Papers
metalhydrides, such as NaBH4, was known to give the
17-hydroxy product 2a because of steric hindrance from
the 18-methyl group in 1. There is only one example of the
reduction of the 17-oxo group in estrone methyl ether to a
17␣-hydroxy group by employing a chiral reducing agent
(diphenylsilane-Rh-(Ϫ)-diop) (vide infra).8 We wished to
avoid steric hindrance from the 18-methyl group in 1 by
using electron-transfer and protonation. Substrate 1 was
allowed to react with a sodium-methanol system, but the
same compound 2a was obtained as the sole product. Thus,
direct reduction of the 17-oxo group to a 17␣-hydroxy
group was not successful.
Next, nucleophilic inversion of stereochemistry at C-17
in 3 was carried out. Compound 2a was prepared by the
reduction of 17-oxo substrate 1 using NaBH4 in almost
quantitative yield and identified by the hydrolysis to 5␣-
androstane-3,17-diol (2b). Then p-toluenesulfonation of
2a gave 3. Substitution of the 17-p-toluenesulfonate group
in 3 with acetate anion yielded a mixture of the desired
17␣-acetate product and several by-products, results similar
to those in the literature. We had been attempting to obtain
4 selectively, but could not achieve this.
Above substitution reaction afforded a mixture of 4, 5a,
and 6 followed with small amounts of other compounds on
thin-layer chromatography, so transformation of by-product
6 to 5b was examined with epoxidation, reduction, and
hydrolysis. The reactions proceeded smoothly to give the
desired product 5b in good yield. That is, a reaction mixture
from substitution was exposed to epoxidation by peracetic
acid, reduction with sodium borohydride, and hydrolysis
with sodium hydroxide to yield the 17␣-hydroxy compound
5b in 55% yield after recrystallization from 3. Overall yield
of 5b from 1 was 54%, the best among the reported values.
The method described in this report has some advan-
tages: 1) isolation of the desired intermediate 4 from a
reaction mixture by column chromatography is not needed
because the crude mixture can be used for epoxidation and
reduction without loss of 4; 2) reduction and hydrolysis are
performed at the same time by use of the combination of
sodium borohydride and sodium hydroxide; and 3) after
reduction-hydrolysis, simple recrystallization affords the
desired product in pure form.
stereochemistry also results from steric hindrance by the
18-methyl group, which blocks hydride attack at C-17 in the
epoxide.
In conclusion, the 17␣-hydroxy product 5b could be
obtained through the epoxidation and reduction-hydrolysis
of the mixture formed by the reaction of 3 with acetate
anion without purification of the intermediate in good yield.
Purification by recrystallization was improved with cyclo-
hexane as well.
Acknowledgments
We thank Dr. Takayuki Yamashita for helpful discussions
during the course of this work. This work was partially
supported by a grant to RCAST at Doshisha University
from the Ministry of Education, Japan.
References
1.
Sokolov VE, Kagan MZ, Vasil’eva VS, Prihodko VI, Zinkevich EP
(1987). Musk deer (Moschus moschiferus): Reinvestigation of main
lipid components from preputial gland secretion. J Chem Ecol
13:71–83.
2.
3.
4.
5.
Morishita S, Mishima Y, Shoji M (1987). Pharmacological proper-
ties of musk. Gen Pharmacol 18:253–261.
Do JC, Kitatsuji E, Yoshii E (1975). Components of musk. I. Ether
soluble components. Chem Pharm Bull 23:629–635.
Han G, Huang G (1992). Synthesis of some musk androgens.
Zhongguo Yiyao Gongye Zazhi 23:301–303.
Han G-D, Lin Z-Y, Yan C-P (1994). Synthesis of musk androgen
5␣-androstane-3,17␣-diol. Zhongguo Yiyao Gongye Zazhi
25:490–491.
6.
7.
Bose AK, Lal B, Hoffman III WA, Mangas BS (1973). Steroids. IX.
Facile inversion of unhindered sterol configuration. Tetrahedron
Lett 14:1619–1622.
Henbest HB, Jackson WR (1962). The use of aprotic solvents for
nucleophilic substitution reactions at C(3) and C(17) in steroids.
J Chem Soc 954–959.
8.
Go¨ndo¨s G, Orr JC (1982). Reduction of steroid 17-ketones by
enantiomeric chiral reducing agents. J Chem Soc Chem Commun
1238–1239.
9.
Ohta T, Zhang H, Torihara Y, Furukawa I (1997). Improved syn-
thetic route to dexamethasone acetate from tigogenin. Org Proc Res
Dev 1:420–424.
10.
11.
Klyne W, Marshall-Jones P (1961). Optical rotatory dispersion. Part
II. 3-Monohydroxysteroids, 3,17-dihydroxysteroids, and their deriv-
atives. J Chem Soc 5415–5418.
Ruzicka L, Goldberg MW, Rosenberg HR (1935). Sexual hormone
X. Herstellung des 17-methyltestosterons und anderer androsten-
und androstanderivate. Zusammenha¨nge zwischen chemischer kon-
stitution und ma¨nnlicher Hormonwirkung. Helv Chim Acta 18:
1487–1498.
As shown in the Chart, the ␣ stereochemistry of the
12.
13.
Dictionary of Organic Compounds, 5th Ed., Vol. 1. (1982). Chap-
man and Hall, New York, A-02842, p. 353.
Ruzicka L, Goldberg MW, Bosshard W (1937). Sexual hormone
XXII. Herstellung von ⌬5-3-epi-Oxy-17-trans-oxy-androsten und
3-epi-Oxy-17-trans-oxy-a¨tio-cholan. Helv Chim Acta 20:541–547.
epoxide is expected because of steric hindrance to approach
of the peracid by the 18-methyl group. The 17␣-alcohol
632 Steroids, 1998, vol. 63, December