Epalons: 6-substituted derivatives of 7-norepiallopregnanolone

Article abstract of DOI:10.1016/S0040-4020(00)00263-5

The target compounds (3α-hydroxy-5,6-epoxy-7-nor-5α-pregnan-20-one, 3α-hydroxy-5,6β-epoxy-7-nor-5β-pregnan-20-one and 3α-hydroxy-7-nor-5α- pregnane-6,20-dione) were prepared from 5,6β-dihydroxy-20-oxo-5α-pregnan- 3β-yl acetate via the corresponding 5,6-se

Full text of DOI:10.1016/S0040-4020(00)00263-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3559±3565
Epalons: 6-Substituted Derivatives of 7-Norepiallopregnanolone
*
Alexander Kasal
Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Fleming Square 2, CZ16610 Prague 6, Czech Republic
Received 10 January 2000; revised 6 March 2000; accepted 23 March 2000
AbstractÐThe target compounds (3a-hydroxy-5,6-epoxy-7-nor-5a-pregnan-20-one, 3a-hydroxy-5,6b-epoxy-7-nor-5b-pregnan-20-one
and 3a-hydroxy-7-nor-5a-pregnane-6,20-dione) were prepared from 5,6b-dihydroxy-20-oxo-5a-pregnan-3b-yl acetate via the corresponding
5,6-seco acid and 3b-acetoxy-20-oxo-7-nor-5b,6a-pregnane-6,5-carbolactone-actone. Intermediate 3b-hydroxy-7-norpregn-5-en-20-one
was converted into the corresponding 5a,6a and 5b,6b epoxides. The latter was isomerized into 3b-hydroxy-7-nor-5a-pregnane-6,20-
dione. The con®guration of the 3b-hydroxy group in these compounds was inverted by Mitsunobu reactions. q 2000 Elsevier Science Ltd.
All rights reserved.
In a search1±4 for new positive modulators of g-amino-butyric
acid receptors of the brain we prepared5 an analogue of
`epiallopregnanolone' with a ¯atter B ring, i.e. `7-norepiallo-
pregnanolone' (3a-hydroxy-7-nor-5a-pregnan-20-one, 1,
see Scheme 1). Here we report on the synthesis of analogues
containing an additional oxygen atom in the B ring (e.g.
compound 2) which makes the substrates more soluble in
body ¯uids and thus potentially more useful for the treat-
ment of pain, anxiety and sleep disorders.6±9
The above inversion of con®guration was manifested by the
change of multiplicity of the H-3 signal in 1H NMR spectra:
compounds 12 and 13 had a narrow multiplet at d 5.36 and
4.2, respectively (width of signalˆ15 Hz), in contrast to a
broad multiplet of starting alcohol 10 at d 3.96 (width of
signalˆ35 Hz). The 5b,6b-epoxide 14 was easily prepared
from alkene 9 via the corresponding bromohydrin 15 which
was generated from compound 9 and hypobromous acid
(see Scheme 2). A lipophilic side product was assigned
the structure of a 17b-H pregnane derivative 16: its strongly
negative Cotton effect (D128727.47) contrasts with the posi-
tive values for 17a-isomers (e.g. D128813.57 for compound
11). The C-17 inversion was also accompanied by the
collapse13 of the triplet of H-17a in the `normal' pregnane
derivatives (e.g. ketone 14) into a doublet in the 17b-H
isomer 16 (see Experimental). The above isomerization at
carbon 17 was prevented when the dehydrobromination of
bromohydrin 15 was carried out under milder conditions
(potassium carbonate at room temperature).
The contraction of the B ring was carried out as previously
reported,10 i.e. from 20-oxopregn-5-en-3b-yl acetate (3) via
the corresponding 5,6-seco acid 4 (see Scheme 1). Unfortu-
nately, the above oxidation leads mostly to the product of
allylic oxidation 5. The acidic product consisted of an
inseparable mixture of the acid sought 4 and the product
of the C17±C20-bond cleavage, 20,21-dinor acid 6 (12%
1
according to H NMR spectrum). However, if the alkene 3
was ®rst converted into diol 7, the 5,6-seco steroid produc-
tion was cleanly carried out under milder conditions.11 On
treatment of acid 4 with benzoyl chloride in pyridine and
then on pyrolysis we obtained compounds10 8 and 9.
The 5b,6b-epoxides 14 and 17 turned out to be much more
acid-sensitive than 5a,6a-epoxide 10, therefore their NMR
and IR spectra had to be quickly measured in freshly
puri®ed deuteriochloroform, otherwise the H-6 signal (d
3.22) was reduced in intensity and a new CvO absorption
band at 1732 cm21 emerged.14 The ease of isomerization
corresponds to a lower barrier to the hydride ion migration
from C-6 to C-5 in 5b,6b-epoxides (e.g. 14) in comparison
with that of 5a,6a-epoxides (e.g. 10).
Epoxidation of 7-norsteroids is known to afford almost
exclusively12 5a,6a-epoxides. Thus, compound 10 formed
on oxidation of alkene 11 with 4-chloroperoxybenzoic acid
was ascribed the 5a,6a-epoxide structure. Its treatment with
formic acid in the presence of diethyl azodicarboxylate and
triphenylphospine produced formate 12 with the reversed
con®guration at carbon 3. The hydrolysis of the ester
grouping in compound 12 led to a 5,7-cyclo analogue of
`6-oxa-epiallopregnanolone', compound 13.
The above acid-sensitivity of 5b,6b-epoxides was utilized
in the preparation of 5a-ketone 18 from epoxide 14 and
boron tri¯uoride diethyl etherate.14 When acetoxy ketone
17 was treated similarly, two by-products 19 and 20 were
isolated besides the sought ketone 21. Their structure
assignment was based on spectral evidence (see MS and
1H NMR spectra in Experimental).
Keywords: steroids; Mitsunobu reaction; epoxides; isomerisation; halo-
hydrins.
* Tel.: 14-202-20183-314; fax: 14-202-24310-090;
e-mail: kasal@uochb.cas.cz
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00263-5

3560
A. Kasal / Tetrahedron 56 (2000) 3559±3565
Scheme 1. Reagents: (a) MPA, then HClO4 in THF; (b) CrO3 in AcOH, 508C; (c) Jones reagent, acetone, toluene, 508C; (d) BzCl, py; (e) pyrolysis; (f) DEAD,
triphenylphospine and formic acid, then KHCO3 in MeOH.
The desired 3a-hydroxy diketone 2 was ®rst prepared from
the 3b-hydroxy derivative 18 in low yield by Mitsunobu
reaction via formate 22. The yield was reduced by intra-
molecular cyclisation leading to cyclopropano-ketone 23
(see Experimental for the IR frequency of C6vO absorption
decreased by conjugation with the cyclopropane ring and for
the proton signal of this ring). The ef®ciency of the sequence
was further lessened by lability of 5a-ketones in the 7-nor
series: hydrolysis of formate 22 produced not only the
expected 3a-alcohol 2 but also a by-product 24. The latter
had a much diminished positive Cotton effect (see the value
of D1 in Experimental) and a wide signal of the 3b proton in
was followed with the Lewis acid treatment of epoxide 26).
In this way, the diketone 2 was produced without compli-
cations.
The binding of the target compounds 2, 13 and 26 to the
GABAA receptor, measured through effects on [3H]muscimol
and [35S]TBPS binding, will be published elsewhere.
Experimental
General. Whenever aqueous solutions of hydrochloric acid,
potassium hydrogen carbonate and potassium carbonate
were used, their concentration was always 5%. Prior to
evaporation on a rotary evaporator in vacuo (bath tempera-
ture 508C), solutions in organic solvents were dried over
anhydrous sodium sulfate. Thin-layer chromatography
(TLC) was performed on silica gel (ICN Biochemicals),
preparative TLC (PLC) was carried out on 200£200 mm
plates coated with an 0.7 mm thick layer of the same
material. For column chromatography, silica gel 60±
120 mm was used. Analytical samples were dried over
phosphorus pentoxide at 508C/100 Pa. Melting points were
determined on a micro melting point apparatus (Boetius,
Germany) and are uncorrected. Optical rotations were
measured in chloroform ([a]D values are given in
1021 deg cm2 g21), IR spectra were recorded on a Bruker
IFS 88 spectrometer, proton NMR spectra were measured
on a Varian UNITY-200 FT-NMR spectrometer (at
1
its H NMR spectrum (further, the 5a-H signal15 at d 2.35
disappeared). Both the patterns indicated a con®gurational
change at carbon C-5. A model experiment with ketone 2
showed that alkalinity, needed to hydrolyse the formate
grouping, was strong enough to cause the isomerization.
Earlier, it was found16 that 6-oxo-7-nor-5a-steroids could
equilibrate to 5b,8b- and even to 5b,8a-isomers. From
Morisawa's data17 on molecular rotation differences we
could easily identify the product structures since the con-
version into the former isomer was accompanied with a
smaller negative difference (DMˆ22998) than the con-
version into the latter one (DMˆ26138). The DM value of
compound 24 (22868) con®rmed the 5b,8b-con®guration.
In an alternative route, the epoxide isomerization to ketone
and the Mitsunobu reaction were swapped (i.e. an alkaline
hydrolysis of the formate was realized in epoxide 25 which

A. Kasal / Tetrahedron 56 (2000) 3559±3565
3561
Scheme 2. Reagents: (a) NBS, HClO4; (b) K2CO3 or KOH, MeOH; (c) KOH, MeOH; (d) DEAD, triphenylphosphine, HCOOH, then KHCO3, MeOH;
(e) BF3´Et2O.
200 MHz) in CDCl3 with tetramethylsilane as internal
reference. Chemical shifts of selected signals are given in
ppm (d-scale), coupling constants and width of multiplets in
Hz. Unless otherwise stated, the data were interpreted as the
®rst-order spectra.
besides white crystals of 3a-hydroxy-7-nor-5b-pregnane-
6,20-dione (24, 9 mg, 13%), mp 162±1648C (acetone±
heptane); [a]Dˆ198 (c 0.8, CHCl3). Circular dichroism:
D1292 12.54 (methanol); dH (200 MHz, CDCl3) 3.75±
3.56 (1H, m, H-3), 2.51 (1H, t, Jˆ9.0 Hz, H-17a), 2.15
(3H, s, 3£H-21), 0.99 (3H, s, 3£H-19), 0.62 (3H, s, 3£
H-18).
3a-Hydroxy-7-nor-5a-pregnane-6,20-dione (2). (a) By
hydrolysis. A solution of potassium hydrogencarbonate
(75 mg, 0.75 mmol) in water (1 mL) was added to a boiling
solution of formate 22 (90 mg, 0.26 mmol) in methanol
(9 mL). After 5 min, the solution was evaporated to dryness
in vacuo. The residue was partitioned between water and
chloroform, the organic layer was dried over sodium sulfate
and concentrated in vacuo. PLC (two plates, benzene±ethyl
acetate 1:1, double development) yielded the title
compound 2 (50 mg, 73%) as white crystals, mp 166±
1678C (acetone); [Found: C, 75.21; 9.69. C20H30O3 requires
C, 75.43; 9.50%]; [a]Dˆ1188 (c 1.1, CHCl3). nmax (CHCl3)
(b) By isomerisation. A solution of epoxide 26 (36 mg,
0.11 mmol) in tetrahydrofuran (3 mL) was treated with
boron tri¯uoride diethyl etherate (0.005 mL, 0.004 mmol)
as in the preparation of compound 18. The title compound 2
(32 mg), identical with the above product, was produced in
88% yield.
3b-Acetoxy-5,20-dioxo-5,6-seco-5b-pregnan-6-oic acid
(4). (a) Jones reagent11 (91 mL) was added to a solution of
diol 7 (37.9 g, 96.6 mmol) in a mixture of acetone (760 mL)
and toluene (200 mL) under stirring at 508C. After 2 h, an
excess of the reagent was reduced with propan-2-ol and
solvents were evaporated in vacuo. The residue was
dissolved in dichloromethane and washed subsequently
with a saturated aqueous solution of oxalic acid and
3613, 3505, 999, 986 (OH); 1729, 1701, 1360 (CvO) cm21
.
Circular dichroism: D1296 16.38 (methanol); dH (200 MHz,
CDCl3) 4.22 (1H, p, Jˆ2.7 Hz, H-3), 2.51 (1H, t, Jˆ9.0 Hz,
H-17a), 2.35 (1H, dd, Jˆ12.2, 2.4 Hz, H-5), 2.15 (3H, s,
3£H-21), 0.83 (3H, s, 3£H-19), 0.63 (3H, s, 3£H-18),

3562
A. Kasal / Tetrahedron 56 (2000) 3559±3565
water. The extract was dried over sodium sulfate and evapo-
rated. Part (84 mg) of the oily title compound (38.0 g, 97%)
was puri®ed for analysis by PLC (2 plates, benzene±ether
1:1). The product failed to crystallize from common
solvents (earlier reported sample18 was not characterized).
[a]Dˆ190 (c 1.2, CHCl3); [Found: C, 69.86; H, 8.57.
C23H34O6 requires C, 67.96; H, 8.43%]; nmax (CHCl3)
3525 (COOH-monomer), 3032, 2684, 1421, 1291 (COOH-
dimer); 1733, 1249, 1025 (AcO, COOH); 1704 (CvO)
cm21; dH (200 MHz, CDCl3) 5.45±5.34 (1H, m, H-3),
3.21 (1H, dd, Jˆ14.9 Hz, 4.3, H-4a), 2.13 (3H, s, 3£
H-21), 2.02 (3H, s, CH3COO), 1.05 (3H, s, 3£H-19), 0.65
(3H, s, 3£H-18).
(5.85 g, 15.1 mmol) was heated to 1908C according to
Ref. 10 The title compound 9 (3.09, 60%) was found
identical with the authentic sample. nmax (CHCl3) 1727,
1250 (AcO); 1699 (COCH3); 1635 (CvC) cm21; dH
(200 MHz, CDCl3) 5.39 (1H, bs, H-6), 4.72±4.55 (1H, m,
H-3), 2.64 (1H, ddd, Jˆ13.7, 4.9, 1.8 Hz, H-4a), 2.14 (3H,
s, 3£H-21), 2.04 (3H, s, CH3COO), 0.90 (3H, s, 3£H-19),
0.64 (3H, s, 3£H-18).
3b-Hydroxy-5,6a-epoxy-7-nor-5a-pregnan-20-one (10).
Compound 11 (850 mg, 2.81 mmol) was treated with
4-chloroperoxybenzoic acid (550 mg, 3.19 mmol) in
dichloromethane (20 mL) at 08C. After 2 h, the mixture
was washed with the potassium hydrogencarbonate solution
and water. After evaporation of the solvent, crystallization
yielded the title compound 10 (610 mg, 70%), mp 220±
2218C (dichloromethane±heptane); [a]Dˆ113 (c 1.1,
CHCl3); [Found: C, 75.23; H, 9.60. C20H30O3 requires C,
75.43; H, 9.50%]; nmax (CHCl3) 3611, 3463, 1034 (OH);
1699, 1358 (COCH3); 1386 (CH3) cm21; dH (200 MHz,
CDCl3) 4.05±3.87 (1H, m, H-3), 3.28 (1H, s, H-6b), 2.56
(1H, t, Jˆ9.0 Hz, H-17), 2.13 (3H, s, 3£H-21), 0.90 (3H, s,
3£H-19), 0.60 (3H, s, 3£H-18). Thin layer chromatography
of the mother liquor (7 plates, benzene±ethyl acetate 2:1,
double development) yielded an additional crop of the
a-epoxide 10 (134 mg, 15%).
(b) A solution of chromium trioxide (4.0 g, 40.0 mmol) in
aqueous acetic acid (50%, 20 mL) was added into a stirred
solution of alkene 3 (4.5 g, 12.55 mmol) in acetic acid
(50 mL) during 1 h at 508C. After an additional hour at
this temperature, an excess of the oxidizing agent was
reduced with methanol (30 mL) and the solvent was evapo-
rated at 458C in vacuo. The dry residue was partitioned
between ether and water, the combined ethereal extracts
were washed with water and dried and concentrated in
vacuo. The residue was dissolved in acetone (7 mL) applied
on a silica gel column (200 g). A mixture of chloroform and
2-propanol (98:2) eluted the ketone 5 (2.124 g, 45%); nmax
(CHCl3) 1730, 1366, 1035 (AcO); 1701, 1360 (COCH3);
1671, 1633 (CvC±CO) cm21 (the spectrum was identical
with that of an authentic sample19). More polar fractions
gave the title compound 4 (1.892 g, 37%) as colourless
3b-Hydroxy-7-norpregn-5-en-20-one (11). Acetate
9
(877 mg, 2.55 mmol) was treated with potassium carbonate
(2.0 g, 14.47 mmol) at room temperature in aqueous
methanol (4%, 50 mL) under nitrogen. After 2 h, the
mixture was ®ltered, the ®ltrate was concentrated to a
quarter of its volume and diluted with brine (50 mL). The
precipitate of the title compound 11 was taken up in chloro-
form, washed with water and dried. After evaporation in
vacuo, the residue (690 mg, 92%) crystallized from toluene
to yield white crystals. Mp 133±1358C, undepressed on
admixture of the authentic sample. [a]Dˆ226 (c 1.4,
CHCl3). Circular dichroism: D1288ˆ13.57 (methanol);
nmax (CHCl3) 3608, 3464, 1036 (OH); 1698, 1385, 1358
(COCH3); 1635 (CvC) cm21; dH (200 MHz, CDCl3) 5.39
(1H, bs, H-6), 3.67±3.49 (1H, m, H-3), 2.62 (1H, ddd,
Jˆ13.7, 4.9, 1.8 Hz, H-4a), 2.13 (3H, s, 3£H-21), 0.89
(3H, s, 3£H-19), 0.64 (3H, s, 3£H-18).
1
oil; H NMR spectrum proves the presence of 3b-acetoxy-
5,20-dioxo-5,6-secoandrostan-6-oic acid (6, 12%). For
comparison, the compound 6 was prepared from 17-oxo-
androst-5-en-3b-yl acetate according to Ref. 20 dH
(200 MHz, CDCl3) 5.42±5.33 (1H, m, H-3), 3.23 (1H, dd,
Jˆ14.9, 4.3 Hz, H-4a), 2.01 (3H, s, CH3COO), 1.07 (3H, s,
3£H-19), 0.89 (3H, s, 3£H-18).
5,6b-Dihydroxy-20-oxo-5a-pregnan-3b-yl acetate (7).
Compound 7 was prepared according to Ref. 21 by epoxi-
dation of 20-oxopregn-5-en-3b-yl acetate (3) and hydration
of the mixture of 5a,6a- and 5b,6b-epoxides. The hydration
was modi®ed as follows: a mixture of epoxides 3 (54 g,
0.15 mol) was dissolved in tetrahydrofuran (245 mL) and
treated with perchloric acid (7%, 54 mL) at room tempera-
ture (20 h) and then at 08C (6 h). A white precipitate of
the title compound 7 (43.1 g, 73%) was ®ltered off, an
additional crop (12.9 g, 22%) was obtained on precipitation
of the mother liquor with brine.
5,6a-Epoxy-20-oxo-7-nor-5a-pregnan-3a-yl formate (12).
A solution of alcohol 10 (467 mg, 1.47 mmol) in toluene
(90 mL) was heated until azeotropic mixture (30 mL)
distilled off. A solution of triphenylphosphine (900 mg,
3.43 mmol) in toluene (30 mL) was added to this solution
under stirring. The reaction mixture was stirred at 08C for
10 min and then diethyl azodicarboxylate (30 drops,
3.7 mmol) was added. After additional 20 min, formic
acid (9 drops, 4.3 mmol) was dripped in. The solution was
left aside for 18 h. A precipitate formed was ®ltered off and
washed with toluene, the ®ltrate was applied on a column of
silica gel (40 mL). Toluene±ether (10:1) eluted the title
compound 12 which crystallized from a mixture of heptane
and acetone. Mp 161±1628C (304 mg, 57%); [a]Dˆ143 (c
1.2, CHCl3); [Found: C, 72.7; H, 8.69. C21H30O4 requires C,
72.80; H, 8.73%]; nmax (CHCl3) 1716, 1194, 926 (formate);
1701, 1358 (COCH3); 1387 (CH3) cm21; dH (200 MHz,
CDCl3) 8.08 s, 1 H (HCOO), 5.40±5.32 (1H, m, H-3),
3b-Acetoxy-20-oxo-7-nor-5b,6a-pregnane-6,5-carbolac-
tone (8). Oxo acid 4 (12.7 g, 31.24 mmol) was cyclised by
treatment with benzoyl chloride (12 mL) in pyridine
(50 mL) according to Ref. 10. The title compound 8
(5.85 g, 48%), a colourless oil, was found identical with
the authentic sample. nmax (CHCl3) 1819, 1086 (b-lactone);
1729, 1252, 1021 (AcO); 1703 (COCH3) cm21; dH
(200 MHz, CDCl3) 5.08±4.93 (1H, m, H-3), 3.19 (1H, d,
Jˆ7.3 Hz, H-6), 2.53 (1H, t, Jˆ9.0 Hz, H-17), 2.13 (3H, s,
3£H-21), 2.06 (3H, s, CH3COO), 1.47 (3H, s, 3£H-19), 0.66
(3H, s, 3£H-18).
20-Oxo-7-norpregn-5-en-3b-yl acetate (9). b-Lactone 8

A. Kasal / Tetrahedron 56 (2000) 3559±3565
3563
3.21 (1H, s, H-6b), 2.58 (1H, t, Jˆ9.0 Hz, H-17), 2.37 (1H,
ddd, Jˆ15.0, 3.4, 0.9 Hz, H-4), 2.13 (3H, s, 3£H-21), 0.89
(3H, s, 3£H-19), 0.61 (3H, s, 3£H-18). Further fractions
yielded the starting compound (10, 99 mg, 21%).
(OH); 1738, 1250, 1230, 1045 (OAc); 1700 (CvO); 595
(Br) cm21; dH (200 MHz, CDCl3) 5.3525.24 (1H, m, H-3),
4.34 (1H, d, Jˆ6.1 Hz, H-6), 2.56 (1H, t, Jˆ9.3 Hz, H-17),
2.14 (3H, s, 3£H-21), 2.07 (3H, CH3COO), 0.95 (3H, s,
3£H-19), 0.68 (3H, s, 3£H-18).
3a-Hydroxy-5,6a-epoxy-7-nor-5a-pregnan-20-one (13).
Formate 12 (120 mg, 0.35 mmol) was treated with potas-
sium hydrogencarbonate (120 mg, 1.20 mmol) in aqueous
methanol (90%, 12 mL) under stirring at room temperature.
After 24 h, the solution was concentrated in vacuo, and
diluted with brine (20 mL). A precipitate of the title
compound 13 was ®ltered off, washed with water and
dried. Crystallization yielded compound 13 (78 mg, 71%)
as white crystals, mp 131±1328C (acetone±heptane);
[a]Dˆ114 (c 1.0); [Found: C, 75.37; H, 9.53. C20H30O3
requires C, 75.43; H, 9.50%]; nmax (CHCl3) 3575, 1024,
984 (OH); 1700, 1358 (COCH3); 1386 (CH3) cm21; dH
(200 MHz, CDCl3) 4.23±4.15 (1H, m, H-3), 3.24 (1H, s,
H-6b), 2.59 (1H, t, Jˆ9.0 Hz, H-17), 2.37 (1H, dd,
Jˆ15.4, 3.9 Hz, H-4), 2.14 (3H, s, 3£H-21), 0.87 (3H, s,
3£H-19), 0.61 (3H, s, 3£H-18).
3b-Hydroxy-5,6b-epoxy-7-nor-5b,17b-pregnan-20-one
(16). The mother liquor of the above example (sub a, 68 mg)
was chromatographed using 3 PLC plates in benzene±ethyl
acetate, 1:1. The polar component was identical with the
above epoxide 14 (33 mg, additional 17%), the less polar
component is the title compound 16 (27 mg, 14%), mp 175±
1768C (white crystals from acetone±heptane), nmax (CHCl3)
3610, 3480, 1037 (OH); 1700, 1382, 1359 (COCH3) cm21
;
dH (200 MHz, CDCl3) 4.01±3.83 (1H, m, H-3), 3.20 (1H, s,
H-6), 2.80 (1H, d, Jˆ7.5 Hz, H-17b), 2.14 (3H, s, 3£H-21),
0.86 (6H, s, 3£H-19 and 3£H-18). Circular dichroism:
D1287 27.47 (methanol); m/z (EI): 318 (M1, 100), 300
(26), 285 (14), 257 (20), 248 (28); HRMS (EI): found
318.2181. C20H30O3 requires 318.2195.
20-Oxo-5,6b-epoxy-7-nor-5b-pregnan-3b-yl acetate (17).
Epoxide 14 (270 mg, 0.75 mmol) was treated with acetic
anhydride (1.0 mL, 10.6 mmol) in pyridine (1.0 mL) at
room temperature. After 18 h, the mixture was poured
onto ice, the precipitate of the title compound was extracted
with ether, the extract was washed with the solution of
potassium hydrogen carbonate and water and dried with
sodium sulfate. The solvent was evaporated, the residue
was dissolved in toluene (10 mL) and repeatedly evaporated
to remove traces of pyridine. The product 17 (285 mg,
93%), a colourless oil, failed to crystallize from common
solvents. [a]Dˆ156 (c 0.9, CHCl3); [Found: C, 73.19; H,
9.11. C22H32O4 requires C, 73.30; H, 8.95%]; nmax (CHCl3)
1729, 1252, 1030 (AcO); 1702, 1361 (COCH3) cm21; dH
(200 MHz, CDCl3) 5.03±4.87 (1H, m, H-3), 3.20 (1H, s,
H-6), 2.52 (1H, d, Jˆ9.1 Hz, H-17), 2.12 (3H, s, 3£H-21),
2.05 (3H, s, CH3COO), 0.89 (3H, s, 3£H-19), 0.59 (3H, s,
3£H-18).
3b-Hydroxy-5,6b-epoxy-7-nor-5b-pregnan-20-one (14).
(a) At elevated temperature. Bromohydrin 15 (275 mg,
0.62 mmol) was treated with a boiling solution of potassium
carbonate (3 g, 21.7 mmol) in aqueous methanol (80%,
50 mL) under nitrogen. After 2 h, the solution was concen-
trated in vacuo, diluted with brine (100 mL) and a white
crystalline precipitate of the title compound 14 was
extracted with dichloromethane. The extract was washed
with water, dried and evaporated. The epoxide 14 crystal-
lized from acetone±heptane, mp 171±1738C (118 mg,
59%); [a]Dˆ171 (c 1.0, CHCl3); [Found: C, 74.45; H,
9.59. C20H30O3 requires C, 75.43; H, 9.50%]; nmax
(CHCl3) 3609, 3482, 1039 (OH); 1700, 1388, 1358
(COCH3); 1233 (epoxide) cm21; dH (200 MHz, CDCl3)
4.01±3.83 (1H, m, H-3), 3.20 (1H, s, H-6), 2.53 (1H, t,
Jˆ8.3 Hz, H-17), 2.12 (3H, s, 3£H-21), 0.89 (3H, s, 3£
H-19), 0.59 (3H, s, 3£H-18).
(b) At room temperature. A solution of potassium carbonate
(720 mg, 5.21 mmol) in water (3 mL) was added to a solu-
tion of bromohydrin 15 (67 mg, 0.15 mmol) in methanol
(10 mL). The mixture was left under nitrogen. After 24 h,
the solution was concentrated in vacuo to a half, a product,
precipitated on addition of brine (20 mL), was extracted
with dichloromethane and washed with water and dried.
The white solid (48 mg, 99%) had 1H NMR spectrum
identical with that of the title compound 14.
3b-Hydroxy-7-nor-5a-pregnane-6,20-dione (18). A solu-
tion of epoxide 14 (85 mg, 0.27 mmol) in a mixture of ether
(4 mL) and tetrahydrofuran (1.5 mL) was treated with boron
tri¯uoride diethyl etherate (0.01 mL, 0.08 mmol) at room
temperature. After 3 h, the reaction was stopped by the
solution of potassium hydrogencarbonate and the product
was extracted with ether and washed with water. The extract
was dried and concentrated in vacuo. The residue was
puri®ed by PLC (3 plates, benzene±ethyl acetate, 1:1), the
major component represented the title compound 18
(63 mg, 74%) which crystallized from acetone±heptane as
white crystals. Mp 181±1838C; [a]Dˆ1170 (c 1.1, CHCl3);
[Found: C, 75.40; H, 9.53. C20H30O3 requires C, 75.43; H,
9.50% H]; nmax (CHCl3) 3610, 3458, 1054 (OH); 1732
(CvO); 1701, 1357 (COCH3); 1390, 1385, 1377 (CH3)
cm21; dH (200 MHz, CDCl3) 3.76±3.58 (1H, m, H-3),
2.50 (1H, t, J 9.0 Hz, H-17), 2.14 (3H, s, 3£H-21), 0.89
(3H, s, 3£H-19), 0.63 (3H, s, 3£H-18).
6a-Bromo-5-hydroxy-20-oxo-7-nor-5b-pregnan-3b-yl
acetate (15). N-Bromo acetamide (140 mg, 1.0 mmol) was
added to a solution of alkene 9 (300 mg, 0.87 mmol) in
dioxane (3 mL) and perchloric acid (1 M, 0.3 mL) at
1158C. After 30 min, a saturated solution of sodium hydro-
gensul®te was added. The precipitate of the title compound
15 was ®ltered off, dissolved in chloroform and washed with
water and dried. The product (227 mg, 59%) crystallized
from methanol, additional crop of white crystals (56 mg,
15%) was obtained by PLC of the mother liquor on 3 PLC
plates in benzene±ether 3:1. Mp 144±1458C; [a]Dˆ126 (c
1.2, CHCl3); [Found: C, 59.51; H, 7.39. C22H33BrO4
requires C, 59.86; H, 7.54%]; nmax (CHCl3) 3581, 1017
Reaction of epoxide 17 with boron tri¯uoride etherate
Epoxide 17 (220 mg, 0.61 mmol) was dissolved in ether
(12 mL) and treated with boron tri¯uoride diethyl etherate

3564
A. Kasal / Tetrahedron 56 (2000) 3559±3565
(0.02 mL, 0.16 mmol) at room temperature. The mixture
was worked up as in the preparation of diketone 18. Thin-
layer chromatography (6 plates, benzene-ethyl acetate, 2:1)
of the residue yielded:
6,20-Dioxo-7-nor-5a-pregnan-3b-yl acetate (21, 175 mg,
71%), mp 89±908C (white crystals from acetone±heptane);
was added to this solution under stirring. After 5 min, the
reaction mixture was cooled to 08C and diethyl azodicarboxy-
late (10 drops, 1.11 mmol) was added. After additional
10 min, formic acid (3 drops, 1.43 mmol) was dripped in.
The mixture was left aside for 18 h, then a precipitate was
®ltered off and washed with toluene. The ®ltrate was
concentrated in vacuo and applied on four PLC plates
which were developed with toluene±ether (9:1). The
major zone gave 137 mg (77%) of the title compound 25
as white crystals, mp 139±1408C (heptane±acetone);
[a]Dˆ173 (c 1.2, CHCl3); [Found: C, 72.82; H, 8.77.
C21H30O4 requires C, 72.80; H, 8.73%]; nmax (CHCl3)
1719, 1169 (formate); 1704, 1358 (COCH3); 1387 (CH3)
cm21; dH (200 MHz, CDCl3) 8.06 (1H, s, HCOO), 5.40±
5.27 (1H, m, H-3), 3.22 (1H, s, H-6), 2.59 (1H, t, Jˆ9.0 Hz,
H-17), 2.13 (3H, s, 3£H-21), 0.88 (3H, s, 3£H-19), 0.61
(3H, s, 3£H-18).
[a]Dˆ155 (c 1.1, CHCl3). Circular dichroism: D1296
ˆ
14.55 (methanol); [Found: C, 73.22; H, 8.97. C22H32O4
requires C, 73.30; H, 8.95%]; nmax (CHCl3) 1729 (CvO);
; dH
1702, 1357(COCH3); 1252, 1030 (C±O) cm21
(200 MHz, CDCl3) 4.79±4.61 (1H, m, H-3), 2.50 (1H, s,
Jˆ8.9 Hz, H-17), 2.14 (3H, s, 3£H-21), 2.04 (3H, s,
CH3COO), 0.89 (3H, s, 3£H-19), 0.63 (3H, s, 3£ H-18), and
5-Hydroxy-6a-¯uoro-20-oxo-7-nor-5a-pregnan-3b-yl
acetate (19, 8 mg, 4%), mp 185±68C (white crystals from
acetone±heptane), nmax (CHCl3) 3612, 3487, 1047 (OH);
1729 (AcO); 1700, 1363, 1032 (COCH3); 1378, 1363
(CH3) cm21; dH (200 MHz, CDCl3) 5.27±5.08 (1H, s,
H-3), 3.80 (1H, dd, Jˆ25.3, 4.9 Hz, H-6), 2.58 (1H, t, Jˆ
8.8 Hz, H-17), 2.14 (3H, s, 3£H-21), 2.04 (3H, s, CH3COO),
1.01 (3H, s, 3£H-19), 0.64 (3H, s, 3£H-18); m/z: 380 (M1,
24), 362 (M1-H2O, 40), 358 (46), 343 (42), 300 (81), 283
(100); HRMS (EI): found: 380.2333. C22H33O4F requires
380.2363, and
5,6a-Dihydroxy-20-oxo-7-nor-5a-pregnan-3b-yl acetate
(20, 24 mg, 10%), mp 173±1768C (white crystals from
methanol); dH (200 MHz, CDCl3) 5.14 (1H, p, Jˆ2.6 Hz,
H-3), 4.12 (1H, d, Jˆ7.0 Hz, H-6), 3.50 (1H, d, Jˆ7.2 Hz,
H-4), 2.50 (1H, t, Jˆ8.8 Hz, H-17), 2.14 (3H, s, 3£H-21),
2.07 (3H, s, CH3COO, 1.07 (3H, s, 3£H-19), 0.67 (3H, s,
3£H-18); m/z: 360 (M1-H2O, 7), 300 (100), 285 (23), 267
(7).
3a-Hydroxy-5,6b-epoxy-7-nor-5b-pregnan-20-one (26).
A solution of sodium methoxide in methanol (0.87 M,
0.3 mL) was added to a solution of formate 25 (83 mg,
0.24 mmol) in methanol (3 mL). After 2 min, the mixture
was diluted with brine (12 mL) and cooled to 2158C to
yield the title compound 26 (71 mg, 93%) as white crystals.
Mp 188±1898C (acetone), [a]Dˆ172 (c 0.9, CHCl3);
[Found: C, 75.26; H, 9.55. C20H30O3 requires C, 75.43; H,
9.50%]; Circular dichroism: D1288ˆ14.47 (methanol); nmax
(CHCl3) 3610, 3400, 1031 (OH); 1700, 1358 (COCH3)
cm21; dH (200 MHz, CDCl3) 4.27±4.15 (1H, m, H-3),
3.23 (1H, s, H-6), 2.58 (1H, t, Jˆ9.0 Hz, H-17), 2.14 (3H,
s, 3£H-21), 0.85 (3H, s, 3£H-19), 0.60 (3H, s, 3£H-18).
Equilibration of 3a-hydroxy-7-nor-5a-pregnane-6,20-
dione (2). Potassium hydrogencarbonate (160 mg) was
dissolved in water (2.7 mL). One tenth of this solution
(0.16 mmol) was added to a solution of compound 2
(27 mg, 0.08 mmol) in methanol (2.5 mL). The mixture
was held at 708C for 15 min, then it was diluted with
brine and the product was extracted with chloroform. The
extract was concentrated in vacuo and the two components
were separated by PLC (one plate) in benzene-ethyl acetate
(1:1). The more polar one (9 mg, 33%) was found identical
with 5b,8b-ketone 24. The less polar component (2, 10 mg,
37%) was the starting material.
6,20-Dioxo-7-nor-5a-pregnan-3a-yl formate (22). 3b-
Hydroxy derivative 18 (108 mg, 0.34 mmol) was treated
with triphenyl phosphine (240 mg, 0.92 mmol) and diethyl
azodicarboxylate (7 drops, 1.0 mmol) as in the preparation
of compound 12. The title compound 22 (60 mg, 51%)
crystallized from acetone±heptane as white crystals. Mp
177±1788C, [a]D1173 (c 1.1, CHCl3); [Found: C, 72.78;
H, 8.80. C21H30O4 requires C, 72.80; H, 8.73%]; nmax
(CHCl3) 1732 (sh, C6vO), 1720 and 1191, 1164 (HCOO),
1703 and 1359 (OAc) cm21; dH (200 MHz, CDCl3) 5.32
(1H, p, Jˆ2.6 Hz, H-3), 2.50 (1H, t, Jˆ8.8 Hz, H-17),
2.15 (3H, s, 3£H-21), 0.87 (3H, s, 3£H-19), 0.64 (3H, s,
3£H-18).
Acknowledgements
A side product was isolated (3a,5-cyclo-7-nor-5a-preg-
nane-6,20-dione, 23, 34 mg, 33%) as white crystals. Mp
202±2038C (acetone); [a]Dˆ157 (c 1.0, CHCl3); [Found:
C, 75.45; H, 9.61. C20H30O3 requires C, 75.43; H, 9.50%];
nmax (CCl4) 1708, 1356 (CH3CvO), 1723 (C6vO), 3066,
3029, 2990 (sh), 1025 (cyclopropane) cm21; m/z: 300 (M1,
100), 282 (12), 256 (8), 230 (9), 215 (48), 55 (44), 43 (64);
dH (200 MHz, CDCl3) 2.50 (1H, t, Jˆ8.8 Hz, H-17), 2.15
(3H, s, 3£H-21), 1.00 (3H, s, 3£H-19), 0.93 (1H, t,
Jˆ4.7 Hz, H-4), 0.66 (3H, s, 3£H-18).
Skillful technical assistance was provided by Mrs M.
ÂÏ
Sedlackova. This work was supported by the Ministry of
Health of the Czech Republic (grant No. 4668-3).
Â
References
1. For a recent review on neuropsychopharmacological properties
of neuroactive steroids see Rupprecht, A.; Holsboer, F. Steroids
1999, 64, 83±91.
Â
2. Chodounska, H.; Kasal, A. Coll. Czech. Chem. Commun. 1998,
63, 1543±1548.
5,6b-Epoxy-20-oxo-7-nor-5b-pregnan-3a-yl formate (25).
From a solution of alcohol 14 (164 mg, 0.51 mmol) in
benzene (15 mL), azeotropic mixture (10 mL) was distilled
off. A solution of triphenylphosphine (300 mg, 1.14 mmol)
in a mixture of benzene and tetrahydrofuran (20 mL, 1:1)
  ÏÏÂ
Â
3. Slavõkova, B.; Kasal, A.; Budesõnsky, M. Coll. Czech. Chem.
Commun. 1999, 64, 1125±1143.

A. Kasal / Tetrahedron 56 (2000) 3559±3565
3565
Ï
12. Joska, J.; Fajkos, J.; Sorm, F. Collect. Czech. Chem. Commun.
Â
4. Slavõkova, B.; Kasal, A. Coll. Czech. Chem. Commun. 1999, 64,
Â
Ï
1479±1484.
1963, 28, 82±100.
13. Kasal, A.; Polman, J.; Budesõnsky, M. Collect. Czech. Chem.
Commun. 1998, 63, 1549±1563.
5. Kasal, A. Coll. Czech. Chem. Commun. 1999, 64, 1471±1478.
6. Shen, W.; Mennerick, S.; Zorumski, E. C.; Covey, D.;
Zorumski, C. F. Neuropharmacology 1999, 38, 267±271.
7. Robel, P.; Baulieu, E. E. Trends Endocrinol. Metab. 1996, 5, 1±8.
8. Anderson, A.; Boyd, A. C.; Byford, A.; Campbell, A. C.;
Gemmell, D. K.; Hamilton, N. M.; Hill, D. R.; Hill-Venning, C.;
Lambert, J. J.; Maidment, M. S.; May, V.; Marshall, R. J.; Peters,
J. A.; Rees, D. C.; Stevenson, D.; Hardy, S. J. Med. Chem. 1997,
40, 1668±1681.
ÏÏÂ
Â
Ï
14. Joska, J.; Fajkos, J. Collect. Czech. Chem. Commun. 1963, 28,
2605±2610.
Ï
Â
Â
Â
Â
Â
Â
15. Sõdova, R.; Stransky, K.; Kasal, A.; Slavõkova, B.; Kohout, L.
Collect. Czech. Chem. Commun. 1998, 63, 1528±1542.
16. Dauben, W. G.; Boswell Jr., G. A.; Templeton, W.; McFarland,
J. W. J. Am. Chem. Soc. 1963, 85, 2302±2305.
17. Morisawa, Y. Chem. Pharm. Bull. 1964, 12, 1066±1071.
18. Kerwin, J.F. USP 3, 072 681; Chem. Abstr. 1963, 59, 1723f.
19. Marshall, C. W.; Ray, R. E.; Laos, I.; Riegel, B. J. Am. Chem.
Soc. 1957, 79, 6308±6313.
Ï
20. Joska, J.; Sorm, F. Collect. Czech. Chem. Commun. 1958, 23,
1377±1381.
9. Hawkinson, J. E.; Acosta-Burruel, M.; Yang, K. C.; Hogen-
kamp, D. J.; Chen, J. S.; Lan, N. C.; Drewe, J. A.; Whittemore,
E. C.; Woodward, R. M.; Carter, R. B.; Upasani, R. B. J. Pharm.
Exp. Ther. 1998, 287, 198±207.
Ï
Ï
10. Joska, J.; Achrem, A. A.; Fajkos, J.; Sorm, F. Collect. Czech.
Chem. Commun. 1961, 26, 2050±2057.
21. Cabrera, A.; Rosas, N.; Marquez, C.; Salmon, M.; Angelez, E.;
Miranda, R.; Lozano, R. Gazz. Chim. Ital. 1991, 121, 127±130.
11. de Epifanio, R.; Camargo, W.; Pinto, A. C. Tetrahedron Lett.
1988, 29, 6403±6406.