Efficient synthesis of IPL576,092: a novel anti-asthma agent.

Article abstract of DOI:10.1021/jo0108717

An enantioseletive synthesis of the novel anti-asthma agent IRL576,092 (2) is described. The synthetic route developed involves stereoselective 1,2-reduction of the enone carbonyl functionality of 6 and subsequent hydroboration as the key steps. Starting from the commercially available 5-androsten-3beta-ol-17-one 3, this approach affords IPL576,092 (2) in nine steps with overall yields of 25%, employing a limited number of chromatographic steps.

Full text of DOI:10.1021/jo0108717

3
908
J . Org. Chem. 2002, 67, 3908-3910
Efficien t Syn th esis of IP L576,092: A Novel
An ti-Asth m a Agen t
Yaping Shen* and David L. Burgoyne*
Inflazyme Pharmaceuticals Ltd., Suite 425, 5600 Parkwood
Way, Richmond, British Columbia, Canada V6V 2M2
yshen@inflazyme.com
Received August 27, 2001
F igu r e 1.
Abstr a ct: An enantioseletive synthesis of the novel anti-
asthma agent IRL576,092 (2) is described. The synthetic
route developed involves stereoselective 1,2-reduction of the
enone carbonyl functionality of 6 and subsequent hydro-
boration as the key steps. Starting from the commercially
available 5-androsten-3â-ol-17-one 3, this approach affords
IPL576,092 (2) in nine steps with overall yields of 25%,
employing a limited number of chromatographic steps.
Sch em e 1a
The search for new therapies in the treatment of
asthma has focused on many areas, including mecha-
nism-targeted programs: for example, leukotriene D
LTD ) antagonists, Very Late Antigen-4 (VLA-4) an-
4
(
4
tagonists, and Phosphodiesterase 4 (PDE4) inhibitors.
Despite the vast amount of research in this area, there
remains a need for new safe, effective treatments for
asthma. It was previously reported that contignasterol
1
(Figure 1), a naturally occurring steroid isolated from
specimens of the marine sponge Petrosia contignata
Theile (1899) collected off the coast of Papua New
1
Guinea, possesses biological activity indicative of poten-
2
,3
tial value as a treatment for asthma and other inflam-
4
matory diseases. However, the structural complexity and
potential pharmacokinetic instability led us to undertake
in-depth studies to identify an analogue of compound 1
that demonstrated equivalent or better biological activity
and would be commercially available through synthetic
methodology. This effort has led to the identification of
IPL576,092 (2), a compound which is structurally less
a
Reagents and conditions: (a) (CH2OH)2, TsOH, benzene,
reflux, 99%; (b) TBDMS-Cl, imidazole, DMF, room temperature,
8
6%; (c) RuCl3, 70% t-BuOOH, H2O, cyclohexane, room tempera-
ture, 56% or CrO3, 3,5-dimethylpyrazole, CH2Cl2, -20 °C; (d)
NaBH , CeCl , THF-MeOH-CHCl , room temperature; (e) BH ,
THF, 0 °C, then 30% H2O2, NaOH; (f) 80% aqueous AcOH, room
temperature, 70%, three steps; (g) 2,2-dimethoxypropane, CSA,
room temperature, 85%; (h) EtPPh3Br, t-BuOK, toluene, 91%; (i)
4
3
3
3
5
complex and exhibits a better biological activity profile.
For example, in a rodent model of allergen-induced lung
inflammation, IPL576,092 (2) at an oral dose of 5 mg/kg
caused an 80% inhibition of the inflammatory response,5d
whereas contignasterol at an oral dose of 50 mg/kg in
this model caused a 60% inhibition of the response.5e In
8
0% acetic acid, 98%.
in vitro studies, IPL576,092 showed a significant reduc-
tion in the release of mediators of inflammation, includ-
ing Tumor Necrosis Factor R (TNFR), hexosaminidase,
2 2
Prostaglandin-D (PGD ), and Interleukin 5 (IL5). Fur-
(
1) Burgoyne, D.; Andersen, R. J .; Allen, T. M. J . Org. Chem. 1992,
7, 525.
2) (a) Bramley, A. M.; Langlands, J . M.; J ones, A. K.; Burgoyne,
D. L.; Li, Y.; Andersen, R. J .; Salari, H. Br. J . Pharmacol. 1995, 115,
433. (b) Langlands, J . M.; Hennan, J . K.; Bramley, A. M.; Pendleton,
thermore, a series of studies demonstrated that IPL576,-
092 has a biological profile distinct from glucocorticoids.
Currently in phase II human clinical trials, IPL576,092
displays a biological activity profile which justifies the
continuation of its evaluation as a potential new treat-
ment for asthma. Herein we report for the first time the
structure of IPL576,092 and an efficient, stereochemically
controlled synthetic sequence for its preparation.
5
(
1
N.; Burgoyne, D. L.; Anderson, R. J .; Salari, H. Am. J . Respir. Crit.
Care Med. 1995, 151, A700.
(
3) Bramley, A. M.; Langlands, J . M.; Burgoyne, D. L. Drugs Future
994, 19(8), 738.
4) Takei, M.; Burgoyne, D.; Andersen, R. J . J . Pharm. Sci. 1994,
3, 1234.
5) (a) Kuriakose, N. et al. 57th Annual Meeting of the American
Academy of Allergy, Asthma, & Immunology, New Orleans, LA, March
6-21, 2001; Mosby: St. Louis, 2001; Abstract 326. (b) Langlands, J .
1
(
8
(
The synthesis of 2 from 5-androsten-3â-ol-17-one (3)
is summarized in Scheme 1. Treatment (benzene, reflux)
1
et al. 57th Annual Meeting of the American Academy of Allergy,
Asthma, & Immunology, New Orleans, LA, March 16-21, 2001;
Mosby: St. Louis, 2001; Abstract 327. (c) Kasserra, C. et al. 57th
Annual Meeting of the American Academy of Allergy, Asthma, &
Immunology, New Orleans, LA, March 16-21, 2001; Mosby: St. Louis,
of the ketone 3 with ethylene glycol in the presence of
p-toluenesulfonic acid (TsOH)6 provided the required
ketal 4 (99% yield). Subsequently, the OH group was
protected as the TBDMS ether 5 by treatment of the
alcohol 4 with tert-butyldimethylsilyl chloride (TBDMS-
2
001; Abstract 1027. (d) Kasserra, C. et al. Keystone Asthma Sympo-
sium, Incline Village, NV, J an 1999; Keystone Symposia: CO, 1999.
e) Langlands, J . et al. Am. J . Respir. Crit. Care Med. 1996, 153(4),
A222.
(
(6) Zhou, Q.; Li, Z. Synth. Commun. 1993, 23, 1473.
1
0.1021/jo0108717 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3909
Cl) and imidazole in N,N-dimethylformamide (DMF).7
The allylic oxidation of the C7 position of the steroidal
silyl ether ethylene ketal 5 was achieved using two
different methods. In one method, shown in Scheme 1, a
mixture of compound 5, ruthenium chloride hydrate,
water, and cyclohexane8 was treated by the dropwise
addition of tert-butyl hydroperoxide at room temperature,
to give the enone 6 in 56% yield. Another method that
was employed in the oxidation of the C7 position involved
the use of chromium trioxide-dimethylpyrazole in me-
of the double bond were determined using coupling
constants and ROESY experiments. The stereochemistry
at C3 is not modified during the synthetic process.
Therefore, IPL576,092 (2) has the same 3âOH configu-
ration as the starting material androstenolone. The
1
complex resonance at δ 3.48 ppm in the H NMR
spectrum assigned to the hydrogen attached to C3 is
consistent with the 3âOH configuration. The coupling
1
constants for the resonances in the H NMR spectrum of
IPL576,092 (2) assigned to H6 (δ 3.13 ppm, dd, J ) 8.6,
10.7 Hz) and H7 (δ 3.01 ppm, dd, J ) 8.6, 10.6 Hz) are
consistent with trans diaxial relationships between H5
and H6, H6 and H7, and H7 and H8. Thus, the config-
uration of the hydroxyl groups at C6 and C7 can be
assigned as R and â, respectively. An observed ROESY
correlation between the resonance at δ 1.66 (C21) and
the resonance assigned to one of the C12 methylene
hydrogens (δ 2.28) supports the Z configuration of the
17(20) double bond.
9
thylene chloride to afford compound 6 in 65% yield (85%
based on recovered starting material). This method,
however, uses a 10-fold excess of chromium trioxide-
dimethylpyrazole and, therefore, is not scalable. Stereo-
selective 1,2-reduction of the enone carbonyl function of
6
using sodium borohydride-cerium trichloride in THF-
10
MeOH-CHCl
3
produced the 7â-alcohol 7.
Introduction of the 6R-hydroxyl group was achieved by
treating compound 7 with a 1.0 M solution of BH in
3
THF, followed by oxidative workup to furnish the diol 8.
Both the ketal and TBDMS protecting groups in steroid
In conclusion, we have described a highly efficient
synthesis of the novel anti-asthma agent IPL576,092 (2),
with stereoselective 1,2-reduction of the enone carbonyl
functionality of 6 and subsequent hydroboration as the
key steps. Starting from the 5-androsten-3â-ol-17-one 3,
this approach affords IPL576,092 in nine steps with
overall yields of 25% and only involves three column
chromatography purifications. The synthesis described
herein provides the basis for developmental efforts
toward the commercial-scale synthesis of this potential
new treatment of asthma.
8
were then removed in a one-step process, by treatment
with 80% acetic acid over 3 h to give the triol 9 in 70%
1
yield over three steps. The H NMR spectrum of com-
pound 9 shows a coupling constant between H-6 (δ 3.16
ppm (dd, J ) 8.2, 8.2 Hz)) and H-7 ((δ 3.10 ppm (dd, J )
8
.2, 8.2 Hz)) consistent with a trans diaxial relationship
between these hydrogens and a 6ROH, 7âOH configura-
tion. Reaction of triol 9 with 2,2-dimethoxypropane in
DMF in the presence of camphorsulfonic acid (CSA)
produced compound 10 in 85% yield. The 17-keto steroid
1
9
0 was converted to (Z)-17(20)-ethylidene steroid 11 in
1% yield via the Wittig reaction using toluene as
Exp er im en ta l Section
1
1
Gen er a l Con sid er a tion s. THF, toluene, and Et
dried by distillation over Na/benzophenone under an argon
atmosphere. CH Cl was dried over CaH and distilled before
2
O were
solvent. The use of Wittig olefination in the preparation
of (Z)-17(20)-ethylidene steroids has been previously
demonstrated.12 A ROESY correlation between the reso-
nances assigned to the methyl group at C21 (δ 1.69) and
H12 (δ 2.20) in compound 11 is consistent with the Z
configuration. Approximately 2% of the C20 E isomer is
observed in some of the reactions. Ensuring that the
addition of compound 10 to the Wittig reagent is carried
out at 0 °C using an ice bath minimizes the quantity of
E isomer. Finally, the acetonide moiety in 11 was
hydrolyzed in aqueous 80% acetic acid to afford the
desired IPL576,092 (2) in 98% yield.
2
2
2
use. EtPPh Br was dried by azeotropic distillation with benzene.
3
The starting material 5-androsten-3â-ol-17-one (3) was obtained
from Sigma-Aldrich Fine Chemicals. Unless otherwise noted, all
other starting materials and solvents were obtained from
commercial suppliers and used without further purification. H
and C NMR, ROESY, TOCSY, COSY, HSQC, and HMBC
1
13
spectra were obtained using a Varian Mercury 300 instrument.
Analytical thin-layer chromatography was performed on E.
Merck silica gel 60 F254 plates, and flash chromatography was
performed on 230-240 mesh silica gel.
5
-An d r osten -3â-ol-17-on e Eth ylen e Keta l (4). 5-Andros-
ten-3â-ol-17-one (3; 20.07 g, 69.37 mmol), p-TsOH (501.3 mg,
2.64 mmol), ethylene glycol (20 mL), and benzene (200 mL) were
refluxed under a Dean-Stark trap for 4.5 h. The mixture was
cooled to room temperature, diluted with ether (200 mL), and
One- and two-dimensional NMR experiments were
used to assign the carbon and hydrogen resonances
associated with the intermediates, including compound
washed with saturated NaHCO
saturated NaCl solution (2 × 100 mL). The organic phase was
dried (MgSO ) and evaporated to dryness, giving 4 (22.80 g, 99%)
as a white solid: R
300 MHz, CDCl
3
solution (2 × 100 mL) and
1
1 and the final product IPL576,092 (2). COSY and
TOCSY experiments were used to identify the hydrogen
spin systems within the molecule, and direct and long-
range hydrogen-carbon connectivities were determined
using HSQC and HMBC experiments. The relative
stereochemistry of the hydroxyl groups and the geometry
4
1
f
) 0.25 (2:1 hexanes-ethyl acetate); H NMR
) δ 5.35 (m, 1H), 3.88 (m, 4H), 3.52 (m, 1H),
.34-2.16 (m, 2H), 2.00 (m, 2H), 1.82 (m, 2H), 1.78-1.17 (m,
(
2
1
3
13
2H), 1.02 (m, 2H), 1.01 (s, 3H), 0.86 (s, 3H); C NMR (75 MHz,
) δ 140.8, 121.6, 119.6, 71.8, 65.3, 64.7, 50.7, 50.1, 45.9,
2.4, 37.4, 36.7, 34.4, 32.3, 31.8, 31.4, 30.7, 22.9, 20.6, 19.6, 14.4.
CDCl
3
4
Anal. Calcd for C21
H, 9.84.
5-An d r osten -3â-ol-17-on e Eth ylen e Keta l ter t-Bu tyld i-
m eth ylsilyl Eth er (5). 5-Androsten-3â-ol-17-one ethylene ketal
(4; 22.50 g, 67.77 mmol), imidazole (11.25 g, 165.4 mmol), DMF
(120 mL), and CH Cl (120 mL) were treated with tert-butyldi-
2 2
methylsilyl chloride (15.75 g, 104.5 mmol) for 6 h. The mixture
was diluted with ether (675 mL) and washed with 5% aqueous
32 3
H O : C, 75.86; H, 9.70. Found: C, 76.00;
(
7) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6
4
190. Salmond, W. G.; Barta, M. A.; Havens, J . L. J . Org. Chem. 1978,
3, 2056.
(8) Miller, R. A.; Li, W.; Humphrey, G. R. Tetrahedron Lett. 1996,
3
4
1
7, 3429.
(9) Salmond, W. G.; Barta, M. A.; Havens, J . L. J . Org. Chem. 1978,
3, 2056.
(10) Kumar, V.; Amann, A.; Ourisson, G.; Luu, B. Synth. Commun.
987, 17, 1279. McDonald, R. N.; Steppel, R. N.; Dorsey, J . E. Org.
HCl solution (2 × 135 mL), saturated NaHCO
3
solution (2 ×
Synth. 1970, 50, 15.
11) For reviews of the Wittig reaction, see: Maercker, A. Org. React.
965, 14, 270. Maryanoff, B. E.; Reitz. A. B. Chem. Rev. 1989, 89, 863.
12) Houston, T. A.; Tanaka, Y.; Koreeda, M. J . Org. Chem. 1993,
8, 4287.
1
35 mL), and saturated NaCl solution (2 × 135 mL). The organic
(
phase was dried (MgSO ) and evaporated to dryness. The residue
4
1
(
was then crystallized from methanol-ethyl acetate (3:2, 165 mL)
and afforded 5 (25.84 g, 86%) as a white solid: R ) 0.30 (19:1
5
f

3
910 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
1
hexanes-ethyl acetate); mp 121-122 °C; H NMR (300 MHz,
(2 × 200 mL). To this residue was added diethyl ether (400 mL),
and the mixture was vigorously stirred for 1 h. The resulting
white precipitate was collected by filtration, giving the compound
9 (16.87 g) as a white solid. The filtrate was then chromato-
graphed over a silica gel column with ethyl acetate as eluent
(1000 mL), followed by a 85:15 ethyl acetate-methanol solution
(2000 mL), to afford additional compound 9 (6.40 g). The
precipitate (16.87 g) and the compound purified by chromatog-
CDCl
3
) δ 5.31 (m, 1H), 3.88 (m, 4H), 3.48 (m, 1H), 2.33-2.12
m, 2H), 1.99 (m, 2H), 1.85-1.16 (m, 13H), 0.99 (m, 2H), 0.98
s, 3H), 0.88 (s, 9H), 0.85 (s, 3H), 0.05 (s, 6H); C NMR (75 MHz,
) δ 141.6, 121.1, 119.6, 72.6, 65.3, 64.7, 50.7, 50.1, 45.9,
2.9, 37.5, 36.8, 34.4, 32.3, 32.2, 31.4, 30.7, 26.1, 22.9, 20.6, 19.6,
8.4, 14.4, -4.2. Anal. Calcd for C27 Si: C, 72.59; H, 10.38.
Found: C, 72.89; H, 10.61.
-An d r osten -7,17-d ion e-3â-ol 17-Eth ylen e Keta l ter t-Bu -
tyld im eth ylsilyl Eth er (6). Meth od a . Chromium trioxide
10.2 g, 0.102 mol) was ground with a mortar and pestle before
use and then added to an argon-purged flask, followed by CH
Cl (60 mL). The mixture was stirred and cooled to -20 °C. 3,5-
Dimethypyrazole (9.81 g, 0.102 mmol) was added, and the
mixture was stirred at -20 °C for 1.5 h. 5-Androsten-3â-ol-17-
one ethylene ketal tert-butyldimethylsilyl ether (5; 4.56 g, 0.0102
mol) was added, and the thick, dark mixture was stirred under
argon at -20 °C for 16 h. The mixture was diluted with diethyl
ether (500 mL) and filtered through a pad of Celite to remove
the muddy brown-red precipitate. The filtrate was washed with
(
(
1
3
CDCl
3
4
1
46 3
H O
5
raphy (6.40 g) were combined. The overall yield for the conver-
1
sion of 6 to 9 was 70%: R
MHz, CD
3.10 (dd, J ) 8.2, 8.2 Hz, 1H), 2.40 (dd, J ) 8.1, 19.5 Hz, 1H),
f
) 0.05 (ethyl acetate); H NMR (300
(
3
OD) δ 3.47 (m, 1H), 3.16 (dd, J ) 8.2, 8.2 Hz, 1H),
2
-
1
3
3
2.35-0.95 (m), 0.90 (s, 3H), 0.89 (s, 3H); C NMR (75 MHz, CD -
2
OD) δ 224.3, 80.9, 75.8, 71.7, 53.5, 52.6, 49.3, 41.9, 38.5, 36.9,
36.8, 33.2, 32.7, 31.8, 25.8, 21.8, 14.4, 13.8. Anal. Calcd for
C
19
H
30
O
4
‚H
2
O: C, 70.39; H, 9.63. Found: C, 70.46; H, 9.59.
5r-An d r ost a n -17-on e-3â,6r,7â-t r iol 6,7-a cet on id e (10).
5R-Androstan-3â,6R,7â-triol-17-one (9; 11.13 g, 0.0345 mol), (1S)-
(+)-10-camphorsulfonic acid (445.7 mg, catalytic), and 2,2-
dimethoxypropane (445 mL) were stirred at room temperature
for 2 h. The mixture was diluted with ethyl acetate (890 mL)
water (2 × 200 mL), dried (MgSO
4
), and evaporated to dryness.
The resulting residue was chromatographed (gradient: 49:1, 9:1,
:1 hexanes-ethyl acetate) to give enone 6 (3.05 g, 65%) as a
white solid and starting material 5 (0.91 g, 20%).
and washed with saturated NaHCO
saturated NaCl solution (2 × 445 mL). The organic layer was
dried (MgSO ) and evaporated to dryness. The residue was
3
solution (2 × 445 mL) and
4
4
chromatographed over silica gel (126 g) with 5:1 hexanes-ethyl
acetate (650 mL), which was discarded, and then with 1:1
hexanes-ethyl acetate (1.6 L). The second fraction was evapo-
rated to dryness, affording the acetonide 10 (10.6 g, 85%) as a
white solid: R
f
) 0.20 (1:1 hexanes-ethyl acetate); mp 201-
2
1
1
02 °C; 1H NMR (300 MHz, CDCl
3
) δ 3.62 (m, 1H), 3.23 (dd,
H, J ) 8.1, 10.8 Hz), 3.11 (dd, 1H, J ) 8.7, 10.2 Hz), 2.42 (m,
H), 2.21-1.98 (m, 4H), 1.90-1.63 (m, 8H), 1.63-1.00 (m), 1.41
3
(
s), 1.39 (s), 0.92 (s, 3H), 0.90 (s, 3H), 0.84 (m); 1 C NMR (75
MHz, CD
3
OD) δ 221.0, 109.5, 85.0, 78.4, 70.6, 52.9, 50.3, 47.7,
6.1, 38.8, 37.4, 37.3, 35.9, 32.8, 31.6, 30.9, 27.3, 27.3, 23.8, 20.6,
4.8, 14.0. Anal. Calcd for C22 ‚0.25H O: C, 72.00; H, 9.48.
4
1
H
34
O
4
2
Found: C, 72.01; H, 9.45.
5
r-P r ogest-17(20)-en e-3â,6r,7â-tr iol 6,7-Aceton id e (11).
A flask was charged with EtPPh Br (23.66 g, 21.24 mmol),
3
t-BuOK (7.15 g, 63.72 mmol), and a stir bar under argon. Toluene
(150 mL) was added via syringe, and the suspension was stirred
for 1 h at room temperature. The reaction mixture was cooled
to 0 °C with an ice bath, and a solution of the ketone 10 (7.70 g,
2
1.24 mmol) in toluene (150 mL) was added. The ice bath was
removed, and the reaction mixture was stirred at room temper-
ature under argon for 24 h. Water (150 mL) was added slowly,
and the product was extracted with EtOAc (900 mL). The
combined organic layers were washed with brine, dried over
MgSO
gel with 2:1 hexane-ethyl acetate gave compound 11 as a white
solid (7.20 g, 91%): R ) 0.20 (7:3 hexanes-ethyl acetate); mp
56-157 °C; H NMR (300 MHz, benzene-d ) δ 5.23 (m, 1H),
4
, and evaporated to dryness. Chromatography over silica
f
1
1
3
8
1
6
.34 (m, 1H), 3.32 (dd, 1H, J ) 8.9, 11.5 Hz), 3.05 (dd, 1H, J )
.9, 10.7 Hz,), 2.51-2.10 (m, 4H), 1.66-0.49 (m), 1.69 (m, 3H),
.47 (s, 3H), 1.46 (s, 3H), 0.85 (s, 3H), 0.67 (s, 3H); 13C NMR (75
MHz, benzene-d
6
) 149.5, 114.0, 109.1, 85.6, 78.9, 70.5, 55.2, 52.9,
6.5, 44.5, 39.1, 37.6, 37.5, 37.2, 33.4, 32.2, 31.5, 27.7, 27.5, 27.0,
1.6, 17.1, 14.8, 13.6. Anal. Calcd for C24 ‚0.75H O: C,
4.28; H, 10.26. Found: C, 74.36; H, 10.47.
r-P r ogest-17(20)-en e-3â,6r,7â-tr iol (2). 5R-Progest-17(20)-
4
2
7
H
38
O
3
2
5
ene-3â,6R,7â-triol 6,7-acetonide (11; 1.44 g, 3.87 mmol), acetic
acid (18.2 mL), and water (4.6 mL) were stirred at room
temperature for 3 h. The mixture was then concentrated in vacuo
and triturated in EtOAc and methyl tert-butyl ether to afford
pure compound 2 (1.25 g, 98%) as a white solid: R
f
) 0.40 (9:1
ethyl acetate/methanol); mp 183-184 °C; H NMR (300 MHz,
CD
1
3
OD) δ 5.12 (m, J ) 7.2 Hz, 1H), 3.48 (m, 1H), 3.13 (dd, J )
8
2
3
.3, 10.7, 1H), 3.01 (t, J ) 9.2 Hz, 1H), 2.31 (m, 2H), 2.16 (m,
H), 1.95 (m, 1H), 1.751-1.26 (m, 10H), 1.64 (bd, J ) 7.2 Hz,
1
3
H), 1.12 (m, 2H), 0.92 (s, 3H), 0.88 (s, 3H), 0.85 (m, 1H);
C
NMR (75 MHz, CD
5
1
3
OD) δ 150.7, 114.6, 80.9, 75.9, 71.7, 57.6,
3.7, 49.3, 46.1, 41.8, 38.5, 38.4, 36.7, 33.2, 31.8, 28.3, 22.8, 17.6,
3.9, 13.7. Anal. Calcd for C21 : C, 75.41; H, 10.25. Found:
34 3
H O
C, 75.49; H, 10.28.
next reaction without further purification.
Su p p or tin g In for m a tion Ava ila ble: Spectrometric in-
formation ( H and C NMR) for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
5
r-An d r osta n -17-on e-3â,6r,7â-tr iol (9). The crude com-
1
13
pound 8 (46.80 g), acetic acid (320 mL), and water (80 mL) were
stirred at room temperature for 3 h. The mixture was then
concentrated in vacuo and azeotroped to dryness with methanol
J O0108717