Oppenauer-Type Oxidation of 3â-Hydroxy Steroids
Table 1, entry 6). The alcohols 1e and 1f were easily
oxidized to androstenedione (2e) and 17R-methyltest-
osterone (2f), respectively, in good yields and clean
J . Org. Chem., Vol. 61, No. 19, 1996 6589
(
) 6Hz, 3H), 0.864 (dd, J ) 9, 3 Hz, 6H), 1.187-0.943 (several
m, 8H), 0.713 (s, 3H); 13C NMR δ 199.66, 171.69, 123.72, 56.07,
5.84, 53.78, 42.36, 39.60, 39.47, 38.58, 36.09, 35.73, 35.67,
5.59, 33.97, 32.94, 32.02, 28.16, 27.99, 24.16, 23.79, 22.81,
2.55, 21.00, 18.62, 17.36, 11.93.
5
3
2
manner with either of the catalytic systems 3/K
(Table 1, entries 7-10).
Finally, the corticoid substrate 1g reacted slowly and
2 3
CO or
4
(
24R)-24-Eth ylch olesta -4,22-d ien -3-on e (2b). Oxidation
of (24R)-24-ethylcholesta-5,22-dien-3â-ol (1b, 413 mg, 1.0
mmol) with 4 (5.4 mg, 0.0050 mmol) in acetone (10 mL) for 16
h gave 366 mg (89%) of the product after flash chromatography
was mainly recovered when using the catalytic system
with complex 3. In the presence of catalyst 4, this
compound was converted to a mixture of cortexolone
acetate (2g) and the isomeric 5,6-unsaturated ketone.
These two isomers were easily separated by chromatog-
raphy, and the product 2g was obtained in good yield
(
2 2
CH Cl /ether, 20:1). The spectral data of 2b agree with those
2
1 1
reported: H NMR δ 5.712 (s, 1H), 5.139 (dd, J ) 15, 8.4 Hz,
1
4
1
H), 5.008 (dd, J ) 15, 8.4 Hz, 1H), 2.423-2.263 (several m,
H), 2.048-1.980 (m, 3H), 1.848-1.371 (several m, 10H),
.284-0.888 (several m, 8H), 1.175 (s, 3H), 1.009 (d, J ) 6.5
(Table 1, entry 11). It is important to mention that,
13
Hz, 3H), 0.848-0.770 (complex m, 9H), 0.719 (s, 3H); C NMR
δ 199.64, 171.66, 138.12, 129.40, 123.73, 55.95, 55.85, 53.80,
42.24, 40.48, 39.49, 38.59, 35.67, 35.58, 33.97, 32.93, 32.01,
under our reaction conditions, no rearrangement to the
1
3
6
-membered D-ring was observed.
3
1
1.86, 28.87, 25.40, 24.23, 21.15, 21.10, 20.99, 18.97, 17.37,
2.25, 12.13.
P r egn -4-en e-3,20-d ion e (2c). Oxidation of 3-â-hydroxy-
pregn-5-en-20-one (1c, 119 mg, 0.376 mmol) with 3 (1.8 mg,
In summary, a mild and efficient procedure was
developed for the catalytic oxidation of steroids. Acetone,
which is inexpensive and unreactive toward most organic
functional groups, acts both as solvent and as hydrogen
acceptor in this homogeneous hydrogen transfer reaction.
Employing this method, only a catalytic amount (e1 mol
0
2 3
.0019 mmol) and K CO (5.2 mg, 0.0376 mmol) in acetone (3
mL, containing 0.6% of water) for 24 h gave 96 mg (81%) of
the product after flash chromatography (CH Cl /ether, 10:1).
2
2
%
) of the ruthenium complex is necessary. Moreover,
The product was characterized by comparison with an au-
thentic sample:22 1H NMR δ 5.738 (s, 1H), 2.562-2.517 (m,
under these mild conditions, no side reactions or D-
homosteroid rearrangement occur and no decomposition
products were detected. Thus, the procedure described
offers significant advantages over previous oxidation
methods.
1
H), 2.481-2.146 (several m, 5H), 2.128 (s, 3H), 2.093-2.015
(m, 2H), 1.897-1.838 (m, 1H), 1.764-0.954 (complex m, 11H),
1
1
3
.192 (s, 3H), 0.673 (s, 3H); 13C NMR δ 209.21, 199.35, 170.84,
23.91, 63.47, 56.00, 53.62, 43.89, 38.64, 38.54, 35.70, 35.53,
3.92, 32.74, 31.86, 31.45, 24.33, 22.81, 20.99, 17.34, 13.30.
1
7â-(Ben zoyloxy)a n d r ost-4-en -3-on e (2d ). Oxidation of
1
7â-(benzoyloxy)androst-5-en-3â-ol (1d , 100 mg, 0.253 mmol)
Exp er im en ta l Section
with 4 (1.4 mg, 0.0013 mmol) in acetone (4 mL) for 20 h gave
87 mg (87%) of the product after flash chromatography (CH
Cl /ether, 10:1). The spectral data of 2d agree with those
Gen er a l Meth od s. Melting points were determined on a
2
-
Kofler block and are uncorrected. NMR spectra were recorded
2
using a Varian 300 spectrometer, 1H at 300 MHz
23 1
in CDCl
3
reported: H NMR δ 8.035 (dd, J ) 7.5, 1.5 Hz, 2H), 7.555
(tt, J ) 7.5, 1.5 Hz, 1H), 7.437 (t, J ) 7.5 Hz, 2H), 5.735 (s,
1H), 4.848 (t, J ) 7.8 Hz, 1H), 2.430-2.252 (several m, 5H),
2.064-1.992 (m, 1H), 1.905-1.845 (m, 2H), 1.762-1.555
(several m, 5H), 1.490-1.363 (m, 2H), 1.310-1.048 (several
1
3
1
and C at 75.4 MHz with chloroform-d
C) as internal standard. Yields are given for isolated product
1
(δ 7.26, H; δ 77.0,
1
3
showing one spot on a chromatographic plate and no impurities
detectable in the NMR spectrum. The identity of the products
was checked by comparing their mp, IR and NMR spectra, and
TLC behavior with those of authentic samples. All reactions
were performed in oven-dried glassware, under an atmosphere
of nitrogen. Solvents and solutions were transferred by
syringe-septum and cannula techniques. Acetone (Baker,
grade reagent) was used without further purification and was
degassed by bubbling through a stream of nitrogen for 10 min
prior to cannula transfer. The steroids 1a -g are commercially
available from Sigma, Merck, and Steraloids. The ruthenium
complex 3 was purchased from Strem Chem, and complex 4
1
3
m, 3H), 1.201 (s, 3H), 1.035-0.910 (m, 1H), 0.980 (s, 3H);
C
NMR δ 199.44, 170.91, 166.43, 132.80, 130.57, 129.47, 128.30,
123.93, 82.92, 53.66, 50.24, 42.84, 38.58, 36.68, 35.66, 35.38,
33.90, 32.71, 31.46, 27.63, 23.58, 20.51, 17.38, 12.26.
An dr ost-4-en e-3,17-dion e (2e). Oxidation of 3â-hydroxyan-
drost-5-en-17-one (1e, 200 mg, 0.69 mmol) with 4 (2 mg, 0.0017
mmol) in acetone (4 mL) for 24 h gave 162 mg (81%) of the
2 2
product after flash chromatography (CH Cl /ether, 10:1). The
2
4 1
spectral data of 2e agree with those reported: H NMR δ
5.731 (s, 1H), 2.508-2.284 (several m, 5H), 2.148-1.328
(several m, 10H), 1.197 (s, 3H), 1.309-0.929 (several m, 4H),
0.901 (s, 3H); 13C NMR δ 220.37, 199.26, 170.27, 124.09, 53.75,
50.77, 47.45, 38.58, 35.70, 35.64, 35.08, 33.86, 32.51, 31.21,
30.69, 21.70, 20.26, 17.33, 13.66.
1
9
was prepared according to a literature procedure.
Gen er a l P r oced u r e for Ru th en iu m -Ca ta lyzed Oxid a -
tion of Ster oid s by Aceton e. The substrate, catalyst 3, and
K CO , or the substrate and catalyst 4, were weighed into a
2 3
two-necked round bottom flask equipped with a condenser and
a magnetic stirring bar. The reaction system was purged with
nitrogen for 10 min, and then acetone (containing 0.6% of
water when using complex 3) was added via a cannula. The
17â-Hyd r oxy-17-m eth yla n d r ost-4-en -3-on e (2f). Oxida-
tion of 17â-hydroxy-17-methylandrost-5-en-3â-ol (1f, 200 mg,
0.66 mmol) with 4 (3.6 mg, 0.0033 mmol) in acetone (5 mL)
for 18 h gave 186 mg (93%) of the product after flash
o
resulting solution was refluxed (56 C) with stirring under
2 2
chromatography (CH Cl /ether, 5:1). The spectral data of 2f
2
5 1
nitrogen for the indicated time, until TLC showed the starting
material to be consumed. The reaction mixture was cooled
and the solvent evaporated. The resulting crude mixture was
then chromatographed on silica, using the solvent system
indicated, allowing isolation of the products.
agree with those reported: H NMR δ 5.711 (s, 1H), 2.421-
2.236 (several m, 4H), 2.057-1.984 (m, 1H), 0.855-1.870
(several m, 15H), 1.198 (s, 3H), 1.187 (s, 3H), 0.891 (s, 3H);
1
3
C NMR δ 199.56, 171.29, 123.80, 81.43, 53.74, 50.08, 45.29,
38.80, 38.62, 36.41, 35.68, 33.92, 32.80, 31.64, 31.36, 25.77,
2
2
3.17, 20.62, 17.36, 13.86.
21) Takatsuto, S.; Ikekawa, N. J . Chem. Soc., Perkin Trans. 1 1986,
Ch olest-4-en -3-on e (2a ). Oxidation of cholest-5-en-3â-ol
(
(
1a , 387 mg, 1 mmol) with 4 (5.4 mg, 0.0050 mmol) in acetone
(
5 mL) for 22 h gave 286 mg (74%) of the product after flash
269.
22) Duddeck, H.; Rosenbaum, D.; Hani, M.; Elgamal, A.; Fayez, M.
chromatography (CH
2 2
Cl /ether, 20:1). The spectral data of 2a
(
2
0 1
agree with those reported: H NMR δ 5.753 (s, 1H), 2.224-
B. E. Magn. Reson. Chem. 1987, 25, 25.
(23) Gravestock, M. B.; Morton, D. R.; Boots, S. G.; J ohnson, W. S.
J . Am. Chem. Soc. 1980, 102, 800.
2
2
.483 (several m, 4H), 2.048-1.951 (m, 2H), 1.876-1.745 (m,
H), 1.748-1.2191 (several m, 12H), 1.203 (s, 3H), 0.913 (d, J
(24) Kirk, D. N.; Toms, H. C.; Douglas, C.; White, K. A.; Smith, K.
E.; Latif, S.; Hubbard, R. W. P. J . Chem. Soc., Perkin Trans. 2 1990,
1567.
(25) Hayamizu, K.; Ishii, T.; Yanagisawa, M.; Kamo. O. Magn.
Reson. Chem. 1990, 28, 250.
(
19) Shvo, Y.; Menashe, N. Organometallics 1991, 10, 3885.
(20) Parish, E. J .; Honda, H.; Chitrakorn, S.; Livant, P. Lipids 1991,
2
6, 675.