Synthesis of C-C bonded dimeric steroids by olefin metathesis

Article abstract of DOI:10.1016/j.tet.2009.03.006

Five new C-C bonded steroidal homodimers derived from deoxycholic acid, pregnenolone, and progesterone were synthesized by an olefin metathesis reaction assisted by microwave heating. Microwave improved the yield and accelerated the reaction allowing the use of less catalyst with good results (2.5 mol %). Due to the bulky nature of the steroidal skeleton the more favorable E-dimers were formed as the sole or major products depending on the linker length.

Full text of DOI:10.1016/j.tet.2009.03.006

Tetrahedron 65 (2009) 3615–3623
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of C–C bonded dimeric steroids by olefin metathesis
Valeria C. Edelsztein, Pablo H. Di Chenna, Gerardo Burton *
Departamento de Qu ´ı mica Org a´ nica and UMYMFOR (CONICET-FCEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires,
Ciudad Universitaria, Pabell o´ n 2, C1428EGA Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Five new C–C bonded steroidal homodimers derived from deoxycholic acid, pregnenolone, and
progesterone were synthesized by an olefin metathesis reaction assisted by microwave heating.
Microwave improved the yield and accelerated the reaction allowing the use of less catalyst with good
results (2.5 mol %). Due to the bulky nature of the steroidal skeleton the more favorable E-dimers were
formed as the sole or major products depending on the linker length.
Received 15 January 2009
Received in revised form 24 February 2009
Accepted 2 March 2009
Available online 6 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Dimerization
Metathesis
Dimeric steroids
Microwave
1. Introduction
the connection between the units involves a labile bond such as an
ether, amide, amine, hydrazone or ester moiety. Carbon–carbon
Synthesis of symmetric molecules derived from joining two
identical moieties has gained importance in recent years. These
molecules may act as ligands for proteins and as such, activate
cellular processes,1 or increase the affinity of ligands to their
binding sites by providing an extra anchoring to the active site of
bonded dimeric steroids should be more stable to biological or
harsh chemical media, however they are less common and only
a few examples are found in the literature, most of them involving
,2
13,14
a direct connection between rings.
To the best of our knowledge
the only report of dimeric steroids linked through carbon–carbon
3
15
certain domains. In particular dimeric steroids represent a class of
spacers is that by Morzycki et al., who synthesized a series of
compounds that have attracted attention for their rigid and in-
dimeric pregnane steroids linked via C-20 with long chain hydro-
carbon spacers. The C–C dimerization step was performed by
a Wurtz reaction and Wicha–Bal alkylation–reduction procedure
with very low yields.
4
herently asymmetric architecture. Many dimeric steroids exhibit
5
miscellar, detergent, and liquid crystal behavior. Also, some di-
meric steroids are pharmaceutically important exhibiting various
6
biological activities as cytotoxicity and anticancer potential, anti-
During our work directed toward the preparation of structurally
7
8
malarial, serum cholesterol lowering effect, and insect molting
diverse analogues of bioactive steroids, capable of invoking a broad
alteration.9 They have been also used as molecular umbrellas,
10
spectrum of biological activities,
16,17
we devised a simple route to
11
building blocks for artificial receptors, and catalysts for some or-
ganic reactions.12 The first reports of dimeric derivatives with var-
ious inter-steroid linkages resulted from by-product formation, and
only in recent years preparation of these compounds has been
sought.
prepare C–C linked dimeric steroids by means of a metathesis
coupling reaction process. Despite being a very mild reaction that
18
tolerates the presence of a wide variety of functional groups, its
19
use in steroid chemistry is limited. Poirier et al. prepared some
hybrid inhibitors of type 1 17 -hydroxysteroid dehydrogenase of
b
Dimeric steroids may be linear or cyclic and may be connected
via rings in the steroid nucleus (A–A, B–B, etc.) or through the side
chains, the latter being commonly used to form bile acids dimers.
The individual moieties may be linked by direct connection or
estradiol and an adenosine mimic through a step that involves
a cross-metathesis reaction with a linear terminal olefin that
elongates the side chain at C-16 with moderate but not optimized
yield. The recent synthesis of 6E-hydroxyiminosteroid dimers,
bonded through a linker with an ether functionality at C-3, is the
only example of steroid homodimerization by metathesis. As the
steric and spatial orientation requirements of the catalysts for
metathesis are critical, predicting the feasibility of such reaction on
the proximity of the rigid and highly asymmetric bulky steroidal
4
through spacer groups. In most examples found in the literature,
2
0
*
Corresponding author. Tel./fax: þ54 11 4576 3385.
E-mail address: burton@qo.fcen.uba.ar (G. Burton).
0
040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.006

3616
V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
skeleton is not obvious, even using the most reactive terminal
Table 1
Dimerization reaction of steroid 3 with Grubbs 2nd generation catalysta
21
olefins. We report here the synthesis of dimers at C-20 (ring D), C-
9 and C-6 (ring B) of the steroid skeleton via an olefin metathesis
Yieldc
(%)
1
Entry
Heating
Catalyst
(mol %)
Temp
( C)
Time
(h)
ꢀ
coupling process using Grubbs catalyst (2nd generation) on ter-
minal olefins, with hydrocarbon linkers of different lengths. The
effect of microwave (MW) irradiation on the reaction is also
presented.
1
2
3
4
5
6
Conventional
Conventional
Conventional
Microwaveb
20
10
5
10
5
40
40
25
100
100
100
6.5
6
24
1.7
1.7
2
52
20
7
97
78
71
b
Microwave
Microwaveb
2.5
2
2
. Results and discussion
a
Reactions were carried out in 0.3 M solutions of 3 in dichloromethane.
Performed in a CEM Discover reactor at 300 W, closed vessel method.
Yields calculated over isolated product after column chromatography.
b
c
.1. Homodimerization at the side chain through C-20
Several bile acid related dimers have been synthesized by con-
necting the C-20 side chains through a spacer group using ester or
amide moieties. The unique characteristics of these steroidal acids
in relation to their chiral, rigid, and curved framework, as well as
their chemically diverse hydroxyl groups have made them impor-
tant in tailoring supramolecular hosts. With this in mind we started
our work studying the dimerization metathesis reaction at that
position. We first prepared 20-methylidene pregnanolone 1 from
pregnanolone acetate by a salt-free Wittig reaction (Scheme 1).
Compound 1, a sterically hindered 1,1-disubstituted olefin, did not
dimerize in the presence of Grubbs catalysts (1st and 2nd genera-
tion) even under MW heating conditions that have proved to ef-
fectively accelerate cross-metathesis reaction between deactivated
and terminal olefins.22
below for double bond geometry analysis). Formation of the steri-
cally less favored Z-isomer was not observed.
When dimerization of 3 was carried out under microwave
heating conditions, an important increase in the reaction rate was
observed. Using 10 mol % 2nd generation catalyst, dimer 4 was
obtained in 97% yield (Table 1, entry 4). In addition to the increased
yield and reaction rate the MW reaction could be carried out with
a significantly lower catalyst load (5–2.5 mol %), still with good
yields (Table 1, entries 5 and 6). Grubbs 1st generation catalyst was
unable to dimerize 3, even under MW conditions; in this case, the
unreacted starting material was recovered intact after
chromatography.
Using the optimized conditions found for 3, the microwave
assisted dimerization reaction was then performed at C-20 with
two spacer groups of different length and a different functionali-
zation of the steroid nucleus. The terminal olefins were prepared
The homodimerization reaction at the C-20 side chain was then
attempted on steroid 3, a terminal olefin with a longer chain easily
prepared from deoxycholic acid diacetate 2 (Scheme 1). The deg-
radation of the side chain of 2 was achieved by an oxidative de-
from commercial deoxycholic acid and 3-oxo-4-pregnen-20
carboxyaldehyde (8) (Scheme 2). Deoxycholic acid methyl ester (5)
was reduced with LiAlH to the 3 ,12 ,24-cholanetriol that was
b-
2
3
carboxylation using the methodology developed by Suarez et al.
as an alternative to the classical method with Pb(AcO)
4
applied to
4
a
a
bile acids.24 The homodimerization of 3 with 2nd generation
Grubbs catalyst in dichloromethane under conventional heating
conditions gave a single product but did not proceed to completion
oxidized with PCC to give diketoaldehyde 6. A regioselective
Wittig reaction with salt-free methylidenetriphenylphosphorane
was a direct way to selectively olefinate the aldehyde 6 to the
terminal olefin 7. The salt-free ylide was prepared from the
corresponding phosphonium salt by a methodology previously
developed by our group using sodium amide, ultrasound, and
(Table 1, entries 1–3). The product was characterized as the sym-
metric E-dimer 4, the dimeric nature of the product was confirmed
by electrospray (ESI) exact mass spectrometry with a pseudomo-
þ
26
lecular ion (MþNa) at 855.5729 corresponding to the molecular
a non-polar solvent with very good results. Monomer 9, with an
13
formula C52H
80
O
8
Na. The C NMR spectrum showed 26 signals
a,
b-unsaturated carbonyl system on ring A, was prepared from
with a single olefinic carbon resonance at 134.2 ppm in accordance
with a symmetric dimeric structure. The H NMR spectrum was also
commercial 3-oxo-4-pregnen-20 -carboxyaldehyde using the
same Wittig reaction conditions mentioned above with excellent
yield (Scheme 2).
Dimerization of compounds 7 and 9 was carried out under MW
irradiation with 2.5 mol % of Grubbs 2nd generation catalyst
b
1
consistent with a symmetric dimer and showed the H-22 olefin
1
multiplet at 5.11 ppm. Analysis of H NMR data for compound 4 was
in agreement with the expected E double bond geometry (see
Scheme 1.

V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
3617
Scheme 2.
Scheme 3.
(Scheme 3). Steroid 9 gave one dimeric product in 49% yield; only
2.2. Homodimerization at ring B through C-6
10% of unreacted material was recovered indicating some de-
composition of the product and/or starting material under the re-
action conditions. Spectroscopic data of 11 was consistent with the
symmetric E-dimer structure as described previously for dimer 4. In
the case of monomer 7 with the longer spacer group, dimerization
Functionalization of the pregnane skeleton at C-6 starting from
steroid 12 is shown in Scheme 4; compound 12 can be easily pre-
2
7
pared from pregnenolone acetate. In order to avoid any in-
terference in the metathesis reaction the C-2 double bond was
hydrogenated in the presence of 10% Pd/C to give 6-ketosteroid 13.
Addition of allylmagnesium chloride to the 6-ketone in 13 gave
proceeded with very good yield to give a mixture of E/Z isomers
1
(
9:1 ratio) as observed by H NMR. The small amount of the less
favored Z-isomer (not observed with compounds 4 and 11) prob-
ably arises due to reduced steric hindrance from the steroid nu-
cleus, which is further away from the double bond. As with
compound 3, the dimerization of 7 and 9 did not proceed with 1st
generation Grubbs catalyst in dichloromethane, even under MW
heating.
a mixture of 6
separated. As expected the major product was the 6
generated by attack to the less hindered alpha face; deacetylation at
C-20 was also observed. The mixture of 6-allyl steroids was oxi-
dized with PCC to give after column chromatography the corre-
sponding 20-ketones16 (72%) and 17 (9%). Steroid 13 was also
a
and 6
b
allyl steroids (14 and 15) that could not be
-allyl steroid
a
Scheme 4.

3618
V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
converted to olefin 18 via a Wittig reaction with methylidene-
triphenylphosphorane. The three olefins were then submitted to
MW mediated metathesis reaction with 2nd generation Grubbs
catalyst. Compound 17, with the allyl group oriented in an axial
position did not dimerize; the same happened when reaction was
attempted with the 1,1-disubstituted alkene 18. On the other hand,
steroid 16 reacted to give the E-dimer 19 as the major product, with
a 5% of the Z-isomer detected by NMR (Scheme 5). This mixture
could not be separated by chromatography, and compound 19 was
purified by recrystallization from 2-propanol. The dimeric nature of
possibility to oppose both b faces that, added to the rigidity of the
steroid framework may give rise to a cavity, either hydrophobic or
hydrophilic depending on the functionalities present on the steroid
nucleus. There is only one example of a C-19 dimeric steroid
reported in the literature, this was detected as a by-product in the
reaction mixture of a Simmons–Smith methylenation and was
2
5
connected through a linker containing two ether moieties.
To apply the metathesis reaction to the synthesis of C-19 linked
homodimers, we first prepared the C-19 aldehyde steroid 20 and its
homologue 22 with one extra methylene group using a methodol-
2
6
1
9 was confirmed by exact mass spectrometry (ESI) with a pseu-
ogy previously developed by our group (Scheme 6). The alde-
hydes were converted to the corresponding terminal olefins 21 and
23 by a salt free Wittig reaction; the olefins were fully characterized
by NMR, mass spectrometry, and elemental analysis. Both mono-
meric olefins were subjected to metathesis under the microwave
conditions previously described for preparation of the other di-
mers. While olefin 21 did not dimerize (the starting material was
quantitatively recovered after chromatography) its analogue 23,
with a longer chain, and thus less hindered olefin, gave the E-dimer
24 in 64% yield. Only 13% of unreacted monomer was recovered
after chromatography, accounting for some side reactions probably
due to the presence of the C-5 double bond. Spectroscopic data was
þ
domolecular ion (MþNa) at 711.5323 corresponding to the mo-
13
72 4
lecular formula C46H O Na. The C NMR spectrum showed 23
signals with a single olefinic carbon resonance at 129.51 ppm that
showed correlation in the HSQC spectrum with the olefinic multi-
plet at 5.35 ppm in accordance with a symmetric dimeric structure.
1
Complete analysis of the H NMR spectrum (500 MHz) together
with 2D spectra (HSQC, HMBC, and COSY) was consistent with
a symmetric dimer. The Z-isomer could not be separated and was
analyzed in the NMR spectra of the mixture, showing also 23 car-
bon resonances with only one olefinic carbon at 127.38 ppm that
correlated with a proton at 5.51 ppm (HSQC). When the mixture of
olefins 16 and 17 was submitted to MW metathesis reaction con-
ditions, monomer 16 homodimerized to give 19 while monomer 17
was recovered unreacted after chromatography proving that even
13
in agreement with the dimeric nature of the product. The C NMR
spectra of 24 showed the presence of 26 carbon atoms consistent
with a symmetric structure with only three olefinic carbon reso-
nances at 124.4 (C-6), 137.1 (C-5), and 129.2 (C-22). The latter car-
bon showed a 1-bond correlation (HSQC) with the hydrogen at
the cross-metathesis between the
possible under the conditions used.
a and b allylic groups is not
5.42 ppm (H-22) and a long-range correlation (HMBC) with both H-
1
9 at 2.45 and 2.03 ppm. The E geometry of the double bond of all
2
.3. Homodimerization through C-19
dimers was confirmed by a computational and matching procedure
of the H NMR resonance as described in the following section.
1
Dimerization at C-19 was particularly interesting, since the
angular methyl group has an axial orientation on the face of
the steroid. A dimeric steroid connected through C-19 has the
b
2
.4. 1H NMR analysis of the symmetric double bond geometry
Geometry assignment of the symmetric double bond present on
the dimers was not straightforward. Even though we expected the
formation of the less hindered E-isomer as the only or major
product, chemical equivalence of the olefinic protons due to the
symmetric structures precluded using their mutual coupling con-
stant to establish the double bond stereochemistry. However
magnetic non-equivalence due to the vicinal hydrogens results in
a strongly coupled proton system with irregular splitting and
0
0
0
2
intensity ratios (XAA X or X AA X patterns) that contains in-
2
formation on the olefinic protons coupling constant. We solved the
problem by using a computational and matching procedure. The
1
simulations ( H NMR, 500 MHz) were carried out using the ex-
perimental chemical shift data taken from the spectra of the di-
mers; the coupling constants were estimated from the spectra of
the corresponding monomers ( J z10–13 Hz and J z16–17 Hz).
Z E
Scheme 5.
3
3
Scheme 6.

V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
3619
Figure 1. Comparison of the 1H NMR (500 MHz) resonance for the olefinic proton on dimer 11: (a) experimental resonance at
d
Hb¼5.11 ppm, (b) simulated resonance for the Z-
isomer:
d
Hb¼5.109 ppm, coupling constants (Hz) Jab¼8; Jac¼0.2; Jbc¼10; Jad¼0, (c) simulated resonance for the E-isomer: Hb¼5.109 ppm, coupling constants (Hz) Jab¼8; Jac¼0.2;
d
J
bc¼16; Jad¼0 (simulations with NMR-SIM TOPSPIN 2.1).
Using these values we simulated the systems as exemplified for
dimer 11 (Fig. 1). Simulation of the E alkene dimers gave a reso-
nance for the olefinic proton that perfectly matches the experi-
mental result with a splitting between the outer lines of 34–35 Hz
apparatus. Microwave assisted reactions were carried out in a CEM
Discover reactor. Analytical thin layer chromatography (TLC) was
performed on pre-coated silica plates (Merck F254, 0.2 mm thick-
ness); compounds were visualized by staining with cerium mo-
lybdate (Hannessian’s stain). Flash column chromatography was
performed on silica gel Merck 9385 (0.0040–0.0063 mm) or Florisil.
All solvents used were reagent grade. Solvents were evaporated at
(
ca. 2ꢁJ
E
). For the Z isomers the splitting was 22–23 Hz (ca. 2ꢁJ
Z
)
(
see Supplementary data).
ꢀ
3
. Conclusions
Microwave assisted metathesis reaction of terminal steroidal
45 C under vacuum in a rotary evaporator. The homogeneity of all
compounds was confirmed by TLC. Products obtained as solids or
syrups were dried under high vacuum. 3
a,12a-Diacetoxy-5b-
olefins has proven to be a useful methodology for the preparation
of homodimeric steroids. In all cases microwave irradiation accel-
erated the reaction rate and also improved the yield compared with
conventional heating allowing to lower the load of catalyst to
cholan-24-oic acid (2) was prepared from commercial deoxycholic
2
4
acid following the procedure described in the literature.
Dihydroxy-5 -cholanic acid methyl ester (5) was prepared by
esterification of deoxycholic acid with methanol/HCl.
Diacetyloxy-5-pregnen-19-al (20) and 3 ,20 -diacetyloxy-5-pre-
gnen-19-carboxyaldehyde (22) were obtained as described
3a
,12
a-
b
2
5
3
b,20
b-
2
.5 mol % with acceptable yields. Overall five dimeric steroids
b
b
linked through C-6, C-19, and C-20 were obtained and fully char-
acterized, the homodimers had the E geometry although for com-
pounds 10 and 19 a small amount (less than 10%) of Z-isomer was
detected by NMR.
2
6
previously.
4.2. Preparation of ‘salt-free’ methylidenetriphenyl-
phosphorane
4
4
. Experimental
To 420 mg (10.7 mmol) of powdered sodium amide in toluene
(18.5 mL) under argon was added methyltriphenylphosphonium
bromide (2.05 g, 5.7 mmol). The mixture was sonicated in a Cole-
Palmer 8852 ultrasound bath (352 W) at room temperature for
1.5 h, degassed under vacuum (0.5 Torr) with stirring for 30 min,
and then centrifuged to remove the salts. The resulting ylide so-
lution was used without further treatment in the Wittig olefination
reaction.
.1. General
Melting points of crystalline solids were measured on a Fisher
Johns apparatus and are uncorrected. IR spectra were recorded in
thin films using KBr disks on a Nicolet Magna IR 550 FT-IR spec-
trometer. 1H and C NMR spectra were measured on a Bruker
Avance II 500 (500.13 and 125.72 MHz) NMR spectrometer in
deuteriochloroform using TMS as internal standard. The electron
impact mass spectra were measured on a Shimadzu QP-5000 mass
spectrometer at 70 eV or on a VG-Trio 2 at 20 eV, by direct inlet.
Exact mass spectra (ESI) were measured on an Agilent LCTOF, high
resolution TOF analyzer with APCI/ESI ionization. Elemental ana-
lysis was performed on an EAI Exeter Analytical, Inc. CE-440
13
4.3. Wittig reaction with methilidenetriphenylphosphorane
(general procedure)
To a solution of the corresponding aldehyde or ketone
(1.5 mmol) in anhydrous toluene (5 mL) under argon was added the

3620
V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
solution of the salt-free ylide (1.5 mmol). The mixture was stirred at
room temperature for 1 h and directly applied to a flash chroma-
tography column (silica gel), elution with ethyl acetate/hexanes
mixtures of increasing polarity gave the corresponding alkenes.
(C-6), 26.7 (C-7), 25.9 (C-16), 25.7 (C-11), 23.6 (C-15), 23.1 (C-19),
21.5 (CH
3
COO), 21.4 (CH
3
COO), 20.4 (C-21), 12.7 (C-18); HRMS (ESI)
þ
calcd for C52
80
H O
8
Na (MNa ): 855.5745, found: 855.5729.
4
.4.4. 3,20-Dioxo-5
To a solution of 3
b
H-cholan-24-al (6)
,12 -dihydroxy-5b-cholanic acid methyl ester
4
.4. Microwave assisted metathesis dimerization (general
a
a
procedure)
(5, 500 mg, 1.23 mmol) in anhydrous THF (25 mL) was added LiAlH
4
ꢀ
(93 mg, 2.46 mmol) at 0 C under argon. The reaction mixture was
To a solution of the corresponding monomeric alkene in anhy-
stirred for 15 min at room temperature and quenched by succes-
sively adding acetone, HCl 10%, and sodium and potassium tartrate
saturated solution. The mixture was concentrated in vacuo, the
residue was dissolved in dichloromethane, and washed with aque-
ous sodium bicarbonate, brine, and water. The organic layer was
drous dichloromethane (0.3 M) was added Grubbs 2nd generation
catalyst (2.5% mol) at room temperature under argon. The reaction
tube was sealed and irradiated in a microwave reactor at the in-
dicated temperature for the appropriate time. All microwave irra-
diations were carried out at 300 W, in a closed vessel, with power
max on. The reaction mixture was directly applied to a flash chro-
matography column on silica gel and eluted with ethyl acetate/
hexanes mixtures to give the corresponding dimers.
2 4
dried over anhydrous Na SO , filtered, and the solvent evaporated to
give 3 ,12 ,24-5 H-cholanetriol. The crude triol was oxidized
a
a
b
without further purification with PCC (1.2 g, 5.54 mmol), barium
carbonate (631 mg, 3.20 mmol), and 4 Å molecular sieves in anhy-
drous dichloromethane (20 mL) at room temperature under a ni-
trogen atmosphere for 30 min. The reactionwas diluted with diethyl
ether and the mixture was concentrated in vacuo. The residue was
redissolved in diethyl ether and the resulting solutionwas applied to
a flash chromatography column (Florisil) and eluted with diethyl
4
.4.1. 3b-Acetyloxy-20-methylidenepregnane (1)
Prepared from pregnanolone acetate (323 mg, 0.9 mmol) fol-
lowing the general methodology for the Wittig reaction compound
ꢀ
1
(
(
was obtained as a white solid (281 mg, 87%). Mp 110–112 C; IR
ꢂ1
1
ꢀ
KBr, cm ) 2934, 2909, 2843, 1732, 1632, 1266, 1033, 889; H NMR
500 MHz, CDCl
4.84 (t, 1H, J¼1.4 Hz, 22a-H), 4.69 (m, 2H, 22-Hb
ether to give 6 (368 mg, 83%) as a crystalline solid. Mp 108–110 C; IR
ꢂ1
1
3
)
d
(KBr, cm
(500 MHz, CDCl
13.2 Hz, 1H, 4
)
n
2967, 1707, 1657, 1460, 1083, 1219, 891; H NMR
and 3-H), 2.02 (m, 3H, acetate), 1.75 (s, 3H, 21-H), 0.82 (s, 3H, 19-H),
.56 (s, 3H, 18-H); 13C NMR (125 MHz, CDCl
170.7 (COO), 145.8
C-20), 110.6 (C-22), 73.8 (C-3), 57.3 (C-17), 56.2 (C-14), 54.4 (C-9),
4.7 (C-5), 43.3 (C-13), 38.9 (C-1), 36.8 (C-12), 35.8 (C-8), 35.5 (C-
0), 34.0 (C-4), 31.9 (C-7), 28.6 (C-6), 27.5 (C-2), 25.4 (C-21), 24.7 (C-
5), 24.2 (C-16), 21.5 (CH COO), 21.3 (C-11), 12.9 (C-19), 12.3 (C-18).
: C, 80.4; H, 10.7%. Found: C, 80.1; H, 10.8%;
3
) d
9.78 (t, 1H, J¼1.7 Hz, 24-H), 2.59 (dd, J¼15.0,
0
(
4
1
3
)
d
a
-H), 2.50 (ddd, J¼9.5, 5.4, 0.8 Hz,1H, 23a-H), 2.43 (dt,
J¼7.7, 1.0 Hz, 1H, 23b-H), 2.33 (dd, J¼14.7, 5.4 Hz, 1H, 2a-H), 2.19
(ddd, J¼14.7, 6.4, 3.1 Hz, 1H, 2b-H), 1.12 (s, 3H, 19-H), 1.06 (s, 3H, 18-
13
H), 0.86 (d, J¼6.6 Hz, 3H, 21-H); C NMR (125 MHz, CDCl
3
) d 214.1
1
3
(C-12), 212.1 (C-3), 203.0 (C-24), 58.5 (C-9), 57.6 (C-13), 46.5 (C-17),
44.3 (C-14), 43.7 (C-5), 42.1 (C-4), 41.2 (C-23), 38.4 (C-11), 36.9 (C-2),
36.8 (C-1), 35.6 (C-10), 35.6 (C-20), 35.4 (C-8), 27.6 (C-22), 27.4 and
26.6 (C-7, C-15), 25.5 (C-6), 24.3 (C-16), 22.1 (C-19), 18.7 (C-21), 11.7
Anal. Calcd for C24
H
38
O
2
þ
MS (EI) m/z 358 (M) , 298 (Mꢂacetate), 283, 229, 215, 149, 133, 119,
1
07, 93, 81, 55, 43.
(
C-18). Anal. Calcd for C24
H
36
O
3
: C, 77.4; H, 9.7%. Found: C, 77.3; H,
þ
4.4.2. 3
a,12a-Diacetoxy-5bH-22-cholene (3)
9.7%; MS (EI) m/z 372 (M) , 354, 344, 329, 247,121,107, 93, 81, 55, 41.
A solution of 2 (5.4 g, 8.75 mM), Cu(AcO)
2
(422 mg, 1.75 mmol),
and pyridine (0.66 mL) in anhydrous toluene (53 mL) under argon
was stirred at room temperature for 15 min. The mixturewas heated
under reflux and iodobenzene diacetate was added portionwise
every 90 min (5ꢁ430 mg, 5 mmol). After the addition was com-
pleted heating was continued for 8 h. The reaction mixture was
cooled to room temperature and extracted with 5% HCl. The organic
4.4.5. 5
b
H-24-Cholene-3,12-dione (7)
Prepared from 3,20-dioxo-5
1.35 mmol) following the general Wittig methodology described
above compound 7 was obtained as a white crystalline solid
(424 mg, 85%). Mp 121–122 C; IR (KBr, cm
b
H-cholan-24-al (6) (500 mg,
ꢀ
1
ꢂ1
) n
2970, 2948, 2906,
5.79 (ddt,
2869, 1709, 1507, 1452, 1028; H NMR (500 MHz, CDCl
3
)
d
layer was washed with water, dried over anhydrous Na
2
SO
4
, filtered,
J¼17.1, 10.2, 6.7 Hz, 1H, 24-H), 4.98 (ddt, J¼17.2, 2.0, 1.7 Hz, 1H, 25a-
and the solvent evaporated. The residue was purified by flash col-
umn chromatography on silica gel with hexane/ethyl acetate mix-
tures to give 3 as a white solid (2.8 g, 57%). Further elution gave
a second fraction of unreacted 1 (648 mg,12%). Spectroscopic data of
H), 4.91 (ddt, J¼10.1, 2.1, 1.2 Hz, 1H, 25b-H), 2.61 (t, J¼12.5 Hz, 1H,
11
b
-H), 2.59 (dd, J¼14.8,13.6 Hz,1H, 4
a-H),1.11 (s, 3H,19-H),1.05 (s,
13
3H, 18-H), 0.86 (d, J¼6.6 Hz, 3H, 21-H); C NMR (125 MHz, CDCl
214.2 (C-12), 212.1 (C-3), 139.5 (C-24), 114.1 (C-25), 58.6 (C-9), 57.6
(C-13), 46.8 (C-17), 44.3 (C-14), 43.7 (C-5), 42.1 (C-4), 38.4 (C-11),
6.9 (C-2), 36.8 (C-1), 35.7 (C-20), 35.6 (C-10), 35.5 (C-8), 34.8 (C-
22), 30.9 (C-23), 27.6 and 26.6 (C-7, C-15), 25.5 (C-6), 24.4 (C-16),
22.2 (C-19), 18.8 (C-21), 11.7 (C-18). Anal. Calcd for C25 : C,
3
)
d
1
23
compound 3 ( H NMR, IR) was identical to that found in literature.
3
4.4.3. (E)-1,2-Bis-(3a,12a-hydroxy-5bH-pregnan-20-yl)-ethene (4)
Method A. Prepared from 3 (25 mg, 0.06 mmol) following the
MW assisted metathesis general methodology compound 4 was
obtained as a white solid (24 mg, 97%).
Method B. Alternatively, 4 was prepared by adding Grubbs-type
second generation catalyst (20 mol %) to a solution of 3 (128 mg,
38 2
H O
þ
81.0; H, 10.3%. Found: C, 81.0; H, 10.3%; MS (EI) m/z 370 (M) , 355,
337, 328 (Mꢂketene), 273, 247, 135, 121, 107, 93, 81, 55, 41.
4.4.6. 20-Ethenyl-4-pregnen-3-one (9)
0
.30 mmol) in anhydrous dichloromethane (0.2 M) at room tem-
perature under argon. The reaction mixture was then stirred for
.5 h and directly applied to a flash chromatography column (silica
gel) to afford 4 (65 mg, 52%) and unreacted 3 (50 mg, 39%). Mp 201–
Prepared from 3-oxo-4-pregnen-20b-carboxyaldehyde (8,
500 mg, 1.5 mmol) following the general Wittig methodology de-
6
scribed above compound 9 was obtained as a white crystalline solid
ꢀ
ꢂ1
) n
(426 mg, 87%). Mp 116–117 C; IR (KBr, cm
2951, 2865, 2843,
5.72 (s, 1H,
ꢀ
ꢂ1
1
1
2
(
02 C; IR (KBr, cm
500 MHz, CDCl 5.08 (m, 1H, 22-H), 5.06 (m, 1H, 12-H), 4.71 (m,
H, 3-H), 2.11 (s, 3H, acetate), 2.04 (s, 3H, acetate), 0.91 (s, 3H,19-H),
)
n
2940, 2857, 1729, 1234, 1125; H NMR
1671, 1452, 1230, 911, 864; H NMR (500 MHz, CDCl
3
)
d
3
)
d
4-H), 5.66 (ddd, J¼17.1, 10.2, 8.4 Hz, 1H, 22-H), 4.91 (dd, J¼17.1,
1
0
CDCl
3
(
2.0 Hz, 1H, 23a-H), 4.82 (dd, J¼10.2, 2.0 Hz, 1H, 23b-H), 1.19 (s, 3H,
13
13
.86 (d, J¼6.7 Hz, 3H, 21-H), 0.73 (s, 3H, 18-H); C NMR (125 MHz,
170.6 (COO), 170.5 (COO), 134.2 (C-22), 75.8 (C-12), 74.2 (C-
), 49.5 (C-14), 47.8 (C-17), 44.9 (C-13), 41.9 (C-5), 39.4 (C-20), 35.7
C-9), 34.8 (C-10), 34.5 (C-1), 34.1 (C-8), 32.3 (C-4), 27.9 (C-2), 26.9
19-H), 1.04 (d, J¼6.6 Hz, 3H, 21-H), 0.74 (s, 3H, 18-H); C NMR
3
)
d
3
(125 MHz, CDCl ) d 199.6 (C-3), 171.6 (C-5), 145.1 (C-22),123.8 (C-4),
111.7 (C-23), 55.9 (C-14), 55.4 (C-17), 53.8 (C-9), 42.4 (C-13), 41.2 (C-
20), 39.5 (C-12), 38.6 (C-10), 35.7 (C-1), 35.6 (C-8), 34.0 (C-2), 32.9

V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
3621
þ
(
1
C-6), 32.0 (C-7), 28.3 (C-16), 24.2 (C-15), 21.0 (C-11), 20.1 (C-21),
12.5 (C-18); MS (EI) m/z 360 (M) , 300, 285, 124, 107, 95, 81, 55, 43.
Anal. Calcd for C23 : C, 76.6; H, 10.1%. Found: C, 76.8; H, 10.1%.
7.4 (C-19), 12.2 (C-18). Anal. Calcd for C23
H
34O: C, 84.6; H, 10.5%.
36 3
H O
þ
Found: C, 84.6; H, 10.8%; MS (EI) m/z 326 (M) , 298, 284
(
Mꢂketene), 269, 229, 203, 147, 133, 124, 107, 91, 79, 55, 41.
4.4.11. 6
b
-Hydroxy-6
a
-(1-propenyl)-5
aH-pregnan-20-one (16)
and 6 -hydroxy-6
a
b
-(1-propenyl)-5a
H-pregnan-20-one (17)
4
.4.7. 1,4-Bis-(3,12-dioxo-5 H-pregnan-20-yl)-2E-butene (10)
Prepared from 7 (20 mg, 0.05 mmol) following the general MW
b
To a solution of allylmagnesium chloride (2.0 M in THF, 1.2 mL)
ꢀ
at 0 C was added a solution of 20
b
-acetyloxy-6-methylidene-5
a
H-
assisted metathesis methodology compound 10 was obtained as
pregnane (13, 200 mg, 0.56 mmol) in THF (0.8 mL). The mixture
was stirred at room temperature for 30 min and quenched with
saturated aqueous NH Cl (1 mL). The solvent was evaporated and
4
ꢀ
ꢂ1
) n
a white solid (16 mg, 89%). Mp 246–249 C; IR (KBr, cm
2926,
1
2
862, 2249, 1705, 1646, 1460, 1383, 1272, 919; H NMR (500 MHz,
CDCl
9-H), 1.06 (s, 3H, 18-H), 0.86 (d, J¼6.6 Hz, 3H, 21-H); C NMR
125 MHz, CDCl 214.3 (C-12), 212.2 (C-3),130.5 (C-24), 58.6 (C-9),
7.6 (C-13), 46.8 (C-17), 44.3 (C-14), 43.7 (C-5), 42.2 (C-4), 38.4 (C-
1), 36.9 (C-2), 36.8 (C-1), 35.8 (C-20), 35.6 (C-10), 35.5 (C-8), 35.5 (C-
2), 29.7 (C-23), 27.6 and 26.6 (C-7, C15), 25.5 (C-6), 24.4 (C-16), 22.2
C-19), 18.9 (C-21), 11.8 (C-18). Anal. Calcd for C48 : C, 80.9; H,
3
)
d
5.38 (m,1H, 24-H), 2.62 (2H, m, 4
a
-H and 11-H
b
),1.12 (s, 3H,
the residue was dissolved in dichloromethane (5 mL). The organic
layer was washed with water (5 mL) and dried over anhydrous
13
1
(
5
1
2
(
3
)
d
Na
rified by flash column chromatography (silica gel, hexane/ethyl
acetate) to give the mixture of 6 -OH and 6 -OH isomers of 5 -H-
20 ,6-dihydroxy-6-(1-propenyl) (8:2 ratio, 170 mg, 84%). An ana-
lytical sample of 6
2 4
SO , filtered, and the solvent evaporated. The residue was pu-
a
b
a
b
1
H
72
O
4
3
b-OH isomer 14: H NMR (500 MHz, CDCl ) d 5.76
1
5
0.2%. Found: C, 81.0; H, 10.3%; MS (EI) m/z 671 (Mꢂketene), 626,
(ddt, 1H, J¼17.1, 7.5, 10.0 Hz, 1H, 23-H), 5.07 (dd, J¼9.9, 2.2 Hz, 1H,
91, 491, 336, 312, 284, 269, 243, 215, 145, 105, 91, 79, 55, 40.
24b-H), 5.05 (dd, J¼16.8, 2.5 Hz, 1H, 24a-H), 2.22 (dd, J¼14.0, 7.9 Hz,
1
H, 22a-H), 2.17 (dd, J¼13.7, 7.7 Hz, 1H, 22b-H),1.14 (d, J¼6.1 Hz, 3H,
13
4.4.8. (E)-1,2-Bis-(3-oxo-4-pregnen-20-yl)-ethene (11)
21-H), 1.02 (s, 3H, 19-H), 0.77 (s, 3H, 18-H); C NMR (125 MHz,
CDCl 134.4 (C-23), 118.0 (C-24), 73.7 (C-6), 70.6 (C-20), 58.6 (C-
Prepared from 9 (82 mg, 0.25 mmol) following the general MW
3
) d
assisted metathesis methodology, after chromatography (silica gel,
17), 55.7 (C-14), 54.3 (C-9), 50.9 (C-5), 46.9 (C-22), 43.1 (C-7), 42.5
(C-13), 40.8 (C-1), 40.2 (C-12), 36.7 (C-10), 30.8 (C-8), 26.9 (C-3),
25.6 (C-15), 24.4 (C-16), 23.6 (C-21), 21.8 (C-2), 20.5 (C-11), 20.4 (C-
ethyl acetate/hexanes) compound 11 was obtained as a white solid
ꢀ
ꢂ1
) n
(
2
38 mg, 49%). Mp 250–254 C (dec); IR (KBr, cm
2968, 2937,
5.73 (s,
1
865, 1635, 1458, 1269, 1227; H NMR (500 MHz, CDCl
3
)
d
4), 15.5 (C-19), 12.6 (C-18). Anal. Calcd for C24
H
40
O
2
: C, 79.9; H,
-OH iso-
5.86 (dddd, J¼17.4, 9.9, 6.9,
1
H, 4-H), 5.11 (m, 1H, 22-H), 1.19 (s, 3H, 19-H), 0.98 (d, J¼6.6 Hz, 3H,
11.2%. Found: C, 79.9; H, 11.1%. An analytical sample of 6
a
13
1
21-H), 0.72 (s, 3H, 18-H); C NMR (125 MHz, CDCl
3
)
d
199.7 (C-3),
3
mer 15: H NMR (500 MHz, CDCl ) d
1
4
8
71.7 (C-5), 134.3 (C-22), 123.8 (C-4), 56.0 (C-14, C-17), 53.8 (C-9),
2.3 (C-13), 40.1 (C-20), 39.5 (C-12), 38.6 (C-10), 35.7 (C-1), 35.6 (C-
), 34.0 (C-2), 33.0 (C-6), 32.0 (C-7), 28.8 (C-16), 24.3 (C-15), 21.0 (C-
8.1 Hz, 1H, 23-H), 5.19 (dd, J¼10.2, 2.3 Hz, 1H, 24b-H), 5.14 (dd,
J¼17.1, 2.3 Hz, 1H, 24a-H), 3.74 (m, 1H, 20-H), 2.29 (dd, J¼13.7,
6.7 Hz, 1H, 22a-H), 1.97 (dd, J¼13.7, 8.1 Hz, 1H, 22b-H), 1.13 (d,
13
1
8
5
1), 20.9 (C-21), 17.4 (C-19), 12.1 (C-18). Anal. Calcd for C44
H
64
O
2
: C,
J¼6.1 Hz, 3H, 21-H), 1.12 (s, 3H, 19-H), 0.76 (s, 3H, 18-H); C NMR
þ
4.6; H, 10.3%. Found: C, 84.4; H, 10.4%; MS (EI) m/z 624 (M) , 609,
82 (Mꢂketene), 269, 147, 131, 119, 107, 95, 81, 55, 41. Further elu-
3
(125 MHz, CDCl ) d 133.4 (C-23), 119.4 (C-24), 75.0 (C-6), 70.6 (C-
20), 58.7 (C-17), 55.8 (C-14), 52.2 (C-5), 46.4 (C-22), 42.7 (C-13), 41.1
(C-9), 40.3 (C-12), 39.7 (C-7), 38.8 (C-1), 36.3 (C-10), 32.0 (C-8), 27.7
tion rendered a fraction of unreacted 9 (8 mg, 10%).
(C-19), 26.9 (C-3), 25.7 (C-15), 25.0 (C-4), 24.5 (C-16), 23.6 (C-21),
4
.4.9. 20
b
-Acetyloxy-5
a
H-2-pregnen-6-one (12)
40 2
20.9 (C-2), 20.5 (C-11), 12.6 (C-18). Anal. Calcd for C24H O : C, 79.9;
Prepared from pregnenolone acetate (200 mg, 0.56 mmol) using
the method described by Mori et al. compound 12 was obtained
H, 11.2%. Found: C, 79.8; H, 11.2%.
2
8
The mixture of 6a and 6b isomers obtained above (170 mg,
ꢂ1
as an amorphous solid (164 mg, 82%). IR (KBr, cm
)
n
2942, 2906,
5.69
m, 1H, 3-H), 5.56 (m, 1H, 2-H), 4.85 (br s, 1H, 20-H), 2.02 (s, 3H,
acetate), 1.16 (d, J¼5.8 Hz, 3H, 21-H), 0.71 (s, 3H, 19-H), 0.65 (s, 3H,
8-H); 13C NMR (125 MHz, CDCl
211.6 (C-6), 170.3 (COO), 125.0
C-2), 124.5 (C-3), 72.7 (C-20), 56.1 (C-14), 54.9 (C-17), 53.9 (C-9),
0.47 mmol) was oxidized with PCC (253 mg, 0.94 mmol), barium
carbonate (172 mg, 0.71 mmol), and 4 Å molecular sieves in anhy-
drous dichloromethane (15 mL) at room temperature under a ni-
trogen atmosphere for 45 min. The reaction was diluted with
diethyl ether, concentrated in vacuo, and the residue purified by
flash column chromatography on silica gel (hexanes/ethyl acetate)
1
1
(
3
730, 1708, 1433, 1373, 1075, 1024; H NMR (500 MHz, CDCl ) d
1
(
3
) d
5
3.5 (C-5), 46.9 (C-7), 42.6 (C-13), 40.0 (C-10), 39.4 (C-1), 39.0 (C-
COO),
1.0 (C-11), 19.9 (C-21), 13.5 (C19), 12.5 (C-18); MS (ESI) m/z 381
to give in order of elution: 6
pregnan-20-one (17, 15 mg, 9%), a mixed fraction (16þ17, 8 mg) and
-hydroxy-6 -(1-propenyl)-5 H-pregnan-20-one (16, 121 mg,
a-hydroxy-6b-(1-propenyl)-5aH-
12), 37.5 (C-8), 25.2 (C-16), 24.0 (C-15), 21.6 (C-4), 21.5 (CH
3
2
6b
a
a
þ
þ
(
C
MþNa) , 359 (MþH) , 298, 105, 93, 81, 55, 43. Anal. Calcd for
72%). 6
b
-Hydroxy-6
a
-(1-propenyl)-5
a
H-pregnan-20-one (16): mp
ꢀ
ꢂ1
H
23 34
O
3
: C, 77.0; H, 9.6%. Found: C, 76.6; H, 9.3%.
105–107 C; IR (KBr, cm
)
n
3406, 2920, 2848, 1716, 1457, 1261,
5.75 (ddt, J¼17.0, 10.0, 7.5 Hz, 1H,
23-H), 5.08 (d, J¼10.0 Hz, 1H, 24b-H), 5.04 (d, J¼17.0 Hz, 1H, 24a-H),
1
1
3
096; H NMR (500 MHz, CDCl ) d
4.4.10. 20
b-Acetyloxy-5aH-pregnan-6-one (13)
13
2
0b
-Acetyloxy-5
a
H-2-pregnen-6-one (12, 150 mg, 0.42 mmol)
2.12 (s, 3H, 21-H), 1.01 (s, 3H, 19-H), 0.63 (s, 3H, 18-H); C NMR
(125 MHz, CDCl 209.6 (C-20), 134.3 (C-23), 118.1 (C-24), 73.6 (C-
was dissolved in ethyl acetate (15 mL), 10% Pd/C (15 mg) added and
the mixture hydrogenated at 3 bar for 8 h. The catalyst was filtered
and the residue purified by column chromatography (silica gel,
ethyl acetate/hexanes) to give 13 as a white solid (148 mg, 98%). Mp
3
) d
6), 63.9 (C-17), 56.5 (C-14), 54.2 (C-9), 50.9 (C-5), 46.9 (C-22), 44.2
(C-13), 43.0 (C-7), 40.8 (C-1), 39.1 (C-12), 36.7 (C-10), 31.5 (C-21),
31.0 (C-8), 26.9 (C-2), 24.4 (C-15), 22.8 (C-16), 21,8 (C-11), 20.7 and
ꢀ
ꢂ1
þ
1
1
1
63–165 C; IR (KBr, cm
)
n
2981, 2937, 2873, 1732, 1646, 1372,
244, 1075, 1019, 877; H NMR (500 MHz, CDCl
4.83 (dq, J¼6.0,
0.6 Hz, 1H, 20-H), 2.28 (dd, J¼4.5, 13.1 Hz, 1H, 7a-H), 2.13 (dd,
J¼3.2, 12.3 Hz, 1H, 5-H), 2.02 (s, 3H, acetate), 1.15 (d, J¼6.1 Hz, 3H,
20.4 (C-4, C-3), 15.5 (C-19), 13.5 (C-18); MS (EI) m/z 358 (M ), 340
1
3
)
d
2
(M-H O), 317 (M-C
3
5
H ), 299, 281, 189, 161, 107, 81, 55, 43. Anal.
Calcd for C24
H
38
O
2
$1/2H O: C, 78.1; H, 10.8%. Found: C, 77.9; H,
2
y
10.5%.
6
a-Hydroxy-6
b
-(1-propenyl)-5
a
H-pregnan-20-one (17):
13
ꢂ1
2
1-H), 0.72 (s, 3H, 19-H), 0.62 (s, 3H, 18-H); C NMR (125 MHz,
CDCl 212.5 (C-6), 170.4 (COO), 72.7 (C-20), 58.9 (C-5), 56.2 (C-
4), 54.9 (C-17), 54.4 (C-9), 46.8 (C-7), 42.8 (C-13), 41.8 (C-10), 39.0
C-12), 38.2 (C-1), 37.8 (C-8), 25.3 (C-16), 25.2 (C-15), 24.0 (C-3), 21.5
CH COO), 21.4 (C-2), 21.1 (C-11), 20.5 (C-4), 19.9 (C-21), 13.1 (C-19),
amorphous solid; IR (KBr, cm
) n 3406, 2920, 2848, 1716, 1457,
3
) d
1
(
(
y
Attempts to further dry these compounds failed; the content of water was
determined based on found and calculated elemental analysis data.
3

3622
V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
1
) 1H
1H NMR (500 MHz, CDCl
1
7
261, 1096; H NMR (500 MHz, CDCl
.7, 5.5 Hz, 1H, 23-H), 5.22 (dd, J¼10.2, 2.1 Hz, 1H, 24b-H), 5.17 (dd,
J¼17.1, 2.0 Hz, 1H, 24a-H), 2.56 (t, J¼8.9 Hz, 1H, 17-H), 2.14 (s, 3H,
3
d
5.88 (dddd, J¼17.3, 9.9,
3
)
d
5.76 (ddt, J¼22.0, 10.0, 5.0 Hz, 1H, 22-
H), 5.57 (td, J¼5.2, 1.8 Hz, 1H, 6-H), 5.05 (ddd, J¼17.2, 2.1, 1.5 Hz, 1H,
23b-H), 4.96 (dt, J¼10.1, 2.0 Hz, 1H, 23a-H), 4.83 (dq, J¼10.9, 6.0 Hz,
1H, 20-H), 4.63 (tt, J¼11.5, 5.0 Hz, 1H, 3-H), 2.57 (ddt, J¼14.5, 5.0,
1.9 Hz, 1H, 19a-H), 2.09 (dd, J¼15.1, 9.8 Hz, 1H, 19b-H), 2.04 (s, 3H,
acetate), 2.03 (s, 3H, acetate), 1.15 (d, J¼6.1 Hz, 3H, 21-H), 0.62 (s,
13
2
1H), 1.14 (s, 3H, 19-H), 0.65 (s, 3H, 18-H); C NMR (125 MHz,
CDCl 209.9 (C-20), 133.2 (C-23), 119.6 (C-24), 74.9 (C-6), 63.9 (C-
7), 56.6 (C-14), 52.1 (C-9), 46.4 (C-5), 44.5 (C-22), 41.1 (C-13), 39.6
C-7), 39.2 (C-1), 38.8 (C-12), 36.3 (C-10), 31.5 (C-21), 30.9 (C-8),
3
) d
1
(
13
3
3H, 18-H); C NMR (125 MHz, CDCl ) d 170.6 (COO), 170.5 (COO),
2
3
7.6 (C-19), 26.9 (C-2), 25.0 (C-15), 24.5 (C-16), 22.9 (C-11), 20.9 (C-
137.3 (C-22), 136.8 (C-5), 124.7 (C-6), 115.3 (C-23), 73.9 (C-3), 72.9
(C-20), 57.2 (C-14), 54.8 (C-17), 51.4 (C-9), 42.4 (C-13), 39.7 (C-10),
39.5 (C-12), 38.2 (C-4), 37.2 (C-1), 36.5 (C-19), 32.5 (C-8), 31.4 (C-7),
þ
), 20.6 (C-4), 13.5 (C-18); MS (EI) m/z 358 (M ), 340 (MꢂH
2
O), 317
(
MꢂC
3 5
H ), 299, 281, 189, 161, 107, 81, 55, 43. Anal. Calcd for
y
C
H
24 38
O
2
$1/2H
2
O: C, 78.1; H, 10.8%. Found: C, 77.8; H, 10.4%.
3 3
27.7 (C-2), 25.4 (C-16), 24.2 (C-15), 21.6 (CH COO), 21.4 (CH COO),
2
1.2 (C-11), 19.9 (C-21), 12.7 (C-18); MS (EI) m/z 387 (Mꢂallyl), 368
4
.4.12. 20
b
-Acetyloxy-6-methylidene-5
aH-pregnane (18)
(MꢂAcOH), 327, 309, 267, 143, 133, 121, 105, 91, 79, 55, 43. Anal.
y
Prepared from 20
b
-acetyloxy-5 H-pregnan-6-one (13, 250 mg,
a
Calcd for C27
40
H O
4
$1/2H
2
O: C, 74.1; H, 9.4%. Found: C, 74.2; H, 9.1%.
0
.69 mmol) using the general Wittig methodology compound 18
ꢀ
was obtained as a white solid (178 mg, 71%). Mp 156–157 C; IR
4.4.16. E-1,2-Bis-(3
b
,20b
-diacetoxy-5-pregnen-19-yl)-ethene (24)
ꢂ1
(
KBr, cm
)
n
2981, 2937, 2873, 2862, 2845, 2826, 1732, 1646, 1372,
Prepared from 23 (22 mg, 0.05 mmol) following the general MW
assisted metathesis methodology, after chromatography (silica gel,
ethyl acetate/hexanes) compound 24 was obtained as a white solid
1
3
1244, 1075, 1019, 877; H NMR (500 MHz, CDCl ) d 4.84 (m, 1H, 20-
H), 4.67 (d, J¼1.1 Hz, 1H, 22a-H), 4.42 (d, J¼1.1 Hz, 1H, 22b-H), 2.01
ꢀ
ꢂ1
) n
(
s, 3H, acetate), 1.15 (d, J¼5.8 Hz, 3H, 21-H), 0.66 (s, 3H, 18-H), 0.61
(12.4 mg, 64%). Mp 195–198 C; IR (KBr, cm
1367, 1247, 1031, 926; H NMR (500 MHz, CDCl
2939, 2873, 2850,1733,
5.48 (d, J¼5.0 Hz,1H,
(
s, 3H, 19-H); 13C NMR (125 MHz, CDCl
3
)
d
170.4 (COO), 150.8 (C-6),
1
3
)
d
105.6 (C-22), 72.9 (C-20), 55.9 (C-14), 55.2 (C-9), 55.1 (C-17), 51.4 (C-
6-H), 5.40 (m, 1H, 22-H), 4.83 (dq, J¼10.4, 6.0 Hz, 1H, 20-H), 4.62 (tt,
J¼11.7, 5.0 Hz, 1H, 3-H), 2.44 (dd, J¼15.7 Hz, 5.2, 1H, 19a-H), 2.05 (3H, s,
acetate), 2.04 (3H, s, acetate),1.16 (d, J¼6.1 Hz, 3H, 21-H), 0.65 (3H, s,18-
5
), 42.5 (C-13), 42.2 (C-7), 39.3 (C-12), 38.5 (C-10), 38.3 (C-1), 37.4
(
(
C-8), 26.4 (C-3), 25.5 (C-16), 24.3 (C-2), 24.1 (C-15), 22.0 (C-4), 21.5
13
CH
3
COO), 21.0 (C-11), 19.9 (C-21), 12.6 (C-19), 12.4 (C-18); MS (EI)
3
H); C NMR (125 MHz, CDCl ) d 170.6 (COO), 170.5 (COO), 137.1 (C-5),
þ
m/z 358 (M) , 298, 229, 161, 147, 133, 122, 105, 93, 81, 55, 43. Anal.
129.2 (C-22), 124.4 (C-6), 73.9 (C-3), 72.9 (C-20), 57.1 (C-14), 54.9 (C-17),
51.3 (C-9), 42.3 (C-13), 40.1 (C-10), 39.4 (C-12), 38.4 (C-4), 37.1 (C-1), 35.5
Calcd for C24H
38
O
2
: C, 80.4; H, 10.7%. Found: C, 80.2; H, 10.8%.
(
C-19), 32.7 (C-8), 31.6 (C-7), 27.7 (C-2), 25.6 (C-16), 24.2 (C-15), 21.5 (C-
11), 21.5 (CH COO), 21.5 (CH COO), 19.9 (C-21), 12.7 (C-18); MS (ESI) m/z
387, 327, 267, 143, 121, 58, 43. Anal. Calcd for C52 : C, 75.3; H, 9.2%.
4
.4.13. 1,4-Bis-(6
b
-hydroxy-20-oxo-5 H-pregnan-6-yl)-2E-
a
3
3
butene (19)
76 8
H O
Prepared from 16 (60 mg, 0.016 mmol) following the general
MW assisted metathesis methodology, after chromatography (silica
gel, ethyl acetate/hexanes) homodimer 19 was obtained as a white
Found: C, 75.8; H, 9.5%. Further elution rendered a fraction of unreacted
23 (3 mg, 14%).
ꢀ
ꢂ1
solid (53 mg, 97%). Mp 240–245 C (dec); IR (KBr, cm
)
n
3401,
5.38
Acknowledgements
1
2
931, 2906, 1696, 1197, 1144, 750; H NMR (500 MHz, CDCl
3
)
d
(
2
dd, J¼5.1, 3.4 Hz, 1H, 23-H), 2.32 (dd, J¼13.5, 4.5 Hz, 1H, 22a-H),
This work was supported by grants from Universidad de Buenos
Aires, ANPCyT and CONICET (Argentina).
.14 (s, 3H, 21-H),1.98 (dd, J¼6.3,13.7 Hz,1H, 22b-H),1.05 (s, 3H,19-
1
3
H), 0.67 (s, 3H, 18-H); C NMR (125 MHz, CDCl
3
)
d
209.4 (C-20),
1
5
29.5 (C-23), 74.3 (C-6), 64.0 (C-17), 56.8 (C-14), 54.6 (C-9), 50.2 (C-
), 45.6 (C-22), 44.2 (C-13), 42.7 (C-7), 40.9 (C-1), 39.3 (C-12), 36.7
Supplementary data
(
2
(
C-10), 31.5 (C-21), 31.0 (C-8), 27.0 (C-3), 24.4 (C-15), 22.8 (C-16),
Supplementary data includes 1H and 13C NMR spectra for all
1.8 (C-2), 20.7 (C-11), 20.6 (C-4), 15.5 (C-19), 13.5 (C-18); HRMS
þ
monomers and dimeric steroids with the complete E/Z geometry
ESI) calcd for C46
H
72
O
4
Na (MþNa) : 711.5328, found: 711.5323.
1
analysis data of dimers by the H NMR simulation-matching
method. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.03.006.
4
.4.14. 3
Prepared from
00 mg, 1.2 mmol) using the general Wittig methodology com-
b
,20
b
-Diacetyloxy-19-methylidene-5-pregnene (21)
3
b
,20 -diacetyloxy-5-pregnen-19-al (20,
b
5
pound 21 was obtained as a white solid (338 mg, 78%). Mp 87–
References and notes
ꢀ
ꢂ1
1
8
8 C; IR (KBr, cm
)
n
2936, 2905, 2869, 1729, 1370, 1241, 1033; H
5.65 (dd, J¼17.6, 10.6 Hz, 1H, 19-H), 5.63
dd, J¼5.1, 1.9 Hz, 1H, 6-H), 5.29 (dd, J¼10.6, 1.8 Hz, 1H, 22b-H), 4.96
NMR (500 MHz, CDCl
(
3
)
d
1. Clemons, P. A. Curr. Opin. Chem. Biol. 1999, 3, 112–115.
2
3
. Diver, S. T.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 5106–5109.
. Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Wissinger, N.; Smethurst, C.; Enderman,
R. Angew. Chem., Int. Ed. 2000, 39, 3823–3828.
(
dd, J¼17.5, 1.8 Hz, 1H, 22a-H), 4.83 (m, 1H, 3-H), 4.64 (m, 1H, 20-H),
13
2
.03 (s, 3H, acetate), 2.02 (s, 3H, acetate), 0.56 (s, 3H, 18-H);
170.6 (COO), 170.4 (COO), 142.1 (C-22),
36.1 (C-5), 125.1 (C-6), 117.8 (C-19), 73.9 (C-3), 72.9 (C-20), 55.5 (C-
4), 54.9 (C-17), 50.2 (C-9), 44.7 (C-10), 42.2 (C-13), 39.2 (C-12), 38.4
C-4), 35.6 (C-1), 31.7 (C-7), 31.0 (C-8), 28.3 (C-2), 25.4 (C-16), 24.3
C
4. For reviews on dimeric steroids see: Nahar, L.; Turner, A. B. Curr. Med. Chem.
007, 14, 1349–1370 and Li, Y. X.; Dias, J. R. Chem. Rev. 1997, 97, 283–304.
2
3
NMR (125 MHz, CDCl ) d
1
1
(
(
(
5. (a) Mc Kenna, J.; Mc Kenna, J. M.; Thornthwaite, D. W. J. Chem. Soc., Chem.
Commun. 1977, 809–811; (b) Hoffman, S.; Kumpf, W. Z. Chem. 1986, 8, 293–295.
6. L o´ pez-Ant o´ n, N.; Rudy, A.; Barth, N.; Schmitz, L. M.; Pettit, G. R.; Schulze-
Osthoff, K.; Dirsch, V. M.; Vollmar, A. M. J. Biol. Chem. 2006, 281, 33078–33086.
7
. Opsenica, D.; Pocsfalvi, G.; Juramic, Z.; Tinant, B.; Declercq, J.-P.; Kyle, D. E.;
C-15), 21.5 (CH
3
COO), 21.4 (CH
3
COO), 21.2 (C-11), 19.9 (C-21), 12.3
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þ
C-18); MS (EI) m/z 354 (MꢂAcO) , 294, 161, 117, 91, 79, 55, 43. Anal.
8. Gouin, S.; Zhu, X. X. Langmuir 1998, 14, 4025–4029.
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Calcd for C26H
38
O
4
: C, 75.3; H, 9.2%. Found: C, 75.5; H, 9.2%.
10. Janout, V.; Jing, B. W.; Regent, S. L. Bioconjugate Chem. 2002, 13, 351–356.
1
1. Pandey, P. S.; Rai, R.; Singh, R. B. J. Chem. Soc., Perkin Trans. 1 2002, 918–923.
4
.4.15. 19-Ethenyl-3
Prepared from
b
,20
3
b
-diacetyloxy-5-pregnene (23)
,20 -diacetyloxy-5-pregnen-19-carboxy-
12. Guthrie, J. P.; Cossar, J.; Darson, B. A. Can. J. Chem. 1986, 64, 2456–2469.
b
b
13. Templeton, J. F.; Majgier-Baranowska, H.; Marat, K. Steroids 2000, 65, 219–223.
1
4. DellaGreca, M.; Iesce, M. R.; Previtera, L.; Tamussi, F.; Zarrelli, A. J. Org. Chem.
002, 67, 9011–9015.
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10579–10590.
aldehyde (22, 40 mg, 0.1 mmol) using the general Wittig method-
ology compound 23 was obtained as a white solid (30 mg, 76%). Mp
2
1
ꢀ
ꢂ1
) n
125–127 C; IR (KBr, cm
2956, 2868,1740,1727,1370,1034, 737;

V.C. Edelsztein et al. / Tetrahedron 65 (2009) 3615–3623
3623
1
6. Di Chenna, P. H.; Veleiro, A. S.; Sonego, J. M.; Ceballos, N. R.; Garland, M. T.;
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1
7. Veleiro, A. S.; Taich, P. J.; Alvarez, L. D.; Di Chenna, P. H.; Burton, G. Tetrahedron
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1
1
2
2
8. Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
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1
2
28. Aburatani, N.; Takeuchi, T.; Mori, K. Synthesis 1987, 181–183.