol), imidazole (10.41 g, 152.9 mmol), and DMAP (500 mg)
in dry DMF (100 mL) was added TESCl (12.3 mL, 73.3 mmol).
After being stirred for 1 h, the solution was concentrated in
vacuo. The residue was dissolved in EtOAc, which was washed
with saturated NaHCO3 solution and brine and then dried over
MgSO4 and concentrated in vacuo. The residue was purified
by flash column chromatography (petroleum ether-EtOAc,
30:1 to 20:1) to afford 18 (17.09 g, 93%) as a pale yellow
as a white solid, and recovered starting material 13 (169 mg,
1
20%). 14: [R]25 -56.67 (c 0.99 CHCl3); H NMR (300 MHz,
D
CDCl3) 5.30 (1H, d, J ) 4.2), 4.28 (1H, m), 3.97 (4H, m), 3.47
(1H, m), 1.12 (3H, d, J ) 7.0), 0.98 (3H, s), 0.88 (9H, s), 0.77
(3H, s), 0.04 (6H, s); 13C NMR (75 MHz, CDCl3) 141.55, 120.95,
115.68, 82.42, 75.93, 72.57, 65.79, 64.40, 49.88, 49.56, 48.04,
45.29, 42.80, 37.21, 36.45, 33.26, 32.77, 32.05, 31.84, 31.30,
29.68, 28.12, 25.93, 22.73, 20.41, 19.40, 18.23, 14.30, 13.08,
-4.60; EIMS m/z: 575, 361, 143. Anal. Calcd for C35H62O5Si:
C, 71.14; H, 10.57. Found: C, 70.99; H, 10.90.
syrup: [R]20 -220.38 (c 1.01 CHCl3); 1H NMR (300 MHz,
D
CDCl3) 8.10-6.90 (9H, m), 4.99 (1H, d, J ) 3.7), 4.90 (1H, dd,
J ) 3.7, 9.4), 4.72 and 4.45 (2H, AB, J ) 12.6), 4.10 (1H, dd,
J ) 7.9), 3.89 (3H, s), 3.80-3.50 (3H, m), 0.97 and 0.85 (each
9H, each t, J ) 7.9), 0.65 and 0.55 (each 6H, each q); EIMS
m/z: 573, 495, 135. Anal. Calcd for C32H50O7Si2: C, 63.75; H,
8.36. Found: C, 63.51; H, 8.25.
r-Hyd r oxy Keton e (15). To a cooled solution (-78 °C) of
ClCOCOCl (0.11 mL, 1.26 mmol) in CH2Cl2 (2 mL) was added
dropwise a solution of DMSO (0.18 mL, 2.54 mmol) in CH2Cl2
(0.5 mL), and the mixture was stirred for 15 min, before a
solution of 14 (287 mg, 0.486 mmol) in CH2Cl2 (5 mL) was
added. After being stirred for another 15 min, the reaction was
quenched with Et3N (0.68 mL, 4.88 mmol) and warmed to room
temperature. The mixture was then extracted with CH2Cl2.
The organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo to give a residue, which was purified
by flash column chromatography (petroleum ether-EtOAc,
50:1 to 20:1) to afford 15 (222 mg, 78%) as a white solid and
3,4-Di-O-t r iet h ylsilyl-2-O-(4-m et h oxylb en zoyl)-r/â-D-
xylop yr a n ose (19). A suspension of 18 (12.84 g, 21.30 mmol),
triethylamine (1 mL) and 10% Pd/C (2.5 g) in EtOAc (200 mL)
was stirred at 50 °C under H2 atmosphere (40 atm) for 1 d
and then filtered. The filtrates were concentrated in vacuo.
The residue was purified by flash column chromatography
(petroleum ether-EtOAc, 20:1 to 5:1 and then 3:1) to afford
19 (8.34 g, 76%) as a syrup, which could slowly become a solid,
recovered starting material 14 (40 mg, 14%). 15: [R]25
D
and recovered starting material 18 (2.63 g, 20%). 19: [R]29
D
-150.33 (c 1.13 CHCl3); 1H NMR (300 MHz, CDCl3) 5.30 (1H,
d, J ) 5.2), 4.05-3.90 (4H, m), 3.47 (1H, m), 2.72 (1H, q, J )
7.4), 1.02 (3H, s), 1.01 (3H, d, J ) 7.4), 0.87 (9H, s), 0.05 (6H,
(27) Sivakumaran, T.; J ones,J . K. N. Can. J . Chem. 1967, 45, 2493.

Total Synthesis of Anticancer Saponin, OSW-1
J . Org. Chem., Vol. 64, No. 1, 1999 207
+54.81 (c 1.28 CHCl3). Anal. Calcd for C25H44O7Si2: C, 58.56;
1, 5:1, 4:1, and then 2:1) to give 25 (0.50 g), a mixture of 25
H, 8.65. Found: C, 58.70; H, 8.76.
and 26 (5.83 g), and a small amount of 26 (overall 100% yield).
1
25: [R]16 +78.35 (c 2.16 CHCl3); H NMR (300 MHz, CDCl3)
D
3,4-Di-O-t r iet h ylsilyl-2-O-(4-m et h oxylb en zoyl)-r/â-D-
xylop yr a n osyl tr ich lor oa cetim id a te (20). To a solution of
19 (7.17 g, 13.98 mmol) and CCl3CN (7 mL, 70 mmol) in
CH2Cl2 (60 mL) was added DBU (three drops), and the
resulting solution was stirred at room temperature for 3 h,
and concentrated in vacuo. The residue was purified by flash
column chromatography (petroleum ether-EtOAc with 1% of
triethylamine: 20:1 to 15:1) to afford a colorless syrup 20 (7.27
g, 79%) as a mixture of R and â anomer (2:3, from 1H NMR):
7.99 and 6.89 (4H, AB), 7.30-7.20 (5H, m), 5.05-4.94 (3H,
m), 4.69 (1H, d, J ) 6.6), 4.65 and 4.34 (2H, AB, J ) 12.1),
4.06-4.02 (2H, m), 3.96 (1H, dd, J ) 4.3, 11.7), 3.85 (1H, m),
3.84 (3H, s), 3.75 (1H, t, J ) 7.1), 3.75-3.64 (2H, m), 3.27 (1H,
dd, J ) 8.2), 1.65 (3H, s), 0.95 (9H, t, J ) 8.2), 0.85 (9H, t, J
) 8.0), 0.62 (6H, q, J ) 8.2), 0.51 (6H, q, J ) 8.0); 13C NMR
(75 MHz, CDCl3) 170.04, 164.78, 163.47, 137.32, 131.82,
128.32, 127.76, 127.61, 122.43, 113.55, 101.68, 95.87, 75.61,
74.39, 73.04, 71.03, 69.82, 69.61, 68.38, 65.08, 61.74, 55.40,
20.24, 6.80, 5.00; EIMS m/z: 748, 640, 135. Anal. Calcd for
[R]13 +14.88 (c 0.87 CHCl3); 1H NMR (300 MHz, CDCl3) 8.58
D
(0.6H, s), 8.45 (0.4H, s), 8.05-7.95 (2H, m), 6.92-6.85 (2H,
m), 6.41 (0.4H, d, J ) 3.4), 6.03 (0.6H, d, J ) 4.2), 5.17-5.10
(1H, m), 4.23 (0.6H, dd, J ) 3.3, 11.8), 4.16 (0.4H, m), 3.90-
3.70 (5H, m), 3.55 (0.4H, m), 1.00-0.50 (30H, m); EIMS m/z:
627, 495, 135.
C
39H60O12Si2: C, 60.28; H, 7.78. Found: C, 60.61; H, 7.91. 26:
1H NMR (300 MHz, CDCl3) 8.00 and 6.90 (4H, AB), 7.30-7.20
(5H, m), 5.08-5.02 (2H, m), 4.85 (1H, dd, J ) 3.5, 10.0), 4.68
and 4.47 (2H, AB, J ) 12.3), 4.63 (1H, d, J ) 6.3), 4.04 (1H,
dd, J ) 4.3, 11.2), 3.92 (1H, dd, J ) 4.0), 3.85 (3H, s), 3.88-
3.70 (5H, m), 3.28 (1H, dd, J ) 8.2), 2.00 (3H, s), 0.96 and
0.87 (18H, each t, J ) 7.7), 0.70-0.50 (12H, m).
Ben zyl 2-O-Acetyl-3,4-O-isop r op ylid en e-â-L-a r a bin op y-
r a n osid e (23). A solution of L-arabinose (12.0 g, 80 mmol) in
HCl saturated BnOH (60 mL) was stirred overnight at room
temperature and then diluted with ether (180 mL) and placed
in a refrigerator for 4 h. The resulting solid was filtered to
afford a crude product (15.44 g, 80%), which was recrystalized
from ethanol to give pure benzyl â-L-arabinopyranoside (21)28
(12.97 g): 1H NMR (300 MHz, CD3SOCD3) 7.40-7.20 (5H, m),
4.75 (1H, brs), 4.66 and 4.45 (2H, AB, J ) 12.4), 3.72-3.6 (4H,
m), 3.46 (1H, dd, J ) 2.7); EIMS m/z: 241, 223, 91.
A mixture of 21 (5.65 g, 23.53 mmol), 2,2-dimethoxylpropane
(5.8 mL, 47.2 mmol), and TsOH‚H2O (280 mg) in DMF (50 mL)
was stirred at room temperature for 5 h, and triethylamine (1
mL) was added, diluted with EtOAc. The organic layer was
washed with saturated NaHCO3 solution and brine, dried over
MgSO4, and concentrated in vacuo to afford a colorless syrup,
which was dissolved in Ac2O (10 mL) and Py (10 mL), and
stirred overnight at room temperature. After being quenched
with MeOH, the mixture was diluted with EtOAc. The organic
layer was washed with diluted HCl, saturated NaHCO3, and
brine, respectively, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (petroleum ether-EtOAc, 10:1 to 8:1) to afford 2328 (6.77
g, 89%) as a syrup: 1H NMR (300 MHz, CDCl3) 7.40-7.25 (5H,
m), 4.98 (1H, d, J ) 3.4), 4.90 (1H, dd, J ) 8.1), 4.71 and 4.48
(2H, AB, J ) 12.3), 4.36 (1H, dd, J ) 5.5), 4.24 (1H, brd), 4.00
(1H, brs), 2.06 (3H, s), 1.52 and 1.34 (each 3H, each s); EIMS
m/z: 321, 263, 91.
Ben zyl 2-O-Acet yl-3-O-(3,4-d i-O-t r iet h ylsilyl-2-O-(4-
m eth oxyben zoyl)-â-D-xylop yr a n osyl)-4-O-(tr ieth ylsilyl)-
â-L-a r a bin op yr a n osid e (29) a n d Ben zyl 2-O-Acetyl-4-O-
(3,4-d i-O -t r ie t h y ls ily l-2-O -(4-m e t h o x y b e n zo y l)-â-D -
x y l o p y r a n o s y l ) -3 -O -t r i e t h y l s i l y l -â-L -a r a b i n o -
p yr a n osid e (30). A mixture of 25 and 26 (5.67 g, 7.30 mmol),
2,6-lutidine (4.3 mL, 36.9 mmol), and TESOTf (3.2 mL, 14.2
mmol) in CH2Cl2 (50 mL) was stirred at -20 °C for 1 h and
poured into saturated NaHCO3 solution. The mixture was
extracted with CH2Cl2, and the organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified with flash column chromatography
(petroleum ether-EtOAc, 10:1 to 8:1) to give 29 (4.58 g, 70%)
as a pale yellow syrup and 30 (1.38 g, 21%) as a white solid.
1
29: [R]18 +94.87 (c 1.10 CHCl3); H NMR (300 MHz, CDCl3)
D
7.93 and 6.87 (4H, AB), 7.34-7.20 (5H, m), 5.10-4.94 (3H,
m), 4.69 (1H, d, J ) 7.5), 4.64 and 4.34 (2H, AB, J ) 12.1),
4.10 (1H, brs), 3.95 (1H, dd, J ) 3.0, 9.6), 3.90 (1H, dd, J )
3.8, 11.2), 3.83 (3H, s), 3.82-3.64 (3H, m), 3.50 (1H, dd, J )
3.1, 11.9), 3.21 (1H, dd, J ) 9.0), 1.73 (3H, s), 1.00-0.45 (45H,
m); 13C NMR (75 MHz, CDCl3) 169.84, 164.43, 163.26, 137.57,
131.63, 128.30, 127.76, 122.92, 113.46, 102.50, 95.87, 76.03,
74.75, 74.04, 71.92, 70.72, 70.41, 69.52, 65.87, 64.33, 55.35,
20.52, 6.83, 5.17, 5.12, 4.85; EIMS m/z: 863, 495, 363, 135.
Anal. Calcd for
C45H74O12Si3‚0.5H2O: C, 60.03; H, 8.40.
Found: C, 60.17; H, 8.52. 30: 1H NMR (300 MHz, CDCl3), 8.03
and 6.85 (4H, AB), 7.28 (5H, m), 5.04 (1H, d, J ) 3.3), 5.01
(1H, t, J ) 6.0, 7.6), 4.89 (1H, d), 4.66 and 4.25 (2H, AB, J )
12.4), 4.61 (1H, dd, J ) 9.9), 4.10 (1H, dd, J ) 2.9), 4.03 (1H,
dd, J ) 3.0, 11.5), 3.84 (3H, s), 3.84-3.66 (5H, m), 3.23 (1H,
dd, J ) 8.6), 1.88 (3H, s), 1.00-0.50 (45H, m). Anal. Calcd for
Ben zyl 2-O-Acetyl-â-L-a r a bin op yr a n osid e (24). A solu-
tion of 23 (6.52 g, 20.22 mmol) in 70% HOAc (100 mL) was
stirred at 70 °C for 1 h and then concentrated in vacuo, and
the traces of HOAc and water were removed by coevaporation
with toluene several times. The residue was purified by flash
column chromatography (petroleum ether-EtOAc, 1.2:1 to 1:1
and then 1:2) to afford 24 (5.35 g, 94%) as a colorless syrup,
C
45H74O12Si3-0.5H2O: C, 60.03; H, 8.40. Found: C, 60.24; H,
8.38.
2-O-Acetyl-3-O-(3,4-d i-O-tr ieth ylsilyl-2-O-(4-m eth oxy-
which slowly became a solid: [R]20 +229.58 (c 1.35 CHCl3);
D
1H NMR (300 MHz, CDCl3) 7.40-7.20 (5H, m), 5.06 (1H, d, J
) 3.6), 4.99 (1H, dd, J ) 9.9), 4.74 and 4.51 (2H, AB, J ) 12.4),
4.10 (1H, dd, J ) 3.4), 4.02 (1H, brs), 3.93 and 3.76 (2H, AB,
J ) 12.6), 2.11 (3H, s); EIMS m/z 283, 265, 205, 91. Anal. Calcd
for C14H18O6: C, 59.57; H, 6.43. Found: C, 60.06; H, 6.46.
b en zoyl)-â-D-xylop yr a n osyl)-4-O-(t r iet h ylsilyl)-â-L-a r a -
bin op yr a n ose (31). A suspension of 29 (2.60 g, 2.91 mmol),
10% Pd/C (3 g), and triethylamine (1.5 mL) in EtOAc (20 mL)
and EtOH (20 mL) was stirred under H2 atmosphere (50 atm)
and 50 °C for 3 d and filtered. The filtrate was concentrated
in vacuo to give a residue, which was purified by flash column
chromatography to give 31 (1.17 g, 50%) as a syrup, mainly
Ben zyl 2-O-Acet yl-3-O-(3,4-d i-O-t r iet h ylsilyl-2-O-(4-
m eth oxyben zoyl)-â-D-xylop yr a n osyl)-â-L-a r a bin op yr a n o-
side (25) an d Ben zyl 2-O-Acetyl-4-O-(3,4-di-O-tr ieth ylsilyl-
2 -O -(4 -m e t h o x y b e n z o y l )-â-D -x y l o p y r a n o s y l )-â-L -
a r a bin op yr a n osid e (26). A suspension of imidate donor 20
(7.18 g, 10.92 mmol), acceptor 24 (2.28 g, 8.09 mmol) and 4 Å
MS (10 g) in dry CH2Cl2 (60 mL) was stirred at room
temperature for 15 min and then cooled to -60 °C, and a
solution of BF3-OEt2 (5.7 mL, 0.07 M) in CH2Cl2 was slowly
added to the reaction. After 30 min, the reaction was quenched
with triethylamine (0.5 mL) and filtered. The filtrate was
concentrated in vacuo to give a residue, which was purified
by flash column chromatography (petroleum ether-EtOAc, 10:
as the R anomer, and recovered starting material 29 (0.92 g,
1
36%). 31: [R]29 +13.27 (c 1.27 CHCl3); H NMR (300 MHz,
D
CDCl3) 7.96 and 6.90 (4H, AB, J ) 9.9), 5.21 (1H, brs), 5.00
(1H, t, J ) 7.6, 7.6), 4.91 (1H, dd, J ) 3.0, 8.8), 4.68 (1H, d, J
) 7.1), 4.05 (1H, brs), 3.86 (3H, s), 4.00-3.64 (5H, m), 3.54
(1H, dd, J ) 4.5, 11.7), 3.21 (1H, dd, J ) 8.5, 11.3), 1.86 (3H,
s), 1.00-0.80 (27H, m), 0.70-0.40 (18H, m); 13C NMR (75 MHz,
CDCl3) 169.98, 164.56, 163.31, 131.66, 122.74, 113.48, 102.06,
90.97, 75.57, 74.50, 73.86, 71.69, 70.91, 65.60, 64.27, 55.36,
20.64, 6.80, 5.07, 4.90, 4.78; EIMS m/z: 772, 495, 135. Anal.
Calcd for C38H68O12Si3: C, 56.97; H, 8.55. Found: C, 57.05;
H, 8.91.
2-O-Acetyl-3-O-(3,4-d i-O-tr ieth ylsilyl-2-O-(4-m eth oxy-
b en zoyl)-â-D-xylop yr a n osyl)-4-O-(t r iet h ylsilyl)-â-L-a r a -
(28) Ballou, C. E. J . Am. Chem. Soc. 1957, 79, 165. (b) Rammler, D.
H.; MacDonald, D. L. Arch. Biochem. Biophs. 1958, 78, 359.

208 J . Org. Chem., Vol. 64, No. 1, 1999
Deng et al.
bin op yr a n osyl tr ich lor oa cetim id a te (3). A solution of 31
(139 mg, 0.174 mmol), CCl3CN (0.2 mL, 2 mmol), and DBU
(one drop) in CH2Cl2 (5 mL) was stirred at room temperature
for 6 h, the solution was concentrated in vacuo, and the
resulting residue was purified by flash column chromatogra-
phy (petroleum ether-EtOAc with 1% of triethylamine, 15:1
to 10:1) to give 3 (106 mg, 65%) as a syrup. Imidate 3 was
found to quickly decompose in the NMR tube and therefore
was immediately used in the next glycosylation without
further identification.
P r otected OSW-1 (32). A solution of donor 3 (96 mg, 0.10
mmol), aglycone 2 (50 mg, 0.085 mmol), and 4 Å MS (200 mg)
in dry CH2Cl2 (2 mL) was stirred at room temperature for 15
min and then cooled to -20 °C, and a solution of TMSOTf (1
mL, 0.0045 M) in CH2Cl2 was slowly added to the reaction.
After being stirred for another 20 min, the reaction was
quenched with triethylamine (0.1 mL) and filtered. The
filtrates were concentrated in vacuo to give a residue, which
was purified by flash column chromatography (petroleum
ether-EtOAc, 9:1 to 6:1) to afford 32 (80 mg, 69%) as a white
foam: [R]25D -41.62 (c 0.78 CHCl3); 1H NMR (300 MHz, CDCl3)
8.03 and 6.98 (4H, AB), 5.30 (1H, d, J ) 4.5), 5.11 (1H, dd, J
) 0.9, 3.4), 4.98 (1H, brs), 4.90 (1H, brs), 4.55 (1H, brs), 3.68
(3H, s), 2.64 (1H, q, J ) 7.4), 2.01 (3H, s), 0.054 (6H, s); 13C
NMR (75 MHz, CDCl3) 168.45, 164.62, 163.33, 141.34, 132.06,
122.81, 121.24, 116.52, 113.29, 100.96, 87.16, 72.62, 71.05,
69.21, 68.99, 64.18, 62.43, 55.38, 49.80, 48.12, 48.01, 42.85,
37.23, 36.50, 35.24, 33.32, 32.45, 32.09, 31.89, 29.67, 28.18,
25.93, 22.28, 21.67, 20.87, 20.72, 19.26, 18.24, 12.77, 12.35,
6.94, 6.76, 5.04, 4.90, 4.77, -4.58; ESIMS m/z: 1420 (M + 2Na
+ 2), 1393. Anal. Calcd for C73H128O16Si4‚2H2O: C, 62.18; H,
9.43. Found: C, 62.05; H, 9.34.
solution was directly concentrated in vacuo to give a residue,
which was purified by flash column chromatography (CH2Cl2-
MeOH, 15:1) to give 1 (18 mg, 79%) as a pale yellow solid: Rf
0.56 (CH2Cl2-MeOH, 15:1); [R]26 -45.2 (c 0.25 MeOH), lit.3
D
1
-43.2 (c 0.25 MeOH); H NMR (600 MHz, C5D5N) 8.31 (2H,
d), 7.07 (2H, d), 5.67 (1H, dd, J ) 8.0, 9.2), 5.55 (1H, t, J )
6.3, 7.5), 5.37 (1H, d, J ) 3.6), 5.11 (1H, d, J ) 8.0), 4.79 (1H,
s), 4.57 (1H, d, J ) 6.0), 4.39 (1H, brs), 4.31 (1H, dd, J ) 5.2,
11.1), 4.26-4.20 (2H, m), 4.20-4.12 (3H, m), 3.81 (1H, brs),
3.73 (3H, s), 3.18 (1H, q, J ) 7.4), 1.96 (3H, s), 1.27 (3H, d, J
) 7.5), 1.06 (3H, s), 0.98 (3H, s), 0.87 (3H, d, J ) 6.4), 0.84
(3H, d, J ) 6.4); 13C NMR (75 MHz, C5D5N) 218.96, 169.27,
165.47, 163.91, 141.95, 132.45, 121.13, 114.15, 103.68, 100.86,
88.36, 85.72, 80.99, 76.35, 75.15, 72.05, 71.31, 70.75, 67.85,
67.06, 65.59, 55.52, 50.20, 48.58, 46.57, 46.33, 43.55, 39.29,
37.80, 36.90, 34.64, 32.73, 32.28, 32.08, 27.76, 22.85, 22.51,
20.93, 19.64, 13.64, 11.91; IR (KBr) 3467, 2957, 2934, 1726,
1695, 1607, 1513, 1465, 1373, 1258, 1232, 1170, 1044, 988, 972;
FABMS m/z: 896 (M + 1 + Na); ESIMS m/z: 895 (M + Na+),
919 (M + 1 + 2Na+), 1769 (2 × (M + 1) + Na+).
Ack n ow led gm en t. We thank the Ministry of Sci-
ence and Technology of China for financial support. B.Y.
is grateful to Prof. Y. Sashida for helpful discussion on
the target molecule OSW-1.
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
NMR spectra for compounds 1, 2, 6-11, 13-15, 18, 20, and
23-32, 13C NMR spectra for compounds 1, 2, 7, 8, 10, 11, 13-
15, 25, 29, 31, 32 (36 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
OSW-1 (1). A solution of 32 (36 mg, 0.026 mmol) and
Pd(MeCN)2Cl2 (∼2 mg) in acetone and water (2 mL, v:v, 20:1)
was stirred overnight at room temperature, and then the
J O981685C