A new strategy for synthesizing the steroids with side chains from steroidal sapogenins: Synthesis of the aglycone of OSW-1 by using the intact skeleton of diosgenin

Article abstract of DOI:10.1016/j.tetlet.2003.09.227

The protected aglycone of saponin OSW-1, a new antitumor natural product, was synthesized in 13 linear steps in 9.5% overall yield by utilizing the intact skeleton of diosgenin. This strategy demonstrated a higher efficiency than the routine synthesis of

Full text of DOI:10.1016/j.tetlet.2003.09.227

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9375–9377
A new strategy for synthesizing the steroids with side chains
from steroidal sapogenins: synthesis of the aglycone of OSW-1
by using the intact skeleton of diosgenin
Qi-hai Xu, Xiao-wen Peng and Wei-sheng Tian*
Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 2 June 2003; revised 19 August 2003; accepted 22 September 2003
Abstract—The protected aglycone of saponin OSW-1, a new antitumor natural product, was synthesized in 13 linear steps in 9.5%
overall yield by utilizing the intact skeleton of diosgenin. This strategy demonstrated a higher efficiency than the routine synthesis
of steroids with side chains.
© 2003 Elsevier Ltd. All rights reserved.
OSW-1 (1) and its analogues (2–5) were isolated from
Ornithogalum saundersiae bulbs.1 They are members of
the cholestane glycoside family characterized by the
attachment of a disaccharide to the C-16 position of the
steroid aglycone, whereas compounds 4 and 5 have
another glycosyl sugar connected at the C-3 position of
the steroid (Fig. 1). Their IC50 values against human
leukemia HL-60 cells range from 0.1 nM to 0.3 nM.2
OSW-1 (1), the main constituent of the bulbs, exhibits
extraordinary cytostatic activities against various
human malignant tumor cells. Its anticancer activities
are 10- to 100-fold more potent than some of the
well-known anticancer agents currently in clinical use,
such as mitomycin C, adriamycin, cisplatin, camp-
tothecin, and taxol, but its toxicity to normal human
pulmonary cells is significantly lower (IC50 1500 nM).
ing a stereoselective 1,4-addition of a-alkoxy vinyl
cuprate to a steroid D17(20)-en-16-one,7 in which epi-
androsterone was still used as the starting material. In
contract to the synthetic strategies mentioned above, we
planned to synthesize the aglycone of OSW-1 and
analogues with related side chains from the intact sapo-
genin skeletons rather than from their degradation
products.
It is well known that side chain-containing natural
steroids, such as vitamin D, brassinolide and cephalo-
OSW-1 (1) has been a very attractive synthetic target
owing to its highly potent anticancer activities, novel
structure and low content in natural plants.1 Fuchs first
reported the synthesis of the protected aglycone of
OSW-1 starting from epiandrosterone,3 which was pre-
pared through the degradation of diosgenin (6) even
though it is commercially available. The overall yield of
epiandrosterone from 6 ranged from 25 to 50%
(Scheme 1).4,5 In 1999, Hui’s group reported the total
synthesis of OSW-1 by using a similar approach.6
Recently, Jin and his co-workers presented a somewhat
different approach to the synthesis of OSW-1 employ-
Figure 1. The structures of OSW-1 and its analogues.
Keywords: OSW-1; antitumor; aglycone; diosgenin; steroids.
* Corresponding author. Tel: 086-021-64163300-83225; e-mail: wstian
@pub.sioc.ac.cn
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.227

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Q. Xu et al. / Tetrahedron Letters 44 (2003) 9375–9377
our previous exploration.15 The 26-thioacetal 7 under-
went reductive desulfurization catalyzed by W-2 Raney
nickel14b to realize the needed conversion at C-26. For
further modification of the E ring, the D5(6)-double
bond and C-3 hydroxyl group in the A/B rings of 8
were protected via a classical carbocation rearrange-
ment.16 The oxidation of the A/B rings protected com-
pound 9 by dimethyldioxirane which was generated in
situ from Oxone® and acetone in a buffer of 4×10−4
mol/l aqueous ethylenediaminetetraacetic acid disodium
salt (EDTADS)17,18 directly resulted in the formation of
the expected E-ring opened compound 10 (32%) and
C-16 hydroxylation product 20 (61%). The latter could
be transformed to compound 10 by further oxidation
(Scheme 3).
After deprotection of the double bond, compound 11
was obtained, which had the same side chain and A/B
rings as OSW-1. However, low conversion of 11 ham-
pered the application of the similar strategy of con-
structing the 16,17-alkene from the 16-keto with PhSH
in the presence of BF3·Et2O.19 Fortunately, 11 or its
acetate 21 underwent 16-thioketalization with
ethanedithiol regioselectively leaving the C-22 carbonyl
group intact.14b The thioketal-opening-acetylization
(TOA reaction) took place when the 16-thioketal was
treated with Ac2O in the presence of 70% HClO4 or
BF3·Et2O to produce the 16,17-alkene 12. We also
found that 11 could be converted to 12 in one-pot with
BF3·Et2O catalyzing the acetylization, thioketalization
and TOA reaction (Scheme 4).19 The conversion from
11 to 12 is another key step in our route.20
Scheme 2. Reagents and conditions: (a) PhSH, BF3·Et2O,
CH2Cl2, rt, 88.3%; (b) W-2 Raney Ni, anhydrous EtOH,
reflux, 93.1%; (c) i. TsCl, Py, rt, ii. KOAc, acetone/H2O,
reflux, iii. Ac2O, Py, DMAP, rt, 75.2%; (d) Oxone®, NaHCO3,
buffer, CH2Cl2/acetone, 80% after four-time oxidation; (e)
TsOH, dioxane/H2O, reflux, 0.5 h, 97%; (f) HSCH2CH2SH,
BF3·Et2O, HOAc, 2.5 h, then Ac2O, 20 min, 63.5%; (g) W-2
Raney Ni, anhydrous EtOH, rt, 0.5 h, 90%; (h)
HOCH2CH2OH, HC(OEt)3, TsOH, rt, 6.5 h, 85%; (i) OsO4,
Py, ether, −78°Cꢀrt, 4 h, then H2S bubbled through, 57.1%;
(j) Swern oxidation, 87%; (k) K2CO3, MeOH, 100%; (l)
TBSCl, imidazole, DMF, 87%; (m) NaBH4, CeCl3·7H2O,
THF, 94%.
Desulfurization of 12 with W-2 Raney nickel at room
temperature produced compound 13, which is a known
intermediate in the synthetic strategies of Fuchs and
statins and other marine steroids, are usually synthe-
sized from steroid 17-ketones, or 20-ketones or 22-alde-
hydes.8,9 There have been only a few reports on their
synthesis by exploiting the intact skeletons of steroidal
sapogenins.10 Comparing OSW-1 with the E/F ring-
opened form of diosgenin, one notices that they both
have related side chains and the same disposal of the
C-16 hydroxyl and the 21-methyl groups. Using the
open side chain of diosgenin directly to synthesize
OSW-1, one only needs to move a hydroxyl group at
C-26 to C-17 (Scheme 1). Obviously, it is a more
reasonable synthetic strategy according to atom econ-
omy.11 We present herein for the first time a successful
synthesis of the aglycone of OSW-1 using the intact
skeleton of diosgenin (Scheme 2).
Scheme 3.
The opening of the E/F rings was the first key step for
utilizing the intact skeleton of sapogenins to synthesize
the aglycone of OSW-1. Diosgenin (6), an abundant
and cheap plant-derived steroidal sapogenin, readily
reacted with thiols or dithiols in the presence of a Lewis
acid such as BF3·Et2O to afford directly the 26-thioac-
etal 7.12,13 Attempts to open the E/F rings by thioketal-
ization of the C-22 spiroketal were unsuccessful due to
intramolecular redox reaction between the C-22 and the
C-26 functional groups.12–14 Lewis acid catalyzed acetyl-
ation at the C-16 and C-26 hydroxyl groups failed in
Scheme 4.

Q. Xu et al. / Tetrahedron Letters 44 (2003) 9375–9377
9377
Hui.3,6 We performed the further transformations
according to the literature,3,6 that is, ethylene glycol
ketal protection of the 22-ketone 13, dihydroxylation of
the 16,17-alkene function in 14 with OsO4, Swern oxi-
dation of the 16a-OH group in 15, conversion of 3-OAc
in 16 to 3-OTBS in 18, and stereoselective reduction of
the 16-keto group in 18 to the 16b-OH group in 19.
Therefore, we completed the synthesis of the protected
aglycone of saponin OSW-1 (compound 19), which
displayed identical spectral data with those reported.21
Further optimization and synthesis of the disaccharide
moiety of OSW-1 are currently in progress in our
laboratory.
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solution of 11 (2.08 g, 5.0 mmol) in 35 ml of HOAc, were
added HSCH2CH2SH (1.06 ml, 12.6 mmol) and
BF3·Et2O (1.30 ml, 10.3 mmol) dropwise. The mixture
was stirred at room temperature for 2.5 h and 20 ml of
Ac2O was added. The resultant mixture was stirred for an
additional 20 min. The reaction was quenched with
aqueous saturated NaHCO3 solution, and then solid
NaHCO3 was added until no alveoli bubbled up. The
mixture was extracted with EtOAc (50 ml×3). The com-
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CDCl3): l 5.40 (1H, d, J=3.9 Hz, 6-H), 4.64–4.58 (1H,
m, 3-H), 3.68 (1H, q, J=6.8 Hz, 20-H), 3.00–2.95 and
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46.8, 38.6, 38.0, 36.7, 36.7, 35.1, 34.4, 33.0, 31.3, 30.6,
30.1, 29.8, 27.6, 22.4, 22.4, 21.4, 20.4, 19.2, 17.1, 14.3; MS
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3.89–3.87 (1H, m, 16-H), 3.47–3.39 (1H, m, 3-H), 2.59
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49.6, 47.8, 47.8, 42.7, 37.2, 36.5, 35.8, 33.9, 33.1, 32.7,
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18.2, 12.5, 11.9, −4.6; MS (EI) m/z (intensity): 575 (M+−
15, 0.9), 533 (M+−57, 6.8), 485 (18.9); IR (KBr): 3545,
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