A total synthesis of OSW-1

Article abstract of DOI:10.1021/jo7018812

(Chemical Equation Presented) A new and practical method was developed to synthesize OSW-1, a natural saponin with potent antitumor activities, from (+)-dehydroisoandrosterone, L-arabinose, and D-xylose on gram scale. The synthesis was achieved in 10 linear steps with an overall yield of 6.4% starting from (+)-dehydroisoandrosterone.

Full text of DOI:10.1021/jo7018812

A Total Synthesis of OSW-1
Jie Xue, Peng Liu, Yanbin Pan, and Zhongwu Guo*
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202
zwguo@chem.wayne.edu
ReceiVed August 27, 2007
A new and practical method was developed to synthesize OSW-1, a natural saponin with potent antitumor
activities, from (+)-dehydroisoandrosterone, L-arabinose, and D-xylose on gram scale. The synthesis was
achieved in 10 linear steps with an overall yield of 6.4% starting from (+)-dehydroisoandrosterone.
Introduction
independently developed total syntheses of OWS-1, while other
groups have reported the synthesis of OSW-1 aglycon and other
partial structures,10-13 as well as OSW-1 analogues.14-30
OSW-1 (1) is a steroidal saponin isolated from Ornithogalum
saundersid,1 which belongs to a group of cholestane glycosides.
The structure of OSW-1 is rather unique in that its disaccharide
moiety linked to the steroidal aglycon O-16 position contains a
p-methoxybenzoyl group. OSW-1 has exhibited exceptionally
potent cytotoxicity,2,3 with IC50 between 0.1 and 0.7 nM, to a
variety of malignant tumor cells, including leukemia, mastro-
carcinoma, lung adenocarcinoma, pulmonary large cell carci-
noma, and pulmonary squamous cell carcinoma. Therefore,
OSW-1 is a promising lead compound for development of novel
antitumor drugs.4,5
(3) Tamura, K.; Honda, H.; Mimaki, Y.; Sashida, Y.; Kogo, H. Brit. J.
Pharmacol. 1997, 121, 1796.
(4) Morzycki, J. W.; Wojtkielewicz, A. Phytochem. ReV. 2006, 4, 259.
(5) Zhou, Y.; Garcia-Prieto, C.; Carney, D. A.; Xu, R.; Pelicano, H.;
Kang, Y.; Yu, W.; Lou, C.; Kondo, S.; Liu, J.; Harris, D. M.; Estrov, Z.;
Keating, M. J.; Jin, Z.; Huang, P. J. Natl. Cancer Inst. 2005, 97, 1781.
(6) Deng, S.; Yu, B.; Lou, Y.; Hui, Y. J. Org. Chem. 1999, 64, 202.
(7) Shi, B.; Tang, P.; Hu, X.; Liu, J. O.; Yu, B. J. Org. Chem. 2005, 70,
10354.
(8) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369.
(9) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2002, 124, 6576.
(10) Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 1099.
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1269.
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J. W. Pol. J. Chem. 2006, 80, 611.
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2007, 48, 3475.
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Maruyama, S.; Kamoshita, K.; Nemoto, H.; Eustache, J. Bioorg. Med. Chem.
Lett. 2007, 17, 5101.
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kowski, M.; Renkiewicz, J.; Strnad, M.; Swaczynova, J.; Wilczewska, A.
Z.; Wojcik, J. J. Med. Chem. 2007, 50, 3667 and references cited therein.
(20) Matsuya, Y.; Masuda, S.; Ohsawa, N.; Adam, S.; Tschamber, T.;
Eustache, J.; Kamoshita, K.; Sukenaga, Y.; Nemoto, H. Eur. J. Org. Chem.
2005, 803.
Owing to its interesting structure and highly potent anticancer
activity, OSW-1 has been an attractive synthetic target for
organic chemists. For example, Yu6,7 and Jin8,9 groups have
* To whom correspondence should be addressed. Phone: 313-577-2557.
Fax: 313-577-8822.
(1) Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaido, T.; Ohmoto,
T. Phytochemistry 1992, 31, 3969.
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Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J. A. Bioorg. Med.
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10.1021/jo7018812 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/08/2007
J. Org. Chem. 2008, 73, 157-161
157

Xue et al.
SCHEME 1
4 in an excellent yield upon recrystallization. As both isomers
could be used in the next step, we did not try to separate them
further. However, we discovered that, when the reaction was
quenched at room temperature, instead of -78 °C, the yield of
4 was poor, while the starting material was recovered, suggesting
that the retro-aldol condensation reaction was prominent at
higher temperature. Further elongation of the side chain by
refluxing 4 with a Grignard reagent in benzene proceeded
smoothly, but the addition reaction was accompanied by
â-elimination to give 5 as well as a small amount of 6 and 7 as
an inseparable mixture. We have also tested some other reaction
conditions, e.g., using THF or diethyl ether as the reaction
solvent, but the reaction in benzene gave the best results.
According to the literature,31 5, 6, and 7 would reach an
equilibrium under basic conditions to give the thermodynami-
cally more stable 7 as the major product. Therefore, we treated
the mixture of 5, 6, and 7 with NaOH in MeOH. The NMR
spectrum of the newly formed mixture revealed 4:3:5 ratios of
5, 6, and 7. Although these three compounds were inseparable
on TLC or by silica gel column chromatography, fortunately,
the desired product 7 could be separated from the other two
isomers by recrystallization from hexane. Moreover, after 7 was
collected, the mother liquid could be concentrated, and the
residue was treated with NaOH again to yield another crop of
7 upon recrystallization from hexane. This procedure was
repeated another time to finally obtain 7 in a good yield (73%).
The stereochemistry of epimers 6 and 7 was determined through
analysis of their 1H NMR spectra. According to the literature,31
the proton NMR signal of 21-CH3 in 6 appears downfield (δ
1.25) compared to that of 21-CH3 in 7 (δ 1.15). The configu-
ration of 7 was further confirmed by comparing the physical
data of its subsequent products with those of the same structures
reported in the literature. For example, after selective protection
of 3-OH in 7 by tert-butyldimethylsilyl (TBS) via reacting with
TBS chloride and imidazole in DMF and then protection of the
C-22 carbonyl group by ethylene glycol to form a ketal, the
Structure-activity relationship studies on OSW-1 analogues
have revealed new compounds that have potent antitumor
activity.7,19,21 In this paper, we have described a new, efficient,
and practical synthesis of OSW-1, which can be performed on
gram scales.
1
product 9 gave H and 13C NMR spectra identical with that
reported by Yu et al.6 Both reactions were very clean and gave
excellent yields. Eventually, the key intermediate 9 was obtained
from 3 in only 4 separate steps, in contrast to 7 to 9 steps
described in the literature.6 In addition, the reactions were very
reliable and the reaction products were easily purified through
recrystallization, facilitating large-scale synthesis.
Compound 9 was transformed into 2 in 3 steps as described
in the literature.6,10 First, 9 was regioselectively dihydroxylated
to afford 16R,17R-diol 10 in a moderate yield with the recovery
of some starting material and the observation of some polar
byproducts which might be derived from excessive oxidation.
The inversion of C-16 stereochemistry was conveniently realized
after regioselective Swern oxidation of 16-OH with DMSO and
oxalyl chloride and then reduction of the resultant ketone 11
by NaBH4 in the presence of CeCl3 to give 2 exclusively.
Consequently, 2 was obtained from (+)-dehydroisoandrosterone
in 7 steps and an overall yield of 15%.
Results and Discussion
Synthesis of the Aglycon. Our overall synthetic design for
OSW-1 was to first prepare the aglycon and the disaccharide
moiety, which have different properties, separately and then
couple them together to obtain the synthetic target. Scheme 1
has outlined the preparation of the aglycon, using commercially
available (+)-dehydroisoandrosterone 3 as the starting material.
In this synthesis, a key step was to introduce a side chain to
the C-17, as described by Yu6,7 and Jin.8,9 For this purpose, we
first added propanenitrile to 3 at -78 °C by an aldol condensa-
tion reaction catalyzed by LDA to obtain an epimeric mixture
(24) Ma, X.; Yu, B.; Hui, Y.; Miao, Z.; Ding, J. Carbohydr. Res. 2001,
334, 159.
(25) Ma, X.; Yu, B.; Hui, Y.; Miaob, Z.; Ding, J. Bioorg. Med. Chem.
Lett. 2001, 11, 2153.
(26) Ma, X.; Yu, B.; Hui, Y.; Xiao, D.; Ding, J. Carbohydr. Res. 2000,
329, 495.
(27) Morzycki, J. W.; Gryszkiewicz, A.; Jastrzebska, I. Tetrahedron Lett.
2000, 41, 3751.
(28) Guo, C.; LaCour, T. G.; Fuchs, P. L. Bioorg. Med. Chem. Lett.
1999, 9, 419.
(29) Deng, L.; Wu, H.; Yu, B.; Jiang, M.; Wu, J. Bioorg. Med. Chem.
Lett. 2004, 14, 2781.
Synthesis of the Disaccharide Moiety. Monosaccharides as
glycosyl acceptors and donors employed in this synthesis were
prepared from L-arabinose and D-xylose, respectively (Scheme
2). After 12 was obtained from L-arabinose as reported,32 it was
regioselectively p-methoxybenzylated with the assist of dibu-
tyltin complex to afford 13, which was directly subjected to
(30) Peng, W.; Tang, P.; Hu, X.; Liu, J. O.; Yu, B. Bioorg. Med. Chem.
Lett. 2007, 17, 5506.
(31) Chaudhurrio, N. K.; Nickolson, R.; Williams, J. G.; Gut, M. J. Org.
Chem. 1969, 94, 3767.
158 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of OSW-1
SCHEME 2
SCHEME 3
acetolysis to give the desired glycosyl acceptor 14. In contrast
to galactose derivatives in which 3-OH is usually more reactive
than 4-OH, in 12, 4-OH was more reactive than 3-OH, probably
because, as a pentose, arabinose has a less hindered 4-OH.
Compound 14 had an acetyl group attached to its 2-OH, while
its 4-OH and 1-OH groups were protected by a p-methoxybenzyl
(PMB) group and an acetyl group, respectively. It was expected
that its anomeric acetyl group could be selectively removed,
after the desired disaccharide was constructed, to subsequently
convert the disaccharide into a glycosyl donor used for
glycosylation of the aglycon. Eventually, 14 was synthesized
from L-arabinose on multigram scales in an overall yield of 56%.
Monosaccharide donors 15 and 16 were prepared according
to Jin’s method9 with modified workup procedures. In brief,
D-xylose was transformed into 15 through a series of reactions
without isolation of the reaction intermediates, and only 15 was
finally purified by column chromatography to get an overall
yield of 74% on a multigram scale. Thereafter, 15 was converted
to Schmidt donor 16 following oxidative deprotection of the
anomeric center with N-bromosuccinimide (NBS) and H2O and
then trichloroacetimidation of the resultant hemiacetal. The R-
and â-anomers of 16 were separable and both isomers were
individually characterized, but their mixture was employed in
subsequent glycosylation.
We first tried the glycosylation of 14 using 15 as glycosyl
donor and N-iodosuccinimide (NIS) and triflic acid (TfOH) as
promoter. Instead of the desired disaccharide, the reaction gave
17 as the major product with complete recovery of 14. This
result indicated that 15 was activated by NIH/TfOH, but the
resultant reactive intermediate reacted with the byproduct of
NIS, rather than 14, suggesting that the former might be more
nucleophilic than the latter. To avoid this problem, we then used
bromine as promoter in the presence, as well as in the absence,
of silver triflate (AgOTf). This reaction also failed to yield the
desired disaccharide; instead, 18 was obtained as the major
product. These results suggest that 14 is a particularly poor
glycosyl acceptor, which is consistent with the relative reactivity
shown by the two hydroxyl groups in 12. Fortunately, the
glycosylation of 14 with 16 as glycosyl donor went well to give
19 in a good yield and stereoselectivity, and the reaction was
also proved to be very reliable. Finally, 19 was converted to
glycosyl donor 21 as an R- and â-anomeric mixture upon selec-
tive removal of the anomeric acetyl group and then trichloro-
acetimidation of the resultant hemiacetal 20.
SCHEME 4
Synthesis of OSW-1. With both the aglycon 2 and the
disaccharide donor 21 in hand, the finally assembly of OSW-1
was straightforward (Scheme 4). The glycosylation of 2 by 21
was achieved with trimethylsilyl triflate (TMSOTf) as promoter
to produce the protected OSW-1 22. Global deprotection of 22
was accomplished in two separate steps. First, the TBS and ketal
groups at O-3 and C-22 positions of the aglycon, respectively,
were removed under mild acidic conditions. Next, the PMB
groups on the disaccharide moiety of 23 were removed by 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) oxidation to afford
the synthetic target OSW-1 (1). The physical data of our final
product were identical with the reported data of OSW-1.1,6,9
In summary, OSW-1 was synthesized from (+)-dehydroiso-
androsterone 3 in 10 linear steps and an overall yield of 6.4%,
with new and efficient procedures developed to prepare the agly-
con as well as the monosaccharide and disaccharide building
blocks. This synthesis is highlighted by the reliability of all in-
volved transformations and the simple workup procedures. For
example, in the preparation of the aglycon and the monosac-
charide building blocks, most intermediates were either purified
through recrystallization or directly used in subsequent reactions
without purification, which enabled large-scale synthesis. Conse-
quently, OSW-1 was obtained in gram scale. This new synthetic
strategy is currently employed to prepare various derivatives
of OSW-1 for studies of its structure-activity relationships and
for exploration of novel anticancer therapeutics.
(32) Magnus, V.; Vikic-Topic, D.; Iskric, S.; Kveder, S. Carbohydr. Res.
1983, 114, 209.
J. Org. Chem, Vol. 73, No. 1, 2008 159

Xue et al.
column chromatography to give 9 (1.46 g, 96%) as a white solid.
[R]25D +38.4 (c 1.0, CH2Cl2). 1H NMR (CDCl3, 200 MHz): δ 5.66
(br, 1H), 5.35 (br, 1H), 3.96 (s, 4H), 3.60-3.40 (m, 1H), 2.44 (q,
J ) 7.0 Hz, 1H), 2.32-2.18 (m, 3H), 2.18-1.90 (m, 2H), 1.90-
1.38 (m, 21H), 1.38-1.10 (m, 6H), 1.10-0.92 (m, 9H), 0.92-
0.76 (m, 11H). 13C NMR (CDCl3, 75 MHz): δ 156.6, 141.1, 124.0,
121.6, 113.9, 71.7, 65.9, 65.3, 57.3, 47.5, 42.4, 39.2, 37.2, 36.8,
34.9, 34.0, 32.5, 31.7, 31.4, 30.7, 28.4, 22.7, 20.9, 19.4, 17.4, 15.7,
-4.5. EI MS: calcd for C35H60O3Si 556.4, found 557.6 (M + H+).
Compound 10.6 To the solution of 9 (0.40 g, 0.71 mmol) in 10
mL of diethyl ether and 0.5 mL of pyridine was added OsO4 (0.35
g, 1.38 mmol) at -60 °C. Then, the reaction mixture was warmed
to rt and stirred for 3 h. The reaction was quenched with saturated
aq NaHSO3 solution and the suspension was stirred overnight. The
mixture was extracted with ethyl acetate, and the combined organic
layer was dried over anhydrous Na2SO4. After concentration, the
Experimental Section
Compound 4.31 To the solution of (+)-dehydroisoandrosterone
(3, 3.06 g, 10.6 mmol) and propanenitrile (5 mL, 70 mmol) in 200
mL of THF was added LDA in THF (20 mL, 40 mmol) at -78
°C. After the reaction mixture was stirred for another 30 min, it
was diluted with diethyl ether and then quenched with saturated
aq NH4Cl solution at -78 °C. The organic layer was separated
and dried over anhydrous Na2SO4. After filtration and removal of
the solvent, the residue was recrystallized from diethyl ether and
hexane to give 4 (3.5 g, 96%) as colorless crystals. 1H NMR
(CDCl3, 400 MHz): δ 5.33 (br, 1H), 4.58-4.46 (m, 1H), 2.84-
2.70 (q, J ) 6.8 Hz, 1H), 2.32-2.20 (m, 2H), 2.04-1.83 (m, 6H),
1.76-1.40 (m, 12H), 1.35 (d, J ) 6.8 Hz, 3H), 1.18-1.10 (m,
1H), 1.04 (s, 3H), 0.94 (s, 3H). HR ESI MS: calcd for C22H33NO2
343.2511, found 343.2507 (M+).
Compound 7.31 To the solution of 4 (2.78 g, 8.1 mmol) in 200
mL of benzene was added freshly prepared 3-methylbutylmagne-
sium bromide in benzene (80 mL, 64 mmol). The reaction mixture
was refluxed overnight. TLC indicated the complete consumption
of starting materials. Then, the organic solvent was removed under
reduced pressure, and 200 mL of aq HCl solution (1 N) was added.
After the mixture was stirred at rt overnight, it was extracted with
diethyl ether. The combined organic layer was dried with anhydrous
Na2SO4 and condensed. The residue was purified with a silica gel
column briefly to afford an inseparable mixture of 5, 6, and 7 (1.78
g, 55%). To a solution of 2.98 g of the mixture of 5, 6, and 7 in 40
mL of MeOH and 12 mL of H2O was added 6 g of NaOH. After
the mixture was refluxed for 4 h, MeOH was removed under
reduced pressure. The remaining mixture was extracted with diethyl
ether. The combined organic layer was dried with anhydrous
Na2SO4 and condensed. The residue was then dissolved in 100 mL
of hot hexane for recrystallization to obtain 1.10 g of the desired
product 7. The mother liquid was condensed and the residue was
dissolved in MeOH and H2O and treated with NaOH again.
Following the same workup and recrystallization protocol, another
crop of pure 7 was obtained. After repeating this procedure one
more time, a total of 2.20 g of 7 was obtained (73%). [R]20D +11.0
(c 1.0, CH2Cl2). 1H NMR (CDCl3, 400 MHz): δ 5.37 (s, 2H), 3.35
(m, 1H), 3.20 (q, J ) 6.8 Hz, 1H), 2.53-2.45 (m, 1H), 2.39-2.20
(m, 3H), 2.18-1.80 (m, 7H), 1.70-1.24 (m, 13H), 1.15 (d, J )
6.8 Hz, 3H), 1.14-0.96 (m, 4H), 0.90-0.80 (m, 7H). 13C NMR
(CDCl3, 100 MHz): δ 154.5, 141.3, 125.4, 121.6, 71.8, 57.3, 50.8,
47.5, 45.9, 42.5, 38.5, 37.4, 36.9, 34.9, 33.3, 31.8, 31.7, 31.5, 30.8,
27.8, 22.7, 22.5, 21.0, 19.5, 17.1, 16.5. EI MS: calcd for C27H42O2
398.3, found 399.5 (M + H+).
residue was purified by column chromatography to give 10 (0.21
1
g, 50%) as a white solid. [R]25 56.67 (c 0.99 CHCl3). H NMR
D
(CDCl3, 300 MHz): δ 5.30 (1H, d, J ) 4.2 Hz), 4.28 (1H, m),
3.97 (4H, m), 3.47 (1H, m), 1.12 (3H, d, J ) 7.0 Hz), 0.98 (3H, s),
0.88 (9H, s), 0.77 (3H, s), 0.04 (6H, s). 13C NMR (CDCl3, 75
MHz): δ 141.5, 120.9, 115.7, 82.4, 75.9, 72.6, 65.8, 64.4, 49.9,
49.6, 48.0, 45.3, 42.8, 37.2, 36.5, 33.3, 32.8, 32.1, 31.8, 31.3, 29.7,
28.1, 25.9, 22.7, 20.4, 19.4, 18.2, 14.3, 13.1, -4.6. EI MS: calcd
for C35H62O5Si 590.4, found 591.5 (M + H+).
Compound 11.6 After the solution of oxalyl chloride (0.11 mL)
and DMSO (0.18 mL) in 2 mL of CH2Cl2 was stirred at -50 °C
for 15 min, a solution of 10 (0.26 g, 0.44 mmol) in CH2Cl2 (5 mL)
was added. The mixture was stirred at -50 °C for another 15 min,
and then 1.0 mL of triethylamine was added. After the reaction
mixture was warmed to rt slowly, the product was extracted with
CH2Cl2, dried with anhydrous Na2SO4, and condensed. The residue
was purified by column chromatography to give 11 (0.24 g, 92%)
1
as a white solid. [R]25 -150 (c 1.13, CHCl3). H NMR (CDCl3,
D
300 MHz): δ 5.30 (1H, d, J ) 5.2 Hz), 4.05-3.90 (4H, m), 3.47
(1H, m), 2.72 (1H, q, J ) 7.4 Hz), 1.02 (3H, s), 1.01 (3H, d, J )
7.4 Hz), 0.87 (9H, s), 0.05 (6H, s). 13C NMR (CDCl3, 75 MHz):
δ 215.5, 141.6, 120.7, 115.4, 85.4, 72.5, 63.4, 63.3, 49.5, 46.9,
45.4, 42.7, 41.2, 37.2, 37.1, 36.7, 32.7, 32.2, 32.0, 30.8, 30.2, 28.3,
25.9, 22.7, 22.4, 20.1, 19.4, 18.2, 15.0, 14.3, -4.6. EI MS: calcd
for C35H60O5Si 588.4, found 589.7 (M + H+).
Compound 2.8 To a solution of 11 (0.40 g, 0.07 mmol) in 50
mL of THF was added 0.80 g of CeCl3‚7H2O and 0.40 g of NaBH4
at 0 °C. The reaction mixture was stirred at 0 °C for 4 h and then
extracted with CH2Cl2. The organic layer was dried and concen-
trated, and the residue was purified by column chromatography to
provide 2 (0.36 g, 90%) as a white solid. [R]25D -36 (c 1.0, CHCl3).
1H NMR (CDCl3, 400 MHz): δ 5.30 (d, 1 H, J ) 4.2 Hz, H-6),
4.05 (m, 1 H), 3.94-4.07 (m, 4 H), 3.48 (m, 1 H), 2.59 (q, 1 H, J
) 7.5 Hz), 1.18 (s, 3 H), 1.02 (d, 3 H, J ) 7.5 Hz), 0.90 (s, 3 H),
0.87 (s, 9 H), 0.89, 0.87 (2d, 6 H, J ) 6.5 Hz), 0.02 (s, 6 H). 13C
NMR (CDCl3, 100 MHz): δ 141.6, 121.3, 116.7, 92.5, 87.0, 81.8,
72.8, 64.3, 63.0, 49.8, 48.1, 48.0, 43.0, 37.5, 36.7, 36.1, 34.1, 33.3,
33.0, 32.9, 32.3, 32.1, 28.5, 26.1, 22.9, 22.5, 20.9, 19.6, 18.4, 112.7,
12.2, -4.4. HR FAB MS: calcd for C35H61O5Si (M - H+)
589.4288, found 589.4250.
Compound 14. A mixture of 12 (5.55 g, 26.9 mmol) and
Bu2SnO (6.72 g, 27 mmol) in 100 mL of toluene was refluxed
with azeotropic removal of H2O for 2 h. The reaction mixture was
concentrated under reduced pressure. To the residue were added
DMF (50 mL), CsF (7.6 g, 50 mmol), KI (6 g, 40 mmol), and
p-methoxylbenzyl chloride (4.38 mL, 32 mmol) at 0 °C. The
mixture was stirred at rt overnight and then diluted with CH2Cl2.
The organic phase was washed with brine, dried over Na2SO4, and
concentrated to obtain 13. The crude product 13 was dissolved in
50 mL of AcOH, stirred at rt for 1 h, and then concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 and washed
with brine, dried over Na2SO4, and concentrated. Flash column
chromatography of the product gave 14 as colorless syrup (6.0 g,
Compound 8.6 To the solution of 7 (1.03 g, 2.58 mmol) and
imidazole (0.45 g, 7.76 mmol) in 20 mL of CH2Cl2 was added
TBSCl (0.58 g, 3.87 mmol) at rt. After the reaction mixture was
stirred for 2 h, aq HCl solution (1 N) was added to quench the
reaction, and the reaction mixture was extracted with diethyl ether.
The combined organic layer was washed with saturated NaHCO3,
dried over anhydrous Na2SO4, and then condensed. The residue
was purified by column chromatography to give 8 (1.37 g, 99%)
as a white solid. [R]20 +18.6 (c 1.0, CH2Cl2). H NMR (CDCl3,
1
D
200 MHz): δ 5.34 (br, 2H), 3.55-3.40 (m, 1H), 3.18 (q, J ) 6.8
Hz, 1H), 2.58-1.80 (m, 7H), 1.80-1.40 (m, 17H), 1.15 (d, J )
6.8 Hz, 3H), 1.09 (s, 6H). 13C NMR (CDCl3, 50 MHz): δ 211.6,
154.4, 141.9, 125.2, 120.9, 72.6, 57.2, 50.8, 47.4, 45.7, 42.9,
38.3, 37.4, 36.9, 34.7, 33.1, 32.1, 31.6, 31.3, 30.7, 27.7, 25.0, 25.7,
22.6, 22.3, 20.8, 19.4, 18.3, 16.9, 16.3, 4.5. EI MS: calcd for
C33H56O2Si 512.4, found 513.7 (M + H+).
Compound 9.6 To the solution of 8 (1.39 g, 2.71 mmol), ethylene
glycol (0.5 mL, 8.94 mmol), and triethyl orthoformate (0.5 mL,
3.00 mmol) in 20 mL of benzene was added PTS‚H2O (20 mg,
0.10 mmol). The mixture was stirred at rt for 2 days and then
quenched with saturated aq NaHCO3 solution. The mixture was
then extracted with Et2O. After the organic layer was dried over
anhydrous Na2SO4 and condensed, the product was purified by
160 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of OSW-1
1
63%). [R]25 +51.2 (c 1.0, CHCl3). H NMR (CDCl3, 400 MHz):
1.98 (s, 3H), 1.14 (d, J ) 7.6 Hz, 3H), 0.92 (s, 3H), 0.89 (s, 9H),
0.85 (s, 3H), 0.67 (d, J ) 6.8 Hz, 3H), 0.57 (d, J ) 5.6 Hz, 3H),
0.05 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ 169.2, 165.2, 164.1,
163.7, 159.3, 159.1, 141.2, 132.3, 130.6, 130.4, 130.3, 129.8, 129.5,
128.8, 122.3, 121.6, 116.6, 113.9, 113.8, 113.7, 101.2, 92.1, 87.4,
72.9, 71.6, 71.3, 64.6, 62.8, 55.6, 55.5, 55.3, 49.9, 48.3, 48.2, 46.1,
43.0, 37.5, 36.6, 35.4, 33.7, 32.6, 32.5, 32.3, 31.9, 31.8, 29.9, 28.4,
26.2, 22.9, 22.7, 22.1, 21.2, 20.9, 19.6, 18.5, 12.7, -4.3. ESI MS:
calcd for C79H110O19Si 1390.7, found 1429.2 (M + K+).
D
δ 7.26 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 5.58 (d, J )
6.4 Hz, 1H), 5.10 (t, J ) 6.4 Hz, 1H), 4.66 (d, J ) 11.2 Hz, 1H),
4.48 (d, J ) 11.2 Hz, 1H), 4.08 (dd, J ) 13.2, 3.2 Hz, 1H), 3.80
(s, 3H), 3.75 (br, 2H), 3.52 (d, J ) 13.2 Hz, 1H), 2.09 (s, 3H),
2.08 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 170.4, 169.7, 159.8,
129.8, 129.4, 114.2, 92.2, 74.1, 71.5, 71.4, 70.7, 62.4, 55.5, 21.2,
21.1. ESI MS: calcd for C17H22O8 354.1, found 377.0 (M + Na+).
HR EI MS: calcd for C17H22O8 354.1315, found 354.1324 (M+).
Disacharide 19. After a mixture of 16 (13.4 g, 20 mmol), 14
(3.55 g, 10 mmol), and 4 Å MS (5.0 g) in dry CH2Cl2 (50 mL)
was stirred at rt for 3 h and then cooled to -15 °C, BF3‚Et2O (2
mmol, 10%) was added. The reaction mixture was stirred at -15
to -10 °C for another 2 h, and the 1H NMR spectrum of the mixture
showed the completion of reaction. Et3N (1.0 mL) was added to
quench the reaction, and the mixture was filtered off to remove
molecular sieves. The filtrate was combined and concentrated under
reduced pressure, and the residue was purified by silica gel column
Partially Protected OSW-1 (23). After a solution of 22 (0.55
g, 0.39 mmol) in a mixture of AcOH and H2O (1:5, 5 mL) was
stirred at 70 °C for 2 h, the solvent was removed under reduced
pressure. The residue was purified by flash column chromatography
to give 23 (0.44 g, 90%) as a white solid. [R]25 -22.8 (c 1.0,
D
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.97 (d, J ) 9.2 Hz, 2H),
7.24 (d, J ) 8.8 Hz, 2H), 7.21 (d, J ) 8.4 Hz, 2H), 7.16 (d, J )
8.8 Hz, 2H), 6.86 (d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.4 Hz, 2H),
6.82 (d, J ) 8.4 Hz, 2H), 6.69 (d, J ) 8.8 Hz, 2H), 5.30 (br, 1H),
5.18 (t, J ) 4.8 Hz, 1H), 4.79 (br, 2H), 4.67 (d, J ) 11.2 Hz, 1H),
4.63 (d, J ) 12.4 Hz, 1H), 4.58 (d, J ) 11.2 Hz, 1H), 4.53 (d, J )
11.6 Hz, 1H), 4.52 (d, J ) 11.2 Hz, 1H), 4.49 (d, J ) 11.2 Hz,
1H), 4.29 (br, 1H), 4.21 (d, J ) 4.0 Hz, 1H), 3.94 (dd, J ) 11.2,
7.6 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H),
3.59 (q, J ) 4.0 Hz, 1H), 3.52 (m, 1H), 3.42 (m, 2H), 3.03 (q, J )
7.2 Hz, 1H), 1.89 (s, 3H), 1.13 (d, J ) 7.6 Hz, 3H), 0.95 (s, 3H),
0.79 (s, 3H), 0.74 (d, J ) 6.8 Hz, 3H), 0.73 (d, J ) 6.8 Hz, 3H).
13C NMR (CDCl3, 100 MHz): δ 169.1, 164.9, 163.7, 159.4, 159.2,
159.1, 140.5, 139.6, 132.1, 130.6, 130.3, 130.2, 129.6, 129.4, 129.1,
122.4, 121.8, 113.9, 113.8, 113.7, 113.6, 100.3, 85.8, 72.0, 71.9,
71.4, 55.6, 55.4, 55.2, 49.6, 48.1, 46.1, 46.0, 42.4, 39.1, 37.3, 36.5,
32.3, 32.2, 31.9, 31.8, 31.7, 27.5, 22.6, 22.3, 20.9, 20.7, 19.5, 13.7,
11.9. ESI MS: calcd for C71H92O18 1232.6, found 1255.2 (M +
Na+), 1271.2 (M + K+).
chromatography to afford 19 (6.9 g, 80%) as a white foamy solid.
[R]25 +6.6 (c 1.0, CHCl3). H NMR (CDCl3, 500 MHz): δ 7.92
1
D
(d, J ) 9.0 Hz, 2H), 7.26 (d, J ) 8.5 Hz, 2H), 7.24 (d, J ) 9.0 Hz,
2H), 7.09 (d, J ) 9.0 Hz, 2H), 6.87 (d, J ) 9.0 Hz, 2H), 6.86 (d,
J ) 9.0 Hz, 2H), 6.84 (d, J ) 8.5 Hz, 2H), 6.67 (d, J ) 8.5 Hz,
2H), 5.53 (d, J ) 5.5 Hz, 1H), 5.20 (t, J ) 7.5 Hz, 1H), 5.17 (t, J
) 7.5 Hz, 1H), 4.70 (d, J ) 6.0 Hz, 1H), 4.66 (d, J ) 11.5 Hz,
2H), 4.63 (d, J ) 11.5 Hz, 1H), 4.62 (d, J ) 11.5 Hz, 1H), 4.58
(d, J ) 11.5 Hz, 1H), 4.53 (d, J ) 11.5 Hz, 1H), 3.98 (dd, J ) 7.0,
4.5 Hz, 1H), 3.92 (dd, J ) 7.5, 6.0 Hz, 1H), 3.86 (s, 3H), 3.81 (s,
3H), 3.79 (s, 3H), 3.72 (s, 3H), 3.50 (dd, J ) 12.5, 2.5 Hz, 1H),
3.27-3.39 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 169.9, 169.2,
164.9, 163.7, 159.6, 159.4, 159.3, 132.1, 130.5, 130.3, 129.9, 129.8,
122.5, 114.1, 113.9, 113.8, 102.0, 95.0, 92.2, 79.2, 76.8, 73.9, 72.8,
72.0, 71.8, 69.9, 63.1, 55.6, 55.5, 55.3, 21.0, 20.8. ESI MS: calcd
for C46H52O16 860.3, found 883.3 (M + Na+), 899.3 (M + K+).
HR EI MS: calcd for C46H52O16 860.3255, found 860.3267 (M+).
Protected OSW-1 (22). To a solution of compound 19 (3.45 g,
4.0 mmol) in THF (40 mL) was added benzylamine (4 mL). After
the reaction mixture was stirred at rt overnight, it was diluted with
CH2Cl2. The organic layer was sequentially washed with aq HCl
solution (1 N) and H2O and then dried over Na2SO4. The solvent
was removed under reduced pressure, and the product was purified
by silica gel column chromatography to give an R- and â-anomeric
mixture of 20 as colorless syrup. To a solution of 20 in dry
CH2Cl2 (20 mL) was added trichloroacetonitrile (1.0 mL) and DBU
(2 drops), and the mixture was stirred at rt overnight before the
solvent was removed under reduced pressure. The residue was
purified by flash column chromatography on a Et3N deactivated
silica gel column to afford 21 (2.87 g), which was directly applied
to the next step of synthesis. A solution of 21 (1.5 g, 1.6 mmol),
2 (0.69 g, 1.1 mmol), and 4 Å MS (1.0 g) in dry CH2Cl2 (10 mL)
was stirred at rt for 3 h. After the mixture was cooled to -20 °C,
TMSOTf (10.6 µL, 0.055 mmol) was added. The reaction mixture
was stirred at -15 to -10 °C for 4 h and then quenched with Et3N
(0.3 mL). After the reaction solution was filtered off to remove
molecular sieves and the filtrate was condensed under reduced
pressure, the residue was purified by flash column chromatography
on a Et3N deactivated silica gel column to afford 22 (0.58 g, 58%)
as a white foamy solid, with the recovery of some 2 (0.25 g). 22:
[R]25D -19.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ 7.96
(d, J ) 9.2 Hz, 2H), 7.26 (d, J ) 8.8 Hz, 2H), 7.25 (d, J ) 8.8 Hz,
2H), 7.16 (d, J ) 8.8 Hz, 2H), 6.81 (d, J ) 9.2 Hz, 2H), 6.80 (d,
J ) 8.0 Hz, 2H), 6.79 (d, J ) 8.8 Hz, 2H), 6.73 (d, J ) 8.0 Hz,
2H), 5.25 (br, 2H), 5.09 (br, 1H), 5.02 (br, 1H), 4.76 (d, J ) 11.2
Hz, 1H), 4.11 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H),
3.72 (s, 3H), 3.07 (q, J ) 7.2 Hz, 1H), 2.64 (q, J ) 7.6 Hz, 1H),
OSW-1 (1).1,6,9 To a mixture of 23 (0.68 g, 0.5 mmol) in
CH2Cl2 and H2O (10:1, 50 mL) was added DDQ (0.40 g, 1.8 mmol)
at rt. The reaction mixture was stirred at rt overnight and then
concentrated in vacuum. The residue was purified by column
chromatography to give 1 (0.32 g, 79%) as a white solid. [R]25
D
-40 (c 0.3, CH3OH) [lit.1 -43 (c 0.25, CH3OH)]. 1H NMR (C5D5N,
500 MHz): δ 8.31 (d, 2 H, J ) 8.8 Hz), 7.07 (d, 2 H, J ) 8.8 Hz),
5.67 (dd, 1 H, J ) 9.1, 7.8 Hz), 5.55 (d, 1 H, J ) 7.9, 6.3 Hz),
5.37 (d, 1 H, J ) 3.9 Hz), 5.11 (d, 1 H, J ) 7.6 Hz), 4.79 (s, 1 H),
4.57 (d, 1 H, J ) 6.0 Hz), 4.39 (br s, 1 H,), 4.31 (dd, 1 H, J ) 5.2,
11.1 Hz), 4.26-4.20 (m, 2 H), 4.20-4.12 (m, 3 H), 3.81 (br s, 1
H), 3.73 (s, 3 H), 3.18 (q, J ) 7.4 Hz, 1 H), 1.96 (s, 3 H), 1.27 (d,
3 H, J ) 7.5 Hz), 1.06 (s, 3 H), 0.98 (s, 3 H), 0.87 (d, 3 H, J ) 6.4
1
Hz), 0.84 (d, 3 H, J ) 6.4 Hz). H NMR (CD3OD, 500 MHz): δ
8.04 (d, J ) 6.8 Hz, 2 H), 7.02 (d, J ) 6.8 Hz, 2 H), 5.33 (d, J )
4.0 Hz, 1 H), 4.93 (t, J ) 6.0 Hz, 1 H), 4.86 (m, 1 H), 4.66 (d, J
) 5.6 Hz, 1 H), 4.14 (d, J ) 4.8 Hz, 1 H), 3.96 (m, 2 H), 3.87 (s,
3 H), 3.82 (dd, J ) 10.0, 3.6 Hz, 1 H), 3.76 (m, 2 H), 3.62 (m, 4
H), 3.47 (dd, J ) 9.6, 1.6 Hz, 1 H), 2.92 (q, J ) 5.6 Hz, 1 H),
2.47 (m, 1 H), 2.14-2.25 (m, 4 H), 1.70 (s, 3 H), 1.11 (d, J ) 6.0
Hz, 3 H), 1.02 (s, 3 H), 0.82 (m, 9 H). HR FAB MS: calcd for
C47H68NaO15 895.4456, found 895.4459 (M + Na+).
Acknowledgment. This work was partially supported by a
research grant from NIH/NCI (R01 CA95142).
Supporting Information Available: Experimental procedures
to prepare 15, 16, and 18, as well as the NMR spectra of 1, 2, 7,
10, 14, 16R, 16â, 19, 22, and 23. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO7018812
J. Org. Chem, Vol. 73, No. 1, 2008 161