Synthesis of 14,16-dien-17-yl acetates of androstane series. NMR and mass spectrometry data

Article abstract of DOI:10.1134/S1070363211090234

On the basis of dehydroepiandrosterone through the δ¹⁴- and δ ¹⁵-androst-17-ones a series of androsta-14,16-dienyl acetates was obtained, the key compounds in the synthesis of 14-substituted steroids. By the methods of two-dimensional NMR spectroscopy the structure of compounds was proved and a full assignment of signals in the ¹H and ¹³C NMR spectra was performed. With the use of tandem mass spectrometry the main directions of fragmentation of protonated molecules of the synthesized ketones and dienyl acetates were studied.

Full text of DOI:10.1134/S1070363211090234

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 9, pp. 1877–1885. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.V. Baranovskii, D.A. Bolibrukh, V.V. Gromak, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 9, pp. 1540–1548.
Synthesis of 14,16-dien-17-yl Acetates of Androstane Series.
NMR and Mass Spectrometry Data
A. V. Baranovskii, D. A. Bolibrukh, and V. V. Gromak
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus’,
ul. Kuprevicha 5/2, Minsk, 220141 Belarus’
e-mail: baranovsky@iboch.bas-net.by
Received August 17, 2010
Abstract—On the basis of dehydroepiandrosterone through the Δ14- and Δ15-androst-17-ones a series of
androsta-14,16-dienyl acetates was obtained, the key compounds in the synthesis of 14-substituted steroids. By
the methods of two-dimensional NMR spectroscopy the structure of compounds was proved and a full
1
assignment of signals in the H and 13C NMR spectra was performed. With the use of tandem mass
spectrometry the main directions of fragmentation of protonated molecules of the synthesized ketones and
dienyl acetates were studied.
DOI: 10.1134/S1070363211090234
Among the most effective methods of introducing a
variety of alkyl and other substituents in the C14
position of a steroid molecule is the Diels–Alder
reaction of steroidal dienes with various dienophiles.
This approach is widely used in the estrane [1–3] and
androstane [ 4, 5] series. In developing an approach to
the synthesis of analogs of brassinosteroids with a
substituent in the D ring [6, 7], in particular, with the
substituent at C14, we obtained dienyl acetates of
androstane series as a key compound for further
transformations at C14 and in the side chain. In order to
identify the compounds and to study their
physicochemical characteristics a full assignment of
signals in the NMR spectra was carried out by the
technique of two-dimensional spectroscopy and the
fragmentation of the protonated molecular ion by the
methods of tandem mass spectrometry in the mode of
chemical ionization was studied.
ineffective. The reaction of dienyl acetate formation
proceeded with a rather low yield (maximum 51%),
probably owing to dehydration of alcohol group in the
acidic conditions. To prevent this unwanted process,
the alcohols IV and V were converted into 3-acetoxy-
and 3-benzoyloxy derivatives VI–IX. The acetylation
of the derivatives VI–IX proceeded with a higher
yield, but a complete conversion of dienylacetates X
and XI could not be achieved: the yield was 64–71%,
and we isolated from the mixture only the unreacted
Δ14-ketone. Further increase in reaction time resulted
in the tarring and a reduced yield.
The formation of the dienylacetate from enone XII
under acidic conditions (acetic anhydride, isopropenyl
acetate, TsOH) led to a mixture of difficultly separable
products. Carrying out the reaction in two stages, with
the removal of protective groups and subsequent
acetylation, gave the triacetate XIII in a low yield
(43%). Therefore we decided to use the kinetic method
of generating dienol ether by converting the ketone
XII into the enolate under the action of LDA (lithium
diisopropylamide) and acetylation of the enolate with
acetic anhydride or acetyl chloride. The protecting
groups, being stable in basic medium, were retained at
this approach that was necessary for further
transformations. After some experiments it was found
that the removal of a proton from the γ-position under
the action of LDA does not occur, and for the synthesis
Starting compounds II and XII were obtained from
dehydroepiandrosterone (I) by the previously described
methods [7, 8]. In the case of hydrolysis of compound
II we registered the formation of a nonconjugated
ketone V, which was not observed in the original
investigation. The ratio of ketones IV and V was 6:1
with a total yield 87%. A direct acetylation of alcohols
IV and V for obtaining 3β,17-diacetate X in a mixture
of acetic anhydride and isopropenyl acetate in the
presence of TsOH (p-toluenesulfonic acid) was
1877

1878
BARANOVSKII et al.
Scheme 1.
O
O
O
O
O
O
O
O
HO
+
HO
I
III
II
O
OAc
O
II
RO
RO
RO
X, XI
OAc
V, VII, IX
IV, VI,
VIII→VIIIa
O
O
O
AcO
AcO
III
O
O
O
XIII
XII→XIIa
OAc
O
O
O
O
O
O
O
O
O
XIV
XV
R = H (IV, V), Ac (VI, VII, X), Bz (VIII, VIIIа, IX, XI); VIII, XII – 14α-H, VIIIа, XIIа – 14β-H.
of dienylacetate the conjugation of the double bond
should be eliminated.
ketone XIV in 76% yield. In this reaction also a
mixture of the parent ketone XII and its 14β-isomer
XIIa was isolated, which was used for re-conversion.
In the case of the ketone XIV the enolization and
acetylation proceeded without complications, and
dienyl acetate XV was synthesized in 68% yield.
Apparently, this fact explains why after acetylation
in acidic conditions only the Δ14 derivative could be
isolated: Obviously the Δ15-steroid initially underwent
rearrangement in nonconjugated ketone [9], and the
latter was subjected to enolization and acetylation. The
isomerization was carried out under the influence of
diisopropylamine on silica gel [10], which gave the
The resulting compounds IV–XV were investigated
using two-dimensional NMR spectroscopy and tandem
mass spectrometry, which allowed us to assign all the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

SYNTHESIS OF 14,16-DIEN-17-YL ACETATES OF ANDROSTANE SERIES
Table 1. Data of 13C NMR spectra, δC, ppma
1879
Atom
1
IV
V
VI
VII
VIII
VIIIa
36.29
27.51
74.42
38.01
IX
X
XI
XIIа
41.99
72.78
72.63
22.12
45.53
XIII
XIV
XV
37.17
31.71
71.70
42.38
37.06
31.62
71.74
42.25
36.94
27.82
73.77
38.27
36.84
27.77
73.82
38.14
36.97
27.93
74.36
38.35
36.91
27.90
74.43
38.26
37.37
27.82
73.93
38.18
37.43
27.92
74.51
38.26
37.93
69.06
68.10
24.94
51.69
42.68
72.90
72.88
22.08
45.40
43.23
72.97
72.91
22.10
45.47
2
3
4
5
141.73 140.28 140.68 139.24 140.65 140.31 139.28 139.17 139.15
6
120.53 121.01 121.46 121.97 121.61 122.04 122.11 122.38 122.50 109.44 210.15 109.66 109.78
7
30.79
29.03
51.48
37.01
20.19
29.25
50.89
28.33
31.70
51.02
37.25
20.65
32.90
51.06
30.79
29.02
51.40
37.11
20.15
29.24
50.85
28.37
31.67
50.94
37.35
20.62
32.88
51.04
30.82
29.01
51.38
37.17
20.16
29.22
50.87
57.42
30.34
29.87
42.46
38.74
19.17
33.55
47.64
28.42
31.72
51.00
37.43
20.67
32.93
51.06
28.65
31.46
53.60
37.37
20.90
34.62
50.41
28.67
31.46
53.60
37.45
20.91
34.62
50.40
40.11
31.15
44.65
38.85
19.30
33.10
47.39
43.60
36.93
56.97
42.38
21.08
34.52
50.53
38.07
33.22
53.59
38.53
20.51
33.15
51.07
38.25
32.81
56.41
38.54
20.75
34.90
50.38
8
9
10
11
12
13
14
15
16
17
18
19
57.49 152.64
57.42 152.51
53.72 152.55 151.11 151.09
54.03 149.16 152.57 150.96
158.64 114.39 158.50 114.54 158.62 165.04 114.56 117.55 117.56 163.70 117.34 113.73 116.88
132.09 41.49 132.13 41.51 132.11 134.73 41.51 111.06 111.05 133.87 110.89 41.57 110.96
213.22 222.52 213.06 222.44 213.19 216.15 222.37 162.60 162.59 215.41 162.78 222.32 162.55
20.27
19.54
19.68
19.35
20.26
19.45
19.70
19.28
20.29
19.52
22.87
17.75
19.70
19.35
17.49
19.51
17.48
19.57
22.22
12.04
17.91
13.71
19.83
13.46
17.72
13.74
a
Compounds VI, VII, and X: the signals of the acetyl group at C3 21.56 (Me) and 170.67 (CO). Compounds VIII, VIIIa, IX, and XI:
signals of the benzoyl group at C3 130.89 (1), 129.67 (2), 128.41 (3), 132.89 (4), 166.11 (CO). Compound XIII: signals of acetyl groups
at C2 and C3 21.14 and 21.21 (Me), 170.08 and 170.39 (CO). Compounds XIIa, XIV, and XV: signals of acetonide group 26.70 (β-Me),
28.73 (α-Me), 107.80 (CMe2); signals of dioxolane group 64.47 (α-CH2), 65.70 (β-CH2). Compounds X, XI, XIII, XV: the signals of
acetyl group at C17 –21.36 (Me) and 168.17 (CO).
signals in the H and 13C NMR spectra, confirm the
configuration of chiral centers, and define the main
directions of fragmentation of protonated molecular
ions in the APCI ionization mode. As expected, the
signals in the NMR spectra undergo a shift that
dependent directly on the changes in chemical
structure of the molecules near the monitored nuclei.
The data obtained from the analysis of NMR spectra
are listed in Tables 1 and 2. NMR data for compound
XII were given in [11]. In order to avoid errors in
assigning the configuration at the C14 atom in the Δ15-
ketones, a mixture of ketones VIII and IX was
subjected to acidic isomerisation under the influence of
HCl [9], which led to 14β-ketone VIIIa. Characteristics
of NMR spectra of this compound differ significantly
from those of compounds IV, VI, and VIII, owing to
changes in the C/D ring junction. Thus, in the 13C
NMR spectrum differences are observed in the
chemical shifts of the nuclei near the C14 from 2.5
(C18) to 9 (C9) ppm, and in 1H NMR spectra, from 0.22
(8β-H) to 0.59 (11α-H) ppm. These data, along with
the correlations found in the NOESY spectra (in the α-
series interactions of the 14α-H with the 9α and 12α
protons, and in the β-isomer, of the 14β-H proton with
the protons of 18-methyl group were observed),
confirm the validity of our assignment of the
configuration of the C14 center. Similar patterns were
observed for the pair XII and XIIa.
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

1880
BARANOVSKII et al.
Table 2. Data of 1H NMR spectraa
Atom
1α
IV
V
VI
VII
1.13
1.90
1.88
1.61
4.61
2.35
2.35
5.47
2.14
2.14
2.30
1.04
1.69
1.61
1.26
1.81
–
VIII
1.25
1.94
2.04
1.75
4.87
2.51
2.51
5.48
1.82
2.32
1.90
1.17
1.77
1.69
1.60
1.92
2.35
7.51
6.06
1.10
1.15
VIIIa
1.07
1.82
1.98
1.74
4.85
2.52
2.42
5.50
2.20
2.09
2.12
1.17
1.18
1.39
1.77
1.42
2.66
7.83
6.31
1.12
1.08
IX
X
XI
XIIa
0.94
1.82
–
XIII
1.66
1.82
–
XIV
1.04
1.93
–
XV
1.07
1.93
–
1.11
1.86
1.86
1.52
3.54
2.35
2.26
5.41
1.77
2.29
1.88
1.11
1.74
1.67
1.57
1.90
2.32
7.50
6.05
1.08
1.08
1.07
1.88
1.85
1.53
3.54
2.35
2.26
5.44
2.14
2.14
2.30
1.02
1.69
1.62
1.25
1.81
–
1.16
1.88
1.89
1.60
4.61
2.35
2.35
5.43
1.78
2.29
1.90
1.12
1.74
1.66
1.58
1.90
2.33
7.49
6.04
1.08
1.09
1.21
1.96
2.03
1.77
4.88
2.52
2.52
5.53
2.18
2.18
2.33
1.10
1.73
1.63
1.28
1.83
–
1.15
1.88
1.87
1.62
4.61
2.35
2.35
5.48
2.19
2.19
2.33
0.97
1.63
1.53
1.02
1.96
–
1.24
1.94
2.02
1.78
4.88
2.51
2.51
5.54
2.21
2.21
2.36
1.02
1.67
1.57
1.04
1.97
–
1β
2α
2β
4.09
4.28
2.16
1.77
–
4.95
5.37
1.88
1.88
–
4.11
4.28
2.20
1.80
–
4.12
4.28
2.20
1.83
–
3α/β
4α
4β
6
7α
1.59
1.83
2.10
0.87
1.20
1.31
1.68
1.40
2.56
7.69
6.24
1.11
0.81
2.57
2.57
2.62
1.41
1.74
1.41
1.12
2.02
–
1.50
1.98
2.33
0.85
1.73
1.44
1.23
1.77
–
1.55
2.04
2.35
0.77
1.65
1.36
0.99
1.95
–
7β
8β
9α
11α
11β
12α
12β
14α/β
15
5.53
2.84
1.14
1.07
5.54
2.85
1.14
1.08
5.56
2.87
1.16
1.14
5.79
6.12
1.08
1.11
5.82
6.14
1.11
1.18
5.78
6.12
1.06
0.91
5.49
2.83
1.11
0.89
5.74
6.09
1.05
0.92
16α
18
19
a
Compounds V, VII, IX, and XIV: 3.02 (16β-H). Compound XIIa: 1.79 (5α-H). Compound XIII: 2.61 (5α-H). Compounds XIV and XV:
1.84 (5α-H). Compounds VI, VII, and X: the signals of acetyl group at C3 2.04. Compounds X, XI, XIII, and XV: the signals of acetyl
group at C17 2.21 (Me). Compounds VIII, VIIIa, IX, and XI: the signals of benzoyl group at C3 8.5 (2-H), 7.45 (3-H), 7.56 (4-H).
Compound XIII: the signals of acetyl groups at C2 and C3 1.97 (Me) and 2.05 (Me). Compounds XIIa, XIV, and XV: acetonide group
signals, 1.32 (β-Me), 1.45 (α-Me); dioxolane 3.80 and 3.98 (α-CH2), 3.95 and 4.00 (β-CH2).
The object of mass-spectrometric studies was the
little information. The peculiarity of the spectra of Δ14-
ketones consists in the appearance of a peak of the
molecular ion equal in intensity to the M +H+ peak (if
in the spectrum peaks close to the molecular weight
are present). This feature was not observed in the
spectra of Δ15-ketones or enol acetates. The
fragmentation of the M+H+ of all Δ5-ketones proceeds
analogously (Scheme 2). In the first stage the
protonation and enolization of the carbonyl group
occur, and then successively the substituent at C3 and
water from the C17 are eliminated with the formation
fragmentation pathways of the protonated molecular
ion and its most intense daughter ions (the MS2–MS3
experiments). The fragmentation of the molecular ion
in the studied compounds, in general, corresponds to
the assumptions based on the stability of the products
of fragmentation, and correlates with the data obtained
by electron ionization. For the MH+ ion at the chemical
ionization most characteristic and intense ions arise at
the splitting off
a
substituent, while further
fragmentation of the steroid ring, in general, provides
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

SYNTHESIS OF 14,16-DIEN-17-YL ACETATES OF ANDROSTANE SERIES
1881
Scheme 2.
+
+
O
OH2
OH2
−ROH
RO
RO
m/z 269
IV−IX
+
+
−H2O
OH2
OH2
+
O
O
X
−AcOH
−AcOH
m/z 251
−H2O
AcO
+
m/z 311
−ketone
+
+
OH2
OH2
O
O
+
XI
(1) −BzOH,( 2) −H2O
or ketone
+
m/z 269
m/z 293
+
OH2
OH2
BzO
+
+
O
O
O
O
−H2O,
−acetone
−H2O
(CH2)2O
XII,
XIV
O
O
O
O
O
O
m/z 345
m/z 283
m/z 265
−ketone
−CO
−H2O
O
OH2
O
+
+
+
O
O
O
−AcOH
XV−acetone
O
O
O
O
+
m/z 265
−H2O
m/z 387
m/z 255
m/z 327
OAc
OAc
O
OAc
AcO
XIII
−ketone
−AcOH
−AcOH
AcO
AcO
OH2
OH2
OH2
OH2
+
+
+
+
m/z 325
m/z 385
m/z 283
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

1882
BARANOVSKII et al.
of the ion m/z = 251. The decay of M+H+ ions in Δ5-
dienyl acetates X–XI eventually also leads to the
formation of the ion with m/z 251, therewith in the first
stage protonation and enolization of acetyl group at C17
occur. After splitting off the substituent at C3 in
compound X AcOH is immediately released, while in
the case of compound XI there is an intermediate stage
of the formation of ions m/z 293 and 269 with equal
intensities, after which the ions lose the elements of
water and ketene to form the ion m/z 251.
was carried out according to the usual practice [12], all
reactions were performed under argon. The reactions
were monitored by TLC on the Merck plates
(Kieselgel 60 F 254). Chromatographic separation of
reaction mixtures was performed on silica gel 40/60
(Kieselgel 60, Merck).
3β-Hydroxyandrosta-5,15-dien-17-one (IV) and
3β-hydroxyandrosta-5,14-dien-17-one (V). To a
solution of 7.61 g (23.2 mmol) of ketal II in 370 ml of
acetone and 37 ml of water (10:1) was added 0.37 g
(2.15 mmol) of TsOH, and the mixture was stirred for
18 h. The solution was diluted with 100 ml of water
and evaporated to half volume at 25°C [8]. The
precipitate was filtered off, washed with water, dried,
and chromatographed on a silica gel column (eluent
toluene–EtOAc, 80:20). 0.8 g (12%) of ketone V was
isolated, mp 150–152°C (methanol, published [13]:
167–168°C, acetone). Rt 2.67. IR spectrum (KBr, cm–1):
3500 (OH), 2950, 2860, 1750 (CO), 1070, 810. MS:
287 ([MH]+, 30), 286 ([M]+, 40), 269 ([MH–H2O]+,
100), 268 ([MH2O]+, 39), 267 ( 35), 251 ([MH–2H2O]+,
23), 241 ([MH–H2O–CO]+, 11). MS2 (286): 271 ([M–
Me]+, 38), 268 ([MH2O]+, 100), 258 ([M–CO]+, 19),
257 (20), 253 ([M–Me–H2O]+, 20), 250 ([M–2H2O]+,
15), 240 ([MH2O–CO]+, 11), 190 (32), 174 (39), 172
(54). MS2 (287): 269 ([MH–H2O]+, 100), 251 ([MH–
2H2O]+, 49), 173 (12). MS3 (269): 254 ([MH–H2O–
Me]+, 25), 251 ([MH–2H2O]+, 100), 236 ([MH–2H2O–
Me]+, 1912 ), 225 (26), 213 (10), 211 (11), 209 (15),
173 (19), 159 (13). Further elution gave 5.0 g (75%) of
ketone (IV), mp 195–197°C (ether–hexane, published
[8]: 202–205, EtOAc). Rt 2.41. IR spectrum (KBr, cm–1):
3440, 2930, 1705 (CO), 1055. MS: 287 ([MH]+, 100),
269 ([MH–H2O]+, 74), 251 ([MH–2H2O]+, 18). MS2
(287): 269 ([MH–H2O]+, 100), 251 ([MH–2H2O]+, 54),
123 (15). MS3 (269): 251 ([MH–2H2O]+, 100), 241
([MH–H2O–CO]+, 10), 211 (13), 209 (12), 197 (10),
195 (10), 173 (22), 159 (26).
The fragmentation scheme of compounds XII,
XIV, and XV is similar: it proceeds through the
enolization of the carbonyl function of D ring in the
first stage, followed by elimination of acetone and
cleavage of the elements of water (XII, XIV) or acetic
acid (XV), and ethylene oxide to form an ion with m/z
283, which then loses CO or water.
Compound XIII is characterized by a different
scheme of forming daughter ions, in contrast to
compounds X, XI, and XV. This is due to the presence
of carbonyl group at C-6, which is protonated readily
in the first stage. The sequential cleavage from this ion
of the three molecules of acetic acid leads to the ion m/
z 265.
EXPERIMENTAL
Melting points were determined on a Köffler block
and were not corrected. 1H and 13C NMR spectra were
obtained on
a
Bruker AVANCE 500-Biospin
spectrometer with an operating frequency 500.13 and
1
125.77 MHz for the nuclei H and 13C, respectively,
using 5-mm probe (QNP) with Z-gradient. The spectra
were recorded at a sample temperature of 293 K from
solutions in CDCl3, as internal reference the residual
signals of the solvent were used, δ 7.26 (1H), 77.16
(13C). Correlation spectra (HSQC, COSY, HMBC,
NOESY) were recorded and processed using standard
Bruker-Biospin software. The IR spectra were
recorded on a Michelson Bomem 100 FTIR spectro-
photometer (KBr tablets). MS and MSn spectra were
recorded on an Accela HPLC complex with a LCQ-
Fleet mass detector (three-dimensional ion trap) using
chemical ionization at atmospheric pressure (APCI),
detection of positive ions, CID 35%. The m/z ratio and
relative intensity (%) are given for the most intense
peaks. The HPLC conditions: column HYPERSIL
Gold (50 mm × 2.1 mm × 1.9 mm), mobile phase
water/acetonitrile (100 ml min–1, 80% MeCN), the
volume of injected sample 40 ng. Solvent preparation
3β-Acetoxyandrosta-5,15-dien-17-one (VI) and
3β-acetoxyandrosta-5,14-dien-17-one (VII). To a
solution of 1.44 g (5 mmol) of a mixture of steroids IV
and V (ratio 6:1) in 10 ml of methylene chloride was
added 0.6 ml (6 mmol) of acetic anhydride, 0.5 ml
(6 mmol) of pyridine, and 0.072 g (0.6 mmol) of
dimethylaminopyridine. The solution was stirred for
24 h, then diluted with methylene chloride, washed
with water, NaHCO3 and saturated NaCl solution, and
dried over Na2SO4. After removing the solvent, the
residue was purified by chromatography on a silica gel
column (eluent toluene–EtOAc, 95: 5). 1.60 g (98%)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

SYNTHESIS OF 14,16-DIEN-17-YL ACETATES OF ANDROSTANE SERIES
1883
of a mixture of steroids VI and VII was isolated in 7:1
ratio (according to the integration of the H NMR
3β-Benzoyloxy-14β-androsta-5,15-dien-17-one
(VIIIa). To a solution of 0.05 g of the reaction mixture
containing ketones VIII and IX in 10 ml of ethanol
was added 0.5 ml of hydrochloric acid and the solution
was stirred for 24 h [9]. After removing the solvent the
residue was separated by chromatography, giving
compound IX and ketone VIIIa, mp 209–211°C
(EtOAc–hexane). Rt 5.86. IR spectrum (KBr, cm–1):
2935, 2900, 2860, 1710 (CO, Bz), 1275, 1115, 715.
MS: 269 ([MH–BzOH]+, 100), 251 ([MH–BzOH–H2O]+,
12). MS2 (269): 251 ([MH–BzOH–H2O]+, 100), 241
([MH–BzOH–CO]+, 12), 195 (12), 173 (19), 159 (12),
157 (15), 155 (16). MS3 (251): 236 ([MH–BzO–H2O–
Me]+, 10), 223 (18), 209 (57), 195 (100) 181 (15), 169
(11), 159 (11), 157 (16), 155 (11).
1
spectrum). For analytical purposes, a part of the
mixture was separated by chromatography, which gave
ketone VII, mp 131–133°C (EtOAc–hexane, published
[13]: 130–132). Rt 4.25. IR spectrum (KBr, cm–1):
2940, 2860, 1740 (CO), 1730 (Ac), 1240, 1030. MS:
329 ([MH]+, 5), 311 ([MH–H2O]+, 5), 269 ([MH–
AcOH]+, 100), 268 ([M–AcOH]+, 45); 251 (MH–
AcOH–H2O]+, 29). MS2 (329): 269 ([MH–AcOH]+,
100), 251 (MH–AcOH–H2O]+, 36), 227 (11). MS3
(269): 251 (MH–AcOH–H2O]+, 100), 241 ([MH–
AcOH–CO]+, 80), 195 (12), 175 (28), 173 (17) 159
(14), and ketone VI, mp 179–181°C (hexane,
published [8]: 193–196°C, hexane–acetone). Rt 3.54.
IR spectrum (KBr, cm–1): 2940, 2875, 1730 (Ac), 1710
(CO), 1245, 1035. MS: 329 ([MH]+, 5), 269 ([MH–
AcOH]+, 100), 251 (MH–AcOH–H2O]+, 19). MS2
(329): 269 ([MH–AcOH]+, 100), 251 (MH–AcOH–
H2O]+, 16). MS3 (269): 251 (MH–AcOH–H2O]+, 100),
241 ([MH–AcOH–CO]+, 30), 195 (11), 187 (12), 173
(37) 159 (21).
3β,17-Diacetoxyandrosta-5,14,16-triene (X). To a
solution of 1.58 g (5.52 mmol) of steroid V in 40 ml of
isopropenylacetate and 8 ml of acetic anhydride was
added 0,6 g (3.5 mmol) of TsOH. The solution was
refluxed for 48 h, then cooled, evaporated to half
volume, and poured into cold water. To the mixture
obtained was added in portions at stirring NaHCO3 to
pH = 7, then it was extracted with EtOAc, the extract
was washed with saturated NaCl solution and dried
over Na2SO4. After removing the solvent, the residue
was purified by chromatography on a silica gel column
(eluent toluene). 4.1 g (51%) of diacetate X was
isolated, mp 152–153°C (methanol, published [13]:
154–156°C). Rt 5.98. IR spectrum (KBr, cm–1): 2970,
2940, 1750 (Ac), 1730 (Ac), 1615, 1250, 1200, 1030.
MS: 371 ([MH]+, 21), 328 ([MH–ketene]+, 39), 311
([MH–AcOH]+, 49), 269 ([MH–AcOH–ketene]+, 100)
251 ([MH–2AcOH]+, 46). MS2 (371): 311 ([MH–
AcOH]+, 100), 269 ([MH–AcOH–ketene]+, 15), 251
([MH–2AcOH]+, 47). MS3 (311): 269 ([MH–AcOH–
ketene]+, 34). 251 ([MH–2AcOH]+, 100), 159 (14).
3β-Benzoiyloxyandrosta-5,15-dien-17-one (VIII)
and 3β-benzoiyloxyandrosta-5,14-dien-17-one (IX).
To a solution of 1.32 g (4.63 mmol) of a mixture of
steroids IV and V (ratio 6:1) in 10 ml of pyridine was
added 0.8 ml (6.9 mmol) of benzoyl chloride and
0.072 g (0.6 mmol) of dimethylaminopyridine. The
solution was stirred for 8 h at 40°C, then cooled and
poured into water. The precipitate (2 g) was filtered
off, washed with water, dried and purified by chro-
matography on a silica gel column (eluent toluene–
EtOAc, 95: 5). 1.73 g (96%) of a mixture of steroids
VIII and IX was obtained. For analytical purposes, a
part of the mixture was separated by chromatography,
giving compound IX, mp 226–228°C (methanol). Rt
7.68. IR spectrum (KBr, cm–1): 2945, 2865, 1745
(CO), 1715 (Bz), 1270, 1115, 714. MS: 391 ([MH]+,
1), 269 ([MH–BzOH]+, 100). MS2 (391): 373 ([MH–
H2O]+, 19), 283 (17), 279 (19), 269 ([MH–BzOH]+,
100), 260 (17), 241 ([MH–BzOH–CO]+, 35), 211 (15),
209 (22), 182 (16). MS3 (269): 251 ([MH–BzOH–
H2O]+, 100), 241 ([MH–BzOH–CO]+, 89), 195 (22),
175 (23), 173 (11) 159 (13), 157 (11), 155 (15), and
compound VIII, mp 249–251°C (EtOAc–hexane). Rt
5.18. IR spectrum (KBr, cm–1): 2940, 2855, 1710 (Bz),
1700 (CO), 1275, 1115, 720. MS: 269 ([MH–BzOH]+,
100), 251 ([MH–BzOH–H2O]+, 15). MS2 (269): 251
([MH–BzOH–H2O]+, 100), 241 ([MH–BzOH–CO]+,
32).
17-Acetoxy-3β-benzoiyloxyandrosta-5,14,16-
triene (XI). Along the above procedure, from 2.22 g
(5.7 mmol) of a mixture of steroids VIII and IX after
separation on a silica gel column (eluent toluene–
hexane, 1:1) was obtained 1.75 g (71%) of acetate XI,
mp 160–162°C (methanol). Rt 11.88. IR spectrum
(KBr, cm–1): 2967, 1755 (Ac), 1715 (Bz), 1260, 1100,
1030, 805. MS: 433 ([MH]+, 12), 390 ([MH–ketene]+,
53), 311 ([MH–BzOH]+, 35), 269 ([MH–BzOH–
ketene]+, 100) 251 ([MH–BzOH–AcOH, 45). MS2
(433): 373 ([MH–AcOH, 16), 311 ([MH–BzOH]+, 63),
293 ([MH–BzOH–H2O]+, 100), 275 ([MH–BzOH –
2H2O]+, 10), 269 ([MH–BzOH–ketene]+, 93), 251
([MH–BzOH–AcOH]+, 42). MS2 (269): 251 ([MH–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

1884
BARANOVSKII et al.
BzOH–AcOH]+, 100). Further elution gave 0.38 g of
ketone IX.
idendioxy-6,6-ethylenedioxy-5α,14β-androst-15-en-
17-one (XIIa). To a solution of 0.75 g (1.87 mmol) of
steroid XII in 25 ml of water-free benzene was added
5.10 ml (74.8 mmol) of diisopropylamine and 4.5 g of
silica gel (60 mesh), and the mixture was refluxed for
12 h. The mixture was cooled, evaporated in a vacuum,
and the residue was chromatographed on a silica gel
column (eluent petroleum ether:EtOAc, 95:5). 0.57 g
(76%) of steroid XIV was isolated, mp 176–178°C
(hexane). IR spectrum (KBr, cm–1): 2945, 2875, 1740
(CO), 1240, 1060. Rt: 3.55. MS: 403 ([MH]+, 15), 402
([M]+, 13), 387 ([M–Me]+, 21), 385 ([MH–H2O]+, 21),
346 ( 21), 345 ([MH–acetone]+, 100), 327 ([MH–
acetone–H2O]+, 12). MS2 (403): 375 ([MH–CO]+, 17),
345 ([MH–acetone]+, 100), 327 [MH–acetone–H2O]+,
31). MS2 (345): 327 ([MH–acetone–H2O]+, 43), 317
([MH–acetone–CO]+, 11), 301 {[MH–acetone–(CH2)2O]+,
38}, 283 {[MH–acetone–H2O–(CH2)2O]+, 100}, 265
{[MH–acetone–2H2O–(CH2)2O]+, 31}, 255 (25). MS3
(283): 265 {[MH–acetone–2H2O–(CH2)2O]+, 69}, 255
{[MH–acetone–H2O–(CH2)2O–CO]+, 100}, 241 (15),
237 {[MH–acetone–2H2O–(CH2)2O–CO]+, 25}, 225
(20), 223 (16), 213 (13), 197 (16). Further elution gave
a mixture (0.15 g, 20%) of the initial steroid XII and
its 14β-isomer XIIa. By crystallization from hexane
from the mixture of steroids was isolated steroid XIIa,
mp 216–218°C (hexane). IR spectrum (KBr, cm–1):
2940, 2870, 1710 (CO), 1240, 1070. Rt: 2.73. MS: 345
([MH–acetone]+, 100). MS2 (345): 327 ([MH–acetone–
H2O]+, 13), 301 {[MH–acetone–(CH2)2O]+, 43}, 287
([MH–acetone–C3H6O]+, 90), 283 {[MH–acetone–
H2O–(CH2)2O]+, 100}, 265 {[MH–acetone–2H2O–
(CH2)2O]+ 24}.
2α,3α-Isopropylidenedioxy-6,6-ethylenedioxy-
5α-androst-15-en-17-one (XII) was obtained from the
ketone III by the previously described method [7], mp
216–218°C (methanol). Rt 2.82. IR spectrum (KBr,
cm–1): 2945, 2875, 1704 (CO), 1240, 1060. MS: 403
([MH]+, 17), 385 ([MH–H2O]+, 10), 345 ([MH–
acetone]+, 100). MS2 (403): 345 ([MH–acetone]+, 100),
327 ([MH–acetone–H2O]+, 25). MS3 (345): 327 ([MH–
acetone–H2O]+, 21), 301 {[MH–acetone–(CH2)2O]+,
33}, 287 ([MH–acetone–C3H6O]+, 68), 283 {[MH–
acetone–H2O–(CH2)2O]+, 100}, 265 {[MH–acetone–
2H2O–(CH2)2O]+ 23}. MS4 (283): 265 {[MH–acetone–
2H2O–(CH2)2O]+, 100}, 225 (17).
2α,3α,17-Triacetoxy-5α-androsta-14,16-dien-6-
one (XIII). To a solution of 0.055 g (0.137 mmol) of
steroid XII in 5.5 ml of THF:H2O (10:1) was added
0.002 g (0.014 mmol) of TsOH. The mixture was
refluxed for 6 h. Then the solvent was evaporated in a
vacuum, the residue was dissolved in 10 ml of CHCl3,
washed with saturated NaHCO3, and dried over
Na2SO4. After removing the solvent in vacuo, the
residue (0.05 g) was dissolved in 15 ml of isopropenyl
acetate, and 0.002 g (0.014 mmol) of TsOH and
0.16 ml (1.64 mmol) of acetic anhydride was added.
The mixture was boiled for 5 h, cooled, evaporated in a
vacuum to 1/5 volume, then dissolved in 10 ml of
CH2Cl2, washed with saturated NaHCO3, and dried
over Na2SO4. After removing the solvent in vacuo, the
residue was chromatographed on a silica gel column
(eluent petroleum ether:EtOAc, 90:10), and 0.026 g
(43%) of triacetate XIII was isolated, mp 203–205°C
(EtOAc–hexane). IR spectrum (KBr, cm–1) 2950,
2880, 1740 (Ac), 1715 (Ac), 1265: Rt: 3.04. MS: 445
([MH]+, 35), 402 ([M–ketene]+, 100), 385 ([MH–
AcOH]+, 82), 343 ([MH–AcOH–ketene]+, 97), 325
([MH–2AcOH]+, 50). MS2 (445): 385 ([MH–AcOH]+,
100), 325 ([MH–2AcOH]+, 18), 265 ([MH–3AcOH]+,
15). MS3 (385): 343 ([MH–AcOH–ketene]+, 77), 325
([MH–2AcOH]+, 100), 283 ([MH–2AcOH–ketene]+,
53), 265 ([MH –3AcOH]+, 10). MS4 (325): 307 ([MH–
2AcOH–H2O]+, 10), 283 ([MH–2AcOH–ketene]+,
100), 265 ([MH–3AcOH]+, 31). MS2 (402): 342 ([M–
AcOH–ketene]+, 26), 300 ([M–AcOH–2keten]+, 100),
282 (19). MS3 (300): 285 ([M–AcOH–2ketene–Me]+, 74),
283 ([MH–2AcOH–ketene]+, 100), 282 (35), 242 (14).
17-Acetoxy-2α,3α-isopropylidendioxy-6,6-ethyl-
enedioxy-5α-androsta-14,16-diene (XV). To a solu-
tion of 0.02 ml (0.1 mmol) of diisopropylamine in 8 ml
of THF at 20°C was added a crystal of o-phen-
athroline. The solution was cooled to 0°C, and 0.17 ml
of 2.0 M solution of LDA in THF/heptane/ethyl-
benzene was added to it. The mixture was cooled to
–78°C and under vigorous stirring in one portion
0.127 g (0.32 mmol) of steroid XIV in 2 ml of
anhydrous THF was added to it. 2 min latter 0.03 ml
(0.35 mmol) of acetic anhydride was added, and the
mixture was brought to room temperature within
15 min. Then 0.04 ml (0.32 mmol) of triethylamine
was added and the mixture was stirred for 15 min. The
organic fraction was washed with saturated NaHCO3
and dried over Na2SO4. After removing the solvent in
vacuo, the residue was chromatographed on a silica gel
2α,3α-Isopropylidendioxy-6,6-ethylenedioxy-5α-
androst-14-en-17-one (XIV) and 2α,3α-isopropyl-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

SYNTHESIS OF 14,16-DIEN-17-YL ACETATES OF ANDROSTANE SERIES
1885
3. Bull, J.R., Grundler, C., and Niven, M.L., J. Chem. Soc.,
Chem. Commun., 1993, p. 271.
4. Kirsch, G., Golde, R., and Neef, G., Tetrahedron Lett.,
1989, vol. 30, no. 34, p. 4497.
5. Fell, J.D. and Heathcock, C.H., J. Org. Chem., 2002,
column (eluent petroleum ether:EtOAc, 70:30), and
0.095 g (68%) dienyl acetate XV was isolated, mp
135–137°C (hexane). Rt: 5.35. IR spectrum (KBr, cm–1):
2945, 2875, 1730 (Ac), 1260, 1060. MS: 445 ([MH]+,
45), 402 ([M–ketene]+, 37), 387 ([MH–acetone]+, 100).
MS2 (445): 387 ([MH–acetone]+, 100), 369 ([MH–
acetone–H2O]+, 17), 327 ([MH–acetone–AcOH]+, 30).
MS3 (387): 369 ([MH–acetone–H2O]+, 40), 345 ([MH–
acetone–ketene]+, 100), 327 ([MH–acetone–AcOH]+,
94), 325 {[MH–acetone–H2O–(CH2)2O]+, 27}, 301
([MH–acetone–ketene–(CH2)2O]+, 19), 283 {[MH–
acetone–AcOH–(CH2)2O]+, 34}, 265 {[MH–acetone–
AcOH–H2O–(CH2)2O]+, 21}, 247 (17).
vol. 67, no. 14, p. 4742.
6. Baranovskii, A.V., Litvinovskaya, R.P., and Khripach, V.A.,
Zh. Org. Khim., 2004, vol. 40, no. 11, p. 1656.
7. Litvinovskaya, R.P., Baranovskii, A.V., Aver’kova, M.A.,
and Khripach, V.A., Bioorg. Khim., 2007, vol. 33, no. 3,
p. 342.
8. Kelly, R.W. and Sykes, P.J., J. Chem. Soc. (C), 1968,
p. 416.
9. Cerny, I., Pouzar, V., Budesinsky, M., Drasar, P., and
Havel, M., Coll. Czech. Chem. Comm., 1990, vol. 55,
p. 2510.
ACKNOWLEDGMENTS
10. Cleve, A., Neef, G., Ottow, E., Scholz, S., and Schwede, W.,
This work was performed as part of research grant
B-RFFR X09M-094 and GPOFI “Biorational
pesticides-2”, State registration no. 20093013.
Tetrahedron, 1995, vol. 51, p. 5563.
11. Baranovskii, A.V., Litvinovskaya, R.P., Aver’kova, M.A.,
Khripach, N.B., and Khripach, V.A., Zh. Prikl. Spektr.,
2007, vol. 74, no. 5, p. 583.
REFERENCES
12. Armarego, W.L.F. and Chai, C.L.L., Purification of
Laboratory Chemicals, 5th ed., Oxford: Butterworth–
Heinemann, 2003.
1. Bull, J.R. and Bischofberger, K., J. Chem. Soc., Perkin
Trans. 1, 1991, p. 2859.
2. Beckmann, M., Meyer, T., Schulz, F., and Winterfeldt, E.,
13. Pataki, J. and Siade, G., J. Org. Chem., 1972, vol. 37,
Chem. Ber., 1994, vol. 127, p. 2505.
no. 13, p. 2127.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011