Protecting group effect on the 1,2-dehydrogenation of 19-hydroxysteroids: a highly efficient protocol for the synthesis of estrogens

Article abstract of DOI:10.1016/j.tetlet.2010.04.070

19-O-Acylation was found to be indispensable for 1,2-dehydrogenation of 19-hydroxyandrost-4-ene-3,17-dione 1a with DDQ as an oxidant after exploring a variety of C-19 substituents. 1,2-Dehydrogenation in combination with subsequent A-ring aromatization via retro-aldol reaction provided a flexible and efficient protocol for the synthesis of estrogens. To demonstrate the utility of the protocol, pharmaceutically attractive estrogens were synthesized from easily available 19-hydroxy-4-ene-3-keto steroids.

Full text of DOI:10.1016/j.tetlet.2010.04.070

Tetrahedron Letters 51 (2010) 3242–3245
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Protecting group effect on the 1,2-dehydrogenation of 19-hydroxysteroids:
a highly efficient protocol for the synthesis of estrogens
a
a
a,b,
Yu Jing a, Cheng-Gong Xu b, Kai Ding b, , Jing-Rong Lin , Rong-Hua Jin , Wei-Sheng Tian
*
*
a Laboratory of Resource Chemistry, Shanghai Normal University, 100 Guiling Road, Shanghai 200234, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
19-O-Acylation was found to be indispensable for 1,2-dehydrogenation of 19-hydroxyandrost-4-ene-
3,17-dione 1a with DDQ as an oxidant after exploring a variety of C-19 substituents. 1,2-Dehydrogena-
tion in combination with subsequent A-ring aromatization via retro-aldol reaction provided a flexible
and efficient protocol for the synthesis of estrogens. To demonstrate the utility of the protocol, pharma-
ceutically attractive estrogens were synthesized from easily available 19-hydroxy-4-ene-3-keto steroids.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 March 2010
Revised 13 April 2010
Accepted 16 April 2010
Available online 20 April 2010
Keywords:
Estrogen
Retro-aldol reaction
Dehydrogenation
Steroid
The important physiological properties of estrogens have cre-
ated a strong demand for practical preparation of this type of com-
pounds from more abundant steroid resources.1 Recently, new
biological discoveries2 have renewed the interest in the explora-
tion of their structure diversity aiming at SAR study and drug
development. So far, diversity-oriented synthesis (DOS) of estro-
gens has been problematic with conventional method such as
structural modification of estrone3 or expulsion of the 19-angular
methyl groups of 1,4-diene-3-keto steroids via pyrolytic aromati-
zation,4 or reductive aromatization5 with Zn or Li, and develop-
ment of a flexible strategy for the synthesis of estrogens with
structural diversity is therefore needed.
The key step in the synthesis of estrogens is the aromatization
of A ring. A route via retro-aldol-type fragmentation reaction of
19-hydroxyandrost-1,4-diene-3-ones 2 seemed particularly attrac-
tive (Scheme 1).6 The advantages of this protocol are (1) starting
material is easily available from an important industrial intermedi-
ate, which is prepared from abundant dehydroepiandrosterone
(DHEA);7 (2) non-aromatic starting materials are easily amendable
for DOS; (3) retro-aldol reaction is favored due to the stabilization
after aromatization.
oxidants (such as SeO2 and DDQ8) for the 1,2-dehydrogenation of
androst-4-ene-3-ones often lead to low yield for 19-hydroxyl-
substituted substrates 1.6 In our studies, we found that the success
of the 1,2-dehydrogenation of 19-hydroxy-4-ene-3-keto steroids
depended crucially on the nature of 19-O-protecting group. 1,2-
Dehydrogenation of 19-hydroxy-4-ene-3-keto steroids combined
with subsequent A-ring aromatization via retro-aldol reaction pro-
vided a flexible and efficient protocol for the synthesis of estrogens.
A variant of the protocol provided an unprecedented approach to
synthesize estrone 3-alkyl ethers without using toxic alkylating
reagents.
Initially, we examined the direct dehydrogenation of 19-
hydroxyandrost-4-ene-3,17-dione 1a. Conventional reagents,
SeO2 and DDQ, did not provide the desired dehydrogenation or aro-
matization product (Table 1, entry 1). Considering the success of
1,2-dehydrogenation of 19-methyl-androst-4-ene-3,17-dione,8b
we envisioned that the protection of 19-hydroxyl group may facil-
itate the reaction. However, methoxymethyl ether 1b and tetrahy-
dropyranyl ethers 1c did not react with DDQ at all; and the starting
materials remained intact in various solvents (entries 2 and 3). Less
hindered methyl ether 1d also is inactive (entry 4). The use of
benzyl- and silyl-protecting group did not improve the reactivity
(entries 5–7).
However, this promising method was rarely used as an efficient
approach to prepare estrogens due to the difficulties in the prepa-
ration of retro-aldol reaction precursors 2 from 1. Conventional
Interestingly, treatment of 19-acetoxyandrost-4-ene-3,17-
dione 1h with DDQ resulted in a complete conversion in less than
3 h (entry 8). It is notable that all acylated substrates can be dehy-
drogenated smoothly with DDQ (entries 9–13), albeit with a
slower reaction rate compared to 19-acetoxyandrost-4-ene-3,17-
dione. Trace of 6,7-dehydrogenation by-product can be removed
* Corresponding authors. Tel.: +86 21 54925089; fax: +86 21 64166128 (K.D.);
tel.: +86 21 54925176; fax: +86 21 64166128 (W.-S.T.).
E-mail addresses: dingkai@mail.sioc.ac.cn (K. Ding), wstian@mail.sioc.ac.cn
(W.-S. Tian).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.070

Y. Jing et al. / Tetrahedron Letters 51 (2010) 3242–3245
3243
O
O
O
RO
RO
19
1
retro-aldol reaction
HO
dehydrogenation
2
O
O
1
2
estrone
Scheme 1. Synthetic strategy via retro-aldol reaction.
Table 1
Table 2
Dehydrogenation of protected 19-hydroxyandrost-4-ene-3,17-dionea
Retro-aldol reaction of 19-hydroxyandrost-1,4-diene-3,17-dionea
O
O
O
O
RO
RO
AcO
DDQ
catalyst
dioxane,reflux
MeOH
O
O
HO
O
1a-1m
2a-2m
2h
Estrone
Entry
Substrate
R=
Time (h)
Product
Yieldb (%)
Entry
Catalyst (equiv)
Temp (°C)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
—
—
—
—
—
—
—
3
4
5
3
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
NR
NR
NR
NR
Complex
NR
1
2
3
4
NaOH (4)
K2CO3 (4)
TsOH (4)
TsOH (0.1)
rt
rt
rt
Reflux
3 min
5 min
5 h
90
88
91
90
MOM
THP
Me
Bn
TMS
TBS
7 h
a
Conditions: substrate (ꢀ0.5 mmol), methanol (5 mL).
NR
b
Isolated yield.
Ac
88 (77c)
83d
88
COCF3
COOMe
Piv
Bz
C(O)H
1j
1k
1l
2j
2k
2l
82
85
87
O
O
1m
3
2m
AcO
AcO
b
a
a
b
c
Conditions: substrate (0.5 mmol), DDQ (1.2 equiv), dioxane (5 mL), 110 °C.
NMR yield.
1a
Isolated yield on gram-scale after treatment with m-CPBA.
Unstable 2i cannot be separated.
O
O
d
3
1h
O
O
by treatment with m-CPBA.9 The preparation of 2h on up to gram-
scale has been performed with no drop in efficiency.
AcO
d
c
The data listed in Table 1 provided useful information for DDQ
dehydrogenation. Inductive effect of electron-withdrawing acyl
group seemed to be responsible for the successful dehydrogena-
tion. An additional evidence is that 19-mesyloxyandrost-4-ene-
3,17-dione can be dehydrogenated with DDQ in high yield.10 Steric
effect was found not to be crucial after comparing reaction rate of
formyl ester 1m, acetyl ester 1h, and pivaloyl ester 1k (entries 8,
11, and 13).
HO
O
4
6,7-dehydroestrone 5
Scheme 2. Reagents and conditions: (a) Ac2O, DMAP, rt, 20 min; (b) chloranil, t-
BuOH, reflux, 2 h; (c) DDQ, dioxane, reflux, 3 h; (d) TsOH, MeOH, rt, 5 h, (69% over
four steps).
With 19-acetoxyandrost-1,4-diene-3,17-dione in hand, we at-
tempted to synthesize estrone via retro-aldol reaction. As ex-
pected, removal of acetyl group with NaOH or K2CO3 rapidly
afforded estrone in excellent yield under mild condition (Table 2,
entries 1 and 2). Deprotection with acid also provided estrone in
excellent yield but with a much slower rate (entries 3 and 4). In
all cases, no 19-hydroxyandrost-1,4-diene-3,17-dione intermedi-
ate was detected, which indicated that the retro-aldol reaction is
very fast and the deprotection step is rate-determining step.
The synthesis of 6,7-dehydroestrone 5 demonstrated the effi-
ciency and generality of the new protocol (Scheme 2). Conven-
tional synthesis of 6,7-dehydroestrone 5 requires five steps to
introduce 6,7-double bond from estrone,11 namely, protection of
phenol and 17-carbonyl group, oxidation at 6-position, elimina-
tion, and deprotection. In contrast, our protocol can directly intro-
duce the double bond with chloranil as oxidant.12 With 1a as
starting material, the 6,7-dehydrogenation with chloranil provided
dienone in 70–80% yield.13 Notably, acetylation of 19-hydroxyl
group also facilitated 6,7-dehydrogenation, and dienone 3 was
obtained quantitatively under otherwise identical conditions. The
1,2-dehydrogenation of dienone 3 with DDQ was accomplished
smoothly and provided 1,4,6-trien-3-one 4 as the precursor of ret-
ro-aldol reaction. Finally, 6,7-dehydroestrone was synthesized
from 1a in four steps and 69% overall yield.14
Our protocol provided an unprecedented approach to produce
3-etherified estrogens without the use of toxic alkylating agents.
3-Etherified estrogens, such as mestranol, quinestrol, and prome-
striene, have been commercially available as long-acting oral drug
or biologically inactive prodrug (Fig. 1), which were generally syn-
thesized by alkylation of estrone.15 However, electrophilic alkylat-
ing agents, such as MeI and Me2SO4, are often very toxic.
The stability of 2h under acidic condition (Table 2, entries 3 and
4) prompted us to explore a new synthetic approach to estrone 3-
alkyl ethers, via a retro-ene reaction (Scheme 3). To our delight,
treatment of 2h with trimethyl orthoformate and TsOH (10 wt %)
provided the desired estrone 3-methyl ether 6a in 82% yield within
an hour (Table 3, entry 1).16 The efficiency of this process was sur-
prising because no by-product formed. The analogous reaction
with triethyl orthoformate proceeded smoothly to afford ethyl

3244
Y. Jing et al. / Tetrahedron Letters 51 (2010) 3242–3245
HO HO
O
O
O
O
Promestriene
Quinestrol
Figure 1. 3-Etherified estrogenic drugs.
Mestranol
References and notes
O
O
O
1. (a) Windholz, T. B.; Windholz, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 353; (b)
Morand, P.; Lyall, J. Chem. Rev. 1968, 68, 85.
2. (a) Chun, T. Y.; Gregg, D.; Sarkar, D. K.; Gorski, J. Proc. Natl. Acad. Sci. 1998, 95,
2325; (b) Hess, R. A.; Bunick, D.; Lee, K. H.; Bahr, J.; Taylor, J. A.; Korach, K. S.;
Lubahn, D. B. Nature 1997, 390, 509.
3. (a) Lupon, P.; Gomez, J.; Bonet, J. J. Angew. Chem., Int. Ed. Engl. 1983, 22, 711; (b)
Kiesewetter, D. O.; Katzenellenbogen, J. A.; Kilbourn, M. R.; Welch, M. J. J. Org.
Chem. 1984, 49, 4900; (c) Tietze, L. F.; Schneider, G.; Wolfling, J.; Nobel, T.;
Wulff, C.; Schubert, I.; Rubeling, A. Angew. Chem., Int. Ed. 1998, 37, 2469; (d)
Purohit, A.; Wyatt, J.; Hynd, G.; Wright, J.; El-Shafey, A.; Swamy, N.; Ray, R.;
Jones, G. B. Tetrahedron Lett. 2001, 42, 8579; (e) Labaree, D. C.; Zhang, J. X.;
Harris, H. A.; O’Connor, C.; Reynolds, T. Y.; Hochberg, R. B. J. Med. Chem. 2003,
46, 1886; (f) Saeed, M.; Zahid, M.; Rogan, E.; Cavalieri, E. Steroids 2005, 70, 173;
(g) Schon, U.; Messinger, J.; Buchholz, M.; Reinecker, U.; Thole, H.; Prabhu, M. K.
S.; Konda, A. Tetrahedron Lett. 2005, 46, 7111; (h) Liu, Y.; Kim, B.; Taylor, S. D. J.
Org. Chem. 2007, 72, 8824.
O
HC(OR)3
TsOH,ROH
RO
O
H
6a-c
2h
82-85%
RO
8
7
Scheme 3. Proposed retro-ene mechanism.
Table 3
Synthesis of 3-etherified estrogensa
O
O
4. (a) Hershberg, E. B.; Rubin, M.; Schwenk, E. J. Org. Chem. 1950, 15, 292; (b)
Kaufmann, S.; Pataki, J.; Rosenkranz, G.; Romo, J.; Djerassi, C. J. Am. Chem. Soc.
1950, 72, 4531.
5. (a) Tsuda, K.; Ohki, E.; Nozoe, S.; Ikekawa, N. J. Org. Chem. 1961, 26, 2614; (b)
Dryden, H. L.; Webber, G. M.; Wieczorek, J. J. J. Am. Chem. Soc. 1964, 86, 742; (c)
French, A. N.; Wilson, S. R.; Welch, M. J.; Katzenellenbogen, J. A. Steroids 1993,
58, 157; (d) Bourke, D. G.; Collins, D. J.; Bannister, J. D.; Doherty, C. L.; Fallon, G.
D.; Lim, Y.; Ting, T. L. P.; Ward, B. R. Aust. J. Chem. 1998, 51, 353.
6. (a) Broka, C. A. J. Org. Chem. 1988, 53, 575; (b) Ehrenstein, M.; Otto, K. J. Org.
Chem. 1959, 24, 2006; (c) Templeton, J. F.; Lin, W. Y.; Ling, Y. Z.; Majgier-
AcO
(RO)3CH, TsOH
ROH
R
O
O
6a-c
2h
Entry
R
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
Me
Et
MeOH
EtOH
60
70
80
80
1
82
84
NR
85
Baranowska, H.; Marat, K. J. Chem. Soc., Perkin Trans.
1 1997, 2037; (d)
2.5
5
Numazawa, M.; Yamashita, K.; Kimura, N.; Takahashi, M. Steroids 2009, 74, 208.
7. Ueberwasser, H.; Heusler, K.; Kalvoda, J.; Meystre, C.; Wieland, P.; Anner, G.;
Wettstein, A. Helv. Chim. Acta 1963, 46, 344.
3
iPr
iPr
iPrOH
iPrOHb
4b
17
a
8. (a) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153; (b) Zinczuk, J.;
Bacigaluppo, J. A.; Colombo, M. I.; Cravero, R. M.; Gonzalez-Sierra, M.; Ruveda,
E. A. J. Braz. Chem. Soc. 2003, 14, 970.
Conditions: substrate (200 mg, 0.58 mmol), orthoester (1 mL), solvent (3 mL),
TsOH (10 wt %).
b
TsOH (50 wt %).
9. General procedure for the preparation of 2h: (Warning: Most of the steroids are
biologically active. The materials, reaction, and its work-up should be handled
with special care!) A mixture of steroid 1h (7.90 g, 22.9 mmol) and DDQ
(6.25 g, 27.5 mmol) in dry dioxane (50 mL) was refluxed at 110 °C for 3 h. After
completion of the reaction (monitored with 1H NMR), the solvent was removed
under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL). The
insoluble portion was removed by filtration and washed with CH2Cl2
(3Â20 mL). The combined filtrates were washed with aqueous NaHSO3 and
water, dried (MgSO4), filtered, and concentrated. The residue was filtered
through a short silica column to afford 6.90 g of crude 2h as a light brown oil.
Crude 2h (500 mg) was solved in 10 mL of CHCl3 and m-CPBA (85%, 140 mg,
0.70 mmol) was sequentially added to CHCl3 (10 mL). The solution was
vigorously stirred for 12 h at room temperature, upon which it was diluted
with CH2Cl2 (20 mL) and washed with Na2SO3 solution (20 mL), and brine
(20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by column chromatography to afford pure 2h (438 mg,
77% for two steps from 1h).
ether 6b in 84% yield (entry 2). However, bulky isopropyl orthofor-
mate did not react with dienone 2h with TsOH (10 wt %) as cata-
lyst. Fortunately, increasing the amount of TsOH to 50 wt %
accelerated the reaction and afforded the desired product 6c in
85% yield (entry 4). Rapid retro-ene aromatization resulted in no
observable formation of intermediates 7 and 8.
In summary, our study demonstrates that the acylation of 19-
hydroxyandrost-4-ene-3-ones significantly facilitated 1,2-dehy-
drogenation with DDQ as oxidant. The efficient dehydrogenation
in combination with subsequent retro-aldol-type aromatization
provides a practical protocol for the synthesis of estrogens from
easily available 19-hydroxyandrost-4-ene-3,17-dione 1a. Based
on the current protocol, pharmaceutically attractive estrogens
were efficiently synthesized. Further synthetic application is in
progress.
10. Wieland, P.; Anner, G. Helv. Chim. Acta 1968, 51, 1932.
11. (a) Rao, P. N.; Wang, Z. Q. Steroids 1997, 62, 487; (b) Li, H. Q.; Song, Y. X.; Peng,
X. F. Steroids 2008, 73, 488.
12. Agnello, E. J.; Laubach, G. D. J. Am. Chem. Soc. 1960, 82, 4293.
13. Direct oxidation of 1a formed a by-product, which can only be removed by
recrystallization and resulted in decrease of isolated yield (40–50%).
O
Acknowledgment
HO
chloranil
70-80% (NMR yield)
40-50% (isolated yield)
1a
We are grateful for financial support of this work by the Na-
tional Natural Science Foundation of China (No. 20902098).
O
14. Preparation of 6,7-dehydroestrone: According to the previous procedure, 300 mg
of 1a (1 mmol) provided crude acetyl ester 1h (390 mg), which was used
without further purification.
Supplementary data
The mixture of crude acetyl ester 1h (390 mg) and chloranil (417 mg,
1.70 mmol) in t-BuOH (10 mL) was refluxed for 2 h, then the solvent was
removed under reduced pressure and the residue was dissolved in MeOH
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.070.

Y. Jing et al. / Tetrahedron Letters 51 (2010) 3242–3245
3245
(30 mL). The insoluble portion was removed by filtration and washed with
MeOH (3 Â 10 mL). Solvent removal afforded the acetyl ester 4 (550 mg) as a
yellow oil, which was used without further purification. According to the
previous procedure, dehydrogenation of crude 4 with DDQ and subsequent
acid-catalyzed hydrolysis provided 6,7-dehydroestrone (184 mg, 69% from 1a)
as a white powder after purification by column chromatography.
15. (a) Kanojia, R. M.; Allen, G. O.; Killinger, J. M.; Mcguire, J. L. J. Med. Chem. 1979,
22, 1538; (b) Ercoli, A.; Gardi, R. Chem. Ind. 1961, 1037.
16. General procedure for the preparation of compound 6a: To a solution of steroid
2h (200 mg, 0.58 mmol) and TsOH (20 mg, 0.10 mmol) in dry MeOH (3 mL),
trimethyl orthoformate (1 mL) was added slowly. The mixture was heated for
1 h (60 °C). After completion (monitored with TLC), the solvent was removed
under reduced pressure. The resulting residue was purified by column
chromatography to afford estrone 3-methyl ether 6a (136 mg, 82%).
According to the previous procedure, dehydrogenation of crude 4 with DDQ
and subsequent acid-catalyzed hydrolysis provided 6,7-dehydroestrone
(184 mg, 69% from 1a) as
a white powder after purification by column
chromatography.