Synthesis of 17-dihydroisoxazolyl steroids of the androstane and estrone series

Article abstract of DOI:10.1023/A:1012317215582

1,3-Dipolar cycloaddition of nitrile oxides to 17β-hydroxy-17α-vinyl steroids of the estrone series proceeds both regio- and stereoselectively. The stereoselectivity of the process decreases in going to steroids of the androstane series. The major epimer has S configuration of the new chiral center.

Full text of DOI:10.1023/A:1012317215582

Russian Journal of Organic Chemistry, Vol. 37, No. 1, 2001, pp. 46 51. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 1, 2001,
pp. 57 62.
Original Russian Text Copyright
2001 by Litvinovskaya, Drach, Lapchinskaya, Khripach.
Synthesis of 17-Dihydroisoxazolyl Steroids
*
of the Androstane and Estrone Series
R. P. Litvinovskaya, S. V. Drach, Yu. I. Lapchinskaya, and V. A. Khripach
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akademika Kuprevicha 5/2, Minsk, 220141 Belarus
Received February 18, 2000
Abstract 1,3-Dipolar cycloaddition of nitrile oxides to 17 -hydroxy-17 -vinyl steroids of the estrone series
proceeds both regio- and stereoselectively. The stereoselectivity of the process decreases in going to steroids
of the androstane series. The major epimer has S configuration of the new chiral center.
We previously studied 1,3-dipolar cycloaddition of
nitrile oxides to unsaturated steroid compounds with
The present communication reports on the results
of our study on 1,3-dipolar cycloaddition of nitrile
oxides to 17 -hydroxy-17-vinyl derivatives of the
estrone and androstane series. The starting compound
was estrone (I) whose 3-hydroxy group was protected
by alkylation with dimethyl sulfate in the presence
of sodium methoxide. We thus obtained methoxy
2
0
22
23
the double bond located at C , C , and C and
examined properties of the resulting dihydroisoxazolyl
derivatives [1 5]. In some cases, the stereoselectivity
of the addition can be varied over a wide range
through variation of the reactant structure [6].
Scheme 1.
I, R = H; II, IV, V, VIII, IX, R = Me; VI, VII, X, XI, R = i-Pr; VIII, X: 5 S; IX, XI: 5 R.
_
___________
*
This study was financially supported by the Foundation for Basic Research of Belarus Republic (project no. x97-079) and by
the INTAS Foundation (grant no. 96-1109).
1
070-4280/01/3701-0046$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS OF 17-DIHYDROISOXAZOLYL STEROIDS
47
1
derivative II in 76% yield. It showed in the H NMR
spectrum a three-proton signal at 3.78 ppm from
the methoxy group, whereas its IR spectrum lacked
absorption typical of hydroxy group.
proton singlets from methyl protons of the 3 -CH3
group ( 1.98 2.00 ppm); compounds VI and VII
showed in the H NMR spectra signals from protons
1
of the 3 -CH(CH ) fragment: a multiplet at 2.70 ppm
3
2
(
1H) and a doublet at 1.20 ppm (6H). The IR spectra
The Normant reaction of compound II with vinyl-
magnesium bromide in anhydrous THF at 0 C (3 h)
afforded 88% of 17 -hydroxy-3-methoxy-17 -vinyl-
estra-1,3,5(10)-triene (III) as an unsaturated com-
pound which can be used as dipolarophile in 1,3-di-
polar cycloaddition. Product III is formed as a result
of the reagent approach from the least sterically
hindered -side of the steroid molecule. The vinyl
of dihydroisoxazolyl derivatives contained a band at
1
1
610 cm , belonging to stretching vibrations of the
C N bond in the isoxazole ring. The mass spectra
of the products contained peaks of the molecular ions
whose fragmentation patterns were consistent with the
proposed structures.
We failed to effect acetylation of the 17 -hydroxy
group under various conditions. Treatment of epimeric
mixture IV/V with chlorotrimethylsilane in methylene
chloride in the presence of imidazole gave a mixture
of trimethylsilyl ethers VIII and IX in an overall yield
of 95%. Under the same conditions, from epimeric
mixture VI/VII we obtained a mixture of ethers X and
XI. These mixtures were separated into the pure
epimeric trimethylsilyl ethers by chromatography. In
1
proton signals in the H NMR spectrum of III
appeared as two doublets at 5.07 (J = 1 Hz) and
5
.15 ppm (J = 17 Hz) and a doublet of doublets at
.10 ppm (J = 10, J = 17 Hz). In the IR spectrum
6
1
2
of III we observed stretching vibration band of the
1
hydroxy group at 3440 cm , while carbonyl absorp-
tion typical of initial ketone II was absent.
Allyl alcohol III was brought into 1,3-dipolar
cycloaddition with nitrile oxides generated in situ
1
the H NMR spectra of VIII XI we observed a singlet
at
0.12 ppm from the trimethylsilyl group; also,
(
to reduce self-condensation) from the corresponding
a downfield shift of the 13-CH , 4 -H, and 5 -H
aldehyde oximes by the action of N-chlorosuccinimide
in the presence of triethylamine as a base. Using acet-
aldehyde oxime, we obtained a mixture of dihydro-
isoxazolyl derivatives IV and V which are epimers
with respect to C . The overall yield of IV/V was
9
3
signals was observed. No hydroxy group absorption
was present in the IR spectra of these compounds.
17-Hydroxy-17-dihydroisoxazolyl derivatives of
the androstane series were obtained by 1,3-dipolar
cycloaddition of nitrile oxides to vinyl steroid XIII
which was synthesized from 3-hydroxyandrost-6-en-
17-one (XII) by the Normant reaction. Compound
XIII was brought into reactions with acetonitrile
oxide and isobutyronitrile oxide, and its 3-O-acetyl
derivative XIV, with acetonitrile oxide. As with the
5
1
3%, and the ratio, 10:1 (according to the H NMR
spectrum of the reaction mixture). Hence we can state
that the reaction is highly stereo- and regioselective
and that the major product is 17 -(dihydroisoxazol-
5
-yl) steroid which can readily be isolated by crystal-
lization.
Starting from isobutyraldehyde oxime, a mixture
19-nor analog, the cycloaddition was regioselective,
but its stereoselectivity was very low. In the reaction
with isobutyronitrile oxide, the ratio of epimeric
products (5 S)-XVII and (5 R)-XVIII was 3:1, and
with acetonitrile oxide almost equimolar mixtures of
compounds XVa/XVIa and XVb/XVIb were formed
of compounds VI and VII was formed in an overall
yield of 83% and at a ratio of 5:1 (according to the
1
H NMR data). Both epimers were isolated in the pure
state by column chromatography. The absolute con-
figurations of the chiral centers in VII were deter-
mined by X-ray analysis [7]. The structures of the
other dihydroisoxazolyl steroids were established by
(Scheme 2).
The structure of products XV XVIII is proved by
1
1
the presence of characteristic signals in their H NMR
spectra: one-proton triplets from 5 -H at 4.72 4.75
and 4.52 4.56 ppm for the (S)- and (R)-isomers, re-
spectively, and one-proton multiplets from 4 -H at
comparing the H NMR spectra of the pure isomers.
The signal from methyl protons of the 18-CH group
3
in (5 S)-IV and (5 S)-VI is located in a stronger field
(
0.91 0.92 ppm) than the corresponding signal of
2
.80 3.18 ppm; vinyl protons signals typical of the
their (5 R)-epimers. The 5 -H signal appears as a triplet
at 4.82 4.84 ppm (J = 10 Hz) and 4.63 4.66 ppm
initial olefin were absent.
(
J = 10.5 Hz) for compounds of the (5 S)- and (5 R)-
Epimeric mixture XVII/XVIII was converted into
17-O-trimethylsilyl derivatives XIX and XX by treat-
ment with a tenfold excess of chlorotrimethylsilane
and imidazole in methylene chloride at room tempera-
ture. It was surprising that the 3-hydroxy group in
XVII and XVIII remained unchanged (after treatment
4
series, respectively. Methylene protons on C give
a two-proton signal as a double doublet of doublets at
3
.05 ppm (5 S; J = 10, J = 10.5, J = 17 Hz) or
1 2 3
3
.00 ppm (5 R; J = 10, J = 10.5, J = 17 Hz). The
1 2 3
spectra of compounds IV and V also contained three-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

4
8
LITVINOVSKAYA et al.
Scheme 2.
XIII, XVa, XVIa, XVII, XVIII, R = H; XIV, XVb, XVIb, R = Ac; XVa, XVb, XVIa, XVIb, R = Me; XVII, XVIII, R = i-Pr;
XIX: 5 S; XX: 5 R.
with water and extraction with chloroform). Therefore,
this procedure can be regarded as a method for selec-
tive protection of the 17-hydroxy group in steroid
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
A-200 instrument (200 MHz) in chloroform-d using
TMS as internal reference. The IR spectra were ob-
tained on a UR-20 spectrometer from thin films or
KBr discs. The mass spectra were measured using
a Hewlett Packard 5970 mass-selective detector
coupled with an HP 5890 gas chromatograph (DB-17
column). The melting points were determined on
a Koefler heating block. The progress of reactions was
monitored by TLC on Silufol UV-254 and Kieselgel
0 F254 (Merck) plates. Preparative chromatographic
separation of product mixtures was performed on
Kieselgel 60 silica gel (40/60 m, Merck).
Estrone methyl ether. Metallic sodium, 3 g
(0.13 mol), was added in small pieces under argon
to 60 ml of anhydrous methanol. When the vigorous
reaction ceased, 10 g (36.5 mmol) of estrone (I)
dissolved in a small amount of anhydrous methanol
was added. Dimethyl sulfate, 16 ml (0.13 mol), was
slowly added (from a dropping funnel), the mixture
1
compounds. Products XIX and XX showed in the H
NMR spectra signals from the trimethylsilyl group,
and the 3-H signal did not shift downfield. The IR1
spectra contained an absorption band at 3415 cm
due to stretching vibrations of the 3-hydroxy group.
The presence of the latter was additionally proved by
acetylation with acetic anhydride in pyridine to obtain
1
3
-acetoxy-17-trimethylsilyloxy steroid XXI. Its H
NMR spectrum contained a three-proton singlet from
the acetoxy group, and a downfield shift of the 3-H
signal was observed. The hydroxy group absorption
disappeared from the IR spectrum, while bands typical
6
1
of ester moiety appeared at 1760 and 1260 cm .
Thus, our study showed that 1,3-dipolar cycloaddi-
tion of nitrile oxides to 17-hydroxy-17-vinyl steroids
of the estrone series is characterized by high stereo-
selectivity which depends on the 1,3-dipole structure.
The stereoselectivity of 1,3-cycloaddition to andro-
stane derivatives is considerably lower.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

SYNTHESIS OF 17-DIHYDROISOXAZOLYL STEROIDS
49
was refluxed for 5 h, 1.5 g (0.065 mol) of sodium
methoxide and 16 ml (0.13 mol) of dimethyl sulfate
were added, and the mixture was refluxed for
an additional 4 h. The solvent was distilled off, the
residue was diluted with water, and the product was
17-Dihydroisoxazolyl steroids IV VII and XV
XVIII. Acetaldehyde oxime or isobutyraldehyde
oxime, 17 mmol, was added dropwise to a suspension
of 2.3 g (17 mmol) of N-chlorosuccinimide in 7 ml
of chloroform and 0.07 ml of pyridine. The mixture
extracted into chloroform. The extract was dried over was stirred until it became homogeneous, and a solu-
sodium sulfate, the solvent was evaporated, and the
residue was subjected to column chromatography on
silica gel using toluene ethyl acetate (98:2) as eluent.
tion of 3.5 mmol of unsaturated steroid in 10 ml of
chloroform was added. The mixture was stirred for
a short time, and a solution of 2.5 ml (17 mmol)
Yield 7.6 g (76%) of 3-methoxyestra-1,3,5(10)-trien- of triethylamine in 10 ml of chloroform was added
1
7-one (II). mp 184 185 C (from toluene ethyl
very slowly in a dropwise manner (over a period
of 3 h). The mixture was kept for 24 h at room tem-
perature and washed with water. The organic layer
was dried over sodium sulfate and evaporated, and
the residue was subjected to column chromatography
on silica gel using 5:1 hexane ethyl acetate as eluent.
1
acetate). H NMR spectrum, , ppm: 0.90 s (3H,
1
6
1
2
8-Me), 3.78 s (3H, OMe), 6.63 br.s (1H, 4-H),
.72 d.d (1H, 2-H, J = 8, J = 2 Hz), 7.20 d (1H,
1
2
1
-H, J = 8 Hz). IR spectrum (KBr), , cm : 2920,
880, 1745, 1620, 1510, 1460, 1260.
1
7 -Hydroxy-17-vinylsteroids III and XIII.
17 -Hydroxy-3-methoxy-17 -[(5S)-3-methyl-4,5-
dihydroisoxazol-5-yl]estra-1,3,5(10)-triene (IV).
From 1 g of olefin III and acetaldehyde oxime we
obtained 1.1 g (93%) of isomeric mixture IV/V at
a ratio of 10:1 ( H NMR data). Recrystallization from
hexane ethyl acetate gave 0.3 g of the major isomer
A flask (which was preliminarily calcined) equipped
with a dropping funnel and a reflux condenser (cooled
with a dry ice acetone mixture) was charged in
a stream of argon with 1.1 g (54.8 mmol) of magne-
sium and several crystals of iodine. The mixture was
heated until violet color appeared, cooled to 0 C,
and a solution of 1.1 g (69.6 mmol) of vinyl bromide
in 15 ml of anhydrous THF was added dropwise with
stirring. A solution of 4.76 mmol of appropriate
1
(IV). mp 183 184 C (from hexane ethyl acetate).
1
H NMR spectrum, , ppm: 0.92 s (3H, 18-Me),
2
1
.00 s (3H, 3 -Me), 3.05 d.d.d (2H, 4 -H, J = 10, J =
1 2
0.5, J = 17 Hz), 3.78 s (3H, OMe), 4.84 t (1H, 5 -H,
3
1
7-oxo steroid in 15 ml of anhydrous THF was then
J = 10 Hz), 6.63 br.s (1H, 4-H), 6.72 d.d (1H, 2-H,
J = 8.6, J = 2 Hz), 7.20 d (1H, 1-H, J = 8.6 Hz).
added at 0 C, and the mixture was stirred for 3 h
at room temperature, several drops of a saturated
solution of ammonium chloride was added, and the
mixture was extracted with ethyl acetate. The extract
was dried over sodium sulfate and evaporated, and the
residue was subjected to column chromatography on
silica gel using toluene ethyl acetate (9:1) as eluent.
1
3
2
1
C NMR spectrum, C, ppm: 13.8 q, 14.4 q, 24.0 t,
7.1 t, 28.2 t, 30.4 t, 34.6 d.d, 40.1 d, 41.1 t, 44.2 d,
7.7 s, 51.5 d, 55.9 q, 84.2 d, 85.1 s, 112.1 d,
2
4
1
14.4 d, 127.8 d, 133.2 s, 138.5 s, 156.9 s, 158.1 s.
1
IR spectrum (KBr), , cm : 3440, 2950, 2880, 1610,
+
1
2
2
585, 1510, 1260. Mass spectrum, m/z: 369 [M] ,
1
7 -Hydroxy-3-methoxy-17 -vinylestra-1,3,-
+
+
84 [M heteroring] , 267 [M heteroring H O] ,
2
5
(10)-triene (III). From 1 g of 3-O-methylestrone (II)
we obtained 0.99 g (88%) of compound III as an oily
substance. H NMR spectrum, , ppm: 0.95 s (3H,
8-Me), 3.78 s (3H, OMe), 5.07 d (1H, 2 -H, J =
Hz), 5.15 d (1H, 2 -H, J = 9 Hz), 6.10 d.d (1H,
-H, J = 10, J = 17 Hz), 6.68 s (1H, 4-H), 6.75 d.d
27, 171, 147.
1
17 -Hydroxy-3-methoxy-17 -[(5R)-3-methyl-4,5-
dihydroisoxazol-5-yl]estra-1,3,5(10)-triene (V) was
1
1
1
1
isolated as an oily substance. H NMR spectrum, ,
ppm: 0.95 s (3H, 18-Me), 1.98 s (3H, 3 -Me),
1
2
(
8
1
1H, 2-H, J = 8, J = 2 Hz), 7.19 d (1H, 1-H, J =
Hz). IR spectrum (film), , cm : 3440, 2935, 2880,
620, 1510, 1460, 1260, 910.
3.00 d.d.d (2H, 4 -H, J = 10, J = 10.5, J = 17 Hz),
1
2
1
2
3
1
3.78 s (3H, OMe), 4.66 t (1H, 5 -H, J = 10.5 Hz),
6.63 br.s (1H, 4-H), 6.72 d.d (1H, 2-H, J = 8.6, J =
1
2
2
Hz), 7.20 d (1H, 1-H, J = 8.6 Hz). IR spectrum
3
,17 -Dihydroxy-17 -vinylandrost-6-ene (XIII)
1
(
film), , cm : 3440, 2950, 2880, 1610, 1585, 1510,
was synthesized from 2.75 g of androstane (XII).
Yield 2.5 g (83%). mp 88 89 C (from hexane ethyl
acetate). H NMR spectrum, , ppm: 0.90 s (3H,
+
1260. Mass spectrum, m/z: 369 [M] , 284 [M hetero-
ring] , 267 [M heteroring H O] , 227, 171, 147.
1
+
+
2
1
8-Me), 1.02 s (3H, 19-Me), 3.52 m (1H, 3-H), 5.06 d
17 -Hydroxy-17 -[(5S)-3-isopropyl-4,5-di-
hydroisoxazol-5-yl]-3-methoxyestra-1,3,5(10)-triene
(VI). From 0.8 g of olefin III and 4.5 ml of isobutyr-
aldehyde oxime we isolated 0.86 g (83%) of a mixture
of isomers VI and VII at a ratio of 5:1 (according to
(1H, 2 -H, J = 1 Hz), 5.15 d (2H, 2 -H, J = 9 Hz),
5
.35 m (1H, 6-H), 6.03 d.d (1H, 1 -H, J = 10, J =
1 2
1
1
2
7 Hz). IR spectrum (KBr), , cm : 3445, 2940,
880, 1620, 1510, 1465, 1255, 910.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

5
0
LITVINOVSKAYA et al.
1
the H NMR data). mp 83 84 C (from hexane ethyl
4 -H), 3.52 m (1H, 3-H), 4.75 t (1H, 5 -H, J =
10.5 Hz), 5.35 m (1H, 6-H).
1
acetate). H NMR spectrum, , ppm: 0.91 s (3H,
1
8-Me), 1.20 d [6H, CH(CH ) , J = 3 Hz], 2.70 m
3 2
3 ,17 -Dihydroxy-17 -[(5R)-3-isopropyl-4,5-di-
hydroisoxazol-5-yl]androst-6-ene (XVII). Oily sub-
stance. H NMR spectrum, , ppm: 0.94 s (3H,
[1H, CH(CH ) ], 3.05 d.d.d (2H, 4 = H, J = 10, J =
3 2 1 2
1
0.5, J = 17 Hz), 3.78 s (3H, OMe), 4.82 t (1H, 5 -H,
1
3
J = 10 Hz), 6.63 br.s (1H, 4-H), 6.72 d.d (1H, 2-H,
J = 8.6, J = 2 Hz), 7.20 d (1H, 1-H, J = 8.6 Hz).
1
8-Me), 1.03 s (3H, 19-Me), 1.18 d [6H, CH(CH ) ,
3 2
1
2
J = 7 Hz], 2.68 m [1H, CH(CH ) ], 2.82 3.18 m
1
3 2
IR spectrum (KBr), , cm : 3440, 2940, 2880, 1610,
(2H, 4 -H), 3.54 m (1H, 3-H), 4.56 t (1H, 5 -H, J =
1
3
1
580, 1510, 1470, 1400, 1260. Mass spectrum, m/z:
10 Hz), 5.35 m (1H, 6-H).
+
+
+
67 [M] , 346 [M i-Pr] , 284 [M heteroring] , 227,
Trimethylsilyl ethers VIII XI, XIX, and XX.
71, 147.
To a solution of 0.54 mmol of epimeric mixture of
7-hydroxy-17-dihydroisoxazolyl steroid in 2 ml of
1
7 -Hydroxy-17 -[(5R)-3-isopropyl-4,5-di-
1
hydroisoxazol-5-yl]-3-methoxyestra-1,3,5(10)triene
methylene chloride we added 0.6 ml (2.7 mmol) of
chlorotrimethylsilane and 0.2 g (2.7 mmol) of imid-
azole. The mixture was left to stand for 24 h at room
temperature and washed with water, and the products
were extracted into chloroform. The extract was dried
over sodium sulfate and evaporated, and the residue
was subjected to column chromatography on silica gel
using 9:1 hexane ethyl acetate as eluent.
1
(VII). mp 210 212 C (from hexane ethyl acetate). H
NMR spectrum, , ppm: 0.95 s (3H, 18-Me), 1.20 d
[
6H, CH(CH ) , J = 3 Hz], 2.70 m [1H, CH(CH ) ],
3 2 3 2
3
3
6
2
.00 d.d.d (2H, 4 -H, J = 10, J = 10.5, J = 17 Hz),
1 2 3
.78 s (3H, OMe), 4.63 t (1H, 5 -H, J = 10.5 Hz),
.63 br.s (1H, 4-H), 6.72 d.d (1H, 2-H, J = 8.6, J =
1
2
Hz), 7.20 d (1H, 1-H, J = 8.6 Hz). IR spectrum
1
(KBr), , cm : 3440, 2940, 2880, 1610, 1580, 1510,
+
From 0.3 g of epimeric mixture IV/V we obtained
0.36 g (95%) of a mixture of trimethylsilyl ethers
VIII and IX.
1
470, 1400, 1260. Mass spectrum, m/z: 367 [M] , 346
+
+
[M i-Pr] , 284 [M heteroring] , 227, 171, 147.
3
,17 -Dihydroxy-17 -[(5 )-3-methyl-4,5-di-
3
-Methoxy-17-[(5S)-3-methyl-4,5-dihydroisoxa-
dihydroisoxazol-5-yl]androst-6-ene (XVa/XVIa).
From 0.5 g of compound XIII and acetaldehyde
oxime we obtained 0.5 g (83%) of iosmeric mixture
XVa/XVIa at a ratio of 6:5 (according to the H
NMR data) as an oily substance. H NMR spectrum,
zol-5-yl]-17 -trimethylsiloxyestra-1,3,5(10)-triene
1
(
VIII). Oily substance. H NMR spectrum, , ppm:
0.12 s (9H, OSiMe3), 0.88 s (3H, 18-Me), 1.99 s (3H,
-Me), 2.62 3.14 m (3H, 4 -H and 6-H), 3.78 s
1
3
1
(
(
3H, OMe), 4.74 t (1H, 5 -H, J = 10 Hz), 6.63 s
,
ppm: 0.84 s and 0.89 s (3H, 18Me), 1.02 s (3H,
1H, 4-H), 6.72 d.d (1H, 2-H, J = 8.6, J = 2 Hz),
1
2
1
3
4
9-Me), 1.94 s (3H, 3 -Me), 2.80 3.16 m (2H, 4 -H),
.50 m (1H, 3-H), 4.32 br.s (1H, OH), 4.52 t and
.72 t (1H, 5 -H, J = 10 Hz), 5.35 m (1H, 6-H).
7
.20 d (1H, 1-H, J = 8.6 Hz). IR spectrum (film), ,
1
cm : 2950, 2875, 1610, 1510, 1265.
-Methoxy-17-[(5R)-3-methyl-4,5-dihydroisoxa-
zol-5-yl]-17 -trimethylsiloxyestra-1,3,5(10)-triene
3
3
-Acetoxy-17 -hydroxy-17 -[(5 )-3-methyl-4,5-
dihydroisoxazol-5-yl]androst-6-ene (XVb/XVIb).
From 0.6 g of compound XIV and acetaldehyde
oxime we obtained 0.59 g (78%) of isomeric mixture
XVb/XVIb at a ratio of 9:7 (according to the H
NMR data) as an oily substance. H NMR spectrum,
1
(IX). Oily substance. H NMR spectrum, , ppm:
0
.12 s (9H, OSiMe ), 0.85 s (3H, 18-Me), 1.97 s
3
(
3H, 3 -Me), 2.62 3.12 m (3H, 4 -H and 6-H), 3.78 s
3H, OMe), 4.56 t (1H, 5 -H, J = 10.5 Hz), 6.63 s
1H, 4-H), 6.72 d.d (1H, 2-H, J = 8.6, J = 2 Hz),
1
(
(
1
1
2
,
ppm: 0.89 s and 0.92 s (3H, 18Me), 1.02 s (3H,
7
.20 d (1H, 1-H, J = 2 Hz).
From 0.9 g of epimeric mixture VI/VII we ob-
tained 1.05 g (94%) of trimethylsilyl ethers X and XI.
7 -[(5S)-3-Isopropyl-4,5-dihydroisoxazol-5-yl]-
-methoxy-17 -trimethylsiloxyestra-1,3,5(10)-triene
19-Me), 1.96 s (3H, 3 -Me), 2.04 s (3H, OAc), 2.86
3.18 m (2H, 4 -H), 4.38 br.s (1H, OH), 4.58 t and
4.78 t (1H, 5 -H, J = 10 Hz), 5.31 m (1H, 3-H),
5.35 m (1H, 6-H).
1
3
From 0.9 g of compound XIII and isobutyralde-
1
(
X). Oily substance. H NMR spectrum, , ppm:
hyde oxime we obtained 0.66 g (60%) of isoxazolyl
steroid XVII and 0.20 g (18%) of its isomer XVIII.
0
.12 d (9H, OSiMe ), 0.90 s (3H, 18-Me), 1.20 d [6H,
3
CH(CH ) , J = 7 Hz], 2.68 m [1H, CH(CH ) ], 2.80
3
2
3 2
3
,17 -Dihydroxy-17 -[(5S)-3-isopropyl-4,5-di-
3.06 m (3H, 4 -H and 6-H), 3.78 s (3H, OMe), 4.73 t
(1H, 5 -H, J = 10 Hz), 6.63 br.s (1H, 4-H), 6.72 d.d
(1H, 2-H, J = 8.5, J = 2 Hz), 7.20 d (1H, 1-H, J =
hydroisoxazol-5-yl]androst-6-ene (XVII). Oily sub-
stance. H NMR spectrum, , ppm: 0.90 s (3H,
1
1
1
2
1
8-Me), 1.02 s (3H, 19-Me), 1.16 d [6H, CH(CH ) ,
8.5 Hz). IR spectrum (film), , cm : 2940, 2880,
1610, 1260.
3
2
J = 7 Hz], 2.68 m [1H, CH(CH ) ], 3.02 m (2H,
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

SYNTHESIS OF 17-DIHYDROISOXAZOLYL STEROIDS
51
1
7 -[(5R)-3-Isopropyl-4,5-dihydroisoxazol-5-yl]-
From 3,17-diol XIII we obtained 95% of 3 -acet-
oxy-17 -hydroxy-17 -vinylandrost-6-ene (XIV). Oily
substance. H NMR spectrum, , ppm: 0.91 s (3H,
3
(
0
-methoxy-17 -trimethylsiloxyestra-1,3,5(10)-triene
XI). Oily substance. H NMR spectrum, , ppm:
.12 s (9H, OSiMe ), 0.86 s (3H, 18-Me), 1.24 d [6H,
CH(CH ) , J = 7 Hz], 2.68 m [1H, CH(CH ) ], 2.80
.06 m (3H, 4 -H and 6-H), 3.78 s (3H, OMe), 4.55 t
1H, 5 -H, J = 10.5 Hz), 6.63 br.s (1H, 4-H), 6.72 d.d
1H, 2-H, J = 8.6, J = 2 Hz), 7.20 d (1H, 1-H, J =
.6 Hz). IR spectrum (film), , cm : 2940, 2880,
610, 1260.
1
1
18-Me), 1.03 s (3H, 19-Me), 2.04 s (3H, OAc), 5.06 d
3
(1H, 1 -H, J = 1 Hz), 5.15 d (2H, 2 -H, J = 9 Hz),
3
2
3 2
3
(
(
8
1
5.30 m (1H, 3-H), 5.37 m (1H, 6-H). IR spectrum
1
(KBr), , cm : 3440, 2940, 2880, 1740, 1620, 1510,
1465, 1260, 910.
1
2
1
From 3-hydroxy-20-dihydroisoxazolyl-17-tri-
methylsiloxy steroid XIX we obtained 3-acetoxy-17 -
(3-isopropyl-4,5-dihydroisoxazol-5-yl)-17 -trimethyl-
From 0.9 g of epimeric mixture XVII/XVIII, using
0 equiv of chlorotrimethylsilane, we obtained 1.01 g
1
1
siloxyandrost-6-ene (XXI). Oily substance. H NMR
(
95%) of a mixture of 17-trimethylsiloxy derivatives
spectrum, , ppm: 0.12 s (9H, OSiMe ), 0.86 s
3
XIX and XX.
(3H, 18-Me), 1.03 s (3H, 19-Me), 1.16 d and 1.19 d
[6H, CH(CH3)2, J = 7], 2.04 s (3H, OAc), 2.68 m
[1H, CH(CH ) ], 2.86 m (2H, 4 -H), 3.61 m (2H,
3
-Hydroxy-17 -[(5S)-3-isopropyl-4,5-dihydro-
isoxazol-5-yl]-17 -trimethylsiloxyandrost-6-ene
3
2
1
(XIX). Oily substance. H NMR spectrum, , ppm:
3-H and 5 -H), 5.38 m (1H, 6-H). IR spectrum (film),
1
0
.12 s (9H, OSiMe ), 0.86 s (3H, 18-Me), 1.02 s
, cm : 2980, 2960, 2880, 2860, 1745, 1480, 1450,
3
(3H, 19-Me), 1.21 d [6H, CH(CH ) , J = 7 Hz],
1385, 1370, 1255.
3
2
2
.68 m [1H, CH(CH ) ], 2.86 m (2H, 4 -H), 3.54 m
3 2
(
1H, 3-H), 4.63 t (1H, 5 -H, J = 10 Hz), 5.36 m
1H, 6-H). IR spectrum, , cm : 3415, 2950, 1760,
REFERENCES
1
(
1
250, 1100, 845.
-Hydroxy-17 -[(5R)-3-isopropyl-4,5-dihydro-
isoxazol-5-yl]-17 -trimethylsiloxyandrost-6-ene
1. Khripach, V.A., Litvinovskaya, R.P., and Baranov-
skii, A.V., Zh. Org. Khim., 1990, vol. 26, no. 6,
pp. 1274 1278.
3
1
(XX). Oily substance. H NMR spectrum, , ppm:
2. Khripach, V.A., Litvinovskaya, R.P., Baranov-
skii, A.V., and Akhrem, A.A., Dokl. Akad. Nauk
SSSR, 1991, vol. 318, no. 3, pp. 597 600.
0
1
.12 s (9H, OSiMe ), 0.90 s (3H, 18-Me), 1.03 s (3H,
3
9-Me), 1.21 d [6H, CH(CH ) , J = 7 Hz], 2.68 m
3
2
[
3
1H, CH(CH ) ], 2.89 m (2H, 4 -H), 3.53 m (1H,
3 2
3. Verenich, A.I., Govorova, A.A., Galitskii, N.M.,
Baranovskii, A.V., Litvinovskaya, R.P., and Khri-
pach, V.A., Zh. Strukt. Khim., 1992, no. 5, pp. 552
-H), 4.46 t (1H, 5 -H, J = 10 Hz), 5.35 m (1H, 6-H).
1
IR spectrum, , cm : 3415, 2950, 1760, 1250,
1
100, 845.
5
54.
Acetylation of steroid alcohols XIII and XIX.
4
5
6
.
.
.
Khripach, V.A., Litvinovskaya, R.P., and Drach, S.V.,
Zh. Org. Khim., 1993, vol. 29, no. 4, pp. 717 723.
Compound XIII or XIX, 0.2 mmol, was dissolved in
ml of pyridine, and 0.5 ml of acetic anhydride was
dropwise added. The mixture was left to stand for
8 20 h at room temperature and was then diluted
with water, and the product was extracted into ether.
The extract was washed with 0.5% hydrochloric acid
until neutral reaction, dried over anhydrous sodium
sulfate, and evaporated. The residue was dissolved in
a small amount of chloroform, and the solution was
passed through a layer of silica gel. Yield 90 95%.
1
Litvinovskaya, R., Drach, S., and Khripach, V.,
Mendeleev Commun., 1995, no. 6, pp. 215 216.
1
Litvinovskaya, R.P., Koval’, N.V., and Khri-
pach, V.A., Khim. Geterotsikl. Soedin., 1998, no. 2,
pp. 267 273.
7. Litvinovskaya, R.P., Lyakhov, A.S., Drach, S.V.,
Khripach, V.A., and Govorova, A.A., Russ. J. Gen.
Chem., 2000, vol. 70, no. 9, pp. 1476 1479.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001