Synthesis of derivatives of (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) modified at the 1-aromatic moiety as novel NMDA receptor antagonists: The aromatic group is essential for the activity

Bioorganic & Medicinal Chemistry 10 (2002) 3829–3848

Synthesis of Derivatives of (1S,2R)-1-Phenyl-2-[(S)-1-

aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC)

Modiﬁed at the 1-Aromatic Moiety as Novel NMDA Receptor

Antagonists: The Aromatic Group is Essential for the Activity

Yuji Kazuta,^aRyuichi Tsujita,^bKanako Yamashita,^bShigeo Uchino,^cShinichi Kohsaka,^c

Akira Matsuda^aand Satoshi Shuto^a,*

^aGraduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan

^bInstitute for Life Science Research, Asahi Chemical Co., Ltd., Ohito-cho, Shizuoka 410-2321, Japan

^cDepartment of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan

Received 24May 2002; accepted 1 August 2002

Abstract—(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC, 4a), which is a conformationally

restricted analogue of antidepressant milnacipran [(ꢀ)-1], is a new class of potent noncompetitive NMDA receptor antagonists. A

series of PPDC analogues modiﬁed at the 1-phenyl moiety, that is, the analogue 6 lacking 1-phenyl group, the 1-(ﬂuorophenyl)

analogues 4b,c,d, the 1-(methylphenyl) analogues 4e–g and the 1-(naphthyl) analogues 4h,i were synthesized. Analogue 6, lacking

the 1-phenyl group, was completely inactive showing that the aromatic moiety is essential for the NMDA receptor binding. Among

the analogues synthesized, the 1-o-ﬂuorophenyl and 1-m-ﬂuorophenyl analogues 4b and 4c showed potent aﬃnities for the NMDA

receptor [IC₅₀=0.16ꢀ0.001 mM (4b), 0.15ꢀ0.02 mM (4c)], which were improved to some extent compared to those of the parent

compound PPDC (IC₅₀=0.20ꢀ0.02 mM). On the other hand, compounds 4b and 4c showed none of the 5-HT-uptake inhibitory

eﬀect, while PPDC turned out to be a weak 5-HT-uptake inhibitor.

Introduction

(ꢀ)-(Z)-2-Aminomethyl-1-phenyl-N,N-diethylcyclo-

propanecarboxamide [milnacipran, (ꢀ)-1],⁷a clinically

eﬃcient antidepressant due to competitive inhibition of

the re-uptake of serotonin (5-HT) in the CNS,⁸is also

recognized as a non-competitive NMDA receptor

antagonist.⁹Although the binding aﬃnity of (ꢀ)-1 for

the NMDA receptor is not very high, the compound has

the advantage of suﬃciently penetrating the brain with-

out serious side eﬀects,^8d,emaking 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.

There have been attempts to develop novel agents that

block the activation of NMDA (N-methyl-d-aspartic

acid) receptors by glutamate or related excitatory neu-

rotransmitters, and a large number of competitive and

non-competitive NMDA receptor antagonists have been

developed.^1ꢁ3Although a number of studies clearly

indicate that these competitive and noncompetitive

antagonists are eﬀective in experimental models of epi-

lepsy and stroke, clinical studies of these NMDA

receptor antagonists have proven unsuccessful.^1ꢁ3Non-

competitive inhibitors have produced serious behavioral

eﬀects⁴and have caused neuronal vacuolization in some

cases,⁵while competitive inhibitors are often inactive in

vivo because of poor transport to the brain.⁶Consider-

ing these results, the development of another type of

eﬃcient NMDA receptor antagonists is eagerly desired.

We designed and synthesized four types of conform-

ationally restricted analogues of (ꢀ)-1, each having a

diﬀerent stereochemistry; that is, Type-1 (2 and 4a),

Type-2 (3 and 5), and their enantiomers Type-3 (ent-2 and

ent-4a) and Type-4( ent-3 and ent-5), as shown in Figure

1.¹⁰In these analogues, an alkyl group introduced at the

a-position of the amino function of (ꢀ)-1 restricts the

*Corresponding author. Tel.: +81-11-706-3229; fax: +81-11-706-

4980; e-mail: shu@pharm.hokudai.ac.jp

PII: S0968-0896(02)00346-2

3830

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

Figure 1. Milnacipran and its conformationally restricted analogues.

location of the amino group in space, which is essential

for binding to the NMDA receptor,⁹due to steric

repulsion of the diethylcarbamoyl group.^11aTherefore,

we expected the conformation of these compounds to be

determined by the conﬁguration of the alkyl group

introduced; conformer B would be predominant in the

conformationally restricted analogues with the Type-1

conﬁguration and its enantiomer (Type-3), while con-

former A would be predominant in Type-2 analogues

and its enantiomer (Type-4), as shown in Figure 2. In

fact, the structural analysis by X-ray crystallographic,

NMR, and computational calculation studies showed

that these compounds are conformationally restricted,

as we had hypothesized (Fig. 3).^10a,k,m

tional restriction can improve activity;^10d(2) analogues

with a (1S,2R)-conﬁguration (Type-1 and Type-2) are

more potent than the corresponding enantiomers (Type-

3 and Type-4), and Type-1 analogues are more potent

than the corresponding Type-2 analogues,^10dꢁfand (3)

introduction of a substituent bulkier than an ethyl

group, such as a propyl or isobutyl group, at the 1⁰-

position signiﬁcantly reduces the activity.^10dThus, we

found that analogues with a Type-1 conﬁguration, i.e.,

the 1⁰-methyl analogue 2 and the 1⁰-ethyl analogue 4a

(PPDC) were potent NMDA receptor antagonists

which signiﬁcantly inhibited the binding of [³H] MK-

801 with IC₅₀values approximately 30-fold stronger

than (ꢀ)-1.^10e,fAmong these compounds, PPDC (4a) is

likely to be the most desirable, since the compound is a

potent NMDA receptor antagonist almost devoid of

inhibitory eﬀect on 5-HT-uptake, while the 1⁰-methyl

analogue 2 is a strong 5-HT-uptake inhibitor, like the

parent compound milnacipran.^10h

The biological evaluations of these conformationally

restricted analogues demonstrated that: (1) the conforma-

Pharmacological studies on PPDC have shown that: (1)

it 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(2) the release of PPDC and the pre-

vious 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 sig-

niﬁcantly accelerated under outward current conditions

in the voltage-clamp experiments,^10fand (3) PPDC was

selective to GluRe2/z1, GluRe3/z1 and GluRe4/z1 sub-

types, while previous antagonists were nonselective or

selective to the GluRe1/zl, GluRe2/zl and/or GluRe3/zl

subtypes.^10jThese results, together with the structural

features of PPDC, which are clearly diﬀerent from those

of the previous antagonists, suggest that it is a new class

of NMDA receptor antagonists.

Figure 2. Conformational restriction of milnacipran by introducing an

alkyl substituent at the 1⁰-position.

These encouraging results prompted us to synthesize

PPDC analogues in the hope of ﬁnding further useful

compounds and of clarifying their structure–activity

relationship. Therefore, we designed the PPDC deriva-

tive 6 without a 1-phenyl group. Biological evaluation

of 6 showed that the aromatic ring was essential for the

NMDA receptor binding aﬃnity. Consequently, we

designed and synthesized the novel 1⁰-aromatic group-

modiﬁed PPDC analogues 4b–i (Fig. 3) with the same

stereochemistry as for PPDC. In this paper we describe

the results of these studies.

Figure 3. Derivatives of the PPDC modiﬁed at the 1-aromatic moiety.

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3831

Results and Discussion

Compound 6 was successfully synthesized as summarized

in Scheme 2. Aminolysis of the (1R,2S)-1-(phenylsulfonyl)-

cyclopropane derivative 9, prepared via the condensa-

tion between 7 and 8 under basic conditions, with

Et₂NH/AlCl₃gave the cyclopropylmethyl alcohol 11,

the optical purity of which was determined as 98% ee by

chiral HPLC analysis. Grignard reaction of the alde-

hyde 12, which was prepared by Swern oxidation of 11,

with EtMgBr in THF gave a major addition product 13

in 52% yield and its 1⁰-diastereomer 14 in 19% yield.

Synthesis of the PPDC analogue lacking the phenyl group

We ﬁrst tried to synthesize the PPDC derivative 6,

which lacks the 1-phenyl group. Biological evaluation of

6 would clarify the role of the phenyl group for the

binding to the receptor in PPDC and its congeners. For

the synthesis of 6, an eﬃcient construction of a chiral

1,2-cis-carbonsubstituted cyclopropane structure was

needed. In recent years, stereoselective preparation of

biologically important cyclopropane derivatives has

been extensively studied.^11ꢁ14We have developed a syn-

thetic procedure for chiral cyclopropanes with (R)- or (S)-

epichlorohydrin as a synthon.^10aꢁc,15The procedure is

particularly useful, since the both chiral epichloro-

hydrins are commercially available in high optical purity

and also cyclopropane products of high optical purity

can be obtained on a rather large scale. Thus, we planned

to synthesize the target 6 using (R)-epichlorohydrin (7)

as a synthon. The retrosynthetic analysis is shown in

Scheme 1. The ﬁnal product 6 is obtained by reductive

removal of the phenylsolfonyl group of 10, can be

obtained from the (1R,2S)-1-(phenylsulfonyl)cyclopro-

pane derivative 9. The cyclopropane structure having a

phenylsulfonyl group is constructed from (R)-epi-

chlorohydrin (7) and phenylsulfonylacetonitrile (8) by

the procedure recently developed by us.¹⁵

The relative stereochemistries were conﬁrmed by ¹H

NMR analysis. We previously demonstrated that the 1⁰-

conﬁgurations of the conformationally rigid 1⁰S-methyl

lactone 20 and its 1⁰R-diastereomer 21 can be deter-

mined based on their ¹H NMR coupling constant

between the H-2 and the H-1⁰, as shown in Figure 4.

Thus, in this study, the major and minor products 13

and 14 of the Grignard reaction were heated with HCl in

MeOH to convert them into the corresponding lactones

22 and 23, and their 1⁰-conﬁguration were conﬁrmed as S

0

(J_2,1=0 Hz) and R (J_2,1=4.6 Hz), respectively.

0

Mitsunobu-type azidation of 13 with a NaN₃/Ph₃P/

CBr₄system¹⁶in HMPA gave the 1⁰-azido derivative 16

in 54% yield and its diastereomer 15 in 29% yield. As

described below, similar reactions with the correspond-

ing 1-phenyl substrates 29a–i proceeded stereoselectively

via the neighboring amido-oxygen-participation pathway.

In the reaction of 13, such a neighboring participation

would not work eﬀectively due to the electron-withdrawing

sulfony group at the 1-position. Although the 1⁰-S-azide

16 is required for synthesizing the target compound 6,

the 1⁰-conﬁguration of the major product 16 was deter-

mined as R by its X-ray crystallographic analysis. Cat-

alytic hydrogenation of 15 with Pd-C in MeOH gave the

corresponding amine 10. The reductive removal of the

phenylsulfonyl group of 10 with Mg/MeOH^15,17was

performed, and the products were isolated after protec-

tion of the amino function by a trityl group. Treatment

of 10 with Mg/MeOH at 50 ^ꢂC gave only the trans pro-

duct 18. However, the desired cis-product 17 was

Scheme 1.

Scheme 2.

3832

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

obtained as the major product, when the reductive

treatment of 10 was carried out at 0 ^ꢂC. Although we

also examined desulfonylation by SmI2, it was unsuc-

cessful and 10 was recovered. Finally, acidic detrityla-

tion of 17 with HCl/MeOH gave the target compound 6

as a hydrochloride. The corresponding trans-isomer 19

was obtained by a similar deprotection of 18. The cis/

trans-geometry of 6 and 19 were conﬁrmed by the NOE

experiments as shown in Figure 5.

Synthesis of PPDC analogues having a Substituted-

phenyl group at the 1-position

The target compounds 4b–i were synthesized, as shown in

Scheme 3, according to the procedure developed previously

for the synthesis of a series of conformationally restric-

ted analogues of milnacipran, such as PPDC, having a

phenyl group at the 1-position on the cyclopropane

ring.¹⁰In the previous synthesis, all of the target

compounds with Type-1 stereochemistry [(1S,2R,1⁰S)-

conﬁguration] were prepared via the key-intermediate

(1S,2R)-lactone 25a, which was readily prepared

from (R)-epichlorohydrin (7) and phenylacetonitrile

(24a).^10aTherefore, similar reactions with the

substituted phenylacetonitriles 24b–i and 7 were thought

to provide the corresponding (1S,2R)-lactones 25b–i,

from which the target compounds 4b–i would be

synthesized.

Reactions of 7 and the carbanions, prepared by treating

the substituted phenylacetonitriles 24b–i with NaNH₂,

in benzene at room temperature, followed by alkaline

hydrolysis of the nitrile group and subsequent acidic

treatment gave the desired (1S,2R)-lactone 25a–i in 28–

63% yields with a high optical purity (94–96% ee).¹⁸

Diethyl-aminolyses of the lactones 25b–i and sub-

sequent Swern oxidation readily gave the cyclopro-

pylcarbaldehydes 27b–i.

Figure 4. Determinations of the 1⁰-conﬁgurations of 13 and 14.

Grignard reactions of 27b–i with EtMgBr in THF were

performed to give the corresponding 1⁰S-products 28b–i

highly diastereoselectively in 77–94% yields. The 1⁰-

0

conﬁgurations of 28b–i were determined by the J_2,1

values, after converting 28b–i into the lactones 30b–i. As

we previously reported,^10a,baddition of the Grignard

reagent to the cyclopropylcarbaldehydes 27b–i would

proceed from the least-hindered si-face in the bisected

s-trans conformation, which would be preferred due to

the peculiar stereo-electronic eﬀect of the cyclopropane

ring, to produce 1⁰S-addition products 28b–i highly ste-

reoselectively.^10a,bTreatment of 28b–i with a NaN₃/

PPh₃/CBr₄system¹⁶gave the 1⁰S-azide 29b–i with

retention of conﬁguration in 69–99% yield. We have

demonstrated that the reaction occurs via the neighboring

amido-oxygen-participation to give the corresponding

azido derivatives with retention of conﬁguration.^10a,d,e

The 1⁰-conﬁgurations of 29a–i were supported by the

Figure 5. Determinations of stereochemistry of 6 and 19.

1

chemical shifts in H NMR spectra as summarized in

Table 1. The 1⁰-cyclopropylazide derivatives show a

typical chemical shift pattern depending on the 1⁰-con-

1

ﬁguration. Table 1 shows the H NMR spectral data

of the known stereochemistry of the 1⁰R-azides 32^10a

and 33,^10aand the 1⁰S-azides 31^10aand 29a.^10aIn

the 1⁰S-azide series, the H-2, H-3a, and H-3b signals are

separately observed around d 2.0, 0.9, and 1.6 ppm,

respectively, while signals of the three protons overlap in

the spectra of the 1⁰R azides. Thus the 1⁰-conﬁgurations

of 29b–i were conﬁrmed as S based on the separately

observed signals of the three protons, as shown in

Table 1.

Catalytic hydrogenations of 29b–i ﬁnally gave the target

compounds 4b–i in high yields.

Scheme 3.

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

Table 1. ¹H NMR chemical shifts of the 1⁰-azido derivatives in CDCl₃

3833

Chemical shift, d (multiplicity)

Compd

R

1⁰-Conﬁg.

H-1⁰

H-2

H-3a

H-3b

31

29a

32

Me

Et

Me

Et

S

R

S

2.98–3.08 (m)

2.86 (ddd)

3.33–3.38 (m)

3.12–3.26 (m)

2.87 (m)

2.86 (m)

2.87 (m)

2.85–2.94(m)

2.85 (m)

1.95 (ddd)

1.96 (ddd)

1.48–1.52 (m)

1.47–1.60 (m)

2.05 (ddd)

1.91 (ddd)

1.89 (ddd)

2.05 (ddd)

1.95 (ddd)

2.15–2.20 (m)

2.10 (ddd)

0.91 (dd)

0.95 (dd)

1.48–1.52 (m)

1.47–1.60 (m)

0.89 (dd)

0.97 (m)

0.92 (dd)

0.73 (dd)

0.93 (dd)

0.92 (dd)

0.88 (dd)

1.01 (dd)

1.61 (dd)

1.65 (dd)

1.48–1.52 (m)

1.47–1.60 (m)

1.93 (dd)

1.67 (dd)

1.64(dd)

1.99 (dd)

1.64(dd)

33

29b

29c

29d

29e

29f

29g

29h

29i

1.62 (dd)

2.15–2.20 (m)

1.73 (dd)

3.00–3.07 (m)

2.97 (m)

Aﬃnity for the NMDA receptor of rat cerebral cortex

(IC₅₀=0.20ꢀ0.02mM). However, when a ﬂuoro sub-

stituent was introduced at the ortho- or the meta-position,

i.e., 4b and 4c, respectively, the aﬃnity was somewhat

improved [IC₅₀=0.16ꢀ0.001 mM (4b), 0.15ꢀ0.02 mM

(4c)], compared with the parent compound PPDC.

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.¹⁹The results, together with those

of several previously reported compounds,^10d,eare

shown in Table 2.

On the other hand, the binding aﬃnity of the methyl-

phenyl and naphthyl derivatives was relatively weak

compared with that of the ﬂuoro compounds above.

The o-methylphenyl (4e), m-methylphenyl (4f) and 2-

naphthyl (4h) derivatives showed rather potent binding

aﬃnity for the receptor (IC₅₀=0.24ꢀ0.03 mM,

0.29ꢀ0.4 mM, and 0.38ꢀ0.05 mM, respectively), whereas

the values were weaker than those of PPDC. The binding

aﬃnity for the p-methylphenyl (4g) and 3-naphthyl (4i)

derivatives was insigniﬁcant.

Compound 6, a PPDC analogue lacking the phenyl group,

completely lost the aﬃnity for the receptor. Thus, it is clear

that the aromatic moiety is essential for the activity.

In the ﬂuorophenyl series, 4b, 4c, and 4d, the para-sub-

stituted 4d showed the binding aﬃnity with IC₅₀value

of 2.8ꢀ0.04 mM, which was lower than that of PPDC

Table 2. Eﬀects of the compounds on NMDA receptor binding and 5-HT uptake

Compd

Ar

R

NMDA receptor binding^a(IC₅₀, mM)

5-HT uptake^b(K_i, mM)

Selectivity index^c(5-HT/NMDA)

(ꢀ)-1

2

4a

6

4b

4c

4d

4e

4f

4g

4h

4i

Ph

H

Me

Et

6.3ꢀ0.3

0.35ꢀ0.08

0.20ꢀ0.02

>100

0.0085ꢀ0.0006

0.014ꢀ0.002

24ꢀ0.9

>100

0.0013

0.040

120

—

o-F–Ph

m-F–Ph

p-F–Ph

o-Me–Ph

m-Me–Ph

p-Me–Ph

2-Naphthyl

3-Naphthyl

0.16ꢀ0.001

0.15ꢀ0.02

2.8ꢀ0.04

0.24ꢀ0.03

0.29ꢀ0.4

33ꢀ2.1

>100

>630

>670

36

420

340

3.0

210

>24

0.48ꢀ0.05

4.2ꢀ0.2

^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 (K_i)/NMDA receptor binding (IC₅₀).

3834

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

These results suggested that although the presence of a

substituent at the ortho- or the meta-position of the 1-

phenyl moiety of PPDC is tolerated in binding to the

receptor, a para-substituent is likely to disturb this

binding, probably due to a steric eﬀect.

600 mmol) slowly at 0 ^ꢂC, and the mixture was stirred at

room temperature for 5 h. After addition of 1 N HCl,

the resulting mixture was partitioned. The organic layer

was washed with 1 N HCl and brine, dried (Na₂SO₄),

evaporated. The residue was puriﬁed by column chro-

matography (silica gel; AcOEt/hexane 1:3) to give 11 as

yellow crystals (45.2 g, 96.8%), of which optical purity

was determined as 98% ee by a chiral HPLC (CHIR-

ALCEL OJ, 0.46Â25 cm, Daicel Chemical Industries

Co., Ltd.; hexane/EtOH, 1:1; 0.5 mL/min; 265 nm): mp

(hexane, AcOEt, Et₂O) 61 ^ꢂC; [a]_D²⁸ꢁ45.34 (c 1.010,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 1.14(3H, t,

Inhibition on the 5-HT-Uptake

The inhibitory eﬀects of the compounds on the uptake

of 5-HT by nerve terminals of cerebral cortical synaptic

membrane from rats were next evaluated with [³H] par-

oxetine as a radioligand,^10dsince the lead compound

milnacipran [(ꢀ)-1] is a potent inhibitor of 5-HT

uptake. The results are also summarized in Table 1.

Compound 2, the 1⁰-methyl congener of PPDC, sig-

niﬁcantly inhibits the 5-HT uptake, whereas PPDC has

a very weak inhibitory eﬀect.

–NCH₂CH₃, J=7.1 Hz), 1.24(1H, dd, H-3a, J_3a,3b

=

5.5, J_3a,2=5.5 Hz), 1.26 (3H, t, –NCH₂CH₃, J=7.1 Hz),

2.16 (1H, m, H-3b), 2.23 (1H, dd, H-3b, J_3b,3a=5.5,

J_3b,2=9.5 Hz), 2.84(1H, ddd, H-1 ⁰a, J_{1 a,OH}=1.5,

0

J_{1 a,2}=12.0, J_{1 a, 1 b}=12.0 Hz), 3.23 (1H, m, –NCH₂CH₃),

0

3.47–3.58 (2H, m, –NCH₂CH₃), 3.85 (1H, dd, –OH,

0

As a result, all of the newly synthesized compounds

were completely inactive in this system, which explains

the absence of aﬃnity for the nerve terminal 5-HT-

transporter when a substitution is introduced at the

1-phenyl moiety. The selectivity index [5-HT uptake

inhibition (Ki)/NMDA receptor binding (IC₅₀)] of the

ﬂuoro derivatives 4b and 4c surpassed that of PPDC.

J_{OH,1 a}= 1.5, J_{OH,1 b}=12.0 Hz), 3.91–4.00 (2H, m,

–NCH₂CH₃and H-1⁰), 7.56 (2H, dd, H-3⁰⁰and H-5⁰⁰,

J=7.5, J=7.5 Hz), 7.67 (1H, dd, H-4⁰⁰, J=7.5,

J=7.5 Hz), 7.86 (2H, d, H-2⁰⁰and H-6⁰⁰, J=7.5 Hz);

¹³C NMR (67.8 MHz, CDCl₃) d 12.02 (–NCH₂CH₃),

13.48 (–NCH₂CH₃), 15.89 (C-3), 28.09 (C-2), 40.06

(–NCH₂CH₃), 43.13 (–NCH₂CH₃), 49.35 (C-1), 62.63

(C-1⁰), 128.75 (C-2⁰⁰and C-6⁰⁰), 128.79 (C-3⁰⁰and C-5⁰⁰),

133.96 (C-4⁰⁰), 137.86 (C-1⁰⁰), 163.56 (C¼O); HR-MS

(EI) calcd C₁₅H₂₁NO₄S 311.1191; obs 311.1203 (M⁺).

Anal. calcd for C₁₅H₂₁NO₄S: C, 57.86; H, 6.80; N, 4.50;

S, 10.30. Found: C, 57.67; H, 6.78; N, 4.42; S, 10.24.

Conclusion

We have synthesized a series of PPDC analogues mod-

iﬁed at the 1-phenyl moiety as novel NMDA receptor

antagonists. Analogue 6, which lacked the 1-phenyl

group, was completely inactive, while all of the other

synthesized analogues with an aromatic ring at the

1-position had aﬃnity for the receptor, indicating that

the aromatic moiety is essential for activity. The ortho-

and meta-ﬂuorophenyl derivatives 4b and 4c were iden-

tiﬁed as the most selective NMDA receptor antagonists

in this series of compounds. Further pharmacological

evaluations of 4b and 4c are now in progress.²⁰

(1R,2S)-1-Phenylsulfonyl-2-formyl-N,N-diethylcyclo-

propanecarboxamide (12). To a solution of oxalyl chloride

(6.11 mL, 70.0 mmol) in CH₂Cl₂(20 mL) was slowly

added a mixture of DMSO (9.93 mL, 140 mmol) and

CH₂Cl₂(10 mL) at ꢁ78 ^ꢂC, and then 11 (10.9 g,

35.0 mmol) in CH₂Cl₂(30 mL) was added dropwise. The

resulting mixture was stirred at the same temperature

for 2 h, and then Et₃N (39.4mL, 280 mmol) was added.

After being stirring at ꢁ78 ^ꢂC for further 30 min, the

reaction was quenched with saturated NH₄Cl, and then

CH₂Cl₂was added and partitioned. The organic layer

was washed with brine, dried (Na₂SO₄), and evapo-

rated. The residue was puriﬁed by column chromato-

graphy (silica gel; AcOEt/hexane 1:4) to give 12 as white

an oil (9.27 g, 85.6%): [a]²_D⁶ꢁ49.39 (c 1.166, CHCl₃); ¹H

NMR (270 MHz, CDCl₃) d 1.09 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.27 (4H, m, –NCH₂CH₃and H-3a), 2.11

(1H, m, H-3b), 3.27–3.49 (3H, m, –NCH₂CH₃), 3.86

(1H, m, –NCH₂CH₃), 7.57 (2H, m, aromatic), 7.65 (1H,

m, aromatic), 7.83 (2H, m, aromatic), 9.13 (1H, d, H-1⁰,

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,-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 (quartet),

m (multiplet), or br (broad). Mass spectra were measured

on a Jeol JMS-D300 spectrometer. Thin-layer chroma-

tography was done on Merck coated plate 60F₂₅₄. Silica

gel chromatography was done with Merck silica gel

5715. Reactions were performed under argon.

J_{1 ,2}=4.0 Hz); ¹³C NMR (67.8 MHz, CDCl3) d 12.56 (–

0

NCH₂CH₃), 14.00 (–NCH₂CH₃), 18.04(C-3), 33.28 (C-

2), 40.42 (–NCH₂CH₃), 43.38 (–NCH₂CH₃), 54.22 (C-1),

128.79 (C-2⁰⁰and C-6⁰⁰), 129.47 (C-3⁰⁰and C-5⁰⁰), 134.83

(C-4⁰⁰), 137.75 (C-1⁰⁰), 160.41 (C¼O), 195.04(C-1 ⁰); HR-

MS (EI) calcd C₁₅H₁₉NO₄S 309.1035; obs 309.1044

(M⁺). Anal. calcd for C₁₅H₁₉NO₄S: C, 58.23; H, 6.19; N,

4.53; S, 10.36. Found: C, 58.06; H, 6.19; N, 4.46; S, 10.32.

(1R,2S)-1-Phenylsulfonyl-2-(hydroxymethyl)-N,N-diethyl-

cyclopropanecarboxamide (11). To a mixture of 9

(35.7 g, 150 mmol) and AlCl₃(40.0 g, 300 mmol) in

CH₂Cl₂(400 mL) was added Et₂NH (62.7 mL,

(1R,2S)-1-Phenylsulfonyl-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (13) and (1R,2S)-1-

Phenylsulfonyl-2-[(R)-1-hydroxypropyl]-N,N-diethylcyclo-

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3835

propanecarboxamide (14). A mixture of 12 (7.43 g,

24.0 mmol) and EtMgBr (0.95 M in THF, 100 mL,

95.0 mmol) in THF (10 mL) was stirred at ꢁ20 ^ꢂC for

5 h. The reaction was quenched with saturated NH₄Cl,

and the resulting mixture was concentrated in vacuo

(for removing THF and Et₂O), to which AcOEt and

H₂O was added and partitioned. The organic layer was

washed with brine, dried (Na₂SO₄), and evaporated The

reside was puriﬁed by column chromatography (silica

gel; AcOEt/hexane 1:4) to give 13 as an oil (4.26 g,

52.3%) and 14 as an oil (1.57 g, 19.3%). 13: mp (hexane,

AcOEt, CHCl₃) 95 ^ꢂC; [a]_D²⁰ꢁ45.57 (c 1.055, CHCl₃); ¹H

white crystals (2.14g, 29%). 15: mp (hexane, AcOEt,

CHCl₃, Et₂O, H₂O) 73–74 ^ꢂC; [a]²_D⁶ꢁ71.07 (c 1.135,

CHCl₃); ¹H NMR (270MHz, CDCl₃) d 0.88 (3H, t, H-3⁰,

0

J_{3 ,}₂=7.4Hz), 1.14 (3H, t, –NCH CH₃, J=7.1 Hz),

2

1.24(3H, t, –NCH ₂CH₃, J=7.0 Hz), 1.44 (1H, m, H-2⁰a),

1.52–1.67 (2H, m, H-3a and H-2⁰b), 1.79 (1H, m, H-2),

2.21 (1H, dd, H-3b, J_3b,3a=5.8, J_3b,2=9.7 Hz), 3.17–

3.27 (2H, m, –NCH₂CH₃and H-1⁰), 3.34–3.58 (2H, m,

–NCH₂CH₃), 3.89 (1H, m, –NCH₂CH₃), 7.54(2H, m,

aromatic), 7.65 (1H, m, aromatic), 7.80 (2H, m, aromatic);

¹³C NMR (67.8 MHz, CDCl₃) d 10.17 (C-3⁰), 12.19

(–NCH₂CH₃), 13.55 (–NCH₂CH₃), 15.69 (C-3), 28.14

(C-2⁰), 28.38 (C-2), 39.93 (–NCH₂CH₃), 42.81

(–NCH₂CH₃), 47.42 (C-1), 62.23 (C-1⁰), 128.73 (C-2⁰⁰

and C-6⁰⁰), 128.88 (C-3⁰⁰and C-5⁰⁰), 133.93 (C-4⁰⁰),

138.17 (C-1⁰⁰), 161.76 (C¼O); HR-MS (EI) calcd

C₁₇H₂₅N₄O₃S 365.1647; obs 365.1654 (M+1)⁺. Anal.

calcd for C₁₇H₂₄N₄O₃S: C, 56.02; H, 6.64; N, 15.37; S,

8.80. Found: C, 55.98; H, 6.60; N, 15.10; S, 8.80. 16: mp

(hexane, AcOEt, CHCl₃, Et₂O, H₂O) 88–89 ^ꢂC; [a]_D²⁶

0

,

NMR (500 MHz, CDCl₃)

d

0.94(3H, t, H-3

0

J_{3 ,2}=7.5 Hz), 1.13 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.22

(1H, dd, H-3a, J_3a,3b=5.8, J_3a,2=5.8 Hz), 1.26 (3H, m,

–NCH₂CH₃, J=7.1 Hz), 1.54–1.68 (2H, m, H-2⁰), 1.90

0

(1H, ddd, H-2, J_2,3a=5.8, J_2,3b=9.6, J_2,1=9.6 Hz), 2.23

(1H, dd, H-3b, J_3b,3a=5.8, J_3b,2=9.6 Hz), 2.74(1H, m,

H-1⁰), 3.20 (1H, m, –NCH₂CH₃), 3.49–3.58 (2H, m,

–NCH₂CH₃), 3.97 (1H, m, –NCH₂CH₃), 4.42 (1H, d,

00

–OH, J_OH,1=0.6 Hz), 7.55 (2H, dd, H-3 and H-5⁰⁰,

ꢁ67.98 (c 1.110, CHCl₃); ¹H NMR (270 MHz, CDCl₃) d

0

J=7.5, J=7.8 Hz), 7.65 (1H, dd, H-4⁰⁰, J=7.5, J=

7.5Hz), 7.85 (2H, d, H-2⁰⁰and H-6⁰⁰, J=7.8 Hz); ¹³C NMR

(67.8 MHz, CDCl₃) d 9.98 (C-3⁰), 12.02 (–NCH₂CH₃),

13.52 (–NCH₂CH₃), 16.12 (C-3), 28.65 (C-2⁰), 32.29 (C-2),

40.02 (–NCH₂CH₃), 43.07 (–NCH₂CH₃), 48.34 (C-1),

73.71 (C-1⁰), 128.79 (C-2⁰⁰and C-6⁰⁰), 129.22 (C-3⁰⁰and

C’-5), 133.98 (C-4⁰⁰), 137.83 (C-1⁰⁰), 163.70 (C¼O);

HR-MS (EI) calcd C₁₇H₂₅NO₄S 339.1504; obs 339.1516

(M⁺). Anal. calcd for C₁₇H₂₅NO₄S: C, 60.15; H,7.42;

N, 4.13; S, 9.45. Found: C, 60.19; H,7.36; N, 3.97; S,

9.37. 14: [a]²_D⁵ꢁ83.54( c 0.505, CHCl₃); ¹H NMR

0.94(3H, t, H-3

0

0 0

, J_{3 , 2}=7.4Hz), 1.13 (3H, t,

–NCH₂CH₃J=7.1 Hz), 1.23–1.36 (4H, m, –NCH₂CH₃

and H-3a), 1.53–1.62 (2H, m, H-2⁰), 1.91 (1H, br, H-2),

2.17 (1H, br, H-3b), 2.93 (1H, br, H-1⁰), 3.27 (1H, m,

–NCH₂CH₃), 3.42–3.54 (2H, m, –NCH₂CH₃), 3.96 (1H,

m, –NCH₂CH₃), 7.54(2H, m, aromatic), 7.65 (1H, m,

aromatic), 7.86 (2H, m, aromatic); ¹³C NMR

(67.8 MHz, CDCl₃) d 10.19 (C-3⁰), 12.15 (–NCH₂CH₃),

13.61 (–NCH₂CH₃), 15.85 (C-3), 27.46 (C-2⁰), 29.98

(C-2), 40.22 (–NCH₂CH₃), 43.27 (–NCH₂CH₃), 49.45

(C-1), 62.39 (C-1⁰), 128.77 (C-2⁰⁰and C-6⁰⁰), 129.22 (C-3⁰⁰

and C-5⁰⁰), 134.34 (C-4⁰⁰), 138.58 (C-1⁰⁰), 162.08 (C¼O);

HR-MS (EI) calcd C₁₇H₂₄N₄O₃S 364.1569; obs 364.1595.

Anal. calcd for C₁₇H₂₄N₄O₃S: C, 56.02; H,6.64; N, 15.37;

S, 8.80. Found: C, 55.95; H, 6.64; N, 15.24; S, 8.84.

(270 MHz, CDCl₃) d 0.90 (3H, t, H-3⁰, J_{3 , 2}=7.4Hz),

1.12 (3H, t, –NCH₂CH₃, J=7.0 Hz), 1.24(3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.37 (1H, m, H-2⁰a), 1.46 (1H,

0

m, H-2⁰b) 1.62 (1H, dd, H-3a, J_3a,3b=5.3, J_3a,2

=

7.6 Hz), 1.84(1H, m, H-3b), 2.05–2.12 (2H, m, –OH

and H-2), 3.24(1H, m,-NCH CH₃), 3.41–3.52 (2H, m,

(1R,2S)-1-Phenylsulfonyl-2-[(S)-1-aminopropyl]-N,N-di-

ethylcyclopropanecarboxamide Hydrochloride (10). A

mixture of 15 (500 mg, 1.37 mmol) and 10% Pd-char-

coal (100 mg) in MeOH (10 mL) was stirred under

atmospheric pressure of hydrogen at room temperature

for 15h, and then the catlayst was ﬁltered oﬀ. The ﬁltrate

was evaporated, and the residue was puriﬁed by column

chromatography (silica gel; CHCl₃/MeOH 10:1) to give

2

–NCH₂CH₃), 3.78 (1H, m, H-1⁰), 3.94(1H, m,

–NCH₂CH₃), 7.54(2H, m, aromatic), 7.65 (1H, m,

aromatic), 7.82 (2H, m, aromatic); ¹³C NMR

(67.8 MHz, CDCl₃) d 9.81 (C-3⁰), 11.97 (–NCH₂CH₃),

13.37 (–NCH₂CH₃), 14.02 (C-3), 29.11 (C-2⁰), 30.42

(C-2), 39.93 (–NCH₂CH₃), 43.16 (–NCH₂CH₃), 46.87

(C-1), 67.66 (C-1⁰), 128.63 (C-2⁰⁰and C-6⁰⁰), 129.20 (C-3⁰⁰

00

and C-5⁰⁰), 133.64(C-4 ), 138.53 (C-1⁰⁰), 163.70 (C¼O);

the free amine of 10 as an oil (456 mg, 99%): H NMR

(270 MHz, CDCl₃) d 0.91 (3H, t, H-3⁰, J_{3 , 2}=7.6 Hz),

1

0

HR-MS (EI) calcd C₁₇H₂₅NO₄S 339.1504; obs 339.1505

(M⁺). Anal. calcd for C₁₇H₂₅NO₄S: C, 60.15; H,7.42; N,

4.13; S, 9.45. Found: C, 59.95; H,7.35; N, 4.02; S, 9.30.

1.14(3H, t, –NCH CH₃J=7.0 Hz), 1.19–1.26 (4H, m,

2

–NCH₂CH₃and H-3a), 1.36–1.74(5H, m, H-2 and H-2 ⁰

and –NH₂), 2.00 (1H, m, H-1⁰), 2.21 (1H, dd, H-3b, J_3b,3a

=

(1R,2S)-1-Phenylsulfonyl-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (15) and (1R,2S)-1-Phenyl-

sulfonyl-2-[(R)-1-azidopropyl]-N,N-diethylcyclopropane-

carboxamide (16). A mixture of 15 (289 mg, 1.00 mmol),

PPh₃(787 mg, 3.00 mmol), and CBr₄(995 mg,

3.00 mmol) in HMPA (10 mL) was stirred at 0 ^ꢂC for

30 min. After addition of NaN₃(650 mg, 10.0 mmol),

the resulting mixture was stirred at room temperature

for 8 h, and then AcOEt and H₂O were added and par-

titioned. The organic layer was washed with brine, dried

(Na₂SO₄), and evaporated. The reside was puriﬁed by

ﬂash column chromatography (silica gel; AcOEt/hexane

1:9) to give 16 as white crystals (3.95 g, 54%) and 15 as

5.6, J_3b,2=9.9 Hz), 3.21 (1H, m, –NCH₂CH₃), 3.41–3.54

(2H, m, –NCH₂CH₃), 3.95 (1H, m, –NCH₂CH₃), 7.55

(2H, m, aromatic), 7.64(1H, m, aromatic), 7.86 (2H, m,

aromatic); HR-MS (EI) calcd C₁₇H₂₇N₂O₃S 339.1742;

obs 339.1728 (M+1)⁺. Anal. calcd for C₁₇H₂₆N₂O₃S:

C, 60.33; H, 7.74; N, 8.28; S, 9.47. Found: C, 60.01; H,

7.61; N, 8.09; S, 9.58. A solution of the free amine of 10

(338 mg, 1.00 mmol) in MeOH was put on a column of

Diaion WA-30 resin (Cl^ꢁform), and the column was

developed with MeOH. The solvent was evaporated,

and the residue was treated with i-Pr₂O to give hydro-

chloride of 10 as white crystals (372 mg, quant): mp

(hexane, AcOEt, CHCl₃, Et₂O) 224–225.5 ^ꢂC; [a]_D²⁸ꢁ37.84

3836

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

1

(c 1.065, MeOH); H NMR (500MHz, CD₃OD) d 0.96

aromatic, J=7.0, J=7.0 Hz), 7.23 (6H, dd, aromatic,

J=7.0, J=8.0 Hz), 7.54(6H, d, aromatic, J=8.0 Hz);

¹³C NMR (125 MHz, CDCl₃) d 9.69 (C-3⁰), 13.24

(–NCH₂CH₃), 14.68 (C-3), 14.79 (–NCH₂CH₃), 17.50

(C-2), 27.27 (C-1), 28.38 (C-2⁰), 40.68 (–NCH₂CH₃),

41.79 (–NCH₂CH₃), 57.15 (C-1⁰), 71.24(– CPh₃), 126.16,

127.59, 128.84, 147.00 (the above mentioned, aromatic),

172.02 (C¼O); HR-MS (EI) calcd C₃₀H₃₆N₂O 440.2828;

obs 440.2839 (M⁺).

(3H, t, H-3⁰, J_{3 , 2}=7.5Hz), 1.01 (3H, t, –NCH₂CH₃,

J=7.1Hz), 1.11 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.60

(1H, dd, H-3a, J_3a,3b=6.5, J_3a,2=6.5 Hz), 1.76 (1H, m,

H-2⁰), 1.95 (1H, ddd, H-2, J_2,3a=6.5, J_2,3b=9.8,

0

J_2,1=9.8 Hz), 2.22 (1H, dd, H-3b, J_3b,3a=6.5,

J_3b,2=9.8 Hz), 2.45 (1H, m, H-1⁰), 3.09 (1H, m,

–NCH₂CH₃), 3.23 (1H, m, –NCH₂CH₃), 3.45 (1H, m,

–NCH₂CH₃), 3.57 (1H, m, –NCH₂CH₃), 7.59 (2H, dd,

H-3⁰⁰and H-5⁰⁰, J=7.5, J=7.5 Hz), 7.71 (1H, dd, H-4⁰⁰,

J=7.5, J=7.5 Hz), 7.79 (2H, d, H-2⁰⁰and H-6⁰⁰,

J=7.5 Hz); ¹³C NMR (67.8 MHz, CD₃OD) d 10.29 (C-

3⁰), 12.49 (–NCH₂CH₃), 13.48 (–NCH₂CH₃), 18.42 (C-

3), 27.15 (C-2⁰), 27.58 (C-2), 41.51 (–NCH₂CH₃), 44.67 (–

NCH₂CH₃), 50.33 (C-1), 55.92 (C-1⁰), 130.31 (C-2⁰⁰and

C-6⁰⁰), 130.74(C-3 ⁰⁰and C-5⁰⁰), 135.88 (C-4⁰⁰), 138.70 (C-

1⁰⁰), 164.70 (C¼O); HR-MS (FAB) calcd C₁₇H₂₇N₂O₃S

339.1742; obs 339.1760 (M-Cl)⁺. Anal. calcd for

C₁₇H₂₇ClN₂O₃S: C, 54.46; H, 7.26; Cl, 9.46; N, 7.47; S,

8.55. Found: C, 54.35; H, 7.12; Cl, 9.52; N, 7.52; S, 8.63.

(1S,2R)-2-[(S)-1-Aminopropyl]-N,N-diethylcyclopropane-

carboxamide Hydrochloride (6). A solution of 17

(100 mg, 227 mol) in MeOH (3.0 mL) and 1 N HCl

(2.0 mL) was stirred at room temperature for 1 h. The

solvent was evaporated, and the residue was partitioned

between H₂O and AcOEt. The aqueous layer was

washed with Et₂O and evaporated, and the residue was

puriﬁed by column chromatography (silica gel; AcOEt/

hexane 1:1 then MeOH/CHCl₃1:9) to give the hydro-

chloride of 6 as a solid (53 mg, 99%): [a]²_D³+65.82 (c

1

0.165, MeOH); H NMR (500 MHz, CD₃OD) d 0.80

(3H, br, H-3a), 1.00 (3H, t, H-3⁰, J_{3 , 2}=7.4Hz) 1.04(3H,

t, –NCH₂CH₃, J=7.0 Hz), 1.16 (3H, t, –NCH₂CH₃,

J=7.0 Hz), 1.21–1.29 (2H, m, H-2 and H-3b), 1.68–1.78

(2H, m, H-2⁰), 1.92 (1H, m, H-1⁰), 3.07 (1H, m, H-1⁰),

3.26 (1H, m, –NCH₂CH₃), 3.36 (1H, m, –NCH₂CH₃),

3.50 (2H, m, –NCH₂CH₃); NOE (400 MHz, CD₃OD)

35.2% (H-1!–NCH₂CH₃), 20.0% (H-1!–NCH₂CH₃),

3.4% (H-1!H-2), 1.7% (H-1!H-3a); ¹³C NMR

(125 MHz, CD₃OD) d 10.48 (C-3⁰), 13.17 (–NCH₂CH₃),

13.66 (C-3), 14.50 (–NCH₂CH₃), 17.96 (C-2), 22.46 (C-1),

0

(1S,2R)-2-[(S)-1-Triphenylmethylaminopropyl]-N,N-di-

ethylcyclopropanecarboxamide (17) and (1R,2R)-2-[(S)-

1-Triphenylmethylaminopropyl]-N,N-diethylcyclopropane-

carboxamide (18). A mixture of Mg turnings (100 mg) in

dry MeOH (10 mL) was heated to 55 ^ꢂC with stirring

until gas evolution started (15 min). To the mixture a

solution of 10 (135 mg, 0.40 mmol) in dry MeOH

(10 mL) was added in one portion and the resulting

mixture was stirred at 0 ^ꢂC for 36 h. The resulting mix-

ture was ﬁltered through Celite, the ﬁltrate was evapo-

0

rated.

A

mixture of the residue, TrCl (167 mg,

28.14(C-2 ), 41.81 (–NCH₂CH₃), 43.91 (–NCH₂CH₃),

0.60 mmol), Et₃N (83.6 mL, 0.60 mmol) and DMAP

(9.80 mg, 8.00 mmol) in CH₂Cl₂(10 mL) was stirred at

room temperature for 24h, and the reaction was quen-

ched with MeOH. The resulting mixture was con-

centrated in vacuo (for removing methanol), and the

residue was partitioned between H₂O and AcOEt. The

organic layer was washed with brine, dried (Na₂SO₄)

and evaporated. The residue was puriﬁed by column

chromatography (silica gel; AcOEt/hexane 1:4) to give

17 (44 mg, 25%) and 18 (29 mg, 17%) as yellow solids.

17: ¹H NMR (500 MHz, CDCl₃) d 0.46 (3H, t, H-3⁰, J_{3 ,}

0

₂=7.4Hz), 0.77 (3H, t, –NCH ₂CH₃, J=7.1 Hz), 0.94

(1H, m, H-3a), 1.05 (1H, m, H-2), 1.17–1.23 (5H, t,

–NCH₂CH₃and H-3b and H-2⁰a), 1.43 (1H, m, H-2⁰b),

1.62 (1H, m, H-1), 1.87 (1H, brs, –NH–), 2.06

(1H, dt, H-1⁰, J_{1 , 2}=2.2, J_{1 , 2}=9.0 Hz), 3.07

(1H, m, –NCH₂CH₃), 3.15 (2H, m, –NCH₂CH₃), 3.71

(1H, m, –NCH₂CH₃), 7.13 (3H, dd, aromatic, J=7.0,

J=7.0 Hz), 7.23 (6H, dd, aromatic, J=7.0, J=8.0 Hz),

7.46 (6H, d, aromatic, J=8.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 10.56 (C-3⁰), 11.57 (C-3), 12.92 (–NCH₂CH₃),

14.72 (–NCH₂CH₃), 15.57 (C-2), 28.33 (C-2⁰), 28.38

(C-1), 40.39 (–NCH₂CH₃), 42.08 (–NCH₂CH₃), 54.94

(C-1⁰), 70.44 (–CPh₃), 125.95, 127.33, 129.40, 146.90

(the above mentioned, aromatic), 169.60 (C¼O); HR-MS

(EI) calcd C₃₀H₃₆N₂O 440.2828; obs 440.2830 (M⁺). 18:

¹H NMR (500 MHz, CDCl₃) d 0.59 (1H, m, H-3a),

0.66–0.71 (4H, m, H-3⁰and H-2), 1.02–1.15 (8H, m,

–NCH₂CH₃Â6 and H-3b and H-1), 1.70 (2H, m, H-2⁰),

1.81 (1H, m, H-1⁰), 1.84(1H, m, –NH–), 3.23 (2H,

m, –NCH₂CH₃), 3.35 (2H, m, –NCH₂CH₃), 7.15 (3H, dd,

55.32 (C-1⁰), 172.89 (C¼O); HR-MS (EI) calcd

C₁₁H₂₂N₂O 198.1732; obs 198.1739 (M–HCl)⁺. Anal.

.

calcd for C₁₁H₂₃ClN₂O 3H₂O: C, 45.75; H, 10.12; N,

9.70. Found: C, 45.36; H, 10.01; N, 9.44.

(1R,2R)-2-[(S)-1-Aminopropyl]-N,N-diethylcyclopropane-

carboxamide Hydrochloride (19). Compound 19 was

prepared from 18 in 60% yield as described above for 6:

[a]²_D²ꢁ69.10 (c 0.210, MeOH); ¹H NMR (500 MHz,

CD₃OD) d 0.92 (1H, m, H-3a), 0.95–1.02 (7H, m,

–NCH₂CH₃and H-3⁰and H-3b), 1.19 (1H, m,

–NCH₂CH₃, J=7.1 Hz), 1.53 (1H, m, H-2), 1.70 (2H,

m, H-2⁰), 2.01 (1H, m, H-1), 2.56 (1H, m, H-1⁰), 3.23

(1H, m, –NCH₂CH₃), 3.30–3.42 (2H, m, –NCH₂CH₃),

3.69 (1H, m, –NCH₂CH₃); ¹³C NMR (125 MHz,

CD₃OD) d 10.48 (C-3⁰), 13.32 (–NCH₂CH₃), 14.67 (C-

3), 14.91 (–NCH₂CH₃), 18.09 (C-2), 23.44 (C-1), 27.70

(C-2⁰), 42.33 (–NCH₂CH₃), 43.59 (–NCH₂CH₃), 57.44

(C-1⁰), 172.86 (C¼O); NOE (400 MHz, CD₃OD) 5.7%

(H-1!H-3a), 3.1% (H-1!H-1⁰), 2.9% (H-1!–

NCH₂CH₃); HR-MS (EI) calcd C₁₁H₂₂N₂O 199.1810;

0

obs

199.1826

.

(MꢁHCl)⁺.

Anal.

calcd

for

C₁₁H₂₃ClN₂O H₂O: C, 52.27; H, 9.97; N, 11.08. Found:

C, 52.64; H, 9.42; N, 10.84.

(1R,4S,5S)-2-Oxo-4-ethyl-1-phenylsulfonyl-3-oxabicyclo

[3.1.0]hexane (22). A solution of 13 (169 mg, 0.50 mmol)

in MeOH (5 mL) and 6 N HCl (5 mL) was heated under

reﬂux for 2 h. The solvent was evaporated, and then the

residue was partitioned between saturated aqueous

NaHCO₃and AcOEt. The organic layer was washed

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3837

with brine, dried (Na₂SO₄) and evaporated. The residue

was puriﬁed by column chromatography (silica gel;

AcOEt/hexane 1:4) to give 22 as white crystals (106 mg,

80%): mp (hexane, AcOEt, H₂O) 84.5–85^ꢂC; [a]_D²⁴ꢁ92.30

(c 1.160, CHCl₃); ¹H NMR (270MHz, CDCl₃) d 0.92 (3H,

(1S,5R)-2-Oxo-1-(3-ﬂuorophenyl)-3-oxabicyclo[3.1.0]-

hexane (25c). Compound 25c with 96% ee (CHIR-

ALPAK AD-RH, 0.46Â15 cm, Daicel; H₂O/CH₃CN,

4:1; 0.5 mL/min; 265 nm) was obtained as an oil in 63%

yield: [a]²_D³ꢁ91.96 (c 1.390, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 1.38 (1H, dd, H-6a, J_6a,6b=5.0,

t, H-2⁰, J_{2 , 1}=7.3 Hz), 1.44 (1H, dd, H-6a, J_6a,6b=5.3,

J_6a,5=5.3 Hz), 1.66 (2H, m, H-1⁰), 2.15 (1H, dd, H-6b,

J_6b,6a=5.3, J_6b,5=8.6 Hz), 2.89 (1H, dd, H-5, J_5,6a=5.3,

0

J_6a,5=5.0 Hz), 1.62 (1H, dd, H-6b, J_6b,6a=5.0, J_6b,5

=

7.9 Hz), 2.59 (1H, ddd, H-5, J_5,4b=4.7, J_5,4a=5.0,

J_5,6b=7.9 Hz), 4.27 (1H, d, H-4a, J_4a,4b=9.3 Hz), 4.44

(1H, dd, H-4b, J_4b,5=4.7, J_4b,4a=9.3 Hz), 6.97 (1H, m,

aromatic), 7.18 (2H, m, aromatic), 7.30 (1H, m, aro-

matic); ¹³C NMR (125 MHz, CDCl₃) d 20.59 (C-6),

25.31 (C-5), 31.09 (C-1), 67.88 (C-4, J_C,F=5 Hz), 114.44

(C-4⁰, J_C,F=21 Hz), 115.21 (C-2⁰, J_C,F=21 Hz), 123.50

(C-6⁰, J_C,F=3 Hz), 130.02 (C-5⁰, J_C,F=9 Hz), 136.59 (C-1⁰,

J_C,F=8 Hz), 162.63 (C-3⁰, J_C,F=244 Hz), 175.30 (C¼O);

HR-MS (EI) calcd C₁₁H₉FO₂192.0586; obs 192.0588

(M⁺). Anal. calcd for C₁₁H₉FO₂: C, 68.74; H, 4.72.

Found: C, 68.75; H, 4.86.

0

J_5,6b=8.6 Hz), 4.24 (1H, t, H-4, J_4,1= 6.3 Hz), 7.59 (2H,

m, H-3⁰⁰and H-5⁰⁰), 7.67 (1H, m, H-4⁰⁰), 8.03 (2H, m, H-2⁰⁰

and H-6⁰⁰); HR-MS (EI) calcd C₁₃H₁₄O₄S 266.0613; obs

266.0594(M ⁺). Anal. calcd for C₁₃H₁₄O₄S: C, 58.62; H,

5.30; S, 12.04. Found: C, 58.57; H, 5.39; S, 12.04.

(1R,4R,5S)-2-Oxo-4-ethyl-1-phenylsulfonyl-3-oxabicyclo

[3.1.0]hexane (23). Compound 23 was prepared from 14

in 59% yield as described above for 22: mp (hexane,

AcOEt, H₂O) 113 ^ꢂC; [a]_D²⁵ꢁ111.60 (c 1.160, CHCl₃);

0

¹H NMR (270 MHz, CDCl₃) d 1.00 (3H, t, H-2 , J_{2 , 1}

0

=

7.3 Hz), 1.49 (1H, dd, H-6a, J_6a,6b=5.3, J_6a,5=5.3 Hz),

1.53 (1H, m, H-1⁰a), 1.67 (1H, m, H-1⁰b), 2.02 (1H, dd,

H-6b, J_6b,6a=5.3, J_6b,5=8.6 Hz), 3.12 (1H, ddd, H-5,

J_5,4=4.6, J_5,6a=5.3, J_5,6b=8.6 Hz), 4.52 (1H, dt, H-4,

(1S,5R)-2-Oxo-1-(4-ﬂuorophenyl)-3-oxabicyclo[3.1.0]-

hexane (25d). Compound 25d with 94% ee (CHIR-

ALPAK AD-RH, 0.46Â15 cm, Daicel; H₂O/CH₃CN,

4:1; 0.5 mL/min; 265 nm) was obtained as an oil in 34%

yield: [a]²_D²ꢁ60.44 (c 1.205, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 1.35 (1H, dd, H-6a, J_6a,6b=4.9,

0

J_4,5=4.6, J_4,1=6.6 Hz), 7.61 (2H, m, aromatic), 7.69

(1H, m, aromatic), 8.07 (2H, m, aromatic); HR-MS (EI)

calcd C₁₃H₁₄O₄S 266.0613; obs 266.0621 (M⁺). Anal.

calcd for C₁₃H₁₄O₄S: C, 58.62; H, 5.30; S, 12.04. Found:

C, 58.55; H, 5.38; S, 11.86.

J_6a,5=4.9 Hz), 1.59 (1H, dd, H-6b, J_6b,6a=4.9, J_6b,5

=

7.8 Hz), 2.54(1H, ddd, H-5, J_5,4b=4.7, J_5,6a=4.9,

J_5,6b=7.8 Hz), 4.27 (1H, d, H-4a, J_4a,4b=9.3 Hz), 4.45

(1H, dd, H-4b, J_4b,5=4.7, J_4b,4a=9.3 Hz), 7.01–7.06

(2H, m, aromatic), 7.37–7.40 (2H, m, aromatic); ¹³C

NMR (125 MHz, CDCl₃) d 20.10 (C-6), 24.87 (C-5),

31.14 (C-1), 68.01 (C-4), 115.43 (C-3⁰and C-5⁰,

General procedure for preparing lactones 25b–i. To a

suspension of NaNH₂(858 mg, 22.0 mmol) in benzene

(20 mL) was added slowly a solution of phenylacetoni-

trile (24b–i, 10.0 mmol) in benzene (10 mL) at 0 ^ꢂC, and

the mixture was stirred at room temperature for 2 h.

(R)-epichlorohydrin was added to the resulting mixture

at 0 ^ꢂC, and the whole was stirred at room temperature

for 2 h. After the solvent was evaporated, AcOEt was

added to residue. Insoluble salts were ﬁltered oﬀ, and

the ﬁltrate was washed with brine, dried (Na₂SO₄), and

evaporated. The residue was puriﬁed by column chro-

matography (silica gel; AcOEt/hexane, 1:4) to give 25b–i

as an oil or crystals.

0

J_C,F=21 Hz), 129.87 (C-1⁰, J_C,F=3 Hz), 130.14(C-2

and C-6⁰, J_C,F=9 Hz), 162.16 (C-4⁰, J_C,F=245 Hz),

175.85 (C¼O); HR-MS (EI) calcd C₁₁H₉FO₂192.0586;

obs 192.0603 (M⁺). Anal. calcd for C₁₁H₉FO₂: C,

68.74; H, 4.72. Found: C, 68.53; H, 4.82.

(1S,5R)-2-Oxo-1-(2-methylphenyl)-3-oxabicyclo[3.1.0]-

hexane (25e). Compound 25e with 94% ee (CHIR-

ALPAK AD-RH, 0.46Â15 cm, Daicel; H₂O/CH₃CN,

4:1; 0.5 mL/min; 265 nm) was obtained as crystals in

28% yield: mp (hexane/AcOEt) 105–106 ^ꢂC; [a]_D²²+9.04

(1S,5R)-2-Oxo-1-(2-ﬂuorophenyl)-3-oxabicyclo[3.1.0]-

hexane (25b). Compound 25b with 96% ee (CHIR-

ALCEL OJ, 0.46Â25 cm, Daicel; hexane/EtOH, 4:1;

0.5 mL/min; 265 nm) was obtained as crystals in 28%

yield: mp (hexane, AcOEt) 82 ^ꢂC; [a]_D²³ꢁ20.55 (c 1.080,

1

(c 1.105, CHCl₃); H NMR (500 MHz, CDCl₃) d 1.34

(1H, dd, H-6a, J_6a,6b=4.7, J_6a,5=4.7 Hz), 1.64 (1H, dd,

H-6b, J_6b,6a=4.7, J_6b,5=7.8 Hz), 2.37 (3H, s, Me-Ph-),

2.38 (1H, ddd, H-5, J_5,4b=4.5, J_5,6a=4.7, J_5,6b=

1

CHCl₃); H NMR (500 MHz, CDCl₃) d 1.32 (1H, dd,

7.8 Hz), 4.31 (1H, d, H-4a, J_4a,4b=9.3 Hz), 4.52 (1H, dd,

H-4b, J_4b,5=4.5, J_4b,4a=9.3 Hz), 7.15–7.24(H4, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 18.26 (C-6),

19.44 (Me-Ph-), 24.59 (C-5), 31.82 (C-1), 68.22 (C-4),

125.96, 128.39, 130.29, 130.34, 132.44, 138.81 (the above

mentioned, aromatic), 175.90 (C¼O); HR-MS (EI)

calcd C₁₂H₁₂O₂188.0837; obs 188.0823 (M⁺). Anal.

calcd for C₁₂H₁₂O₂: C, 76.57; H, 6.43. Found: C, 76.73;

H, 6.55.

H-6a, J_6a,6b=5.0, J_6a,5=5.0 Hz), 1.70 (1H, dd, H-6b,

J_6b,6a=5.0, J_6b,5=7.8 Hz), 2.43 (1H, ddd, H-5,

J_5,4b=4.6, J_5,6a=5.0, J_5,6b=7.8 Hz), 4.29 (1H, d, H-4a,

J_4a,4b=9.3 Hz), 4.52 (1H, dd, H-4b, J_4b,5=4.6, J_4b,4a

=

9.3 Hz), 7.06 (1H, m, aromatic), 7.13 (1H, m, aromatic),

7.27–7.36 (2H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 16.96 (C-6), 24.46 (C-5, J_C,F=5.5 Hz), 27.80

(C-1), 68.28 (C-4), 115.37 (C-3⁰,₀J_C,F=20 Hz), 115.21

(C-1⁰, J_C,F=14Hz), 124.14 (C-6 , J_C,F=4Hz), 130.02

(C-4⁰, J_C,F=9 Hz), 131.44 (C-5⁰, J_C,F=8 Hz), 162.03 (C-2⁰,

J_C,F=246 Hz), 175.42 (C¼O); HR-MS (EI) calcd

C₁₁H₉FO₂192.0586; obs 192.0589 (M⁺). Anal. calcd

for C₁₁H₉FO₂: C, 68.74; H, 4.72. Found: C, 68.97; H,

4.92.

(1S,5R)-2-Oxo-1-(3-methylphenyl)-3-oxabicyclo[3.1.0]-

hexane (25f). Compound 25f with 94% ee (CHIR-

ALPAK AD-RH, 0.46Â15 cm, Daicel; H₂O/CH₃CN,

4:1; 0.5 mL/min; 265 nm) was obtained as an oil in 46%

yield: [a]²_D³ꢁ76.21 (c 2.025, CHCl₃); ¹H NMR

3838

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

(500 MHz, CDCl₃) d 1.29 (1H, dd, H-6a, J_6a,6b=4.8,

J_6a,5=4.8 Hz), 1.60 (1H, dd, H-6b, J_6b,6a=4.8,

J_6b,5=7.8 Hz), 2.33 (3H, s, Me-Ph-), 2.50 (1H, ddd, H-5,

J_5,4b=4.6, J_5,6a=4.8, J_5,6b=7.8 Hz), 4.22 (1H, d, H-4a,

J_4a,4b=9.2 Hz), 4.40 (1H, dd, H-4b, J_4b,2=4.6,

J_4b,4a=9.2 Hz), 7.08 (1H, m, aromatic), 7.17–7.23 (3H,

m, aromatic); ¹³C NMR (125 MHz, CDCl₃) d 19.76

(C-6), 21.15 (Me–Ph–), 24.88 (C-5), 31.49 (C-1), 67.92

(C-4), 125.17, 128.23, 128.26, 128.97, 133.88, 138.01 (the

above mentioned, aromatic), 175.98 (C¼O); HR-MS

(EI) calcd C₁₂H₁₂O₂188.0837; obs 188.0851 (M⁺).

Anal. calcd for C₁₂H₁₂O₂: C, 76.57; H, 6.43. Found: C,

76.64; H, 6.51.

J_4b,4a=9.3 Hz), 7.43–7.48 (3H, m, aromatic), 7.78–7.81

(3H, m, aromatic), 7.88 (1H, d, aromatic, J=0.7 Hz);

¹³C NMR (125 MHz, CDCl₃) d 20.16 (C-6), 25.15 (C-5),

31.80 (C-1), 68.04(C-4), 125.92, 126.11, 126.28, 127.22,

127.53, 127.72, 128.29, 131.45, 132.59, 133.08 (the above

mentioned, aromatic), 175.95 (C¼O); HR-MS (EI)

calcd C₁₅H₁₂O₂224.0837; obs 224.0817 (M⁺). Anal.

calcd for C₁₅H₁₂O₂: C, 80.34; H, 5.39. Found: C, 80.38;

H, 5.47.

General procedure for preparing compounds 26b–i. To a

solution of 25b–i (5.00 mmol) and AlCl₃(1.33 g,

10.0 mmol) in CH₂Cl₂(10 mL) was slowly added Et₂NH

(2.08 mL, 20.0 mmol) at 0 ^ꢂC, and the resulting mixture

was stirred at room temperature for 8 h. The reaction

was quenched with 1 N HCl, and then CH₂Cl₂and H₂O

was added and partitioned. The organic layer was

washed with 1 N HCl and brine, dried (Na₂SO₄), eva-

porated. The residue was puriﬁed by column chroma-

tography (silica gel; AcOEt/hexane 1:4, 3:7, 1:2, and 1:1)

to give 26b–i.

(1S,5R)-2-Oxo-1-(4-methylphenyl)-3-oxabicyclo[3.1.0]-

hexane (25g). Compound 25g with 95% ee (CHIR-

ALCEL OJ, 0.46Â25 cm, Daicel; hexane/EtOH, 9:1;

0.5 mL/min; 265 nm) was obtained as an oil in 47%

yield: [a]²_D²ꢁ74.89 (c 2.075, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 1.24(1H, dd, H-6a, J_6a,6b=4.8,

J_6a,5=4.8 Hz), 1.54 (1H, dd, H-6b, J_6b,6a=4.8,

J_6b,5=7.8 Hz), 2.30 (3H, s, Me–Ph–), 2.45 (1H, ddd, H-

5, J_5,4b=4.7, J_5,6a=4.8, J_5,6b=7.8 Hz), 4.18 (1H, d, H-

4a, J_4a,4b=9.3 Hz), 4.36 (1H, dd, H-4b, J_4b,5=4.7,

J_4b,4a=9.3 Hz), 7.12 (2H, d, aromatic, J=8.0 Hz), 7.27

(2H, m, aromatic, J=8.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 19.64(C-6), 20.73 ( Me–Ph–), 24.70 (C-5),

31.14(C-1), 67.82 (C-4), 127.99, 128.90, 130.91, 136.99

(the above mentioned, aromatic), 175.99 (C¼O); HR-MS

(EI) calcd C₁₂H₁₂O₂188.0837; obs 188.0842 (M⁺).

Anal. calcd for C₁₂H₁₂O₂: C, 76.57; H, 6.43. Found: C,

76.46; H, 6.44.

(1S,2R)-1-(2-Fluorophenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26b). Compound 26b

was obtained as crystals quantitatively: mp (AcOEt,

23

Hexane) 63–64 ^ꢂC; [a]_D+42.79 (c 1.185, CHCl₃); H

NMR (500 MHz, CDCl₃) d 0.89 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.09 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.16

(1H, dd, H-3a, J_3a,3b=5.0, J_3a,2=5.0 Hz), 1.62–1.70

1

(2H, m, H-3b and H-2), 3.20 (1H, dd, H-1⁰a, J_{1 a,}

0

₂=10.0, J_{1 b, 1 a}=12.0 Hz), 3.28 (1H, m, –NCH₂CH₃),

0

3.38 (1H, m, –NCH₂CH₃), 3.63 (2H, m, –NCH₂CH₃),

4.04 (1H, dd, H-1⁰b, J_{1 b, 2}=4.5, J_{1 b, 1 a}=12.0 Hz), 7.00

(1H, m, aromatic), 7.11 (1H, m, aromatic), 7.22 (1H, m,

aromatic), 7.50 (1H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 12.34(–NCH ₂CH₃), 13.23 (–NCH₂CH₃),

16.66 (C-3, J_C,F=15 Hz), 29.57 (C-2), 30.63 (C-1), 39.89

(–NCH₂CH₃), 41.77 (–NCH₂CH₃), 64.35 (C-1⁰), 116.06

(C-3⁰⁰, J_C,F=23 Hz), 124.43 (C-6⁰⁰, J_C,F=4Hz), 127.22

(C-1⁰⁰, J_C,F=13 Hz), 128.86 (C-4⁰⁰, J_C,F=9 Hz), 131.26

(C-5⁰⁰, J_C,F=4Hz), 161.18 (C-2 ⁰⁰, J_C,F=248 Hz), 170.38

(C¼O); HR-MS (EI) calcd C₁₅H₂₀FNO₂265.1478; obs

265.1456 (M⁺). Anal. calcd for C₁₅H₂₀FNO₂: C, 67.90;

H, 7.60; N, 5.28. Found: C, 67.97; H, 7.64; N, 5.09.

0

(1S,5R)-2-Oxo-1-(1-naphthyl)-3-oxabicyclo[3.1.0]hexane

(25h). Compound 25h with 96% ee (CHIRALCEL OJ,

0.46Â25 cm, Daicel; hexane/EtOH, 3:2; 0.5 mL/min;

265 nm) was obtained as crystals in 50% yield: mp

(hexane, AcOEt, EtOH, CHCl₃) 172–173 ^ꢂC; [a]_D²⁴

1

+72.43 (c 1.555, CHCl₃); H NMR (500 MHz, CDCl₃)

d 1.53 (1H, dd, H-6a, J_6a,6b=4.8, J_6a,5=4.8 Hz), 1.76

(1H, dd, H-6b, J_6b,6a=4.8, J_6b,5=7.7 Hz), 2.54(1H,

ddd, H-5, J_5,6a=4.8, J_5,4b=5.0, J_5,6b=7.7 Hz), 4.45

(1H, d, H-4a, J_4a,4b=9.5 Hz), 4.74 (1H, dd, H-4b,

J_4b,5=5.0, J_4b,4a=9.5 Hz), 7.42–7.58 (4H, m, aromatic),

7.82–7.89 (2H, m, aromatic), 7.97 (1H, d, aromatic,

J=8.4Hz); ¹³C NMR (125 MHz, CDCl₃) d 18.71 (C-6),

24.75 (C-5), 31.29 (C-1), 68.36 (C-4), 124.05, 125.19,

126.05, 126.72, 128.48, 128.86, 129.26, 130.52, 132.67,

133.88 (the above mentioned, aromatic), 176.03 (C¼O);

HR-MS (EI) calcd C₁₅H₁₂O₂224.0837; obs 224.0837

(M⁺). Anal. calcd for C₁₅H₁₂O₂: C, 80.34; H, 5.39.

Found: C, 80.28; H, 5.34.

(1S,2R)-1-(3-Fluorophenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26c). Compound 26c

was obtained as crystals in 92% yield: mp (AcOEt,

22

Hexane) 75–76 ^ꢂC; [a]_D+63.11 (c 1.610, CHCl₃); H

1

NMR (500 MHz, CDCl₃) d 0.93 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.14(1H, dd, H-3a,

J_3a,2=5.5 Hz), 1.15 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.57

J_3a,3b=5.5,

0

(1H, dddd, H-2, J_{2,1 b}=5.0, J_2,3a=5.5, J_2,3b=8.8,

0

(1S,5R)-2-Oxo-1-(2-naphthyl)-3-oxabicyclo[3.1.0]hexane

(25i). Compound 25i with 94% ee (CHIRALPAK AD-

RH, 0.46Â15 cm, Daicel; H₂O/CH₃CN, 3:2; 0.5 mL/

min; 265 nm) was obtained as crystals in 45% yield: mp

(hexane/AcOEt) 116 ^ꢂC; [a]_D²²ꢁ64.51 (c 1.230, CHCl₃);

¹H NMR (500 MHz, CDCl₃) d 1.38 (1H, dd, H-6a,

J_6a,6b=4.8, J_6a,5=4.8 Hz), 1.69 (1H, dd, H-6b,

J_6b,6a=4.8, J_6b,5=7.8 Hz), 2.59 (1H, dd, H-5, J_5,4b=4.6,

J_5,6a=4.8, J_5,6b=7.8 Hz), 4.27 (1H, d, H-4a,

J_4a,4b=9.3 Hz), 4.74 (1H, dd, H-4b, J_4b,5=4.6,

J_{2,1 a}=11.0 Hz), 1.62 (1H, dd, H-3b, J_3b,3a=5.5,

0

J_3a,2=8.8 Hz), 3.18 (1H, dd, H-1⁰a, J_{1 a, 2}=11.0, J_{1 b,}

0

_{1 a}=11.0 Hz), 3.24–3.56 (4H, m, –NCH₂CH₃), 4.02 (1H,

0

ddd, H-1⁰b, J_{1 b, 2}=5.0, J_{1 b, OH}=9.3, J_{1 b, 1 a}=11.0 Hz),

0

4.69 (1H, d, –OH, J_{OH, 1 b}=9.3 Hz), 6.92 (2H, m, aro-

matic), 7.01 (1H, m, aromatic), 7.27 (1H, m, aromatic);

¹³C NMR (125 MHz, CDCl₃) d 12.25 (–NCH₂CH₃),

13.07 (–NCH₂CH₃), 17.08 (C-3), 32.22 (C-2), 34.12 (C-1),

39.53 (–NCH₂CH₃), 41.96 (–NCH₂CH₃), 64.59 (C-1⁰),

112.67 (C-4⁰⁰, J_C,F=23 Hz), 113.52 (C-2⁰⁰, J_C,F=21 Hz),

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3839

121.25 (C-6⁰⁰, J_C,F=3 Hz), 130.15 (C-5⁰⁰, J_C,F=9 Hz),

143.05 (C-1⁰⁰, J_C,F=8 Hz), 163.01 (C-3⁰⁰, J_C,F=245 Hz),

170.57 (C¼O); HR-MS (EI) calcd C₁₅H₂₀FNO₂

265.1478; obs 265.1483 (M⁺). Anal. calcd for

C₁₅H₂₀FNO₂: C, 67.90; H, 7.60; N, 5.28. Found: C,

68.05; H, 7.67; N, 5.18.

(1H, dd, H-1⁰a, J_{1 a, 2}=10.4, J_{1 b, 1 a}=12.2 Hz), 3.32–

0

3.45 (3H, m, –NCH₂CH₃), 3.52 (1H, m, –NCH₂CH₃),

4.02 (1H, dd, H-1⁰b, J_{1 b,}₂=4.8, J_{1 b, 1 a}=12.2 Hz),

7.01–7.06 (3H, m, aromatic), 7.17 (1H, m, aromatic);

¹³C NMR (125 MHz, CDCl₃) d 12.23 (–NCH₂CH₃),

13.02 (–NCH₂CH₃), 16.66 (C-3), 21.33 (Me–Ph–), 31.61

(C-2), 34.25 (C-1), 39.40 (–NCH₂CH₃), 41.88

(–NCH₂CH₃), 64.76 (C-1⁰), 122.58, 126.56, 127.28,

128.43, 138.19, 140.14 (the above mentioned, aromatic),

171.23 (C¼O); HR-MS (EI) calcd C₁₆H₂₃NO₂261.1729;

obs 261.1719 (M⁺). Anal. calcd for C₁₆H₂₃NO₂: C,

73.53; H, 8.87; N, 5.36. Found: C, 73.16; H, 8.91; N,

5.44.

0

(1S,2R)-1-(4-Fluorophenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26d). Compound 26d

was obtained as an oil in 94% yield: [a]²_D³+63.64( c

1.390, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.91 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.09 (1H, dd, H-3a,

J_3a,3b=5.5, J_3a,2=6.1 Hz), 1.12 (3H, t, –NCH₂CH₃,

0

J=7.1 Hz), 1.51 (1H, dddd, H-2, J_{2,1 b}=4.8, J_2,3a=6.1,

0

J_2,3b=8.8, J_{2,1 a}=11.7 Hz), 1.60 (1H, dd, H-3b,

0

(1S,2R)-1-(4-Methylphenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26g). Compound 26g

was obtained as an oil in 89% yield: [a]²_D²+50.46 (c

3.620, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.92 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.05 (1H, dd, H-3a,

J_3a,3b=5.2, J_3a,2=5.2 Hz), 1.13 (3H, t, –NCH₂CH₃,

J_3b,3a=5.5, J_3b,2=8.8 Hz), 3.16 (1H, dd, H-1⁰a, J_{1 a, 2}

=

11.7, J_{1 b, 1 a}=11.7 Hz), 3.32–3.43 (3H, m, –NCH₂CH₃),

0

3.50 (3H, m, –NCH₂CH₃), 4.02 (1H, ddd, H-1⁰b, J_{1 b, 2}

=

4.8, J_{1 b, OH}=9.1, J_{1 b, 1 a}=11.7 Hz), 4.73 (1H, d, –OH,

0

J_{OH, 1 b}=9.1 Hz), 6.96–7.01 (2H, m, aromatic), 7.22–

7.26 (2H, m, aromatic); ¹³C NMR (125 MHz, CDCl₃) d

12.28 (–NCH₂CH₃), 13.13 (–NCH₂CH₃), 16.55 (C-3),

31.55 (C-2), 33.87 (C-1), 39.53 (–NCH₂CH₃), 41.89

J=7.1 Hz), 1.51 (1H, dddd, H-2, J_{2,1 b}=4.8, J_2,3a=5.2,

0

J_2,3b=8.7, J_{2,1 a}=10.4Hz), 1.61 (1H, dd, H-3b,

0

J_3b,3a=5.2, J_3b,2=8.7 Hz), 2.31 (3H, s, Me–Ph–), 3.15

(1H, dd, H-1⁰a, J_{1 a, 2}=11.7, J_{1 b, 1 a}=11.7 Hz), 3.32–

(–NCH₂CH₃), 64.69 (C-1⁰), 115.47 (C-3⁰⁰and C-5⁰⁰,

0

00

J_C,F=23 Hz), 127.64(C-2

and C-₀6₀⁰⁰, J_C,F=8 Hz),

3.44 (3H, m, –NCH₂CH₃), 3.52 (1H, m, –NCH₂CH₃),

136.01 (C-1⁰⁰, J_C,F=4Hz), 161.54 (C-4 , J_C,F=244 Hz),

170.95 (C¼O); HR-MS (EI) calcd C₁₅H₂₀FNO₂

265.1478; obs 265.1464 (M⁺). Anal. calcd for

C₁₅H₂₀FNO₂: C, 67.90; H, 7.60; N, 5.28. Found: C,

67.71; H, 7.57; N, 5.12.

4.03 (1H, dd, H-1⁰b, J_{1 b,}₂=4.8, J_{1 b, 1 a}=11.7 Hz),

7.09–7.13 (4H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 12.26 (–NCH₂CH₃), 13.07 (–NCH₂CH₃),

16.54(C-3), 20.81 ( Me–Ph–), 31.51 (C-2), 34.05 (C-1),

39.41 (–NCH₂CH₃), 41.87 (–NCH₂CH₃), 64.78 (C-1⁰),

125.65, 129.24, 136.13, 137.22 (the above mentioned,

aromatic), 171.28 (C¼O); HR-MS (EI) calcd

C₁₆H₂₃NO₂261.1729; obs 261.1728 (M⁺). Anal. calcd

for C₁₆H₂₃NO₂: C, 73.53; H, 8.87; N, 5.36. Found: C,

73.53; H, 8.87; N, 5.36.

0

(1S,2R)-1-(2-Methylphenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26e). Compound 26e

was obtained as an oil in 95% yield: [a]²_D³+31.91 (c

2.025, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.55 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.07 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.31 (1H, dd, H-3a, J_3a,3b=4.8,

J_3a,2=6.0 Hz), 1.62 (1H, dd, H-3b, J_3b,3a=4.8,

0

J_3b,2=8.8 Hz), 1.72 (1H, dddd, H-2, J_{2,1 b}=5.3,

0

J_2,3a=6.0, J_2,3b=8.8, J_{2,1 a}=9.7 Hz), 2.49 (3H, s, Me—

Ph–), 3.22–3.30 (2H, m, –NCH₂CH₃), 3.41 (1H, dd, H-

1⁰a, J_{1 a,}₂=9.7, J_{1 b, 1 a}=12.0 Hz), 3.47 (1H, m, –

NCH₂CH₃), 3.55 (1H, m, –NCH₂CH₃), 4.02 (1H, dd,

H-1⁰b, J_{1 b, 2}=5.3, J_{1 b, 1 a}=12.0 Hz), 7.13–7.15 (3H, m,

aromatic), 7.27 (1H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 12.44 (–NCH₂CH₃), 12.79 (–NCH₂CH₃),

16.90 (C-3), 20.24( Me–Ph–), 28.35 (C-2), 34.47 (C-1),

40.55 (–NCH₂CH₃), 42.11 (–NCH₂CH₃), 63.95 (C-1⁰),

125.74, 127.07, 128.46, 130.99, 138.62, 140.28 (the above

mentioned, aromatic), 170.18 (C¼O); HR-MS (EI)

calcd C₁₆H₂₃NO₂261.1729; obs 261.1728 (M⁺). Anal.

calcd for C₁₆H₂₃NO₂: C, 73.53; H, 8.87; N, 5.36. Found:

C, 73.25; H, 8.94; N, 5.33.

(1S,2R)-1-(1-Naphthyl)-2-(hydroxymethyl)-N,N-diethyl-

cyclopropanecarboxamide (26h). Compound 26h was

obtained as crystals in 67% yield: mp (hexane/AcOEt)

136 ^ꢂC; [a]²_D²ꢁ28.91 (c 1.580, CHCl₃); ¹H NMR

(500 MHz, CDCl₃)

d

0.46 (3H, t, –NCH₂CH₃,

0

J=7.0 Hz), 0.99 (3H, t, –NCH₂CH₃, J=7.0 Hz), 1.46

(1H, dd, H-3a, J_3a,3b=5.0, J_3a,2=8.5 Hz), 1.52 (1H, dd,

H-3b, J_3b,3a=5.0, J_3b,2=5.0 Hz), 1.92 (1H, m, H-2),

3.21 (2H, m, –NCH₂CH₃), 3.49–3.58 (2H, m, H-1⁰a and

–NCH₂CH₃), 3.70 (1H, m, –NCH₂CH₃), 4.11 (1H, m,

H-1⁰b), 7.41 (1H, t, aromatic, J=7.7 Hz), 7.49 (1H, m,

aromatic), 7.58 (1H, m, aromatic), 7.77 (1H, d, aro-

matic, J=8.2 Hz), 7.83 (1H, d, aromatic, J=8.2 Hz),

7.41 (1H, d, aromatic, J=8.2 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 12.23 (–NCH₂CH₃), 12.72 (–NCH₂CH₃),

17.32 (C-3), 27.72 (C-2), 34.26 (C-1), 40.51

(–NCH₂CH₃), 42.16 (–NCH₂CH₃), 63.49 (C-1⁰), 124.89,

125.61, 125.86, 126.13, 126.33, 128.01, 128.16, 133.38,

133.82, 136.92 (the above mentioned, aromatic), 170.39

(C¼O); HR-MS (EI) calcd C19H23NO2 297.1729; obs

297.1730 (M+). Anal. calcd for C19H23NO2: C, 76.73;

H, 7.80; N, 4.71. Found: C, 76.75; H, 7.72; N, 4.66.

0

(1S,2R)-1-(3-Methylphenyl)-2-(hydroxymethyl)-N,N-di-

ethylcyclopropanecarboxamide (26f). Compound 26f

was obtained as an oil in 88% yield: [a]²_D³+54.12 (c

2.620, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.91 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.07 (1H, dd, H-3a,

J_3a,3b=5.3, J_3a,2=5.3 Hz), 1.14(3H, t, –NCH ₂CH₃,

0

J=7.1 Hz), 1.55 (1H, dddd, H-2, J_{2,1 b}=4.8, J_2,3a=5.3,

0

J_2,3b=8.8, J_{2,1 a}=10.4Hz), 1.62 (1H, dd, H-3b,

J_3b,3a=5.3, J_3b,2=8.8 Hz), 2.31 (3H, s, Me–Ph–), 3.18

(1S,2R)-1-(2-Naphthyl)-2-(hydroxymethyl)-N,N-diethyl-

cyclopropanecarboxamide (26i). Compound 26i was

obtained as crystals in 91% yield: mp (hexane/AcOEt)

23

161–162 ^ꢂC; [a]_D+61.76 (c 1.325, CHCl₃); H NMR

1

3840

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

(500 MHz, CDCl₃)

J=7.1 Hz), 1.15 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.17

d

0.88 (3H, t, –NCH₂CH₃,

H-3b, J_3b,3a=5.6, J_3b,2=5.6 Hz), 2.45 (1H, ddd, H-2,

0

J_2,3b=5.6, J_2,1=5.9, J_2,3a=8.4Hz), 3.21 (1H, m,

(1H, dd, H-3a, J_3a,3b=5.5, J_3a,2=5.5 Hz), 1.64(1H,

–NCH₂CH₃), 3.28 (1H, m, –NCH₂CH₃), 3.37–3.49 (2H,

m, –NCH₂CH₃), 6.98 (2H, m, aromatic), 7.06 (1H, m,

0

ddd, H-2, J_2,3a=5.5, J_{2,1 b}=8.5, J_2,3b=8.8, J_{2,1 a}

0

=

11.2 Hz), 1.79 (1H, dd, H-3b, J_3b,3a=5.5, J_3b,2=8.8 Hz),

3.23 (1H, dd, H-1⁰a, J_{1 a, 2}=8.8, J_{1 a, 1 b}=11.2 Hz), 3.33–

aromatic), 7.32 (1H, m, aromatic), 9.07 (1H, d, H-1⁰, J_{1 , 2}

=

12.20

0

5.9 Hz); ¹³C NMR (125 MHz, CDCl₃)

d

0

3.4 8 (3H, m, –NCH₂CH₃), 3.57 (1H, m, –NCH₂CH₃), 4.07

(–NCH₂CH₃), 12.82 (–NCH₂CH₃), 20.06 (C-3), 36.48

(C-2), 39.66 (–NCH₂CH₃), 39.70 (C-1, J_C,F=10 Hz),

41.54 (–NCH₂CH₃), 113.02 (C-4⁰⁰, J_C,F=23 Hz), 114.53

(C-2⁰⁰, J_C,F=21 Hz), 121.51 (C-6⁰⁰, J_C,F=3 Hz), 130.57

(C-5⁰⁰, J_C,F=9 Hz), 140.59 (C-1⁰⁰, J_C,F=8 Hz), 163.06

(C-3⁰⁰, J_C,F=246 Hz), 166.83 (C¼O), 197.55 (C-1⁰); HR-

MS (EI) calcd C₁₅H₁₈FNO₂263.1321; obs 263.1315

(M⁺). Anal. calcd for C₁₅H₁₈FNO₂: C, 68.42; H, 6.89;

N, 5.32. Found: C, 68.32; H, 6.98; N, 5.33.

(1H, m, H-1⁰b, J_{1 b, 2}=8.5, J_{1 b, 1 a}=11.2Hz), 4 .78 (1H, bs,

–OH), 7.42–7.48 (3H, m, aromatic), 7.64 (1H, s, aromatic),

7.76–7.80 (3H, m, aromatic); ¹³C NMR (125 MHz, CDCl₃)

d 12.35 (–NCH₂CH₃), 13.19 (–NCH₂CH₃), 16.64(C-3),

31.87 (C-2), 34.67 (C-1), 39.55 (–NCH₂CH₃), 41.96

(–NCH₂CH₃), 64.85 (C-1⁰), 124.20, 124.41, 125.78,

126.26, 127.53, 127.61, 128.49, 132.21, 133.35, 137.77

(the above mentioned, aromatic), 171.14(C ¼O); HR-

MS (EI) calcd C₁₉H₂₃NO₂297.1729; obs 297.1733

(M⁺). Anal. calcd for C₁₉H₂₃NO₂: C, 76.73; H, 7.80; N,

4.71. Found: C, 76.48; H, 7.79; N, 4.70.

0

(1S,2R)-1-(4-Fluorophenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27d). Compound 27d was

obtained as an oil in 82% yield: [a]²_D²ꢁ125.10 (c 3.365,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.75 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.10 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.73 (1H, dd, H-3a, J_3a,3b=5.5,

J_3a,2=8.4Hz), 2.25 (1H, dd, H-3b, J_3b,3a=5.5,

General procedure for preparing compounds 27b–i. To a

solution of oxalyl chloride (3.49 mL, 40.0 mmol) in

CH₂Cl₂(30 mL) was slowly added a mixture of DMSO

(6.19 mL, 80.0 mmol) in CH₂Cl₂(20 mL) at ꢁ78 ^ꢂC, and

then 26b–i (20.0 mmol) in CH₂Cl₂(10 mL) was added

dropwise. The resulting mixture was stirred at the same

temperature for 2 h, and then Et₃N was added. After

stirring at ꢁ78 ^ꢂC for further 30 min, the reaction was

quenched with saturated NH₄Cl, and then CH₂Cl₂was

added and partitioned. The organic layer was washed

with brine, dried (Na₂SO₄), and evaporated. The residue

was puriﬁed by column chromatography (silica gel;

AcOEt/hexane 1:4) to give 29b–i as an oil.

0

J_3b,2=5.5 Hz), 2.42 (1H, ddd, H-2, J_2,3b=5.5, J_2,1=6.1,

J_2,3a=8.4Hz), 3.19–3.30 (2H, m, –N CH₂CH₃), 3.38–

3.47 (2H, m, –NCH₂CH₃), 7.00–7.08 (2H, m, aromatic),

7.26–7.31 (2H, m, aromatic), 9.06 (1H, d, H-1⁰, J_{1 , 2}

=

12.18

0

6.1 Hz); ¹³C NMR (125 MHz, CDCl₃)

d

(–NCH₂CH₃), 12.81 (–NCH₂CH₃), 19.80 (C-3), 36.32

(C-2), 39.55 (C-1), 39.63 (–NCH₂CH₃), 41.45

(–NCH₂CH₃), 115.86 (C-3⁰⁰and C-5⁰⁰, J_C,F=23 Hz),

127.79 (C-2⁰⁰and C-6⁰⁰, J_C,F=8 Hz), 133.77 (C-1⁰⁰,

00

J_C,F=3 Hz), 161.94(C-4

,

J_C,F=245 Hz), 167.16

(1S,2R)-1-(2-Fluorophenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27b). Compound 27b was

obtained as an oil in 87% yield: [a]²_D²ꢁ130.50 (c 2.375,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.66 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.07 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.75 (1H, dd, H-3a, J_3a,3b=5.4,

J_3a,2=8.6 Hz), 2.39 (1H, dd, H-3b, J_3b,3a=5.4,

(C¼O), 197.77 (C-1⁰); HR-MS (EI) calcd C₁₅H₁₈FNO₂

263.1321; obs 263.1310 (M⁺). Anal. calcd for

C₁₅H₁₈FNO₂: C, 68.42; H, 6.89; N, 5.32. Found: C,

68.48; H, 6.96; N, 5.20.

(1S,2R)-1-(2-Methylphenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27e). Compound 27e was

obtained as an oil in 79% yield: [a]²_D²ꢁ114.64 (c 2.620,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.42 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.06 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.56 (1H, dd, H-3a, J_3a,3b=5.5,

J_3a,2=8.7 Hz), 2.41 (3H, s, Me–Ph–), 2.46 (2H, m, H-3b

and H-2), 3.13–3.21 (2H, m, –NCH₂CH₃), 3.36 (1H, m,

–NCH₂CH₃), 3.49 (1H, m, –NCH₂CH₃), 7.16–7.26 (4H,

0

J_3b,2=5.4Hz), 2.57 (1H, ddd, H-2, J_2,3b=5.4, J_2,1=6.1,

J_2,3a=8.6 Hz), 3.21–3.31 (2H, m, –NCH₂CH₃), 3.51

(1H, m, –NCH₂CH₃), 3.51 (1H, m, –NCH₂CH₃), 7.06

(1H, m, aromatic), 7.15 (1H, m, aromatic), 7.29₀(1H, m,

0

aromatic), 7.4 1 (1H, m, aromatic), 9.08 (1H, d, H-1, J_{1 , 2}

=

6.1 Hz); ¹³C NMR (125 MHz, CDCl₃)

(–NCH₂CH₃), 12.74(–NCH CH₃), 19.66 (C-3, J_C,F

d

12.18

=

2

m, aromatic), 9.06 (1H, d, H-1⁰, J_{1 ,}₂=6.2 Hz); ¹³C

0

9.5 Hz), 35.22 (C-2), 36.08 (C-1), 40.15 (–NCH₂CH₃),

41.33 (–NCH₂CH₃), 116.33 (C-3⁰⁰, J_C,F=21 Hz), 124.67

(C-6⁰⁰, J_C,F=4Hz), 125.38 (C-1 ⁰⁰, J_C,F=13 Hz), 129.56

(C-4⁰⁰, J_C,F=9 Hz), 129.84(C-5 ⁰⁰, J_C,F=4Hz), 161.00

(C-2⁰⁰, J_C,F=249 Hz), 166.79 (C¼O), 198.29 (C-1⁰); HR-

MS (EI) calcd C₁₅H₁₈FNO₂263.1321; obs 263.1330

(M⁺). Anal. calcd for C₁₅H₁₈FNO₂: C, 68.42; H, 6.89;

N, 5.32. Found: C, 68.48; H, 6.90; N, 5.10.

NMR (125 MHz, CDCl₃) d 12.36 (–NCH₂CH₃), 12.55

(–NCH₂CH₃), 19.38 (C-3), 19.89 (Me–Ph–), 35.69 (C-2),

39.92 (C-1), 41.01 (–NCH₂CH₃), 41.77 (–NCH₂CH₃),

126.05, 127.67, 127.69, 131.10, 136.62, 138.98 (the above

mentioned, aromatic), 167.25 (C¼O), 199.08 (C-1⁰);

HR-MS (EI) calcd C₁₆H₂₃NO₂259.1572; obs 259.1573

(M⁺). Anal. calcd for C₁₆H₂₃NO₂: C, 74.10; H, 8.16; N,

5.40. Found: C, 74.22; H, 8.06; N, 5.28.

(1S,2R)-1-(3-Fluorophenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27c). Compound 27c was

obtained as crystals in 87% yield: mp (AcOEt, Hexane)

68–69 ^ꢂC; [a]_D²²ꢁ136.91 (c 3.300, CHCl₃); ¹H NMR

(1S,2R)-1-(3-Methylphenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27f). Compound 27f was obtained

as an oil in 94% yield: [a]²_D³ꢁ141.04 (c 2.795, CHCl₃);

¹H NMR (500 MHz, CDCl₃) d 0.71 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.10 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.70

(1H, dd, H-3a, J_3a,3b=5.5, J_3a,2=8.5 Hz), 2.26 (1H, dd,

(500 MHz, CDCl₃)

d 0.77 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.12 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.74

(1H, dd, H-3a, J_3a,3b=5.6, J_3a,2=8.4Hz), 2.27 (1H, dd,

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3841

H-3b, J_3b,3a=5.5, J_3b,2=5.5 Hz), 2.33 (3H, s, Me–Ph–),

0

2.48 (1H, ddd, H-2, J_2,3b=5.5, J_2,1=6.2, J_2,3a=8.5 Hz),

(3H, t, –NCH₂CH₃, J=7.1 Hz), 1.83 (1H, dd, H-3a,

J_3a,3b=5.5, J_3a,2=8.3 Hz), 2.34(1H, dd, H-3b,

J_3b,3a=5.5, J_3b,2=5.5 Hz), 2.59 (1H, ddd, H-2,

3.18 (1H, m, –NCH₂CH₃), 3.26 (1H, m, –NCH₂CH₃),

3.38–3.44 (2H, m, –NCH₂CH₃), 7.03–7.09 (3H, s, aro-

0

J_2,3b=5.5, J_2,1=6.1, J_2,3a=8.3 Hz), 3.19–3.32 (2H, m, –

0

matic), 7.22 (1H, s, aromatic), 9.04(1H, d, H-1 , J_{1 ,}

NCH₂CH₃), 3.43–3.51 (2H, m, –NCH₂CH₃), 7.41 (1H,

dd, aromatic, J=1.5, J=8.3 Hz), 7.46–7.51 (2H, m,

aromatic), 7.69 (1H, s, aromatic), 7.78–7.83 (3H, m,

₂=6.2 Hz); ¹³C NMR (125 MHz, CDCl₃) d 12.13

(–NCH₂CH₃), 12.66 (–NCH₂CH₃), 19.92 (C-3), 21.24

(Me–Ph–), 36.22 (C-2), 39.51 (–NCH₂CH₃), 39.97 (C-1),

41.43 (–NCH₂CH₃), 122.68, 126.65, 128.14, 128.73,

137.75, 138.61 (the above mentioned, aromatic), 167.44

(C¼O), 198.10 (C-1⁰); HR-MS (EI) calcd C₁₆H₂₃NO₂

259.1572; obs 259.1595 (M⁺). Anal. calcd for

C₁₆H₂₃NO₂: C, 74.10; H, 8.16; N, 5.40. Found: C,

74.43; H, 8.24; N, 5.35.

aromatic), 9.12 (1H, d, H-1⁰, J_{1 , 2}=6.1 Hz); ¹³C NMR

0

(125 MHz, CDCl₃)

d

12.24(–NCH ₂CH₃), 12.83

(–NCH₂CH₃), 20.09 (C-3), 36.35 (C-2), 39.64

(–NCH₂CH₃), 40.31 (C-1), 41.52 (–NCH₂CH₃), 124.07,

124.47, 126.25, 126.56, 127.57, 127.67, 128.87, 132.47,

133.25, 135.37 (the above mentioned, aromatic), 167.33

(C¼O), 198.03 (C-1⁰); HR-MS (EI) calcd C₁₉H₂₁NO₂

295.1572; obs 295.1581 (M⁺). Anal. calcd for

C₁₉H₂₁NO₂: C, 77.26; H, 7.17; N, 4.74. Found: C,

77.17; H, 7.27; N, 4.83.

(1S,2R)-1-(4-Methylphenyl)-2-formyl-N,N-diethylcyclo-

propanecarboxamide (27g). Compound 27g was

obtained as an oil in 81% yield: [a]²_D²ꢁ138.88 (c 3.465,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.72 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.10 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.70 (1H, dd, H-3a, J_3a,3b=5.5,

J_3a,2=8.2 Hz), 2.23 (1H, dd, H-3b, J_3b,3a=5.5,

J_3b,2=5.5 Hz), 2.33 (3H, s, Me–Ph–), 2.44 (1H, ddd, H-

General procedure for preparing compounds 28b–i. A

mixture of 28b–i (10.0 mmol) and EtMgBr (3.00 M in

Et₂O, 13.3 mL, 40.0 mmol) in THF (20 mL) was stirred

at ꢁ15 ^ꢂC for 4h. The reaction was quenched with

saturated NH₄Cl, and the resulting mixture was con-

centrated in vacuo (for removing THF and Et₂O), to

which AcOEt and H₂O was added and partitioned. The

organic layer was washed with brine, dried (Na₂SO₄),

and evaporated The reside was puriﬁed by column chro-

matography (silica gel; AcOEt/hexane 1:4) to give 30b–i.

0

2, J_2,3b=5.5, J_2,1=6.2, J_2,3a=8.2 Hz), 3.19 (1H, m,

–NCH₂CH₃), 3.26 (1H, m, –NCH₂CH₃), 3.38–3.48 (2H,

m, –NCH₂CH₃), 7.14(4H, s, aromatic), 9.04(1H, d, H-

1⁰, J_{1 , 2}=6.2 Hz); ¹³C NMR (125 MHz, CDCl₃) d 12.20

0

(–NCH₂CH₃), 12.75 (–NCH₂CH₃), 19.94(C-3), 20.87

(Me–Ph–), 36.29 (C-2), 39.55 (–NCH₂CH₃), 39.83 (C-1),

41.46 (–NCH₂CH₃), 125.75, 129.55, 134.88, 137.20 (the

above mentioned, aromatic), 167.51 (C¼O), 198.17 (C-

1⁰); HR-MS (EI) calcd C₁₆H₂₃NO₂259.1572; obs

259.1575 (M⁺). Anal. calcd for C₁₆H₂₃NO₂: C, 74.10;

H, 8.16; N, 5.40. Found: C, 74.16; H, 8.14; N, 5.35.

(1S,2R)-1-(2-Fluorophenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (28b). Compound 28b

was obtained as crystals in 77% yield: mp (AcOEt,

22

Hexane) 105–106 ^ꢂC; [a]_D+61.13 (c 2.335, CHCl₃); H

1

NMR (500 MHz, CDCl₃) d 0.93 (3H, t, –NCH₂CH₃,

J=7.1 Hz), 1.00 (3H, t, H-3⁰, J_{3 , 2}=7.5 Hz), 1.08 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.12 (1H, dd, H-3a,

J_3a,3b=5.5, J_3a,2=5.5 Hz), 1.35 (1H, ddd, H-2,

J_2,3a=5.5, J_2,3b=8.8, J_2,1=8.8 Hz), 1.60–1.72 (2H, m,

H-2⁰), 1.76 (1H, dd, H-3b, J_3b,3a=5.5, J_3b,2=8.8 Hz),

3.08 (1H, m, H-1⁰), 3.28 (1H, m, –NCH₂CH₃), 3.40 (1H,

m, –NCH₂CH₃), 3.63–3.68 (2H, m, –NCH₂CH₃), 5.26

(1H, bs, –OH), 6.99 (1H, m, aromatic), 7.09 (1H, m,

aromatic), 7.21 (1H, m, aromatic), 7.51 (1H, m, aro-

matic); ¹³C NMR (125 MHz, CDCl₃) d 10.23 (C-3⁰),

12.38 (–NCH₂CH₃), 13.35 (–NCH₂CH₃), 17.03 (C-3,

J_C,F=17 Hz), 29.23 (C-2⁰), 29.66 (C-1), 34.31 (C-2),

39.82 (–NCH₂CH₃), 41.78 (–NCH₂CH₃), 75.27 (C-1⁰),

116.05 (C-3⁰⁰, J_C,F=23 Hz), 124.44 (C-6⁰⁰, J_C,F=4Hz),

127.26 (C-1⁰⁰, J_C,F=11 Hz), 128.84(C-4 ⁰⁰, J_C,F=9 Hz),

131.62 (C-5⁰⁰, J_C,F=4Hz), 161.12 (C-2 ⁰⁰, J_C,F=246 Hz),

170.71 (C¼O); HR-MS (EI) calcd C₁₇H₂₄FNO₂

293.1791; obs 293.1795 (M⁺). Anal. calcd for

C₁₇H₂₄FNO₂: C, 69.60; H, 8.25; N, 4.77. Found: C,

69.68; H, 8.24; N, 4.82.

0

(1S,2R)-1-(1-Naphthyl)-2-formyl-N,N-diethylcyclopropane-

carboxamide (27h). Compound 27h was obtained as

crystals in 73% yield: mp (hexane/AcOEt) 109 ^ꢂC; [a]_D²²

ꢁ79.36 (c 2.235, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d

0.35 (3H, t, –NCH₂CH₃, J=7.0 Hz), 0.97 (3H, t,

–NCH₂CH₃, J=7.0 Hz), 1.66 (1H, bs, H-3a), 2.46 (2H,

bs, H-3b and H-2), 3.07 (1H, m, –NCH₂CH₃), 3.24(1H,

m, –NCH₂CH₃), 3.33 (1H, m, –NCH₂CH₃), 3.65 (1H,

m, –NCH₂CH₃), 7.43 (1H, t, aromatic, J=7.5 Hz), 7.48

(1H, d, aromatic, J=6.3 Hz), 7.53 (1H, m, aromatic),

7.59 (1H, m, aromatic), 7.81 (1H, d, aromatic,

J=8.0 Hz), 7.86 (1H, d, aromatic, J=8.0 Hz), 8.66 (1H,

0

d, aromatic, J=8.5 Hz), 9.15 (1H, d, H-1⁰, J_{1 ,}

=

2

5.9 Hz); ¹³C NMR (125 MHz, CDCl₃)

d

12.23

(–NCH₂CH₃), 12.75 (–NCH₂CH₃), 19.80 (C-3), 35.63

(C-2), 39.40 (C-1), 40.91 (–NCH₂CH₃), 41.71

(–NCH₂CH₃), 124.96, 125.26, 125.58, 126.30, 126.99,

128.39, 128.79, 133.07, 133.92, 134.67 (the above men-

tioned, aromatic), 167.48 (C¼O), 198.85 (C-1⁰); HR-MS

(EI) calcd C₁₉H₂₁NO₂295.1572; obs 295.1545 (M⁺).

Anal. calcd for C₁₉H₂₁NO₂: C, 77.26; H, 7.17; N, 4.74.

Found: C, 77.36; H, 6.99; N, 4.71.

(1S,2R)-1-(3-Fluorophenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (28c). Compound 28c

was obtained as an oil in 83% yield: [a]²_D²+72.50 (c

3.000, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.96 (3H,

(1S,2R)-1-(2-Naphthyl)-2-formyl-N,N-diethylcyclopropane-

carboxamide (27i). Compound 27i was obtained as

crystals in 85% yield: mp (hexane/AcOEt) 90–91 ^ꢂC;

t, –NCH₂CH₃, J=7.1 Hz), 1.00 (3H, t, H-3⁰, J_{3 , 2}

0

=

7.4Hz), 1.10 (1H, dd, H-3a, J_3a,3b=6.1, J_3a,2=6.1 Hz),

1.15 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.27 (1H, ddd, H-

0

2, J_2,3a=6.0, J_2,3b=9.4, J_2,1=9.4Hz), 1.60–1.74 (3H,

[a]²_D²ꢁ192.74( c 1.505, CHCl₃); H NMR (500 MHz,

1

CDCl₃) d 0.67 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.12

3842

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

m, H-3b and H-2⁰), 3.07 (1H, m, H-1⁰), 3.33–3.53 (4H, m,

–NCH₂CH₃), 5.38 (1H, s,–OH), 6.91 (2H, m, aromatic),

7.01 (1H, m, aromatic), 7.26 (1H, m, aromatic); ¹³C

t, –NCH₂CH₃, J=7.1 Hz), 1.00 (3H, t, H-3⁰, J_{3 , 2}

7.5 Hz), 1.05 (1H, dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz),

0

=

1.14(3H, t, –NCH CH₃, J=7.1 Hz), 1.25 (1H, ddd, H-

2

2, J_2,3a=6.0, J_2,3b=8.8, J_2,1=8.8 Hz), 1.60–1.73 (2H,

NMR (125 MHz, CDCl₃)

d

10.22 (C-3⁰), 12.29

0

(–NCH₂CH₃), 13.15 (–NCH₂CH₃), 17.42 (C-3), 29.07

(C-2⁰), 33.12 (C-1, J_C,F=10 Hz), 37.07 (C-2), 39.50

(–NCH₂CH₃), 41.95 (–NCH₂CH₃), 75.57 (C-1⁰), 112.64

(C-4⁰⁰, J_C,F=23 Hz), 113.50 (C-2⁰⁰, J_C,F=21 Hz), 121.27

(C-6⁰⁰, J_C,F=3 Hz), 130.15 (C-5⁰⁰, J_C,F=9 Hz), 143.14

(C-1⁰⁰, J_C,F=6 Hz), 163.05 (C-3⁰⁰, J_C,F=244 Hz), 170.88

(C¼O); HR-MS (EI) calcd C₁₇H₂₄FNO₂293.1791; obs

293.1820 (M⁺). Anal. calcd for C₁₇H₂₄FNO₂: C, 69.60;

H, 8.25; N, 4.77. Found: C, 69.73; H, 8.29; N, 4.81.

m, H-2⁰), 1.69 (1H, dd, H-3b, J_3b,3a=6.0, J_3b,2=8.8 Hz),

2.31 (3H, s, Me–Ph–), 3.07 (1H, m, H-1⁰), 3.32–3.46

(3H, m, –NCH₂CH₃), 3.53 (1H, m, –NCH₂CH₃), 5.51

(1H, s,–OH), 7.00–7.06 (3H, m, aromatic), 7.17 (1H, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 10.22 (C-3⁰),

12.25 (–NCH₂CH₃), 13.08 (–NCH₂CH₃), 16.98 (C-3),

21.34( Me–Ph–), 29.07 (C-2⁰), 33.16 (C-1), 36.42 (C-2),

39.33 (–NCH₂CH₃), 41.86 (–NCH₂CH₃), 75.66 (C-1⁰),

122.54, 126.52, 127.24, 128.40, 138.18, 140.17 (the above

mentioned, aromatic), 171.51 (C¼O); HR-MS (EI)

calcd C₁₈H₂₇NO₂289.2042; obs 289.2026 (M⁺). Anal.

calcd for C₁₈H₂₇NO₂: C, 74.70; H, 9.40; N, 4.84. Found:

C, 74.49; H, 9.55; N, 4.81.

(1S,2R)-1-(4-Fluorophenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (28d). Compound 28d

was obtained as an oil in 94% yield: [a]²_D²+75.68 (c

2.530, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.94(3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.00 (3H, t, H-3⁰, J_{3 , 2}

(1S,2R)-1-(4-Methylphenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (28g). Compound 28g

was obtained as crystals in 78% yield: mp (i-Pr₂O/

0

=

7.5 Hz), 1.06 (1H, dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz),

1.13 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.51 (1H, ddd, H-

22

2, J_2,3a=6.0, J_2,3b=9.2, J_2,1=9.2 Hz), 1.59–1.73 (3H,

AcOEt) 63–64 ^ꢂC; [a]_D+77.48 (c 1.785, CHCl₃); H

1

0

m, H-3b and H-2⁰), 3.05 (1H, m, H-1⁰), 3.32–3.44 (3H,

m, –NCH₂CH₃), 3.52 (1H, m, –NCH₂CH₃), 5.43 (1H,

s,–OH), 6.96–7.01 (2H, m, aromatic), 7.22–7.25 (2H, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 10.22 (C-3⁰),

12.30 (–NCH₂CH₃), 13.18 (–NCH₂CH₃), 16.87 (C-3),

29.07 (C-2⁰), 32.82 (C-1), 36.33 (C-2), 39.47

(–NCH₂CH₃), 41.87 (–NCH₂CH₃), 75.60 (C-1⁰), 115.45

NMR (500 MHz, CDCl₃) d 0.94(3H, t, –NCH CH₃,

2

J=7.1 Hz), 1.00 (3H, t, H-3⁰, J_{3 , 2}=7.5 Hz), 1.03 (1H,

dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz), 1.13 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.22 (1H, ddd, H-2, J_2,3a=6.0,

0

J_2,3b=8.4, J_2,1=8.4Hz), 1.59–1.73 (3H, m, H-3b and

H-2⁰), 2.30 (3H, s, Me–Ph–), 3.06 (1H, m, H-1⁰), 3.31–3.45

(3H, m, –NCH₂CH₃), 3.53 (1H, m, –NCH₂CH₃), 5.43

(1H, s,–OH), 7.08–7.13 (4H, m, aromatic); ¹³C NMR

(125MHz, CDCl₃) d 10.29 (C-3⁰), 12.35 (–NCH₂CH₃),

13.20 (–NCH₂CH₃), 16.91 (C-3), 20.90 (Me–Ph–), 29.13

(C-2⁰), 33.02 (C-1), 36.40 (C-2), 39.41 (–NCH₂CH₃), 41.90

(–NCH₂CH₃), 75.73 (C-1⁰), 125.69, 129.30, 136.18, 137.34

(the above mentioned, aromatic), 171.63 (C¼O); HR–MS

(EI) calcd C₁₈H₂₇NO₂289.2042; obs 289.2055 (M⁺).

Anal. calcd for C₁₈H₂₇NO₂: C, 74.70; H, 9.40; N, 4.84.

Found: C, 74.70; H, 9.52; N, 4.90.

00

(C-3⁰⁰and C-5⁰⁰, J_C,F=8 Hz), 127.64(C-2 and C-6⁰⁰,

J_C,F=8 Hz), 136.06 (C-1⁰⁰, J_C,F=1 Hz), 161.53 (C-4⁰⁰,

J_C,F=245 Hz), 171.23 (C¼O); HR-MS (EI) calcd

C₁₇H₂₄FNO₂293.1791; obs 293.1766 (M⁺). Anal. calcd

for C₁₇H₂₄FNO₂: C, 69.60; H, 8.25; N, 4.77. Found: C,

69.56; H, 8.29; N, 4.76.

(1S,2R)-1-(2-Methylphenyl)-2-[(S)-1-azidopropyl]-N,N-

diethylcyclopropanecarboxamide (28e). Compound 28e

was obtained as an oil in 67% yield: [a]²_D³ꢁ316.62 (c

2.020, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.17 (3H,

t, –NCH₂CH₃, J=7.0 Hz), 0.73 (1H, dd, H-3a,

(1S,2R)-1-(1-Naphthyl)-2-[(S)-1-hydroxypropyl]-N,N-di-

ethylcyclopropanecarboxamide (28h). Compound 28h

was obtained as crystals in 91% yield: mp (hexane/

J_3a,3b=4.2, J_3a,2=9.0 Hz), 1.08 (3H, t, H-3⁰, J_{3 ,}

0

=

2

23

AcOEt) 95–96 ^ꢂC; [a]_D+26.58 (c 2.455, CHCl₃); H

NMR (500 MHz, CDCl₃) d 0.50 (3H, t, –NCH₂CH₃,

J=7.0 Hz), 0.99 (3H, t, –NCH₂CH₃, J=7.0 Hz), 1.04

1

7.5 Hz), 1.11 (3H, t, –NCH₂CH₃, J=7.0 Hz), 1.78–1.91

(2H, m, H-2⁰), 1.99 (1H, dd, H-3b, J_3b,3a=4.2,

J_3b,2=6.2 Hz), 2.05 (1H, ddd, H-2, J_2,3b=6.2,

J_2,3a=9.0, J_2,1=9.0 Hz), 2.29 (3H, s, Me–Ph–), 2.85–

0

(3H, t, H-3⁰, J_{3 ,}₂=7.4Hz), 1.41 (1H, dd, H-3a,

J_3a,3b=5.0, J_3a,2=5.0 Hz), 1.54(1H, dd, H-3b,

J_3b,3a=5.0, J_3b,2=8.7 Hz), 1.63 (1H, ddd, H-2,

0

2.94(2H, m, H-1

and –NCH₂CH₃), 3.13 (1H, m,

–NCH₂CH₃), 3.42 (1H, m, –NCH₂CH₃), 3.89 (1H,

m, –NCH₂CH₃), 7.11–7.18 (3H, m, aromatic), 7.29 (1H,

m, aromatic); ¹³C NMR (125MHz, CDCl₃) d 10.28 (C-

3⁰), 11.77 (–NCH₂CH₃), 12.43 (–NCH₂CH₃), 19.04(C-3),

19.63 (Me–Ph–), 28.18 (C-2), 28.61 (C-2⁰), 35.28 (C-1),

41.22 (–NCH₂CH₃), 42.45 (–NCH₂CH₃), 63.95 (C-1⁰),

125.96, 126.82, 128.20, 130.43, 139.63, 139.75 (the above

mentioned, aromatic), 169.35 (C¼O); HR-MS (EI)

calcd C₁₈H₂₆N₄O 314.2106; obs 314.2119 (M⁺). Anal.

calcd for C₁₈H₂₆N₄O: C, 68.76; H, 8.33; N, 17.82.

Found: C, 68.94; H, 8.24; N, 17.94.

0

J_2,3a=5.0, J_2,3b=8.7, J_2,1=8.7 Hz), 1.73 (2H, m, H-2 ),

3.16 (1H, m, –NCH₂CH₃), 3.26 (1H, m, –NCH₂CH₃),

3.32 (1H, m, H-1⁰), 3.58 (1H, m, –NCH₂CH₃), 3.71 (1H,

m, –NCH₂CH₃), 4.75 (1H, bs,–OH), 7.39 (1H, t, aro-

matic, J=7.7 Hz), 7.47 (1H, t, aromatic, J=7.7 Hz),

7.51 (1H, d, aromatic, J=7.7 Hz), 7.58 (1H, t, aromatic,

J=7.7 Hz), 7.75 (1H, d, aromatic, J=8.2 Hz), 7.81 (1H,

d, aromatic, J=8.2 Hz), 8.90 (1H, d, aromatic,

J=8.6 Hz); ¹³C NMR (125 MHz, CDCl₃) d 10.16 (C-3⁰),

12.26 (–NCH₂CH₃), 12.78 (–NCH₂CH₃), 17.80 (C-3),

29.77 (C-2⁰), 32.50 (C-2), 33.56 (C-1), 40.43

(–NCH₂CH₃), 42.29 (–NCH₂CH₃), 75.23 (C-1⁰), 124.80,

125.75, 125.82, 126.31, 126.42, 128.09, 128.10, 133.25,

133.83, 136.81 (the above mentioned, aromatic), 170.67

(C¼O); HR-MS (EI) calcd C₂₁H₂₇NO₂325.2042; obs

(1S,2R)-1-(3-Methylphenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (28f). Compound 28f

was obtained as an oil in 91% yield: [a]²_D³+72.75(c

2.845, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.94(3H,

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3843

325.2035 (M⁺). Anal. calcd for C₂₁H₂₇NO₂: C, 77.50;

H, 8.36; N, 4.30. Found: C, 77.76; H, 8.58; N, 4.16.

was obtained as an oil in 75% yield: [a]²_D²ꢁ169.35 (c

2.070, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.47 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 0.97 (1H, dd, H-3a,

(1S,2R)-1-(2-Naphthyl)-2-[(S)-1-hydroxypropyl]-N,N-di-

ethylcyclopropanecarboxamide (28i). Compound 28i

was obtained as crystals in 85% yield: mp (hexane/

J_3a,3b=5.0, J_3a,2=9.3 Hz), 1.07 (3H, t, H-3⁰, J_{3 ,}

0

=

2

7.4Hz), 1.13 (3H, t, –NCH ₂CH₃, J=7.1 Hz), 1.67 (1H,

dd, H-3b, J_3b,3a=5.0, J_3b,2=6.4Hz), 1.73–1.86 (2H, m,

25

AcOEt) 99 ^ꢂC; [a]_D+83.52 (c 1.660, CHCl₃); H NMR

H-2⁰), 1.91 (1H, ddd, H-2, J_2,3b=6.4, J_2,3a=9.3,

1

0

J_2,1=9.3 Hz), 2.86 (1H, m, H-1 ), 3.07 (1H, m,

(500 MHz, CDCl₃)

J=7.1 Hz), 1.02 (3H, t, H-3⁰, J_{3 , 2}=7.4Hz), 1.13–1.16

(4H, t, –NCH₂CH₃and H-3a), 1.32 (1H, ddd, H-2,

d

0.91 (3H, t, –NCH₂CH₃,

0

–NCH₂CH₃), 3.19 (1H, m, –NCH₂CH₃), 3.55 (1H, m,

–NCH₂CH₃), 3.67 (1H, m, –NCH₂CH₃), 6.94(2H, m,

aromatic), 7.05 (1H, m, aromatic), 7.27 (1H, m, aro-

matic); ¹³C NMR (125 MHz, CDCl₃) d 10.17 (C-3⁰),

11.94(–NCH ₂CH₃), 12.24(–NCH ₂CH₃), 19.84(C-3),

27.86 (C-2), 28.18 (C-2⁰), 35.58 (C-1), 39.96 (–

NCH₂CH₃), 42.04 (–NCH₂CH₃), 64.00 (C-1⁰), 113.62

(C-4⁰⁰, J_C,F=23 Hz), 113.80 (C-2⁰₀⁰₀, J_C,F=23 Hz), 122.63

(C-6⁰⁰, J_C,F=4Hz), 130.24 (C-5 , J_C,F=9 Hz), 143.51

(C-1⁰⁰, J_C,F=8 Hz), 163.02 (C-3⁰⁰, J_C,F=244 Hz), 168.86

(C¼O); HR-MS (EI) calcd C₁₇H₂₃FN₄O 318.1856; obs

318.1882 (M⁺). Anal. calcd for C₁₇H₂₃FN₄O: C, 64.13;

H, 7.28; N, 17.60. Found: C, 64.30; H, 7.44; N, 17.60.

0

J_2,3a=5.6, J_2,3b=8.5, J_2,1=8.5 Hz), 1.62–1.76 (2H, m,

H-2⁰), 1.85 (1H, dd, H-3b, J_3b,3a=5.6, J_3b,2=8.5 Hz),

3.13 (1H, m, H-1⁰), 3.33–3.49 (3H, m, –NCH₂CH₃), 3.58

(1H, m, –NCH₂CH₃), 5.51 (1H, s,–OH), 7.42–7.47 (3H,

m, aromatic), 7.64(1H, s, aromatic), 7.75–7.79 (3H, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 10.30 (C-3⁰),

12.35 (–NCH₂CH₃), 13.22 (–NCH₂CH₃), 17.01 (C-3),

29.17 (C-2⁰), 33.62 (C-1), 36.62 (C-2), 39.47

(–NCH₂CH₃), 41.93 (–NCH₂CH₃), 75.62 (C-1⁰), 124.17,

124.40, 125.73, 126.23, 127.52, 127.61, 128.45, 132.18,

133.35, 137.85 (the above mentioned, aromatic), 171.40

(C¼O); HR-MS (EI) calcd C₂₁H₂₇NO₂325.2042; obs

325.2046 (M⁺). Anal. calcd for C₂₁H₂₇NO₂: C, 77.50;

H, 8.36; N, 4.30. Found: C, 77.48; H, 8.25; N, 4.22.

(1S,2R)-1-(4-Fluorophenyl)-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (29d). Compound 29d

was obtained as an oil in 92% yield: [a]²_D²ꢁ154.68 (c

1.945, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.42 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 0.92 (1H, dd, H-3a,

General procedure for preparing compounds 29b–i. A

mixture of 28b–i (3.00 mmol), PPh₃2.36g, 9.00mmol),

and CBr₄(2.978g, 9.00mmol) in HMPA (10 mL) was

stirred at 0 ^ꢂC for 30min. After addition of NaN₃(1.95g,

30.0 mmol), the resulting mixture was stirred at room

temperature for 8 h, and then AcOEt and H₂O were

added and partitioned. The organic layer was washed

with brine, dried (Na₂SO₄), and evaporated. The residue

was puriﬁed by ﬂash column chromatography (silica gel;

AcOEt/hexane 0:1, 1:9, and 1:4) to give 29b–i.

J_3a,3b=4.9, J_3a,2=9.3 Hz), 1.07 (3H, t, H-3⁰, J_{3 ,}

0

=

2

7.4Hz), 1.12 (3H, t, –NCH ₂CH₃, J=7.1 Hz), 1.64(1H,

dd, H-3b, J_3b,3a=4.9, J_3b,2=6.1 Hz), 1.72–1.86 (2H, m,

H-2⁰), 1.89 (1H, ddd, H-2, J_2,3b=6.1, J_2,3a=9.3,

0

J_2,1=9.6 Hz), 2.87 (1H, m, H-1 ), 3.04(1H, m,

–NCH₂CH₃), 3.18 (1H, m, –NCH₂CH₃), 3.53 (1H, m,

–NCH₂CH₃), 3.70 (1H, m, –NCH₂CH₃), 6.98–7.02 (2H,

m, aromatic), 7.20–7.25 (2H, m, aromatic). ¹³C NMR

(125 MHz, CDCl₃) d 10.21 (C-3⁰), 12.03 (–NCH₂CH₃),

12.30 (–NCH₂CH₃), 19.55 (C-3), 27.69 (C-2), 28.23 (C-

2⁰), 35.30 (C-1), 40.02 (–NCH₂CH₃), 42.00

(–NCH₂CH₃), 64.16 (C-1⁰), 115.60 (C-3⁰⁰and C-5⁰⁰,

J_C,F=23 Hz), 128.70 (C-2⁰⁰and C-6⁰⁰, J_C,F=8 Hz),

136.75 (C-1⁰⁰, J_C,F=4Hz), 161.52 (C-4 ⁰⁰, J_C,F=245 Hz),

169.24(C ¼O); HR-MS (EI) calcd C₁₇H₂₃FN₄O

318.1856; obs 318.1835 (M⁺). Anal. calcd for

C₁₇H₂₃FN₄O: C, 64.13; H, 7.28; N, 17.60. Found: C,

64.43; H, 7.28; N, 17.36.

(1S,2R)-1-(2-Fluorophenyl)-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (29b). Compound 29b

was obtained as an oil in 99% yield: [a]²_D²ꢁ249.30 (c

3.075, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.33 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 0.89 (1H, dd, H-3a,

J_3a,3b=4.6, J_3a,2=9.3 Hz), 1.08 (3H, t, H-3⁰, J_{3 ,}

0

=

2

7.4Hz), 1.12 (3H, t, –NCH ₂CH₃, J=7.1 Hz), 1.73–1.86

(2H, m, H-2⁰), 1.93 (1H, dd, H-3b, J_3b,3a=4.6,

J_3b,2=6.5 Hz), 2.05 (1H, ddd, H-2, ₀J_2,3b=6.5,

0

J_2,3a=9.3, J_2,1=9.3 Hz), 2.87 (1H, m, H-1 ), 3.01 (1H,

m, –NCH₂CH₃), 3.18 (1H, m, –NCH₂CH₃), 3.47 (1H,

m, –NCH₂CH₃), 3.78 (1H, m, –NCH₂CH₃), 7.03 (1H,

m, aromatic), 7.11 (1H, m, aromatic), 7.23 (1H, m,

aromatic), 7.30 (1H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 10.25 (C-3⁰), 11.88 (–NCH₂CH₃), 12.29 (–

NCH₂CH₃), 19.36 (C-3), 27.41 (C-2), 28.12 (C-2⁰), 31.34

(C-1), 40.64 (–NCH₂CH₃), 42.03 (–NCH₂CH₃), 63.74

(C-1⁰), 115.92 (C-3⁰⁰, J_C,F=23 Hz), 124.39 (C-6⁰⁰,

J_C,F=4Hz), 128.55 (C-1 ⁰⁰, J_C,F=11 Hz), 128.61 (C-4⁰⁰,

J_C,F=8 Hz), 129.27 (C-5⁰⁰, J_C,F=4Hz), 161.93 (C-2 ⁰⁰,

J_C,F=246 Hz), 168.75 (C¼O); HR-MS (EI) calcd

C₁₇H₂₃FN₄O 318.1856; obs 318.1842 (M⁺). Anal. calcd

for C₁₇H₂₃FN₄O: C, 64.13; H, 7.28; N, 17.60. Found: C,

64.53; H, 7.40; N, 17.66.

(1S,2R)-1-(2-Methylphenyl)-2-[(S)-1-hydroxypropyl]-N,N-

diethylcyclopropanecarboxamide (29e). Compound 29e

was obtained as crystals in 87% yield: mp (hexane/

22

AcOEt) 137–138 ^ꢂC; [a]_D+94.76 (c 1.515, CHCl₃); H

1

NMR (500 MHz, CDCl₃) d 0.60 (3H, t, –NCH₂CH₃,

J=7.0 Hz), 1.01 (3H, t, H-3⁰, J_{3 , 2}=7.5 Hz), 1.07 (3H,

t, –NCH₂CH₃, J=7.0 Hz), 1.20 (1H, dd, H-3a,

J_3a,3b=5.5, J_3a,2=5.5 Hz), 1.36 (1H, ddd, H-2,

0

J_2,3a=5.5, J_2,3b=8.8, J_2,1=8.8 Hz), 1.51 (1H, dd, H-3b,

J_3b,3a=5.5, J_3b,2=8.8 Hz), 1.65–1.74(2H, m, H-2 ⁰), 2.53

(3H, s, Me–Ph–), 3.20–3.38 (3H, m, H-1⁰and

–NCH₂CH₃), 3.53–3.57 (2H, m, –NCH₂CH₃), 4.66 (1H,

bs,–OH), 7.13–7.14(3H, m, aromatic), 7.27 (1H, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 10.22 (C-3⁰),

12.45 (–NCH₂CH₃), 12.84(–NCH ₂CH₃), 17.37 (C-3),

20.36 (Me–Ph–), 29.66 (C-2⁰), 33.25 (C-2), 33.67 (C-1),

40.45 (–NCH₂CH₃), 42.17 (–NCH₂CH₃), 75.18 (C-1⁰),

(1S,2R)-1-(3-Fluorophenyl)-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (29c). Compound 29c

3844

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

125.67, 127.05, 128.55, 131.05, 138.60, 140.33 (the above

mentioned, aromatic), 170.48 (C¼O); HR–MS (EI)

calcd C₁₈H₂₇NO₂289.2042; obs 289.2045 (M⁺). Anal.

calcd for C₁₈H₂₇NO₂: C, 74.70; H, 9.40; N, 4.84. Found:

C, 74.99; H, 9.22; N, 4.79.

aromatic), 7.76 (1H, t, aromatic, J=8.2 Hz), 7.83 (1H, t,

aromatic, J=7.7 Hz), 8.40 (1H, t, aromatic, J=8.2 Hz);

¹³C NMR (125 MHz, CDCl₃) d 10.33 (C-3⁰), 11.97

(–NCH₂CH₃), 12.38 (–NCH₂CH₃), 19.61 (C-3), 28.30

(C-2⁰), 28.59 (C-2), 35.12 (C-1), 41.26 (–NCH₂CH₃),

42.44 (–NCH₂CH₃), 64.01 (C-1⁰), 124.99, 125.23,

125.70, 125.99, 126.60, 127.81, 128.38, 133.53, 133.74,

137.82 (the above mentioned, aromatic), 169.73 (C¼O);

HR-MS (EI) calcd C₂₁H₂₆N₄O 350.2106; obs 350.2111

(M⁺). Anal. calcd for C₂₁H₂₆N₄O: C, 71.97; H, 7.48; N,

15.99. Found: C, 72.23; H, 7.67; N, 15.78.

(1S,2R)-1-(3-Methylphenyl)-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (29f). Compound 29f

was obtained as an oil in 69% yield: [a]²_D³ꢁ160.13 (c

2.730, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.39 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 0.93 (1H, dd, H-3a,

J_3a,3b=4.8, J_3a,2=9.2 Hz), 1.07 (3H, t, H-3⁰, J_{3 ,}

0

=

2

7.5 Hz), 1.13 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.64(1H,

dd, H-3b, J_3b,3a=4.8, J_3b,2=5.5 Hz), 1.72–1.88 (2H, m,

(1S,2R)-1-(2-Naphthyl)-2-[(S)-1-azidopropyl]-N,N-diethyl-

cyclopropanecarboxamide (29i). Compound 29i was

obtained as an oil in 81% yield: [a]²_D³ꢁ252.85 (c 2.200,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.29 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.01 (1H, dd, H-3a,

H-2⁰), 1.95 (1H, ddd, H-2, J_2,3b=5.5, J_2,3a=9.2,

0

J_2,1=9.2 Hz), 2.32 (3H, s, Me–Ph–), 2.85 (1H, m, H-1 ),

3.03 (1H, m, –NCH₂CH₃), 3.16 (1H, m, –NCH₂CH₃),

3.54(1H, m, –N CH₂CH₃), 3.72 (1H, m, –NCH₂CH₃),

7.02–7.07 (3H, m, aromatic), 7.19 (1H, m, aromatic);

¹³C NMR (125 MHz, CDCl₃) d 10.25 (C-3⁰), 11.84

(–NCH₂CH₃), 12.28 (–NCH₂CH₃), 19.64(C-3), 21.31

(Me–Ph–), 27.22 (C-2), 28.27 (C-2⁰), 35.83 (C-1), 39.92

(–NCH₂CH₃), 42.05 (–NCH₂CH₃), 64.25 (C-1⁰), 123.83,

127.35, 127.79, 128.59, 138.36, 140.72 (the above men-

tioned, aromatic), 169.60 (C¼O); HR-MS (EI) calcd

C₁₈H₂₆N₄O 314.2106; obs 314.2100 (M⁺). Anal. calcd

for C₁₈H₂₆N₄O: C, 68.76; H, 8.33; N, 17.82. Found: C,

69.12; H, 8.56; N, 17.95.

J_3a,3b=5.0, J_3a,2=9.3 Hz), 1.10 (3H, t, H-3⁰, J_{3 ,}

0

₂=7.4Hz), 1.15 (3H, t, –NCH ₂CH₃, J=7.0 Hz), 1.73

(1H, dd, H-3b, J_3b,3a=5.0, J_3b,2=6.2 Hz), 1.77–1.92

(2H, m, H-2⁰), 2.10 (1H, ddd, H-2, J_2,3b=6.2, J_2,3a=9.3,

0

J_2,1=9.3 Hz), 2.92 (1H, m, H-1 ), 3.07 (1H, m,

–NCH₂CH₃), 3.19 (1H, m, –NCH₂CH₃), 3.56 (1H, m,

–NCH₂CH₃), 3.78 (1H, m, –NCH₂CH₃), 7.39–7.48 (3H,

m, aromatic), 7.66 (1H, d, aromatic, J=0.7 Hz), 7.77–

7.80 (3H, m, aromatic); ¹³C NMR (125 MHz, CDCl₃) d

0

10.24(C-3 ), 11.98 (–NCH₂CH₃), 12.31 (–NCH₂CH₃),

19.89 (C-3), 27.61 (C-2), 28.28 (C-2⁰), 36.09 (C-1), 39.94

(–NCH₂CH₃), 42.03 (–NCH₂CH₃), 64.23 (C-1⁰), 124.75,

125.73, 125.80, 126.29, 127.56, 128.42, 132.14, 133.44,

138.40 (the above mentioned, aromatic), 169.36 (C¼O);

HR-MS (EI) calcd C₂₁H₂₆N₄O 350.2106; obs 350.2096

(M⁺). Anal. calcd for C₂₁H₂₆N₄O: C, 71.97; H, 7.48; N,

15.99. Found: C, 72.36; H, 7.45; N, 15.79.

(1S,2R)-1-(4-Methylphenyl)-2-[(S)-1-azidopropyl]-N,N-di-

ethylcyclopropanecarboxamide (29g). Compound 29g

was obtained as an oil in 90% yield: [a]²_D³ꢁ160.87 (c

2.545, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.40 (3H,

t, –NCH₂CH₃, J=7.0 Hz), 0.92 (1H, dd, H-3a,

J_3a,3b=4.8, J_3a,2=9.2 Hz), 1.06 (3H, t, H-3⁰, J_{3 ,}

0

=

2

7.4Hz), 1.12 (3H, t, –NCH ₂CH₃, J=7.0 Hz), 1.62 (1H,

dd, H-3b, J_3b,3a=4.8, J_3b,2=5.2 Hz), 1.74–1.87 (2H, m,

General procedure for preparing 4b–i. A mixture of 29b–

i (1.00 mmol) and 10% Pd-charcoal (50 mg) in MeOH

(5 mL) was stirred under atmospheric pressure of

hydrogen at room temperature for 3 h, and then the

catalyst was ﬁltered oﬀ. The ﬁltrate was evaporated,

and the residue was puriﬁed by column chromato-

graphy (silica gel; AcOEt/hexane 1:1 then CHCl₃/

MeOH 4:1) to give free amine 4b–i as an oil. A solution

of the oil in MeOH (5 mL) was put on a column of

Diaion WA-30 resin (Cl^ꢁform), and the column was

developed with MeOH. The solvent was evaporated,

and the residue was treated with Et₂O to give white

crystals of 4b–i as hydrochloride.

H-2⁰), 1.92 (1H, ddd, H-2, J_2,3b=5.2, J_2,3a=9.2,

0

J_2,1=9.2 Hz), 2.31 (3H, s, Me–Ph–), 2.85 (1H, m, H-1 ),

3.03 (1H, m, –NCH₂CH₃), 3.18 (1H, m, –NCH₂CH₃),

3.51 (1H, m, –NCH₂CH₃), 3.71 (1H, m, –NCH₂CH₃),

7.09–7.15 (4H, m, aromatic). ¹³C NMR (125 MHz,

CDCl₃) d 10.21 (C-3⁰), 11.93 (–NCH₂CH₃), 12.30

(–NCH₂CH₃), 19.53 (C-3), 20.91 (Me–Ph–), 27.33 (C-2),

0

28.24(C-2 ), 35.55 (C-1), 39.92 (–NCH₂CH₃), 42.05

(–NCH₂CH₃), 64.23 (C-1⁰), 126.84, 129.33, 136.24,

137.84(the above mentioned, aromatic), 169.63 (C ¼O);

HR-MS (EI) calcd C₁₈H₂₆N₄O 314.2106; obs 314.2107

(M⁺). Anal. calcd for C₁₈H₂₆N₄O: C, 68.76; H, 8.33; N,

17.82. Found: C, 69.08; H, 8.58; N, 17.47.

(1S,2R)-1-(2-Fluorophenyl)-2-[(S)-1-aminopropyl]-N,N-di-

ethylcyclopropanecarboxamide hydrochloride (4b). Yield

95%: [a]²_D²+153.87 (c 1.005, MeOH); mp (Et₂O) 231–

232 ^ꢂC; ¹H NMR (500 MHz, CD₃OD) d 0.85 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.07 (3H, t, –NCH₂CH₃,

(1S,2R)-1-(1-Naphthyl)-2-[(S)-1-azidopropyl]-N,N-diethyl-

cyclopropanecarboxamide (29h). Compound 29h was

obtained as crystals in 82% yield: mp (hexane/AcOEt)

94–95 ^ꢂC; [a]_D²²ꢁ281.31 (c 1.115, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d ꢁ0.06 (3H, t, –NCH₂CH₃,

J=7.0 Hz), 0.88 (1H, dd, H-3a, J_3a,3b=3.6,

J=7.1 Hz), 1.09 (3H, t, H-3⁰, J_{3 , 2}=7.5 Hz), 1.20 (1H,

0

ddd, H-2, J_2,3a=6.0, J_2,3b=9.0, J_2,1=9.0 Hz), 1.40 (1H,

dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz), 1.77–1.96 (2H, m,

H-2⁰), 2.17 (1H, dd, H-3b, J_3b,3a=6.0, J_3b,2=9.0 Hz),

2.87 (1H, m, H-1⁰), 3.28–3.39 (2H, m, –NCH₂CH₃), 3.50

(1H, m, –NCH₂CH₃), 3.76 (1H, m, –NCH₂CH₃), 7.14

(1H, m, aromatic), 7.22 (1H, m, aromatic), 7.36 (1H, m,

aromatic), 7.51 (1H, m, aromatic); ¹³C NMR (125 MHz,

CD₃OD) d 10.45 (C-3⁰), 12.58 (–NCH₂CH₃), 13.38

J_3a,2=8.3 Hz), 1.02 (3H, t, –NCH₂CH₃, J=7.0 Hz), 1.12

0

(3H, t, H-3⁰, J_{3 , 2}=7.4Hz), 1.83–1.95 (2H, m, H-2 ),

2.15–2.20 (2H, m, H-3b and H-2), 2.93 (1H, m,

–NCH₂CH₃), 3.00–3.07 (2H, m, H-1⁰and –NCH₂CH₃),

3.39 (1H, m, –NCH₂CH₃), 4.04 (1H, m, –NCH₂CH₃),

7.42 (1H, t, aromatic, J=7.7 Hz), 7.46–7.54 (3H, m,

0

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3845

(–NCH₂CH₃), 18.19 (C-3), 27.71 (C-2⁰), 30.25 (C-1),

30.82 (C-2), 41.34 (–NCH₂CH₃), 43.44 (–NCH₂CH₃),

57.62 (C-1⁰), 117.13 (C-3⁰⁰, J_C,F=23 Hz), 126.05 (C-6⁰⁰,

J_C,F=3 Hz), 127.68 (C-1⁰⁰, J_C,F=13 Hz), 131.06 (C-4⁰⁰

and C-5⁰⁰, J_C,F=8 Hz), 163.46 (C-2⁰⁰, J_C,F=246 Hz),

171.55 (C¼O); HR-MS (EI) calcd C₁₇H₂₅FN₂O

292.1951; obs 292.1927 (M⁺–HCl). Anal. calcd for

C₁₇H₂₆FClN₂O: C, 62.09; H, 7.97; N, 8.52; Cl, 10.78.

Found: C, 61.76; H, 7.91; N, 8.52; Cl, 10.91.

0

J_2,1=9.0 Hz), 1.30 (1H, dd, H-3a, J_3a,3b=6.0,

J_3a,2=6.0 Hz), 1.81–1.94(2H, m, H-2 ), 2.18 (1H, dd,

0

H-3b, J_3b,3a=6.0, J_3b,2=9.0 Hz), 2.50 (3H, s, Me–Ph–),

2.91 (1H, m, H-1⁰), 3.23–3.39 (3H, m, –NCH₂CH₃), 3.78

(1H, m, –NCH₂CH₃), 7.19–7.22 (3H, m, aromatic), 7.41

(1H, m, aromatic); ¹³C NMR (125 MHz, CD₃OD) d

10.56 (C-3⁰), 12.78 (–NCH₂CH₃), 13.14(–NCH CH₃),

2

19.20 (C-3), 21.07 (Me–Ph–), 27.98 (C-2⁰), 30.18 (C-2),

35.08 (C-1), 41.81 (–NCH₂CH₃), 43.65 (–NCH₂CH₃),

58.19 (C-1⁰), 127.67, 129.04, 130.10, 132.45, 138.17,

140.34 (the above mentioned, aromatic), 172.22 (C¼O);

HR-MS (EI) calcd C₁₈H₂₈N₂O 288.2201; obs 288.2225

(M⁺–HCl). Anal. calcd for C₁₈H₂₉ClN₂O: C, 66.54; H,

9.00; N, 8.62; Cl, 10.91. Found: C, 66.49; H, 9.06; N,

8.52; Cl, 10.93.

(1S,2R)-1-(3-Fluorophenyl)-2-[(S)-1-aminopropyl]-N,N-di-

ethylcyclopropanecarboxamide hydrochloride (4c). Yield

86%: mp (Et₂O) 203–204 ^ꢂC; [a]²_D³+87.22 (c 1.115,

1

MeOH); H NMR (500 MHz, CD₃OD) d 0.93 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.09 (3H, t, H-3⁰, J_{3 ,}

7.5 Hz), 1.15 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.23 (1H,

0

=

2

0

ddd, H-2, J_2,3a=6.4, J_2,3b=9.1, J_2,1=9.1 Hz), 1.42 (1H,

(1S,2R)-1-(3-Methylphenyl)-2-[(S)-1-aminopropyl]-N,N-

diethylcyclopropanecarboxamide hydrochloride (4f).

Yield 93%: mp (Et₂O) 185–187 ^ꢂC: [a]_D²³ꢁ160.13 (c

2.730, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 0.39 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 0.93 (1H, dd, H-3a,

dd, H-3a, J_3a,3b=6.4, J_3a,2=6.4Hz), 1.76–1.91 (2H, m,

H-2⁰), 2.17 (1H, dd, H-3b, J_3b,3a=6.4, J_3b,2=9.1 Hz),

2.78 (1H, m, H-1⁰), 3.39 (1H, m, –NCH₂CH₃), 3.43–3.50

(3H, m, –NCH₂CH₃), 7.00–7.16 (3H, m, aromatic), 7.39

(1H, m, aromatic); ¹³C NMR (125 MHz, CD₃OD) d

J_3a,3b=4.8, J_3a,2=9.2 Hz), 1.07 (3H, t, H-3⁰, J_{3 ,}

0

=

2

10.33 (C-3⁰), 12.52 (–NCH₂CH₃), 13.24(–NCH CH₃),

7.5 Hz), 1.13 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.64(1H,

dd, H-3b, J_3b,3a=4.8, J_3b,2=5.5 Hz), 1.72–1.88 (2H, m,

2

18.99 (C-3), 27.72 (C-2⁰), 33.19 (C-2), 34.31 (C-1), 41.00

0

(–NCH₂CH₃), 43.60 (–NCH₂CH₃), 57.64(C-1 ), 113.88

H-2⁰), 1.95 (1H, ddd, H-2, J_2,3b=5.5, J_2,3a=9.2,

(C-4⁰⁰, J_C,F=23 Hz), 115.15 (C-2⁰⁰, J_C,F=21 Hz), 122.71

(C-6⁰⁰, J_C,F=3 Hz), 131.95 (C-5⁰⁰, J_C,F=9 Hz), 143.26

(C-1⁰⁰, J_C,F=8 Hz), 164.60 (C-3⁰⁰, J_C,F=244 Hz), 172.14

(C¼O); HR-MS (EI) calcd C₁₇H₂₅FN₂O 292.1951; obs

292.1944 (M⁺–HCl). Anal. calcd for C₁₇H₂₆FClN₂O:

C, 62.09; H, 7.97; N, 8.52; Cl, 10.78. Found: C, 62.25;

H, 7.87; N, 8.41; Cl, 10.68.

J_2,1=9.2 Hz), 2.32 (3H, s, Me–Ph–), 2.85 (1H, m, H-1 ),

0

3.03 (1H, m, –NCH₂CH₃), 3.16 (1H, m, –NCH₂CH₃),

3.54(1H, m, –N CH₂CH₃), 3.72 (1H, m, –NCH₂CH₃),

7.02–7.07 (3H, m, aromatic), 7.19 (1H, m, aromatic);

¹³C NMR (125 MHz, CDCl₃) d 10.25 (C-3⁰), 11.84

(–NCH₂CH₃), 12.28 (–NCH₂CH₃), 19.64(C-3), 21.31

(Me–Ph–), 27.22 (C-2), 28.27 (C-2⁰), 35.83 (C-1), 39.92

(–NCH₂CH₃), 42.05 (–NCH₂CH₃), 64.25 (C-1⁰), 123.83,

127.35, 127.79, 128.59, 138.36, 140.72 (the above men-

tioned, aromatic), 169.60 (C¼O); HR-MS (EI) calcd

C₁₈H₂₆N₄O 314.2106; obs 314.2100 (M⁺). Anal. calcd

for C₁₈H₂₆N₄O: C, 68.76; H, 8.33; N, 17.82. Found: C,

69.12; H, 8.56; N, 17.95.

(1S,2R)-1-(4-Fluorophenyl)-2-[(S)-1-aminopropyl]-N,N-di-

ethylcyclopropanecarboxamide hydrochloride (4d). Yield

85%: mp (Et₂O) 215–217 ^ꢂC; [a]²_D²+95.11 (c 1.115,

1

MeOH); H NMR (500 MHz, CD₃OD) d 0.90 (3H, t,

–NCH₂CH₃, J=7.1 Hz), 1.08 (3H, t, H-3⁰, J_{3 ,}

7.5 Hz), 1.12 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.16 (1H,

0

=

2

0

ddd, H-2, J_2,3a=6.2, J_2,3b=9.1, J_2,1=10.1 Hz), 1.37

(1S,2R)-1-(4-Methylphenyl)-2-[(S)-1-aminopropyl]-N,N-

diethylcyclopropanecarboxamide hydrochloride (4g).

Yield 87%; mp (Et₂O) 218–219 ^ꢂC; [a]_D²³+88.74( c

(1H, dd, H-3a, J_3a,3b=6.2, J_3a,2=6.2 Hz), 1.75–1.90

(2H, m, H-2⁰), 2.13 (1H, dd, H-3b, J_3b,3a=6.2,

J_3b,2=9.1 Hz), 2.75 (1H, m, H-1⁰), 3.36 (1H, m,

–NCH₂CH₃), 3.41 (1H, m, –NCH₂CH₃), 3.44–3.52 (2H,

m, –NCH₂CH₃), 7.06–7.10 (2H, m, aromatic), 7.35–7.38

(2H, m, aromatic); ¹³C NMR (125 MHz, CD₃OD) d

10.35 (C-3⁰), 12.55 (–NCH₂CH₃), 13.28 (–NCH₂CH₃),

18.70 (C-3), 27.72 (C-2⁰), 32.60 (C-2), 34.04 (C-1), 40.96

(–NCH₂CH₃), 43.53 (–NCH₂CH₃), 57.71 (C-1⁰), 116.75

1

1.275, MeOH); H NMR (500 MHz, CD₃OD) d 0.90

(3H, t, –NCH₂CH₃, J=7.1 Hz), 1.09 (3H, t, H-3⁰, J_{3 , 2}

7.5 Hz), 1.13 (3H, t, –NCH₂CH₃, J=7.1 Hz), 1.15 (1H,

0

=

0

ddd, H-2, J_2,3a=6.0, J_2,3b=9.0, J_2,1=9.0 Hz), 1.35 (1H,

dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz), 1.78–1.91 (2H, m,

H-2⁰), 2.12 (1H, dd, H-3b, J_3b,3a=6.0, J_3b,2=9.0 Hz),

2.30 (3H, s, Me–Ph–), 2.76 (1H, m, H-1⁰), 3.36 (1H, m,

–NCH₂CH₃), 3.41–3.48 (3H, m, –NCH₂CH₃), 7.16–7.21

(4H, m, aromatic); ¹³C NMR (125 MHz, CD₃OD) d

10.35 (C-3⁰), 12.55 (–NCH₂CH₃), 13.23 (–NCH₂CH₃),

18.60 (C-3), 20.98 (Me–Ph–), 27.72 (C-2⁰), 32.66 (C-2),

34.19 (C-1), 40.90 (–NCH₂CH₃), 43.53 (–NCH₂CH₃),

57.81 (C-1⁰), 126.82, 130.67, 137.27, 138.29 (the above

mentioned, aromatic), 172.85 (C¼O); HR-MS (EI)

calcd C₁₈H₂₈N₂O 288.2201; obs 288.2192 (M⁺–HCl).

Anal. calcd for C₁₈H₂₉ClN₂O: C, 66.54; H, 9.00; N,

8.62; Cl, 10.91. Found: C, 66.69; H, 9.09; N, 8.62; Cl,

10.87.

00

(C-3⁰⁰and C-5⁰⁰, J_C,F=21 Hz), 129.14(C-2 and C-6⁰⁰),

136.33 (C-1⁰⁰), 163.34(C-4 ⁰⁰, J_C,F=244 Hz), 172.47

(C¼O); HR-MS (EI) calcd C₁₇H₂₅FN₂O 292.1951; obs

292.1956 (M⁺–HCl). Anal. calcd for C₁₇H₂₅FN₂O: C,

62.09; H, 7.97; N, 8.52; Cl, 10.78. Found: C, 61.64; H,

7.87; N, 8.51; Cl, 11.10.

(1S,2R)-1-(2-Methylphenyl)-2-[(S)-1-aminopropyl]-N,N-

diethylcyclopropanecarboxamide hydrochloride (4e).

Yield 89%: mp (Et₂O) 192–193 ^ꢂC ; [a]_D²²+230.34( c

1

1.225, MeOH); H NMR (500 MHz, CD₃OD) d 0.61

(3H, t, –NCH₂CH₃, J=7.1 Hz), 1.07 (3H, t,

0

–NCH₂CH₃, J=7.1 Hz), 1.10 (3H, t, H-3⁰, J_{3 ,}

7.5 Hz), 1.14(1H, ddd, H-2, J_2,3a=6.0, J_2,3b=9.0,

(1S,2R)-1-(1-Naphthyl)-2-[(S)-1-aminopropyl]-N,N-diethyl-

cyclopropanecarboxamide hydrochloride (4h). Yield

0

=

2

3846

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

80%: mp (Et₂O) 132–134 ^ꢂC; [a]²_D²+68.91 (c 1.075,

J_4,1=6.7 Hz), 7.07 (1H, m, aromatic ), 7.14(1H, m,

aromatic), 7.30–7.36 (2H, m, aromatic); ¹³C NMR

(125 MHz, CDCl₃) d 9.23₀(C-2⁰), 17.53 (C-6), 28.40 (C-1),

0

1

MeOH); H NMR (500 MHz, CD₃OD) d 0.47 (3H, t,

–NCH₂CH₃, J=7.0 Hz), 0.99 (3H, t, –NCH₂CH₃,

J=7.0 Hz), 1.11 (3H, t, H-3⁰, J_{3 , 2}=7.4Hz), 1.22 (1H,

28.94(C-5), 29.16 (C-1 ), 81.83 (C-4), 115.62 (C-3 ,

00

0

J_C,F=21 Hz), 121.77 (C-1⁰⁰, J_C,F=14Hz), 124.25 (C-6 ,

0

ddd, H-2, J_2,3a=6.0, J_2,3b=8.4, J_2,1=8.4Hz), 1.44(1H,

dd, H-3a, J_3a,3b=6.0, J_3a,2=6.0 Hz), 1.79–1.92 (2H, m,

H-2⁰), 2.33 (1H, dd, H-3b, J_3b,3a=6.0, J_3b,2=8.4Hz),

3.05 (1H, m, –NCH₂CH₃), 3.07 (1H, m, H-1⁰), 3.26 (1H,

m, –NCH₂CH₃), 3.42 (1H, m, –NCH₂CH₃), 3.83 (1H,

m, –NCH₂CH₃), 7.48–7.55 (2H, m, aromatic), 7.61–7.67

(2H, m, aromatic), 7.86 (1H, d, aromatic, J=8.0 Hz),

7.92 (1H, d, aromatic, J=8.0 Hz), 8.61 (1H, d, aro-

matic, J=8.5 Hz); ¹³C NMR (125 MHz, CD₃OD) d

10.45 (C-3⁰), 12.71 (–NCH₂CH₃), 13.10 (–NCH₂CH₃),

19.12 (C-3), 28.09 (C-2⁰), 30.78 (C-2), 35.09 (C-1), 41.89

(–NCH₂CH₃), 43.73 (–NCH₂CH₃), 57.99 (C-1⁰), 125.56,

126.59, 127.12, 127.82, 127.88, 130.03, 130.05, 134.33,

135.41, 136.34 (the above mentioned, aromatic), 172.72

(C¼O); HR-MS (EI) calcd C₂₁H₂₈N₂O 324.2202; obs

J_C,F=4Hz), 130.09 (C-4 ⁰⁰, J_C,F=9 Hz), 131.63 (C-5⁰⁰,

J_C,F=3 Hz), 162.03 (C-2⁰⁰, J_C,F=246 Hz), 175.01

(C¼O); HR-MS (EI) calcd C₁₃H₁₃FO₂220.0899; obs

220.0881 (M⁺).

(1S,4S,5R)-2-Oxo-4-ethyl-1-(3-ﬂuorophenyl)-3-oxabicyclo

[3.1.0]hexane (30c). Compound 30c was obtained quan-

1

titatively as an oil: H NMR (500 MHz, CDCl₃) d 1.06

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.38 (1H, dd, H-6a,

J_6a,5=4.7, J_6a,6b=4.9 Hz), 1.62 (1H, dd, H-6b,

J_6b,6a=4.9, J_6b,5=7.9 Hz), 1.81 (2H, m, H-1⁰), 2.36 (1H,

dd, H-5, J_5,6a=4.7, J_5,6b=7.9 Hz), 4.36 (1H, t, H-4,

0

J_4,1=5.9 Hz), 6.98 (1H, m, aromatic ), 7.16 (2H, m,

aromatic), 7.31 (1H, m, aromatic); ¹³C NMR (125 MHz,

CDCl₃) d 8.47 (C-2⁰), 20.47 (C-6), 29.20 (C-5), 29.86 (C-

1⁰), 31.68 (C-1), 80.63 (C-4), 114.54 (C-4⁰⁰, J_C,F=21 Hz),

115.26 (C-2⁰⁰, J_C,F=23 Hz), 123.59 (C-6⁰⁰, J_C,F=3 Hz),

130.10 (C-5⁰⁰, J_C,F=9 Hz), 136.75 (C-1⁰⁰, J_C,F=8 Hz),

162.74(C-3 ⁰⁰, J_C,F=244 Hz), 174.93 (C¼O); HR-MS

(EI) calcd C₁₃H₁₃FO₂220.0899; obs 220.0879 (M⁺).

324.2181

(M⁺–HCl).

Anal.

calcd

for

.

C₂₁H₂₉ClN₂O H₂O: C, 66.56; H, 8.25; N, 7.39; Cl, 9.36.

Found: C, 66.72; H, 9.94; N, 7.06; Cl, 9.46.

(1S,2R)-1-(2-Naphthyl)-2-[(S)-1-aminopropyl]-N,N-diethyl-

cyclopropanecarboxamide hydrochloride (4i). Yield 90%:

mp (Et₂O) 216–217 ^ꢂC; [a]²_D²+99.57 (c 1.285, MeOH); ¹H

NMR (500MHz, CD₃OD) d 0.77 (3H, t, –NCH₂CH₃,

(1S,4S,5R)-2-Oxo-4-ethyl-1-(4-ﬂuorophenyl)-3-oxabicyclo

[3.1.0]hexane (30d). Compound 30d was obtained as an

J=7.1 Hz), 1.02 (3H, t, H-3⁰, J_{3 , 2}= 7.5 Hz), 1.07 (3H,

t, –NCH₂CH₃, J=7.1 Hz), 1.17 (1H, ddd, H-2,

0

1

oil in 94% yield: H NMR (500 MHz, CDCl₃) d 1.06

J_2,3a=6.2, J_2,3b=9.0, J_2,1=9.0 Hz), 1.37 (1H, dd, H-3a,

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.35 (1H, dd, H-6a,

J_6a,5=4.6, J_6a,6b=4.8 Hz), 1.58 (1H, dd, H-6b,

J_6b,6a=4.8, J_6b,5=7.8 Hz), 1.81 (2H, m, H-1⁰), 2.32 (1H,

dd, H-5, J_5,6a=4.6, J_5,6b=7.8 Hz), 4.35 (1H, t, H-4,

0

J_3a,3b=6.2, J_3a,2=6.2 Hz), 1.70–1.81 (2H, m, H-2⁰), 2.24

(1H, dd, H-3b, J_3b,3a=6.2, J_3b,2=9.0 Hz), 2.74(1H, m,

H-1⁰), 3.30 (1H, m, –NCH₂CH₃), 3.35–3.44 (3H, m,

–NCH₂CH₃), 7.36–7.41 (3H, m, aromatic), 7.69 (1H, s,

aromatic), 7.73–7.78 (3H, m, aromatic); ¹³C NMR

(125 MHz, CD₃OD) d 10.34(C-3 ⁰), 12.57 (–NCH₂CH₃),

13.21 (–NCH₂CH₃), 18.69 (C-3), 27.76 (C-2⁰), 32.98 (C-

2), 34.75 (C-1), 40.98 (–NCH₂CH₃), 43.58

(–NCH₂CH₃), 57.77 (C-1⁰), 124.97, 125.55, 127.32,

127.68, 128.70, 129.88, 133.93, 134.93, 137.68, (the

above mentioned, aromatic), 172.66 (C¼O); HR-MS

(EI) calcd C₂₁H₂₈N₂O 324.2202; obs 324.2181 (M⁺–

HCl). Anal. calcd for C₂₁H₂₉ClN₂O: C, 69.88; H, 8.10;

N, 7.76; Cl, 9.82. Found: C, 69.81; H, 8.08; N, 7.74; Cl,

9.75.

0

J_4,1=6.0 Hz), 7.03 (2H, t, aromatic, J=8.5 Hz), 7.35–

7.38 (2H, m, aromatic); ¹³C NMR (125 MHz, CDCl₃) d

8.61 (C-2⁰), 20.07 (C-6), 29.37 (C-1⁰), 29.52 (C-5), 31.75

(C-1), 80.79 (C-4), 115.56 (C-3⁰⁰and C-5⁰⁰, J_C,F=23 Hz),

130.11 (C-1⁰⁰, J_C,F=3 Hz), 130.21 (C-2⁰⁰and C-6⁰⁰,

J_C,F=9 Hz), 162.27 (C-4⁰⁰, J_C,F=245 Hz), 175.55

(C¼O); HR-MS (EI) calcd C₁₃H₁₃FO₂220.0899; obs

220.0889 (M⁺).

(1S,4S,5R)-2-Oxo-4-ethyl-1-(2-methylphenyl)-3-oxabicyclo

[3.1.0]hexane (30e). Compound 30e was obtained as an

1

oil in 62% yield: H NMR (500 MHz, CDCl₃) d 1.12

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.39 (1H, dd, H-6a,

J_6a,5=4.4, J_6a,6b=4.6 Hz), 1.52 (1H, dd, H-6b,

0

General procedure for preparing 30b–i. A solution of

28a–i (1.00 mmol) and 6 N HCl (1 mL) in MeOH (2 mL)

was heated under reﬂux for 2 h. The solvent was evapo-

rated, and then the residue was partitioned between

saturated aqueous NaHCO₃and AcOEt. The organic

layer was washed with brine, dried (Na₂SO₄) and eva-

porated. The residue was puriﬁed by column chroma-

tography (silica gel; AcOEt/hexane 1:4) to give 32b–i.

0

J_6b,6a=4.6, J_6b,5=7.8 Hz), 1.84(1H, m, H-1 a), 1.94

(1H, m, H-1⁰b), 2.35 (1H, dd, H-5, J_5,6a=4.5,

J_5,6b=7.8 Hz), 2.47 (3H, s, Me–Ph–), 4.31 (1H, t, H-4,

J_4,1=6.6 Hz), 7.13–7.25 (4H, m, aromatic); ¹³C NMR

0

(125 MHz, CDCl₃) d 9.24(C-2 ), 19.77 (Me–Ph–), 19.79

(C-6), 28.99 (C-5), 29.38 (C-1⁰), 32.33 (C-1), 81.51 (C-4),

125.78, 128.37, 130.07, 130.59, 132.32, 139.46 (the above

mentioned, aromatic), 175.16 (C¼O); HR-MS (EI)

calcd C₁₄H₁₆O₂216.1150; obs 216.1139 (M⁺).

(1S,4S,5R)-2-Oxo-4-ethyl-1-(2-ﬂuorophenyl)-3-oxabicyclo

[3.1.0]hexane (30b). Compound 30b was obtained quan-

titatively as crystals: mp (AcOEt, hexane) 85–86 ^ꢂC; H

(1S,4S,5R)-2-Oxo-4-ethyl-1-(3-methylphenyl)-3-oxabicyclo

[3.1.0]hexane (30f). Compound 30f was obtained as an

1

NMR (500 MHz, CDCl₃) d 1.09 (3H, t, H-2⁰, J_{2 ,}

0

1

0

₁=7.5 Hz), 1.35 (1H, dd, H-6a, J_6a,5=4.6, J_6a,6b

=

oil in 49% yield: H NMR (500 MHz, CDCl₃) d 1.07

5.0 Hz), 1.69 (1H, dd, H-6b, J_6b,6a=5.0, J_6b,5=7.8 Hz),

1.82 (1H, m, H-1⁰a), 1.95 (1H, m, H-1⁰b), 2.30 (1H, dd,

H-5, J_5,6a=4.6, J_5,6b=7.8 Hz), 4.32 (1H, d, H-4,

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.33 (1H, dd, H-6a,

J_6a,5=4.6, J_6a,6b=4.8 Hz), 1.62 (1H, dd, H-6b,

J_6b,6a=4.8, J_6b,5=7.8 Hz), 1.82 (2H, m, H-1⁰), 2.31 (1H,

0

Y. Kazuta et al. / Bioorg. Med. Chem. 10 (2002) 3829–3848

3847

dd, H-5, J_5,6a=4.6, J_5,6b=7.8 Hz), 2.35 (3H, s, Me–Ph–),

0

4.34 (1H, d, H-4, J_4,1=6.0 Hz), 7.10 (1H, d, aromatic,

mined and reﬁned from 21 reﬂections in the range

26.7^ꢂ<ꢀ<29.9^ꢂ.

colorless crystal (0.30Â0.20Â

A

J=7.5 Hz), 7.18 (1H, m, aromatic), 7.22–7.26 (2H, m,

aromatic); ¹³C NMR (125 MHz, CDCl₃) d 8.66 (C-2⁰),

19.82 (C-6), 21.38 (Me–Ph–), 29.38 (C-1⁰), 29.59 (C-5),

32.20 (C-1), 80.75 (C-4), 125.35, 128.46, 128.49, 129.16,

134.12, 138.29 (the above mentioned, aromatic), 175.72

(C¼O); HR-MS (EI) calcd C₁₄H₁₆O₂216.1150; obs

216.1165 (M⁺).

0.12 mm) was mounted on a Mac Science MXC18 dif-

fractometer with graphite-monochromated CuK_aradiation

(l=1.54178 A). Data collection using the !/2ꢀ scan tech-

nique gave 1791 reﬂections at room temperature, 1715

unique, of which 1365 with I>2.00 ꢁ(I) reﬂections were

used in calculations. The intensities were corrected for

the Lorentz, polarization, and the extinction eﬀect, but

not for the absorption. The structure was solved by the

direct method and reﬁned by full-matrix least squares

technique using maXus (ver. 2.0) as the computer program.

The non-hydrogen atoms were reﬁned anisotropically.

The hydrogen atoms were included by calculation, but

these positions were not reﬁned. The unweighted and

weighted values were 0.057 and 0.081, respectively. No

peak above 0.26 eA^ꢁ3in the last Fourier-diﬀerence map.

(1S,4S,5R)-2-Oxo-4-ethyl-1-(4-methylphenyl)-3-oxabicyclo

[3.1.0]hexane (30g). Compound 30g was obtained as an

1

oil in 61% yield: H NMR (500 MHz, CDCl₃) d 1.06

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.32 (1H, dd, H-6a,

J_6a,6b=4.6, J_6a,5=4.6 Hz), 1.60 (1H, dd, H-6b,

J_6b,6a=4.6, J_6b,5=7.8 Hz), 1.81 (2H, m, H-1⁰), 2.29 (1H,

dd, H-5, J_5,6a=4.6, J_5,6b=7.8 Hz), 2.33 (3H, s, Me–Ph–),

0

4.34 (1H, t, H-4, J_4,1=6.0 Hz), 7.16 (2H, d, aromatic,

J=8.0 Hz), 7.28 (2H, m, aromatic, J=8.0 Hz); ¹³C

NMR (125 MHz, CDCl₃) d 8.58 (C-2⁰), 19.75 (C-6),

21.04( Me–Ph–), 29.32 (C-5), 29.52 (C-1⁰), 31.98 (C-1),

80.70 (C-4), 128.26, 129.26, 131.19, 137.44 (the above

mentioned, aromatic), 175.81 (C¼O); HR-MS (EI)

calcd C₁₄H₁₆O₂216.1150; obs 216.1165 (M⁺).

Binding assay. The binding aﬃnity for the NMDA

receptor was investigated according to previously

reported methods.¹⁹

Inhibitory eﬀects on the uptake of 5-HT. The assay

was investigated according to the previously reported

method.^10d

(1S,4S,5R)-2-Oxo-4-ethyl-1-(1-naphthyl)-3-oxabicyclo

[3.1.0]hexane (30h). Compound 30h was obtained as an

1

oil in 93% yield: H NMR (500 MHz, CDCl₃) d 1.18

Acknowledgements

(3H, t, H-2⁰, J_{2 ,}₁=7.4Hz), 1.61 (1H, dd, H-6a,

J_6a,5=4.6, J_6a,6b=4.6 Hz), 1.61 (1H, dd, H-6b,

J_6b,6a=4.6, J_6b,5=7.5 Hz), 1.95 (1H, m, H-1⁰a), 2.05

(1H, m, H-1⁰b), 2.48 (1H, dd, H-5, J_5,6a=4.6,

0

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 the gift of chiral epichlorohydrins.

0

J_5,6b=7.5 Hz), 4.42 (1H, t, H-4, J_4,1=6.0 Hz), 7.41 (2H,

d, aromatic, J=4.8 Hz), 7.52 (1H, t, aromatic,

J=7.5 Hz), 7.58 (1H, t, aromatic, J=7.5 Hz), 7.84(1H, t,

aromatic, J=4.8 Hz), 7.87 (1H, d, aromatic, J=8.2 Hz),

8.25 (1H, d, aromatic, J=8.2 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 9.26 (C-2⁰), 20.25 (C-6), 29.00 (C-5), 29.65 (C-

1⁰), 31.73 (C-1), 81.47 (C-4), 124.87, 124.95, 126.06,

126.46, 127.69, 128.62, 129.19, 130.52, 133.01, 133.98

(the above mentioned, aromatic), 175.22 (C¼O); HR-

MS (EI) calcd C₁₇H₁₆O₂252.1150; obs 252.1142 (M⁺).

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Article Doi

Synthesis of derivatives of (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) modified at the 1-aromatic moiety as novel NMDA receptor antagonists: The aromatic group is essential for the activity

DOI: 10.1016/S0968-0896(02)00346-2

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