Synthesis of (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecar-boxamide (PPDC) derivatives modified at the carbamoyl moiety as a new class of NMDA receptor antagonists

Article abstract of DOI:10.1016/S0968-0896(02)00030-5

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, 4a), which is a conformationally restricted analogue of the antidepressant milnacipran [(±)-1], represents a new class of potent NMDA receptor antagonists. A series of PPDC a

Full text of DOI:10.1016/S0968-0896(02)00030-5

Bioorganic & Medicinal Chemistry 10 (2002) 1777–1791
Synthesis of (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,
N-diethylcyclopropanecarboxamide (PPDC) Derivatives
Modified at the Carbamoyl Moiety As a New Class of
NMDA Receptor Antagonists
Yuji Kazuta,a Ryuichi Tsujita,b Kiyoshi Ogawa,b Tadami Hokonohara,b
Kanako Yamashita,b Kiyoko Morino,a Akira Matsudaa and Satoshi Shutoa,*
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
bInstitute of Life Science Research, Asahi Chemical Industry Co., Ltd., Ohito-cho, Shizuoka 410-2321, Japan
Received 19 November 2001; accepted 10 January 2002
Abstract—(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, 4a), which is a conformationally
restricted analogue of the antidepressant milnacipran [(ꢀ)-1], represents a new class of potent NMDA receptor antagonists. A
series of PPDC analogues modified at the carbamoyl moiety were synthesized. Among these, (1S,2R)-1-phenyl-2-[(S)-1-aminopro-
pyl]-N,N-dipropylcyclopropanecarboxamide (4d) was identified as the most potent NMDA receptor antagonist in this series and
clearly reduced the MMDA receptor mediated potentiation of rat hippocampal slices, a model of long-term potentiation (LTP).
The three-dimensional structure of 4d was also analyzed in detail to clarify the receptor-binding conformation. # 2002 Elsevier
Science Ltd. All rights reserved.
Introduction
the NMDA receptor is not very high, the compound has
the advantage of sufficiently penetrating into the brain
without serious side effects,8d,e making it a clinically
useful antidepressant and therefore a good lead for an
efficient NMDA receptor antagonist. This may be
because the structure of milnacipran is clearly different
from that of previous NMDA receptor antagonists.
Various antagonists of NMDA (N-methyl-d-aspartic
acid) receptors have been developed,1ꢁ3 since the recep-
tors may be involved in both chronic and acute neuro-
degenerative disorders.1 Some have been shown to be
effective in experimental models of epilepsy and
stroke.1ꢁ3 Unfortunately, the non-competitive inhibitors
currently available, such as MK-801, frequently have
serious behavioral effects4 and cause neuronal vacuoli-
zation,5 while competitive inhibitors are often inactive
in vivo because of their poor permeability through the
blood–brain barrier.6 Therefore, another type of effi-
cient NMDA receptor antagonist is eagerly desired.
We previously reported the design of conformationally
restricted analogues of (ꢀ)-1 using a new method to
restrict the conformation of cyclopropane derivatives to
increase their specific affinity for the NMDA receptor.10
Adjacent substituents on a cyclopropane ring exert sig-
nificant mutual steric repulsion, since they are fixed in
an eclipsed conformation relative to each other. Conse-
quently, the conformations of substituents on a cyclo-
propane ring can be restricted by the steric effects of
adjacent substituents, especially when they are bulky
enough. Because the primary amino function of (ꢀ)-1 is
essential for the binding affinity for the NMDA recep-
tor,9 we assumed that the conformation of the amino-
methyl moiety would significantly affect the activity of
the compound. While the aminomethyl moiety is not so
bulky and may freely rotate at least to some extent, the
conformers A and B may be preferable to conformer C
(ꢀ)-(Z)-2-Aminomethyl-1-phenyl-N,N-diethylcyclo-
propanecarboxamide [milnacipran, (ꢀ)-1],7 a clinically
efficient antidepressant due to competitive inhibition of
the re-uptake of serotonin (5-HT) in the CNS,8 is also
recognized as a non-competitive NMDA receptor
antagonist.9 Although the binding affinity of (ꢀ)-1 for
*Corresponding author. Tel.: +81-11-706-3229; fax: +81-11-706-
4980; e-mail: shu@pharm.hokudai.ac.jp
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00030-5

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Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
because of the serious steric repulsion with the bulky
diethylcarbamoyl group in conformer C, as shown in
Figure 2. Based on these considerations, we designed
and synthesized four types of conformationally restric-
ted analogues of (ꢀ)-1 with different stereochemistries,
that is, Type-1 and Type-2, and their enantiomers Type-
3 and Type-4, as shown in Figure 1.10a In these analo-
gues, an alkyl group introduced at the a-position of the
amino function of (ꢀ)-1 restricts the location of the
amino group in space due to steric repulsion from the
diethylcarbamoyl group.10a Therefore, the conformation
of these compounds can be limited depending on the
configuration of the alkyl group introduced; conformer B
would be predominant in Type-1 and its enantiomer
Type-3, while conformer A would be predominant in
Type-2 and its enantiomer Type-4, as shown in Figure 2.
with a Type-1 configuration, that is, 2 (PEDC), 4a
(PPDC), and 6 (PPEDC), were potent non-competitive
NMDA receptor antagonists which significantly inhib-
ited the binding of [3H] MK-801, with IC50 values about
30-fold stronger than that of (ꢀ)-1.10dꢁf
These previous studies suggested that PPDC (4a) was
likely to be the most desirable, since it was a potent
NMDA receptor antagonist virtually devoid of the
inhibitory effect on 5-HT-uptake, while 2 and 6 are
strong 5-HT-uptake inhibitors like the parent com-
pound milnacipran.10
h
Pharmacological studies on
PPDC have shown: (1) that PPDC binds to the receptor
in an agonist-independent manner, whereas the binding
affinities of known non-competitive NMDA receptor
antagonists are affected by agonist concentration;10h
and (2) that the release of PPDC and the previous non-
competitive antagonists, such as MK-801, from their
binding sites was quite different with respect to their
dependence on the direction of ionic currents flowing
through the channel pores of NMDA receptors, that is,
outward currents had no effect on the channel block of
PPDC, while the release of MK-801 was significantly
accelerated under outward current conditions in the
voltage-clamp experiments.10f These results, together
with the structural features of PPDC, which are clearly
different from those of the previous antagonists, suggest
that PPDC represents a new class of NMDA receptor
antagonists.
Biological evaluations of these compounds showed: (1)
that the conformational restriction can improve the
activity; (2) that analogues with a (1S,2R,10S)-config-
uration (Type-1) are the most active ones in the four
types of analogues, and (3) that C-2 alkyl groups, such
as ethyl, ethenyl, and ethynyl groups, are suitable for
the 10-substituents.10d Thus, we found that analogues
The above results prompted us to plan further studies
on PPDC (4a). Thus, we synthesized derivatives of
PPDC modified at the 1-carbamoyl moiety for develop-
ing useful NMDA receptor antagonists and for further
clarifying the structure–activity relationship (SAR). We
previously modified the structure of milnacipran, the
parent compound of PPDC, and recognized that the
substituent having the amide structure (-CONR1R2) at
the 1-position is essential for the NMDA receptor
Figure 2. Conformational restriction of milnacipran by introducing an
alkyl substituent at the 10-position.
Figure 1. Milnacipran and its conformationally restricted analogues.

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1779
Scheme 2.
previously for the synthesis of PPDC.10a Thus, after
Swern oxidation of 8c–i, a Grignard reaction of the
resulting aldehydes 9c–i with EtMgBr gave stereo-
selectively the 10S-addition products 10c–i. However,
Swern oxidation of the N-ethylamide 8b gave none of
the corresponding aldehyde but gave instead the
cyclized aminal 12. However, the Grignard reaction of
12 with EtMgBr did not proceed.
We demonstrated earlier that the 10-configurations of
10R-methyl derivative 13a and its 10S-diastereomer 15a
can be determined based on the their 1H NMR coupling
constant between the 2-H and the 10-H after their con-
version into the corresponding lactones 16 and 18,10a as
shown in Scheme 2. Thus, in this study, after conversion
of 14a and 10c–i into the 10-ethyllactones 17 and 19,
respectively, the 10-configuration of 17 was confirmed as
Scheme 1.
antagonist activity.9 Accordingly, we designed the car-
bamoyl moiety-modified analogues of PPDC, 4b–i, pre-
serving the amide structure, as shown in Figure 1.
Among the newly synthesized compounds, 1-phenyl-2-
[(S)-1-amino - 3 - propyl] - N,N - dipropylcyclopropane-
carboxamide (4d) was identified as the most potent
compound in this series. We also investigated detailed
three-dimensional structure of 4d to clarify the receptor-
binding conformation. In this paper we describe the
results of these studies.
0
0
R (J2,1 =4.4 Hz) and that of 19 as S (J2,1 =0 Hz).
Therefore the Grignard reaction of the cyclopropy-
laldehydes 9c–i with EtMgBr would proceed highly ste-
reoselectively via the stereoelectronically favored
bisected s-trans conformation I (Scheme 1), similarly as
in previous examples.10a,d,e
Introduction of an azido group by a Mitsunobu-type
reaction was performed by treating 10d–i with a NaN3/
Ph3P/CBr4 system11 in HMPA to give the correspond-
ing 10S-azides 11d–i. As we previously reported,10a,d,e
this reaction is likely to occur via the neighboring group
participation intermediate II (Scheme 1). Accordingly,
the reaction should produce the corresponding config-
uration-retained azides. On the other hand, when the
N,N-dimethylamide 10c was treated with the same
NaN3/Ph3P/CBr4 system in HMPA, the lactone 17
(Scheme 2) with the 10R-configuration, instead of the
expected 10S-azide 11c, was obtained as the major pro-
duct. The formation of 17 may support the neighboring
group participation reaction pathway, since it should be
the hydrolysis product of the intermediate II. The 10-
configurations of azides 11d–i were confirmed by the
Results and Discussion
Chemistry
The target compounds were synthesized from an opti-
cally active lactone 7 with a (1S,2R)-configuration,
which was readily prepared from (R)-epichloro-
hydrin,10a as shown in Scheme 1.
In the previous synthesis of PPDC, the diethylamino-
lysis of the lactone 7 was performed with LiNEt2 in
THF at ꢁ78 ꢂC. We found that AlCl3 effectively pro-
moted aminolysis of 7 with various secondary amines in
CH2Cl2 at room temperature. Consequently, the corre-
sponding ring-opened amides 8b–i were readily prepared
in high yields. From 8d–i, the target compounds 4d–i
were synthesized according to the procedure developed
1
chemical shifts in H NMR spectra as summarized in
1
Table 1. The table shows the H NMR spectral data of
the previously synthesized 10R-azides 20R10a and

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Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
Table 1. 1H NMR chemical shifts of the 10-azide derivatives in CDCl3
Compd
R1R2N
R3
10-config.
Chemical shift, d (multiplicity)
H-10
H-2
H-3a
H-3b
20S
21S
20R
21R
11d
11e
11f
11g
11 h
11i
Et2N
Et2N
Et2N
Et2N
Pr2N
Bu2N
i-Bu2N
Bn2N
Pyrrodidyl
Piperidyl
Me
Et
Me
Et
Et
Et
Et
Et
Et
Et
S
S
R
R
S
S
S
S
S
S
2.98–3.08 (m)
2.86 (ddd)
3.33–3.38 (m)
3.12–3.26 (m)
2.84–2.90 (m)
2.83–2.93 (m)
3.09 (m)
3.05 (m)
3.16 (dt)
2.88 (m)
1.95 (ddd)
1.96 (ddd)
1.48–1.52 (m)
1.47–1.60 (m)
1.95 (ddd)
0.91 (dd)
0.95 (dd)
1.48–1.52 (m)
1.47–1.60 (m)
0.97 (dd)
0.96 (dd)
1.33 (dd)
1.20 (dd)
0.92 (dd)
1.00 (dd)
1.61 (dd)
1.65 (dd)
1.48–1.52 (m)
1.47–1.60 (m)
1.63 (dd)
1.64 (dd)
1.37 (dd)
1.57 (dd)
1.63–1.73 (m)
1.59 (dd)
1.96 (ddd)
1.61–1.77 (m)
1.74–1.85 (m)
1.94 (ddd)
1.94 (ddd)
21R,10a and 10S-azides 20S,10a 21S,10a the stereo-
chemistries of which were determined earlier. The che-
mical shift pattern of the 10S azides is clearly different
from that of the 10R-azides; in the 10S-azide series, the
H-2, H-3a, and H-3b signals are separately observed
around d 1.9, 1.0 and 1.6, respectively, while the three
protons signals overlap in the spectra of the 10R azides.
The signals of the H-2, H-3a, and H-3b in the azides
11d–i, prepared in the present study, were observed
separately as shown in Table 1 supporting their 10S-
configurations. Hydrogenation of the azides 11d–i with
Pd-C afforded the target compounds 4d–i.
The N,N-dimethyl- and N-ethylcarbamoyl analogues, 4c
and 4b, respectively, which could not be synthesized by
the above procedure, were obtained from PPDC (4a), as
shown in Scheme 3. Acidic hydrolysis of 4a, followed by
protection of the amino group with a Boc group, gave
an amino acid derivative 22. Condensation between 22
and dimethylamine or ethylamine with EDC, and sub-
sequent deprotection gave the desired 4b and 4c, even
though the overall yields were not high. In the proce-
dure, 1,2-cis substituents were easily cyclized to produce
the lactam 24, which made the yields low.
Scheme 3.
4d significantly inhibited the binding of [3H] MK-801
with an IC50 value of 0.13ꢀ0.016 mM, which is about
2-fold stronger than that of PPDC (IC50=0.20ꢀ0.02
mM). The derivatives having a carbamoyl moiety bulk-
ier than dipropylcarbamoyl group, such as 4e, 4f, and
4g, showed a weaker affinity than PPDC. The affinities
of the cyclic carbamoyl derivatives, 4 h and 4i, were also
insignificant.
Binding affinity for NMDA receptor
The N,N-dipropylcarbamoyl derivative 4d had the most
significant affinity for the receptor among the com-
pounds described.
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, and the results are shown in Table 2.
Inhibitory effects on the uptake of 5-HT
The binding affinity was significantly affected by the
alkyl substituents on the nitrogen of the carbamoyl
moiety. The binding affinities of the N-ethylcarbamoyl
(4b) and N,N-dimethylcarbamoyl (4c) derivatives were
weaker than that of the parent diethyl derivative 4a
(PPDC). Notably, the N,N-dipropylcarbamoyl derivative
The inhibitory effects of the compounds on the uptake
of 5-HT by nerve terminals of cerebral cortical synaptic
membrane from rats were evaluated with [3H] parox-
etine, one of the most potent competitive 5-HT uptake
inhibitor, as a radioligand, and the results are shown in
Table 2. Although previous potent NMDA receptor

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
Table 2. Effects of the compounds on NMDA receptor binding and 5-HT uptake
1781
Compd
X
R
NMDA receptor bindinga
5-HT-uptakeb
Selectivity indexc
(5-HT/NMDA)
(IC50, mM)
(Ki, mM)
(ꢀ)-1
Et2N
Et2N
Et2N
H
Me
6.3ꢀ0.3
0.35ꢀ0.08
0.16ꢀ0.02
0.20ꢀ0.02
2.2ꢀ0.52
1.1ꢀ0.1
0.0085ꢀ0.0006
0.014ꢀ0.002
0.023ꢀ0.0007
24ꢀ0.9
>100
0.0013
0.040
0.14
120
>45
>91
>770
6.3
2 (PEDC)
6 (PPEDC)
CH¼CH2
4a (PPDC)
4b
4c
4d
4e
4f
4g
4 h
4i
Ketamine
Et2N
Et
Et
Et
Et
Et
Et
Et
Et
Et
EtHN
Me2N
Pr2N
Bu2N
i-Bu2N
Bn2N
>100
>100
22ꢀ4.4
11ꢀ2.3
NTd
0.13ꢀ0.02
3.5ꢀ0.3
1.5ꢀ0.1
7.3
—
83
38
14ꢀ0.11
1.2ꢀ0.3
Pyrrodidyl
Piperidyl
>100
>100
2.6ꢀ0.01
0.61ꢀ0.46
aAssay was done with cerebral cortical synaptic membrane of rats using [3H]MK-801.
bAssay was done with cerebral cortical synaptic membrane of rats using [3H]paroxetine.
cThe ratio: 5-HT uptake inhibition (Ki)/NMDA receptor binding (IC50).
dNot tested.
antagonists, such as 2 (PEDC) and 6 (PPEDC), were
also strong 5-HT uptake inhibitors like the parent com-
pound milnacipran [(ꢀ)-1], all of the newly synthesized
compounds were virtually inactive in this system. It
should be noted that the N,N-dipropylcarbamoyl deri-
vative 4d, which showed the most potent binding affinity
for NMDA receptor in this series, was completely inac-
tive as a 5-HT-uptake inhibitor, while a weak 5-HT-
uptake inhibition activity remained with PPDC (4a).
Thus the selectivity index on the NMDA receptor
binding and the 5-HT uptake inhibition of 4d (NMDA/
5-HT > 770) is clearly superior to that of PPDC
(NMDA/5-HT=120). While, as reported previously,
the 5-HT uptake inhibitory effects of the compounds
significantly affected by the alkyl group at the 10 posi-
ton,10d,e this study showed that the effects are also
affected by the structure of the carbamoyl moiety.
that of MK-801 at 1 Â 10ꢁ7 M (Fig. 3a). These results
suggest that 4d can prevent the overstimulation of the
NMDA receptor which may cause neuronal damage.
Conformational analysis of 4d
Our hypothesis regarding conformational restriction
based on the structural feature of the cyclopropane ring
described above has been supported by X-ray crystal-
lographic analysis of ent-4a, the enantiomer of PPDC,
and its 10-diastereomer ent-5a.10a However, the con-
formation of a compound in the solid state may be dif-
ferent from that in solution. Therefore, we investigated
the conformation of 4d in aqueous solution based on
NOE data. The three-dimensional structure in aqueous
solution was constructed by MM2 calculations with a
simulated annealing method based on the NOE con-
straints of the intramolecular proton pairs measured in
D2O.14 The structures of 4d obtained by the calculation
based on the NOE data shown in Figure 4 was in agree-
ment with the speculated conformer B, shown in Figure 2.
Effects on NMDA receptor mediated LTP in rat
hippocampal CA1 area
NMDA receptors mediate the induction of long-term
potentiation (LTP) in hippocampus. It has been shown
that NMDA receptor antagonists block the induction of
LTP correlating with their potency as NMDA receptor
antagonists.1ꢁ3 We investigated the effect of the most
active compound 4d in this series and a well-known
non-competitive antagonist MK-801 on the MMDA
receptor mediated LTP with rat hippocampal slices. The
LTP was induced by perfusing the slice with Mg2+-free
artificial cerebrospinal fluid (ACSF).13 The results are
shown in Figure 3. The application of Mg2+ free ACSF
evoked an increase of excitability in hippocampal pyr-
amidal cells. This potentiation could only be reversed in
part by perfusing with normal ACSF. Although 4d was
inactive at 3 Â 10ꢁ7 M, it clearly reduced the LTP at 1
 10ꢁ6 M (Fig. 3b), the potency of which was similar to
The results suggest that the conformation of the sub-
stituents on a cyclopropane ring of 4d would be restric-
ted by the steric effect of adjacent substituents even in
solution, as we hypothesized, and that the compound
would bind to the NMDA receptor in a conformation
like conformer B (Fig. 2).
Conclusion
We have developed a series of conformationally restric-
ted analogues of milnacipran [(ꢀ)-1] and identified
(1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-dipro-
pylcyclopropanecarboxamide (4d) as the most potent
compound in this series of NMDA receptor antagonists.
Compound 4d clearly reduced the MMDA receptor

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Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
Experimental
Melting points were determined on a Yanagimoto MP-3
micro-melting point apparatus and are uncorrected. The
NMR spectra were recorded with a JEOL EX-270 and-
400, or Bruker AMX 500 spectrometer with tetra-
methylsilane as an internal standard. Chemical shifts
were reported in parts per million (d), and signals are
expressed as s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet), or br (broad). Mass spectra were
measured on a JEOL JMS-D300 spectrometer. Thin-
layer chromatography was done on Merck coated plate
60F254. Silica gel chromatography was done with Merck
silica gel 5715. Reactions were performed under argon.
General
cyclopropylcarboxamides 8b–i
procedure
for
the
preparation
of
To a solution of 7 (10.5 g, 60.0 mmol) in CH2Cl2 (200
mL) was added AlCl3 (16.0 g, 120 mmol) and then the
mixture was cooled to 0 ꢂC, and then an amine (240
mmol, a 2.0 M solution of the amine in THF was used
in the synthesis of 8b and 8c) was added slowly. The
mixture was stirred at room temperature for 24 h, and
then the reaction was quenched with saturated aqueous
NH4Cl. After addition of CH2Cl2 and H2O, the result-
ing mixture was partitioned. The organic layer was
washed with 1 N HCl and brine, dried (Na2SO4), eva-
porated, and purified by column chromatography (silica
gel; AcOEt/hexane, 1:4) to give the corresponding
cyclopropylcarboxamide.
Figure 3. Effects of MK-801 (a) and 4d (b) on NMDA receptor
mediated LTP induced by perfusion of Mg2+ free ACSF in rat hip-
pocampal CA1 area (n=2). Mg2+ free medium was perfused 0–20
min. Compounds were prefused for 65 min before and during perfu-
sion of Mg2+ free ACSF. Ordinate: percent of amplitude of popula-
tion spikes when the amplitude before perfusion of Mg2+ free ACSF
was defined as 100. Abscissa: time in min with control.
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N-ethylcyclopropa-
necarboxamide (8b). Yield 25%, crystal; mp (hexane/
AcOEt) 104–105 ꢂC; [a]D22 ꢁ56.60 ꢂ (c 1.405, CHCl3); 1H
NMR (500 MHz, CDCl3) d 1.02 (3H, t,–NCH2CH3,
J=7.2 Hz), 1.29 (1H, dd, H-3a, J3a,3b=4.6, J3a,2=9.2
Hz), 1.65 (1H, dd, H-3b, J3b,3a=4.6, J3b,2=6.6 Hz),
0
0
1.78 (1H, dddd, H-2, J2, 1 b=4.1, J2,3b=6.6, J2,1 a=8.6,
J2,3a=9.2 Hz), 3.21 (2H, t,-NCH2CH3), 3.53 (1H, br
s,–OH), 3.76 (1H, dd, H-10a, J1 a,2=8.6, J1 a,1 b=12.0
Hz), 4.09 (1H, dd, H-10b, J1 b,2=4.1, J1 b,1 a=12.0
Hz), 5.63 (1H, br s,–NH–), 7.29 (1H, m, aromatic),
0
0
0
0
0
0
13
7.31–7.40 (4H, m, aromatic);
C NMR (125 MHz,
CDCl3) d 14.58 (–NCH2CH3), 17.54 (C-3), 30.32 (C-2),
34.87 (–NCH2CH3), 35.80 (C-1), 60.97 (C-10), 127.68
(C-400), 128.91 (C-200 and C-600), 129.81 (C-300 and C-500),
140.69 (C-100), 172.76 (C¼O); HR-MS (EI) calcd
C13H17NO2 219.1259, found 219.1249 (M+). Anal.
calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found:
C, 71.32; H, 8.00; N, 6.32.
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-dimethylcyclo-
propanecarboxamide (8c). Yield 82%, crystal; mp (hex-
ane/AcOEt) 76–77 ꢂC; [a]2D7ꢁ83.30 (c 0.980, MeOH);
ꢂ
1H NMR (500 MHz, CDCl3) d1.09 (1H, dd, H-3a,
J3a,3b=5.0, J3a,2=5.0 Hz), 1.60 (1H, dddd, H-2,
Figure 4. The MM2 calculation structure of 4d by simulated annealing
method based on the NOE data.
0
0
J2,1 a=4.6, J2,3a=5.0, J2,3b=8.7, J2,1 =10.4 Hz), 1.65
(1H, dd, H-3b, J3b,3a=5.0, J3b,2=8.7 Hz), 2.98 (3H, s,–
NCH3), 3.01 (3H, s,–NCH3), 3.18 (1H, dd, H-10a,
mediated potentiation of rat hyppocampal slices, a
model of LTP. These results suggest that 4d is a new
candidate as a drug for preventing NMDA receptor
related neuronal damage.
J1 a,2=10.4, J1 a,1 b=12.2 Hz), 4.04 (1H, dd, H-10b,
0
0
0
0
J1 b,2=4.6, J1 b,1 a=12.2 Hz), 4.66 (1H, br s,–OH), 7.20–
7.23 (3H, m, aromatic), 7.28–7.31 (2H, m, aromatic);
0
0

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1783
13C NMR (125 MHz, CDCl3) d 17.34 (C-3), 32.11 (C-2),
34.19 (C-1), 35.65 (–NCH3), 37.71 (–NCH3), 64.78 (C-
10), 125.76 (C-200 and C-600), 126.62 (C-400), 128.68 (C-300
and C-500), 139.84 (C-100), 171.80 (C¼O); HR-MS (EI)
calcd C13H17NO2 219.1259, found 219.1266 (M+).
Anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.52; H, 7.81; N, 6.39.
(hexane/AcOEt) 63–64 ꢂC; [a]D24 +70.87 ꢂ (c 1.175, CHCl3);
1H NMR (500 MHz, CDCl3) d 0.41 (3H, d,–NCH2-
CH(CH3)2, J=6.6 Hz), 0.82 (9H, m,–NCH2CH(CH3)2
 9), 1.00 (1H, dd, H-3a, J3a,3b=J3a,2=6.0 Hz), 1.46
(1H, m, H-2), 1.76–1.82 (2H, m,–NCH2CH(CH3)2
and H-3b), 1.97 (1H, m,–NCH2CH(CH3)2), 3.02 (1H,
dd,–NCH2CH(CH3)2, J=7.0, 13.5 Hz), 3.14 (1H, ddd,
H-10a, J1 a,OH=2.5, J1 a,1 b=11.8, J1 a,2=12.7 Hz), 3.25
(2H, d,–NCH2CH(CH3)2 Â 2, J=7.8 Hz), 3.46 (1H,
dd,–NCH2CH(CH3)2, J=8.1, 13.5 Hz), 4.04 (1H, ddd,
0
0
0
0
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-dipropylcyclo-
propanecarboxamide (8d). Yield 84%, crystal; mp (hex-
ane/AcOEt) 60–61 ꢂC; [a]D24 +63.74 ꢂ (c 1.020, CHCl3); 1H
NMR (500MHz, CDCl3) d 0.70 (3H, t,–NCH2CH2CH3,
J=7.4 Hz), 0.88 (3H, t,–NCH2CH2CH3, J=7.4 Hz),
1.06 (1H, dd, H-3a, J3a,3b=5.9, J3a,2=5.9 Hz), 1.16
(1H, m,–NCH2CH2CH3), 1.37 (1H, m,–NCH2CH2CH3),
1.50–1.62 (3H, m–NCH2CH2CH3 and H-2), 1.68 (1H,
dd, H-3b, J3b,3a=5.9, J3b,2=8.8 Hz), 3.17 (1H, ddd, H-
H-10b, J1 b,2=4.7, J1 b,1 a=11.3, J1 b, OH=11.8 Hz), 4.90
0
0
0
0
0
0
(1H, dd,–OH, JOH,1 a=2.5, JOH,1 b=11.3 Hz), 7.20 (1H,
m, H-400), 7.29 (2H, m, H-300 and H-500), 7.34 (2H, m, H-
200 and H-600); 13C NMR (100MHz, CDCl3) d 16.09 (C-3),
19.07 (–NCH2CH(CH3)2), 20.08 (–NCH2CH(CH3)2),
20.19 (–NCH2CH(CH3)2), 20.22 (–NCH2CH(CH3)2),
25.70 (–NCH2CH(CH3)2), 25.80 (–NCH2CH(CH3)2),
32.12 (C-2), 35.04 (C-1), 50.06 (–NCH2CH(CH3)2),
53.89 (–NCH2CH(CH3)2), 65.11 (C-10), 126.52 (C-200
and C-600), 126.74 (C-400), 128.50 (C-300 and C-500), 139.98
(C-100), 172.47 (C¼O); HR-MS (EI) calcd C19H29NO2
303.2198, found 303.2204 (M+). Anal. calcd for
C19H29NO2: C, 74.14; H, 9.15; N, 5.09. Found: C,
73.92; H, 9.32; N, 5.07.
10a, J1 a,OH=2.0, J1 a,1 b=11.8, J1 a,2=11.8 Hz), 3.14
0
0
0
0
(1H, ddd, H-10a, J1 a, OH=2.5, J1 a,1 b=11.8, J1 a,2=12.7
Hz), 3.22–3.36 (4H, m,–NCH2CH2CH3), 4.04 (1H, ddd,
H-10b, J1 b,2=4.9, J1 b,OH=10.9, J1 b,1 a=11.8 Hz), 4.86
0
0
0
0
0
0
0
0
0
0
(1H, dd,–OH, JOH,1 a=2.0, JOH,1 b=10.9 Hz), 7.20–7.36
(5H, m, aromatic); 13C NMR (100MHz, CDCl3) d 11.15
(–NCH2CH2CH3), 11.45 (–NCH2CH2CH3), 16.52 (C-3),
20.33 (–NCH2CH2CH3), 21.16 (–NCH2CH2CH3), 31.99
(C-2), 34.61 (C-1), 46.65 (–NCH2CH2CH3), 49.43 (–
NCH2CH2CH3), 64.96 (C-10), 125.87 (C-200 and C-600),
126.62 (C-400), 128.58 (C-300 and C-500), 140.14 (C-100),
171.51 (C¼O); HR-MS (EI) calcd C17H25NO2 275.1885,
found 275.1867 (M+). Anal. calcd for C17H25NO2: C,
74.14; H, 9.15; N, 5.09. Found: C, 73.92; H, 9.32; N,
5.07.
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-dibenzylcyclo-
propanecarboxamide (8g). Yield 91%, crystal; mp (hex-
ꢂ
ane/AcOEt) 89–90 ꢂC; [a]D21 +31.92 (c 1.110, CHCl3);
1H NMR (500 MHz, CDCl3) d 1.11 (1H, dd, H-3a,
J3a,3b=5.3, J3a,2=5.7 Hz), 1.59 (1H, dddd, H-2,
0
0
J2,1 b=5.3, J2,3a=5.7, J2,3b=8.8, J2,1 a=12.0 Hz), 1.65
(1H, dd, H-3b, J3b,3a=5.3, J3b,2=8.8 Hz), 3.30 (1H,
ddd, H-10a, J1 a,OH=2.4, J1 a,2=12.0, J1 a,1 b=12.6 Hz),
4.04 (1H, ddd, H-10b, J1 b,2=4.6, J1 b,OH=11.0,
0
0
0
0
0
0
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-dibutylcyclo-
propanecarboxamide (8e). Yield 94%, oil; [a]D23
+59.92 ꢂ(c 1.040, CHCl3); 1H NMR (500 MHz,
CDCl3) d 0.79 (3H, t, –NCH2CH2CH2CH3, J=7.1
Hz), 0.93 (3H, t, –NCH2CH2CH2CH3, J=7.4 Hz), 1.06
(1H, dd, H-3a, J3a,3b=5.4, J3a,2=6.0 Hz), 1.09–1.16 (3H,
m, –NCH2CH2CH2CH3 Â 2 and –NCH2CH2CH2CH3 Â
1), 1.24–1.35 (3H, m, –NCH2CH2CH2CH3 Â 2 and
–NCH2CH2CH2CH3 Â 1), 1.47–1.56 (3H, m, –NCH2-
CH2CH2CH3 Â 2 and H-2), 1.66 (1H, dd, H-3b,
J3b,3a=5.4, J3b,2=8.7 Hz), 3.17 (1H, ddd, H-10a,
0
0
J1 b,1 a=12.6 Hz), 4.41 (1H, d, –NCH2Ph, J=4.7 Hz),
4.55 (1H, d,–NCH2Ph, J=5.9 Hz), 4.58 (1H, d, –NCH2Ph,
J=4.7 Hz), 4.68 (1H, d, –NCH2Ph, J=5.9 Hz), 4.76
0
0
(1H, dd, –OH, JOH,1 a=2.4, JOH,1 b=11.0 Hz), 6.83
(2H, m, aromatic), 7.08 (2H, m, aromatic), 7.21–7.29
(9H, m, aromatic), 7.34 (2H, m, aromatic); 13C NMR
(125MHz, CDCl3) d 15.71 (C-3), 31.31 (C-2), 34.62 (C-1),
47.00 (–NCH2Ph), 50.20 (–NCH2Ph), 65.02 (C-10),
126.63, 127.02, 127.09, 127.44, 127.57, 128.16, 128.54,
128.70, 128.78, 135.57, 136.58, 139.55 (aromatic), 172.41
(C¼O); HR-MS (EI) calcd C25H25NO2 371.1885, found
371.1888 (M+). Anal. calcd for C25H25NO2: C, 80.83;
H, 6.78; N, 3.77. Found: C, 80.88; H, 6.96; N, 3.96.
0
0
0
0
J1 a,OH=2.6, J1 a,1 b=10.4, J1 a,2=12.5 Hz), 3.25–3.41
(4H, m,–NCH2CH2CH2CH3), 4.07 (1H, ddd, H-10b,
0
0
0
0
J1 b,2=4.9, J1 b,1 a=10.4, J1 b, OH=11.0 Hz), 4.76 (1H,
0
0
dd,–OH, JOH,1 a=2.6, JOH, 1 b=11.0 Hz), 7.19–7.31
(5H, m, aromatic); 13C NMR (67.8 MHz, CDCl3) d
13.52 (–NCH2CH2CH2CH3), 13.64 (–NCH2CH2-
CH2CH3), 16.46 (C-3), 19.84 (–NCH2CH2CH2CH3),
20.06 (–NCH2CH2CH2CH3), 28.93 (–NCH2CH2CH2-
CH3), 29.74 (C-2), 31.63 (–NCH2CH2CH2CH3), 34.38
(C-1), 44.69 (–NCH2CH2CH2CH3), 47.48 (–NCH2-
CH2CH2CH3), 64.66 (C-10), 125.70 (C-200 and C-600),
126.45 (C-400), 128.45 (C-300 and C-500), 140.09 (C-100),
171.28 (C¼O); HR-MS (EI) calcd C19H29NO2 303.2198,
found 303.2178 (M+). Anal. calcd for C19H29NO2: C,
75.12; H, 9.63; N, 4.62. Found: C, 74.96; H, 9.51; N,
4.62.
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-cyclopentyle-
necyclopropanecarboxamide (8h). Yield 90%, crystal;
ꢂ
mp (AcOEt, Hexane) 127 ꢂC; [a]D24 +113.41 (c 1.095,
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.00 (1H, dd,
H-3a, J3a,3b=5.1, J3a,2=5.1 Hz), 1.46–1.56 (2H, m, H-
3b and H-2), 1.66–18.5 (4H, m, –NCH2CH2– Â 4),
3.11–3.22 (2H, m, H-10a and –NCH2CH2– Â 1),
3.38–3.49 (3H, m, –NCH2CH2– Â 3), 4.04 (1H, ddd, H-
10b, J1 b,2=4.1, J1 b,OH=11.0, J1 b,1 a=12.2 Hz), 4.69
0
0
0
0
0
0
(1H, dd,–OH, JOH,1 a=2.4, JOH,1 b=11.0 Hz), 7.12–7.25
(5H, m, aromatic); 13C NMR (100 MHz, CDCl3) d
16.77 (C-3), 23.99 (–NCH2CH2–), 25.88 (–NCH2CH2–),
31.93 (C-2), 35.40 (C-1), 46.23 (–NCH2CH2–), 46.82
(–NCH2CH2–), 64.79 (C-10), 125.91 (C-200 and C-600),
126.51 (C-400), 128.53 (C-300 and C-500), 139.43 (C-100),
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-di-i-butyl-
cyclopropanecarboxamide (8f). Yield: 93%, crystal; mp

1784
Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
170.02 (C¼O); HR-MS (EI) calcd C15H19NO2 245.1416,
found 245.1416 (M+). Anal. calcd for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.56; H, 7.98; N,
5.71.
(500 MHz, CDCl3) d 0.60 (3H, t, –NCH2CH2CH3,
J=7.3 Hz), 0.87 (3H, t,–NCH2CH2CH3, J=7.3 Hz),
0.98 (1H, m, –NCH2CH2CH3), 1.15 (1H, m, –NCH2-
CH2CH3), 1.53 (1H, m, –NCH2CH2CH3), 1.76 (1H, dd,
H-3a, J3a,3b=5.5, J3a,2=8.3 Hz), 2.23 (1H, dd, H-3b,
J3b,3a=5.5, J3b,2=5.5 Hz), 3.07 (1H, ddd, H-2, J2,3b=5.5,
(1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-cyclohexylene-
cyclopropanecarboxamide (8i). Yield: 95%, cꢂrystal; mp
(AcOEt, Hexane) 105–106 ꢂC; [a]D22 +68.73 (c 1.060,
0
J2,1 =6.2, J2,3a=8.3 Hz), 3.07 (1H, m,–NCH2CH2CH3),
3.17 (1H, m, –NCH2CH2CH3), 3.25–3.37 (2H, m, –
NCH2CH2CH3), 7.26–7.36 (5H, m, aromatic), 9.06 (1H,
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.06 (1H, dd,
d, H-10, J1 ,2=6.2 Hz); 13C NMR (125 MHz, CDCl3) d
0
H-3a, J3a,3b=4.9, J3a,2=6.1 Hz), 1.16 (1H, m,–NCH2-
CH2CH2–), 1.38 (1H, m, –NCH2CH2CH2–), 1.49–1.66
(6H, m, H-3b and H-2 and-NCH2CH2CH2– Â 2 and
10.80 (–NCH2CH2CH3), 11.26 (–NCH2CH2CH3), 19.65
(C-3), 20.12 (–NCH2CH2CH3), 20.70 (–NCH2CH2-
CH3), 36.20 (C-2), 40.28 (C-1), 46.84 (–NCH2CH2CH3),
48.93 (–NCH2CH2CH3), 126.00 (C-200 and C-600), 127.48
(C-400), 128.84 (C-300 and C-500), 137.95 (C-100), 167.69
(C¼O), 197.98 (C-10); HR-MS (EI) calcd C17H23NO2
273.1729, found 273.1724 (M+). Anal. calcd for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C,
74.94; H, 8.16; N, 4.77.
–NCH2CH2CH2–
Â
2), 3.17 (1H, ddd, H-10a,
0
0
0
0
J1 a,OH=2.7, J1 a,2=10.5, J1 a,1 b=12.5 Hz), 3.46–3.57
(3H, m,–NCH2CH2CH2– Â 3), 3.66 (1H, m, –NCH2-
CH2CH2–), 4.05 (1H, ddd, H-10b, J1 b,2=4.6,
0
0
J1 b,OH=11.2, J1 b,1 a=12.5 Hz), 4.74 (1H, dd, –OH,
0
0
0
0
JOH,1 a=2.7, JOH,1 b=11.2 Hz), 7.19–7.32 (5H, m, aro-
matic); 13C NMR (100 MHz, CDCl3) d 17.15 (C-3),
24.20 (–NCH2CH2CH2–), 25.40 (–NCH2CH2CH2–), 25.58
(–NCH2CH2CH2–), 31.66 (C-2), 34.05 (C-1), 43.05
(–NCH2CH2CH2–), 46.94 (–NCH2CH2CH2–), 64.68 (C-
10), 125.66 (C-200 and C-600), 126.40 (C-400), 128.44 (C-300
and C-500), 139.95 (C-100), 169.86 (C¼O); HR-MS (EI)
calcd C16H21NO2 259.1572, found 259.1593 (M+).
Anal. calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40.
Found: C, 73.94; H, 8.24; N, 5.21.
(1S,2R)-1-Phenyl-2-formyl-N,N-dibutylcyclopropanecar-
boxamide (9e). Yield 96%; mp (AcOEt/Hexane/Et2O)
ꢂ
142–143 ꢂC; [a]D23ꢁ145.61 (c 0.400, CHCl3); H NMR
1
(400 MHz, CDCl3) d 0.71 (3H, t, –NCH2CH2CH2CH3,
J=7.1 Hz), 0.82–0.94 (4H, m, –NCH2CH2CH2CH3 Â 3
and –NCH2CH2CH2CH3 Â 1), 0.95–1.15 (3H, m,–NCH2-
CH2CH2CH3 Â 1 and –NCH2CH2CH2CH3 Â 2),
1.23–1.33 (2H, m, –NCH2CH2CH2CH3), 1.44–1.52 (2H,
m, –NCH2CH2CH2CH3), 1.74 (1H, dd, H-3a, J3a,3b=5.4,
J3a,2=8.3 Hz), 2.25 (1H, dd, H-3b, J3b,3a=5.4, J3b,2=5.8
General procedure for preparing cyclopropylcarbalde-
hydes 9c–i. To a solution of oxalyl chloride (5.23 mL,
60.0 mmol) in CH2Cl2 (30 mL) was added a solution of
DMSO (8.53 mL, 120 mmol) in CH2Cl2 (20 mL) slowly
over 30 min at ꢁ78 ꢂC for 30 min. A solution of 8 (30.0
mmol) in CH2Cl2 (20 mL) was added, and the mixture
was stirred at the same temperature for 2 h. After addi-
tion of Et3N (33.7 mL, 240 mmol), the resulting mixture
was further stirred at the same temperature for 30 min,
and then the reaction was quenched with saturated
aqueous NH4Cl. The organic layer separated was
washed with brine, dried (Na2SO4), evaporated, and
purified by column chromatography (silica gel; AcOEt/
hexane, 1:4) to give 9 as crystals.
0
Hz), 2.45 (1H, ddd, H-2, J2,3b=5.8, J2,1 =6.3, J2,3a=8.3
Hz), 3.06 (1H, m, –NCH2CH2CH2CH3), 3.17 (1H, m,
–NCH2CH2CH2CH3), 3.27–3.42 (2H, m, –NCH2CH2-
CH2CH3), 7.19–7.31 (5H, m, aromatic), 9.04 (1H, d, H-10,
J1 ,2=6.3 Hz); 13C NMR (100MHz, CDCl3) d 13.77
0
(–NCH2CH2CH2CH3), 13.93 (–NCH2CH2CH2CH3),
20.01 (–NCH2CH2CH2CH3), 20.05 (C-3), 20.35
(–NCH2CH2CH2CH3), 29.13 (–NCH2CH2CH2CH3),
29.75 (–NCH2CH2CH2CH3), 36.31 (C-2), 40.33 (C-1),
45.24 (–NCH2CH2CH2CH3), 47.32 (–NCH2CH2CH2-
CH3), 125.86 (C-200 and C-600), 127.37 (C-400), 128.77 (C-
300 and C-500), 137.77 (C-100), 167.38 (C¼O), 197.83 (C-
10); HR-MS (EI) calcd C19H27NO2 301.2042, found
301.2020 (M+). Anal. calcd for C19H27NO2: C, 75.71;
H, 9.03; N, 4.65. Found: C, 75.96; H, 9.01; N, 4.62.
(1S,2R)-1-Phenyl-2-formyl-N,N-dimethylcyclopropane-
carboxamide (9c). Yield 91%; mp (hexane/AcOEt)
ꢂ
73–74 ꢂC; [a]2D6 ꢁ161.00 (c 0.980, MeOH); H NMR
1
(500 MHz, CDCl3) d 1.74 (1H, dd, H-3a, J3a,3b=5.5,
J3a,2=8.5 Hz), 2.26 (1H, dd, H-3b, J3b,2=5.5,
J3b,3a=5.5 Hz), 2.50 (1H, ddd, H-2, J2,3b=5.5,
(1S,2R)-1-Phenyl-2-formyl-N,N-di-i-butylcyclopropane-
carboxamide (9f). Yield 77%; mp (hexane/AcOEt/
ꢂ
Et2O) 96–97 ꢂC; [a]2D3ꢁ82.76
(c 1.260, CHCl3); 1H
0
J2,1 =6.1, J2,3a=8.5 Hz), 2.87 (3H, s,–NCH3), 2.97 (3H,
NMR (500 MHz, CDCl3) d 0.52 (3H, d,–NCH2-
CH(CH3)2, J=6.6 Hz), 0.64 (3H, d,–NCH2CH(CH3)2,
J=6.6 Hz ), 0.83 (6H, m,–NCH2CH(CH3)2 Â 6, J=6.6
Hz), 1.76 (1H, m,–NCH2CH(CH3)2), 1.94 (1H, m,
–NCH2CH(CH3)2), 1.95 (1H, dd, H-3a, J3a,3b=5.7,
J3a,2=8.3 Hz), 2.12 (1H, dd, H-3b, J3b,2=5.7,
J3b,3a=5.7 Hz), 2.26 (1H, ddd, H-2, J2,3b=5.7,
s,–NCH3), 7.22–7.36 (5H, m, aromatic), 9.08 (1H, d, H-
0
10, J1 2=6.1 Hz); 13C NMR (125 MHz, CDCl3) d 20.67
(C-3), 35.85 (C-2), 36.76 (–NCH3), 37.26 (–NCH3),
39.72 (C-1), 125.66 (C-200 and C-600), 127.54 (C-400),
129.05 (C-300 and C-500), 137.54 (C-100), 168.18 (C¼O),
198.13 (C-10); HR-MS (EI) calcd C13H15NO2 217.1103,
found 217.1129 (M+). Anal. calcd for C13H15NO2: C,
71.89; H, 6.91; N, 6.45. Found: C, 71.75; H, 7.00; N,
6.47.
0
J2,1 =5.9, J2,3a=8.3 Hz), 3.05 (1H, m,–NCH2-
CH(CH3)2), 3.16–3.26 (3H, m, –NCH2CH(CH3)2),
7.25–7.37 (5H, m, aromatic), 9.11 (1H, d, H-10,
J1 ,2=5.9 Hz); 13C NMR (100 MHz, CDCl3) d 18.85 (C-
0
(1S,2R)-1-Phenyl-2-formyl-N,N-dipropylcyclopropane-
carboxamide (9d). Yieldꢂ 94%; mp (hexane/AcOEt)
3), 19.38 (–NCH2CH(CH3)2), 19.55 (–NCH2CH(CH3)2),
20.15 (–NCH2CH(CH3)2), 20.19 (–NCH2CH(CH3)2),
25.70 (–NCH2CH(CH3)2), 25.77 (–NCH2CH(CH3)2),
167–168 ꢂC; [a]D23ꢁ116.89 (c 1.165, CHCl3); H NMR
1

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1785
37.04 (C-2), 41.17 (C-1), 50.68 (–NCH2CH(CH3)2),
53.66 (–NCH2CH(CH3)2), 126.51 (C-200 and C-600),
127.54 (C-400), 128.71 (C-300 and C-500), 137.92 (C-100),
168.45 (C¼O), 197.68 (C-10); HR-MS (EI) calcd
C19H27NO2 301.2042, found 301.2029 (M+). Anal.
calcd for C19H27NO2: C, 75.71; H, 9.03; N, 4.65. Found:
C, 75.67; H, 9.09; N, 4.65.
166.26 (C¼O), 198.03 (C-10); HR-MS (EI) calcd
C16H19NO2 257.1416, found 257.1403 (M+). Anal.
calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.81; H, 7.62; N, 5.38.
General procedure for the Grignard reaction of 9
To a solution of 9 (3.28 g, 12.0 mmol) in THF (50
mL), EtMgBr (3.0 M in Et2O, 16.0 mL, 48.0 mmol)
was added at ꢁ15 ꢂC, and the mixture was stirred at
the same temperature for 3 h, and then the reaction
was quenched with saturated aqueous NH4Cl. The
resulting mixture was concentrated in vacuo (for
removing THF and Et2O), and then AcOEt and H2O
were added. The organic layer separated was washed
with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; AcOEt/hexane,
1:4) to give 10.
(1S,2R)-1-Phenyl-2-formyl-N,N-dibenzylcyclopropane-
carboxamide (9g). Yield 97%; mp (hexane/AcOEt/
ꢂ
Et2O) 67–68 ꢂC; [a]D21 ꢁ75.02 (c 1.185, CHCl3); 1H
NMR (500 MHz, CDCl3) d 1.87 (1H, dd, H-3a,
J3a,3b=5.6, J3a,2=8.2 Hz), 1.65 (1H, dd, H-3b, J3b,3a=5.6,
0
J3b,2=5.6 Hz), 2.39 (1H, m, H-2, J2, 1 =5.3, J2,3b=5.6,
J2,3a=8.2 Hz), 4.25 (1H, d, –NCH2Ph, J=4.5 Hz), 4.35
(1H, d,–NCH2Ph, J=5.8 Hz), 4.63 (1H, d, –NCH2Ph,
J=5.8 Hz), 4.66 (1H, d,–NCH2Ph, J=4.5 Hz), 6.75
(2H, m, aromatic), 7.09 (2H, m, aromatic), 7.21–7.31
(9H, m, aromatic), 7.36 (2H, m, aromatic), 9.32 (1H, d,
H-10, J1 ,2=5.3 Hz); 13C NMR (125 MHz, CDCl3) d
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-dimethyl-
cyclopropanecarboxamide (10c). Yield 93%, oil; [a]D26
ꢁ12.50 ꢂ (c 0.982, MeOH); 1H NMR (500 MHz, CDCl3)
0
18.78 (C-3), 36.70 (C-2), 41.16 (C-1), 47.30 (–NCH2Ph),
49.90 (–NCH2Ph), 126.73, 127.17, 127.47, 127.56,
127.84, 128.44, 128.49, 128.63, 129.05, 135.25, 136.52,
137.48 (the above mentioned, aromatic), 168.57 (C¼O),
197.76 (C-10); HR-MS (EI) calcd C25H23NO2 369.1729,
found 369.1721 (M+). Anal. calcd for C25H23NO2: C,
81.27; H, 6.27; N, 3.79. Found: C, 80.87; H, 6.50; N,
4.04.
d 1.00 (3H, t, H-30, J3 ,2 =7.5 Hz), 1.07 (1H, dd, H-3a,
0
0
J3a,3b=J3a,2=5.5 Hz), 1.30 (1H, ddd, H-2, J2,3a=5.5,
0
0
J2,3b=J2, 1 =8.5 Hz), 1.66 (1H, m, H-2 ), 1.71 (1H, dd,
H-3b, J3b,3a=5.5, J3b,2=8.5 Hz), 2.98 (3H, s, –NCH3),
3.02 (3H, s, –NCH3), 3.08 (1H, m, H-10), 5.38 (1H, br
s,–OH), 7.19–7.23 (3H, m, aromatic), 7.28–7.31 (2H, m,
aromatic); 13C NMR (125 MHz, CDCl3) d 10.24 (C-30),
17.65 (C-3), 29.04 (C-20), 33.10 (C-1), 35.60 (–NCH3),
36.76 (C-2), 37.71 (–NCH3), 75.64 (C-10), 125.75 (C-200
and C-600), 126.55 (C-400), 128.62 (C-300 and C-500), 139.81
(C-100), 172.02 (C¼O); HR-MS (EI) calcd C15H21NO2
247.1572, found 247.1579 (M+). Anal. calcd for
C15H21NO2: C, 72.87; H, 8.50; N, 5.67. Found: C,
72.88; H, 8.54; N, 5.67.
(1S,2R)-1-Phenyl-2-formyl-N,N-cyclopentylenecyclopro-
panecarboxamide (9h). Yield 96%; mp (hexane/AcOEt)
ꢂ
1
120–121 ꢂC; [a]D24ꢁ124.37 (c 1.565, CHCl3); H NMR
(400 MHz, CDCl3) d 1.67–1.85 (5H, m, –NCH2CH2– Â
4 and H-3a), 2.24 (1H, dd, H-3b, J3b,3a=5.9, J3b,3a=8.5
0
Hz), 2.42 (1H, ddd, H-2, J2,3b=5.9, J2, 1 =6.3,
J2,3a=8.1 Hz), 3.10–3.28 (2H, m, –NCH2CH2– Â 2),
3.41–3.51 (2H, m, –NCH2CH2– Â 2), 7.17–7.35 (5H, m,
aromatic), 9.06 (1H, d, H-10, J1 ,2=6.3 Hz); 13C NMR
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-dipropyl-
cyclopropanecarboxamide (10d). Yield 73%, oil; [a]D22
+76.36ꢂ (c 1.375, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.71 (3H, t, –NCH2CH2CH3, J=7.4 Hz), 0.88 (3H, t,
–NCH2CH2CH3, J=7.4 Hz), 1.00 (3H, t, H-30,
0
(100 MHz, CDCl3) d 20.00 (C-3), 23.78 (–NCH2CH2–),
25.87 (–NCH2CH2–), 36.17 (C-2), 40.79 (C-1), 46.34
(–NCH2CH2–), 46.49 (–NCH2CH2–), 125.93 (C-200 and
C-600), 127.31 (C-400), 128.75 (C-300 and C-500), 136.99 (C-
100), 166.25 (C¼O), 198.12 (CHO); HR-MS (EI) calcd
C15H17NO2 243.1259, found 243.1264 (M+). Anal.
calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found:
C, 74.03; H, 7.05; N, 5.70.
0
0
J3 ,2 =7.5 Hz), 1.04 (1H, dd, H-3a, J3a,3b=5.5,
J3a,2=6.6 Hz), 1.18 (1H, m, –NCH2CH2CH3), 1.23 (1H,
0
ddd, H-2, J2,3a=6.0, J2,3b=8.8, J2,1 =9.2 Hz), 1.41 (1H,
m, –NCH2CH2CH3), 1.56 (2H, m, –NCH2CH2CH3),
1.65 (2H, m, H-20), 1.72 (1H, dd, H-3b, J3a,3b=5.5,
J3a,2=8.8 Hz), 3.07 (1H, m, H-10), 3.22–3.38 (4H, m,
(1S,2R)-1-Phenyl-2-formyl-N,N-cyclohexylenecyclopro-
panecarboxamide (9i). Yꢂield 96%; mp (hexane/AcOEt)
0
–NCH2CH2CH3), 5.47 (1H, d, –OH, JOH, 1 =1.1 Hz),
80–81 ꢂC; [a]2D4ꢁ154.98
(c 1.240, CHCl3);1H NMR
7.19–7.30 (5H, m, aromatic): 13C NMR (125 MHz,
CDCl3) d 10.22 (C-30), 10.98 (–NCH2CH2CH3), 11.27
(–NCH2CH2CH3), 16.75 (C-3), 20.18 (–NCH2CH2-
CH3), 21.03 (–NCH2CH2CH3), 29.36 (C-20), 33.43 (C-
2), 36.55 (C-1), 46.51 (–NCH2CH2CH3), 49.32
(–NCH2CH2CH3), 75.67 (C-10), 125.83 (C-200 and C-600),
126.52 (C-400), 128.52 (C-300 and C-500), 140.27 (C-100),
171.80 (C¼O); HR-MS (EI) calcd C19H29NO2 303.2198,
found 303.2191 (M+). Anal. calcd for C19H29NO2: C,
75.21; H, 9.63; N, 4.62. Found: C, 75.19; H, 9.79; N,
4.46.
(400MHz, CDCl3) d 1.15 (2H, m, –NCH2CH2CH2–),
1.50 (4H, m,–NCH2CH2CH2– Â 2 and –NCH2CH2CH2–
 2), 1.71 (1H, dd, H-3a, J3a,3b=5.3, J3a,2=8.3 Hz), 2.27
(1H, dd, H-3b, J3b,3a=5.3, J3b,2=5.6 Hz), 2.52 (1H, dd,
0
H=2, J2,3b=5.6, J2, 1 =6.1, J2,3a=8.3 Hz), 3.26–3.41 (2H,
m,–NCH2CH2CH2– Â 2), 3.52 (1H, m,–NCH2CH2-
CH2–), 3.62 (1H, m, –NCH2CH2CH2–), 7.24–7.36 (5H,
0
m, aromatic), 9.06 (1H, d, H-10, J1 , 2=6.1 Hz); 13C NMR
(100 MHz, CDCl3) d 20.43 (C-3), 24.13 (–NCH2CH2-
CH2–), 25.32 (–NCH2CH2CH2–), 25.37 (–NCH2CH2-
CH2–), 36.47 (C-2), 39.58 (C-1), 43.28 (–NCH2CH2CH2–),
46.54 (–NCH2CH2CH2–), 125.51 (C-200 and C-600),
127.28 (C-400), 128.78 (C-300 and C-500), 137.65 (C-100),
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-dibutyl-
cyclopropanecarboxamide (10e). Yield 69%, oil; [a]D27

1786
Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
ꢂ
+75.06
(c 1.340, CHCl3); 1H NMR (500 MHz,
127.46, 127.61, 128.20, 128.56, 128.75, 128.79, 135.64,
136.59, 139.65 (aromatic), 172.68 (C¼O); HR-MS (EI)
calcd C27H29NO2 399.2198, found 399.2220 (M+).
Anal. calcd for C27H29NO2: C, 81.17; H, 7.32; N, 3.51.
Found: C, 81.04; H, 7.41; N, 3.64.
CDCl3) d 0.80 (3H, t, –NCH2CH2CH2CH3, J=7.0 Hz),
0.93 (3H, t, –NCH2CH2CH2CH3, J=7.2 Hz), 1.00 (3H,
t, H-30, J3 ,2 =7.5 Hz), 1.03 (1H, dd, H-3a, J3a,3b=5.5,
J3a,2=6.0 Hz), 1.09–1.18 (3H, m, H-20a and–NCH2-
CH2CH2CH3 Â 2), 1.20–1.40 (4H, m, H-2 and H-20b
and–NCH2CH2CH2CH3 Â 2), 1.47–1.57 (2H, m,–NCH2-
CH2CH2CH3), 1.66 (2H, m, –NCH2CH2CH2CH3), 1.71
(1H, dd, H-3b, J3b,3a=5.5, J3b,2=8.7 Hz), 3.07 (1H, m,
H-10), 3.29–3.38 (4H, m, –NCH2CH2CH2CH3), 5.48
0
0
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-cyclopen-
tylenecyclopropanecarboxamide (10h). Yield 82%, oil;
ꢂ
1
[a]2D4 +116.01 (c 1.315, CHCl3); H NMR (400 MHz,
CDCl3) d 1.00 (3H, t, H-30, J3 ,2 =7.6 Hz), 1.06 (1H, dd,
H-3a, J3a,3b=5.6, J3a2=6.2 Hz), 1.27 (1H, m, H-2),
1.61–1.92 (7H, m, –NCH2CH2– Â 4 and H-3b and H-
20), 3.28 (1H, m, –NCH2CH2–), 3.45–3.57 (3H, m,
0
0
0
(1H, d, –OH, JOH, 1 =1.7 Hz), 7.18–7.30 (5H, m, aro-
matic); 13C NMR (100MHz, CDCl3) d 10.46 (C-30), 13.85
(–NCH2CH2CH2CH3), 13.95 (–NCH2CH2CH2CH3),
16.98 (C-3), 20.16 (–NCH2CH2CH2CH3), 20.37 (–NCH2-
CH2CH2CH3), 29.18 (–NCH2CH2CH2CH3), 29.22
(–NCH2CH2CH2CH3), 30.06 (C-20), 33.52 (C-1), 36.79
(C-2), 44.91 (–NCH2CH2CH2CH3), 47.67 (–NCH2-
CH2CH2CH3), 75.72 (C-10), 125.64 (C-200 and C-600),
126.39 (C-400), 128.42 (C-300 and C-500), 140.07 (C-100),
171.42 (C¼O); HR-MS (EI) calcd C21H33NO2 331.2511,
found 331.2528 (M+). Anal. calcd for C21H33NO2: C,
76.09; H, 10.03; N, 4.23. Found: C, 76.10; H, 10.09; N,
4.15.
0
–NCH2CH2– Â 3), 5.42 (1H, d, –OH, JOH, 1 =1.7 Hz),
7.21–7.32 (5H, m, aromatic); 13C NMR (100 MHz,
CDCl3) d 10.29 (C-30), 17.04 (C-3), 23.95 (–NCH2CH2–),
25.85 (–NCH2CH2–), 29.09 (C-20), 34.31 (C-1), 36.65
(C-2), 46.16 (–NCH2CH2–), 46.79 (–NCH2CH2–), 75.69
(C-10), 125.86 (C-200 and C-600), 126.40 (C-400), 128.45 (C-
300 and C-500), 139.47 (C-100), 170.20 (C¼O); HR-MS
(EI) calcd C17H23NO2 273.1729, found 273.1709 (M+).
Anal. calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12.
Found: C, 74.50; H, 8.58; N, 5.01.
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-di-i-bu-
tylcyclopropanecarboxamide (10f). Yield 82%, crystal;
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxylpropyl]-N,N-cyclo-
hexylenecyclopropanecarboxamide (10i). Yield 94%,
ꢂ
ꢂ
mp (hexane/AcOEt) 80–81 ꢂC; [a]D25 +76.76 (c 1.165,
crystal; mp (hexane/AcOEt) 98 ꢂC; [a]D24 +80.06 (c
1
CHCl3); H NMR (500 MHz, CDCl3) d 0.40 (3H, d,
1.060, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.00 (3H,
t, H-30, J3 ,2 =7.6 Hz), 1.05 (1H, dd, H-3a, J3a,3b=5.5,
J3a,2=6.4 Hz), 1.15 (1H, m, –NCH2CH2CH2–), 1.28
0
0
–NCH2CH(CH3)2, J=6.6 Hz), 0.83 (9H, m,–NCH2-
CH(CH3)2 Â 9), 0.97–1.00 (4H, m, H-3a and H-30), 1.18
(1H, m, H-2), 1.66 (2H, m, H-20), 1.77–1.85 (2H, m,
–NCH2CH(CH3)2 and H-3b), 1.98 (1H, m,–NCH2-
CH(CH3)2), 3.00–3.07 (2H, m, –NCH2CH(CH3)2 and
H-10), 3.26 (2H, d, –NCH2CH(CH3)2 Â 2, J=7.7 Hz),
3.46 (1H, dd, –NCH2CH(CH3)2, J=8.1, 13.5 Hz), 5.58
(1H, s, –OH), 7.20 (1H, m, H-400), 7.28 (2H, m, H-300
and H-500), 7.34 (2H, m, H-200 and H-600); 13C NMR
(100 MHz, CDCl3) d 10.39 (C-30), 16.57 (C-3), 19.07
(–NCH2CH(CH3)2), 20.09 (–NCH2CH(CH3)2 Â 2),
20.20 (–NCH2CH(CH3)2), 25.66 (–NCH2CH(CH3)2),
25.81 (–NCH2CH(CH3)2), 29.14 (C-20), 33.94 (C-1),
36.64 (C-2), 50.05 (–NCH2CH(CH3)2), 53.93 (–NCH2-
CH(CH3)2), 75.88 (C-10), 126.48 (C-200 and C-600), 126.67
(C-400), 128.46 (C-300 and C-500), 140.03 (C-100), 172.68
(C¼O); HR-MS (EI) calcd C21H33NO2 331.2511, found
331.2508 (M+). Anal. calcd for C21H33NO2: C, 76.09;
H, 10.03; N, 4.23. Found: C, 75.92; H, 10.03; N, 4.20.
0
(1H, ddd, H-2, J2,3a=6.4, J2, 3b=9.0, J2, 1 =9.8 Hz),
1.40 (1H, m, –NCH2CH2CH2–), 1.49–1.61 (4H, m,
–NCH2CH2CH2– Â 2 and –NCH2CH2CH2– Â 2),
1.62–1.73 (3H, m, H-3b and H-20), 3.30 (1H, m, H-10),
3.46–3.54 (3H, m, –NCH2CH2CH2– Â 3), 3.69 (1H, m,
0
–NCH2CH2CH2–), 5.48 (1H, d, –OH, JOH,1 =2.7 Hz),
7.17–7.31 (5H, m, aromatic); 13C NMR (100 MHz,
CDCl3) d 10.35 (C-30), 17.46 (C-3), 24.29 (–NCH2-
CH2CH2–), 25.47 (–NCH2CH2CH2–), 25.69 (–NCH2-
CH2CH2–), 29.11 (C-20), 33.07 (C-1), 36.55 (C-2), 43.12
(–NCH2CH2CH2–), 47.04 (–NCH2CH2CH2–), 75.62 (C-
10), 125.78 (C-200 and C-600), 126.44 (C-400), 128.49 (C-300
and C-500), 140.04 (C-100), 170.24 (C¼O); HR-MS (EI)
calcd C18H25NO2 287.1885, found 287.1867 (M+).
Anal. calcd for C18H25NO2: C, 75.23; H, 8.77; N, 4.87.
Found: C, 75.23; H, 8.80; N, 4.83.
General procedure for preparing cyclopropylmethylazides
11d–i. To a solution of 10 (1.00 mmol) in HMPA (10
mL) were added PPh3 (787 mg, 3.00 mmol) and CBr4
(995 mg, 3.00 mmol) at 0 ꢂC, the mixture was stirred for
30 min at the same temperature. After addition of NaN3
(650 mg, 10.0 mmol), the resulting mixture was stirred
at room temperature for 6 h, and then AcOEt and H2O
were added. The resulting mixture was partitioned, and
the organic layer was washed with brine, dried
(Na2SO4), evaporated, and purified by flash column
chromatography (silica gel; AcOEt/hexane, 1:9) to give
11.
(1S,2R)-1-Phenyl-2-[(S)-1-hydroxypropyl]-N,N-dibenzyl-
cyclopropꢂanecarboxamide (10g). Yield 90%, oil; [a]D22
+32.33
(c 1.265, CHCl3); 1H NMR (500 MHz,
CDCl3) d 1.03 (3H, t, H-30, J3 ,2 =7.5 Hz), 1.09 (1H, dd,
H-3a, J3a,3b=6.0, J3a, 2=6.0 Hz), 1.31 (1H, ddd, H-2,
0
0
0
J2,3a=6.0, J2,1 =J2,3b=9.2), 1.63–1.77 (3H, m, H-3b
and H-20), 3.20 (1H, m, H-10), 4.38 (1H, d, –NCH2Ph,
J=4.6 Hz), 4.52 (1H, d, –NCH2Ph, J=6.0 Hz), 4.63
(1H, d, –NCH2Ph, J=4.6 Hz), 4.71 (1H, d, –NCH2Ph,
J=6.0 Hz), 5.45 (1H, br s, –OH), 6.85 (2H, m, aro-
matic), 7.07 (2H, m, aromatic), 7.21–7.29 (9H, m, aro-
matic), 7.33–7.35 (2H, m, aromatic); 13C NMR
(125 MHz, CDCl3) d 10.35 (C-30), 16.16 (C-3), 29.15 (C-
20), 33.63 (C-1), 35.89 (C-2), 47.00 (–NCH2Ph), 50.22
(–NCH2Ph), 75.82 (C-10), 126.64, 126.99, 127.09,
(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-dipropylcy-
clopropanecarboxamide (11d). Yield 68%, crystal; mp
ꢂ
(hexane/AcOEt) 71–72 ꢂC; [a]D21 ꢁ147.16
(c 1.600,

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1787
1
CHCl3); H NMR (500 MHz, CDCl3) d 0.26 (1H, m,
–NCH2CH(CH3)2 Â 2), 7.19–7.35 (5H, m, aromatic);
13C NMR (100MHz, CDCl3) d 10.26 (C-30), 17.72 (C-3),
19.02 (–NCH2CH(CH3)2), 20.59 (–NCH2CH(CH3)2),
20.24 (–NCH2CH(CH3)2), 20.38 (–NCH2CH(CH3)2),
25.71 (–NCH2CH(CH3)2), 26.04 (–NCH2CH(CH3)2),
28.11 (C-20), 30.33 (C-2), 35.97 (C-1), 50.90 (–NCH2-
CH(CH3)2), 53.73 (–NCH2CH(CH3)2), 63.59 (C-10),
126.77 (C-400), 127.02 (C-200 and C-600), 128.58 (C-300 and
C-500), 140.70 (C-100), 170.38 (C¼O); HR-MS (EI) calcd
C21H32N4O 356.2576, found 356.2585 (M+). Anal.
calcd for C21H32N4O: C, 70.75; H, 9.05; N, 15.72.
Found: C, 70.40; H, 9.06; N, 15.49.
–NCH2CH2CH3), 0.47 (3H, t, –NCH2CH2CH3, J=7.3
Hz), 0.89 (3H, t, –NCH2CH2CH3, J=7.4 Hz), 0.97 (1H,
dd, H-3a, J3a,3b=4.8, J3a,2=9.2 Hz), 1.06 (3H, t, H-30,
J3 ,2 =7.4 Hz), 1.16 (1H, m, –NCH2CH2CH3), 1.54 (1H,
m, –NCH2CH2CH3), 1.60 (1H, m, –NCH2CH2CH3),
1.63 (1H, dd, H-3b, J3b,3a=4.8, J3b,2=6.2 Hz), 1.82 (2H,
m, H-20), 1.95 (1H, ddd, H-2, J2,3b=6.2, J2,3a=J2,1 =9.2
Hz), 2.84–2.90 (2H, m, –NCH2CH2CH3 and H-10), 3.10
(1H, m, –NCH2CH2CH3), 3.37 (1H, m, –NCH2CH2-
CH3), 3.57 (1H, m, –NCH2CH2CH3), 7.19–7.31 (5H, m,
aromatic); 13C NMR (125 MHz, CDCl3) d 10.19 (C-30),
10.90 (–NCH2CH2CH3), 11.45 (–NCH2CH2CH3), 19.43
(C-3), 20.24 (–NCH2CH2CH3), 20.31 (–NCH2CH2CH3),
27.40 (C-2), 28.19 (C-20), 35.96 (C-1), 47.76 (–NCH2-
CH2CH3), 49.86 (–NCH2CH2CH3), 64.04 (C-10), 126.67
(C-200 and C-600), 127.02 (C-400), 128.64 (C-300 and C-500),
140.94 (C-100), 169.61 (C¼O); HR-MS (EI) calcd
C19H28N4O 328.2263, found 328.2254 (M+). Anal.
calcd for C19H28N4O: C, 69.48; H, 8.59; N, 17.06.
Found: C, 69.66; H, 8.66; N, 16.80.
0
0
0
(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-dibenzylcy-
clopropanecarboxamide (11g). Yield 43%, oil; [a]D22
ꢁ89.24 ꢂ (c 1.085, CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.06 (3H, t, H-30, J3 ,2 =7.5 Hz), 1.20 (1H, dd, H-3a,
J3a,3b=5.1, J3a,2=9.2 Hz), 1.57 (1H, dd, H-3b,
J3b,3a=5.1, J3b,2=6.6 Hz), 1.74–1.85 (3H, m, H-2 and
H-20), 3.05 (1H, m, H-10), 3.95 (1H, d, –NCH2Ph,
J=4.6 Hz), 4.22 (1H, d, –NCH2Ph, J=6.1 Hz), 4.91
(1H, d,–NCH2Ph, J=6.1 Hz), 4.96 (1H, d, –NCH2Ph,
J=4.6 Hz), 6.59 (2H, m, aromatic), 7.08–7.30 (11H, m,
aromatic), 7.33 (2H, m, aromatic); 13C NMR (125 MHz,
CDCl3) d 10.14 (C-30), 18.12 (C-3), 27.83 (C-20), 29.05
(C-2), 35.90 (C-1), 47.63 (–NCH2Ph), 50.48 (–NCH2Ph),
63.46 (C-10), 126.97, 127.06, 127.25, 127.29, 127.62,
128.23, 128.40, 128.51, 128.86, 135.72, 137.18, 140.12
(the above mentioned, aromatic), 170.75 (C¼O); HR-
MS (EI) calcd C27H28N4O 424.2263, found 424.2274
(M+). Anal. calcd for C27H28N4O: C, 76.39; H, 6.65; N,
13.20. Found: C, 76.20; H, 6.78; N, 12.85.
0
0
(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-dibutylcy-
clopropanecarꢂboxamide (11e). Yield 62%, oil;
[a]2D5ꢁ149.20 (c 1.155, CHCl3); H NMR (400 MHz,
1
CDCl3) d 0.16 (1H, m, –NCH2CH2CH2CH3), 0.62 (3H,
t, –NCH2CH2CH2CH3, J=7.2 Hz), 0.81 (1H, m, –NCH2-
CH2CH2CH3), 0.92 (1H, m, –NCH2CH2CH2CH3), 0.93
(3H, t, –NCH2CH2CH2CH3, J=7.2 Hz), 0.96 (1H, dd,
H-3a, J3a,3b=4.8, J3a,2=9.5 Hz), 1.09 (3H, t, H-30,
0
0
J3 ,2 =7.4 Hz), 1.10 (1H, m, –NCH2CH2CH2CH3), 1.31
(2H, m ,–NCH2CH2CH2CH3), 1.47 (1H, m,–NCH2-
CH2CH2CH3), 1.54 (1H, m, –NCH2CH2CH2CH3), 1.64
(1H, dd, H-3b, J3b,3a=4.8, J3b2=6.4 Hz), 1.72–1.87 (2H,
m, H-20), 1.96 (1H, ddd, H-2, J2,3b=6.4, J2.3a=9.5, J2,
4(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-cyclopenty-
lenecyclopropanecarboxamide (11h). Yield 86%, oil;
ꢂ
1 =9.5 Hz), 2.83–2.93 (2H, m, –NCH2CH2CH2CH3 and
[a]2D6ꢁ136.62 (c 1.230, CHCl3); H NMR (400 MHz,
1
0
H-10), 3.11 (1H, m, –NCH2CH2CH2CH3), 3.41 (1H, m,
–NCH2CH2CH2CH3), 3.60 (1H, m, –NCH2CH2CH2-
CH3), 7.19–7.32 (5H, m, aromatic); 13C NMR
(100 MHz, CDCl3) d 10.29 (C-30), 13.70 (–NCH2CH2-
CH2CH3), 13.87 (–NCH2CH2CH2CH3), 19.65 (C-3),
20.12 (–NCH2CH2CH2CH3), 20.45 (–NCH2CH2-
CH2CH3), 27.31 (C-2), 28.27 (–NCH2CH2CH2CH3), 29.15
(–NCH2CH2CH2CH3), 29.23 (C-20), 35.98 (C-1), 45.99
(–NCH2CH2CH2CH3), 48.23 (–NCH2CH2CH2CH3),
64.06 (C-10), 126.53 (C-400), 126.93 (C-200 and C-600),
128.58 (C-300 and C-500), 140.79 (C-100), 169.44 (C¼O);
HR-MS (EI) calcd C21H32N4O 356.2576, found 356.2574
(M+). Anal. calcd for C21H32N4O: C, 70.75; H, 9.05; N,
15.72. Found: C, 71.02; H, 9.15; N, 15.44.
CDCl3) d 0.92 (1H, dd, H-3a, J3a,3b=4.6, J3a,2=9.3
Hz), 1.45 (3H, t, H-20, J2 ,1 =6.4 Hz), 1.63–1.76 (4H, m,
–NCH2CH2– Â 3 and H-3b), 1.94 (1H, ddd, H-2,
0
0
0
J2,3b=6.3, J2,3a=9.3, J2, 1 =9.3 Hz), 2.48 (1H, m,
–NCH2CH2–), 3.16 (1H, m), 3.60 (1H, m, –NCH2CH2–),
7.17–7.32 (5H, m, aromatic); 13C NMR (100 MHz,
CDCl3) d 10.38 (C-30), 19.91 (C-3), 23.81 (–NCH2CH2–),
26.23 (–NCH2CH2–), 27.92 (C-20), 28.23 (C-2), 36.22
(C-1), 47.08 (–NCH2CH2–), 47.71 (–NCH2CH2–), 64.33
(C-10), 126.44 (C-400), 127.02 (C-200 and C-600), 128.55 (C-
300 and C-500), 140.10 (C-100), 168.41 (C¼); HR-MS (EI)
calcd C17H22N4O 298.1793, found 298.1802 (M+).
Anal. calcd for C17H22N4O: C, 68.43; H, 7.43; N, 18.78.
Found: C, 68.42; H, 7.41; N, 18.65.
(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-di-i-butyl-
cyclopropaneꢂcarboxamide (11f). Yield 68%, oil;
[a]2D3ꢁ13.42 (c 1.265, CHCl3); 1H NMR (500 MHz,
CDCl3) d 0.39 (3H, d, –NCH2CH(CH3)2, J=6.6 Hz),
0.53 (3H, d, –NCH2CH(CH3)2, J=6.6 Hz ), 0.85–0.88
(6H, m, –NCH2CH(CH3)2 Â 6), 1.01 (3H, t, H-30,
(1S,2R)-1-Phenyl-2-[(S)-1-azidopropyl]-N,N-cyclohexyle-
necyclopropanecarboxamide (11i). Yield: 78%, oil;
ꢂ
1
[a]2D5ꢁ140.94 (c 1.460, CHCl3); H NMR (400 MHz,
CDCl3) d 0.72 (1H, m, –NCH2CH2CH2–), 1.00 (1H, dd,
H-3a, J3a,3b=4.9, J3a,2=9.3 Hz), 1.07 (3H, t, H-30,
0
0
J3 ,2 =7.3 Hz), 1.13 (1H, m, –NCH2CH2CH2–), 1.41–1.56
(4H, m, –NCH2CH2CH2– Â 2 and –NCH2CH2CH2– Â
2), 1.59 (1H, dd, H-3b, J3b,3a=4.9, J3b, 2=6.3 Hz),
0
0
J3 ,2 =7.4 Hz), 1.33 (1H, dd, H-3a, J3a,3b=5.1,
J3a,2=6.6 Hz), 1.37 (1H, dd, H-3b, J3b,3a=5.1,
J3b,2=9.3 Hz), 1.61–1.77 (4H, m, H-2 and H-20 and
–NCH2CH(CH3)2), 1.97 (1H, m, –NCH2CH(CH3)2),
3.05 (1H, m, –NCH2CH(CH3)2), 3.09 (1H, m, H-10),
3.18 (1H, m, –NCH2CH(CH3)2), 3.25–3.31 (2H, m,
1.71–1.86 (2H, m, H-20), 1.94 (1H, ddd, H-2, J2, 3b=6.3,
0
0
J2, 3a=9.3, J2,1 =9.5 Hz), 2.88 (1H, m, H-1 ), 3.11–3.25
(2H, m, –NCH2CH2CH2– Â 2), 3.55 (1H, m, –NCH2-
CH2CH2–), 3.97 (1H, m,–NCH2CH2CH2–), 7.19–7.33

1788
Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
(5H, m, aromatic); 13C NMR (100 MHz, CDCl3) d
10.42 (C-30), 19.93 (C-3), 24.37 (–NCH2CH2CH2–),
24.75 (–NCH2CH2CH2–), 25.56 (–NCH2CH2CH2–),
27.87 (C-20), 28.41 (C-2), 35.63 (C-1), 43.92
(–NCH2CH2–), 47.37 (–NCH2CH2–), 64.53 (C-10), 126.23
(C-200 and C-600), 126.48 (C-400), 128.67 (C-300 and C-500),
140.66 (C-100), 168.43 (C¼O); HR-MS (EI) calcd
C18H24N4O 312.1950, found 312.1953 (M+). Anal. calcd
for C18H24N4O: C, 69.20; H, 7.74; N, 17.93. Found: C,
69.12; H, 7.54; N, 17.65.
(1H, m, –NCH2CH2CH2CH3), 1.74 (2H, m, H-20), 2.11
(1H, dd, H-3b, J3b,3a=5.9, J3b,2=9.0 Hz), 2.66 (1H, m,
H-10), 3.20–3.34 (4H, m, –NCH2CH2CH2CH3), 7.16
(1H, m, H-400), 7.17–7.28 (4H, m, H-200 and H-300 and H-
500 and H-600); 13C NMR (100 MHz, CD3OD) d 10.43
(C-30), 14.09 (–NCH2CH2CH2CH3), 14.23 (–NCH2-
CH2CH2CH3), 18.53 (C-3), 20.99 (–NCH2CH2-
CH2CH3), 21.28 (–NCH2CH2CH2CH3), 27.74 (C-20),
30.17 (–NCH2CH2CH2CH3), 30.17 (–NCH2CH2-
CH2CH3), 33.06 (C-2), 34.60 (C-1), 46.18 (–NCH2-
CH2CH2CH3), 49.15 (–NCH2CH2CH2CH3), 57.80 (C-
10), 126.83 (C-200 and C-600), 128.31 (C-400), 129.99 (C-300
and C-500), 140.16 (C-100), 172.78 (C¼O); HR-MS (EI)
calcd C21H34N2O 330.2671, found 330.2651 (M+).
Anal. calcd for C21H35ClN2O: C, 68.73; H, 9.61; Cl,
9.66; N, 7.63. Found: C, 68.55; H, 9.60; Cl, 9.71; N,
7.61.
General
cyclopropylethylamines 4d–i
procedure
for
preparing
the
target
A mixture of 11 (1.00 mmol) and 10% Pd-charcoal (50
mg) in MeOH (5 mL) was stirred under atmospheric
pressure of hydrogen at room temperature for 18 h, and
then the catalyst was filtered off. The filtrate was eva-
porated, and the residue was purified by column chro-
matography (silica gel; AcOEt/hexane 1:1 then CHCl3/
MeOH 9:1) to give free amine of 11 as an oil. The free
amine was dissolved in MeOH, and the solution was put
on a column of Diaion WA-30 resin (Clꢁ form). The
column was developed with MeOH, and the appropriate
fractions were evaporated. The residue was treated with
Et2O to give white crystals of amine 4 as a hydrochlo-
ride.
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-di-i-butyl-
cyclopropanecarboxamide hydrochloride (4f). Yield
87%; mp (i-Pr2O/Et2O/t-BuOMe/hexane) 172–173 ꢂC;
ꢂ
1
[a]2D4 +92.46 (c 1.055, MeOH); H NMR (500 MHz,
CDCl3) d 0.29 (3H, d, –NCH2CH(CH3)2, J=6.7 Hz),
0.72–0.78 (9H, m, –NCH2CH(CH3)2), 0.98 (3H, t, H-30,
0
J3 ,2 =7.5 Hz), 1.05 (1H, ddd, H-2, J2,3a=6.4,
0
0
J2,3b=9.0, J2,1 =10.4 Hz), 1.18 (1H, dd, H-3a,
J3a,3b=6.4, J3a,2=6.4 Hz), 1.67–1.81 (3H, m, H-20 and
–NCH2CH(CH3)2), 1.90 (1H, m, –NCH2CH(CH3)2),
2.19 (1H, dd, H-3b, J3b,3a=6.4, J3b,2=9.0 Hz), 2.57
(1H, m, H-10), 3.00 (1H, dd, –NCH2CH(CH3)2, J=7.0,
13.4 Hz), 3.11–3.23 (2H, m, –NCH2CH(CH3)2), 3.35
(1H, dd, –NCH2CH(CH3)2, J=7.0, 13.4 Hz), 7.16–7.33
(5H, m, aromatic); 13C NMR (100 MHz, CDCl3) d
10.48 (C-30), 18.41 (C-3), 19.43 (–NCH2CH(CH3)2),
20.48 (–NCH2CH(CH3)2), 20.54 (–NCH2CH(CH3)2),
20.65 (–NCH2CH(CH3)2), 26.91 (C-20), 26.98 (–NCH2-
CH(CH3)2), 27.70 (–NCH2CH(CH3)2), 32.74 (C-2),
35.12 (C-1), 51.37 (C-10), 55.38 (–NCH2CH(CH3)2),
58.09 (–NCH2CH(CH3)2), 127.52 (C-200 and C-600),
128.49 (C-400), 129.97 (C-300 and C-500), 140.04 (C-100),
173.80 (C¼O); HR-MS (EI) calcd C21H34N2O 330.2671,
found 330.2651 (M+). Anal. cxalcd for C21H35ClN2O:
C, 68.73; H, 9.61; Cl, 9.66; N, 7.63. Found: C, 68.57; H,
9.72; Cl, 9.74; N, 7.48.
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-dipropyl-
cyclopropanecarboxamide hydrochloride (4d). Yield
93%; mp (i-Pr2O/Et2O/t-BuOMe/hexane) 200–201 ꢂC;
ꢂ
1
[a]2D6 +91.01 (c 1.110, MeOH); H NMR (500 MHz,
CD3OD) d 0.59 (3H, t,–NCH2CH2CH3, J=7.3 Hz),
0.79 (3H, t, –NCH2CH2CH3, J=7.4 Hz), 0.97 (1H, m,
–NCH2CH2CH3), 0.99 (3H, t, H-30, J3 ,2 =7.5 Hz), 1.08
0
0
0
(1H, ddd, H-2, J2,3a=6.1, J2,3b=9.0, J2,1 =10.4 Hz),
1.25 (1H, dd, H-3a, J3a,3b=J3a,2=6.1 Hz), 1.37 (1H, m,
–NCH2CH2CH3), 1.45 (1H, m, –NCH2CH2CH3), 1.53
(1H, m, –NCH2CH2CH3), 1.74 (2H, m, H-20), 2.10 (1H,
dd, H-3b, J3b,3a=6.1, J3b,2=9.0 Hz), 2.66 (1H, m, H-10),
3.17–3.31 (4H, m, –NCH2CH2CH3), 7.17 (1H, m, H-
400), 7.25–7.28 (4H, m, aromatic); 13C NMR (125 MHz,
CD3OD) d 10.37 (C-30), 11.25 (–NCH2CH2CH3), 11.69
(–NCH2CH2CH3), 18.49 (C-3), 21.22 (–NCH2CH2-
CH3), 21.84 (–NCH2CH2CH3), 27.69 (C-20), 32.86 (C-
2), 34.64 (C-1), 47.97 (–NCH2CH2CH3), 50.91
(–NCH2CH2CH3), 57.86 (C-10), 127.01 (C-200 and C-600),
128.44 (C-400), 130.09 (C-300 and C-500), 140.26 (C-100),
173.11 (C¼O); HR-MS (EI) calcd C19H30N2O 302.2358,
found 302.2361 (M+). Anal. calcd for C19H31ClN2O: C,
67.33; H, 9.22; Cl, 10.46; N, 8.27. Found: C, 67.03; H,
9.13; Cl, 10.48; N, 8.22.
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-dibenzylcy-
clopropanecarboxamide hydrochloride (4g). Yield 89%;
ꢂ
mp (Et2O, i-Pr2O) 137–139 ꢂC; [a]D22 +92.46 (c 1.235,
1
MeOH); H NMR (500 MHz, CD3OD) d 1.11 (3H, t,
H-30, J3 ,2 =7.5 Hz), 1.23 (1H, ddd, H-2, J2,3a=6.6,
0
0
0
J2,3b=9.1, J2,1 =10.4), 1.38 (1H, dd, H-3a, J3a,3b=6.2,
J3a,2=6.6 Hz), 1.86 (2H, m, H-20), 2.17 (1H, dd, H-3b,
J3b,3a=6.2, J3b,2=9.1 Hz), 2.89 (1H, m, H-10), 4.40 (1H,
d, –NCH2Ph, J=4.8 Hz), 4.57 (1H, d, –NCH2Ph,
J=4.8 Hz), 4.61 (1H, d, –NCH2Ph, J=6.0 Hz), 4.66
(1H, d, –NCH2Ph, J=6.0 Hz), 6.85 (2H, m, aromatic),
7.09 (2H, m, aromatic), 7.20–7.30 (7H, m, aromatic),
7.34 (2H, m, aromatic), 7.43 (2H, m, aromatic); 13C
NMR (125 MHz, CD3OD) d 10.37 (C-30), 17.90 (C-3),
27.73 (C-20), 32.30 (C-2), 34.84 (C-1), 48.61 (–NCH2Ph),
52.00 (–NCH2Ph), 57.81 (C-10), 127.70, 128.52, 128.62,
128.76, 128.80, 129.63, 129.71, 129.80, 130.27, 136.56,
137.77, 139.74 (the above mentioned, aromatic), 173.83
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-dibutylcy-
clopropanecarboxamide hydrochloride (4e). Yield 96%;
mp (i-Pr2O/Et2O/t-BuOMe/hexane) 148 ꢂC; [a]D24
ꢂ
+92.14
(c 1.145, MeOH); 1H NMR (400 MHz,
CD3OD) d 0.67 (3H, t, –NCH2CH2CH2CH3, J=7.3
Hz), 0.85 (3H, t, –NCH2CH2CH2CH3, J=7.4 Hz), 0.87
(1H, m, –NCH2CH2CH2CH3), 1.00 (4H, m, H-30 and-
NCH2CH2CH2CH3), 1.06 (1H, m, H-2), 1.23 (3H, m, H-
3a and –NCH2CH2CH2CH3 Â 2), 1.34 (1H, m, –NCH2-
CH2CH2CH3), 1.41 (1H, m, –NCH2CH2CH2CH3), 1.49

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1789
(C¼O); HR-MS (EI) calcd C27H30N2O 398.2358; found
398.2377 (M+). Anal. calcd for C27H31ClN2O: C, 74.55;
H, 7.18; Cl, 8.15; N, 6.44. Found: C, 74.88; H, 7.19; Cl,
8.05; N, 6.43.
(1S,4R,5R)-2-Oxo-4-ethyl-1-phenyl-3-oxabicyclo[3.1.0]-
hexane (17). Yield 94% (from 14a10a); 1H NMR
(500 MHz, CDCl3) d 1.07 (3H, t, H-20, J2 ,1 =7.5 Hz),
1.42 (1H, dd, H-6a, J6a,5=5.0, J6a,6b=5.0 Hz), 1.48 (1H,
dd, H-6b, J6b,6a=5.0, J6b,5=7.7 Hz), 1.65 (1H, m, H-
10a), 1.82 (1H, m, H-10b), 2.52 (1H, ddd, H-5, J5,4=4.4,
J5,6a=5.0, J5,6b=7.7 Hz), 4.36 (1H, dt, H-4, J4,5=4.4,
0
0
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-cyclopenty-
lenecyclopropanecarboxamide hydrochloride (4 h). Yꢂield
69%; mp (Et2O/hexane) 187–190 ꢂC; [a]D24 +89.04 (c
J4,1 =6.9 Hz), 7.26–7.43 (5H, m, aromatic); 13C NMR
0
1.030, MeOH); H NMR (400 MHz, CD3OD) d 1.10
(125 MHz, CDCl3) d 9.79 (C-20), 16.78 (C-6), 25.34 (C-
5), 28.47 (C-10), 32.71 (C-1), 79.48 (C-4), 127.55 (C-400),
128.15 (C-200 and C-600), 128.55 (C-300 and C-500), 134.32
(C-100), 175.67 (C¼O); HR-MS (EI) calcd C13H14O2
202.0994, found 202.1003 (M+).
1
(3H, t, H-30, J=7.6 Hz), 1.23 (1H, ddd, H-2, J2,3a=6.0,
0
J2,3b=8.9, J2,1 =10.5 Hz), 1.46 (1H, dd, H-3a, J3a,3b=6.0,
J3a,2=6.0 Hz), 1.71–1.96 (6H, m, –NCH2CH2– Â 4 and
H-20), 2.05 (1H, dd, H-3b, J3b,3a=6.0, J3b,2=8.9 Hz),
2.89 (1H, m, H-10), 3.19 (1H, m, –NCH2CH2–), 3.39–3.55
(2H, m, –NCH2CH2– Â 2), 3.64 (1H, m, –NCH2CH2–),
7.24–7.37 (5H, m, aromatic); 13C NMR (100 MHz,
CD3OD) d 10.39 (C-30), 18.81 (C-3), 24.91 (–NCH2CH2–),
26.72 (C-20), 27.71 (–NCH2CH2–), 32.85 (C-2), 35.31
(C-1), 47.56 (–NCH2CH2–), 48.28 (–NCH2CH2–), 57.70
(C-10), 126.91 (C-200 and C-600), 128.21 (C-400), 129.92
(C-300 and C-500), 139.44 (C-100), 171.24 (C¼O); HR-MS
(EI) calcd C17H24N2O 272.1889, found 272.1872 (M+).
Anal. calcd for C17H24N2O: C, 66.11; H, 8.16; Cl,
11.48; N, 9.07. Found: C, 65.73; H, 8.14 ; Cl, 11.51; N,
8.84.
(1S,4S,5R)-2-Oxo-4-ethyl-1-phenyl-3-oxabicyclo[3.1.0]-
hexane (19). Yields 99% (from 10c), 61% (from 10d),
97% (from 10e), 85% (from 10f), 89% (from 10g), 90%
1
(from 10 h), and 99% (from 10i); H NMR (500 MHz,
CDCl3) d 1.07 (3H, t, H-20, J2 ,1 =7.4 Hz), 1.35 (1H, dd,
H-6a, J6a,5=4.6, J6a,6b=4.8 Hz), 1.63 (1H, dd, H-6b,
J6b,6a=4.8, J6b,5=7.8 Hz), 1.82 (2H, m, H-10), 2.33 (1H,
0
0
dd, H-5, J5,6a=4.6, J5,6b=7.8 Hz), 4.36 (1H, t, H-4,
13
0
J4,1 =6.0 Hz), 7.28–7.41 (5H, m, aromatic); C NMR
(125 MHz, CDCl3) d 8.60 (C-20), 19.90 (C-6), 29.32 (C-
5), 29.57 (C-10), 32.20 (C-1), 80.72 (C-4), 127.63 (C-400),
128.31 (C-200 and C-600), 128.58 (C-300 and C-500), 134.20
(C-100), 175.63 (C¼O); HR-MS (EI) calcd C13H14O2
202.0994, found 202.0999 (M+).
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-cyclohexy-
lenecyclopropanecarboxamide hydrochloride (4i). Yiꢂeld:
75%; mp (Et2O/hexane) 236–239 ꢂC; [a]D24 +63.63 (c
1
1.040, MeOH); H NMR (400 MHz, CD3OD) d 1.06
(1S,2R)-1-Phenyl-2-[(S)-1-t-butoxycarbonylaminopro-
pyl]cyclopropanecarboxylic acid (22). A solution of 4a
(1.35 g, 5.30 mmol) in 5 N HCl (200 mL) was heated at
100 ꢂC for 18 h, and then the solvent was evaporated. A
mixture of the residue, Et3N (7.40 mL, 53.0 mmol), and
Boc2O (2.44 mL, 11.0 mmol) in MeOH (53 mL) was
stirred at room temperature for 18 h. The resulting
mixture was concentrated in vacuo, and then CHCl3
and 0.1 N HCl was added. The organic layer separated
was washed with brine, dried (Na2SO4), evaporated,
and purified by column chromatography (silica gel;
MeOH/CHCl3, 1:30) to give 22 as crystals (1.40 g,
(1H, m, –NCH2CH2CH2–), 1.09 (3H, t, H-30, J3 ,2 =7,6
Hz), 1.22 (1H, ddd, H-2, J2,3a=6.4, J2,3b=9.0,
0
0
0
J2,1 =10.5 Hz), 1.39 (1H, dd, H-3a, J3a,3b=6.1,
J3a,2=6.4 Hz), 1.45 (2H, m, –NCH2CH2CH2– Â 2),
1.55–1.58 (3H, m, –NCH2CH2CH2– Â 1 and –NCH2-
CH2CH2– Â 2), 1.84 (2H, m, H-20), 2.12 (1H, dd, H-3b,
J3b,3a=6.1, J3b,2=9.0 Hz), 2.79 (1H, m, H-10), 3.33 (1H,
m, –NCH2CH2CH2–), 3.48 (1H, m,–NCH2CH2CH2–),
3.60 (1H, m, –NCH2CH2CH2–), 3.84 (1H, m, –NCH2-
CH2CH2–), 7.26 (1H, m, H-400), 7.32–.38 (4H, m,
aromatic); 13C NMR (100 MHz, CD3OD) d 10.43 (C-
30), 19.05 (C-3), 25.15 (–NCH2CH2CH2–), 26.46
(–NCH2CH2CH2–), 26.67 (–NCH2CH2CH2–), 27.73
(C-20), 32.74 (C-2), 34.24 (C-1), 44.31 (–NCH2-
CH2CH2–), 49.64 (–NCH2CH2CH2–), 57.65 (C-10),
126.88 (C-200 and C-600), 128.24 (C-400), 129.96 (C-300
and C-500), 140.10 (C-100), 171.22 (C¼O); HR-MS (EI)
calcd C18H26N2O 286.2045, found 286.2054 (M+).
Anal. calcd for C18H27ClN2O: C, 66.96; H, 8.43; Cl,
10.98; N, 8.68. Found: C, 67.01; H, 8.36; Cl, 10.87;
N, 8.49.
ꢂ
83%): mp (EtOH) 62–63 ꢂC; [a]D26 ꢁ114.10 (c 0.980,
1
MeOH); H NMR (500 MHz, CDCl3) d 0.87 (3H, t, H-
30, J=7.5 Hz), 1.21 (1H, br s, H-3a), 1.35 (9H, s,
–C(CH3)3), 1.48–1.63 (4H, m, H-2 and H-3b and H-20),
3.44–3.47 (2H, m, H-10 and –NH–), 7.08–7.27 (5H, m,
aromatic); 13C NMR (125 MHz, CDCl3) d 9.09 (C-30),
19.80 (C-3), 28.02 (C-20), 28.42 (–C(CH3)3), 30.24 (C-2),
34.93 (C-1), 56.10 (C-10), 126.99 (C-200 and C-600), 127.10
(C-400), 128.63 (C-300 and C-500), 135.84 (C-100), 177.32
(C¼O); HR-MS (EI) calcd C13H17NO2 219.1259, found
219.1271 ((MH-Boc)+).
General procedure for preparing lactones 17 and 19
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-dimethylcy-
clopropanecarboxamide hydrochloride (4c). A mixture of
22 (315 mg, 1.00 mmol), Me2NH (0.55 mL, 2.00 M in
THF), and EDC (210 mg, 1.10 mmol) in CH2Cl2 (10
mL) was stirred at room temperature for 18 h. After
addition of CH2Cl2 and H2O, the resulting mixture was
partitioned, and the organic layer was washed with
brine, dried (Na2SO4), evaporated, and purified by col-
umn chromatography (silica gel; MeOH/CHCl3, 1:30)
To a solution of various alcohols 14a or 10a–c (1 mmol)
in MeOH (5 mL) was added 6 N HCl (5 mL), and the
mixture was heated under reflux for 2 h. The solvent
was evaporated, and then the residue was partitioned
between saturated aqueous NaHCO3 and AcOEt. The
organic phase was washed with brine, dried (Na2SO4)
and evaporated. The residue was purified by column
chromatography (silica gel; AcOEt/hexane 1:4) to give
17 or 19 as an oil.
1
to give 23c as white crystals (84 mg, 24%): H NMR

1790
Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
(270 MHz, CDCl3) d 0.96 (3H, t, H-30, J3 ,2 =7.3 Hz),
1.10 (1H, br, H-2), 1.44 (9H, s, (CH3)3C–), 1.56 (1H, br,
H-3a), 1.72–1.91 (3H, m, H-20 and H-3b), 2.80 (3H, s,–
NCH3), 2.97 (3H, s, –NCH3), 3.22 (1H, m, H-10), 4.71
(1H, br s, –NH–), 7.17–7.33 (5H, m, aromatic); LR-MS
(EI) m/z 346 (M+). A solution of 23c (84 mg, 0.24
mmol) in 1 N HCl/MeOH (2.4 mL) was heated under
reflux for 90 min. The solvent was evaporated, and then
residue was treated with Et2O to give white crystals of
Effects on NMDA receptor mediated LTP in rat
hippocampal CA1 area
0
0
The brains of 7-weeks-old male Wistar rats were rapidly
removed and placed in an ice-cold Kreb’s solution bub-
bled continuously with a gas mixture (95% O2 and 5%
ꢂ
CO2). A block was removed by making cut at a 30
angle from the coronal plane. Sections (450 mm in
thickness) were cut from the entire block using a
vibratome. The slices were allowed to recover in a
submersion type slice chamber at 35 ꢂC for at least 1.5
h. The ACSF (pH 7.4) contained NaCl 126 mM, KCl 5
mM, CaCl2 2.4 mM, MgSO4 1.3 mM, NaHPO4 1.26
mM, NaHCO3 26 mM, and d-glucose 10 mM, and was
bubbled continuously with the O2–CO2 mixture. The
LTP was prolonged upon perfusion with Mg2+ free
ACSF for 20 min. A single slice was transferred to a
recording chamber through which flowed ACSF (3
mL/min) at 35 ꢂC. Field potentials from the pyr-
amidal layer of CA1 to electrical stimulation of the
Schaffer collateral–commissural fiber pathway were
recorded with a single-barrel micropipette filled with
2 M NaCl. The stimuli were square wave pulses of 0.1
ms duration, applied at a frequency of 0.25 Hz; the
intensity of stimulation was submaximal voltage. The
micropipette was advanced into the CA1 area until
the activity of a neuron was detected on the oscillo-
scope. Electrode signals were amplified and mon-
itored on an oscilloscope. The compound dissolved in
ACSF was applied in the bath. The percentage of the
amplitude was calculated by comparing the baseline
amplitude. At each concentration of compounds, dif-
ferences were statistically determined by the Wilcoxon
rank sum test to compared the experimental groups
with their controls.
4c as a hydrochloride (60 mg, 88%): mp (Et2O) 116–
ꢂ
118 ꢂC; [a]2D5 ꢁ168.10
(c 0.975, CHCl3); 1H NMR
(500 MHz, CDCl3) d 1.10 (3H, t, H-30, J3 ,2 =7.5 Hz),
0
0
0
1.23 (1H, ddd, H-2, J2,3a=6.0, J2,3b=J2,1 =9.0 Hz), 1.43
(1H, dd, H-3a, J3a,3b=J3a,2=6.0 Hz), 1.83 (2H, m, H-
20), 2.11 (1H, dd, H-3b, J3b,3a=6.0, J3b,2=9.0 Hz), 2.79
(1H, m, H-10), 2.99 (3H, s, –NCH3), 3.02 (3H, s,
–NCH3), 7.25–7.37 (5H, m, aromatic); 13C NMR
(125 MHz, CDCl3) d 10.33 (C-30), 19.38 (C-3), 27.72 (C-20),
33.14 (C-2), 34.31 (C-1), 36.04 (–NCH3), 38.31 (–NCH3),
57.68 (C-10), 126.75 (C-200 and C-600), 128.37 (C-400),
130.13 (C-300 and C-500), 139.93 (C-100), 173.19 (C¼O);
HR-MS (EI) calcd C15H22N2O 246.1732, found 246.1728
+
.
((M-HCl) ). Anal. calcd for C15H23ClN2O 0.5H2O: C,
61.74; H, 8.29; N, 9.60. Found: C, 61.34; H, 8.15; N, 9.80.
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N-ethylcyclopro-
panecarboxamide hydrochloride (4b). Compound 23b
was obtained as an oil, as described above for the
synthesis of 23c in 18% yield, with EtNH (0.55 mL,
2.00 M in THF) instead of Me2NH: 1H NMR
(270 MHz, CDCl3) d 0.98 (3H, t, H-30, J3 ,2 =7.3 Hz),
1.00 (3H, t, –NCH2CH3, J=7.5 Hz), 1.18–1.29 (2H, m,
H-2 and H-3a), 1.46 (9H, s, (CH3)3C–), 1.69–1.85 (3H, m,
H-3b and H-20), 3.07–3.30 (2H, m, H-10 and –NCH2CH3),
3.57 (1H, m, –NCH2CH3), 5.21 (1H, br s, –NH), 5.37
(1H, br s, –NH), 7.26–7.41 (5H, m, aromatic). LR-MS
(EI) m/z 346 (M+). From 23b, compound 4b (hydro-
chloride) was obtained as white crystals in 75% yield, as
described above for the ꢂsynthesis of 4c: mp (Et2O)
0
0
Conformational analysis of 4d
112–114 ꢂC; [a]2D6 +15.90 (c 0.760, MeOH); H NMR
The NMR spectra of 4d (hydrochloride, 15 mM) were
measured in D2O (400 MHz) at 37 ꢂC. NOESY spectra
were recorded in the phase-sensitive mode using the
methods of States and coworkers.15 The intensities of
the NOE cross peaks in the NOESY spectrum recorded
with the mixing time of 200 ms were used to obtained
inter-proton distances. NOE cross peaks were separated
into three distance categories depending on cross peak
intensity. Strong NOE were given an upper distance
constraint of 2.5 A while medium and weak NOEs were
given values of 3.0 and 3.5 A, respectively. For distance
constraints that involved nonequivalent methylene,
methyl and aromatic ring protons which could not be
stereospecifically assigned, the pseudoatom treatment
was used. These provided the distance constraints which
were used for the subsequent structure calculation.
Three-dimensional structures which satisfy the NOE
constraints of the intramolecular proton pairs were
constructed by simulated annealing calculations14 using
Discover-Insight (MSI) as the program. All calcula-
tions of other potential functions were performed fol-
lowing the protocol in the program Discover using the
standard parameters on IRIS Indogo2 Solid Impact
R10000.
1
(500 MHz, CD3OD : CDCl3, 1:4) d 1.07 (3H, t,
–NCH2CH3, J=7.2 Hz), 1.11 (3H, t, H-30, J3 ,2 =7.5
Hz), 1.49 (1H, dd, H-3a, J3a,3b=5.0, J3a,2=5.0 Hz),
1.55–1.62 (2H, m, H-2 and H-3b), 1.84–2.01 (2H, m, H-
20), 3.06 (1H, m, H-10), 3.18 (1H, m, –NCH2CH3), 3.24
(1H, m, –NCH2CH3), 5.33 (1H, br s, –NH–), 7.30 (1H, t,
aromatic, J=7.3 Hz), 7.37 (2H, t, aromatic, J=7.3 Hz),
7.44 (2H, t, aromatic, J=7.3 Hz); 13C NMR (100 MHz,
CD3OD : CDCl3, 1:4) d 9.82 (C-30), 13.88 (–NCH2CH3),
18.93 (C-3), 26.51 (C-20), 28.15 (C-2), 34.83 (–NCH2CH3),
35.41 (C-1), 54.36 (C-10), 127.73 (C-400), 128.72 (C-200
and C-300 and C-500 and C-600), 138.60 (C-100), 172.11 (C¼O);
0
0
HR-MS (EI) calcd C15H22N2O 246.1732, found 246.1719
+
.
(M ). Anal. calcd for C15H23ClN2O 0.25H2O: C, 62.71; H,
8.24; N, 9.75. Found: C, 62.90; H, 8.34; N, 9.36.
Binding assay. The binding affinity for the NMDA
receptor was investigated according to previously
reported methods.12
Inhibitory effects on the uptake of 5-HT. The assay was
investigated according to the previously reported
method.10d

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 1777–1791
1791
Acknowledgements
Papart, P.; Troisfontaines, B.; Bartholome, F.; Bataille, M.;
Charles, G.; Schittecatte, M.; Darimont, P.; Devoitille, J. M.
Psychopharmacology 1994, 114, 131. (e) Artigas, F. CNS
Drugs 1995, 4, 79.
9. Shuto, S.; Takada, H.; Mochizuki, D.; Tsujita, R.; Hase,
Y.; Ono, S.; Shibuya, N.; Matsuda, A. J. Med. Chem. 1995,
38, 2964.
This investigation was supported by a Grant-in-Aid for
Creative Scientific Research (13NP0401) from the Japan
Society for Promotion of Science. We are grateful to
Daiso Co., Ltd. for gift of chiral epichlorohydrins.
10. (a) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada,
H.; Yamashita, K.; Matsuda, A. J. Org. Chem. 1996, 61, 915.
(b) Ono, S.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 1996,
37, 221. (c) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.;
Matsuda, A. Tetrahedron Lett. 1996, 37, 641. (d) Shuto, S.;
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suda, A. J. Med. Chem. 1996, 39, 4844. (e) Shuto, S.; Ono, S.;
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S.; Ono, S.; Matsuda, A.; Yoshii, K. Synapse 1999, 31, 87. (g)
Kazuta, Y.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 2000,
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macol. 2001, 85, 207. (i) Kazuta, Y.; Shuto, S.; Abe, H.; Mat-
suda, A. J. Chem. Soc., Perkin Trans. 1 2001, 599. (j) Uchino,
S.; Watanabe, W.; Nakamura, T.; Shuto, S.; Kazuta, Y.;
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