First synthesis of a steroid containing an unstable 19-nor-androsta-1,5-dien-3-one system

Article abstract of DOI:10.1016/j.tet.2006.02.063

Mechanisms involved in the maintenance of human pregnancy and initiation of labour are poorly defined. A novel steroid hormone named estradienolone (ED), and having an unusual 19-nor-androsta-1,5-dien-3-one system, was previously reported. However, ED is scarcely available from urine, placenta and blood of pregnant women. For this reason, we have synthesized ED in order to verify its proposed structure. Although a 1,5-dien-3-one system had already been described for a C19-steroid (androstane) nucleus (no possible aromatization), the synthesis of the 19-nor-analogue is a major challenge because this system is very sensitive to aromatization. We now describe the successful construction and characterization of this unstable system. Starting from nortestosterone, the synthesis of 17β-hydroxy-19-nor-androsta-1,5-dien-3-one (1) is based on a protection of the 5,6-double bond, the introduction of the second 1,2-double bond, the careful recovery of the exo double bond and a final regioselective oxidation or reduction.

Full text of DOI:10.1016/j.tet.2006.02.063

Tetrahedron 62 (2006) 4384–4392
First synthesis of a steroid containing an unstable
19-nor-androsta-1,5-dien-3-one system
b,
Christine Cadot,a Donald Poiriera, and Anie Philip
*
*
aMedicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center,
´
´
CHUQ-Pavillon CHUL and Universite Laval, Quebec Qc, Canada G1V 4G2
bPlastic Surgery Research, Department of Surgery, and Department of Obstetrics and Gynecology,
´
McGill University, Montreal Qc, Canada H3G 1A4
Received 6 January 2006; revised 17 February 2006; accepted 21 February 2006
Available online 22 March 2006
Abstract—Mechanisms involved in the maintenance of human pregnancy and initiation of labour are poorly defined. A novel steroid
hormone named estradienolone (ED), and having an unusual 19-nor-androsta-1,5-dien-3-one system, was previously reported. However, ED
is scarcely available from urine, placenta and blood of pregnant women. For this reason, we have synthesized ED in order to verify its
proposed structure. Although a 1,5-dien-3-one system had already been described for a C19-steroid (androstane) nucleus (no possible
aromatization), the synthesis of the 19-nor-analogue is a major challenge because this system is very sensitive to aromatization. We now
describe the successful construction and characterization of this unstable system. Starting from nortestosterone, the synthesis of
17b-hydroxy-19-nor-androsta-1,5-dien-3-one (1) is based on a protection of the 5,6-double bond, the introduction of the second 1,2-double
bond, the careful recovery of the exo double bond and a final regioselective oxidation or reduction.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the new steroid, was based on similar kinds of evidence
and, in addition, on ultraviolet absorption spectra and
solubility characteristics. Furthermore, ED can transform
into estradiol in alkali conditions, suggesting a dearoma-
tized form of the potent estrogenic hormone estradiol. Thus,
the proposed structure of ED is 17b-hydroxy-19-nor-
androsta-1,5-dien-3-one (1), a C18-steroid (estrane) nucleus
comprising an unusual and unstable 1,5-dien-3-one system
(Scheme 1). Since it is scarcely available from urine,
placenta and blood from pregnant women, the low quantity
of natural ED thus isolated has not allowed confirming its
chemical structure yet. Its chemical synthesis thus seemed
an attractive approach for confirming, or invalidating, the
proposed structure, as well as for providing a substantial
quantity of the hormone for biological studies.
Mechanisms involved in the maintenance of human
pregnancy and initiation of labour are poorly defined.
Philip’s group isolated a novel steroid hormone, namely
estradienolone (ED), which may have the potential to
maintain pregnancy.1 Since the levels of ED in plasma,
placenta and urine are high during pregnancy, but markedly
decrease both in the placenta and blood at the moment of
term or premature labour, this decrease may provide the
signal to initiate parturition in humans. This new steroid was
identified along with three other low-polarity ligands of sex
hormone-binding globulin (SHBG) in pregnant women.2,3
These included two weakly-bound and well-known steroids,
5a-pregnane-3,20-dione and progesterone, and two
strongly-bound substances, 2-methoxyestrone and the new
steroid named ED. The identification of the first three
ligands was based on chromatographic elution patterns,
binding characteristics and gas chromatography–mass
spectrometry. The identification of the fourth peak,
Keywords: Steroid; Total synthesis; Nortestosterone; 1,5-Dien-3-one
system; Protecting group; NMR.
*
Corresponding authors. Tel.: C1 418 654 2296; fax: C1 418 654 2761
(D.P.); tel.: C1 514 934 1934x44533; fax: C1 514 934 8289 (A.P.);
e-mail addresses: donald.poirier@crchul.ulaval.ca;
anie.philip@mcgill.ca
Scheme 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.063

C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
4385
Although the elaboration of 1,5-dien-3-one systems is well
documented for C19- and C21-steroids,4–8 as exemplified
by compound 2 in Scheme 1, this is not the case for the C18-
steroid derivative 1 (ED), which is expected to be very
sensitive to aromatization under an acid or base treatment,
giving estradiol (3). Contrary to 1, a steroid like 2 is stable
because the aromatization of ring A is not possible with the
presence of an angular methyl group at position 10.
Considering the serious constraints associated with the
instability of the 1,5-dien-3-one system in a C18-steroid
(19-nor-androstane), the synthesis of 1 represents an
interesting challenge. In this paper, we report the successful
chemical synthesis of compound 1 from nortestosterone.
2. Results and discussion
Two retrosynthetic approaches (A and B) were tested for the
synthesis of 1 (Scheme 2). These strategies have in common
the double bond deconjugation of nortestosterone, but differ
by the nature of the protecting group for the double bond, a
5,6-dibromo or a 6-ketal derivative. In the first approach
(A), depicted more comprehensively in Scheme 3, the 4,5-
double bond of nortestosterone was first deconjugated with
KO-t-Bu to form the 5,6-double bond,9 and the 3-ketone
was reduced with LiAlH4 to avoid reconjugation of the
double bond.10 The resulting diol 4, obtained in 77% yield,
was then acetylated in standard conditions to afford the
Scheme 3. Reagents and conditions. (a) KO-t-Bu, t-BuOH, THF, rt, 18 h;
(b) LiAlH4, THF, 0 8C, 2.5 h (77%, two steps); (c) Ac2O, pyridine, DMAP,
rt, 3 h (91%); (d) AcOH, Br2, KOAc, Et2O, 0 8C, 2 h and rt, 12 h (57%);
(e) Na2S$9H2O, DMF, rt, 3 h (99%); (f) K2CO3, MeOH, CH2Cl2, H2O,
80 8C, 5 h (59%); (g) PCC, CH2Cl2, rt, 3 h (95%); (h) THF, LDA, 0 8C,
10 min; CDCl3, rt, 12 h; or neat, rt, 12 h; (i) AcOH, Br2, Et2O, 0 8C, 2 h and
rt, 12 h (91%); (j) CaCO3, DMA, 170 8C, 10 min or CaCO3, DMA, C6H6,
80 8C, 10 min; (k) (i) NaBH4, MeOH, THF, 0 8C, 1.5 h; (ii) Ac2O, pyridine,
DMAP, rt, 12 h (77%, two steps); (iii) DBU, C6H6, rt, 12 h or 80 8C, 8 h.
diacetylated compound 5. The 5,6-double bond of 5 was
protected by bromination using Br2 in acetic acid11 to give
the dibromo compound 6 in 57% yield; this product was
found to be quite stable when left for a long time at rt in an
inert and dark atmosphere. The double bond deprotection
was tested and found satisfactory. In an attempt to recover
the 5,6-double bond, it was not possible to use the standard
NaI procedure described for the C19-steroids;11 the C18-
steroid
6 was successfully treated instead with
Na2S$H2O.12–14 Thereafter, the 3-acetate group of 6 was
hydrolyzed selectively with K2CO3 in MeOH and the
resulting alcohol submitted to oxidative conditions
(PCC/NaOAc, PDC or TPAP/NMO) to obtain ketone 7.
The latter was not very stable, however, being easily
converted into estradiol (3). Only PCC gave 7 in 95% yield,
but this compound cannot be purified by chromatography
and is only stable in inert atmosphere and at low
temperature in darkness. Using LDA in the presence of
PhSeBr or PhSeCl15 followed by a treatment with H2O2
did not allow introducing the 1,2-double bond because 7
was instead transformed into 3. Alternatively, an additional
Scheme 2. Two retrosynthetic approaches for the synthesis of ED.

4386
C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
bromide was introduced at position 2 using Br2 in acetic
acid to give the tribromide derivative 8. Unfortunately, the
methods we tried for the dehydrobromination16–18 failed to
provide the enone system of compound 9.
In the second approach (B), briefly outlined in Scheme 2 and
reported in details in Schemes 4 and 5, the 5,6-double bond of
5 was hydroxylated at position 6 using BH3$THF and H2O2/
NaOH at rt.19 The alcohol 10 was obtained in 62% yield, but
two more compounds, deacetylated in C-17 or in C-3, were
also observed in 28% yield. Before introducing the 1,2-double
bond, 10 was first oxidized into 11 with PCC and then
protected as ketal 12 in 96% yield. The regio-deprotection by
removal of the 3-acetate group with K2CO3 was less selective
than previously observed for approach A. Thus, when 12 was
treated with K2CO3 in MeOH/H2O, only 15% yield of 13 was
obtained after 3 h. A better yield of 51% was, however,
obtained with aq NaHCO3. Furthermore, the by-products of
this reaction, alcohol 14 and diol 15, can be recycled by an
acetylation step allowing the recovery of 12.
Scheme 5. Reagents and conditions. (a) NaBH4, CeCl3$7H2O, EtOH,
MeOH, K78 8C, 1.5 h; (b) Ac2O, pyridine, DMAP, rt, 3 h (99%, two steps);
(c) 1% HCl in acetone, rt, 0.5 h (64%); (d) K-Selectride, THF, K78 8C,
5.5 h (72%); (e) POCl3, pyridine, rt, 1 h; (f) K2CO3, MeOH, H2O, 100 8C,
1 h (63%, two steps); (g) BaMnO4/Al2O3 (neutral), CuSO4$5H2O, CH2Cl2,
rt, 4 h (13%).
corresponding ketone 16, followed by the double bond
introduction giving 17. Previously, we successfully applied
classical methods for the introduction of a double bond,
such as LiBr/Li2CO3,20 N-bromosuccinimide/DBU,16
TMSCl/Pd(OAc)2,21,22 PhSeBr,15 or PySO2CH3,23 to a
model compound (19-nor-dihydrotestosterone-17b-O-
TBDMS), allowing the formation of 1,2-conjugated
3-ketone in 41–61% yields. Unfortunately, these methods
were not compatible with the functional group of 16. The
double bond was, however, introduced using Reich’s
methodology,15 modified so as not to require LDA.24
Thus, a sequential treatment of PhSeCl in anhydrous EtOAc
and H2O2/pyridine at rt and then at reflux yielded the
conjugated ketone 17 in 70% yield from 16.
After successfully elaborating the 1-en-3-one system, the
next step was to regenerate the 5,6-double bond carefully
in order to avoid the aromatization of ring A. In order to
do this, the C-3 carbonyl of 17 was first reduced with
NaBH4/CeCl3$7H2O and the resulting allylic alcohol
protected as diacetate 18 in excellent yield (Scheme 5).
The ketal group was next hydrolyzed at rt in acetone and
p-TsOH (1.4 equiv),25 but ketone 19 was found to be quite
unstable under these conditions, with only 19% isolated.
However, carrying out the same reaction using 1% HCl in
acetone instead resulted in a mixture of 5a-H and 5b-H
isomers in a ratio of 67:33 and a much better yield of 64%
for 19 after chromatography. The conditions for the
transformation of 19 into 20 were first studied with 11 as
a model compound. Indeed, it is known that a 5a-H and a
6b-OH in trans diaxial configuration can be eliminated with
POCl3 in pyridine in order to regenerate the 5,6-double
bond.26 When 11 was reduced with NaBH4 in MeOH at
0 8C, the 6a-OH derivative 10 and 6b-OH analogue were
obtained in a ratio of 45:55, according to 1H NMR analysis
(3.30 ppm for 6b-CH of 6a-OH derivative 10 and 3.80 ppm
for 6a-CH of 6b-OH analogue). When this reduction was
performed using NaBH4/CeCl3$7H2O in MeOH at K78 8C
only the 6a-alcohol 10 was obtained.27 However, we could
Scheme 4. Reagents and conditions. (a) (i) BH3$THF, THF, rt, 2 h; (ii)
H2O2, NaOH, 0 8C, 0.5 h and rt, 1 h (62%); (b) PCC, CH2Cl2, rt, 3 h (97%);
(c) ethylene glycol, HC(OEt)3, p-TsOH, CH2Cl2, rt, 3.5 h (99%);
(d) NaHCO3, MeOH, H2O, 67 8C, 72 h (51%); (e) Ac2O, pyridine,
DMAP, rt, 3 h (99%); (f) PCC, CH2Cl2, rt, 3 h (96%); (g) (i) PhSeCl,
AcOEt, rt, 3 h; (ii) pyridine, H2O2, rt, 15 min then 80 8C, 15 min (70%).
The construction of the 1-en-3-one system was finally
achieved by oxidation of the 3-hydroxy group of 13 to its

C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
4387
not proceed to the inversion of 6a-OH into 6b-OH because
the well known modified Mitsunobu methodology (PPh3,
DEAD and PNBA followed by an ester hydrolysis)28,29 is
not compatible with acetate groups, and accordingly we
changed the reductive reagent. Thus, the 6b-OH epimer of
10 was the single isomer isolated using K-Selectride in THF
at K78 8C. Finally, the preparation of 21 was completed by
(1) a stereoselective reduction of 19 into 20 using the
K-Selectride methodology discussed above; (2) a dehy-
dration of the 6b-OH group with POCl3 in pyridine; and (3)
a deprotection by removal of diacetate groups with K2CO3.
Before the last step in the synthesis of 1—a compound
expected to be very sensitive to usual acid and base
conditions—the precursor compound 21 was fully analyzed
by NMR spectroscopy. We were especially interested in
confirming the 10b-H stereochemistry, because this
stereocenter will not be modified in the last step of
compound 1 synthesis. Using a combination of NMR
experiments (COSY, HSQC, HMBC, and NOESY),30 all
proton and carbon signals were fully identified (see Section
4 and Supporting information). Using the signal at
2.46 ppm (10-CH), the NOESY spectra allowed identifying
four interactions of different intensity with 11b-CH
(strong), 4b-CH (medium), 8b-CH (weak) and 1-CH
(weak) (Fig. 1). Furthermore, no NOE was observed
between the hydrogen atoms at positions 10 and 9a. Taken
together, these data clearly established the 10b-H stereo-
chemistry in compound 21.
Scheme 6. The reagents and conditions are reported in Table 1 except for
the reduction of 23 into 1 (NaBH4, MeOH, CH2Cl2, K35 8C, 13 min).
A-ring aromatization and B-ring oxidation. No reaction was
observed when benzene and CH2Cl2 were used as aprotic
solvents. Diol 21 was next treated with Dess–Martin
periodinane (2 equiv), which resulted in the isolation of
diketone 23 in 72% yield after 30 min (entry 2). In an
attempt to capitalise on the less reactive character of the
hindered 17b-OH versus the more reactive allylic 3b-OH,
diol 21 was reacted with only 1 equiv of Dess–Martin
reagent. A mixture of compounds 21, 23, 24, and 1 was,
however, obtained (entry 3), clearly showing the non
regioselectivity of this methodology. Furthermore, it was
not possible to separate the compounds by chromatography.
IBX–polystyrene, a polymer-supported version of iodoxy-
benzoic acid reported to be selective for allylic alcohol, was
also tested for the oxidation of 21. Considering the low
stability expected for compound 1, we found worthy using
this polymer-supported reagent for its mild reactivity, its
more hindered nature, and the simple workup (only filtration
is needed). Although this reagent is less reactive than
hypervalent iodine analogue reagent (Dess–Martin period-
inane), a selective oxidation was nonetheless not possible
(entries 4–8).
Figure 1. 2D and 3D representations of 21. The important NOE results are
represented by four arrows. The 3D structure was generated with CSChem
3D std 5.0 (Cambridge Soft Corporation, Cambridge, MA). The
stereocenters at C-8, 9, 13, 14, and 17 were already fixed in the starting
natural steroid and were not affected by the following sequence of
reactions.
The last reagent tested was a solid mixture of BaMnO4 on
basic or neutral alumina and CuSO4$5H2O. We previously
obtained promising results with a model diol containing
two secondary alcohols. In fact, a mixture of starting
material, 3b,17b-dihydroxy-4-androstene, and of the
desired compound, 17b-hydroxy-4-androsten-3-one, was
obtained in a ratio of 1:2 following the conditions described
in the literature (basic alumina, benzene). The same ratio
was obtained with CH2Cl2, as well as when replacing basic
alumina by neutral alumina, a kind of alumina much more
compatible with the low stability of 1. These results
prompted us to employ this selective oxidizing agent with
diol 21. In the last two assays (entries 9 and 10), ratios of
60:40 and 63:37 were determined for 21 and 1 by 1H NMR.
The last crucial step in the synthesis of 1 was the
regioselective oxidation of the allylic 3-OH versus the 17-
OH of diol 21 in neutral and mild conditions avoiding the
aromatization of the 1,5-dien-3-one system. Four methods,
MnO2,16,31–33 Dess–Martin,34 IBX–polystyrene,35 and
BaMnO4 on alumina,36,37 were selected to be tested for
this transformation (Scheme 6 and Table 1). With MnO2 in
acetone, the transformation of 21 switched toward the
aromatized compound 22 (entry 1 of Table 1). The weak
basicity (pH 8) and oxidative property of MnO2 explain the

4388
C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
Table 1. Yields (%) under different conditions tested for the regioselective oxidation of 21 into 1
Entry
Reagents and conditions
21
22
23
24
1
1
2
3
4
5
6
7
0
9
10
MnO2 (15 equiv), acetone, rt, 12 h
Dess–Martin (2 equiv), CH2Cl2, rt, 30 min
Dess–Martin (1 equiv), CH2Cl2, rt, 1 h
IBX–polystyrene (4 equiv), CH2Cl2, rt, 15 min
IBX–polystyrene (4 equiv), CH2Cl2 rt, 30 min
IBX–polystyrene (2 equiv), CH2Cl2, rt, 10 min
IBX–polystyrene (2 equiv), CH2Cl2, rt, 20 min
IBX–polystyrene (2 equiv), CH2Cl2, rt, 45 min
BaMnO4/Al2O3 (neutral), CuSO4$5H2O, CH2Cl2, rt, 6 h
BaMnO4/Al2O3 (neutral), CuSO4$5H2O, CH2Cl2, rt, 4 h
32a
0
37
0
0
0
0
0
0
0
0
0
72
23
8
18
13
19
38
0
0
0
23
13
20
6
3
20
0
0
0
22b
65
32
14
19
16
16
23
40
13 (37)
43
65
62
19
60
63 (63)
0
0
0
a Isolated yield (%) after purification by silica gel chromatography (normal characters).
b Percentage of compounds as determined by 1H NMR analysis (italic characters).
In the last assay, ketone 1 was isolated in 13% yield after
careful reverse-phase chromatographic steps, which also
permitted recovery of the starting diol 21 in 63% yield. This
regioselective oxidation remains to be optimized, especially
regarding the workup and purification procedures.
In chloroform, 23 underwent only aromatization of the
steroidal A-ring giving estrone (100%) after 4 weeks,
while it was fully degraded in acetic acid. The formation
of aromatized and degraded compounds gradually
occurred in methanol, ethanol, or dimethylsulfoxide, but
w70 and 40% of 23 still remained after 1 and 4 weeks.
However, the 1,5-dien-3-one system was fully stable in
benzene, pyridine, or acetone until 14 days and few
degradation (15–34%) was observed at the end of the
experiment. We then selected C6D6 for our NMR
analysis, and data for ketone 1, diketone 23, and model
compounds 25 and 26 are reported in Table 2. Clearly
the CH-1 and CH-2 signals of 1 and 23 are close to the
corresponding signals observed for model compound 25.
The same conclusion was also obtained for the C-5 and
CH-6 signals of 1 and 23 when compared to the exo 5,6-
double bond of 26. Taken together these data clearly
confirmed the 1,5-dien-3-one system of 23 and 1.
As an alternative strategy to obtain 1 more easily,
we attempted the regioselective reduction of 23 into 1
(Scheme 6). Indeed, a ketone can be reduced in the presence
of a conjugated enone using the conditions reported by
Ward et al. (NaBH4 in MeOH/CH2Cl2 (50/50) at
K78 8C).38 In our case, the ketone at C17 was reduced
before the conjugated ketone at C3. No reaction was
observed at K78 8C, but the reduction proceeds with a good
regioselectivity between K40 and K35 8C. Although the
reaction temperature and time appear to be critical for
selectivity, an interesting ratio of 41:54:5, for 1:23:21 was
obtained at K35 8C. Compound 1 was thus isolated in a
better yield (40%) and much more easily by the
regioselective reduction than by the regioselective
oxidation.
Table 2. Characteristic NMR signals (ppm) in C6D6 observed for
compounds 25, 26, 23, and 1
Compounds 23 and 1 were analysed by 1H and 13C NMR to
confirm the formation of the 1,5-estradien-3-one system.
We had previously assessed the stability of 23 at rt during a
period of 1 month when dissolved in various deuterated
solvents (Fig. 2).
Carbon
number
25a
H, C
26b
H, C
23
H, C
1
H, C
1
2
3
5
6
6.48, 150.6
6.02, 129.7
—, 198.0
—
—
—
6.24, 149.4
5.99, 128.9
—, 196.4
—, 132.4
5.16, 122.8
6.33, 149.8
6.00, 128.7
—, 196.7
—, 132.2
5.18, 123.2
—, 206.8
—, 135.7
5.20, 122.2
—
a Compound 25 was obtained by treatment of 19-nor-dihydrotestosterone-
17b-O-TBDMS with Pd(OAc)2 followed by a TBDMS hydrolysis.
b Compound 26 was obtained as an intermediate during the synthesis of 4.
3. Conclusion
The successful synthesis of 23 and 1, two dearomatized
forms of potent estrogenic hormones estrone and estradiol,
respectively, was described starting from nortestosterone.
To the best of our knowledge, the synthesis of a steroidal
1,5-dien-3-one system without a methyl 19 group at position
10 had never been reported before. This unusual chemical
Figure 2. Stability of 23 (1 mg) at rt when dissolved in deuterated solvents
as determined by NMR analysis.

C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
4389
arrangement explains the low stability of 23 and 1 that
complicated the chemical synthesis. In fact a careful
planning of the sequence of reactions was necessary to
overcome the synthetic difficulty associated with the high
reactivity of a 19-nor-androsta-1,5-dien-3-one system toward
acids and bases. As reported for natural ED,3 1 was treated
with 3 N NaOH in acetone at rt giving as expected the
aromatized compound 3 (estradiol) in 70% yield. However, 1
may not be identical to natural ED since a biological assay
has shown its potency to be lower (20% of that of natural
ED). LC/MS analysis and Sephadex chromatography also
confirmed the non-identity of 1 and natural ED. They
nonetheless have in common certain unstable properties and
it is possible that both compounds contain the same unusual
1,5-dien-3-one system. Preliminary studies also determined
the range of stability of this 19-nor-androsta-1,5-dien-3-one
system under different solvents.
60.21 mmol) in dry THF (675 mL) at 0 8C. After being
stirred at 0 8C for 2.5 h, the reaction mixture was quenched
with saturated aq NH4Cl (100 mL) and extracted with
EtOAc. The combined organic layer was washed with brine,
dried over MgSO4, and evaporated. The crude residue was
purified by chromatography (hexanes/EtOAc, 80:20) to
afford diol 4 (11.68 g, 77% yield) as a white solid. IR (film)
n 3362 (OH); 1H NMR (300 MHz, MeOH-d4) d 0.76 (s, 18-
CH3), 0.80–2.05 (m, 19H, CH and CH2 of steroid skeleton),
2.40 (m, 1H), 3.40 (m, 3a-CH), 3.58 (t, JZ8.5 Hz, 17a-
CH), 5.44 (dd, J2Z5.7 Hz, J1Z1.5 Hz, 6-CH); 13C NMR
(75 MHz, MeOH-d4) d 11.5 (C18), 24.1, 28.0, 30.6, 31.4,
31.6, 36.1, 37.8, 38.0, 44.1, 44.2, 45.7, 47.2, 51.7, 71.8 (C3),
82.5 (C17), 122.1 (C6), 138.8 (C5); HRMS calcd for
C18H29O2 [MCH]C277.21621, found 277.21689.
4.2.2. Synthesis of 3b,17b-diacetoxy-19-nor-androst-5-
ene (5).39 To a stirred solution of 4 (11.68 g, 42.32 mmol) in
CH2Cl2 (640 mL) were added pyridine (7.50 mL), Ac2O
(6.83 mL) and a catalytic amount of DMAP. The reaction
mixture was stirred under nitrogen for 3 h at rt, poured into
ice cold aq 1 M HCl (230 mL), and extracted with EtOAc.
The combined organic layer was washed with saturated aq
NaHCO3, dried over MgSO4, and evaporated. The crude
product was purified by chromatography (hexanes/EtOAc,
90:10) to afford 5 (13.86 g, 91% yield) as a white solid. IR
(film) n 1732 (C]O, esters); 1H NMR (400 MHz, CDCl3) d
0.80 (s, 18-CH3), 0.80–2.10 (m, 19H, CH and CH2 of steroid
skeleton), 2.02 (s, 2!OCOCH3), 2.50 (m, 1H), 4.59 (m, 3a-
CH and 17a-CH), 5.46 (dd, J2Z5.7 Hz, J1Z1.5 Hz, 6-CH);
13C NMR (75 MHz, CDCl3) d 11.9 (C18), 21.1 (OCOCH3),
21.4 (OCOCH3), 23.3, 26.5, 27.4, 30.0, 30.2, 31.5, 36.1,
36.5, 40.7, 42.6, 42.7, 45.2, 49.9, 73.2 (C3), 82.7 (C17),
122.2 (C6), 136.1 (C5), 170.5 (OCOCH3), 171.2
(OCOCH3); HRMS calcd for C22H33O4 [MC
H]C361.23734, found 361.23767.
4. Experimental
4.1. General remarks
Anhydrous reactions were performed in oven-dried glass-
ware under positive argon pressure using commercially
available anhydrous solvents, except THF, which was
distilled from sodium/benzophenone ketyl under argon.
Flash chromatography was performed on Silicycle 60 230–
400-mesh silica gel. Thin-layer chromatography (TLC) was
performed on 0.25-mm silica gel 60 F254 plates and
compounds were visualized by exposure to UV light
(254 nm), a solution of ammonium molybdate/sulphuric
acid/water and/or a solution of para-anisaldehyde/sulphuric
acid/acetic acid/ethanol (plus heating). Infrared (IR) spectra
were obtained from a thin film of the solubilized compound
on NaCl pellets (usually in CH2Cl2) or in a KBr pellets
containing the solid compound. Only significant bands are
reported (in cmK1). 1H and 13C spectra were recorded,
respectively, at 300 and 75.5 MHz or at 400 (1H) and 100
(13C) MHz. The chemical shifts (d) are expressed in ppm
and referenced to chloroform (7.26 and 77.0 ppm),
methanol (3.31 and 49.0 ppm) or benzene (7.16 and
128.0 ppm) for 1H and 13C, respectively. All new
compounds were determined to be O95% pure by 1H
NMR spectroscopy. Melting points were recorded on an
Electrothermal IA9300 SERIES Digital Melting Point
Apparatus and are uncorrected. High-resolution mass
spectra (HRMS) were obtained with a dual spray ESI
source on positive mode.
4.2.3. Synthesis of 3b,17b-diacetoxy-6a-hydroxy-19-nor-
5a-androstane (10). To a solution of 5 (16.32 g,
45.33 mmol) in dry THF (620 mL) was added 1 M BH3 in
THF (91 mL) dropwise at 0 8C, and the mixture was stirred
for 2 h at rt. Then 3 N NaOH (40 mL) and H2O2 (33% w/v,
15 mL) were added at 0 8C, and the mixture was stirred
0.5 h at 0 8C and 1 h at rt. The mixture was poured into H2O
(500 mL). The aq phase was extracted with CH2Cl2, and the
organic phase was washed with brine, dried over MgSO4,
and evaporated. Purification by flash chromatography
(hexanes/EtOAc, 70:30) afforded 10 (10.62 g, 62%) as a
white solid. Mp 199–200 8C (Et2O/MeOH); IR (film) n 3528
1
(OH), 1736 and 1709 (C]O, esters); H NMR (400 MHz,
4.2. Synthesis of compounds 1 and 23
CDCl3) d 0.61 (m, 1H), 0.75 (s, 18-CH3), 0.78–2.20 (m,
19H, CH and CH2 of steroid skeleton), 1.98 (s, OCOCH3),
2.00 (s, OCOCH3), 2.40 (m, 1H), 3.24 (m, 6b-CH), 4.55 (t,
JZ8.4 Hz, 17a-CH), 4.66 (m, 3a-CH); 13C NMR (75 MHz,
CDCl3) d 12.0 (C18), 21.2 (OCOCH3), 21.4 (OCOCH3),
23.3, 25.2, 27.4, 28.0, 31.5, 34.5, 36.6, 38.6, 39.7, 42.7,
43.9, 47.2, 48.2, 49.5, 72.7 (C3 or C6), 73.7 (C6 or C3), 82.7
(C17), 170.6 (OCOCH3), 171.2 (OCOCH3); HRMS calcd
for C22H34O5Na [MCNa]C401.22985, found 401.22938.
4.2.1. Synthesis of 3b,17b-dihydroxy-19-nor-androst-5-
ene (4).39 A mixture of nortestosterone (15.00 g,
54.74 mmol) and KO-t-Bu (13.82 g, 136.85 mmol) in
t-BuOH (260 mL) and THF (150 mL) was stirred under
nitrogen for 18 h at rt and then quenched by the rapid
addition of 10% aq AcOH (930 mL) to the resulting slurry.
Saturated aq NaHCO3 was added and the product was
isolated by an extraction with diethyl ether. The combined
organic layer was washed with excess aq NaHCO3, dried
over MgSO4, and evaporated. The crude unconjugated
ketone was added to a stirred solution of LiAlH4 (2.29 g,
4.2.4. Synthesis of 3b,17b-diacetoxy-6-oxo-19-nor-5a-
androstane (11). A solution of 10 (18.40 g, 48.67 mmol)
and PCC (26.16 g, 121.69 mmol) in dry CH2Cl2 (270 mL)

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C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
was stirred for 3 h at rt. Celite was then poured into the
mixture and the resulting suspension was filtered through a
cake of Celite and silica gel. The filter cake was washed
with hexanes/EtOAc, 50:50 (1.5 L), and the filtrate was
concentrated under reduced pressure. The crude product
was purified by chromatography (hexanes/EtOAc, 70:30) to
afford 11 (17.70 g, 97% yield) as a white solid. Mp 187–
188 8C (Et2O/MeOH); IR (film) n 1736 and 1708 (C]O,
21.70 mmol) and PCC (11.66 g, 54.25 mmol) in dry CH2Cl2
(140 mL) was stirred for 3 h at rt. Then Celite was poured
into the mixture and the resulting suspension was filtered
through a cake of Celite and silica gel. The filter cake was
washed with hexanes/EtOAc, 50:50 (0.5 L), and the filtrate
was concentrated under reduced pressure. The crude
product was purified by chromatography (hexanes/EtOAc,
70:30) to afford 16 (7.80 g, 96% yield) as a white solid. Mp
136–138 8C (Et2O); IR (film) n 1736 (C]O, ester), 1720
1
esters and ketone); H NMR (400 MHz, CDCl3) d 0.79 (s,
1
18-CH3), 1.10–2.38 (m, 21H, CH and CH2 of steroid
skeleton), 2.03 (s, OCOCH3), 2.05 (s, OCOCH3), 4.65 (t,
JZ8.4 Hz, 17a-CH), 4.70 (m, 3a-CH); 13C NMR (75 MHz,
CDCl3) d 11.9 (C18), 21.1 (OCOCH3), 21.3 (OCOCH3),
23.1, 25.2, 27.3, 29.0, 30.8, 31.0, 36.3, 42.2, 43.0, 45.8,
47.2, 47.4, 50.3, 52.3, 72.3 (C3), 82.3 (C17), 170.6
(OCOCH3), 171.2 (OCOCH3), 209.7 (C6); HRMS calcd
for C22H33O5 [MCH]C377.23225, found 377.23253.
(C]O, ketone); H NMR (400 MHz, CDCl3) d 0.75 (m,
1H), 0.83 (s, 18-CH3), 1.05–1.90 (m, 14H, CH and CH2 of
steroid skeleton), 2.04 (s, OCOCH3), 2.10–2.50 (m, 6H, CH
and CH2 of steroid skeleton), 3.85 (m, 1H of OCH2CH2O),
3.95 (m, 3H of OCH2CH2O), 4.60 (t, JZ8.4 Hz, 17a-CH);
13C NMR (75 MHz, CDCl3) d 12.1 (C18), 21.1 (OCOCH3),
23.2, 25.3, 27.4, 30.3, 36.6, 37.4, 39.3, 39.6, 40.8, 42.3,
42.8, 47.2, 49.4, 49.6, 64.9 (OCH2), 65.4 (OCH2), 82.6
(C17), 108.9 (C6), 171.1 (OCOCH3), 212.2 (C3); HRMS
calcd for C22H33O5 [MCH]C377.23225, found 377.23210.
4.2.5. Synthesis of 3b,17b-diacetoxy-6,6-ethylenedioxy-
19-nor-5a-androstane (12). A mixture of 11 (17.70 g,
47.07 mmol), triethyl orthoformate (28.5 mL), ethylene
glycol (26 mL), and a catalytic amount of p-TSA in
CH2Cl2 (1 L) was stirred for 3.5 h at rt. The reaction was
quenched by addition of H2O, then the organic phase was
washed with H2O, dried over MgSO4, and evaporated to
afford 12 (19.60 g, 99%) as a white solid. Mp 135–136 8C
4.2.8. Synthesis of 17b-acetoxy-6,6-ethylenedioxy-3-oxo-
19-nor-5a-androst-1-ene (17). Phenylselenyl chloride
(2.49 g, 13.10 mmol) was added to 16 (7.80 g,
10.42 mmol) in dry EtOAc (110 mL) and the resulting
reaction mixture was stirred for 3 h at rt. Pyridine (3.14 mL)
was then added to the reaction mixture cooled at 0 8C,
followed by the addition of H2O2 (33% w/v, 2.66 mL) over
a period of 6 min. The reaction mixture was stirred at rt for
15 min, then refluxed for 15 min, cooled, and diluted with
EtOAc (110 mL). The organic layer was washed with brine
(25 mL) and saturated aq NaHCO3 (25 mL), dried over
MgSO4, and evaporated. The crude residue was purified by
chromatography (hexanes/EtOAc, 75:25) to afford 17
(5.40 g, 70% yield) as a white solid. Mp 137–139 8C
(Et2O); IR (film) n 1709 (C]O, ester), 1664 (C]O,
conjugated ketone); 1H NMR (400 MHz, CDCl3) d 0.85 (s,
18-CH3), 0.80–2.35 (m, 16H, CH and CH2 of steroid
skeleton), 2.04 (s, OCOCH3), 2.60 (dd, J2Z16.4 Hz, J1Z
2.6 Hz, 4-CH), 3.95 (m, OCH2CH2O), 4.63 (t, JZ8.0 Hz,
17a-CH), 5.99 (dd, J2Z10.2 Hz, J1Z2.2 Hz, 2-CH), 7.07
(dd, J2Z10.2 Hz, J1Z1.6 Hz, 1-CH); 13C NMR (75 MHz,
CDCl3) d 12.2 (C18), 21.1 (OCOCH3), 23.1, 24.9, 27.4,
36.5, 36.8, 38.0, 39.1, 42.9, 43.2, 45.1, 47.8, 49.4, 65.2
(OCH2), 65.4 (OCH2), 82.4 (C17), 108.2 (C6), 129.3 (C2),
151.2 (C1), 171.2 (OCOCH3), 199.9 (C3); HRMS calcd for
C22H31O5 [MCH]C375.21660, found 375.21681.
1
(Et2O/pentane); IR (film) n 1732 (C]O, esters); H NMR
(400 MHz, CDCl3) d 0.64 (m, 1H), 0.79 (s, 18-CH3), 0.90–
2.20 (m, 20H, CH and CH2 of steroid skeleton), 2.01 (s,
OCOCH3), 2.02 (s, OCOCH3), 3.93 (m, OCH2CH2O), 4.58
(t, JZ8.4 Hz, 17a-CH), 4.68 (m, 3a-CH); 13C NMR
(75 MHz, CDCl3) d 12.0 (C18), 21.1 (OCOCH3), 21.4
(OCOCH3), 23.2, 25.1, 27.4, 28.5, 29.8, 31.3, 36.7, 37.5,
39.6, 42.6, 42.8, 47.4, 47.7, 49.5, 64.9 (OCH2), 65.3
(OCH2), 73.1 (C3), 82.7 (C17), 109.2 (C6), 170.5
(OCOCH3), 171.2 (OCOCH3); HRMS calcd for C24H37O6
[MCH]C421.25847, found 421.25801.
4.2.6. Synthesis of 17b-acetoxy-6,6-ethylenedioxy-3b-
hydroxy-19-nor-5a-androstane (13). Compound 12
(9.80 g, 23.44 mmol) was dissolved in MeOH (290 mL)
and a solution of NaHCO3 (1.97 g, 23.44 mmol) in H2O
(96 mL) was added. The resulting mixture was warmed at
67 8C for 72 h. Then, the mixture was extracted with
CH2Cl2 and the combined organic layer was dried over
MgSO4 and evaporated. The crude residue was purified by
chromatography (hexanes/EtOAc, 70:30 to 50:50) to afford
13 (4.49 g, 51% yield) as a white amorphous solid. In
addition to 13, purification yielded 12 (1.86 g, 19% yield),
14 (0.74 g, 8% yield) and 15 (1.94 g, 25% yield), all as
white solids. Data are reported only for 13. IR (film) n 3434
4.2.9. Synthesis of 3b,17b-diacetoxy-6,6-ethylenedioxy-
19-nor-5a-androst-1-ene (18). NaBH4 (21 mg,
0.555 mmol) in EtOH (2.5 mL) was added to a cooled
(K78 8C) solution of 17 (176 mg, 0.473 mmol) and
CeCl3$7H2O (194 mg, 0.520 mmol) in MeOH (6 mL) over
a period of 0.25 h. After the mixture was stirred for 1.5 h,
the reaction was quenched by addition of a saturated aq
NH4Cl solution and the extraction was performed with
CH2Cl2. The organic phase was washed with brine, dried
over Na2SO4, and evaporated to dryness. To obtain the
protected C-3 alcohol, the crude product (176 mg) was
dissolved in dry CH2Cl2 (2 mL), and pyridine (50 mL),
Ac2O (50 mL) and a catalytic amount of DMAP were added.
The reaction mixture was stirred under nitrogen for 3 h at rt,
poured into an ice-cold aq 1 M HCl (2 mL), and extracted
with CH2Cl2. The combined organic layer was washed with
1
(OH), 1736 (C]O, ester); H NMR (400 MHz, CDCl3) d
0.65 (m, 1H), 0.81 (s, 18-CH3), 0.80–2.20 (m, 20H, CH and
CH2 of steroid skeleton), 2.04 (s, OCOCH3), 3.60 (m, 3a-
CH), 3.95 (m, OCH2CH2O), 4.60 (t, JZ8.4 Hz, 17a-CH);
13C NMR (75 MHz, CDCl3) d 12.1 (C18), 21.2 (OCOCH3),
23.2, 25.2, 27.4, 28.8, 33.7, 35.2, 36.7, 37.5, 39.8, 42.6,
42.8, 47.6, 47.9, 49.6, 65.0 (OCH2), 65.4 (OCH2), 70.6 (C3),
82.7 (C17), 109.5 (C6), 171.2 (OCOCH3); HRMS calcd for
C22H35O5 [MCH]C379.24790, found 379.24827.
4.2.7. Synthesis of 17b-acetoxy-6,6-ethylenedioxy-3-oxo-
19-nor-5a-androstane (16). A solution of 13 (8.16 g,

C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
4391
saturated aq NaHCO3, dried over Na2SO4, and evaporated.
Purification of the crude compound by flash chromato-
graphy (hexanes/EtOAc, 75:25) afforded 18 (195 mg, 99%
yield) as a white amorphous solid. IR (film) n 1736 (C]O,
esters); 1H NMR (400 MHz, CDCl3) d 0.75 (m, 1H), 0.82 (s,
18-CH3), 1.05–2.35 (m, 16H, CH and CH2 of steroid
skeleton), 2.04 (s, OCOCH3), 2.05 (s, OCOCH3), 3.95 (m,
OCH2CH2O), 4.61 (t, JZ8.4 Hz, 17a-CH), 5.42 (m, 3a-
CH), 5.60 (d app, JZ10.3 Hz, 2-CH), 5.97 (d app, JZ
10.3 Hz, 1-CH); 13C NMR (75 MHz, CDCl3) d 12.2 (C18),
21.1 (OCOCH3), 21.3 (OCOCH3), 23.2, 24.9, 27.2, 27.4,
36.6, 38.3, 39.5, 42.8, 43.0, 46.3 (2!), 49.5, 65.2 (OCH2),
65.3 (OCH2), 71.2 (C3), 82.6 (C17), 108.9 (C6), 127.2 (C2),
132.3 (C1), 170.7 (OCOCH3), 171.1 (OCOCH3); HRMS
calcd for C24H34O6Na [MCNa]C441.22476, found
441.22587.
4.2.12. Synthesis of 3b,17b-dihydroxy-19-nor-androsta-
1,5-diene (21). POCl3 (1.45 mL)wasaddedtoasolutionof20
(545 mg, 1.45 mmol) in pyridine (14 mL) under argon atm at
rt. After the mixture was stirred for 1 h, the reaction was
diluted with CH2Cl2 (50 mL), quenched by addition of aq 1 M
HCl, and extracted with CH2Cl2. The combined organic layer
was washed with saturated aq NaHCO3, dried over MgSO4,
and evaporated to dryness. The crude alkene (534 mg) was
dissolved in MeOH (20 mL) and a solution of K2CO3 (1.00 g,
7.24 mmol)inH2O(6.5 mL)wasadded.Theresultingmixture
was refluxed for 1 h. Then, the mixture was extracted with
CH2Cl2 and the combined organic layer was dried over
MgSO4 and evaporated. The crude residue was purified by
chromatography (hexanes/EtOAc, 70:30) to afford 21
(250 mg, 63% yield) as a white solid. Mp 150–151 8C
(Et2O); IR (film) n 3364 (OH); 1H NMR (400 MHz, CDCl3)
d 0.79 (s, 18-CH3), 0.85 (ddd, J3Z22.0 Hz, J2Z10.6 Hz, J1Z
4.5 Hz, 9a-CH), 1.01 (m, 14a-CH), 1.14 (td, J2Z12.9 Hz,
J1Z3.9 Hz, 12a-CH2), 1.26 (m, 11b-CH2 and 15b-CH2),
1.40–1.70 (m, 7b-CH2, 8b-CH, 15a-CH2 and 16b-CH2), 1.84
(dt, J2Z12.3 Hz, J1Z3.2 Hz, 12b-CH2), 1.95–2.20 (m, 4b-
CH2, 7a-CH2, 11a-CH2 and 16a-CH2), 2.46 (d app, JZ
9.8 Hz, 10b-CH), 2.64 (ddd, J3Z11.8 Hz, J2Z5.9 Hz, J1Z
1.2 Hz, 4a-CH2), 3.66 (t, JZ8.5 Hz, 17a-CH), 4.25 (m, 3a-
CH), 5.50 (s app, 6-CH), 5.68 (d app, JZ10.1 Hz, 2-CH), 5.84
(d app, JZ10.1 Hz, 1-CH); 13C NMR (75 and 100 MHz,
CDCl3) d 11.0 (C18), 23.1 (C15), 26.1 (C11), 30.2 (C7), 30.4
(C16), 36.3 (C12), 36.7 (C8), 42.5 (C4 and C10), 42.9 (C13),
44.0(C9), 50.4(C14),69.2(C3), 81.8(C17),122.0(C6), 130.6
(C1), 131.2 (C2), 134.3 (C5); HRMS calcd for C18H26O2Na
[MCNa]C297.18250, found 297.18303.
4.2.10. Synthesis of 3b,17b-diacetoxy-6-oxo-19-nor-5a-
androst-1-ene (19). A solution of 18 (12 mg, 0.032 mmol) in
acetone (1 mL) was treated with concentrated HCl (0.01 mL).
The resulting mixture was stirred at rt for 0.5 h. The reaction
was neutralized with saturated aq NaHCO3 and the crude
product was extracted with CH2Cl2. The organic phase was
washed with brine and dried over Na2SO4. The crude ketone
was a 67:33 mixture of 5a-CH and 5b-CH diastereomers.
Purificationofthismixture byflashchromatography(hexanes/
EtOAc, 90:10) afforded the 5a-CH diastereomer 19 (7.0 mg,
64% yield) and the 5b-CH analogue (3.0 mg, 27% yield) as
white solids. Data are reported only for 19. Mp 201–203 8C
(Et2O); IR (film) n 1736 and 1708 (C]O, esters and ketone);
1HNMR(400 MHz,CDCl3) d0.81(s, 18-CH3),1.10–2.50(m,
17H, CH and CH2 of steroid skeleton), 2.05 (s, OCOCH3),
2.06 (s, OCOCH3), 4.65 (t, JZ8.4 Hz, 17a-CH), 5.42 (m, 3a-
CH), 5.64 (d app, JZ10.3 Hz, 2-CH), 6.00 (d app, 1H, JZ
10.3 Hz, 1-CH); 13C NMR (75 MHz, CDCl3) d 12.0 (C18),
21.2 (OCOCH3), 21.3 (OCOCH3), 23.1, 25.0, 27.3, 27.7, 36.2,
42.7, 43.1, 45.5, 46.3, 46.8, 50.2, 50.6, 70.3 (C3), 82.2 (C17),
128.2 (C2), 130.9 (C1), 170.8 (OCOCH3), 171.2 (OCOCH3),
209.0 (C6); HRMS calcd for C22H30O5Na [MC
Na]C397.19855, found 397.19885.
4.2.13. Synthesis of 19-nor-androsta-1,5-dien-3,17-dione
(23). Dess–Martin periodinane (37 mg, 0.088 mmol) was
added to a solution of 21 (12 mg, 0.044 mmol) in dry
CH2Cl2 (4.5 mL) under argon atm at rt. After the mixture
was stirred for 30 min, the reaction was diluted with CH2Cl2
(50 mL), quenched by addition of H2O, and extracted with
CH2Cl2. The combined organic layer was dried over
Na2SO4, and evaporated to dryness. The crude diketone
was purified with a preparative silica gel TLC (hexanes/
EtOAc, 50:50) to afford 23 (8.5 mg, 72% yield) as a white
solid. Mp 161–163 8C (Et2O/MeOH); IR (film) n 1734, 1676
(C]O, ketones); 1H NMR (400 MHz, C6D6) d 0.58 (s, 18-
CH3), 0.49–2.09 (m, 14H, CH and CH2 of steroid skeleton),
2.84 (dd, J2Z16.5 Hz, J1Z1.5 Hz, 4-CH), 3.05 (d app, JZ
16.5 Hz, 4-CH), 5.16 (dd, J2Z5.2 Hz, J1Z2.3 Hz, 6-CH),
5.99 (dd, J2Z10.1 Hz, J1Z2.8 Hz, 2-CH), 6.24 (dd, J2Z
10.1 Hz, J1Z1.9 Hz, 1-CH); 13C NMR (75 MHz, C6D6) d
13.5 (C18), 21.4, 25.7, 29.1, 31.6, 35.4, 36.0, 42.8, 43.3,
47.4, 47.9, 50.3, 122.8 (C6), 128.9 (C2), 132.4 (C5), 149.4
(C1), 196.4 (C3), 217.5 (C17); HRMS calcd for C18H23O2
[MCH]C271.16926, found 271.16866.
4.2.11. Synthesis of 3b,17b-diacetoxy-6b-hydroxy-19-
nor-5a-androst-1-ene (20). To a solution of 19 (1.23 g,
3.28 mmol) in dry THF (30 mL) under argon atm at K78 8C
was added 1 M K-Selectride in THF (4.93 mL, 4.93 mmol).
The mixture was stirred for 5.5 h at K78 8C, and then
quenched by additionof a saturated aq NH4Cl solution. The aq
phase was extracted with CH2Cl2, and the organic phase was
washed with brine, dried over MgSO4, and evaporated. The
crude residue was purified by chromatography (hexanes/
EtOAc, 90:10 to 80:20)to afford19(0.15 g, 12% yield) and 20
(0.89 g, 72%) as a white solid. Mp 123–125 8C (Et2O); IR
(film) n 3474 (OH), 1732 (C]O, esters); 1H NMR (400 MHz,
CDCl3) d 0.84(s, 18-CH3), 0.80–2.30 (m, 17H, CH and CH2 of
steroid skeleton), 2.04 (s, OCOCH3), 2.06 (s, OCOCH3), 3.90
(br s, 6a-CH), 4.60 (t, JZ8.4 Hz, 17a-CH), 5.46 (m, 3a-CH),
5.56 (d app, JZ10.3 Hz, 2-CH), 6.00 (d app, JZ10.3 Hz, 1-
CH); 13C NMR (75 MHz, CDCl3) d 12.2 (C18), 21.2
(OCOCH3), 21.4 (OCOCH3), 23.2, 24.8, 27.4, 32.6, 35.0,
36.6, 37.7, 38.8, 42.9, 43.3, 46.9, 49.5, 70.1 (C3), 71.5 (C6),
82.7 (C17), 126.7 (C2), 132.8 (C1), 171.0 (OCOCH3), 171.3
(OCOCH3); HRMS calcd for C22H32O5Na [MC
Na]C399.21420, found 399.21367.
4.2.14. Synthesis of 17b-hydroxy-19-nor-androsta-1,5-
dien-3-one (1). Method A (from 21). To a mixture of
BaMnO4 (192 mg, 3.36 mmol) and neutral Al2O3 (94 mg,
0.94 mmol) in dry CH2Cl2 (1.6 mL) under argon atm was
added CuSO4$5H2O (15 mg, 0.06 mmol) and 21 (35 mg,
0.128 mmol). After 4 h at rt, the adsorbed reagent was
removed by filtration on Celite and washed with CH2Cl2. The
filtrate wasevaporatedand thecrude product was purifiedwith
three reverse-phase (C18 silica gel) column chromatographies

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C. Cadot et al. / Tetrahedron 62 (2006) 4384–4392
7. Shapiro, E. L.; Legatt, T.; Weber, L.; Oliveto, E. P.; Tanabe, M.;
Crowe, D. F. Steroids 1964, 3, 183–188.
[(CH3CN/H2O, 4:3)/MeOH, 91:9]. The organic layer of
chromatographic tubes was extracted with CH2Cl2, dried
over Na2SO4, and evaporated to afford 1 (4.6 mg, 13% yield).
8. Tanabe, M.; Crowe, D. F. Tetrahedron 1967, 23, 2115–2121.
9. Ringold, H. J.; Malhotra, S. K. Tetrahedron Lett. 1962, 3,
669–672.
Method B (from 23). NaBH4 (10.2 mg, 0.268 mmol) was
added to a solution of 23 (18.0 mg, 0.067 mmol) in dry
CH2Cl2/MeOH (1/1) (0.5 mL) under argon at K78 8C. The
resulting mixture was then stirred for 13 min at K35 8C,
quenched by addition of H2O at K35 8C, and the crude
productsisolatedbyanextractionwithCH2Cl2. Thecombined
organic layer was dried over Na2SO4 and evaporated to
dryness. The mixture was purified with a preparative silica gel
TLC (hexanes/EtOAc, 50:50) to afford the starting material23
(9.8 mg, 54% yield) and 1 (7.3 mg, 40% yield).
10. Birch, A. J. J. Chem. Soc. 1950, 2325–2326.
11. Solo, A. J.; Singh, B. J. Org. Chem. 1965, 30, 1658–1659.
12. Fukunaga, K.; Yamaguchi, H. Synthesis 1981, 879–880.
13. Nakayama, J.; Machida, H.; Hoshino, M. Tetrahedron Lett.
1983, 24, 3001–3004.
14. Landini, D.; Milesi, L.; Quadri, M. L.; Rolla, F. J. Org. Chem.
1984, 49, 152–153.
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White solid. Mp 137–139 8C (Et2O); IR (film) n 1665 (C]O,
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2.09 (m, 14H, CH and CH2 of steroid skeleton), 2.94 (dd, J2Z
16.5 Hz, J1Z1.4 Hz, 4-CH), 3.06 (d app, JZ16.5 Hz, 4-CH),
3.36 (t, JZ8.5 Hz, 17a-CH), 5.18 (dd, J2Z5.3 Hz, J1Z
2.3 Hz, 6-CH), 6.00 (dd, J2Z10.1 Hz, J1Z3.0 Hz, 2-CH),
6.33 (dd, J2Z10.1 Hz, J1Z2.0 Hz, 1-CH); 13C NMR
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36.7, 42.9, 43.1, 43.5, 47.9, 50.2, 81.4(C17), 123.2(C6), 128.7
(C2), 132.2 (C5), 149.8 (C1), 196.7 (C3); HRMS calcd for
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Acknowledgements
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We thank the Canadian Institutes of Health Research
(CIHR) for an operating grant (#FRN 43926 to A.P.). We
are grateful to Richard Labrecque for providing the
optimized conditions of diketone reduction, to Dr. Jean-
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´
Yves Sanceau for helpful discussions and to Patrick
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´
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manuscript by Sylvie Methot is also greatly appreciated.
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Supplementary data
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Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2006.02.063. NMR
experimental data (COSY, HSQC, HMBC, and NOESY) for
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