Synthesis of 15β-hydroxyalkyl-substituted (17Z)-pregn-17-enes, their ethers and esters

Article abstract of DOI:10.1007/s11178-005-0067-4

Proceeding from Δ¹⁵-17-ketosteroids via copper(I)-catalyzed 1,4-addition of Grignard reagent followed by modification of the 15-alkenyl substituent, introduction of a 17-ethylidene component via Wittig reaction, and transformations in the A and B rings of the steroid molecule we obtained a series of 15β-hydroxyalkyl-substituted (17Z)-pregn-17-enes, their ethers and esters. 2004 MAIK "Nauka/Interperiodica".

Full text of DOI:10.1007/s11178-005-0067-4

Russian Journal of Organic Chemistry, Vol. 40, No. 11, 2004, pp. 1608-1616. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11,
2004, pp. 1656-1664.
Original Russian Text Copyright Ó 2004 by Baranovskii, Litvinovskaya, Khripach.
Synthesis of 15b-Hydroxyalkyl-substituted (17Z)-Pregn-17-enes,
Their Ethers and Esters
A.V. Baranovskii, R.P. Litvinovskaya, and V.A. Khripach
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus
Minsk, 220141 Belarus
e-mail: litvin@iboch.bas-net.by
Received March 4, 2004
Abstract-- Proceeding from D15-17-ketosteroids via copper(I)-catalyzed 1,4-addition of Grignard reagent followed
by modification of the 15-alkenyl substituent, introduction of a 17-ethylidene component via Wittig reaction, and
transformations in theAand B rings of the steroid molecule we obtained a series of 15b-hydroxyalkyl-substituted
(17Z)-pregn-17-enes, their ethers and esters.
the protons H15a and H16b would be close to 90° and con-
sequently their coupling constant would be close to zero.
At the addition to the 15a-position the 15b-proton would
be in an anti-periplanar position with respect to both 14a-
and 16a-protons. In this case the signals of both protons
attached to C16 would have appeared as doublet of dou-
blets, and the pattern of the signal from the proton at C15
would be still more complicated, also the coupling con-
stants would have been larger that those observed in the
spectrum of compound III. A case of the Michael addi-
tion of imidazole to a cyclopentanone derivative was also
reported formerly [8].
This study was aimed at the synthesis of a series of
pregn-17-enes with interesting biological activity and fit
as initial compounds for building up side chains of C27–
C29 steroids via an ene reaction [1–4]. The main feature
of the target compounds was the presence of an additional
b-substituent in the C15 position of the steroid molecule.
As initial compound for the synthesis 15b-substituted
pregnenes was chosen 3b-hydroxyandrost-5,15-dien-17-
one (I) prepared from 3-acetoxydehydroepiandrostrone
17-ethylene ketal [5]. It should be noted that in the course
of protecting the hydroxy group in compound I by con-
version into a tert-butyldimethylsilyl ether II in tetrahy-
drofuran [6] an addition of imidazole along Michael reac-
tion was observed with formation of compound III in a
5% yield. The imidazole addition across the D15-bond was
proved by 1H NMR spectroscopy. Alongside the lack of
signals from the olefin protons of the C15 =C16 double bond
the spectrum contained resonances characteristic of the
protons from the imidazole ring: one-proton singlets at
7.03, 7.08, and 7.64 ppm belonging to protons H4', H5',
and H2'. The structure of compound III was additionally
confirmed by the presence in the 13C NMR spectrum of
the signals from the imidazole ring carbon atoms appear-
ing as doublets at 118.8, 129.7, and 136.8 ppm. 15b-Con-
figuration was assigned to the substituent both on the
strength of the coupling constant of protons linked to C16
and by analogy to the most known cases of addition to
the D15-bond [7]. Obviously only when the imidazole ring
is located in the 15b-position the dihedral angle between
The introduction of an alkenyl chain was carried out
by adding to unsaturated ketone II the Grignard reagent
prepared from 5-bromopentene [9] under catalysis with
copper bromide complex with dimethyl sulfide [7, 10, 11].
Adding to the reaction mixture the trimethylsilyl chloride
(TMSCl) and the hexamethylphosphoramide (HMPA)
[12] we raised the yield of adduct IV from 85 to 95%.
The configuration of the substituent attached to C15 in
compound IV was established in the same fashion as
described above for compound III.
The modification of the alkenyl substituent at C15 in
compound IV with the goal to introduce oxygen-
containing functions first of all involved the formation of
a terminal aldehyde group. The hydroxylation was
effected in the presence of 4-methylmorpholine N-oxide
and a catalytic amount of osmium tetroxide affording diole
1070-4280/04/4011-1608Ó2004 MAIK “Nauka/Interperiodica”

SYNTHESIS OF 15b-HYDROXYALKYL-SUBSTITUTED(17Z)-PREGN-17-ENES
1609
2
2
1
2
ꢀ
<2
<2
+2
1
,,
,,,
,
2
2
2
2+
ꢁ&+ ꢂ
+2
ꢁ&+ ꢂ
ꢁ&+ ꢂ
2
,9
9
9,
2
2
ꢁ&+ ꢂ 2+
ꢁ&+ ꢂ
2
+2
9,,
9,,,
YO = t-BuMe2Si.
V that underwent cleavage at treating with sodium
periodate [13–15] to yield aldehyde VI. This procedure
was chosen because at selective ozonolysis of the terminal
double bond it would be difficult to protect the D5-bond in
the B ring of the steroid. Moreover, the yield of aldehyde
VI proved to be considerably higher (88%) than the one
usually obtained by ozonolysis (70–80%). The structure
of aldehyde VI formation was proved by the appearance
in its IR spectrum of an additional absorption band
belonging to the stretching vibrations of the aldehyde
procedure optimization by decreasing the acidity
(addition of sodium hydrogen carbonate) resulted only
in decelerating the oxidation. The reaction took 3 days
and afforded the same aldehyde VII.
The presence of two carbonyl groups in the molecule
of steroid VI required the use of a selective reagent for
reduction of the aldehyde function into an alcohol. The
first attempt at reduction with triethylaminoborate complex
(BH3·Et3N) was not successful [18]. The heating at
reflux in THF for 48 h resulted only in partial reduction
of the aldehyde into alcohol VIII. Much better was the
efficiency of lithium tris(tert-butoxy)hydroaluminate [19].
However a two-fold excess of the reagent was required
to attain an effective reduction of the aldehyde group at
low temperature (–70°C). Under these conditions the yield
of the target alcohol was 97%. At the use of an equivalent
amount of the reductant the yield decreased to 67%.
The structure of alcohol VIII thus prepared was confirmed
by IR spectrum (appearance of the band of hydroxy
–1
group (n 1730 cm ) and in the1H NMR spectrum of a
one-proton triplet (d 9.77 ppm) characteristic of aldehydes.
We also attempted to effect the olefin IV cleavage
with sodium periodate in the presence of catalytic amounts
of ruthenium chloride [16, 17]. This method provides
aldehyde in one stage, like ozonolysis. However in our
case the aldehyde formation was accompanied by the
hydrolysis of the protecting group, and instead of the target
product aldehyde VII was obtained. The attempt at the
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1610
BARANOVSKII et al.
2
2
ꢀ&+ ꢁ
2+
ꢀ&+ ꢁ
;,,, ;9,
25ꢂ
ꢀ&+ ꢁ
,; ;,,
25ꢂ
52
9,,,
,9
ꢀ&+ ꢁ
;9,,
R = t-BuMe2Si (VIII–XVI); R’= t-BuMe2Si (IX, XIII); THP (X, XIV); Piv (XI, XV);Ac (XII); H (XVI).
–1
group stretching vibrations at 3480 cm ) and 1H NMR
spectrum [a two-proton triplet of the methylene protons
attached to the carbon bearing the hydroxy group (d
3.65 ppm)].
methylsilyl)amide proceeded slowly, with low conversion
and low yield of target diene XVII.
The double bond configuration in 17-ethylidenesteroids
XIII–XVII was determined by comparing with published
1H NMR spectra of these compounds.Atotal coincidence
was found for the proton signals of the group 21-CH3
and the proton at C20 in the known 17Z-pregnenes and
synthesized compounds XIII–XVII. For 17Z-olefins a
characteristic signal of H21 appears at 1.66 ppm [2, 3, 5,
21, 22] whereas ub the spectra of 17E-olefins this signal
is observed at 1.55 ppm [23].Asimilar trend exists in the
signals from protons attached to C20 (d 5.15 for Z- and
5.05 ppm for E-isomer).
By an example of 15b-substituted olefin XIV we
attempted to perform a transformation in the cyclic part
of the steroid molecule in order to prepare D2-6-keto-
steroids, intermediates in the synthesis of brassinosteroids
and ecdysteroids [24, 25]. The removal of tert-butyl-
dimethylsilyl protection, tosylation, isosteroid rearrange-
ment, oxidation of 3a,5-cycloalcohol XX with pyridinium
chlorochromate (PCC), and the replacement of a
protective group on the substituent at C15 occurred without
complications and with high yields. However at iso-
merization of 3a,5-cycloketone XXIII into D2-derivative
under treatment with pyridinium hydrobromide in
dimethylformamide at 150°C [26] occurred both the
isomerization of the C20 center and the displacement of
the D17-bond into the ring furnishing unseparable mixture
of isomers XXIV and XXV in a 1:1 ratio. This unwanted
result is proved by the presence in the 1H NMR spectrum
of two signals from groups 21-CH3 of intensity cor-
Further transformations required protection of the
hydroxy group, and therefore we synthesized a series of
alcohol VIII derivatives: tert-butyldimethylsilyl IX and
tetrahydropyranyl X ethers, pivaloyl XI and acetyl XII
esters.
The approach to pregnane derivatives was performed
by bringing ketones IX–XI into Wittig reaction. The
presence of an alkyl chain in the 15bposition might affect
both the yield and Z/E-selectivity of the reaction, therefore
we tested various conditions of the reaction using as a
rule potassium-containing bases since lithium salts were
known [20] to inhibit ylide reaction with 17-ketosteroids.
Wittig reaction with ketone IX where the ylide was
generated from ethyltriphenylphosphonium bromide with
the use of potassium bis(trimethylsilyl)amide afforded
compound XIII in a 77% yield, and with ketone XI 17-
ethylene derivative XV was obtained in a 67% yield. From
pivalate XI alongside compound XV a product of the ester
group hydrolysis XVI was obtained in 4% yield. The best
procedure proved to be that applying potassium tert-
butylate which had been shown to be the reagent of choice
in olefination of 17-ketosteroids lacking alkyl substituents
at C15 [21, 22]. For instance, boiling the ylide with 17-
ketosteroid X in benzene in the presence of potassium
tert-butylate afforded the target compound XIV in a
90% yield. It should be mentioned that Wittig reaction
with ketone IV in the presence of sodium bis(tri-
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

SYNTHESIS OF 15b-HYDROXYALKYL-SUBSTITUTED(17Z)-PREGN-17-ENES
1611
for use along standard procedures [28], the reactions were
carried out in an argon atmosphere. The reaction progress
was monitored by TLC on the plates Merck (Kieselgel
60 F254). The chromatographic separation of reaction
mixtures was performed using silica gel 40/60 (Kieselgel
60, Merck).
tert-Butyldimethylsilyl ether. In 20 ml of THF was
dissolved 1.26 g (4.45 mmol) of 3b-hydroxy-androst-
5,15-dien-17-one (I) prepared in 5 stages from
dehydroepiandrosterone acetate by the method [5], 0.775
g (11.4 mmol) of imidazole, and 0.863 g (5.75 mmol) of
tert-butyldimethylsilyl chloride, and the mixture was
stirred till disappearance of the original alcohol. The
reaction mixture was diluted with hexane (80 ml), washed
with a saturated solution of NaHCO3, a saturated solution
of NaCl, and dried with Na2SO4. On removal of the
solvent the residue was separated on a column packed
with silica gel (eluent toluene–ethyl acetate, 9:1). We
obtained 1.65 g (94%) of ketone II and 0.11 g (5%) of
imidazole derivative III.
responding to 1.5 proton each with chemical shifts (d,
ppm) of 1.55 d XXIV and 1.09 XXV, and also by
appearance in the downfield region of a multiplet at 5.46
ppm of intensity corresponding to 0.5 proton assigned to
H20 of compound XXV. A similar result of double bond
isomerization was obtained at oxidation of (17Z)-pregn-
17-ene in the presence of a Ru–porphyrin [27].
In this manner a series of 15b-hydroxyalkyl-sub-
stituted (17Z)-pregn-17-enes, their ethers and esters was
prepared by copper-catalyzed Grignard reagent addition
to D15-17-ketosteroids followed by further modifications
of 15-alkenyl substituent, introduction of an ethylene
component to atom C17 by Wittig reaction, and
transformations in the A and B rings of the steroid
molecules.
EXPERIMENTAL
Melting points were measured on Koeffler heating
1
block. H and 13C NMR spectra were registered on
3b-(tert-Butyldimethylsilyloxy)androsta-5,15-
dien-17-one (II). mp 110–112°C (hexane) (111–112°C
spectrometer Bruker A-200 (operating frequency for
protons 200 MHz) in CDCl3, internal reference TMS. IR
spectra were recorded on spectrophotometer UR-20
from samples prepared as films or KBr pellets. Mass
spectra (electron impact) were measured on a Hewlett-
Packard 5890 instrument with linear temperature
programming from 40 to 280°C at a rate 10 deg/min and
ionizing electrons energy 70eV.All solvents were prepared
–1
[29]). IR spectrum, cm : 2930, 1730 (CO), 1250, 1090,
1
830. H, d, ppm: 0.04 s (6H, Me2Si), 0.87 s (9H, t-BuSi),
1.05 s (3H, 18-Me), 1.06 s (3H, 19-Me), 3.47 m (1H,
C3 , Jw/2 32 Hz) 5.35 m (1H, H6, Jw/2 9 Hz), 6.03 d.d
a
(1H, H16, J1 6.1, J2 3 Hz), 7.48 d.d (1H, H15, J1 6.1, J2
1.2 Hz). Mass spectrum (EI), m/z (Irel, %): 385 [M –
Me]+ (3), 343 [M–t-Bu]+ (60), 315 [M – t-Bu-CO]+ (5).
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1612
BARANOVSKII et al.
3b-(tert-Butyldimethylsilyloxy)-15b-(1H-1-
washed with a saturated solution of NaCl, and dried on
Na2SO4. On removal of the solvent the residue was
separated on a column packed with silica gel (eluent
toluene–petroleum ether, 1:1). We obtained 0.281 g (95%)
of ketone IV.
imidazolyl)androst-5-en-17-one (III). mp 170–171°C
–1
(EtOAc). IR spectrum, cm : 2930, 2860, 1750 (CO),
1
1650, 1260, 1090, 840. H NMR spectrum, d, ppm:
0.05 s (6H, Me2Si), 0.81 s (3H, 18-Me), 0.88 s (9H,
t-BuSi), 1.02 s (3H, 19-Me), 2.84 d.d (1H, Ha16, J1 19.5,
J2 7.3 Hz), 3.05 d (1H, Hb16, J 19.5 Hz), 3.48 m (1H, Ha3,
Jw/2 32 Hz), 4.89 t (1H, Ha15, J 6.1 Hz), 5.34 m (1H, H6,
Jw/2 9 Hz), 7.03 s and 7.08 s (2H, H4' and H5'), 7.64 s
(1H, H2'). 13C NMR spectrum, d, ppm: –4.6 q, 16.5 q,
18.2 s, 19.2 q, 20.1 t, 25.9 q, 29.4 d, 31.1 t, 31.8 t, 34.3 t,
36.9 s, 37.2 t, 42.5 t, 44.3 t, 45.7 s, 51.2 d, 52.9 d, 56.6 d,
72.2 d, 118.8 d, 119.2 d, 129.7 d, 136.8 d, 142.3 s, 217.1 s.
Mass spectrum (ESI), m/z (Irel, %): 469 [M + 1]+ (100).
3b-(tert-Butyldimethylsilyloxy)-15b-(4,5-
dihydroxypentyl)androst-5-en-17-one (V). In 40 ml
of acetone and 4 ml of water was dissolved 0.959 g
(2.04 mmol) of steroid IV, and 3.45 ml (0.26 mmol) of
0.075 M OsO4 solution in t-BuOH and 0.33 g
(2.44 mmol)of 4-methylmorpholine N-oxide was added
thereto. The solution was stirred for 6 h, then a solution
of Na2SO3 was added, and the stirring was continued for
30 min. Then the reaction mixture was diluted with
EtOAc, washed with a saturated solution of NaCl, and
dried on Na2SO4. On removal of the solvent the residue
was purified on a column packed with silica gel (eluent
toluene–ethyl acetate, 1:1). We obtained 1.005 g (98%)
of diol V, mp 150–154°C (MeOH–H2O). IR spectrum,
3b-(tert-Butyldimethylsilyloxy)-15b-(4-
pentenyl)androst-5-en-17-one (IV). (a) To the cooled
at –20°C Grignard reagent solution obtained by adding
1.29 ml (8.64 mmol) of 5-bromopentene in 10 ml of THF
to 0.288 g (9.47 mmol) of Mg in 30 ml of THF followed
by boiling for 1 h was added in one portion 0.356 g
(1.72 mmol) of a complex CuBr·(CH3)2S. After 5 min to
the black solution obtained was added 1.141 g (2.85 mmol)
of steroid II in 10 ml of THF. The mixture was stirred
for15 min, cooled to –50°C, and was treated with a
saturated solution of NH4Cl. The organic substances
were extracted into EtOAc, the extract was washed with
a saturated solution of NaCl, and dried on Na2SO4. On
removal of the solvent the residue was separated on a
column packed with silica gel (eluent toluene–petroleum
ether, 1:1). We obtained 1.133 g (85%) of ketone IV, mp
–1
1
cm : 3450, 2940, 2870, 1760 (CO), 1260, 1095. H NMR
spectrum, d, ppm: 0.06 s (6H, Me2Si), 0.89 s (9H,
t-BuSi), 0.98 s (3H, 18-Me), 1.04 s (3H, 19-Me), 3.47 m
(2H, Ha3 and H5'), 3.69 m (2H, H4' and H5', Jw/2 29 Hz),
5.34 m (1H, H6, Jw/2 9 Hz). Mass spectrum (EI), m/z
(Irel, %): 503 [M – 1]+ (10), 447 [M – t-Bu]+ (100), 429
[M – t-Bu–H2O]+ (65), 411 (45).
3b-(tert-Butyldimethylsilyloxy)-15b-(4-oxo-
butyl)androst-5-en-17-one (VI). To 0.898 g (1.78
mmol) of steroid V dissolved in 60 ml of ethanol was
added 0.514 g (2.4 mmol) NaIO4 in 5 ml of water. The
solution was stirred for 30 min, the separated precipitate
was filtered off and washed with EtOAc. The filtrate
was evaporated without heating to a minimal volume,
diluted with EtOAc, washed with a saturated solution of
NaCl, and dried on Na2SO4. On removal of the solvent
the residue was purified on a column packed with silica
gel (eluent toluene–ethyl acetate, 7:3). We obtained
0.756 g (90%) of aldehyde VI, mp 97–98°C (hexane).
–1
100–102°C (hexane). IR spectrum, cm : 2930, 2860,
1750 (CO), 1650, 1090. 1H NMR spectrum, d, ppm: 0.06
s (6H, Me2Si), 0.88 s (9H, t-BuSi), 0.99 s (3H, 18-Me),
3
1.05 s (3H, 19-Me), 3.49 m (1H, Ha , Jw/2 32 Hz), 4.95 m
5'
(1H, H5cis Jw/2 14 Hz), 5.01 m (1H, H
Jw/2 21 Hz),
trans
5.35 m (1H, H6, Jw/2 9 Hz), 5.79 m (1H, H4', Jw/2 40
Hz). Mass spectrum (EI), m/z (Irel, %): 455 [M Me]+ (3),
413 [M – t-Bu]+ (40).
(b) To the cooled at –20°C Grignard reagent solution
obtained by adding 0.23 ml (1.95 mmol) of 5-bromopentene
in 3 ml of THF to 0.051 g (2.15 mmol) of Mg in 6 ml of
THF followed by boiling for 1 h was added in one portion
0.080 g (0.39 mmol) of a complex CuBr·(CH3)2S. In
5 min the solution was cooled to –78°C, and thereto was
added in succession 0.41 ml ( 3.35 mmol) of TMSCl,
0.565 ml (3.25 mmol) of HMPA, and 0.250 g (0.63 mmol)
of steroid II. The mixture was stirred for 10 min and
then treated with a saturated NH4Cl solution. The organic
substances were extracted into EtOAc, the extract was
–1
IR spectrum (film), cm : 2940, 2860, 2740 (CHO),
1
1750 (CO), 1730 (CO), 1260, 1095. H NMR spectrum,
d, ppm: 0.05 s (6H, Me2Si), 0.88 s (9H, t-BuSi), 0.97 s
(3H, 18-Me), 1.03 s (3H, 19-Me), 3.47 m (1H, Ha3, Jw/2
32 Hz), 5.33 m (1H, H6, Jw/2 9 Hz), 9.77 t (1H, H4', J 1.3
Hz). 13C NMR spectrum, d, ppm: –4.6 q, 17.5 q, 18.2 s,
19.3 q, 20.2 t, 21.8 t, 25.9 q, 28.9 d, 30.4 t, 30.8 t, 31.9 t,
33.8 t, 34.3 d, 36.9 s, 37.3 t, 42.3 t, 42.6 t, 43.7 t, 46.6 s,
50.8 d, 54.0 d, 72.4 d, 120.2 d, 142.0 s, 202.0 d, 221.0 s.
Mass spectrum (EI), m/z (Irel, %): 415 [M – t-Bu]+ (100).
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

SYNTHESIS OF 15b-HYDROXYALKYL-SUBSTITUTED(17Z)-PREGN-17-ENES
1613
–1
3b-Hydroxy-15b-(4-oxobutyl)androst-5-en-17-
one (VII). To a solution of 0.045 g (0.1 mmol) of steroid
IV in 6 ml of acetonitrile was added 0.001 g (0.005 mmol)
of RuCl3 and 43 mg (0,2 mmol) of NaIO4 in 1 ml of
water. The solution was stirred for 3 h, then it was poured
into water. The organic substances were extracted into
EtOAc, the extract was washed with a saturated solution
of NaCl, and dried on Na2SO4. On removal of the solvent
the residue was separated on a column packed with silica
gel (eluent toluene–ethyl acetate, 4:1. We obtained
0.026 g (73%) of steroid VII, oily substance. IR spectrum
IX, oily substance. IR spectrum (film), cm : 2940, 2870,
1750 (CO), 1260, 1095. 1H NMR spectrum, d, ppm:
0.03 s (6H, Me2Si), 0.05 s (6H, Me2Si), 0.88 s (18H,
t-BuSi), 0.98 s (3H, 18-Me), 1.04 s (3H, 19-Me), 3.48 m
(1H, Ha3, Jw/2 31 Hz), 3.59 t (2H, H4', J 6.1 Hz), 5.34 m
(1H, H6, Jw/2 9 Hz). 13C NMR spectrum, d, ppm: –5.3 q,
–4.6 q, 17.5 q, 18.2 s, 18.3 s, 19.3 q, 20.2 t, 25.8 t, 25.9 q,
28.9 d, 30.7 t, 30.8 t, 31.9 t, 32.7 t, 33.8 t, 34.3 d, 36.9 s,
37.3 t, 42.6 t, 42.7 t, 46.7 s, 50.8 d, 54.2 d, 63.0 t, 72.4 d,
120.3 d, 141.9 s, 221.7 s.
3b-(tert-Butyldimethylsilyloxy)-15b-[4-(tetra-
hydropyran-2-yloxy)butyl]androst-5-en-17-one (X).
To a solution of 0.876 g (1.85 mmol) of steroid VIII in 25
ml of THF was added 0.418 ml (4.63 mmol) of dihydro-
pyran and 49 mg (0.19 mmol) of pyridinium p-toluene-
sulfonate. The solution was heated at reflux for 30 min,
then cooled, diluted with EtOAc, the catalyst was filtered
off, the filtrate was washed with a saturated solution of
NaCl, and dried on Na2SO4. On removal of the solvent
the residue was separated on a column packed with silica
gel (eluent toluene–petroleum ether, 1:1). We obtained
0.960 g (93%) of steroid X, oily substance. IR spectrum
–1
(film), cm : 3480, 2940, 2740 (CHO), 1750 (CO),
1
1730 (CO). H NMR spectrum, d, ppm: 0.97 s (3H, 18-
Me), 1.04 s (3H, 19-Me), 3.53 m 1H, Ha3, Jw/2 32 Hz),
5.39 m (1H, H6, Jw/2 9 Hz), 9.77 t (1H, H4', J 1.3 Hz).
Mass spectrum (ESI), m/z (Irel, %): 381 [M + Na]+ (40).
3b-(tert-Butyldimethylsilyloxy)-15b-(4-hydr-
oxybutyl)androst-5-en-17-one (VIII). To a solution
of 0.756 g (1.6 mmol) of steroid VI in 35 ml of THF was
added at –70°C 0.904 g (3.56 mmol) of (t-BuO)3LiAlH.
The solution was stirred for 1 h at–70°C, then thereto
was added in succession 1 ml of acetone, 1 ml of saturated
NH4Cl solution, and the mixture was stirred for 30 min.
Then it was diluted with CHCl3 and filtered through a
bed of Na2SO4. On removal of the solvent the residue
(0.895 g) was crystallized from hexane to furnish
0.597 g of reaction product. The mother liquor (0.281 g)
was subjected to chromatography on a column packed
with silica gel (eluent toluene–ethyl acetate, 4:1) to isolate
additionally 0.144 g of steroid VIII. Overall yield of
ketoalcohol VIII 0.741 g (97%), mp 109–112°C (hexane).
–1
1
(film), cm : 2940, 1750 (CO), 1095. H NMR spectrum,
d, ppm: 0.04 s (6H, Me2Si), 0.86 s (9H, t-BuSi), 0.97 s
(3H, 18-Me), 1.02 s (3H, 19-Me), 3.43 m (3H, Ha , H4'
3
and H6'', Jw/2 52 Hz), 3.77 m (2H, H4' and H6'', Jw/2 46
Hz), 4.54 m (1H, H2''), 5.32 m (1H, H6, Jw/2 9 Hz).
3b-(tert-Butyldimethylsilyloxy)-15b-(4-pivaloyl-
oxybutyl)androst-5-en-17-one (XI). To a solution of
0.170 g (0.36 mmol) of steroid VIII in 2 ml of pyridine
was added 0.093 g (0.5 mmol) of trimethylacetic
anhydride and 9 mg (0.08 mmol) of dimethylaminopyridine.
The solution was stirred for 12 h, then poured into water.
The organic substances were extracted into EtOAc, the
extract was washed with a saturated solution of NaHCO3,
a saturated solution of NaCl, and dried on Na2SO4. On
removal of the solvent the residue was separated on a
column packed with silica gel (eluent toluene–petroleum
ether, 1:1). We obtained 0.145 g (72%) of steroid XI, mp
–1
IR spectrum, cm : 3480, 2940, 2870, 1750 (CO), 1260,
1
1095. H NMR spectrum, d, ppm: 0.05 s (6H, Me2Si),
0.88 s (9H, t-BuSi), 0.99 s (3H, 18-Me), 1.04 s (3H,
19-Me), 3.48 m (1H, Ha3, Jw/2 31 Hz), 3.65 t (2H, H4',
J 6.4 Hz), 5.34 m (1H, H6, Jw/2 9 Hz). Mass spectrum
(ESI), m/z (Irel, %): 497 [M + Na]+ (100).
3b-(tert-Butyldimethylsilyloxy)-15b-[(4-tert-
butyldimethylsilyloxy)butyl]androst-5-en-17-one
(IX). To a solution of 0.085 g (0.18 mmol) of alcohol
VIII in 5 ml of THF was added 0.029 g (0.43 mmol) of
imidazole, 0.032 g (0.22 mmol) of t-BuMe2SiCl, and the
mixture was stirred till disappearance of the initial alcohol
(TLC monitoring). The reaction mixture was diluted with
hexane, washed with a saturated solution of NaHCO3,
with a saturated solution of NaCl, and dried on Na2SO4.
On removal of the solvent the residue was separated on
a column packed with silica gel (eluent toluene–petroleum
ether, 1:1). We obtained 0.090 g (85%) of reaction product
–1
108–110°C (hexane). IR spectrum, cm : 2940, 2870,
1
1750 (CO), 1260, 1040. H NMR spectrum, d, ppm:
0.06 s (6H, Me2Si), 0.89 s (9H, t-BuSi), 0.99 s (3H,
18-Me), 1.04 s (3H, 19-Me), 1.18 s (9H, Me3C), 3.48 m
(1H, H3a, Jw/2 31 Hz), 4.05 t (2H, H4', J 6.4 Hz), 5.34 m
(1H, H6, Jw/2 9 Hz). Mass spectrum (EI), m/z (Irel, %):
501 [M – t-Bu]+ (40), 426 (5), 325 (40).
15b-(4-Acetoxybutyl)-3b-(tert-butyldimethyl-
silyloxy)androst-5-en-17-one (XII). To a solution of
0.028 g (0.06 mmol) of steroid VIII in 4 ml of
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1614
BARANOVSKII et al.
dichloromethane was added 0.012 ml (0.12 mmol) of
acetic anhydride and 18 mg (0.15 mmol) of dimethyl-
aminopyridine. The solution was stirred for 12 h, then
diluted with dichloromethane, washed with water, with a
solution of NaHCO3, a saturated solution of NaCl, and
dried on Na2SO4. On removal of the solvent the residue
was separated on a column packed with silica gel (eluent
toluene–petroleum ether, 1:1). We obtained 24 mg (79%)
filtered through a bed of Na2SO4. On removal of the
solvent the residue was separated on a column packed
with silica gel (eluent toluene–petroleum ether, 9:1). We
obtained 0.769 g (90%) of compound XIV, oily substance.
IR spectrum (film), cm : 2940, 2870, 1040. H NMR
spectrum, d, ppm: 0.05 s (6H, Me2Si), 0.88 s (9H, t-BuSi),
1.03 s (3H, 18-Me), 1.05 s (3H, 19-Me), 1.65 d (3H, 21-
Me, J 7.3 Hz), 3.36 m (1H, H4', Jw/2 23 Hz), 3.49 m (2H,
H3a and H6'', Jw/2 25 Hz), 3.72 m (1H, H4', Jw/2 25 Hz),
3.86 m (1H, H6'', Jw/2 24 Hz), 4.56 m (1H, H2'', Jw/2 8 Hz),
5.15 q.t (1H, H20, J1 7.3, J2 1.8 Hz), 5.33 br.d (1H, H6,
J 4.8 Hz).
–1
1
–1
of steroid XII, oily substance. IR spectrum (film), cm :
1
2940, 2870, 1750 (CO), 1740 (MeCO), 1260, 1095. H
NMR spectrum, d, ppm: 0.06 s (6H, Me2Si), 0.89 s (9H,
t-BuSi), 0.99 s (3H, 18-Me), 1.05 s (3H, 19-Me), 2.03 s
(3H, OAc), 3.49 m (1H, H3a, Jw/2 31 Hz), 4.06 t (2H, H4',
J 6.4 Hz), 5.35 br.d (1H, H6, J 4.9 Hz).
(17Z)-3b-(tert-Butyldimethylsilyloxy)-15b-(4-
pivaloyloxybutyl)pregna-5,17-diene (XV). Along the
procedure applied to the synthesis of compound XIII from
0.120 g (0.21 mmol) of ketone XI we obtained 0.080 g
(67%) of steroid XV, oily substance. IR spectrum (film),
(17Z)-3b-(tert-Butyldimethylsilyloxy)-15b-[(4-
tert-butylsilyldimethyloxy)butyl]-pregna-5,17-diene
(XIII). To a solution obtained by adding 1.36 ml (0.68
mmol) of 0.5 M solution of potassium bis(trimethylsilyl)-
amide in toluene to 0.303 g (0.81 mmol) of ethyltriphenyl-
phosphonium bromide in 1 ml of THF was added at
–78°C 0.080 g (0.14 mmol) of steroid IX in 1 ml of THF.
The mixture was stirred for 30 min, the cooling was
removed, and the solution was heated at reflux for 6 h.
Then the solution was cooled and treated with a saturated
solution of NH4Cl. The organic substances were extracted
into EtOAc, the extract was washed with a saturated
solution of NaCl, and dried on Na2SO4. On removal of
the solvent the residue was dissolved in hexane, 0.5 ml
of methyl iodide was added, and the reaction mixture
was stirred for 24 h. The precipitate was filtered off, the
filtrate was evaporated, and the obtained oily substance
was separated on a column packed with silica gel (eluent
toluene–petroleum ether, 9:1). We obtained 0.063 g
(77%) of reaction product XIII, oily substance. IR
–1
1
cm : 2940, 2870, 1745 (CO), 1040. H NMR spectrum,
d, ppm: 0.05 s (6H, Me2Si), 0.88 s (9H, t-BuSi), 1.03 s
(3H, 18-Me), 1.04 s (3H, 19-Me), 1.18 s (9H, Me3C),
1.66 d (3H, 21-Me, J 7 Hz), 3.48 m (1H, H3a, Jw/2 31 Hz),
4.03 t (2H, H4', J 6.4 Hz), 5.15 q.t (1H, H20, J1 7, J2
1.5 Hz), 5.32 m (1H, H6, Jw/2 9 Hz). 13C NMR spectrum,
d, ppm: –4.6 q, 13.4 q, 18.3 s, 19.3 q, 20.2 q, 21.1 t,
25.9 q, 26.1 t, 27.2 q, 28.8 t, 28.9 d, 30.9 t, 31.6 t, 32.1 t,
36.8 s, 37.0 d, 37.4 t, 38.7 s, 39.2 t, 39.2 t, 42.7 t, 43.5 s,
50.8 d, 59.3 d, 64.4 t, 72.6 d, 114.1 d, 120.9 d, 141.8 s,
150.7 s, 178.6 s. Further elution with the mixture toluene–
petroleum ether, 9:1, furnished 0.004 g (4%) of (17Z)-
3b-(tert-butyldimethylsilyloxy)-15b-(4-hydroxy-
butyl)pregna-5,17-diene (XVI), oily substance. IR
–1
1
spectrum (film), cm : 3500, 2940, 2870, 1040. H NMR
spectrum, d, ppm: 0.06 s (6H, Me2Si), 0.89 s (9H, t-BuSi),
1.04 s (3H, 18-Me), 1.06 s (3H, 19-Me), 1.66 d (3H, 21-
Me, J 7 Hz), 3.49 m (1H, H3a, Jw/2 31 Hz), 3.62 t (2H, H4',
J 6.4 Hz), 5.15 q.t (1H, H20, J1 7, J2 1.5 Hz), 5.34 m (1H,
H6, Jw/2 9 Hz).
–1
spectrum (film), cm : 2940, 2870, 1095. 1H NMR
spectrum, d, ppm: 0.04 s (6H, Me2Si), 0.05 s (6H, Me2Si),
0.88 s (18H, t-BuSi), 1.02 s (3H, 18-Me), 1.05 s (3H, 19-
Me), 1.65 d (3H, 21-Me, J 7.3 Hz), 3.48 m (1H, H3a),
3.58 t (2H, H4', J 6.4 Hz), 5.15 q.t (1H, H20, J1 7.3, J2
1.5 Hz), 5.33 m (1H, H6, Jw/2 9 Hz).
(17Z)-3b-(tert-Butyldimethylsilyloxy)-15b-(4-
pentenyl)pregna-5,17-diene (XVII). To a solution
obtained from 0.324 g (0.87 mmol) of ethyltriphenyl-
phosphonium bromide and 0.137 g (0.75 mmol) of sodium
bis(trimethylsilyl)amide in 1 ml of THF was added at
–78°C 0.115 g (0.24 mmol) of steroid IV in 1 ml of THF.
After stirring for 1 h the cooling was removed, the solution
was heated at reflux for 10 h, then the reaction mixture
was cooled, diluted with hexane, washed with a saturated
solution of NH4Cl, a saturated solution of NaCl, and dried
on Na2SO4. On removal of the solvent the residue was
separated on a column packed with silica gel (eluent
toluene–petroleum ether, 9:1). We obtained 0.052 g of
(17Z)-3b-(tert-Butyldimethylsilyloxy)-15b-[4-
(tetrahydropyran-2-yloxy)butyl]-pregna-5,17-diene
(XIV). To a solution of ylide prepared by stirring 0.560 g
(5 mmol) of potassium tert-butylate and 2.4 g (6.5 mmol)
of ethyltriphenylphosphonium bromide in 6 ml of benzene
at 40°C for 0.5 h was added 0.836 g (1.5 mmol) of steroid
X in 8 ml of benzene at 10°C. The solution obtained was
heated at reflux for 4 h, cooled, and excess acetone was
added. In 30 min the solution was treated with 3 ml of
saturated NH4Cl solution, diluted with hexane, and
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

SYNTHESIS OF 15b-HYDROXYALKYL-SUBSTITUTED(17Z)-PREGN-17-ENES
1615
original ketone IV and 0.010 g (8%) of reaction product
toluene). We obtained 0.325 g (63%) of compound XXI,
–1
–1
XVII, oily substance. IR spectrum (film), cm : 2940,
oily substance. IR spectrum (film), cm : 2940, 2870, 1700
1
1
(CO), 1040. H NMR spectrum, d, ppm: 0.74 t (1H, H4,
2870, 1655, 1270, 1060, 810. H NMR spectrum, d, ppm:
0.04 s (6H, Me2Si), 0.86 s (9H, t-BuSi), 1.04 s (3H,
J 4.9 Hz), 1.03 s (3H, 18-Me), 1.10 s (3H, 19-Me), 1.66
br.d (3H, 21-Me, J 7 Hz), 3.35 m (1H, H4', Jw/2 24Hz),
3.48 m (1H,H6'', Jw/2 23 Hz), 3.72 m (1H, H4', Jw/2
25 Hz), 3.85 m (1H, H6'', Jw/2 24 Hz), 4.57 m (1H, H2'',
Jw/2 8 Hz), 5.16 q.t (1H, H20, J1 7, J2 1.8 Hz). 13C NMR
spectrum, d, ppm: 11.9 t, 13.3 q, 19.6 t, 19.7 q, 20.5 q,
22.9 t, 25.5 t, 25.8 t, 26.5 t, 29.9 t, 30.7 t, 31.1 t, 31.7 d,
33.5 t, 35.7 d, 37.1 d, 39.1 t, 39.2 t, 43.8 s, 44.5 t, 46.4 s,
46.7 s, 46.8 d, 59.6 d, 62.3 t, 67.6 t, 98.8 d, 114.4 d,
150.0 s, 209.4 s.
18-Me), 1.06 s (3H, 19-Me), 1.65 br.d (3H, 21-Me,
5'
J 7 Hz), 3.48 m (1H, H3a, Jw/2 28 Hz), 4.91 d (1H, H , J
cis
8 Hz), 4.99 br.d (1H, H5tr'ans, J 17 Hz), 5.16 br.q (1H, H20,
J 7 Hz), 5.33 m (1H, H6, Jw/2 9 Hz), 5.81 m (1H, H4',
Jw/2 40 Hz).
(17Z)-3b-Hydroxy-15b-[4-(tetrahydropyran-2-
yloxy)butyl]pregna-5,17-diene (XVIII). To a solution
of 0.867 g (1.52 mmol) of steroid XIV in 5 ml of THF
was added 4.56 ml of 1 Msolution of tetrabutylammonium
fluoride in THF, and the mixture was stirred. In 2 h
additionally 2.28 ml of 1Msolution of tetrabutylammonium
fluoride in THF was added, and the stirring was continued
for 3 h. Then the mixture was diluted with EtOAc, washed
with a saturated solution of NaHCO3, a saturated solution
of NaCl, and dried on Na2SO4. On removal of the solvent
the residue was separated on a column packed with silica
gel (eluent toluene). We obtained 0.683 g (99%) of steroid
(17Z)-15b-(4-Acetoxybutyl)-3a,5-cyclo-5a-
pregn-17-en-one (XXIII). To a solution of 0.425 g (0.94
mmol) of steroid XXI in 15 ml of methanol and 1.5 ml of
water was added 0.016 g (0.09 mmol) of p-toluenesulfonic
acid. The solution was stirred for 12 h, then poured into
water, methanol was distilled off, the organic substances
were extracted into chloroform, the extract was washed
with a saturated solution of NaHCO3, a saturated solution
of NaCl, and dried on Na2SO4. On removing the solvent
the residue was dissolved in 10 ml of dichloromethane,
and then were added in succession 0.122 g (1 mmol) of
dimethylaminopyridine, 0.24 ml (3 mmol) of pyridine, and
0.3 ml (3 mmol) of acetic anhydride. The solution was
stirred for 1 h, diluted with chloroform, washed with a
saturated solution of NaHCO3, a saturated solution of
NaCl, and dried on Na2SO4. On removal of the solvent
the residue was separated on a column packed with silica
gel (eluent toluene). We obtained 0.288 g (74%) of
reaction product XXIII, oily substance. IR spectrum
–1
XVIII, oily substance. IR spectrum (film), cm : 3480,
2940, 2870, 1040. 1H NMR spectrum, d, ppm: 1.04 s
(3H, 18-Me), 1.06 s (3H, 19-Me), 1.65 d (3H, 21-Me,
J 7 Hz), 3.36 m (1H, H4', Jw/2 24 Hz), 3.52 m (2H, Ha3,
H6''), 3.72 m (1H, H4', Jw/2 25 Hz), 3.86 m (1H, H6'', Jw/2
24 Hz), 4.56 m (1H, H2'', Jw/2 8 Hz), 5.14 q.t (1H, H20,
J1 7, J2 1.8 Hz), 5.36 br.d (1H, H6, J 5.1 Hz).
15b-[4-(Tetrahydropyran-2-yloxy)butyl]-3a,5-
cyclo-5a-pregn-17-en-6-one (XXI). To a solution of
0.520 g (1.14 mmol) of steroid XVIII in 10 ml of pyridine
was added 0.724 g (3.8 mmol) of p-toluenesulfonyl
chloride and 78 mg (0.15 mmol) of dimethylaminopyridine.
The solution was stirred for 24 h, then poured into water,
the precipitated reaction product was filtered off, washed
with water, dried, and dissolved in 90 ml of acetone. To
the solution thus obtained was added 0.6 g (6.1 mmol) of
potassium acetate in 6 ml of water. The solution was
heated at reflux for 48 h, cooled, and acetone was
evaporated. The residue was dissolved in EtOAc, washed
with a saturated solution of NH4Cl, a saturated solution
of NaCl, and dried on Na2SO4. On removing the solvent
the residue was dissolved in 10 ml of dichloromethane,
and 0.450 g (5 mmol) of potassium acetate and 0.431 g
(2 mmol) of pyridinium chlorochromate was added in
succession. The mixture was stirred for 2 h, then 0.431 g
(2 mmol) of PCC again was added, and the stirring was
continued. After 6 h of stirring the reaction mixture was
subjected to column chromatography on silica gel (eluent
–1
(film), cm : 2940, 2870, 1750 (MeCO), 1700 (CO), 1250,
1
1040. H NMR spectrum, d, ppm: 0.75 t (1H, H4, J 4.9
Hz), 1.04 s (3H, 18-Me), 1.09 s (3H, 19-Me), 1.65 br.d
(3H, 21-Me, J 7 Hz), 4.02 t (2H, H4', J 6.4 Hz), 5.16 q.t
(1H, H20, J1 7, J2 1.8 Hz).
(17E)-15b-(4-Acetoxybutyl)pregna-2,17-diene-
6-one (XXIV) and 15b-(4-acetoxybutyl)pregna-2,16-
diene-6-one (XXV). To a solution of 0.231 g (0.56 mmol)
of steroid XXIII in 5 ml of DMF was added 0.358 g
(2.24 mmol) of pyridinium hydrobromide The reaction
mixture was boiled for 6 h, then cooled and poured in
water. The organic compounds were extracted with
EtOAc, the extract was washed with a saturated solution
of NaCl, and dried on Na2SO4. On removing the solvent
the residue was separated on a column packed with silica
gel (eluent toluene–petroleum ether, 1:1). We obtained
0.095 g (43%) of a mixture of steroids XXIV and XXV.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1616
BARANOVSKII et al.
–1
Sugiyama, Y., andYamada, S., J. Org. Chem., 1998, vol. 63,
p. 4449.
13. Bojack, G. and Kunzer, H., Tetrahedron Lett., 1994, vol. 35,
p. 9025.
14. Kihira, K. and Hoshita, T., Steroids, 1985, vol. 46, p. 767.
15. Katoch, R., Korde, S.S., Deodhar, K.D., and Trivedi, G.K.,
Tetrahedron, 1999, vol. 55, p. 1741.
16. Yang, D. and Zhang, C., J. Org. Chem., 2001, vol. 66,
p. 4814.
17. Corey, E.J. and Wood, H.B., J. Am. Chem. Soc., 1996,
vol. 118, p. 11982.
18. Hill, J., Sutherland, J.K., and Crowley, P., J. Chem. Soc.,
Perkin, Trans. I, 1992, p. 969.
19. Krishnamurthy, S., J. Org. Chem., 1981, vol. 46, p. 4628.
20. Vedejs, E., Cabaj, J., and Peterson, M.J., J. Org. Chem.,
1993, vol. 58, p. 6509.
21. Trost, B.M. and Verhoeven, T.R., J. Org. Chem., 1976,
vol. 41, p. 3416.
22. Shen, Y. and Burgoyne, D.L., J. Org. Chem., 2002, vol. 67,
p. 3908.
23. Shull, B.K. and Koreeda, M., J. Org. Chem., 1990, vol. 55,
p. 99.
24. Khripach, V.A., Zhabinskii, V.N., and de Groot, A.,
Brassinosteroids: A New Class of Plant Hormones,
Academic Press, 1999, 456 p.
25. Sakurai,A., Yokota, T., and Clouse, S.D., Brassinosteroids:
Steroidal Plant Hormones, Tokyo: Springer, Verlag, 1999,
253 p.
26. Anastasia, M., Allevi, P., Ciuffreda, P., and Oleotti, A.,
Steroids, 1985, vol. 45, p. 561.
27. Tavares, M., Ramasseul, R., Marchon, J.C., Vallee-
Goyet, D., and Gramain, J.C., J. Chem. Res. Synop., 1994,
p. 74.
28. Perrin, D.D. andArmarego, W.L.F., Purification of Labor-
atory Chemicals, Oxford: Pergamon, Press, 1988, 391 p.
29. Takahashi, T., Ootake, A., Tsuji, J., and Tachibana, K.,
Tetrahedron, 1985, vol. 41, p. 5747.
IR spectrum (film), cm : 3030, 2950, 2860, 1750
1
(MeCO), 1720 (CO), 1250, 1040. H NMR spectrum, d,
ppm: 0.75 s and 0.77 s (3H, 18-Me and 19-Me), 0.89 s
and 0.95 s (3H, 18-Me and 19-Me), 1.09 t and 1.55 br.d
(3H, 21-Me, J 7 Hz), 2.05 s (3H, OAC), 4.05 t.d (2H,
H4', J1 6.5, J2 2.2 Hz), 5.08 m (0.5H, H20, Jw/2 20 Hz),
5.46 m (0.5H, H16, Jw/2 6.7 Hz), 5.57m (1H, H3, Jw/2
16 Hz), 5.70 m (1H, H2, Jw/2 18 Hz). Mass spectrum
(EI), m/z (Irel, %): 412 [M]+ (60), 397 [M – Me]+ (90),
384 [M –CO]+ (50), 337 [M – Me-AcOH]+ 45), 323
[M– CO–AcOH]+ (30), 297 [M – (CH2)4OAc]+ (100).
REFERENCES
1. Mikami, K., Kishino, H., and Loh, T.P., Chem. Commun.,
1994, p. 495.
2. Hazra, B.G., Pore, V.S., and Joshi, P.L., J. Chem. Soc., Perkin,
Trans, I, 1993, p. 1819.
3. Houston, T.A., Tanaka, Y., and Koreeda, M., J. Org. Chem.,
1993, vol. 58, p. 4287.
4. Mikami, K., Loh, T., and Nakai, T., Tetrahedron Asymmetry.,
1990, vol. 1, p. 13.
5. Liu, D., Stuhmiller, L.M., and McMorris, T.C., J. Chem. Soc.,
Perkin, Trans. I, 1988, p. 2161.
6. Corey, E.J. and Venkateswarlu,A., J. Am. Chem. Soc., 1972,
vol. 94, p. 6190.
7. Bull, J.R. and Loedolff, M., J. Chem. Soc., Perkin Trans. I,
1996, p. 1269.
8. Mongelli, N.,Andreoni,A., Zuliani, L, and Gandolfi, C.A.,
Tetrahedron Lett., 1983, vol. 24, p. 3527.
9. Luppa, P., Hauck, S., Schwab, I., Birkmayer, C., and
Hauptmann, H., Bioconjugate Chem., 1996, vol. 7, p. 332.
10. Schmuff, N.R. and Trost, B.M., J. Org. Chem., 1983, vol. 48,
p. 1404.
11.Adamczyk,Y.Y., Chen, D.D., and Johnson, R.E., Tetrahedron,
1997, vol. 53, p. 12855.
12. Yamamoto, K., Ogura, H., Jukuta, J., Inoue, H., Hamada, K.,
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004