Stereospecific synthesis of drospirenone

Article abstract of DOI:10.1002/cjoc.201201147

A procedure for the stereospecific synthesis of drospirenone has been developed. The key steps included the stereospecific reduction of the C ⁷-tertiary alcohol with ZnI₂/Et₃SiH, a novel mild and stereospecific tertiary alcohol reduction system, and the tandem oxidation/cyclopropanation reactions. Copyright

Full text of DOI:10.1002/cjoc.201201147

COMMUNICATION
DOI: 10.1002/cjoc.201201147
Stereospecific Synthesis of Drospirenone†
Gang Deng,a Zuogang Huang,b Xiaolong Zhao,a Zheng Li,c Yuanchao Li,*,c and Biao Jiang*,a,b
a Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
b Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
c Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shang-
hai 201203, China
A procedure for the stereospecific synthesis of drospirenone has been developed. The key steps included the
stereospecific reduction of the C7-tertiary alcohol with ZnI2/Et3SiH, a novel mild and stereospecific tertiary alcohol
reduction system, and the tandem oxidation/cyclopropanation reactions.
Keywords drospirenone, stereospecific synthesis, ionic hydrogenation, Oppenauer oxidation, cyclopropanation
Introduction
15β,16β-methylene androst-5-ene-17-one (3) was
stereoselectively transformed into the 5β-allylic alcohol
4, which directed the Simmon-Smith methylenation
(Zn-Cu/CH2I2) to stereospecifically deliver the 6β,7β-
methylene compound 5 (Scheme 1). These transforma-
tions encountered with long steps, highly toxic and ex-
pensive reagents, which could eventually present a haz-
ard to the environment. In order to prepare greater
quantities of compound 1, it is desirable to develop a
greener method for the stereoselective introduction of
the 6β,7β-methylene group.
Drospirenone (1) (Figure 1) is a unique progestogen
derived from 17α-spirolactone, with a pharmacologic
profile very similar to that of endogenous progesterone.
In contrast with other available progestins, compound 1
is a progestogen with aldosterone receptor antagonism
(PARA) through its affinity for the mineralocorticoid
receptor. It is able to act on the renin-angiotensin-al-
dosterone system (RAAS), which prevents excessive
sodium loss and regulates blood pressure.[1]
O
Scheme 1 Reported synthetic methods for drospirenone (1)
O
11
H
16
Corey Methylenation
O
1
15
H
H
7
O
O
6
Figure 1 Structure of drospirenone (1)
O
O
O
2
6β,7β-1
6α,7α-1
The synthesis of 1 is quite complicated. Initially 1
was prepared by treatment of diene 2 with dimethyl-
sulfoxonium methylide (Corey methylenation) in mod-
erate yields as a mixture of 6β,7β- and 6α,7α-methylene
(ca. 2∶1). The desired 6β,7β-dropirenone could be ob-
tained only in low yield by tedious separation and puri-
fication of the mixture.[2] Wiechert et al.[3] reported the
first stereoselective synthesis of 1 by applying the
Wieland’s procedure for prorenone synthesis[4] starting
from androstenolone in 15 steps with 2.6% overall yields.
Later Petzoldzt et al.[5] improved the synthesis by com-
bining synthetic and microbiological processes in an
overall yield of 9.5%. The key precursor 3β-hydorxy-
Simmon-Smith Methylenation
O
H
7 steps
RO
OH
RO
HO
OH
3
4
5
Results and Discussion
As we recently reported an efficient and stereocon-
trolled access to the 6β,7β-methylene unit in steroid,[6]
*
E-mail: jiangb@sioc.ac.cn, ycli@mail.shcnc.ac.cn; Tel.: 0086-021-54925181, 0086-021-50806600-3502; Fax: 0086-021-64166128, 0086-021-50807288
Received November 19, 2012; accepted December 21, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201147 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 15—17
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15

Deng et al.
COMMUNICATION
we started the synthesis from commercially available
3β-hydorxy-15β,16β-methylene androst-5-ene-17-one
(3) (Scheme 2). The 17-ketone in 3 was transferred into
C-17 hydroxyl by reduction with NaBH4 in methanol,
and followed masking of both the C-3 and C-17 hy-
droxyl with TBSCl (tert-butyldimethylsilyl chloride)/
imidazole gave 6 in quantitative yield. Using an im-
proved allylic oxidation method,[7] a C-7 ketone group
in steroidal frame was introduced by oxidation of 6 with
N-hydroxyphthalimide/Na2Cr2O7•2H2O in acetone at 40
℃ in 78% yield. Treatment of α,β-unsaturated ketone 7
with (isopropoxydimethylsilyl)methyl Grignard reagent
(Tamao’s reagent),[8] followed by oxidative cleavage of
the C－Si bond by H2O2 gave the 7α-hydroxylmethyl
and tertiary alcohol 8 in 83% yield.[9]
fically in 90% yield without ring opening (Scheme 3).
Similarly, treatment of tertiary alcohol 11 with this
novel ionic hydrogenation conditions provided 7β-hy-
droxymethyl compound 12 in 93% yield.
Scheme 3 Reduction of tertiary alcohol
OTBS
OTBS
TBSO
TBSO
OH
TBSO
TBSO
OH
OH
8
10
90%
a
OTBS
OTBS
Scheme 2 Synthesis of compound 8
OH
OH
OH
11
12
O
OTBS
93%
a
Reagent and condition: (a) ZnI2 (2.5 equiv.), 1,2-dichloroethane,
H
H
Et3SiH (10 equiv.), r.t., 2 h.
H
H
H
H
H
HO
TBSO
3
6
With successful entry to 7β-hydroxymethyl com-
pound 10, the synthesis of target drospirenone (1) was
outlined in Scheme 4. Global removal of the TBS group
in 10 with acetic acid/water (V∶V＝4∶1) at 45 ℃
afforded triol 13. We envisioned that the C-3 hydroxyl
and C-7 methyl primary alcohol in 13 could be selec-
tively protected with TBSCl due to the stereohindered
environment of C-17 hydroxyl group. Indeed, the C-3
hydroxyl and C-7 methyl hydroxyl could be selectively
masked with 2.5 equiv. of TBSCl/imidazole (89% yield).
Then the 17-OH in 14 was affected by Oppenauer oxi-
dation to afford 17-keone 15 in 85% yield. A C3 side
chain was introduced in 16 by the alkynylation of 15
with propargyl alcohol and t-BuOK in 96% yield. The
17α-spirolactone 18 was achieved smoothly by hydro-
genation of the triple bond in 16 (10% Pd/C) and Op-
penauer oxidation of the 17α-hydroxypropanyl 17. Fi-
nally, the target drospirenone (1) was obtained through
a three-step sequence involving silyl ether deprotection
(TBAF, 99%), mesylation (MsCl, Et3N, 89%), and tan-
dem Oppenauer oxidation/cyclopropanation reactions
(73%). The spectral data (1H and 13C NMR) of our syn-
thetic drospirenone (1) matched exactly with those re-
ported in the literature.[11]
b
OTBS
OTBS
c
H
H
H
H
H
O
TBSO
OH
OH
8
TBSO
7
d
OTBS
OH
H
H
H
H
H
OH
HO
TBSO
OH
9
10
Reagent and condition: (a) (1) NaBH4, MeOH, 0 oC, 1 h, 99%; (2)
TBSCl/imidazole, DMF, r.t., 5 h, 99%; (b) N-hydroxyphthalimide/
Na2Cr2O7•2H2O, acetone, 40 C 36 h, 78%; (c) Tamao’s reagent,
THF, 0 C, 2 h, 81%; (d) BF3•Et2O/Et3SiH, CH2Cl2, 0 C, 10 min,
o
o
o
57%.
However, when ionic hydrogenation conditions
(BF3•Et2O/Et3SiH) were applied to remove the C-7 ter-
tiary alcohol moiety in 8,[6] the 15β,16β-methylene ring
expansion compound 9 was isolated in 57% yield in-
stead of the desired 7β-hydroxymethyl product 10. This
is reasoned for that the strong Lewis acid BF3•Et2O had
caused the 15β,16β-methylene ring opening. Then we
had to seek a mild Lewis acid for catalyzed reduction
with Et3SiH. After screening various Lewis acids, we
found that ZnI2 could promote the ionic hydrogenation
efficiently in high yield.[10] When 8 was treated with 10
equiv. Et3SiH and 2.5 equiv. ZnI2, the reaction went
smoothly at room temperature and gave 10 stereospeci-
Conclusions
In summary, we have demonstrated a novel stereo-
specific synthesis of drospirenone in 19% overall yield
starting from the commercially available 3. The key
steps involved a novel mild reduction of tertiary alcohol
with ZnI2/Et3SiH to stereoselectively prepare the
7β-hydroxyl methyl steroid and a tandem oxidation/
16
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 15—17

Stereospecific Synthesis of Drospirenone
Scheme 4 Synthesis of drospirenone (1)
cyclopropanation method for the stereospecific con-
struction of the 6β,7β-methylene ring. Besides, all the
reactions proceed under mild conditions with benign
reagents. The new ionic hydrogenation condition is
useful for the reduction of tertiary alcohol compounds
bearing sensitive functional groups to strong Lewis ac-
ids.
OH
OH
a
b
10
HO
CH2OHTBSO
CH2OH
CH2OTBS
13
14
c
Acknowledgement
O
OH
d
This research was financially supported in part by
the China Postdoctoral Science Foundation and the Na-
tional Basic Research Program of China (Nos.
2010CB833200, 2010CB833300), the National Natural
Science Foundation of China (Nos. 20832007,
21102167), the Science and Technology Commission of
Shanghai Municipality (No. 12DZ1930902) and the
Knowledge Innovation Program of Chinese Academy of
Sciences. We thank Zhejiangshenzhou Pharmaceutical
Co., Ltd for providing starting materials.
H
H
TBSO
CH2OTBS
TBSO
CH2OTBS
15
16
e
O
OH
O
OH
f
H
TBSO
CH2OTBS
TBSO
CH2OTBS
17
18
References
g
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O
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O
O
h
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i
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O
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o
Reagent and condition: (a) AcOH/H2O (V∶V＝4∶1), 40 C, 6 h,
99%; (b) TBSCl (2.5 equiv.), imidazole, DMF, 10 h, 90%; (c)
Al(OPr-i)3, cyclohexanone, refluxe, 1 h, 85%; (d) propargyl alcohol,
t-BuOK, THF, 0 ℃ to r.t., 2 h, 96%; (e) 10% Pd/C, H2, MeOH, r.t.,
2 h, 90%; (f) Al(OPr-i)3, cyclohexanone, refluxe, 1 h, 80%; (g) TBAF,
THF, 40 ℃, 1 h, 99%; (h) MsCl, TEA, THF, 0 oC, 89%; (i) Al(OPr-i)3,
cyclohexanone, toluene, 1 h, 73%.
(Zhao, C.)
Chin. J. Chem. 2013, 31, 15—17
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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