A practical and facile route for the preparation of 18-norandrostan-17- ones from androstan-17-ones using SmI2-promoted cyclization and dehydroxylation

Full text of DOI:10.1021/jo991906u

J . Org. Chem. 2000, 65, 3555-3557
3555
Sch em e 1a
A P r a ctica l a n d F a cile Rou te for th e
P r ep a r a tion of 18-Nor a n d r osta n -17-on es
fr om An d r osta n -17-on es Usin g
Sm I2-P r om oted Cycliza tion a n d
Deh yd r oxyla tion
Xin J iang, Cunde Wang, Yuefei Hu,* and Hongwen Hu
Department of Chemistry, Nanjing University,
Nanjing 210093, People’s Republic of China
a
Conditions: (a) NH2OH‚HCl/NaOAc, reflux in EtOH, 2 h; (b)
DCC-DMSO/CF3CO2H, rt, overnight.
Douglas F. Covey*
Sch em e 2a
Department of Molecular Biology and Pharmacology,
Washington University School of Medicine, St. Louis,
Missouri 63110
Received December 13, 1999
Because of their utility in biological research, signifi-
cant effort has been made to develop synthetic routes to
18-norsteroids.1 Although previous routes to 18-nor-17-
ketosteroids have been published,2 there remains a need
for a more efficient and practical route for the laboratory-
scale synthesis of these steroids from commercially
available 17-ketosteroid precursors. Herein, we report a
novel synthetic route that satisfies this need. The route
has been applied to the synthesis of the C-13 epimers of
(3R,5R)- and (3â,5R)-3-hydroxy-18-norandrostan-17-ones
(14-17).
A significant drawback to the “abnormal” Beckmann
rearrangement route to 18-nor-17-ketosteroids, which
proceeds via alkene-nitrile rearrangement products (e.g.,
3 and 4, Scheme 1), has been the lengthy reaction
sequence required for the reconstruction of the 18-
norandrostan-17-one D-ring.2h Realizing that products 3
and 4 are readily converted into ketone-nitriles 5 and 6,
this drawback can be obviated by application of newly
developed intramolecular ketone-nitrile reductive cou-
pling reactions.3-6 SmI2 effects intramolecular ketone-
nitrile reductive coupling reactions to give R-hydroxyke-
tones and can also reduce these products to their
corresponding ketones.7,8 Hence, these two SmI2-pro-
a
Conditions: (a) O3/Me2S, -78 °C, 91% for 5 and 86% for 6; (b)
SmI2/BuOH-t, irradiation, 0-10 °C, 3 h, 79% for 7 and 66% for
8/9; (c) SmI2/MeOH, rt, 10 min, 93% for 10/11 and 91% for 12/13;
(d) NaOH(aq)/MeOH, rt, 2 h, 98% for 14/15 and 96% for 16/17.
moted reactions make possible an expeditious route from
abnormal Beckmann rearrangement products to 18-nor-
17-ketosteroids.
(1) See, for example: (a) Corey, E. J .; Virgil, S. C. J . Am. Chem.
Soc. 1990, 112, 6429. (b) Meyer, A. I.; Elworthy, T. R. J . Org. Chem.
1992, 57, 4732. (c) Bi, H.; Messe, R.; J ust, G. Steroids 1992, 57, 306.
(d) Corey, E. J .; Virgil, S. C.; Cheng, H.; Baker, C. H.; Matsuda, S. P.
T.; Singh, V.; Sarshar, S. J . Am. Chem. Soc. 1995, 117, 11819. (e) Corey,
E. J .; Daley, D. C.; Cheng, H. Tetrahedron Lett. 1996, 37, 3287. (f)
Nagaya, H.; Itokawa, S.; Takeya, K. J pn. Kokai Tokkyo Koho J P 09
221,496, Aug 26, 1997; Chem. Abstr. 1997, 127, 268012p.
(2) (a) J ohnson, W. S.; Bannister, B.; Pappo, R. J . Am. Chem. Soc.
1956, 78, 6331. (b) J ohns, W. F. J . Am. Chem. Soc. 1958, 80, 6456. (c)
Stork, G.; Khastgir, H. N.; Solo, A. J . J . Am. Chem. Soc. 1958, 80,
6457. (d) Yorka, K. V.; Truett, W. L.; J ohnson, W. S. J . Org. Chem.
1962, 27, 4580. (e) Chapman, J . C.; Pinhey, J . T. Aust. J . Chem. 1974,
27, 2421. (f) Engel, Ch. R.; Lachance, P.; Capitaine, J .; Zee, J .;
Mukherjee, D.; Merand, Y. J . Org. Chem. 1983, 48, 1954. (g) Davioud,
E.; Schambel, P.; Viger, A.; Marquet, A. Steroids 1993, 58, 141. (h)
Han, M.; Covey, D. F. J . Org. Chem. 1996, 61, 7614. (i) Kuhl, A.; Karele,
H.; Kreiser, W. Helv. Chim. Acta 1999, 82, 30.
Accordingly, the commercially available (3R,5R)-3-
(benzoyloxy)androstan-17-one 17-oxime (1) and (3â,5R)-
3-(acetyloxy)androstan-17-one 17-oxime (2) were con-
verted into their corresponding alkene-nitriles 3 and 4,
respectively (Scheme 1).2e,2h As shown in Scheme 2,
ozonolysis of compounds 3 and 4 at -78 °C yielded
ketone-nitriles 5 (91%) and 6 (86%), respectively. Fol-
lowing the general procedure of Molander,7c compound
5 or 6 was combined with SmI2 in THF and irradiated
with a 500-W lamp. Typically, the reductive coupling
reactions finished in ∼3 h at 0-10 °C. Under these
(3) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
(4) Clive, D. L. J .; Beaulieu, P. L.; Set, L. J . Org. Chem. 1984, 49,
1313.
(5) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J .
Org. Chem. 1992, 57, 7175.
(6) (a) Yamamoto, Y.; Matsumi, D.; Itoh, K. Chem. Commun. 1998,
875. (b) Yamamoto, Y.; Matsumi, D.; Hattori, R.; Itoh, K. J . Org. Chem.
1999, 64, 3224.
(7) (a) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111,
8236. (b) Kraus, G. A.; Sy, J . O. J . Org. Chem. 1989, 54, 77. (c)
Molander, G. A.; Wolfe, C. N. J . Org. Chem. 1998, 63, 9031.
(8) (a) Molander, G. A.; Hahn, G. J . J . Org. Chem. 1986, 51, 1135.
(b) White, J . D.; Somers, T. C. J . Am. Chem. Soc. 1987, 109, 4424. (c)
Holton, R. A.; Williams, A. D. J . Org. Chem. 1988, 53, 5981. (d) Castro,
J .; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericas, M. A.;
Greene, A. E. J . Am. Chem. Soc. 1990, 112, 9388.
10.1021/jo991906u CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/02/2000

3556 J . Org. Chem., Vol. 65, No. 11, 2000
Notes
[1S-(1r,4aâ,4br,7â,8aâ,10ar)]-7-(Ben zoyloxy)tetr adecah y-
d r o-4b -m et h yl-2-oxo-1-p h en a n t h r en ep r op a n en it r ile (5).
Ozone was passed through a solution of compound 3 (11.0 g,
28.1 mmol) in methanol (180 mL) and dichloromethane (20 mL)
at -78 °C until a blue color persisted. The excess ozone was
removed by a stream of oxygen. After dimethyl sulfide (10.4 mL,
140.5 mmol) was added, the mixture was allowed to warm to
room temperature and was stirred for 1 h. The solvent was
removed to give a residue, which was purified by chromatogra-
phy [silica gel, 20% EtOAc in petroleum ether (60-90 °C)] to
yield 10.1 g (91%) of compound 5 as a colorless oil: IR 2230,
conditions, ketone-nitrile 5 gave only R-hydroxyketone
product 7 in 79% yield. The 13â-hydroxy epimer of
compound 7 was not found. By contrast, ketone-nitrile 6
gave a mixture (65%) of the epimeric R-hydroxyketone
products 8 and 9 in a ratio of 7:1 (R:â).
Dehydroxylation of isolated R-hydroxyketone 7 was
achieved in 93% yield using SmI2 in THF at room
temperature for 10 min. The dehydroxylation product
was an epimeric mixture of the 13R-H product 10 and
the 13â-H product 11 in a ratio of 5:4. Similarly, dehy-
droxylation of R-hydroxyketone 8 or 9, or the mixture of
these compounds, gave a mixture of products 12 (13R-
H) and 13 (13â-H) in excellent yield (91%). These
epimeric products are expected because the SmI2-
promoted reduction of R-hydroxyketones proceeds via an
enolic intermediate.8a The epimeric products 10/11 and
12/13 are separated easily by chromatography.
As expected, saponification of either the pure 13R-H
epimer 10 or the pure 13â-H epimer 11 with aqueous
NaOH solution in methanol at room temperature gave,
in high yield (98%), a mixture of epimerization products
14 (13R-H) and 15 (13â-H). Similarly, either ester 12 or
ester 13 upon saponification gave a mixture of epimer-
ization products 16 (13R-H) and 17 (13â-H). Whereas for
characterization purposes we separated the epimeric
products formed during the dehydroxylation and saponi-
fication steps, there is no practical advantage to separat-
ing the epimers formed after the dehydroxylation step.
Hence, these two steps can be conveniently combined in
a one-pot reaction, as described in the Experimental
Section.
The stereochemistry for the C,D-ring fusion at C-13
in 18-norsteroids is generally assigned on the basis of
NMR spectroscopic data. For compounds 8 and 14, we
used single crystal X-ray diffraction analysis to establish
unambiguously the structures of these compounds (see
Supporting Information). The structures of compounds
9-13 and 15-17 were based on the crystallographic
results obtained for compounds 8 and 14. The fact that
enolization of the 18-nor-17-ketosteroids prepared herein
always gave the 13R-H epimers as the major products
indicates that the cis-C,D-ring fusion is more stable than
the trans-C,D-ring fusion. This conclusion is in agreement
with literature data on the stability of fused rings of this
type.9
1705 cm-1 1H NMR δ 8.08 (d, J ) 7.3, 2H), 7.58 (t, J ) 7.3,
;
1H), 7.48 (t, J ) 7.3, 2H), 5.32 (d, J ) 2.6, 1H), 0.81 (s, 3H); MS
m/z (%) 393 (M+, 0.2), 105 (100). Anal. Calcd for C25H31NO3: C,
76.30; H, 7.94; N, 3.56. Found: C, 76.57; H, 7.90; N, 3.62.
[1S-(1r,4a â,4br,7r,8a â,10a r)]-7-(Acetyloxy)tetr a d eca h y-
d r o-4b -m et h yl-2-oxo-1-p h en a n t h r en ep r op a n en it r ile (6).
Compound 6 was obtained as white crystals in 86% yield (3.47
g) from compound 410 (4.0 g, 12.2 mmol) using the above-
described ozonolysis procedure: mp 99.5-101 °C [from EtOAc/
petroleum ether (60-90 °C)], lit.10 mp 95 °C; IR 2280, 1731, 1700
cm-1; 1H NMR δ 4.72 (m, 1H), 2.05 (s, 3H), 0.78 (s, 3H); MS m/z
(%) 331 (M+, 2.1), 43 (100). Anal. Calcd for C20H29NO3: C, 72.48;
H, 8.82; N, 4.23. Found: C, 72.48; H, 8.78; N, 4.29.
(3r,5r,13r)-3-(Ben zoyloxy)-13-h ydr oxy-18-n or an dr ostan -
17-on e (7). To a slurry of Sm powder (1.5 g, 10.0 mmol) was
added a solution of I2 (1.48 g, 6.0 mmol) in THF (60 mL) by
syringe under Ar. The resultant slurry was stirred at room
temperature for 2 h. After a dark blue SmI2 solution was formed,
the mixture was cooled to 0 °C, and a solution of compound 5
(786 mg, 2.0 mmol) and tert-butyl alcohol (296 mg, 4.0 mmol) in
THF (20 mL) was added. The reaction mixture was irradiated
with a lamp (500 W) at 0-10 °C for 3 h and monitored by TLC.
The excess Sm was filtered off, and most of the solvent was
removed. Then 3% aqueous HCl (100 mL) was added, and the
solution was extracted with CH2Cl2. The combined organic layers
were washed successively with 5% aqueous NaHCO3 and H2O
and dried over Na2SO4. The solvent was removed to give a
residue that was purified by chromatography [silica gel, 15%
EtOAc in petroleum ether (60-90 °C)] to yield compound 7 (626
mg, 79%) as colorless crystals: mp 148.5-150 °C (Et2O/
petroleum ether); IR 3400, 1738, 1707 cm-1; 1H NMR δ 8.06 (d,
J ) 7.5, 2H), 7.57 (t, J ) 7.5, 1H), 7.47 (t, J ) 7.5, 2H), 5.28 (s,
1H), 2.48 (m, 1H), 0.69 (s, 3H); MS m/z (%) 396 (M+, 47.9), 256
(50.4), 105 (100). Anal. Calcd for C25H32O4: C, 75.73; H, 8.13.
Found: C, 75.67; H, 8.33.
(3â,5r,13r)-3-(Acetyloxy)-13-h yd r oxy-18-n or a n d r osta n -
17-on e (8) a n d (3â,5r,13â)-3-(Acetyloxy)-13-h yd r oxy-18-
n or a n d r osta n -17-on e (9). Compounds 8 and 9 as a mixture
were obtained in 66% yield from compound 6 (662 mg, 2.0 mmol)
using the procedure reported for the preparation of compound
7. The products were separated by chromatography [silica gel,
15% EtOAc in petroleum ether (60-90 °C)] to give the 13R-
hydroxy epimer 8 (348 mg, 57%) and the 13â-hydroxy epimer 9
(59 mg, 9%).
Compound 8: mp 121-123 °C (from Et2O/petroleum ether);
IR 3315, 1724 cm-1; 1H NMR δ 4.68 (m, 1H), 2.44 (m, 1H), 2.01
(s, 3H), 0.66 (s, 3H); MS m/z (%) 334 (M+, 100), 278 (48.9), 222
(42.7). Anal. Calcd for C20H30O4: C, 71.83; H, 9.04. Found: C,
71.89; H, 9.02.
In summary, a practical method for the laboratory-
scale preparation of 18-nor-17-ketosteroids from 17-
ketosteroids has been developed. The reaction sequence
proceeds via ozonolysis of an abnormal Beckmann rear-
rangement product followed by SmI2-promoted intra-
molecular ketone-nitrile reductive coupling and dehy-
droxylation reactions. The synthetic route features ac-
cessible starting materials, a short reaction sequence,
simple procedures, and high overall yields (51-62%).
Compound 9: mp 162-164 °C (from Et2O/petroleum ether);
1
IR 3455, 1718 cm-1; H NMR δ 4.68 (1H, m), 2.53 (dd, J ) 8.6
and 19.4, 1H), 2.01 (s, 3H), 0.84 (s, 3H); MS m/z (%) 334 (M+,
100), 278 (42.3), 274 (50.4), 256 (72.3). Anal. Calcd for
C20H30O4: C, 71.83; H, 9.04. Found: C, 72.06; H, 9.16.
Exp er im en ta l Section
(3r,5r,13r)-3-(Ben zoyloxy)-18-n or a n d r osta n -17-on e (10)
an d (3r,5r,13â)-3-(Ben zoyloxy)-18-n or an dr ostan -17-on e (11).
To a slurry of Sm powder (600 mg, 4.0 mmol) was added a
solution of I2 (762 mg, 3.0 mmol) in THF (30 mL) by syringe
under Ar. The resultant slurry was stirred at room temperature
for 2 h. The resultant dark blue SmI2 solution was treated with
a solution of compound 7 (393 mg, 1.0 mmol) and anhydrous
MeOH (2.0 mL) in THF (10 mL). After 10 min at room
temperature, the reaction solution was poured into saturated
The 1H NMR spectra were recorded on a Bruker ACF-500
spectrometer with TMS as the internal reference. The J values
are given in hertz. The MS spectra were obtained on a ZAB-HS
mass spectrometer with 70 eV. Steroids 3 and 4 were prepared
according to a standard procedure for performing the abnormal
Beckmann rearrangement on steroid 17-oximes.2e
(9) (a) Allinger, N. L.; Hermann, R. B. J . Org. Chem. 1960, 25, 922.
(b) House, H. O.; Rasmusson, G. H. J . Org. Chem. 1963, 28, 31.
(10) Diatta, L.; Longevialle, P. Bull. Soc. Chim. Fr. 1973, 1159.

Notes
J . Org. Chem., Vol. 65, No. 11, 2000 3557
aqueous NaHCO3 and extracted with EtOAc. The combined
organic layers were washed with H2O and dried over Na2SO4.
The solvent was removed to give a residue that was purified
and separated by chromatography [silica gel, 5% Et2O in
petroleum ether (60-90 °C)] to give compounds 10 and 11 (93%)
as a mixture in a ratio of 5:4.
J ) 8.9 and 18.9, 1H), 0.76 (s, 3H); MS m/z (%) 276 (M+, 100),
258 (50.4), 243 (65.0). Anal. Calcd for C18H28O2: C, 78.22; H,
10.21. Found: C, 78.35; H, 10.17.
(3â,5r,13r)-3-Hyd r oxy-18-n or a n d r osta n -17-on e (16) a n d
(3â,5r,13â)-3-Hyd r oxy-18-n or a n d r osta n -17-on e (17). Com-
pounds 16 and 17 (530 mg, 96.0%) were obtained from a mixture
of compounds 12 and 13 (636 mg, 2.0 mmol) by the same
procedure used for the preparation of compounds 14 and 15. The
products were separated by chromatography [silica gel, 25%
EtOAc in petroleum ether (60-90 °C)].
Compound 10 (52%): mp 125-127 °C (from petroleum ether);
1
IR 1728, 1705 cm-1; H NMR δ 8.06 (d, J ) 7.5, 2H), 7.57 (t, J
) 7.5, 1H), 7.46 (t, J ) 7.5, 2H), 5.28 (s, 1H), 0.69 (s, 3H); MS
m/z (%) 258 (100), 243 (31.9), 105 (36.5). Anal. Calcd for
C25H32O3: C, 78.92; H, 8.48. Found: C, 79.21; H, 8.29.
Compound 11 (41%): mp 43-46 °C (foam); IR 1732, 1701
cm-1; 1H NMR δ 8.05 (d, J ) 7.5, 2H), 7.54 (t, J ) 7.5, 1H), 7.46
(t, J ) 7.5, 2H), 5.29 (s, 1H), 2.38 (dd, J ) 8.5 and 18.6, 1H),
0.83 (s, 3H); MS m/z (%) 258 (100), 243 (39.0), 105 (93.4). Anal.
Calcd for C25H32O3: C, 78.92; H, 8.48. Found: C, 78.95; H, 8.66.
(3â,5r,13r)-3-(Acetyloxy)-18-n or an dr ostan -17-on e (12) an d
(3â,5r,13â)-3-(Acetyloxy)-18-n or an dr ostan -17-on e (13). Com-
pounds 12 and 13 were obtained as a mixture in 91% yield from
the mixture of 8 and 9 (334 mg) by the same procedure used to
prepare compounds 10 and 11. They were separated by chro-
matography [silica gel, 5% Et2O in petroleum ether (60-90 °C)].
Compound 12 (56%): mp 100-103 °C (from petroleum ether),
lit.2e mp 104-105 °C.
Compound 16 (58%): mp 169-171 °C (Et2O/petroleum ether);
IR 1721 cm-1; 1H NMR δ 3.59 (m, 1H), 0.66 (s, 3H); MS m/z (%)
276 (M+, 100), 258 (14.9), 243 (20.5). Anal. Calcd for C18H28O2:
C, 78.22; H, 10.21. Found: C, 78.47; H, 9.98.
Compound 17 (38%): mp 152-155 °C (Et2O/petroleum ether);
1
IR 3430, 1735 cm-1; H NMR δ 3.61 (m, 1H), 2.36 (dd, J ) 8.3
and 18.5, 1H), 0.80 (s, 3H); MS m/z (%) 276 (M, 100), 258 (23.7),
243 (25.7). Anal. Calcd C18H28O2: C, 78.22; H, 10.21. Found: C,
78.01; H, 10.25.
On e-P ot P r oced u r e for Deh yd r oxyla tion a n d Sa p on i-
fica tion . After the Sm-promoted dehydroxylation of 9 was
complete (10 min) as described by the above procedure, a
saturated aqueous solution of NaHCO3 (1 mL) was added to
quench the reaction, followed by MeOH (10 mL) and NaOH (1.0
g) dissolved in water (2.0 mL). The mixture was stirred for 2 h
at room temperature (monitored by TLC) and neutralized with
2 N aqueous HCl. The product mixture was extracted with
EtOAc, and the combined organic layers were washed with brine
and dried over Na2SO4. The solvent was removed to give crude
compounds 14 and 15 as a mixture, which was separated and
characterized by the previously described procedure.
Similarly, a mixture of compounds 10 and 11 was dehydroxy-
lated and saponified in a one-pot procedure to give compounds
16 and 17.
Compound 13 (35%): mp 145-147 °C (from petroleum ether),
lit.2e mp 147-149 °C.
(3r,5r,13r)-3-Hyd r oxy-18-n or a n d r osta n -17-on e (14) a n d
(3r,5r,13â)-3-Hydr oxy-18-n or an dr ostan -17-on e (15). A stirred
solution of epimers 10 and 11 (380 mg, 1.0 mmol) in MeOH (20
mL) was treated with a solution of NaOH (500 mg) in water
(1.0 mL) at room temperature for 2 h. The solution was
neutralized with 2 N aqueous HCl. The product mixture was
extracted with EtOAc, and the combined organic layers were
washed with brine and dried over Na2SO4. The solvent was
removed to give a residue that was purified and separated by
chromatography [silica gel, 25% EtOAc in petroleum ether (60-
90 °C)] to give compounds 14 and 15 (270 mg, 98%).
Ack n ow led gm en t. We are grateful to the Education
Ministry of China for financial support.
Compound 14 (58%): mp 168-170 °C (Et2O/petroleum ether);
IR 3455, 1720 cm-1 1H NMR δ 4.04 (d, 1H, J ) 1.7), 0.63 (s,
;
3H); MS m/z (%) 276 (M+, 44.0), 258 (36.5), 243 (41.6), 41 (100).
Anal. Calcd for C18H28O2: C, 78.22; H, 10.21. Found: C, 77.99;
H, 10.08.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
for compounds 8 and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
Compound 15 (40%): mp 158-160 °C (Et2O/petroleum ether);
1
IR 3465, 1720 cm-1; H NMR δ 4.05 (d, 1H, J ) 2.3), 2.36 (dd,
J O991906U