Synthesis and biological activity of novel α-substituted β-phenylpropionic acids having pyridin-2-ylphenyl moiety as antihyperglycemic agents

Article abstract of DOI:10.1016/j.bmc.2004.01.048

We previously reported the identification of novel oximes having 5-benzyl-2,4-thiazolidinedione with antihyperglycemic activity. We now report the synthesis and biological activity of a novel series of oximes and amides having α-substituted-β-phenylpropionic acids. In this series, we obtained potent PPARα/γ dual agonist (S)-9d, with which activation of PPARα and PPARγ was considerably more potent than that of the reference compounds GW9578 22 and rosiglitazone 3, respectively. This means (S)-9d is of the strongest class of PPARα/γ dual agonists. In the course of this study, we also obtained 8h, which indicated potent plasma glucose lowering effect in spite of weak PPARα/γ agonistic activity.

Full text of DOI:10.1016/j.bmc.2004.01.048

Bioorganic & Medicinal Chemistry 12 (2004) 2419–2439
Synthesis and biological activity of novel a-substituted
b-phenylpropionic acids having pyridin-2-ylphenyl moiety as
antihyperglycemic agents
Makoto Takamura,a,* Mitsuya Sakurai,b Eriko Yamada,a Sachie Fujita,a Makoto Yachi,c
Toshiyuki Takagi,d Aya Isobe,d Yuka Hagisawa,d Toshihiko Fujiwarad and
Hiroaki Yanagisawae
aMedicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
bCorporate Planning Department, Sankyo Co., Ltd., Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan
cLead Discovery Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
dPharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
eChemtech Labo., Inc., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 23 October 2003; accepted 31 January 2004
Abstract—We previously reported the identification of novel oximes having 5-benzyl-2,4-thiazolidinedione with antihyperglycemic
activity. We now report the synthesis and biological activity of a novel series of oximes and amides having a-substituted-b-phen-
ylpropionic acids. In this series, we obtained potent PPARa=c dual agonist (S)-9d, with which activation of PPARa and PPARc was
considerably more potent than that of the reference compounds GW9578 22 and rosiglitazone 3, respectively. This means (S)-9d is
of the strongest class of PPARa=c dual agonists. In the course of this study, we also obtained 8h, which indicated potent plasma
glucose lowering effect in spite of weak PPARa=c agonistic activity.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and lipid lowering fibrates (e.g., bezafibrate) are high
affinity ligands for the nuclear receptor peroxisome
proliferators-activated receptor c (PPARc) and PPARa,
respectively, has provided new tools for the discovery of
novel compounds for the treatment of type 2 diabetes.8;9
PPARa agonists are effective in lowering serum trigly-
cerides and increasing HDL cholesterol, in some cases
accompanied by lowering serum fibrinogen.10 Further-
more, PPARa activation has also been shown to pro-
duce antiinflammatory effects in vascular cells.11 The
combined profile of a dual PPARa=c agonist is thought
to be beneficial for the treatment of hyperglycemia since
it is accompanied by prevention of cardiovascular dis-
ease in type 2 diabetes. Several compounds have been
reported to have both PPARa and PPARc agonistic
activity, and AZ-242 (Astrazeneca) 4,12 KRP-297
(Kyorin) 5,13 and MCC-555 (Mitsubishi Chemical) 614
(Fig. 2) are now in clinical trial.
After the discovery of the thiazolidinedione (TZD)-
based compound ciglitazone1;2 as a novel oral antihyper-
glycemic agent having significant effects on improving
peripheral insulin resistance, many reports on new TZD
derivatives have appeared, and troglitazone (Sankyo) 1,3
pioglitazone (Takeda) 2,4 and rosiglitazone (GSK) 35
(Fig. 1) have been developed and marketed. Since the
launch of TZDs, however, several reports of treatment-
related toxicity have been released. Troglitazone 1, the
first TZD approved, was withdrawn because of unac-
ceptable levels of hepatotoxicity.6 Rosiglitazone 3, the
second TZD marketed, has been associated with liver,
cardiovascular, and hematological toxicity.7
The mechanism of action of TZDs is still not fully
understood, but the recent identification that the TZDs
Historically, despite an exhaustive search to replace the
TZD ring with other moieties, an effective replacement
giving significant advantages over the TZD ring had
remained unsuccessful for a long time. However,
Keywords: Antihyperglycemic agent; PPARa; PPARc; KK mouse.
* Corresponding author. Tel.: +81-3-3492-3131; fax: +81-3-5436-8563;
e-mail: takamu@shina.sankyo.co.jp
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.01.048

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M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
O
O
O
NH
NH
O
NH
O
O
S
N
N
S
O
S
O
N
O
O
HO
Rosiglitazone 3
Troglitazone 1
Pioglitazone 2
Figure 1.
O
NH
O
O
CO2H
Me
O
F
S
N
H
NH
O
S
O O
OEt
O
S
O
F3C
MeO
O
AZ242 4
KRP297 5
MCC555 6
Figure 2.
research groups at Pfizer and Glaxo revealed that the
TZD ring can be replaced by a substituted alkanoic acid
moiety,15–18 and recent reports showed these compounds
have very potent in vitro and in vivo activities. On the
other hand, we have already reported the TZD 7 (Fig. 3)
having pyridin-2-ylphenyl moiety indicates potent
PPARc agonistic activity.19 Using compound 7 as a
template, we examined the effects of replacing TZD by
various substituted phenylpropionic acids in activation
of PPARa=c.20–22 Herein we describe our efforts to
identify novel potent dual PPARa=c agonists. The series
was evaluated for antihyperglycemic activity in the
genetically diabetic KK mice in vivo and in PPARa=c
transactivation in vitro assay to classify and characterize
these compounds.
2. Chemistry
Oxime derivatives 8a–k were prepared as follows
(Scheme 1). Ethyl a-substituted b-(4-hydroxyphen-
yl)propionates 14a–d, 17a,b, 19a–e were subjected to
Mitsunobu reaction with the oxime alcohol 10 or alkyl-
ation with mesylate 11. Subsequent alkaline hydrolysis
gave the desired oxime derivatives 8a–k. Amide deriva-
tives 9a–g were prepared as follows (Scheme 2). Ethyl a-
(4-substituted
phenoxy)-b-(4-hydroxyphenyl)propio-
nates 19b–g, 21 were subjected to Mitsunobu reaction
with N-Boc-ethanolamine. Subsequent deprotection of
the N-Boc group, acylation using diethyl phosphoryl
cyanide (DEPC) and alkaline hydrolysis gave the desired
amide derivatives 9a–g. The starting materials were
prepared as shown in Schemes 3–7. Ethyl a-alkyl
and phenylalkyl-b-(4-hydroxyphenyl)propionates 14a–d
were prepared as follows (Scheme 3). Alkylation of
O
ethyl
a-alkyl
malonates
12a–d
with
4-benzyloxybenzyl chloride gave 13a–d, which were
converted to 14a–d by hydrolysis, decarboxylation,
esterification, and subsequent removal of the benzyl
group. Ethyl a-methylthio and phenylthio-b-(4-hy-
droxyphenyl)propionates 17a and 17b were, respectively,
prepared from ethyl 3-(4-hydroxyphenyl)lactate 15
(Scheme 4). Compound 15 was converted to mesylate 16
after protection of the phenol group. Compound 16 was
NH
O
S
N
O
O
N
7
Figure 3.
CO2H
O
N
X
O
R1
CO2Et
a,b
N
O
R1
N
HO
N
10; X=OH
11; X=OMs
14a-d,
17a, b,
19a-e
8a-k
Scheme 1. Reagents and conditions: (a) DEAD, Ph3P, 10 or NaH, 11; (b) NaOH.

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2421
O
O
R2
CO2H
HO
R2
CO2Et
a,b,c,d
N
H
O
O
N
R3
R3
19b-g,
21
9a-g
Scheme 2. Reagents and conditions: (a) DEAD, Ph3P, BocNHCH2CH2OH; (b) HCl, dioxane; (c) 2-Py-benzoic acid, Et3N, DEPC; (d) NaOH.
CO2Et
CO2Et
a
CO2Et
CO2Et
b, c, d, e
R1
R1
R1 CO2Et
HO
BnO
12a-d
13a-d
14a-d
R1 =n-Pr, i-Pr, n-Bu, 3-Phenylpropyl
Scheme 3. Reagents and conditions: (a) NaH, 4-benzyloxybenzyl chloride; (b) KOH; (c) xylene, reflux; (d) H2SO4, EtOH; (e) H2, Pd–C.
CO2Et
CO2Et
OH
CO2Et
OMs
a, b
c, d
R1
HO
HO
MOMO
15
16
17a, b
R1=MeS, PhS
Scheme 4. Reagents and conditions: (a) methoxymethyl chloride, NaH; (b) MsCl, Et3N; (c) MeSNa or PhSH/K2CO3; (d) HCl, dioxane.
CO2Et
CO2Et
CO2Et
OH
c
a, b
R1
R1
HO
BnO
HO
15
18a-g
19a-g
R1 =EtO, ArO
Scheme 5. Reagents and conditions: (a) benzyl bromide, K2CO3; (b) ArOH, DEAD, Ph3P or NaH, EtI; (c) H2, Pd–C or HBr in AcOH.
CO2Et
CO2Et
CO2Et
a, b, c, d
a, b
R1
R1
O
HO
BnO
HO
O
CO2Et
18d-g
(S) -19d-g
20
21
Scheme 7. Reagents and conditions: (a) NaOH; (b) ())-norephedrine;
(c) H2SO4, EtOH; (d) H2, Pd–C.
Scheme 6. Reagents and conditions: (a) lithium isopro-
pylcyclohexylamide, 4-benzyloxybenzyl chloride; (b) H2, Pd–C.
lowed by alkylation of 15 with ethyl iodide or Mitsunobu
reaction with phenol gave 18a–g. Subsequent removal of
the benzyl group gave 19a–g. Ethyl a-(4-isopropyl-
phenoxy)-a-methyl-b-(4-hydroxyphenyl)propionate 21
was prepared by alkylation of ethyl a-(4-isopropyl-
phenoxy)propionate 2023 with 4-benzyloxybenzyl
reacted with sodium thiomethoxide or benzenethiol.
Compounds 17a,b were obtained after removal of the
methoxymethyl group. Ethyl a-ethoxy and phenoxy-b-
(4-hydroxyphenyl)propionates 19a–g were prepared as
follows (Scheme 5). Protection of the phenol group fol-

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M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
chloride and removal of the benzyl group (Scheme 6).
Optically active ethyl a-aryloxy-b-(4-hydroxyphenyl)-
propionates (S)-19d–g were prepared as follows (Scheme
7). Racemic ethyl a-aryloxy-b-(4-benzyloxy)phenylpro-
pionates 18d–g were hydrolyzed and optical resolution
using ())-norephedrine was performed. The optically
active carboxylic acids obtained were subjected to
esterification and removal of the benzyl group to give
(S)-19d–g in >99% ee. The absolute configuration of (S)-
9d was determined by chiral column HPLC analysis
using an authentic sample synthesized from (S)-19e in a
previous synthetic study.24
rosiglitazone 3 are defined as 100% for PPARa and
PPARc, respectively.
At first, we prepared oximes 8a–k having a-substituted-
b-phenylpropionic acid. In the series of a-alkyl or
phenylalkyl-b-phenylpropionic acids 8a–d, a-propyl
derivative 8a indicated potent plasma glucose lowering
activity compared with its isopropyl, butyl, and phen-
ylpropyl analogues 8b,c,d. All of these compounds
showed only weak PPARa and c agonistic activity and a
longer alkyl or aralkyl chain in particular caused a
marked decrease in PPARa and c activity. Next,
derivatives having an oxygen or sulfur atom at the
a-position were synthesized (8e–h). a-Methylthio deriv-
ative 8e showed better PPARa and c agonistic activity
than a-alkyl or phenylalkyl derivatives without affecting
its in vivo activity. As reported in the literature,16
a-ethoxy compound 8g showed potent PPARc agonistic
activity comparable to rosiglitazone 3 and sufficient in
vivo activity. Interestingly a-phenoxy compound 8h also
showed potent plasma glucose lowering activity in spite
of weak PPARc agonistic activity. On the other hand,
its sulfur analogue 8f, having greater PPARc agonistic
activity compared with 8h, showed only a weak blood
glucose lowering activity. Interested in the potent in vivo
activity of 8h, we synthesized substituted phenoxy
compounds 8i–k. Although PPARc activation of these
compounds was weak, their potent in vivo activities
were confirmed. Pure S enantiomer (S)-8j was prepared
to evaluate the enantiomeric effect on biological activity.
Compound (S)-8j showed more potent in vivo and
3. Results and discussion
The results of the biological activity of the synthesized
compounds compared with GW9578 228 and rosiglit-
azone 3, reported as a potent PPARa and c agonist,
respectively, are summarized in Tables 1 and 2. The
oximes 8a–k and amides 9a–g prepared above were
evaluated for their PPARa and c agonistic activity and
for their plasma glucose lowering activity in hypergly-
cemic KK mice. To compare the efficacy of PPARa and
c agonistic activity, maximum fold activation (% max)
relative to the maximum efficacy of PPAR activation of
GW9578 22 and rosiglitazone 3 are listed. The maxi-
mum efficacy of PPAR activation of GW9578 22 and
Table 1. PPARa and c agonistic activity and antihyperglycemic activity of oximes
CO2H
*
O
R1
N
O
N
Compound
R1
*
hPPARa
% Maxa
hPPARc
% Maxb
PGc (%)
EC50 (lM)
EC50 (lM)
8a
8b
n-Pr
i-Pr
RS
RS
RS
RS
RS
RS
RS
RS
RS
RS
S
>10
>10
>10
>10
>10
>10
4.5
11
39
<5
<5
98
8
>10
>10
>10
>10
>10
3.3
80
76
56
4
8cd
n-Bu
48
11
26
47
20
20
47
65
64
52
62
69
66
––
8dd
8e
PhCH2CH2CH2
MeS
PhS
148
159
110
40
8f
8g
EtO
PhO
52
<5
12
72
15
8
0.034
>10
>10
>10
4.6
8h
8i
>10
>10
>10
>10
>10
>10
0.68
4-F-PhO
4-Me-PhO
4-Me-PhO
4-t-Bu-PhO
46
97
8j
(S)-8j
42
35
8k
Rosiglitazone 3
GW9578 22
RS
2.6
0.054
0.60
10
100
100
103
a The maximum efficacy of PPARa activation of GW9578 22 is defined as 100%.
b The maximum efficacy of PPARc activation of rosiglitazone 3 is defined as 100%.
c The test compounds were mixed with powdered feed F-2 (Funabashi Farms) in a ratio of 0.01% (about 10 mg/kg/day). The mixture was admin-
istered orally to hyperglycemic male KK mice (4–6 months of age) for 3 days. Values (mean SE) are the % change in plasma glucose concentration
of the drug-treated mice relative to vehicle controls. All values are the mean of n ¼ 4 or 5.
d Biological activities were evaluated as sodium salts.

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
Table 2. PPARa and c agonistic activity and antihyperglycemic activity of amides
2423
O
O
R2
N
H
*
CO2H
O
N
R3
Compound
R2
R3
*
hPPARa
% Maxa
hPPARc
% Maxb
PGc (%)
EC50 (lM)
EC50 (lM)
9a
9b
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
RS
RS
S
>10
>10
>10
1.0
<5
22
0.69
0.61
0.10
0.070
5.8
82
84
22
66
69
64
52
73
70
15
62
49
60
73
68
66
Me
Me
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
F
(S)-9b
9c
57
81
98
RS
R
141
53
(R)-9c
(S)-9c
>10
0.71
0.69
>10
0.21
>10
>10
>10
0.087
>10
55
59
S
153
88
0.046
0.033
>10
9d
(R)-9d
RS
R
96
94
<5
103
12
(S)-9d
9e
S
0.011
2.2
8.7
72
85
RS
RS
S
9f
(S)-9f
9g
Cl
Cl
11
47
132
73
2.5
0.011
0.054
i-Pr
RS
106
10
82
100
Rosiglitazone
3
GW9578 22
0.68
100
0.60
103
––
a The maximum efficacy of PPARa activation of GW9578 22 is defined as 100%.
b The maximum efficacy of PPARc activation of rosiglitazone 3 is defined as 100%.
c The test compounds were mixed with powdered feed F-2 (Funabashi Farms) in a ratio of 0.01% (about 10 mg/kg/day). The mixture was admin-
istered orally to hyperglycemic male KK mice (4–6 months of age) for 3 days. Values (mean SE) are the % change in plasma glucose concentration
of the drug-treated mice relative to vehicle controls. All values are the mean of n ¼ 4 or 5.
in vitro activity than its racemate 8j. The result gave
good agreement with that of the Glaxo group.25
more potent PPARa and c agonistic activity. The S
enantiomers of 9b–d,f, the 4-methylphenoxy, 4-isopro-
pylphenoxy, 4-tert-butylphenoxy, and 4-chlorophenoxy
derivatives and the R enantiomers of 9c–d the 4-iso-
propylphenoxy and 4-tert-butylphenoxy derivatives
were prepared to estimate the enantiomeric effect.
Among these compounds, all of the S enantiomers had
more potent PPARa and c agonistic activity than their
R enantiomers and racemates, and this tendency was
also shown in plasma glucose lowering activity. The
results indicate that PPARc agonistic activity is essential
for potent plasma glucose lowering activity compared
with that of oxime series. Surprisingly, (S)-9d, having a
4-tert-butylphenoxy group at the a-position, indicated
more potent PPARa and c agonistic activity than the
reference compounds 22 and 3, respectively. This means
(S)-9d is of the strongest class of PPARa=c dual
agonists.
All the prepared oximes 8a–k except for 8g showed only
weak PPARa and c agonistic activities, but it is inter-
esting that a-phenoxy derivatives 8h–k showed potent
plasma glucose lowering activity. Among these oxime
derivatives, correlation between PPARc agonistic
activity and plasma glucose lowering activity was not
clear. Compounds 8h–k had no significant activity for
PPARd, and exerted only a little adipogenic activity in
murine 3T3L1 cells in accordance with its weak PPARc
activity (data not shown). One possible explanation is
that these compounds may be selective modulators of
PPARc.26 Another possibility is that these compounds
may activate another receptor, GPR40/FFAR, that is
expressed in islet b cells.27;28 Thus, the studies concerning
binding for PPAR and other receptors, as well as in vivo
pharmacological and pharmacokinetic profiles, would
be needed to elucidate the plasma glucose lowering
activity of these compounds.
Then, we prepared compound 9g having a methyl group
at the a-position of the propionic acid moiety. In
designing 9g, we referred to the structure of antihyper-
glycemic agent 2323 (Fig. 4) reported by the Pfizer
research group. Its mechanism of action was suggested
to involve the enhancement of the intrinsic activity of
the glucose transporter GLUT1 or GLUT4. Our eval-
uation of 23 for PPARa and c agonistic activity gave
selective PPARa agonistic activity (data not shown).
Interestingly, despite the racemic form, 9g indicated the
most potent PPARa and c agonistic activity in our study
Next, searching for our initial target dual PPARa=c
agonists, we synthesized compounds 9a–g, which have
the amide moiety instead of the oxime moiety. Although
9a showed only moderate plasma glucose lowering
activity, almost all of the 4-substituted phenoxy deriv-
atives 9b–g indicated potent in vivo activity, and there
was a tendency that compounds having a more bulky
group at the para-position of the a-phenoxy group had

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M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
CO2H
F
O
CO2H
O
O
Cl
N
H
N
F
nC7H15
GW9578 22
23
Figure 4.
with potent in vivo activity. A methyl group at the
a-position might be important for PPARa activation.
However, we selected (S)-9d for further investigation
because of synthetic feasibility.
75 cm2 flask. Under nearly confluent growth conditions,
cells were transfected with 3 lg of pFR-Luc in combi-
nation with 12 lg of pM-hPPARa or pM-hPPARc,
using FuGENE6 transfection reagent (Roche Diagnos-
tics). After 20–24 h of the transfection, cells were
trypsinized, suspended in 250 mL of medium, seeded
into 96-well plates at 100 lL/well, then incubated for 20–
24 h. The test compound was dissolved in dimethyl-
sulfoxide at a series of concentrations (1 lM–10 mM),
and diluted to 1% (v/v) with the medium, then added to
the cells at 10 lL/well. After 20–24 h of incubation,
100 lL of PicaGene LT2.0 Luminescence Reagent
(Wako Pure Chemical Ltd.) was added, and lumines-
cence was counted using a TopCount HTS (Packard
Instruments).
4. Conclusion
We synthesized and evaluated a-substituted b-phenyl-
propionic acids having a pyridin-2-ylphenyl moiety as
antidiabetic agents. We obtained potent PPARa=c dual
agonists (S)-9d and 9g in comparison with known
PPARa and c agonists. Compound (S)-9d was selected
for further investigation because of synthetic feasibility.
We also obtained 8h, which indicated potent plasma
glucose lowering effect in spite of weak PPARa=c ago-
nistic activity. Further development work on these
compounds is in progress.
5.1.3. Statistics. EC50 values were calculated via logistic
sigmoidal regression using SigmaPlot 2001 software
(SPSS Inc.). The results are expressed as means of n ¼ 4.
To obtain the maximum efficacy values (% max), the
maximum efficacy of the reference PPAR agonist
(GW9578 22 and rosiglitazone 3 for PPARa and
PPARc, respectively) was defined as 100%, % max was
calculated using the equation:
5. Experimental
5.1. PPARa and PPARc transactivation assays
5.1.1. Plasmids. cDNA encoding the ligand binding
domain of human PPARa (amino acids 168–468) or
PPARc2 (amino acids 175–475) was generated by
reverse transcript polymerase chain reaction (RT-PCR)
using total RNAs from human hepatocarcinoma
HepG2 cells (ATCC HB-8065). The forward and reverse
primers were 50-GGATCCACAACGCGATTCGTT-
TT GGACGA-30 and 50-AAGCTTTGTGGCTGAT-
CTGAAGGAACTCA-30 toward PPARa, and 50-
GGATCCATAATGCCATCAGGTTTGGGCGG-30
and 50-AAGCTTCTAGTACAAGTCCTTGTAGAT-
CTC-30 toward PPARc. The PCR products were cloned
into pCRII (Invitrogen Corporation), and after
sequence verification, subcloned into the pM vector
(CLONTECH Laboratories, Inc.) including a yeast
GAL4 (amino acids 1–147) sequence, at the BamHI-
HindIII site. The plasmid, pM-hPPARa or pM-
hPPARc, including the PPARa or PPARc ligand
binding domain fused to the GAL4 DNA binding
domain, was used for the PPARa or c transactivation
assay, respectively. A GAL4-responsive reporter plas-
mid, pFR-Luc, was also obtained from STRATAGENE
Cloning Systems.
100 ꢀ ðLmax=Lref Þ;
where Lmax is the mean luminescence of maximum
response concentration in test compound-treated
groups, and Lref is the mean luminescence of maximum
response concentration in reference PPAR agonist-
treated groups.
5.1.4. In vivo studies. The test compounds were mixed
with powdered feed F-2 (Funabashi Farms) in a ratio of
0.01% (about 10 mg/kg/day). The mixture was adminis-
tered orally to hyperglycemic male KK mice (4–
6 months of age) for 3 days. Values (mean SE) are the
% change in plasma glucose concentration of the drug-
treated mice relative to vehicle controls. All values are
the mean of n ¼ 4 or 5.
5.2. Synthesis
Melting points (mp) were determined with a Yanaco
melting point apparatus and are not corrected. Infrared
(IR) spectra were measured with a Nic 5SXCFT-IR
spectrophotometer. 1H NMR and 13C NMR spectra
were recorded on a Varian Mercury 400 or 500 spec-
trometer. Chemical shifts are expressed in d ppm from
the internal standard tetramethylsilane (TMS). All
NMR spectra were consistent with the structures
5.1.2. Assay. MG-63 (ATCC CRL 1427) cells were
grown at 37 °C, 5% CO2 in Dulbeccoꢀs modified Eagleꢀs
medium with 10% fetal calf serum and antibiotics in a

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2425
assigned. MS or high-resolution mass spectra (HRMS)
were obtained on a JEOL JMS-D 300 mass spectrome-
ter. HPLC spectra were obtained using a Shimadzu
HPLC system consisting of the following: pump, LC-
10Advp; and detector, SPD-M10Avp, measured at
254 nm. Column chromatography was performed with
silica gel Merck 60 (230–400 mesh ASTM). TLC anal-
yses were performed on Merck reagent silica gel 60 F254
(0.25 mm thickness).
(5H, m). IR (CDCl3) cmꢁ1 2961, 2931, 1722, 1511, 1239,
1176, 1026. HRMS m=z 326.1878 (Mþ) (calcd for
C21H26O3 326.1882).
5.3.3. Ethyl 2-(4-hydroxybenzyl)pentanoate (14a). A
mixture of ethyl 2-(4-benzyloxybenzyl)pentanoate (4.0 g,
12.3 mmol) and 5% Pd–C (0.4 g) in EtOH (45 mL) was
stirred under H2 atmosphere at 50 °C for 2 h. The
reaction mixture was filtered to remove Pd–C and the
filtrate was concentrated in vacuo to afford the title
compound as a colorless syrup (2.9 g, yield 99%).
5.3. 2-[4-[2-[1-(4-Pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]pentanoic acid (8a)
1H NMR (CDCl3) d 0.88 (3H, t, J ¼ 7:0 Hz), 1.15 (3H,
t, J ¼ 7:0 Hz), 1.20–1.70 (4H, m), 2.53–2.62 (1H, m),
2.67 (1H, dd, J ¼ 6:0, 13.0 Hz), 2.84 (1H, dd, J ¼ 8:5,
13.0 Hz), 4.05 (2H, q, J ¼ 7:0 Hz), 4.77–4.81 (1H, m),
6.72 (2H, d, J ¼ 8:5 Hz), 7.02 (2H, d, J ¼ 8:5 Hz). IR
(liquid film) cmꢁ1 3401, 2960, 2935, 1731, 1705, 1516,
1222. HRMS m=z 236.1408 (Mþ) (calcd for C14H20O3
236.1413).
5.3.1. Diethyl 2-(4-benzyloxybenzyl)-2-propylmalonate
(13a). A mixture of NaH (55% dispersion in oil)
(1.13 g, 25.9 mmol), diethyl 2-propylmalonate 12a (5.0 g,
24.7 mmol) in toluene (25 mL) and DMF (25 mL) was
stirred at 40 °C for 1 h. 4-Benzyloxybenzyl chloride
(6.32 g, 27.2 mmol) was added and the reaction mixture
was stirred at room temperature for 16 h. Water was
added, and the mixture was extracted with EtOAc. The
organic phase was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was
subjected to column chromatography (hexane/EtOAc,
10/1) to give the title compound as a colorless syrup
(9.85 g, yield 99%).
5.3.4. Ethyl 2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylidene-
aminooxy]ethoxy]benzyl]pentanoate. A mixture of NaH
(0.10 g, 2.33 mmol) and ethyl 2-(4-hydroxybenzyl)penta-
noate 14a (0.50 g, 2.11 mmol) in toluene (5.0 mL) and
DMF (5.0 mL) was stirred at 40 °C for 1 h. 2-[1-(4-
Pyridin-2-ylphenyl)ethylideneaminooxy]ethyl mesylate
11 (0.74 g, 2.22 mmol) was added. The mixture was
stirred at room temperature for 16 h. Water was added
and the mixture was extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was subjected to col-
umn chromatography (hexane/EtOAc, 7/3) to give the
title compound as a colorless oil (1.0 g, yield 43%).
1H NMR (CDCl3) d 0.92 (3H, t, J ¼ 7:0 Hz), 1.23 (6H,
t, J ¼ 7:0 Hz), 1.24–1.38 (2H, m), 1.71–1.78 (2H, m),
3.18 (2H, s), 4.16 (2H, q, J ¼ 7:0 Hz), 4.17 (2H, q,
J ¼ 7:0 Hz), 5.02 (2H, s), 6.86 (2H, d, J ¼ 8:5 Hz), 6.99
(2H, d, J ¼ 8:5 Hz), 7.30–7.44 (5H, m). IR (CDCl3)
cmꢁ1 2966, 2256, 1727, 1112, 1248, 1220, 1179. HRMS
m=z 398.2086 (Mþ) (calcd for C24H30O5 398.2094).
5.3.2. Ethyl 2-(4-benzyloxybenzyl)pentanoate. A mixture
of diethyl ester 13a (9.85 g, 24.7 mmol) and KOH
(5.25 g, 80.0 mmol) in 2-methoxyethanol (100 mL) and
H2O (10 mL) was stirred at 130 °C for 2 h. The reaction
mixture was evaporated in vacuo and mixed with tolu-
ene. The mixture was acidified with 6 N HCl and
extracted with EtOAc. The organic phase was separated,
washed with brine, dried over Na2SO4, and evaporated
in vacuo. The obtained oil was dissolved in xylene
(100 mL) and the solution was refluxed for 1 h. The
solvent was removed in vacuo and the residue was dis-
solved in EtOH (100 mL). To this solution was added
concd H2SO4 (2.0 mL) and the mixture was stirred at
80 °C for 16 h. The solvent was evaporated in vacuo, and
the residue was extracted with EtOAc. The organic
phase was washed with water and brine, and dried over
Na2SO4. The solvent was removed in vacuo and the title
compound was obtained after purification by column
chromatography (hexane/EtOAc, 4/1) as a colorless
syrup (4.11 g, yield 51%).
1H NMR (CDCl3) d 0.88 (3H, t, J ¼ 7:0 Hz), 1.15 (3H,
t, J ¼ 7:0 Hz), 1.20–1.70 (4H, m) 2.28 (3H, s), 2.52–2.62
(1H, m), 2.67 (1H, dd, J ¼ 6:0, 13.0 Hz), 2.86 (1H, dd,
J ¼ 8:0, 13.0 Hz), 4.05 (2H, q, J ¼ 7:0 Hz), 4.27 (2H, t,
J ¼ 5:0 Hz), 4.55 (2H, t, J ¼ 5:0 Hz), 6.87 (2H, d,
J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz), 7.20–7.25 (1H, m),
7.75–7.78 (4H, m), 8.01 (2H, d, J ¼ 8:5 Hz), 8.70 (1H, d,
J ¼ 5:0 Hz). IR (CDCl3) cmꢁ1 2961, 2930, 1722, 1588,
1512, 1469, 1245. HRMS m=z 475.2609 (M+Hþ) (calcd
for C29H35N2O4 475.2597).
5.3.5. 2-[4-[2-[1-(4-Pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]pentanoic acid (8a). To a solution of
ethyl 2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]pentanoate (0.43 g, 0.91 mmol) in
ethanol (10 mL) was added 1 N NaOH (3.5 mL), and the
mixture was stirred at room temperature for 16 h. After
the reaction mixture was evaporated in vacuo, the resi-
due was diluted with water and carefully acidified with
1 N HCl and extracted with EtOAc. The organic phase
was washed with brine, dried over Na2SO4, and evap-
orated in vacuo. The solids were collected by filtration
using the mixture of isopropyl ether and hexane to give
the title compound as a colorless solid (0.37 g, yield
92%).
1H NMR (CDCl3) d 0.89 (3H, t, J ¼ 7:0 Hz), 1.14 (3H,
t, J ¼ 7:0 Hz), 1.20–1.70 (4H, m), 2.55–2.64 (1H, m),
2.68 (1H, dd, J ¼ 6:0, 13.0 Hz), 2.86 (1H, dd, J ¼ 8:0,
13.0 Hz), 4.05 (2H, q, J ¼ 7:0 Hz), 5.04 (2H, s), 6.88
(2H, d, J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:05 Hz), 7.28–7.45

2426
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
1
Mp: 115–117 °C. 1H NMR (CDCl3) d 0.91 (3H, t,
J ¼ 7:0 Hz), 1.25–1.71 (4H, m), 2.27 (3H, s), 2.62–2.74
(2H, m), 2.86–2.95 (1H, m), 4.30 (2H, t, J ¼ 5:0 Hz),
4.55 (2H, t, J ¼ 5:0 Hz), 6.88 (2H, d, J ¼ 8:5 Hz), 7.10
(2H, d, J ¼ 8:5 Hz), 7.23–7.30 (1H, m), 7.65–7.81 (4H,
m), 7.95 (2H, d, J ¼ 8:5 Hz). 8.70 (1H, d, J ¼ 5:0 Hz).
IR (KBr) cmꢁ1 2958, 1694, 1511, 1243, 953, 780. MS m=z
447 (M+Hþ). Anal. Calcd for C27H30N2O4: C, 72.62; H,
6.77; N, 6.27. Found: C, 72.44; H, 6.91; N, 6.27.
102 °C (yield 88%). H NMR (CDCl3) d 1.01–1.07 (6H,
m), 1.88–2.02 (1H, m), 2.26 (3H, s), 2.43–2.51 (1H, m),
2.74–2.83 (2H, m), 4.30 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t,
J ¼ 5:0 Hz), 6.86 (2H, d, J ¼ 8:5 Hz), 7.10 (2H, d,
J ¼ 8:5 Hz), 7.23–7.28 (1H, m), 7.65–7.81 (4H, m), 7.94
(2H, d, J ¼ 8:5 Hz), 8.68 (1H, d, J ¼ 5:0 Hz). IR (KBr)
cmꢁ1 2960, 1722, 1512, 1470, 1246, 955, 783. MS m=z
447 (M+Hþ). Anal. Calcd for C27H30N2O4Æ2/3H2O: C,
70.71; H, 6.89; N, 6.11. Found: C, 70.90; H, 6.69; N,
6.14.
Similarly 8b–d were prepared.
5.5. 2-[4-[2-[1-(4-Pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]hexanoic acid (8c)
5.4. 3-Methyl-2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylidene-
aminooxy]ethoxy]benzyl]butyric acid (8b)
5.5.1. Diethyl 2-(4-benzyloxybenzyl)-2-butylmalonate
1
5.4.1. Diethyl 2-(4-benzyloxybenzyl)-2-isopropylmalonate
1
(13c). Mp: 72–73 °C (yield 92%). H NMR (CDCl3) d
(13b). Colorless syrup (yield 92%). H NMR (CDCl3) d
0.91 (3H, t, J ¼ 7:0 Hz), 1.24 (6H, t, J ¼ 7:0 Hz), 1.20–
1.37 (4H, m), 1.74–1.80 (2H, m), 3.18 (2H, s), 4.11–4.23
(4H, m), 5.02 (2H, s), 6.86 (2H, d, J ¼ 8:5 Hz), 6.99 (2H,
d, J ¼ 8:5 Hz), 7.31–7.44 (5H, m). IR (KBr) cmꢁ1 2962,
1724, 1513, 1270, 1242, 1206, 1015. MS m=z 412 (Mþ).
Anal. Calcd for C25H32O5: C, 72.79; H, 7.82. Found: C,
72.65; H, 7.68.
1.04 (6H, d, J ¼ 7:0 Hz), 1.18 (6H, t, J ¼ 7:0 Hz), 2.30
(1H, septet, J ¼ 7:0 Hz), 3.19 (2H, s), 4.01–4.21 (4H, m),
5.02 (2H, s), 6.84 (2H, d, J ¼ 8:5 Hz), 7.08 (2H, d,
J ¼ 8:5 Hz), 7.28–7.46 (5H, m). IR (CDCl3) cmꢁ1 2981,
2929, 1719, 1510, 1263, 1239, 1179. HRMS m=z
398.2060 (Mþ) (calcd for C24H30O5 398.2094).
5.4.2. Ethyl 2-(4-benzyloxybenzyl)-3-methylbutyrate.
1
5.5.2. Ethyl 2-(4-benzyloxybenzyl)hexanoate. Colorless
syrup (yield 86%). 1H NMR (CDCl3) d 0.87 (3H, t,
J ¼ 7:0 Hz), 1.14 (3H, t, J ¼ 7:0 Hz), 1.20–1.37 (4H, m),
1.40–1.70 (2H, m), 2.51–2.72 (2H, m), 2.85 (1H, dd,
J ¼ 8:5, 13.5 Hz), 4.05 (2H, q, J ¼ 7:0 Hz), 5.03 (2H, s),
6.88 (2H, d, J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz), 7.31–
7.45 (5H, m). 13C NMR (125 MHz, CDCl3) d 13.92,
14.23, 22.57, 29.51, 31.82, 37.76, 47.90, 60.03, 70.01,
114.70, 127.44, 127.87, 128.54, 129.85, 131.92, 137.17,
157.29, 175.78. IR (liquid film) cmꢁ1 2956, 2933, 1731,
1512, 1242, 1176, 1159. HRMS m=z 340.2044 (Mþ)
(calcd for C22H28O3 340.2039).
Colorless syrup (yield 53%). H NMR (CDCl3) d 0.96–
1.12 (9H, m), 1.84–1.98 (1H, m), 2.41 (1H, q,
J ¼ 7:0 Hz), 2.79 (2H, d, J ¼ 7:0 Hz), 3.94–4.05 (2H, m),
5.03 (2H, s), 6.87 (2H, d, J ¼ 8:5 Hz), 7.07 (2H, d,
J ¼ 8:5 Hz), 7.28–7.44 (5H, m). IR (CDCl3) cmꢁ1 2964,
2929, 1721, 1511, 1239, 1176, 1025. HRMS m=z
326.1890 (Mþ) (calcd for C21H26O3 326.1882).
5.4.3. Ethyl 2-(4-hydroxybenzyl)-3-methylbutyrate (14b).
1
Colorless syrup (yield 99%). H NMR (CDCl3) d 0.97
(3H, d, J ¼ 7:0 Hz), 1.02 (3H, d, J ¼ 7:0 Hz), 1.12 (3H,
t, 7.0 Hz), 1.83–2.01 (1H, m), 2.37–2.48 (1H, m), 2.71–
2.82 (2H, m), 4.00 (2H, q, J ¼ 7:0 Hz), 5.26–5.38 (1H,
m), 6.68 (2H, d, J ¼ 8:5 Hz), 7.00 (2H, d, J ¼ 8:5 Hz).
IR (CDCl3) cmꢁ1 2965, 2933, 1718, 1614, 1515, 1375,
1173. HRMS m=z 236.1406 (Mþ) (calcd for C14H20O3
236.1413).
5.5.3. Ethyl 2-(4-hydroxybenzyl)hexanoate (14c). Color-
1
less syrup (yield 95%). H NMR (CDCl3) d 0.87 (3H, t,
J ¼ 7:0 Hz), 1.16 (3H, t, J ¼ 7:0 Hz), 1.20–1.35 (4H, m),
1.40–1.70 (2H, m), 2.53–2.72 (2H, m), 2.84 (1H, dd,
J ¼ 8:5, 13.5 Hz), 4.06 (2H, q, J ¼ 7:0 Hz), 4.93 (1H, s),
6.72 (2H, d, J ¼ 8:5 Hz), 7.02 (2H, d, J ¼ 8:5 Hz). 13C
NMR (125 MHz, CDCl3) d 13.91, 14.17, 22.55, 29.53,
31.87, 37.79, 48.15, 60.40, 115.24, 129.91, 131.06,
154.43, 176.57. IR (liquid film) cmꢁ1 3401, 2958, 2934,
1705, 1516. HRMS m=z 250.1568 (Mþ) (calcd for
C15H22O3 250.1569).
5.4.4. Ethyl 3-methyl-2-[4-[2-[1-(4-pyridin-2-ylphenyl)-
ethylideneaminooxy]benzyl]butyrate. Colorless syrup
(yield 46%). 1H NMR (CDCl3) d 0.96 (3H, d,
J ¼ 7:0 Hz), 1.01 (3H, d, J ¼ 7:0 Hz), 1.11 (3H, t,
J ¼ 7:0 Hz), 1.86–1.98 (1H, m), 2.28 (3H, s), 2.37–2.45
(1H, m), 2.79 (2H, d, J ¼ 7:0 Hz), 3.94–4.06 (2H, m),
4.26 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t, J ¼ 5:0 Hz), 6.85
(2H, d, J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz), 7.20–7.25
(1H, m), 7.71–7.78 (4H, m), 8.01 (2H, d, J ¼ 8:5 Hz),
8.70 (1H, d, J ¼ 5:0 Hz). IR (CDCl3) cmꢁ1 2964, 2930,
1721, 1588, 1511, 1469, 1246. HRMS m=z 475.2601
(M+Hþ) (calcd for C29H35N2O4 475.2597).
5.5.4. Ethyl 2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylidene-
aminooxy]ethoxy]benzyl]hexanoate. Colorless syrup
(yield 48%). 1H NMR (CDCl3)
d 0.87 (3H, t,
J ¼ 7:0 Hz), 1.16 (3H, t, J ¼ 7:0 Hz), 1.20–1.40 (4H, m),
1.40–1.70 (2H, m), 2.28 (3H, s), 2.51–2.72 (2H, m), 2.86
(1H, d, d, J ¼ 8:5, 13.5 Hz), 4.06 (2H, q, J ¼ 7:0 Hz),
4.27 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t, J ¼ 5:0 Hz), 6.87
(2H, d, 8.5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz), 7.21–7.27 (1H,
5.4.5. 2-[4-[2-[1-(4-Pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]-3-methylbutyric acid (8b). Mp: 100–

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2427
m), 7.71–7.80 (4H, m), 8.01 (2H, d, J ¼ 8:5 Hz), 8.71
(1H, d, J ¼ 5:0 Hz). HRMS m=z 489.2759 (M+Hþ)
(calcd for C30H37N2O4 489.2753).
CDCl3) d 14.22, 29.13, 31.62, 35.69, 37.72, 47.73, 60.11,
70.01, 114.71, 125.74, 127.44, 127.89, 128.29, 128.55,
129.86, 131.74, 137.16, 142.11, 157.32, 175.56. IR (liquid
film) cmꢁ1 2938, 1730, 1511, 1241, 1177. HRMS m=z
402.2193 (Mþ) (calcd for C27H30O3 402.2195).
5.5.5. 2-[4-[2-[1-(4-Pyridin-2-ylphenyl)ethylideneamino-
oxy]ethoxy]benzyl]hexanoic acid (8c). Colorless syrup
(yield 78%). 1H NMR (CDCl3)
d 0.88 (3H, t,
5.6.3. Ethyl 2-(4-hydroxybenzyl)-5-phenylpentanoate
1
(14d). Colorless syrup (yield 99%). H NMR (CDCl3)
J ¼ 6:5 Hz), 1.23–1.37 (4H, m), 1.43–1.73 (2H, m), 2.23
(3H, s), 2.60–2.74 (2H, m), 2.90 (1H, dd, J ¼ 8:5,
13.5 Hz), 4.30 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t,
J ¼ 5:0 Hz), 6.87 (2H, d, J ¼ 8:5 Hz), 7.10 (2H, d,
J ¼ 8:5 Hz), 7.24–7.28 (1H, m), 7.68–7.81 (4H, m),
7.95 (2H, d, J ¼ 8:5 Hz), 8.70 (1H, d, J ¼ 5:0 Hz).
HRMS m=z 461.2445 (M+Hþ) (calcd for C28H33N2O4
461.2440).
d 1.14 (3H, t, J ¼ 7:0 Hz), 1.51–1.72 (4H, m), 2.53–2.70
(4H, m), 2.79–2.88 (1H, m), 4.05 (2H, q, J ¼ 7:0 Hz),
4.84 (1H, s), 6.72 (2H, d, J ¼ 8:5 Hz), 7.00 (2H, d,
J ¼ 8:5 Hz), 7.12–7.30 (5H, m). 13C NMR (125 MHz,
CDCl3) d 14.15, 29.13, 31.65, 35.64, 37.72, 47.95, 60.45,
115.24, 125.76, 128.30, 128.35, 129.91, 130.91, 142.05,
154.53, 176.29. IR (liquid film) cmꢁ1 3340, 2939, 1705,
1516, 1222. HRMS m=z 312.1715 (Mþ) (calcd for
C20H24O3 312.1726).
The analytical sample was obtained as sodium salts as
follows. To a solution of 8c in EtOH (10 mL) was added
1 N NaOH (1.50 mL), and the reaction mixture was
evaporated in vacuo. The residual water was removed
by co-distillation with EtOH in vacuo. The Na salt of 8c
was collected by filtration using diethyl ether as a col-
orless solid (0.65 g, yield 90%).
5.6.4. Ethyl 5-phenyl-2-[4-[2-[1-(4-pyridin-2-ylphenyl)-
ethylideneaminooxy]ethoxy]benzyl]pentanoate. Mp: 53–
55 °C (yield 89%). 1H NMR (CDCl3) d 1.14 (3H, t,
J ¼ 7:0 Hz), 1.49–1.75 (4H, m), 2.28 (3H, s), 2.56–2.71
(4H, m), 2.84 (1H, dd, J ¼ 7:5, 12.5 Hz), 4.05 (2H, q,
J ¼ 7:0 Hz), 4.27 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t,
J ¼ 5:0 Hz), 6.86 (2H, d, J ¼ 8:5 Hz), 7.05 (2H, d,
J ¼ 8:5 Hz), 7.12–7.29 (6H, m), 7.75–7.78 (4H, m), 8.01
(2H, d, J ¼ 8:5 Hz), 8.70 (1H, d, J ¼ 5:0 Hz). IR (KBr)
cmꢁ1 2944, 1733, 1249, 1163, 956. MS m=z 551 (M+Hþ).
Anal. Calcd for C35H38N2O4: C, 76.34; H, 6.96; N, 5.09.
Found: C, 76.52; H, 6.88; N, 5.16.
1H NMR (DMSO-d6) d 0.79 (3H, t, J ¼ 6:5 Hz), 1.04–
1.30 (5H, m), 1.30–1.49 (1H, m), 2.09–2.25 (1H, m), 2.23
(3H, s), 2.39 (1H, dd, J ¼ 7:5, 13.5 Hz), 2.78 (1H, dd,
J ¼ 7:5, 13.5 Hz), 4.23 (2H, t, J ¼ 4:5 Hz), 4.47 (2H, t,
J ¼ 4:5 Hz), 6.83 (2H, d, J ¼ 8:5 Hz), 7.07 (2H, d,
J ¼ 8:5 Hz), 7.33–7.41 (1H, m), 7.80 (2H, d, J ¼ 8:5 Hz),
7.85–7.95 (1H, m), 8.00 (1H, d, J ¼ 8:0 Hz), 8.13 (2H, d,
J ¼ 8:5 Hz), 8.69 (1H, d, J ¼ 5:0 Hz). IR (KBr) cmꢁ1
2931, 1567, 1513, 1415, 1251, 1064, 779. MS m=z 505
(M+Naþ). Anal. Calcd for C28H32N2O4Na: C, 68.42; H,
6.56; N, 5.70; Na, 4.68. Found: C, 68.27; H, 6.37; N,
5.67; Na, 5.01.
5.6.5. 5-Phenyl-2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylid-
eneaminooxy]ethoxy]benzyl]pentanoic acid (8d). Color-
1
less syrup (yield 93%). H NMR (CDCl3) d 1.52–1.75
5.6. 5-Phenyl-2-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylidene-
aminooxy]ethoxy]benzyl]pentanoic acid (8d)
(4H, m), 2.25 (3H, s), 2.54–2.70 (4H, m), 2.86–2.93 (1H,
m), 4.26 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t, J ¼ 5:0 Hz),
6.85 (2H, d, J ¼ 8:5 Hz), 7.06 (2H, d, J ¼ 8:5 Hz), 7.11–
7.17 (3H, m), 7.22–7.26 (3H, m), 7.70–7.78 (4H, m), 7.94
(2H, d, J ¼ 8:5 Hz), 8.70 (1H, d, J ¼ 5:0 Hz).
HRMS m=z 523.2602 (M+Hþ) (calcd for C33H35N2O4
523.2597).
5.6.1. Diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)-
1
malonate (13d). Colorless syrup (yield 82%). H NMR
(CDCl3) d 1.21 (6H, t, J ¼ 7:0 Hz), 1.57–1.66 (2H, m),
1.76–1.85 (2H, m), 2.61 (2H, t, J ¼ 6:5 Hz), 3.14 (2H, s),
4.15 (4H, d, q, J ¼ 1:5, 7.0 Hz), 5.01 (2H, s), 6.79 (2H, d,
J ¼ 8:5 Hz), 6.89 (2H, d, J ¼ 8:5 Hz), 7.15–7.44 (10H,
m). 13C NMR (125 MHz, CDCl3) d 14.05, 26.03, 31.03,
35.85, 37.07, 58.76, 61.11, 69.95, 114.57, 125.87, 127.46,
127.92, 128.35, 128.49, 128.56, 130.79, 137.08, 141.80,
157.71, 171.26. IR (liquid film) cmꢁ1 2980, 2938, 1731,
1512, 1245. HRMS m=z 475.2486 (M+Hþ) (calcd for
C30H35O5 475.2485).
The sodium salt of 8d was obtained by the same pro-
cedure as described for the preparation of the sodium
salt of 8c.
1H NMR (DMSO-d6) d 1.40–1.67 (5H, m), 2.24 (3H, s),
2.36–2.51 (4H, m), 2.83 (2H, dd, J ¼ 7, 13.5 Hz), 4.23
(2H, t, J ¼ 4:0 Hz), 4.48 (2H, t, J ¼ 4:0 Hz), 6.81 (2H, d,
J ¼ 8:5 Hz), 7.06–7.12 (5H, m), 7.17–7.23 (2H, m), 7.35
(1H, dd, J ¼ 5:0, 6.0 Hz), 7.79 (2H, d, J ¼ 8:5 Hz), 7.87
(1H, dt, J ¼ 1:5, 8.0 Hz), 7.97 (1H, d, J ¼ 8:0 Hz), 8.12
(2H, d, J ¼ 8:5 Hz), 8.67 (1H, d, J ¼ 5:0 Hz). IR (KBr)
cmꢁ1 3403, 2935, 1556, 1413, 1249, 948, 783. MS m=z
567 (M+Naþ). Anal. Calcd for C33H33N2O4Na: C,
72.88; H, 6.15; N, 5.11; Na, 4.22. Found: C, 72.78; H,
6.11; N, 5.14; Na, 4.08.
5.6.2. Ethyl 2-(4-benzyloxybenzyl)-5-phenylpentanoate.
1
Colorless syrup (yield 96%). H NMR (CDCl3) d 1.14
(3H, t, J ¼ 7:0 Hz), 1.49–1.73 (4H, m), 2.56–2.71 (4H,
m), 2.80–2.89 (1H, m), 4.04 (2H, q, J ¼ 7:0 Hz), 5.03
(2H, s), 6.87 (2H, d, J ¼ 8:5 Hz), 7.05 (2H, d,
J ¼ 8:5 Hz), 7.11–7.46 (10H, m). 13C NMR (125 MHz,

2428
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
5.7. 2-Methylthio-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
fideneaminooxy]ethoxy]phenyl]propionic acid (8e)
7.13 (2H, d, J ¼ 8:5 Hz). IR (liquid film) cmꢁ1 1727,
1512, 1235, 1153, 1079, 1007. HRMS m=z 284.1082 (Mþ)
(calcd for C14H20O4S 284.1083).
5.7.1. Ethyl 2-hydroxy-3-[4-(methoxymethoxy)phenyl]pro-
pionate. After a mixture of NaH (55% dispersion in oil)
(1.15 g, 26.5 mmol), ethyl 3-(4-hydroxyphenyl)lactate 15
(5.56 g, 26.5 mmol), and a catalytic amount of 18-crown-
6 in toluene (25 mL) and DMF (25 mL) was stirred at
room temperature for 1 h, a solution of chlorometh-
ylmethyl ether (4.42 mL, 58.2 mmol) in toluene (10 mL)
was added. The reaction mixture was stirred at room
temperature for 16 h. Water was added and the mixture
was extracted with EtOAc. The organic phase was sep-
arated, washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was subjected to col-
umn chromatography (hexane/EtOAc, 7/3) to give the
title compound as a colorless syrup (1.98 g, yield 29%).
5.7.4. Ethyl 3-(4-hydroxyphenyl)-2-methylthiopropionate
(17a). A mixture of the above-mentioned methoxy-
methyl ether (356 mg, 1.25 mmol) and 4 N HCl in
dioxane (5.0 mL) was stirred at room temperature for
30 min. Saturated aqueous NaHCO3 was added, and the
mixture was extracted with EtOAc. The organic phase
was washed with brine, dried over Na2SO4, and evap-
orated in vacuo to give 17a as solids. The solids were
collected by filtration using hexane to afford the title
compound as colorless solids (0.30 g, yield 99%).
Mp: 49–50 °C. 1H NMR (CDCl3) d 1.22 (3H, t,
J ¼ 7:5 Hz), 2.17 (3H, s), 2.89 (1H, dd, J ¼ 6:5,
14.0 Hz), 3.13 (1H, dd, J ¼ 9:5, 14.0 Hz), 3.41 (1H, dd,
J ¼ 6:5, 9.5 Hz), 4.09–4.20 (2H, m), 4.97–5.11 (1H, br s),
6.74 (2H, d, J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz). IR
(KBr) cmꢁ1 3400, 1702, 1520, 1251, 1178. HRMS m=z
241.0900 (M+Hþ) (calcd for C12H17O3S 241.0899).
Anal. Calcd for C12H16O3S: C, 59.97; H, 6.71; S, 13.34.
Found: C, 59.78; H, 6.56; S, 13.40.
1H NMR (CDCl3) d 1.29 (3H, t, J ¼ 7:0 Hz), 2.73 (1H,
d, J ¼ 6:0 Hz), 2.92 (1H, dd, J ¼ 6:5, 14.0 Hz), 3.08 (1H,
dd, J ¼ 4:5, 14.0 Hz), 3.47 (3H, s), 4.22 (2H, q,
J ¼ 7:0 Hz), 4.37–4.45 (1H, m), 5.15 (2H, s), 6.97 (2H, s,
J ¼ 8:5 Hz), 7.14 (2H, d, J ¼ 8:5 Hz). IR (liquid film)
cmꢁ1 3469, 2957, 1738, 1512, 1234, 1200, 1007. HRMS
m=z 254.1163 (Mþ) (calcd for C13H18O5 254.1155).
5.7.2. Ethyl 2-methanesulfonyloxy-3-[4-(methoxymeth-
oxy)phenyl]propionate (16). To a solution of ethyl 2-hy-
droxy-3-[4-(methoxymethoxy)phenyl]propionate (2.58 g,
10.2 mmol) and methanesulfonyl chloride (1.74 g,
15.2 mmol) in dichloromethane (30 mL) was added tri-
ethylamine (2.12 mL, 15.2 mmol) at 0 °C and the reac-
tion mixture was stirred at the same temperature for 1 h.
Water was added and the mixture was extracted with
EtOAc. The organic phase was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was
subjected to column chromatography (hexane/EtOAc, 2/
1) to give the title compound as a colorless syrup (2.79 g,
yield 68%).
5.7.5. Ethyl 2-methylthio-3-[4-[2-[1-(4-pyridin-2-ylphenyl)-
ethylideneaminooxy]ethoxy]phenyl]propionate. Colorless
syrup (yield 91%). 1H NMR (CDCl3) d 1.22 (3H, t,
J ¼ 7:0 Hz), 2.16 (3H, s), 2.28 (3H, s), 2.90 (1H, dd,
J ¼ 6:5, 14 Hz), 3.15 (1H, dd, J ¼ 9:0, 14.0 Hz), 3.40
(1H, dd, J ¼ 6:5, 9.0 Hz), 4.13 (2H, dq, J ¼ 3:0, 7.0 Hz),
4.28 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t, J ¼ 5:0 Hz), 6.89
(2H, d, J ¼ 8:5 Hz), 7.13 (2H, d, J ¼ 8:5 Hz), 7.22–7.27
(1H, m), 7.75–7.78 (4H, m), 8.01 (2H, d, J ¼ 8:5 Hz),
8.71 (1H, d, J ¼ 4:5 Hz). HRMS m=z 479.2011 (M+Hþ)
(calcd for C27H31N2O4S 479.2005).
5.7.6. 2-Methylthio-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
ideneaminooxy]ethoxy]phenyl]propionic acid (8e). Mp:
113–115 °C (yield 95%). H NMR (CDCl3) d 2.22 (3H,
1H NMR (CDCl3) d 1.28 (3H, t, J ¼ 7:0 Hz), 2.87 (3H,
s), 3.10 (1H, dd, J ¼ 8:0, 14.5 Hz), 3.23 (1H, dd, J ¼ 4:5,
14.5 Hz), 3.47 (3H, s), 4.24 (2H, q, J ¼ 7:0 Hz), 5.10–
5.25 (3H, m), 6.99 (2H, d, J ¼ 8:5 Hz), 7.17 (2H, d,
J ¼ 8:5 Hz). IR (liquid film) cmꢁ1 2940, 1754, 1513,
1365, 1176, 1003. HRMS m=z 332.0929 (Mþ) (calcd for
C14H20O7S 332.0930).
1
s), 2.25 (3H, s), 2.91 (1H, dd, J ¼ 5:5, 14.0 Hz), 3.18
(1H, dd, J ¼ 10:0, 14.0 Hz), 3.44 (1H, dd, J ¼ 5:0,
10.0 Hz), 4.33 (2H, t, J ¼ 4:5 Hz), 4.55 (2H, t,
J ¼ 4:5 Hz), 6.89 (2H, d, J ¼ 8:5 Hz), 7.15 (2H, d,
J ¼ 8:5 Hz), 7.26–7.32 (1H, m), 7.63 (2H, d, J ¼ 8:5 Hz),
7.71–7.84 (2H, m), 7.87 (2H, d, J ¼ 8:5 Hz), 8.70 (1H, d,
J ¼ 4:5 Hz). IR (KBr) cmꢁ1 2922, 1693, 1511, 1244, 952,
782. MS m=z 451 (M+Hþ). Anal. Calcd for
C25H26N2O4S: C, 66.65; H, 5.82; N, 6.22; S, 7.12.
Found: C, 66.80; H, 5.84; N, 6.27; S, 7.03.
5.7.3. Ethyl 3-[4-(methoxymethoxy)phenyl]-2-methylthio-
propionate. A mixture of 16 (1.0 g, 3.0 mmol), sodium
thiomethoxide (257 mg, 3.7 mmol) in DMF (10 mL) was
stirred at 50 °C for 6 h. Water was added, and the mix-
ture was extracted with EtOAc. The organic phase was
washed with brine, dried over Na2SO4, and evaporated
in vacuo. The residue was subjected to column chro-
matography (hexane/EtOAc, 4/1) to give the title com-
pound as a colorless syrup (660 mg, yield 77%). 1H
NMR (CDCl3) d 1.22 (3H, t, J ¼ 7:0 Hz), 2.17 (3H, s),
2.91 (1H, dd, J ¼ 6:5, 14.0 Hz), 3.15 (1H, dd, J ¼ 9:0,
14.0 Hz), 3.41 (1H, dd, J ¼ 6:5, 9.0 Hz), 3.47 (3H, s),
4.09–4.23 (2H, m), 5.15 (2H, s), 6.96 (2H, d, J ¼ 8:5 Hz),
5.8. 2-Phenylthio-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
ideneaminooxy]ethoxy]phenyl]propionic acid (8f)
5.8.1. Ethyl 3-[4-(methoxymethoxy)phenyl]-2-phenylthio-
propionate. A mixture of 16 (1.0 g, 3.0 mmol), benze-
nethiol (398 mg, 3.6 mmol), and K2CO3 (0.5 g,
3.61 mmol) in DMF (10 mL) was stirred at 50 °C for 1 h.
Water was added and the mixture was extracted with

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2429
EtOAc. The organic phase was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was
subjected to column chromatography (hexane/EtOAc,
4/1) to give the title compound as a colorless syrup
(880 mg, yield 84%).
7.43–7.49 (2H, m), 7.64 (2H, d, J ¼ 8:5 Hz), 7.68–7.80
(2H, m), 7.85 (2H, d, J ¼ 8:5 Hz), 8.66 (1H, d,
J ¼ 5:5 Hz). IR (KBr) cmꢁ1 2930, 1719, 1511, 1437,
1247, 1066, 782. MS m=z 513 (M+Hþ). Anal. Calcd for
C20H28N2O4SÆ1/3H2O: C, 69.51; H, 5.57; N, 5.40; S,
6.19. Found: C, 69.31; H, 5.48; N, 5.27; S, 6.42.
1H NMR (CDCl3) d 1.09 (3H, t, J ¼ 7:0 Hz), 3.01 (1H,
dd, J ¼ 6:5, 14.0 Hz), 3.15 (1H, dd, J ¼ 9:0, 14.0 Hz),
3.48 (3H, s), 3.87 (1H, dd, J ¼ 6:5, 9.0 Hz), 4.00–4.08
(2H, m), 5.15 (2H, s), 6.95 (2H, d, J ¼ 8:5 Hz), 7.12 (2H,
d, J ¼ 8:5 Hz), 7.29–7.36 (3H, m), 7.44–7.48 (2H, m). IR
(liquid film) cmꢁ1 1732, 1512, 1235, 1153, 1079, 1006.
HRMS m=z 346.1229 (Mþ) (calcd for C19H22O4S
346.1239).
5.9. 2-Ethoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylidene-
aminooxy]ethoxy]phenyl]propionic acid (8g)
5.9.1. Ethyl 3-(4-benzyloxyphenyl)lactate. A mixture of
15 (15.83 g, 75.3 mmol), benzyl chloride (10.73 mL,
90.4 mmol), and K2CO3 (25.0 g, 0.18 mol), in DMF
(160 mL) was stirred at 60 °C for 4 h. Water was added,
and the mixture was extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was subjected to col-
umn chromatography (hexane/EtOAc, 7/3) to give the
title compound as an oil (22.6 g, yield 99%).
5.8.2. Ethyl 3-(4-hydroxyphenyl)-2-phenylthiopropionate
(17b). The same procedure as for the preparation of 17a
was performed.
1
Colorless syrup (yield 99%). H NMR (CDCl3) d 1.08
(3H, t, J ¼ 7:0 Hz), 2.99 (1H, dd, J ¼ 6:5, 14.0 Hz), 3.11
(1H, dd, J ¼ 9:5, 14.0 Hz), 3.85 (1H, dd, J ¼ 6:5,
9.5 Hz), 3.91–4.08 (2H, m), 6.72 (2H, d, J ¼ 8:5 Hz),
7.05 (2H, d, J ¼ 8:5 Hz), 7.16–7.40 (3H, m), 7.44 (2H, d,
J ¼ 8:5 Hz). IR (liquid film) cmꢁ1 3406, 1729, 1710,
1516, 1232, 1175. HRMS m=z 302.0974 (Mþ) (calcd for
C17H18O3S 302.0977).
1H NMR (CDCl3) d 1.28 (3H, t, J ¼ 7:0 Hz), 2.73 (1H,
d, J ¼ 6:5 Hz), 2.92 (1H, dd, J ¼ 6:5, 14.0 Hz), 3.07 (1H,
dd, J ¼ 4:5, 14.0 Hz), 4.21 (2H, q, J ¼ 7:0 Hz), 4.36–
4.42 (1H, m), 5.04 (2H, s), 6.91 (2H, d, J ¼ 8:5 Hz), 7.14
(2H, d, J ¼ 8:5 Hz), 7.29–7.45 (5H, m). 13C NMR
(125 MHz, CDCl3) d 14.04, 39.51, 61.45, 69.80, 71.21,
114.59, 127.29, 127.74, 128.39, 128.55, 130.40, 136.93,
157.62, 174.15. IR (liquid film) cmꢁ1 3489, 1734, 1512,
1242, 1177, 1026. HRMS m=z 323.1257 (M+Naþ) (calcd
for C18H20O4Na 323.1260).
5.8.3. Ethyl 2-phenylthio-3-[4-[2-[1-(4-pyridin-2-ylphen-
a
yl)ethylideneaminooxy]ethoxy]phenyl]propionate. To
solution of 17b (303 mg, 1.0 mmol) in toluene (3.0 mL)
were added 10 (384 mg, 1.5 mmol) and triphenylphos-
phine (393 mg, 1.5 mmol). To the mixture was added
diethyl azodicarboxylate (590 lL, 1.5 mmol) slowly over
1 h at 0 °C, and the mixture was stirred for another 16 h
at room temperature. The residue was subjected to
column chromatography (hexane/EtOAc, 4/1 and 7/3) to
give the title compound as a colorless syrup (420 mg,
yield 78%).
5.9.2. Ethyl 3-(4-benzyloxyphenyl)-2-ethoxypropionate
(18a). A mixture of NaH (55% dispersion in oil)
(2.76 g, 63.3 mmol) and ethyl 3-(4-benzyloxyphen-
yl)lactate (17.3 g, 57.5 mmol) in toluene (100 mL) and
DMF (100 mL) was stirred at 40 °C for 1 h. Ethyl iodide
(2.76 g, 69.0 mmol) was added and the mixture was
stirred at room temperature for 16 h. Water was added,
and the mixture was extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was subjected to col-
umn chromatography (hexane/EtOAc, 5/1) to give the
title compound as a colorless syrup (10.6 g, yield 56%).
1H NMR (CDCl3) d 1.07 (3H, t, J ¼ 7:0 Hz), 2.27 (3H,
s), 3.00 (1H, dd, J ¼ 6:5, 14.0 Hz), 3.14 (1H, dd, J ¼ 9:5,
14.0), 3.85 (1H, dd, J ¼ 6:5, 9.5 Hz), 3.98–4.06 (2H, m),
4.27 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t, J ¼ 5:0 Hz), 6.87
(2H, d, J ¼ 8:5 Hz), 7.11 (2H, d, J ¼ 8:5 Hz), 7.20–7.30
(4H, m), 7.40–7.45 (2H, m), 7.72–7.78 (4H, m), 8.00 (2H,
d, J ¼ 8:5 Hz), 8.69–8.71 (1H, m). IR (CDCl3) cmꢁ1
2929, 1728, 1588, 1512, 1469, 1249. HRMS m=z
541.2167 (M+Hþ) (calcd for C32H33N2O4S 541.2161).
1H NMR (CDCl3) d 1.17 (3H, t, J ¼ 7:0 Hz), 1.21 (3H,
t, J ¼ 7:0 Hz), 2.95 (2H, d, J ¼ 6:5 Hz), 3.30–3.41 (1H,
m), 3.55–3.66 (1H, m), 3.97 (1H, d, J ¼ 6:5 Hz), 4.16
(2H, q, J ¼ 7:0 Hz), 5.04 (2H, s), 6.89 (2H, d,
J ¼ 8:5 Hz), 7.16 (2H, d, J ¼ 8:5 Hz), 7.27–7.44 (5H, m).
HRMS m=z 329.1749 (M+Hþ) (calcd for C20H25O4
329.1753).
5.8.4. 2-Phenylthio-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
ideneaminooxy]ethoxy]phenyl]propionic acid (8f). The
same procedure as for the preparation of 8a was per-
formed.
5.9.3. Ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate
(19a). The same procedure as for the preparation of
14a was performed.
1
Colorless foam (yield 83%). H NMR (CDCl3) d 2.24
1
(3H, s), 3.01 (1H, dd, J ¼ 6:0, 14.0 Hz), 3.15 (1H, dd,
J ¼ 9:5, 14.0 Hz), 3.87 (1H, dd, J ¼ 6:0, 9.5 Hz), 4.30
(2H, t, J ¼ 4:5 Hz), 4.54 (2H, t, J ¼ 4:5 Hz), 6.87 (2H, d,
J ¼ 8:5 Hz), 7.13 (2H, d, J ¼ 8:5 Hz), 7.23–7.32 (4H, m),
Colorless syrup (yield 99%). H NMR (CDCl3) d 1.17
(3H, t, J ¼ 7:0 Hz), 1.23 (3H, t, J ¼ 7:0 Hz), 2.94 (2H, d,
J ¼ 6:5 Hz), 3.31–3.42 (1H, m), 3.55–3.66 (1H, m), 3.98
(1H, t, J ¼ 6:5 Hz), 4.16 (2H, q, J ¼ 7:0 Hz), 6.74 (2H,

2430
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
d, J ¼ 8:5 Hz), 7.10 (2H, d, J ¼ 8:5 Hz). 13C NMR
(125 MHz, CDCl3) d 14.18, 15.02, 38.44, 61.05, 66.28,
80.45, 115.24, 128.65, 130.49, 154.71, 172.98. IR (KBr)
cmꢁ1 3405, 2980, 1730, 1517, 1116. HRMS m=z 239.1279
(M+Hþ) (calcd for C13H19O4 239.1284).
5.10.2. Ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate
(19b). The same procedure as for the preparation of 14a
was performed.
1
Mp: 67–68 °C (yield 96%). H NMR (CDCl3) d 1.19
(3H, t, J ¼ 7:0 Hz), 3.11–3.22 (2H, m), 4.17 (2H, q,
J ¼ 7:0 Hz), 4.72–4.76 (1H, m), 4.92 (1H, s), 6.75 (2H, d,
J ¼ 8:5 Hz), 6.83 (2H, d, J ¼ 8:5 Hz), 6.95 (1H, t,
J ¼ 8:5 Hz), 7.16 (2H, d, J ¼ 8:5 Hz), 7.25 (2H, t,
J ¼ 8:5 Hz). IR (KBr) cmꢁ1 3406, 1728, 1516, 1488,
1277, 1267, 1224. MS m=z 286 (Mþ). Anal. Calcd for
C17H18O4Æ1/10 n-hexane: C, 71.67; H, 6.63. Found: C,
71.76; H, 6.63.
5.9.4. Ethyl 2-ethoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)-
ethylideneaminooxy]ethoxy]phenyl]propionate. The same
procedure as for the preparation of the ethyl ester of 8a
was performed.
Mp: 59–61 °C (yield 77%). 1H NMR (CDCl3) d 1.16
(3H, t, J ¼ 7:0 Hz), 1.23 (3H, t, J ¼ 7:0 Hz), 2.28 (3H,
s), 2.95 (2H, d, J ¼ 6:5 Hz), 3.29–3.40 (1H, m), 3.54–
3.65 (1H, m), 3.97 (1H, t, J ¼ 6:5 Hz), 4.17 (2H, q,
J ¼ 7:0 Hz), 4.28 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t,
J ¼ 5:0 Hz), 6.88 (2H, d, J ¼ 8:5 Hz), 7.16 (2H, d,
J ¼ 8:5 Hz), 7.22–7.27 (1H, m), 7.75–7.80 (2H, m), 7.76
(2H, d, J ¼ 8:5 Hz), 8.01 (2H, d, J ¼ 8:5 Hz), 8.70 (1H,
d, J ¼ 5:0 Hz). HRMS m=z 477.2383 (M+Hþ) (calcd for
C28H33N2O5 477.2390).
5.10.3. Ethyl 2-phenoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)-
ethylideneaminooxy]ethoxy]phenyl]propionate. The same
procedure as for the preparation of the ethyl ester of 8f
was performed.
1
Colorless syrup (yield 69%). H NMR (CDCl3) d 1.19
(3H, t, J ¼ 7:0 Hz), 2.26 (3H, s), 3.17–3.20 (2H, m), 4.17
(2H, q, J ¼ 7:0 Hz), 4.27 (2H, t, J ¼ 5:0 Hz), 4.54 (2H, t,
J ¼ 5:0 Hz), 4.74 (1H, dd, J ¼ 5:5, 6.5 Hz), 6.82–6.96
(5H, m), 7.21–7.26 (5H, m), 7.74–7.77 (4H, m), 8.01 (2H,
d, J ¼ 8:5 Hz), 8.70 (1H, d, J ¼ 5:0 Hz). HRMS m=z
525.2385 (M+Hþ) (calcd for C32H33N2O5 525.2390).
5.9.5. 2-Ethoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethylide-
neaminooxy]ethoxy]phenyl]propionic acid (8g). The same
procedure as for the preparation of 8a was performed.
1
Mp: 133–135 °C (yield 80%). H NMR (CDCl3) d 1.18
(3H, t, J ¼ 7:0 Hz), 2.28 (3H, s), 2.95 (1H, dd, J ¼ 7:5,
14.0 Hz), 3.08 (1H, dd, J ¼ 4:5, 14.0 Hz), 3.39–3.50 (1H,
m), 3.55–3.66 (1H, m), 4.04 (1H, dd, J ¼ 4:5, 7.5 Hz),
4.29 (2H, t, J ¼ 5:0 Hz), 4.56 (2H, t, J ¼ 5:0 Hz), 6.89
(2H, d, J ¼ 8:5 Hz), 7.17 (2H, d, J ¼ 8:5 Hz), 7.25–7.30
(1H, m), 7.74 (2H, d, J ¼ 8:5 Hz), 7.76–7.80 (2H, m),
7.96 (2H, d, J ¼ 8:5 Hz), 8.72 (1H, d, J ¼ 4:5 Hz). IR
(KBr) cmꢁ1 2939, 2479, 1918, 1718, 1514, 1240, 950. MS
m=z 449 (M+Hþ). Anal. Calcd for C26H28N2O5: C,
69.69; H, 6.29; N, 6.25. Found: C, 69.53; H, 6.42; N,
6.09.
5.10.4. 2-Phenoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
ideneaminooxy]ethoxy]phenylpropionic acid (8h). The
same procedure as for 8a was performed.
1
Mp: 138–140 °C (yield 93%). H NMR (CDCl3) d 2.25
(3H, s), 3.22 (2H, d, J ¼ 6:0 Hz), 4.29 (2H, t,
J ¼ 4:5 Hz), 4.54 (2H, t, J ¼ 4:5 Hz), 4.81 (1H, t,
J ¼ 6:0 Hz), 6.86–6.97 (5H, m), 7.21–7.31 (5H, m), 7.67–
7.89 (6H, m), 8.72 (1H, d, J ¼ 5:0 Hz). IR (KBr) cmꢁ1
2926, 1727, 1600, 1512, 1491, 1237, 1058. MS m=z 497
(M+Hþ). Anal. Calcd for C30H28N2O5: C, 72.56; H,
5.68; N, 5.64. Found: C, 72.37; H, 5.77; N, 5.56.
5.10. 2-Phenoxy-3-[4-[2-[1-(4-pyridin-2-ylphenyl)ethyl-
ideneaminooxy]ethoxy]phenyl]propionic acid (8h)
Similarly 8i–k were prepared.
5.10.1. Ethyl 3-(4-benzyloxyphenyl)-2-phenoxypropionate
(18b). To a solution of ethyl 3-(4-benzyloxyphen-
yl)lactate (300 mg, 1.0 mmol), phenol (113 mg,
1.2 mmol), and triphenylphosphine (315 mg, 1.2 mmol)
in toluene (3.5 mL) was added diethyl azodicarboxylate
(40% solution in toluene) (471 lL, 1.2 mmol) at 0 °C and
the mixture was stirred at room temperature for 16 h.
The reaction mixture was evaporated in vacuo and
purified by column chromatography (hexane/EtOAc,
20/1 and 10/1) to give the title compound as an oil
(215 mg, yield 57%).
5.11. 2-(4-Fluorophenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphen-
yl)ethylideneaminooxy]ethoxy]phenyl]propionic acid (8i)
5.11.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-fluorophen-
1
oxy)propionate (18c). Colorless syrup (yield 76%). H
NMR (CDCl3) d 1.18 (3H, t, J ¼ 7:0 Hz), 3.16 (2H, d,
J ¼ 6:5 Hz), 4.16 (2H, q, J ¼ 7:0 Hz), 4.66 (1H, t,
J ¼ 6:5 Hz), 5.04 (2H, s), 6.72–6.80 (2H, m), 6.89–6.97
(4H, m), 7.21 (2H, d, J ¼ 8:5 Hz), 7.31–7.48 (5H, m). IR
(KBr) cmꢁ1 1734, 1504, 1243, 1020, 830. HRMS m=z
417.1484 (M+Naþ) (calcd for C24H23FO4Na 417.1443).
Anal. Calcd for C24H23FO4Æ1/10H2O: C, 72.75; H, 5.90;
F, 4.79. Found: C, 72.87; H, 5.83; F, 4.75.
1H NMR (CDCl3) 1.18 (3H, t, J ¼ 7:0 Hz), 3.12–3.24
(2H, m), 4.16 (2H, q, J ¼ 7:0 Hz), 4.71–4.79 (1H, m),
5.04 (2H, s), 6.81–6.98 (5H, m), 7.20–7.47 (9H, m). IR
(liquid film) cmꢁ1 1753, 1512, 1495, 1240, 1179, 1754.
HRMS m=z 376.1677 (Mþ) (calcd for C24H24O4
376.1675).
5.11.2. Ethyl 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)-
1
propionate (19c). Mp: 80–81 °C (yield 99%). H NMR
(CDCl3) d 1.19 (3H, t, J ¼ 7:0 Hz), 3.15 (2H, d,

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2431
J ¼ 6:5 Hz), 4.17 (2H, q, J ¼ 7:0 Hz), 4.65 (1H, t,
J ¼ 6:5 Hz), 4.76 (1H, s), 6.71–6.80 (4H, m), 6.87–6.95
(2H, m), 7.16 (2H, d, J ¼ 8:5 Hz). IR (liquid film) cmꢁ1
3412, 1735, 1506, 1205, 830. HRMS m=z 305.1188
(M+Hþ) (calcd for C17H18FO4 305.1189).
1222. HRMS m=z 301.1431 (M+Hþ) (calcd for
C18H21O4 301.1440).
5.12.3. Ethyl 2-(4-methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-
ylphenyl)ethylideneaminooxy]ethoxy]phenyl]propionate.
1
Colorless syrup (yield 42%). H NMR (CDCl3) d 1.19
5.11.3. Ethyl 2-(4-fluorophenoxy)-3-[4-[2-[1-(4-pyridin-2-
ylphenyl)ethylideneaminooxy]ethoxy]phenyl]propionate.
Colorless syrup (yield 84%). H NMR (CDCl3) d 1.19
(3H, t, J ¼ 7:0 Hz), 2.25 (3H, s), 2.26 (3H, s), 3.15–3.18
(2H, m), 4.16 (2H, q, J ¼ 7:0 Hz), 4.27 (2H, t,
J ¼ 4:5 Hz), 4.54 (2H, t, J ¼ 4:5 Hz), 4.69 (1H, dd,
J ¼ 5:5, 6.5 Hz), 6.72 (2H, d, J ¼ 8:5 Hz), 6.82 (2H, d,
J ¼ 8:5 Hz), 7.02 (2H, d, J ¼ 8:5 Hz), 7.22 (2H, d,
J ¼ 8:5 Hz), 7.22–7.27 (1H, m), 7.73–7.80 (4H, m), 7.99
(2H, d, J ¼ 8:5 Hz), 8.70 (1H, d, J ¼ 5:0 Hz). HRMS
m=z 539.2540 (M+Hþ) (calcd for C33H35N2O5 539.2546).
1
(3H, s), 2.27 (3H, s), 3.16 (2H, d, J ¼ 6:5 Hz), 4.17 (2H,
q, J ¼ 7:0 Hz), 4.28 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t,
J ¼ 5:0 Hz), 4.66 (1H, t, J ¼ 6:5 Hz), 6.77 (2H, dd,
J ¼ 4:5, 9.0 Hz), 6.90 (2H, d, J ¼ 8:5 Hz), 6.91 (2H, dd,
J ¼ 8:5, 9.0 Hz), 7.20 (2H, d, J ¼ 8:5 Hz), 7.24–7.27
(1H, m), 7.74–7.77 (4H, m), 8.00 (2H, d, J ¼ 8:5 Hz),
8.70 (1H, d, J ¼ 5:0 Hz). HRMS m=z 543.2291 (M+Hþ)
(calcd for C28H32N2FO5 543.2295).
5.12.4. 2-(4-Methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-yl-
phenyl)ethylideneaminooxy]ethoxy]phenyl]propionic acid
(8j). Mp: 54–56 °C (yield 66%). 1H NMR (CDCl3) d
2.25 (6H, s), 3.21 (2H, d, J ¼ 6:0 Hz), 4.29 (2H, t,
J ¼ 4:5 Hz), 4.55 (2H, t, J ¼ 4:5 Hz), 4.78 (1H, t,
J ¼ 6:0 Hz), 6.77 (2H, d, J ¼ 8:5 Hz), 6.88 (2H, d,
J ¼ 8:5 Hz), 7.03 (2H, d, J ¼ 8:5 Hz), 7.21 (2H, d,
J ¼ 8:5 Hz), 7.26–7.31 (1H, m), 7.69–7.83 (4H, m), 7.89
(2H, d, J ¼ 8:5 Hz), 8.72 (1H, d, J ¼ 5:0 Hz). IR (KBr)
cmꢁ1 2926, 1510, 1241, 1178, 1070. MS m=z 511
(M+Hþ). Anal. Calcd for C31H30N2O5Æ1/2H2O: C,
71.66; H, 6.01; N, 5.39. Found: C, 71.89; H, 5.89; N,
5.24.
5.11.4. 2-(4-Fluorophenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphen-
yl)ethylideneaminooxy]ethoxy]phenyl]propionic acid (8i).
Mp: 88–90 °C (yield 94%). 1H NMR (CDCl3) d 2.25
(3H, s), 3.20 (1H, d, J ¼ 7:0 Hz), 3.21 (1H, d,
J ¼ 5:5 Hz), 4.30 (2H, t, J ¼ 5:0 Hz), 4.55 (2H, t,
J ¼ 5:0 Hz), 4.72 (1H, dd, J ¼ 5:5, 7.0 Hz), 6.81 (2H, dd,
J ¼ 4:5, 9.0 Hz), 6.89 (2H, d, J ¼ 8:5 Hz), 6.91 (2H, dd,
J ¼ 8:5, 9.0 Hz), 7.22 (2H, d, J ¼ 8:5 Hz), 7.27–7.32
(1H, m), 7.69 (2H, d, J ¼ 8:5 Hz), 7.72 (1H, d,
J ¼ 7:5 Hz), 7.80 (2H, dd, J ¼ 2:0, 7.5 Hz), 7.86 (2H, d,
J ¼ 8:5 Hz), 8.72 (1H, d, J ¼ 5:0 Hz). IR (KBr) cmꢁ1
2930, 1728, 1505, 247, 1204. MS m=z 515 (M+Hþ). Anal.
Calcd for C30H27FN2O5: C, 70.03; H, 5.29; F, 3.69; N,
5.44. Found: C, 69.92; H, 5.18; F, 3.84; N, 5.43.
5.13. 2-(4-tert-Butylphenoxy)-3-[4-[2-[1-(4-pyridin-2-yl-
phenyl)ethylideneaminooxy]ethoxy]phenyl]propionic acid
(8k)
5.12. 2-(4-Methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphen-
yl)ethylideneaminooxy]ethoxy]phenyl]propionic acid (8j)
5.13.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-tert-butylphen-
oxy)propionate (18e). Colorless syrup (yield 50%). H
1
NMR (CDCl3) d 1.19 (3H, t, J ¼ 7:0 Hz), 1.26 (9H, s),
3.12–3.21 (2H, m), 4.17 (2H, q, J ¼ 7:0 Hz), 4.70 (1H,
dd, J ¼ 5:5, 7.5 Hz), 5.04 (2H, s), 6.76 (2H, d,
J ¼ 8:5 Hz), 6.90 (2H, d, J ¼ 8:5 Hz), 7.20–7.26 (4H, m),
7.31–7.45 (5H, m). 13C NMR (125 MHz, CDCl3) d
14.12, 31.46, 34.08, 38.31, 61.19, 69.98, 78.23, 114.78,
126.25, 127.42, 127.89, 128.54, 128.82, 130.51, 137.07,
144.31, 155.54, 157.77, 171.43. IR (liquid film) cmꢁ1
2962, 1754, 1512, 1240, 1186. HRMS m=z 455.2203
(M+Naþ) (calcd for C28H32O4Na 455.2199).
5.12.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-methylphen-
1
oxy)propionate (18d). Colorless syrup (yield 56%). H
NMR (CDCl3) d 1.23 (3H, t, J ¼ 7:0 Hz), 2.30 (3H, s),
3.15–3.28 (2H, m), 4.15–4.25 (2H, m), 4.70–4.79 (1H,
m), 5.08 (2H, s), 6.78 (2H, d, J ¼ 8:5 Hz), 6.95 (2H, d,
J ¼ 8:5 Hz), 7.07 (2H, d, J ¼ 8:5 Hz), 7.26 (2H, d,
J ¼ 8:5 Hz), 7.32–7.60 (5H, m). 13C NMR (125 MHz,
CDCl3) d 14.10, 20.46, 38.28, 61.18, 69.98, 78.37, 114.78,
115.28, 127.89, 128.54, 128.77, 129.90, 130.49, 130.96,
137.07, 155.71, 157.77, 171.38. IR (liquid film) cmꢁ1
1752, 1510, 1239, 1178, 1026. HRMS m=z 413.1738
(M+Naþ) (calcd for C25H26O4Na 413.1729).
5.13.2. Ethyl 2-(4-tert-butylphenoxy)-3-(4-hydroxyphen-
yl)propionate (19e). Colorless syrup (yield 99%). 1H
NMR (CDCl3) d 1.20 (3H, t, J ¼ 7:0 Hz), 1.26 (9H, s),
3.13–3.20 (2H, m), 4.18 (2H, q, J ¼ 7:0 Hz), 4.69 (1H,
dd, J ¼ 5:5, 7.5 Hz), 4.81 (1H, br s), 6.75 (2H, d,
J ¼ 8:5 Hz), 6.76 (2H, d, J ¼ 8:5 Hz), 7.17 (2H, d,
J ¼ 8:5 Hz), 7.24 (2H, d, J ¼ 8:5 Hz). 13C NMR
(125 MHz, CDCl3) d 14.11, 31.46, 34.09, 38.29, 61.30,
78.28, 114.80, 115.26, 126.29, 128.50, 130.68, 144.39,
154.57, 155.51, 171.59. IR (liquid film) cmꢁ1 3421, 2963,
1731, 1514, 1238, 1187. HRMS m=z 365.1739 (M+Naþ)
(calcd for C21H26O4Na 365.1729).
5.12.2. Ethyl 3-(4-hydroxyphenyl)-2-(4-methylphen-
1
oxy)propionate (19d). Colorless syrup (yield 99%). H
NMR (CDCl3) d 1.19 (3H, t, J ¼ 7:0 Hz), 2.25 (3H, s),
3.09–3.18 (2H, m), 4.16 (2H, q, J ¼ 7:0 Hz), 4.64–4.72
(1H, m), 4.76 (1H, br s), 6.65–6.79 (4H, m), 7.02 (2H, d,
J ¼ 8:5 Hz), 7.16 (2H, s, J ¼ 8:5 Hz). 13C NMR
(125 MHz, CDCl3) d 14.07, 20.46, 38.25, 61.41, 78.44,
115.31, 115.36, 127.87, 129.94, 130.57, 131.07, 155.03,
155.63, 171.84. IR (KBr) cmꢁ1 3443, 1719, 1509, 1267,

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M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
5.13.3. Ethyl 2-(4-tert-butylphenoxy)-3-[4-[2-[1-(4-pyr-
idin-2-ylphenyl)ethylideneaminooxy]ethoxy]phenyl]propi-
onate. Colorless syrup (yield 77%). H NMR (CDCl3) d
1.20 (3H, t, J ¼ 7:0 Hz), 1.26 (9H, s), 2.27 (3H, s), 3.15–
3.18 (2H, m), 4.17 (2H, q, J ¼ 7:0 Hz), 4.27 (2H, t,
J ¼ 5:0 Hz), 4.53 (2H, t, J ¼ 5:0 Hz), 4.70 (1H, dd,
J ¼ 5:5, 7.5 Hz), 6.76 (2H, d, J ¼ 8:5 Hz), 6.92 (2H, d,
J ¼ 8:5 Hz), 7.20–7.27 (5H, m), 7.74–7.77 (4H, m), 8.00
(2H, d, J ¼ 8:5 Hz), 8.71 (1H, d, J ¼ 4:5 Hz). HRMS
m=z 581.3009 (M+Hþ) (calcd for C36H41N2O5 581.3016).
dioxane (4.0 mL) was stirred at room temperature for
1 h. The solvent was removed in vacuo and the residual
HCl was removed by co-distillation with toluene several
times to give the HCl salt of ethyl 3-[4-(2-aminoeth-
oxy)phenyl]-2-phenoxypropionate. To the HCl salt were
added DMF (4.0 mL) and Et3N (410 lL, 2.94 mmol),
and the mixture was stirred for 10 min. Then 4-(pyridin-
2yl)benzoic acid (205 mg, 1.03 mmol) and diethylphos-
phoryl cyanide (DEPC, 168 lL, 1.03 mmol) were added
and the mixture was stirred for 1 h. The reaction mixture
was diluted with EtOAc. The organic phase was sepa-
rated, washed with water, aq NaHCO3, and brine, dried
over Na2SO4, and concentrated in vacuo. The residue
was subjected to column chromatography (hexane/
EtOAc, 1/1 and 2/3) to give the title compound as col-
orless crystals (155 mg, yield 33%).
1
5.13.4. 2-(4-tert-Butylphenoxy)-3-[4-[2-[1-(4-pyridin-2-yl-
phenyl)ethylideneaminooxy]ethoxy]phenyl]propionic acid
1
(10k). Mp: 148–150 °C (yield 99%). H NMR (CDCl3)
d 1.30 (9H, s), 2.31 (3H, s), 3.26 (2H, d, J ¼ 6:0 Hz), 4.34
(2H, t, J ¼ 5:0 Hz), 4.59 (2H, t, J ¼ 5:0 Hz), 4.84 (1H, t,
J ¼ 6:0 Hz), 6.86 (2H, d, J ¼ 9:0 Hz), 6.93 (2H, d,
J ¼ 8:5 Hz), 7.25–7.35 (5H, m), 7.74–7.88 (4H, m), 7.95
(2H, d, J ¼ 8:5 Hz), 8.76 (1H, d, J ¼ 4:5 Hz). 13C NMR
(125 MHz, CDCl3) d 12.79, 31.45, 34.05, 38.10, 66.60,
72.61, 77.99, 114.63, 114.76, 121.56, 122.63, 126.26,
126.51, 127.26, 128.98, 130.54, 137.23, 137.78, 138.92,
144.25, 148.91, 154.86, 155.49, 156.63, 157.79, 174.74.
IR (KBr pellet) cmꢁ1 2960, 1512, 1242, 1185, 1071, 783.
HRMS m=z 553.2698 (M+Hþ) (calcd for C34H37N2O5
553.2703). Anal. Calcd for C34H36N2O5: C, 73.89; H,
6.57; N, 5.07. Found: C, 74.02; H, 6.57; N, 4.99.
Mp: 119–120 °C. 1H NMR (CDCl3) d 1.19 (3H, t,
J ¼ 7:0 Hz), 3.17–3.22 (2H, m), 3.89 (2H, dt, J ¼ 5:0,
5.5 Hz), 4.13–4.22 (4H, m), 4.74 (1H, dd, J ¼ 5:5,
7.0 Hz), 6.63–6.69 (1H, m), 6.84 (2H, d, J ¼ 9:0 Hz),
6.87 (2H, d, J ¼ 9:0 Hz), 6.94 (1H, t, J ¼ 7:5 Hz), 7.20–
7.30 (5H, m), 7.75–7.80 (2H, m), 7.90 (2H, d,
J ¼ 8:5 Hz), 8.07 (2H, d, J ¼ 8:5 Hz), 8.72 (1H, d,
J ¼ 4:5 Hz). IR (KBr) cmꢁ1 3352, 1748, 1633, 1543,
1246. HRMS m=z 511.2246 (M+Hþ) (calcd for
C31H31N2O5 511.2233). Anal. Calcd for C31H30N2O5: C,
72.92; H, 5.92; N, 5.49. Found: C, 73.05; H, 5.98; N,
5.46.
5.14. 2-Phenoxy-3-[4-[2-[(4-pyridin-2-ylbenzoyl)-
amino]ethoxy]phenyl]propionic acid (9a)
5.14.3. 2-Phenoxy-3-[4-[2-[(4-pyridin-2-ylbenzoyl)amino]-
ethoxy]phenyl]propionic acid (9a). The same procedure
as for the preparation of 8a was performed.
5.14.1. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-phenoxypropionate. To
a
solution of
3-(4-hydroxyphenyl)-2-phenoxypropionate 19b (291 mg,
1.02 mmol) in toluene (3.0 mL) were added N-(tert-
butoxycarbonyl)aminoethanol (410 mg, 2.54 mmol) and
triphenylphosphine (666 mg, 2.54 mmol). To the mix-
ture, was slowly added a solution of DEAD (40%
solution in toluene) (996 lL, 2.54 mmol) over 1 h at 0 °C,
and the mixture was stirred for another 16 h at room
temperature. The organic solvent was removed in vacuo.
The residue was subjected to column chromatography
(hexane/EtOAc, 9/1 and 7/3) to give the title compound
as a colorless syrup (421 mg, yield 96%).
1
Mp: 149–151 °C (yield 91%). H NMR (CDCl3) d 3.21
(2H, d, J ¼ 7:0 Hz), 3.87 (2H, dt, J ¼ 5:0, 5.5 Hz), 4.14–
4.18 (2H, m), 4.74 (1H, t, J ¼ 7:0 Hz), 6.84–6.94 (6H,
m), 7.19–7.31 (5H, m), 7.75–7.80 (2H, m), 7.88 (2H, d,
J ¼ 8:5 Hz), 8.05 (2H, d, J ¼ 8:5 Hz), 8.71 (1H, d,
J ¼ 4:5 Hz). HRMS m=z 483.1928 (M+Hþ) (calcd for
C29H27N2O5 483.1920). Anal. Calcd for C29H26N2O5Æ1/
2H2O: C, 70.60; H, 5.56; N, 5.68. Found: C, 70.60; H,
5.56; N, 5.68.
Similarly 9b–g were prepared.
1H NMR (CDCl3) d 1.19 (3H, t, J ¼ 7:0 Hz), 1.45 (9H,
s), 3.13–3.23 (2H, m), 3.49–3.53 (2H, m), 3.99 (2H, t,
J ¼ 5:0 Hz), 4.17 (2H, q, J ¼ 7:0 Hz), 4.73 (1H, dd,
J ¼ 5:5, 7.5 Hz), 4.98 (1H, br s), 6.82 (2H, d,
J ¼ 8:5 Hz), 6.83 (2H, d, J ¼ 8:5 Hz), 6.94 (1H, t,
J ¼ 7:5 Hz), 7.21–7.25 (4H, m). 13C NMR (125 MHz,
CDCl3) d 14.116, 28.39, 38.23, 40.13, 61.28, 67.15, 78.04,
79.50, 114.39, 115.31, 121.67, 128.85, 129.47, 130.57,
155.88, 157.57, 157.77, 171.21. IR (liquid film) cmꢁ1
3392, 2979, 1513, 1243, 1177. HRMS m=z 452.2056
(M+Naþ) (calcd for C24H31NO6Na 452.2049).
5.15. 2-(4-Methylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9b)
5.15.1. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-methylphenoxy)propionate. Colorless syrup
(yield 99%). 1H NMR (CDCl3)
d 1.20 (3H, t,
J ¼ 7:0 Hz), 1.45 (9H, s), 2.25 (3H, s), 3.12–3.18 (2H,
m), 3.45–3.55 (2H, m), 3.99 (2H, t, J ¼ 5:0 Hz), 4.17
(2H, q, J ¼ 7:0 Hz), 4.69 (1H, dd, J ¼ 5:5, 7.5 Hz), 4.96
(1H, br s), 6.72 (2H, d, J ¼ 8:5 Hz), 6.82 (2H, d,
J ¼ 8:5 Hz), 7.02 (2H, d, J ¼ 8:5 Hz), 7.21 (2H, d,
J ¼ 8:5 Hz). 13C NMR (125 MHz, CDCl3) d 14.13,
20.47, 28.39, 38.25, 40.13, 61.22, 67.15, 78.35, 79.50,
114.37, 115.27, 128.95, 129.91, 130.55, 130.99, 155.71,
5.14.2. Ethyl 2-phenoxy-3-[4-[2-[(4-pyridin-2-ylbenzoyl)-
amino]ethoxy]phenyl]propionate. A mixture of the above-
mentioned ester (421 mg, 0.98 mmol) and 4 N HCl in

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2433
155.89, 157.55, 171.36. IR (KBr) cmꢁ1 3393, 2979, 1715,
1511, 1243. HRMS m=z 466.2196 (M+Naþ) (calcd for
C25H33NO6Na 466.2206).
5.16.3. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-isopropylphenoxy)propionate. Colorless syr-
up (yield 99%). H NMR (CDCl3) d 1.18–1.22 (9H, m),
1
1.44 (9H, s), 2.78–2.83 (1H, m), 3.10–3.20 (2H, m), 3.47–
3.52 (2H, m), 3.95–3.98 (2H, m), 4.13–4.20 (2H, m), 4.67
(1H, dd, J ¼ 5:5 Hz, 7.5 Hz), 4.96 (1H, br s), 6.74 (2H, d,
J ¼ 8:5 Hz), 6.79 (2H, d, J ¼ 8:5 Hz), 7.06 (2H, d,
J ¼ 8:5 Hz), 7.19 (2H, d, J ¼ 8:5 Hz). IR (KBr) cmꢁ1
3335, 2961, 1719, 1512, 1247. HRMS m=z 494.2516
(M+Naþ) (calcd for C27H37NO6Na 494.2519). Anal.
Calcd for C27H37NO6Æ1/7H2O: C, 68.40; H, 7.93; N,
2.95. Found: C, 68.47; H, 7.78; N, 2.92.
5.15.2. Ethyl 2-(4-methylphenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionate.
Colorless
syrup (yield 90%). 1H NMR (CDCl3) d 1.23 (3H, t,
J ¼ 7:0 Hz), 2.28 (3H, s), 3.14–3.22 (2H, m), 3.88–3.96
(2H, m), 4.11–4.27 (4H, m), 4.73 (1H, t, J ¼ 6:0 Hz),
6.62–6.71 (1H, m), 6.76 (2H, d, J ¼ 8:5 Hz), 6.90 (2H, d,
J ¼ 8:5 Hz), 7.05 (2H, d, J ¼ 8:5 Hz), 7.22–7.33 (3H, m),
7.78–7.83 (2H, m), 7.92 (2H, d, J ¼ 8:5 Hz), 8.11 (2H, d,
J ¼ 8:5 Hz), 8.71–8.78 (1H, m). IR (KBr) cmꢁ1 3360,
1741, 1644, 1510, 1233. MS m=z 525 (M+H). Anal.
Calcd for C32H32N2O5: C, 73.26; H, 6.15; N, 5.34.
Found: C, 73.07; H, 6.23; N, 5.34.
5.16.4. Ethyl 2-(4-isopropylphenoxy)-3-[4-[2-[(4-pyridin-
2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Mp: 77–
1
79 °C (yield 90%). H NMR (CDCl3) d 1.14–1.25 (9H,
m), 2.72–2.90 (1H, m), 3.12–3.19 (2H, m), 3.89 (2H, dt,
J ¼ 5:0, 5.5 Hz), 4.11–4.22 (4H, m), 4.69 (1H, dd,
J ¼ 5:5, 7.5 Hz), 6.65 (1H, br t), 6.75 (2H, d, J ¼8:5 Hz),
6.86 (2H, d, J ¼ 8:5 Hz), 7.08 (2H, d, J ¼ 8:5 Hz), 7.20–
7.31 (3H, m), 7.76–7.81 (2H, m), 7.88 (2H, d, J ¼
8:5 Hz), 8.07 (2H, d, J ¼ 8:5 Hz), 8.69–8.75 (1H, m). IR
(KBr) cmꢁ1 3363, 2959, 1510, 1241, 1182. MS m=z 553
(M+H). Anal. Calcd for C34H36N2O5Æ1/6H2O: C, 73.51;
H, 6.59; N, 5.04. Found: C, 73.89; H, 6.57; N, 5.07.
5.15.3. 2-(4-Methylphenoxy)-3-[4-[2-[(4-pyridin-2-ylbenzoyl)-
amino]ethoxy]phenyl]propionic acid (9b). Mp: 129–131 °C
(yield 99%). 1H NMR (CDCl3) d 2.25 (3H, s), 3.21 (2H, d,
J ¼ 6:0 Hz), 3.81–3.90 (2H, m), 4.15–4.21 (2H, m), 4.80
(1H, t, J ¼ 6:0 Hz), 6.68–6.75 (1H, m), 6.79 (2H, d,
J ¼ 8:5 Hz), 6.85 (2H, d, J ¼ 8:5 Hz), 7.03 (2H, d,
J ¼ 8:5 Hz), 7.21 (2H, d, J ¼ 8:5 Hz), 7.29–7.36 (1H, m),
7.70–7.88 (4H, m), 7.92 (2H, d, J ¼ 8:5 Hz), 8.69–8.73 (1H,
m). HRMS m=z 497.2076 (M+Hþ) (calcd for C30H29N2O5
497.2077). Anal. Calcd for C30H28N2O5Æ1/2H2O: C, 71.27;
H, 5.78; N, 5.54. Found: C, 71.54; H, 5.51; N, 5.47.
5.16.5. 2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9c). Mp:
1
84–85 °C (yield 99%). H NMR (CDCl3) d 1.16 (6H, d,
J ¼ 7:0 Hz), 2.70–2.88 (1H, m), 3.19 (2H, d, J ¼ 6:0 Hz),
3.80–3.89 (2H, m), 4.11–4.18 (2H, m), 4.77 (1H, t,
J ¼ 6:0 Hz), 6.77–6.88 (5H, m), 7.07 (2H, d, J ¼ 8:5 Hz),
7.21 (2H, d, J ¼ 8:5 Hz), 7.25–7.35 (1H, m), 7.70 (1H, d,
J ¼ 8:5 Hz), 7.75–7.86 (3H, m), 7.89 (2H, d, J ¼ 8:5 Hz),
8.70–8.77 (1H, m). HRMS m=z 525.2374 (M+Hþ) (calcd
for C32H33N2O5 525.2390). Anal. Calcd for
C32H32N2O5Æ1/2H2O: C, 72.03; H, 6.23; N, 5.25. Found:
C, 72.01; H, 6.06; N, 5.22.
5.16. 2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9c)
5.16.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-isopropylphen-
oxy)propionate (18f). Colorless syrup (yield 56%). 1H
NMR (CDCl3) d 1.16–1.20 (9H, m), 2.78–2.87 (1H, m),
3.10–3.20 (2H, m), 4.12–4.21 (2H, m), 4.68 (1H, dd,
J ¼ 5:5 Hz, 7.5 Hz), 5.02 (2H, s), 6.73 (2H, d,
J ¼ 8:5 Hz), 6.87 (2H, d, J ¼ 8:5 Hz), 7.06 (2H, d,
J ¼ 8:5 Hz), 7.19 (2H, d, J ¼ 8:5 Hz), 7.23–7.41 (5H, m).
13C NMR (125 MHz, CDCl3) d 14.11, 24.12, 33.26,
38.32, 61.19, 69.98, 78.32, 114.79, 115.19, 127.28,
127.42, 127.89, 128.54, 128.82, 130.51, 137.07, 142.07,
155.89, 157.78, 171.43. IR (KBr) cmꢁ1 2959, 1753, 1511,
1239, 1179. HRMS m=z 441.2048 (M+Naþ) (calcd for
C27H30O4Na 441.20).
5.17. 2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9d)
5.17.1. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-tert-butylphenoxy)propionate.
Colorless
syrup (yield 99%). 1H NMR (CDCl3) d 1.21 (3H, t,
J ¼ 7:0 Hz), 1.26 (9H, s), 1.45 (9H, s), 3.13–3.19 (2H,
m), 3.51 (2H, q, J ¼ 5:0 Hz), 3.99 (2H, t, J ¼ 5:0 Hz),
4.18 (2H, q, J ¼ 7:0 Hz), 4.66–4.72 (1H, m), 4.90–5.02
(1H, m), 6.76 (2H, d, J ¼ 8:5 Hz), 6.82 (2H, d,
J ¼ 8:5 Hz), 7.22 (2H, d, J ¼ 8:5 Hz), 7.24 (2H, d,
J ¼ 8:5 Hz). 13C NMR (125 MHz, CDCl3) d 14.14,
28.39, 31.46, 34.08, 38.27, 40.13, 61.21, 67.15, 78.22,
79.47, 114.37, 114.77, 126.25, 128.99, 130.57, 144.35,
155.53, 155.88, 157.54, 171.40. IR (liquid film) cmꢁ1
3392, 2966, 1716, 1512, 1244. HRMS m=z 508.2674
(M+Naþ) (calcd for C28H39NO6Na 508.2675).
5.16.2. Ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphen-
oxy)propionate (19f). Colorless syrup (yield 99%). 1H
NMR (CDCl3) d 1.13–1.22 (9H, m), 2.75–2.88 (1H, m),
3.11–3.18 (2H, m), 4.17 (2H, q, J ¼ 7:5 Hz), 4.69 (1H,
dd, J ¼ 5:5 Hz, 7.5 Hz), 4.77 (1H, br s), 6.76 (4H, d,
J ¼ 8:5 Hz), 7.08 (2H, d, J ¼ 8:5 Hz), 7.17 (2H, d,
J ¼ 8:5 Hz). 13C NMR (125 MHz, CDCl3) d 14.09,
24.13, 33.27, 38.31, 61.32, 78.41, 115.22, 115.31, 127.31,
128.11, 130.63, 142.15, 154.94, 155.85, 171.71. IR (liquid
film) cmꢁ1 3419, 2962, 1733, 1512, 1374. HRMS m=z
351.1567 (M+Naþ) (calcd for C20H24O4Na 351.1573).
5.17.2. Ethyl 2-(4-tert-butylphenoxy)-3-[4-[2-[(4-pyridin-
2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Colorless

2434
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
foam (yield 90%). 1H NMR (CDCl3) d 1.21 (3H, t,
J ¼ 7:0 Hz), 1.25 (9H, s), 3.15–3.20 (2H, m), 3.89 (2H, q,
J ¼ 5:0 Hz), 4.10–4.22 (4H, m), 4.69 (1H, dd, J ¼ 5:5,
7.5 Hz), 6.66 (1H, t, J ¼ 5:0 Hz), 6.76 (2H, d,
J ¼ 8:5 Hz), 6.86 (2H, d, J ¼ 8:5 Hz), 7.23–7.30 (5H, m),
7.74–7.80 (2H, m), 7.89 (2H, d, J ¼ 8:5 Hz), 8.07 (2H, d,
J ¼ 8:5 Hz), 8.72 (1H, d, J ¼ 4:5 Hz). IR (KBr) cmꢁ1
3362, 2961, 1511, 1243, 1186. HRMS m=z 567.2858
(M+Hþ) (calcd for C35H39N2O5 567.2859). Anal. Calcd
for C35H38N2O5Æ1/9H2O: C, 73.90; H, 6.78; N, 4.92.
Found: C, 73.93; H, 6.81; N, 4.83.
C29H26FN2O5
501.1826).
Anal.
Calcd
for
C29H25FN2O5Æ1/3H2O: C, 68.75; H, 5.11; N, 5.53; F,
3.75. Found: C, 68.93; H, 4.84; N, 5.43; F, 3.69.
5.19. 2-(4-Chlorophenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9f)
5.19.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-chlorophen-
oxy)propionate (18g). The same procedure as for 18b
was performed.
1
Mp: 63–64 °C (yield 56%). H NMR (CDCl3) d 1.18
5.17.3. 2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9d). Mp:
94–96 °C (yield 99%). H NMR (CDCl3) d 1.24 (9H, s),
(3H, t, J ¼ 7:0 Hz), 3.17 (2H, d, J ¼ 6:5 Hz), 4.16 (2H,
q, J ¼ 7:0 Hz), 4.69 (1H, t, J ¼ 6:5 Hz), 5.04 (2H, s),
6.75 (2H, d, J ¼ 9:0 Hz), 6.91 (2H, d, J ¼ 8:5 Hz), 7.13–
7.23 (4H, m), 7.25–7.55 (5H, m). IR (KBr) cmꢁ1 1736,
1513, 1491, 1244, 826. HRMS m=z 410.1260 (Mþ) (calcd
for C24H23ClO4 410.1285). Anal. Calcd for C24H23ClO4:
C, 70.15; H, 5.64; Cl, 8.63. Found: C, 69.96; H, 5.60; Cl,
8.56.
1
3.20 (2H, d, J ¼ 6:0 Hz), 3.80–3.90 (2H, m), 4.13–4.20
(2H, m), 4.79 (1H, t, J ¼ 6:0 Hz), 6.76 (1H, t,
J ¼ 5:0 Hz), 6.82 (2H, d, J ¼ 8:0 Hz), 6.85 (2H, d,
J ¼ 8:0 Hz), 7.22 (2H, d, J ¼ 8:0 Hz), 7.25 (2H, d,
J ¼ 8:0 Hz), 7.28–7.35 (1H, m), 7.70–7.90 (4H, m), 7.91
(2H, d, J ¼ 8:5 Hz), 8.73 (1H, d, J ¼ 4:5 Hz). HRMS
m=z 539.2548 (M+Hþ) (calcd for C33H35N2O5 539.2546).
Anal. Calcd for C33H34N2O5Æ1/2H2O: C, 72.38; H, 6.44;
N, 5.12. Found: C, 72.58; H, 6.55; N, 4.98.
5.19.2. Ethyl 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-
propionate (19g). A mixture of 18g (3.45 g, 8.40 mmol)
and 30 wt % HBr solution in AcOH (35 mL) was stirred
at room temperature for 4 h. The reaction mixture was
concentrated in vacuo and purified by column chroma-
tography (hexane/EtOAc, 4/1) to give a mixture of the
title compound and ethyl 3-(4-acetoxyphenyl)-2-(4-
chlorophenoxy)propionate. To this mixture were added
EtOH (30 mL) and K2CO3 (2.8 g, 20.3 mmol), and the
mixture was stirred at 60 °C for 4 h. Water was added,
and the mixture was extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The title compound was col-
lected by filtration using isopropyl ether and hexane
(1.94 g, yield 78%).
5.18. 2-(4-Fluorophenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid (9e)
5.18.1. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-fluorophenoxy)propionate. Colorless syrup
(yield 99%). 1H NMR (CDCl3)
d 1.20 (3H, t,
J ¼ 7:0 Hz), 1.45 (9H, s), 3.16 (2H, d, J ¼ 7:0 Hz), 3.38–
3.59 (2H, m), 3.99 (2H, t, J ¼ 5:0 Hz), 4.17 (2H, q,
J ¼ 7:0 Hz), 4.65 (1H, t, J ¼ 7:0 Hz), 4.93–5.02 (1H, m),
6.70–6.79 (2H, m), 6.82 (2H, d, J ¼ 8:5 Hz), 6.88–6.95
(2H, m), 7.20 (2H, d, J ¼ 8:5 Hz). IR (liquid film) cmꢁ1
3386, 2979, 1713, 1507, 1246. HRMS m=z 470.1952
(M+Naþ) (calcd for C24H30FNO6Na 470.1955).
Mp: 90–93 °C. 1H NMR (CDCl3) d 1.19 (3H, t,
J ¼ 7:0 Hz), 3.16 (2H, d, J ¼ 6:5 Hz), 4.17 (2H, q,
J ¼ 7:0 Hz), 4.69 (1H, t, J ¼ 6:5 Hz), 4.95 (1H, br s),
6.76 (4H, d, J ¼ 8:5 Hz), 7.15 (2H, d, J ¼ 8:5 Hz), 7.18
(2H, d, J ¼ 8:5 Hz). HRMS m=z 343.0730 (M+Naþ)
(calcd for C17H17ClO4Na 343.0713). Anal. Calcd for
C17H17ClO4: C, 63.65; H, 5.34; Cl, 11.05. Found: C,
63.65; H, 5.36; Cl, 11.02.
5.18.2. Ethyl 2-(4-fluorophenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionate.
Mp:
116–
1
118 °C (yield 90%). H NMR (CDCl3) d 1.20 (3H, t,
J ¼ 7:0 Hz), 3.17 (2H, d, J ¼ 6:5 Hz), 3.80–3.91 (2H, m),
4.08–4.21 (4H, m), 4.66 (1H, t, J ¼ 6:5 Hz), 6.62–6.70
(1H, m), 6.70–6.80 (2H, m), 6.80–6.92 (4H, m), 7.20–
7.30 (3H, m), 7.71–7.80 (2H, m), 7.88 (2H, d,
J ¼ 8:5 Hz), 8.07 (2H, d, J ¼ 8:5 Hz), 8.71 (1H, d,
J ¼ 5:0 Hz). IR (KBr) cmꢁ1 3358, 1632, 1543, 1503,
1198. HRMS m=z 529.2135 (M+Hþ) (calcd for
C31H30FN2O5 529.2139).
5.19.3. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-chlorophenoxy)propionate. Colorless syrup
(yield 99%). 1H NMR (CDCl3)
d 1.20 (3H, t,
J ¼ 7:0 Hz), 1.45 (9H, s), 3.17 (2H, t, J ¼ 6:5 Hz), 3.43–
3.57 (2H, m), 3.99 (2H, t, J ¼ 5:0 Hz), 4.17 (2H, q,
J ¼ 7:0 Hz), 4.69 (1H, t, J ¼ 6:5 Hz), 4.96 (1H, br s),
6.76 (2H, d, J ¼ 8:5 Hz), 6.82 (2H, d, J ¼ 8:5 Hz), 7.10–
7.20 (4H, m). 13C NMR (125 MHz, CDCl3) d 14.12,
28.40, 38.16, 40.13, 61.42, 67.17, 78.42, 79.53, 114.44,
116.70, 126.66, 128.61, 129.38, 130.54, 155.88, 156.41,
157.65, 170.82. IR (liquid film) cmꢁ1 3369, 2979, 1713,
1513, 1492. HRMS m=z 486.1659 (M+Naþ) (calcd for
C24H30ClNO6Na 486.1660).
5.18.3. 2-(4-Fluorophenoxy)-3-[4-[2-[(4-pyridin-2-ylben-
zoyl)amino]ethoxy]phenyl]propionic acid (9e). Mp: 139–
140 °C (yield 99%). H NMR (CDCl3) d 3.20 (2H, d,
J ¼ 6:5 Hz), 3.80–3.91 (2H, m), 4.16–4.22 (2H, m), 4.74
(1H, t, J ¼ 6:5 Hz), 6.69–6.77 (1H, m), 6.77–6.92 (6H,
m), 7.19 (2H, d, J ¼ 8:5 Hz), 7.30–7.37 (1H, m), 7.69–
7.80 (3H, m), 7.80–7.90 (3H, m), 8.71 (1H, d,
J ¼ 4:0 Hz). HRMS m=z 501.1828 (M+Hþ) (calcd for
1

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2435
5.19.4. Ethyl 2-(4-chlorophenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionate. Mp: 134–
135 °C (yield 90%). H NMR (CDCl3) d 1.20 (3H, t,
153.27, 157.85, 173.87. IR (CDCl3) cmꢁ1 2963, 1731,
1510, 1116, 909. HRMS m=z 455.2198 (M+Naþ) (calcd
for C28H32O4Na 455.2199).
1
J ¼ 7:0 Hz), 3.17 (2H, d, J ¼ 6:5 Hz), 3.83–3.92 (2H, m),
4.08–4.21 (4H, m), 4.69 (1H, t, J ¼ 6:5 Hz), 6.60–6.68
(1H, m), 6.75 (2H, d, J ¼ 8:5 Hz), 6.87 (2H, d,
J ¼ 8:5 Hz), 7.13–7.30 (5H, m), 7.72–7.79 (2H, m), 7.89
(2H, d, J ¼ 8:5 Hz), 8.08 (2H, d, J ¼ 8:5 Hz), 8.70–8.73
(1H, m). IR (KBr) cmꢁ1 3346, 2936, 1740, 1490, 1239.
HRMS m=z 545.1849 (M+Hþ) (calcd for C31H30ClN2O5
545.1834). Anal. Calcd for C31H29ClN2O5: C, 68.32; H,
5.36; Cl, 6.50; N, 5.14. Found: C, 68.15; H, 5.22; Cl,
6.41; N, 5.32.
5.20.2. Ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphen-
oxy)-2-methylpropionate (21). Colorless syrup (yield
99%). 1H NMR (CDCl3) d 1.20 (6H, d, J ¼ 7:0 Hz), 1.22
(3H, t, J ¼ 7:5 Hz), 1.38 (3H, s), 2.83 (1H, septet,
J ¼ 7:0 Hz), 3.10 (1H, d, J ¼ 13:5 Hz), 3.24 (1H, d,
13.5 Hz), 4.20 (2H, q, J ¼ 7:5 Hz), 4.81 (1H, s), 6.75
(4H, d, J ¼ 8:5 Hz), 7.06 (2H, d, J ¼ 8:5 Hz), 7.13 (2H,
d, J ¼ 8:5 Hz). 13C NMR (125 MHz, CDCl3) d 14.05,
20.55, 24.10, 33.30, 44.97, 58.49, 82.17, 114.98, 119.47,
126.93, 131.77, 142.76, 153.22, 155.05, 174.14. IR (liquid
film) cmꢁ1 2962, 1732, 1509, 1232, 1112. HRMS m=z
342.1821 (Mþ) (calcd for C21H26O4 342.1831).
5.19.5. 2-(4-Chlorophenoxy)-3-[4-[2-[(4-pyridin-2-ylben-
zoyl)amino]ethoxy]phenyl]propionic acid (9f). Mp: 155–
1
156 °C (yield 99%). H NMR (CDCl3) d 3.21 (2H, d,
J ¼ 6:0 Hz), 3.80–3.90 (2H, m), 4.12–4.22 (2H, m), 4.76
(1H, t, J ¼ 6:0 Hz), 6.70–6.88 (5H, m), 7.15 (2H, d,
J ¼ 8:5 Hz), 7.20 (2H, d, J ¼ 8:5 Hz), 7.30–7.38 (1H, m),
7.79–7.90 (6H, m), 8.70–8.74 (1H, m). HRMS m=z
517.1519 (M+Hþ) (calcd for C29H26ClN2O5 517.1530).
Anal. Calcd for C29H25ClN2O5Æ1/6H2O: C, 67.00; H,
4.91; N, 5.39; Cl, 6.82. Found: C, 67.09; H, 4.87; N,
5.42; Cl, 6.86.
5.20.3. Ethyl 3-[4-(2-tert-butoxycarbonyaminoethoxy)-
phenyl]-2-(4-isopropylphenoxy)-2-methyl-propionate.
Colorless syrup (yield 99%). H NMR (CDCl3) d 1.15–
1
1.28 (9H, m), 1.37 (3H, s), 1.45 (9H, s), 2.83 (1H, septet,
J ¼ 7:0 Hz), 3.10 (1H, d, J ¼ 13:5 Hz), 3.25 (1H, d,
J ¼ 13:5 Hz), 3.46–3.58 (2H, m), 4.00 (2H, t,
J ¼ 5:0 Hz), 4.21 (2H, q, J ¼ 7:0 Hz), 4.95–5.05 (1H, m),
6.75(2H, d, J ¼ 8:5 Hz), 6.81 (2H, d, J ¼ 8:5 Hz), 7.06
(2H, d, J ¼ 8:5 Hz). 7.17 (2H, d, J ¼ 8:5 Hz). 13C NMR
(125 MHz, CDCl3) d 14.09, 20.61, 21.46, 24.10, 28.41,
33.30, 40.16, 44.82, 61.32, 67.13, 79.51, 82.01, 113.99,
119.40, 126.91, 131.76, 137.86, 142.70, 153.25, 155.90,
157.60, 173.88. IR (liquid film) cmꢁ1 3392, 2963, 1718,
1509, 1245. HRMS m=z 508.2686 (M+Naþ) (calcd for
C28H39NO6Na 508.2675).
5.20. 2-(4-Isopropylphenoxy)-2-methyl-3-[4-[2-[(4-pyri-
din-2-ylbenzoyl)amino]ethoxy]phenyl]propionic acid (9g)
5.20.1. Ethyl 3-(4-benzyloxyphenyl)-2-(4-isopropylphen-
oxy)-2-methylpropionate. To a solution of N-isopro-
pylcyclohexylamine (18.1 mL, 0.11 mol) in THF
(300 mL) was slowly added 1.54 M n-butyl lithium in
hexane (71.4 mL, 0.11 mol) at )78 °C. After removal of
the cooling bath, the mixture was stirred for 1 h at room
temperature and then cooled again to )78 °C. To the
mixture was added a solution of 23.63 g (0.10 mol) of
ethyl 2-(4-isopropylphenoxy)propionate 22 in THF
(20 mL) dropwise over 30 min. The reaction mixture was
stirred at )78 °C for 20 min and then added a solution of
4-benzyloxybenzyl chloride (46.5 g, 0.20 mol) in THF
(100 mL). The reaction mixture was stirred overnight at
)78 °C and allowed to warm to room temperature. After
removal of the solvent in vacuo, the residue was treated
with water, and then the pH was adjusted to 5–6 with
2 N HCl. The mixture was extracted with EtOAc and the
organic phase was washed with water, dried over
Na2SO4, and evaporated in vacuo. The residue was
subjected to column chromatography (hexane/EtOAc,
9/1) to give the title compound as a colorless syrup (23 g,
yield 53%).
5.20.4. Ethyl 2-(4-isopropylphenoxy)-2-methyl-3-[4-[2-
[(4-pyridin-2-ylbenzoyl)amino]ethoxy]phenyl]propionate.
Mp:89–90 °C (yield 90%). 1H NMR (CDCl3) d 1.19 (6H,
d, J ¼ 7:0 Hz), 1.23 (3H, t, J ¼ 7:0 Hz), 1.37 (3H, s),
2.83 (1H, septet, J ¼ 7:0 Hz), 3.10 (1H, d, J ¼ 13:5 Hz),
3.26 (1H, d, J ¼ 13:5 Hz), 3.90 (2H, dt, J ¼ 5:0, 5.0 Hz),
4.17 (2H, t, J ¼ 5:0), 4.21 (2H, q, J ¼ 7:0 Hz), 6.69 (1H,
br t, J ¼ 5:0 Hz), 6.75 (2H, d, J ¼ 8:5 Hz), 6.86 (2H, d,
J ¼ 8:5 Hz), 7.06 (2H, d, J ¼ 8:5 Hz), 7.19 (2H, d, J ¼
8:5 Hz), 7.26–7.32 (1H, m), 7.76–7.82 (2H, m), 7.89 (2H,
d, J ¼ 8:5 Hz), 8.08 (2H, d, J ¼ 8:5 Hz), 8.71–8.73 (1H,
m). IR (KBr) cmꢁ1 3374, 2959, 1734, 1636, 1509. MS
m=z 567 (M+Hþ). Anal. Calcd for C35H38N2O5: C, 74.18;
H, 6.76; N, 4.94. Found: C, 74.04; H, 6.81; N, 4.92.
5.20.5. 2-(4-Isopropylphenoxy)-2-methyl-3-[4-[2-[(4-pyr-
idin-2-ylbenzoyl)amino]ethoxy]phenyl]propionic acid (9g).
1H NMR (CDCl3) d 1.20 (6H, d, J ¼ 7:0 Hz), 1.21 (3H,
t, J ¼ 7:5 Hz), 1.38 (3H, s), 2.83 (1H, septet,
J ¼ 7:0 Hz), 3.11 (1H, d, J ¼ 13:5 Hz), 3.25 (1H, d,
J ¼ 13:5 Hz), 4.20 (2H, q, J ¼ 7:5 Hz), 5.05 (2H, s), 6.75
(2H, d, J ¼ 8:5 Hz), 6.91 (2H, d, J ¼ 8:5 Hz), 7.06 (2H,
d, J ¼ 8:5 Hz), 7.18 (2H, d, J ¼ 8:5 Hz), 7.30–7.45 (5H,
m). 13C NMR (125 MHz, CDCl3) d 14.70, 20.60, 24.10,
33.29, 44.89, 61.29, 69.98, 82.04, 114.40, 119.38, 126.90,
127.46, 127.90, 128.02, 128.55, 131.69, 137.10, 142.66,
Mp: 141–143 °C (yield 99%). H NMR (CDCl3) d 1.20
1
(6H, d, J ¼ 7:0 Hz), 1.43 (3H, s), 2.84 (1H, septet,
J ¼ 7:0 Hz), 3.15 (1H, d, J ¼ 14:0 Hz), 3.25 (1H, d,
J ¼ 14:0 Hz), 3.83–3.93 (2H, m), 4.17 (2H, t,
J ¼ 5:0 Hz), 6.70 (1H, br t, J ¼ 6:0 Hz), 6.85 (2H, d,
J ¼ 8:5 Hz), 6.86 (2H, d, J ¼ 8:5 Hz), 7.09 (2H, d,
J ¼ 8:5 Hz), 7.21 (2H, d, J ¼ 8:5 Hz), 7.27–7.33 (1H, m),
7.27–7.80 (2H, m), 7.83 (2H, d, J ¼ 8:5 Hz), 8.00 (2H, d,
J ¼ 8:5 Hz), 8.72 (1H, d, J ¼ 4:5 Hz). HRMS m=z

2436
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
539.2545 (M+Hþ) (calcd for C33H35N2O5 539.2546).
Anal. Calcd for C33H34N2O5Æ4/5H2O: C, 71.67; H, 6.49;
N, 5.07. Found: C, 71.69; H, 6.12; N, 5.26.
vent was removed in vacuo and the title compound was
obtained as a colorless syrup (39.0 g, 99%).
1
The H NMR, IR, and mass spectra were identical to
the racemate.
5.21. (S)-2-(4-Methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-ylphen-
yl)ethylideneaminooxy]ethoxy]phenyl]propionic acid ((S)-
8j)
5.21.4. Ethyl (S)-3-(4-hydroxyphenyl)-2-(4-methylphen-
oxy)propionate ((S)-19d). Mp: 64–65 °C (yield 99%).
The H NMR, IR, and mass spectra were identical to
1
5.21.1. 3-(4-Benzyloxyphenyl)-2-(4-methylphenoxy)prop-
ionic acid. To a solution of 18d (0.36 g, 0.91 mmol) in
ethanol (10 mL) was added 1 N NaOH (3.5 mL), and the
mixture was stirred at room temperature for 16 h. After
the reaction mixture was evaporated in vacuo, the resi-
due was diluted with water and carefully acidified with
1 N HCl and extracted with EtOAc. The organic phase
was washed with brine, dried over Na2SO4, and evap-
orated in vacuo. The solids obtained were collected by
filtration using the mixture of isopropyl ether and hex-
ane to give the title compound as a colorless solid
(0.33 g, yield 92%).
the racemate. Anal. Calcd for C18H20O4Æ1/5H2O: C,
70.89; H, 7.07. Found: C, 71.03; H, 7.23.
5.21.5. Ethyl (S)-2-(4-methylphenoxy)-3-[4-[2-[1-(4-pyr-
idin-2-ylphenyl)ethylideneaminooxy]ethoxy]phenyl]propi-
1
onate. Colorless syrup (yield 84%). H NMR, IR, and
mass spectra were identical to the racemate.
5.21.6. (S)-2-(4-Methylphenoxy)-3-[4-[2-[1-(4-pyridin-2-
ylphenyl)ethylideneaminooxy]ethoxy]phenyl]propionic
1
acid (8j). Mp: 54–56 °C (yield 94%). The H NMR, IR,
1
and mass spectra were identical to the racemate. The
enantiomeric excess was determined as >99% ee by
HPLC analysis using Chiralpak OJ-R (CH3CN/pH 2.2
buffer solution of phosphoric acid and Et3N, 7/3). Anal.
Calcd for C31H30N2O5Æ1/3H2O: C, 72.06; H, 5.98; N,
5.42. Found: C, 72.10; H, 5.98; N, 5.35.
Mp: 129–130 °C. H NMR (CDCl3) d 2.25 (3H, s), 3.18
(2H, d, J ¼ 6:0 Hz), 4.74 (1H, t, J ¼ 6:0 Hz), 5.00 (2H,
s), 6.71 (2H, d, J ¼ 8:5 Hz), 6.87 (2H, d, J ¼ 8:5 Hz),
7.01 (2H, d, J ¼ 8:5 Hz), 7.18 (2H, d, J ¼ 8:5 Hz), 7.22–
7.40 (5H, m). MS m=z 385 (M+Naþ). IR (KBr) cmꢁ1
3031, 1731, 1711, 1511, 1232. Anal. Calcd for C23H22O4:
C, 76.22; H, 6.12. Found: C, 76.31; H, 6.13.
5.22. (S)-2-(4-Methylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9b)
5.21.2. (S)-3-(4-Benzyloxyphenyl)-2-(4-methylphenoxy)-
propionic acid. To a solution of the above racemic pro-
pionic acid (114 g, 313 mmol) in EtOH (300 mL) was
added ())-norephedrine (23.7 g, 157 mmol) and the
mixture was refluxed for 1 h and then allowed to cool to
room temperature. The white precipitates were collected
by filtration and washed with EtOH. Repeated crystal-
lization from EtOH gave 51.4 g of ())-norephedrine salt
of the title compound. The enantiomeric excess was
determined as >99% ee by HPLC analysis using
Chiralpak OJ-R (CH3CN/pH 2.2 buffer solution of
phosphoric acid and Et3N, 7/3). To the obtained ())-
norephedrine salt was added 1 N HCl until the mixture
became acidified and the product was extracted with
EtOAc. The organic phase was washed with water and
brine, and dried over Na2SO4. The solvent was removed
in vacuo and the title compound was collected by fil-
tration using isopropyl ether (36.2 g, 32%).
5.22.1. Ethyl (S)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-methylphenoxy)propionate. Colorless
1
syrup (yield 99%). The H NMR, IR, and mass spectra
were identical to the racemate.
5.22.2. Ethyl (S)-2-(4-methylphenoxy)-3-[4-[2-[(4-pyridin-
2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Mp: 102–
103 °C (yield 90%). The 1H NMR, IR, and mass spectra
were identical to the racemate. Anal. Calcd for
C32H32N2O5: C, 73.26; H, 6.15; N, 5.34. Found: C,
73.07; H, 6.01; N, 5.36.
5.22.3. (S)-2-(4-Methylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9b).
Mp: 76–78 °C (yield 99%). The 1H NMR, IR, and
mass spectra were identical to the racemate. The enan-
tiomeric excess was determined as >99% ee by HPLC
analysis using Chiralpak OJ-R (CH3CN/pH 2.2 buffer
solution of phosphoric acid and Et3N, 7/3). Anal. Calcd
for C30H28N2O5Æ1/2H2O: C, 71.27; H, 5.78; N, 5.54.
Found: C, 71.22; H, 5.75; N, 5.49.
1
Mp: 118–119 °C. The H NMR, IR, and mass spectra
were identical to the racemate. Anal. Calcd for C23H22
O4Æ1/10H2O: C, 75.85; H, 6.14. Found: C, 75.85; H, 6.03.
5.21.3. Ethyl (S)-3-(4-benzyloxyphenyl)-2-(4-methylphen-
oxy)propionate. A solution of the (S)-propionic acid
(36.2 g, 100 mmol) and concd H2SO4 (2.0 mL) in ethanol
(360 mL) was stirred at room temperature for 16 h. The
solvent was removed in vacuo and the residue was
extracted with EtOAc. The organic phase was washed
with water and brine, and dried over Na2SO4. The sol-
5.23. (R)-2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((R)-9c)
5.23.1. 3-(4-Benzyloxyphenyl)-2-(4-isopropylphenoxy)pro-
pionic acid. Alkaline hydrolysis of 18f was performed.

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2437
1
Mp: 118–119 °C (yield 99%). H NMR (CDCl3) d 1.19
Calcd for C25H26O4: C, 76.90; H, 6.71. Found: C, 77.05;
H, 6.56.
(6H, d, J ¼ 7:0 Hz), 2.82 (1H, septet, J ¼ 7:0 Hz), 3.19
(2H, d, J ¼ 6:0 Hz), 4.74 (1H, t, J ¼ 6:0 Hz), 5.00 (2H,
s), 6.75 (2H, d, J ¼ 9:0 Hz), 6.87 (2H, d, J ¼ 8:5 Hz),
7.07 (2H, d, J ¼ 8:5 Hz), 7.19 (2H, d, J ¼ 9:0 Hz), 7.21–
7.40 (5H, m). MS m=z 413 (M+Naþ). IR (KBr) cmꢁ1
2958, 1727, 1511, 1231, 827. Anal. Calcd for C25H26O4:
C, 76.90; H, 6.71. Found: C, 76.87; H, 6.69.
5.24.2. Ethyl (S)-3-(4-benzyloxyphenyl)-2-(4-isopropyl-
phenoxy)propionate ((S)-18f). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
1
tical to the racemate.
5.23.2. (R)-3-(4-Benzyloxyphenyl)-2-(4-isopropylphen-
oxy)propionic acid. Resolution of the racemate was
done using (+)-norephedrine.
5.24.3. Ethyl (S)-3-(4-hydroxyphenyl)-2-(4-isopropyl-
phenoxy)propionate ((S)-19f). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
1
Mp: 88–89 °C. The 1H NMR, IR, and mass spectra were
identical to the racemate. Anal. Calcd for C25H26O4: C,
76.90; H, 6.71. Found: C, 76.69; H, 6.88.
tical to the racemate.
5.24.4. Ethyl (S)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-isopropylphenoxy)propionate. Colorless
1
syrup (yield 99%). The H NMR, IR, and mass spectra
were identical to the racemate.
5.23.3. Ethyl (R)-3-(4-benzyloxyphenyl)-2-(4-isopropyl-
phenoxy)propionate ((R)-18f). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
1
tical to the racemate.
5.24.5. Ethyl (S)-2-(4-isopropylphenoxy)-3-[4-[2-[(4-pyri-
din-2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Color-
less syrup (yield 90%). The 1H NMR, IR, and mass
spectra were identical to the racemate.
5.23.4. Ethyl (R)-3-(4-hydroxyphenyl)-2-(4-isopropyl-
phenoxy)propionate ((R)-19f). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
1
tical to the racemate.
5.24.6. (S)-2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9c).
Mp: 100–101 °C (yield 99%). The H NMR, IR, and
mass spectra were identical to the racemate. The enan-
tiomeric excess was determined as >99% ee by HPLC
analysis using Chiralpak OJ-R (CH3CN/pH 2.2 buffer
solution of phosphoric acid and Et3N, 7/3). Anal. Calcd
for C32H32N2O5ÆH2O: C, 70.83; H, 6.32; N, 5.16. Found:
C, 70.63; H, 6.26; N, 5.11.
5.23.5. Ethyl (R)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-isopropylphenoxy)propionate. Colorless
syrup (yield 99%). The H NMR, IR, and mass spectra
were identical to the racemate.
1
1
5.23.6. Ethyl (R)-2-(4-isopropylphenoxy)-3-[4-[2-[(4-pyr-
idin-2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Color-
1
less syrup (yield 90%). H NMR, IR, and mass spectra
were identical to the racemate.
5.25. (R)-2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionic acid ((R)-9d)
5.23.7. (R)-2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionic acid ((R)-9c).
Mp: 100–101 °C (yield 99%). The H NMR, IR, and
mass spectra were identical to the racemate. The enan-
tiomeric excess was determined as >99% ee by HPLC
analysis using Chiralpak OJ-R (CH3CN/pH 2.2 buffer
solution of phosphoric acid and Et3N, 7/3). Anal. Calcd
for C32H32N2O5Æ1/3H2O: C, 72.44; H, 6.20; N, 5.28.
Found: C, 69.47; H, 5.97; N, 5.11.
5.25.1. 3-(4-Benzyloxyphenyl)-2-(4-tert-butylphenoxy)pro-
pionic acid. Mp: 124–125 °C (yield 99%). 1H NMR
(CDCl3) d 1.26 (9H, s), 3.19 (2H, d, J ¼ 6:0 Hz), 4.75 (1H,
t, J ¼ 6:0 Hz), 5.01 (2H, s), 6.75 (2H, d, J ¼ 9:0 Hz), 6.87
(2H, d, J ¼ 8:5 Hz), 7.19 (2H, d, J ¼ 8:5 Hz), 7.24 (2H, d,
J ¼ 9:0 Hz), 7.28–7.40 (5H, m). MS m=z 427 (M+Naþ).
IR (KBr) cmꢁ1 2963, 1718, 1512, 1248, 1232. Anal. Calcd
for C26H28O4: C, 77.20; H, 6.98. Found: C, 77.09; H, 7.05.
1
5.24. (S)-2-(4-Isopropylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9c)
5.25.2. (R)-3-(4-Benzyloxyphenyl)-2-(4-tert-butylphen-
oxy)propionic acid. (+)-Norephedrine was used as an
optical resolution agent.
The same procedure for the preparation of (R)-9c was
performed except using ())-norephedrine for optical
resolution.
1
Mp: 90–91 °C (yield 99%). The H NMR, IR, and mass
spectra were identical to the racemate. Anal. Calcd for
C26H28O4: C, 76.90; H, 6.71. Found: C, 77.34; H, 7.04.
5.24.1.
(S)-3-(4-Benzyloxyphenyl)-2-(4-isopropylphen-
1
oxy)propionic acid. Mp: 88–89 °C. The H NMR, IR,
and mass spectra were identical to the racemate. Anal.
5.25.3. Ethyl (R)-3-(4-benzyloxyphenyl)-2-(4-tert-butyl-
phenoxy)propionate ((R)-18e). Colorless syrup (yield

2438
M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
1
1
99%). The H NMR, IR, and mass spectra were iden-
tical to the racemate.
syrup (yield 99%). The H NMR, IR, and mass spectra
were identical to the racemate.
5.25.4. Ethyl (R)-2-(4-tert-butylphenoxy)-3-(4-hydroxy-
phenyl)propionate ((R)-19e). Colorless syrup (yield 99%).
The H NMR, IR, and mass spectra were identical to
5.26.5. Ethyl (S)-2-(4-tert-butylphenoxy)-3-[4-[2-[(4-pyr-
idin-2-ylbenzoyl)amino]ethoxy]phenyl]propionate.
Mp:
72–73 °C (yield 90%). The 1H NMR, IR, and mass
spectra were identical to the racemate. Anal. Calcd for
C35H38N2O5: C, 74.18; H, 6.76; N, 4.94. Found: C,
74.32; H, 6.82; N, 4.87.
1
the racemate.
5.25.5. Ethyl (R)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-tert-butylphenoxy)propionate. Colorless
syrup (yield 99%). The H NMR, IR, and mass spectra
1
5.26.6. (S)-2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9d). Mp:
93–95 °C (yield 99%). The 1H NMR, IR, and mass spectra
were identical to the racemate. The enantiomeric excess
was determined as >99% ee by HPLC analysis using
Chiralpak OJ-R (CH3CN/pH 2.2 buffer solution of
phosphoric acid and Et3N, 7/3). Anal. Calcd for
C33H34N2O5Æ1/2H2O: C, 72.38; H, 6.44; N, 5.12. Found:
C, 73.59; H, 6.36; N, 5.20.
were identical to the racemate.
5.25.6. Ethyl (R)-2-(4-tert-butylphenoxy)-3-[4-[2-[(4-pyr-
idin-2-ylbenzoyl)amino]ethoxy]phenyl]propionate.
Mp:
72–73 °C (yield 90%). The 1H NMR, IR, and mass
spectra were identical to the racemate. Anal. Calcd for
C35H38N2O5Æ1/5H2O: C, 73.71; H, 6.79; N, 4.91. Found:
C, 73.88; H, 6.88; N, 4.77.
5.27. (S)-2-(4-Chlorophenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9f)
5.25.7. (R)-2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-
ylbenzoyl)amino]ethoxy]phenyl]propionic acid ((R)-9d).
Mp: 93–95 °C (yield 99%). The 1H NMR, IR, and
mass spectra were identical to the racemate. The enan-
tiomeric excess was determined as >99% ee by HPLC
analysis using Chiralpak OJ-R (CH3CN/pH 2.2 buffer
solution of phosphoric acid and Et3N, 7/3). Anal. Calcd
for C33H34N2O5Æ1/2H2O: C, 72.38; H, 6.44; N, 5.12.
Found: C, 72.40; H, 6.59; N, 5.20.
The same procedure as for the preparation of 9f was
performed from (S)-19g.
5.27.1. 3-(4-Benzyloxyphenyl)-2-(4-chlorophenoxy)prop-
ionic acid. Mp: 129–130 °C (yield 99%). 1H NMR
(CDCl3) d 3.14–3.26 (2H, m), 4.73 (1H, dd, J ¼ 5:0,
6.5 Hz), 5.01 (2H, s), 6.74 (2H, d, J ¼ 9:0 Hz), 6.88 (2H,
d, J ¼ 8:5 Hz), 7.15–7.18 (4H, m), 7.27–7.40 (5H, m).
MS m=z 405 (M+Naþ). IR (KBr) cmꢁ1 3032, 1724, 1490,
1236, 1227. Anal. Calcd for C22H19ClO4Æ1/2H2O: C,
68.89; H, 5.01; Cl, 9.24. Found: C, 68.93; H, 4.87; Cl, 9.26.
5.26. (S)-2-(4-tert-Butylphenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenyl]propionic acid ((S)-9d)
The same procedure as for the preparation of (R)-9d was
performed using ())-norephedrine as an optical resolu-
tion agent.
5.27.2. (S)-3-(4-Benzyloxyphenyl)-2-(4-chlorophenoxy)-
propionic acid. Mp: 129–130 °C (yield 99%). The 1H
NMR, IR, and mass spectra were identical to the race-
mate. Anal. Calcd for C22H19ClO4: C, 69.02; H, 5.00; Cl,
9.26. Found: C, 69.03; H, 4.85; Cl, 9.22.
5.26.1. (S)-3-(4-Benzyloxyphenyl)-2-(4-tert-butylphenoxy)-
propionic acid. Mp: 90–91 °C. The 1H NMR, IR, and
mass spectra were identical to the racemate. Anal. Calcd
for C26H28O4: C, 77.20; H, 6.98. Found: C, 77.14; H, 7.03.
5.27.3. Ethyl (S)-3-(4-benzyloxyphenyl)-2-(4-chlorophen-
oxy)propionate ((S)-18g). Colorless syrup (yield 99%).
The H NMR, IR, and mass spectra were identical to
1
5.26.2. Ethyl (S)-3-(4-benzyloxyphenyl)-2-(4-tert-butyl-
phenoxy)propionate ((S)-18e). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
the racemate.
1
tical to the racemate.
5.27.4. Ethyl (S)-2-(4-chlorophenoxy)-3-(4-hydroxyphen-
yl)propionate ((S)-19g). Mp: 93–94 °C (yield 78%). The
1H NMR, IR, and mass spectra were identical to the
racemate. Anal. Calcd for C17H17ClO4Æ1/3H2O: C,
62.53; H, 5.45; Cl, 10.86. Found: C, 62.55; H, 5.47, Cl,
10.98.
5.26.3. Ethyl (S)-2-(4-tert-butylphenoxy)-3-(4-hydroxy-
phenyl)propionate ((S)-19e). Colorless syrup (yield
99%). The H NMR, IR, and mass spectra were iden-
1
tical to the racemate.
5.26.4. Ethyl (S)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-tert-butylphenoxy)propionate. Colorless
5.27.5. Ethyl (S)-3-[4-(2-tert-butoxycarbonyaminoeth-
oxy)phenyl]-2-(4-chlorophenoxy)propionate.
Colorless

M. Takamura et al. / Bioorg. Med. Chem. 12 (2004) 2419–2439
2439
1
10. Fruchart, J. C.; Durietz, P.; Staels, B. Curr. Opin. Lipidol.
1999, 10, 245.
syrup (yield 99%). The H NMR, IR, and mass spectra
were identical to the racemate.
11. Kockx, M.; Gervois, P. P.; Poulain, P.; Derudas, B.;
Peters, J. M.; Gonzalez, F. J.; Princen, H. M. G.;
Kooistra, T.; Staels, B. Blood 1999, 93, 2991.
12. Kjellsted, A.; Oakes, N.; Svensson, L.; Carlson, A. C.;
Ljung, B. Diabetes 2001, 50(Suppl. 2), A121.
13. Nomura, M.; Kinoshita, S.; Satoh, H.; Maeda, T.;
Murakami, K.; Tsunoda, M.; Miyachi, H.; Awano, K.
Bioorg. Med. Chem. Lett. 1999, 9, 533.
14. Ueno, H.; Oe, T.; Suehiro, I.; Nakamura, F. EP604983, 1994.
15. Hulin, B.; Newton, L. S.; Lewis, D. M.; Genereux, P. E.;
Gibbs, E. M.; Clark, D. A. J. Med. Chem. 1996, 39, 3897.
16. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.;
Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley,
R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Ram, H.
K.; Smith, D. G.; Smith, S. A. Bioorg. Med. Chem. Lett.
1996, 6, 2121.
17. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.;
Coyle, P. J.; Dean, D. K.; Faller, A.; Pinto, I. L.; Rami, H.
K.; Smith, D. G.; Smith, S. A. Bioorg. Med. Chem. Lett.
1996, 6, 2127.
5.27.6. Ethyl (S)-2-(4-chlorophenoxy)-3-[4-[2-[(4-pyridin-
2-ylbenzoyl)amino]ethoxy]phenyl]propionate. Mp: 135–
136 °C (yield 90%). The 1H NMR, IR, and mass spectra
were identical to the racemate. Anal. Calcd for
C31H29ClN2O5: C, 68.32; H, 5.36; Cl, 6.50; N, 5.14.
Found: C, 68.20; H, 5.35; Cl, 6.51; N, 5.12.
5.27.7. (S)-2-(4-Chlorophenoxy)-3-[4-[2-[(4-pyridin-2-yl-
benzoyl)amino]ethoxy]phenylpropionic acid ((S)-9f). Mp:
1
152–155 °C (99%). The H NMR, IR, and mass spectra
were identical to the racemate. The enantiomeric excess
was determined as >99% ee by HPLC analysis using
Chiralpak OJ-R (CH3CN/pH 2.2 buffer solution of
phosphoric acid and Et3N, 7/3). Anal. Calcd for
C29H25ClN2O5: C, 67.38; H, 4.87; Cl, 6.86; N, 5.42.
Found: C, 67.26; H, 4.90; Cl, 6.82; N, 5.39.
18. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B.
R. J. Med. Chem. 2000, 43, 527.
19. Yanagisawa, H.; Takamura, M.; Yamada, E.; Fujita, S.;
Fujiwara, T.; Yachi, M.; Isobe, A.; Hagisawa, Y. Bioorg.
Med. Chem. Lett. 2000, 10, 373.
References and notes
20. Yanagisawa, H.; Takamura, M.; Fujita, T.; Fujiwara, T.
JP9323967, 1997.
21. Sakurai, M.; Takamura, M.; Fujiwara, T.; Yanagisawa,
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