C3′-cis-Substituted carboxycyclopropyl glycines as metabotropic glutamate 2/3 receptor agonists: Synthesis and SAR studies

Article abstract of DOI:10.1016/j.bmc.2005.07.036

The synthesis of a series of C3′-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is repo

Full text of DOI:10.1016/j.bmc.2005.07.036

Bioorganic & Medicinal Chemistry 13 (2005) 6556–6570
0
C3 -cis-Substituted carboxycyclopropyl glycines as metabotropic
glutamate 2/3 receptor agonists: Synthesis and SAR studies
a,
Rosario Gonz a´ lez, Iv a´ n Collado, Beatriz L o´ pez de Uralde, Alicia Marcos,
a
a
a
*
a
Luisa M. Mart ´ı n-Cabrejas, Concepci o´ n Pedregal, Jaime Blanco-Urgoiti,
a
b
b
Javier P e´ rez-Castells, M. Alejandro Fern a´ ndez, Sherri L. Andis, Bryan G. Johnson,
c
d
d
d
Rebecca A. Wright, Darryle D. Schoepp and James A. Monn
d
d
a
Lilly, SA. Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU, Urb. Montepr ı´ ncipe,
8668 Boadilla del Monte, Madrid, Spain
b
2
Departamento de Qu ı´ mica Org a´ nica e Inorg a´ nica, Universidad de Oviedo, 33071 Oviedo, Spain
c
d
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 2 March 2005; revised 6 July 2005; accepted 13 July 2005
Available online 8 September 2005
0
Abstract—The synthesis of a series of C3 -cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is
described, and the structure–activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1. Introduction
CO
2
H
HO C
2
Most of the excitatory synapses in the central nervous
system use the amino acid glutamate (Glu, 1) as a chem-
ical messenger (Fig. 1). Glutamate mediates its effects
via two distinct receptor families, the ionotropic Glu
H
H N
H N CO H
2 2
2
CO
H
2
1
Glu 1
ACPD 2
(
iGlu) receptors and metabotropic Glu (mGlu) recep-
H
H
tors. iGlu receptors are homomeric or heteromeric
ligand-gated, cation-specific ion channels, which are
classified further into three groups, which are selectively
activated by the agonists a-amino-3-hydroxy-5-meth-
ylisoazolepropionic acid (AMPA), N-methyl-D-aspar-
tate (NMDA), and kainate, from which they take their
X
X1
HO C
HO C
X3
2
2
X2
CO H
CO H
2
H
2
H
NH2
NH2
X = CH , X = H, X = F
X = CH , X = F, X = H
X = CO, X = F, X = H
1 2 3
6
7
8
X = CH2 LY354740 3
1
2
2
3
X = O
X = S
LY379268 4
LY389795 5
1
2
2
3
2
names. On the other hand, the mGlu receptors are cou-
pled to GTP-binding proteins (G-proteins) to activate
systems that generate second messengers within the cell.
The mGlu receptor family comprises of eight different
receptor subtypes and has been separated into three
groups based on their sequence homology, second mes-
senger transduction mechanisms, and pharmacological
properties. Group I mGlu receptors (mGlu1, mGlu5)
Figure 1. Glutamate and glutamate receptor agonists.
are positively coupled to phospholipase C activation,
whereas groups II (mGlu2, mGlu3) and III (mGlu4,
mGlu6-8) are negatively coupled to adenylate cyclase.
The search for potent and selective ligands as pharmaco-
logical tools to understand the functions of the different
metabotropic glutamate receptor subtypes has been an
area of intense research over the last decade. Recent
advances in molecular biology, pharmacology, and
medicinal chemistry of the metabotropic glutamate
3
Keywords: Carboxycyclopropyl glycine; CCG; Metabotropic gluta-
mate 2/3 receptor.
4
*
Corresponding author. Tel.: +34 91 66 33417; fax: +34 91 66
3411; e-mail: gonzalez_rosario@lilly.com
3
0
968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.07.036

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6557
receptors have led to new therapeutic opportunities. In
Agonists
this sense, it has been proposed that agonists for group
II and/or group III mGlu receptors might be useful for
the treatment of brain disorders and diseases, such as
X1
HO C
2
X
2
H
H
H
5
ischemia, anxiety, drug addiction, and schizophrenia.
H N
2
2
CO H
In this context, the first agonist shown to be selective
for mGlu receptors compared to iGlu receptors was
X 1
X 2
(
(
(
1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
6
acid
ACPD) 2. Although lacking in subtype selectivity,
1S,3R)-ACPD has served as a template for the design
H
H
L-CCG-I
L-F2CCG-I 10
9
F
F
H
CO
2
H
DCG-IV
11
12
of new and more selective group II mGlu receptor
7
H
cis-MCG-I
CH
H
2
OMe
ligands.
On the other hand, (+)-2-aminobicy-
CH
2
OMe
trans-MCG-I 12
clo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 3, a
constrained glutamic acid analog, has been described
as a nanomolar potent, highly selective, and orally ac-
tive group II mGlu receptor agonist with anxiolytic
Antagonists
8
and antipsychotic properties. More recently, some
closely related analogs to LY354740 have also been
reported as potent and selective group II mGluR ago-
nists. These include heterobicyclic compounds as the
O
H
H
HO C
HO C
2
2
2
-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid
LY379268) 4 and the 2-thia-4-aminobicyclo[3.1.0]hex-
H
H
CO H
H
H
CO H
H
H
(
ane-4,6-dicarboxylic acid (LY389795) 5 and the ana-
9
H N
N
2
2
2
logs incorporating fluorine atoms at the C3 and C6
0
positions 6–8 (Fig. 1).
PCCG-4 14
XM-CCG-I 15
1
Another class of conformationally constrained analogs
of glutamate, the 2-(carboxy-cyclopropyl)glycines
H
HO C
H
H
H
O
2
(
CCGs), have also been described as ligands for mGlu
0
HO C
2
0
0
receptors. Thus, (2S,1 S,2 S)-2-(2 -carboxycyclopro-
pyl)glycine (L-CCG-I, 9) is a potent and rather selective
agonist for group II mGlu receptors. The C3-difluoro
derivative L-F2CCG-I (10) is a more potent agonist at
mGlu2, although activity at other Glu receptors has
not been reported, while the C3 -substituted carboxy
derivative DCG-IV 11 displays potent group II mGlu
and NMDA receptor agonist activities, as well as group
H
O
H
H
H
H N
2
CO H
1
1
2
H N
2
CO H
2
XE-CCG-I 16
LY341495 17
1
2
0
Figure 2.
1
3
III antagonist effects.
H
H
HO C
CH3
HO C
2
2
OH
Introduction of a methoxymethyl substituent at the C3
position led to the cis-MCG-I and trans-MCG-I ago-
H
H
H
H
H
H
1
4
H
2
N
H N
2
nists 12 and 13. By contrast, the stereoselective intro-
duction of bulky and hydrophobic groups at C3, as in
CO
2
H
CO H
2
1
5
18
(+)-19
the case of the phenyl substituted PCCG-4 14 or in
the xanthenylmethyl and xanthenylethyl substituted
Figure 3.
1
6
derivatives 15 and 16, results in group II antagonism.
Moreover, it has been described that substitution at the
position of L-CCG-I also converts it into group II
mGlu antagonists, a prominent example being the nano-
2
cines, with the aim of finding the structural requirements
at this position for Group II metabotropic glutamate
receptors selective agonism. Here, we describe the syn-
thesis and structure–activity relationship studies of this
family of compounds.
17
molar potency antagonist LY341495 (17, Fig. 2).
In our search for more potent and selective group II
0
mGlu agonists, we recently reported that the C3 -cis-
methyl substituted carboxycyclopropyl glycine 18, de-
signed as the ring opened version of LY354740, is also
a potent and selective group II mGlu receptor agonist
2. Chemistry
1
8
0
with anxiolytic properties. Moreover, we found that
0
Our goal was to synthesize the C3 -cis-substituted CCGs
as racemic mixtures for SAR studies. This is supported
introduction of a hydroxymethyl group at the C3 -cis-
position in analog (+)-19 results in a potent group II
0
by the fact that the activity of C3 -cis-hydroxymethyl
CCG resides only in the enantiomer (+)-19, but biolog-
ical results for the racemic mixture provided a reason-
able estimate of its potency (Table 1). In
1
9
and group III (mGluR6/8) agonist. (Fig. 3). These
findings prompted us to explore further the substitution
0
at the C3 -cis position of these carboxycyclopropyl gly-
a

6558
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
0
Table 1. mGlu receptor affinity, potency, and selectivity C3 -cis-substituted CCGs reported in nM values
0
a
i
b
Compound
C3 -cis-Substituent
K
EC50
mGlu2
mGlu3
mGlu8
mGlu2
mGlu3
1
8
Me
87.4
66.1
23
162.2
7.9
17,087
4161
8.4
5.2
38.7
11.5
7
(
(
(
±)-19
+)-19
ꢀ)-19
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
OH
OH
3
4
OH
>10,000
660
276
>10,000
292
71
>1,00,000
139
70
>1,00,000
3440
52
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
5
3a
3b
5a
5b
6b
8
OCONHEt
OCONHPh
SH
34,343
20,817
4439
c
59
213
602
254
466
47
94
SPh
5136
1270
2320
d
SO
2
Ph
4201
2547
7095
1050
85
d
d
d
e
N
3
418
2901
315
2855
13,280
50,680
n.t.
n.t.
e
2a
2b
3a
3b
4
NHCOMe
363
342
2800
121
2080
1710
1310
2080
189
167
3060
d
d
e
NHCOPh
NHCONHEt
NHCONHPh
1245
1236
1315
n.t.
11,960
12,313
2840
7200
346
d
d
d
678
115
530
d
d
d
NHSO
NH
2
Ph
294
10,830
350
2354
6808
6440
5130
600
d
d
d
d
5
2
55,630
27,380
46,990
26,793
d
d
8a
8b
0
CONHMe
CONHPh
CN
4398
1687
2745
d
2641
170
6440
64
50
3258
d
5
2a
CH
CH
2
CH
CH
3
2
1722
2649
6736
53,190
3610
12,655
d
d
d
2
OH
4540
a
Displacement of specific [3H]341495 binding to membranes expressing recombinant human mGlu2, mGlu3, or mGlu8 receptors, as described in
Refs. 28a and 30. Unless otherwise noted, reported data are mean values from at least two independent determinations. Typical error limits (±20ꢀ).
b
Functional agonist activity in cells expressing recombinant human mGlu2 or mGlu3 receptor subtypes, as described in Ref. 8b. Reported data are
mean values from at least two independent determinations.
c
d
e
Functional antagonist activity (IC50, nM).
n = 1.
n.t.: not tested.
0
retrosynthetic analysis and considering the synthesis of
protected C3 -carbamoyloxymethyl derivatives 22. Basic
hydrolysis, followed by the N-Boc deprotection using
1 N HCl in ethyl acetate, led, after ion-exchange chro-
matography, to compounds 23 (Scheme 1). Alternative-
ly, the reaction of 20 with thioacetic acid under
0
19
the racemic C3 -cis-hydroxymethyl CCG (±)-19, its
precursor 20 is a versatile intermediate for the prepara-
tion of most of our target molecules in this series. Thus,
transformation of the hydroxy group into different het-
eroatom-containing functionalities would allow a rapid
expansion of the SAR at this position (Fig. 4). More-
over, the masked aldehyde present in 21, a precursor
to 20, would allow the preparation of alkyl substituted
2
0
Mitsunobu conditions, or the treatment with diph-
2
1
enyldisulfide and tributylphosphine in THF afforded
the protected thiomethyl derivatives 24, which led to
compounds 25 after hydrolysis under acidic conditions.
Oxidation of the protected thio derivative 24b with
0
CCGs at the C3 -cis-position through a Wittig olefin-
ation, reduction sequence.
CO Et
The preparation of intermediate 20 has already been de-
9
CO Et
2
2
1
scribed by our group. Treatment of 20 with ethyl or
phenylisocyanate in pyridine led to the corresponding
a
EtO C
EtO C
2
2
H
H
40-70%
NHBoc
O
O
NHBoc OH
2
0
2
2a, R = Et
NHR
CO H
CO Et
2
22b, R = Ph
2
HO C
EtO C
2
2
H
H
b, c, d
47-55%
NH2
X
NHBoc OH
2
0
CO H
2
HO C
2
CO Et
2
H
NH2
O
O
H
H
2
3a, R = Et
NHR
HO
O
23b, R = Ph
2
1
Scheme 1. Reagents and condition: (a) RNCO, Py, rt; (b) 1 N LiOH,
THF; (c) 1 N HCl/EtOAc; (d) Dowex 50 · 8 ꢀ 100.
0
Figure 4. Retrosynthesis of C3 -cis-substituted CCGs.

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6559
CO Et
chlorides, afforded the protected CCGs 30 and 31,
respectively. In these cases, it was necessary to modify
the reaction conditions and the reduction was carried
out using platinum oxide (IV) as catalyst in ethyl ace-
tate. Application of standard hydrolysis conditions to
2
a
EtO C
2
60%
H
NHBoc SR
2
4a, R = COCH3
CO H
CO Et
2
2
29, 30, and 31 gave rise to the azamethyl CCG deriva-
tives 32, 33, and 34, respectively. Hydrolysis under acid-
ic conditions of 29a afforded the C3 -cis-aminomethyl
CCG 35 (Scheme 4).
c, d
HO C
EtO C
2
2
H
NH2
0
H
74-83%
SR
NHBoc OH
20
25a, R = H
25b, R = Ph
CO Et
2
Hydroxymethyl intermediate 20 has also been used as a
precursor to a series of CCGs having a carboxamide
b
EtO C
2
H
7
0%
0
NHBoc SR
functionality at the C3 position. The synthesis of these
compounds was achieved through a synthetic sequence
involving Jones oxidation of 20 to the corresponding
2
4b, R = Ph
2
3
4
7% e, c, d
pyroglutamate analog 36 and its subsequent reaction
with different amines. The reaction conditions for the
second step depend on the nature of the amine. In the
case of aliphatic primary amines, the reaction takes
place in THF in the presence of catalytic potassium cya-
CO H
2
HO C
2
H
2
4
NH2
SO Ph
nide to give protected carboxamides 37. However,
addition of aromatic amines to 36 required the presence
2
2
6b, R = Ph
2
5
of aluminum trichloride to effect this conversion.
Scheme 2. Reagents and condition: (a) CH
THF; (b) Ph , Bu P, THF, rt; (c) 6 N HCl, reflux; (d) Dowex
0 · 8 ꢀ 100; (e) MCPBA, CH Cl , 0 ꢁC.
3
COSH, Ph
3
P, DEAD,
Treatment of the protected carboxamides 37 under the
standard hydrolysis conditions afforded the correspond-
ing CCGs 38. The analog 37c was treated further with
trifluoroacetic anhydride to produce cyano derivative
2
S
2
3
5
2
2
40 after hydrolysis of the corresponding protected ana-
log 39 (Scheme 5).
m-CPBA gave rise, after hydrolysis, to the sulfone deriv-
ative 26b (Scheme 2).
As mentioned above, the preparation of the ethyl substi-
tuted compound 45 was carried out starting from lactol
To prepare a series of nitrogen-containing analogs, the
azidomethyl substituted intermediate 27 was synthesized
in good yield from alcohol 20 by the Mitsunobu reaction
using diphenylphosphorylazide as a source of azide.
The azidomethyl CCG 28 was obtained by deprotection
of 27 under the standard hydrolysis conditions (Scheme
21, which was converted into aldehyde 43 in three steps
2
2
by the Wittig reaction with methyltriphenylphosphoni-
um bromide, followed by catalytic hydrogenation of
the carbon–carbon double bond and further oxidation
2
6
of alcohol 42 under Swern conditions in good overall
yield. The Strecker reaction on aldehyde 43 led to a mix-
ture of diastereomeric aminonitriles 44 after acetylation.
From this mixture of diasteromeric aminonitriles, the
isomer 44b was crystallized from diethyl ether. Its rela-
tive configuration at the amine-bearing carbon was
shown by X-ray diffraction to be R, as indicated in Fig-
ure 5. Therefore, the soluble S diastereoisomer, 44a, was
subjected to acid hydrolysis to give the desired aminoac-
id 45 (Scheme 6).
3
). Intermediate 27 has proven to be pivotal for the
preparation of other CCGs bearing different nitrogen-
linked functionalities. Thus, catalytic hydrogenation of
2
corresponding protected amides 29 (Scheme 4). In an
analogous manner, hydrogenation in the presence of
other electrophiles, such as isocyanates and sulfonyl
7 in the presence of acid anhydrides gave rise to the
CO Et
CO Et
2
2
a
EtO C
EtO C
With the aim of getting information on the optimal dis-
tance for the hydroxy group and other functionalities,
relative to the cyclopropyl ring, a synthetic route for
the synthesis of the hydroxyethyl analog 52a was devel-
oped. The key step is the cyclopropanation of the 2-
2
2
H
78%
H
NHBoc OH
NHBoc N3
20
27
2
7
cyclopenten-1-one 46 with the Payne ylide, which led
to the bicyclic intermediate 47 in good yield and with
the desired stereochemistry. Treatment of 47 under Bae-
yer–Villiger conditions gave rise to the lactone 48, which
was reduced with DIBAL-H to afford lactol 49 and sub-
jected further to the Strecker reaction giving rise to a 1:1
mixture of diastereomeric aminonitriles 50, which were
separated by chromatography (Scheme 7). After conver-
sion of both isomers into the corresponding hydroxyeth-
yl-protected compounds, 51a and 51b, configuration
of the aminoacid center was determined through their
b, c, d
73%
CO H
2
HO C
2
H
NH2
N3
28
Scheme 3. Reagents: (a) DPPA, Ph
3
P, DEAD, THF; (b) 1 N LiOH,
THF; (c) 1 N HCl/EtOAc; (d) Dowex.

6560
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
CO H
2
g, f
HO C
2
H
NH2
4
0%
NH2
R = Me
3
5
CO Et
CO H
2
2
a
d, e, f
EtO C
HO C
2
2
H
H
6
5-72%
25-30%
NHBoc HN
R
NH
HN
R
2
O
O
2
2
9a, R = Me
9b, R = Ph
32a, R = Me
32b, R = Ph
CO Et
CO Et
CO H
2
2
2
d, e, f
b
EtO C
EtO C
HO C
2
2
2
H
63-64%
H
42-56%
H
NH2
NHBoc N3
HN
NHR
HN
NHR
NHBoc
2
7
O
O
3
3
0a, R = Me
0b, R = Ph
33a, R = Et
33b, R = Ph
CO Et
CO H
2
2
c
6%
d, e, f
44%
EtO C
HO C
5
2
2
H
H
HN
NH2
HN
NHBoc
SO Ph
2
SO Ph
2
3
1
34
Scheme 4. Reagents and condition: (a) H
THF; (e) 1 N HCl/EtOAc; (f) Dowex 50 · 8 ꢀ 100 or propylene oxide, MeOH; (g) 2 N HCl, 60 ꢁC.
2 2 2 2 2 2 2
, 10ꢀ Pd/C, EtOH, (RCO) O; (b) H , PtO , EtOAc, RNCO; (c) H , PtO , EtOAc, PhSO Cl; (d) 1 N LiOH,
CO Et
CO Et
2
2
b or c or d
50-80 %
a
EtO C
H
H
2
H
97%
EtO C
O
NHBoc OH
2
N
boc
20
36
CO Et
CO H
2
2
e, f, g
5-50%
EtO C
NHR
HO C
NHR
2
2
H
H
NH2
4
NHBoc
O
O
37a, R = Me
37b, R = Ph
37c, R = H
38a, R = Me
38b, R = Ph
h
79%
Figure 5. X-ray structure of 44b.
CO Et
CO H
2
2
e, f, g
0%
EtO C
HO C
oxidation with PDC to afford the lactams 53a and 53b.
NOE experiments were performed with both diastereo-
mers by irradiation of H2, indicating that the lactam
2
2
CN
CN
H
H
NH2
4
NHBoc
3
9
40
5
3a presents a NOE effect between this H2 and the
H1, and no effect with H7. However, in the lactam 53b
the NOE effect between H2 and H7 is much higher than
in 53a, indicating that in the lactam 53b the H2 and H7
are in the same side of the ring system (Fig. 6). Hydro-
Scheme 5. Reagents and condition: (a) Jones reagent, acetone; (b)
MeNH , KCN, ultrasound, THF; (c) PhNH , AlCl , CH Cl ; (d)
NH , AlMe , CH Cl ; (e) 1 N LiOH, THF; (f) 1 N HCl/EtOAc; (g)
Dowex 50 · 8–100; (h) TFAA, Py.
2
2
3
2
2
3
3
2
2

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6561
CO Et
CO Et
CO
2
Et
3. Biochemical methods
2
2
a
b
c
H
H
Test compounds were evaluated for their ability to dis-
place H-LY341495 from membranes expressing indi-
85%
80%
90%
3
HO
O
OH
OH
vidual recombinant human mGlu2, mGlu3, or mGlu8
2
2
1
41
42
8a,29,30
receptor subtypes.
from the IC values employing the Cheng–Prusoff
The K values were calculated
i
5
0
CO Et
CO Et
CO H
31
2
2
2
equation. Test compounds were also evaluated for
their ability to influence the production of second mes-
sengers in AV12-664 cells co-expressing both GLAST
d, e
0%
f, g, h
65%
NC
H
HO C
2
7
H
OHC
NHAc
44
NH2
(a recombinant glutamate transporter to minimize con-
stituent glutamate activity) and recombinant human
4
3
45
8
b
mGlu2 or mGlu3 receptor.
Scheme 6. Reagents and condition: (a) CH
3
PPh
N, CH Cl
; (f) recrystallization; (g) 1 N HCl, reflux;
h) propylene oxide, MeOH.
3
Br, KHMDS, THF;
(
(
(
b) H
2
, Pd/C; (c) DMSO, (COCl)
2
, Et
3
2
2
; (d) NH Cl, KCN;
4
i
e) AcCl, Pr
2
2 2
EtN, CH Cl
4. Results and discussion
0
In our previous studies on the C3 -cis-substituted carb-
0
CO Et
CO Et
2
oxycyclopropyl glycines, we described the C3 -cis-meth-
2
a
b
c
yl substituted CCG 18 as a potent and selective group II
mGlu receptor agonist, and its hydroxymethyl substitut-
ed analog (+)-19, which turned out to be an equally po-
H
H
H
O
H
O
82%
60%
85%
O
O
48
1
9
4
6
47
tent group II and group III (mGluR6/8) agonist.
Considering these results, we decided to explore the ef-
fect of a variety of substituents at this position on their
CO Et
CO Et
2
CO Et
2
2
d
NC
NC
28
H
HO
H
affinity (displacement of [3H]LY341495) and function-
al activity (influence on cAMP formation in cells
expressing recombinant human mGlu2 or mGlu3 recep-
+
O
70%
H
H
NH2
NH2
O
O
2
9
4
9
50a
50b
tors at group II mGlu receptors). Since (+)-19 also
shows affinity for the mGlu8 receptor, compounds were
also tested in a binding assay using membranes from
e,f
51%
3
0
RGT cells expressing human mGluR8. All new com-
pounds were prepared and tested as racemic mixtures.
The results are given in Table 1.
CO Et
2
CO Et
2
EtO C
2
EtO C
2
H
H
NHBoc
0
NHBoc
C3 -cis-substituted CCGs 23, 25, 26, 28, 32–35, 38, 40,
5, and 52 all displaced [3H]341495 binding to both
OH
OH
4
5
1a
5
1b
mGlu2 and mGlu3 receptors, though with generally
lower affinity than those observed for 18 and (+)-19,
though several of them maintain sub-micromolar affini-
ty for these targets. Affinity for mGlu8 was also ob-
CO Et
CO H
2
2
g,h
EtO C
HO C
2
2
H
69%
H
NHBoc
NH2
OH
OH
served, albeit generally weak, with K values in the
i
51a
52a
micromolar potency range.
Scheme 7. Reagents and condition: (a) EtO
CHCl ; (b) MCPBA, CH Cl
KCN, MeCN, ultrasound; (e) satd HCl/EtOH, H
NaHCO , dioxane; (g) 1 N HCl, reflux; (h) propylene oxide, MeOH.
2
CCH
2
SMe
2
Br, DBU,
Replacement of the methyl group of analog 18 (mGlu2
K = 87.4 nM, mGlu3 K = 162.2 nM) with a sterically
3
2
2
; (c) DIBAL-H, THF, ꢀ78 ꢁC (d) NH
4
Cl,
O,
i
i
2
O; (f) Boc
2
comparable but electron-withdrawing cyano group re-
sults in full agonist activity at both receptors and a slight
loss of binding affinity at mGlu2 (K = 170 nM) and a
3
i
modest increase in affinity at mGlu3 (K = 50 nM) for
i
analog 40. On the other hand, extending the methyl
group of 18 to ethyl (compound 45) or the hydroxy-
methyl group of (+)-19 to hydroxyethyl (compound
52a) results in a substantial decrease in binding affinity
and agonist potency for each of these analogs at both
mGlu2 and mGlu3, suggesting that the beneficial effect
of hydroxyl group substitution in compound (+)-19
may be due to a specific polar interaction with a receptor
site residue adjacent to the C3 position of bound CCGs.
Replacement of the hydroxyl functionality of (+)-19
Figure 6.
0
lysis of the intermediate with the desired relative stereo-
chemistry 51a with 1 N HCl was carried out, leading to
with sulfhydryl results in some loss affinity and agonist
potency at mGlu2 for 25a (mGlu2 K = 213 nM,
EC50 = 47 nM). However, while this analog maintains
0
the C3 -hydroxyethyl CCG 52a after the treatment with
propylene oxide (Scheme 7).
i

6562
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
mGlu3 affinity (K = 254 nM) it produces a full antago-
i
of the described analogs displaying mGlu3 subtype selec-
tivity and one, 25a, possessing a unique mGlu2 agonist/
mGlu3 antagonist profile. In contrast to the observed
conversion of CCG-based agonists to antagonists upon
addition of large aryl or alkylaryl substituents at the
nist response against this target (IC50 = 59 nM).
Replacement of the hydroxyl functionality of (+)-19
by a polar uncharged azido group (compound 28) re-
sults in full agonist activity at both mGlu2 and mGlu3
receptors with some loss potency, while introduction
of a basic (CH NH ) group results in a significant loss
0
15,16
C3 position,
agonist activity for mGlu2/3 receptors
0
is maintained for nearly all of the C3 -substituted ana-
logs evaluated, regardless of the size of this substituent.
It is possible that the presence of certain heteroatom
2
2
of both affinity and agonist potency for 35 (mGlu2
K = 10,830 nM, mGlu2 EC = 1710 nM).
i
50
0
combinations within the C3 -substituent chain (amides,
Given these results and the known conversion of agonist
to antagonist pharmacology by incorporating large lipo-
carbamates, and ureas) is responsible for maintaining
the agonist response in these analogs, though the molec-
ular basis for this effect remains unclear.
1
5–17
philic substituents onto monocyclic
carboxycyclo-
propyl glycine derivatives, we were interested in
exploring limits of agonist activity within this series.
Replacement of the sulfhydryl in 25a with thiophenyl
5. Experimental
5.1. General
(
25b) results in loss of affinity at both mGlu2 and
mGlu3, but also in maintenance of full agonist activity
at each of these targets. In this case, the antagonist effect
observed for 25a at mGlu3 is reversed by the addition of
a large lipophilic phenyl substituent. This profile is
maintained, though with additional loss in potency, in
the phenylsulfonyl analog 26b. Similarly, carbamate
analogs of (+)-19 (23a and 23b), while less potent than
All solvents and reagents were purchased from commer-
cial sources and used as received, unless otherwise indicat-
1
13
ed. H NMR and C NMR data were recorded on a
Bruker AC-200P (200 MHz) or Brucker AM-300
(300 MHz) spectrometer. Chemical shifts are reported
as ppm (d), relative to TMS as internal standard. Analyt-
ical TLC was performed on Merck TLC glass plates pre-
coated with F254silica gel 60 (UV, 254 nm and
phosphomolybdic acid). Chromatographic separations
were performed by using 230–400 mesh silica gel (Merck).
Mass spectra were obtained on an Agilent 1100 series
instrument. High resolution mass spectra (HRMS) were
acquired on a Thermo Electron LTQ-FT Fourier Trans-
form Ion Cyclotron Resonance mass spectrometer with
an instrument resolution of 2,00,000 for m/z 500, using
external calibration. Sample ionization was achieved
using electrospray and measurement of pseudo-molecular
(
+)-19, maintain submicromolar binding affinity and
agonist potency at both mGlu2 and mGlu3, with the ste-
rically larger phenyl carbamate analog 23b demonstrat-
ing potency superior to that of ethyl carbamate variant
2
3a. A parallel trend is also observed for ethyl and phen-
yl ureas 33a and 33b. Amide pair 32a/32b, while main-
taining full agonist activity in both mGlu2 and
mGlu3-expressing cells, does not clearly differentiate
from one another as in the aforementioned ethyl and
phenyl urea/carbamate pairs. In all cases, acylation or
sulfonylation of the primary amino group of 35 provides
compounds with generally superior affinity and agonist
potency at mGlu2 and mGlu3 receptors. We were inter-
+
+
ion clusters [M+H] or [M+Na] was carried out. Infra-
red spectra (IR) were recorded on a Perkin-Elmer 1310
spectrophotometer. Melting points were measured with
a capillary melting point apparatus and are uncorrected.
13
ested in whether amide variants of DCG-IV (11) might
also retain mGlu 2/3 receptor agonist activity. Indeed,
both the N-methyl and N-phenyl amide analogs of 11
(
38a and 38b, respectively) retain full agonist activity
in cells expressing each of these receptors, though with
substantial loss in potency.
5.2. General hydrolysis procedure A
A 2.5 M solution of LiOHÆH O (40 equiv) in H O was
2
2
Finally, some of the analogs in this account display
modest subtype selectivity between mGlu2 and mGlu3.
Thus, compounds 23b and 33b demonstrate 4-fold selec-
tivity for mGlu3 over mGlu2 based on receptor affinity,
but this difference is not maintained in the whole cell func-
tional assay. In contrast, 40 demonstrates 3-fold selectiv-
ity for mGlu3 in both the binding and functional assays,
and 25a, while possessing equivalent affinity for both
mGlu2 and mGlu3, produces agonist responses in cells
expressing the mGlu2 and reverses agonist responses
added to a 0.1 M solution of the corresponding protect-
ed aminoacid in THF and the mixture was stirred at
room temperature overnight. EtOAc was added, the
organic layer was separated, and the aqueous layer
was washed with EtOAc (3·). The aqueous layer was
acidified to pH 1 with 1 N HCl and extracted in EtOAc
(5·). The combined organic layers were dried over
MgSO , filtered, and concentrated under vacuum. The
4
residue was dissolved in a 1 N solution of HCl in EtOAc
and the solution (0.12 N) was stirred overnight at room
temperature. It was then concentrated under vacuum
(
i.e., is an antagonist) in cells expressing mGlu3.
and the resulting solid was washed with Et O. The prod-
2
uct amino acids were isolated as zwitterions by ion-
exchange chromatography.
0
In conclusion, we have described a series of C3 -cis-
substituted CCGs bearing a wide variety of functional
groups as potent group II mGlu receptor agonists. Most
of the compounds in this series have been synthesized
from a common and versatile synthetic intermediate
5.3. General hydrolysis procedure B
20. The binding affinity for the group II mGlu receptors
0
depends on the nature of the C3 -substituent, with some
A 2.5 M solution of LiOHÆH O (40 eq) in H O was
added to a 0.1 M solution of the corresponding pro-
2
2

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6563
0
0
0
0
tected aminoacid in THF and the mixture was stirred
at room temperature overnight. EtOAc was added,
the organic layer was separated, and the aqueous layer
was washed with EtOAc (3·). The aqueous layer was
acidified to pH 1 with 1 N HCl and extracted in EtOAc
5.6. (2SR,1 SR,2 RS,3 RS)-2-(3 -ethylcarbamoyloxy-
methyl-2 -carboxycyclopropyl)glycine 23a
0
Prepared from 22a following the general hydrolysis pro-
cedure A. Yield: 47ꢀ. H NMR (D O/Py-d , 200 MHz)
1
2
5
(
MgSO , filtered, and concentrated under vacuum.
The residue was dissolved in a 1 N solution of HCl
in EtOAc and the solution (0.12 N) was stirred over-
night at room temperature. It was then concentrated
under vacuum and the resulting solid was washed with
5·). The combined organic layers were dried over
d: 4.0 (dd, J = 12, 5 Hz, 1H), 3.7 (dd, J = 12, 7 Hz, 1H),
3.2 (d, J = 10 Hz, 1H), 2.6 (q, J = 8 Hz, 2H), 1.6–1.4 (m,
3H), 0.6 (t, J = 8 Hz, 3H) ppm. C NMR (D O/MeOH-
d4, 50 MHz) d: 179.7, 173.2, 158.0, 63.4, 54.6, 35.5, 26.9,
25.9, 24.6, 14.2 ppm.
4
1
3
2
0
0
0
0
Et O. The resulting hydrochloride salt of the title com-
2
5.7. (2SR,1 SR,2 RS,3 RS)-2-(3 -phenylcarbamoyloxy-
methyl-2 -carboxycyclopropyl)glycine 23b
0
pound was dissolved in methanol (0.2 M) and propyl-
ene oxide (25 mL/mmol) was added. The mixture was
stirred overnight and the precipitate was filtered and
washed with diethyl ether to give the product amino
acid as zwitterion.
Prepared from 22b following the general hydrolysis pro-
cedure A. Yield: 55ꢀ. H NMR (D O/Py-d , 200 MHz)
1
2
5
d: 7.0 (d, J = 8 Hz, 2H), 6.9 (dd, J = 8, 7 Hz, 2H), 6.6 (t,
J = 7 Hz, 1H), 4.3 (dd, J = 12, 5 Hz, 1H), 3.9 (dd,
J = 12, 7 Hz, 1H), 3.4 (d, J = 10 Hz, 1H), 1.8–1.6 (3H,
5
.4. General hydrolysis procedure C
1
3
m) ppm. C NMR (D O/Py-d , 50 MHz) d: 179.6,
2
5
1
72.7, 154.8, 137.3, 129.0, 123.2, 119.3, 63.4, 54.3,
A 0.1 M solution of the corresponding protected amino-
acid in 6 N HCl was heated under reflux for 16 h. The
solvent was then removed under vacuum and the result-
ing solid was washed with diethyl ether to give the
corresponding hydrochloride salt. After purification by
ion-exchange chromatography, the final aminoacids
were isolated as zwitterions.
26.7, 24.8, 23.8 ppm. HRMS (M+1): calcd for
C H O N 309.10811. Found: 309.10810.
14 17
6
2
0 0 0
.8. Ethyl (2SR,1 RS,2 RS,3 RS)-N-(tert-butoxycarbon-
5
0
0
yl)-2-[2 -(ethoxycarbonyl)-3 -(acetylthiomethyl)cyclo-pro-
pyl]-glycinate 24a
Diethyl azodicarboxylate (0.091 mL, 0.58 mmol) was
added dropwise to a solution of triphenylphosphine
5
.5. General procedure for the preparation of 22
(
0
152 mg, 0.58 mmol) in anhydrous THF (1.8 mL) at
ꢁC under argon. The mixture was stirred for 20 min
and then a solution of thioacetic acid (0.042 mL,
.58 mmol) and 20 (100 mg, 0.29 mmol) in anhydrous
Two equivalents (2.8 mmol) of the corresponding isocy-
anate were added to a 0.1 M solution of 20 (500 mg,
1
.4 mmol) in pyridine at room temperature and the mix-
ture was stirred for two days. EtOAc and H O were add-
0
2
THF (0.9 mL) was added via cannula and the mixture
was stirred overnight at rt. Silica gel was added to the
mixture. The solvent was removed under vacuum and
the residue was purified by flash chromatography using
hexane/ethyl acetate (4:1) as eluent to give 70 mg of 24a
(
ed, the organic layer was separated, and the aqueous
layer was extracted with EtOAc (3·). The combined
organic layers were washed with H O (5·), dried over
2
MgSO , filtered, and concentrated under vacuum. The
4
corresponding glycinates 22 were purified by column
chromatography using a 2:1 hexane/EtOAc mixture as
eluent.
1
60ꢀ yield). H NMR (200 MHz, CDCl ) d: 5.02 (br s,
3
1
2
H), 4.21–3.98 (dc, 6H), 3.20 (m, 1H), 3.00 (m, 1H),
.27 (s, 3H), 1.74 (m, 1H), 1.38 (s, 9H), 1.19 (dt, 6H)
1
3
ppm. C NMR (50 MHz, CDCl ) d: 195.0, 172.2,
170.8, 155.1, 80.1, 61.8, 60.8, 51.9, 30.8, 30.4, 27.9,
27.0, 25.2, 24.9, 14.0 ppm.
3
0
0
0
5.5.1. Ethyl (2SR,1 SR,2 RS,3 RS)-N-(tert-butoxy-carbon-
yl)-2-[2 -(ethoxycarbonyl)-3 -ethylcarbamoyl-oxy-methylcy-
0
0
1
clopropyl] glycinate 22a. Yield: 40ꢀ. H NMR (CDCl ,
3
0 0 0
5.9. Ethyl (2SR,1 RS,2 RS,3 RS) N-(tert-butoxycarbon-
yl)-2-[2 -(ethoxycarbonyl)-3 -(phenylthiomethyl)-cyclo-
propyl] glycinate 24b
2
(
2
00 MHz) d: 5.5 (d, J = 8 Hz, 1H), 5.2 (br s, 1H), 4.4
dd, J = 11, 4 Hz, 1H), 4.2–4.0 (m, 6H), 3.1 (m, 2H),
.0–1.7 (m, 3H), 1.4 (s, 9H), 1.3–1.1 (m, 6H), 1.0 (t,
0
0
1
3
J = 7 Hz, 3H) ppm. C NMR (CDCl , 50 MHz) d:
3
1
2
72.4, 170.7, 155.7, 155.0, 79.8, 61.5, 60.6, 51.8, 35.5,
8.8, 27.9, 25.5, 22.9, 14.9, 13.8 ppm.
A mixture of tributylphosphine (0.26 mL, 1.04 mmol),
diphenyl disulfide (170 mg, 0.78 mmol), and 20 (90 mg,
0
.26 mmol) in anhydrous THF (2 mL) was stirred at
0
0
0
5.5.2. Ethyl (2SR,1 SR,2 RS,3 RS)-N-(tert-butoxy-car-
bonyl)-2-[3 -phenylcarbamoyloxymethyl-cyclopropyl] gly-
room temperature under argon for 20 h. Then, silica
gel was added to the mixture and the solvent was re-
moved under vacuum. The resulting residue was purified
by flash chromatography using hexane and ethyl acetate
4:1 as eluent to afford 80 mg (70ꢀ yield) of 24b. H NMR
(200 MHz, CDCl ) d: 7.25 (m, 5H), 5.20 (br d, 1H), 4.10
(m, 5H), 3.30 (dd, 1H), 2.85 (m, 1H), 1.75 (m, 3H), 1.40
(s, 9H), 1.25 (m, 6H) ppm. C NMR (50 MHz, CDCl3)
d: 172.3, 170.9, 155.2, 135.2, 130.5, 128.9, 126.6, 80.2,
61.7, 60.7, 52.1, 33.3, 30.2, 28.1, 26.9, 25.7, 14.0 ppm.
0
1
cinate 22b. Yield: 70ꢀ. H NMR (CDCl , 200 MHz) d:
.6 (s, 1H), 7.4 (d, J = 8 Hz, 2H), 7.3 (dd, J = 8, 7 Hz,
3
7
2
1
H), 7.0 (t, J = 7 Hz, 1H), 5.5 (d, J = 8 Hz, 1H), 4.6
dd, J = 12, 5 Hz, 1H), 4.4–4.1 (m, 6H), 2.1–1.7 (m,
(
3
3
1
3
H), 1.5 (s, 9H), 1.3–1.2 (m, 6H) ppm. C NMR
1
3
(
CDCl , 50 MHz) d: 172.6, 171.1, 155.4, 153.0, 138.0,
28.9, 123.1, 118.4, 80.2, 61.8, 60.9, 60.3, 51.7, 29.2,
8.1, 25.5, 22.6, 14.0 ppm.
3
1
2

6564
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
0
0
0
0
0
5.10. (2SR,1 RS,2 RS,3 RS)-2-[3 -Mercaptomethyl-2 -
carboxycyclopropyl]glycine 25a
act at rt for 3 days. The reaction mixture was quenched
with water and the organic layer was extracted with
EtOAc (2· 25 mL). The combined organic layers were
Prepared from 24a following the general hydrolysis pro-
dried over MgSO , filtered, and concentrated under vac-
4
1
3
cedure C. Yield: 80ꢀ C NMR (50 MHz, D O/Py-d ) d:
uum. The product was purified by column chromatogra-
phy using hexane and ethyl acetate 4:1 as eluent to give
250 mg (78ꢀ yield) of 27 as a colorless oil. H NMR
2
5
1
78.1, 171.5, 52.7, 28.4, 27.2, 26.6, 21.7 ppm. IR (film):
437; 1631; 1385; 1234 and 889 cm . MS (ES+) = 228
ꢀ
1
1
3
+
M +23). HRMS (M+1): calcd for C H O N S1
32
(
(CDCl , 200 MHz) d: 5.2 (d, J = 8 Hz, 1H), 4.3–3.9
7
12
4
1
3
2
2
06.04816. Found: 206.04823. Melting point: 200–
02 ꢁC
(m, 5H), 3.6 (dd, J = 13, 5 Hz, 1H), 3.3 (dd, J = 13,
7 Hz, 1H), 1.9–1.7 (m, 3H), 1.4 (s, 9H), 1.3–1.2 (m,
1
3
6
H) ppm. C NMR (CDCl , 50 MHz) d: 172.1, 170.7,
3
0
0
0
0
0
5.11. (2SR,1 RS,2 RS,3 RS)-2-[3 -(phenylthiomethyl)-2 -
carboxycyclopropyl]glycine 25b
155.2, 80.2, 61.8, 61.0, 52.0, 49.4, 29.0, 28.1, 25.4, 24.0,
14.0 ppm.
0
0
0
0
0
Prepared from 24b following the general hydrolysis pro-
cedure C. Yield: 83ꢀ. H NMR (200 MHz, D O/Py-d )
5.14. (2SR,1 SR,2 SR,3 RS)-2-(3 -azidomethyl-2 -
carboxycyclopropyl)glycine 28
1
2
5
d: 6.99–6.47 (m, 5H), 3.11–3.01 (m, 2H), 2.32–2.21 (m,
1
1
H), 1.57–1.41 (m, 2H), 1.24–1.19 (t, 1H) ppm. C
3
Prepared from 27 following the general hydrolysis pro-
cedure B as a white solid. Yield: 73ꢀ. H NMR (D O,
1
NMR (50 MHz, D O/Py-d ) d: 179.3, 173.0, 135.4,
2
5
2
1
29.6, 129.4, 126.3, 54.9, 32.9, 29.4, 27.7, 25.8 ppm. IR
film): 3059, 1716, 1678, 1585, 1514, 1385, 1184, 1014
200 MHz) d: 3.6 (dd, J = 13, 5 Hz, 1H), 3.3 (d,
J = 10 Hz, 1H), 3.2 (dd, J = 13, 8 Hz, 1H), 1.9–1.7 (m,
(
and 897cm
ꢀ
1
+
MS (ES+) = 282 (M +1). HRMS
13
.
M+1): calcd for C H O N S1 282.07946. Found:
3H) ppm. C NMR (D O/MeOH-d , 50 MHz) d:
2
4
3
2
(
177.4, 173.2, 54.7, 50.1, 27.4, 26.9, 25.7 ppm. MS
(FAB+): 215 (M +1). Anal. Calcd for C H N O : C,
1
3
16
4
1
+
2
82.07947.
7
10
4
4
39.25; H, 4.71; N, 26.16. Found: C, 39.36; H, 4.79; N,
26.26.
0
0
0
0
5
.12. (2SR,1 RS,2 RS,3 RS)-2-[3 -(phenylsulfonylmeth-
yl)-2 -carboxycyclopropyl]glycine 26b
0
0 0 0
.15. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
bonyl)-2-[2 -(ethoxycarbonyl)-3 -(acetylaminomethyl)-
cyclopropyl] glycinate 29a
5
0
0
m-Chloroperoxybenzoic acid (54.3 mg, 0.22 mmol) was
added to a solution of 24b (50 mg, 0.11 mmol) in anhy-
drous CH Cl (1 mL) at 0 ꢁC under N and the mixture
was stirred for 3 h at this temperature. Then, the residue
was diluted with CH Cl and washed with a 15ꢀ aque-
ous solution of sodium bisulfite and with a saturated
aqueous solution of sodium bicarbonate. The organic
layer was dried over magnesium sulfate and the solvent
was removed under vacuum. The residue was purified by
flash chromatography using hexane and ethyl acetate 2:1
as eluent to afford 42 mg of the protected aminoacid.
Hydrolysis, following the general hydrolysis procedure
B, afforded 26b as a white solid (overall yield: 47ꢀ).
2
2
2
Acetic anhydride (0.3 mL, 2.7 mmol) and 10ꢀ palladi-
um on activated carbon (90 mg) were added to a solu-
tion of 27 (500 mg, 1.35 mmol) in ethanol (15 mL) and
2
2
the resulting mixture was stirred at rt under H for
2
2 h. Then, it was filtered through Celite and concentrat-
ed under vacuum. The resulting residue was purified by
column chromatography using hexane and ethyl acetate
1
1:1 as eluent to afford 375 mg (72ꢀ yield) of 29a. H
NMR (CDCl , 200 MHz) d: 6.6 (broad s, 1H), 5.3 (d,
3
J = 8 Hz, 1H,), 4.3–3.9 (m, 6H), 2.9–2.8 (m, 1H), 1.9
(s, 3H), 1.9–1.7 (m, 3H), 1.4 (s, 9H), 1.3–1.1 (m, 6H)
1
H NMR (200 MHz, D O/Py-d ) d: 7.40 (d, 2H), 7.15
m, 3H), 3.65 (d, 1H), 3.45 (m, 1H), 2.90 (m, 1H), 1.40
m, 3H) ppm. C NMR (50 MHz, D O/Py-d ) d:
2
5
1
3
(
(
1
2
(
3
ppm. C NMR (CDCl , 50 MHz) d: 172.1, 171.6,
3
1
3
169.9, 155.5, 80.4, 62.1, 60.9, 52.4, 37.7, 28.9, 28.1,
26.6, 23.2, 14.0 ppm.
2
5
78.1, 172.7, 136.6, 134.7, 129.8, 128.1, 55.3, 54.7,
8.6, 25.0, 19.3 ppm. MS (ES+) = 314 (M +1). HRMS
+
3
M+1): calcd for C H O N S1 314.06929. Found:
2
0 0 0
5.16. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
1
3
16
6
1
0
0
14.06926.
bonyl)-2-[2 -(ethoxycarbonyl)-3 -(benzoylaminomethyl)-
cyclopropyl]glycinate 29b
0
0
0
5
.13. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
bonyl)-2-[2 -(ethoxycarbonyl)-3 -(azidomethyl)cyclopro-
pyl] glycinate 27
0
0
Benzoic anhydride (0.23 mL, 2.0 mmol) and platinum
(IV) oxide (61 mg, 0.27 mmol) were added to a solution
of 27 (500 mg, 1.35 mmol) in EtOAc (15 mL) and the
Diethyl azodicarboxylate (1.08 mmol, 0.17 mL) was
added dropwise to a solution of triphenylphosphine
resulting mixture was stirred at rt under H for 2 h.
2
Then, the mixture was filtered through Celite and con-
centrated under vacuum. The residue was purified by
column chromatography using hexane and ethyl acetate
(
1.08 mmol, 0.285 g) in anhydrous THF (20 mL) at
20 ꢁC under N and the reaction mixture was stirred
ꢀ
2
1
at the same temperature for 10 min. A solution of 20
0.87 mmol, 300 mg) in anhydrous THF (5 mL) was
then added and the resulting mixture was stirred for
1:1 as eluent to afford 363 mg (65ꢀ yield) of 29b. H
NMR (CDCl , 200 MHz) d: 7.9 (m, 2H), 7.6–7.4 (m,
(
3
3H), 5.3 (d, J = 8 Hz, 1H), 4.5 (m, 1H), 4.4–4.1 (m,
5H), 3.1–3.0 (m, 1H), 2.0–1.8 (m, 3H), 1.5 (s, 9H),
1
0 min at ꢀ20 ꢁC. After that time, diphenylphosphoryl
1
3
azide (1.13 mmol, 0.25 mL) was added to the reaction
mixture at the same temperature and then allowed to re-
1.3–1.2 (m, 6H) ppm. C NMR (CDCl , 50 MHz) d:
3
172.1, 171.7, 167.0, 155.4, 134.2, 131.3, 128.4, 127.0,

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6565
0
0
0
0
80.5, 62.4, 61.0, 52.5, 38.0, 28.9, 28.2, 26.6, 23.0, 14.0
ppm.
5.21. (2SR,1 SR,2 SR,3 RS)-2-(3 -phenylureidomethyl-
2 -carboxycyclopropyl)glycine 33b
0
0
0
0
0
5
2
.17. (2SR,1 SR,2 SR,3 RS)-2-(3 -acetylaminomethyl-
-carboxycyclopropyl)glycine 32a
Prepared from 30b following the general hydrolysis pro-
1
cedure A. Yield 56ꢀ. H NMR (D
0
O, 200 MHz) d: 7.6–
.0 (m, 7H), 4.3 (dd, J = 10, 5 Hz, 1H), 3.9 (m, 1H), 3.3
(d, J = 10 Hz, 1H), 1.8–1.5 (m, 3H) ppm. C NMR
(D O/Py-d , 50 MHz) d: 180.1, 173.4, 157.7, 138.2,
129.1, 123.7, 120.9, 54.3, 38.7, 26.8, 26.1, 25.8 ppm.
2
7
1
3
Prepared from 29a following the general hydrolysis pro-
cedure B as a white solid. Yield: 30ꢀ. H NMR (D O/
MeOH-d , 200 MHz) d: 3.7 (dd, J = 14, 6 Hz, 1H), 3.2
1
2
2
5
4
(
d, J = 10 Hz, 1H), 3.0 (dd, J = 14, 7 Hz, 1H), 1.9 (s,
1
3
H), 1.8–1.6 (m, 3H) ppm. C NMR (D O/MeOH-d ,
0 0 0
5.22. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
bonyl)-2-[2 -(ethoxycarbonyl)-3 -benzene-sulfonylami-
nomethyl-cyclopropyl]glycinate 31
3
5
2
2
4
0
0
0 MHz) d: 175.4, 172.3, 171.4, 52.8, 36.9, 26.0, 25.2,
3.5, 21.0 ppm.
0
0
0
0
PtO (0.27 mmol, 60 mg) was added to a solution of 27
2
5
2
.18. (2SR,1 SR,2 SR,3 RS)-2-(3 -benzoylaminomethyl-
-carboxycyclopropyl)glycine 32b
0
(1.35 mmol, 500 mg) in EtOAc (15 mL) and the reaction
mixture was stirred at rt under H for 4 h. Then, benze-
2
nesulfonyl chloride (2.7 mmol) was added and the mix-
ture was stirred under N overnight. The mixture was
Prepared from 29b following the general hydrolysis pro-
cedure A as a white solid. Yield: 25ꢀ. H NMR (D O/
1
2
2
filtered through Celite and concentrated under vacuum.
The residue was chromatographed using a 2:1 hexane/
EtOAc mixture as eluent giving rise to 31. Yield: 56ꢀ.
Py-d , 200 MHz) d: 7.6–7.1 (m, 5H), 3.8 (dd, J = 14,
5
5
8
Hz, 1H), 3.3 (d, J = 10 Hz, 1H), 2.7 (dd, J = 14,
Hz, 1H), 1.7–1.5 (m, 3H) ppm. C NMR (D O/Py-
1
3
2
1
H NMR (CDCl , 200 MHz) d: 7.8 (m, 2H), 7.5 (m,
d5, 50 MHz) d: 179.7, 173.3, 169.1, 133.2, 132.2, 128.8,
27.3, 54.6, 38.8, 27.1, 26.4, 25.0 ppm. HRMS (M+1):
calcd for C H O N 293.11320. Found: 293.11319.
3
3
4
1
H), 5.8 (dd, J = 9, 3 Hz, 1H), 5.2 (d, J = 8 Hz, 1H),
.3–4.0 (m, 4H), 3.8 (m, 1H), 3.5 (m, 1H), 2.8 (m, 1H),
1
1
4
17
5
2
1
3
.9–1.6 (m, 3H), 1.4 (s, 9H), 1.3–1.1 (m, 6H) ppm.
C
NMR (CDCl , 50 MHz) d: 171.7, 171.1, 155.1, 140.0,
3
5
.19. General procedure for the preparation of 30
132.3, 128.9, 126.6, 80.0, 62.1, 60.7, 52.0, 41.9, 28.8,
2
7.9, 26.1, 23.2, 13.8, 13.7 ppm.
Two equivalents of the corresponding isocyanate
2.7 mmol) and 0.2 equivalents of PtO2 (0.27 mmol,
(
0
0
0
0
5.23. (2SR,1 SR,2 SR,3 RS)-2-(3 -benzenesulfonylamino-
methyl-2 -carboxycyclopropyl)glycine 34
6
0 mg) were added to a solution of 27 (1.35 mmol,
0
5
at rt under H for 4 h. The mixture was filtered through
00 mg) in EtOAc (15 mL), and the mixture was stirred
2
Prepared from 31 following the general hydrolysis
procedure A. Yield: 44ꢀ. C NMR (D O/MeOH-d ,
5
5
Celite and concentrated under vacuum. The residue was
chromatographed using a 2:1 hexane/EtOAc mixture as
eluent giving rise to 30.
1
3
2
4
0 MHz) d: 179.5, 173.8, 139.3, 134.6, 130.7, 127.8,
5.0, 43.3, 27.6, 27.1, 25.7 ppm. HRMS (M+1): calcd
3
2
for C H O N S1 329.08018. Found: 329.08017.
6
0 0 0
.19.1. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
bonyl)-2-[2 -(ethoxycarbonyl)-3 -ethylureidomethyl-cyclo-
13 17
2
5
0
0
0 0 0 0 0
.24. (2SR,1 SR,2 SR,3 RS)-2-[3 -aminomethyl-2 -carb-
oxycyclopropyl]glycine 35
5
1
3
propyl]glycinate 30a. Yield: 64ꢀ. C NMR (CDCl3,
5
0 MHz) d: 172.3, 171.5, 158.2, 155.3, 79.7, 61.6, 60.5,
5
2.4, 38.5, 34.8, 28.7, 28.0, 27.3, 23.3, 15.2, 13.8 ppm.
A solution of 29a (300 mg, 0.77 mmol) in 2 N HCl
(5 mL) was stirred at room temperature for 24 h and
0 0 0
.19.2. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxy-car-
bonyl)-2-[2 -(ethoxycarbonyl)-3 -phenylureido-methylcy-
5
then heated at 55 ꢁC for 60 h. The solvent was removed
under vacuum to give the corresponding hydrochloride
salt of the title compound. After purification by ion-
exchange chromatography, 58 mg (40ꢀ yield) of 35
0
0
1
clopropyl]glycinate 30b. Yield: 63ꢀ. H NMR (CDCl ,
3
2
00 MHz) d: 7.5–7.2 (m, 5H), 7.1–7.0 (m, 1H), 5.9 (t,
J = 6 Hz, 1H), 5.4 (d, J = 8 Hz, 1H), 4.2–4.0 (m, 5H),
.8–3.7 (m, 1H), 3.3–3.1 (m, 1H), 2.0–1.7 (m, 3H), 1.5
1
was obtained as a white solid. H NMR (D O/Py-d ,
2
5
3
2
00 MHz) d: 3.3 (m, 1H), 3.3 (d, J = 11 Hz, 1H), 2.7
1
3
(
s, 9H), 1.3–1.2 (m, 6H) ppm. C NMR (CDCl3,
13
(dd, J = 13, 10 Hz, 1H), 1.8–1.5 (m, 3H) ppm.
C
5
1
2
0 MHz) d: 172.4, 171.5, 155.7, 155.4, 138.9, 129.7,
28.9, 123.0, 120.4, 80.4, 62.0, 60.9, 52.4, 38.5, 28.9,
8.1, 27.2, 23.3, 14.0 ppm.
NMR (D O/Py-d , 50 MHz) d: 178.3, 172.7, 53.8, 38.2,
2
5
27.0, 25.6, 21.8 ppm. HRMS (M+1): calcd for
C H O N 189.08698. Found: 189.08698.
7
13
4
2
0
0
0
0
0
5.20. (2SR,1 SR,2 SR,3 RS)-2-(3 -ethylureidomethyl-2 -
carboxycyclopropyl)glycine 33a
5.25. Ethyl (1SR,2SR,5RS,6RS)3-tert-butoxycarbonyl-4-
oxo-3-azabicyclo[3.1.0]-hexane-2,6-dicarboxylate 36
Prepared from 30a following the general hydrolysis
Jones reagent solution (3.8 mL) was added dropwise at
0 ꢁC to a solution of 20 (740 mg, 2.14 mmol) in acetone
(17 mL) and the reaction mixture was stirred for 1 h at
1
3
procedure A. Yield: 42ꢀ. C NMR (D O, 50 MHz) d:
2
1
77.6, 172.8, 53.7, 38.4, 34.9, 26.7, 26.7, 24.6, 14.2
+
i
ppm. MS (ES+) = 260 (M +1). HRMS (M+1): calcd
for C H O N 260.12410. Found: 260.12405.
0 ꢁC and for 2 h at rt. Then, H O (17 mL) and PrOH
2
1
0
18
5
3
(17 mL) were added and the reaction mixture was

6566
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
extracted with ethyl acetate (3· 20 mL). The combined
AlMe (0.88 mmol) was added and the mixture was stir-
3
organic layers were dried over MgSO and the solvent
was removed under vacuum. The residue was chromato-
graphed (EtOAc) to give 710 mg of 36 (97ꢀ yield). H
red for 20 h at rt. The mixture was quenched with HCl
(0.1 N) at 0 ꢁC and stirred for 15 min. The white solid
formed was filtered, and the filtrate was concentrated
under vacuum. The residue was chromatographed (hex-
4
1
NMR (200 MHz, CDCl ) d: 4.73 (d, J = 5.9 Hz, 1H),
3
4
1
1
.26 (dq, J = 7.2, 3.4 Hz, 2H), 2.62 (dt, J = 3.2, 6.6Hz,
H), 2.52 (dd, J = 2.8, 6.6 Hz, 1H), 2.32 (t, J = 3.0 Hz,
H), 1.44 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), (t,
ane/ethyl acetate 2:1) to give 114 mg of 37c (54ꢀ yield).
H NMR (200 MHz, CDCl ) d: 6.15 (br s, 2H), 5.25 (br
1
3
s, 1H), 4.53 (dd, 1H), 4.12 (dc, 4H), 2.55 (t, 1H), 2.26
(dd, 1H), 2.04 (m, 1H), 1.43 (s, 9H), 1.24 (dt, 6H)
1
3
J = 7.1 Hz, 3H) ppm. C NMR (50 MHz, CDCl ) d:
3
1
3
1
2
2
68.9, 168.7, 168.1, 148.1, 83.3, 61.7, 61.4, 58.1, 28.6,
7.2, 21.7, 21.5, 13.6 and 13.5 ppm. IR (film): 3380,
982, 1797, 1732, 1371, 1305, 1194, 1094, 1018, 850 cm
ppm. C NMR (50 MHz, CDCl ) d: 171.8, 171.1,
3
170.7, 155.1, 80.0, 61.6, 61.4, 50.3, 30.5, 28.3, 28.1,
ꢀ
1
+
.
25.5, 14.0 ppm. MS (ES+) = 259 (M +1ꢀ100). HRMS
2
M+Na): calcd for C H O N Na 381.16322.
3
(
Found: 381.16323.
1
6
26
7
2
1
0
0
0
5
.26. Ethyl (2SR,1 SR,2 RS,3 RS) N-(tert-butoxycar-
0
0
bonyl)-2-[2 -ethoxycarbonyl-3 - (methylaminocarbonyl)-
cyclopropyl]glycinate 37a
0
0
0
0
0
5.29. (2SR,1 SR,2 RS,3 RS)-2-[2 -carboxy-3 -(methyl-
aminocarbonyl) cyclopropyl]glycine 38a
Methylamine (2.74 mL, 5.4 mmol) and potassium cya-
nide (3 mg, 0.05 mmol) were added to a solution of 36
Prepared from 37a following the general hydrolysis pro-
cedure A. Yield: 50ꢀ. H NMR (200 MHz, D O/Py-d )
1
(
312 mg, 0.9 mmol) in anhydrous THF (6 mL) under
2
5
argon. After stirring overnight in an ultrasound bath,
the solvent was removed under vacuum. The residue
was chromatographed (hexane/ethyl acetate 1:1) to give
d: 3.65 (d, J = 10.5 Hz, 1H), 2.28 (s, 3H), 1.97–1.62 (m,
13
1H), 1.75–1.62 (m, 1H) ppm. C NMR (50 MHz, D O/
2
Py-d ) d: 177.5, 172.7, 170.7, 51.7, 27.5, 27.4, 26.9, 25.7
5
1
+
ppm. MS (ES+) = 217 (M +1). HRMS (M+1): calcd for
2
72 mg of 37a (80ꢀ yield). H NMR (200 MHz, CDCl )
3
d: 6.00 (d, 1H), 5.22 (s, 1H), 4.53 (t, J = 8.6 Hz, 1H),
.13 (q, 4H), 2.82 (d, 3H), 2.59 (s, 1H), 2.25 (d,
J = 4.7 Hz, 1H), 1.91 (s,1H), 1.43 (s, 9H), 1.24 (t, 6H)
C H O N 217.08190. Found: 217.08194.
8
13
5
2
4
0
0
0
0
0
5.30. (2SR,1 SR,2 RS,3 RS)-2-[2 -carboxy-3 -(phenyl-
aminocarbonyl) cyclopropyl]glycine 38b
1
3
ppm. C NMR (50 MHz, CDCl ) d: 172.3, 171.5,
3
1
69.0, 155.0, 80.4, 61.9, 61.6, 51.8, 30.6, 29.5, 28.6,
+
2
HRMS (M+1): calcd for C H O N 373.19693.
7.1, 25.7, 14.5 ppm. MS (ES+) = 273 (M +1ꢀ100).
Prepared from 37b following the general hydrolysis pro-
cedure A. Yield: 45ꢀ. H NMR (200 MHz, D O/Py-d )
1
1
7
29
7
2
2
5
Found: 373.19704.
d: 7.99 (d, 2H), 7.52 (m, 3H), 4.65 (d, J = 10Hz, 1H),
13
3
.17 (m, 1H), 2.98 (m, 1H), 2.81 (m, 1H) ppm.
C
0 0 0
.27. Ethyl (2SR,1 SR,2 RS,3 RS) N-(tert-butoxycar-
5
NMR (50 MHz, D O/Py-d ) d: 177.9, 173.1, 169.2,
2
5
0
0
bonyl)-2-[2 -ethoxycarbonyl-3 -(phenylaminocarbonyl)-
cyclopropyl]glycinate 37b
137.3, 129.0, 124.8, 124.2, 120.9, 120.7, 52.3, 28.6, 28.3,
28.1 ppm. MS (ES+) = 279 (M +1). HRMS (M+1):
+
calcd for C H O N 279.09755. Found; 279.09754.
1
3
15
5
2
A solution of aniline (70 ll, 0.77 mmol) in anhydrous
0
0
0
CH Cl (0.5 mL) was added dropwise to a solution of
AlCl3 (53.8 mg, 0.40 mmol) in anhydrous CH Cl2
5.31. Ethyl (2SR,1 SR,2 RS,3 RS) N-(tert-butoxycar-
bonyl)-2-[2 -ethoxycarbonyl-3 -cyanocyclopropyl]glycin-
ate 39
2
2
0
0
2
(
1
1 mL) at 0 ꢁC and the mixture was stirred at rt for
0 min. Then, a solution of 36 (106 mg 0.31 mmol) in
anhydrous CH Cl (0.5 mL) was added and the mixture
Pyridine (0.17 mL, 2.48 mmol) was added to a solution
of 37c (223 mg, 0.62 mmol) in anhydrous THF (4 mL).
Then, trifluoroacetic anhydride (0.11 mL, 1.48 mmol)
was added dropwise and the mixture was stirred at rt
for 19 h. The reaction was quenched with water and
extracted with CH Cl . The residue was chromato-
2
2
was stirred at rt for 4 h. A mixture of ice and water was
added, the organic layer was separated, and the aqueous
layer was extracted with CH Cl (X3). The combined
2
2
organic layers were dried over MgSO and the solvent
4
was removed under vacuum. The residue was chromato-
graphed (hexane/ethyl acetate 1:1) to give 67.5 mg 37b
2
2
graphed using AcOEt/hexane (1:1) as eluent to give 39
(79ꢀ yield). H NMR (200 MHz, CDCl ) d: 5.28 (br
1
1
(
50ꢀ yield). H NMR (200 MHz, CDCl ) d: 7.50 (d,
3
3
2
4
1
H), 7.25–7.15 (m, 3H), 5.43 (br d, 1H), 4.61 (t, 1H),
.10 (m, 4H), 2.70 (t, 1H), 2.40 (m, 1H), 2.10 (br s,
d, 1H), 4.34–4.11 (dq, 5H), 2.60 (m, 1H), 2.23–2.16
(dd, 1H), 2.06–1.94 (m, 1H), 1.45 (s, 9H), 1.37–1.21
1
3
13
H), 1.45 (s, 9H), 1.20 (t, 3H), 1.10 (t, 3H) ppm.
C
(dt, 6H) ppm. C NMR (50 MHz, CDCl ) d: 169.5,
3
NMR (50 MHz, CDCl ) d: 172.3, 171.2, 166.2, 155.0,
169.4, 116.5, 80.6, 62.4, 61.9, 53.0, 30.8, 28.8, 28.1,
3
+
1
38.0, 129.2, 128.8, 124.1, 119.7, 115.0, 79.9, 61.7,
1.4, 50.5, 30.8, 29.8, 28.1, 25.5, 14.0, 13.8 ppm.
25.4, 13.9 ppm. MS (ES+) = 241 (M +1ꢀ100). HRMS
2
(M+Na): calcd for C H O N Na 363.15266.
3
6
1
6
24
6
2
1
Found: 363.15275.
0 0 0
.28. Ethyl (2SR,1 SR,2 RS,3 RS) N-(tert-butoxycar-
bonyl)-2-[2 -ethoxycarbonyl-3 -(aminocarbonyl) cyclo-
propyl]glycinate 37c
5
0
0
0
0
0
0
5.32. (2SR,1 SR,2 RS,3 RS)-2-[2 -carboxy-3-cyano-
cyclopropyl]glycine 40
NH (g) was bubbled for 15 min to a solution of 36
3
Prepared from 39 following the general hydrolysis
procedure A. Yield: 40ꢀ. H NMR (200 MHz, D O/
1
(
200 mg, 0.58 mmol) in anhydrous CH Cl (3 mL). Then
2
2
2

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6567
Py-d ) d: 3.65 (d, 1H), 2.73 (d, 1H), 2.41–2.22 (m, 2H)
The combined organic layers were dried (Na SO ), fil-
2 4
5
1
3
ppm. C NMR (50 MHz, D O/Py-d ) d: 174.6, 171.2,
tered, and evaporated to dryness. The resulting residue
was purified by column chromatography using EtOAc/
hexane 1:4 as eluent to afford 310 mg (90ꢀ yield) of
2
5
118.5, 54.8, 28.5, 27.2, 25.1 ppm. HRMS (M+1): calcd
for C H O N 185.05568. Found: 185.05566.
7
9
4
2
1
4
3. H NMR (200 MHz, CDCl ) d: 0.9 (t, 3H), 1.2
3
5.33. Ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-vinyl
cyclopropanecarboxylate 41
(t, 3H), 1.4–1.5 (m, 1H), 1.6–1.7 (m, 1H), 1.9–2.0 (m,
1H) 2.3 (m, 1H), 2.4–2.5 (m, 1H), 4.1 (q, 2H), 9.5 (d,
1
3
1
H) ppm. C NMR (50 MHz, CDCl ) d: 13.7, 14.0,
3
A 0.5M solution of KHMDS in toluene (24.4 mL,
1
nylphosphonium bromide (5.2 g, 14.5 mmol) in anhy-
drous dioxane (75 mL) at rt under nitrogen
atmosphere. After 1 h, the mixture was added via cannu-
la to a solution of 21 (1 g, 2.62 mmol) in dioxane
19.7, 28.0, 33.4, 35.6, 61.0, 171.2, 197.7 ppm. IR
ꢀ
1
2.2 mmol) was added to a suspension of methyltriphe-
(film): 2960, 2620, 1720, 1700 cm . Anal. calcd for
C H O : C, 63.51; H, 8.29. Found: C, 63.60; H, 8.34.
9
14
3
0
0
0
0
5.36. (2SR,1 SR,2 RS,3 RS)-N-acetyl-2-[2 -(ethoxy-car-
bonyl)-3 -ethylcyclopropyl]glycinonitrile 44
0
(
25 mL) under nitrogen atmosphere and the reaction
mixture was stirred for 1 h. Then, the mixture was
poured onto a mixture of Et O and H O, and the layers
were separated. The aqueous layer was extracted with
A
suspension of ammonium chloride (5.53 g,
103.5 mmol) and neutral aluminum oxide (10.35 g) in
anhydrous acetonitrile (70 mL) was ultrasonicated for
1 h. A solution of 43 (1.76 g, 10.3 mmol) in anhydrous
acetonitrile (70 mL) was added and ultrasonicated for
1 h. Potassium cyanide (8.10 g, 124.3 mmol) finely pow-
dered was then added, and the mixture was allowed to
react for 2 days. The mixture was filtered through Celite
and the solvent was evaporated. The resulting residue
(1.92 g) was taken into anhydrous CH Cl (100 mL)
2
2
Et O (2· 100 mL) and the combined organic layers were
2
dried (Na SO ), filtered, and concentrated to dryness.
The residue was purified by column chromatography
using AcOEt/hexane (1:2) as eluent to give 840 mg
2
4
1
(
85ꢀ yield) of 41. H NMR (200 MHz, CDCl ) d: 1.2
3
(
t, J = 7.1 Hz, 3H), 1.7 (t, J = 4.7 Hz, 1H), 1.8–2.0 (m,
1
1
H), 2.1–2.2 (m, 1H), 3.5–3.6 (m, 1H), 3.7–3.8 (m,
H), 4.1 (q, J = 7.1 Hz, 2H), 5.1–5.3 (m, 2H), 5.5–5.6
2
2
and the mixture was cooled to 0 ꢁC. Then, N,N-diiso-
propylethylamine (2.23 mL, 12.7 mmol) was added
1
3
(
m, 1H) ppm. C NMR (50 MHz, CDCl ) d: 172.7,
3
1
33.1, 117.7, 60.7, 60.6, 29.5, 29.4, 25.7, 14.1 ppm. IR
film): 3420, 2980, 1720 cm . Anal. Calcd for
to the mixture under N , and the reaction mixture was
2
ꢀ
1
(
C H O : C, 63.51; H, 8.29. Found: C, 63.45; H, 8.22.
stirred for 15 min. Then, acetylchloride (0.84 mL,
11.8 mmol) was added, and the reaction mixture was
stirred at rt for 3 h. The reaction was quenched with
water (40 mL), the organic layer separated, and the
aqueous layer was extracted with CH Cl (2· 100 mL).
9
14
3
5.34. Ethyl (1SR,2SR,3RS)-3-ethyl-2-hydroxymethyl
cyclopropanecarboxylate 42
2
2
The combined organic layers were dried (Na SO ), fil-
2
4
A suspension of a mixture of 41 (500 mg, 2.94 mmol)
and 5ꢀ Pd/C (70 mg) in MeOH (25 mL) was stirred un-
der hydrogen atmosphere overnight. The catalyst was
then filtered through Celite and the solvent was removed
under vacuum. The residue was purified by column
chromatography using EtOAc/hexane 1:2 as eluent to
tered, and concetrated. The residue was purified by col-
umn chromatography using ethyl acetate and hexane
(1:1) as eluent to give 1.73 g (70ꢀ yield) of a 1:1 mixture
of the acetylated aminonitriles 44. Both isomers were
separated by recrystallization. Isomer B was precipitated
by recrystallization in diethyl ether, while isomer A
1
1
give 380 mg (80ꢀ yield) of 42. H NMR (200 MHz,
CDCl ) d: 1.1 (t, J = 7.1Hz, 3H), 1.3 (t, J = 7.1Hz,
remained in the solvent. Isomer A: (44a). H NMR
(300 MHz, CDCl ) d: 1.1 (t, 3H), 1.2 (t, 3H), 1.4–1.7
(m, 4H), 1.9–2.0 (m, 1H), 2.1 (s, 3H), 4.1 (m, 2H), 4.6
3
3
3
2
H), 1.3 (t, J = 4.4Hz, 1H), 1.4–1.6 (m, 3H), 1.8 (m,
H), 3.7 (d, J = 7.1Hz, 2H), 4.1 (q, J = 7.1Hz, 2H)
1
3
(dd, 1H), 6.5 (d,1H) ppm. C NMR (75 MHz, CDCl3)
d: 13.8, 14.1, 20.9, 22.8, 25.8, 28.6, 29.0, 38.9, 61.1,
117.7, 169.4, 172.5 ppm. IR (film): 3375, 2980, 2240,
1
3
ppm. C NMR (50 MHz, CDCl ) d: 13.9, 14.2, 20.7,
3
2
2
6
5.1, 28.8, 29.1, 60.5, 60.9, 173.8 ppm. IR (film): 3430,
ꢀ1
ꢀ1
960, 2870, 1720 cm . Anal. Calcd for C H O : C,
16
1710, 1685 cm . Anal. Calcd for C H N O : C
3
9
3
12 18
2
2.77; H, 9.36. Found: C, 62.84; H, 9.44.
60.49; H 7.61; N 11.76. Found: C, 60.54; H, 7.69; N,
1
1
1.79. Isomer B: (44b) H NMR (300 MHz, CDCl ) d:
3
5.35. Ethyl (1SR,2SR,3RS)-2-formyl-3-ethylcyclopro-
pane carboxylate 43
1.0 (t, 3H), 1.3 (t, 3H), 1.3–1.5 (m,d4H), 1.9 (m,1H),
2.0 (s, 3H), 4.1 (q, 2H), 4.6 (dd, 1H), 6.8 (d,1H) ppm.
1
3
C NMR (75 MHz, CDCl ) d: 13.6, 14.0, 20.3, 22.5,
3
Dimethylsulfoxide (0.36 mL, 5.0 mmol) was added to a
solution of oxalyl chloride (0.21 mL, 2.4 mmol) in anhy-
drous CH Cl (30 mL) at ꢀ78 ꢁC under N and the reac-
25.1, 28.4, 29.6, 39.0, 61.3, 118.1, 169.3, 172.7 ppm. IR
ꢀ
1
(film): 3400, 2970, 2230, 1700, 1680 cm . Anal. Calcd
for C H N O : C, 60.49; H, 7.61; N, 11.76. Found:
C, 60.50; H, 7.63; N, 11.80.
2
2
2
12 18
2
3
tion mixture was stirred for 30 min. A solution of 42
(
350 mg, 2.0 mmol) in anhydrous CH Cl (20 mL) was
2 2
0
0
0
0
0
added and the reaction mixture was stirred at the same
temperature for 45 min. Then, triethylamine (1.4 mL,
5.37. (2SR,1 SR,2 SR,3 RS)-2-(3 -ethyl-2 -carboxycy-
clopropyl) glycine 45
1
0 mmol) was added and the mixture was allowed to re-
act at rt for 30 min. The reaction was quenched with
water (30 mL), the organic layer separated, and the
aqueous layer was extracted with CH Cl (2· 50 mL).
Prepared from 44a following the general hydrolysis
procedure C. Yield: 65ꢀ. H NMR (300 MHz, D O)
d: 0.8 (t, 3H), 1.0 (m, 1H), 1.1 (m, 1 H), 1.3 (m, 1H),
1
2
2
2

6568
R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
1
.4 (m, 1H), 1.5 (m, 1H), 3.2 (d,1H) ppm. C NMR
3
1
(
(150 mL) at ꢀ78 ꢁC under argon was added dropwise
via cannula to a solution of 48 (15.2 g, 82.8 mmol) in
anhydrous THF (300 mL) at ꢀ78 ꢁC under argon. The
solution was stirred for 6 h at this temperature and then
diluted with EtOAc (200 mL) and quenched with a sat-
urated aqueous solution of sodium tartrate (200 mL).
The resulting mixture was stirred at rt overnight. The
75 MHz, D O) d: 15.6, 23.8, 29.9, 30.5, 31.9, 57.3,
2
1
1
76.4, 184.0 ppm. Isomer B: (44b)
H
NMR
(
(
300 MHz, CDCl ) d: 1.0 (t, 3H), 1.3 (t, 3H), 1.3–1.5
3
m,d4H), 1.9 (m,1H), 2.0 (s, 3H), 4.1 (q, 2H), 4.6 (dd,
1
3
1
1
1
5
H), 6.8 (d,1H) ppm. C NMR (75 MHz, CDCl ) d:
3
3.6, 14.0, 20.3, 22.5, 25.1, 28.4, 29.6, 39.0, 61.3, 118.1,
69.3, 172.7 ppm. Anal. Calcd for C H NO : C,
1.33; H, 7.00; N, 7.48. Found: C 51.21; H 6.90; N 7.44.
organic layer was separated, dried over MgSO , filtered,
4
8
13
4
and evaporated under vacuum. The residue was chro-
matographed using EtOAc and hexane 1:2 as eluent to
afford 12.3 g (85ꢀ yield) of 49 as a colorless oil, which
5.38. Ethyl (1SR,5RS,6SR)-2-oxo-bicyclo[3.1.0]hexane-
6-carboxylate 47
exists with their corresponding open hydroxyaldehyde
1
forms. H NMR (300 MHz, CDCl ) d: 1.19–1.24 (m),
3
To a suspension of ethyl (dimethylsulfonium)acetate
bromide (13.9 g, 60.9 mmol) in CHCl (60 mL), DBU
1.49–1.52 (m), 1.60–1.94 (m), 2.00–2.08 (m), 2.30–2.34
(m), 2.53–2.58 (m), 3.25–3.30 (m), 3.34–3.50 (m), 3.58–
3.63 (m), 3.81–3.90 (m), 4.04–4.09 (m), 5.24 (dd,
J = 5.5, 4.4 Hz), 5.29 (d, J = 3.3 Hz), 9.60 (dd, J = 3.3,
3
(
9.18 mL, 60.9 mmol) was added. The resulting suspen-
sion was vigorously stirred at rt for 30 min. Then, cyclo-
pentenone (5.10 mL, 60.9 mmol) was added and the
mixture was stirred overnight at rt. The following day
1
3
1.1 Hz) ppm. C NMR (75 MHz, CDCl ) d: 13.9,
3
14.0, 14.1, 18.5, 20.6, 20.9, 21.0, 21.3, 23.7, 25.0, 25.7,
27.3, 28.6, 28.7, 34.8, 54.2, 59.9, 60.5, 60.6, 61.1, 61.6,
89.0, 90.0, 171.3, 173.3, 173.5 ppm. IR (film): 3420,
additional CHCl (60 mL) was added. The organic layer
3
was washed with 40 mL of 0.5 N HCl, dried over
MgSO , filtered, and concentrated under vacuum. The
ꢀ1
2985, 2920, 1720, 1700 cm
.
4
residue was purified chromatographed using ethyl ace-
tate:hexane 1:9 as eluent to give 8.4 g (82ꢀ yield) of
0
0
0
0
5.41. (2SR) and (2RS)-2-(1 SR,2 SR,3 RS)-2 -(ethoxy-
carbonyl)-3 -(2 - hydroxyethyl)cyclopropyl] glycinonitrile
50
1
0
0 0
4
7 as a colorless oil. H NMR (300 MHz, CDCl ) d:
3
1
.22 (t, J = 7.1 Hz, 3H), 1.95–2.24 (m, 6H), 2.44–2.49
m, 1H), 4.10 (q, J = 7.1 Hz, 2H) ppm. C NMR
1
3
(
(
75 MHz, CDCl ) d: 14.0, 22.3, 26.3, 29.1, 31.7, 35.6,
A
suspension of ammonium chloride (29.3 g,
3
6
1
7
1.1, 170.3, 211.8 ppm. IR (film): 2960, 1735,
547.3 mmol) and neutral aluminum oxide (54.7 g) in
acetonitrile (600 mL) was ultrasonicated for 1 h. A solu-
tion of 49 (10.2 g, 54.7 mmol) in acetonitrile (200 mL)
was added, and sonication was continued for an addi-
tional hour. Then, powdered potassium cyanide
(42.8 g, 656.7 mmol) was added and the reaction mix-
ture was ultrasonicated for seven days. After that time,
the mixture was filtered through Celite and the inorgan-
ics were washed with acetonitrile. The solvent was evap-
orated under vacuum to give a residue that contained a
1:1 racemic mixture of the two possible diastereomers
50. Both racemic aminonitriles were purified and sepa-
rated by column chromatography using acetone/hexane
1:2 as eluent to give 3.89 g of 50a and 3.67 of 50b.
ꢀ
1
715 cm . Anal. Calcd for C H O : C, 64.27; H,
9
12
3
.19. Found: C, 64.34; H, 7.23.
5.39. Ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]-
heptane-7-carboxylate 48
To a stirred solution of 47 (34.8 g, 207.2 mmol) in
(
300 mL), 70ꢀ m-chloroperbenzoic acid (51.1 g,
07.2 mmol) was added and the mixture was refluxed
2
overnight. The following day, additional 70ꢀ m-chlor-
operbenzoic acid (51.1 g, 207.2 mmol) was added and
the mixture was refluxed for 15 h. The reaction mixture
was diluted with CH Cl (200 mL), filtered, and washed
2
2
with 10ꢀ Na SO (2· 200 mL) and with a saturated
2
3
0 0 0
5.42. Ethyl (2SR,1 SR,2 SR,3 RS)-N-(tert-butoxycar-
bonyl)-2-[2 -(ethoxycarbonyl)-3 - (2 -hydroxyethyl)-
cyclopropyl] glycinate 51a
aqueous solution of NaHCO (2· 200 mL). The organic
3
0
0
0 0
layer was dried over MgSO , filtered, and evaporated
4
under vacuum. The residue was purified chromato-
graphed using ethyl acetate and hexane 1:2 as eluent
to give 22.89 g (60ꢀ yield) of 48 as a colorless oil. H
1
To a solution of 50a (3.88 g, 18.3 mmol) in EtOH satu-
NMR (300 MHz, CDCl ) d: 1.24 (t, J = 7.1 Hz, 3H),
rated with HCl (200 mL) at 0 ꢁC, distilled H O
3
2
1
.97–2.04 (m, 1H), 2.13–2.28 (m, 3H), 2.38 (dd,
(0.99 mL, 54.9 mmol) was added. The reaction was stir-
red at rt for four days. Then, the solvent was removed
under vacuum and the residue was dissolved in EtOH
J = 8.3, 3.3 Hz, 1H), 2.53 (t, J = 3.9 Hz, 1H), 4.02 (td,
J = 8.8, 3.3 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.23–
1
3
4
1
1
.31 (m, 1H) ppm. C NMR (75 MHz, CDCl ) d:
(100 mL), neutralized with NaHCO (solid), and stirred
3
3
4.1, 19.4, 21.4, 22.2, 24.2, 61.5, 64.3, 167.8,
70.0 ppm. IR (film): 3420, 2980, 1710, 1680 cm
for 30 min. The inorganics were filtered and the solvent
was removed under vacuum. The resulting residue was
taken into dioxane (150 mL), and a saturated solution
ꢀ
1
.
Anal. Calcd for C H O : C, 58.69; H, 6.57. Found:
4
9
12
C, 58.66; H, 6.50.
of NaHCO (50 mL) was added. To this mixture, a solu-
3
tion of di-tert-butyldicarbonate (4.80 mg, 22.8 mmol) in
dioxane (25 mL) was added and the mixture was stirred
overnight at rt. The layers were then separated and the
aqueous layer was extracted with EtOAc (2· 200 mL).
The combined organic layers were dried over Na SO ,
5
3
.40. (2RS) and (2SR) Ethyl (1SR,6RS,7SR)-2-hydroxy-
-oxa-bicyclo[4.1.0]heptane-7-carboxylate 49
A 1.5 M solution of diisobutylaluminum hydride in
toluene (82.8 mL, 124.2 mmol) in anhydrous THF
2
4
filtered, and concentrated. The residue was chromato-

R. Gonz a´ lez et al. / Bioorg. Med. Chem. 13 (2005) 6556–6570
6569
graphed using ethyl acetate/hexane 1:2 as eluent to
afford 3.34 g (56ꢀ yield) of 51a as a yellow oil. H
Neurosci. Lett. 1990, 109, 157; (c) Schoepp, D. D.;
Johnson, B. G.; Monn, J. A. J. Neurochem. 1992, 58,
1
1
184; (d) Cartmell, J.; Curtis, A. R.; Kemp, J. A.; Kendall,
NMR (300 MHz, CDCl ) d: 1.25 (t, J = 7.1 Hz, 3H),
3
D. A.; Alexander, S. P. H. Neurosci. Lett. 1993, 153, 107.
. (a) Monn, J. A.; Valli, M. J.; Jonson, B. G.; Salhoff, C. R.;
Wright, R. A.; Howe, T.; Bond, A.; Lodge, D.; Spangle, L.
A.; Paschal, J. W.; Campbell, J. B.; Griffey, K.; Tizzano, J.
P.; Schoepp, D. D. J. Med. Chem. 1996, 39, 2990; (b)
Kozikowsky, A. P.; Araldi, G. L.; T u¨ ckmantel, W.;
Pshenichkin, S.; Surina, E.; Wroblewsky, J. T. Bioorg.
Med. Chem. Lett. 1999, 9, 1721; (c) Br a¨ uner-Osborne, H.;
Madsen, U.; Mikiciuk-Olasik, E.; Curry, K. Eur. J.
Pharmacol. 1997, 332, 327; (d) Kozikowsky, A. P.;
Steensma, D.; Araldi, G. L.; T u¨ ckmantel, W.; Wang, S.;
Pshenichkin, S.; Surina, E.; Wroblewsky, J. T. J. Med.
Chem. 1998, 41, 1641.
. (a) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R.
A.; Salhoff, C. R.; Johnson, B. G.; 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) Schoepp, D. D.; Johnson, B. G.;
Wright, R. A.; Salhoff, C. R.; Mayne, N. G.; Wu, S.;
Cockerham, S. L.; Burnett, J. P.; Belegaje, R.; Bleakman,
D.; Monn, J. A. Neuropharmacology 1997, 36, 1; (c)
Schoepp, D. D.; Monn, J. A.; Marek, G. J.; Aghajanian,
G.; Moghaddam, B. CNS Drug Rev. 1999, 5, 1; (d)
Moghaddam, B.; Adams, B. W. Science 1998, 281, 1349.
. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J.
L.; Wright, R. A.; Johnson, B. G.; Andis, S. L.; Kingston,
A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.; Tizzano, J.
P.; Schoepp, D. D. J. Med. Chem. 1999, 42, 1027.
1
.30 (t, J = 7.1 Hz, 3H), 1.45 (s, 9H), 1.67–1.69 (m,
H), 1.97–2.00 (m, 1H), 3.76–3.78 (m, 2H), 4.04 (t,
7
2
J = 9.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.23 (q,
J = 7.1 Hz, 2H), 5.33 (d, J = 8.2 Hz, 1H) ppm.
NMR (75 MHz, CDCl ) d: 14.0, 14.1, 24.3, 24.8, 28.2,
2
1
1
3
C
3
9.6, 30.9, 52.1, 60.7, 61.7, 62.0, 80.1, 155.3, 171.4,
73.2 ppm. IR (film): 3480, 3360, 2970, 1720, 1700
ꢀ
1
cm . Anal. Calcd for C H NO : C, 56.81; H, 8.13;
1
7
29
7
N, 3.90. Found: C, 56.74; H, 8.06; N, 3.83. MS
(
ESꢀ) = 358 (Mꢀ1).
0
0
0
0
0 0
5
2
.43. (2SR,1 SR,2 SR,3 RS)-2-[(3 -(2 -hydroxyethyl)-
-carboxy)cyclopropyl]glycine 52a
8
0
Prepared from 51a following the general hydrolysis pro-
cedure B. Yield: 60ꢀ. H NMR (200 MHz, D O) d:
1
J = 10.5 Hz, 1H), 3.71 (br t, J = 6.4 Hz, 2H) ppm.
NMR (50 MHz, D O) d: 24.8, 25.7, 26.9, 29.8, 54.0,
6
4
6
1
2
.46–1.84 (m, 4H), 1.92–2.05 (m, 1H), 3.44 (d,
C
1
3
2
0.9, 173.0, 178.0 ppm. Anal. Calcd for C H NO : C,
7.29; H, 6.45; N, 6.89. Found: C, 47.21; H, 6.36; N,
.81. MS (ES+) = 204 (M +1). HRMS (M+1): calcd
8 13 5
+
9
for C H O N 204.08665. Found: 204.08664.
8
14
5
1
Acknowledgments
1
0. Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa,
R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi,
S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893.
We are grateful to Peter Callow (Eli Lilly & Co. Ltd., Lil-
ly Research Centre, Erl Wood Manor, UK) for collecting
HRMS data, Dr. Juan F. Espinosa (Lilly, S.A., Alcoben-
das, Spain) for the NOE experiments, and Dr. Gregory
A. Stephenson (Eli Lilly and Company, Indianapolis,
USA) for the X-ray crystallography. We also thank
Dr. Thomas C. Britton (Eli Lilly and Company, India-
napolis, USA) for critical reading of the manuscript.
1
1
1
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