Steroids modified at C15. Synthesis and spectra-structure correlations

Article abstract of DOI:10.1134/S1070363211100185

A synthesis of 15-benzoyloxybutyl-20-hydroxymethylpregn-16-enes, the intermediates in the synthesis of brassino-and ecdysteroids modified in the D ring was performed starting with 2α,3α-isopropylidenedioxy-6,6- ethylenedyoxy-5α-androst-15-ene-17-one and its 2β,3β-isomer through a sequence of reactions involving Michael addition, Wittig reaction and ene reaction. Structures of the compounds were proved by the methods of two-dimensional NMR spectroscopy. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070363211100185

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 10, pp. 2142–2150. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.V. Baranovskii, V.A. Khripach, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 10, pp. 1690–1698.
Steroids Modified at C15.
Synthesis and Spectra-Structure Correlations
A. V. Baranovskii and V. A. Khripach
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 September 6, 2010
Abstract—A synthesis of 15-benzoyloxybutyl-20-hydroxymethylpregn-16-enes, the intermediates in the
synthesis of brassino- and ecdysteroids modified in the D ring was performed starting with 2α,3α-
isopropylidenedioxy-6,6-ethylenedyoxy-5α-androst-15-ene-17-one and its 2β,3β-isomer through a sequence of
reactions involving Michael addition, Wittig reaction and ene reaction. Structures of the compounds were
proved by the methods of two-dimensional NMR spectroscopy.
DOI: 10.1134/S1070363211100185
Modified steroids are the most important part of the
steroid drugs used in medicine, because the structural
modification allows revealing and improving some
components of a wide range of physiological effects of
steroids, and thus provides a possibility of the
focused application of steroids in therapy. Another
important area of applications of modified steroids is
diagnostics, where they are used as the haptens for
immunochemical analysis, tracers for biochemical
research, references and labels for studying the
mechanism of action. Among the many types of
modified steroids, of special interest are the steroids
containing an additional carbon substituent in the D
ring, since many known compounds of this type, such
as 16-alkylsteroids or steroid D-pentaranes [1–6] have
valuable pharmacological properties. Among the D-
modified steroids, the least studied and very
inaccessible are the derivatives containing function-
alized carbon substituent at C15 [7–11]. Along with the
possible validity as a new physiologically active
compounds, such derivatives are of interest as haptens
in the immunochemical analysis of natural hormones
containing pharmacophore features in the ring and the
side chain, such as ecdy- and brassinosteroids. Being
spatially distant from the structural fragments
responsible for biofunctionality of the hormone
molecule, such a substituent must not impede its
recognition by a receptor or antibody. The recognition
O
O
(CH2)3CH=CH2
RO
(CH2)4OAc
(CH2)3OPiv
RO
O
2142

STEROIDS MODIFIED AT C15
2143
is, in particular, of crucial significance for obtaining
adequate information about the structure of the
molecule at the immunochemical analysis.
scheme for synthesis, where the cyclic fragment is
formed in the early stages, which eliminated such
problems. The source ketone I and its isomer II were
prepared along the scheme described in [14], which
allowed us to synthesize 2α,3α- and 2β,3β-dihydroxy-
derivatives of 15-substituted pregnanes.
This work continues of our studies on the synthesis
of 15-substituted steroids related to brassinosteroid.
Initially, our approach to 15-substituted 2,3-
dihydroxypregnanes was based on the introduction of
the chain in C15 position of the unsaturated ketone with
a further modification of the rings A and B [12, 13].
This way, as it turned out, has significant limitations
due to the instability of pregna-17-ene structure at the
modification of rings and due to the competitive
reactions involving the protective groups that led to
elongation of the reaction scheme and reduced yield of
the end product. In this study, we chose another
Bromide III, the reagent for the Michael addition to
ketones I and II, was prepared in two stages from
tetrahydrofuran by splitting it with hydrobromic acid
[15] and the subsequent protection of the hydroxyl
group through silyl ether. Such a procedure reduces the
number of stages compared to the previous approach
[12], where was used 5-bromopentene while the
hydroxyl function in the C15 chain was introduced at a
later stage.
TBDMSCl, Et3N
Br
HBr
Br
OH
OTBDMS
O
III
O
OTMS
O
III, Mg, CuBr, Me2S,
O
O
HMPA, TMSCl
+
O
O
(CH2)4OTBDMS
(CH2)4OTBDMS
I, II
IVa
IV, V
EtPh3PBr,
t-BuOK
K2CO3
(1) Bu4NF,
(2) BzCl, Py
(CH2)4OTBDMS
VI, VII
(CH2)4OBz
VIII, IX
OR
OH
O
O
(CH2O)n, Et2AlCl
+
(CH2)4OBz
O
(CH2)4OBz
RO
XII
XIIa
Ac2O, Py
X, XI
2α,3α: I, IV, IVa, VI, VIII, X; 2β,3β: II, V, VII, IX, XI; R = H (XII), Ac (XIIa); TMSCl is trimethylsilyl chloride,
TBDMSCl is tert-butylmethylsilyl chloride.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

2144
BARANOVSKII, KHRIPACH
Table 1. 1H NMR data of compounds IV–XI
21
22
18
20
12
OH
17
11
13
19
16
1
4
9
2
3
8
β-Me
α-Me
O
O
14
15
10
1'
5
7
6
2'
4'
O
O
3'
OR
α-CH2
β-CH2
Chemical shift, δ, ppm
Atom
IVа
VIа
VIIIb
Xb,c
Vа
VIIа
IXb
XI b,c
1α
1.08
1.94
4.10
4.28
2.16
1.82
1.85
1.13
1.90
1.92
0.89
1.67
1.30
1.23
1.06
1.93
4.11
4.28
2.16
1.83
1.84
1.07
1.84
1.80
0.85
1.59
1.33
1.45
1.06
1.93
4.10
4.27
2.15
1.82
1.83
1.08
1.84
1.81
0.87
1.61
1.34
1.47
1.05
1.93
4.09
4.29
2.14
1.83
1.84
1.12
1.91
1.83
0.90
1.63
1.36
1.33
1.34
2.24
4.21
4.06
1.91
1.54
1.35
1.08
1.91
1.92
0.79
1.65
1.41
1.22
1.34
2.24
4.21
4.06
1.90
1.54
1.33
1.02
1.86
1.82
0.76
1.59
1.44
1.45
1.33
2.24
4.20
4.05
1.89
1.53
1.33
1.03
1.85
1.80
0.77
1.58
1.45
1.45
1.32
2.22
4.20
4.06
1.88
1.53
1.34
1.06
1.91
1.84
0.81
1.61
1.48
1.32
1β
2β(2α)
3β(3α)
4α
4β
5α
7α
7β
8β
9α
11α
11β
12α
12β
14α
1.77
1.50
2.18
1.35
2.20
1.37
1.72
1.52
1.78
1.47
2.20
1.33
2.20
1.34
1.73
1.50
15α
16α
16β
18
19
20
21
1'
2.14
2.37
1.81
2.47
2.21
1.03
0.87
5.14
1.65
1.83
2.50
2.23
1.04
0.87
5.15
1.65
2.32
5.60
2.14
2.37
1.80
2.47
2.22
1.05
1.16
5.15
1.65
1.82
2.49
2.32
5.60
2.31
–
2.31
2.24
–
0.97
0.98
0.99
1.06
0.98
0.88
0.89
1.17
1.14
1.16
–
2.40
–
5.15
2.40
–
1.02
–
1.65
1.03
1.31, 1.50
1.21, 1.42
1.48, 1.54
3.60
1.17, 1.36 1.21, 1.49
1.13, 1.36 1.26, 1.50
1.29, 1.52
1.37, 1.50
1.76 (2)
4.32
1.30, 1.51
1.25, 1.43
1.48, 1.56
3.61
1.16, 1.37
1.13, 1.37
1.46, 1.54
3.59
1.21, 1.50
1.26, 1.50
1.77 (2)
4.31
1.32, 1.50
1.36, 1.50
1.76 (2)
4.32
2'
3'
1.44, 1.52
3.58
1.74 (2)
4.31
4'
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

STEROIDS MODIFIED AT C15
2145
Table 1. (Contd.)
Chemical shift, δ, ppm
Atom
IVа
VIа
VIIIb
Xb,c
Vа
VIIа
IXb
XI b,c
Proton signals of acetonide and dioxolane protecting groupsd
α-Me
1.47
1.33
3.76
3.95
4.02
3.88
1.48
1.32
3.73
3.92
3.99
3.86
1.47
1.33
3.70
3.86
3.96
1.46
1.32
3.72
3.90
3.99
3.89
1.33
1.55
3.81
3.96
4.03
3.89
1.33
1.54
3.77
3.93
4.03
3.87
1.32
1.54
3.74
3.86
3.99
3.85
1.32
1.54
3.77
3.90
4.01
3.87
β-Me
αA-СH2
αB-СH2
βA-СH2
βB-СH2
3.83
a
b
c
t-BuMe2Si, δ, ppm: 0.03 (Me2Si), 0.88 (Me3S). Bz, δ, ppm: 7.44 (meta), 7.56 (para), 8.04 (ortho). 20-Hydroxymethyl, δ, ppm: 3.52
and 3.61 (CH2). d (A) indicates the position of the proton CH2 group in the side of the ring A; (B) indicates the position of the proton CH2
group in the side of the ring B.
Table 2. 1H and 13C NMR parameters of compounds XII and XIIa
13C NMR, δ, ppm
13C NMR, δ, ppm
13C NMR, δ, ppm
13C NMR, δ, ppm
Atom
Atom
XIIа
XIIaa,b
XIIа
1.00
1.87
4.07
4.25
1.99
2.04
1.51
–
XIIaa,b
XIIа
127.19
157.27
22.24
15.25
35.35
18.27
66.85
29.84
25.55
28.99
64.68
XIIaa,b
127.15
156.51
22.11
14.84
31.53
18.83
68.78
29.92
25.70
29.15
64.84
XIIа
5.59
–
XIIaa,b
5.59
–
1α
1β
2β
3β
4α
4β
5α
6
43.73
43.84
0.99
1.87
4.08
4.26
1.93
2.04
1.49
–
16
17
18
19
20
21
22
1'
73.02
73.27
22.82
73.16
73.46
22.85
0.96
0.93
2.38
1.02
0.96
0.92
2.48
1.05
42.53
77.79
35.78
42.74
77.70
35.57
3.51, 3.59 3.93, 4.14
1.29, 1.50 1.25, 1.50
1.37, 1.50 1.39, 1.50
7α
7β
8β
9α
1.07
1.78
1.80
0.80
1.05
1.80
1.84
0.80
2'
3'
1.73 (2)
1.74 (2)
27.21
55.13
27.12
55.35
4'
4.30 (2)
4.32 (2)
13C and 1H signals of acetonide protecting group
and substituents at C6
10
37.38
20.41
37.52
20.48
–
–
α-Me
28.75
26.68
107.54
9.44
28.80
26.76
107.50
9.42
1.45
1.31
1.46
1.32
11α
11β
12α
12β
13
1.62
1.34
1.30
1.71
–
1.62
1.36
1.30
1.71
–
β-Me
Ме2С
–
–
36.97
37.02
CH3CH2
CH3CH2
OCH2CH2OR
OCH2CH2OR
0.83
0.83
28.90
60.86
62.70
28.74
58.17
64.40
1.50 (2)
3.34, 3.39
3.65 (2)
1.45, 1.55
3.44 (2)
4.12, 4.16
47.32
57.89
43.79
47.47
57.77
43.91
14α
15α
1.50
2.35
1.49
2.35
a Bz, δH, ppm: 7.44 (meta), 7,55 (para), 8.03 (ortho); δC, ppm, 128.5 (C3), 129.6 (C2), 130.5 (C1), 133.0 (C4), 166.7 (PhСО).
b Acetonates, δH, ppm: 2.01 (6-Me), 2.03 (22-Me); δC, ppm: 21.08 (6,22-Me), 171.08 [6-OC(O)], 171.21 [22-OC(O)].
The conjugate addition of the Grignard reagent
prepared from the bromide III to the ketones I and II
in the presence of copper(I) bromide complex with
dimethyl sulfide, trimethylsilyl chloride and HMPA
[12, 16, 17] gave the products IV and V, respectively,
in almost quantitative yield. However, the reaction
involves a two-stage procedure because during the process-
sing, the intermediate enol silyl ether IVa is not com-
pletely hydrolyzed. Ether IVa was converted to the
ketone IV by additional treatment with K2CO3 in methanol.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

2146
BARANOVSKII, KHRIPACH
Table 3. 13C NMR data of compounds IV–XI
Chemical shift, δ, ppm
Atom
IVа
Vа
VIа
VIIа
VIIIb
IXb
Xb,c
XIb,c
1
42.95
73.00
72.91
22.10
45.95
109.54
39.90
30.21
53.89
38.43
20.13
33.89
46.90
53.26
34.49
42.89
221.37
17.73
13.47
–
41.05
73.82
75.81
24.01
49.23
109.65
39.79
30.00
55.21
36.65
20.17
33.96
47.03
53.38
34.43
42.71
221.51
17.71
15.17
–
42.89
73.15
73.03
22.11
45.86
109.82
40.58
30.06
53.77
38.38
20.99
39.20
43.81
58.29
37.12
39.44
150.69
20.44
13.44
114.18
13.48
31.26
26.12
33.36
63.46
28.77
26.73
107.73
64.41
65.53
41.08
73.82
75.59
24.24
49.17
109.65
40.82
30.06
55.39
36.64
21.19
39.26
43.86
58.37
37.10
39.40
150.73
20.47
15.21
114.18
13.47
31.22
26.12
33.33
63.46
26.31
28.82
107.91
64.47
65.47
42.91
73.15
73.04
22.14
45.91
109.79
40.71
30.11
53.81
38.40
21.01
39.21
43.82
58.31
37.13
39.45
150.49
20.48
13.45
114.37
13.48
31.04
26.35
29.07
65.12
28.78
26.74
107.75
64.44
65.61
41.07
73.80
75.56
24.23
49.17
109.60
40.92
30.08
55.37
36.63
21.18
39.24
43.84
58.34
37.09
39.37
150.50
20.48
15.21
114.34
13.47
31.00
26.32
29.04
65.12
26.28
28.81
107.93
64.49
65.53
42.81
73.11
73.03
22.16
46.18
109.76
40.71
29.81
54.48
38.46
20.54
36.87
47.41
57.62
43.88
127.42
157.21
22.18
13.39
35.43
18.29
29.95
25.82
29.19
64.88
28.76
26.72
107.77
64.46
65.63
40.99
73.77
75.57
24.31
49.50
109.59
40.91
29.81
56.06
36.73
20.75
36.97
47.47
57.70
43.89
127.43
157.21
22.24
15.14
35.47
18.28
29.95
25.80
29.19
64.89
26.28
28.82
107.93
64.52
65.58
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1'
–
–
30.93
26.08
33.14
63.17
28.76
26.71
107.82
64.52
65.63
30.75
26.14
33.35
63.24
26.29
28.74
107.96
64.47
65.24
2'
3'
4'
α-Me
β-Me
Ме2С
α-СH2
β-СH2
a
b
t-BuMe2Si, δC, ppm: –5.09 (Me2Si), 18.46 (Ме3С), 26.10 (Ме3С). Bz, δC, ppm: 128.49 (C3), 129.66 (C2), 130.57 (C1), 133.0 (С4),
166.79 (PhСО). c 20-Hydroxymethyl, δC, ppm: 66.93 (CH2).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

STEROIDS MODIFIED AT C15
2147
Synthesis of pregnenes VI and VII is based on the
well-developed procedure [18–20]. The Wittig reaction
of ketones IV and V in boiling benzene with the ylide
prepared from ethyltriphenylphosphonium bromide led
selectively to the 17Z-pregnenes in 90–92% yield.
Configuration of the 17-center is confirmed according
to the NMR data (Tables 1–3), which are quite
consistent with the literature.
interact with 7β,8β protons and weakly with the
protons of 19-methyl group.
It could be assumed that the formation of XII is
associated either with an excess of reagent, or with the
temperature factor. However, the change in the ratio of
the paraform–diethylaluminum chloride complex, or
performing the reaction at different temperatures did
not lead to a decrease in the yield of XII. So, it was
found that the temperature of reaction initiation was
about –30°C, but even at this temperature was
observed formation of both the products. The
compound X and XII formed in 1:1 ratio and were
obtained in a total yield of 75–85%. Solving the
problem was quite simple and consisted in the use of
strict anhydrous conditions. A slight amount of
moisture in the reaction mixture initiates the addition
leading to the formation of XII. Prolonged pre-drying
of substrates allowed us to obtain steroids X and XI in
73% yield.
The next stage of the synthesis required repla-
cement of the protective silyl group, which proved to
be unstable under the conditions of ene reaction. The
benzoate protection was chosen owing to its stability
under the reaction conditions and the need for further
discrimination of the two primary hydroxyl groups,
(the second is formed in the ene reaction). The two-
stage transformation gave esters VIII and IX in 86%
and 92% yield, respectively. Consecutive approach
through the formation of C22 aldehyde in the synthesis
of brassinosteroid side chain was preferred, since the
use of functionalized aldehydes for the introduction of
the C22–C28 fragment has been shown leading to the
20-unnatural steroids [21].
Compounds X–XII are synthetic precursors of the
new D-modified brassino- and ecdysteroids and will be
further used in the synthesis of analogues of these
hormones to study their physiological activity and use
for analytical purposes.
Unexpectedly, the carbonyl ene reaction [22–24]
required selection of a specific Lewis acid. The typical
reagents for a similar conversion were ineffective in
the steroid series. For example, boron trifluoride
etherate or Me2AlCl caused partial hydrolysis of the
protecting group, and, for example, t-BuMe2SiCl [25]
did not even initiated the reaction. We then returned to
diethylaluminum chloride [19, 26], which showed
good results in our previous work [13]. This reagent
was tested initially with compound IX: the reaction led
to the corresponding alcohol XI. Similar good result
was obtained with steroid VIII. However, further
attempts of scaling the experiment under various
conditions were complicated by the formation of by-
product. The by-product in some cases has been
isolated as the main product of the reaction. The
isolated by-product was thoroughly analyzed. For this
purpose it was acetylated, and according to the data of
NMR spectroscopy and mass spectrometry, to the
acetate was assigned the structure XIIa. It turned out
that under the reaction conditions, diethylaluminum
chloride can attack the dioxolane ring of the molecule,
giving a product XII of the ring cleavage. Stereo-
chemistry of addition at C6 follows from the data of the
NOESY spectrum of XIIa. The cross-peaks were
detected between the methyl protons of ethyl group
and 4α- and 7α-protons, whereas the OCH2 protons
EXPERIMENTAL
Melting points were determined on a Kofler block
1
and were not adjusted. The H and 13C NMR spectra
were obtained on a Bruker AVANCE 500-Biospin
spectrometer with operating frequencies 500.13 and
1
13
125.77 MHz for H and C nuclei, respectively, using
5-mm probe (QNP) with Z-gradient. The spectra were
recorded at a sample temperature 293 K for solutions
in CDCl3, as an internal reference we used the residual
solvent signals δ 7.26 (1H) and 77.16 (13C). The
correlation spectra (HSQC, COSY, HMBC, NOESY)
were recorded and processed using a standard Bruker-
Biospin software. The NMR data are listed in
Tables 1–3. The IR spectra were obtained on an UR 20
instrument. The mass-spectra were recorded on an
Accela HPLC device with the mass detector LCQ-
Fleet (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.
Preparation of solvent was carried out according to
the usual practice [27]. All reactions were performed
under argon. The reactions were monitored by TLC on
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

2148
BARANOVSKII, KHRIPACH
Merck (Kieselgel 60 F254) plates. Chromatographic
separation of reaction mixtures was performed on
40/60 silica gel (Kieselgel 60, Merck).
K2CO3 (0.02 g) was added, and the mixture was stirred
for 1 h. After hydrolysis, the solvent was evaporated,
the resulting oil was dissolved in EtOAc, the solution
was washed successively with saturated solutions of
NH4Cl and NaCl, and dried over Na2SO4. After solvent
evaporation, the residue was chromatographed on a
silica gel column, which gave an additional 0.453 g of
ketone IV. The overall yield 1.989 g (99%). Colorless
oil. IR spectrum (film), cm–1: 2960, 1760, 1250, 1100,
850, 790. Mass spectrum, m/z, (I, %): 591 ([M + 1]+,
5), 590 ([M]+, 9), 533 ([M + 1 – (CH3)2CO]+, 100), 515
([M + 1 – (CH3)2CO – H2O]+, 25), 471 ([M + 1 –
(CH3)2CO – H2O-(CH2)2O]+, 16). Mass spectrum, m/z
(I, %) (MS2), (590): 575 ([M – Me]+, 61), 532 ([M –
(CH3)2CO]+, 100), 475 ([M – t-BuSiMe2]+, 52).
4-Bromobutoxydimethyl-tert-butylsilane (III). A
solution of 4-brombutanol [15] (4.59 g, 30 mmol),
dimethyl-t-butylsilyl chloride (3.8 g, 25 mmol) and tri-
ethylamine (68 ml, 50 mmol) in 20 ml of dichloro-
methane was stirred at room temperature for 72 h.
Then the solution was diluted with hexane, washed
with saturated solutions of NaHCO3 and NaCl, dried
over Na2SO4. After evaporation of the solvent, the
crude product was purified by chromatograpy on a
silica gel column (petroleum ether), which gave
compound III (4.6 g, 70% yield based on dimethyl-
tert-butylsilyl chloride). Colorless liquid, bp 75–76°C
(2 mm Hg). IR (film), cm–1: 2970, 2870, 1260, 1110,
15β-(4-(Dimethyl-tert-butylsilyloxy)butyl)-2β,3β-
isopropylidenedihydroxy-6,6-ethylenedioxy-5α-
androstan-17-one (V). Along the above procedure,
from 0.286 g (0.71 mmol) of steroid II after separation
was obtained 0.394 g (94%) of steroid V, mp 130–
133°C (hexane). IR spectrum (KBr), cm–1: 2950, 2870,
1740, 1250, 1110, 850, 790. Mass spectrum, m/z, (I,
%): 591 ([M + 1]+, 100), 533 ([M + 1 – (CH3)2CO]+,
61), 515 ([M + 1 – (CH3)2CO – H2O]+, 16). Mass
spectrum, m/z, (I, %) (MS2) (590): 572 ([M – H2O]+,
60), 532 ([M – (CH3)2CO]+, 100). Found, %: C 69.40,
H 9.96. C34H58O6Si. Calculated, %: C, 69.11; H, 9.89.
1
840, 790. H NMR spectrum, δppm: 0.06 (6H, s,
Me2Si), 0.90 (9H, s, t-BuSi), 1.65 m (2H, CH2), 1.94 m
(2H, CH2), 3.45 t (2H, CH2Br, J = 7 Hz), 3.66 t (2H,
CH2O, J = 7 Hz).
15β-(4-(Dimethyl-tert-butylsilyloxy)butyl)-2α,3α-
isopropylidenedihydroxy-6,6-ethylenedioxy-5α-
androstan-17-one (IV). To a cooled to –20°C solution
of Grignard reagent (prepared by adding a solution of
bromide III (3.12 g, 11.69 mmol) in THF (12 ml) to
magnesium chips (0.31 g, 12.89 mmol) in THF (12 ml)
followed by reflux for 1 h) was added CuBr·Me2S
complex (0.482 g, 2.35 mmol). After 5 min, the solu-
tion was cooled to –78°C and were added subsequently
Me3SiCl (2.47 ml, 19.58 mmol), phosphoric hexa-
methyltriamide (3.4 ml, 19.58 mmol) and then a
solution of steroid I (1.362 g, 3.39 mmol) in THF
(15 ml). The mixture was stirred for 10 min and then
treated with a saturated solution of NH4Cl. The organic
phase was extracted with EtOAc, the resulting solution
was washed with saturated NaCl solution and dried
over Na2SO4. After solvent evaporation, the residue
was chromatographed on a silica gel column (EtOAc–
petroleum ether, 10:90). The first fraction (0.8 g)
contained Me3Si-derivative IVa as the main com-
ponent. IR (film), cm–1: 2960, 2860, 1640, 1260, 1110,
(17Z)-15β-(4-(Dimethyl-tert-butylsilyloxy)butyl)-
2α,3α-isopropylidenedioxy-6,6-ethylenedioxy-5α-
pregna-17-ene (VI). To a solution of ylide (prepared
by stirring 30 min a mixture of potassium t-butoxide
(1.235 g, 3.11 mmol) and triphenylethylphosphonium
bromide (4.5 g, 12.13 mmol) in benzene (20 ml) at 40°C
was added 2.58 g of steroid IV (4.37 mmol ) in
benzene (20 ml) at 10°C. The resulting solution was
refluxed for 2.5 h, then cooled, and acetone (1.5 ml)
was added to the mixture. After 30 min it was treated
with a saturated solution of NH4Cl (3 ml), diluted with
hexane and passed through a layer of MgSO4. After
solvent evaporation, the residue was chromatographed
on a silica gel column (EtOAc–petroleum ether, 3:97),
which gave 2.42 g of olefin VI (92%). Colorless oil.
IR spectrum (film), cm–1: 2950, 2870, 1740, 1100, 850,
790. Mass spectrum, m/z, (I, %), m/z: 603 ([M + 1]+,
10), 545 ([M + 1 – (CH3)2CO]+, 100). Mass spectrum,
m/z, (I, %) (MS2) (602): 587 ([M – Me]+, 100), 544
([M – (CH3)2CO, 13]+), 487 ([M – t-BuSiMe2]+, 52).
1
850, 790, H NMR spectrum (C6D6), δppm: 0.06 s
(6H, Me2Si), 0.21 s (9H, Me3Si), 0.88 s (3H, 19-Me),
0.93 s (3H, 18-Me), 0.98 s (9H, Me3C), 1.40 s (3H,
β-Me, acetonide), 1.59 s (3H, α-Me, acetonide), 3.55 t
(2H, 4'-H, J = 6.2), 3.56 m (4H, dioxolane), 4.04 m
(1H, 2β-H), 4.19 m (1H, 3β-H ), 4.90 d (1H, 16-H, J =
3.0).
(17Z)-15β-(4-(Dimethyl-t-butylsilyloxy)butyl)-
2β,3β-isopropylidenedioxy-6,6-ethylenedioxy-5α-
Further elution gave ketone IV (1.536 g). Fraction
of the enol ether was dissolved in methanol (10 ml),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

STEROIDS MODIFIED AT C15
2149
pregna-17-ene (VII). Similarly, from 0.361 g
(0.61 mmol) of steroid V after separation was
obtained 0.332 g (90%) of olefin VII, mp 157–159°C
(hexane). IR spectrum (KBr), cm–1: 2940, 2870, 1110,
850, 790. Mass spectrum, m/z, (I, %): 603 ([M + 1]+,
100), 545 ([M + 1 – (CH3)2CO]+, 100). Mass spectrum,
m/z, (I, %) (MS2) (603): 544 ([M – (CH3)2CO]+, 100),
501 ([M – Me – MeCH – (CH3)2CO]+, 33), 485 ([M –
117]+, 34) . Found, %: C 71.87, H 10.02. C36H62O5Si.
Calculated, %: C 71.71, H 10.36.
(20S)-15β-(4-Benzoyloxybutyl)-20-hydroxymethyl-
2α,3α-isopropylidenedihydroxy-6,6-ethylenedioxy-
5α-pregna-16-ene (X). To a stirred solution of 0.022 g
of paraform (0.75 mmol) in methylene chloride (5 ml)
was added 1M solution of diethylaluminum chloride in
hexane (1 ml) at –78°C. After 5 min, to the resulting
complex was added 0.148 g of steroid VIII
(0.25 mmol) in methylene chloride (3 ml), and the
mixture was stirred at riseing temperature to 0°C for
3 h. Then was added a solution of pyridine (0.2 ml) in
methanol (1 ml ) and, after the cessation of gas
evolution, the mixture was poured into a saturated
solution of NaHCO3 and NaCl (1: 1) the organic phase
was extracted with chloroform, washed with saturated
NaCl solution and dried over Na2SO4. After solvent
evaporation, the residue was separated on a silica gel
column (EtOAc–toluene, 20:80), the fraction of
alcohol X (0.113 g, 73%) was collected. Colorless
foam. IR spectrum (film), cm–1: 2950, 2880, 1730,
1280, 1060, 760, 720. Mass spectrum, m/z, (I, %): 623
([M + 1]+, 19), 593 ([M + 1 – CH2OH]+, 7), 565 ([M +
1 – (CH3)2CO]+, 100), 535 ([M + 1 – (CH3)2CO –
CH2OH]+, 35). Mass spectrum, m/z, (I, %) (MS2)
(623): 579 ([M + 1 – (CH2)2O]+, 100), 565 ([M + 1 –
(CH3)2CO]+, 48), 547 ([M + 1 – (CH3)2CO – H2O]+,
42), 521 ([M + 1 – (CH3)2CO – (CH2)2O]+, 34). Further
elution gave the product of disclosure dioxolane ring
XII (0.009 g, 6%). Colorless oil. IR spectrum (film),
cm–1: 2950, 2870, 1730, 1280, 750, 720. Mass
spectrum, m/z, (I, %): 653 ([M + 1]+, 0.1), 591 ([M + 1 –
(CH2OH)2]+, 13), 533 ([M + 1 – (CH2OH)2 – (CH3)2CO]+,
100), 515 ([M + 1 – (CH2OH)2 – (CH3)2CO – H2O]+,
58). Mass spectrum, m/z, (I, %) (MS2) (652): 634
([M – H2O]+, 97), 622 ([M – C2H6]+, 18), 619 ([M –
H2O – Me]+, 38), 594 ([M – (CH3)2CO]+, 100), 576
([M – (CH3)2CO – H2O]+, 60), 532 ([M – (CH2OH)2 –
(CH3)2CO]+, 21).
(17Z)-15β-(4-Benzoyloxybutyl)-2α,3α-isopropyl-
idenedioxy-6,6-ethylenedihydroxy-5α-pregna-17-
ene (VIII). To a solution of 3.393 g of steroid VI
(5.64 mmol) in THF (20 ml) was added 1M solution of
Bu4NF in THF (11 ml). The resulting mixture was
stirred for 2 h, then diluted with EtOAc, washed
consecutively with saturated solutions of NaHCO3 and
NaCl, and dried over MgSO4. The solvent was eva-
porated, the residue (3.4 g) was dissolved in methylene
chloride (40 ml), then were added consecutively a
solution of pyridine (1.1 ml, 13.56 mmol) and benzoyl
chloride (1.32 ml, 11.3 mmol). The mixture was stirred
at room temperature for 2.5 h, then to it was added
methanol (0.6 ml) and stir was continued for 0.5 h. The
solution was then diluted with chloroform, washed
with saturated solutions of NaHCO3 and NaCl, and
dried over MgSO4. After solvent evaporation, the
residue was purified by chromatography on a silica gel
column (EtOAc–petroleum ether, 10:90), which gave
2.871 g of steroid VIII (86%), mp 162–164°C
(methanol). IR spectrum (KBr), cm–1: 2950, 2870,
1720, 1280, 720. Mass spectrum, m/z, (I, %): 593
([M + 1]+, 39), 535 ([M + 1 – (CH3)2CO]+, 100). Mass
spectrum, m/z, (I, %) (MS2) (592): 577 ([M – Me,
100), 549 ([M – Me – MeCH, 61) 535 ([M + 1 –
(CH3)2CO, 20), 491 ([M – Me – MeCH – (CH3)2CO]+,
20). Found, %: C 75.17, H 8.98. C37H52O6. Calculated,
%: C 74.96, H 8.84.
(20S)-15β-(4-benzoyloxybutyl)-20-hydroxymethyl-
2β,3β-isopropylidenedihydroxy-6,6-ethylenedioxy-
5α-pregna-16-ene (XI). Similarly, from 0.144 g
(0.24 mmol) of compound IX after the separation was
obtained 0.110 g (74%) of the alcohol XI, mp 146–
147°C (hexane). IR spectrum (film), cm–1: 2950, 2870,
1730, 1280, 1060, 760, 720. Mass spectrum, m/z, (I,
%): 623 ([M + 1]+, 100), 579 ([M + 1 – C2H4]+, 13),
565 ([M + 1 – (CH3)2CO]+, 15) . Mass spectrum, m/z,
(I, %) (MS2) (623): 579 ([M + 1 – C2H4]+, 100), 565
([M + 1 – (CH3)2CO]+, 79), 547 ([M + 1 – (CH3)2CO –
H2O]+, 19), 521 ([M + 1 – (CH3)2CO – (CH2)2O]+, 95),
503 ([M + 1 – (CH3)2CO – (CH2)2O – H2O]+, 75), 485
(17Z)-15β-(4-Benzoyloxybutyl)-2β,3β-isopropyl-
idenedioxy-6,6-ethylenedihydroxy-5α-pregna-17-
ene (IX). Similarly, from 0.189 g (0.31 mmol) of
compound VII after the separation was obtained
0.169 g (92%) of steroid IX. Colorless oil. IR
spectrum (film), cm–1: 2950, 2870, 1730, 1280, 1120,
720. Mass spectrum, m/z, (I, %): 593 ([M + 1]+, 100),
535 ([M + 1 – (CH3)2CO]+, 35). Mass spectrum, m/z,
(I, %) (MS2) (593): 549 ([M – Me – MeCH]+, 100),
535 ([M + 1 – (CH3)2CO]+, 38), 491 ([M – Me –
MeCH – (CH3)2CO]+, 49).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 10 2011

2150
BARANOVSKII, KHRIPACH
([M + 1 – (CH3)2CO –(CH2)2O – 2H2O]+, 41). Found,
%: C 72.92, H 8.93. C38H54O7. Calculated, %: C 73.28;
H 8.74.
7. Cerny, I., Pouzar, V., Lapcik, O., and Hampl, R., Coll.
Czech. Chem. Comm., 1997, vol. 62, no. 12, p. 1931.
8. Dionne, P., Ngatcha, B.T., and Poirier, D., Steroids,
1997, vol. 62, no. 10, p. 674.
9. Kirschning, A., Harmrolfs, K., Mennecke, K., Messin-
ger, J., Schoen, U., and Grela, K., Tetrahedron Lett.,
2008, vol. 49, no. 18, p. 3019.
10. Solvay Pharmaceuticals GmbH, Patent no. WO2008/
34796 (2008).
11. Solvay Pharmaceuticals GmbH, Patent no. US2008/
255075 (2008).
12. Baranovskii, A.V., Litvinovskaya, R.P., and Khripach, V.A.,
Zh. Org. Khim., 2004, vol. 40, no. 11, p. 1656.
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Zh. Org. Khim., 2007, vol. 43, no. 8, p. 1159.
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and Khripach, V.A., Bioorganich. Khim., 2007, vol. 33,
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(6R,20S)-20-Acetoxymethyl-6-(2-acetoxyethyloxy)-
15β-(4-benzoyloxybutyl)-2α,3α-isopropylidendioxy-
6-ethyl-5α-pregna-6-ene (XIIa). To a solution of
0.170 g of steroid XII (0.26 mmol) in methylene
chloride (3 ml) were added consecutively pyridine
(0.15 ml, 1.86 mmol) and acetic anhydride (0.15 ml,
1.47 mmol). The mixture was stirred at room
temperature for 24 h, diluted with methylene chloride
(15 ml), washed with saturated solutions of NaHCO3
and then NaCl, and dried over Na2SO4. After solvent
evaporation, the residue was purified by chromato-
graphy on a silica gel column (EtOAc–toluene, 20:80),
which gave 0.114 g of compound XIIa (60%).
Colorless oil. IR spectrum (film), cm–1: 2950, 2880,
1755, 1735, 1280, 1250, 1240, 720. Mass spectrum,
m/z, (I, %), m/z: 633 ([M + 1 – AcOCH2CH2OH]+, 7),
575 ([M + 1 – AcOCH2CH2OH – (CH3)2CO]+, 64),
557 ([M + 1 – AcOCH2CH2OH – (CH3)2CO – H2O]+,
27), 515 ([M + 1 – AcOCH2CH2OH – (CH3)2CO –
AcOH]+, 100). Mass spectrum, m/z, (I, %) (MS2)
(736): 721 ([M – Me]+, 30), 678 ([M – (CH3)2CO]+,
41), 676 ([M – AcOH]+, 28), 650 ([M – AcOCH=CH2]+,
100), 618 ([M – AcOH – (CH3)2CO]+, 65).
17. Adamczyk, M., Chen, Y.Y., Johnson, D.D., and
Reddy, R.E., Tetrahedron, 1997, vol. 53, no. 38, p. 12855.
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ACKNOWLEDGMENTS
no. 2, p. 159.
This work was performed as part of research on the
grant MNTTs B-1332 and GPOFI “Biorational
pesticides-2, State registration no. 20093013.
21. Watanabe, B., Yamamoto, S., Sasaki, K., Nakagawa, Y.,
and Miyagawa, H., Tetrahedron Lett., 2004, vol. 45,
no. 13, p. 2767.
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lich, P.M., and Uskokovic, M., Helv. Chim. Acta, 1981,
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