Homo- and heterogeneous Ru-based metathesis catalysts in cross-metathesis of 15-allylestrone-towards 17β-hydroxysteroid dehydrogenase type 1 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2008.02.134

The cross-metathesis of allylestrone with acrylic acid derivatives using homogeneous and heterogenized Ru-catalysts was evaluated for the synthesis of a new 17β-hydroxysteroid dehydrogenase type 1 inhibitor. Hoveyda-type catalyst containing an additional diethylamino group turned out to be comparably active as homogeneous Grubbs II catalyst after immobilization on an acidic ion exchange resin which greatly facilitated workup.

Full text of DOI:10.1016/j.tetlet.2008.02.134

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3019–3022
Homo- and heterogeneous Ru-based metathesis catalysts
in cross-metathesis of 15-allylestrone—towards
17b-hydroxysteroid dehydrogenase type 1 inhibitors
a,
a
a
b
*
Andreas Kirschning , Kirsten Harmrolfs , Klaas Mennecke , Josef Messinger ,
Uwe Scho¨n b, Karol Grela c
a Institut fu¨r Organische Chemie and Zentrum fu¨r Biomolekulare Wirkstoffe (BMWZ), Leibniz Universita¨t Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
b Solvay Pharmaceutical Research Laboratories, Hans-Bo¨ckler-Allee 20, D-30173 Hannover, Germany
c Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 18 January 2008; revised 19 February 2008; accepted 22 February 2008
Available online 29 February 2008
Abstract
The cross-metathesis of allylestrone with acrylic acid derivatives using homogeneous and heterogenized Ru-catalysts was evaluated
for the synthesis of a new 17b-hydroxysteroid dehydrogenase type 1 inhibitor. Hoveyda-type catalyst containing an additional diethyl-
amino group turned out to be comparably active as homogeneous Grubbs II catalyst after immobilization on an acidic ion exchange
resin which greatly facilitated workup.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Catalysis; Enzyme inhibitor; Immobilization; Cross-olefin metathesis; Ru-catalyst; Steroids
The estradiol-synthesizing enzyme 17b-hydroxysteroid
dehydrogenase type 1 (17bHSD1) is mainly responsible
for the conversion of estrone (E1) to the potent estrogen
estradiol (E2). It is a key player in controlling the tissue
levels of E2. It is therefore an attractive target in estradiol
dependent diseases like breast cancer or endometriosis.1
Non-steroidal structures like pyrimidone,2a biphenyl2b
and naphthalene derivatives2c and steroidal structures
namely estrone and estradiol derivatives2d–i show inhibi-
tory activity of 17bHSD1. We have been focussing on the
synthesis of C15 estrone derivatives leading to a new drug
candidate 4.2d For further development a scalable process
had to be developed which is practical and allows to access
other side chain analogues of 4. Compound 2 can straight-
forwardly be prepared following the sequence described by
Kunzer,2j starting from O-benzyl-15,16-dehydro estrone 1.
¨
The protected 15-allyl estrone 2 finally can be used in a
cross-metathesis reaction with acrylic acid derivatives
yielding the protected and unsaturated key intermediate 3
en route to 4 (deprotection, hydrogenation) (Scheme 1).
During recent years, olefin metathesis using modern
ruthenium catalysts such as Grubbs I–III (5, 6, 9), Hov-
eyda–Grubbs carbene (7) and Hoveyda–Blechert–Grubbs
carbene (8) as well as therefrom derived indenyl and
phenylthio carbenes 10–12 has become a key reaction in
organic synthesis.3 Heterogenization of homogeneous
catalysts for removing catalysts at the end of the catalytic
process is an active field of research4 with an increasing
impact on industrial processes.5
In this context, the removal of various ruthenium
byproducts6 has been achieved following diverse strategies
such as scavengers,7a–d biphasic extraction,7e,h and silica-
gel chromatography.7f–h An alternative concept is the
immobilization of these homogeneous catalyst on a solid
*
Corresponding author.
E-mail address: andreas.kirschning@oci.uni-hannover.de (A. Kirschning).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.134

3020
A. Kirschning et al. / Tetrahedron Letters 49 (2008) 3019–3022
O
Br
L
L
L
O
Cl
Cl
Cl
Cl
Cl
Ru
Ru
Ru
N
H
Ph
H
a., b.
BnO
Cl
Ph
PCy3
O
N
H
H
H
H
5, 6
BnO
Br
7, 8
9
O
O
1
2
cross olefin
metathesis
L
L
SPh
Ph
H
O
H
O
Cl
Cl
Cl
Cl
Ru
Ru
PCy3
H
H
H
H
PCy3
HO
BnO
12
10, 11
3
4
N
N
L
L
Cl
Cl
Cl
Ru
Ru
N
Cl
O
O
Ph
O
N
Scheme 1. Synthesis of estrone derivative 4 with 17bHSD1 inhibitory
property. Reagents and conditions: (a) allyl-MgBr, THF, 2.5 h, 0 °C, 85%;
(b) KH, 18-crown-6, THF, 12 h, rt, 75%.
NHEt2 O3S
Br
14
13
5, 7, 10, 12: L- = :PCy3
support which has been achieved for carbenes 5 and 6 via
ligand L or via the alkylidene moiety.8 Hoveyda esta-
blished catalysts 7 and 89 as remarkably robust complexes
promoting olefin metathesis by a release/return mecha-
nism.10 Recently, various Hoveyda–Grubbs carbenes were
attached to different resins or soluble supports preferen-
tially via the 2-alkoxy-benzylidene fragment.11 As a part
of our research dedicated to catalysis under continuous-
flow conditions12 which ideally requires facile regeneration
of immobilized homogeneous catalysts we developed two
modified Grubbs-type catalysts 1313 and 1414 which are
attached to a polymeric phase by coordinative attachment
or ion exchange, respectively.15
NMes
11 : L- =
MesN
6, 8, 9, 13, 14: L- =
NMes
MesN
Fig. 1. Ru-complexes 5–14 (Cy = cyclohexyl, Mes = 2,4,6-trimethyl-
phenyl).
after 5.5 h (70% and 95%, respectively). Hoveyda’s
Ru-complex 8 operates with similar efficiency, however, it
reacts more sluggishly compared to complex 6. Industrial
catalysts 10–12 did not yield appreciable amounts (<10%)
of methyl ester 15 under these conditions. Surprisingly,
also Grubbs III catalyst 9 did not perform as well as its
immobilized variant 13 as coupling product 15 was only
formed in about 40% yield even after prolonged reaction
time. The performance of 9 could not be improved when
the cross-metathesis was carried out in toluene or 1,2-
dichloroethane at 40 °C and 80 °C, respectively (<20% con-
version). The solvent switch was only beneficial for immo-
bilized catalyst 13 as the yield of transformation could be
raised to 95% in 1,2-dichloroethane at 80 °C after a reac-
tion time of 5.5 h. In essence, the two immobilized
Ru-complexes 13 and 14 perform with similar efficiency
as the homogeneous counterparts 6 and 8 while all other
homogeneous catalysts 9–12 are not well suited for the
model cross-metathesis.18
Therefore, the following studies were exclusively con-
ducted with Ru-complexes 6, 13 and 14 (Table 1). The data
presented in Table 1 show that no single catalyst outper-
forms any other in the cases listed. For example, in the
CM of three acrylamide derivatives, Grubbs catalyst 6 gave
best conversion in two cases (entries 4 and 5), while the
immobilized complex 14 was the most optimal catalyst
for the third amide (entry 6). This observation is another
indication for the current difficulty in anticipating the
activity of pre-catalysts with respect to a specific sub-
strate.19 Still, the very good results achieved with complex
14 are noteworthy because in comparison to Grubbs II 6 it
allows easy purification of reaction mixtures and facile
regeneration (see Scheme 2).
In the present work, we disclose a detailed evaluation of
several Ru-based metathesis catalysts including heteroge-
nized catalysts 13 and 14 (powder) in the cross-metathesis
reaction16 between alkene 2 and several acrylic acid deriv-
atives (see Fig. 1).
Cross-metathesis of alkene 2 with methyl acrylate using
Ru-complex 6 proceeded in dichloromethane at 40 °C led
to 97% conversion (determined by LCMS–ELSD; liquid
chromatography mass spectrometry with evaporative light
scattering detection) within 2.5 h. The reaction can be
accelerated under microwave irradiating conditions17
(10 min at 80 °C; 79%) but the conversion never exceeded
80% even at elevated temperatures (100–120 °C). The use
of sealed microwave vials can be made responsible because
the byproduct ethylene inside the vial is trapped at an inter-
nal pressure of 3–7 bar. Besides dichloromethane, also
1,2-dichloroethane (80 °C) gave satisfactory results. In
contrast, conversions in toluene, chlorobenzene, dichloro-
benzene and ethyl acetate ranged between 25% and 30%
yield while in dioxane, THF, chloroform, acetone, metha-
nol, DMF and DMSO it was determined to be between
10% and 0%.
From a practical point of view, it was important for us
that not only Grubbs II catalyst 6 can be employed for this
cross-metathesis reaction but also heterogenized Ru-com-
plexes 13 and 14 gave excellent yields in dichloromethane

A. Kirschning et al. / Tetrahedron Letters 49 (2008) 3019–3022
3021
Table 1
O
22
Cross-metathesis of 15-propenyl estrone 2 with various alkenes using
Ru-complexes 6, 13 and 14a
H
2
O
H
H
O
mol% Ru-cat 6a
14b
quant.
quant.
quant.
95%
72%
11%
3%
BnO
R
2
1
97%
9%
H
H
X
CO2Me
H
H
0.5
0.34
0.25
0.17
0.08
< 2%
H
H
X
BnO
BnO
O
2
3, 15 - 20
H
0%
H
H
Entry
X
R
Product
Yieldb (%)
BnO
6
13
14
MeO
15
1
2
3
4
–CO2Me
–CO2Me
–CO2H
H
Me
H
15
15
16
17
97
94
88
61
95
58
0
95
73
99
12
O
Scheme 3. Comparison of Grubbs II catalyst
6 with immobilized
–CONH2
H
0
Hoveyda-type catalyst 14. Reagents and conditions: a2/alkene 1:2,
CH2Cl2, 40 °C, 2.5 h; b2/alkene 1:2, CH2Cl2, 40 °C, 8 h (only E-isomer).
O
N
5
H
H
3
51
1
3
O
still is dramatically lower than typically determined for
homogeneous Ru-catalysts. Here, ruthenium contamina-
tions are in the range between 11,000 and 22,000 ppm. As
previously described by us, reuse is easily possible through
reloading of the active catalyst by simple washing steps typ-
ical for ion exchange resins,14 which creates an additional
advantage during a planned scale-up of this process.21 In
essence, we showed that our Hoveyda-type olefin metathe-
sis precatalyst 14, immobilized by ion exchange, is a highly
reactive species for cross- olefin metathesis with improved
properties over common homogeneous Ru-complexes as
it allows facile purification and regeneration without sub-
stantial loss of activity. The attractive conceptual feature
of complex 14 is the activation by immobilization.
Currently, work is in progress for utilizing immobilized
catalyst 14 for the large scale, continuous production of
17bHSD1 inhibitors.
O
6
18
62
58
85
NHPh
7
8
a
–OAc
–Ph
H
H
19
20
86
76
0
55
32
74
Conditions: 6: CH2Cl2, 40 °C, 2.5 h; 13: (CH2Cl)2, 80 °C, 5.5 h; 14:
CH2Cl2, 40 °C, 5.5 h.
b
Isolated yields (only E-isomers).
O
O
H
H
CO2Me
H
H
H
H
3-5 mol% cat.
BnO
BnO
2
MeO2C
15
Catalyst
Optimized conditions
. 6
8
9
13
14
CH2Cl2, 40˚C, 2.5h; 97%
CH2Cl2, 40˚C, 4h; 90%
CH2Cl2, 40˚C, 5.5h; 34%
(ClCH2)2, 80˚C, 5.5h; 95%
CH2Cl2, 40˚C, 5.5h; 95%
Acknowledgements
The work was funded by the Deutsche Forschungsge-
meinschaft—Polisch Academy of Sciences joint project
‘Synthetische Nutzung von immobilisierten Ruthenium–
Carben–Katalysatoren in Durchflussmikroreaktoren’ (436
POL 113/109/0-1) and the Fonds der Chemischen
Industrie.
Scheme 2. Optimization of cross-metathesis of 15-allylestrone 2 with
methyl acrylate.
Even more importantly, the concentration of catalyst 14
could be reduced to <0.5 mol % in contrast to the Grubbs
II catalyst 6 which has to be added in at least 2 mol % to
achieve complete transformation (Scheme 3). This result
may be attributed to the enhanced activity exhibited by
the EWG-activated20 Hoveyda catalyst 14 combined with
its pronounced thermal stability,14 although Nolan
et al.19 clearly state that the indenylidene catalyst possesses
even improved stability. In our case, this catalyst failed in
the present study. The reaction time for 14 is doubled com-
pared to 6, which is a common phenomenon for biphasic
systems. At the end of the reaction, catalyst 14 can be sim-
ply removed by filtration and rinsed with minimal amounts
of dichloromethane, producing minimal solvent waste. The
ruthenium contamination in the crude products was deter-
mined to be <3500 ppm which is not an excellent value but
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.134.
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21. Prolonged heating times and low amount of catalyst lead to complete
deactivation of 14 after the first run.
22. General procedure for cross-metathesis reaction. Estrone derivative 2
(30 mg, 75 lmol) and 150 lmol of the olefin (entries 1–8; Table 1 and
Supplementary data) were dissolved in 10 ml CH2Cl2 under nitrogen.
Ru-catalyst (3–5 mol %) was added and the mixture was stirred at
40 °C (80 °C in ethylene dichloride for catalyst 13) for 1–5 h (depends
on catalyst, substrate and solvent employed). The products were
9. Complex 7: (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799; Complex 8:
(b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
isolated by flash column chromatography using
cyclohexane/ethyl acetate as eluent.
a mixture of