Synthesis and structure-activity relationship studies of novel 2-diarylethyl substituted (2-carboxycycloprop-1-yl)glycines as high-affinity group II metabotropic glutamate receptor ligands.

Article abstract of DOI:10.1016/S0968-0896(02)00387-5

The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid , activates both ionotropic and metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed great

Full text of DOI:10.1016/S0968-0896(02)00387-5

Bioorganic & Medicinal Chemistry 11 (2003) 197–205
Synthesis and Structure–Activity Relationship Studies of Novel
2-Diarylethyl Substituted (2-Carboxycycloprop-1-yl)glycines as
High-Affinity Group II Metabotropic Glutamate Receptor Ligands
Ulrik S. Sørensen, Thomas J. Bleisch, Anne E. Kingston, Rebecca A. Wright,
Bryan G. Johnson, Darryle D. Schoepp and Paul L. Ornstein*
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC 1523 Indianapolis, IN 46285, USA
Received 14 March 2002; accepted 5 August 2002
Abstract—The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid (1), activates both ionotropic and
metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed
great attention to the development of compounds that modulate the effects of this endogenous ligand. Whereas l-carboxy-
cyclopropylglycine (l-CCG-1, 2) is a potent agonist at, primarily, group II metabotropic glutamate receptors, alkylation of 2 at the
a-carbon notoriously result in group II mGluR antagonists, of which the most potent compound described so far, LY341495 (12),
displays IC50 values of 23 and 10 nM at the group II receptor subtypes mGlu2 and mGlu3, respectively. In this study we synthesized
a series of structural analogues of 12 in which the xanthyl moiety is replaced by two substituted-phenyl groups. The pharmacolo-
gical characterization shows that these novel compounds have very high affinity for group II mGluRs when tested as their race-
mates. The most potent analogues demonstrate Ki values in the range of 5–12 nM, being thus comparable to LY341495 (12).
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
macologically as the ionotropic glutamate receptors, but
it is generally agreed that all classes of EAA receptors
play important roles in the CNS, and that ligands
affecting ionotropic12,13 as well as metabotropic12ꢀ17
receptors would serve as useful therapeutic targets in
relation to various neurologic disorders.
(S)-Glutamic acid (1) is the major excitatory neuro-
transmitter in the central nervous system (CNS), and
activates both ionotropic and metabotropic excitatory
amino acid (EAA) receptors. The three subclasses of
ionotropic EAA receptors are N-methyl-d-aspartic
(NMDA),1,2 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-
yl)propanoic acid (AMPA),3ꢀ6 and kainic acid (KA)
receptors.3ꢀ5,7,8 In contrast to these ligand gated ion
channel receptors, the metabotropic glutamate receptors
(mGluRs) are G-protein coupled receptors, linked to
multiple signal transduction pathways, including
phosphatidylinositide and cyclic-AMP production.9ꢀ11
A large number of mGluR ligands have been developed,
of which l-carboxycyclopropylglycine (l-CCG-1, 2),18
2-amino-4-phosphonobutanoic acid (l-AP4, 3),19 and
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
acid
(1S,3R)-ACPD, 4)20 were among the first potent ago-
nists identified. Compound 3 is a relatively selective
groupIII agonist whereas 4 shows activity at both
groupI and groupII mGluRs. Also, the potent groupII
mGluR agonist 2 shows some activity at groupI
mGluRs. These structures have helped lead the way for
further development aimed at understanding the phar-
macology of the mGluRs. An example of a potent and
selective groupII agonist is LY354740 ( 5).21ꢀ25 The
recently described heterocyclic derivatives of 5,
LY379268 (6) and LY389795 (7),22,26 have displayed
EC50 values between 3 and 8 nM, and are among the
most potent group II mGluR agonists known to date.
Also, modification of 3 led to a-methyl-AP4 (MAP-4,
Based on sequence homology and pharmacological
properties, three subclasses of mGluRs have so far been
identified; group I (comprising the receptor subtypes
mGlu1 and mGlu5), groupII (mGlu2 and mGlu3), and
groupIII (mGlu4, mGlu6, mGlu7, and mGlu8). The
mGluRs have not yet been as well characterized phar-
*Corresponding author. Tel.: +1-317-276-3226; fax: +1-317-277-
2035; e-mail: ornstein_paul@lilly.com
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00387-5

198
U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
8), a selective but relatively nonpotent group III mGluR
antagonist.27
when we used aqueous hydrochloric acid in either tet-
rahydrofuran or acetonitrile. The resulting diaryl acet-
aldehydes 16 were subsequently reduced with NaBH4 to
give the primary alcohols 17. Iodination of 17 with tri-
phenylphosphine diiodide gave iodides 18 that were
used in the palladium-mediated acid chloride/organo-
zincate coupling. The iodides were generally quite
stable, and could all be purified by flash chromato-
graphy on silica gel. Compounds 18 were treated with
Zn(Cu) couple and the formed organozincate species
were subsequently reacted in situ with Pd(PPh3)4 and
racemic trans-carboxylic acid chloride 19 to afford
ketones 20 containing the diarylethyl as well as the
cyclopropyl moieties.36 After hydrolysis of the ester
group, conversion into hydantoins 21 was accomplished
by reaction with potassium cyanide and ammonium
carbonate. All synthesized hydantoins were subse-
quently hydrolyzed using 1 M NaOH at 200 ꢁC to yield
amino acids 22, as a mixture of two or three racemic
diastereomers.
We previously made a detailed structure activity rela-
tionship(SAR) study showing that substitution of 2 in
the a-position of the amino acid moiety with an alkyl or
especially arylalkyl substituent has a marked effect on both
potency and selectivity.28,29 Thus, systematic substitution
with unbranched and branched alkyl chains led to com-
pound 9 with an IC50 in glutamate binding of 1.4 mM.28
Further elaboration of 9 to the cyclohexylmethyl ana-
logue 10 and the phenylethyl derivative 11 led to a fur-
ther increase in glutamate binding affinity (IC50 0.23
and 0.32 mM, respectively). The most potent compound
synthesized in this series was the 9-xanthylmethyl deri-
vative,28 of which the S,S,S-stereoisomer, LY341495
(12),28,30 displayed IC50 values of 23 and 10 nM at
mGlu2 and mGlu3 receptors, respectively. LY341495
has now been developed into a useful radioligand.31ꢀ33
Modification of 12 into its 30-ethyl analogue CECXG
(13) improves overall group II selectivity but also gives
a 5-fold loss of potency.34
The two stepconversion from ketone 20 to amino acid
22 had previously been optimized.28 However, for the
compounds described here, the steric demands of the
two phenyl groups required the use of excessive
amounts of KCN and (NH4)2CO3 and longer reaction
times. The subsequent hydantoin hydrolyses were car-
ried out in 1 M aqueous NaOH at 200 ꢁC by heating the
reaction mixture in a sealed stainless steel high-pressure
vessel as previously reported.28 In contrast to our prior
experience with these type of compounds, these hydantoin
and amino acid analogues containing two aromatic
rings generally precipitated readily and were therefore
quite easily purified. Thus, most hydantoins 21 were
recrystallized from MeOH/H2O, and all amino acids,
except 22a and 22o, were isolated by precipitation
without the use of ion exchange chromatography. By
these methods, no signficant change in the diaster-
eomeric ratio was observed. The above described route
to the desired amino acid analogues resulted in
successful preparation of amino acids 22b, 22d, 22i,
22k, 22l, and 22s (Table 2), as mixtures of racemic
diastereoemers.
Compared to compound 11, the introduction of an
additional phenyl group to give compound 14 gives not
only improved potency (IC50 0.24 mM) but also a 16-
fold increase in selectivity for mGlu3 relative to
mGlu2.28 This finding has prompted us to study whe-
ther substituents on the phenyl groups of 14 would fur-
ther improve selectivity as well as potency. This paper
reports the synthesis and pharmacological characteriza-
tion of a number of analogues of 14 containing a variety
of different phenyl ring substituents.
Chemistry
A number of the novel amino acid derivatives 22 pre-
sented in this paper were synthesized by our previously
published pathway with only minor changes in the pro-
cedure (Scheme 1).28,29 All of the compounds that we
prepared contain multiple racemic diastereomers.
Through the synthetic methods utilized, we typically
obtained a nearly 1:1 or 1:1:1 ratio of diastereomers,
and no attempt was made to separate these diaster-
eomers; nor did we do anything to separate the different
enantionmeric pairs.
A major limitation of this route was the availability of
substituted benzophenones. To further broaden and
Table 1. Isolated yields (%) of compounds 15–18b, d, i, k, l, s
Thus, ketones of the general structure 20 were prepared
in five steps from commercially available substituted
benzophenones (Scheme 1). In the first step, methyl
diarylenol ethers 15 are synthesized from these benzo-
phenones by Wittig methylenation35 using (methoxy-
methyl)triphenylphosphonium chloride and sodium
bis(trimethylsilyl)amide as base. This transformation is
very efficient, typically affording enol ethers 15 in
quantitative yields (Table 1).
15
16
17
18
R=2,5-diMe, R0=H
R=R0=4-Me
R=R0=2-Cl
b
d
i
k
l
97
77
95
78
100
67
84
82
68
74
76
60
87
86
83
81
100
100
100
100
R=R0=4-F
R=R0=3-F
Enol ethers 15 were hydrolyzed with 70% aqueous per-
chloric acid in diethyl ether to give the corresponding
aldehydes 16. These reaction conditions were found to
be the best; less than favorable results were obtained
From
s
100
81
81
82

U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
199
Scheme 1.
complete the SAR study it was essential to synthesize a
wider range of analogues with both ortho, meta, and
para substituted benzene rings. We therefore had to find
an alternative route to prepare these target amino acids
and focused on a strategy that introduces the two
phenyl groups one at a time. Our approach was to
start by first incorporating a phenyl group through a
Wittig–Horner–Emmons methylenation reaction to give
an a,b-unsaturated ketone 24 (Scheme 2).
The use of this transformation is already well estab-
lished through our synthesis of derivatives of the phenyl
ethyl compound 11.29 Dimethyl phosphonate 2329 was
deprotonated using sodium bis(trimethylsilyl)amide as

200
U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
Table 2. Structure and yield of ketones 20a–s, hydantoins 21a–s and amino acids 22a–s
a
b
c
d
e
f
63
62
65
54
86
97
61
37
52
64
70
71
73
83
61
84
95
81
99
74
43
31
51
45
38
48
18
26
67
32
k
l
68
17
65
72
54
95
80
85
50
89
56
83
58
93
87
81
69
80
58
32
26
32
30
34
15
29
35
m
n
o
p
q
r
g
h
i
s
j
Scheme 2.
base and subsequently condensed with a benzaldehyde
to give 24a–k in moderate to good yields.
phenyl iodide to the a,b-unsaturated ketone 24. React-
ing 24b with 2-iodotoluene in a Heck-type37 coupling
reaction using palladium acetate as catalyst and formic
acid as a proton donor afforded the desired addition
product 20e in 86% yield with no detectable amounts of
A crucial step is the incorporation of the second phenyl
moiety by a 1,4 conjugate addition of a substituted

U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
201
the unreduced product. It is thus possible to achieve, in
one step, ketone 20, thereby avoiding a reduction of the
C–C double bond in a later step. Regarding the
mechanism, it has been suggested that migratory inser-
tion of the reactive palladium species to the C–C double
bond is followed by release of palladium, generating an
anionic intermediate which reacts with the formic acid
present.38 Another mechanism suggested, involves
enones in a palladotropic shift to give a palladium eno-
late which after reduction gives the Michael addition
product.37
similar to the one used for mGlu2 and mGlu3 receptors.
As previously mentioned, all of the compounds pre-
pared in this study were obtained as mixtures of racemic
diastereomers, and no effort was made to separate these
isomers.
Concerning the symmetrically substituted analogues,
substitution at the ortho position results in a substantial
decrease in potency, as seen for 22b, 22e, and 22i which
were all several orders of magnitude less potent when
compared to analogues substituted in the meta and para
positions (Table 3).
The reductive Heck type coupling was carried out on
several enones 24 using differently substituted iodo-
benzenes (Table 2). In most cases, good yields were
obtained, except for enones 24e and 24j, containing the
electron withdrawing substituents fluorine and 3,5-
bis(trifluoromethyl), for which only trace amounts of
product was formed (according to 1H NMR). However,
3-methyl-4-fluoro enone 24h successfully couples with
both iodobenzene and 2-fluoro-5-iodotoluene to give
ketones 20m and 20n, respectively. With the phenyl
substituent being 3-chloro or 3-trifluoromethyl, pro-
ducts 20h and 20o were isolated, albeit in moderate
yields. Whereas all of these observations concern the
nature of the enone 24, no limitations in the reactivity
was experienced regarding the choice of aryl iodides,
and substrates containing either electron withdrawing
or donating substituents give the desired coupling
products 20 in good yield.
The introduction of more than one substituent on each
aromatic ring does not lead to further increased bind-
ing. Thus, 22f, having a methyl groupat all four meta
positions, is three-fold less potent than 22c, having two
symmetric meta-Me substituents. Although less sig-
nificant, the same can be concluded from 22n (para-
fluoro, meta-Me) being slightly less active than 22k
(para-fluoro). An explanation to this finding can be the
larger steric bulk of the substituents leading to weaker
binding between receptor and ligand. The importance of
steric factors is also demonstrated by compounds sub-
stituted at only one of the phenyl rings, which, in most
cases, show slightly higher binding affinity than the
symmetrically disubstituted analogues. The differences
are nevertheless small, but the tendency is found when
pairwise comparing 22a/22c, 22m/22n and 22p/22q.
Exceptions to this are the mono- and di-halogen sub-
stituted analogues, demonstrated by 22h, displaying
approximately five-fold higher binding than 22g, and
22k being slightly more potent than 22j.
In summary, the route including a reductive Heck type
coupling (Scheme 2) has numerous advantages com-
pared to the pathway first applied (Scheme 1). First of
all, only two steps are needed from methyl phosphonate
23 to ketone 20, compared to the five steps required
when starting from a benzophenone. Second, the abun-
dance of inexpensive commercially available benzalde-
hydes as well as their corresponding phenyl iodides
makes it possible to synthesize a much greater variety of
ketones 20. Thus, we were able to synthesize amino
acids 22 with symmetrically as well as unsymmetrically
substituted aromatic rings (Table 2), and thereby reach
the target compounds required to complete the SAR
study.
Whereas racemic 14 was previously reported to show
16-fold selectivity for mGlu3 over mGlu2,28 none of the
synthesized amino acids with the general structure 22
displayed significant subtype selectivity between mGlu2
and mGlu3. The compounds are, however, still far more
potent at group II than at group I and III. The most
potent analogues, displaying low nanomolar affinities at
mGlu2 and mGlu3, are also the compounds being most
active at groups I and III (although with Ki and IC50
values in the mM range).
It should be noticed that the compounds presented here
are synthesized and tested as racemic mixtures. For
already resolved racemates, like 14 and the xanthyl-
methyl analogue LY341495 (12), theS,S,S-stereoisomer
is the most active component. Racemic 12 displays
between two and eight times weaker binding at mGlu2
and mGlu3 as compared to the resolved S,S,S-iso-
mer,28,29 and the most active racemates synthesized in
the present study are thus comparable to the racemic
form of this very potent ligand 12.
Pharmacology
We found that all of the a-alkylated analogues of
l-CCG-1 (2) described in our earlier studies were potent
antagonists at groupII mGlu receptors.
28,29
Therefore,
we only tested compounds synthesized in this study for
their binding affinity to the two cloned human mGluR
groupII subtypes, mGlu2 and mGlu3. These assays
were performed in competition with radiolabelled
LY341495 (12).32,33,39 Furthermore, to show whether
group I activity is also present, all compounds were
tested on mGlu1 and mGlu5 expressing RGT cells for
their ability to antagonize a response induced by the
agonist quisqualic acid.23,30 To represent group III
mGlu receptors, membranes from RGT cells expressing
human mGlu8 receptors were used in a binding assay
In conclusion, a number of high affinity ligands for
groupII mGlu receptors have been synthesized and
characterized pharmacologically. With varying patterns
of aromatic substitution, subtype selectivity between
mGlu2 and mGlu3 was not achieved. The most potent
of these compounds, 22h, 22k, and 22m, that all con-
tained chloro- or fluoro-substituents in the meta or para

202
U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
Table 3. Pharmacological data of synthesized amino acids 22a–s
MGlu2
mGlu3
Relative potencya
mGlu1
mGlu5
mGlu8
Ki (mM)
Relative potencya
Ki (mM)
IC50 (mM)
Ki (mM)
22a
22b
22c
22d
22e
22f
22g
22h
22i
0.049
21
0.062
47
2700
160
560
12,000
530
34
72
>100
>100
>100
>100
>100
36
54
>100
>100
>100
>100
>100
6
2.8
35
1.8b
0.086
0.17
800
38
75
6000
113
17
3
3.6b
0.21
0.73b
15
1.9
1.1b
>100
9.3
14
0.26
0.69
0.045
0.010
1.2b
0.040
0.007
0.73b
0.29
0.80
1.8
8
43
49
320
12
5
903
7
>100
3
>100
62
64b
22j
0.009
0.005
—
0.85
0.34
0.25c
0.86
0.68
0.90
0.50
5.6
22k
22l
0.012
0.019
0.012
0.019
0.045
0.034
0.067
0.25b
4
3c
14
8
—
38
61
22m
22n
22o
22p
22q
22r
5
0.009
0.024
0.16
0.049
0.10
0.29
7
29
23
8
18
9
44
20
15
29
108
125
38
28
38
92
>100
>100
38
79
>100
83
220
2.2b
22s
0.031
13
0.014
11
5
27
0.83b
aPotency of LY341495 relative to tested compound based on a Ki for Ly341495 of 0.0023 mM and 0.0013 mM at mGlu2 and mGlu3 respectively.
Each compound is tested once except in the following cases (average used). b n=2. c n=3.

U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
203
positions of the benzene rings, demonstrated Ki values
in the range of 5–12 nM. Thus, the best compounds
from this SAR study were comparable to one of the
most potent group II antagonists known, LY341495
(12). Also, the compounds are far more potent at group
II than at mGlu1, mGlu5 and mGlu8 and can thus serve
as useful tools for the differentiation between groupII
and groupI/III mGluRs.
mixture stirred 30 min at room temperature. 4,40-Dime-
thylbenzophenone (25.0 g, 119 mmol) was added and
stirring continued 2 h at reflux temperature. After cool-
ing to room temperature, H2O (500 mL) was added and
the mixture extracted with EtOAc. The combined
organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo. CC (5% EtOAc/hexane) of the resi-
due afforded 15d as a colorless oil (28.5 g, 100%).
1H NMR (CDCl3) d 2.34 (s, 6H), 3.74 (s, 3H), 6.41 (s,
1H), 7.10–7.35 (m, 8H); 13C NMR (CDCl3) d 21.0, 21.2,
60.4, 120.4, 128.1, 128.7, 128.9, 129.7, 134.9, 136.0,
136.1, 137.7, 145.6. MS(ES) m/z 239 ([M+1]+, 32%).
Anal. (C17H18O) C, H.
Supportinginformation available
For the synthesized structures, experimental data
obtained from NMR spectroscopy, elemental analyses,
and mass spectroscopy are included, together with the
assigned compound names. Supporting information is
available as a Microsoft Word file upon request to the
corresponding author.
General procedure for the preparation of diaryl acetalde-
hydes. Synthesis of 2,2-bis(4-tolyl)acetaldehyde (16d).
Compound 15d (27.0 g, 113 mmol) was dissolved in
Et2O (400 mL) and to this solution was slowly added a
70% aqueous solution of HClO4 (115 mL). After stir-
ring overnight at room temperature the mixture was
added slowly to saturated NaHCO3 (aq) (1.2 L). The
organic phase was isolated and the aqueous phase
extracted with Et2O. The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo. CC of
the residue (10% EtOAc/hexane) afforded 24.1 g (95%) of
16d as a colorless oil. 1H NMR (CDCl3) d 2.34 (s, 6H), 4.81
(s, 1H), 7.01–7.20 (m, 8H), 9.90 (s, 1H); 13C NMR (CDCl3)
d 21.0, 63.4, 129.0, 129.7, 133.5, 137.3, 198.8. MS(FD+)
m/z 224 (M+, 100%). Anal. (C16H16O) C, H.
Experimental
General methods. Pharmacology. Receptor binding
assays on cloned cells expressing metabotropic gluta-
mate receptors were performed as previously descri-
bed:32,33,39 Membranes, from cells expressing
recombinant human mGlu receptors, were prepared by
scraping attached cells from T-150 flasks, centrifuging,
and freezing resultant pellets. Frozen cell pellets were
thawed on the day of assay, suspended in ice-cold assay
buffer (10 mM potassium phosphate pH 7.6+100 mM
potassium bromide), homogenized and washed 3 times
by centrifugation at 50,000g for 10 min. To start the
reaction, washed tissue (0.05–0.20 mg protein) was
added to deep-well polypropylene microtiter plates
containing [3H]-LY341495 (1 nM for mGlu2 and
mGlu3, and 10 nM for mGlu6, mGlu7, and mGlu8) and
appropriate concentrations of test compounds in assay
buffer. Final assay volume was 0.5 mL. Nonspecific
binding was defined with 1 mM l-serine-O-phosphate
General procedure for the preparation of diaryl ethanols.
Synthesis of 2,2-bis(4-tolyl)ethanol (17d). Compound
16d (23.0 g, 103 mmol) was dissolved in EtOH (300 mL)
and added NaBH4 (3.88 g, 103 mmol). The mixture was
stirred at room temperature for 4 h and then con-
centrated in vacuo. H2O (300 mL) was added and the
solution extracted with EtOAc. The combined organic
extracts were dried (MgSO4), filtered, and concentrated
in vacuo. CC (10–20% EtOAc/hexane) afforded 17d as
(for mGlu7) or
1 mM L-glutamate (all other
1
receptors). Assay plates were incubated on ice for 45
min and the reaction was terminated by rapid
filtration.
a white solid (19.2 g, 82%). H NMR (CDCl3) d 1.48 (s
br, 1H), 2.31 (s, 6H), 4.12–4.13 (m, 3H), 7.14–7.17 (m,
8H); 13C NMR (CDCl3) d 21.0, 52.9, 66.3, 128.2, 129.4,
136.3, 138.6. MS(FD+) m/z 226 (M+, 100%). Anal.
(C16H18O) C, H.
Chemistry. Solvents and reagents were purchased from
commercial sources and used without further purifica-
tion unless otherwise stated. Elemental and MS analyses
were performed by the Physical Chemistry Department
of Lilly Research Laboratories. Column chromato-
graphy (CC) was carried out using silica gel 60 (230–
400 mesh) from Merck. Compounds were visualized on
TLC plates (5 ꢂ 10 cm, 0.25 mm thickness, silica gel 60
F254, Merck) using UV light followed by either a ceric
ammonium molybdate28 or ninhydrin solution. Anion
exchange chromatography was performed on a Bio-
Rad AG1-X8 resin by the procedure previously
described.28
General procedure for the preparation of Iodo diaryle-
thanes. Synthesis of 1,1-bis(4-tolyl)-2-iodoethane (18d).
Triphenylphosphine (30.1 g, 115 mmol) dissolved in
dry CH2Cl2 (250 mL) was added iodine (29.1 g, 115
mmol) and stirred 5 min at room temperature. Imida-
zole (13.0 g, 191 mmol) was added and the mixture
stirred 15 min followed by addition of alcohol 17d (17.3
g, 76.4 mmol) dissolved in dry CH2Cl2 (35 mL). After
stirring overnight at room temperature the reaction
mixture was quenched by addition of 10% aqueous
NaHSO4 (200 mL). The solution was extracted with
CH2Cl2 and the combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. After CC
(10% EtOAc/hexane) compound 18d was isolated as a
General procedure for the preparation of methyl diaryle-
nol ethers. Synthesis of 1,1-bis(4-tolyl)-2-methoxyethene
(15d). (Methoxymethyl)triphenylphosphonium chloride
(57.0 g, 167 mmol) was suspended in dry dioxane (250
mL). A 1 M solution of sodium bis(trimethylsilyl)amide
(166 mL) in THF was added dropwise and the reaction
1
colorless oil in 87% yield (22.3 g). H NMR (CDCl3)
d 2.31 (s, 6H), 3.71 (d, J=8.0 Hz, 2H), 4.27 (t, J=8.0
Hz, 1H), 7.11–7.12 (m, 8H); 13C NMR (CDCl3) d 10.0,
21.0, 53.6, 127.5, 129.3, 136.5, 139.8. MS(FD+) m/z 336

204
U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
(M+, 100%). Anal. (C16H17I) H; C: calcd 57.16; found,
58.03.
mixture was neutralized with 5 M HCl (aq) (Caution:
evolution of HCN gas) and extracted with EtOAc. The
combined organic extracts were washed with 10% aqu-
eous NaHSO4, dried (MgSO4), filtered, and con-
centrated in vacuo. The residual solid was recrystallized
from MeOH/H2O, filtered, washed with water, and
Method A. General procedure for the preparation of ke-
tones by Zn(Cu) couple mediated couplingof iodo diary-
lethanes and carboxylic acid chloride 19. Synthesis of
2,2-bis(4-tolyl)ethyl (1RS,2RS)-2-carbethoxycycloprop-
1-yl ketone (20d). A solution of 18d (22.0 g, 65.4 mmol)
and Zn(Cu) couple (10.2 g, 157 mmol) in dry toluene
(250 mL) and N,N-dimethylacetamide (35 mL) was
heated to 60 ꢁC for 3 h. The heating bath was removed
and tetrakis(triphenylphosphine)palladium(0) (3.0 g, 2.6
mmol) added. After 5 min acyl chloride 19 (11.6 g, 65.7
mmol) was added and the reaction mixture stirred at
room temperature overnight. The solution was then fil-
tered through Celite and the filtrate washed with 10%
aqueous NaHSO4 and brine. The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. CC
of the residue (10–15% EtOAc/hexane) afforded 20d as
1
dried to afford 21d as a white solid (8.94 g, 83%). H
NMR (DMSO) d 0.68–0.74 (m, 1H), 0.83–0.89 (m, 2H),
0.93–0.99 (m, 1H), 1.21–1.27 (m, 1H), 1.50–1.61 (m,
3H), 2.23 (s, 12H), 2.25–2.40 (m, 2H), 2.73–2.94 (m,
2H), 3.94–3.97 (m, 2H), 7.00–7.21 (m, 16H), 7.73 (s,
1H), 7.83 (s, 1H), 10.30 (s, 1H), 10.38 (s, 1H); 13C NMR
(DMSO) d 9.1, 10.2, 14.9, 15.7, 20.5, 20.6, 27.4, 27.9,
41.2, 45.8, 45.9, 63.2, 63.4, 127.0, 127.1, 127.5, 127.6,
128.6, 128.7, 128.9, 128.9, 134.8, 134.8, 135.0, 135.1,
140.3, 140.8, 142.4, 142.6, 156.4, 173.7, 174.0, 176.0,
176.2. MS(ES) m/z 391 ([M-1]+, 100%), 392 (M+,
31%). Anal. (C23H24N2O40.1H2O) C, H, N.
1
a colorless oil (12.4 g, 54%). H NMR (CDCl3) d 1.25–
General procedure for the hydantoin hydrolysis into
amino acid. synthesis of (2SR)- and (2RS)-2-amino-4,4-
bis(4-tolyl)-2-((1RS,2RS)-2-carboxycycloprop-1-yl)buta-
noic Acid (22d). Hydantoin 21d (6.21 g, 15.8 mmol) dis-
solved in 1 M NaOH (aq) (100 mL) was heated to
200 ꢁC for 24 h in a sealed stainless steel high-pressure
vessel. After cooling to room temperature the reaction
mixture was filtered and pH adjusted to 4 with 5 M
aqueous HCl. The resulting precipitate was filtered off,
washed with H2O, dried, and washed with Et2O to give
amino acid 22d as an off white solid in 45% yield (2.60
1.34 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.99–2.05 (m, 1H),
2.28 (s, 6H), 2.39–2.45 (m, 1H), 3.31 (d, J=7.7 Hz, 2H),
4.12 (q, J=7.0 Hz, 2H), 4.52 (t, J=7.7 Hz, 1H), 7.05–
7.11 (m, 8H); 13C NMR (CDCl3) d 14.2, 17.1, 20.9, 24.1,
29.5, 45.5, 50.2, 61.0, 127.5, 129.2, 135.9, 140.8, 172.0,
205.8. MS(ES) m/z 350 (M+, 17%). Anal. (C23H26O3)
C, H.
Method B. General procedure for the preparation of
ketones by a Heck type 1,4 conjugate addition. Synthesis
of of 2,2-bis(2-tolyl)ethyl (1RS,2RS)-2-carbethoxycyclo-
prop-1-yl ketone (20e). Enone 24b (4.89 g, 18.9 mmol)
in triethylamine (6.51 g, 64.4 mmol) was added 2-iodo-
toluene (9.91 g, 45.4 mmol), palladium(II)acetate (21.2
mg, 0.095 mmol), dry CH3CN (11 mL) and formic acid
(1.97 g, 49.2 mmol). After stirring overnight at 80 C the
reaction mixture was added additional palladium(II)a-
cetate (21.2 mg, 0.095 mmol) and stirred for another 16
h at 80 C. After cooling to room temperature the mix-
ture was added H2O (50 mL) and extracted with EtOAc.
The combined organic phases were dried (MgSO4), fil-
tered, and concentrated in vacuo. Column chromato-
graphy (10% EtOAc/hexane) of the residue afforded 20e
1
g). H NMR (DMSO) d 0.22–0.35 (m, 1H), 0.55–0.62
(m, 1H), 0.80–0.89 (m, 1H), 1.15–1.25 (m, 2H), 1.40–
1.50 (m, 2H), 1.82–1.93 (m, 1H), 2.23 (s, 12H), 4.15–
4.23 (m, 2H), 4.35–4.42 2H), 7.02–7.20 (m, 16H).
MS(ES) m/z 366 ([M-1]+, 100%), 367 (M+, 32%).
Anal. (C22H25NO40.3H2O) C, H, N.
General procedure for the preparation of aryl enones by
WittigHorner–Emmons methylenation. Synthesis of
(1RS,2RS)-2-carboxycycloprop-1-yl
2-(2-tolyl)ethenyl
ketone (24b). Dimethyl phosphonate 23 (6.60 g, 24.5
mmol) dissolved in dry THF (80 mL) was added a 1 M
solution of sodium bis(trimethylsilyl)amide (27 mL) in
THF dropwise. After stirring 30 min at room tempera-
ture 2-tolualdehyde (3.24 g, 27 mmol) was added drop-
wise. After 1 h the reaction mixture was quenched with
H2O (100 mL) and extracted with Et2O. The combined
organic phases were dried (MgSO4), filtered, and con-
centrated in vacuo. CC (5–10% EtOAc/hexane) of the
1
as a colorless oil (5.72 g, 86%). H NMR (CDCl3) d
1.26 (t, J=7.1 Hz, 3H), 1.30–1.37 (m, 2H), 1.99–2.05
(m, 1H), 2.26 (s, 3H), 2.30 (s, 3H), 2.39–2.45 (m, 1H),
3.20 (d, J=7.6 Hz, 2H), 4.12 (q, J =7.1 Hz, 2H), 4.90
(t, J=7.6 Hz, 1H), 7.02–7.23 (m, 8H); 13C NMR
(CDCl3) d 14.2, 17.0, 19.4, 24.2, 29.4, 38.8, 49.1, 61.0,
126.0, 126.1, 126.4, 126.4, 126.7, 126.9, 130.7, 130.7,
135.9, 136.00, 140.9, 141.0, 171.9, 205.8. MS(ES) m/z
351 ([M+1]+, 22%). Anal. (C23H26O3) C, H.
1
residue afforded 24b as a colorless oil (5.10 g, 81%). H
NMR (CDCl3) d 1.29 (t, J=7.2 Hz, 3H), 1.50–1.59 (m,
2H), 2.28–2.34 (m, 1H), 2.46 (s, 3H), 2.73–2.79 (m, 1H),
4.18 (q, J=7.2 Hz, 2H), 6.83 (d, J=15.9 Hz, 1H), 7.21–
7.62 (m, 4H), 7.95 (d, J=16.0 Hz, 1H); 13C NMR
(CDCl3) d 14.2, 17.6, 19.8, 24.5, 28.4, 61.1, 126.4, 126.5,
127.0, 130.4, 130.9, 133.3, 138.3, 141.0, 172.3, 196.4.
MS(ES) m/z 259 ([M+1]+, 66%). Anal. (C16H18O3) C, H.
General procedure for the carboxylic ester hydrolysis
and subsequent hydantoin formation. Synthesis of
(5SR)- and (5RS)-5-(2,2-bis(4-tolyl)ethyl)-5-((1RS,2RS)-
2-carboxycycloprop-1-yl)imidazolidine-2,4-dione (21d).
Ketone 20d (9.60 g, 27.4 mmol) dissolved in EtOH (200
mL) and H2O (200 mL) was added 1 M NaOH (aq) (41
mL) and stirred at 55 ꢁC for 6 h. KCN (17.8 g, 273
mmol) and (NH4)2CO3 (47.4 g, 493 mmol) was added in
two portions during the next 5 days while stirring at
55 ꢁC. After cooling to room temperature the reaction
Acknowledgements
The authors thank the Physical Chemistry Department
of Lilly Research Laboratories for 13C NMR spectra as

U. S. Sørensen et al. / Bioorg. Med. Chem. 11 (2003) 197–205
205
well as MS and elemental analyses. Also a special
thanks to Jack Campbell, Lilly Research Labora-
tories, for the liberal use of his high-pressure hydro-
genation equipment.
22. Kingston, A. E.; O’Neill, M. J.; Lam, A.; Bales, K. R.;
Monn, J. A.; Schoepp, D. D. Eur. J. Pharmacol. 1999, 377,
155.
23. 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.
24. 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.
References and Notes
1. McBain, C. J.; Mayer, M. L. Physiol. Rev. 1994, 74, 723.
2. Kyle, D. J.; Patch, R. J.; Karbon, E. W.; Ferkany, J. W. In
Excitatory Amino Acid Receptors: Design of Agonists and
Antagonists, Krogsgaard-Larsen, P.; Hansen, J. J., Eds.; Ellis
Horwood: Chichester, 1992; pp 121–161.
25. Battaglia, G.; Monn, J. A.; Schoepp, D. D. Neurosci. Lett.
1997, 229, 161.
3. Lees, G. J. Drugs 2000, 59, 33.
4. Bleakman, D.; Lodge, D. Neuropharmacology 1998, 37,
1187.
5. Fletcher, E. J.; Lodge, D. Pharmacol. Ther. 1996, 70, 65.
6. Borges, K.; Dingledine, R. Progr. Brain Res. 1998, 116,
153.
26. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J. L.,
Jr.; 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.
27. Jane, D. E.; Jones, P. L.; St, J.; Pook, P. C.-K.; Tse, H-W.;
Watkins, J. C. Br. J. Pharmacol. 1994, 112, 809.
28. Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Wright,
R. A.; Johnson, B. G.; Schoepp, D. D. J. Med. Chem. 1998,
41, 346.
7. Chittajallu, R.; Braithwaite, S. P.; Clarke, V. R. J.; Henley,
J. M. Trends Pharmacol. Sci. 1999, 20, 26.
8. Shinozaki, H. In Excitatory Amino Acid Receptors: Design
of Agonists and Antagonists; Krogsgaard-Larsen, P., Hansen,
J. J., Eds.; Ellis Horwood: Chichester, 1992; pp 261–291.
9. Schoepp, D. D. J. Pharmacol. Exp. Ther. 2001, 299, 12.
10. Ozawa, S.; Kamiya, H.; Tsuzuki, K. Progr. Neurobiol.
1998, 54, 581.
29. Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Kennedy,
J. H.; Wright, R. A.; Johnson, B. G.; Tizzano, J. P.; Helton,
D. R.; Kallman, M. J.; Schoepp, D. D. J. Med. Chem. 1998,
41, 358.
11. Schoepp, D. D.; Conn, P. J. Trends Pharmacol. Sci. 1993,
14, 13.
12. Brauner-Osborne, H.; Egebjerg, J.; Nielsen, E. Ø.; Mad-
sen, U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609.
13. Parsons, C. G.; Danysz, W.; Quack, G. Drug News Per-
spect. 1998, 11, 523.
30. Kingston, A. E.; Ornstein, P. L.; Wright, R. A.; Johnson,
B. G.; Mayne, N. G.; Burnett, J. P.; Belagaje, R.; Wu, S.;
Schoepp, D. D. Neuropharmacology 1998, 37, 1.
31. Ornstein, P. L.; Arnold, M. B.; Bleisch, T. J.; Wright,
R. A.; Wheeler, W. J.; Schoepp, D. D. Bioorg. Med. Chem.
Lett. 1998, 8, 1919.
14. Bruno, V.; Battaglia, G.; Copani, A.; D’Onofrio, M.;
Iorio, P. D.; Blasi, A. D.; Melchiorri, D.; Flor, P. J.; Nicoletti,
F. J. Cereb. Blood Flow Metab. 2001, 21, 1013.
15. Monn, J. A.; Schoepp, D. D. Annu. Rep. Med. Chem.
2000, 35, 1.
16. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharma-
cology 1999, 38, 1431.
17. Pin, J.-P.; De Colle, C.; Bessis, A.-S.; Acher, F. Eur. J.
Pharmacol. 1999, 375, 277.
32. Johnson, B. G.; Wright, R. A.; Arnold, M. B.; Wheeler,
W. J.; Ornstein, P. L.; Schoepp, D. D. Neuropharmacology
1999, 38, 1519.
33. Wright, R. A.; Arnold, M. B.; Wheeler, W. J.; Ornstein,
P. L.; Schoepp, D. D. J. Pharmacol. Exp. Ther. 2001, 298, 453.
´
34. Collado, I.; Ezquerra, J.; Mazon, A.; Pedregal, C.; Yrur-
etagoyena, B.; Kingston, A. E.; Tomlinson, R.; Wright, R. A.;
Johnson, B. G.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
1998, 8, 2849.
18. Hayashi, Y.; Tanabe, Y.; Aramori, I.; Masu, M.; Shima-
moto, K.; Ohfune, Y.; Nakanishi, S. Br. J. Pharmacol. 1992,
107, 539.
35. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
36. Tamaru, Y.; Ochiai, H.; Sanda, F.; Yoshida, Z.-i. Tetra-
hedron Lett. 1985, 26, 5529.
19. Tanabe, Y.; Nomura, A.; Masu, M.; Shigemoto, R.;
Mizuno, N.; Nakanishi, S. J. Neurosci. 1993, 13, 1372.
20. Palmer, E.; Monaghan, D. T.; Cotman, C. W. Eur. J.
Pharmacol. 1989, 166, 585.
21. Schoepp, D. D.; Monn, J. A.; Marek, G. J.; Aghajanian,
G.; Moghaddam, B. CNS Drug Rev. 1999, 5, 1.
37. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
38. Cacchi, S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236.
39. Wright, R. A.; Arnold, M. B.; Wheeler, W. J.; Ornstein,
P. L.; Schoepp, D. D. Naunyn-Schmiedeberg’s Arch. Pharma-
col. 2000, 362, 546.