A Method for Designing Conformationally Restricted Analogues Based on Allylic Strain: Synthesis of a Novel Class of Noncompetitive NMDA Receptor Antagonists Having the Acrylamide Structure

Article abstract of DOI:10.1021/jm030226n

A series of conformationally restricted analogues of milnacipran, a weak NMDA receptor antagonist, were designed by a method based on allylic strain. The conformational analysis study showed that the allylic-strain-based conformational restriction indeed

Full text of DOI:10.1021/jm030226n

5326
J . Med. Chem. 2003, 46, 5326-5333
A Meth od for Design in g Con for m a tion a lly Restr icted An a logu es Ba sed on
Allylic Str a in : Syn th esis of a Novel Cla ss of Non com p etitive NMDA Recep tor
An ta gon ists Ha vin g th e Acr yla m id e Str u ctu r e
Yutaka Ohmori,*,† Akitake Yamashita,† Ryuichi Tsujita,† Tamotsu Yamamoto,† Kaku Taniuchi,†
Akira Matsuda,‡ and Satoshi Shuto*,‡
Institute for Life Science Research, Asahi Kasei Co., Ltd., Ohito-cho, Shizuoka 410-2321, J apan, and Graduate School of
Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan
Received May 13, 2003
A series of conformationally restricted analogues of milnacipran, a weak NMDA receptor
antagonist, were designed by a method based on allylic strain. The conformational analysis
study showed that the allylic-strain-based conformational restriction indeed occurred and that
the affinity for the NMDA receptor was efficiently improved by the conformational restriction.
In tr od u ction
Neurotransmitters such as serotonin and acetylcho-
line perform many functions because of their impressive
conformational flexibility to bind several receptor sub-
types in their various conformations. For example, the
conformation of a transmitter binding to a receptor
subtype, i.e., the bioactive conformation for a subtype,
may be different from those for other receptor subtypes.
Accordingly, one can expect to get high selectivity by
controlling the conformation of the substrate for a
certain target receptor subtype. Therefore, the synthesis
of conformationally restricted analogues of a lead com-
pound often results in improvement of the specific
F igu r e 1. Conformational restriction based on the cyclopro-
pylic strain (a) and the allylic strain (b).
binding affinity for the target molecule.1 Restricting the
conformation of a biologically active compound is also
effective in determining the bioactive conformation.1c
In the design of conformationally restricted analogues,
it is essential that the analogues should be as similar
as possible to the parent compound in size, shape, and
molecular weight.1a Conformationally restricted ana-
logues have usually been designed and synthesized by
introducing bulky cyclic moieties into the lead com-
pounds. Consequently, the chemical and physical prop-
erties of these analogues can be quite different from
those of the original leads. Because of the small and
rigid ring structure, cyclopropane is likely to be effective
in restricting the conformation of a molecule without
significantly changing the chemical and physical prop-
erties of the lead compound.2 We recently devised a new
F igu r e 2. Structure of milnacipran and its conformationally
restricted analogues.
method for restricting the conformation of cyclopropane
derivatives based on the “cyclopropylic strain”.3,4 Adja-
Milnacipran (1, Figure 2) a clinically effective anti-
cent substituents on a cyclopropane ring exert signifi-
cant mutual steric repulsion, because they are fixed in
the eclipsed orientation, which we call “cyclopropylic
strain”. Consequently, conformations of the substituents
on a cyclopropane ring can be restricted by the steric
effect of adjacent substituents, especially when they are
bulky, as indicated in Figure 1.3
depressant due to competitive inhibition of the reuptake
of serotonin (5-HT) and noradrenaline in the central
nervous system, is also recognized as a noncompetitive
NMDA receptor channel blocker.4a,5 Although the bind-
ing affinity of milnacipran for the NMDA receptor is not
high enough, it may be a desirable lead for an efficient
NMDA receptor antagonist, since its structural feature
is clearly different from those of the known antagonists
showing serious side effects and its clinical studies have
shown that it can be transported to the brain.4f The
cyclopropylic-strain-based method has been successfully
applied to the design of the conformational restriction
* To whom all correspondence and reprint requests should be
addressed. Phone: +81-11-706-3228. Fax: +81-11-706-4980. E-mail:
shu@pharm.hokudai.ac.jp.
† Asahi Kasei Co., Ltd.
‡ Hokkaido University.
10.1021/jm030226n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003

Designing Conformationally Restricted Analogues
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5327
Ta ble 1. Binding Affinity of Compounds for the NMDA
Receptor
of milnacipran to result in the development of a new
class of NMDA receptor antagonists, PPDC (2, Figure
2).4 PPDC binds to the NMDA receptor in an agonist-
independent manner, whereas the binding affinities of
known noncompetitive NMDA receptor antagonists are
affected by agonist concentration,4c and the release of
PPDC and the previous noncompetitive antagonists,
such as MK-801, from their binding sites was quite
different with respect to their dependence on the direc-
tion of ionic currents.4c Furthermore, the NMDA recep-
tor subtype selectivity of PPDC was shown to be
different from those of the previous antagonist.4e The
conformation of the aminomethyl moiety of PPDC,
which is essential for the biological activity,5 proved to
be restricted to the B conformer in Figure 1a by X-ray
crystallographic, 1H NMR, and computational analyses.3
However, one drawback of this conformational restric-
tion method with the cyclopropylic strain is that the
synthesis of the target compounds is rather troublesome
because of the contiguous three asymmetric carbons.
On the basis of these findings and considerations, we
newly designed the conformationally restricted ana-
logues of milnacipran based on allylic strain to develop
efficient NMDA receptor antagonists. In this report, we
describe the results of these studies.
Resu lt a n d Discu ssion
a
Design of th e Com p ou n d s Usin g th e Allylic-
Str a in -Ba sed Con for m a tion a l Restr iction Meth od .
We speculated that the conformational restriction,
similar to the above-mentioned method using a cyclo-
propane ring shown in Figure 1a, might possibly occur
when the cyclopropane ring is replaced with an ethylene
group, since the cyclopropane ring system is known to
have a chemical and structural feature similar to a C-C
double bond.6 It is known that, in the 3-disubstituted
allylic system, the minima in conformational energy are
given by Figure 1b with one substituent (or proton) in
the allylic position eclipsing the double bond.7 Accord-
ingly, the adjacent cis-substituents on an alkenyl bond
mutually exert quite significant steric repulsion because
of their eclipsed conformation. This kind of steric
repulsion is known as “allylic strain”,7,8 which is often
the determining factor for regio- and/or stereoselectivity
in organic reactions.7,9 Conformation of the allylic
position can be restricted to avoid allylic strain, as
shown in Figure 1b,10 as in a cyclopropane ring (Figure
1a). Therefore, we assumed that an ethylene group could
be used as a conformational restriction unit similar to
the cyclopropane ring in our previous study.3,4 On the
other hand, the synthesis of these allylic strain-based
conformationally restricted analogues would be easier
than those of the corresponding cyclopropane-based
analogues having three contiguous asymmetric carbons.
Assay was done with cerebral cortical synaptic membrane of
rats using [3H]MK-801.
type analogues, the three important functional groups,
i.e., the phenyl, carbamoyl, and amino groups, should
assume the three-dimensional arrangement similar to
that in PPDC. Thus, a new acrylamide-type NMDA
receptor antagonist would be produced.
The NMDA receptor, one of the ionotropic glutamate
receptor subtypes, is associated with various neurode-
generative disorders.11a A number of studies have
indicated that the competitive and noncompetitive
antagonists are effective in experimental models of
epilepsy and stroke.11 However, clinical studies of these
NMDA receptor antagonists have been unsuccessful.11
Noncompetitive inhibitors, such as the channel blocker
MK-801, have had serious behavioral effects12 and have
caused neuronal vacuolization,13 while competitive in-
hibitors were often inactive in vivo because of poor
transport to the brain.14 Although the glycine site
antagonists and subtype selective antagonists, such as
ifenprodil, have also been developed, their pharmaco-
logical effects in the clinical studies are unclear.11
Consequently, the development of another type of ef-
ficient NMDA receptor antagonist for use in the treat-
ment of epilepsy, stroke, Huntington’s, and/or Parkin-
son’s diseases is desired.
Ch em istr y. It was important to determine whether
the allylic-strain-based conformational restriction occurs
and also whether the acrylamide-type compounds actu-
ally bind to the NMDA receptor. Therefore, we planned
to prepare a series of the acrylamide-type conforma-
tionally restricted analogues, the structures of which
are shown in Table 1, as racemates because of the ease
of synthesis. As shown in Schemes 1 and 2, we synthe-
sized the target compounds via Z-alkenes, which could
be prepared by the Horner-Wadsworth-Emmons (HWE)
reaction.15
To test this hypothesis and also to develop novel
NMDA receptor antagonists, we designed the allylic
strain-based acrylamide-type analogues of milnacipran,
3, and 4 (Figure 2). The conformation of 3 and 4 can be
restricted by an alkyl group introduced at the R-position
to the amino function, which is essential for binding to
the NMDA receptor,5 due to steric repulsion with the
N,N-diethylcarbamoyl group. Accordingly, their confor-
mations can be restricted to the conformer B, as shown
in Figure 1b. If this is indeed true, in these acrylamide-

5328 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Ohmori et al.
Sch em e 1
Sch em e 3a
Sch em e 2
a
Reagents: (a) Swern oxidation; (b) 6, LiCl, DBU; (c) NaOH/
aq EtOH; (d) Pr2NH, EDC, BOP, TEA; (e) RuHCl(CO)(PPh3)3; (f)
aq TFA.
aminobutanal 16′ under Masamune conditions did not
give the desired Z-alkene but only the corresponding
E-alkene. Although a variety of HWE conditions were
examined, the desired Z-alkene was not obtained. We
found that when the fully protected aminoalkanal 16
was used, the HWE reaction gave the desired Z-alkene
17, although the yield was low. Hydrolysis of the alkene
17 followed by condensation with dipropylamine gave
the N,N-dipropylamide 19, which was further treated
with RuHCl(CO)(PPh3)3 17 to provide 20. Acidic removal
of the protecting groups of 20 resulted in 3b.
Bin d in g Affin ity for th e NMDA Recep tor . The
synthesized compounds were evaluated for their binding
affinity for the NMDA receptor of cerebral cortical
synaptic membranes from rats with [3H]MK-801 as a
radioligand.18 As seen in Table 1, most of the compounds
showed the expected binding affinity for the NMDA
receptor. Initially, we tested the effect of the carbamoyl
alkyl substituents of the pyrrolidine-type analogues
4a -g on the affinity. The N,N-diethylamide analogue
4a showed weak activity (IC50 ) 3.6 ( 1.0 µM) similar
to the parent milnacipran (IC50 ) 6.3 ( 0.3 µM), which
was 18 times less active than PPDC (2, IC50 ) 0.20 (
0.02 µM), although these have the same N,N-diethyl-
carbamoyl moiety. Although the racemic N,N-diethyla-
mide 4a was somewhat weaker than the corresponding
cyclopropane-type chiral congener 21 (IC50 ) 1.0 ( 0.2
µM),4f it may be because 21 is the eutomer. The affinity
of the N,N-dipropylamide 4b (IC50 ) 0.54 ( 0.10 µM)19,20
was about 7 times greater than those of 4a and the N,N-
dibutylamide 4c. The N-(2-methylallyl)-N-ethyl amide
4d and the N-propyl-N-cyclopropylmethyl amide 4e
showed efficient IC50 values of 0.52 ( 0.30 and 0.74 (
0.11 µM, which were similar to those of the N,N-
dipropylamide 4b. The cyclic amides 4f and 4g showed
only weak activity, with the piperazine-derived amide
4g being inactive. Therefore, bulkiness of the carbamoyl
moiety is likely to significantly affect their affinity.
On the basis of the binding affinities described above,
the compounds having an N,N-dipropylcarbamoyl group
were synthesized for further studies. The effect of the
substituent on the benzene ring was next examined. All
of the para-substituted derivatives showed low affinity.
Compounds 4h , with a m-methyl group, and 4j, with
We first examined the HWE reaction of N-Boc-
prolinal 5, which was easily prepared from Boc-proline,
and triethyl phenylphosphonoacetate (6) (Scheme 1).
The HWE reaction conditions using LiCl/DBU reported
by Masamune et al.16 were employed to give the Z-
alkene 7 with excellent stereoselectivity (Z/E ) 11/1).
After hydrolysis of 7, which provided the carboxylic acid
8, the amidation was carried out using a solution-phase
combinatorial technique with various commercially
available amines. As shown in Scheme 1, the procedure
consisted of (1) mixing the carboxylic acid, the resin-
bound carbodiimide (PS-C), 1-hydroxybenzotriazole
(HOBT), and the amine in CH2Cl2, (2) addition of
tetrafluorophthalic anhydride (TFPA) to trap the excess
amine as its salt, (3) addition of resin-bound amine (PS-
A) to trap the unreacted carboxylic acid and TFPA-
derived carboxylic acids, (4) filtration of the resins, (5)
silica gel column chromatography, if needed, and (6)
deprotection of the Boc group with TFA. After this
sequence, evaporation of the TFA gave the pyrrolidine-
type analogues 4a -g with >95% purity on HPLC.
As mentioned below, among the pyrrolidine-type
analogues 4a -g, the N,N-dipropylamide 4b was shown
to have potent binding affinity for the NMDA receptor.
We synthesized a series of dipropylamide-type ana-
logues 4h -m having a substituent on the phenyl group
by the same procedure via the HWE reaction products
9-14 (Scheme 2).
We next tried to synthesize the ethyl congener 3b by
a method similar to the one described above (Scheme
3). However, the HWE reaction of 6 and N-Boc-2-

Designing Conformationally Restricted Analogues
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5329
F igu r e 3. X-ray crystallographic structures of PPDC (2, left)
and 3b (right).
F igu r e 4. Superimposition of the calculated structures of
PPDC (2, yellow) and 3a (magenta).
an o-fluoro group, showed moderate IC50 values of 1.1
( 0.4 and 1.7 ( 0.6 µM, respectively. In this series, the
m-fluoro compound 4k showed the strongest affinity
(IC50 ) 0.42 ( 0.07 µM). These results suggested that
although the presence of a substituent at the ortho- or
meta-position of the 2-phenyl moiety is tolerated in the
binding to the receptor, a para-substituent is likely to
disturb the binding, probably due to a steric effect in
these acrylamide-type derivatives.
On the other hand, the acyclic primary amino com-
pound 3b, which is the ethylene congener of the cyclo-
propane-type compound PPDC, showed a high affinity
(IC50 ) 0.53 ( 0.16 µM) comparable not only to 4b but
also to PPDC.
of 3a obtained by the above calculations was rotated
from 0° to 360° at 30° intervals, the conformations of
which were optimized. The minimum-energy conformer
was observed around 180°, where the dihedral angle
was similar to those observed in the above X-ray and
NMR analyses. Although two other local minimum
energy values were observed around 60° and 300°, these
were more than 3.5 kcal/mol higher compared with the
minimum energy at 180°. These results support our
hypothesis of the allylic-strain-based conformational
restriction.
These conformational analyses showed that the al-
lylic-strain-based conformational restriction actually
occurred. Thus, the conformational results together with
the above biological results suggest that the allylic-
strain-based method can be applicable for the design of
various conformational restriction analogues of phar-
macologically active compounds.
As described above, the acrylamide-type conforma-
tionally restricted analogues showed greater binding
affinity to the NMDA receptor than the parent mil-
nacipran, and the affinity was comparable to that of
PPDC.
Con clu sion . A method for designing conformation-
ally restricted analogues based on allylic strain, which
can be an alternative for the efficient “cyclopropylic-
strain”-based method, was devised and applied to the
design of a series of conformationally restricted ana-
logues of milnacipran. Compound 3b, the ethylene
congener of the cyclopropane derivative PPDC (2),
showed high affinity for the NMDA receptor, compa-
rable to that of PPDC, and the structural analysis
confirmed that the conformational restriction took place
as we had hypothesized. Thus, the method can be
effective for conformational restriction of various phar-
macologically active compounds.
Con for m a tion a l An a lyses. We analyzed the con-
formation of the allylic strain based conformational
restriction analogue 3b by X-ray crystallography. The
X-ray crystallographic structures of 3b as well as PPDC
(2)3 are shown in Figure 3. The crystallographic struc-
ture of 3b clearly demonstrates that it is restricted to
the conformation corresponding to the conformer B in
Figure 1b, in which the aminopropyl moiety is arranged
to avoid the allylic strain, as we hypothesized. When
the structure is compared with that of PPDC, the
ethylene moiety proved to be structurally equivalent to
the cyclopropane in PPDC, which determines the ori-
entation of the three important functional groups, i.e.,
the phenyl, carbamoyl, and amino groups.
Exp er im en ta l Section
The calculations based on the modified Karplus
equation21 with the coupling constant (9.9 Hz) between
the vinylic and allylic protons of 3b suggested that the
Hallylic-C-C-Hvinylic torsion angle is 168° (or 192°), in
The NMR spectra were recorded with a J EOL EX-270 or
AL-300 spectrometer with tetramethylsilane as an internal
standard. Chemical shifts were reported in parts per million
(δ), and signals are expressed as s (singlet), d (doublet), q
(quartet), m (multiplet), or br (broad). MASS spectra were
measured on a J EOL J MS-SX102 spectrometer. Purity mea-
surement was performed by Shimadzu LC-10Avp series chro-
matograph (column:, YMC-pack A-303; solvent, 0.1% trifluo-
roacetic acid-MeCN; flow rate, 1.0 mL/min; detect, 254 nm).
Thin-layer chromatography was done on Merck silica gel
coated plates (60F254). Silica gel chromatography was done
with Merck silica gel 5715.
(()-(Z)-2-P h en yl-3-(2-N-ter t-b u t oxyca r b on ylp yr r oli-
d in yl)p r op en oic Acid (8). To a solution of oxalyl chloride
(1.3 mL, 15 mmol) in CH2Cl2 (30 mL) was added slowly a
mixture of DMSO (2.3 mL, 32 mmol) at -78 °C under argon,
and the mixture was stirred at the same temperature for 30
min. To the resulting mixture was added slowly N-tert-
butoxycarbonylpyrrolidinemethanol (2.5 g, 12 mmol) in CH2-
Cl2 (20 mL). The resulting solution was stirred at the same
which the two protons are trans, similar to the Hallylic
-
C-C-Hvinylic torsion angle (178.5° ( 5°) obtained by the
X-ray crystallographic analysis of 3b. These results
suggest that the conformation detected in the solid state
would also be stable in solution.
We also carried out conformational analysis by theo-
retical calculations. Thus, the Monte Carlo calculations
of PPDC and compound 3a , which has the same N,N-
diethylcarbamoyl group as PPDC, were performed by
the MacroModel v6.5 program.22 As shown in Figure 4,
both calculated structures of PPDC and 3a are very
similar.3 Moreover, We calculated the rotational barrier
around the Hallylic-C-C-Hvinylic dihedral angle of 3a .
The dihedral angle of the minimum energy conformer

5330 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Ohmori et al.
temperature for 1 h, and then Et3N (8.6 mL, 62 mmol) was
added at -78 °C. The mixture was further stirred at the same
temperature for 20 min and 0 °C for 40 min. After addition of
water, the resulting mixture was extracted with CH2Cl2. The
organic layer was washed with aqueous saturated NH4Cl,
aqueous saturated Na2CO3, and brine, dried (MgSO4), and
evaporated to give crude 5 (2.7 g) as an oil, which was used
immediately in the next reaction. A mixture of LiCl (0.62 g,
15 mmol), triethyl 2-phenylphosphonoacetate 6 (4.0 g, 13
mmol), and DBU (2.2 mL, 15 mmol) in MeCN (100 mL) was
stirred at room temperature under an atmosphere of argon
for 10 min, and then the crude 5 (2.7 g) in MeCN (20 mL) was
added. After stirring of the mixture at room temperature
overnight, aqueous saturated NH4Cl and CHCl3 were added.
The organic layer was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by flash chromatography
(silica gel; hexane/EtOAc 17:3) to give 7 (Z/E ) 11:1, 2.5 g,
49%) as an oil. The Z/E ratio was determined by 1H NMR
spectrum (the peak areas of the hydrogen adjacent to the
amino groups in both isomers).24
To a solution of 7 (Z/E ) 11:1, 2.5 g, 7.4 mmol) in EtOH (43
mL) was added 1 N NaOH (43 mL) at room temperature, and
the mixture was heated at 70 °C overnight. After addition of
CHCl3 and aqueous saturated citric acid, the resulting mixture
was partitioned, and the aqueous layer was extracted with
CHCl3. The combined organic layer was washed with brine,
dried (MgSO4), and evaporated. The residue was purified by
flash chromatography (silica gel; CHCl3/MeOH, 100: 1) to give
8 (2.1 g, 90%) as a white solid: 1H NMR (270 MHz, CDCl3)
1.45 (9H, s, C(CH3)3), 1.79-2.06 (3H, m, CHNCH2CH2CH2,
CHNCH2CH2CH2), 2.18-2.28 (1H, m, CHNCH2CH2CH2), 3.45
(2H, t, CHNCH2CH2CH2, J ) 6.6 Hz), 4.58-4.66 (1H, m,
CHNCH2CH2CH2), 5.79 (1H, d, CdCH, J ) 10.9 Hz), 7.32-
7.48 (5H, m, aromatic). Anal. (C18H23NO4): C, H, N.
(()-(Z)-2-(3-Met h ylp h en yl)-3-(2-N-ter t-b u t oxyca r b on -
ylp yr r olid in yl)p r op en oic Acid (9). Compound 9 was ob-
tained in 66% yield from 5 using triethyl 2-(3-methylphenyl)-
phosphonoacetate as described for the synthesis of 8: 1H NMR
(300 MHz, CDCl3) 1.46 (9H, s, C(CH3)3), 1.77-2.08 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.18-2.33 (1H, m,
CHNCH2CH2CH2), 2.35 (3H, s, CH3), 3.45 (2H, t, CHNCH2-
CH2CH2, J ) 6.6 Hz), 4.56-4.64 (1H, m, CHNCH2CH2CH2),
5.78 (1H, d, CdCH, J ) 10.8 Hz), 7.13-7.20 (1H, m, aromatic),
7.21-7.30 (3H, m, aromatic); MS (FAB) m/z 332 (MH+).
(()-(Z)-2-(4-Met h ylp h en yl)-3-(2-N-ter t-b u t oxyca r b on -
ylp yr r olid in yl)p r op en oic Acid (10). Compound 10 was
obtained in 64% yield from 5 using triethyl 2-(4-methylphenyl)-
phosphonoacetate as described for the synthesis of 8: 1H NMR
(270 MHz, CDCl3) 1.45 (9H, s, C(CH3)3), 1.75-2.11 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.15-2.29 (1H, m,
CHNCH2CH2CH2), 2.34 (3H, s, CH3), 3.44 (2H, t, CHNCH2-
CH2CH2, J ) 6.6 Hz), 4.55-4.64 (1H, m, CHNCH2CH2CH2),
5.76 (1H, d, CdCH, J ) 10.9 Hz), 7.13-7.21 (2H, m, aromatic),
7.34-7.37 (2H, m, aromatic); MS (FAB) m/z 332 (MH+).
(()-(Z)-2-(4-F lu or op h en yl)-3-(2-N-ter t-b u t oxyca r b on -
ylp yr r olid in yl)p r op en oic Acid (13). Compound 13 was
obtained in 48% yield from 5 using triethyl 2-(4-fluorophenyl)-
phosphonoacetate as described for the synthesis of 8: 1H NMR
(270 MHz, CDCl3) 1.46 (9H, s, C(CH3)3), 1.75-2.10 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.19-2.31 (1H, m,
CHNCH2CH2CH2), 3.45 (2H, t, CHNCH2CH2CH2, J ) 6.6 Hz),
4.56-4.64 (1H, m, CHNCH2CH2CH2), 5.75 (1H, d, CdCH, J
) 10.9 Hz), 6.98-7.07 (2H, m, aromatic), 7.41-7.48 (2H, m,
aromatic); MS (FAB) m/z 336 (MH+).
(()-(Z)-2-(4-Met h oxyp h en yl)-3-(2-N-ter t-b u t oxyca r b -
on ylp yr r olid in yl)p r op en oic Acid (14). Compound 15 was
obtained in 23% yield from 5 using triethyl 2-(4-methoxyphe-
nyl)phosphonoacetate as described for the synthesis of 8: 1H
NMR (300 MHz, CDCl3) 1.45 (9H, s, C(CH3)3), 1.75-2.07 (3H,
m, CHNCH2CH2CH2, CHNCH2CH2CH2), 2.18-2.29 (1H, m,
CHNCH2CH2CH2), 3.44 (2H, t, CHNCH2CH2CH2, J ) 6.6 Hz),
3.80 (3H, s, OCH3), 4.56-4.62 (1H, m, CHNCH2CH2CH2), 5.72
(1H, d, CdCH, J ) 10.5 Hz), 6.84-6.89 (2H, m, aromatic),
7.37-7.42 (2H, m, aromatic); MS (FAB) m/z 348 (MH+).
Gen er a l P r oced u r e for th e Syn th esis of th e P yr r oli-
d in e-Typ e Der iva tives (4a -m ). To a solution of a carboxylic
acid 8-15 (0.10 mmol) were added Argonaut PS-carbodiimide
(300 mg), HOBT (27 mg, 0.20 mmol) in CH2Cl2 (4 mL), and
dipropylamine (15 µL, 0.11 mmol). After stirring of the mixture
at room temperature overnight, tetrafluorophthalic anhydride
(110 mg, 0.50 mmol) was added, and the resulting mixture
was further stirred at room temperature overnight. To the
mixture was added Argonaut PS-trisamine (400 mg), and the
resulting mixture was stirred at room temperature for 5 h.
After filtration of mixture, the filtrate was evaporated, and
the residue was purified by flash chromatography (silica gel;
hexane/EtOAc, 3:1) to give a colorless oil. A solution of the oil
obtained in trifluoroacetic acid (1 mL) was stirred at 0 °C for
30 min. After the mixture was evaporated, 4a -m were yielded
as an oil. Typical instrumental analysis data for 4b: 1H NMR
(300 MHz, CDCl3) 0.57 (3H, t, NCH2CH2CH3, J ) 7.2 Hz), 0.94
(3H, t, NCH2CH2CH3, J ) 7.5 Hz), 1.14-1.29 (2H, m, NCH2CH2-
CH3), 1.59-1.70 (2H, m, NCH2CH2CH3), 1.89-2.14 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.24-2.32 (1H, m,
CHNCH2CH2CH2), 2.97-3.03 (2H, m, NCH2CH2CH3), 3.26-
3.44 (4H, m, NCH2CH2CH3, CHNCH2CH2CH2), 4.15-4.23 (1H,
m, CHNCH2CH2CH2), 6.12 (1H, d, CdCH, J ) 9.3 Hz), 7.26-
7.35 (5H, m, aromatic). Anal. (C21H29F3N2O3‚H2O): C, H, N.
(()-(Z)-N,N-Diet h yl-2-p h en yl-3-p yr r olid in -2-yla cr yl-
a m id e tr iflu or oa ceta te (4a ): 92% yield (purity 96% on
HPLC); MS (FAB) m/z 273 (MH+).
(()-(Z)-N,N-Dip r op yl-2-p h en yl-3-p yr r olid in -2-yla cr yl-
a m id e tr iflu or oa ceta te (4b): 69% yield (purity 100% on
HPLC); MS (FAB) m/z 301 (MH+).
(()-(Z)-N,N-Dib u t yl-2-p h en yl-3-p yr r olid in -2-yla cr yl-
a m id e tr iflu or oa ceta te (4c): 74% yield (purity 99% on
HPLC); MS (FAB) m/z 329 (MH+).
(()-(Z)-N-Eth yl-N-(2-m eth ylallyl)-2-ph en yl-3-pyr r olidin -
2-yla cr yla m id e tr iflu or oa ceta te (4d ): 90% yield (purity
100% on HPLC); MS (FAB) m/z 299 (MH+).
(()-(Z)-N-Cyclop r op ylm eth yl-N-p r op yl-2-p h en yl-3-p yr -
r olid in -2-yla cr yla m id e tr iflu or oa ceta te (4e): 94% yield
(purity 96% on HPLC); MS (FAB) m/z 313 (MH+).
(()-(Z)-P ip er id in yl-2-p h en yl-3-p yr r olid in -2-yla cr yl-
a m id e tr iflu or oa ceta te (4f): 83% yield (purity 100% on
HPLC); MS (FAB) m/z 285 (MH+).
(()-(Z)-P ip er a zin yl-2-p h en yl-3-p yr r olid in -2-yla cr yl-
a m id e tr iflu or oa ceta te (4g): 94% yield (purity 100% on
HPLC); MS (FAB) m/z 286 (MH+).
(()-(Z)-N,N-Dip r op yl-2-(3-m eth ylp h en yl)-3-p yr r olid in -
2-yla cr yla m id e tr iflu or oa ceta te (4h ): 93% yield (purity
95% on HPLC); MS (FAB) m/z 315 (MH+).
(()-(Z)-N,N-Dip r op yl-2-(4-m eth ylp h en yl)-3-p yr r olid in -
2-yla cr yla m id e tr iflu or oa ceta te (4i): 18% yield (purity 96%
on HPLC); MS (FAB) m/z 315 (MH+).
(()-(Z)-2-(2-F lu or op h en yl)-3-(2-N-ter t-b u t oxyca r b on -
ylp yr r olid in yl)p r op en oic Acid (11). Compound 11 was
obtained in 5% yield from 5 using triethyl 2-(2-fluorophenyl)-
phosphonoacetate as described for the synthesis of 8: 1H NMR
(300 MHz, CDCl3) 1.47 (9H, s, C(CH3)3), 1.79-2.08 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.21-2.32 (1H, m,
CHNCH2CH2CH2), 3.44 (2H, t, CHNCH2CH2CH2, J ) 6.6 Hz),
4.66-4.73 (1H, m, CHNCH2CH2CH2), 5.84 (1H, d, CdCH,
J ) 10.8 Hz), 7.02-7.20 (2H, m, aromatic), 7.25-7.38 (2H, m,
aromatic); MS (FAB) m/z 336 (MH+).
(()-(Z)-2-(3-F lu or op h en yl)-3-(2-N-ter t-b u t oxyca r b on -
ylp yr r olid in yl)p r op en oic Acid (12). Compound 12 was
obtained in 71% yield from 5 using triethyl 2-(3-fluorophenyl)-
phosphonoacetate as described for the synthesis of 8: 1H NMR
(300 MHz, CDCl3) 1.46 (9H, s, C(CH3)3), 1.79-2.06 (3H, m,
CHNCH2CH2CH2, CHNCH2CH2CH2), 2.19-2.28 (1H, m,
CHNCH2CH2CH2), 3.46 (2H, t, CHNCH2CH2CH2, J ) 6.6 Hz),
4.57-4.64 (1H, m, CHNCH2CH2CH2), 5.82 (1H, d, CdCH, J
) 10.8 Hz), 6.97-7.04 (1H, m, aromatic), 7.17-7.34 (3H, m,
aromatic); MS (FAB) m/z 336 (MH+).
(()-(Z)-N,N-Dip r op yl-2-(2-flu or op h en yl)-3-p yr r olid in -
2-yla cr yla m id e tr iflu or oa ceta te (4j): 20% yield (purity 96%
on HPLC); MS (FAB) m/z 319 (MH+).

Designing Conformationally Restricted Analogues
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5331
(()-(Z)-N,N-Dip r op yl-2-(3-flu or op h en yl)-3-p yr r olid in -
2-yla cr yla m id e tr iflu or oa ceta te (4k ): 32% yield (purity 97%
on HPLC); MS (FAB) m/z 319 (MH+).
(()-(Z)-N,N-Dip r op yl-2-(4-flu or op h en yl)-3-p yr r olid in -
2-yla cr yla m id e tr iflu or oa ceta te (4l): 37% yield (purity 96%
on HPLC); MS (FAB) m/z 319 (MH+).
(()-(Z)-N,N-Dipr opyl-2-(4-m eth oxyph en yl)-3-pyr r olidin -
2-yla cr yla m id e tr iflu or oa ceta te (4m ): 79% yield (purity
96% on HPLC); MS (FAB) m/z 331 (MH+).
mg, 91%) as an oil: 1H NMR (300 MHz, CDCl3) 0.94 (3H, t,
CH2CH3, J ) 7.4 Hz), 1.46 (9H, s, C(CH3)3), 1.56-1.90 (2H,
m, CH2CH3), 3.78 (1H, dd, NCH2CHdCH2, J ) 16.4, 6.3 Hz),
3.96 (1H, dd, NCH2CHdCH2, J ) 16.4, 5.4 Hz), 5.12-5.19 (3H,
m, NCHCH2CH3, CHdCH2), 5.81-5.94 (1H, m, CHdCH2), 6.02
(1H, d, CdCH, J ) 8.7 Hz), 7.26-7.51 (5H, m, aromatic). Anal.
(C20H27NO4‚0.5H2O): C, H, N.
(()-(Z)-N,N-Dip r op yl 4-(N-Allyl-N-ter t-bu toxyca r bon -
yla m in o)-2-p h en yl-2-h exen a m id e (19). A solution of 18 (1.6
g, 4.7 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide
(3.6 g, 19 mmol), BOP (8.5 g, 19 mmol), dipropylamine (5.1
mL, 38 mmol), and Et3N (5.2 mL, 38 mmol) in CH2Cl2 (47 mL)
was stirred at room temperature overnight. The resulting
mixture was partitioned between CHCl3 and water, and the
organic layer was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by flash chromatography
(silica gel; hexane/EtOAc, 5:1) to give 19 (1.1 g, 52%) as an
oil: 1H NMR (300 MHz, CDCl3) 0.57 (3H, t, NCH2CH2CH3,
J ) 7.4 Hz), 0.88 (3H, t, NCH2CH2CH3, J ) 7.4 Hz), 0.95 (3H,
t, NCHCH2CH3, J ) 7.4 Hz), 1.46 (9H, s, C(CH3)3), 1.65-1.73
(6H, m, NCH2CH2CH3, NCH2CH2CH3, NCHCH2CH3), 3.01-
3.04 (2H, m, NCH2CH2CH3), 3.18-3.40 (1H, m, NCH2CH2CH3),
3.41-3.61 (1H, m, NCH2CH2CH3), 3.67 (1H, dd, NCH2CHd
CH2, J ) 16.2, 6.6 Hz), 3.91-4.20 (1H, m, NCH2CHdCH2),
4.35-4.50 (1H, m, NCHCH2CH3), 5.11-5.21 (2H, m, CHd
CH2), 5.81-5.94 (1H, m, CHdCH2), 6.02 (1H, d, CdCH, J )
8.7 Hz), 7.26-7.51 (5H, m, aromatic). Anal. (C26H40N2O3): C,
H, N.
(()-N-Allyl-N-ter t-bu toxyca r bon yl-N-1-(h yd r oxym eth -
yl)p r op yla m in e (15). A solution of dl-2-aminobutanol (890
mg, 10 mmol), diisopropylethylamine (3.5 mL, 20 mmol), and
allyl bromide (870 µL, 10 mmol) was stirred at room temper-
ature overnight. The resulting mixture was partitioned be-
tween CHCl3 and water, and the organic layer was washed
with brine, dried (MgSO4), and evaporated. The residue was
purified by flash chromatography (silica gel; CHCl3/MeOH, 50:
1) to give a colorless oil of 1-(2-hydroxymethyl)propylallylamine
(230 mg, 18%), which was used immediately in the next
reaction.
A solution of 1-(2-hydroxymethyl)propylallylamine (190 mg,
1.5 mmol), Et3N (280 µL, 2.0 mmol), and Boc2O (440 mg, 2.0
mmol) in CH2Cl2 (15 mL) was stirred at room temperature
overnight. The resulting mixture was partitioned between
CHCl3 and water, and the organic layer was washed with
brine, dried (MgSO4), and evaporated. The residue was purified
by flash chromatography (silica gel; CHCl3/MeOH, 100:1) to
give 15 (300 mg, 13%) as an oil: 1H NMR (300 MHz, CDCl3)
0.91 (3H, t, CH2CH3, J ) 7.4 Hz), 1.46 (9H, s, C(CH3)3), 1.50-
1.67 (2H, m, CH2CH3), 1.77-1.86 (1H, br, OH), 2.85-2.95 (1H,
m, NCHCH2CH3), 3.60-3.82 (4H, m, NCH2CHdCH2, OCH2-
CH), 5.10-5.19 (2H, m, CHdCH2), 5.86-5.92 (1H, m,
CHdCH2). Anal. (C12H23NO3‚0.2H2O): C, H, N.
(()-(Z)-Eth yl 4-(N-Allyl-N-ter t-bu toxyca r bon yla m in o)-
2-p h en yl-2-h exen oa te (17). To a solution of oxalyl chloride
(220 µL, 2.5 mmol) in CH2Cl2 (20 mL) was added slowly DMSO
(390 µL, 5.5 mmol) at -78 °C, and the mixture was stirred at
the same temperature under argon for 30 min. To the resulting
mixture was added slowly 15 (260 mg, 1.1 mmol), and the
resulting mixture was stirred at the same temperature for 1
h. After addition of Et3N (1.3 mL, 9.1 mmol), the mixture was
stirred at the same temperature for 30 min further. The
mixture was allowed to warm to room temperature over 1.5 h
and was partitioned between CHCl3 and water. The organic
layer was washed with aqueous saturated NH4Cl, aqueous
saturated Na2CO3, and brine, dried (MgSO4), and evaporated
to give 16′ (250 mg, 96%), which was used immediately in the
next reaction.
To a solution of LiCl (25 mg, 0.60 mmol) in MeCN (3 mL)
were added 6 (160 mg, 0.54 mmol) and DBU (89 µL, 0.54
mmol) in MeCN (1 mL) at 0 °C under argon. After stirring of
the mixture at room temperature for 30 min, 17′ (23 mg, 0.54
mmol) in MeCN (1 mL) was added, and the mixture was
stirred room temperature overnight. The resulting mixture
was partitioned between aqueous saturated NH4Cl and CHCl3,
and the organic layer was washed with brine, dried (MgSO4),
and evaporated. The residue was purified by flash chroma-
tography (silica gel; hexane/EtOAc 20:1) to give 17 (24 mg,
12% from 15) as an oil: 1H NMR (300 MHz, CDCl3) 0.91 (3H,
t, CHCH2CH3, J ) 7.2 Hz), 1.32 (3H, t, OCH2CH3, J ) 7.2
Hz), 1.46 (9H, s, C(CH3)3), 1.67-1.86 (2H, m, CHCH2CH3), 3.74
(1H, dd, NCH2CHdCH2, J ) 16.2, 6.0 Hz), 3.88-4.00 (1H, m,
NCH2CHdCH2), 4.20-4.38 (2H, m, OCH2CH3), 4.72 (1H, dd,
NCHCH2CH3, J ) 15.9, 8.4 Hz), 5.08-5.17 (2H, m, CHdCH2),
5.78-5.91 (1H, m, CHdCH2), 6.24 (1H, d, CdCH, J ) 9.6 Hz),
7.26-7.38 (5H, m, aromatic). Anal. (C22H31NO4): C, H, N.
(()-(Z)-4-(N-Allyl-N-ter t-bu toxycar bon ylam in o)-2-ph en -
yl-2-h exen oic Acid (18). A mixture of 17 (24 mg, 0.064 mmol)
and 1 N NaOH (1.3 mL) in EtOH (1.3 mL) was stirred at room
temperature at 70 °C overnight. The mixture was neutralized
with aqueous saturated citric acid and then extracted with
CHCl3. The organic layer was washed with brine, dried
(MgSO4), and evaporated. The residue was purified by flash
chromatography (silica gel; CHCl3/MeOH, 20:1) to give 18 (20
(()-(Z)-N,N-Dip r op yl-4-(N-ter t-bu toxyca r bon yl-N-p r o-
p en yl)a m in o-2-p h en yl-2-h exen a m id e (20). A mixture of 19
(11 mg, 0.026 mmol) and RuHCl(CO)(PPh3)3 (2.4 mg, 2.5 µmol)
in xylene (130 µL) was stirred at 60 °C under argon overnight.
The resulting mixture was partitioned between CHCl3 and
water, and the organic layer was washed with brine, dried
(MgSO4), and evaporated. The residue was purified by flash
chromatography (silica gel; hexane/EtOAc, 10:1) to give 20 (9.0
mg, 82%) as an oil: 1H NMR (270 MHz, CDCl3) 0.51 (3H, t,
NCH2CH2CH3, J ) 7.2 Hz), 0.86-0.97 (6H, m, NCH2CH2CH3,
NCHCH2CH3),1.47-1.65 (4H, m, NCH2CH2CH3, NCHCH2-
CH3), 1.52 (9H, s, C(CH3)3), 1.69 (3H, d, J ) 6.3 Hz), 1.72-
2.00 (2H, m, NCH2CH2CH3), 2.82-2.97 (1H, m, NCH2CH2CH3),
2.99-3.11 (1H, m, NCH2CH2CH3), 3.13-3.26 (1H, m, NCH2-
CH2CH3), 3.34-3.48 (1H, m, NCH2CH2CH3), 4.47 (1H, q,
NCHCH2CH3, J ) 7.9 Hz), 5.06-5.19 (1H, m, NCHdCHCH3),
6.30 (1H, d, CdCH, J ) 7.9 Hz), 6.63 (1H, d, NCHdCHCH3,
J ) 13.9 Hz), 7.21-7.40 (5H, m, aromatic). Anal. (C26H40
N2O3): C, H, N.
-
(()-(Z)-N ,N -D ip r o p y l-4-a m in o -2-p h e n y l-2-h e x e n -
a m id e Tr iflu or oa ceta te (3b). A solution of 20 (5.0 mg, 0.012
mmol) and trifluoroacetic acid (30 µL) in 1,4-dioxane (60 µL)
and water (30 µL) was stirred at 50 °C for 3 h and then
evaporated. The residue was dissolved in CH2Cl2 and Et2O,
and the resulting solution was concentrated in vacuo to give
3a (4.0 mg, 82%) as a white solid: 1H NMR (300 MHz, DMSO-
d6) 0.47 (3H, t, NCH2CH2CH3, J ) 7.2 Hz), 0.87-0.93 (6H, m,
NCH2CH2CH3, NH2CHCH2CH3), 1.01-1.20 (2H, m, NH2-
CHCH2CH3), 1.51-1.80 (4H, m, NCH2CH2CH3, NCH2CH2-
CH3), 2.94-3.06 (2H, m, NCH2CH2CH3), 3.24-3.58 (2H, m,
NCH2CH2CH3), 3.58 (1H, dt, NH2CHCH2CH3, J ) 4.6, 9.9 Hz),
5.92 (1H, d, CdCH, J ) 9.9 Hz), 7.36-7.47 (5H, m, aromatic).
Anal. (C20H29F3N2O3‚H2O): C, H, N.
Bin d in g Assa y. The binding affinity for the NMDA recep-
tor was investigated according to previously reported meth-
ods.18
X-r a y Cr ysta llogr a p h ic An a lysis of 3b. C20H31F3N2O4,
M ) 420.47 Monoclinic, C2/c, a ) 21.034(9) Å, b ) 7.595(3) Å,
c ) 29.466(8) Å, â ) 97.75(3)°, V ) 4664(3) Å3, Z ) 8, Dcalc
)
1.350. Cell parameters were determined and 26 reflections
refined in the range 26.5° < θ < 30.0°. A colorless crystal (0.50
× 0.40 × 0.30 mm) was mounted on a Mac Science MXC18
diffractometer with graphite-monochromated Cu-KR radia-
tion (λ ) 1.541 78 Å). Data collection using the ω/2θ scan
technique gave 3848 reflections at room temperature, 3666
being unique, of which 2640 with I > 3.00σ(I) reflections were

5332 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Ohmori et al.
NMDA receptor antagonists. J . Med. Chem. 1995, 38, 2964-
2968.
(6) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-Y.; Yip, Y.-C. Tanko, J .;
Hudlicky, T. Use of cyclopropanes and their derivatives in
organic synthesis. Chem. Rev. 1989, 89, 165-198. (b) De Meijero,
A.; Ed. Small Ring Compounds in Organic Synthesis VI. Topic
in Current Chemistry 207; Springer: Berlin, 1999.
used in calculations. The intensities were corrected for Lorentz
and polarization factors and for absorption and extinction
effects. The structure was solved by direct method and refined
by the full-matrix least-squares technique using maXus (v4.3)
as the computer program. The non-hydrogen atoms were
refined isotropically. The unweighted and weighted R values
were 0.081 and 0.140, respectively.
Ca lcu la tion s. The three-dimensional structures of PPDC
and 3a were determined by conformational analysis (MMFF94)
using the BatchMin program included in the MacroModel v6.5
package.22 A 10 000-35 000 step Monte Carlo search was
performed on each compound. The energy minimizations were
performed in a vacuum and water, respectively.
(7) J ohnson, F. Allylic strain in six-membered rings. Chem. Rev.
1968, 68, 375. (b) Berg, U.; Sandstro¨m, J . Static and dynamic
stereochemistry of alkyl and analogous groups. Adv. Phys. Org.
Chem. 1989, 25, 1. (b) Hoffmann, R. W. Allylic 1,3-strain as a
controlling factor in stereoselective transformations. Chem. Rev.
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with defined shape-conformational design. Angew. Chem., Int.
Ed. Engl. 1992, 31, 1124-1134.
(8) In this report, “allylic strain” does not mean the 1,2-allylic strain
but the 1,3-allylic strain.
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) (A.M.) and a Grant-in-Aid for Sci-
entific Research (S.S.) from the J apan Society for the
Promotion of Science.
(9) For examples, see: (a) Haller, J .; Strassner, T.; Houk, K. N.
Models for stereoselective additions to chiral allylic ethers:
Osmium tetroxide bis-hydroxylations. J . Am. Chem. Soc. 1997,
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S. B. A highly diastereoselective dioxetane formation by the
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chiral allylic alcohol. J . Am. Chem. Soc. 1999, 121, 1834-1838.
(d) Adam, W.; Stegmann, V. R.; Saha-Mo¨ller, C. R. Regio- and
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Reaction of Singlet Oxygen, Triazolinedione, and Nitrosoarene
with Chiral Deuterium-Labeled Allylic Alcohols: The Interde-
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Mechanistic Insights into the Hydroxy-Group Directivity J . Am.
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Su p p or tin g In for m a tion Ava ila ble: HPLC charts of the
final compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Designing Conformationally Restricted Analogues
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(22) Schrodinger, 1500 SW First Ave. Suite 1180 Protland, OR 97201;
http://www.schrodinger.com
(20) Compound 4b was hydrogenated to give
a diastereomeric
mixture of the corresponding saturated products 22, the binding
affinity of which to the NMDA receptor was low (IC50 ) 3.6 µM).
(23) The two minimum energy conformers for 3a , which are different
in orientation of the carbamoyl moiety, were obtained by the
calculations.
(24) For the Z-isomer, an NOE between the vinyl and the phenyl
protons was observed.
J M030226N