Partial modifications of hydroxy groups in 5-methyl-5β-estr-9-ene derivatives

Article abstract of DOI:10.1135/cccc19960276

In compounds of the Westphalen type the substituent in position 6 has been removed: the 6β-hydroxyl in 3β, 17β-dibenzoyloxy-5-methyl-5β-estr-9-en-6β-ol (1) by oxidation to ketone 2 and Huang Minion reduction, the 6β-chlorine atom in 3β-acetoxy-6β-chloro-5

Full text of DOI:10.1135/cccc19960276

276
Kasal, Budesinsky:
PARTIAL MODIFICATIONS OF HYDROXY GROUPS
IN 5-METHYL-5β-ESTR-9-ENE DERIVATIVES*
Alexander KASAL and Milos BUDESINSKY
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Received September 15, 1995
Accepted November 14, 1995
In compounds of the Westphalen type the substituent in position 6 has been removed: the 6β-hy-
droxyl in 3β,17β-dibenzoyloxy-5-methyl-5β-estr-9-en-6β-ol (1) by oxidation to ketone 2 and Huang
Minlon reduction, the 6β-chlorine atom in 3β-acetoxy-6β-chloro-5-methyl-5β-estr-9-en-17-one (13)
by reduction with tributyltin hydride. Androstenedione, testosterone and methyltestosterone analogues
4, 5, and 16, respectively, were prepared from 3β,17β-dihydroxy-5-methyl-5β-estr-9-ene (3) by par-
tial oxidation or partial acylation followed by oxidation. Alternatively, these derivatives were pre-
pared from compound 13 without the need of partial transformations.
Key words: Steroids; Conformational analysis; Hormone analogues.
The Westphalen rearrangement of steroid 5-hydroxy derivatives2,3 affords 5β-steroids
with methyl group in position 5 which are interesting from the viewpoint of biological
activities. Thus, e.g., a progesterone analogue of this type (5-methyl-19-nor-5β-pregn-
9-ene-3,20-dione4) affects reproduction5: the compound induces abort in rabbits, how-
ever, its effect is not antigestagenic6 because it is not bonded to the gestagenic
receptor7. With this in mind, we decided to prepare similar analogues of other sex
hormones – androgens, in which the position of the ∆4-double bond and the angular
10β-methyl group is interchanged in an analogous way. In the present study we de-
scribe the preparation and properties of such analogues of androstenedione, testosterone
and 17-methyltestosterone.
As the starting compound for their preparation we have chosen the easily accessible8
3β,17β-dibenzoyloxy-5-methyl-5β-estr-9-en-6β-ol (1) (see Scheme 1) which was oxidized
to give ketone 2. Huang Minlon reduction of compound 2 with simultaneous hydrolysis
of both the benzoate groups afforded derivative 3 with free hydroxy groups in positions
1
3 and 17. As shown by the H NMR spectrum (Table I), the 3-hydroxy group was axial
(in an analogous way, Mousseron-Canet9 proved the axial character of 3β-hydroxyl in
* Part CCCLXXX in the series On Steroids; Part CCCLXXIX: see ref.1.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

On Steroids
277
2
R
OCOC H
6
5
1
R
C H COO
C H COO
6
5
6
5
O
OH
1
2
R
R
2
1
17
19
H
H
OCOC H
6
5
OH
O
O
OH
O
HO
4
3
O
OR
RO
O
5,
6, R = H
R = H
R = CH CO
10, R = CH CO
11,
3
3
R = (CH ) CCO
12,
3 3
2
O
OR
1
CH COO
R O
3
Cl
1
2
R
H
R
13
7
CH CO
3
8
9
CH CO H
3
CH CO CH CO
3
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

278
Kasal, Budesinsky:
compounds similar to the 6β-alcohol 1) which offered the possibility of partial transfor-
mations of the compound.
Partial oxidation of the diol 3 was realized in several ways: with N-bromoacetamide
or N-bromosuccinimide, as well as by Oppenauer or Jones oxidation. Invariably, the
axial 3β-hydroxyl was oxidized faster than the quasiequatorial one in position 17β.
Preparatively the simplest method was the oxidation of compound 3 with one equivalent of
Jones reagent in dilute acetone solution at low temperatures which gave ketone 5 in
47% yield. In addition, we obtained the 17-ketone 6 (12%) and diketone 4 (19%); some
amount of the starting compound (22%) was recovered. The structure of the products
1
was determined on the basis of their H NMR and IR spectra (Table I and Expe-
rimental, respectively).
The selective acylation of the hydroxy groups in compound 3 was proved by acety-
lation with acetic anhydride in a mixture of pyridine and toluene. The equatorial 17β-
hydroxyl was attacked preferentially and the acetate 7 was obtained in 37% yield
whereas its isomer 8 in only 7% yield (the reaction mixture also contained 45% of the
starting compound and 10% of the diacetate 9). The structures were assigned on the
TABLE I
1
Characteristic parameters of 200 MHz H NMR spectra of compounds 2–16 in CDCl3
Compound 13β-Mea 5β-Mea H-3b
H-17c
Other protons
2
3
1.05
0.86
0.89
0.88
1.00
0.91
0.86
0.91
0.92
0.99
0.94
1.01
0.99
0.99
0.99
1.49
1.25
1.05
1.02
1.29
1.25
1.17
1.17
1.01
1.19
1.01
1.28
1.21
1.18
1.01
5.43
4.79
–
4.89 7.52 m, 8.05 m (C6H6)
3.64
4
–
5
–
3.65
6
4.14
4.12
3.64
4.60
–
–
7
4.60 2.04 s (OAc)
5.07 2.06 s (OAc)
5.07 2.04 s (2 × OAc)
4.62 2.04 s (OAc)
8
9
10
11
12
13
14
15
16
5.06
–
–
2.06 s (OAc)
4.58 1.21 s (C(CH3)3)
5.09
4.15
5.08
–
–
–
–
–
2.07 s (OAc); 3.97 dd (H-6; J = 12.5 and 3.8 Hz)
1.27 s (17-Me)
1.20 s (17-Me); 2.06 s (OAc)
1.22 s (17-Me)
a Singlet, 3 H. b Quintet, ΣJ = 15 Hz. c Triplet, J = 8 Hz.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

On Steroids
279
basis of characteristic chemical shifts of the CHOR signals in 1H NMR spectrum before
and after the acylation.
Both the monoacetates 7 and 8 were oxidized to the isomeric acetoxy ketones 10 and
11 which were hydrolyzed to give the above-described hydroxy ketones 5 and 6. The
former isomer represents the desired analogue of testosterone and was characterized by
conversion into the corresponding pivalate 12.
Since the observed difference in reactivity of the hydroxy groups in diol 3 was sur-
prisingly small, we tried an alternative way, starting with the 6β-chloro derivative 13
(ref.10) which already bears different functionalities in the positions 3 and 17. The
chlorine atom in compound 13 was removed by reduction with tributyltin hydride11 to
give the above-mentioned ketone 11 in 96% yield.
For the preparation of the corresponding 17-methyltestosterone analogue 16 the reac-
tion of ketone 11 with methyllithium seemed the method of choice. It is known, how-
ever, that with easily enolizable 17-ketones the reaction gives considerable amount of
lithium enolate products and therefore catalysis with cerium chloride, which favours
the desired addition to the carbonyl group, is recommended12. We performed the reac-
tion of ketone 11 with methylmagnesium iodide in boiling benzene and the addition to
the carbonyl proceeded in high yield even in the absence of cerium chloride (see
Scheme 2): the 17-methyl derivative 14 crystallized directly from benzene in 84%
yield, a further amount (9%) being obtained on chromatography of the mother liquors.
On the other hand, the use of methyllithium in ether (also in the absence of cerium
catalyst) resulted in recovery of 39% of the starting ketone (because of limited solu-
bility, the chromatographic separation was performed after conversion into the acetates
11 and 15). Compound 14 was then oxidized with Jones reagent to give the desired
analogue 16.
For the 6β-hydroxy derivative 1 and the 6-deoxy derivative 8 we tried to find the
energetically most advantageous conformations of the rings A and B using the MOPAC
method (ref.13). The results were compared with the experimental NMR data. For the
ring A the calculations gave invariably a chair form with axial substituent in position 3.
OH
OH
11
O
RO
14,
15,
16
R = H
R = CH3CO
SCHEME 2
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280
Kasal, Budesinsky:
The best conformation of the ring B appeared to be a half-chair form HC7 (Fig. 1)
6
whose geometry was not seriously affected by substitution in position 6β. The alterna-
6
tive half-chair form HC7 (Fig. 1) in the 6β-hydroxy derivative 1 is apparently desta-
bilized by steric interaction of the axial 6β-hydroxyl with the 5β-methyl group (the
calculated energy difference between both forms being about 13 kJ). For the 6-deoxy
TABLE II
Interproton torsion angles of ring B in half-chair conformation and the observed 3J(H,H) in 6β-hy-
droxy derivatives 1, 17–19 and 6-deoxy derivative 8
Interproton torsion angles, °
J, Hz
for 1, 17–19 and 8
from electron
from MOPAC (for 1 and 8)
diffractiona
Protons
6β-OH
6-deoxy
cyclohexene
6β-OH 6-deoxyb
6HC7
6HC7
6HC7
6HC7
6HC7
6HC7
6α,7α
6α,7β
6β,7α
6β,7β
7α,8β
7β,8β
–68
175
–
53
–63
–
–62
180
54
60
–57
175
58
–60
–177
56
60
–56
177
60
3.8
12.0
–
3.1 (2.9)
9.2 (9.3)
8.5 (7.7)
3.2 (3.0)
5.4 (5.5)
5.7 (5.8)
–
–
–62
–82
34
–60
–73
45
–
–79
38
180
–61
180
–61
–162
–43
2.0
7.1
a
b
Calculated from data in ref.14. J-Values calculated using generalized Karplus equation (according
ref.16) and the torsion angles calculated with MOPAC for the equilibrium mixture of HC7 and HC7
6
6
in the ratio 60 : 40 are given in parentheses.
Me
Me
7
6
5
10
8
9
6
7
7
6
HC
HC
6
7
FIG. 1
6
Schematic representation of half-chair conformations HC7 and HC7 of ring B in 5-methyl-5β-estr-9-
6
ene derivatives
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

On Steroids
281
derivative 8 we obtained a substantially lower energy difference (about 1.3 kJ in favour
of the HC7 form). The calculated dihedral angles are very similar to those found by
6
electron diffraction for cyclohexene14 (Table II).
C6H5COO
18
These results were compared with the 1H NMR data obtained from 500 MHz spectra
of the 6β-hydroxy derivatives 1, 17–19 and the 6-deoxy derivative 8 in which we as-
signed all the proton signals (Table III) and determined almost all the coupling con-
stants. For the structural assignment of the interacting protons we made use of
2D-COSY spectra. In some cases the multiplets of partly overlapping protons were
verified by 2D-J-resolved spectra. The stereospecific assignment of protons H-6 and
H-7 in the 6-deoxy derivative 8 was made on the basis of 2D-ROESY spectrum; assign-
ment of protons H-4 was based on the characteristic long-range coupling between equa-
torial protons, J(2β,4β) = 2.6 Hz. Compounds 1 and 17, and the previously prepared8,15
compounds 18 and 19, were studied in order to verify a possible effect of substitution
in position 17 on the conformation of the rings A and B. Analysis of the NMR data has
shown that for all the studied 6β-hydroxy derivatives 1 and 17–19 the coupling con-
stants of protons on the rings A and B are the same within the experimental error and
that the effect of substituent in position 17 is negligible. The observed vicinal coupling
constants (J(1α,2α) = 4.5, J(1α,2β) = 2.9, J(1β,2α) = 13.0, J(1β,2β) = 4.2, J(2α,3α) =
3.9, J(2β,3α) = 2.6, J(3α,4α) = 3.9 and J(3α,4β) = 2.6 Hz) and long-range coupling
constants (J(2β,4β) = 2.6, J(1β,8β) = 2.5 and J(1β,11β) = 1.4 Hz) show unequivocally
that, in solution, the ring A in all the studied compounds 1 and 17–19 assumes the chair
form with axial substituent in position 3, in accord with the above-mentioned energy
calculations.
As concerns the conformation of the ring B, the values of vicinal coupling constants
for the 6β-hydroxy derivatives 1 and 17–19 differ markedly from those for the 6-deoxy
derivative 8 (Table II). Application of the generalized Karplus relation between the
torsion angles and coupling constants16 shows that for the 6β-hydroxy derivatives 1 and
17–19 the set of the observed values 3J(H,H) fits the half-chair conformation 6HC7 (but
not 6HC7), in accord with the above-discussed energy calculations (Fig. 1). On the other
hand, in the case or the 6-deoxy derivative 8 the experimental 3J(H,H) values fit neither
6
the form HC7 nor the form HC7. The found values, J(6α,7α) = 3.1, J(6α,7β) = 9.2,
6
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

282
Kasal, Budesinsky:
TABLE III
Proton chemical shifts of 6β-hydroxy derivatives 1, 17–19 and 6-deoxy derivative 8 in CDCl3 (from
1
500 MHz H NMR spectra)
Chemical shifts
Proton
1a
17b
18b,c
19b
8d
1α
1β
2.58
~2.27
~1.60
2.10
5.39
~1.60
2.33
3.59
–
2.58
2.30
1.61
2.09
5.37
1.59
2.30
3.57
–
2.57
2.28
1.57
2.08
5.36
1.60
2.30
3.58
–
2.58
2.32
~1.61
~2.09
5.36
1.58
2.32
3.59
–
2.50
2.21
1.45
1.92
5.07
1.55
1.70
1.35
1.28
1.19
1.65
1.96
2.65
1.93
1.02
1.82
1.18
1.62
1.31
1.45
2.07
3.64
0.87
1.18
2α
2β
3α
4α
4β
6α
6β
7α
1.59
1.82
~2.28
2.63
1.93
1.22
1.86
1.56
~1.81
1.48
1.70
2.31
4.88
1.09
1.27
1.56
1.79
2.21
2.63
1.92
1.02
185
1.56
1.78
2.15
2.54
1.93
~1.10
2.01
1.42
1.68
1.28
1.85
~1.14
~1.13
0.81
1.25
1.68
1.87
2.34
2.72
1.93
1.22
1.84
~1.61
2.04
~1.61
2.11
2.49
–
7β
8β
11α
11β
12α
12β
14α
15α
15β
16α
16β
17α
13β-Me
5β-Me
~1.37
1.70
~1.37
1.49
2.09
3.68
0.90
1.26
1.02
1.27
a
Other signals of two C6H5COO: 8.06 and 8.07 (H-2′,6′), 7.45 and 7.46 (H-3′,5′), 7.56 and 7.57
(H-4′). Other signals of C6H5COO: 8.07 (H-2′,6′), 7.46 (H-3′,5′), 7.57 (H-4′). c Other signals: 0.87 d
(3 × H-26 and 3 × H-27), 0.90 d (3 × H-21), 1.39 (H-20), 0.99 and 1.32 (2 × H-22), 1.12 (H-23),
1.63 and 1.12 (2 × H-24), 1.51 (H-25). d Other signal: 2.07 s (CH3COO).
b
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283
J(6β,7α) = 8.5, J(6β,7β) = 3.2, J(7α,8β) = 5.4 and J(7β,8β) = 5.7 Hz, indicate a
possible averaging due to conformational equilibrium between the forms HC7 and
6
6
6HC7. Actually, the assumption of such an equilibrium between HC7 and HC7 in the
6
ratio of about 60 : 40 leads to a very good accord between the calculated and observed
values of 3J(H,H) for the derivative 8 (see Table II). The preference of conformer 6HC7
agrees with our calculations (the energy difference of about 1.3 kJ corresponds to the
ratio of about 75 : 25 in favour of the form HC7).
6
The bonding of the synthesized compounds to an androgenic receptor and their other
properties will be the subject of a separate communication17.
EXPERIMENTAL
Melting points were determined on a micro melting point apparatus Boetius (Germany) and are un-
corrected. Optical rotations and infrared spectra (wavenumbers in cm–1) were measured in chloro-
form unless stated otherwise. 1H NMR spectra were measured on an FT NMR spectrometer Varian
UNITY-200 (200 MHz) in deuteriochloroform with tetramethylsilane as internal standard. Proton 1D
and 2D-COSY spectra of compounds 1, 8, 17–19 and 2D-ROESY spectrum of 8 were recorded on a
Varian UNITY-500 instrument (500 MHz). Thin-layer chromatography was performed on silica gel
(ICN Biochemicals), column chromatography on silica gel 60–120 µm.
3β,17β-Dibenzoyloxy-5-methyl-5β-estr-9-en-6-one (2)
Jones reagent was added dropwise at 0 °C to a solution of 6β-alcohol 1 (10 g, 19.4 mmol, ref.8) in
acetone (80 ml) to constant orange coloration. After further 5 min the excess reagent was destroyed
with methanol and the mixture was poured into saturated aqueous solution of potassium hydrogen
carbonate. The precipitated product was taken up in chloroform and the extract was washed with
water. After drying, the solvent was evaporated in vacuo and the residue was crystallized from ether
to give 8.36 g (84%) of the product, m.p. 162–165 °C, [α]D +41° (c 1.6). IR spectrum: 1 712, 1 279
(BzO); 1 712, (C=C); 1 603, 1 585, 1 491, 1 452, 1 315, 1 176, 1 117, 1 070, 1 027 (arom). For
C33H36O5 (512.6) calculated: 77.32% C, 7.08% H; found: 77.19% C, 7.11% H.
5-Methyl-5β-estr-9-ene-3β,17β-diol (3)
Ketone 2 (29.0 g, 56.6 mmol) was refluxed with hydrazine monohydrate (99%, 290 ml, 6 mol). After
4 h, ground potassium hydroxide (29.0 g, 0.52 mol) and triethylene glycol (500 ml) were added and
volatile products were distilled from the mixture until its temperature reached 200 °C. The mixture
was refluxed for 3 h, cooled and poured into saturated solution of sodium chloride (2 l). The de-
posited product (20.9 g) was crystallized from toluene to give 3.9 g of compound 3; chromatography
of the mother liquors on silica gel (200 g, 20% ether in benzene) and subsequent crystallization from
toluene gave further 3.27 g of compound 3 (total yield 44%). M.p. 172–174 °C, [α]D + 58° (c 1.0).
IR spectrum (KBr): 3 300 (OH); 1 100, 1 057, 1 027 (C–O). For C19H30O2 (290.4) calculated:
78.57% C, 10.41% H; found: 78.20% C, 10.63% H.
Oxidation of 3β,17β-dihydroxy-5-methyl-5β-estr-9-ene (3)
A) According to Oppenauer: A solution of diol 3 (250 mg, 0.86 mmol) in toluene (18 ml) and
cyclohexanone (6 ml, 59 mmol) was distilled until 10 ml of azeotrope was collected and then alumi-
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

284
Kasal, Budesinsky:
nium isopropoxide (300 mg, 3.12 mmol) was added. During 45 min 6.5 ml of the distillate was col-
lected. After cooling, the mixture was diluted with chloroform, washed with dilute hydrochloric acid
(5%) and water, and the volatiles were steam-distilled. Thin-layer chromatography afforded:
5-Methyl-5β-estr-9-ene-3,17-dione (4, 41 mg, 17%), m.p. 130–132 °C (methanol), [α]D +110° (c 1.1).
IR spectrum (CCl4): 1 743 (5-membered ring ketone); 1 714 (6-membered ring ketone). For
C19H26O2 (286.4) calculated: 79.68% C, 9.15% H; found: 79.36% C, 9.13% H.
3β-Hydroxy-5-methyl-5β-estr-9-en-17-one (6, 12 mg, 5%), m.p. 167–168 °C (acetone), [α]D +172°
(c 0.9). IR spectrum: 3 615 (OH); 1 732 (C=O). For C19H28O2 (288.4) calculated: 79.12% C, 9.78% H;
found: 79.07% C, 9.86% H.
17β-Hydroxy-5-methyl-5β-estr-9-en-3-one (5, 105 mg, 42%), m.p. 123–125 °C (ether–heptane),
[α]D +14° (c 1.5). IR spectrum: 3 613, 3 458 (OH); 1 703 (C=O); 1 041 (C–O). For C19H28O2 (288.4)
calculated: 79.12% C, 9.78% H; found: 79.35% C, 10.00% H. Starting diol 3 (18 mg, 7%).
B) With Jones reagent: Jones reagent (two drops) was added at –68 °C to a stirred solution of diol 3
(50 mg, 0.172 mmol) in acetone (20 ml). After 5 min the cooling bath was removed and the stirring
was continued for another 30 min. The excess reagent was destroyed with methanol (10 drops) and
the mixture was filtered. The solid on the filter was washed with acetone and the combined filtrates
were concentrated in vacuo to about 0.2 ml. Saturated aqueous solution of potassium hydrogen carbonate
was added and the deposited product was extracted with chloroform. The extract was washed, concen-
trated in vacuo and subjected to preparative TLC on silica gel (3 plates 20 × 20 × 0.1 cm, ether–benzene
1 : 1). Extraction of four zones afforded: dione 4 (9.4 mg, 19%), 3-hydroxy derivative 6 (6.1 mg,
12%), 17-hydroxy derivative 5 (23.1 mg, 47%), and the starting diol 3 (10.9 mg, 22%). The com-
pounds were identical (IR, 1H NMR) with the compounds prepared above.
Acetylation of 5-Methyl-5β-estr-9-en-3β,17β-diol (3)
A solution of diol 3 (2.1 g, 7.23 mmol) in toluene (90 ml) was distilled and 70 ml of azeotrope was
collected. Pyridine (9 ml, 111 mmol) and acetic anhydride (5.5 ml, 58.3 mmol) were added at 20 °C
and after standing for 2.5 h the mixture was diluted with methanol (5.5 ml, 135.8 mmol) and set
aside overnight. The solution was concentrated in vacuo, the dry residue was dissolved in chloroform
and washed successively with dilute hydrochloric acid, water, potassium hydrogen carbonate solution
and again water, and dried over sodium sulfate. The mixture was separated by chromatography on
silica gel (100 g) in 10% toluene in light petroleum, toluene, and finally 10% ether in toluene. In
addition to the starting diol 3, the following compounds were obtained:
3β,17β-Diacetoxy-5-methyl-5β-estr-9-ene (9, 213 mg, 10%), m.p. 113–115 °C (methanol), [α]D
+67° (c 1.0). IR spectrum (CCl4): 1 737, 1 241 (AcO). For C23H34O4 (374.5) calculated: 73.76% C,
9.15% H; found: 73.81% C, 9.09% H.
17β-Acetoxy-5-methyl-5β-estr-9-en-3β-ol (7, 767 mg, 37%), m.p. 146–148 °C (acetone–heptane),
[α]D +70° (c 0.95). IR spectrum: 3 613, 3 505, 3 424 (OH); 1 722, 1 256 (AcO); 1 027 (C–O). For
C21H32O3 (332.5) calculated: 75.86% C, 9.70% H; found: 75.66% C, 9.59% H.
3β-Acetoxy-5-methyl-5β-estr-9-en-17β-ol (8, 144 mg, 7%), m.p. 129–131 °C (acetone–heptane),
[α]D +68° (c 1.05). IR spectrum: 3 612 (OH); 1 725, 1 711 sh, 1 247 (AcO). For C21H32O3 (332.5)
calculated: 75.86% C, 9.70% H; found: 75.90% C, 9.66% H.
17β-Acetoxy-5-methyl-5β-estr-9-en-3-one (10)
Jones reagent was added dropwise at room temperature to a solution of compound 7 (2.66 g, 8.0 mmol)
in a mixture of chloroform (5 ml) and acetone (15 ml) until the orange coloration persisted. After
further 7 min the excess reagent was destroyed with methanol, the precipitate was filtered and the
filtrate concentrated to one fifth of the original volume. The product was precipitated by addition of
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

On Steroids
285
saturated aqueous solution of sodium chloride, collected on filter and washed with water. Crystal-
lization from acetone and heptane afforded compound 10 (2.42 g, 91%), m.p. 116–117 °C, [α]D +15°
(c 1.4). IR spectrum (CCl4): 1 738, 1 245 (AcO); 1 715 (C=O). For C21H30O3 (330.5) calculated:
76.33% C, 9.15% H; found: 76.17% C, 9.27% H.
17β-Hydroxy-5-methyl-5β-estr-9-en-3-one (5)
Acetate 10 (205 mg, 0.62 mmol) was dissolved in methanolic solution of potassium hydroxide
(c 0.12 mol l–1, 15 ml). After standing for 18 h under argon, acetic acid (0.1 ml, 1.75 mmol) was
added. The solution was concentrated in vacuo to one fifth of the original volume, the product was
precipitated by addition of water, collected and washed with water (170 mg, 95%). Crystallization
afforded compound 5, m.p. 124–125 °C (acetone–heptane), [α]D +15° (c 0.9), identical in all respects
with the product obtained by direct oxidation of diol 3.
3β-Acetoxy-5-methyl-5β-estr-9-en-17-one (11)
A) A solution of chloro derivative10 13 (2.63 g, 7.21 mmol) in toluene (20 ml) and 2,2′-azobis(2-
methylpropionitrile) (5 mg) were added to a stirred solution of tributyltin hydride (c 1 mol l–1) and
the solution was refluxed for 7 h under nitrogen. The mixture was concentrated in vacuo and the
residue was partitioned between ether and 10% aqueous solution of potassium fluoride. The ethereal
phase was dried over sodium sulfate and purified by flash chromatography on a column of silica gel
(120 g, 12% ether in light petroleum). The product (2.28 g, 96%) was crystallized from acetone, m.p.
159–161 °C, [α]D +153° (c 1.1). IR spectrum (CCl4): 1 741, 1 241 (AcO), 1 741 (C=O). For
C21H30O3 (330.5) calculated: 76.33% C, 9.15% H; found: 76.06% C, 9.30% H.
B) Compound 8 (350 mg, 1.05 mmol) was oxidized with Jones reagent as described for the prepa-
ration of compound 10. Yield 302 mg (86%) of compound 11, m.p. 158–161 °C, undepressed on
admixture with the compound prepared by procedure A.
17β-Pivaloyloxy-5-methyl-5β-estr-9-en-3-one (12)
Pivaloyl chloride (1.0 ml, 8.1 mmol) was added under cooling with ice to a solution of hydroxy
ketone 5 (310 mg, 1.07 mmol) in pyridine (1 ml). After standing at room temperature for 18 h, the
mixture was poured into water with ice (10 ml), the product was taken up in ether and the extract
was successively washed with 1% hydrochloric acid, saturated aqueous potassium hydrogen carbo-
nate solution and water. The solution was dried over sodium sulfate, the solvent was evaporated and
the product (335 mg, 84%) was crystallized from acetone and heptane. M.p. 133–135 °C, [α]D +22°
(c 1.2). For C24H36O3 (372.6) calculated: 77.38% C, 9.74% H; found: 77.19% C, 9.80% H.
5,17-Dimethyl-5β-estr-9-ene-3β,17β-diol (14)
A) A solution of ketone 11 (3.0 g, 9.08 mmol) in benzene (150 ml) was added dropwise to a stirred
solution of methylmagnesium iodide, prepared from magnesium (2.25 g, 92.6 mmol) and methyl
iodide (6.0 ml, 96.4 mmol) in ether (48 ml). The stirred mixture was heated until 200 ml of distillate
came over. Then the mixture was refluxed for 3 h, cooled and poured on a mixture of ice (100 g) and
concentrated hydrochloric acid (10 ml, 120 mmol). The product was taken up in benzene, the extract
was washed successively with water, sodium thiosulfate, potassium hydrogen carbonate and water.
After drying over sodium sulfate, the solution was concentrated and the crystalline product (2.37 g,
86%) collected, m.p. 114–116 °C, [α]D +40° (c 1.5). IR spectrum (CCl4): 3 613, 3 450 (OH). For
C20H32O2 (304.5) calculated: 78.90% C, 10.59% H; found: 78.87% C, 10.62% H. Chromatography of
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Kasal, Budesinsky:
the mother liquors afforded further portion (237 mg) of the product 14 making the total yield 94%.
Also ketone 6 was isolated (51 mg, 1.8%).
B) A solution of methyllithium in ether ( c 1.6 mol l–1, 0.6 ml) was added at 20 °C to a solution
of compound 14 (100 mg, 0.30 mmol) in tetrahydrofuran (0.2 ml). After 18 h the mixture was de-
composed by pouring on a mixture of ice (5 g) and concentrated hydrochloric acid (0.2 ml) and the
product was extracted with chloroform. The extract was washed with water, potassium hydrogen car-
bonate solution and again with water, and dried over sodium sulfate. According to thin-layer chroma-
tography, the product consisted of compounds 6 and 14; their ratio was determined after acetylation
with acetic anhydride (0.4 ml) in pyridine (0.4 ml). Preparative thin-layer chromatography afforded
acetate 11 (39 mg, 39%) and acetate 15 (57 mg, 54%).
17β-Hydroxy-5,17-dimethyl-5β-estr-9-en-3-one (16)
Jones reagent was added dropwise at room temperature to a stirred solution of diol 14 (2.26 g, 7.42 mmol)
in acetone (70 ml). After 10 min the mixture was worked up as described for the compound 10. The
product 16 (2.16 g, 95%) was crystallized from acetone and heptane, m.p. 98–99 °C, [α]D –10° (c 1.1).
IR spectrum: 3 612, 3 475 (OH); 1 702 (C=O). For C20H30O2 (302.4) calculated: 79.42% C, 10.00% H;
found: 79.57% C, 9.84% H.
3-β-Benzoyloxy-5-methyl-5β-estr-9-ene-6β,17β-diol (17)
Sodium borohydride (60 mg, 1.6 mmol) was added at 0 °C to a stirred solution of compound 19
(ref.13, 210 mg, 0.51 mmol) in ethanol (5 ml). After stirring for 15 min, the mixture was set aside at
room temperature for 2 h and then poured into 1% hydrochloric acid (25 ml). The precipitate was
collected, washed with water and crystallized from acetone to give 146 mg (69%) of product 17, m.p.
238–240 °C, [α]D +136° (c 1.1). For C26H34O4 (410.6) calculated: 76.06% C, 8.35% H; found:
75.95% C, 8.40% H.
The authors are indebted to Mrs M. Sedlackova for technical assistance. IR spectra were measured
by Mrs K. Matouskova and interpreted byl Dr L. Bednarova. NMR spectra were taken by Mrs M.
Snopková. Our thanks are also due to the staff of the Analytical Department (Dr V. Pechanec, Head) for
the elemental analyses. This work was supported by the Grant Agency of the Czech Republic (Grant No.
505/94/0009).
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