A one-step synthesis of 6β-hydroxy-Δ4-3-ketones. Novel oxidation of homoallylic sterols with permanganate ion

Full text of DOI:10.1021/jo960402i

J . Org. Chem. 1996, 61, 5665-5666
5665
A On e-Step Syn th esis of
6â-Hyd r oxy-∆4-3-k eton es. Novel
Oxid a tion of Hom oa llylic Ster ols w ith
P er m a n ga n a te Ion
Edward J . Parish* and Shengrong Li
Department of Chemistry, Auburn University,
Auburn, Alabama 36849
Received February 27, 1996
Steroids with 6â-hydroxy-∆4-3-ketone structural fea-
tures are of interest in metabolic studies and are known
metabolites of microbial and microsomal P-450 oxida-
tion.1 In addition, 6â-hydroxy steroids are key interme-
diates for the functionalization of the C-19 methyl group.2
Functionalization and subsequent modification at C-19
has previously yielded a large number and variety of
potent inhibitors of the enzyme aromatase (estrogen
synthetase).3,4 Aromatase inhibitors have potential phar-
maceutical value in the control of human breast cancer
and in the reduction of prostatic hyperplasia in man.5,6
There has been considerable interest in recent years
in the synthesis of â-epoxides on the steroid nucleus.7-10
Epoxidation with peroxyacids is known to produce pre-
dominantly the â-epoxide because of the steric hindrance
from the angular methyl groups at C-10 and C-13.
Prevailing methods for the synthesis of â-epoxides in-
clude the use of halohydrins as intermediates,2 the use
of 3R-halo substituents that block the entry of reagents
from the R-face,7,8 iodobenzene in the presence of chromyl
diacetate,10 ruthenium tetramesitylporphyrin,11,12 vana-
dium and molybdenum catalysts with alkyl hydroperox-
ides,13 dioxygen species,14 potassium peroxomonosulfate
in acetone,15 ferric acetylacetonate and hydrogen perox-
ide,16 and quaternary phosphonium or ammonium per-
tungstate and hydrogen peroxide.17 Among these meth-
ods, a mixture of KMnO4-CuSO4 in methylene chloride
has been found to be convenient and effectively provided
steroidal â-epoxides in high yields.18,19
F igu r e 1. The oxidation of homoallylic sterols with permang-
nate ion.
which is formed by water and tert-butyl alcohol over the
surface of the inorganic salt, in the epoxidation with
KMnO4-CuSO4 in methylene chloride and in the pres-
ence of water and tert-butyl alcohol.18 In contract to these
results, more hydrophilic substrates produced R-hydroxy
ketones or R-diketones as a predominant product.20 To
further explore this oxidizing reagent system we studied
its reaction with different homoallylic sterol substrates
(Figure 1). These results have further confirmed the
importance of substrate structure as a factor in product
formation.
Earlier â-epoxidations using this reagent system were
conducted on steroid esters.18,19 In the present study we
found that reaction with cholest-5-en-3â-ol (1) results in
the formation of 5â,6â-epoxycholestan-3â-ol (2) in 61%
yield (isolated), 20% unreacted starting material and 5%
5R,6R-epoxycholestan-3â-ol. However, using identical
reaction conditions, sterols with polar side chains gave
6â-hydroxy-∆4-3-ketones as reaction products. 17-Oxoan-
drost-5-en-3â-ol (3) gave 3,17-dioxoandrost-4-en-6â-ol (4)
in 45% isolated yield and 25% recovered starting mate-
rial. 20-Oxopregnen-5-en-3â-ol (5) gave 3,20-dioxopreg-
nen-4-en-6â-ol (6) in 55% isolated yield and 23% recov-
ered starting material. We have also investigated the
influence of other inorganic salts, in equimolar amounts,
which might replace copper sulfate and affect the yield
of the described products (Table 1). These results show
that other selected transition metal salts with noncoor-
dinating anions also give similar yields of products. In
the case of main group metal salts and transition metal
salts with coordinated anions, no product formation was
observed. These results may suggest that the face
selectivity of this oxidizing reagent system results from
the initial copper ion (or other metal ions) coordination
on the less hindered R-face of the double bond forming a
π-complex between the double bond and copper ion or
other metal ions. The following permanganate attack on
the â-face results in the â-epoxide. The formation of a
π-complex also weakens the double bond and makes the
permanganate attack possible. Apparently, the main
group metal ions and metal ions with coordinate anions
cannot form a π-complex with the double bond, so the
reaction will not proceed. Mechanistically, further rear-
This latter reagent system serves as a phase transfer
catalyst and is believed to function in the omega phase,
(1) Waxman, D. J . Biochem. Pharm. 1988, 37, 71-89.
(2) Fried, J .; Edwards, J . A. Organic Reactions in Steroid Chemistry;
Van Nostrand Reinhold: New York, 1972; Vol. 2, pp 1-42, 237-287.
(3) Wright, J . H.; Van Leersum, P. T.; Chamberlin, S. G.; Akhtar,
M. J . Chem. Soc., Perkin Trans. 1 1989, 1647.
(4) Burkhart, J . P.; Norton, P. P.; Wright, C. L.; J ohnston, J . O. J .
Med. Chem. 1991, 34, 1748.
(5) Wright, J . N.; Colder, M. R.; Akhtar, M. J . Chem. Soc., Chem.
Commun. 1985, 733.
(6) Henderson, D. Ann. Med. 1991, 23, 201.
(7) Shiota, M.; Ogihara, T.; Watonable, Y. Bull. Chem. Soc. J pn
1961, 34, 40.
(8) Hanson, J . H.; Trunech, A. J . J . Chem. Soc., Perking Trans. 1
1988, 2001.
(9) Muto, T.; Umehanra, J .; Miura, T.; Kimura, M. Chem. Pharm.
Bull. 1985, 33, 4749.
(10) Galagousky, L. R.; Gros, E. G. J . Chem. Res. (S) 1993, 137.
(11) Marchon, J . C.; Ramasseul, R. Synthesis 1989, 389.
(12) Groves, J . T.; Quinn, R. J . Am. Chem. Soc. 1985, 107, 5790.
(13) Sharpless, K. B.; Michaelson, R. C. J . Am. Chem. Soc. 1973,
95, 6136.
(14) Smith, L. L.; Kulig, M. J .; Miler, D.; Ansar, G. A. S. J . Am.
Chem. Soc. 1978, 100, 6206.
(15) Cicala, G.; Curci, R.; Fiorentino, M.; Laricchinta, O. J . Org.
Chem. 1982, 47, 2670.
(16) Tohma, M.; Tomita, T.; Kimura, M. Tetrahedron Lett. 1973,
4359.
(17) Prandi, I.; Kagan, H. B. Tetrahedron Lett. 1986, 27, 2617.
(18) Parish, E. J .; Li, H. and Li, S. Synth. Commun. 1995, 25, 927.
(19) Syamala, M. S.; Das, J .; Baskaran, S.; Chandrasekaran, S. J .
Org. Chem. 1992, 57, 1928.
(20) Baskaran, S.; Das, J .; Chandrasekaran, S. J . Org. Chem. 1989,
54, 5182.
S0022-3263(96)00402-1 CCC: $12.00 © 1996 American Chemical Society

5666 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
Ta ble 1. In flu en ce of Va r iou s In or ga n ic Sa lts on
â-Ep oxid a tion a n d 6â-Hyd r oxy ∆4-3-Keton e F or m a tion
w ith P er m a n ga n a te Ion a n d Ster oid a l Alk en es
1), 17-oxoandrost-5-ene-3â-ol (3), and 20-oxopregn-5-en-3â-ol (5)
were obtained from the Sigma Chemical Co. (St. Louis, MO).
Procedures for recording melting points (mp) and of infrared (IR),
1H-NMR, and mass (MS) spectra together with details concern-
ing column chromatography have been described.23 The de-
scribed reations were also carried out using equimolar amounts
of the salts shown in Table 1 to replace copper sulfate.
% yielda of
3â-hydroxy
5â,6â-epoxide
(alkene, 1b)
% yielda of
6â-hydroxy
∆4-3-ketone
(alkene, 3b)
% yielda of
6â-hydroxy
∆4-3-ketone
(alkene, 5b)
salt
5â,6â-Ep oxych olesta n -3â-ol (2). Oxidation of 1 (1.00 g 2.58
mmol) in CH2Cl2 (30 mL) with KMnO4 (6.0 g), CuSO4‚5H2O (3.0,
12.0 mmol), H2O (0.4 mL), and t-BuOH (1.5 mL) for 5 min reflux
and 8 h at 25 °C gave, after silica gel column chromatography
(solvent 15% ethyl ether in toluene), 5â,6â-epoxycholestan-3â-
ol (2) in 60% yield: mp 131-132 °C (lit.24 132 °C). IR (KBr)
3433.7, 2947.6, 1468.0, 1215 cm-1. MS (CI, NH3) 402.3 (36% M
- H2O + NH4+), 385.1 (100% M - H3O+). 1H NMR (250 MHz,
CDCl3) δ 0.65 (3H, 18-CH3), 1.05 (3H, 19-CH3), 3.11 (1H, d, J )
1.92 Hz, 6R-H), 5.03 (1H, m, 3R -H); 13C NMR (250 MHz, CDCl3)
δ 71.90 (C-3), 63.54 (C-5), 62.54 (C-6), 56.21, 50.95, 42.29, 39.80,
39.49, 38.09, 37.24, 36.66, 36.14, 35.71, 35.11, 32.50, 29.76, 28.13,
27.98, 27.32, 24.9, 23.81, 22.78, 22.54, 21.93, 18.67, 17.07, 11.75.
3,17-Dioxoa n d r ost-4-en -6â -ol (4). Oxidation of 3 (0.75 g,
2.6 mmol) in CH2Cl2 with the same procedure as the oxidation
of 1 gave, after silica gel column chromatography (solvent 25%
ethyl ether in toluene), 3,17-dioxoandrost-4-en-6â-ol (4) in 45%
yield: mp 194-195 °C (lit.21 mp 194-195 °C). MS (EI) 302.0
CuSO4‚5H2O
61
60
60
65
0
0
0
0
0
45
41
42
49
0
0
0
0
0
55
50
50
57
0
0
0
0
0
Cu(NO3)2‚3H2O
CoSO4‚7H2O
Ni(NO3)2‚6H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
MgSO4‚7H2O
CaSO4‚2H2O
Al2(SO4)3‚18H2O
a
b
Yield of isolated and purified product. Steroidal alkenes:
1,cholest-5-en-3â-ol; 3, 17-oxoandrost-5-en-3â-ol; 5 , 20-oxopregnen-
5-en-3â-ol.
rangement may occur via the concomitant â-epoxidation
of the ∆5 double bond and oxidation of the 3â-hydroxy
group, followed by epoxide ring opening and proton
elimination at C-4 to yield the ∆4 unsaturated ketone.
Several synthetic methods have been reported for the
synthesis of steroidal 6â-hydroxy-∆4-3-ketones, but yields
were moderate to low.21,22 The oxidation with perman-
ganate ion provides an alternative and streamlined
synthesis of this type of structure in one step from
commercially available starting materials.
1
(1.06% M+). IR, H, 13C NMR data were identical to literature
values.25
3,20-Dioxop r egn -4-en -6â-ol (6). Oxidation of 5 (0.82 g, 2.60
mmol) in CH2Cl2 (3.0 mL) with the same procedure as the
oxidation of 1 gave, after silica gel column chromatography
(solvent 20% ethyl ether in toluene), 3,20-dioxopregn-4-en-6â-
ol (6) in 55% yield: mp 175-177 °C (lit.21 mp 174-177 °C). MS
(CI, NH3) 348.2 (14.9%, M + NH4+), 331.2 (26% M + H+). IR,
1H, 13C NMR data were identical to literature values.25
Exp er im en ta l Section
J O960402I
Meth od s a n d Ma ter ia ls. Potassium permanganate, copper
sulfate, and tert-butyl alcohol were obtained from the Aldrich
Chemical Co. (Milwaukee, WI). Cholest-5-en-3â-ol (cholesterol,
(23) Parish, E. J .; Kizito, S. A.; Peng, J .; Heidepriem, R. W.; Livant,
P. Chem. Phys. Lipids 1995, 76, 129.
(24) Chicoye, E.; Powrie, W. D.; and Fennema, O. Lipids 1968, 3,
355.
(21) Gardt, R.; Lusingnani, J . Org. Chem. 1967, 32, 2647.
(22) Chaudhrt, R.; Cooley, G.; Coulson, W. F. Steroids 1978, 31, 495.
(25) Kirk, D. N.; Toms, H. C.; Douglas, C.; White, K. A. J . Chem.
Soc., Perkin Trans. 2 1990, 1567.