Functionalisations of estrone benzyl ether at the 11 and 12 positions

Article abstract of DOI:10.1016/S0040-4039(00)00024-1

The prior protection of estrone as estrone benzyl ether (EBE) facilitated the 9,11 dehydrogenation by DDQ, which is a key step for the 11 functionalisation. The oxidation of estrone benzyl ether by an excess of DDQ in dioxane containing a small amount of methanol allowed for an unusual 12 functionalisation with a methoxy group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00024-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1729–1731
Functionalisations of estrone benzyl ether at the 11 and 12
positions
Elie Stéphan,∗ Patrice Sery and Gérard Jaouen
Laboratoire de chimie organométallique-Ecole Nationale Supérieure de Chimie et CNRS 11 rue Pierre et Marie Curie,
75005 Paris, France
Received 21 October 1999; accepted 23 December 1999
Abstract
The prior protection of estrone as estrone benzyl ether (EBE) facilitated the 9,11 dehydrogenation by DDQ,
which is a key step for the 11 functionalisation. The oxidation of estrone benzyl ether by an excess of DDQ in
dioxane containing a small amount of methanol allowed for an unusual 12 functionalisation with a methoxy group.
© 2000 Elsevier Science Ltd. All rights reserved.
The estradiol derivatives substituted at the 11β position may present an interesting biological
potential.1,2 A protected 11-oxoestrone may be a key compound for the preparation of such estradiols,
and a common way to obtain this estrone is described below (Scheme 1).
Scheme 1.
The first step of the synthesis is an oxidation of estrone 1 by DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone). This reaction requires a large volume of solvent (150 to 270 ml of methanol per g of
estrone) and, usually, a tedious work-up.3–7 The same oxidation reaction has been described in the case
of estrone methyl ether8 but a methoxy group is not that easy to cleave. Curiously, the oxidation of estrone
benzyl ether (EBE), which presents a labile protecting group,9 has never been described. We found that
the oxidation of EBE became regioselective in a mixture of dioxane and methanol (17 ml of solvent per
g of EBE) and the work-up was made very easy. Moreover, the oxidation of EBE with an excess of DDQ
in dioxane containing 5 to 20% of methanol allowed for the further functionalisation at the 12 position
by an oxidative nucleophilic substitution.
∗
Corresponding author. E-mail: stephan@ext.jussieu.fr (E. Stéphan)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00024-1
tetl 16304

1730
EBE 5 was oxidised by 1 to 1.5 equivalents of DDQ, at room temperature in various solvents (Scheme
2).
Scheme 2.
Mixtures of unreacted EBE, 9,11-dehydrocompound 6 and diene 7 (formed by further oxidation of 610)
were obtained in aprotic solvents like dioxane, THF or acetonitrile for reaction times of 3 to 5 h. These
solvents were, therefore, inadequate for the preparation of 6. The oxidation in methanol occurred more
slowly (the reaction was still not achieved after 3 days) and without formation of the diene. A mixture of
dioxane and methanol (1:1, v:v) was used to obtain the regiospecific formation of 6:
1.88 g DDQ (1.5 equiv.) was added to a solution of 2 g EBE in 32 ml of a dioxane:methanol mixture
(1:1) and the medium stirred for 20 h at room temperature. The solvents were then evaporated and
dichloromethane added. The resulting suspension was filtered on neutral alumina (10 g) and washed
with dichloromethane. The crude product obtained after evaporation of the solvent was crystallised in
ether to give 1.2 g of a pink solid (m.p.=135°C), with a 60% yield. 1H NMR (ppm) in CDCl3: 7.55 (d,
J12=8.7 Hz, H-1), 6.81 (dd, J24=2.7 Hz, H-2), 6.72 (d, H-4), 6.16 (m, H-11), 5.07 (s, CH2−Ph), 0.95
(s, CH3−18).
The protected 11-oxoestrone (4, R=Bn) can be prepared as previously described7 with two modifica-
tions: the protection of the 17-keto group required p-toluenesulfonic acid as a catalyst (1% by weight)
and a longer reaction time than for dehydroestrone (14 h reflux versus 2.5 h). The hydroboration step to
generate the alcohol 3 (R=Bn) required only 1 equiv. of a borane–methyl sulfide complex.
When EBE reacted with an excess of DDQ (2 to 2.5 equiv.) in dioxane containing 2 to 20% methanol,
at room temperature for 20 h, the following reaction was observed, 8 being the major product (Scheme
3).
Scheme 3.
Compound 8 was probably formed by the reaction of methanol with a carbocation resulting from a
hydride abstraction from 6 by DDQ. The synthesis of the methoxy compound 8 was best achieved as
follows:
2.4 g DDQ (1.5 equiv.) was added to a solution of 2.5 g of 9,11-dehydro EBE (6) in 150 ml dioxane
containing 6 ml methanol and stirred for 1 h at room temperature. The solvents were evaporated and
dichloromethane added. The resulting suspension was filtered on neutral alumina and washed with
dichloromethane. The crude product obtained after the evaporation of the solvent was crystallised in
methanol to give 2 g of a solid (m.p.=150°C), with a 73.5% yield. 1H NMR (ppm) in CDCl3: 7.6 (d,
J12=8.6 Hz, H-1), 6.83 (dd, J24=2.7 Hz, H-2), 6.72 (d, H-4), 6.35 (d, J11–12=5.2 Hz, H-11), 5.08 (s,
CH2–Ph), 3.83 (d, H-12), 3.47 (s, OMe), 0.88 (s, CH3–18).

1731
An NOE experiment was performed on compound 8 in order to determine its configuration at the
12 position. The strong interaction observed between the CH3–18 and the H-12 indicated a 12α
configuration for the methoxy group.
The debenzylation of compound 8 was achieved by hydrogenolysis on Pd/C,11 this reaction being
accompanied by a hydrogenation of the 9,11 double bond.
Work is in progress to obtain other functionalisations at the 12 position by using other nucleophiles.
Acknowledgements
We thank M. N. Rager for the NOE experiment.
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