4,5-Disubstituted cis-pyrrolidinones as inhibitors of 17β- hydroxysteroid dehydrogenase II. Part 1: Synthetic approach

Article abstract of DOI:10.1016/j.tetlet.2005.01.003

17β-Hydroxysteroid dehydrogenase II (17β-HSD II) antagonists may provide an important way into preventing the onset of osteoporosis. The discovery of 4,5-disubstituted cis-pyrrolidinones as 17β-HSD II inhibitors led to the development of an efficient intr

Full text of DOI:10.1016/j.tetlet.2005.01.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1525–1528
4,5-Disubstituted cis-pyrrolidinones as inhibitors of
17b-hydroxysteroid dehydrogenase II. Part 1: Synthetic approach
James H. Cook,* Jeremy Barzya, Catherine Brennan, Derek Lowe, Yamin Wang,
´
Aniko Redman, William J. Scott and Jill E. Wood
Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA
Received 21 December 2004; accepted 4 January 2005
Available online 20 January 2005
Abstract—17b-Hydroxysteroid dehydrogenase II (17b-HSD II) antagonists may provide an important way into preventing the onset
of osteoporosis. The discovery of 4,5-disubstituted cis-pyrrolidinones as 17b-HSD II inhibitors led to the development of an efficient
intramolecular Michael addition, followed by catalytic hydrogenation to obtain the desired cis configuration.
Ó 2005 Elsevier Ltd. All rights reserved.
A screening effort identified a novel inhibitor of 17b-
hydroxysteroid dehydrogenase II 1 for the treatment
of osteoporosis.1 The screening hit 1 is a close analog
of the natural product clausenamide 2, an active ingredi-
ent in the Clausena lansium leaves used to treat viral
hepatitis (Fig. 1).2
tion process without epimerization at the C-5 position.
Alkylation of the cis aldehyde 9 afforded only one
diastereomer. Chiral chromatography was employed to
obtain the desired (R,R,R)-alcohol 1.
Although the original synthetic approach required eight
steps and resulted in a 20% overall yield, the low diaste-
reoselectivity (2:1) during the decarboxylation step and
the difficulties installing substituents at the C-4 position
greatly affected our analoging efforts. Therefore, a more
versatile route was examined, which would allow C-4
substitution.
The original synthetic approach developed by Hartwig
and Born2 involved a Michael addition followed by a
cyclization with sodium methoxide to obtain pyrrolidi-
none 5 (Scheme 1). Alkylation of the amide and selective
hydrolysis/decarboxylation of one of the ester groups
yielded a 2:1 ratio of the ( )-cis pyrrolidinone 7 and
( )-trans isomer 8. Recrystallization of the two diaste-
reomers afforded the desired ( )-cis pyrrolidinone. The
aldehyde 9 was obtained via a two step reduction/oxida-
A synthetic approach to obtain the cis-pyrrolidinone
was envisioned from an intramolecular Michael addi-
tion of a substituted alkyne (Scheme 2). Literature pre-
cedent confirmed the feasibility of an intramolecular
5-endo-dig Michael addition to an epoxide or alkyne
to obtain the pyrrolinone moiety 10.3
CH3
N
CH3
N
OH
OH
O
O
The alkyne 11 was synthesized via an EDCI coupling of
the appropriate carboxylic acid4 12 with sarcosine ethyl
ester 13. Attempts to produce the pyrrolinone 10 via an
intramolecular Michael addition with lithium bis(tri-
methylsilyl)amide gave low and inconsistent yields.
The side products observed were from the addition of
molecular oxygen to the ester enolate resulting in an
intermediate that decomposed upon work-up to the
alkynyl amide 14. The hydroxy compound 15 was also
observed from the oxygen addition to the ester enolate
of the pyrrolinone. Purging the reaction with argon
prior to treatment with base resulted in improved and
C-2
C-4
HO
C-3
1
2
Figure 1. 17b HSD II inhibitor and clausenamide.
Keywords: Hydroxysteroid dehydrogenase; Intramolecular Michael
addition; 4,5-Disubstituted pyrrolidinones.
*
Corresponding author. Tel.: +1 203 812 3228; fax: +1 203 812
2452; e-mail: James.Cook.b@bayer.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.003

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J. H. Cook et al. / Tetrahedron Letters 46 (2005) 1525–1528
H
O
NaOEt,
N
N
EtO2C
1) NaH,MeI
O
EtOH
reflux
(68%)
O
CO2Et
CO2H
CO2Et
CO2Et
+
HN
CO2Et
CO2Et
2) Ba(OH)2 (aq)
(95%)
3
4
5
6
CH3
N
CH3
N
CH3
N
O
O
O
O
O
O
1) ∆,-CO 2
Crystallization
OEt
OEt
OEt
+
(50%)
(over 2 steps)
7
8
7
(2
: 1)
CH3
N
CH3
N
OH
O
O
O
PhMgBr,THF
(75%)
1) LiB(Et)3H
H
2) (CF3CO)2O,
DMSO
(78%)
9
1
Scheme 1. Synthesis of 2 via Hartwig et al.2 approach.
N
O
N
CO2Et
O
O
CO2Et
N
O
OEt
10
11
7
Scheme 2. Retrosynthetic analysis.
reproducible yields of the pyrrolinone 10 with no trace
of side products (Schemes 3 and 4).
Hydrogenation of the pyrrolinone 10 using catalytic pal-
ladium on carbon produced the desired product in a
N
O
CO2Et
O
O
H
EDCI.HCl
LiN(SiMe3)2
70%
N
N
+
OH
OEt
OEt
76%
O
O
O
12
13
10
11
N
N
CO2Et
H2
O
CO2Et
+
Pd/C
100%
7
8
(10 : 1)
Scheme 3. cis-Pyrrolidinone via intramolecular Michael addition.

J. H. Cook et al. / Tetrahedron Letters 46 (2005) 1525–1528
1527
OH
CO2Me
N
N
O
O
CO2Et
O
LiN(SiMe3)2
+
+
NH
N
OEt
O
O
14
10
11
15
Scheme 4. Side products from the Michael addition.
to the published procedure was performed by Todd
Gane and David Gunn. Mass spectra were obtained
by Mr. Anthony Paiva and Mr. Stuart Coleman.
Assignment of fluorine couplings of 13C NMR spectra
Table 1. Yields of Michael addition product (pyrrolinone) and
hydrogenation product (pyrrolidinone)
Pyrrolinone yield Pyrrolidinone yield
(cis:trans ratio)a
R
O
´ ´
were accomplished by Mr. Laszlo Musza.
N
OEt
O
References and notes
Methyl
Propyl
Phenyl
72
90
70
50
73
35
81
5 (14:1)b
37 (cis only)b
100 (10:1)
100 (12:1)
95 (cis only)
97 (12:1)
1. Turner, R. T. et al. Endocr. Rev. 1994, 15, 275; Lindsay, R.
et al. Lancet 1976, 1, 1038; Stevenson, J. C. et al. Lancet
1990, 336, 265; Lindsay, R. et al. Obstet. Gynecol. 1990, 76,
290; The Pharmacology of Estrogensin Osteoporosis. In
Principles of Bone Biology; Bilezikian, J. P., Raisz, L. G.,
Rodan, G. A., Eds.; Academic Press: San Diego, 1996; p
1063.
2. Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352.
3. Baldwin, J. J. Chem. Soc., Chem. Commun. 1976, 734;
Rudolf, W. D.; Schwartz, R. Synlett 1993, 369, 4; Rudolf,
W. D.; Schwartz, R. Z. Chem. 1988, 28, 58; Rudolf, W. D.;
Schwartz, R. Z. Chem. 1988, 28, 101; Yasuda, N.; Sakane,
K. Chem. Commun. 1997, 281; Wang, J. Q.; Tian, W. S. J.
Chem. Soc., Perkin Trans. 1 1995, 209; Rapoport, H.;
Rosenberg, S. H. J. Org. Chem. 1985, 50, 3979; Lavallee, S.
H. et al. Tetrahedron Lett. 1986, 5455.
4. Carboxylic acids were obtained from either a commercial
source or synthetically prepared via a Castro–Stevens/
Sonogashira coupling, followed by hydrolysis.
5. Ratios determined by comparison to Hartwig and Born
experimental data of the cis (7) and trans (13) isomers.
6. Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217; Herdeis,
C. et al. Tetrahedron: Asymmetry 1994, 5, 351.
7. Representative experimental procedure: Ethyl 2-(N-methyl-
3-phenylprop-2-ynoylamino)acetate (11): To a 0 °C solution
of phenylpropiolic acid (25 g, 0.17 mol), sarcosine ethyl
ester hydrochloride (27 g, 0.17 mol, 1 equiv), 4-dimethyl-
aminopyridine (21 g, 0.17 mol, 1 equiv), and 4-meth-
ylmorpholine (19 mL, 0.17 mol, 1 equiv) in CH2Cl2
(250 mL) was added EDCIÆHCl (33 g, 0.17 mol, 1 equiv)
in small portions. The resulting mixture was allowed to
warm to room temperature and stirrred overnight. The
reaction mixture was diluted with CH2Cl2, then washed
with water, a 0.5 M HCl solution, and a saturated NaHCO3
solution. The organic layer was dried (Na2SO4) and
concentrated under reduced pressure. The crude product
was purified by flash chromatography to give ethyl 2-(N-
methyl-3-phenylprop-2-ynoylamino)acetate (11, 32 g, 76%)
2-Fluorophenyl
2-Methoxyphenyl
3-Fluorophenyl
3-Methoxyphenyl
92 (14:1)
a Ratios determined by HPLC and Hartwig et al. experimental data.
b Yields not optimized.
10:1 ratio of cis 7 to trans 8 isomers.5 Here the ratio
was not dependent on the C-4 substituent (Table 1). Pre-
vious researchers have shown similar results reducing
pyrrolinone derivatives to afford predominantly the cis
isomer.6
As shown by Hartwig and Born,2 the ester 7 could be
carried to the secondary alcohol 1 by reduction with
lithium borohydride to afford the primary alcohol.
Swern oxidation yielded the aldehyde 9, followed by di-
rect alkylation with the appropriate lithio or Grignard
reagent generated the secondary alcohol 1 in high dia-
stereoselectivity. It is noteworthy that the oxidation–
addition steps proved to be difficult (0–30%). In this
sequence, the aldehyde 9 generated from the Swern oxi-
dation was difficult to handle and was used without
purification. However, the use of Dess–Martin reagent
generated a cleaner aldehyde for the addition reaction.
In conclusion, the synthetic approach using an intramo-
lecular Michael addition has two distinct advantages
over the previous approach: an improved diastereoselec-
tivity for cis over trans isomers and a shorter three step
route with an overall yield of 53%.7 Additionally, this
approach led to the opportunity to vary the C-4 position
of the pyrrolidinone core. Further publications of the
pharmacological results will be reported in due course.
1
as an orange oil: TLC (25% EtOAc/hex) Rf 0.32; H NMR
(CDCl3 rotomeric mixture) d 1.28 (t, J = 7.2 Hz, 3H), 3.07
(s, 1.2H), 3.35 (s, 1.8H), 4.18–4.26 (m, 3H), 4.38 (s, 1H);
7.35–7.40 (m, 3H), 7.49–7.57 (m, 2H).
5-Ethoxycarbonyl-1-methyl-4-phenyl-3-pyrrolin-2-one (10):
Argon was bubbled in a solution of ethyl 2-(N-methyl-3-
phenylprop-2-ynoylamino)acetate (11, 20 g, 82 mmol) in
THF (100 mL) for 5 min. The solution was cooled to 0 °C
treated with a solution of LiN(SiMe3)2 (1 M in THF,
82 mL, 82 mmol). The resulting mixture was stirrred for
Acknowledgements
The authors thank Jon Brice for Chiral HPLC work.
Synthesis of racemic (4R,5R)-5-((1R)hydroxyphenyl-
methyl)-1-methyl-4-phenylpyrrolidin-2-one 1 according

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J. H. Cook et al. / Tetrahedron Letters 46 (2005) 1525–1528
2 h, then was slowly treated with water (20 mL), and diluted
yl-3-pyrrolin-2-one (10, 1 g, 4 mmol) and 10% palladium on
carbon (0.1 g) in EtOH (30 mL) was stirred under a H2
atmosphere (1 atm) for 1 h. The reaction mixture was
filtered through a pad of CeliteÒ with the aid of CH2Cl2.
The filtrate was concentrated under reduced pressure to
yield greater than a 10:1 mixture of ( )-(4R*,5R*)-5-ethyl-1-
methyl-4-phenylpyrrolidin-2-one (7) and ( )-(4R*,5S*)-5-
ethyl-1-methyl-4-phenylpyrrolidin-2-one (8) (1 g, 100%).
Ratio of stereoisomers was determined by HPLC and
literature Ref. 2. Experimental data only shown for (7):
TLC (40% EtOAc/hex) Rf 0.13; 1H NMR (CDCl3) d 0.83 (t,
J = 7.4 Hz, 3H), 2.64–2.72 (dd, J = 8.8, 16.5 Hz, 1H), 2.88–
3.0 (m, 4H), 3.65–4.0 (m, 4H), 4.34–4.36 (d, J = 8.9 Hz,
1H), 7.2–7.35 (m, 5H); HPLC ES-MS m/z (rel abundance)
248 (MH+, 100%).
with CH2Cl2 (200 mL). The organic layer was washed with
water (150 mL), a 1 N HCl solution (150 mL), and water
(150 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by flash chroma-
tography (gradient from 0% to 50% EtOAc/hex) to give
racemic 5-ethoxycarbonyl-1-methyl-4-phenyl-3-pyrrolin-2-
one (10, 14 g, 70%) as a brown oil: TLC (40% EtOAc/
1
hex) Rf 0.13; H NMR (CDCl3) d 1.10 (t, J = 7.4 Hz, 3H),
3.03 (s, 3H), 4.12 (m, 2H), 5.13 (s, 1H), 6.46 (s, 1H), 7.39–
7.41 (m, 3H), 7.53–7.60 (m, 2H); HPLC ES-MS m/z (rel
abundance) 246 (MH+, 100%).
( )-(4R*,5S*)-5-Ethyl-1-methyl-4-phenylpyrrolidin-2-one (8)
and
one (7): A mixture of 5-ethoxycarbonyl-1-methyl-4-phen-
( )-(4R*,5R*)-5-ethyl-1-methyl-4-phenylpyrrolidin-2-