TMG catalyzed cyclopropanation of cyclopentenone. Illustration by a simple synthesis of bicyclo[3.1.0]hexane-2-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.03.006

The catalytic preparation of bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester 1 is described by cyclopropanation of cyclopentenone using 1,1,3,3-tetramethylguanidine (TMG) as a catalyst in high yield and high diastereoselectivity. This process has been applied to an efficient synthesis of the important intermediate, β-hydroxyl cyclopentanone 2.

Full text of DOI:10.1016/j.tetlet.2007.03.006

Tetrahedron Letters 48 (2007) 3277–3279
TMG catalyzed cyclopropanation of cyclopentenone. Illustration
by a simple synthesis of bicyclo[3.1.0]hexane-2-one derivatives
*
Fuyao Zhang, Eric D. Moher and Tony Y. Zhang
Chemical Product R&D, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 29 January 2007; revised 27 February 2007; accepted 1 March 2007
Available online 4 March 2007
Abstract—The catalytic preparation of bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester 1 is described by cyclopropanation
of cyclopentenone using 1,1,3,3-tetramethylguanidine (TMG) as a catalyst in high yield and high diastereoselectivity. This process
has been applied to an efficient synthesis of the important intermediate, b-hydroxyl cyclopentanone 2.
ꢀ
2007 Elsevier Ltd. All rights reserved.
L-Glutamic acid is a major neurotransmitter at the vast
majority of excitatory synapses in the mammalian cen-
(TMG) catalyzed cyclopropanation of cyclopentenone
and its application for the efficient synthesis of the
hydroxyl derivative 2, which is an important intermedi-
ate for the mGluRs drug discovery.
1
,2
tral nervous system. L-Glutamate plays an important
role in all major functions of the brain and exerts its
effects via two types of excitatory amino acid receptors:
ionotropic glutamate receptors (iGluRs) and metabotro-
pic glutamate receptors (mGluRs). The mGluRs have
been distinguished into three groups on the basis of ami-
no acid sequence homology, agonist pharmacology and
Typically, DBU was employed stoichiometrically for the
base mediated cyclopropanation of cyclopentenone with
(ethoxycarbonylmethyl)dimethylsulfonium bromide for
8
the preparation of 1. In order to develop a more cost-
3
–7
signal transduction mechanism. Recently, a conform-
ationally constrained analog of glutamic acid,
LY354740, has been discovered to be a highly potent
effective process, we initially screened a variety of less
expensive bases for mediation of this transformation,
such as triethylamine, pyridine and the inorganic base,
K CO (Table 1). It is believed triethylamine, pyridine,
and selective group 2 metabotropic glutamate receptor
2
3
8
(
mGluR2) agonist. Bicyclo[3.1.0]hexane-2-one-6-carb-
and DMAP are ineffective due to their inferior basicity
for generating the ylide from (ethoxycarbonylmethyl)-
dimethylsulfonium bromide. No conversion to the
desired product was observed with the use of these
bases.
oxylic acid ethyl ester (1) is a key intermediate for
the synthesis of LY354740 (Scheme 1). Several methods,
including cyclopropanation of cyclopentenone with
ethyl dimethylsulfonium acetate bromide, for the prepa-
8
–11
ration of 1 have been developed.
In the course of our
route development for LY354740, a practical and low
cost process for the preparation of 1 was desired. Herein
we wish to report a practical and cost-effective approach
for the synthesis of 1 by a 1,1,3,3-tetramethylguanidine
Much to our delight, 1,1,3,3-tetramethylguanidine
(TMG) was found to be an excellent base for mediation
of the cyclopropanation of cyclopentenone. It was
found that 1 was obtained in higher yield with a shorter
OH
H
CO H
2
H
H
EtO C
2
EtO C
EtO C
2
2
H
H
H
H
CO2H
NH2
H
H
H
H N
2
O
CO H
O
2
LY354740
1
2
Scheme 1.
*
0
Corresponding author. Tel.: +1 317 651 1264; fax: +1 317 276 4507; e-mail: zhang_fuyao@lilly.com
040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.006

3278
F. Zhang et al. / Tetrahedron Letters 48 (2007) 3277–3279
Table 1. Cyclopropanation of cyclopentenone with different bases
comparison, precipitates were not observed when DBU
was used under the same conditions.
O
H
Br-
Base
EtO C
2
OEt
Me2S+
With this finding, we thought that the catalytic version
of this cyclopropanation could be realized if the TMG
HBr salt was neutralized in situ with inexpensive inor-
ganic bases. We are pleased to find that a catalytic
amount of TMG can be utilized for this process without
loss of productivity in the presence of saturated K CO
H
O
Acetonitrile
H
O
1
a
b
c
Entry Base
Temperature Reaction Yield (%) dr
(ꢁC)
time (h)
2
3
1
2
3
4
5
6
DMAP
NEt
Pyridine 23
23
23
12
12
12
12
24
5
0
0
0
0
78
89
/
/
/
/
(
Table 2).
3
As we expected, saturated K CO alone was not effective
K
2
CO
3
23
23
23
2
3
DBU
TMG
99:1
99:1
to carry out the reaction (entry 1). Less than 10% yield
of the product was observed after the reaction mixture
was allowed to stir at ambient temperature for 24 h
without TMG. When 5 mol % of TMG was added to
the reaction mixture, 65% of the product was isolated
a
b
c
1
.2 equiv of base was used.
Isolated yields after distillation.
The diastereomer ratio was determined by GC.
(entry 2). The result with 20 mol % of TMG (entry 5)
is equivalent to that of the reaction mediated with stoi-
chiometric TMG (entry 6). It seems to indicate that a
reaction time when 1,1,3,3-tetramethylguanidine (TMG)
16
1
2
was used, compared with 1,8-diazabicyclo[5.4.0]undec-
soluble, strong base such as TMG in a moderately cata-
lytic amount (20 mol %) is required to sustain a reason-
able reaction rate (entry 5). Thus, we have discovered a
catalytic version of the cyclopropanation of cyclopente-
none which proceeds in high yield and excellent
1
3
7
-ene (DBU). Moreover, TMG can be easily recovered
for reuse in good yield due to the high crystallinity of its
HBr salt. During the production of ylide from (ethoxy-
carbonylmethyl)dimethylsulfonium bromide, TMG
scavenges HBr from the substrate to form a TMG
HBr salt which precipitates from the reaction solution.
The TMG HBr salt can be separated easily by filtration
in quantitative yield and TMG can be recovered in 85%
17
diastereoselectivity.
The successful catalytic cyclopropanation of cyclopente-
none encouraged us to apply this new method toward
the development of an efficient synthesis of the hydroxyl
1
4,15
yield after the salt was treated with 50% NaOH.
For
a
Table 2. Catalytic cyclopropanation of cyclopentenone with TMG
Table 3. Direct oxidation of ketone 1 to enone 3
O
H
Br-
Me2S
OEt
TMG/K CO3
2
EtO2C
O
OH
+
I
Acetonitrile/water, 23 oC
H
O
O
H
H
H
O
1
EtO C
EtO2C
2
O
b
c
(IBX)
Entry TMG (equiv) Reaction time (h) Yield (%) dr
H
H
H
H
o
8
5 C
O
1
2
3
4
5
6
0
24
24
12
12
7
<10
65
72
81
89
95:1
99:1
99:1
99:1
99:1
99:1
O
0.05
0.10
0.15
0.20
1.00
1
3
Solvent
IBX
equiv)
p-TsOH
(equiv)
Reaction
time (h)
Isolated
yield (%)
(
5
89
DMSO/toluene
DMSO
DMSO
4.0
4.0
2.5
2.0
0
0
0.3
1.0
72
72
10
6
35
58
67
75
a
b
c
2
.0 equiv of K
Isolated yields after distillation.
The diastereomer ratio was determined by GC.
2
CO
3
was used.
DMSO
NH
Me N NMe (20 mol%)
O
OH
I
2
2
O p-TsOH, DMSO
H
O
K CO , ACN/H O,
Br-
2
3
2
EtO2C
o
O 85 C, 6.0 h
o
OEt
23 C, 7.0 h
H
Me2S
H
75% yield
O
O
8
9% yield
1
Zn, NH Cl
+
-
4
NaOCl, BnEt N Cl (20%)
3
OH
O
H
H
Et O, EtOH, H O
2 2
o
o
O
H
EtO C
toluene, 23 C, 30 min EtO2C
23 C, 24.0 h
82% yield
2
EtO2C
H
H
H
H
H
H
O
97% yield
O
3
4
2
Scheme 2.

F. Zhang et al. / Tetrahedron Letters 48 (2007) 3277–3279
3279
derivative 2, which is an important intermediate for the
mGluR drug discovery effort. Recently, Nicolaou
washed with MTBE (47.0 g, 100% recovery). The filtrate
was washed with 200 mL of water and 100 mL of brine,
dried over sodium sulfate and evaporated. The yellow
residue was distilled at reduced pressure to collect the
desired product (31.2 g, 85–90 ꢁC/0.3 mm Hg) as a color-
less liquid, which was dissolved in 80 mL of hot hexanes
1
8
19
reported an effective method to prepare enones from
ketones with IBX. After several trials, we succeeded
in the direct oxidation of ketone 1 to enone 3 with
IBX in 75% yield (Table 3). It was found that p-toluene-
sulfonic acid significantly accelerated this oxidation.
and crystallized at ambient temperature to afford 29.9 g of
1
the pure desired product 1 (89% yield). H NMR (CDCl
3
)
d 4.18 (q, 2H, J = 7.1 Hz), 2.55 (q, 1H, J = 4.9 Hz), 2.29–
2.00 (m, 6H), 1.26 (t, 3H, J = 7.1 Hz). C NMR (CDCl3)
d 212.2, 170.9, 61.6, 32.4, 29.6, 26.9, 23.0, 14.7.
13. The price of TMG ($3.80/mol) is lower than DBU ($4.20/
mol) in ton quantity.
Using a phase-transfer catalyzed epoxidation,20 enone 3
was converted to epoxide 4 in near quantitative yield.
Reduction of epoxide 4 with zinc and ammonium
chloride afforded the desired hydroxy ketone 2. There-
fore, an efficient synthesis of 2 has been developed in
13
2
1
1
4. Recovery of TMG: 23.5 g of white solid (TMG HBr salt) in
a 500 mL of separation funnel was treated with 100 mL of
5
1% overall yield over four steps without purification
5
0% NaOH aqueous solution. The generated TMG was
by chromatography (Scheme 2).
extracted with methylene chloride (3 · 200 mL). The
combined methylene chloride solutions were dried over
sodium sulfate and evaporated to provide 11.7 g (85%
recovery) of 1,1,3,3-tetramethylguanidine (TMG).
In conclusion, the catalytic cyclopropanation of cyclo-
pentenone using TMG as a catalyst has been developed
for the preparation of bicyclo[3.1.0]hexane-2-one-6-
carboxylic acid ethyl ester (1). This practical and cost-
effective process has also been exemplified for the
efficient synthesis of important derivatives for mGluR
drug discovery effort.
15. TMG can also be recovered by extraction with toluene
(75% recovery) and isopropyl acetate (71% recovery).
16. Preparation of 1 using catalytic TMG: A 500 mL of flask
was charged with (ethoxycarbonylmethyl)dimethylsulfo-
nium bromide (41.6 g, 0.18 mol) and 110 mL of acetoni-
trile. The resulting suspension was treated with 1,1,3,3-
tetramethylguanidine (4.5 mL, 0.036 mol) at ambient
temperature for 15 min. A solution of 2-cyclopenten-1-
one (12.3 g, 0.15 mol) in 20 mL of acetonitrile, and a
References and notes
solution of saturated K
resulting mixture was stirred at ambient temperature for
h. The reaction was quenched by the addition of 200 mL
of water and extracted with MTBE (2 · 300 mL). The
combined MTBE solutions were washed with sat. NH Cl
aqueous solution and brine. After evaporation, the yellow
residue was distilled at reduced pressure to collect the
desired product (22.4 g) as a colorless liquid which
2 3
CO (30 mL) were added. This
1
. Colinridge, G. L.; Lester, R. A. Pharmacol. Rev. 1989, 40,
43.
1
7
2
. Nakanishi, S. Science 1992, 258, 597.
3
. Monaghan, D. T.; Bridges, R. J.; Cotman, C. W. Annu.
Rev. Pharmacol. Toxicol. 1989, 29, 365.
. Pin, L. P.; Duvoisin, R. J. Neurochem. 1992, 58, 1184.
. Schoepp, D. D.; Conn, P. J. Trends Pharmcol. Sci. 1993,
4
4
5
1
4, 13.
solidified after standing at ambient temperature. 89%
6
7
8
. Nakanishi, S.; Masu, M. Annu. Rev. Biophys. Biomol.
Struct. 1994, 23, 319.
. Hollmann, M.; Heinemann, S. Annu. Rev. Neurosci. 1994,
1
yield. H NMR (CDCl
3
) d 4.18 (q, 2H, J = 7.1 Hz), 2.55
(
q, 1H, J = 4.9 Hz), 2.29–2.00 (m, 6H), 1.26 (t, 3H,
13
J = 7.1 Hz). C NMR (CDCl
9.6, 26.9, 23.0, 14.7.
3
) d 212.2, 170. 9, 61.6, 32.4,
1
7, 31.
2
. (a) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. R.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J. P.;
Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528; (b) Rasmy, O. M.; Vaid, R. K.; Semo,
M. J.; Chelius, E. C.; Robey, R. L.; Alt, C. A.; Rhodes, G.
A.; Vicenzi, J. T. Org. Process Res. Dev. 2006, 10, 28.
. Collado, I.; Domingeuz, C.; Ezquerra, J.; Pedregal, C.;
Monn, J. A. Tetrahedron Lett. 1997, 38, 2133.
1
7. Cyclopropanation of 2-cyclohexen-1-one was carried out
under the same condition to give the bicyclo[4.1.0] adduct
5
in 59% yield and 99% dr.
H
EtO2C
9
H
H
1
1
0. Moher, E. D. Tetrahedron Lett. 1996, 37, 8637.
O
1. Domingeuz, C.; Ezquerra, J.; Prieto, L.; Espada, M.;
Perdregal, C. Tetrahedron: Asymmetry 1997, 8, 511.
2. Preparation of 1 using stoichiometric TMG: A 500 mL of
flask was charged with (ethoxycarbonylmethyl)di-
methylsulfonium bromide (55.5 g, 0.24 mol) and 150 mL
of acetonitrile. The resulting suspension was treated with
5
1
18. Massey, S. M.; Monn, J. A.; Valli, M. J. Eur. Pat. Appl.
1998, EP 878463.
19. Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. J. Am. Chem.
Soc. 2000, 122, 7595.
1
,1,3,3-tetramethylguanidine (30.1 mL, 0.24 mol) at ambi-
ent temperature. The mixture became a clear solution after
stirring for 2 min, and then a white precipitate formed.
After stirring at ambient temperature for 10 min, a
solution of 2-cyclopenten-1-one (16.4 g, 0.20 mol) in
20. Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
1
21. Compound 2: H NMR (CD
OD) d 4.60 (d, 1H,
3
J = 5.5 Hz), 4.15 (q, 2H, J = 7.5 Hz), 2.56 (m, 1H), 2.48
(d, 1H, J = 5.5 Hz), 2.44 (dd, 1H, J = 6.0 and 0.5 Hz),
2.24 (m, 1H), 2.16 (dd, 1H, J = 3.5 and 2.5 Hz), 1.88 (d,
4
0 mL of acetonitrile was added at once. This resulting
pale yellow mixture was stirred at ambient temperature for
h, and poured into 1200 mL of MTBE. The white solid
TMG HBr salt) was collected by filtration and was
1
3
1H, J = 19 Hz), 1.26 (t, 3H, J = 7.5 Hz). C NMR
5
(
(CDCl
14.3.
3
) d 209.9, 169.7, 68.4, 61.9, 42.9, 36.5, 34.5, 25.7,