Synthesis and biological activity of some 8α-analogs of steroidal estrogens

Article abstract of DOI:10.1134/S1070428013040180

8α-Analogs of steroidal estrogens containing a methyl group on C ¹ or an oxo group on C⁶ were synthesized with a view to obtain compounds exhibiting selective biological activity, and their steric structure was studied. As shown with 1,3-O-dimethyl-8α-estrone as an example, such compounds in solution can exist as two conformers, whereas the oxo group on C⁶ almost does not affect conformation of the modified derivative as compared to the parent structure. Some newly synthesized compounds exhibited hypocholesterolemic activity in combination with reduced uterotropic effect, which is important for the design of drugs for the treatment of atherosclerosis. 6-Oxo-8α-analogs showed osteoprotective activity, so that introduction of an oxo group into the 6-position is promising from the viewpoint of hormone replacement therapy.

Full text of DOI:10.1134/S1070428013040180

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 4, pp. 603–609. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © S.N. Morozkina, Sh.N. Abusalimov, S.I. Selivanov, A.G. Shavva, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49,
No. 4, pp. 619–625.
Dedicated to the 100th Anniversary of Corresponding Member
of the Russian Academy of Sciences A.A. Petrov
Synthesis and Biological Activity of Some 8α-Analogs
of Steroidal Estrogens
S. N. Morozkina, Sh. N. Abusalimov, S. I. Selivanov, and A. G. Shavva
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: AGShavva@yandex.ru
Received February 6, 2013
Abstract—8α-Analogs of steroidal estrogens containing a methyl group on C1 or an oxo group on C6 were
synthesized with a view to obtain compounds exhibiting selective biological activity, and their steric structure
was studied. As shown with 1,3-O-dimethyl-8α-estrone as an example, such compounds in solution can exist as
two conformers, whereas the oxo group on C6 almost does not affect conformation of the modified derivative as
compared to the parent structure. Some newly synthesized compounds exhibited hypocholesterolemic activity
in combination with reduced uterotropic effect, which is important for the design of drugs for the treatment of
atherosclerosis. 6-Oxo-8α-analogs showed osteoprotective activity, so that introduction of an oxo group into the
6-position is promising from the viewpoint of hormone replacement therapy.
DOI: 10.1134/S1070428013040180
Modified steroidal estrogens are widely used in
medical practice as drugs for hormone replacement
therapy [1–3] despite serious side effects. Among the
latter, the most harmful are increased risks of cancer
[4, 5], thrombosis [6, 7], stroke [8], cardiovascular
diseases [9], and other complications. It is significant
that increased risk of thrombosis was observed not
only for estrogen therapy but also for estrogen-receptor
modulators [10]. The most serious side effect is
increased risk of tumors. It is believed that the main
factor responsible for the carcinogenicity of estrogens
is activation of proliferative processes in target organs
[11, 12] and formation of DNA-damaging metabolites
[13, 14]. In the latter case, irreversible depurination of
DNA occurs with participation of C1 in the steroidal
estrogen molecule. The above stated stimulates search
for new compounds with improved biological prop-
erties on the basis of steroidal estrogens.
Obviously, introduction of an inert substituent into
position 1 of steroidal estrogen molecule should
prevent DNA damage. We previously synthesized
17β-acetoxy-1-methyl-3-methoxy-8α-estra-1,3,5(10)-
triene (I) [15] and determined its structure in the crys-
talline state [16] and in solution [15]. The calculated
(ab initio, PM3, MM+) geometric parameters of mole-
cule I were consistent with those found by X-ray anal-
ysis [15]. Docking of other 1-methyl-8α-analogs of
steroidal estrogens into the ligand-binding pocket of
nuclear estrogen α-receptor [17] showed that such
analogs should exhibit reduced proliferative activity.
As model structures for studying biological activity we
selected compounds II–IV.
There are published data indicating that metabolic
hydroxylation at the C6-position of the estrogen mole-
cule causes damage to DNA [18]. It was interesting to
synthesize 6-oxo-8α-analogs of steroidal estrogens and
O
OAc
OAc
O
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
MeO
MeO
I
II
III
IV
603

MOROZKINA et al.
604
OAc
O
Me
H
Me
H
H
H
H
O
H
O
MeO
MeO
V
VI
examine their biological properties. It was presumed
that the hydroxy group arising from their metabolic
hydroxylation at the C4-position should be involved in
strong intramolecular hydrogen bond with the C6=O
carbonyl group, which should reduce its reactivity and
hence carcinogenic effect. Therefore, compounds V
and VI were selected as the next group of model
structures. Scheme 1 illustrates the synthesis of model
steroidal estrogen analogs.
Compound II was synthesized by condensation of
isothiuronium salt VII [19] with 2-methylcyclopen-
tane-1,3-dione, followed by cyclodehydration of
8,14-seco derivative VIII, catalytic hydrogenation of
estrapentaene IX over Raney nickel in benzene, and
oxidation with the Sarett reagent. Unlike the procedure
proposed previously [19], our version of synthesis of
estrapentaene IX did not include purification of inter-
mediate product VIII; as a result, the yield of IX was
improved from 56 [19] to 69%. Steroid II was thus
obtained in ~36% yield. Its structure was proved by
1
complete assignment of all signals in the H and 13C
NMR spectra with the aid of a combination of shift
correlation techniques DQF-COSY [20], J-COSY [21],
HSQC [22, 23], and NOESY [24].
Optimization of the geometric parameters of mole-
cule II by the PM3 method [25] revealed two possible
conformers A and B (Fig. 1) differing by the con-
formation of the B ring; conformer A is thermody-
namically more stable.
3
The coupling constant J6β,7α = 2.7 Hz in molecule
II (20°C) is higher by 0.4 Hz than that in steroid XI
having no substituent on C1 (Fig. 2). The coupling con-
stants 3J6β,7β for conformers A and B of steroids II and
XI are equal within the experimental error (±0.1 Hz):
5.1 (A) and 5.0 Hz (B). Small differences in the scalar
3J6β,7α values led us to suppose that steroid II in solu-
Scheme 1.
O
NH2
O
Me
O
Me
S
NH2
AcO–
Me
Me
O
HCl–EtOH
Me
Me
O
MeO
MeO
Me
MeO
H
VII
VIII
IX
O
OAc
Me
H
Me
Me
(1) H2, Ni
(2) CrO3–Py
(1) NaBH4
(2) Ac2O–Py
H
H
H
H
MeO
MeO
II
I
O
O
OAc
Me
Me
Me
H
Me
Me
Me
(1) H2, Ni
(2) CrO3–Py
(1) NaBH4
(2) Ac2O–Py
H
H
H
H
H
MeO
MeO
MeO
X
III
IV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SOME 8α-ANALOGS
605
O
Me
Me
H
H
H
MeO
II
A
B
Fig. 1. Conformational equilibrium of steroid II. Calculated (PM3) coupling constants 3J6β,7α (Hz) are given.
16.6 Hz
~0.9 Hz
4.8 Hz
3.7 Hz
II
II
60°C
5.0 Hz
2.7 Hz
O
Me
H
~0.3 Hz
H
20°C
20°C
H
5.1 Hz
2.3 Hz
MeO
XI
XI
1
2
3
4
5
6
7
8
2.88
2.84
2.80
δ, ppm
Fig. 2. Multiplet structure of the 6β-H signal in the 1H NMR spectra of compounds XI and II at 20°C and evolution of that signal in
the spectrum of II with rise in temperature to 60°C.
tion exists in fast (on the NMR time scale) conforma-
conformer is 4.1 Å, and in the minor conformer, 1.9 Å,
whereas the distances between 9α-H and 12α-H in both
conformers are almost similar [2.62 (A) and 2.68 Å
(B)]. The ratio of the intensities of the 9α/12α and
6β/11β cross-peaks for conformer A should be 14.5:1,
and for conformer B, 1:10. The experimental intensity
of the 6β/11β cross-peak is approximately thrice as
high as that calculated for the major conformer, which
provides an additional support to the existence of con-
formational equilibrium. These results can be used to
perform docking of analogous compounds to ligand-
binding pockets of various proteins.
tional equilibrium A
B involving inversion of the
B ring (pseudochair
pseudoboat, Fig. 3).
This assumption was confirmed by studying tem-
3
perature dependence of J6β,7α. Rise in temperature
from 20 to 60°C was accompanied by increase of
3J6β,7α to 3.7 Hz and simultaneous small decrease of
3J6β,7β to 4.8 Hz (Fig. 2). The geminal coupling con-
2
stant J6β,6α remained unchanged (16.6 Hz), and the
sum of all scalar coupling constants (the distance be-
tween lines 1 and 8 in Fig. 2) increased by ~0.9 Hz.
The observed temperature dependence clearly indicat-
ed increase in the population of minor conformer B
of II, where the 6β-H proton occupies axial position.
By oxidation of steroid XII [25] with chromi-
um(VI) oxide we obtained compound V whose hydrol-
ysis and subsequent oxidation of the alcohol thus
formed afforded diketo steroid VI (Scheme 2). The
Thus the conformational equilibrium A
II may be regarded as proved.
B of steroid
1
According to the PM3 calculations, the distance
between the 6β-H and 11β-H protons in the major
structure of compounds V and VI was proved by H
1
and 13C NMR. The H and 13C chemical shifts of the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

MOROZKINA et al.
606
Scheme 2.
OAc
OAc
O
Me
H
Me
H
Me
H
H
H
H
H
H
O
H
O
MeO
MeO
MeO
XII
V
VI
compounds with an oxo group on C6 and without it
were almost similar, indicating that the C6=O group
does not affect their conformation.
Biological testing of 1-methyl-substituted steroidal
derivatives revealed their hypocholesterolemic activity
in combination with weak proliferative effect; there-
fore, these compounds attract interest from the view-
point of design of drugs for the treatment of cardiovas-
cular diseases. 6-Oxo analogs showed osteoprotective
effect, which is important for hormone replacement
therapy.
was used for column chromatography. The mass spec-
tra were recorded on an MKh-1321 instrument (ion
source temperature 200–210°C). The NMR spectra
were measured at 295 K on a Bruker DPX-300 spec-
trometer at 300.130 (1H) and 75.468 MHz (13C) from
solutions of 5–7 (1H) or 30–50 mg (13C) of compounds
in 0.6 ml of CDCl3; the chemical shifts were deter-
mined relative to tetramethylsilane by assigning stand-
ard values (δ 7.26, δC 76.90 ppm) to the solvent signals
(CDCl3–CHCl3, 99.9:0.1) with an accuracy of no less
1
than ±0.01 ppm. The H–1H coupling constants were
measured with an accuracy of ±0.02 Hz after addi-
tional processing of the spectral lines by the Lorentz–
Gauss transformation. The principal parameters for
NMR data acquisition and processing are given below.
EXPERIMENTAL
The progress of reactions was monitored by TLC
on Silufol plates using hexane–ethyl acetate (4:1 or
3:1) as eluent. Silica gel Merck 60 (0.040–0.063 mm)
1H NMR. Time domain TD = 32 K, spectral width
SW = 2.4 kHz, number of scans NS = 128, relaxation
1.9 Å
4.1 Å
A
B
8α
14α 11α 11β 12α
δ, ppm
NOESY
2.50
9α
6α
9α/12α
6β/11β
6β
3.00
6β/7α,7β
3.00
2.50
2.00
1.50
δ, ppm
Fig. 3. Conformational equilibrium of steroid II and a fragment of its NOESY spectrum (mixing time 0.5 s); the 6β/11β cross peak is
enclosed in a circle. The distances between the 6β-H and 11β-H protons in conformers A and B are shown with double-ended arrows.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SOME 8α-ANALOGS
607
delay D1 = 3 s; Lorentz–Gauss parameters: LB =
–2 Hz, GM = 0.2; zero-filling: SI = 64 or 128 K.
(1:8). Yield 1.8 g (69%), mp 99–100°C; published
data [19]: mp 97.5–98.5°C. The product showed no
depression of the melting point on mixing with an
authentic sample; the 1H NMR spectra of both samples
were identical to each other. Found, %: C 81.70;
H 7.90. C21H24O2. Calculated, %: C 81.78; H 7.84.
13C NMR. TD = 32 K, SI = 64 K, SW = 16.5 kHz,
NS = 512, D1 = 5 s, exponential weighting function
equivalent to a line broadening LB of 3 Hz.
2D COSY-90. TD2 = 512, SW1 = SW2 = 2.4 kHz,
NS = 4 for each of 256 t1 increments, D1 = 3 s, 512×
512 spectral matrix, apodization function for the coor-
dinates t1 and t2: sin(pt/tmax); absolute value spectrum.
2D COSY-DQF. TD2 = 2 K, SW1 = SW2 = 2.4 kHz,
NS = 16 for each of 512 t1 increments, D1 = 3 s, phase-
sensitive detection with time-proportional phase
increment (TPPI); apodization function sin(pt/tmax);
2048×1024 spectral matrix.
3-Methoxy-1-methyl-8α-estra-1,3,5(10)-trien-17-
one (II). Raney nickel, 8.0 g, was added to a solution
of 10.14 g (0.034 mol) of compound IX in 270 ml of
benzene, hydrogen was supplied to an initial pressure
of 150 atm, and the mixture was hydrogenated at 40–
90°C until the amount of absorbed hydrogen exceeded
by a factor of 300 that necessary for the hydrogenation
of two double bonds and keto group in the initial
compound. The catalyst was filtered off, the solvent
was distilled off on a rotary evaporator, and the residue
was dissolved in 100 ml of pyridine. The solution was
cooled to 10°C, and the Sarett reagent prepared from
8.3 g of chromium(VI) oxide and 200 ml of pyridine
was added. The mixture was left to stand for 24 h at
room temperature, the inorganic precipitate was
filtered off and repeatedly washed with diethyl ether,
the pyridine filtrate and the ether washings were com-
bined, washed with three portions of water, 10% aque-
ous HCl, a solution of sodium acetate, and several
portions of water until neutral washings, dried over
sodium sulfate, and evaporated on a rotary evaporator,
and the residue was crystallized from ethanol. Yield
13C–1H HETCORR. TD = 1 K, SW1 = 1.2 kHz,
SW2 = 3.5 kHz, NS = 56 for each of 256 t1 increments,
D1 = 2 s, direct heteronuclear coupling evolution
delays D2 = 3.7, D3 = 2.5 ms; exponential apodization
function for t2 (LB = 3 Hz) and sin(pt/tmax + p/2) for t1;
1024×512 spectral matrix of absolute values.
COLOC. TD2 = 1 K, SW1 = 2.4, SW2 = 3.5 kHz;
NS = 256 for each of 128 t1 increments; D1 = 1 s;
heteronuclear coupling evolution delays (nJCH, n =
2, 3): D6 = 62.5, D8 = 41.7 ms; apodization function
sin(pt/tmax) for t2 and sin(pt/tmax + p/2) for t1; 1024×
512 spectral matrix of absolute values.
NOESY. TD2 = 1 K, SW1 = SW2 = 2.4 kHz, NS =
16 for each of 256 t1 increments, D1 = 2 s, mixing time
D8 = 0.5, 1.0 s; phase-sensitive detection with TPPI,
apodization function sin(pt/tmax + p/2), 1024×
512 spectral matrix.
1
3.68 g (36%), mp 137–139°C. H NMR spectrum, δ,
ppm: 1.05 s (3H, C18H3), 1.45 (12α-H), 1.52 (11β-H),
1.81 (12β-H), 1.84 (15β-H), 1.84 (7β-H), 1.84 (7α-H),
1.85 (11α-H), 1.94 (14α-H), 2.04 (16β-H), 2.10
(15α-H), 2.15 (8α-H), 2.30 (1-CH3), 2.50 (16α-H),
2.70 (9α-H), 2.70 (6β-H), 2.87 (6α-H), 6.49 (4-H),
6.59 (2-H). 13C NMR spectrum, δC, ppm: 137.49 (C1),
114.25 (C2), 157.01 (C3), 111.14 (C4), 137.35 (C5),
31.43 (C6), 21.25 (C7), 38.94 (C8), 39.66 (C9), 131.35
(C10), 24.81 (C11), 32.11 (C12), 47.16 (C13), 48.93 (C14),
21.32 (C15), 35.62 (C16), 220.43 (C17), 16.46 (C18),
18.94 (1-CH3), 55.97 (CH3O). Mass spectrum, m/z
(Irel, %): 298 (100), 283 (2.0), 213 (55.0), 200 (19.5),
187 (7.5), 174 (51.5), 159 (16.5). Found, %: C 80.65;
H 8.90. C20H26O2. Calculated, %: C 80.50; H 8.78.
All isolated compounds were racemic.
1-Methyl-3-methoxyestra-1,3,5(10),8,14-penta-
en-17-one (IX). Finely powdered 2-methylpentane-
1,3-dione, 5.0 g (0.004 mol), was added to a 3.0 g
(8.9 mmol) of isothiuronium salt VII [19] in 50 ml of
aqueous ethanol (1:1), the mixture was stirred for 24 h
at 25°C, and the solvent was removed under reduced
pressure. The residue was dissolved in 50 ml of metha-
nol, 3 ml of 37% aqueous HCl was added, and the
mixture was heated for 30 min under reflux in an argon
atmosphere, left to stand for 24 h at 10°C, poured into
300 ml of water, and extracted with 300 ml of chloro-
form. The extract was washed thrice with equal
portions of 3% aqueous sodium acetate, dried over
sodium sulfate, and passed through a layer of alumi-
num oxide (50 g, Brockmann activity grade III). The
solvent was removed under reduced pressure, and the
residue was crystallized from chloroform–methanol
3-Methoxy-1-methyl-8α-estra-1,3,5(10)-trien-
17β-yl acetate (I). Sodium tetrahydridoborate, 0.2 g,
was added at room temperature to a solution of 0.7 g
(2.34 mmol) of compound II in 25 ml of dioxane–
water (10:1), and the mixture was stirred for 1.5 h.
After appropriate treatment, the reduction product was
dissolved in 5 ml of pyridine, 15 ml of acetic anhy-
dride was added, and the mixture was left to stand for
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 4 2013

MOROZKINA et al.
608
24 h at room temperature. After appropriate treatment,
the product was crystallized from ethanol. Yield 0.56 g
(71%), mp 126.5–128.5°C. 13C NMR spectrum, δC,
ppm: 137.8 (C1), 114.2 (C2), 157.0 (C3), 111.1 (C4),
137.6 (C5), 31.6 (C6), 20.6 (C7), 38.0 (C8), 39.9 (C9),
131.9 (C10), 25.1 (C11), 37.5 (C12), 41.9 (C13), 47.8
(C14), 22.3 (C15), 26.8 (C16), 82.5 (C17), 13.7 (C18),
19.0 (1-CH3), 54.9 (CH3O), 21.1 (CH3CO), 171.0
(C=O). Mass spectrum, m/z (Irel, %): 342 (100) [M]+,
282 (21.2), 267 (5.2), 253 (16.6), 213 (5.7), 200 (47.0),
187 (17.2), 174 (3.1), 159 (15.0). Found, %: C 76.89;
H 8.85. C22H30O3. Calculated, %: C 77.16; H 8.83.
M 342.48.
(C10), 24.48 (C11), 32.88 (C12), 48.01 (C13), 48.22
(C14), 25.51 (C15), 26.25 (C16), 37.59 (C17), 215.25
(C17a), 19.05 (C18), 18.66 (1-CH3), 54.78 (CH3O).
Mass spectrum, m/z (Irel, %): 312 (100), 298 (4), 244
(5), 227 (5), 213 (75), 187 (14.5), 174 (32), 159 (12).
Found, %: C 80.65; H 9.21. C21H28O2. Calculated, %:
C 80.73; H 9.03.
3-Methoxy-1-methyl-D-homo-8α-estra-1,3,5(10)-
trien-17a,β-yl acetate (IV) was synthesized from
0.5 g (1.6 mmol) of III as described above for I. The
product was recrystallized from methanol. Yield 0.45 g
1
(79%), mp 138–141°C. H NMR spectrum, δ, ppm:
0.99 (C18H3), 2.05 (CH3CO), 2.29 (1-CH3), 3.75
(CH3O), 6.47 (4-H), 6.59 (2-H). Found, %: C 77.61;
H 9.14. C23H32O3. Calculated, %: C 77.49; H 9.05.
3-Methoxy-1-methyl-D-homoestra-1,3,5(10),8,14-
pentaen-17a-one (X). Finely powdered 2-methylcy-
clohexane-1,3-dione, 10.0 g (0.08 mol), was added to
10.0 g (0.03 mol) of isothiuronium salt VII [19] in
200 ml of aqueous ethanol (1:1), and the mixture was
stirred for 48 h at 30°C. The solvent was removed
under reduced pressure, the residue was dissolved in
250 ml of ethanol, 10 ml of 37% aqueous HCl was
added, and the mixture was heated for 30 min under
reflux and left to stand for 24 h at 10°C. The precip-
itate was filtered off and dissolved in 100 ml of chloro-
form, the solution was washed with water until neutral
washings, dried over sodium sulfate, and passed
through a layer of alumina (50 g, Brockmann activity
grade III), the solvent was removed under reduced
pressure, and the residue was crystallized from chloro-
form–methanol (1:8). Yield 5.2 g (52%), mp 99–
100°C; published data [19]: mp 97.5–98.5°C. The
product showed no depression of the melting point on
3-Methoxy-D-homo-8α-estra-1,3,5(10)-trien-
17aβ-yl acetate (XII) was synthesized according to
the procedure described in [25], mp 172.5–173.5°C;
1
published data [25]: mp 172.5–174.0°C. H NMR
spectrum, δ, ppm: 0.98 (C18H3), 1.25 (12α-H), 1.28
(15α-H), 1.46 (16α-H), 1.47 (14α-H), 1.52 (17β-H),
1.58 (11β-H), 1.62 (15β-H), 1.64 (11α-H), 1.66
(12β-H),1.69 (7β-H), 1.71 (17α-H), 1.75 (7α-H), 1.81
(16β-H), 1.88 (8α-H), 2.04 (CH3CO), 2.62 (6α-H),
2.64 (9α-H), 2.78 (6β-H), 3.77 (CH3O), 4.51 (17aα-H),
6.60 (4-H), 6.72 (2-H), 7.03 (1-H). Found, %: C 77.12;
H 8.87. C22H30O3. Calculated, %: C 77.16; H 8.83.
3-Methoxy-6-oxo-D-homo-8α-estra-1,3,5(10)-tri-
en-17aβ-yl acetate (V). A solution of 7.6 g of sodium
dichromate dihydrate in a mixture of 90 ml of acetic
acid and 45 ml of acetic anhydride was added drop-
wise to a solution of 4.5 g (0.013 mol) of compound
XII in 40 ml of glacial acetic acid. The mixture was
stirred for 5 h at 65°C, a solution of 3.7 g of the same
oxidant in 20 ml of acetic acid was added, and the
mixture was stirred for 6 h at that temperature, poured
into 1 l of water, and extracted with diethyl ether. After
appropriate treatment, the product was purified by
flash chromatography on silica gel, followed by crys-
tallization from methanol. Yield 0.5 g (14%), mp 175–
1
mixing with an authentic sample [19]; the H NMR
spectra of both samples were identical to each other.
Found, %: C 81.70; H 7.90. C21H24O2. Calculated, %:
C 81.78; H 7.84.
3-Methoxy-1-methyl-D-homo-8α-estra-1,3,5(10)-
trien-17a-one (III) was synthesized by catalytic
hydrogenation of 4.32 g (0.014 mol) of compound X,
followed by oxidation of the reduction product with
the Sarett reagent as described above for compound II.
1
176°C. H NMR spectrum, δ, ppm: 1.01 (C18H3), 1.28
1
Yield 1.40 g (32%), mp 121–123°C. H NMR spec-
trum, δ, ppm: 1.19 (C18H3), 1.47 (15α-H), 1.48
(11β-H), 1.70 (16α-H), 1.75 (12β-H), 1.76 (14α-H),
1.77 (11α-H), 1.84 (7β-H), 1.86 (12α-H), 1.87 (7α-H),
1.92 (8α-H), 2.04 (15β-H), 2.08 (16β-H), 2.25
(17α-H), 2.29 (1-CH3), 2.63 (17β-H), 2.65 (9α-H),
2.66 (6α-H), 2.86 (6β-H), 3.75 (CH3O), 6.47 (4-H),
6.59 (2-H). 13C NMR spectrum, δC, ppm: 137.27 (C1),
114.16 (C2), 156.92 (C3), 110.96 (C4), 136.99 (C5),
31.58 (C6), 21.12 (C7), 41.22 (C8), 39.22 (C9), 131.56
(15α-H), 1.30 (12α-H), 1.43 (16α-H), 1.48 (14α-H),
1.53 (17β-H), 1.55 (15β-H), 1.68 (11β-H), 1.73
(12β-H), 1.73 (17α-H), 1.74 (11α-H), 1.82 (16β-H),
2.04 (CH3CO), 2.37 (8α-H), 2.58 (7α-H), 2.69 (7β-H),
2.80 (9α-H), 3.81 (CH3O), 4.51 (17aα-H), 7.08 (2-H),
7.17 (1-H), 7.44 (4-H). Found, %: C 74.05; H 8.12.
C22H28O4. Calculated, %: C 74.13; H 7.92.
3-Methoxy-D-homo-8α-estra-1,3,5(10)-triene-
6,17a-dione (VI). A solution of 2.0 g of sodium hy-
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SYNTHESIS AND BIOLOGICAL ACTIVITY OF SOME 8α-ANALOGS
609
6. Makatsariya, A.D., Saidova, R.A., and Bitsadze, V.O.,
Gormonal’naya kontratseptsiya i trombofilicheskie so-
stoyaniya (Hormonal Contraception and Thrombophilic
States), Moscow: Triada-X, 2004.
droxide in 18 ml of methanol was added to a solution
of 0.7 g (1.96 mmol) of compound V in 25 ml of
benzene. The mixture was heated for 6 h under reflux
on stirring, cooled to room temperature, and poured
into 200 ml of water. Excess alkali was neutralized
with 50% acetic acid to weakly acidic reaction, the
mixture was extracted with chloroform (3×10 ml), the
combined extracts were washed with a 3% solution of
sodium carbonate and with water until neutral wash-
ings, dried over sodium sulfate, filtered from the dry-
ing agent, and evaporated under reduced pressure. The
residue was dissolved in 10 ml of anhydrous acetone,
1.7 g of Jones reagent (prepared from 1.0 g of chromi-
um trioxide and 0.7 g of 20% sulfuric acid) was added
under vigorous stirring and cooling with an ice–water
mixture, and the mixture was stirred for 30 min at
room temperature and poured into 100 ml of cold
water. The precipitate was filtered on a Schott filter,
washed with water until neutral washings, dried under
reduced pressure, and recrystallized from methanol.
Yield 0.37–0.39 g (60–63%), mp 182–184°C. 1H NMR
spectrum, δ, ppm: 1.20 (C18H3), 1.49 (15α-H), 1.66
(16α-H), 1.71 (14α-H), 1.77 (11β-H), 1.79 (12α-H),
1.79 (12β-H), 1.85 (11α-H), 1.99 (15β-H), 2.10
(16β-H), 2.26 (17α-H),2.47 (8α-H), 2.62 (17β-H), 2.70
(7α-H), 2.74 (7β-H), 2.77 (9α-H), 3.80 (CH3O), 7.09
(2-H), 7.20 (1-H), 7.45 (4-H). 13C NMR spectrum, δC,
ppm: 130.02 (C1), 122.26 (C2), 158.53 (C3), 108.64
(C4), 131.96 (C5), 197.70 (C6), 37.05 (C7), 38.80 (C8),
41.21 (C9), 140.72 (C10), 26.21 (C11), 32.57 (C12),
47.71 (C13), 47.33 (C14), 25.08 (C15), 26.05 (C16),
37.64 (C17), 214.99 (C17a), 18.83 (C18), 55.40 (CH3O).
Found, %: C 77.01; H 7.75. C20H24O3. Calculated, %:
C 76.89; H 7.74.
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St. Petersburg State University) for biological testing
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