Synthesis of some novel 3,3-ethylenedioxyandrost-7β-acyloxy-5-ene -17-one derivatives as potent aromatase inhibitors

Article abstract of DOI:10.3184/174751911X13129058638242

3,3,17,17-Diethylenedioxyandrost-5-ene was obtained by ketalisation of androstenedione, which was oxidised with PDC and t-BuOOH to form 3,3,17,17-diethylene-dioxyandrost-5-ene-7-one. Stereoselective reduction of 3,3,17,17- diethylene-dioxyandrost-5-ene-7-

Full text of DOI:10.3184/174751911X13129058638242

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 453
AUGUST, 453–455
Synthesis of some novel 3,3-ethylenedioxyandrost-7β-acyloxy-5-ene
-17-one derivatives as potent aromatase inhibitors
Shao-Rui Chena* and Dong-Zhi Liub
aCollege of Science, Hebei University of Science andTechnology, Shijiazhuang 050018, P. R. China
bSchool of Chemical Engineering andTechnology, Tianjin University, Tianjin 300072, P. R. China
3,3,17,17-Diethylenedioxyandrost-5-ene was obtained by ketalisation of androstenedione, which was oxidised with
PDC and t-BuOOH to form 3,3,17,17-diethylene-dioxyandrost-5-ene-7-one. Stereoselective reduction of 3,3,17,17-
diethylene-dioxyandrost-5-ene-7-one by NaBH4 in the presence of CeCl3.6H2O gave 3,3,17,17-diethylenedioxy-
7β-hydroxy-androst-5-ene, which was deprotected with p-toluenesulfonic acid to gave 3,3-ethylenedioxyandrost-
5-ene-7β-hydroxy and androst-4,6-dien-3,17-dione. A series of androstenedione derivatives were obtained from
3,3-ethylenedioxyandrost-5-ene-7β-hydroxy by the esterification reaction. Their structures were confirmed by MS, 1H
NMR, 13C NMR and HRMS.
Keywords: androstenedione, synthesis, oxidation, reduction, aromatase inhibitors
Steroids have significant biological activities, including anti-
fungal, antibacterical, antitumor, antiparasitic activities,
together with the inhibition of 5α-reductase and aromatase.1–5
Moreover steroids containing hetero-atoms especially nitro-
gen, oxygen and sulfur often exhibit higher biological activi-
ties.6,7 Hetero-atoms such as N, O and S are involved in the
formation of hydrogen bonds and enhace the interaction with
biological receptors.7,8 Many hetero-atom-substituted steroids
have been developed and successfully been applied in clinical
settings.9–11
Androstenedione is an important precursor for preparing
steroidal drugs. Studies on the synthesis and biological activi-
ties arising from introducing hetero-atoms to androstenedione
have become an important direction for the development of
aromatase inhibitors and anticancer drugs. Previous studies
showed that the introduction of hetero-atom at C-7 such as 7α-
(4-amino)phenylthio-androst-4-ene-3,17-dione(7α-APTA)12
enhanced its affinity to aromatase. In order to find novel active
compounds having aromatase inhibitory activity, we now
report the novel synthesis of 7β-acyloxy-3,3-ethylenedioxy-
androst-5-ene-17-one derivatives.
compound 6 was obtained21 while using cerium chloride and
sodium iodide to remove the ketal. Compound 5 was then
treated with the acyl chloride or anhydride in the presence of
pyridine to afford 7β-acyloxy-3,3-ethylenedioxy-androst-5-
ene-17-one derivatives. The EI mass spectra of 7a–i were char-
acterised by molecular ions. The 1H NMR spectrum of 7h for
example, displayed four peaks at 7.94, 7.28, 5.45 and 5.37,
assigned to phenyl proton attached to the methyl, phenyl proton
adjacent to carbonyl group, the double bond proton, and
7α-H proton respectively. The expected signals for the 18-
CH3(δ = 0.94 ppm), 19-CH3(δ = 1.17 ppm), Ph-CH3(δ = 2.41
ppm) and OCH2CH2O(δ = 3.90–3.95 ppm) were also observed.
In the 13C NMR spectrum, the characteristic signals of the
ester(–OCO–), the ketal(–OCH2CH2O–), and 7-C appeared at
166.64 ppm, 64.65 ppm, 64.64 ppm, and 75.73 ppm respec-
tively. The 13C NMR spectrum showed signals at δ = 220.77
(–17-CO–), 144.87(–PhH), 143.96(–C=C–), 129.87(–PhH),
129.37(–PhH), 127.99(–PhH), 122.03(–C=C–).
In conclusion, nine novel 7β-acyloxy-3,3-ethylenedioxyan-
drost-5-ene-17-one derivatives were synthesised. Their struc-
1
tures were characterised by ESI-MS, H NMR, 13C NMR,
Starting from androstenedione(1), the carbonyl groups were
protected by reacting with ethylene glycol in the presence of
p-toluenesulfonic acid to give 3,3,17,17-diethylenedioxyan-
drost-5-ene(2) with 68% yield.13 In compound 2, there are two
conformationally inflexible sites of allylic hydrogens(C-4 and
C-7). The axial hydrogen at C-4 lies above the plane of the
steroid molecule and an approaching oxidant would be hin-
dered by the angular methyl group at C-10. The axial hydrogen
at C-7 being below the plane of the molecule is free from steric
interference and the reaction proceeds at this position to yield
3,3,17,17-diethylenedioxyandrost-5-ene-7-one.14 The allylic
oxidation of compound 2 was conducted using PDC and t-
BuOOH as the oxidant to afford compound 3 in 78% yield.15,16
We also tried CrO3.DMP, CrO3.Py, CrO3.NHS and CuI. t-
BuOOH to oxidise compound 2, but the results were not satis-
factory and the yields were 36%, 47%, 0 % and 29.5% respec-
tively.16–19 Stereoselective reduction of compound 3 using
sodium borohydride/cerium trichloride heptahydrate provided
pure 3,3,17,17-diethylenedioxy-7β-hydroxyandrost-5-ene (4)
in 76% yield. The configuration of the 7β-hydroxy group was
determined based on the 1H and 13C NMR. Treatment of 4 with
p-toluenesulfonic acid (0.2equiv.) in acetone-water yielded 3,3
-ethylenedioxy-7β-hydroxyandrost5-ene-17-one in excellent
yield.20 Increasing the ratio of p-toluenesulfonic acid (4),
decreased the yield of 5 and the yield of 6 increased. Only
HRMS. All these compounds are useful for further study for
their aromatase-inhibiting and anticancer activities.
Experimental
All the reagents were obtained commercially and used without further
purification. Melting points were measured on a X4 apparatus and
uncorrected. IR spectra were determined as KBr pellets on a FTS-135
1
spectrophotometer. H NMR and 13C NMR spectra were measured
with a Varian INOVA 500 spectrometer at 500MHz in CDCl3 as the
solvent with TMS as internal standard. EI-MS were performed on a
VGZAB-HS spectrometer(EI at 70 eV). ESI-MS were performed on
LCQ Advantage MAX spectrometer. HRMS were recorded on a
MicrOTOF-QII10204 spectrometer.
3,3,17,17-Diethylenedioxyandrost-5-ene (2):
A
mixture of
androstenedione(AD) (15.0 g, 52.4 mmol), ethylene glycol (75 mL),
p-toluenesulfonic acid (0.4 g), and benzene (300 mL)was heated
under reflux for 48 h in a 1 L round-bottom flask equipped with a
Dean–Stark trap. Saturated sodium bicarbonate solution (40 mL) was
added to the cooled mixture and the benzene layer was separated,
washed with water (75 mL×3), dried (MgSO4), and concentrated to
dryness under reduced pressure. Recrystallisation from ethanol gave
pure 2 (13.4 g), yield 68.2%. m.p. 169–171 °C (171–173 °C13). IR
(KBr), ν/cm−1: 2972, 2885, 1634, 1460; EI-MS m/z: 374.2(M+), 99.0,
1
55.0; H NMR (CDCl3, 500MHz), δ: 5.36 (m, 1H, 6H), 3.82–3.99
(m, 8H, OCH2CH2O), 1.03 (s, 3H, 19-CH3), 0.87 (s, 3H, 18-CH3).
3,3,17,17-Diethylenedioxyandrost-5-ene-7-one (3): Pyridinium
dichromate (PDC) (24.1 g, 63.8 mmol) was added to a stirred solution
of 2 (6.0 g, 16.0 mmol) in benzene (140 mL) and celite (4.0 g),
followed by the addition of 70% tert-Butyl hydroperoxide(10 mL,
64 mmol). The mixture was stirred at room temperature for 5 h. Ether
* Correspondent. E-mail: sjz_wgq@126.com

454 JOURNAL OF CHEMICAL RESEARCH 2011
7a, R=CH3; 7b, R=C2H5; 7c, R=C3H7; 7d, R=C5H11; 7e, R=C6H13; 7f, R=Ph; 7g, R=PhCl; 7h, R=PhMe; 7i, R=PHOMe
Scheme 1
(150 mL) was added and the mixture was filtered through a pad of
Celite and washed twice with 100 mL ether. The combined filtrate was
evaporated in vacuo. The residue was purified by column chromatog-
raphy on silica gel with petroleum ether /ethyl acetate to afford 2
(1.2 g, 20%), 3 as a white solid, yield 78.2%. m.p. 206–207 °C (206–
207 °C13). IR(KBr), ν/cm−1: 2954, 2884, 1671, 1634, 1461; EI-MS m/
z: 388.2 (M+), 373.2, 99.0, 55.0; 1H NMR (CDCl3, 500MHz), δ: 5.67
(s, 1H, 6H), 3.84–3.98 (m, 8H, OCH2CH2O), 1.20 (s, 3H, 19-CH3),
0.87 (s, 3H, 18-CH3).
3,3,17,17-Diethylenedioxy-7β-hydroxy-androst-5-ene (4): Sodium
borohydride (1.2 g, 31.5 mmol) was added in small portions to a clear
solution of 3 (2.0 g, 5.1 mol) and CeCl3.7H2O (1.9 g, 5.1 mmol) in a
mixture of methanol and methylene chloride (50 mL, 2:3, volume
ratio) at 0 °C. The reaction mixture was stirred for 0.5 h at room
temperature and then treated with acetone. The mixture was poured
into saturated aqueous ammonium chloride (50 mL) and extracted
with methylene chloride (50 mL×3). The organic layer was washed
with brine, dried over anhydrous sodium sulfate, and evaporated in
vacuo. The residue was purified by column chromatography on silica
gel with petroleum ether /ethyl acetate to afford 422(1.5 g, 75.6%)
as white solid. EI-MS m/z: 390.1 (M+), 372.1, 289.1, 99.1;1H NMR
(CDCl3, 500MHz), δ: 5.28 (t, J = 2Hz, 1H, 6H), 3.85–3.99 (m, 9H,
OCH2CH2O+7αH), 1.18 (s, 3H, 19-CH3), 0.88 (s, 3H, 18-CH3); 13C
NMR (CDCl3, 500MHz), δ: 142.98, 126.31, 119.6, 109.41, 73.50,
65.41, 64.77, 64.71, 64.53, 50.07, 47.86, 46.35, 41.60, 41.33, 36.91,
36.25, 34.56, 31.92, 30.41, 25.21, 20.65, 18.90, 14.46.
3,3-Ethylenedioxy-7β-hydroxyandrost-5-ene-17-one (5): p-Tolu-
enesulfonic acid (90 mg, 0.52 mmol) was added to a stirred solution
of 4 (1.0 g, 2.6 mmol) in acetone–water (60 mL, 9:1, volume ratio)
and stirred for 10h at room temperature. Then the mixture was poured
into water (40mL), extracted with methylene chloride (50 mL×3). The
organic layer was washed with saturated sodium bicarbonate, brine,
dried over anhydrous sodium sulfate, and evaporated in vacuo. The
residue was purified by column chromatography on silica gel with
petroleum ether/ethyl acetate to afford 5 (0.7 g, 80.1%) as a white
solid, m.p. 184–185 °C; compound 6 (50 mg) was obtained with the
yield of 8%, m.p. 172–174 °C23. IR(KBr), ν/cm−1: 3490, 2952, 2880,
1736, 1673; EI-MS m/z: 346.0 (M+), 285.0, 99.0, 55.0, 28.0; 1H NMR
(CDCl3, 500MHz), δ: 5.31 (t, J = 2 Hz, 1H, 6H), 3.99 (dd, J = 2.0 Hz,
1H, 7H), 3.75–3.98 (m, 4H, OCH2CH2O), 1.10 (s, 3H, 19-CH3), 0.88
(s, 3H, 18-CH3); 13C NMR (CDCl3, 500MHz), δ: 221.30, 143.41,
126.14, 109.30, 72.95, 64.73, 64.60, 51.42, 48.18, 48.02, 41.66, 40.74,
37.00, 36.23, 36.21, 31.47, 31.24, 24.42, 20.61, 18.95, 13.84; HRMS
(ESI) Calcd for C21H30O5Na [M+Na]+:369.2042. Found: 369.2034.
1
(6): EI-MS m/z: 284.0(M+), 240.0, 136.0, 28.0; H NMR (CDCl3,
500 MHz), δ: 6.19 (s, 2H, 4H, 6H), 5.71 (s, 1H, 7H), 1.15 (s, 3H,
19-CH3), 0.98 (s, 3H, 18-CH3);13C NMR (CDCl3, 500MHz), δ: 219.73,
199.58, 163.14, 138.58, 129.02, 124.43, 50.97, 48.95, 48.52, 37.24,
36.36, 35.85, 34.13, 34.08, 31.49, 21.65, 20.20, 16.57, 13.94.
Synthesis of 7β-acyloxy-3,3-ethylenedioxyandrost-5-ene-17-one deri-
vatives (7a–e); general procedure
The anhydride (0.5 mL) was added to a stirred solution of 5 (100 mg,
0.3 mmol) in pyridine (2 mL) at 0 °C. The mixture was stirred for
12 h at room temperature, poured into water (3 mL), and extracted
with methylene chloride (5 mL×3). The organic layer was washed
with 5% citric acid, saturated sodium carbonate solution, brine, dried
over anhydrous sodium sulfate, and evaporated in vacuo. The residue
was purified by column chromatography on silica gel with petroleum
ether /ethyl acetate to afford 7a–e as white solid.
7β-Acetyl-3,3-ethylenedioxyandrost-5-ene-17-one (7a): Yield
93.2%; m.p. 165–168 °C; EI-MS m/z:388.1 (M+), 329.1, 99.0, 43.0;
1H NMR (CDCl3, 500MHz), δ: 5.23 (m, 2H, 6H–7H), 3.92–3.95 (m,
4H, OCH2CH2O), 2.05 (s, 3H, OCOCH3), 1.12 (s, 3H, 19-CH3),
0.91 (s, 3H, 18-CH3); 13C NMR (CDCl3, 500MHz), δ: 220.68, 171.12,
145.02, 121.74, 109.12, 75.18, 64.64, 64.63, 50.84, 48.13, 47.95,
41.47, 36.88, 36.52, 36.11, 35.98, 31.33, 31.32, 23.25, 21.82,
20.61,18.86, 13.80; HRMS (ESI) Calcd for C23H32O5Na[M+Na]+
411.2147. Found: 411.2152 [M+Na]+.
3,3-Ethylenedioxyandrost-7β-propionyloxy-5-ene-17-one
(7b):
Yield 94.4%; m.p. 183–184 °C; EI-MS m/z: 402.0 (M+), 329.1, 99.0,
29.0; 1H NMR (CDCl3, 500MHz), δ: 5.24(m, 2H, 6H–7H), 3.92–3.95
(m, 4H, OCH2CH2O),1.12(s, 3H, 19-CH3), 0.91(s, 3H, 18-CH3); 13C
NMR (CDCl3, 500MHz), δ: 220.76, 174.52, 144.89, 121.91, 109.14,
75.01, 64.66, 64.64, 50.89, 48.17, 47.96, 41.46, 36.87, 36.53, 36.14,
36.01, 31.35, 31.33, 28.32, 23.40, 20.63, 18.87, 13.81, 9.30; HRMS
(ESI) Calcd for C24H34O5Na[M+Na]+ 425.2304. Found: 425.2308.
7β-Butyloxy-3,3-ethylenedioxyandrost-5-ene-17-one (7c): Yield
90.8%; m.p. 158–159 °C; EI-MS m/z: 416.0(M+), 346.1, 99.0, 43.0;
1H NMR(CDCl3, 500MHz), δ: 5.24(m, 2H, 6H, 7H), 3.92–3.95(m,
4H, OCH2CH2O), 1.12(s, 3H, 19-CH3), 0.90(s, 3H, 18-CH3); 13C NMR
(CDCl3, 500MHz), δ: 220.73, 173.70, 144.86, 121.92, 109.13, 74.88,

JOURNAL OF CHEMICAL RESEARCH 2011 455
64.65, 64.63, 50.91, 48.20, 47.95, 41.47, 36.95, 36.86, 36.53, 36.14,
36.01, 31.36, 31.33, 23.38, 20.64, 18.88, 18.56, 14.05, 13.81; HRMS
(ESI) Calcd for C25H36O5Na[M+Na]+ 439.2460. Found: 439.2472.
3,3-Ethylenedioxyandrost-7β-hexaacyloxy-5-ene-17-one (7d):Yield
89.6%; m.p. 82–83 °C; EI-MS m/z: 444.1 (M+), 346.2, 99.0, 43.0; 1H
NMR (CDCl3, 500MHz), δ: 5.24(m, 2H, 6H–7H), 3.92–3.95(m, 4H,
OCH2CH2O), 1.12(s, 3H, 19-CH3),0.91(s, 3H, 18-CH3); 13C NMR
(CDCl3, 500MHz), δ: 220.76, 173.91, 144.86, 121.91, 109.14, 74.89,
64.65, 64.63, 50.91, 48.19, 47.95, 41.47, 36.86, 36.53, 36.13, 36.00,
34.99, 31.62, 31.35, 31.33, 24.72, 23.38, 22.55, 20.64, 18.87, 14.17,
13.81; HRMS (ESI) Calcd for C27H40O5Na[M+Na]+ 467.2773. Found:
467.2819.
3,3-Ethylenedioxyandrost-7β-acyloxy-5-ene-17-one (7e): Yield
87.2%; m.p. 88–89 °C; EI-MS m/z: 458.1(M+), 346.1, 99.0, 43.0; 1H
NMR (CDCl3, 500MHz), δ: 5.24 (m, 1H, 6H-7H), 3.91–3.95 (m, 4H,
OCH2CH2O), 1.12 (s, 3H, 19-CH3), 0.91 (s, 3H, 18-CH3); 13C NMR
(CDCl3, 500MHz), δ: 220.69, 173.88, 144.85, 121.91, 109.13, 74.89,
64.65, 64.63, 50.92, 48.20, 47.95, 41.47, 36.86, 36.54, 36.14, 35.04,
31.66, 31.35, 31.33, 28.97, 24.93, 23.38, 22.72, 22.69, 20.63, 18.86,
14.43,13.81; HRMS (ESI) Calcd for C28H42O5Na[M+Na]+ 481.2930.
Found: 481.2946.
5.37 (d, J = 2.5Hz, 1H, 7H), 3.96 (s, 3H, Ar-OCH3), 3.87–3.94 (m, 4H,
OCH2CH2O), 1.15 (s, 3H, 19-CH3), 0.94 (s, 3H, 18-CH3);13C NMR
(CDCl3, 500MHz), δ: 220.82, 166.33, 163.66, 144.79, 131.87, 123.13,
122.13, 113.89, 109.18, 75.59, 64.65, 64.64, 55.69, 50.89, 48.16,
47.99, 41.46, 36.99, 36.78, 36.20, 36.06, 31.41, 31.35, 23.69, 20.64,
18.93, 13.85; HRMS (ESI) Calcd for C29H36O6Na[M+Na]+ 503.2410.
Found: 503.2407.
The authors appreciate the financial support from the Doctoral
Foundation of Hebei University of Science and Technology
(QD201058), XiaoLi Foundation of Hebei University of Sci-
ence and Technology(XL201042) and the Program of Science
and Technology of Hebei(10212160).
Received 12 June 2011; accepted 14 July 2011
Paper 1100747 doi: 10.3184/174751911X13129058638242
Published online: 29 August 2011
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2991.
3,3-Ethylenedioxy-7β-p-methylbenzoyloxyandrost-5-ene-17-one
(7h): Yield 68.7%; m.p. 187–189 °C; EI-MS m/z: 464.0(M+), 328.0,
1
284.0, 136.0, 99.0, 55.0; H NMR (CDCl3, 500MHz), δ: 7.94(d, J =
8Hz, 2H, ArH), 7.28 (d, J = 8Hz, 2H, ArH), 5.46 (dd, J = 2.5Hz,
2.5Hz, 1H, 7H), 5.37 (m, 1H, 6H), 3.90–3.95 (m, 4H, OCH2CH2O),
2.41 (s, 3H, Ar-CH3), 1.17 (s, 3H, 19-CH3), 0.94 (s, 3H, 18-CH3); 13
C
NMR (CDCl3, 500MHz), δ: 220.77, 166.64, 144.87, 143.96, 129.87,
129.37, 127.99, 122.03, 109.17, 75.73, 64.65, 64.64, 50.89, 48.17,
47.99, 41.47, 36.99, 36.77, 36.19, 36.05, 31.40, 31.35, 23.67, 21.92,
20.64, 18.92, 13.85; HRMS (ESI) Calcd for C29H36O5Na[M+Na]+
487.2460. Found: 487.2544.
3,3-Ethylenedioxy7β-p-methoxybenzoyloxyandrost-5-ene-17-one
(7i): Yield 59.8%; m.p. 156–157 °C; EI-MS m/z: 480.0(M+), 328.1,
1
135.0, 99.0, 55.0; H NMR (CDCl3, 500MHz), δ: 8.04(d, J = 4.5Hz,
23 M.A.Faramarzi,M.Aghelnejad,M.T.Yazdi,M.AminiandN.Hajarolasvadi,
Steroids, 2008, 73, 13.
2H, ArH), 6.96 (d, J = 2.5Hz, 2H, ArH), 5.45 (d, J = 9Hz, 1H, 6H),