(2S,1′S,2′S,3′R)-2- (2′-carboxy-3′-methylcyclopropyl) glycine is a potent and selective metabotropic group 2 receptor agonist with anxiolytic properties

Article abstract of DOI:10.1021/jm0110486

The asymmetric synthesis and biological activity of (2S,1′S,2′S,3′R)-2- (2′-carboxy-3′-methylcyclopropyl) glycine 7 and its epimer at the C3′ center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate r

Full text of DOI:10.1021/jm0110486

J . Med. Chem. 2002, 45, 3619-3629
3619
(2S,1′S,2′S,3′R)-2-(2′-Ca r boxy-3′-m eth ylcyclop r op yl) Glycin e Is a P oten t a n d
Selective Meta botr op ic Gr ou p 2 Recep tor Agon ist w ith An xiolytic P r op er ties
Iva´n Collado,*,† Concepcio´n Pedregal,*,† Angel Mazo´n,† J uan Fe´lix Espinosa,† J aime Blanco-Urgoiti,‡
Darryle D. Schoepp,§ Rebecca A. Wright,§ Bryan G. J ohnson,§ and Ann E. Kingston§
Lilly, SA. Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain, Facultad de Ciencias Experimentales y de la Salud,
Universidad San Pablo-CEU, Urb. Monteprı´ncipe, 28668 Boadilla del Monte, Madrid, Spain, and Lilly Research Laboratories,
Indianapolis, Indiana 46285
Received October 4, 2001
The asymmetric synthesis and biological activity of (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-methyl-
cyclopropyl) glycine 7 and its epimer at the C3′ center 6 are described. Compound 7 is a highly
potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is
also systemically 4 orders of magnitude more active in the fear-potentiated startle model of
anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown
that high molecular complexity of conformationally constrained bicyclic systems is not a
requirement to achieve highly selective and potent group 2 mGluRs agonists.
Ch a r t 1
In tr od u ction
Excitatory amino acids (EAA) are present in abun-
dance in the brain: it is estimated that around 50% of
neurons in the brain may utilize glutamate (1) as a
neurotransmitter. L-Glutamate (Glu) is the major exci-
tatory neurotransmitter in the mammalian central
nervous system (CNS). Glutamate receptors are subdi-
vided into ionotropic (GluRs)1,2 and metabotropic recep-
tors (mGluRs).3,4 The ionotropic receptors mediate fast
synaptic transmission through ligand-gated ion chan-
nels while metabotropic receptors are G protein-coupled
and have a modulatory role in the CNS. Ionotropic
receptors have been subdivided into three classes on the
basis of their sensitivity to the following ligands: NMDA
(N-methyl-D-aspartate), KA (kainate), and AMPA (R-
amino-3-hydroxy-5-methyl-4-isoxazolepropionate) from
which they take their names.5 On the other hand, there
are currently eight distinct mGluR proteins (mGluR1-
8) that have been pharmacologically distinguished into
three groups based on amino acid sequence homology,
signal transduction mechanisms, and agonist pharma-
cology. Group 1 mGluRs (mGluR1 and 5) are positively
coupled to phospholipase C activation and groups 2
(mGluR2 and 3) and 3 (mGluR4 and 6-8) are negatively
coupled to adenylate cyclase. In recent years, significant
progress has been made in the identification of selective
agents for each of the main groups of mGluR subtypes.
Thus, in Charts 1 and 2, some of the more potent and
selective known group 2 agonists are represented.6
(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid
(ACPD, 2, Chart 1) was the first glutamate analogue
found to activate mGluRs expressed in the rat brain.
However, this ligand has little subtype selectivity, with
similar potency observed across all mGluRs.7,8 In Table
Ch a r t 2
1, the pharmacological profiles for the most potent
known group 2 agonists are shown across all of the
metabotropic receptor subtypes. Conformational con-
straint of the glutamate pharmacophore into a fused
bicyclic [3.1.0] ring system resulted in LY354740 (Chart
1, Table 1).9 This compound is among the most potent
and selective agonists for group 2 receptors described
to date. Also, the oxygen- and sulfur-containing hetero-
cyclic compounds LY379268 and LY389795 (Chart 1)
have been described.10 These heterobicyclic amino acids
are also among the most potent agonists for group 2
mGluRs thus far described (Table 1). Like LY354740,
neither of these analogues showed affinity for native
GluRs nor did they produce agonist or antagonist effects
at group 1 mGluRs. Moreover, these compounds show
* To whom correspondence should be addressed. I.C.: Tel:
+34-91-6633409. Fax: +34-91-6633411. E-mail: collado_ivan@
lilly.com. C.P.: Tel: +34-91-6633426. Fax: +34-91-6633411. E-mail:
pedregal_concepcion@lilly.com.
† Lilly.
‡ Universidad San Pablo-CEU.
§ Lilly Research Laboratories.
10.1021/jm0110486 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/17/2002

3620 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Collado et al.
Ta ble 1. Potency and Subtype Selectivity of Human mGluR Agonists Reported in Nanomolar Values
group 1a
group 2b
group 3b
compd
Glu, 1
ACPD, 2
LY354740
LY379268
LY389795
3
mGluR1
mGluR5
mGluR2
mGluR3
mGluR4
mGluR6
mGluR7
mGluR8
10 000c
42 000
4000c
4000c
12 000
7.9
3
4
29.4
16.6
0.57
300c
90c
100
300
300c
188
8
9000c
860 000
21
5
8
45.4
89
2.7
600
NTe
NTe
NTe
200c
2000
38
12 000c
90 000
>100 000
21 000
20 000c
18 000
3000
400
5 400 000c
1 000 000
>100 000
>100 000
>100 000
>100 000d
>100 000d
>100 000d
47 000
NT
15 000c
45 000
11 500
2000
7000
>100 000d
NTe
>100 000
>100 000
>100 000
>100 000d
>100 000d
>100 000d
23 000
>100 000
>100 000
>100 000
>100 000d
>100 000d
>100 000d
17 000
>100 000
>100 000d
>100 000d
>100 000d
4000
2000
>100d
>100d
>100d
600c
4
5
NTe
L-CCG-I
L-F2CCG-I
cis-MCG-I
trans-MCG-I
DCG-IV
6
400
NTe
NTe
NTe
NTe
NTe
NTe
>100 000
>100 000
>100 000c
>100 000
>100 000
>100 000
>100 000
389 000c
>100 000
>100 000
NTe
NTe
NTe
NTe
NTe
NTe
NTe
NTe
23 000c,f
NTe
40 000c,f
NTe
40 000c,f
NTe
32 000c,f
2800
1320
7
>100 000
1198
>100 000
a
b
Assay used, EC50/PI hydrolysis in nonneuronal cells. Assay used, EC50/inhibition of forskolin c-AMP in nonneuronal cells. c For rat
subreceptors. Ref 11. e NT, not tested. f Antagonist.
d
Ch a r t 3
efficacy in a number of experimental animal models
following systemic administration.9,10
Recently, Nakazato et al.11 have reported that other
substituted fused bicyclic [3.1.0] ring systems, which are
closely related analogues of LY354740 (3-5), have a
similar profile at recombinant human mGluR2 and 3
(Table 1).
On the other hand, (2S,1′S,2′S)-2-(2′-carboxycyclo-
propyl)glycine (L-CCG-I) (Chart 2 and Table 1) shows
nanomolar potency for group 2 and some group 3
this goal, the C3′-methyl C2′-carboxycyclopropyl glycine
7 was designed as a ring-opened version of LY354740.
(mGluR6 and mGluR8) subtypes and micromolar po-
tency at the remaining mGluR subtypes.12,13 The cor-
responding geminal fluoro-substituted L-F2CCG-I is a
more potent agonist at mGluR2; however, activity at
other mGluR subtypes has not been reported.14 Further
investigation of the effect of substitution at the 3′-
position of L-CCG-I has led to the identification of
additional potent group 2 mGluR agonists with im-
proved selectivity but reduced potency. Thus, introduc-
tion of a methoxymethyl substituent on the same face
of the cyclopropane ring as the R-amino acid functional-
ity afforded (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-methoxy-
methylcyclopropyl) glycine (cis-MCG-I) (Chart 2), while
incorporation of the methoxymethyl on the face opposite
to the R-amino acid gave trans-MCG-I.15 Unfortunately,
activities for these two compounds at other mGluR
subtypes have not been reported. (2S,2′R,3′R)-2-(2′,3′-
Dicarboxycyclopropyl) glycine (DCG-IV) displays potent
group 2 activity but has agonist activity at the NMDA
receptors and antagonist effects at all of the group 3
mGluR subtypes (Table 1).16,17
Those data suggest that the cyclopropyl glycine
moiety does not produce as great a potency and selectiv-
ity as the corresponding fused bicyclic [3.1.0] ring
system counterparts. This may be due to the conforma-
tional freedom of these cyclopropyl systems as compared
to the rigid bicyclic form, which imparts a superior
potency and selectivity at group 2 mGluRs.
Despite this, we felt that 2′-carboxy-3′-substituted
cyclopropyl glycine compounds have not been widely
enough explored since only a limited number of com-
pounds are known and their pharmacological charac-
terization is lacking.
The asymmetric synthesis and biological activity of this
molecule is described. In addition, the biological activity
of the epimer at the C3′ center 6 is described to
demonstrate the stereochemical requirement at this
center for affinity at the group 2 mGluRs (Chart 3).
Ch em istr y
We have already published the stereoselective syn-
thesis of 6.18 In a first approach directed toward the
asymmetric synthesis of 7, we explored either the
rhodium- or the palladium-catalyzed cyclopropanation
of olefins 9a ,b (obtained as a 6:1 mixture by a Wittig
reaction of Garner’s aldehyde 8, prepared from D-
serine,19 with methyltriphenyl phosphonium bromide)
with ethyl diazoacetate (Scheme 1). Although a similar
approach has been recently published for the synthesis
of the group 2 antagonist (2R,1′S,2′R,3′S)-2-(2′-carboxy-
3′-phenylcyclopropyl)glycine (PCCG-13)20 and despite a
variety of attempts under different conditions, we were
unable to obtain the corresponding cyclopropane deriva-
tives. Therefore, a more entropically favored intramo-
lecular cyclopropanation was tried as reported by Ohfu-
ne et al.21 The mixture of olefins 9a ,b was converted to
N-Boc-glycyl olefins 10a ,b by removal of the N-Boc
protecting group, followed by condensation of the free
amino group with N-Boc-glycine and further acetonide
formation. Subsequent removal of the N-Boc in the
presence of the acetonide, followed by diazotization, gave
11a ,b, which underwent intramolecular palladium-
catalyzed cyclopropanation to stereoselectively give the
exo-adducts 12a ,b.22
Both isomers were easily separated by flash chroma-
tography, and the structure of the major compound was
In this study, it was our goal to develop novel, potent,
and selective group 2 mGluR agonists. To accomplish
1
established by H nuclear magnetic resonance (NMR).

Receptor Agonist with Anxiolytic Properties
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3621
Sch em e 1a
a
(a) Ph3PCH2CH3, Br, KHMDS, dioxane, room temperature. (b) (i) 1 N HCl/MeOH; (ii) Boc-Gly-Osu, Et3N, MeOH/THF, room
temperature; (iii) Me2(OMe)2, PTSA, PhH, reflux. (c) (i) TMSOTf, 2,6-lutidine, CH2Cl2, room temperature; (ii) NaNO2, 5% citric acid,
Et2O, room temperature. (d) Pd(OAc)2, PhH, 70 °C. (e) Separation: column chromatography, AcOEt/Hexane 1:2. (f) (i) Dowex 50WX8-
100, MeOH, room temperature; (ii) TBSCl, imidazole, DMF, room temperature; (iii) Boc2O, Et3N, DMAP, THF, room temperature. (g) (i)
1 N LiOH, THF, room temperature; (ii) CH2N2, Et2O, 0 °C. (h) (i) CSA, MeOH, room temperature; (ii) Me2(OMe)2, CSA, acetone, 60 °C.
(i) KHMDS, THF, -78 °C to room temperature. (j) CSA, MeOH, room temperature. (k) (i) J ones reagent, acetone, 0 °C to room temperature;
(ii) 2.5 N LiOH, THF, room temperature; (iii) 1 N HCl/AcOEt; (iv) propylene oxide, MeOH, room temperature.
Sch em e 2a
F igu r e 1. NOE correlations of compound 12a .
The results of nuclear Overhauser effect (NOE) experi-
ments showed it to be the desired isomer 12a , which
possessed 1R,7S,8S,9R stereochemistry (Figure 1). Re-
moval of the acetonide and reprotection of the amide
and the hydroxyl groups gave the N-Boc-γ-lactam 13,
which was cleaved by treatment with LiOH to afford
a
(a) Cl2SO2, EtOH, reflux. (b) Boc2O, NaHCO3 (saturated), THF,
14 after esterification with diazomethane. Once the TBS
group was removed and the acetonide was reintroduced,
the C2′ carbon atom was epimerized to isomer 16 upon
treatment with base. Acetonide hydrolysis of 16 followed
by sequential J ones oxidation, ester hydrolysis with
LiOH, removal of the N-Boc, and final treatment with
propylene oxide in methanol afforded 7 with a 6.5%
overall yield from aldehyde 8. Its relative configuration
(1′S,2′S,3′R) at the three cyclopropyl carbons was as-
room temperature.
signed through coupling constant analysis in its N-Boc-
diethyl derivative 19 (Scheme 2). All of the proton and
carbon resonances were assigned through the combina-
tion of one-dimensional (1D) and two-dimensional (2D)
experiments (1H, correlation spectroscopy (COSY),
HSQC, 1D nuclear Overhauser enhancement spectros-
copy (NOESY)). Because it is well-known that for

3622 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Collado et al.
F igu r e 2. Plot of energy (kcal/mol) vs H2-C2-C1′-H1′ dihedral angle (°) for (2S,1′S,2′S,3′R) and (2S,1′R,2′R,3′S) isomers and
conformation of their global minima.
23
cyclopropane derivatives J cis > J trans
,
the coupling
homoallylic diazoacetates using Doyle catalysts.24 The
new synthesis started with the cheap and readily
available crotyl alcohol 20 as starting material (Scheme
3). Using a general procedure for preparing diazoac-
etates, 20 was transformed into its corresponding ac-
etoacetic ester 21 with diketene. Subsequent diazo
transfer followed by base-induced deacylation of the
intermediate R-diazo acetoacetic ester afforded diazoac-
etate 22. Slow addition of a solution of 22 to a solution
of Rh2(5R-MEPY)4 in refluxing dichloromethane gave
the (-)-cyclopropyl lactone 2325 in very good yield. The
enantiomeric excess of 23 was determined to be 64%
by titration with the chiral shift reagent Eu(tfc)3 in C6D6
and integration of suitable diastereotopic protons in the
1H NMR spectrum ((2%), and its absolute configuration
(1S,5R,6R) was assigned based on the opposite one
reported for its antipode, obtained through the same
constant values (J H1′-H3′ ) 9.1 Hz, J H1′-H2′ ) 4.4 Hz,
and J H2′-H3′ ) 4.7 Hz) indicate that H1′ is cis to H3′
and trans to H2′. Furthermore, absolute stereochemistry
of 7 was confirmed based on combination of molecular
modeling calculations and NOE data. Because the
absolute stereochemistry at the amino acid center is
fixed to 1S due to the use of D-serine as starting
material, the two possible absolute configurations
(2S,1′S,2′S,3′R) and (2S,1′R,2′R,3′S) were subjected to
a conformational search around the C1-C1′ bond using
the MMFF94s force field within SYBYL software. From
those, minimum A is the most stable conformer for
(2S,1′S,2′S,3′R) isomer by 5.0 kcal/mol and minimum
B is the most stable conformer for (2S,1′R,2′R,3′S) by
4.3 kcal/mol (Figure 2). It should be noted that both
configurations show a strong preference for an ap-
proximately 180° H2-C2-C1′-H1′ torsion. Indeed, a
large J H2-H1′ value (10.7 Hz) was measured for 19 in
the proton spectrum, indicating that H2 is anti to H1′
as predicted by the calculations. Selective inversion of
the amide proton in a 1D NOESY experiment produced
NOEs to H2, H1′, and H2′, whereas no NOE to the
methyl protons was detected. Because the NH proton
is close to H2′ in minimum A but close to the methyl
group in minimum B (Figure 2), this NOE pattern was
consistent with absolute configuration (2S,1′S,2′S,3′R).
However, because of the difficulties in scaling-up the
intramolecular cyclopropanation step (step d, Scheme
1), this reaction sequence was not suitable for the
preparation of large quantities of 7. Thus, we developed
a new enantioselective synthesis based in the asym-
metric intramolecular cyclopropanation of allylic and
25
method using Rh2(5S-MEPY)4 and upon analogy to
other reported cyclopropyl lactones.26 Alkaline hydroly-
sis of the lactone, followed by treatment of the acidified
product with diazomethane, afforded an intermediate
hydroxy ester 24, which was immediately oxidized to
(+)-aldehyde 25 by treatment with tetra-n-propylam-
monium perruthenate (TPAP) in the presence of N-
methylmorpholine N-oxide (NMO). The epimerization
of aldehyde 25 to epi-aldehyde 26 was studied under a
variety of reaction conditions. The most favorable condi-
tions were found to be the treatment of 25 with strong
base, followed by reesterification with diazomethane to
provide 26 as the major isomer in a c.a. 5:1 (1H NMR)
inseparable mixture. With this mixture of aldehydes (25
and 26) in hand, a diastereoselective Strecker synthesis
was performed.27 Condensation of this mixture with

Receptor Agonist with Anxiolytic Properties
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3623
Sch em e 3a
a
(a) Diketene, AcONa, THF, reflux. (b) (i) p-AcNHC6H4SO2N3, Et3N, CH3CN, room temperature; (ii) LiOH, H2O, room temperature.
(c) Rh2(5R-MEPY)4, CH2Cl2, reflux. (d) (i) 2.8 N LiOH, THF, room temperature; (ii) CH2N2, Et2O, 0 °C. (e) TPAP, NMO, mol sieves (4 Å),
CH2Cl2, room temperature. (f) (i) 10% NaOH, MeOH, room temperature; (ii) CH2N2, Et2O, 0 °C. (g) (i) (R)-Phenylglycinol, MeOH, room
temperature; (ii) TMSCN, room temperature. (h) (i) Pb(Ac)4, CH2Cl2, MeOH, 0 °C; (ii) 6 N HCl; (iii) Dowex 50 × 8-100.
optically active R-(-)-R-phenylglycinol (99% ee), fol-
lowed by nucleophilic addition of a cyanide to the Schiff
base, gave an expected mixture of eight R-amino nitrile
derivatives, in which a major component was detected
and separated from the minor amount of the other
possible diastereoisomers by medium-pressure chroma-
tography in 42% isolated yield (de > 98% high-
performance liquid chromatography (HPLC)). Because
two new contiguous chiral centers are present, each
aldehyde was expected to yield the four corresponding
diastereomeric-substituted R-amino nitriles. Because
R-(-)-R-phenylglycinol preferentially induces opposite
chirality in the newly formed asymmetric center,27 the
absolute configuration of the more abundant constituent
of the mixture of glycinonitriles was assigned as
(2S,1′S,2′S,3′R)-[(R)-(phenylglycinyl)])amino nitrile 27.
After oxidative cleavage of 27 with lead tetraacetate and
further acidic hydrolysis and ion exchange chromatog-
raphy (Dowex 50 × 8-100, 10% Py), (2S,1′S,2′S,3′R)-2-
(2′-carboxy-3′-methylcyclopropyl)glycine 7 was isolated
in 12% overall yield from crotyl alcohol and its physi-
cochemical properties were identical to the one synthe-
sized through the first method reported herein (Scheme
1). To determine the enantiomeric purity of 7, Mosher
amides derived from both R-(+)-R-methoxy-(trifluorom-
ethyl)phenylacetyl chloride (R-(+)-MPTA) and S-(-)-
R-methoxy-(trifluoromethyl) phenylacetyl chloride (S-
(-)-MPTA) of its diethyl ester derivative 18 (Scheme 2)
were prepared.28 Comparison of NMR spectra (Brucker
Avance 500) of the resulting derivatives revealed an
enantiomeric excess >96%.
enosine cyclic 3′,5′-phosphate (c-AMP) formation (groups
2 and 3 mGluRs) or basal [3H]IP formation (group 1
mGluRs) (see Experimental Section). These data are
shown in Table 1 together with other known agonists.
It should be pointed out that a substituent R to the
amino acid center would convert an agonist into an
antagonist.29 As shown in Table 1, compound 7 was
similar to LY354740 in its biological profile on all
mGluRs. On the other hand, 6, the C3′ epimer, was
much less active than predicted. Therefore, the presence
of the methyl group on the same face as the amino acid
center is enough to confer a molecular conformation that
permits effective interaction with the binding site of the
receptor as seen for LY354740.
Beh a vior a l P h a r m a cology
The advent of selective and potent group 2 mGluR
agonists has provided an accumulation of experimental
evidence that implicates group 2 mGluRs as targets for
the treatment of schizophrenia,30 anxiety,31 drug with-
drawal,32 depression,33 neuroprotection,34 pain,35 Alzhe-
imer’s disease,36 epilepsy,37 and Parkinsons disease.38
In this study, the effects of the novel CCG derivative
7 were investigated in the rat fear-potentiated startle
39
assay31a,
in which LY354740 had been previously
shown to be active. This model was specifically chosen,
as it is highly sensitive to mGluR2 agonists and served
as the basis for developing LY354740 for anxiety
disorders in humans. As a positive control in each
experiment, diazepam (0.6 mg/kg ip) was used. All
experiments were performed in fed rats. While LY354740
significantly blocked fear-potentiated startle with an
mean effective dose (MED) of 3 mg/kg (po), 7 was 4
orders of magnitude more potent with an MED of 0.0003
mg/kg (po). Given that the in vitro potencies of LY354740
P h a r m a cology
Compounds 6 and 7 were evaluated in cloned mGluRs
for their ability to influence forskolin-stimulated ad-

3624 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Collado et al.
vacuo and the oily residue was dissolved in AcOEt. The
insoluble material was filtered off, and the filtrate was
concentrated in vacuo to give a residue that was subjected to
column chromatography on silica gel (AcOEt). The resulting
Boc-glycyl compound was dissolved in benzene (25 mL), and
p-toluensulfonic acid (21 mg, 0.11 mmol) and 2,2-dimethoxy-
propane (1.9 mL, 15.4 mmol) were added. The mixture was
stirred under reflux for 24 h. To this solution at room
temperature, MeOH (5 mL) was added and the mixture was
stirred for 30 min. Then, NaHCO3 (1-2 g) was added, and after
it was stirred for 15 min, the insoluble material was filtered
off. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (AcOEt/Hexane 1:5
and then 1:3) to give a 6:1 mixture of 10a ,b, respectively (1.89
g, 86%). 10a : 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 1.56
(s, 3H), 1.66 (s, 3H), 1.76 (dd, J ) 1.6, 7.2 Hz, 3H), 3.86-3.78
(m, 3H), 4.15 (dd, J ) 6.1, 8.8 Hz, 1H), 4.61-4.57 (m, 1H),
5.50-5.39 (m, 2H), 5.74-5.63 ppm (m, 1H).
and 7 are similar across all of the mGluR clones, it is
likely that the increased potency of 7 may be due to a
better bioavailability in rats following oral administra-
tion than for LY354740.
In conclusion, we have shown that enantiomerically
pure (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-methylcyclopropyl)
glycine 7 is a highly potent and selective agonist for
group 2 mGluRs. It has also proven to be systemically
active in the fear-potentiated startle model of anxiety
in rats. Therefore, we have shown that the high molec-
ular complexity of conformationally constrained bicyclic
systems is not a requirement to achieve highly selective
and potent group 2 mGluR agonists. Further studies on
the expanded structure-activity relationship of other
C3′-substituted C2′ carboxy cyclopropyl glycine com-
pounds and their evaluation in additional experimental
animal models will be reported in due course.
(1R ,7S ,8S ,9R )-3-Aza -9-m e t h y l-4,4-d im e t h y l-5-o x a -
tr icyclo[6.1.0.03,7]n on a n -2-on e (12a ). To a solution of the
mixture 10a ,b (2.7 g, 9.05 mmol) and 2,6-lutidine (3.27 mL,
28.06 mmol) in anhydrous CH2Cl2 (30 mL) at room tempera-
ture under nitrogen was added TMSOTf (3.44 mL, 19.0 mmol).
The mixture was stirred for 15 min, cooled to 0 °C, and
quenched with a saturated aqueous solution of NH4Cl (15 mL).
The organic layer was separated, and the aqueous phase was
extracted with Et2O. The combined organic layers were dried
(Na2SO4), filtered, and evaporated under reduced pressure.
The residue was taken into Et2O (75 mL) at room temperature,
and a NaNO2 (3.12 g, 45.25 mmol) solution in H2O (35 mL)
was added with stirring. To this suspension, a 5% solution of
citric acid in H2O was added until the pH was adjusted to ∼3.
The mixture was vigorously stirred for 30 min at room
temperature and then extracted three times with Et2O. The
combined organic layers were washed with a saturated aque-
ous solution of NaHCO3 and H2O, dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting diazoaceta-
mides 11a ,b were dissolved in benzene (200 mL) without
further purification, and Pd(OAc)2 (100 mg, 0.45 mmol) was
added. The mixture was heated at 70 °C for 30 min, and then,
the solvent was removed in vacuo. The residue was purified
by flash chromatography using AcOEt/Hexane (1:1) as eluent
to give the corresponding exo-adducts 12a ,b. The major and
desired isomer 12a was separated by column chromatography
using AcOEt/Hexane (1:2) as eluent (570 mg, 35% overall
Exp er im en ta l Section
Gen er a l. All solvents and reagents were purchased from
commercial sources and used as received, unless otherwise
indicated. Tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl prior to use. All reactions were performed
1
under a positive pressure of nitrogen. H NMR and 13C NMR
data were recorded on a Bruker AC-200P (200 MHz), Brucker
AM-300 (300 MHz), or Brucker Avance 500 (500 MHz)
spectrometer. Chemical shifts are reported as parts per million
(δ) relative to tetramethylsilane (TMS) as internal standard.
Melting points were determined on a Bu¨chi apparatus and are
not corrected. Optical rotations were measured with a Perkin-
Elmer 241 polarimeter. Analytical thin-layer chromatography
(TLC) was performed on Merck TLC glass plates precoated
with F254silica gel 60 (UV, 254 nm and phosphomolibdic acid).
Chromatographic separations were performed by using 230-
400 mesh silica gel (Merck). Elemental analyses were per-
formed by the Universidad Complutense Analytical Centre
(Facultad de Farmacia) Madrid.
(1′Z) a n d (1′E) ter t-Bu tyl (4S)-2,2-Dim eth yl-4-(1′-p r o-
p en yl)-3-oxa zolid in eca r boxyla tes (9a ,b). To a suspension
of Ph3PEtBr (4.86 g, 13.9 mmol) in anhydrous dioxane (100
mL) under nitrogen at room temperature, a 0.5 M solution of
KHMDS in toluene (22.3 mL, 11.7 mmol) was added. After it
was stirred for 1 h, the mixture was added dropwise via
cannula to a solution of the tert-butyl (4R)-4-formyl-2,2-
dimethyl-3-oxazolidinecarboxylate 8 (2.0 g, 8.7 mmol) in
anhydrous dioxane (40 mL) under nitrogen at room temper-
ature. After the addition was completed, the reaction mixture
was stirred for 30 min and then poured onto a (1:1) mixture
of H2O-Et2O (500 mL). Layers were separated, and the
aqueous phase was extracted with Et2O. The combined organic
layers were dried (Na2SO4), filtered, and evaporated to give a
residue, which was purified by chromatography using AcOEt/
Hexane (1:10) as eluent to give 1.8 g (89% yield) of a 6:1
mixture of 9a ,b respectively. 9a : 1H NMR (300 MHz, CDCl3):
δ 1.44 (s, 9H), 1.52 (s, 3H), 1.60 (s, 3H), 1.70 (d, J ) 1.1 Hz,
3H), 3.65 (dd, J ) 3.3, 8.8 Hz, 1H), 4.06 (dd, J ) 6.0, 8.8 Hz,
1H), 4.72-4.62 (m, 1H) and 5.61-5.39 ppm (m, 2H).
(1′Z) a n d (1′E)-3-[N-(ter t-Bu toxyca r bon yl)glycyl]-(4S)-
2,2-d im eth yl-4-(1′-p r op en yl)-1,3-oxa zolid in e (10a ,b). To a
solution of the mixture 9a ,b (1.77 g, 4.48 mmol) in MeOH (10
mL) at 0 °C was added 1 N HCl/MeOH (30 mL). The reaction
mixture was stirred for 1 h and at room temperature overnight.
The solvent was removed in vacuo, and the residue was taken
into H2O (10 mL). This solution was adjusted to pH 7 by
addition of 1 N NaOH and then to pH 9 by Et3N. The solvent
was removed in vacuo, and the residue was dissolved in MeOH
(20 mL) and THF (30 mL) (additional Et3N was added until
the solution became pH 9). To this solution at 0 °C was added
N-hydroxysuccinimide N-(tert-butoxy-carbonyl)glycinate (2.2
g, 8.06 mmol) and then warmed to room temperature. After
the mixture was stirred for 1 h, the solvent was removed in
1
yield); [R]D ) +57.0° (c ) 0.105, CHCl3). H NMR (300 MHz,
CDCl3): δ 1.20 (d, J ) 6.6 Hz, 1H), 1.39 (s, 3H), 1.52-1.40(m,
1H), 1.74 (s, 3H), 1.89 (dd, J ) 6.1, 8.2 Hz, 1H), 2.18-2.07 (m,
1H), 3.51 (dd, J ) 7.1, 9.9 Hz, 1H), 3.82-3.77 (m, 1H), 4.02
ppm (dd, J ) 5.5, 7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
7.8, 17.3, 21.6, 23.8, 28.6, 28.9, 58.4, 67.9, 93.7, 172.8 ppm.
Anal. (C10H15NO2): C, H, N.
(1R,4S,5S,6R)-3-Aza -3-N-(ter t-bu toxyca r bon yl)-4-[(ter t-
bu tyld im eth ylsilyl)oxym eth yl]-6-m eth yl Bicyclo[3.1.0]-
h exa n e-2-on e (13). A mixture of 12a (440 mg, 2.42 mmol)
and Dowex 50W × 8 resin (H+ form, 200 mg) in MeOH (20
mL) was stirred overnight at room temperature. The resin was
then filtered off, and the filtrate was concentrated in vacuo.
To a solution of the residue and imidazole (660 mg, 9.68 mmol)
in DMF (10 mL) was added a solution of tert-butyldimethylsilyl
chloride (1.10 g, 7.26 mmol) in DMF (5 mL). The reaction
mixture was stirred overnight at room temperature and then
poured onto cold water and extracted three times with Et2O.
The combined organic layers were dried (Na2SO4), filtered, and
evaporated under reduced pressure (DMF was removed by
azeotropic distillation with toluene). A solution of the resulting
residue, Et3N (0.68 mL, 4.48 mmol), Boc2O (790 mg, 3.63
mmol), and DMAP (60 mg, 0.48 mmol) in THF (15 mL) was
stirred overnight at room temperature and then poured onto
water and extracted three times with AcOEt. The combined
organic layers were washed successively with 5% aqueous
citric acid and H2O, dried (Na2SO4), and filtered. The solvent
was removed in vacuo, and the resulting residue was purified
by column chromatography (AcOEt/Hexane 1:6) to give the

Receptor Agonist with Anxiolytic Properties
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3625
bicyclic lactam 13 (640 mg, 75%). 1H NMR (300 MHz, CDCl3):
δ 0.04 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 1.05 (d, J ) 6.6 Hz,
3H), 1.42-1.34(m, 1H), 1.49 (s, 9H), 1.87 (dd, J ) 6.6, 7.7 Hz,
1H), 2.05-1.99 (m, 1H), 3.91-3.76 ppm (m, 3H). 13C NMR (75
MHz, CDCl3): δ -5.5 (2C), 7.6, 16.0, 18.1, 19.5, 25.7 (3C), 25.8,
28.0 (3C), 56.7, 63.7, 82.6, 149.5, 172.4 ppm.
was purified by column chromatography (AcOEt/Hexane 1:1)
to give the corresponding alcohol 17 (200 mg, 91%).
(2S,1′S,2′S,3′R)-2-(2′-Ca r b oxy-3′-m et h ylcyclop r op yl)-
glycin e (7). To a solution of 17 (200 mg, 0.73 mmol) in acetone
(5 mL) at 0 °C, J ones Reagent (1.12 mL) previously cooled to
0 °C was added. The mixture was stirred for 2 and 3 h at room
temperature. Then, the reaction was quenched with 2-propanol
(5 mL) and H2O (5 mL), stirred for 15 min, and poured onto
AcOEt (75 mL). The organic layer was washed several times
with H2O, dried (Na2SO4), filtered, and evaporated under
reduced pressure. The residue was dissolved in THF (5 mL),
and 2.5 N LiOH (10 mL) was added. The mixture was
vigorously stirred overnight. The organic layer was separated
and discarded, and the aqueous layer washed with Et2O. After
the aqueous solution was adjusted to pH ∼1 by addition of 1
N HCl at 0 °C, it was extracted four times with AcOEt, and
the combined organic layers were dried (Na2SO4), filtered, and
evaporated under reduced pressure. A solution of the residue
in 1 N HCl/AcOEt (5 mL) was stirred overnight. The solvent
was removed in vacuo, and the resulting solid was washed with
Et2O. The hydrochloride salt was dissolved in MeOH (3 mL),
and propylene oxide (5 mL) was added. The mixture was
stirred overnight, and the resulting insoluble solid was filtered
and washed with Et2O to give 7 (75 mg, 60%) as a white solid;
[R]D ) +22° (c ) 0.23, H2O); mp 178-180 °C. 1H NMR (200
MHz, D2O/KOD): δ 1.20-1.07 (m, 4H), 1.44-1.38(m, 2H), 2.90
ppm (d, J ) 9.8 Hz, 1H). 13C NMR (50 MHz, D2O/KOD): δ
Meth yl (1R,2S,3R,1′S)-2-[1′-[N-(ter t-Bu toxyca r bon yl)-
a m in o]-2′-(ter t-bu tyld im eth ylsilyl)oxy-eth yl]-3-m eth yl-1-
cyclop r op a n eca r boxyla te (14). To a solution of 13 (480 mg,
1.35 mmol) in THF (13.5 mL), 1 N LiOH (13.5 mL) was added.
The mixture was vigorously stirred overnight and then
adjusted to pH ∼3 by addition of 5% aqueous citric acid. The
aqueous layer was extracted three times with AcOEt, and the
combined organic layers were dried (Na2SO4), filtered, and
evaporated under reduced pressure. A solution of the residue
in Et2O (25 mL) at 0 °C was treated with a recently prepared
CH2N2 solution in Et2O (until the yellow color is retained) at
0 °C. After 30 min, the solvent was removed and the residue
was purified by column chromatography (AcOEt/Hexane 1:6)
to afford 14 (380 mg, 73%). [R]D ) -45.0° (c ) 0.132, CHCl3).
1H NMR (300 MHz, CDCl3): δ 0.04 (s, 3H), 0.05 (s, 3H), 0.89
(s, 9H), 1.26-1.18 (m, 1H), 1.31 (d, J ) 6.6 Hz, 3H), 1.42 (s,
9H), 1.52-1.44 (m, 1H), 1.75-1.70 (m, 1H), 3.64 (s, 3H), 3.78-
3.62 (m, 2H), 3.98-3.89 (m, 1H), 4.75 ppm (br s, 1H). 13C NMR
(75 MHz, CDCl3): δ -5.5 (2C), 7.8, 18.3, 19.1, 20.2, 25.7, 25.8
(3C), 28.0 (3C), 47.4, 51.2, 65.1, 78.7, 154.8, 171.8 ppm.
(4S,1′S,2′R,3′R)-3-[N-(ter t-Bu toxyca r bon yl)]-2,2-d im e-
th yl-4-[2′-(m eth oxyca r bon yl)-3′-m eth yl cyclop r op yl]-1,3-
oxa zolid in e (15). A mixture of 14 (380 mg, 1.0 mmol) and
camphorsulfonic acid (11.4 mg, 0.05 mmol) in MeOH (50 mL)
was stirred at room temperature for 4 h. The solvent was then
removed in vacuo, and the residue was taken into acetone. To
this solution under nitrogen atmosphere, 2,2-dimethoxypro-
pane (1.2 mL, 9.8 mmol) was added, and the mixture was
stirred for 2 h at 60 °C. Then, the reaction mixture was cooled
to room temperature and NaHCO3 (50 mg) was added. The
mixture was then filtered, and the filtrate was concentrated
in vacuo. The residue was purified by column chromatography
(AcOEt/Hexane 1:6) to give 15 (300 mg, 98%); [R]D ) -38.0°
13.7, 21.9, 30.9, 32.8, 56.7, 183.4, 184.5 ppm. Anal. (C7H11
NO4): C, H, N.
-
E t h yl N-(ter t-Bu t oxyca r b on yl) (2S,1′S,2′S,3′R)-2-(2′-
(E t h oxyca r b on yl)-3′-m et h ylcyclop r op yl)glycin a t e (19).
To a solution of 7 (49 mg, 0.28 mmol) in anhydrous EtOH (3.0
mL) at 0 °C, thionyl chloride (62.0 µL, 0.85 mmol) was added
dropwise. The mixture was stirred at room temperature for 1
h and then heated at reflux for 3 h. The reaction was cooled
to room temperature, the solvent was removed in vacuo, and
the resulting white solid was taken into CH2Cl2 (10 mL). The
resulting solution was washed with a saturated aqueous
solution of NaHCO3 (3 × 5 mL), and the organic layer was
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure to give 18 (53 mg, 83%) as a colorless oil. To a solution of
18 (50 mg, 0.22 mmol) in THF (3.0 mL), a saturated aqueous
solution of NaHCO3 (1.5 mL) was added and the mixture was
vigorously stirred for 5 min. To this mixture, a solution of
Boc2O (58 mg, 0.26 mmol) in THF (1.5 mL) was added and
the reaction was stirred overnight. Layers were separated, and
the aqueous phase was extracted three times with AcOEt. The
combined organic layers were washed with a saturated aque-
ous solution of NaCl, dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography
(AcOEt/Hexane 1:10) to give 19 (70 mg, 96%) as a colorless
oil. 1H NMR (500 MHz, DMSO-d6): δ 1.13-1.22 (m, 9H), 1.38
(s, 9H), 1.40 (dd, J ) 4.4, 4.7 Hz, 1H), 1.46 (m, 1H), 1.59 (ddd,
J ) 4.4, 9.1, 10.7 Hz, 1H), 3.64 (dd, J ) 6.9, 10.7 Hz, 1H),
3.98-4.16 (m, 4H), 7.65 (d, J ) 6.9 Hz, 1H). 13C NMR (125
MHz, DMSO-d6): δ 12.4, 13.9, 14.0, 21.2, 25.5, 28.0, 28.1 (3C),
52.3, 59.9, 60.5, 78.3, 155.4, 171.3, 172.4 ppm. Anal.
(C7H12O3): C, H, N.
1
(c ) 0.105, CHCl3). H NMR (300 MHz, CDCl3): δ 1.27 (br s,
2H), 1.45 (br s, 15H), 1.60 (s, 3H), 1.87-1.81 (m, 1H), 3.71 (s,
3H), 3.85 (dd, J ) 2.2, 8.8 Hz, 1H), 4.07 (dd, J ) 6.0, 8.8 Hz,
1H), 4.37 ppm (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 7.9,
16.6, 21.1, 24.5, 27.8, 27.9, 28.3 (3C), 51.0, 51.9, 68.6, 79.5,
93.4, 151.8, 171.9 ppm. Anal. (C16H27NO5): C, H, N.
(4S,1′S,2′S,3′R)-3-[N-(ter t-Bu t oxyca r b on yl)]-2,2-d im e-
th yl-4-[2′-(m eth oxyca r bon yl)-3′-m eth ylcy-clop r op yl]-1,3-
oxa zolid in e (16). To a solution of 15 (300 mg, 0.96 mmol) in
anhydrous THF at -78 °C under nitrogen, 0.5 M KHMDS
solution in toluene (5.75 mL, 2.87 mmol) was added. The
mixture was slowly allowed to react at room temperature (over
a period of 4 h) and then stirred at room temperature for 15
min. The reaction mixture was cooled again to -78 °C and
then quenched with a saturated aqueous solution of NH4Cl.
The aqueous layer was extracted twice with Et2O and AcOEt,
and the combined organic layers were dried (Na2SO4), filtered,
and evaporated under reduced pressure. The resulting residue
was purified by column chromatography (AcOEt/Hexane 1:6)
to give the epimerized product 16 (250 mg, 83%); [R]D ) -15.4°
1
tr a n s-2-Bu ten -1-yl Acetoa ceta te (21). To a refluxing
solution of crotyl alcohol 20 (21.5 mL, 252 mmol) and sodium
acetate (1.24 g, 15.12 mmol) in anhydrous THF (70 mL) under
nitrogen, a solution of diketene (21.34 mL, 277.1 mmol) in
anhydrous THF (30 mL) was added dropwise over a period of
1 h. The reaction mixture was heated at reflux for 30 min upon
completion of the addition and then cooled to room tempera-
ture and diluted with Et2O (300 mL). The resulting solution
was washed with a saturated aqueous solution of NaCl (2 ×
50 mL), and the organic layer was dried (Na2SO4), filtered,
and evaporated under reduced pressure. The brown residue
was purified by column chromatography (Hexane/Et2O 5:1) to
afford 21 (33.0 g, 83%) as a colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 1.72 (dd, J ) 6.5 and 0.9 Hz, 3H), 2.27 (s, 3H), 3.46
(s, 2H), 4.56 (d, J ) 6.5 Hz, 2H), 5.65-5.50 (m, 1H), 5.88-
(c ) 0.13, CHCl3). H NMR (300 MHz, CDCl3): δ 1.14 (d, J )
6.1 Hz, 3H), 1.50 (br s, 15H), 1.75-1.57 (m, 3H), 3.66-3.57
(br s, 1H), 3.67 (s, 3H), 3.85 (d, J ) 8.2 Hz, 1H), 4.05-3.97
ppm (m, 1H). 13C NMR (75 MHz, CDCl3): δ 12.5, 19.8, 23.2,
27.0, 27.8, 28.3 (3C), 31.5, 51.4, 56.3, 68.6, 80.1, 94.0, 152.1,
174.2 ppm. Anal. (C16H27NO5): C, H, N.
Met h yl (1S,2S,3R,1′S)-2-[1′-[N-(ter t-Bu t oxyca r b on yl)-
a m in o]-2′-h yd r oxyet h yl]-3-m et h yl-1-cyclo-p r op a n eca r -
boxyla te (17). A mixture of 16 (250 mg, 0.8 mmol) and
camphorsulfonic acid (9.2 mg, 0.04 mmol) in MeOH (40 mL)
was stirred at room temperature overnight. The following day,
additional camphorsulfonic acid (11.0 mg, 0.047 mmol) was
added and the mixture was stirred for 48 h. Then, NaHCO3
(50 mg) was added and the mixture was filtered off. The
filtered mixture was concentrated in vacuo, and the residue

3626 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Collado et al.
5.74 (m, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ 16.9, 29.2,
1H NMR (200 MHz, CDCl3): δ 1.23 (d, J ) 6.1 Hz, 3H), 1.89-
1.78 (m, 1H), 2.00 (dd, J ) 6.1 and 8.7 Hz, 1H), 2.27 (sx, J )
6.1 Hz, 1H), 3.69 (s, 3H), 9.32 (d, J ) 6.6 Hz, 1H) ppm. 13C
NMR (50 MHz, CDCl3): δ 16.3, 22.3, 30.2, 38.4, 52.0, 170.8,
199.0 ppm. Anal. (C7H10O3): C, H, N.
49.2, 65.0, 124.2, 130.8, 166.3, 199.7 ppm.
tr a n s-2-Bu ten -1-yl Dia zoa ceta te (22). To a solution of 21
(40.0 g, 256 mmol) and Et3N (46.0 mL, 330 mmol) in anhydrous
CH3CN (250 mL) at room temperature, a solution of p-
acetamidobenzenesulfonyl azide (80.0 g, 333 mmol) in anhy-
drous CH3CN (250 mL) was added dropwise over a period of
30 min. A white precipitate was observed after 15-20 min and
additional CH3CN (300 mL) was added to facilitate stirring.
The resulting mixture was stirred at room temperature for 1
h, and a solution of LiOH (35.5 g, 845 mmol) in H2O (300 mL)
was added. After it was stirred for one additional hour, the
resulting mixture was poured onto 2:1 Et2O:AcOEt (500 mL)
and the layers were separated. The aqueous layer was
extracted with 2:1 Et2O:AcOEt (500 mL), and the combined
organic layers were washed with a saturated aqueous solution
of NaCl (200 mL), dried (Na2SO4), filtered, and evaporated
under reduced pressure. The residue was purified by column
chromatography (Hexane/AcOEt 9:1) to afford 22 (32.2 g, 90%)
as a yellow oil. 1H NMR (200 MHz, CDCl3): δ 1.72 (dd, J )
6.3 and 1.3 Hz, 3H), 4.58 (dt, J ) 5.7 and 1.0 Hz, 2H), 5.09 (s,
1H), 5.66-5.50 (m, 1H), 5.89-5.72 (m, 1H) ppm. 13C NMR (50
MHz, CDCl3): δ 17.1, 45.5, 64.8, 124.8, 130.8, 166.1 ppm.
(1S,5R,6R)-(-)-6-Met h yl-3-oxa b icyclo[3.1.0]h exa n -2-
on e (23). To a solution of Rh2(5R-MEPY)4 (63.5 mg, 0.082
mmol) in anhydrous CH2Cl2 (250 mL) heated at reflux, a
solution of trans-2-buten-1-yl diazoacetate 22 (5.0 g, 35.7
mmol) in anhydrous CH2Cl2 (500 mL) was added dropwise over
a period of 30 h. After the addition was completed, the mixture
was allowed to react under reflux overnight and then cooled
to room temperature. The solvent was removed in vacuo, and
the residue was purified by column chromatography (Hexane/
AcOEt 5:1 and then 2:1) to give 23 (3.1 g, 77%) as a pale yellow
oil with an enantiomeric excess of 64%; [R]D ) -68.5 (c ) 1.0,
CH2Cl2). 1H NMR (200 MHz, CDCl3): δ 1.16 (d, J ) 4.8 Hz,
3H), 1.29-1.18 (m, 1H), 1.80-1.84 (m, 1H), 1.96-2.04 (m, 1H),
4.34-4.20 (m, 2H) ppm. 13C NMR (50 MHz, CDCl3): δ 14.9,
19.9, 24.0, 24.2, 68.6, 174.9 ppm.
Met h yl (1S,2R,3R)-2-H yd r oxym et h yl-3-m et h ylcyclo-
p r op r op a n e-1-ca r boxyla te (24). To a solution of 23 (3.9 g,
34.7 mmol) in THF (350 mL) at room temperature, a solution
of LiOH (7.29 g, 174 mmol) in H2O (174 mL) was added. The
mixture was stirred overnight at room temperature. The
organic phase was removed in vacuo, and the resulting
aqueous solution was washed with Et2O (2 × 50 mL), cooled
to 0 °C, and adjusted to pH ∼2-3 by addition of 1 N HCl. The
aqueous layer was extracted with AcOEt (6 × 200 mL), and
the combined organic layers were dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting (1S,2R,3R)-
2-hydroxymethyl-3-methylcyclopropropane-1-carboxylic acid
was taken into Et2O (150 mL) and cooled to 0 °C, and a
solution of diazomethane in Et2O was added in small portions
until TLC showed that no starting material remained. The
solvent was removed in vacuo to afford 22 (5.0 g). This crude
was used in the next step without further purification. 1H
NMR (200 MHz, CDCl3): δ 1.16 (d, J ) 6.5 Hz, 3H), 1.60-
1.38 (m, 3H), 3.69 (s, 3H), 3.78 (dd, J ) 7.5 and 12.0 Hz, 1H),
3.96 (dd, J ) 5.5 and 12.0 Hz, 1H) ppm. 13C NMR (50 MHz,
CDCl3): δ 16.8, 20.3, 24.7, 31.5, 50.9, 58.8, 172.8 ppm. Anal.
(C7H12O3): C, H, N.
Meth yl (1S,2R,3R)-2-For m yl-3-m eth ylcyclopr opr opan e-
1-ca r boxyla te (25). To a solution of 24 (5.0 g) in anhydrous
CH2Cl2 (350 mL) at room temperature under nitrogen, molec-
ular sieves (4 Å) (3.5 g) were added. After it was stirred for 15
min, the mixture was cooled to 0 °C and N-methylmorholine-
N-oxide (6.1 g, 52.1 mmol) was added. After 10 min, tetrapro-
pylammonium perruthenate (490 mg, 1.39 mmol) was added
in small portions and the mixture was allowed to react at room
temperature. The solvent was removed in vacuo, and the
residue was taken into AcOEt (200 mL). The resulting suspen-
sion was filtered through a plug of Celite, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (Hexane/AcOEt 6:1 and then 4:1) to give 25
(3.3 g, 67% yield) as an oil; [R]D ) +22.0° (c ) 0.75, CH2Cl2).
Meth yl (1S,2S,3R)-2-For m yl-3-m eth ylcyclopr opr opan e-
1-ca r boxyla te (26). A solution of NaOH (27.0 g, 675 mmol)
in H2O (270 mL) was added to a solution of 25 (3.3 g, 23.5
mmol) in MeOH (330 mL), and the mixture was stirred at room
temperature for 4 days. MeOH was removed under reduced
pressure, and the resulting aqueous layer was washed with
Et2O (2 × 50 mL), cooled to 0 °C, and adjusted to pH ∼2-3 by
addition of an aqueous solution of citric acid (10-25%). The
aqueous layer was extracted with AcOEt (6 × 250 mL), and
the combined organic layers were dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting carboxylic
acid was taken into Et2O (150 mL) and cooled to 0 °C, and a
solution of diazomethane in Et2O was added in small portions
until TLC showed no starting material left. The solvent was
removed in vacuo, and the residue was purified by column
chromatography (Hexane/AcOEt 4:1) to afford an inseparable
5:1 mixture of 26 and starting material 25 (2.77 g, 83%). This
mixture was used in the next step without any other further
purification. 1H NMR (200 MHz, CDCl3): δ 1.26 (d, J ) 6.4
Hz, 3H), 2.06-1.97 (m, 1H), 2.31 (dd, J ) 4.6 and 5.0 Hz, 1H),
2.53 (ddd, J ) 9.4, 4.6 and 3.6 Hz, 1H), 3.69 (s, 3H), 9.60 (d,
J ) 3.7 Hz, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ 11.0, 24.3,
27.6, 28.7, 52.2, 175.5, 198.0 ppm.
(2S,1′S,2′S,3′R,1′′R)-N-[(2′′-Hyd r oxy-1′′-p h en yl)eth yl]2-
(2′-m et h oxyca r b on yl-3′-m et h ylcyclo-p r op yl)glycin on i-
tr ile (27). To a solution of a 5:1 mixture of 26 and epimer 25
(2.7 g, 19.0 mmol) in MeOH (190 mL), (R)-(-)-2-phenylglycinol
(99% ee) (2.9 g, 20.9 mmol) was added. The mixture was stirred
at room temperature for 2 h and then cooled to 0 °C.
Trimethylsilylcyanide (5.1 mL, 38.0 mmol) was added to the
mixture and allowed to react at room temperature overnight.
The solvent was removed in vacuo, and the residue was
purified by column chromatography (Hexane/AcOEt 2:1 and
then 1:1) to afford a mixture of aminonitriles (4.8 g, 88%). The
major diastereoisomer 27 was separated and purified by
medium-pressure chromatography (Hexane/Acetone 7:2) to
give 2.3 g (42% isolated yied) as a colorless oil; [R]D ) -60.5°
(c ) 0.39, CH2Cl2). 1H NMR (200 MHz, CDCl3): δ 1.09 (d, J )
6.4 Hz, 3H), 1.35 (t, J ) 4.7 Hz, 1H), 1.70-1.56 (m, 1H), 1.88
(dt, J ) 4.4 and 9.4 Hz, 1H), 2.99 (br d, J ) 9.1 Hz, 1H), 3.58
(dd, J ) 9.3 and 10.8 Hz, 1H), 3.70 (s, 3H), 3.79 (dd, J ) 4.0
and 10.8 Hz, 1H), 4.10 (dd, J ) 4.0 and 9.3 Hz, 1H), 7.38-
7.24 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3): δ 12.5, 21.3,
27.5, 29.3, 46.9, 52.5, 63.3, 67.6, 119.3, 127.9 (2C), 128.8 (2C),
129.4, 138.4, 173.7 ppm. Anal. (C16H20N2O3): C, H, N.
(2S,1′S,2′S,3′R)-2-(2′-Ca r b oxy-3′-m et h ylcyclop r op yl)-
glycin e (7). Lead tetraacetate (5.16 g, 11.6 mmol) was added
to a solution of 27 (2.8 g, 9.7 mmol) in a 1:1 mixture of MeOH
and CH2Cl2 (100 mL) at 0 °C. After 10 min, H2O (60 mL) was
added and the mixture was filtered off through Celite. The
filtrate was concentrated in vacuo, and the residue was taken
into 6 N HCl (50 mL) and refluxed overnight. The solvent was
removed in vacuo to afford the corresponding hydrochloride
salt of 7. After purification by ion exchange chromatography
(Dowex 50 × 8-100), 7 (1.5 g, 89%) was obtained as a white
1
solid; [R]D ) +28° (c ) 0.28, H2O); mp 179-181 °C. H NMR
(200 MHz, D2O/KOD): δ 1.20-1.07 (m, 4H), 1.44-1.38 (m,
2H), 2.90 ppm (d, J ) 9.8 Hz, 1H). 13C NMR (50 MHz, D2O/
KOD): δ 13.7, 21.9, 30.9, 32.8, 56.7, 183.4, 184.5 ppm. Anal.
(C7H11NO4): C, H, N.
Mod elin g Ca lcu la tion s for Com p ou n d 19. The compu-
tational studies were performed using the molecular modeling
program SYBYL running on a Silicon Graphics Octane work-
station. After energy minimization of the structures with
MMFF94s force field, a systematic conformational search was
carried using the grid search module of the software. The
conformations were generated by rotating the C2-C1′ dihedral
from 0 to 355° by 5° increments, after which each structure
was optimized and its energy was computed.

Receptor Agonist with Anxiolytic Properties
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3627
NMR Sp ectr oscop y. NMR spectra for compound 19 and
for the Mosher’s amides derived from 18 were acquired on a
Bruker Avance 500 spectrometer in DMSO-d6 at 25 °C with
an inverse probe. Proton and carbon chemical shifts were
referenced to residual solvent signal. Absolute value COSY,
phase sensitive HSQC, and HMBC spectra were acquired
using gradient selection techniques. One-dimensional NOESY
experiments were carried out with the selective 1D double-
pulse field-gradient spin-echo module using a mixing time of
500 ms. Data were processed using XWINNMR Bruker
program on a Silicon Graphics computer.
Ack n ow led gm en t. We thank Dr. J . Pe´rez-Castells
and Mrs. Leticia Pe´rez-Serrano for their helpful col-
laboration.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
Mosher amide derivatives of compound 18. This material is
available free of charge via the Internet at http://pubs.acs.org.
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