SYNTHESIS OF SOME EPITESTOSTERONE ANALOGUES

Article abstract of DOI:10.1135/cccc19940435

11β-Hydroxyandrost-4-ene-3,17-dione (III) was converted into a potential metabolite of epitestosterone - 11β,17α-dihydroxyandrost-4-en-3-one (II) in 5 steps, including the inversion of configuration of a 17β-hydroxy group.This inversion was not feasible in the preparation of the analogues X, XIV, XX, and XXII, where the 17α-hydroxy group was introduced first and only then was the rest of molecule modified.

Full text of DOI:10.1135/cccc19940435

On Steroids
435
SYNTHESIS OF SOME EPITESTOSTERONE ANALOGUES*
Hana CHODOUNSKA, Barbora SLAVIKOVA and Alexander KASAL
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, The Czech Republic
Received April 2, 1993
Accepted April 20, 1993
11β-Hydroxyandrost-4-ene-3,17-dione (III) was converted into a potential metabolite of epitesto-
sterone – 11β,17α-dihydroxyandrost-4-en-3-one (II) in 5 steps, including the inversion of configura-
tion of a 17β-hydroxy group. This inversion was not feasible in the preparation of the analogues X,
XIV, XX, and XXII, where the 17α-hydroxy group was introduced first and only then was the rest of
the molecule modified.
Recently1 we published the preparation of several metabolites of epitestosterone
(17α-hydroxyandrost-4-en-3-one, I) needed for metabolic studies of epitestosterone in
man. Now we report on the synthesis of another potential epitestosterone metabolite
and of other analogues which may exert some of its biological properties.
One of the epitestosterone’s potential metabolites is the product of its 11β-hydroxy-
lation, compound II. Lindner2 prepared this compound once by the enzymatic reduction
of 11β-hydroxyandrost-4-ene-3,17-dione (III) without, however, precisely charac-
terizing it.
Commercially available 11β-hydroxyandrost-4-ene-3,17-dione (III) was esterified to
formate IV which was then subjected to partial reduction3 of the 17-oxo group by tri-
tert-butoxy lithium aluminium hydride (see Scheme 1). In the thus formed 17β-alcohol
VI, inversion of the configuration of the 17-hydroxy group was carried out according to
Lattrell and Lohaus4, i.e., by solvolysis of the corresponding tosylate VII with sodium
nitrite in dimethyl sulfoxide. The expected 17α-alcohol V was isolated from the mix-
ture and identified according to its spectral properties (see Experimental). The low
yield (6%) could not be increased using more moderate conditions: lipophilic by-prod-
ucts were formed even in temperatures under which the tosyloxy group survived un-
* Part CCCLXXII in the series On Steroids; Part CCCLXXI: Collect. Czech. Chem. Commun. 58, 3000
(1993).
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Chodounska, Slavikova, Kasal:
changed. For this reason in other experiments the 17α-hydroxy group was introduced
first and then the sensitive A ring modified.
One of the analogues with potential antiandrogenic activity was the epitestosterone
isomer X, containing a 1(2)-double bond, which in some cases increased the 5α-reduc-
tase inhibitory activity (see, e.g., ref.5). Compound X was once prepared from 17β-
hydroxyandrost-1-en-3-one6, but we synthesized (Scheme 2) this compound in 78%
yield from dihydroepitestosterone (VIII, 17α-hydroxy-5α-androstan-3-one1,7); ketone
VIII was brominated by phenyltrimethylammonium tribromide8 and the formed 2α-bromo
ketone9 IX was dehydrobrominated by adding it to a boiling solution of lithium salts in
N,N-dimethylformamide.
Briefly we report on the preparation of two epitestosterone homologues, the syn-
thesis of which has already been described, in order to supply additional data and com-
ment on a modification of the procedure. The first is 17α-hydroxy-17β-methylandrost-
4-en-3-one (XIV), prepared by Miescher10 from diol XII. Compound XII is a lipophilic
SCHEME 1
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SCHEME 2
admixture in the product of the reaction of 17-ketone XI with methylmagnesium iodide.
We found that the purity of both diol XII and hydroxy ketone XIV could easily be
1
checked by H NMR spectroscopy: chemical shift of H-18 protons appears at signifi-
cantly higher field in the 17α-hydroxy derivatives XII and XIV than in the correspond-
ing 17β-isomers XIII and XV, respectively.
The second homologue, 19-nor-epitestosterone (XXII, ref.11) is the major metabolite
of nandrolone (i.e. an anabolic steroid applied in fodder) and its residue in meat had to
be monitored (see, e.g., ref.12). We prepared (see Scheme 3) this compound from es-
trone methyl ether (XVI) via 3-methoxy-1,3,5(10)-estratrien-17α-ol13 – 15 (XIX). The
aromatic system of compound XIX was reduced16 by lithium in ammonia, using tetrahy-
drofuran and 2-methyl-2-propanol as a solvent. The already described11 cleavage of the
enol ether XXI by a methanolic solution of oxalic acid yielded a mixture of the hydroxy
ketones XX and XXII. The same reagent with a lower concentration of acid17 gave rise
mainly to the 3,3-dimethoxy derivative XXIII. It turned out that the best method for the
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Chodounska, Slavikova, Kasal:
conversion of XXI to 5(10)-unsaturated ketone XX was treatment with wet silica gel,
and for the conversion to the unsaturated ketone XXII was treatment with hydrochloric
acid.
SCHEME 3
The results of biochemical and biological experiments with compounds prepared
above will be discussed later.
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EXPERIMENTAL
Melting points were determined on a Kofler block and are uncorrected. Infrared spectra were re-
corded on a Perkin–Elmer PE 580 spectrometer in chloroform, wavenumbers are given in cm−1
.
Proton NMR spectra were taken in deuteriochloroform on an XL-200 (FT mode, 200 MHz) Varian
instrument with tetramethylsilane as the internal reference. Chemical shifts are given in ppm
(δ-scale), coupling constants (J) and multiplet width (W) in Hz. The data were interpreted as the
first-order spectra. The identity of the prepared samples was checked by mixture melting point deter-
mination, thin-layer chromatography (TLC), IR and proton NMR spectra. Preparative TLC was car-
ried out on 200 × 200 mm plates coated with 0.7 mm thick layer of Woelm DC silica gel. The light
petroleum was a fraction boiling at 40 – 62 °C.
3,17-Dioxo-4-androsten-11β-yl Formate3 (IV)
1H NMR spectrum: 8.09 s, 1 H (OCOH); 5.71 d, 1 H (H-4, J(4,6) ≈ 1); 5.64 q, 1 H (H-11α,
J(11α,12α) ≈ J(11α,12β) ≈ J(11α,9α) ≈ 2.5); 1.33 s, 3 H (3 × H-19); 1.06 s, 3 H (3 × H-18).
17β-Hydroxy-3-oxo-4-androsten-11β-yl Formate3 (VI)
1H NMR spectrum: 8.10 s, 1 H (OCOH); 5.71 d, 1 H (H-4, J(4,6) ≈ 1); 5.56 q, 1 H (H-11α,
J(11α,12α) ≈ J(11α,12β) ≈ J(11α,9α) ≈ 2.5); 3.61 dd, 1 H (H-17α, J(16β,17α) = 7.5, J(16α,17α) = 8.5).
3-Oxo-4-androstene-11β,17β-diyl 11-Formate 17-Tosylate (VII)
p-Toluenesulfonyl chloride (2.0 g, 10.5 mmol) was added to a solution of VI (1.6 g, 5.0 mmol) in
pyridine (30 ml) cooled with an ice bath. This mixture was allowed to stand overnight at 40 °C. Then
it was poured onto ice, extracted with ethyl acetate, the organic layer was washed with 5% hydro-
chloric acid, water, 5% aqueous sodium hydrogen carbonate and dried over anhydrous magnesium
sulfate. Evaporation of the solvent in vacuo afforded 2.1 g (86%) of crude product VII, which re-
sisted all attempts at crystallization, even after preparative chromatography on a thin layer of silica
gel, in toluene–ether (1 : 1); [α]D +53° (c 0.9, chloroform). IR spectrum: 1 718 (C=O, formate);
1 666 (C=O, ketone); 1 617 (C=C); 1 168 shoulder (C−O, formate); 1 362, 1 176 (SO2); 1 097,
1
1 020 (C−O). H NMR spectrum: 8.43 s, 1 H (OCOH); 7.75 d, 2 H (H-2′ and H-6′ tosylate, J = 8.5);
7.33 d, 2 H (H-3′ and H-5′, tosylate, J = 8.5); 5.68 d, 1 H (H-4, J(4,6) ≈ 1); 5.46 q, 1 H (H-11α,
J(11α,12α) ≈ J(11α,12β) ≈ J(11α,9α) ≈ 2.5); 4.22 dd, 1 H (H-17α, J(16β,17α) = 7.5, J(16α,17α) = 8.5);
2.45 s, 3 H (CH3, tosylate); 1.28 s, 3 H (3 × H-19); 0.97 s, 3 H (3 × H-18). For C27H34SO6 (468.6)
calculated 66.64% C, 7.04% H, 6.59% S; found: 66.61% C, 7.11% H, 6.47% S.
17α-Hydroxy-3-oxo-4-androsten-11β-yl Formate (V)
A mixture of VII (2.0 g, 4.1 mmol) and sodium nitrite (2.5 g, 36 mmol) in dimethyl sulfoxide
(70 ml) was stirred at 150 °C for 2 h. The mixture was cooled at room temperature, diluted with water
(200 ml) and extracted with ether (3×). The combined organic layers were washed with water (5×),
dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. Chromatography
of the residue (1.8 g) on a column of Silpearl (100 g) in toluene–ether (1 : 1) and then on the thin
layer of silica gel in toluene–ether–methanol (140 : 140 : 1) afforded 80 mg (6%) of V, m.p. 209 –
211 °C (methanol), [α]D +150° (c 0.4, chloroform). IR spectrum: 3 619, 3 435, 3 309 (OH); 1 717
(C=O, formate); 1 662 (C=O, ketone); 1 618 (C=C); 1 193, 1 178 (C−O, formate); 1 057 (C−O,
17-OH); 868 (=C−H). 1H NMR spectrum: 8.40 s, 1 H (OCOH); 5.70 d , 1 H (H-4, J(4,6) ≈ 1);
5.64 q, 1 H (H-11α, J(11α,12α) ≈ J(11α,12β) ≈ J(11α,9α) ≈ 2.5); 3.73 d, 1 H (H-17β, J ≈ 6); 1.31 s, 3 H
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Chodounska, Slavikova, Kasal:
(3 × H-19); 0.84 s, 3 H (3 × H-18). For C20H28O4 (332.4) calculated: 72.26% C, 8.49% H; found:
72.11% C, 8.43% H.
11β,17α-Dihydroxy-4-androsten-3-one (II)
Sodium methoxide in methanol (5%, 30 drops) was added to a solution of V (40 mg, 0.12 mmol) in
methanol (25 ml) and the mixture was stirred at 60 °C. After 8 h the reaction mixture was neu-
tralized with solid carbon dioxide (about 400 mg) and the solvent was evaporated in vacuo. Chroma-
tography of the residue on a thin layer of silica gel in toluene–ether–methanol (15 : 9 : 1) gave 32 mg
(88%) of II, m.p. 207 – 209 °C (methanol–ether); [α]D +114° (c 0.1, methanol–chloroform, 1 : 1). IR
spectrum: 3 617, 3 460 (OH); 1 660 (C=O); 1 616 (C=C); 1 072, 1 053, 1 030, 1 020 (C−O); 867
(=C−H). 1H NMR spectrum: 5.64 d, 1 H (H-4, J(4,6) ≈ 1); 4.44 q, 1 H (H-11α, J(11α,12α) ≈
J(11α,12β) ≈ J(11α,9α) ≈ 2.5); 3.67 d, 1 H (H-17β, J ≈ 6); 1.45 s, 3 H (3 × H-19); 0.95 s, 3 H (3 × H-18).
For C19H28O3 (304.4) calculated: 74.96% C, 9.27% H; found: 74.87% C, 9.30% H.
2α-Bromo-17α-hydroxy-5α-androstan-3-one (IX)
Phenyltrimethylammonium tribromide8 (233 mg, 0.62 mmol) was added to a solution of ketone1 VIII
(150 mg, 0.52 mmol) in tetrahydrofuran (3 ml). The reaction mixture turned turbid immediately and
a white precipitate was formed. The mixture was poured into a saturated aqueous solution of potas-
sium hydrogen carbonate and the product was extracted with ether. The organic layer was washed
with a saturated aqueous solution of potassium hydrogen carbonate, and water and dried over anhy-
drous sodium sulfate. Evaporation of the solvent in vacuo yielded 179 mg (94%) of crude IX, which
was used in the next step without purification. A sample for analysis was crystallized from ether–
heptane, m.p. 128 – 132 °C; [α]D +9° (c 1.5, chloroform). 1H NMR spectrum: 4.75 dd, 1 H (H-2β,
J(2β,1β) = 6.4, J(2β,1α) = 13.4); 3.75 d, 1 H (H-17β, J = 5.8); 1.10 s, 3 H (3 × H-19); 0.68 s, 3 H
(3 × H-18).
17α-Hydroxy-5α-androst-1-en-3-one (X)
A solution of the bromo ketone IX (179 mg, 0.5 mmol) in N,N-dimethylformamide (3 ml) was added
dropwise to a suspension of lithium carbonate (193 mg, 2.6 mmol) and lithium bromide (223 mg,
2.6 mmol) in boiling N,N-dimethylformamide (3.5 ml). After 1 h the mixture was cooled, diluted
with ether, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous
sodium sulfate. The solvent was evaporated in vacuo. Preparative chromatography on a thin layer of
silica gel, (elution with benzene–ether, 1 : 1) afforded 117 mg (83%) of X: m.p. 116 – 118 °C (ether–
heptane); [α]D +30° (c 1.5, chloroform); the literature6 gives m.p. 120 °C. 1H NMR spectrum:
7.18 d, 1 H (H-1, J = 10.4); 5.86 bd, 1 H (H-2, J = 10.4); 3.76 d, 1 H (H-17β, J = 6); 1.02 s, 3 H
(3 × H-19); 0.70 s, 3 H (3 × H-18).
17α-Hydroxy-17β-methylandrost-5-en-3β-ol (XII)
Compound XII was isolated10 from the mother liquors of XIII (see the following experiment) as the
1
more lipophilic admixture. H NMR spectrum: 5.36 d, 1 H (H-6, J ≈ 5.2); 3.53 m, 1 H (H-3, W ≈ 35);
1.20 s, 3 H (CH3-17β); 1.03 s, 3 H (3 × H-19); 0.70 s, 3 H (3 × H-18).
17β-Hydroxy-17α-methylandrost-5-en-3β-ol (XIII)
Compound XIII was prepared18 from the 17-oxoandrost-5-en-3β-yl acetate by reacting it with methyl-
magnesium iodide, the only difference being the solvent: ether was later replaced by benzene. The
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1
precipitate formed consisted of compound XIII. H NMR spectrum: 5.35 d, 1 H (H-6, J ≈ 5.2); 3.52 m,
1 H (H-3, W ≈ 36); 1.21 s, 3 H (CH3-17α); 1.03 s, 3 H (3 × H-19); 0.87 s, 3 H (3 × H-18).
17α-Hydroxy-17β-methylandrost-4-en-3-one (XIV)
The derivative XIV was prepared10 by Oppenauer oxidation of compound XII. 1H NMR spectrum:
5.73 d, 1 H (H-4, J ≈ 1.7); 1.21 s, 3 H (CH3-17β); 1.20 s, 3 H (3 × H-19); 0.73 s, 3 H (3 × H-18).
17β-Hydroxy-17α-methylandrost-4-en-3-one18 (XV)
1H NMR spectrum: 5.73 d, 1 H (H-4, J = 1.5); 1.22 s, 3 H (CH3-17α); 1.21 s, 3 H (3 × H-19); 0.91 s,
3 H (3 × H-18).
3-Methoxy-1,3,5(10)-estratrien-17α-ol (XIX)
Sodium nitrite (12.0 g, 17.0 mmol) was added to a solution of the tosylate XVIII (4.0 g, 9.0 mmol),
prepared14 from compound XVII) in N,N-dimethylformamide (170 ml) and the mixture was stirred at
145 °C for 4 h. After cooling it was poured into a mixture of ether (500 ml) and water (500 ml), the
aqueous layer was extracted with ethyl acetate (300 ml) and the combined organic phases were
washed with water (2×). The solvents were evaporated and the residue (4 g) chromatographed on a
column of Silpearl (200 g). Elution with light petroleum–ether (3 : 1) removed the non-polar side
products (1.0 g, 50%), elution with light petroleum–ether (1 : 1) afforded compound XIX (1.3 g),
m.p. 112 – 114 °C (hexane–ether); [α]D +58° (c 0.8, chloroform). The literature14 gives m.p. 110 –
1
112 °C, [α]D +59°. H NMR spectrum: 7.22 d, 1 H (H-1, J(1,2) = 8.5); 6.71 dd, 1 H (H-2, J(1,2) = 8.5,
J(2,4) = 2.5); 6.63 d, 1 H (H-4, J(4,2) = 2.5); 3.80 d, 1 H (H-17β, J(17,16) = 6); 3.78 s, 3 H (OCH3);
2.85 m, 2 H (2 × H-6, W = 24); 0.70 s, 3 H (3 × H-18). For C19H26O2 (286.4) calculated: 79.68% C;
9.15% H; found: 79.46% C, 9.24% H.
3-Methoxy-2,5(10)-estradien-17α-ol (XXI)
Lithium wire (0.3 g, 50 mmol) was added to a solution of XIX (1.0 g, 3.5 mmol) in a mixture of
tetrahydrofuran (20 ml), 2-methyl-2-propanol (20 ml) and liquid ammonia (100 ml, distilled from
sodium). After stirring under a dry ice condenser for 1/2 h, the ammonia was distilled off and the
mixture was diluted with water and allowed to stand for 2 h. The mixture was then filtered, and
the crude product (1 g) washed with water and dried on air. Filtration of the ethereal solution
through silica gel (pretreated with ammonia vapours) and crystallization from ether–hexane gave
670 mg (68%) of XXI, m.p. 110 – 113 °C; [α]D +96° (c 0.4, chloroform). Literature10 gives m.p.
112 – 114 °C, [α]D +99°. IR spectrum: 3 615, 3 471 (O−H); 2 827 (OCH3); 1 695, 1 665 (C=C);
1
1 026 (C−O). H NMR spectrum: 4.69 t, 1 H (H-2, J = 2.9); 3.62 d, 1 H (H-17β, J = 5.8); 3.50 s,
3 H (3 × H, OCH3); 0.65 s, 3 H (3 × H-18). For C19H28O2 (288.4) calculated: 79.12% C, 9.78% H;
found: 79.32% C, 9.67% H.
17α-Hydroxyestr-5(10)-en-3-one (XX)
A mixture of XXI (200 mg, 0.7 mmol), silica gel (2 g), 2-methyl-2-propanol (0.5 ml), water (0.5 ml)
and toluene (10 ml) was evaporated on a rotatory evaporator in vacuo for 15 min at 50 °C. Elution
of the silica gel with ether and evaporation of the solvent in vacuo gave 160 mg (83%) of XX, m.p.
141 – 150 °C decomposition (ether–hexane), [α]D +160° (c 0.5, chloroform). The literature11 gives
m.p. 144 – 150 °C, [α]D +164°. IR spectrum: 3 616, 3 468 (OH); 1 712 (C=O); 1 434 (CH2−C=O).
1H NMR spectrum: 3.78 d, 1 H (H-17β, J = 5.6); 2.81 d, 1 H (H-4a, J(4a,4b) ≈ 22); 2.67 d, 1 H
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Chodounska, Slavikova, Kasal:
(H-4b, J(4a,4b) ≈ 22); 0.69 s, 3 H (3 × H-18). For C18H26O2 (274.4) calculated: 78.79% C, 9.55% H;
found: 78.79% C, 9.53% H.
3,3-Dimethoxyestr-5(10)-en-17α-ol (XXIII)
A solution of XXI (40 mg, 0.07 mmol) and oxalic acid dihydrate (5 mg, 0.05 mmol) in methanol
(25 ml) was allowed to stand for 48 h at 5 °C. The reaction mixture was diluted with water (25 ml)
and ether (25 ml) and the aqueous layer extracted with ether (20 ml, 3×). The combined organic
layers were washed with an aqueous solution of sodium hydrogen carbonate (25 ml, 5%), dried over
anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a thin
layer of silica gel in light petroleum–ether (1 : 1), affording 36 mg (80%) of product XXIII, m.p. 86 –
88 °C (ether–hexane), [α]D +128° (c 0.7, chloroform). IR spectrum: 3 615, 3 471 (O−H); 2 832
(OCH3); 1 167, 1 130, 1 090, 1 048 (C−O−C−O−C); 930 (OCH3). 1H NMR spectrum: 3.67 d, 2 H
(H-17β, J = 6.5); 3.25 s, 3 H (OCH3); 3.22 s, 3 H (OCH3); 0.68 s, 3 H (3 × H-18). For C20H32O3
(320.5) calculated: 74.96% C, 10.06% H; found: 75.18% C, 9.93% H.
17α-Hydroxyestr-4-en-3-one (XXII)
a) Hydrochloric acid (0.5 ml, 37%) was added to a solution of XXI (30 mg, 0.11 mmol) in chloro-
form (10 ml). The mixture was set aside for 1 h at room temperature, then it was washed with water
(5 ml, 2×), a solution of sodium hydrogen carbonate (5 ml, 5%), and dried over anhydrous magne-
sium sulfate. Evaporation of the solvent and crystallization from ether–hexane gave 22 mg (73%) of
XXII, m.p. 146 – 150 °C (decomposition); [α]D +12° (c 1.7, chloroform). The literature11 gives m.p.
146 – 149 °C; [α]D +9°. IR spectrum: 3 617, 3 742 (O−H); 1 664 (C=O); 1 618 (C=C); 868 (=C−H).
1H NMR spectrum: 5.84 t, 1 H (H-4, J(4,6) ≈ J(4,10) ≈ 1); 3.78 d, 1 H (H-17β, J = 5.6); 0.73 s, 3 H
(3 × H-18). For C18H26O2 (274.4) calculated: 78.79% C, 9.55% H; found: 78.64% C, 9.49% H.
b) A solution of oxalic acid dihydrate (220 mg, 2 mmol) in water (2 ml) was added to a solution
of XXI (200 mg, 0.69 mmol) in methanol (20 ml). After standing for 1 h at room temperature the
mixture was diluted with water (50 ml) and ether (50 ml) and the aqueous layer extracted with ether
(3×). The combined organic layers were washed with an aqueous solution of sodium hydrogen carbo-
nate (30 ml, 5%), dried over anhydrous magnesium sulfate and evaporated in vacuo. Chromatography
of the crude product (178 mg) on a column of Silpearl (60 g), and elution with light petroleum–ether
(1 : 1) gave 110 mg (58%) of XX and 40 mg (22%) of XXII.
The authors are indebted to the Analytical Laboratory (Dr V. Pechanec, Head) for the elemental
1
analyses, the Laboratory of NMR Spectroscopy (Dr M. Budesinsky, Head) for measurement of H NMR
spectra, to Dr P. Fiedler and Dr J. Smolikova for the measurement and interpretation of IR spectra. The
project was supported by a grant of the Czechoslovak Academy of Sciences (GA 45520).
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