A scalable synthesis of 6,19-dihydroxyandrostenedione

Article abstract of DOI:10.1002/cjoc.201201023

Starting from the commercially available 19-hydroxyandrostenedione, a practical protocol for the preparation of 6,19-dihydroxyandrostenedione is reported. This compound is a key intermediate for the synthesis of cyclocitrinols. With the stereospecific epoxidation and following isomerization to allylic alcohol as key steps, a six-step procedure provided desired product in high yield. The sequence is easy to scale-up without the need of laborious chromatography. A key intermediate, 6,19-dihydroxyandrostenedione, was successfully prepared in six steps from commercially available raw material. The process can be carried out on a large scale without laborious chromatography. Copyright

Full text of DOI:10.1002/cjoc.201201023

FULL PAPER
DOI: 10.1002/cjoc.201201023
A Scalable Synthesis of 6,19-Dihydroxyandrostenedione†
Yubo Yan,a Ting Li,b Tao Liu,b Qingyu Dou,b Kai Ding,*,c and Weisheng Tian*,a,c
a Laboratory of Resource Chemistry, Shanghai Normal University, 100 Guiling Road, Shanghai 200234, China
b Department of Chemistry, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
c Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Starting from the commercially available 19-hydroxyandrostenedione, a practical protocol for the preparation of
6,19-dihydroxyandrostenedione is reported. This compound is a key intermediate for the synthesis of cyclocitrinols.
With the stereospecific epoxidation and following isomerization to allylic alcohol as key steps, a six-step procedure
provided desired product in high yield. The sequence is easy to scale-up without the need of laborious chromatog-
raphy.
Keywords 6,19-dihydroxyandrostenedione, allylic alcohol, epoxide, stereospecific, steroid
Introduction
O
O
Steroids bearing a 19-hydroxyl group are important
raw materials for production of steroidal estrogens.[1] In
the synthesis of estrogens, the 19-decarbonylation of
these steroids converts the A ring to an aromatic ring.
Although the process is widely used to prepare the
19-nor-steroids in industry, the easily occurring decar-
bonylation might become a significant side reaction in
organic synthesis.
HO
19
HO
6
O
O
OH
1
R
Cyclocitrinols are a series of usual C25 steroid with
a bicyclo [4.4.1] system at rings A/B.[2] In their total
syntheses, 6,19-dihydroxyandrostenedione is a key in-
termediate (Figure 1). There are a series of methods for
γ-oxidation of α,β-unsaturated ketone, such as direct
oxidation under strong basic condition[3a] or two-step
transformation with dienol ether or ester as intermedi-
ates.[3b] Therefore, we attempted to prepare the key in-
termediate via γ-oxidation of enone from commercially
available 19-hydroxyandrostenedione (1). However,
conventional methods were proved to be inefficient due
to the effect of 19-hydroxyl group. Herein, we describe
a scalable synthesis of 6,19-dihydroxyandrostenedione
from commercially available compound 1. The six-step
route features high yield, high stereoselectivity and
simple operation.
HO
O
Cyclocitrinols
Figure 1 Key synthetic intermediate.
spectrometer. Chemical shifts are reported in parts per
million (ppm) on a δ scale, and referenced to the resid-
ual solvent peak (1H δ 7.26, 13C δ 77.0 for CDCl3). Cou-
pling constants (J) are reported in Hertz. Low- and
high-resolution EI-MS were measured on a Finnigan
MAT 900 XL-Trap mass spectrometer in positive ioni-
zation mode. Optical rotation was measured by JASCO
P1030 polarimeter in the solvent indicated. Melting
points were measured by WRS-1B digital melting-point
apparatus.
Experimental
The six-step synthesis of 19-acetoxy-androst-4-ene-
3,17-dione (7)
General
All NMR experiments were recorded on VARIAN
Mercury 300 MHz spectrometer or Bruker DPX400
The mixture of 0.27 g of DMAP and 27.2 g (90.0
mmol) of 19-hydroxyandrostenedione in 90 mL of ace-
*
E-mail: dingkai@mail.sioc.ac.cn, wstian@mail.sioc.ac.cn
Received October 20, 2012; accepted November 22, 2012; published online December 27, 2012.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 63—66
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
63

Yan et al.
FULL PAPER
tic anhydride was stirred at room temperature for 1 h.
The excess of acetic anhydride was removed under re-
duced pressure. The residue was diluted with ethyl ace-
tate and washed with saturated NaHCO3 and brine. The
combined organic phase was dried with Na2SO4 and
concentrated in vacuo to provide 2 (31 g) as a yellow
oil.
429.2253, found 429.2251.
The mixture of crude 5, 10 mL of acetic anhydride
and 0.1 g of DMAP was stirred at room temperature for
1 h and concentrated under reduced pressure. The resi-
due was solved into 100 mL of ethyl acetate. The solu-
tion was washed with saturated Na2CO3, water and
brine. The solution was concentrated to provide epoxide
6 as a yellow solid.
1
Compound 2: C21H38O4; MW 344.44; wax; H NMR
(CDCl3, 300 MHz) δ: 5.9 (s, 1H), 4.66 (d, J＝11.3 Hz,
1H), 4.16 (d, J＝11.1 Hz, 1H), 1.99 (s, 3H), 0.88 (s,
3H).[4a]
Compound 6: C25H36O7; MW 448.55; white solid;
[α]D −32.8 (1.00, CHCl3); H NMR (CDCl3, 400 MHz)
1
δ: 0.81 (s, 3H, 18-Me), 2.06 (s, 3H, 19-AcH), 2.95 (s,
1H, 6-H), 3.98－3.76 (m, 8H), 4.05 (d, J＝11.3 Hz, 1H,
19-H), 4.34 (d, J＝11.3 Hz, 1H, 19-H); 13C NMR
(CDCl3, 101 MHz) δ: 170.9, 119.2, 109.3, 66.2, 65.1,
64.5, 64.2, 64.0, 60.8, 60.7, 50.3, 47.6, 45.6, 42.5, 38.2,
34.0, 31.4, 31.3, 30.6 (two carbons), 30.2, 22.5, 21.2,
21.2, 14.1; HRMS calcd for C25H36O7＋Na＋: 471.2359,
found 471.2343.
The mixture of epoxide 6 and 0.5 g of TsOH in 20
mL of acetone was stirred at room temperature until the
reaction was complete (30－60 min). Et3N (1 mL) was
added to the solution, which was concentrated in vacuo.
The residue was diluted with ethyl acetate, washed with
water and brine, dried with Na2SO4, concentrated in
vacuo. The resulting solid was recrystallized with ethyl
acetate and hexane to furnish 4.05 g of desire product 7
(75%).
The mixture of 31 g of crude 2, 72 mL of triethyl
orthoformate and 6 drops of concentrated sulfuric acid
in 50 mL of THF was stirred at 60 ℃ for 6 h. The re-
sulting dark solution was added to the mixture of 200
mL of water and 50 mL of saturated NaHCO3, which
was extracted with ethyl acetate (100 mL×2). The or-
ganic phase was washed with water (100 mL) and con-
centrated in vacuo to provide 43 g of crude ketal 3 as a
brown oil.
Compound 3: C25H36O6; MW 433.55; white solid;
1
[α]D 17.5 (1.00, CHCl3); m.p.: 125－126 ℃; H NMR
(CDCl3, 300 MHz) δ: 5.56 (m, 1H), 4.44 (d, J＝11.9 Hz,
1H), 4.06－3.70 (m, 9H), 2.57 (dd, J＝14.3, 2.3 Hz,
1H), 2.14 (d, J＝14.3 Hz, 1H), 2.02 (s, 3H), 0.84 (s,
3H).[4b]
To a solution of 43 g of ketal 3 in 150 mL of
methanol was added 54 g (390 mmol) of K2CO3. The
suspension was heated under reflux for 4 h and was
added to 1000 mL of water. The suspension was fil-
trated with Buchner funnel to provide a wet cake, which
was solved with ethyl acetate (400 mL). The organic
phase was washed with water and dried with Na2SO4,
concentrated in vacuo. The resulting solid was recrys-
tallized with ethyl acetate and hexane to furnish 27 g of
pure 4 as a white solid (77%, 3 steps).
Compound 7: C21H28O5; MW 360.44; [α]D 88.4 (1.00,
1
CHCl3); white solid; m.p.: 175－176 ℃; H NMR
(CDCl3, 300 MHz) δ: 0.94 (s, 3H, 18-Me), 2.03 (s, 3H,
19-AcH), 4.41 (d, J＝11.0 Hz, 2H, 6-H, 19-H), 4.75 (d,
J＝11.0 Hz, 1H, 19-H), 6.00 (s, 1H, 4-H); 13C NMR
(CDCl3,101 MHz) δ: 219.9, 199.7, 170.8, 161.9, 128.9,
72.4, 68.1, 54.1, 51.1, 47.5, 41.2, 37.4, 35.6, 34.7, 34.3,
31.6, 29.9, 21.6, 21.1, 20.8, 13.8; HRMS calcd for
C21H28O5＋Na＋: 383.1829, found 383.1825.
Compound 4: C23H34O5; MW 390.51; white solid;
[α]D −31.7 (1.00, CHCl3); m.p.: 205－206 ℃; 1H NMR
(CDCl3, 400 MHz) δ: 0.91 (s, 3H, 18-Me), 3.62 (dd, J＝
11.4, 9.1 Hz, 1H, 19-H), 4.02－3.75 (m, 9H), 5.87－
5.66 (m, 1H, 4-H).[4c]
To a solution of 5.85 g of pure 4 (15 mmol) in 50
mL of dichromethane was added m-CPBA (22.5 mmol)
at room temperature. After stirring for 30 min, 10 mL of
saturated Na2SO3 was added to remove the excess of
oxidant. The mixture was stirred for 1 h. The organic
phase was washed with saturated Na2CO3 (50 mL), wa-
ter (50 mL) and dried with Na2SO4. The solution was
concentrated under reduced pressure to provide crude
epoxide 5.
Compound 5: C23H34O6; MW 406.51; white solid;
[α]D −5.7 (1.00, CHCl3); m.p.: 119.5－120 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 0.87 (s, 3H, 18-Me), 3.02 (s,
1H, 6-H), 3.55 (d, J＝11.6 Hz, 1H), 3.98－3.76 (m, 8H),
4.07 (d, J＝11.6 Hz, 1H); 13C NMR (CDCl3, 101 MHz)
δ: 119.3, 109.3, 66.8, 65.1, 64.5, 64.2, 64.1, 63.5, 60.8,
50.7, 47.9, 46.0, 41.5, 38.6, 34.0, 31.9, 31.3, 31.0, 30.7,
30.6, 22.4, 20.9, 14.3; HRMS calcd for C23H34O6＋Na＋:
Results and Discussion
There are several known methods to achieve the
γ-oxidation of α,β-unsaturated ketone. However, our
attempts exhibited that these conventional methods were
inefficient to introduce the 6-hydroxyl group into
19-hydroxyandrostenedione or its derivatives in the
presence of 19-hydroxyl group (Figure 2). For example,
oxidation of enol derivatives of raw material 1 only
gave desired product as a mixture of two stereoisomers
in less than 30% yield due to undesired Baeyer-Villiger
oxidation of product.[5]
O
O
PGO
PGO
[O]
O
R
O
OH
R = Me, Ac
< 30%
Figure 2 Unsuccessful attempts to introduce 6-hydroxyl group.
64
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Chin. J. Chem. 2013, 31, 63—66

A Scalable Synthesis of 6,19-Dihydroxyandrostenedione
In this paper, enone 2 was converted into a stable
1,3-dioxolane to avoid the side reactions.[6a] The syn-
thetic route is shown in Scheme 1. The direct ketaliza-
tion of compound 1 with glycol did not give the desired
ketal 4 due to the 19-decarbonylation through a retro-
aldol reaction under acidic conditions. Therefore, the
hydroxyl group must be masked prior to the ketalization.
Reaction of raw material 1 with acetic anhydride pro-
vided compound 2 quantitatively. However, the ketali-
zation of 2 via the azeotropic distillation under conven-
tional conditions gave a cyclic ketal 3 in less than 50%
yield because of the deprotection of 19-acetoxyl group
at elevated temperature. Fortunately, this side reaction
was suppressed and the cyclic ketal 3 was obtained in
72% yield when triethyl orthoformate was used as the
dehydrating agent.[6b] The epoxidation of ketal 3 with
m-CPBA provided two stereoisomers in high yield (α∶
β＝2∶3). However, only β-epoxide 6 can be isomer-
ized to the desired product 7 under acidic condition. The
attempts for the isomerization of α-isomer 6' with
stronger acidic catalysts or extending reaction time were
unsuccessful because the product 7 formed from
β-epoxide was isomerized to 3,6-dicarbonyl by-
product.[7]
to examine the stereoselectivity of epoxidation. Al-
though these stereoisomers could be separated by flash
chromatography, the laborious procedures were not ac-
ceptable for preparative purposes (Table 1).
Table 1 The effect of protective groups on stereoselectivity
O
O
O
O
RO
O
RO
O
m-CPBA
O
O
O
R
Me
MOM
17∶83
Bz
TES
Ac
dr (α∶β)a
10∶90
TBS
23∶77
Piv
40∶60
TBDPS
75∶25
47∶53
50∶50
60∶40
a 1H NMR ratio of stereoisomers.
Finally, a stereospecific three-step synthesis was de-
signed to address this problem. Thus the cyclic ketal 3
was hydrolyzed to the corresponding alcohol 4 in 89%
yield, which reacted with m-CPBA to provide β-epoxide
5 as a single isomer in 93% yield. Unexpectedly, the
direct hydrolysis of epoxide 5 under acidic condition
gave a large amount of 3,6-dicarbonyl by-product. Ace-
tylation of 5 offered epoxide 6 in 96% yield, which was
hydrolyzed to desired product 7 in 92% yield.
This six-step route from raw material 1 to provide
product 7 sufficed for our purposes, however, it is
hardly ideal. We attempted to simplify the operation to
prepare the product 7 on a large-scale without laborious
chromatography. Considering the high yield in the
six-step procedure, intermediates might be used without
purification. However, a six-step procedure, in which
the intermediates only were purified by extraction and
washing gave a mixture of product 7 and by-products,
which could only be purified by chromatography.
Scheme 1 A six steps synthesis of desired product
O
AcO
1
Ac2O,DMAP
O
2
HC(OEt)3,
glycol/THF
O
O
O
K2CO3/MeOH
HO
O
AcO
O
O
O
O
4
3
The preparation of 1,3-dioxolane (2→3) was found
to offer a little by-products, which retarded the subse-
quent reactions and yielded a significant amount of
by-products. Although the crystallization of crude 3 was
unsuccessful, the cyclic ketal 4 was suitable for purifi-
cation by crystallization. Thus, on a 30-gram scale, the
pure 4 was obtained from raw material 1 (77%, 3 steps).
On a 5-gram scale, pure ketal 4 was converted into
product 7 in three steps, which was purified by recrys-
tallization to offer pure product 7 in 75% overall yield.
m-CPBA/DCM
m-CPBA/DCM
two isomers
O
O
O
O
HO
AcO
O
Ac2O,DMAP
O
O
O
O
O
5
6
Conclusions
O
O
O
AcO 19
3
AcO
In summary, 6,19-dihydroxyandrostenedione was
successfully prepared in six steps from commercially
available raw material 1. The migration of double bond
during the ketalization of enone avoided side reactions.
The process can be carried out on a large scale without
laborious chromatography. Its applications in the syn-
thesis of natural products and steroidal drugs are cur-
O
O
6
O
O
OH
7
6'
Several analogues of cyclic ketal 3 were synthesized
Chin. J. Chem. 2013, 31, 63—66
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65

Yan et al.
FULL PAPER
Lobkovsky, E.; Clardy, J.; Crews, P. Org. Lett. 2003, 5, 4393; (c)
Marinho, A. M. D.; Rodrigues, E.; Ferreira, A. G.; Santos, L. S. J.
Braz. Chem. Soc. 2005, 16, 1342; (d) Du, L.; Zhu, T. J.; Fang, Y. C.;
Gu, Q. Q.; Zhu, W. M. J. Nat. Prod. 2008, 71, 1343.
rently pursued and will be reported in due course.
Acknowledgement
[3] (a) Aladro, F. J.; Guerra, F. M.; Moreno-Dorado, F. J.; Bustamante,
J. M.; Jorge, Z. D.; Massanet, G. M. Tetrahedron 2001, 57, 2171; (b)
Nozawa, M.; Suka, Y.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Org.
Lett. 2008, 10, 1365.
We are grateful for financial support of this work by
the National Natural Science Foundation of China (No.
20902098).
[4] (a) Templeton, J. F.; Lin, W. Y.; Ling, Y. Z.; MajgierBaranowska,
H.; Marat, K. J. Chem. Soc., Perkin. Trans. 1 1997, 2037; (b) Lovett,
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Dyer, R. L.; Harrow, T. A. Steroids 1979, 33, 617.
[5] An analogue was obtained smoothly via the oxidation of dienol ether
in our previous work. See: Ding, K.; Sun, Y. S.; Tian, W. S. J. Org.
Chem. 2011, 76, 1495.
[6] (a) de Leeuw, J. W.; de Waard, E. R.; Beetz, T.; Huisman, H. O.
Recueil des Travaux Chimiques des Pays-Bas 1973, 92, 1047; (b)
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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