3
6d
10 (-β-OH)
10 (-β-OH)
MeOH
95.0:5.0
mixture of product and unreacted material was inseparable on
silica gel chromatography. Recrystallization provided pure
product with unacceptable loss of product.9 Another route
involves dehydrogenation and double bond migration. The
oxidation of estrone 1 or its methyl ether 1-Me with DDQ
smoothly provided ∆-9,11 product 13 and 13-Me.10 However,
the acid-catalyzed double bond migration according to reported
methods11 only provided an equilibrium mixture (∆-9,11:∆-8,9 =
9:1). Purification procedure was also proved to be laborious and
quite difficult on large-scale.
MeOH
(10oC)
95.0:5.0
(80% conv.)
7
a substrate: 0.2 mmol, solvent: 2 mL, rt, 1 h.
b HPLC yield.
c Raney Ni as catalyst(500 mg), 70 oC, 5 h.
d Optimal condition.
With practical protocols in hand, we turned to the synthesis of
equilenin and its derivatives. The ∆-6-estrogen 7 were
synthesized on 10-gram scale in four steps with 59% of overall
yield from commercially available 19-hydroxyandrost-4-ene-
3,17-dione 6.5a,b The oxidation of ∆-6-estrogen 7 with DDQ
offered pure 8 in high yield. The reduction of ketone 8 with
NaBH4 offered the 17-β-hydroxy product 10 as the sole product.
Under optimized condition, precursor 10 was hydrogenated to
give pure 10a in 83% yield after recrystallization from MeCN.
Oxidation of the 17-hydroxyl group followed by deprotection
yielded the equilenin 2 in good yield. Spectroscopic data of the
synthetic sample were identical to the reported values.
Demethylation of 8a provided 17-β-dihydroequilenin 4. 17-α-
dihydroequilenin 5 was synthesized from 8a via hydroxyl
inversion as our previously reported method.5c
O
O
HO
a,b,c,d
Scheme 3. Unsuccessful routes from estrone
In this work, we report a practical and robust route for the
semisynthesis of highly pure equilenin and its derivatives from
inexpensive 19-hydroxyandrost-4-ene-3,17-dione 6. The key
intermediate ∆-14-equilenin methyl ether 8 can be efficiently
prepared with high purify and high yield. Based on the method,
three active ingredients in Premarin, equilenin 2, 17-β-
52% in 4 steps
O
O
7
6
O
OH
e
f
dihydroequilenin
synthesized.
4
and 17-α-dihydroequilenin 5, were
85%
99%
O
O
8
10
Acknowledgments
O
OH
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20902098).
h
g
H
H
83%
90%
O
O
References and notes
8a
10a
1. The active ingredients in Premarin are the sulfate of the estrogens. (a)
Hsieh, R. W.; Rajan, S. S.; Sharma, S. K.; Greene, G. L., Steroids
2008, 73 (1), 59-68; (b) Ritter, S., Chem Eng News 2005, 83 (25), 100-
100.
j,k,l,i
i, 88%
i, 90%
71% in 4 steps
O
OH
2. (a) Bachmann, W. E.; Cole, W.; Wilds, A. L., J. Am. Chem. Soc. 1939,
61, 974-975; (b) Bachmann, W. E.; Cole, W.; Wilds, A. L., J. Am.
Chem. Soc. 1940, 62, 824-839; (c) Johnson, W. S.; Petersen, J. W.;
Gutsche, C. D., J. Am. Chem. Soc. 1947, 69 (12), 2942-2955; (d)
Johnson, W. S.; Stromberg, V. L., J. Am. Chem. Soc. 1950, 72 (1),
505-510; (e) Cohen, N.; Banner, B. L.; Blount, J. F.; Tsai, M.; Saucy,
G., J. Org. Chem. 1973, 38 (19), 3229-3239; (f) Daniewski, A. R.;
Kowalczykprzewloka, T., J. Org. Chem. 1985, 50 (16), 2976-2980; (g)
Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M., Tetrahedron Lett.
1999, 40 (5), 907-910.
OH
H
H
H
HO
HO
HO
Equilenin 2
4
5
Scheme 2. Reagents and conditions: (a) Ac2O, DMAP, 30min, (b)
chloranil, t-BuOH, reflux, 1h, (c) DDQ, dioxane, reflux, 1h, (d)
HC(OMe)3, TsOH, MeOH, 60oC, 30 min, (e) DDQ, toluene, rt,1h, (f)
NaBH4,MeOH/THF, rt, 20 min, (g) Pd/C, H2, MeOH, rt, 1h, (h)
Al(OiPr)3, cyclohexanone, toluene, reflux, 3h, (i) BBr3, DCM, 0oC,
30 min, (j) C4F9SO2F,DBU, (k) DBU, AcOH, 40oC, 1h, (l) K2CO3,
MeOH.
3. (a) Bachmann, W. E.; Dreiding, A. S., J. Am. Chem. Soc. 1950, 72 (3),
1323-1329; (b) Choppinet, P.; Jullien, L.; Valeur, B., Chem. Eur. J.
1999, 5 (12), 3666-3678.
4. (a) Dirscherl, W.; Hanusch, F. Z. Physiol. Chem., 1935, 233, 131; (b)
Kaufmann, S.; Pataki, J.; Rosenkranz, G.; Romo, J.; Djerassi, C., J. Am.
Chem. Soc. 1950, 72 (10), 4531-4534; (c) Hylarides, M. D.; Wilbur, D.
S.; Mettler, F. A., Steroids 1983, 41 (5), 657-662; (d) Cao, Z. S.; Liehr,
J. G., Synth. Commun. 1997, 27 (1), 145-155; (e) Rosenkranz, G.;
Djerassi, C.; Stkaufmann; Pataki, J.; Romo, J., Nature 1950, 165
(4203), 814-815; (f) Hoehn, W. M.; Dorn, C. R.; Nelson, B. A., J. Org.
Chem. 1965, 30 (1), 316-&.
Other possible methods for preparing intermediate 8 from
estrone were investigated, but none proved satisfactory. The
direct dehydrogenation of estrone 1 and its methyl ether 1-Me
were reported to provide isoequilenin and its methyl ether,
respectively.3,8 We found that most of materials (>80%) were
consumed in 3h with an equal weight of Pd/C at 250oC. However,
the conversions were less than 95% after 20h. Unfortunately, the
5. (a) Zheng, D.-Q.; Jing, Y.; Zheng, B.-Y.; Ye, Y.-F.; Xu, S.; Tian, W.-
S.; Ma, H.-Y.; Ding, K., Tetrahedron 2016, 72 (17), 2164-2169; (b)
Jing, Y.; Xu, C.-G.; Ding, K.; Lin, J.-R.; Jin, R.-H.; Tian, W.-S.,