The synthesis of a-homo-b-norandrostanes: The effect of a hydroxyl on the course of hydrogenation of the Δ9-double bond

Article abstract of DOI:10.1135/cccc19971631

Acetolysis of 6β-mesyloxy-5-methyl-19-nor-5β-steroids (e.g. 10) was proved to yield 4a-homo-7,19-dinor compounds (e.g. 9) with a hydroxy group in the position 4aα. Hydrogenation of these compounds affords 9β,10β-dihydro derivatives (e.g. 12) predominantly, corresponding 9α, 10α isomers (e.g. 13) are only formed in low yields. This sequence was used for the synthesis of analogues of androgen hormones 4aα-hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β- androstane-3,17-dione (27), 4aα,17β-dihydroxy-4aβ,17a-dirnethyl-4a-homo-7,19-dinor-5α, 9β,10β-androstan-3-one (28) and 4aα,17β-dihydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α, 9β,10β-androstan-3-one (29).

Full text of DOI:10.1135/cccc19971631

On Steroids
1631
THE SYNTHESIS OF A-HOMO-B-NORANDROSTANES: THE EFFECT
OF A HYDROXYL ON THE COURSE OF HYDROGENATION
OF THE ∆9-DOUBLE BOND*
1
2
3
4
Alexander KASAL , Barbora SLAVIKOVA , Ladislav KOHOUT and Milos BUDESINSKY
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
166 10 Prague 6, Czech Republic; e-mail: 1 kasal@marilyn.uochb.cas.cz, 2 barbora@uochb.cas.cz,
3 kohout@uochb.cas.cz, 4 milos.budesinsky@uochb.cas.cz
Received June 23, 1997
Accepted August 29, 1997
Acetolysis of 6β-mesyloxy-5-methyl-19-nor-5β-steroids (e.g. 10) was proved to yield
4a-homo-7,19-dinor compounds (e.g. 9) with a hydroxy group in the position 4aα. Hydrogenation of
these compounds affords 9β,10β-dihydro derivatives (e.g. 12) predominantly, corresponding 9α,10α
isomers (e.g. 13) are only formed in low yields. This sequence was used for the synthesis of
analogues of androgen hormones 4aα-hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-
androstane-3,17-dione (27), 4aα,17β-dihydroxy-4aβ,17α-dimethyl-4a-homo-7,19-dinor-5α,9β,10β-
androstan-3-one (28) and 4aα,17β-dihydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-androstan-
3-one (29).
Key words: NOE experiments; Hormone analogues; Steroid skeletal rearrangement; Ketone circular
dichroism; Steroids.
In a search for new types of antiandrogens we2 had to deal with the problem of hydro-
genation of ∆9-unsaturated 4a-homo-7,19-dinor steroids (e.g. compound 1, Scheme 1):
O
O
O
H
H
H
H
H
+
C H COO
C H COO
C H COO
6 11
6
5
6
11
H
H
H
H
1
2
3
SCHEME 1
two products of cis addition of hydrogen (2 and 3) were formed in comparable yields,
though the same reaction in ∆9-unsaturated 19-nor steroids 4 (Scheme 2) yielded pre-
* Part CCCXC in the series On Steroids; Part CCCLXXXIX see ref.1.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

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Kasal, Slavikova, Kohout, Budesinsky:
dominantly3 products of trans addition of hydrogen, compounds 5 and 6 in addition to
their cis isomer 7. The fourth isomer 8 is only available by diimide reduction3.
Here we report on our experiments to influence the above product distribution by
placing a hydroxy group into a homoallylic 4a position. Compound 9 was prepared4 by
acetolysis of mesylate 10. This reaction was first carried out by Mousseron-Canet5,
H
H
1
1
R O
RO
R O
H
OH
2
2
OR
OR
1
2
1
2
R
= H; R = H
9-α,10-β, R = H; R = H
9, R = C H CO
4,
5,
6,
6
5
1
2
1
2
10, R = C H CO; R = Ms
9-β,10-α, R = H; R = H
11, R = H
6
5
1
2
1
2
9-α,10-β, R = Piv; R = Ac
19, R = Piv; R = OAc
22,
23,
1
2
9-β,10-α, R = Piv; R = Ac
H
H
H
R
H
2
H
H
1
RO
R O
HO
H
OH
OR
OH
8
1
1
2
7,
= Piv; R = Ac
2
12, R = C H CO
11
6
21, R = Piv; R = Ac
14, R = H
26, R = Piv
1
2
24, R = Piv; R = H
1
2
25, R = Piv; R = Ms
H
H
H
H
RO
O
Piv O
H
OH
H
OH
HO
OH
16
20
13, R = C H CO
11
6
15, R = H
OH
H
H
H
H
O
O
H
H
OH
H
18
17
Piv = (CH ) CO; Ms = CH SO
3 3
3
2
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

On Steroids
1633
though, the product formed was given a formula of a 4,5-seco-4,6-cyclo derivative5. Its
skeleton was later corrected4. Here we are correcting a configuration of the 4a hydroxy
group: as no intramolecular hydrogen bond6 exists in diol 11 nor its ester 9, the α-con-
figuration of the 4a hydroxyl is more likely. Experimental evidence has been obtained
1
from H NMR spectra of an androstane analogue of ester 9 (vide infra).
Catalytic hydrogenation of 9 produced a mixture of perhydro products 12 and 13 in
a proportion of 7.6 : 1. They were hydrolyzed to 3β-hydroxy derivatives 14 and 15 and
oxidized to ketones 16 and 17 (ref.4). Circular dichroism of these ketones settled the
question of their 9 and 10 configurations: the strong positive Cotton effect of the latter
isomer (∆ε286 +3.04) is close to the value for 17β-hydroxy-4aβ,17-dimethyl-4a-homo-
7,19-dinor-5α,10α-androstan-3-one7 (18, ∆ε288 +3.55). The strong negative Cotton ef-
fect for ketone 16 (∆ε293 –2.9) suggests the 9β,10β configuration.
A direct proof of the suggested structures was now carried out as follows: West-
phalen diol ester 19, prepared from diol 20, was hydrogenated and a 9β,10β-dihydro
derivative 21 was easily separated from a mixture and identified: it was the only one of
the four possible isomers that had an equatorial (Table I) 3β-acyloxy group (isomers 22
and 23, with an axial 3β-acyloxy group, have very similar chromatographic properties
but differ from compound 21). Mesylate of the 9β,10β isomer, compound 25 was sol-
volyzed to yield a 4a-homo-7-nor compound 26. Its hydrolysis and oxidation afforded
ketone 16 identical with the sample prepared above.
The experience gained was used for the synthesis of analogues of androgen hor-
mones 27, 28 and 29. Mesylate 30 (ref.7, Scheme 3) yielded a mixture of diene 1 and a
hydroxy derivative 31 on solvolysis with potassium acetate in aqueous acetone. De-
tailed analysis of proton 1D, 2D-COSY and 2D-NOESY spectra of compound 31 re-
sulted in a complete structural assignment of all protons in the molecule (see
Experimental). Figure 1 shows schematically the observed non-trivial NOE contacts.
FIG. 1
The observed “non-trivial” NOE contacts (indi-
cated with arrows) in ester 31
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Kasal, Slavikova, Kohout, Budesinsky:
TABLE I
1
Characteristic parameters of the H NMR spectra (in CDCl3)
Compound
H-18a
4a-Mea
H-3b
H-17c
Other signals
9d,e
11d
12d
13d
14d
15d
16d
17d
19d
20d
21d
24d
25d
26d
27
0.75
0.73
0.66
0.66
0.66
0.65
0.71
0.65
0.79
0.68
0.65
0.65
0.65
0.66
0.94
0.91
0.80
0.97
0.73
0.88
0.61
1.22
1.16
1.12
1.21
1.14
1.22
1.14
1.24
–
5.48f
4.25f
5.03
5.18
4.07
4.15
–
–
–
2.87g
2.74g
–
–
–
–
–
–
–
–
–
2.63h and 2.93h
2.35i and 3.19i
1.23k, 1.24l, 2.05m, 3.76n
1.17k, 1.20p, 3.54q
1.16k, 1.06l, 2.08m, 5.15s
0.98l, 1.17k, 3.92s
1.07l, 1.15k, 3.12t, 4.89u
1.17k
–
–
5.08j
5.13o
4.69r
4.80r
4.83r
5.02
–
–
–
–
–
–
–
–
–
–
1.13
1.16
1.16
1.16
1.24
1.11
1.15
1.07
–
–
2.61v and 2.97v
2.69w and 2.89w, 1.22x
2.69w and 2.91w
28
–
–
29
–
3.69
–
31
5.48
5.00
4.99
3.95
–
–
–
–
32
3.62
–
33
34
3.56
a
b
c
Singlet, 3 H; broad triplet (J = 10.7) or m (W = 31.0), unless stated otherwise; dd (J = 8.5 and
d
7.5); cholestane side chain: 0.86 d, 3 H, J = 6.7 (3 × H-26 and 3× H-27) and 0.92 d, 3 H, J = 6.4
e
(3 × H-21); multiplets of aromatic protons at 7.43 (H-2′, H-6′), 7.54 (H-4′) and 8.00 (H-3′, H-5′);
f m, W = 29.1; d, J = 8.7, 1 H, H-5a; AB system, 2 × H-4, J = 11.6; AB system, 2 × H-4, J =
g
h
i
j
k
l
m
n
14.0; m, W = 20.0; s, 9 H, (CH3)3CCOO; s, 3 H, 5β-CH3; s, 3 H, CH3COO; dd, J = 4.0 and
11.6, 1 H, H-6; m, W = 40; s, 3 H, 3 × H-19; m, W = 18, 1 H, H-6; tt, J = 4.0 and 11.6; t,
o
p
q
r
s
t
u
v
J = 8,2, 1 H, H-6; s, 3 H, CH3SO2O; overlapping signal of H-6; AB system, J = 12.1, 2 × H-4;
w
x
AB system, J = 11.6, 2 × H-4; s, 3 H, 17a-CH3.
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On Steroids
1635
The NOE cross-peaks between 4a-methyl group and protons in position 2β, 4β and 8β
clearly indicate the 4aα-OH, 4aβ-CH3 configuration at carbon C-4a.
Compound 31 was hydrogenated using a platinum catalyst in acetic acid. The lipophilic
fraction, a product of hydrogenation and hydrogenolysis8, was oxidized to a mixture of
ketones 2 and 3. The major fraction yielded a single compound 32 whose properties
(see Experimental) were compatible with the structure of 4aα,17β-dihydroxy-4aβ-
methyl-4a-homo-7,19-dinor-5α,9β,10β-androstan-3β-yl cyclohexanecarboxylate. Ketone
33, derived from compound 32, had a strong positive Cotton effect (∆ε298 +2.30) which
compares well with a CD curve of the corresponding 4a-deoxy compound – ketone 2
(ref.7, ∆ε297 +2.78).
O
O
+
1
C H COO
C H COO
6 5
6
5
H
OH
OMs
30
31
2
O
OR
H
H
H
H
1
R O
RO
H
H
2
OH
OR
1
33, R = C H CO
11
6
2
32, R = C H CO; R = H
6
11
1
2
35, R = C H CO; R = THP
6
11
2
1
34, R = H; R = H
1
2
36, R = H; R = THP
OH
O
R
H
H
H
H
O
O
H
OH
H
OH
27
28, R = CH
29, R = H
3
SCHEME 3
Ketone 33 was treated with methylmagnesium iodide and oxidized to yield com-
pound 28, an analogue of methyltestosterone. Triol 34, obtained from ester 32, was
oxidized to another analogue, diketone 27.
Alternatively, hydroxy groups of 17β-alcohol 32 were protected by tetrahydro-
pyranylation and a mixture of isomers produced (35) was subjected to lithium alumi-
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Kasal, Slavikova, Kohout, Budesinsky:
nium hydride treatment which resulted in a hydrolysis of the ester group. 3β-Alcohol
formed (36) was oxidized and after deprotection, a testosterone analogue 29 was produced.
In summary, platinum-catalyzed hydrogenation of the ∆9-double bond in B-nor ste-
roids (i.e. types 1 and 31) yields products of syn addition of hydrogen from the α and
β sides. The homoallylic 4aα-hydroxy group favours the approach of hydrogen from
the opposite (i.e. β) side under the formation of 9β,10β-dihydro products. For example
the cholestane 9β,10β isomer 12 is formed in 88% yield, in the androstane series the
excess of the 9β,10β isomer (i.e. 32) seems to be even higher.
This directing effect of a homoallylic hydroxy group on the catalytic hydrogenation
of olefins has manifested itself in increased addition of hydrogen from the site of the
hydroxyl: e.g. the 19-hydroxyl increased the yield of 5β-steroids9,10. The “hydroxyl
group effect” was observed with platinum11, palladium12 and rhodium13 catalysts. The
discrepancy between earlier findings and our results may be explained in terms of steric
factors: the homoallylic hydroxyl in olefins of the type 9 is a tertiary hydroxyl group
while the most convincing examples of the above hydroxyl group effect are based on
the effect of primary hydroxyl groups9,12
.
Preliminary receptor tests of compound 28 revealed no significant binding to an-
drogen receptors (rat prostates) nor to human gestagen, glucocorticoid, mineralocorti-
coid and estrogen receptors. Compound 28 did not affect the mammary gland14 of male
or female mice. Because of the negative results of these tests, the other analogues 27
and 29 were withdrawn from the testing.
EXPERIMENTAL
Melting points were determined on a melting point micro apparatus Boetius (Germany) and are un-
corrected. Analytical samples were dried over phosphorus pentoxide at 50 °C/100 Pa. Optical rota-
tions were measured in chloroform, circular dichroism in methanol. IR spectra of chloroform
solutions (unless stated otherwise) were recorded on a Bruker IFS 88 spectrometer. Wavenumbers are
1
given in cm–1. H NMR spectra of prepared compounds were measured on a Varian UNITY-200 (at
200 MHz) spectrometer at 23 °C in deuteriochloroform with tetramethylsilane as internal standard.
Chemical shifts are given in ppm (δ-scale), coupling constants and width of multiplets in Hz (see
Table I). Proton 1D, 2D-COSY and 2D-NOESY spectra of compound 9 were run on a Varian
UNITY-500 (at 500 MHz) under the same conditions. Mass spectra were recorded on a VG Analyti-
cal ZAB-EQ spectrometer (energy of ionizing electrons 70 eV, ion source temperature 180–220 °C).
Thin-layer chromatography (TLC) was done on silica gel (ICN Biochemicals). Preparative thin-layer
chromatography (PLC) was carried out on 200 × 200 mm plates coated with a 0.7 mm layer of the
same material. For column chromatography silica gel 60–120 µm was used. Whenever aqueous solu-
tions of hydrochloric acid, potassium hydrogen carbonate and potassium carbonate are used, their
concentration is always 5%.
4aβ-Methyl-4a-homo-7,19-dinor-5α-cholest-9-ene-3β,4aα-diol (11)
A solution of compound4 (9; 150 mg, 0.30 mmol) in tetrahydrofuran (5 ml) was refluxed with lithium
aluminium hydride (ca 50 mg, 1.3 mmol). After 2 h, an excess of hydride was destroyed with
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

On Steroids
1637
acetone, the mixture was acidified with hydrochloric acid (5%, 1 ml) and a precipitate was extracted
with ether. The extract was washed with water, dried over sodium sulfate and evaporated in a vacuum.
Crystallization of the residue from acetone afforded 95 mg (80%) of compound 11, m.p. 126–128 °C.
IR spectrum: 3 609, 3 378 (OH); 1 025 (C–O). Mass spectrum, m/z (%): 402 (M+, 70), 384 (M – H2O,
100). For C27H46O2 (402.7) calculated: 80.54% C, 11.51% H; found: 80.27% C, 11.45% H.
4aα-Hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-cholestan-3-one (16)
a) From compound 9. A solution of olefin 9 (3.1 g, 6.12 mmol) in acetic acid (40 ml) was stirred
with a platinum catalyst (450 mg) in a hydrogen atmosphere at laboratory temperature for 18 h. The
solvent was evaporated in a vacuum. The residue was dissolved in chloroform, washed with the po-
tassium carbonate solution and water, and dried. The residue, i.e. a mixture of compounds 12 and 13,
was dissolved in tetrahydrofuran (25 ml) and treated with lithium aluminium hydride (ca 150 mg, ca 4 mmol)
at reflux. After 2 h, the mixture was worked up as in the preparation of diol 11. The residue was
purified on a column of silica gel (100 g, benzene–ether, 1 : 1). The major product (14; 2.05 g, 83%),
identical with the earlier prepared sample4, was dissolved in acetone (10 ml) and Jones reagent was
added dropwise under stirring at 0 °C. After 10 min, an excess of the oxidant was destroyed by a few
drops of methanol, inorganic products were filtered out and the solution was concentrated in a va-
cuum. The residue was partitioned between ether and the potassium hydrogen carbonate solution. The
organic layer was washed with water, dried over sodium sulfate and evaporated in a vacuum. The
residue (16; 1.99 g, 81% from compound 9) crystallized from acetone, m.p. 118–119 °C, [α]D –48°
(c 1.0). CD: ∆ε293 –2.95. IR spectrum: 3 601 (OH); 1 693 (C=O). Mass spectrum, m/z (%): 402 (M+,
71), 384 (100), 369 (41), 344 (53). For C27H46O2 (402.7) calculated: 80.54% C, 11.51% H; found:
80.49% C, 11.54% H.
b) From diol 14. Jones reagent (0.5 ml) was added to a solution of diol 14 (65 mg, 0.16 mmol) in
acetone (1 ml). The mixture was worked up and crystallized as above to yield 48 mg (74%) of
ketone 16, identical with the above sample.
4aα-Hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,10α-cholestan-3-one (17)
Compound 15 (260 mg, 0.64 mmol), the minor product from the chromatography of compound 16,
was oxidized to 17 according to the preceding experiment. Ketone 17 (235 mg, 91% from alcohol 15
or 9% from olefin 9) crystallized from acetone, m.p. 154–156 °C, [α]D +72° (c 0.9). CD: ∆ε286 +3.04.
IR spectrum (carbon tetrachloride): 3 610, 3 598 (OH); 1 702 (C=O). Mass spectrum, m/z (%): 402
(100). For C27H46O2 (402.7) calculated: 80.54% C, 11.51% H; found: 80.29% C, 11.44% H.
5,6β-Dihydroxy-5α-cholestan-3β-yl Pivalate (20)
Sodium hydrogen phosphate (40.3 g, 0.284 mol) and peracetic acid (32 wt.% solution in dilute acid,
105 ml, 38 mmol) were added to a solution of cholest-5-en-3β-yl pivalate15 (51.89 g, 110 mmol) in
chloroform (250 ml). The mixture was stirred for 2 h, washed with water, the potassium hydrogen
carbonate solution, water, and dried over sodium sulfate. The solvent was evaporated in a vacuum.
The residue was dissolved in dioxane (1 040 ml) and acetone (700 ml). Perchloric acid (5%, 175 ml,
207.5 mmol) was added to the solution under stirring at laboratory temperature. After 3 h the mixture
was concentrated to a quarter of its volume and washed with brine. The product was extracted with
chloroform, dried and the solvent was evaporated in a vacuum. Crystallization of the residue from
toluene afforded compound 20 (37 g, 67%), m.p. 230–232 °C, [α]D –8° (c 1.3). IR spectrum: 3 632,
3 598 (OH); 1 723 (C=O); 1 170, 1 157 (C–O). For C32H56O4 (504.8) calculated: 76.14% C, 11.18% H;
found: 76.38% C, 11.33% H.
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Kasal, Slavikova, Kohout, Budesinsky:
5-Methyl-19-nor-5β-cholest-9-ene-3β,6β-diyl 3-Pivalate 6-Acetate (19)
From a solution of compound 20 (37 g, 73.3 mmol) in acetic anhydride (810 ml) volatile products
(156 ml) were distilled off at atmospheric pressure. Concentrated sulfuric acid (1 ml, 18.76 mmol)
was added dropwise into the stirred mixture below 30 °C. After 2 h the reaction mixture was diluted
with brine (5.5 l). A precipitate was filtered off, dissolved in toluene and washed with the potassium
carbonate solution and brine. An organic layer was filtered over silica gel (30 g) and the solvent was
evaporated. Crystallization of the residue from methanol yielded compound 19 (26.68 g, 69%), m.p.
156–157 °C, [α]D +84° (c 1.3). IR spectrum: 1 739, 1 725 (C=O); 1 242, 1 029, 1 158 (C–O). For
C34H56O4 (528.8) calculated: 77.22% C, 10.67% H; found: 77.47% C, 10.70% H.
5-Methyl-19-nor-5β,9β,10β-cholestane-3β,6β-diyl 3-Pivalate 6-Acetate (21)
Compound 19 (100 mg, 0.19 mmol) was hydrogenated on platinum oxide (80 mg) in acetic acid (30 ml)
at 70 °C for 8 h. The catalyst was filtered off and the filtrate was evaporated in a vacuum. The
residue was purified by PLC (3 plates): elution with petrolether–ether (9 : 1) afforded compound 21
(51 mg, 51%) and a mixture of trans dihydro derivates 22 and 23 (47 mg, 47%). Compound 21 crys-
tallized from methanol (43 mg), m.p. 129–131 °C, [α]D +3° (c 1.3). IR spectrum: 1 739, 1 725
(C=O); 1 240, 1 036, 1 172 (C–O). For C34H58O4 (530.8) calculated: 76.93% C, 11.01% H; found:
77.12% C, 11.23% H.
5-Methyl-6β-hydroxy-19-nor-5β,9β,10β-cholestan-3β-yl Pivalate (24)
A solution of sodium methoxide in methanol (0.87 M, 0.84 ml, 0.73 mmol) was added to a solution
of compound 21 (258 mg, 0.49 mmol) in ethanol (1 ml) and the reaction mixture was refluxed for
1.5 h. The solvent was evaporated in a vacuum, the residue was dissolved in chloroform, washed
with water and dried. After evaporation, compound 24 (213.8 mg, 90%) did not crystallize, [α]D +15°
(c 1.3). IR spectrum: 3 629, 3 466 (OH); 1 722, 1 710 sh (C=O); 1 172 (C–O); 1 054 (C–OH). For
C32H56O3 (488.8) calculated: 78.63% C, 11.55% H; found: 78.51% C, 11.48% H.
5-Methyl-19-nor-5β,9β,10β-cholestane-3β,6β-diyl 3-Pivalate 6-Methanesulfonate (25)
Methanesulfonyl chloride (0.8 ml, 10.34 mmol) was added to a solution of 24 (500 mg, 1.0 mmol)
in pyridine (8 ml) at 0 °C. After 2.5 h, the reaction mixture was diluted with ice water, the product
was extracted with chloroform, washed with aqueous hydrochloric acid, water, the potassium hy-
drogen carbonate solution, water and dried. Evaporation of the solvent afforded compound 25 (540 mg,
93%). IR spectrum: 1 723 (C=O); 1 363, 1 354, 1 340 (SO2); 1 175, 1 160 (C–O). For C33H58O5S
(566.9) calculated: 69.92% C, 10.31% H, 5.66% S; found: 69.85% C, 10.14% H, 5.50% S.
4aα-Hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-cholestan-3β-yl Pivalate (26)
A solution of potassium acetate (400 mg, 4.1 mmol) in water (10 ml) was added to a solution of
mesylate 25 (250 mg, 0.44 mmol) in dioxane (30 ml) and the mixture was refluxed in a nitrogen
atmosphere. After 6 h, the solvent was evaporated in a vacuum, the residue was dissolved in toluene,
washed with the potassium carbonate solution and water, and dried. After evaporation of the solvent,
the residue was purified by PLC (4 plates, benzene–ether, 95 : 5). Compound 26 (90 mg, 42%) did
not crystallize, [α]D +24° (c 1.6). IR spectrum: 3 613, 3 503 (OH); 1 722 (C=O); 1 176 (C–O). For
C32H56O3 (488.8) calculated: 78.63% C, 11.55% H; found: 78.57% C, 11.71% H.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

On Steroids
1639
4aβ-Methyl-4a-homo-7,19-dinor-5α,9β,10β-cholestane-3β,4aα-diol (14)
Lithium aluminum hydride (100 mg, 2.7 mmol) was added to a solution of compound 26 (130 mg,
0.27 mmol) in tetrahydrofuran (5 ml) and the mixture was refluxed for 1 h. After cooling, a solution
of sodium sulfate was added (1 ml), the mixture was filtered over sodium sulfate and the solvent was
evaporated. The residue crystallized from acetone–heptane, m.p. 90–92 °C (75 mg, 70%), [α]D +31°
(c 1.1). IR spectrum: 3 613, 3 371 (OH); 1 022 (C–OH). The compound was identical (IR spectrum)
with a sample prepared before4 (for compound XVII the lit.4 gives the following values: m.p. 90–92 °C,
[α]D +34°).
4aα-Hydroxy-4aβ-methyl-17-oxo-4a-homo-7,19-dinor-5α-androst-9-en-3β-yl Benzoate (31)
a) A solution of 5-methyl-17-oxo-19-nor-5β-androst-9-en-3β,6β-diyl 3-benzoate 6-methanesulfo-
nate7 (30; 4.13 g, 8.5 mmol) and potassium acetate (4.13 g, 42.1 mmol) in aqueous acetone (500 ml,
27%) was refluxed in a nitrogen atmosphere. After 5 h, the solvent was evaporated in a vacuum. The
residue was dissolved in toluene and washed successively with the potassium carbonate solution and
water, and dried. The product was purified by chromatography on a column of silica gel (150 g).
Elution with toluene yielded diene 1 (1.13 g, 34%) identical with the authentic sample7. Elution with
ethyl acetate–toluene (1 : 5) yielded compound 31 (2.42 g, 61%), [α]D +90° (c 0.9). IR spectrum:
3 597 (OH); 1 731, 1 712 (C=O); 1 602, 1 585, 1 452 (arom.); 1 278 (C–O). 1H NMR spectrum (500 MHz):
0.96 s, 3 H (3 × H-18); 1.19 dt, 1 H, J(12α,12β) = 12.8, J(12α,11β) = 13.2, J(12α,11α) = 5.6 (H-12α);
1.24 s, 3 H (4a-Me); 1.29 ddd, 1 H, J(14,8) = 11.6, J(14,15α) = 5.8, J(14,15β) = 12.6 (H-14); 1.62 ddd,
1 H, J(6α,5) = 9.4, J(6α,6β) = 13.6, J(6α,8) = 6.7 (H-6α); 1.64 tt, 1 H, J(15β,15α) = J(15β,14) =
12.6, J(15β,16α) = J(15β,16β) = 9.0 (H-15β); 1.85 ddd, 1 H, J(12β,12α) = 12.8, J(12β,11α) = 1.8,
J(12β,11β) = 5.6 (H-12β); 1.95 m, 1 H (H-15α); 1.98 m, 1 H (H-2β); 2.00 dd, 1 H, J(4α,4β) = 14.6,
J(4α,3) = 3.6 (H-4α); 2.05 m, 1 H (H-11β); 2.09 ddd, 1 H, J(16α,16β) = 19.0, J(16α,15α) = 10.0,
J(16α,15β) = 9.0 (H-16α); 2.12 m, 1 H (H-2α); 2.21 ddd, 1 H, J(6β,6α) = 13.6, J(6β,5) = 2.6,
J(6β,8) = 7.9 (H-6β); 2.23 dd, 1 H, J(4β,4α) = 14.6, J(4β,3) = 5.5 (H-4β); 2.25 m, 1 H (H-1α); 2.47 bddd,
1 H, J(11α,11β) = 14.8, J(11α,12α) = 5.6, J(11α,12β) = 1.8 (H-11α); 2.47 ddd, 1 H, J(16β,16α) =
19.0, J(16β,15α) = 1.1, J(16β,15β) = 9.0 (H-16β); 2.50 m, 1 H (H-1β); 2.67 m, 1 H (H-8); 2.94 m,
1 H (H-5); 5.48 tdd, 1 H, J(3,2α) = J(3,4α) = 3.6, J(3,2β) = 7.3, J(3,4β) = 5.5 (H-3); 7.44 m, 2 H
(H-3 of benzoate); 7.56 m, 1 H (H-4 of benzoate); 8.00 m, 2 H (H-2 of benzoate). For C26H32O4
(408.5) calculated: 76.44% C, 7.90% H; found: 76.14% C, 8.12% H.
b) A solution of mesylate 30 (200 mg, 0.4 mmol) and silver tetrafluoroborate (400 mg, 2.1 mmol)
in toluene (4 ml) was stirred at 20 °C in the dark. After 40 h, the mixture was diluted with chloro-
form, washed with water and dried over sodium sulfate. The residue was resolved by PLC (3 plates,
ether–benzene, 1 : 1) into two products: 1 (51 mg, 32%) and 31 (63 mg, 38%).
Hydrogenation of 4aα-Hydroxy-4aβ-methyl-17-oxo-4a-homo-7,19-dinor-5α-androst-9-en-3β-yl
Benzoate (31)
Compound 31 (2.60 g, 6.24 mmol) was hydrogenated in acetic acid (40 ml) with a platinum catalyst
(460 mg) at laboratory temperature for 24 h. The catalyst was filtered off. The filtrate was evaporated in
a vacuum. The residue (2.6 g) was applied on a column of silica gel (200 ml). Toluene–ethyl acetate
(3 : 1) eluted successively.
Lipophilic fraction (711 mg, 28%), according to 1H NMR spectrum it is a mixture of 4a-deoxy
compounds. Its Jones oxidation afforded a mixture of compounds 2 and 3.
4aα,17β-Dihydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-androstan-3β-yl cyclohexanecar-
boxylate (32; 1.65 g, 63%) crystallized from acetone–heptane, m.p. 121–123 °C, [α]D +10° (c 1.0).
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1640
Kasal, Slavikova, Kohout, Budesinsky:
IR spectrum (carbon tetrachloride): 3 631, 3 617 (OH); 1 723 (C=O); 1 249, 1 192, 1 174 (C–O);
1 134, 1 041 (C–OH). Mass spectrum, m/z (%): 418 (M+, 0.3), 290 (100), 272 (84). For C26H42O4
(418.6) calculated: 74.60% C, 10.11% H; found: 74.59% C, 10.08% H.
4aβ-Methyl-4a-homo-7,19-dinor-5α,9β,10β-androstane-3β,4aα,17β-triol (34)
Lithium aluminium hydride (ca 30 mg, ca 0.8 mmol) was added to a solution of ester 32 (74 mg,
0.18 mmol) in tetrahydrofuran (3 ml) and the mixture was refluxed for 5 min. After 1 h standing at
room temperature, an excess reagent was decomposed by water. The mixture was saturated with anhydrous
sodium sulfate. Inorganic material was filtered off and washed with hot chloroform. The extract was
concentrated in a vacuum and crystallized from acetone. Yield 45 mg (83%), m.p. 211–213 °C, [α]D +22°
(c 0.9). IR spectrum: 3 608, 3 340, 3 232 (OH); 1 075, 1 043, 1 021, 1 013 (C–OH). For C19H32O3
(308.5) calculated: 73.98% C, 10.46% H; found: 73.78% C, 10.39% H.
4aα-Hydroxy-4aβ-methyl-17-oxo-4a-homo-7,19-dinor-5α,9β,10β-androstan-3β-yl Cyclohexane-
carboxylate (33)
Compound 32 (370 mg, 0.88 mmol) was oxidized by Jones reagent in acetone as above. A product
was purified by PLC (5 plates, benzene–ether, 3 : 1) and crystallized from acetone–heptane. Yield
257 mg (69%), m.p. 144–147 °C, [α]D +54° (c 1.2). CD: ∆ε298 +2.30. Mass spectrum, m/z: 416 (M+),
288 (M – C6H11COOH), 270 (288 – H2O). For C26H40O4 (416.6) calculated: 74.96% C, 9.68% H;
found: 74.80% C, 9.72% H.
4aα,17β-Dihydroxy-4aβ,17α-dimethyl-4a-homo-7,19-dinor-5α,9β,10β-androstan-3-one (28)
Ketone 33 (4.9 g, 11.8 mmol) was dissolved in benzene (150 ml) and added to a solution of freshly
prepared methylmagnesium iodide in ether, prepared from magnesium (1.0 g, 41.1 mmol) and methyl
iodide (2.0 ml, 32.1 mmol) in ether (50 ml). After the addition, ether was distilled off, the mixture
was refluxed for 3 h and poured onto ice (200 g) with concentrated hydrochloric acid (15 ml). The
precipitate was filtered off and dissolved in chloroform. The solution was washed with a sodium
thiosulfate solution (5%), water and the potassium hydrogen carbonate solution. The solution was
evaporated in a vacuum and oxidized with Jones reagent as above. Ketone 28 crystallized from toluene.
Yield 2.30 g (64%), m.p. 201–203 °C, [α]D –94° (c 1.1). CD: ∆ε294 –2.16. IR spectrum: 3 604, 3 457
(OH); 1 695 (C=O). For C20H32O3 (320.5) calculated: 74.96% C, 10.06% H; found: 74.68% C,
10.06% H.
4aα-Hydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-androstane-3,17-dione (27)
Jones reagent was added dropwise into a solution of 34 (198 mg, 0.64 mmol) in acetone (5 ml) under
stirring at 20 °C. After 10 min, an excess of the reagent was reduced with a few drops of methanol,
the inorganics were filtered off and the filtrate was evaporated in a vacuum. The residue was dis-
solved in chloroform and washed with the potassium carbonate solution and water, and dried. Crys-
tallization of the residue from acetone–heptane afforded 98 mg (50%) of compound 27, m.p.
202–204 °C, [α]D +26° (c 0.7). CD: ∆ε300 +0.52. IR spectrum: 3 600 (OH); 1 732, 1 685 (C=O);
1 040 (C–O). Mass spectrum, m/z (%): 304 (M+), 286 (100); high resolution, for C19H28O3 calcu-
lated: 304.203845, found: 304.201800. For C19H28O3 (304.4) calculated: 74.96% C, 9.27% H; found:
74.80% C, 9.19% H.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

On Steroids
1641
4aα,17β-Dihydroxy-4aβ-methyl-4a-homo-7,19-dinor-5α,9β,10β-androstan-3-one (29)
A solution of 17β-hydroxy derivative 32 (100 mg, 0.24 mmol) in dichloromethane (20 ml) and 3,4-
dihydro-2H-pyran (ca 200 mg, ca 2.4 mmol) was treated with 4-toluenesulfonic acid monohydrate
(10 mg, 0.05 mmol) at ambient temperature. After 2 h, the mixture was washed with the potassium
hydrogen carbonate solution and dried over magnesium sulfate. The residue (compound 35) was re-
fluxed in a solution of sodium methoxide in methanol (4.7%, 5 ml, 4.4 mmol). After 5 h, the solution
was concentrated in a vacuum and the product was precipitated by and addition of brine (10 ml). The
precipitate was taken up in toluene. The extract was washed with brine and concentrated in a va-
cuum. The residue was dissolved in dichloromethane (1 ml) and added in one portion to a stirred
suspension of pyridinium chlorochromate (130 mg, 0.6 mmol) and sodium acetate (50 mg, 0.61 mmol)
in the same solvent (3 ml). After 3 h, the mixture was diluted with ether (20 ml) and stirred for
another 10 min. The supernatant was decanted and the dark solid was washed twice with ether (5
ml). The solution was filtered through a short column of silica gel (1.5 g). The filtrate was evap-
orated and the residue was treated with 4-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol) in
acetone (3 ml) at ambient temperature. After 18 h, potassium hydrogen carbonate was added (10 mg,
0.1 mmol) and the mixture was concentrated in a vacuum. The residue was dissolved in chloroform,
washed with water, dried and purified by PLC (one plate, benzene–ether, 1 : 1). Compound 29 (21 mg,
29%) melts at 180–182 °C (acetone–heptane), [α]D –73° (c 0.8). IR spectrum: 3 604, 3 464 (OH);
1 696 (C=O); 1 404 (CH2 next to C=O). For C19H33O3 (306.4) calculated: 74.47% C, 9.87% H;
found: 74.26% C, 9.73% H.
This work was supported by grant No. 505/94/0009 of the Grant Agency of the Czech Republic. The
authors are indebted to F. Bouchoux and E. Cerede (ROUSSEL UCLAF, France) for receptor tests and
to Dr J. Skarda (Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Repub-
lic) for in vivo tests.
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