A new synthesis of potent antitumor saponin OSW-1 via Wittig rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.11.087

OSW-1 and its analogues in which thiophene ring was introduced at the side chain were synthesized employing Wittig rearrangement of 17E(20)-ethylidene-16α-(4′-methyl-2′-thienyl)methyloxy steroid. The synthesis required nine steps from the known 17E(20)-ethylidene-16α-hydroxy steroid in 15.6% overall yield.

Full text of DOI:10.1016/j.tetlet.2007.11.087

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 229–232
A new synthesis of potent antitumor saponin OSW-1
via Wittig rearrangement
Masayoshi Tsubuki , Sohichiro Matsuo, Toshio Honda *
*
Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
Received 1 November 2007; revised 13 November 2007; accepted 15 November 2007
Available online 21 November 2007
Abstract
OSW-1 and its analogues in which thiophene ring was introduced at the side chain were synthesized employing Wittig rearrangement
0
0
of 17E(20)-ethylidene-16a-(4 -methyl-2 -thienyl)methyloxy steroid. The synthesis required nine steps from the known 17E(20)-ethyl-
idene-16a-hydroxy steroid in 15.6% overall yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: OSW-1; Analogues; Thiophene; Wittig rearrangement
5
OSW-1 (1), an acylated cholestane diglycoside, has been
isolated from the bulbs of Ornithogalum saundersiae (Lilia-
ceae) by Sashida, Mimaki and co-workers in 1992 (Fig. 1).
of OSW saponin analogues with modified disaccharides,
side chains,
3
d,6
7
and steroidal nuclei have been obtained
by means of chemical synthesis for SAR (structure–activity
relationship) studies.
Fuchs et al. proposed that the active intermediate might
be an 22-oxocarbenium ion, which could be generated from
22-carbonyl and 16a-hydroxy moieties. Yu et al. have
recently reported that both 22-methylene and 23-hetero-
atom (O, S, NH) analogues of OSW-1 were found to be
as potent as the parent natural products against the growth
1
OSW-1 exhibited extremely potent cytotoxic activity
against various human malignant tumor cells. Its cytotoxic
activities are from 10- to 100-fold more potent than some
well-known anticancer agents in clinical use, such as mito-
4
b
2
mycin C, adriamycin, cisplatin, camptothecin, and taxol.
While OSW-1 is exceptionally cytotoxic against various
tumor cells, it showed little toxicity to normal human cells.
Much attention has been paid on the synthesis of OSW-1
6
b–d
of tumor cells.
The precise mechanism by which OSW-1
3
,4
because of its extraordinary potent activity. A number
exerts its effect remains unclear. For further study of a
structure–activity relationship OSW-1 analogues having
heterocyclic ring, such as thiophene and thiazole, at the
side chain were designed. As part of our continuing work
on the synthesis of naturally occurring compounds employ-
ing furan and related compounds as versatile synthons, we
have succeeded in the synthesis of biologically active
steroids with highly oxygenated side chains. In this regard,
we intended to synthesize an extremely potent antitumor
saponin OSW-1 and its analogues by means of the Wittig
O
OH
O
O
AcO
O
O
HO
HO
-MeOC
OH
8
HO
p
6
H
4
CO
2
Fig. 1. Structure of OSW-1 (1).
9
,10
rearrangement
of allyl thiophenemethyl ether for the
*
construction of (20S)-22-hydroxy steroidal side chain. Here
we wish to report the synthesis of OSW-1 and its analogues
having thiophene ring at the side chain.
Corresponding authors. Tel.: +81 3 5498 5793; fax: +81 3 3787 0036
(
M.T.).
E-mail address: tsubuki@hoshi.ac.jp (M. Tsubuki).
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.087

230
M. Tsubuki et al. / Tetrahedron Letters 49 (2008) 229–232
The key feature of our synthesis is based on stereoselec-
tive conversion of 22-hydroxy-22-(4 -methylthienyl) steroid
into OSW-1 thiophene analogue 2 by introduction of
yield (62%) (entry 2). t-BuLi was found to be the base of
choice for the [2,3]-rearrangement (entry 3). The inconsis-
tent diastereoselectivity observed at the C-22 position
would not be rationally explained.
0
3
trans-diol functionality at the C-16 and -17 positions and
glycosylation of aglycone with disaccharide (Scheme 1).
Reductive desulfurization of thiophene analogue 2 would
afford OSW-1 (1). (20S)-22-Hydroxy steroid 3 could be
prepared by Wittig rearrangement of 17E(20)-ethylidene-
The absolute configuration at the C-22 position in 22-
hydroxy steroids 6 and 7 was determined by the modified
1
3
Mosher’s method and is shown in Figure 2.
We then embarked on the synthesis of OSW-1 and its
thiophene analogues employing the Wittig rearrangement
of thiophenemethyl ether (Scheme 2). Requisite thio-
phenemethyl ether 10 was prepared by etherification of
0
0
1
6a-(4 -methyl-2 -thienyl)methyloxy steroid 4.
We first investigated the Wittig rearrangement of allyl
thiophenemethyl ether (Table 1). Model compound 5 was
prepared by etherification of the known 16a-allylic alco-
1
4
the known allylic alcohol 9 with 4-methyl-2-thiophene-
1
1
12
12
hol with 4-methyl-2-thiophenemethyl bromide in 95%
methyl bromide in the presence of 18-crown-6 in 92% yield.
yield. Treatment of 5 with n-BuLi (10 equiv) in THF at
Treatment of 10 with t-BuLi (5 equiv) in THF at ꢀ78 °C
gave [2,3]-rearranged product 11 (22a- and 22-b alcohols
in a ratio of 78:22) in 59% yield. Oxidation of 11 with
ꢀ
78 °C followed by warming to 0 °C gave [2,3]-rearranged
products 6 and 7 and [1,2]-rearranged product 8 in a ratio
of 23:23:54, respectively, in 97% total yield (entry 1),
whereas reaction of 5 with s-BuLi (3 equiv) in THF at
1
5
Dess–Martin periodinane in CH Cl afforded ketone 12
2
2
quantitatively. Attempts to convert 12 into trans-diol 15
via 16a,17a-epoxide were unsuccessful because stereoselec-
tive ring-opening reaction of the epoxide did not occur.
Dihydroxylation of 12 with OsO4 in the presence of
pyridine gave cis-diol 13, which was subjected to Swern
ꢀ
78 °C produced 6–8 in a ratio of 19:34:47 in moderate
O
1
6
oxidation to furnish diketone 14 in 85% yield (two steps).
Reduction of 14 with NaBH in MeOH–CH Cl (1:1, v/v)
OH
S
4
2
2
OH
O
O
S
at ꢀ15 °C occurred chemoselectively to afford the desired
trans-diol 15 in 82% yield. Pleasingly, intramolecular hemi-
acetalization of 15 did not proceed in our synthesis, while
protection of carbonyl moiety at C-22 position was
1
O
AcO
O
HO
HO
-MeOC H CO
2
OH
HO
p
6
4
2
3
4
3
,4
required at an early stage in most syntheses of OSW-1.
S
Glycosylation of steroid aglycone 15 with disaccharide
imidate 16, prepared from D-xylose and L-arabinose by
O
3
a
the reported method,
in the presence of TMSOTf
provided b-glycoside 17 in 72% yield (Scheme 3). All the
Scheme 1. Synthetic strategy for OSW-1 and its analogue.
protecting groups, one MOM and three TES, were
1
7
removed by treatment of 17 with TMSBr to give OSW-
thiophene analogue 2 in 73% yield. Finally, thiophene
ring in 2 was reductively desulfurized with W-2 Raney
1
Table 1
1
8
Witting rearrangement of thiophenemethyl ether 5
Ni under an atmosphere of hydrogen, furnishing OSW-
(1) in 79% yield. The physical data of synthetic OSW-1
1
1
(1) are identical with those reported by Sashida.
OH
S
O
In conclusion, we have succeeded in a new approach to
S
the synthesis of OSW-1 and its thiophene analogues using
(20S)-22-hydroxy steroid with thiophene ring at the side
chain, which was obtained by Wittig rearrangement of
thiophenemethyl ether. Since OSW-1 analogue with thio-
phene 2 is similar to the above mentioned 23-heteroatom
base
THF
°
-
78 C
OMe
5
6
OH
S
OH
(
O, S, NH) analogues of OSW-1 regarding the reactivity
of carbonyl group at the C-22 position, thiophene analogue
+
+
S
7
8
a
c
Entry
Base
Yield (%)
Ratio of 6/7/8
OMTPA
S
+0.022
-
0.016
-
0.050
Me
H
-0.017
H
Me
H
H
S
H
b
1
2
3
a
n-BuLi
s-BuLi
t-BuLi
97
62
90
23:23:54
19:34:47
40:18:42
0.000
-
0.849
-0.052
Me
H -0.091
OMTPA
H
+0.038
Me
H
H
H
+0.061
n-BuLi (10 equiv), s-BuLi (3 equiv), and t-BuLi (5 equiv) were
-
0.119
+0.131
employed.
T (°C): ꢀ78 to 0.
Total yield of 6–8.
b
c
Fig. 2. DdR–S Values obtained for the MTPA esters of (22S)-alcohol 6 and
(22R)-alcohol 7.

M. Tsubuki et al. / Tetrahedron Letters 49 (2008) 229–232
231
Acknowledgments
OH
a
S
This study was supported in part by the Ministry of
Education, Culture, Sports, Science and Technology,
Japan, and by the Open Research Center Project.
O
1
0
MOMO
9
1
b
O
OH
Supplementary data
S
S
c
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2
11
2007.11.087.
d
O
O
S
e
S
References and notes
OH
OH
OH
O
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Scheme 2. Reagents and conditions: (a) NaH (3 equiv), 18-crown-6
3 equiv), 4-methyl-2-thiophenemethyl bromide (2 equiv), benzene,
(
7
7
0 °C, 12 h, 92%; (b) t-BuLi (5 equiv), THF, ꢀ78 °C, 30 min, 59% (a/b =
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(
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Cl
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a
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AcO
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AcO
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HO
OH
HO
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-MeOC
OH
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-MeOC
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p
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p
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, ꢀ78 °C, 1.5 h, 72%; (b) TMSBr (3.9 equiv),
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1