s t e r o i d s 7 1 ( 2 0 0 6 ) 908910

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/steroids

A regioselective cyanohydration of steroidal 17-ketones

and the conguration of the resulted cyanohydrins
Bei Na Zhang a , Min Qin Chen b , Ying Chen a , Qian Zhang a , Peng Xia a,
a
b

Department of Medicinal Chemistry, Pharmacy School, Fudan University, Shanghai 200032, China
Research Centre of Analysis and Measurements, Fudan University, Shanghai 200433, China

a r t i c l e

i n f o

a b s t r a c t

Article history:

Cyanohydration of some 17-keto steroids with 4-en-3-one or 1,4-dien-3-one unit showed

Received 29 April 2006

high regioselectivity to give 17-cyanohydrins with high yields when the reaction was car-

Received in revised form

ried out under acetone cyanohydrin/K2 CO3 in aq. MeOH. The crystal X-ray exhibited the

14 June 2006

conguration of resulted cyanohydrins were depended on the structure of substrates.

Accepted 22 June 2006

2006 Elsevier Inc. All rights reserved.

Published on line 4 August 2006

Keywords:
Cyanohydration
17-Cyano-17-ol
17-Cyano-17-ol

1.

Introduction

The preparation of cyanohydrins has a great potential in

organic synthesis. On one hand, its a common procedure
for protection of carbonyl group since cyanohydration is a
reversible reaction and the produced cyanohydrins are quite
easily regenerate to ketones. On the other hand, the introduced cyano- and hydroxy-moieties are two new reactive sites
which could be converted to diverse molecules.
Cyanohydration of carbonyl compounds generally leads to
a pair of epimers [13]. Its not a question when using it as a
protective method. However, when this reaction is applied as
a strategy to synthesize a stereospecic target molecule, the
conguration of the resulted cyanohydrin is very crucial.
The availability of 17-keto steroids by biodegradation of
side chain-saturated sterols has made them ideal starting
materials for synthesis of progestins and corticosteroids, both
of which contain 17-two carbon side chain [46]. 17-cyano17-ol steroids produced from the corresponding 17-ketones
are attractive precursors for building and elongation of these

Corresponding author. Tel.: +86 21 54237563; fax: +86 21 54237563.

E-mail address: pxia@shmu.edu.cn (P. Xia).

0039-128X/$ see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2006.06.004

two carbon side chains [7]. For these synthetic strategies, many
efforts have been made to obtain 17-cyano-17-ol steroids
stereospecically.
Nitta reported the cyanohydration of androst-4-en-3,17dione with acetone cyanohydrin/K2 CO3 in aq. MeOH could give
17-cyano-17-hydroxyandrost-4-en-3-one with high regioand stereoselectivity [8]. We expanded this method to a
series of steroidal 17-ketones which would be considered
as key intermediates for synthesis of progestins and corticosteroids. The experiments showed the different substrates
offered 17-cyanohydrins with different congurations. 19Norandrost-4-en-3,17-dione (1) and 11-hydroxyandrost-1,4dien-3,17-dione (2) gave the desired 17-cyano-17-ol product
(5) and (6), respectively. On the contrary, androst-1,4-dien3,17-dione (3) offered 17-cyano-17-ol product (7). The congurations of the products were determined by X-ray diffraction. The reaction of these substrates could give quantitative
yields with high regio- and stereoselectivity. All these results
demonstrated that in comparison with androst-4-en-3,17dione, some structural characters such as the 19-demethyl,

s t e r o i d s 7 1 ( 2 0 0 6 ) 908910

909

Fig. 1 Structures of 1, 2, 3, 4 and the 17-cyanohydrins 5, 6, 7.

additional 1,2-en and 11-hydroxy can accommodate this reaction. However, the 17-ketone steroid with 9(11)-en,androst1,4,9(11)-3,17-dione (4), gave a mixture of 17-cyano-17-ol,
17-cyano-17-ol products and starting 17-ketone (4) which
were difcult to separate and purify by simple crystallization
(Fig. 1).

2.

Experimental

2.1.

Materials and analysis

All reagents and solvents used were of analytical grade.

All reactions were monitored by TLC (silica H, Petroleum
ether/ethyl acetate, 10:3, v/v and benzene/acetone, 3:1, v/v).
Melting points were determined in open capillary tubes and
are uncorrected. X-ray data was measured on a Enraf-Nonius
CAD-4 diffractometer using graphite-monochromated Mo K
All diagrams and calculations were
radiation (l = 0.71073 A).
performed using omega/2-theta scans. The structure was
solved by direct method with SHELXS-97 (Sheldrick, 1990)
and rened by a full-matrix least-square method on F2 with
SHELXS-97 (Sheldrick, 1997). The X-ray diffraction of compounds 5, 6 and 7 is shown in Fig. 2.

2.2.

Synthesis

General procedure: 17-keto steroid (25.0 mmol) was mixed

with acetone cyanohydrin (11 mL) and methanol (12 mL). The
reaction became homogeneous after 15 min at room temperature. Then an aqueous solution of potassium carbonate
(potassium carbonate/water, 205 mg/30 mL) was added and a
white slurry developed. The mixture was heated at 4550 C
with stirring for 5 h, cooled to room temperature, ltered and
stirred with 2 N HCl (150 mL) for 0.5 h. The mixture was ltered
again and dried. The solid material is recrystallized from ethyl
acetate to give colorless crystal for X-ray diffraction.

2.2.1. 17-Cyano-17-hydroxy-19-norandrost-4-en-3one (5)

Yield: 87.62%, mp: 220222 C.
Crystallographic data for the structure of compound 5 has
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 610433.

Fig. 2 The X-ray diffraction of compound 5, 6 and 7.

910

s t e r o i d s 7 1 ( 2 0 0 6 ) 908910

Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
C44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Data of
the analysis are follows: C19 H25 NO2 , M = 299.40, crystal size
0.50 mm 0.40 mm 0.30 mm, Orthorhombic, space group
= 90 , = 90 ,
P212121, a = 7.123(5), b = 14.282(3), c = 16.273(4) A,

3
, Z = 4, Dcalcd = 1.201 Mg/m3 , (Mo

= 90 , V = 1655.5(13) A
1
K) = 0.077 mm , measured temperature 295(2) K, reections collected 1853, independent reections 1727, R = 0.0662,
wR = 0.0997, GOF = 1.046.

2.2.2. 17-Cyano-11,17-dihydroxyandrost-1,4-dien-3one (6)

Yield: 94.44%, mp: 218222 C.
Crystallographic data for the structure of compound 6
has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
610434. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: C44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
Data of the analysis are follows: C20 H25 NO3 , M = 327.41,
crystal size 0.50 mm 0.25 mm 0.10 mm, monoclinic,

space group P2(1), a = 11.831(3), b = 6.0630(18), c = 13.250(3) A,

3 , Z = 2,
= 90.00(2) , = 115.260(17) ,
= 90.00(2) , V = 859.6(4) A
Dcalcd = 1.265 Mg/m3 , (Mo K) = 0.084 mm1 , measured temperature 295(2) K, reections collected 1941, independent
reections 1705, R = 0.0791, wR = 0.1192, GOF = 1.065.

2.2.3.

17-Cyano-17-hydroxyandrost-1,4-dien-3-one (7)

Yield: 90.40%, mp: 178181 C.

Crystallographic data for the structure of compound 7 has
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 610347.
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
C44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Data of
the analysis are follows: C20 H25 NO2 , M = 311.41, crystal size
0.30 mm 0.30 mm 0.20 mm, Orthorhombic, space group
= 90 , = 90 ,
P212121, a = 8.468(2), b = 11.715(6), c = 17.085(5) A,
3 , Z = 4, Dcalcd = 1.220 Mg/m3 , (Mo

= 90 , V = 1694.9(11) A
K) = 0.078 mm1 , measured temperature 298(2) K, reections collected 1930, independent reections 1754, R = 0.1168,
wR = 0.1260, GOF = 1.017.

3.

Results and discussion

It is well known that the cyanohydration of carbonyl group

is a reversible reaction and generally produce two congu-

rational epimers. In the cyanohydration of 17-keto steroids,

17-cyano-17-ols are the kinetic products. The reason
of quantitative conversion to stereospecic products 5, 6
and 7 in the reaction mentioned above was due to the
great difference solubility between two epimers in reaction
media, the monocongurational products were precipitated
from reaction solution completely by an appropriate time
equilibrium.
Unfortunately, despite many endeavors have been made,
we failed to nd a suitable reaction media and condition for
the stereospecic cyanohydration of androst-1,4,9(11)-trien3,17-dione (4). In different concentration of aq. methanol, or a
series organic solvents using Et3 N as basic catalyst, the reaction could not be completed and the products were complicated.
In summary, we explored the method to synthesize 17cyano-17-ol products 5, 6 and 17-cyano-17-ol product
7 with high yields by a convenience procedure. The 17cyano-17-ol products 5, 6 will be used as key precursors
for synthesizing progestins and corticosteroids. Although
the 17-cyano-17-ol product 7 was a reverse epimer contrary to our wishes, the high yield and stereoselectivity of the reaction may still have signicance in organic
synthesis.

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