Synthesis of 17-(1,2,3-dithiazole) androstene derivatives

Article abstract of DOI:10.1016/j.mencom.2011.07.003

17-(1,2,3-Dithiazole) androstene derivatives were synthesized from commercially available Pregnenolone acetate involving the reaction between 3b-acetoxy-20-hydroxyimino-5-pregnene with sulfur monochloride as the key step.

Full text of DOI:10.1016/j.mencom.2011.07.003

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 186–187
Synthesis of 17-(1,2,3-dithiazole) androstene derivatives
Stanislav A. Amelichev, Alexander S. Shashkov, Igor V. Zavarzin and Oleg A. Rakitin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: orakitin@ioc.ac.ru
DOI: 10.1016/j.mencom.2011.07.003
1
7-(1,2,3-Dithiazole) androstene derivatives were synthesized from commercially available Pregnenolone acetate involving the reaction
between 3b-acetoxy-20-hydroxyimino-5-pregnene with sulfur monochloride as the key step.
The enzyme 17a-hydroxylase-17,20-lyase (CYP17) is human
derivatives, was obtained from commercial Pregnenolone by two-
cytochrome P-450 that catalyzes the conversion of progesterone
step procedure including acetylation with acetic anhydride in the
presence of phosphoric acid followed by oximation with hydroxyl-
amine hydrochloride and pyridine in ethanol (Scheme 1).13
The structure of oxime 1 was confirmed by analysis of its
1
and pregnenolone into androgens, which play an important role
in the development and progression of several prostatic diseases,
most notably, benign prostatic hypertrophy and prostatic cancer.
Inhibitors of this enzyme can block androgen synthesis in its
early step, and thereby may be useful in the treatment of prostatic
1
13
NMR spectra. Signals in the 1D H and C NMR spectra were
1
13
assigned using 2D COSY, ROESY, HSQC, and H/ C HMBC
experiments (Table 1). The H NMR spectrum of 1 contained the
2
1
cancer. Steroids bearing heterocycles attached to the D-ring
have recently attracted much attention as inhibitors of the cyto-
chrome P-450. A number of P-450 inhibitors containing at C-17
only peak for OH of the oxime at 10.32 ppm. Pre-irradiation of
the protons for 0.5 s in 1D NOE experiment revealed a positive
NOE for protons at C-21 (1.2%) indicating spatial proximity of
3
nitrogen heterocycles, such as imidazole, pyrazole, isoxazole,
triazole, oxazole, thiazole, indazole, piperazine and pyrazole,
4
5
6
7
8
1
15
OH and Me characteristic of E-isomer of the oxime. H/ N HMBC
experiment showed correlation peaks for H-21 and H-17 with a
nitrogen at –26 ppm (external nitromethane 0.0 ppm). Recently,
it was found that only E-acetoximes formed 1,2,3-dithiazoles in
has been recently described. Sulfur-containing heterocycles, for
example, 1,2,3-dithiazoles are known to possess significant anti-
9,10
11,12
proliferative activity. In 1994 and 1997 Rees and co-workers
1
4
reported the formation of 5-oxo- and 5-arylimino-1,2,3-dithiazoles
from the reaction of acetophenone oxime (or its p-nitro deri-
vative) and sulfur monochloride. Recently we have found that
various ethanone oximes can be used for the synthesis of 5-oxo-,
the reaction with S Cl .
2 2
For the synthesis of steroid-tethered 1,2,3-dithiazole-5-thione
†
2 (Scheme 2) we decided to employ our method elaborated for
10
various acetoximes. However, the treatment of oxime 1 (1 equiv.)
5
-thioxo- and 5-phenylimino-1,2,3-dithiazoles with various sub-
with S Cl (2 equiv.) and pyridine (3 equiv.) in acetonitrile at
2
2
stituents at the 4-position by a one-pot reaction with sulfur mono-
chloride, pyridine in acetonitrile followed by treatment with the
corresponding nucleophiles.10 However, steroid oximes contain-
0°C followed by addition of thioacetamide (1.1 equiv.) gave no
reaction; the starting compound was recovered. We proposed that
this could be attributed to poor solubility of oxime 1 in aceto-
nitrile. On moving to THF, the target product 2 was really formed,
however, it was contaminated with some impurities which com-
ing different CH, CH and Me groups and double C=C bond
2
which also can be sensitive to the action of S Cl , have never been
2
2
involved in the preparation of 1,2,3-dithiazoles. Here we report
the study of the reaction between steroid acetoxime and S Cl
and the first preparation of steroids bearing a 1,2,3-dithiazole
moiety at C-17.
2
2
†
New compounds 2 and 3 were characterised by 1H and 13C NMR
(
Table 1), mass, IR spectra and elemental analysis.
For 2: pyridine (0.5 ml, 7 mmol) was added dropwise to a stirred solu-
3
b-Acetoxy-20-hydroxyimino-5-pregnen-20-one 1, a key
tion of oxime 1 (170 mg, 0.45 mmol) and sulfur monochloride (0.4 ml,
5 mmol) in chloroform (15 ml) under argon at –5–0°C. The mixture was
stirred at 0°C for 15 min. Then thioacetamide (100 mg, 1.3 mmol) was
added, the mixture was stirred at room temperature for 2 h, filtered and
solvents were evaporated. The residue was separated by column chromato-
graphy (Silica gel Merck 60, light petroleum and then light petroleum–
CH Cl mixtures) to yield 41 mg (20%) of 2 as a dark red crystalline
precursor for the synthesis of 17-(1,2,3-dithiazolyl)androstene
O
O
Me
Me
Me
Me
Me
Me
OH
2
2
Ac2O
H3PO4
–1
solid, mp 236–237°C, R 0.48 (CH Cl ). IR (KBr, n/cm ): 2932, 2904,
f
2
2
+
2
852, 2828 (C–H), 1732 (C=O). MS (EI, 70 eV), m/z (%): 449 (M , 4), 389
HO
AcO
(62), 356 (12), 325 (13), 281 (31), 253 (52), 210 (54). Found (%): C,
6
1.28; H, 7.19; N, 2.90. Calc. for C H NO S (%): C, 61.43; H, 6.95;
23 31 2 3
N, 3.11.
For 3: mercury acetate (40 mg, 0.125 mmol) was added to the solution
of thione 2 (40 mg, 0.09 mmol) in a chloroform–acetic acid (10:2 ml)
mixture. The reaction mixture was stirred at room temperature for 15
min, filtered and concentrated. The residue was separated by column
chromatography (Silica gel Merck 60, CH Cl ) to yield 21 mg (53%) of
N
8
21
Me
1
1
2
Me 20
1
9
17
1
1
13
1
6
Me
NH2OH
1
4
9
6
14
2
2
2
3
10
5
8
15
–
1
3
as a white solid, mp 179–180°C, R 0.36 (CH Cl ). IR (KBr, n/cm ):
7
f 2 2
2960, 2940, 2852, 2828 (C–H), 1732 (C=O). MS (EI, 70 eV), m/z (%): 373
AcO
[M–SC(O), 100], 358 (24), 340 (15), 312 (16), 281 (42), 266 (68), 213
1
(
35). Found (%): C, 63.56; H, 7.07; N, 3.45. Calc. for C H NO S (%):
23
31
3 2
Scheme 1
C, 63.71; H, 7.21; N, 3.23.
©
2011 Mendeleev Communications. All rights reserved.
– 186 –

Mendeleev Commun., 2011, 21, 186–187
Table 1 NMR data for oxime 1, thione 2 and ketone 3.
Oxime 1a
Thione 2
Ketone 3
1
13
Number
of atom
Important correlation peaks in H/ C
and H/ N HMBC spectra
1
15
dC
dH
dC
dH
dC
dH
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
36.4
27.3
73.1
37.6
139.5
121.9
31.2
31.5
49.5
36.1
20.5
38.1
42.9
55.4
23.8
22.6
56.1
12.9
18.9
154.9
15.0
21.0
169.6
1.85, 1.08
1.79, 1.56
4.46
37.0
27.7
73.9
38.1
139.8
122.3
31.8
32.3
49.9
36.6
21.0
38.5
46.8
56.6
25.0
29.1
50.1
13.4
19.3
173.0
210.7
21.4
170.5
1.86, 1.15
1.88, 1.59
4.62
37.0
27.7
73.9
38.0
139.8
122.3
31.8
32.3
49.9
36.6
20.9
38.1
46.1
56.4
24.8
27.2
51.6
13.7
19.3
162.0
191.9
21.4
170.5
1.86, 1.15
1.87, 1.58
4.60
2.28, 2.28
2.34, 2.34
2.34, 2.34
5.35
1.95, 1.56
1.41
5.40
2.04, 1.62
1.55
5.39
2.04, 1.62
1.53
0.98
1.03
1.01
1
1
1
1
1
1
1
1
1
1
2
2
1.56, 1.40
1.85, 1.29
1.55, 1.38
1.60, 1.49
1.57, 1.40
1.66, 1.42
1.12
1.38
1.30
1.61, 1.13
2.13, 1.58
2.19
0.56
0.99
1.82, 1.40
2.18, 2.06
3.72
0.71
1.02
1.80, 1.38
2.34, 2.03
3.01
0.63
1.02
C-12, C-13, C-16, C-18, C-20, C-21; N-20
C-12, C-13, C-14, C-17
C-1, C-5, C-9, C-10
1.73c
1.98
C-17, C-20; N-20b
MeCO2
MeCO2
OH
2.03
2.03
10.32c
C-20b
a
b
c
Spectral data for oxime 1 are given in ref. 13. For oxime 1 only. A spatial closeness of the protons was observed in 1D NOE spectrum.
†
S
temperature for 15 min (Scheme 2). Note that direct conver-
S
N
sion of 5H-1,2,3-dithiazole-3-thiones into 5H-1,2,3-dithiazol-
1
13
Me
X
3-ones has never been reported. H and C NMR data for com-
pound 3, which confirm 1,2,3-dithiazole ring retaining, are given
in Table 1.
Me
MeC(S)NH2
CHCl3
1
+ S2Cl2 / pyridine
The biological properties of steroidal 1,2,3-dithiazoles 2 and
3
are under investigation.
AcO
2
3
X = S, 20%
X = O, 53%
References
CHCl3/AcOH Hg(OAc)2
1
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of the molecule was confirmed by analysis of its NMR spectra
7
8
1
15
(
Table 1). H/ N HMBC experiment displayed correlation peak
for H-17 with a nitrogen at –48 ppm.
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Unfortunately, all our endeavours to directly prepare ketone 3
from oxime 1 by our recently published procedure10 (with replace-
ment of thioacetamide by formic acid at the last step of the reac-
tion) were unsuccessful. Treatment of thione 2 with mercury(ii)
acetate in AcOH which was previously used to convert 1,2-dithiole-
1
1
3
-thiones into 1,2-dithiol-3-ones,15 afforded in fact low yield of
ketone 3. This could be due to poor solubility of thione 2 in AcOH
which led to prolonged reaction time and formation of several
by-products. The similar situation was observed with chloroform
used as a solvent: the reaction was incomplete within 10 h because
1
4 O. I. Bol’shakov, PhD Thesis, 2009, N. D. Zelinsky Institute of Organic
Chemistry RAS, Moscow.
1
5 D. M. McKinnon, in Comprehensive Heterocyclic Chemistry II,ed.I.Shinkai,
Pergamon, Oxford, 1996, vol. 3, p. 571.
Hg(OAc) is practically insoluble in chloroform. The best yield
2
of keto derivative 3 (53%) was achieved when the reaction was
carried out in a mixture of chloroform and acetic acid at room
Received: 11th February 2011; Com. 11/3685
–
187 –