A highly efficient synthesis of 22-deoxy-OSW-1 by utilizing the intact skeleton of diosgenin

Article abstract of DOI:10.1016/j.tetlet.2006.03.065

22-Deoxy-OSW-1 (1), an analogue of OSW-1 with the potent anticancer activity, was synthesized by utilizing the intact skeleton of diosgenin in 11 steps in 13.7% overall yield. This synthesis demonstrated an effective and reasonable synthetic strategy for

Full text of DOI:10.1016/j.tetlet.2006.03.065

Tetrahedron Letters 47 (2006) 3217–3219
A highly efficient synthesis of 22-deoxy-OSW-1 by utilizing
the intact skeleton of diosgenin
b
Hong-Jian Qin,a,b Wei-Sheng Tiana,b, and Cui-Wu Lin
*
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
bSchool of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China
Received 31 December 2005; revised 8 March 2006; accepted 9 March 2006
Available online 29 March 2006
Abstract—22-Deoxy-OSW-1 (1), an analogue of OSW-1 with the potent anticancer activity, was synthesized by utilizing the intact
skeleton of diosgenin in 11 steps in 13.7% overall yield. This synthesis demonstrated an effective and reasonable synthetic strategy
for bioactive steroids with side chains.
Ó 2006 Elsevier Ltd. All rights reserved.
OSW-1 and its analogues were isolated from Ornitho-
galum saundersiae bulbs.1 They are members of the cho-
lestane glycoside family characterized by the
attachment of a disaccharide to the C-16 position of
the steroid aglycone. Their IC50 values against human
leukemia HL-60 cells range from 0.1 to 0.3 nM.2
OSW-1, the main constituent of the bulbs, exhibits
extraordinary cytostatic activities against various hu-
man malignant tumor cells. Its anticancer activities are
10–100 times more potent than some of the well-known
anticancer agents currently in clinical use, such as mito-
mycin C, adriamycin, cisplatin, camptothecin, and tax-
ol, but its toxicity to normal human pulmonary cells is
significantly lower (IC50 1500 nM). Recently, Yu and
co-worker synthesized some OSW-1 analogues for
exploring the structure–activity relationship (SAR) of
OSW-1 and found that 22-deoxy-OSW-1 (1) (Fig. 1),
with the 22-one (of OSW-1) being saturated into a
CH2, was slightly more potent than OSW-1 against
the tested three cancer cell lines [including AGS (stom-
ach cancer cells) IC50 1.38 lM, 7404 (liver carcinoma
cells) IC50 0.063 lM, and MCF-7 (breast cancer cells)
0.060 lM].3
ment reaction.5 In connect with our project on the study
of rational utilization of resource compounds,6 we wish
to explore a new synthesis of 22-deoxy-OSW-1 (1) di-
rectly from diosgenin rather than its degraded prod-
uct—epiandrosterone. Different from routine synthesis
of 22-deoxy-OSW-1, the basic skeleton, 27-carbon
atoms and functional groups of starting material dios-
genin were fully expressed in the structure of 22-deoxy-
OSW-1 in our new synthetic strategy (Scheme 1).
Comparing 22-deoxy-OSW-1 with the E/F ring-opened
reduction product 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 E/F ring-opened reduction product of diosgenin
directly to synthesize the aglycone of 22-deoxy-OSW-1
(1), one only needs to move a hydroxyl group at C-26
to C-17 (Scheme 1). Obviously, it is a highly reasonable
synthetic strategy according to atom economy.7
According to our synthetic strategy shown in Scheme 2,
diosgenin (2) was reacted with benzyl bromide in the
presence of NaH to protect the C3-OH of diosgenin in
98% yield. On treatment of 3 with Zn–Hg and hydro-
chloric acid in refluxing ethanol according to the litera-
ture8 afforded the E/F ring-opening reduction product,
16b,26-dihydroxyl cholesterol 4 in 84.7% yield. Removal
of the C26-OH of synthetic intermediate 4 was achieved
via reduction of its tosylate 5 with LiAlH4 in 73% overall
yield in two steps. Subsequent oxidation of the C16-OH
with Jones reagent provided the C16-ketone product
7 in excellent yield (91%). An attempt to introduce
The routine synthesis for OSW-1 and analogues start
from epiandrosterone.3,4 It was prepared through the
degradation of diosgenin, a procedure including thermal
fragmentation in 200 °C acetic acid, chromic oxide in-
duced oxidation, elimination, oximation and rearrange-
*
Corresponding author. Tel.: +86 021 64163300 832; e-mail: wstian@
pub.sioc.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.065

3218
H.-J. Qin et al. / Tetrahedron Letters 47 (2006) 3217–3219
O
OH
OH
O
O
AcO
O
O
AcO
O
O
O
O
HO
HO
HO
HO
OH
OH
HO
HO
OMBz
OMBz
22-deoxy-OSW-1 (1)
OSW-1
Figure 1. The structures of OSW-1 and 22-deoxy-OSW-1.
O
OH
O
OH
OH
Present
OH
Route
HO
HO
Diosgenin
Previous Route
22-deoxy-OSW-1
O
O
OAc
O
AcO
AcO
AcO
Epaindrosterone
Scheme 1.
O
O
OR
O
OH
O
a
b
HO
BnO
BnO
Diosgenin
3
R = H
4
d
c
R = Ts
5
OAc
OH
O
f
e
BnO
BnO
BnO
8
6
7
g
OH
OH
OH
OH
O
O
O
AcO
h
i
O
O
TESO
TESO
OTES
BnO
BnO
BnO
OMBz
11
10
9
+
j, k
OTES
OC (NH)CCl3
O
O
TESO
TESO
O
22-deoxy-OSW-1
OAc
OMBz
Scheme 2. Reagents and conditions: (a) BnBr, NaH, THF/DMF (1:2), 90 °C, 98%; (b) Zn, HCl, EtOH, reflux, 84.7%; (c) TsCl, pyridine, 0 °C to rt;
(d) LiAlH4, THF, rt, 73% (two steps); (e) Jones oxidation, 91%; (f) Ac2O, HClO4 (0.01 equiv), CCl4, 86%; (g) (i) t-BuOK, THF, 0 °C; (ii) Davis
reagent, ꢀ78 °C, 75%; (h) LiAlH4, THF, ꢀ78 °C, 90%; (i) TMSOTf (0.1 equiv), ꢀ20 °C, CH2Cl2, 59%; (j) W-2 Raney Ni, anhydrous EtOH, rt, 93%;
(k) AcOH–THF–H2O (V/V, 8:8:1), 45 °C, 77%.
C17a-hydroxyl group in 7 through air oxidation in the
presence of potassium tert-butoxide was unsuccessful.
In order to functionalize C17, the 16-oxycholesterol 7
was converted to the corresponding enol acetate 8 with
treatment of acetic anhydride and HClO4 (0.01 equiv)
as the catalyst.9 Generation of the enolate from 8
by potassium ethoxide or potassium tert-butoxide10
followed by in situ oxidation by Davis reagent stereo-
selectively gave 17a-hydroxy-16-oxocholesterol 9 in 75%
yield. Stereoselective reduction of 9 by LiAlH4 at
ꢀ78 °C provided the requisite 16b,17a-dihydroxyl cho-
lesterol 10 in 90% yield.11 Thus, the protected aglycone
of 22-deoxy-OSW-1 was synthesized with eight opera-
tions in 32.1% overall yield. The glycosylation of agly-
cone 10 with disaccharide trichloroacetimidate 1212
provided the corresponding protected 22-deoxy-OSW-1

H.-J. Qin et al. / Tetrahedron Letters 47 (2006) 3217–3219
3219
5. (a) Marker, R. E. J. Am. Chem. Soc. 1940, 62, 3350–3352;
(b) Rosenkranz, G.; Mancera, O.; Sondheimer, F.; Djer-
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11 in 59% yield. Removal of all of the protecting groups
by sequential treatment of compound 11 with W-2 Ra-
ney nickel at room temperature (for the deprotection of
the benzyl groups) and AcOH–THF–H2O (V/V, 8:8:1)
at 45 °C (for the removal of the silyl groups) afforded
the desired 22-deoxy-OSW-1 (1) in 77% yield. Its spectral
data13 were identical with that reported in the literature.3
6. (a) Tian, W. S. Acta Chim. Sinica 1992, 50, 72–77; (b)
Tian, W. S.; Guan, H. P.; Pan, X. F. Chin. Chem. Lett.
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In conclusion, the highly potent anticancer agent 22-
deoxy-OSW-1 was successfully synthesized by utilizing
the intact skeleton of diosgenin in 11 steps in 13.7%
overall yield. This new synthetic strategy resulted in a
remarkable improvement of synthetic efficiency, and
more importantly, it enhanced the utilization efficiency
of the resource compound diosgenin, decreased the pro-
duction of chemical wastes without using some highly
toxic reagents such as OsO4 in the synthesis of 22-
deoxy-OSW-1 compared with known procedures.3
11. Duhamel, P.; Cahard, D.; Poirier, J. M. J. Chem. Soc.,
Perkin Trans. 1 1993, 21, 2509–2511.
12. Disaccharide trichloroacetimidate 12 was synthesized
according to the methods reported in Ref. 4.
References and notes
13. Analytical data for our synthesized 22-deoxy-OSW-1 (1):
25
½aꢁD ꢀ18.6 (c 0.40, CH3OH, lit.3 ꢀ17.2 (c 0.40, CH3OH));
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1H NMR (300 MHz, C5D5N): d 8.27 (d, J = 9.0 Hz, 2H),
7.02 (d, J = 9.0 Hz, 2H), 6.17 (br s, 1H), 5.85 (t,
0J = 7.5 Hz, 1H), 5.65 (t-like, J = 8.4, 7.8 Hz, 1H), 5.32
(br d, J = 4.5 Hz, 1H), 5.08 (d, J = 8.0 Hz, 1H), 4.73 (d,
J = 7.2 Hz, 1H), 4.59 (br s, 2H), 4.48 (s, 1H), 4.33–4.15
(6H, m), 3.68 (s, 3H), 2.53 (br d, J = 6.8 Hz, 2H), 1.85 (s,
3H), 1.28 (d, J = 6.6 Hz, 3H), 1.22 (s, 3H), 0.93 (s, 3H),
0.81 (s, 3H). 13C NMR (75 MHz, C5D5N): d 169.35,
165.69, 164.00, 142.11, 132.56, 121.40, 114.23, 103.67,
102.60, 88.13, 86.99, 80.85, 76.31, 75.26, 71.95, 71.49,
70.96, 68.67, 67.10, 55.65, 50.64, 49.56, 49.06, 47.27, 43.67,
40.66, 37.98, 37.08, 35.83, 34.29, 33.42, 32.42, 30.83, 29.40,
28.43, 25.83, 23.24, 23.00, 21.20, 19.76, 17.89, 14.49, 13.36;
HRMS (MALDI) calcd for C47H70O14Na [M+Na]+:
881.46480; found: 881.46578.