Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558

Article abstract of DOI:10.1016/j.bmc.2015.07.028

GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats.

Full text of DOI:10.1016/j.bmc.2015.07.028

Accepted Manuscript
Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent
GPR40 agonist DS-1558
Rieko Takano, Masao Yoshida, Masahiro Inoue, Takeshi Honda, Ryutaro
Nakashima, Koji Matsumoto, Tatsuya Yano, Tsuneaki Ogata, Nobuaki
Watanabe, Masakazu Hirouchi, Takako Kimura, Narihiro Toda
PII:
S0968-0896(15)00612-4
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.07.028
BMC 12457
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 June 2015
15 July 2015
16 July 2015
Please cite this article as: Takano, R., Yoshida, M., Inoue, M., Honda, T., Nakashima, R., Matsumoto, K., Yano,
T., Ogata, T., Watanabe, N., Hirouchi, M., Kimura, T., Toda, N., Optimization of 3-aryl-3-ethoxypropanoic acids
and discovery of the potent GPR40 agonist DS-1558, Bioorganic & Medicinal Chemistry (2015), doi: http://
dx.doi.org/10.1016/j.bmc.2015.07.028
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Bioorganic & Medicinal Chemistry
Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40
agonist DS-1558
Rieko Takano*,a, Masao Yoshida a, Masahiro Inoue b, Takeshi Honda c, Ryutaro Nakashima d, Koji
Matsumoto d, Tatsuya Yano d, Tsuneaki Ogata e, Nobuaki Watanabe f, Masakazu Hirouchi f, Takako Kimura
g and Narihiro Toda *,c
a Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Venture Science Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
c New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
d Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
e Global Project Management Department, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
f Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
g Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
ARTICLE INFO
ABSTRACT
GPR40 agonists stimulate insulin secretion only under the presence of high glucose
concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel
insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-
ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound
Article history:
Received
Received in revised form
Accepted
29r
(DS-1558),
(3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-
Available online
yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-
dependent insulin secretion after intravenous glucose injection in SD rats.
Keywords:
GPR40
agonist
2009 Elsevier Ltd. All rights reserved.
glucose-dependent
insulin secretagogues
DS-1558
hereditary factors, environmental factors and disease conditions.
That means it is desirable for various choices of treatments to
1. Introduction
The worldwide epidemic of diabetes has become a serious
problem. According to the Diabetes Atlas on 2014 by the
International Diabetes Federation, the population suffering from
diabetes has reached 380 million, and it will reach to 590 million
within 20 years. The expanding tendency is seen in every country.
China and India where a strong economic growth has been
achieved are especially faced with the problems of the rapidly
rising rates of diabetes.
There are three main types of diabetes, type 1, type 2 and
gestational diabetes. Among them, Type 2 diabetics account for
up to 90% of all patients. Type 2 diabetes is characterized by the
impairment of the regulation of blood glucose levels due to the
dysfunction of pancreatic insulin secretion and peripheral insulin
sensitivity. Hyperglycemia may cause diabetics complications
and be a risk factor for cardiovascular diseases. Therefore, it is
important for diabetics to keep control of their blood glucose
levels throughout their lives. The approach of treatment is
different from case to case, and depends on each patient’s
exist. There are already several kinds of medicines for treatment
of type 2 diabetes. The sulfonylureas are the most commonly
used as insulin secretagogues, however, they have side effects
such as hypoglycemia or exhaustion of pancreatic -cells because
of their mechanism of releasing insulin regardless of the glucose
levels.1 These days, novel action mechanism agents with a low
risk of hypoglycemia, such as -glucosidase inhibitors, SGLT2
inhibitors, DPP-4 inhibitors and GLP-1 analogues are being
used.2
TAK-875
AMG-837
LY2881835
TUG-770
GW9508
* Corresponding authors. Tel.: +81 3 3492 3131; fax: +81 3 5436 8563
Figure 1. Typical structures for GPR40 agonists.
E-mail addresses: takano.rieko.u2@daiichisankyo.co.jp (R. Takano),
toda.narihiro.jw@daiichisankyo.co.jp (N. Toda)

GPR40 agonist has been also investigated as one of the novel
agents which have a strong efficacy and a minimum risk of
causing hypoglycemia.3 GPR40 is a Gq protein-coupled receptor
preferentially expressed in pancreatic β-cells. Medium- and long-
chain free fatty acids are found to activate the receptor as natural
ligands. Furthermore, the GPR40 receptor is activated only under
a high glucose concentration.4 Once the activation has occurred,
the intra cellular levels of inositol 1,4,5-triphosphate, and
diacylglycerol are accumulated, and result in a Ca2+ release from
the endoplasmic reticulum. At the same time, the voltage-gated
Ca2+channels are also stimulated. These increases of intracellular
Ca2+ concentrations enhance the insulin secretion.5 Several
GPR40 agonists have proceeded in clinical or preclinical phases.
These molecules contain a common structure, phenyl propanoic
acid moiety (Figure 1).6-10 We have also reported a lead
compound 1, however, it showed modest agonistic activity and
poor PK profiles (Figure 2).11
the primary alcohol, and we obtained the amide linked 11a.
Compound 12 was obtained from 8 by hydrogenation of the nitro
group using Pd-C under H2 atmosphere. Aniline 12 was alkylated
by 3,4-dichlorobenzylbromide with K2CO3 as a base to give 13.
After saponification, we obtained the amine linked compound
11b.
Scheme 3 shows the synthesis of the derivatives for the parts
B and C. Compounds 20a-q were synthesized via common
intermediate 18. Aldehyde 15 derived from 14a was reacted with
AcOEt using LHMDS as a base to give -hydroxy ester 16.
Ethylation of the resulting alcohol in 16 was conducted in the
neutral condition of EtI and Ag2O to avoid retro aldol reaction.
Deprotection of the TBS group of 17 provided the phenol
intermediate 18. Mitsunobu reaction or alkylation of 18 afforded
ester 19a-q. Hydrolysis of the ester group in ethanol at room
temperature gave compounds 20a-q.
For aryl ether derivatives 20r and 20s, aryl moieties were
introduced by SNAr reaction to 14a in the first step. Aldol
reaction of aldehyde 21a, b gave alcohol 22a, b. Alkylation of
alcohol 22a, b yielded 19r, s. Saponification of 19r and 19s gave
20r and 20s, respectively.
Derivatives for the part B (20t-y) were synthesized in a
similar manner as compound 20r, s. Compounds 14b-g were
reacted with 3,4-dichlorobenzylalcohol by Mitsunobu reaction in
the first step. Aldol reaction of aldehydes 21c-h gave -hydroxy
esters 22c-h. Ethylation of alcohols 22c-h yielded -ethoxy esters
19t-y. Saponification of 19t-y gave derivatives 20t-y. Compound
23 was synthesized by a similar route to 20t-y starting from 3-
hydroxybenzaldehyde.12
In this article, we describe the optimization of compound 1 in
terms of in vitro activity to obtain a promising candidate.
2. Chemistry
2.1 Synthesis of racemic compounds
A
B
C
*
Lead compound 1
Figure 2. Optimization of lead compound 1. The structure was divided
into 3 parts.
(i)
(ii),(iii)
3
4a
We divided compound 1 into 3 parts and optimized each
region (Figure 2).
(iv)
(v),(vi)
2
For the part A, the carboxylic acid bioisosteres were
introduced as shown in scheme 1. Tetrazole 4a, -difluorinated
carboxylic acid 4b and sulfonimide 4c were synthesized from the
common intermediate 2. A cyano group was introduced to the
intermediate 2 by aldol reaction. The 3 + 2 cycloaddition of the
compound 3 and Bu3SnN3 under the microwave conditions gave
the tetrazole 4a. A Reformatsky reaction afforded the -
difluorinated ester 5, and subsequent hydrolysis provided -
difluorinated carboxylic acid 4b. Sulfonimide 4c was synthesized
by the condensation reaction of acyl benzotriazole derived from 1
and MeSO2NH2 by using an excess amount of NaH as a base.
Scheme 2 shows the synthesis of derivatives with amide 11a
or amino linker 11b. 4-Nitrobenzaldehyde (6) was converted to 8
by aldol reaction and ethylation. Ester moiety of 8 was reduced to
give alcohol 9. The alcohol was protected by a silyl group, and a
nitro group was hydrogenated into an amine group using PtO2.
After condensation of the aniline 10 and 2-methylbenzoyl
chloride, the carboxylic acid was established by the oxidation of
5
4b
(vii),(ii),(vi)
(viii)
1
4c
Scheme 1. Synthesis of the carboxylic acid bioisosteres.
Reagents and conditions: (i) n-BuLi, acetonitrile, THF, -78 °C, 93%; (ii)
Ag2O, EtI, toluene, 100 °C; (iii) Bu3SnN3, dioxane, microwave 130 °C,
37%; (iv) BrF2CCO2Et, Zn, CeCl3.7H2O, THF, 80 °C, 81%; (v) NaH, EtI,
DMF, r.t., 20%; (vi) 1 N NaOH, EtOH, r.t.; (vii) AcOEt, LHMDS, THF, -78
to 0 °C, 84%; (viii) HBTU, DIPEA, MeSO2NH2, NaH, THF, r.t., 50%.
(iv),(v)
(vi)-(ix)
(iii)
11a
9
10
(i)
(ii)
(x)
6
7
8
(xi)
(xii)
12
13
11b
Scheme 2. Synthesis of amide and amino linker derivatives.
Reagents and conditions: (i) AcOEt, LHMDS, THF, -78 to 0 °C, 54%; (ii) Ag2O, EtI, toluene, 100 °C, 46%; (iii) DIBAL, CH2Cl2, -78 to 0 °C, 98%; (iv) TBSCl,
imidazole, DMF, r.t., 89%; (v) H2, PtO2, AcOEt, EtOH, r.t., 81%; (vi) 2-methylbenzoyl chloride, DMA, .r.t., 44%; (vii) TBAF, THF, r.t., 94%; (viii) Dess-Martin
periodinane, DCM, r.t., 59%; (ix) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, THF, H2O, r.t. 59%; (x) H2, Pd-C, AcOEt, r.t., 100%; (xi) 2,3-
dichloronebezylbromide, K2CO3, acetone, r.t., 45%; (xii) 1 N NaOH aq., EtOH, THF, r.t., 20%.

(iv)
(ii)
(iii)
14a; (i)
(v)
15
16
17
18
(vi)
(ii)
14a; (vii)
(iii)
14a-g
14b-g; (viii)
19a-q,r,s; R1 = same as 20a-q,r,s (Table 3)
20a-q,r,s (Table 3)
20t-y (Table 2)
19t-y; R1, R2, R3 = same as 20t-y (Table 2)
21a-h
22a-h
14a; R2=R3=H
21a; R1=3,4-diCl-phenyl, R2=H, R3=H
21b; R1=4-Cl-naphtyl, R2=H, R3=H
22a; R1=3,4-diCl-phenyl, R2=H, R3=H
22b; R1=4-Cl-naphtyl, R2=H, R3=H
14b; R2=F, R3=H
14c; R2=Me R3=H
21c; R1=3,4-diCl-benzyl, R2=F, R3=H
21d; R1=3,4-diCl-benzyl, R2=Me, R3=H
22c; R1=3,4-diCl-benzyl, R2=F, R3=H
22d; R1=3,4-diCl-benzyl, R2=Me, R3=H
22e; R1=3,4-diCl-benzyl, R2=NO2, R3=H
14d; R2=NO2, R3=H
14e; R2=H, R3=F
14f; R2=H, R3=Cl
14g; R2=H, R3=OMe
21e; R1=3,4-diCl-benzyl, R2=NO2, R3=H
21f; R1=3,4-diCl-benzyl, R2=H, R3=F
21g; R1=3,4-diCl-benzyl, R2=H, R3=Cl
21h; R1=3,4-diCl-benzyl, R2=H, R3=OMe
22f; R1=3,4-diCl-benzyl, R2=H, R3=F
22g; R1=3,4-diCl-benzyl, R2=H, R3=Cl
22h; R1=3,4-diCl-benzyl, R2=H, R3=OMe
Scheme 3. Synthesis of racemic derivatives.
Reagents and conditions: (i) TBSCl, imidazole, THF, r.t.; (ii) AcOEt, LHMDS, THF, -78 to 0 °C; (iii) Ag2O, EtI, toluene, 100 °C; (iv) TBAF, THF, r.t.; (v)
R1OH, PPh3, DEAD, THF, 60 °C or R1X, K2CO3, acetone, r.t; (vi) 1 N NaOH aq., EtOH, THF, r.t.; (vii) R1X, Cs2CO3, DMF, 100 °C; (viii) 3,4-dichlorobenzyl
alcohol, PPh3, DEAD, THF, 60 °C.
2.2 Synthesis of chiral compounds
(i)
(ii)
(iii)
(iv)
(v)
1
24
25
26
27
28a-t*; R = same as 29
29a-t*
(viii)
(vi), (vii)
(ix)
(x)
(xi),(xii)
30
31
32
33
34a,b
35a,b
Scheme 4. Synthesis of chiral -ethoxy compounds via intermediate 27 and 33.Reagents and conditions: (i) HCO2H, Et3N, RuCl[(S,S)-Tsdpen](p-cymene),
35 °C, 58%, 97% ee; (ii) Ag2O, EtI, toluene, 100 °C, 74%; (iii) TBAF, THF, r.t., 100%; (iii) LiAlH4, THF, 0 °C, 70%; (iv) R1OH, PPh3, DEAD, THF, 60 °C; (v)
1N NaOH aq., EtOH, THF, r.t.; (vi) (R)-,,-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol, CH3CHO, DMF, r.t.; (vii) NaBH4, THF, MeOH, -40 °C,
33% (2 steps), 94% ee; (viii) imidazole, TIPSCl, DMF, 0 °C , 66%; (ix) EtI, NaH, DMF, THF, 0 °C, 77%; (x) R1OH, KOH, 18-crown-6, toluene, 100 °C; (xi)
TBAF, THF, 0 °C; (xii) TEMPO, NaClO2, NaClO, pH 6.86 phosphate buffer, acetonitrile, 0 to 10 °C. * a,i,m,r were synthesized by other routes described in the
supporting information.
Scheme 4 shows the general synthesis of chiral derivatives (Table 4). Ru-catalyzed asymmetric transfer hydrogenation on 2413
gave -hydroxy ester 25 with high enantiopurity (97% ee).14 After the alkylation of the secondary alcohol by EtI with Ag2O, the
TBS group was deprotected by TBAF to provide the common intermediate 27. Derivatization of the C part was achieved by
Mitsunobu or alkylation reaction (28a-t). The carboxylic acid 29a-t were obtained by saponification of the corresponding ester 28a-
t.15
The synthesis of compound 35a, b which have pyridine in the part B is also shown in scheme 4. We applied the organocatalyzed
aldol reaction for the enantioselective synthesis of the pyridine derivatives.16 Aldehyde 30 was reacted with acetaldehyde using the
TMS-protected prolinol catalyst, followed by NaBH4 reduction of the resulting aldehyde to provide diol 31 with 94% ee. The
primary alcohol of 31 was selectively protected with the TIPS group to give 32. Alcohol 32 was alkylated by EtI with NaH as a base
to give the intermediate 33. The C part was introduced to 33 by SNAr reaction. The primary alcohol was generated by the
deprotection of TIPS group, subsequently it was oxidized into the carboxylic acid to obtain 35a, b.
3. Results and discussion
3.1 SAR of the part A
Table 1. Exploration of the part A.
A

We investigated the carboxylic acid bioisosteres in the A part
(Table 1, 4a-4c). Replacement of carboxylic acid with
bioisosteres such as tetrazole and sulfonimide resulted in a
significant loss of the activity. Introduction of di-fluoride to the
-position was also not tolerated.
compound
A
hEC50(nM)a
20
1
4a
4b
4c
1700
3800
580
3.2 SAR of the part B
The ether linker in the part B was replaced by an amide or
amino linker (Table 2). Though the amide linker lost the activity
(11a), amino linker was tolerant (11b). Introduction of several
substituents to the central phenyl ring resulted in the decrease of
the activity especially in the case of bulky substituents (20t-y).
a A calcium flux assay in transfected-GPR40 CHO cells. Assay results are
the average of triplicates. Standard deviation was ± 20%.
Table 2. Exploration of part B.
compd
R1
R2
H
R3
H
X
hEC50(nM)a
1600
11a
NH
11b
H
H
NH
27
20t
20u
20v
20w
20x
20y
F
Me
NO2
H
H
H
O
O
O
O
O
O
210
1500
3100
12
H
F
H
Cl
98
H
OMe
970
a A calcium flux assay in transfected-GPR40 CHO cells. Assay results are
the average of triplicates. Standard deviation was ± 20%.
3.3.SAR of the part C
Table 3. Exploration of part C.
1,20a-s
23
compound
R1
hEC50(nM)a
20
1

3.3.1 SAR of racemic compounds
20a
20b
20c
20d
20e
20f
35
370
30
We studied the structure-activity relationships in the part C
(Table 3). From the results of a methyl scan (1, 20a, 20b), the
ortho- or meta-position seemed to be better than the para-
position to keep agonistic activity. The survey on meta-position
revealed that halogen substituents such as fluoro and chloro kept
the activity (20c, d). The electron-donating substitution (20e, f)
as well as electron-withdrawing substitution (20h, i) did not
show good effect. Though the phenoxy derivative (20g)
represented activity as strong as 1, it showed inhibition of the
mitochondrial respiratory chain complex 1 concerning cell
toxicity (68% inhibition @ 100 M).11 The chloro and
trifluoromethyl groups showed potent activity even on the para-
position (20j, k). Accordingly, we put chloro substituents on
both meta- and para-positions, and found that they represented
very strong in vitro activity (20l). The aliphatic group resulted in
the decrease of the activity (20m). The heteroaromatic groups
were also found to diminish the activity (20n, o). The naphtyl
group having a 4-fluoro substituent kept the activity (20p). With
concern to the length of the linker, a benzyl linker was
preferable (20l, q, r). The direction of the part C also seems to
be important because the meta-substituted derivative (23)
showed weaker agonistic activity than the para-substituted
derivative (20l).
19
89
100
23
20g
20h
20i
53
63
20j
12
20k
20l
7.2
6.2
35
3.3.2 SAR of chiral compounds
We separated the racemic compound 20l by chiral HPLC and
confirmed that (S)-enantiomer was more active than (R)-
enantiomer (Table 4, (S)-20l, (R)-20l). Chiral compound 29a
also showed stronger activity than racemic 20k.
20m
Next we synthesized cyclized derivatives for further
improvement of the activity. The indan derivative 29e was more
potent than the tetralin derivative 29f. With concern to the
absolute stereochemistry of the indanol moiety, the (R)-
configuration was favorable (29d, e). The 1-indan derivative had
more preferable orientation than a 2-indan derivative (29g).
Though some heteroaromatic rings were tried, they did not have
advantage in raising activity (29h, i). Based on this information,
we focused on the optimization around 29e. Alkyl derivatives
(29j-m) showed better activities than alkoxy derivatives (29n,
o). The trifluoromethoxy substituent showed even better activity
than them (29q). Halogen substitutions such as Cl (29p) and
trifluoromethyl (29r) improved the agonistic activity, especially
compound 29r was highly potent.
20n
20o
2100
3200
20p
20q
20r
13
65
49
We investigated the effect of a heteroatom by replacing the
part B with a pyridine ring (35a). The indan moiety in the part C
was also replaced with dihydrofuran (35b). Compound 35b
showed lower protein binding compared to 29r (97.5% and
99.2%, respectively), however, its activity reduced to one-tenth
of 29r. Possible diastereomers were synthesized. From the
results of in vitro assay, the appropriate configurations of both
two stereo centers were essential to exhibit the GPR40 agonistic
activity.17 This compound 29r was named DS-1558 as a clinical
candidate, and was used to carry out further investigations.
20s
560
23
147
a A calcium flux assay in transfected-GPR40 CHO cells. Assay results are
the average of triplicates. Standard deviation was ± 20%.

Table 4. Optimization of part C with a chiral -ethoxy propanoic acid.
S
S
29a-t
35a,b
compound
R1
hEC50(nM)a
3.9
(S)- 20l
360
5.3
13
(R)-20l
29a
29b
29c
7.5
69
29d
29e
31
62
29f
82
29g
29h*
29i
5600
120
29
29j
29k
29l
12
12
29m
29n*
13
190

29o
29p
29q
29r
29s
29t
63
5.0
9.9
3.7
13
21
35a
35b
20
36
a A calcium flux assay in transfected-GPR40 CHO cells. Assay results are
the average of triplicates. Standard deviation was ± 20%. * Diastereomer
mixtures
3.3.3 Docking study of 29r with hGPR40
We tried induced-fit docking study of 29r using the X-ray structure of hGPR40 reported as co-complex with TAK-875 (Figure
3).18 As a result, 29r docked very well to the same binding site for TAK-875 with slightly rotated sidechain of Trp174. Our model
can explain the obtained SAR reasonably. The carboxylic acid moiety was highly coordinated by Arg183 and Arg258 forming
anchor point. The trifluoromethyl group on the indan moiety has hydrophobic interaction with both protein and hydrophobic portion
of lipid bilayer (yellow thin stick model). It showed better agonistic activity than other kinds of substituents. The R stereochemistry
of the indan moiety is favorable than the S form to fit into the binding cavity, especially having the substituent on 4 position due to
the steric hindrance of the protein. Furthermore, the ethoxy moiety extending from propanoic acid is accommodated well into the
small side pocket not used by TAK-875. As mentioned above, 29r docked well to the binding site using binding pockets effectively.
It was confirmed as the value of ligand efficacy (29r: 0.41, TAK-875: 0.29).6,19
Figure 3. The docking model of 29r in crystal structure of the hGPR40.

3.4 Evaluation of the profile of 29r
Compound 29r was assessed in a panel of in vitro ADME assays (Table 5). The risk of drug-drug interactions seemed to be low
because of a very weak potential for CYP inhibition and induction. The result of hERG inhibition also indicated that compound 29r
had the low risk of QT interval prolongation.
Table 5. In vitro ADME assays of 29r.
EC50 human / rat (nM)
logD (pH 7.4)
3.7 / 11
2.4
Solubility JP1 (pH1.2) / JP2 (pH6.8)
(g/mL)
0 / 720
Protein binding (human) (%)
99.2
No inhibition (up to 30M)
hERG inhibition
CYP inhibition at 10M
1A2 / 2C9 / 2D6 / 3A4 (%)
7 / 21 / 0 / 5
Pharmacokinetic studies of 1, 29a and 29r in F344 rats were summarized in Table 6. Compounds 29a and 29r showed improved
clearance and half-life when compared with 1 due to the improvement of metabolic liability of benzylic carbon by electron-
withdrawing substitution and steric hindrance, respectively. Compound 29r demonstrated better oral bioavailability than 29a,
probably related to the difference of the vehicles and the solubility of compounds (JP2 (pH6.8) 29a; 350 g/mL, 29r; 720 g/mL).
The effect of 29r on insulin secretion after intravenous
glucose injection in Sprague Dawley rats was evaluated. (Figure
Table 6. Pharmacokinetic parameters in rats.
compound
i.v.
1a
29aa
29rb
4) The plasma insulin levels were measured after treatment with
29r (0.03 and 0.3 mg/kg) in the euglycemic (Saline) and
hyperglycemic conditions (Glucose). The mean plasma glucose
levels of all groups in each condition were from 68 to 88 mg/dL
and 428 to 482 mg/dL, respectively. There was no significant
difference between 29r treatment groups and the controls in the
euglycemic condition. On the other hand, the plasma insulin
levels of the 29r treatment were significantly higher than that of
the controls in the hyperglycemic condition. Furthermore, the
amount of insulin secretion by 29r treatment was dose-
dependent. These results represent that 29r dose-dependently
stimulate insulin secretion only in the hyperglycemic condition,
namely depending on the blood glucose levels.
Dose (mg/kg)
Cl (L/h/kg)
Vdss (L/kg)
T1/2 (h)
2
1
1
0.37
0.16
0.37
0.012
0.38
22
0.020
0.19
6.0
p.o.
Dose (mg/kg)
Cmax (g/mL)
AUC (g*h/mL)
F (%)
3
1
0.95
14
1
3.3
5.3
64
3.1
40
80
32
a Data is the mean of experiments (n = 2). b The statistics are shown in the
supporting information. (n = 4).

Figure 4. Plasma insulin levels in the euglycemic (Saline) and hyperglycemic conditions (Glucose) in SD rats treated with 29r. (7-week old, control and 29r
(0.3 mg/kg): n = 7, 29r (0.03 mg/kg): n= 6). The results are represented as the arithmetic mean + standard error. * Significant difference P < 0.05 compared to
control by Dunnett’s test.
4. Conclusion
In conclusion, starting from compound 1, we have explored 3-aryl-3-ethoxypropanoic acid derivatives that possess potent
agonistic activity. The introduction of a suitable substituent and cyclized structure were effective in improving in vitro activity and
PK profiles. The divergent synthesis of chiral derivatives was established. The enhancing effect of 29r on glucose-dependent insulin
secretion was confirmed in vivo experiments. In addition, we have reported that 29r increased insulin secretion and improved
glucose tolerance in oGTT.17,20 According to these results, 29r will be a promising candidate as a novel insulin secretagogue with a
low risk of hypoglycemia. GPR40 agonists are promising to be used as a monotherapy, but the combination usage with other anti
diabetic drugs is also expected for the therapy of type 2 diabetes in the near future.
5 Experimental
5.1 Synthesis
General Information
Starting reagents were purchased from commercial suppliers and used without further purification. Reactions were monitored
using thin layer silica gel chromatography (TLC) using 0.25 mm silica gel 60F plates with fluorescent indicator from Merck. Plates
were visualized by treatment with UV. Microwave reactions were carried out using a Biotage Initiator (400 W) microwave
1
apparatus. Products were purified by column chromatography using the solvent systems indicated. H NMR and 13C NMR spectra
were measured on a Varian Unity 400 or 500 spectrometer or a JEOL JNM-ECA 500 spectrometer. Spectra were taken in the
indicated solvent at ambient temperature. Chemical shifts () are given in parts per million (ppm) with tetramethylsilane as an
internal standard. Multiplicities are recorded as follows: s (singlet), d (doublet), t (triplet), q (quartet), br (broad), m (multiplet).
Coupling constants (J values) are given in Hz. Infrared spectra were recorded on KBr discs with a Jasco FT/IR-6100 typeA. Mass
spectra were obtained on a JEOL JMS-LC mate or Agilent HP1100 or LC-MS system composed of Waters Xevo Q-Tof MS and
Acuity UPLC systems. The purity of test compounds were confirmed as over 95% by DAD signal area% performed on a Agilent
Infinity 1260 LCMS system. Conditions [column : Develosil Combi-RP-5 2.0 mmID x 50 mmL, gradient elution : 0.1% HCO2H-
H2O / 0.1% HCO2H-MeCN = 98/2 to 0/100 (v/v), flow rate : 1.2 mL/min, UV detection : 254 nm, column temperature : 40 °C,
ionization : APCI/ ESI]. Elemental analyses for CHN and F were determined on a Microcoder JM10 and Dionex ICS-1500,
respectively. Optical rotations were determined on an Autopol V Plus polarimeter (Rudolph Reseach Analytical, Hackettstown, NJ,
USA).
5.1.1. 4-[(2-Methylbenzyl)oxy]benzaldehyde (2)
To a solution of 4-Hydroxybenzaldehyde (10.0 g, 81.9 mmol) and 2-methylbenzylbromide (40.0 g, 98.4 mmol) in DMF (100
mL), Cs2CO3 (18.2 g, 123 mmol) was added, and stirred under N2 atmosphere at room temperature for 1 h. Water was added to the
reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and
filtered. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography

(hexane: AcOEt = 100:0 to 60:40 (v/v)), and 2 was obtained as colorless oil (19.2 g, 100%). 1H NMR (400 MHz, CDCl3) δ 2.39 (3H,
s), 5.13 (2H, s), 7.10 (2H, d, J = 8.6 Hz), 7.21-7.31 (3H, m), 7.39 (1H, d, J = 7.4 Hz), 7.86 (2H, d, J = 8.6 Hz), 9.90 (1H, s).
5.1.2. 3-Ethoxy-3-{4-[(2-methylbenzyl)oxy]phenyl}propanoic acid (1)11
To a solution of AcOEt (9.00 g, 102 mmol) in THF (200 mL), 1.0 M lithium bis(trimethylsilyl)amide hexane solution (102 mL,
102 mmol) was added at -78 °C under N2 atmosphere. After stirred for 20 min, a THF solution of 2 (19.2 g, 84.9 mmol) was added,
and stirred for 30 min. Saturated NH4Cl aq. was added to the reaction mixture, followed by extraction with AcOEt. The organic
layer was washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The residue was
washed with hexane:AcOEt (34:1 (v/v)), then crude ethyl 3- hydroxy-3{4-[(2-methlbenzyl)oxy]phenyl}propanoate was obtain as a
white solid (22.4 g, 84%). To the solution of the crude ethyl 3- hydroxy-3{4-[(2-methlbenzyl)oxy]phenyl}propanoate (392 mg, 1.25
mmol) in toluene (10 mL), EtI (140 L, 1.75 mmol) and Ag2O (347 mg, 1.50 mmol) were added., and stirred for 10 h at 100 °C
under N2 atmosphere. After cooling to room temperature, the reaction solution was filtered, and the solvent was distilled off under
reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt =100:0 - 60:40 (v/v)), and ethyl 3-
ethoxy-3{4-[(2-methlbenzyl)oxy]phenyl}propanoate was obtained as colorless oil (120 mg, 28%). 1 N NaOH aq. (3.00 mL) was
added to the solution of ethyl 3- ethoxy-3{4-[(2-methlbenzyl)oxy]phenyl}propanoate (120 mg, 0.350 mmol) in ethanol (5.0 mL) at
room temperature, and stirred for 4 h. The solvent was distilled off under reduced pressure. 1 N HCl aq. was added to the residue,
and the organic material was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and filtered. The
solvent was distilled off under reduced pressure. The residue was washed with hexane/diethyl ether (3/1 (v/v)) to obtain 1 as a white
solid (71 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 2.63 (1H, dd, J = 4.3, 16.0 Hz), 2.84 (1H,
dd, J = 9.4, 16.0 Hz), 3.36- 3.49 (2H, m), 4.68 (1H, dd, J = 4.3, 9.4 Hz), 5.03 (2H, s), 6.99 (2H, d, J = 8.6 Hz), 7.20-7.28 (5H, m),
7.40 (1H, d, J = 7.4 Hz). LCMS (ESI): m/z 313 (M-H)-.
5.1.3. 3-Hydroxy-3-{4-[(2-methylbenzyl)oxy]phenyl}propanenitrile (3)
To a solution of MeCN (427 mg, 10.4 mmol) in THF (50.0 mL) n-BuLi hexane solution (1.60 M, 6.50 mL, 10.4 mmol) was
added dropwise at -78 °C under N2 atmosphere and stirred for 2 h. A solution of 2 (1.57 g, 6.94 mmol) in THF (5.0 mL) was added,
and stirred for 0.5 h at -78°C. Saturated NH4Cl aq. was poured to the reaction mixture, and followed by extraction with AcOEt. The
organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel column chromatography (hexane:AcOEt =100:0 to 50:50 (v/v)) to give 3 as colorless oil (1.73 g,
93%). 1H NMR (400 MHz, CDCl3) δ 2.23 (1H, d, J = 2.4 Hz), 2.36 (3H, s), 2.75 (2H, dd, J = 4.4, 6.4 Hz), 4.98-5.01 (1H, m), 5.21
(2H, s), 6.99 (2H, d, J = 8.4 Hz), 7.18-7.27 (3H, m), 7.33 (2H, d, J = 8.4 Hz), 7.38 (1H, d, J = 7.2 Hz).
5.1.4. 5-(2-Ethoxy-2-{4-[(2-methylbenzyl)oxy]phenyl}ethyl)-1H-tetrazole (4a)
To a solution of 3 (1.73 g, 6.49 mmol) in toluene (100 mL), EtI (1.03 mL, 13.0 mmol) and Ag2O (3.00 g, 13.0 mmol) were added,
and stirred at 100 °C for 2 h. After cooling to room temperature, the reaction solution was filtered through a celite pad, and the
solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt =
100:0 to 50:50 (v/v)) to give 3-ethoxy-3-{4-[(2-methylbenzyl)oxy]phenyl}propanenitrile was obtained as colorless oil (701 mg,
37%). The solution of 3-ethoxy-3-{4-[(2-methylbenzyl)oxy]phenyl}propanenitrile (350 mg, 1.18 mmol) and tributhyltin azide (490
L, 1.78 mmol) in 1,4-dioxane (3.00 mL) was heated under microwave irradiating conditions at 130 °C for 1 h. Saturated NaHCO3
aq. was poured into the reaction mixture, and followed by extraction with AcOEt. The organic layer was washed with 2 N HCl aq.
and brine, then dried over Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The residue was purified by
silica gel column chromatography (hexane:AcOEt =100:0 to 0:100 (v/v)), and triturated by AcOEt and hexane (1/2, (v/v)), and 4a
was obtained as a white solid (148 mg, 12%). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 6.8 Hz). 2.37 (3H, s), 3.24 (1H, dd, J =
9.2, 15.6 Hz), 3.29- 3.51 (3H, m), 4.53 (1H, dd, J = 2.8, 9.2 Hz), 5.02 (2H, s), 6.98 (2H, d, J = 8.4 Hz), 7.19-7.26 (5H, m), 7.38 (1H,
d, J = 7.2 Hz). LCMS (ESI): m/z 337 (M-H)-.
5.1.5. Ethyl 2,2-difluoro-3-hydroxy-3-{4-[(2-methylbenzyl)oxy]phenyl}propanoate (5)
To a solution of 2 (1.00 g, 4.42 mmol), zinc powder (433 mg, 5.85 mmol) and CeCl3.7H2O (32.0 mg, 0.0884 mmol) in THF
(50.0 mL), ethyl bromodifluoro acetate (1.35 g, 5.85 mol) in THF (3.0 mL) was added dropwise, and stirred at 80 °C for 1 h.
Saturated NH4Cl aq. (100 mL) was added to the reaction mixture, followed by extraction with AcOEt. The organic layer was
washed with brine, and dried over Na2SO4. After filtration, the solvent was distilled off under reduced pressure, and the residue was
1
purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 60:40 (v/v)) to give 5 as colorless oil (1.26 g, 81%). H
NMR (500 MHz, CDCl3) δ 1.33 (3H, t, J = 7.0 Hz), 2.40 (3H, s), 2.61 (1H, d, J = 4.0 Hz), 4.34 (2H, q, J = 7.0 Hz), 5.07 (2H, s),
5.16 (1H, ddd, J = 5.0, 8.0, 14.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.23-7.31 (3H, m), 7.40-7.43 (3H, m).
5.1.6. 3-Ethoxy-2,2-difluoro-3-{4-[(2-methylbenzyl)oxy]phenyl}propanoic acid (4b)
To a solution of 5 (430 mg, 1.23 mmol) and NaH (63% in mineral oil, 100 mg, 2.45 mmol) in DMF (20.0 mL), EtI (196 L, 2.45
mmol) was added, and stirred for 1 h at room temperature. H2O was added to the reaction mixture, and followed by extraction with
AcOEt. The organic layer was washed with brine, and dried over Na2SO4. After filtration, the solvent was distilled off under

reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 70:30 (v/v)), then ethyl
3-ethoxy-2,2-difluoro-3-{4-[(2-methylbenzyl)oxy]phenyl}propanoate was obtained as colorless oil (90.0 mg, 20%). To the solution
of ethyl 3-ethoxy-2,2-difluoro-3-{4-[(2-methylbenzyl)oxy]phenyl}propanoate (90.0 mg, 0.240 mmol) in ethanol (5.0 mL), 1 N
NaOH aq. (5.0 mL, 5.0 mmol) was added, and stirred at room temperature for 2 h. To the reaction mixture, 1 N HCl aq. (8.0 mL,
8.0 mmol) was added, followed by the extraction with AcOEt. The organic layer was washed with brine, and dried over Na2SO4.
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt
= 100:0 to 0:100 (v/v)) to give 4b as a white solid (41.0 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz) 2.36 (3H,
s), 3.42-3.50 (1H, m), 3.54-3.61 (1H, m), 4.76 (1H, dd, J = 6.4, 17.6 Hz), 5.03 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.19-7.27 (3H, m),
7.35 (2H, d, J = 8.4 Hz), 7.38 (1H, d, J = 7.2 Hz). LCMS (ESI) m/z 349 (M-H)-.
5.1.7. 3-Ethoxy-3-{4-[(2-methylbenzyl)oxy]phenyl}-N-(methylsulfonyl)propaneamide (4c)
To a solution of 1 (109 mg, 0.350 mmol) in THF (20.0 mL), HBTU (262 mg, 0.690 mmol) and iPr2NEt (120 L, 0.690 mmol)
were added, and stirred at room temperature for 2 h. To the reaction mixture, 1 N HCl aq. (3.0 mL) was added, and followed by
extraction with AcOEt. The solvent was distilled off under reduced pressure, the residue was passed through silica gel
(hexane:AcOEt = 100:0 to 50:50 (v/v)). After evaporation, the residue was dissolved in THF (2.0 mL), and methylsulfoneamide
(66.0 mg, 0.690 mmol) and NaH (63% in mineral oil, 67.0 mg, 1.75 mmol) in THF (20.0 mL) were added, and stirred for 1 h at
room temperature. Saturated NH4Cl aq. was added to the reaction mixture, followed by extraction with AcOEt. The organic layer
was washed with brine, and dried over Na2SO4. After filtration, the solvent was distilled off under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 0:100 (v/v)) to give 4c as colorless oil (68.0 mg, 50%).
1H NMR (500 MHz, CDCl3) δ 1.28 (3H, t, J = 7.0 Hz), 2.41 (3H, s), 2.61 (1H, dd, J = 2.5, 16.0 Hz), 2.82 (1H, dd, J = 10.0, 16.0
Hz), 3.31 (3H, s), 3.40-3.47 (1H, m), 3.50-3.55 (1H, m), 4.65 (1H, dd, J = 2.0, 9.5 Hz), 5.06 (2H, s), 7.02 (2H, d, J = 8.5 Hz), 7.24-
7.31 (5H, m), 7.42 (1H, d, J = 6.5 Hz), 9.57 (1H, s). LCMS (ESI) m/z 390 (M-H)-.
5.1.8. Ethyl 3-hydroxy-3-(4-nitrophenyl)propionate (7)
To a solution of AcOEt (3.55 g, 40.3 mmol) in THF (100 mL), 1.0 M lithium bis(trimethylsilyl)amide hexane solution (40.0 mL,
40.0 mmol) was added at -78 °C under a N2 atmosphere. After stirred for 20 min, a THF solution of 4-nitrobenzaldehyde (5.08 g,
33.6 mmol) was added and stirred for 30 min. Saturated NH4Cl aq. was added to the reaction solution, followed by extraction with
AcOEt. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off under reduced
pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 20:80 (v/v)) to give 7 as
colorless oil (4.31 g, 54%). 1H NMR (400 MHz, CDCl3) δ 1.28 (3H, t, J = 7.0 Hz). 2.68-2.79 (2H, m), 3.65 (1H, d, J = 3.5 Hz), 4.21
(2H, q, J = 7.0 Hz), 5.24 (1H, dt, J = 3.5, 8.6 Hz), 7.57 (2H, d, J = 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz).
5.1.9. Ethyl 3-ethoxy-3-(4-nitrophenyl)propionate (8)
To the solution of 7 (4.31 g, 18.0 mmol) in toluene (150 mL), and EtI (4.32 mL, 54.1 mmol) and Ag2O (12.5 g, 54.1 mmol) were
added, and stirred under N2 atmosphere at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered, and
the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt
= 100:0 to 30:70 (v/v)), to obtain 8 as colorless oil (2.20 g, 46%). 1H NMR (500 MHz, CDCl3) δ 1.18 (3H, t, J = 7.3 Hz), 1.24 (3H, t,
J = 7.3 Hz), 2.57 (1H, dd, J = 5.4, 15.6 Hz), 2.80 (1H, dd, J = 8.8, 15.6 Hz), 3.36-3.45 (2H, m), 4.12-4.17 (2H, m), 4.85 (1H, dd, J =
5.3, 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz).
5.1.10. 3-Ethoxy-3-(4-nitrophenyl)propane-1-ol (9)
To a solution of 8 (598 mg, 2.24 mmol) in CH2Cl2 (10 mL), and DIBAL (0.99 M in toluene, 6.78 mL, 6.71 mmol) was added
under N2 atmosphere at -78 °C, then stirred at 0 °C for 2 h. Saturated NH4Cl aq. was added, the reaction mixture was filtered
through a celite pad and washed with CH2Cl2. The solvent was distilled off under reduced pressure. The residue was purified by
1
silica gel column chromatography (hexane:AcOEt = 90:10 to 40:60 (v/v)) to give 9 as colorless oil (249 mg, 49%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz), 1.80-1.87 (1H, m), 1.92-1.97 (1H, m), 2.41 (1H, dd, J = 4.4, 6.4 Hz), 3.37 (2H, q, J = 6.9
Hz), 3.74-3.79 (2H, m), 4.59 (1H, dd, J = 4.0, 9.2 Hz), 7.46 (2H, d, J = 8.4 Hz), 8.19 (2H, d, J = 8.8 Hz).
5.1.11. 4-(3-{[tert-Butyl(dimethyl)silyl]oxy}-1-ethoxypropyl)aniline (10)
To a solution of 9 (249 mg, 1.10 mmol) in DMF (5.0 mL), imidazole (194 mg, 2.85 mmol) and tert-butyldimethylsilyl chloride
(97%, 266 mg, 1.71 mmol) were added, and stirred at room temperature for 3 h. Water was poured into the reaction mixture, and
followed by extraction with AcOEt. The organic layer was washed with brine, then dried over Na2SO4 and filtered. The solvent was
distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to
90:10 (v/v)), and tert-butyl[3-ethoxy-3-(4-nitrophenyl)propoxy]dimethylsilane was obtained as colorless oil (351 mg, 94%). To the
solution of tert-butyl[3-ethoxy-3-(4-nitrophenyl)propoxy]dimethylsilane (352mg, 1.03 mmol) in EtOH (2.0 mL) and AcOEt (2.0
mL), PtO2 (24.0 mg, 0.104 mmol) was added under H2 atmosphere, and stirred for 3 h at room temperature. The reaction mixture
was filtered through the celite pad, and washed with CH2Cl2. The solvent was distilled off under reduced pressure. The residue was
purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 70:30 (v/v)) to give 10 as a white solid (247 mg, 77%). 1H

NMR (400 MHz, CDCl3) δ 0.005 (6H, s), 0.87 (9H, s), 1.11 (3H, t, J = 7.0 Hz), 1.68-1.76 (1H, m), 1.90-2.01 (1H, m), 3.19-3.26
(1H, m), 3.28-3.61 (1H, m), 3.49-3.54 (1H, m), 3.59 (2H, brs), 3.66-3.72 (1H, m), 4.27 (1H, dd, J = 5.2, 8.0 Hz), 6.62 (2H, d, J =
8.4 Hz), 7.05 (2H, d, J = 8.8 Hz).
5.1.12. 3-Ethoxy-3-{4-[(2-methylbenzoyl)amino]phenyl}propanoic acid (11a)
To a solution of 10 (322 mg, 1.04 mmol) in N,N-dimethylacetamide (7.0 mL), 2-methylbenzoyl chloride (205 L, 1.56 mmol)
was added at 0 °C, and stirred at room temperature for 12 h. Saturated NaHCO3 aq. was added to the reaction mixture, and followed
by extraction with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off
under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 90:10 to 40:60 (v/v)) and
obtained N-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-ethoxypropyl)phenyl]-2-methylbenzamide as colorless oil (197 mg, 44%). To
the solution of N-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-ethoxypropyl)phenyl]-2-methylbenzamide (197 mg, 0.461 mmol) in THF
(3.0 mL), 1.0 M tetrabutylammonium fluoride solution in THF (1.38 mL, 1.38 mmol) was added, and stirred at room temperature
for 2 h. Saturated NaHCO3 aq. was added to the reaction mixture, followed by extraction with AcOEt. The organic layer was
washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The residue was purified
by silica gel column chromatography (hexane:AcOEt = 80:20 to 35:65 (v/v)) to give N-[4-(1-ethoxy-3-hydroxypropyl)phenyl]-2-
methylbenzamide was obtained as colorless oil (136 mg, 94%). To a solution of N-[4-(1-ethoxy-3-hydroxypropyl)phenyl]-2-
methylbenzamide (306 mg, 0.976 mmol) in CH2Cl2 (10.0 mL), Dess-Martin periodinane (620 mg, 1.46 mol) was added, and stirred
at room temperature for 30 min. After the reaction mixture was cooled to 0 °C, an aqueous solution of Na2S2O3 was added, and
followed by extraction with diethyl ether. The organic layer was washed with brine, and dried over Na2SO4 and filtered. The solvent
was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 90:10 to
50:50 (v/v)) to give N-[4-(1-ethoxy-3-oxopropyl)phenyl]-2-methylbenzamide was obtained as colorless oil (179 mg, 59%). To a
solution of N-[4-(1-ethoxy-3-oxopropyl)phenyl]-2-methylbenzamide (179 mg, 0.57 mmol) in t-BuOH (5.0 mL), THF (2.0 mL) and
H2O (2.0 mL), 2-methyl-2-butene (485 L, 4.55 mmol), NaHPO4 (443 mg, 2.84 mmol), and NaClO2 (80%, 321 mg, 2.84 mmol)
were added, and stirred at room temperature for 1 h. Water was poured into the reaction mixture, and followed by extraction with
AcOEt. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was distilled off under reduced
pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 80:20 to 30:70 (v/v)) to obtain 11a as a
1
white solid (110 mg, 59%). H NMR (400 MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz), 2.49 (3H, s), 2.63 (1H, dd, J = 4.4, 15.6 Hz),
2.84 (1H, dd, J = 9.6, 15.6 Hz), 3.37-3.46 (2H, m), 4.71 (1H, dd, J = 4.4, 9.2 Hz), 7.23-7.27 (1H, m), 7.32-7.38 (3H, m), 7.45-7.49
(2H, m), 7.62 (2H, d, J = 7.6 Hz). LCMS (ESI): m/z 326 (M-H)-
5.1.13. Ethyl 3-(4-aminophenyl)-3-ethoxypropionate (12)
To a solution of 8 (300 mg, 1.12 mmol) in AcOEt (10.0 mL), 10% palladium carbon (100 mg) was added, and stirred under H2
atmosphere at room temperature for 2 h. The reaction mixture was filtered through a celite pad, and the solvent was distilled off
under reduced pressure. The crude product of 12 was obtained as colorless oil (310 mg, 100%). 1H NMR (500 MHz, CDCl3) δ 1.13
(3H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.3 Hz), 2.54 (1H, dd, J = 5.4, 15.1 Hz), 2.78 (1H, dd, J = 8.8, 15.1 Hz), 3.28-3.40 (2H, m), 3.66
(2H, brs), 4.11-4.15 (2H, m), 4.63 (1H, dd, J = 5.4, 8.8 Hz), 6.66 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz).
5.1.14. Ethyl 3-{4-[(3,4-dichlorobenzyl)amino]phenyl}-3-ethoxypropionate (13)
To a solution of 12 (310 mg, 1.30 mmol) in acetone (10.0 mL), 3,4-dichlorobenzyl bromide (313 mg, 1.30 mmol) and K2CO3
(180 mg, 1.30 mmol) were added, and stirred under N2 atmosphere at room temperature for 4 h. Water was added to the reaction
mixture, and followed by extraction with AcOEt. The organic layer was washed with brine, then dried over Na2SO4 and filtered.
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt
= 100:0 to 60:40 (v/v)) to obtain 13 as colorless oil (235 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 7.0 Hz), 1.23 (3H,
t, J = 7.0 Hz), 2.53 (1H, dd, J = 5.1, 14.9 Hz), 2.78 (1H, dd, J = 9.0, 14.9 Hz), 3.27-3.41 (2H, m), 4.09-4.15 (2H, m), 4.31 (2H, s),
4.62 (1H, dd, J = 5.1, 9.0 Hz), 6.56 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.21 (1H, dd, J = 2.0, 8.2 Hz), 7.41 (1H, d, J = 8.2
Hz), 7.47 (1H, d, J = 2.0 Hz).
5.1.15. 3-{4-[(3,4-Dichlorobenzyl)amino]phenyl}-3-ethoxy propionic acid (11b)
To a solution of 13 (235 mg, 0.593 mmol) in THF (5.0 mL) and EtOH (5.0 mL), 1 N NaOH aq. (3.0 mL) was added, and stirred
at room temperature for 4 h. The solvent was distilled off under reduced pressure. To the residue 1 N HCl aq. (6.0 mL) was added,
then followed by extraction with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was
distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to
0:100 (v/v)) to give 11b as a yellow solid (43.0 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 1.18 (3H, t, J = 7.0 Hz), 2.60 (1H, dd, J =
4.0, 15.6 Hz), 2.82 (1H, dd, J = 9.8, 15.6 Hz), 3.32-3.47 (2H, m), 4.31 (2H, s), 4.61 (1H, dd, J = 4.0, 9.8 Hz), 6.57 (2H, d, J = 8.6
Hz), 7.12 (2H, d, J = 8.6 Hz), 7.21 (1H, dd, J = 2.0, 8.2 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 2.0 Hz). LCMS (ESI) m/z 366
(M-H)-.
5.1.16. Ethyl 3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-hydroxypropionate (16)

In the same manner as the preparation of 7 starting from 4-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde (15)21, 16 was obtained
as colorless oil (24.9 g, 100%). 1H NMR (400 MHz, CDCl3) δ 0.18 (6H, s), 0.98 (9H, s), 1.26 (3H, t, J = 7.1 Hz), 2.65-2.79 (2H, m),
3.15 (1H, d, J = 3.2 Hz), 4.18 (2H, q, J = 7.1 Hz), 5.08 (1H, dt, J = 3.2, 9.1 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz).
5.1.17. Ethyl 3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-ethoxypropionate (17)
In the same manner as the preparation of 8, 17 was obtained as colorless oil (3.06 g, 70%). 1H NMR (400 MHz, CDCl3) δ 0.19
(6H, s), 0.98 (9H, s), 1.13 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz), 2.54 (1H, dd, J = 5.1, 14.8 Hz), 2.76 (1H, dd, J = 9.0, 15.2
Hz), 3.30-3.40 (2H, m), 4.13 (2H, q, J = 7.2 Hz), 4.68 (1H, dd, J = 5.1, 9.0 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz).
5.1.18. Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (18)
To a solution of 17 (3.06 g, 8.68 mmol) in THF (100 mL) cooled to 0 °C, tetrabutyl ammonium fluoride THF solution (1.0 M,
13.0 mL, 13.0 mmol) was added dropwise, and stirred at room temperature for 3 h. Water was added to the reaction solution and
followed by extraction with AcOEt. The organic layer was washed with brine and dried over Na2SO4 and filtered. The solvent was
distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to
75:25 (v/v)) to obtain 18 as a white solid (2.11 g, 98%). 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, t, J = 7.1 Hz), 1.23 (3H, t, J = 7.0
Hz), 2.55 (1H, dd, J = 5.0, 14.8 Hz), 2.80 (1H, dd, J = 9.0, 15.2 Hz), 3.29-3.41 (2H, m), 4.13 (2H, q, J = 7.1 Hz), 4.68 (1H, dd, J =
5.0, 8.9 Hz), 6.81 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz).
5.1.19.1. Ethyl 3-ethoxy-3-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)propionate (19k)
To a solution of 18 (100 mg, 0.420 mmol) and [4-(trifluoromethyl)phenyl]methanol (111 mg, 0.630 mmol) in THF (10.0 mL),
PPh3 (178 mg, 0.68 mmol), a 40% diethyl azodicarbonate toluene solution (309 L, 0.680 mmol) were added at room temperature,
and stirred under N2 atmosphere at 60 °C for 4 h. After cooling to room temperature, the solvent was distilled off under reduced
pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 95:5 (v/v)) to obtain 19k as
colorless oil (125 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, t, J = 7.1 Hz), 1.23 (3H, t, J = 7.1 Hz), 2.56 (1H, dd, J = 5.5,
15.3 Hz), 2.80 (1H, dd, J = 9.0, 15.3 Hz), 3.31-3.39 (2H, m), 4.14 (2H, q, J = 7.0 Hz), 4.69 (1H, dd, J = 5.1, 8.6 Hz), 5.02 (2H, s),
6.92 (2H, d, J = 8.6 Hz), 7.26 (3H, t, J = 4.3 Hz), 7.36 (3H, s).
5.1.20.1. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]phenyl}3-ethoxypropionate (19l)
To a solution of 18 (124 mg, 0.520 mmol) and 3,4-dichlorobenzylbromide (87.0 L, 0.620 mmol) in acetone (5.0 mL), K2CO3
(108 mg, 0.780 mmol) was added at room temperature, and stirred under N2 atmosphere at 60 °C for 4 h. After cooling to room
temperature, the reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by
1
silica gel column chromatography (hexane:AcOEt = 100:0 to 60:40 (v/v)) to obtain 19l as colorless oil (164 mg, 79%). H NMR
(400 MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.0 Hz), 2.54 (1H , dd, J = 5.5, 15.3 Hz), 2.80 (1H, dd, J = 9.0, 15.3
Hz), 3.30-3.41 (2H, m), 4.14 (2H, q, J = 7.0 Hz), 4.71 (1H, dd, J = 5.5, 9.0 Hz), 5.01 (2H, s), 6.93 (2H, d, J = 9.0 Hz), 7.25-7.29
(3H, m), 7.46 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 2.0 Hz).
5.1.21. Ethyl 3-ethoxy-3-{4-[(3-methylbenzyl)oxy]phenyl}propanoate (19a)
In the same manner as the preparation of 19k, the title compound was obtained as yellow oil (64 mg, 44%). 1H NMR (400 MHz,
CDCl3) δ 1.11 (3H, t, J = 7.0 Hz), 1.19 (3H, t, J = 7.0 Hz), 2.32 (3H, s), 2.51 (1H, dd, J = 4.8, 15.2 Hz), 2.76 (1H, dd, J = 8.8, 15.2
Hz), 3.25-3.38 (2H, m), 4.09 (2H, q, J = 6.9 Hz), 4.65 (1H, dd, J = 5.2, 8.4 Hz), 4.97 (2H, s), 6.92 (2H, d, J = 8.4 Hz), 7.10 (1H, d, J
= 7.6 Hz), 7.18-7.26 (4H,m).
5.1.22. Ethyl 3-ethoxy-3-{4-[(4-methylbenzyl)oxy]phenyl}propanoate (19b)
In the same manner as the preparation of 19k, the title compound was obtained as yellow oil (134 mg, 91%). 1H NMR (400 MHz,
CDCl3) δ 1.11 (3H, t, J = 7.0 Hz), 1.19 (3H, t, J = 7.0 Hz), 2.32 (3H, s), 2.51 (1H, dd, J = 4.8, 14.8 Hz), 2.75 (1H, dd, J = 8.8, 15.2
Hz), 3.25-3.38 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 4.65 (1H, dd, J = 4.8, 8.8 Hz), 4.97 (2H, s), 6.91 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J
= 7.6 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 7.6 Hz).
5.1.23. Ethyl 3-ethoxy-3-{4-[(3-fluorobenzyl)oxy]phenyl}propanoate (19c)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (142 mg, 98%). H NMR (400
MHz, CDCl3) δ 1.12 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.0 Hz), 2.53 (1H, dd, J = 4.8, 14.8 Hz), 2.78 (1H, dd, J = 8.8, 15.2 Hz),
3.28-3.40 (2H, m), 4.11 (2H, q, J = 7.0 Hz), 4.67 (1H, dd, J = 5.2, 9.2 Hz), 5.04 (2H, s), 6.92 (2H, d, J = 8.8 Hz), 7.00 (1H, td, J =
2.8, 8.8 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.30-7.36 (1H, m).
5.1.24. Ethyl 3-{4-[(3-chlorobenzyl)oxy]phenyl}-3-ethoxypropanoate (19d)

1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (140 mg, 92%). H NMR (400
MHz, CDCl3) δ 1.12 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.2 Hz), 2.53 (1H, dd, J = 4.8, 14.8 Hz), 2.78 (1H, dd, J = 8.8, 15.2 Hz),
3.28-3.40 (2H, m), 4.11 (2H, q, J = 7.2 Hz), 4.68 (1H, dd, J = 5.2, 9.2 Hz), 5.01 (2H, s), 6.92 (2H, d, J = 8.8 Hz), 7.23-7.30 (5H, m),
7.42 (1H, brs).
5.1.25. Ethyl 3-ethoxy-3-{4-[(3-methoxybenzyl)oxy]phenyl}propanoate (19e)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (141 mg, 94%). H NMR (400
MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.0 Hz), 2.53 (1H, dd, J = 4.8, 15.2 Hz), 2.77 (1H, dd, J = 8.8, 14.8 Hz),
3.27-3.40 (2H, m), 3.80 (3H, s), 4.11 (2H, q, J = 7.1 Hz), 4.67 (1H, dd, J = 5.2, 9.2 Hz), 5.02 (2H, s), 6.85 (1H, dd, J = 2.4, 8.0 Hz),
6.93 (2H, d, J = 8.8 Hz), 6.97-7.00 (2H, m), 7.23-7.30 (3H, m).
5.1.26. Ethyl 3-ethoxy-3-(4-{[3-(methoxymethoxy)benzyl]oxy}phenyl)propanoate (19f)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (133 mg, 83%). H NMR (400
MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 2.53 (1H, dd, J = 4.8, 14.8 Hz), 2.77 (1H, dd, J = 8.8, 14.8 Hz),
3.27-3.41 (2H, m), 3.46 (3H, s), 4.11 (2H, q, J = 7.1 Hz), 4.67 (1H, dd, J = 5.2, 8.8 Hz), 5.00 (2H, s), 5.17 (2H, s), 6.93 (2H, d, J =
8.8 Hz), 6.98 (1H, dd, J = 2.4, 8.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.10 (1H, t, J = 1.8 Hz), 7.22-7.30 (3H, m).
5.1.27. Ethyl 3-ethoxy-3-{4-[(3-phenoxybenzyl)oxy]phenyl}propanoate (19g)
1
In the same manner as the preparation of 19l, the title compound was obtained as colorless oil (165 mg, 93%). H NMR (400
MHz, CDCl3) δ 1.14 (3H, t, J = 7.1 Hz), 1.23 (3H, t, J = 7.1 Hz), 2.55 (1H, dd, J = 5.1, 15.3 Hz), 2.79 (1H, dd, J = 9.0, 15.3 Hz),
3.27-3.42 (2H, m), 4.13 (2H, q, J = 7.1 Hz), 4.69 (1H, dd, J = 5.1, 9.0 Hz), 5.03 (2H, s), 6.91-6.98 (3H, m), 7.00-7.05 (2H, m), 7.09-
7.19 (3H, m), 7.24-7.29 (2H, m), 7.32-7.38 (3H, m).
5.1.28. Ethyl 3-{4-[(3-cyanobenzyl)oxy]phenyl}-3-ethoxypropanoate (19h)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (108 mg, 73%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J = 7.0 Hz), 2.58 (1H, dd, J = 5.5, 15.0 Hz), 2.82 (1H, dd, J = 8.5, 15.0 Hz),
3.34-3.44 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 4.73 (1H, dd, J = 5.0, 9.0 Hz), 5.11 (2H, s), 6.96 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J =
9.0 Hz), 7.53 (1H, t, J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.77 (1H, s).
5.1.29. Ethyl 3-ethoxy-3-{4-[(3-nitrobenzyl)oxy]phenyl}propanoate (19i)
1
In the same manner as the preparation of 19l, the title compound was obtained as colorless oil (278 mg, 89%). H NMR (500
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J = 7.0 Hz), 2.58 (1H, dd, J = 5.4, 15.1 Hz), 2.82 (1H, dd, J = 8.8, 15.1 Hz),
3.33-3.44 (2H, m), 4.16 (2H, q, J = 7.0 Hz), 4.73 (1H, dd, J = 5.4, 8.8 Hz), 5.18 (2H, s), 6.99 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J =
8.8 Hz), 7.60 (1H, t, J = 8.3 Hz), 7.80 (1H, d, J = 7.8 Hz), 8.22 (1H, d, J = 8.3 Hz), 8.35 (1H, s).
5.1.30. Ethyl 3-{4-[(4-chlorobenzyl)oxy]phenyl}-3-ethoxypropanoate (19j)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (89 mg, 58%). H NMR (400
MHz, CDCl3) δ 1.10 (3H, t, J = 7.0 Hz), 1.19 (3H, t, J = 7.0 Hz), 2.51 (1H, dd, J = 4.8, 14.8 Hz), 2.75 (1H, dd, J = 8.8, 15.2 Hz),
3.25-3.37 (2H, m), 4.09 (2H, q, J = 7.0 Hz), 4.65 (1H, dd, J = 5.2, 8.4 Hz), 4.99 (2H, s), 6.89 (2H, d, J = 8.8 Hz), 7.23 (3H, t, J = 4.4
Hz), 7.32 (3H, brs).
5.1.31. Ethyl 3-[4-(cyclohexylmethoxy)phenyl]-3-ethoxypropanoate (19m)
In the same manner as the preparation of 19k, the title compound was obtained as yellow oil (123 mg, 88%). 1H NMR (500 MHz,
CDCl3) δ 1.07 (2H, ddd, J = 3.0, 12.5, 24.5 Hz), 1.16 (3H, t, J = 7.0 Hz), 1.22-1.36 (6H, m), 1.72-1.90 (6H, m), 2.57 (1H, dd, J =
4.5, 15.0 Hz), 2.82 (1H, dd, J = 8.5, 15.0 Hz), 3.32-3.43 (2H, m), 3.77 (2H, d, J = 6.0 Hz), 4.16 (2H, q, J = 7.5 Hz), 4.71 (1H, dd, J
= 5.0, 9.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz).
5.1.32. Ethyl 3-ethoxy-3-{4-[(2-methylpyridin-3-yl)methoxy]phenyl}propanoate (19n)
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (144 mg, 100%). H NMR (400
1
MHz, CDCl3) δ 1.11 (3H, t, J = 7.2 Hz), 1.20 (3H, t, J = 7.2 Hz), 2.52 (1H, dd, J = 5.2, 14.8 Hz), 2.56 (3H, s), 2.77 (1H, dd, J = 8.8,
15.2 Hz), 3.27-3.39 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 4.67 (1H, dd, J = 5.2, 9.2 Hz), 5.00 (2H, s), 6.92 (2H, d, J = 8.8 Hz), 7.13 (1H,
dd, J = 5.2, 8.0 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.69 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J = 5.2 Hz).
5.1.33. Ethyl 3-{4-[(1,3-dimethyl-1H-pyrazol-4-yl)methoxy]phenyl}-3-ethoxypropanoate (19o)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (106 mg, 74%). H NMR (400
MHz, CDCl3) δ 1.13 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz), 2.24 (3H, s), 2.53 (1H, dd, J = 4.8, 14.8 Hz), 2.78 (1H, dd, J = 8.4,

14.8 Hz), 3.28-3.40 (2H, m), 3.82 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 4.68 (1H, dd, J = 5.2, 9.2 Hz), 4.96 (2H, s), 6.08 (1H, s), 6.92
(2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz).
5.1.34. Ethyl 3-ethoxy-3-{4-[(4-fluoronaphthalen-1-yl)methoxy]phenyl}propanoate (19p)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (148 mg, 89%). H NMR (400
MHz, CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.55 (1H, dd, J = 5.2, 15.0 Hz), 2.79 (1H, dd, J = 9.2, 14.8 Hz),
3.29-3.42 (2H, m), 4.13 (2H, q, J = 7.2 Hz), 4.70 (1H, dd, J = 4.8, 8.8 Hz), 5.40 (2H, s), 7.01 (2H, d, J = 8.8 Hz), 7.11 (1H, dd, J =
8.8, 10 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 5.6, 8.0 Hz), 7.55-7.60 (2H, m), 8.02-8.04 (1H, m), 8.13-8.17 (1H, m).
5.1.35. Ethyl 3-{4-[2-(3,4-dichlorophenyl)ethoxy]phenyl}-3-ethoxypropanoate (19q)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (100 mg, 48%). H NMR (400
MHz, CDCl3) δ 1.11 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.0 Hz), 2.52 (1H, dd, J = 5.2, 15.2 Hz), 2.76 (1H, dd, J = 8.8, 15.2 Hz),
3.02 (2H, t, J = 6.6 Hz), 3.26-3.38 (2H, m), 4.08-4.14 (4H, m), 4.66 (1H, dd, J = 5.2, 9.2 Hz), 6.83 (2H, d, J = 8.4 Hz), 7.11 (1H, d,
J = 8.4 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz).
5.1.36. 3-Ethoxy-3-{4-[(3-methylbenzyl)oxy]phenyl}propanoic acid (20a)
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (118 mg, 100%). 1H NMR (400
MHz, CDCl3) δ 1.13 (3H, t, J = 7.0 Hz), 2.34 (3H, s), 2.59 (1H, dd, J = 4.0, 16 Hz), 2.80 (1H, dd, J = 9.2, 16 Hz), 3.29-3.40 (2H, m),
4.64 (1H, dd, J = 4.0, 9.6 Hz), 4.98 (2H, s), 6.93 (2H, d, J = 8.8 Hz), 7.11 (1H, d, J = 7.2 Hz), 7.18-7.26 (5H,m). LCMS (ESI): m/z
313 (M-H)-.
5.1.37. 3-Ethoxy-3-{4-[(4-methylbenzyl)oxy]phenyl}propanoic acid (20b)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (100 mg, 81%). H NMR (400
MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 2.33 (3H, s), 2.59 (1H, dd, J = 3.3, 16 Hz), 2.80 (1H, dd, J = 9.6, 16 Hz), 3.31-3.42 (2H, m),
4.63 (1H, dd, J = 4.0, 9.6 Hz), 4.98 (2H, s), 6.93 (2H, d, J = 9.2 Hz), 7.16 (2H, d, J = 7.6 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.28 (2H, d,
J = 7.6 Hz). HRMS (ESI): m/z calcd. for C19H22O4 [M-H]-: 313.1518; found: 313.1449.
5.1.38. 3-Ethoxy-3-{4-[(3-fluorobenzyl)oxy]phenyl}propanoic acid (20c)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (78 mg, 60%). H NMR (400
MHz, CDCl3) δ 1.13 (3H, t, J = 7.2 Hz), 2.58 (1H, dd, J = 4.4, 16 Hz), 2.80 (1H, dd, J = 9.2, 15.6 Hz), 3.29-3.41 (2H, m), 4.65 (1H,
dd, J = 4.4, 9.2 Hz), 5.02 (2H, s), 6.91 (2H, d, J = 8.4 Hz), 6.98 (1H, dd, J = 8.4, 8.4 Hz), 7.14 (2H, dd, J = 7.6, 14 Hz), 7.23 (2H, d,
J = 8.0 Hz), 7.31 (1H, dd, J = 7.6, 13.6 Hz). LCMS (ESI): m/z 317 (M-H)-.
5.1.39. 3-{4-[(3-Chlorobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (20d)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (115 mg, 88%). H NMR (400
MHz, CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 2.59 (1H, dd, J = 3.6, 15.6 Hz), 2.80 (1H, dd, J = 9.6, 15.6 Hz), 3.32-3.44 (2H, m), 4.64
(1H, dd, J = 3.6, 9.2 Hz), 5.00 (2H, s), 6.92 (2H, d, J = 8.4 Hz), 7.21-7.24 (3H, m), 7.28 (2H, d, J = 3.2 Hz), 7.40 (1H, s). LCMS
(ESI): m/z 333 (M-H)-.
5.1.40. 3-Ethoxy-3-{4-[(3-methoxybenzyl)oxy]phenyl}propanoic acid (20e)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (101mg, 78%). H NMR (400
MHz, CDCl3) δ 1.16 (3H, t, J = 6.8 Hz), 2.59 (1H, dd, J = 3.6, 15.6 Hz), 2.80 (1H, dd, J = 9.2, 15.6 Hz), 3.31-3.42 (2H, m), 3.79
(3H, s), 4.64 (1H, dd, J = 4.0, 9.6 Hz), 5.01 (2H, s), 6.84 (1H, dd, J = 2.4, 8.4 Hz), 6.92-6.98 (4H, m), 7.21 (2H, d, J = 9.2 Hz), 7.27
(1H, dd, J = 7.8, 7.8 Hz). LCMS (ESI): m/z 329 (M-H)-.
5.1.41. 3-Ethoxy-3-(4-{[3-(methoxymethoxy)benzyl]oxy}phenyl)propanoic acid (20f)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (93 mg, 75%). H NMR (400
MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 2.60 (1H, dd, J = 4.4, 15.6 Hz), 2.82 (1H, dd, J = 9.2, 15.6 Hz), 3.31-3.42 (2H, m), 3.47
(3H, s), 4.66 (1H, dd, J = 4.4, 9.2 Hz), 5.01 (2H, s), 5.17 (2H, s), 6.95 (2H, d, J = 8.0 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.01 (1H, d, J =
7.6 Hz), 7.10 (1H, s), 7.24 (2H, d, J = 6.0 Hz), 7.29 (1H, dd, J = 8.0, 8.0 Hz). LCMS (ESI): m/z 359 (M-H)-.
5.1.42. 3-Ethoxy-3-{4-[(3-phenoxybenzyl)oxy]phenyl}propanoic acid (20g)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (165 mg, 93%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.1 Hz), 2.63 (1H, dd, J = 3.8, 16.0 Hz), 2.84 (1H, dd, J = 9.6, 16.0 Hz), 3.35-3.48 (2H, m), 4.68
(1H, dd, J = 3.8, 9.6 Hz), 5.04 (2H, s), 6.93-6.99 (3H, m), 7.00-7.05 (2H, m), 7.08-7.19 (3H, m), 7.23-7.30 (2H, m), 7.32-7.39 (3H,
m). MS (FAB): m/z 431 (M+K)+.

5.1.43. 3-{4-[(3-Cyanobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (20h)
1
In the same manner as the preparation of 11b, the title compound was obtained as colorless oil (75 mg, 75%). H NMR (400
MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 2.60 (1H, dd, J = 4.4, 15.6 Hz), 2.82 (1H, dd, J = 8.8, 15.6 Hz), 3.31-3.43 (2H, m), 4.67
(1H, dd, J = 4.4, 9.2 Hz), 5.07 (2H, s), 6.93 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 7.2, 7.2 Hz), 7.63 (2H,
dd, J = 8.0, 16 Hz), 7.73 (1H, s). LCMS (ESI): m/z 324 (M-H)-.
5.1.44. 3-Ethoxy-3-{4-[(3-nitrobenzyl)oxy]phenyl}propanoic acid (20i)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (30 mg, 30%). H NMR (500
MHz, CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 2.59 (1H, dd, J = 4.0, 15.6 Hz), 2.80 (1H, dd, J = 9.2, 15.6 Hz), 3.31-3.43 (2H, m), 4.65
(1H, dd, J = 4.0, 9.2 Hz), 5.12 (2H, s), 6.94 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.54 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J =
7.6 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.29 (1H, s). LCMS (ESI): m/z 344 (M-H)-.
5.1.45. 3-{4-[(4-Chlorobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (20j)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (98 mg, 100%). H NMR (400
MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 2.59 (1H, dd, J = 4.0, 16 Hz), 2.80 (1H, dd, J = 9.2, 15.6 Hz), 3.31-3.42 (2H, m), 4.64 (1H,
dd, J = 3.6, 9.2 Hz), 4.99 (2H, s), 6.91 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 7.2 Hz), 7.33 (4H, s). LCMS (ESI): m/z 333 (M-H)-.
5.1.46. 3-Ethoxy-3-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)propanoic acid (20k)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (103 mg, 78%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.1 Hz), 2.64 (1H, dd, J = 4.7, 15.7 Hz), 2.85 (1H, dd, J = 9.3, 15.6 Hz), 3.33-3.43 (2H, m), 4.69
(1H, dd, J = 4.3, 9.4 Hz), 5.12 (2H, s), 6.94 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 7.8 Hz), 7.64 (2H, d, J =
8.2 Hz). LCMS (ESI): m/z 367 (M-H)-.
5.1.47. 3-{4-[(3,4-Dichlorobenzyl)oxy]phenyl}3-ethoxy propanoic acid (20l)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (121 mg, 79%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz), 2.63 (1H, dd, J = 4.3, 15.6 Hz), 2.83 (1H, dd, J = 9.8, 15.6 Hz), 3.35-3.46 (2H, m), 4.70
(1H, dd, J = 4.3, 9.8 Hz), 5.01 (2H, s), 6.94 (2H, d, J = 8.6 Hz), 7.25-7.28 (3H, m), 7.46 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 2.0 Hz).
LCMS (ESI) m/z 367 (M-H)-.
5.1.48.
(3S)-3-{4-[(3,4-Dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoic
acid
(S)-20l
and
(3R)-3-{4-[(3,4-
Dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (R)-20l
(S)-20l and (R)-20l were obtained by the chiral separation of 20l.
3-{4-[(3,4-Dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (20l) (150 mg) was dissolved in hexane (6.0 mL) and
isopropanol (3.0 mL), and the resulting solution was subjected to optical resolution by high performance liquid chromatography
using a CHIRALPAK AS semi-preparative column (2.0 cm x 25.0 cm, manufactured by Daicel Chemical Industries, Ltd.)
[Conditions; flow rate : 20 mL/min, solvent : hexane/isopropanol/trifluoroacetic acid = 95/5/0.1 (v/v/v), detection wavelength : 220
nm]. The solvent in the solution having been subjected to optical resolution was distilled off under reduced pressure, and a
compound with a retention time of 25 min was obtained as (S)-20l (a white solid, 39 mg, 26%), and a compound with a retention
time of 17 min was obtained as (R)-20l (a white solid, 37 mg, 25%). (S)-20l : HRMS (ESI): m/z calcd. for C18H18Cl2O4 [M-H]-:
367.0582; found: 367.0502.
5.1.49. 3-[4-(Cyclohexylmethoxy)phenyl]-3-ethoxypropanoic acid (20m)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (102 mg, 91%). H NMR (500
MHz, CDCl3) δ 0.98-1.08 (2H, m), 1.17 (3H, t, J = 8.8 Hz), 1.19-1.33(3H, m), 1.67-1.86 (6H, m), 2.60 (1H, dd, J = 4.5, 20.0 Hz),
2.82 (1H, dd, J = 12.0, 20.0 Hz), 3.32- 3.46 (2H, m), 3.72 (2H, d, J = 8.0 Hz), 6.64 (1H, dd, J = 5.0, 12.0 Hz), 6.86 (2H, d, J = 11.5
Hz), 7.21 (2H, d, J = 10.5 Hz). HRMS (ESI): m/z calcd. for C18H26O4 [M-H]-: 305.1831; found: 305.1744.
5.1.50. 3-Ethoxy-3-{4-{(2-methylpyridin-3-yl)methoxy}phenyl}propanoic acid (20n)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (104 mg, 79%). H NMR (500
MHz, CDCl3) δ 1.17 (3H, t, J = 8.5 Hz), 2.56 (3H, s), 2.62 (1H, dd, J = 6.0, 19.5 Hz), 2.84 (1H, dd, J = 11.0, 19.5 Hz), 3.36-3.44
(2H, m), 4.69 (1H, dd, J = 6.0, 11.0 Hz), 5.02 (2H, s), 6.95 (2H, d, J = 11.0 Hz), 7.17 (1H, dd, J = 6.5, 10.0 Hz), 7.28 (2H, d, J =
11.0 Hz), 7.72 (1H, d, J = 8.0 Hz), 8.47 (1H, dd, J = 2.0, 6.5 Hz). LCMS (ESI): m/z 314 (M-H)-.
5.1.51. 3-{4-[(1,3-Dimethyl-1H-pyrazol-5-yl)methoxy]phenyl}-3-ethoxypropanoic acid (20o)

1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (30 mg, 30%). H NMR (400
MHz, CDCl3) δ 1.18 (3H, t, J = 7.0 Hz), 2.23 (3H, s), 2.61 (1H, dd, J = 4.0, 15.6 Hz), 2.82 (1H, dd, J = 9.2, 16.0 Hz), 3.36-3.45 (2H,
m), 3.82 (3H, s), 4.66 (1H, dd, J = 4.4, 9.6 Hz), 4.96 (2H, s), 6.08 (1H, s), 6.94 (2H, d, J = 9.2 Hz), 7.25 (2H, d, J = 8.0 Hz). LCMS
(ESI): m/z 317 (M-H)-.
5.1.52. 3-Ethoxy-3-{4-[(4-fluoronaphthalen-1-yl)methoxy]phenyl}propanoic acid (20p)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (125 mg, 91%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz), 2.66 (1H, dd, J = 4.3, 15.6 Hz), 2.87 (1H, dd, J = 9.4, 15.6 Hz), 3.35-3.46 (2H, m), 4.71
(1H, dd, J = 4.3, 9.4 Hz), 5.43 (2H, s), 7.04 (2H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 7.8, 10.1 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.52 (1H,
dd, J = 5.4, 7.4 Hz), 7.60 (2H, t, J = 4.5 Hz), 8.04-8.06 (1H, m), 8.17 (1H, t, J = 4.7 Hz). LCMS (ESI): m/z 367 (M-H)-.
5.1.53. 3-{4-[2-(3,4-Dichlorophenyl)ethoxy]phenyl}-3-ethoxypropanoic acid (20q)
1
In the same manner as the preparation of 11b the title compound was obtained as a white solid (71 mg, 73%). H NMR (500
MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 2.64 (1H, dd, J = 4.5, 16.0 Hz), 2.85 (1H, dd, J = 10.0, 16.0 Hz), 3.07 (2H, t, J = 6.5 Hz),
3.38-3.45 (2H, m), 4.18 (2H, t, J = 6.3 Hz), 4.70 (1H, dd, J = 4.5, 9.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 7.16 (1H, d, J = 8.5 Hz), 7.27
(2H, d, J = 9.0 Hz), 7.39-7.42 (2H, m). LCMS (ESI): m/z 381 (M-H)-.
5.1.54. 4-(3,4-Dichlorophenoxy)benzaldehyde (21a)
To a solution of 3,4-dichlorophenol (597 mg, 3.66 mmol) in N,N-dimethylacetamide (10.0 mL), 4-fluorobenzaldehyde (14a, 599
mg, 4.03 mmol) and Cs2CO3 (1.79 g, 5.49 mmol) were added at room temperature, and stirred under N2 atmosphere at 150 °C for 3
h. After cooling to the room temperature, water was added to the reaction mixture, and followed by extraction with AcOEt. The
organic layer was washed with brine, and dried over Na2SO4 and filtered. After the solvent was distilled off under reduced pressure,
the residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 85:15 (v/v)) to obtain 21a as a white solid
1
(387 mg, 40%). H NMR (500 MHz, CDCl3) δ 6.98 (1H, dd, J = 3.0, 9.0 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.23 (1H, d, J = 2.5 Hz),
7.50 (1H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.8 Hz), 9.99 (1H, s).
5.1.55. 4-[(4-Chloronaphthalen-1-yl)oxy]benzaldehyde (21b)
In the same manner as the preparation of 21a, the title compound was obtained as yellow oil (396 mg, 33%). 1H NMR (400 MHz,
CDCl3) δ 7.04 (3H, m), 7.53 (2H, d, J = 8.0 Hz), 7.64 (1H, ddd, J = 1.2, 6.8, 8.4 Hz), 7.84 (2H, d, J = 8.8 Hz), 8.00 (1H, d, J = 8.4
Hz), 8.28 (1H, d, J = 8.4 Hz), 9.90 (1H, s).
5.1.56. 4-[(3,4-Dichlorobenzyl)oxy]-3-fluorobenzaldehyde (21c)
1
In the same manner as the preparation of 19k, the title compound was obtained as colorless oil (680 mg, 80%). H NMR (400
MHz, CDCl3) δ 5.16 (2H, s), 7.08 (1H, d, J = 8.2 Hz), 7.18 (1H, dd, J = 2.0, 8.2 Hz), 7.27 (1H, dd, J = 2.0, 8.2 Hz), 7.41 (1H, d, J =
8.2 Hz), 7.47 (1H, m), 7.54 (1H, d, J = 2.0 Hz), 9.85 (1H, s).
5.1.57. 4-[(3,4-Dichlorobenzyl)oxy]-3-methylbenzaldehyde (21d)
1
In the same manner as the preparation of 19k, the title compound was obtained as a white solid (542 mg, 69%). H NMR (400
MHz, CDCl3) δ 2.31 (3H, s), 5.10 (2H, s), 6.92 (1H, d, J = 8.2 Hz), 7.26 (1H, m), 7.46 (1H, d, J = 8.2 Hz), 7.52 (1H, m), 7.68 (1H,
m), 7.71 (1H, s), 9.85 (1H, s).
5.1.58. 4-[(3,4-Dichlorobenzyl)oxy]-3-nitrobenzaldehyde (21e)
1
In the same manner as the preparation of 19k, the title compound was obtained as a yellow solid (351 mg, 40%). H NMR (400
MHz, CDCl3) δ 5.26 (2H, s), 7.22 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 2.0, 8.6 Hz), 7.48 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 2.0
Hz), 8.06 (1H, dd, J = 2.0, 8.6 Hz), 8.38 (1H, d, J = 2.0 Hz), 9.93 (1H, s).
5.1.59. 4-[(3,4-Dichlorobenzyl)oxy]-2-fluorobenzaldehyde (21f)
1
In the same manner as the preparation of 19k, the title compound was obtained as a white solid (411 mg, 60%). H NMR (400
MHz, CDCl3) δ 5.08 (2H, s), 6.71 (1H, dd, J = 2.3, 12.1 Hz), 6.85 (1H, dd, J = 2.3, 8.4 Hz), 7.24-7.28 (1H, m), 7.50 (1H, d, J = 8.4
Hz), 7.54 (1H, d, J = 2.3 Hz), 7.86 (1H, t, J = 8.4 Hz), 10.2 (1H, s).
5.1.60. 2-Chloro-4-[(3,4-Dichlorobenzyl)oxy]benzaldehyde (21g)
1
In the same manner as the preparation of 19k, the title compound was obtained as a white solid (244 mg, 37%). H NMR (400
MHz, CDCl3) δ 5.06 (2H, s), 6.93 (1H, dd, J = 2.4, 8.8 Hz), 6.99 (1H, d, J = 2.0 Hz), 7.24 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.51
(1H, d, J = 2.0 Hz), 7.90 (1H, d, J = 8.4 Hz), 10 3 (1H, s).

5.1.61. 4-[(3,4-Dichlorobenzyl)oxy]-2-methoxybenzaldehyde (21h)
1
In the same manner as the preparation of 19k, the title compound was obtained as a white solid (801 mg, 96%). H NMR (400
MHz, CDCl3) δ 3.91 (3H, s), 5.08 (2H, s), 6.53 (1H, m), 6.58 (1H, m), 7.42 (1H, m), 7.48 (1H, d, J = 8.2 Hz), 7.55 (1H, m), 7.82
(1H, d, J = 8.6 Hz), 10.3 (1H, s).
5.1.62. Ethyl 3-[4-(3,4-dichlorophenoxy)phenyl]-3-hydroxypropanoate (22a)
In the same manner as the preparation of 7, the title compound was obtained as a white solid (476 mg, 92%). 1H NMR (400 MHz,
CDCl3) δ 1.26 (3H, t, J = 7.0 Hz), 2.71 (2H, d, J = 4.4 Hz), 3.35 (1H, s), 4.19 (2H, q, J = 7.2 Hz), 5.10-5.14 (1H, m), 6.83 (1H, dd, J
= 2.8, 8.8 Hz), 6.99 (2H, d, J = 9.2 Hz), 7.05 (1H, d, J = 2.4 Hz), 7.35 (2H, d, J = 9.2 Hz), 7.37 (1H, d, J = 8.4 Hz).
5.1.63. Ethyl 3-{4-[(4-chloronaphthalen-1-yl)oxy]phenyl}-3-hydroxypropanoate (22b)
In the same manner as the preparation of 7, the title compound was obtained as yellow oil (455 mg, 89%). 1H NMR (400 MHz,
CDCl3) δ 1.26 (3H, t, J = 7.2 Hz), 2.71 (1H, d, J = 4.0 Hz), 2.73 (1H, d, J = 9.2 Hz), 3.31 (1H, d, J = 3.2 Hz), 4.18 (2H, q, J = 7.2
Hz), 5.12 (1H, dt, J = 3.6, 9.2 Hz), 6.83 (1H, d, J = 8.0 Hz), 7.00 (2H, d, J = 11.6 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4
Hz), 7.54 (1H, ddd, J = 1.2, 7.2, 8.4 Hz), 7.64 (1H, ddd, J = 1.2, 7.2, 8.4 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.25 (1H, d, J = 8.4 Hz).
5.1.64. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-3-fluorophenyl}-3-hydroxypropanoate (22c)
In the same manner as the preparation of 7, the title compound was obtained as colorless oil (251 mg, 84%). 1H NMR (400 MHz,
CDCl3) δ 1.26 (3H, t, J = 7.0 Hz), 2.63-2.73 (2H, m), 3.38 (1H, d, J = 3.1 Hz), 4.18 (2H, q, J = 7.0 Hz), 5.05 (1H, m), 5.07 (2H, s),
6.92 (1H, dd, J = 8.2, 8.2 Hz), 7.04 (1H, m), 7.16 (1H, dd, J = 2.0, 12.1 Hz), 7.27 (1H, dd, J = 2.0, 8.2 Hz), 7.45 (1H, d J = 8.2 Hz),
7.53 (1H, d, J = 2.0 Hz).
5.1.65. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-3-methylphenyl}-3-hydroxypropanoate (22d)
In the same manner as the preparation of 7, the title compound was obtained as a white solid (610 mg, 83%). 1H NMR (400 MHz,
CDCl3) δ 1.27 (3H, t, J = 7.0 Hz), 2.28 (3H, s), 2.68 (1H, dd, J = 3.5, 16.4 Hz), 2.75 (1H, dd, J = 9.4, 16.4 Hz), 3.17 (1H, d, J = 3.5
Hz), 4.19 (2H, q, J = 7.0 Hz), 5.02 (2H, s), 5.06 (1H, ddd, J = 3.5, 3.5, 9.4 Hz), 6.79 (1H, d, J = 8.2 Hz), 7.15 (1H, m), 7.20 (1H, m),
7.27 (1H, m), 7.45 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 2.0 Hz).
5.1.66. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-3-nitrophenyl}-3-hydroxypropanoate (22e)
1
In the same manner as the preparation of 7, the title compound was obtained as a yellow solid (390 mg, 87%). H NMR (400
MHz, CDCl3) δ 1.28 (3H, t, J = 7.0 Hz), 2.70-2.74 (2H, m), 3.55 (1H, d, J = 3.5 Hz), 4.20 (2H, q, J = 7.0 Hz), 5.13 (1H, m), 5.17
(2H, s), 7.07 (1H, d, J = 8.2 Hz), 7.32 (1H, dd, J = 2.0, 8.2 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.54-7.58 (2H, m), 7.92 (1H, d, J = 2.0 Hz).
5.1.67. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-2-fluorophenyl}-3-hydroxypropanoate (22f)
In the same manner as the preparation of 7, the title compound was obtained as a white solid (491 mg, 92%) 1H NMR (400 MHz,
CDCl3) δ 1.27 (3H, t, J = 7.0 Hz), 2.69-2.80 (2H, m), 3.43 (1H, d, J = 3.9 Hz), 4.20 (2H, q, J = 7.0 Hz), 5.00 (2H, s), 5.32-5.38 (1H,
m), 6.65 (1H, dd, J = 2.4, 12.1 Hz), 6.77 (1H, dd, J = 2.4, 9.0 Hz), 7.23-7.29 (1H, m), 7.41-7.49 (2H, m), 7.53 (1H, d, J = 1.1 Hz).
5.1.68. Ethyl 3-{2-chloro-4-[(3,4-dichlorobenzyl)oxy]phenyl}-3-hydroxypropanoate (22g)
In the same manner as the preparation of 7, the title compound was obtained as a white solid (280 mg, 90%). 1H NMR (400 MHz,
CDCl3) δ 1.26 (3H, t, J = 7.0 Hz), 2.56 (1H, dd, J = 9.8, 16.8 Hz), 2.79 (1H, dd, J = 2.7, 16.8 Hz), 3.50 (1H, d, J = 3.5 Hz), 4.18 (2H,
q, J = 7.0 Hz), 4.97 (2H, s), 5.41 (1H, ddd, J = 2.7, 3.5, 9.8 Hz), 6.87 (1H, dd, J = 2.3, 8.6 Hz), 6.92 (1H, d, J = 2.3 Hz), 7.22 (1H,
dd, J = 2.3, 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.50 (1H, m), 7.51 (1H, d, J = 8.6 Hz).
5.1.69. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-2-methoxyphenyl}-3-hydroxypropanoate (22h)
In the same manner as the preparation of 7, the title compound was obtained as a white solid (1.01 g, 98%). 1H NMR (400 MHz,
CDCl3) δ 1.23 (3H, t, J = 7.0 Hz), 2.67 (1H, dd, J = 9.1, 16.0 Hz), 2.76 (1H, dd, J = 3.9, 16.0 Hz), 3.40 (1H, brs), 3.79 (3H, s), 4.14
(2H, q, J = 7.0 Hz), 4.97 (2H, s), 5.26 (1H, m), 6.46-6.50 (2H, m), 7.23 (1H, dd, J = 2.0, 8.2 Hz), 7.29 (1H, d, J = 8.2 Hz), 7,42 (1H,
d, J = 8.2 Hz), 7.51 (1H, d, J = 2.0 Hz).
5.1.70. Ethyl 3-[4-(3,4-dichlorophenoxy)phenyl]-3-ethoxypropanoate (19r)
In the same manner as the preparation of 8, the title compound was obtained as a white solid (398 mg, 77%). 1H NMR (400 MHz,
CDCl3) δ 1.13 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.4 Hz), 2.54 (1H, dd, J = 5.2, 15.2 Hz), 2.77 (1H, dd, J = 9.2, 15.2 Hz), 3.32-
3.40 (2H, m), 4.11 (2H, q, J = 7.2 Hz), 4.71 (1H, dd, J = 5.2, 9.2 Hz), 6.83 (1H, dd, J = 2.8, 8.4 Hz), 6.95 (2H, d, J = 8.4 Hz), 7.05
(1H, d, J = 2.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.35 (1H, d, J = 8.8 Hz).

5.1.71. Ethyl 3-{4-[(4-chloronaphthalene-1-yl)oxy]phenyl}-3-ethoxypropanoate (19s)
In the same manner as the preparation of 8, the title compound was obtained as yellow oil (400 mg, 83%). 1H NMR (400 MHz,
CDCl3) δ 1.13 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.4 Hz), 2.54 (1H, dd, J = 5.2, 15.6 Hz), 2.77 (1H, dd, J = 9.2, 14.8 Hz), 3.23-
3.42 (2H, m), 4.12 (2H, q, J = 7.2 Hz), 4.70 (1H, dd, J = 5.2, 9.2 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.29 (2H, d,
J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.53 (1H, ddd, J = 1.2, 6.4, 8.0 Hz), 7.62 (1H, ddd, J = 1.6, 7.2, 8.4 Hz), 8.20 (1H, d, J = 8.8
Hz), 8.24 (1H, d, J = 8.0 Hz).
5.1.72. Ethyl 3-{4-[(3,4-dochlorobenzyl)oxy]-3-fluorophenyl}3-ethoxypropanoate (19t)
In the same manner as the preparation of 8, the title compound was obtained as colorless oil (125 mg, 48%). 1H NMR (400 MHz,
CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 1.23 (3H, t, J = 7.0 Hz), 2.53 (1H, dd, J = 5.1, 15.2 Hz), 2.76 (1H, dd, J = 8.6, 15.2 Hz), 3.30-
3.42 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 4.67 (1H, dd, J = 5.1, 8.6 Hz), 5.07 (2H, s), 6.92 (1H, dd, J = 8.2, 8.2 Hz), 7.01 (1H, m), 7.12
(1H, dd, J = 2.0, 11.7 Hz), 7.28 (1H, dd, J = 2.0, 8.2 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 2.0 Hz).
5.1.73. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-3-methylphenyl}-3-ethoxypropanoate (19u)
In the same manner as the preparation of 8, the title compound was obtained as colorless oil (533mg, 82%). 1H NMR (400 MHz,
CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 1.23 (3H, t, J = 7.0 Hz), 2.28 (3H, s), 2.54 (1H, dd, J = 5.1, 14.9 Hz), 2.78 (1H, dd, J = 9.0, 14.9
Hz), 3.29-3.42 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 4.66 (1H, dd, J = 5.1, 9.0 Hz), 5.02 (2H, s), 6.78 (1H, d, J = 8.2 Hz), 7.11 (1H, m),
7.15 (1H, m), 7.27 (1H, m), 7.46 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 2.0 Hz).
5.1.74. Ethyl 3-{4-[(3,4-dichlorobenzyl)oxy]-3-nitrophenyl}-3-ethoxypropanoate (19v)
In the same manner as the preparation of 8, the title compound was obtained as yellow oil (232 mg, 56%). 1H NMR (400 MHz,
CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz), 2.54 (1H, dd, J = 5.5, 15.6 Hz), 2.78 (1H, dd, J = 8.6, 15.6 Hz), 3.36 (2H,
q, J = 7.0 Hz), 4.12 (2H, q, J = 7.0 Hz), 4.72 (1H, dd, J = 5.5, 8.6 Hz), 5.15 (2H, s), 7.05 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 2.0,
8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.50 (1H, dd, J = 2.0, 8.6 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.85 (1H, d, J = 2.0 Hz).
5.1.75. Ethyl 3-[{4-[(3,4-dichlorobenzyl)oxy]-2-fluorophenyl}-3-ethoxypropanoate (19w)
In the same manner as the preparation of 8, the title compound was obtained as colorless oil (223 mg, 85%). 1H NMR (400 MHz,
CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz), 2.63 (1H, dd, J = 4.7, 15.3 Hz), 2.77 (1H, dd, J = 9.1, 15.3 Hz), 3.41 (2H,
q, J = 7.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 5.00 (2H, s), 5.03 (1H, dd, J = 4.7, 9.1 Hz), 6.65 (1H, dd, J = 2.7, 11.7 Hz), 6.76 (1H, dd, J
= 2.4, 8.4 Hz), 7.24-7.28 (1H, m), 7.35 (1H, t, J = 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 2.4 Hz)
5.1.76. Ethyl 3-{2-chloro-4-[(3,4-dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoate (19x)
In the same manner as the preparation of 8, the title compound was obtained as colorless oil (248 mg, 83%). 1H NMR (400 MHz,
CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.0 Hz), 2.57 (1H, dd, J = 9.4, 15.2 Hz), 2.63 (1H, dd, J = 3.9, 15.2 Hz), 3.38 (2H,
q, J = 7.0 Hz), 4.10-4.20 (2H, m), 4.97 (2H, s), 5.12 (1H, dd, J = 3.9, 9.4 Hz), 6.87 (1H, dd, J = 2.3, 8.6 Hz), 6.92 (1H, d, J = 2.3
Hz), 7.23 (1H, m), 7.40 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.50 (1H, d, J = 2.3 Hz).
5.1.77. Ethyl 3-[{4-[(3,4-dichlorobenzyl)oxy]-2-methoxyphenyl}-3-ethoxypropanoate (19y)
In the same manner as the preparation of 8, the title compound was obtained as colorless oil (324 mg, 77%). 1H NMR (400 MHz,
CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.0 Hz), 2.56 (1H, dd, J = 9.4, 15.2 Hz), 2.63 (1H, dd, J = 3.9, 15.2 Hz), 3.32-
3.46 (2H, m), 3.78 (3H, s), 4.11-4.18 (2H, m), 4.98 (2H, s), 5.05 (1H, dd, J = 3.9, 9.4 Hz), 6.48-6.52 (2H, m), 7.24 (1H, dd, J = 2.0,
8.2 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 2.0 Hz).
5.1.78. 3-[4-(3,4-Dichlorophenoxy)phenyl]-3-ethoxypropanoic acid (20r)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (318 mg, 86%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 2.62 (1H, dd, J = 4.4, 15.6 Hz), 2.82 (1H, dd, J = 9.6, 15.6 Hz), 3.38-3.42 (2H, m), 4.70
(1H, dd, J = 4.4, 9.2 Hz), 6.84 (1H, dd, J = 2.8, 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.07 (1H, d, J = 3.2 Hz), 7.30 (2H, d, J = 8.8 Hz),
7.36 (1H, d, J = 9.2 Hz). MS (FAB) m/z 377 (M+Na)+.
5.1.79. 3-{4-[(4-Chloronaphthalen-1-yl)oxy]phenyl}-3-ethoxypropanoic acid (20s)
In the same manner as the preparation of 11b, the title compound was obtained as a yellow solid (330 mg, 89%). 1H NMR (500
MHz, CDCl3) δ 1.17 (3H, t, J = 7.2 Hz), 2.62 (1H, dd, J = 4.4, 15.6 Hz), 2.82 (1H, dd, J = 9.6, 15.6 Hz), 3.34-3.47 (2H, m), 4.69
(1H, dd, J = 4.4, 9.2 Hz), 6.85 (1H, d, J = 8.4 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 11.6 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.53
(1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.25 (1H, d, J = 8.4 Hz). LCMS (ESI) m/z 369 (M-H)-.
5.1.80. 3-{4-[(3,4-Dichlorobenzyl)oxy]-3-fluorophenyl}-3-ethoxypropanoic acid (20t)

1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (93 mg, 80%). H NMR (400
MHz, CDCl3) δ 1.18 (3H, t, J = 7.0 Hz), 2.61 (1H, dd, J = 4.3, 15.6 Hz), 2.80 (1H, dd, J = 9.0, 15.6 Hz), 3.33-3.45 (2H, m), 4.66
(1H, dd, J = 4.3, 9.0 Hz), 5.08 (2H, s), 6.93 (1H, dd, J = 8.2, 8.2 Hz), 7.01 (1H, m), 7.12 (1H, dd, J = 2.0, 11.7 Hz), 7.28 (1H, dd, J
= 2.0, 8.2 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 2.0 Hz). LCMS (ESI): m/z 385 (M-H)-.
5.1.81. 3-{4-[(3,4-Dichlorobenzyl)oxy]-3-methylphenyl}-3-ethoxypropanoic acid (20u)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (431 mg, 78%). H NMR (400
MHz, CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 2.27 (3H, s), 2.60 (1H, dd, J = 4.3, 15.6 Hz), 2.81 (1H, dd, J = 9.4, 15.6 Hz), 3.30-3.45 (2H,
m), 4.63 (1H, dd, J = 4.3, 9.4 Hz), 5.00 (2H, s), 6.78 (1H, d, J = 8.2 Hz), 7.09 (1H, m), 7.12 (1H, m), 7.25 (1H, m), 7.44 (1H, d, J =
8.2 Hz), 7.52 (1H, d, J = 2.0 Hz). LCMS (ESI): m/z 381 (M-H)-.
5.1.82. 3-{4-[(3,4-Dichlorobenzyl)oxy]-3-nitrophenyl}-3-ethoxypropanoic acid (20v)
1
In the same manner as the preparation of 11b, the title compound was obtained as a yellow solid (51 mg, 70%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.0 Hz), 2.64 (1H, dd, J = 5.1, 16.0 Hz), 2.85 (1H, dd, J = 9.0, 16.0 Hz), 3.41 (2H, q, J = 7.0 Hz),
4.74 (1H, dd, J = 5.1, 9.0 Hz), 5.18 (2H, s), 7.09 (1H, d, J = 8.2 Hz), 7.33 (1H, dd, J = 2.0, 8.6 Hz), 7.48 (1H, d J = 8.2 Hz), 7.52
(1H, dd, J = 2.0, 8.6 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.88(1H, d, J = 2.0 Hz). LCMS (ESI): m/z 412 (M-H)-.
5.1.83. 3-{4-[(3,4-Dichlorobenzyl)oxy]-2-fluorophenyl}-3-ethoxypropanoic acid (20w)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (150 mg, 72%). H NMR (400
MHz, CDCl3) δ 1.21 (3H, t, J = 7.1 Hz), 2.70 (1H, dd, J = 4.0, 15.9 Hz), 2.83 (1H, dd, J = 9.4, 15.9 Hz), 3.42-3.50 (2H, m), 5.00
(2H, s), 5.03 (1H, dd, J = 4.0, 9.4 Hz), 6.66 (1H, dd, J = 2.2, 11.8 Hz), 6.78 (1H, dd, J = 2.2, 8.6 Hz), 7.24-7.29 (1H, m), 7.33 (1H, t,
J = 8.6 Hz), 7.48 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 2.2 Hz). LCMS (ESI) m/z 385 (M-H)-.
5.1.84. 3-{2-Chloro-4-[(3,4-dichlorobenzyl)oxy]phenyl]3-ethoxypropanoic acid (20x)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (203 mg, 81%). H NMR (400
MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 2.64 (1H, dd, J = 9.8, 16.0 Hz), 2.73 (1H, dd, J = 3.5, 16.0 Hz), 3.44 (2H, q, J = 7.0 Hz),
5.00 (2H, s), 5.15 (1H, dd, J = 3.5, 9.8 Hz), 6.91 (1H, dd, J = 2.3, 8.6 Hz), 6.96 (1H, d, J = 2.3 Hz), 7.25 (1H, m), 7.43 (1H, d, J =
8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 2.3 Hz). LCMS (ESI): m/z 401 (M-H)-.
5.1.85. 3-{4-[(3,4-Dichlorobenzyl)oxy]-2-methoxyphenyl}-3-ethoxypropanoic acid (20y)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (279 mg, 84%). H NMR (400
MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 2.64 (1H, dd, J = 3.9, 15.6 Hz), 2.70 (1H, dd, J = 9.4, 15.6 Hz), 3.38-3.54 (2H, m), 3.79
(3H, s), 4.99 (2H, s), 5.07 (1H, dd, J = 3.9, 9.4 Hz), 6.49-6.54 (2H, m), 7.24 (1H, m), 7,27 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 8.2
Hz), 7.53 (1H, d, J = 2.0 Hz). LCMS (ESI): m/z 397 (M-H)-.
5.1.86. 3-{3-[(3,4-Dichlorobenzyl)oxy]phenyl}-3-ethoxypropanoic acid (23)
1
23 was obtained as colorless oil (240 mg, 100%). The synthsis procedure is described in the supporting information. H NMR
(400 MHz, CDCl3) δ 1.16 (3H, t, J = 7.2 Hz), 2.62 (1H, dd, J = 4.0, 15.6 Hz), 2.80 (1H, dd, J = 10.0, 16.0 Hz), 3.34-3.44 (2H, m),
4.69 (1H, dd, J = 3.6, 9.2 Hz), 5.00 (2H, s), 6.88 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 6.93 (1H, d, J = 2.4 Hz), 7.25-5.29 (2H, m), 7.44
(1H, d, J = 8.0 Hz), 7.53 (1H, d, J = 1.6 Hz). LCMS (ESI): m/z 367 (M-H)-.
5.1.87. Methyl (3S)-3-(4-benzyloxyphenyl)-3-hydroxy propionate (25)
To a mixture of triethylamine (21.6 g, 213 mmol) and formic acid (11.5 g, 250 mmol), Methyl 3-[4-(tert-
butyldimethylsilyloxybenzyl)phenyl]-3-oxopropanoate (24) (22.0 g, 71.3 mmol) prepared in accordance with WO200320690(A1),
and chloro[(1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium(II) (0.900 g, 1.61 mmol) were added at
room temperature, and stirred at 35 °C for 8 h. The solvent was distilled off under reduced pressure, and the residue was purified by
silica gel column chromatography (hexane:AcOEt = 90:10 to 80:20 (v/v)) to obtain 25 as light yellow oil (12.8 g, 58%, 97% ee)
[HPLC condition: CHIRALPAK AS 4.6 mmID x 250 mmL column by isocratic elution: hexane/2-propanol = 49/1 (v/v) at a flow
rate of 1.0 mL/min, with UV detection at 254 nm, at column temperature of 25°C]. Retention time: minor product (R) 9.0 min,
major product 25 (S) 10.5 min. 1H NMR (400 MHz, CDCl3) δ 0.19 (6H, s), 0.98, (9H, s), 2.68 (1H, dd, J = 3.5, 16.4 Hz), 2.76 (1H,
dd, J = 9.4, 16.4 Hz), 3.08 (1H, d, J = 3.1 Hz), 3.72 (3H, s), 5.08 (1H, ddd, J = 3.1, 3.5, 9.4 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.23 (2H,
d, J = 8.6 Hz).
5.1.88. Methyl (3S)-3-[4-(tert-butyldimethylsilyloxy)phenyl]-3-ethoxypropanoate (26)

In the same manner as the preparation of 8, the title compound was obtained as colorless oil (10.2 g, 74%). 1H NMR (400 MHz,
CDCl3) δ 0.20 (6H, s), 0.98 (9H, s), 1.13 (3H, t, J = 7.0 Hz), 2.56 (1H, dd, J = 4.7, 15.2 Hz), 2.80 (1H, dd, J = 9.0, 15.2 Hz), 3.28-
3.41 (2H, m), 3.67 (3H, s), 4.68 (1H, dd, J = 4.7, 9.0 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz).
5.1.89. Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propanoate (27)
1
In the same manner as the preparation of 18, the title compound was obtained as a white solid (6.70 g, 100%). H NMR (500
MHz, CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 2.59 (1H, dd, J = 4.9, 15.1 Hz), 2.84 (1H, dd, J = 8.8, 15.1 Hz), 3.32-3.44 (2H, m), 3.70
(3H, s), 4.71 (1H, dd, J = 4.9, 8.8 Hz), 5.01 (1H, brs), 6.84 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz).
5.1.90. Methyl (3S)-3-ethoxy-3-(4-{[2-fluoro-4-(trifluoromethyl)benzyl]oxy}phenyl)propanoate (28b)
In the same manner as the preparation of 19k using 27 and 2-fluoro-4-trifluoromethyl benzylalcohol, the title compound was
1
obtained as colorless oil (127 mg, 72%). H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 6.8 Hz), 2.55 (1H, dd, J = 5.2, 15.2 Hz),
2.80 (1H, dd, J = 9.2, 15.2 Hz), 3.28-3.40 (2H, m), 3.66 (3H, s), 4.69 (1H, dd, J = 5.2, 9.2 Hz), 5.03 (2H, s), 6.92 (2H, d, J = 8.8 Hz),
7.21 (1H, t, J = 10.0 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.59-7.62 (1H, m), 7.66 (1H, d, J = 6.8 Hz).
5.1.91. Methyl (3S)-3-ethoxy-3-(4-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}phenyl)propanoate (28c)
In the same manner as the preparation of 19k using 27 and 3-fluoro-4-trifluoromethoxyl benzylalcohol, the title compound was
1
obtained as colorless oil (160 mg, 90%). H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 6.8 Hz), 2.55 (1H, dd, J = 5.2, 15.2 Hz),
2.80 (1H, dd, J = 9.2, 15.2 Hz), 3.28-3.40 (2H, m), 3.66 (3H, s), 4.68 (1H, dd, J = 5.2, 9.2 Hz), 5.03 (2H, s), 6.92 (2H, d, J = 8.8 Hz),
7.19-7.33 (5H, m).
5.1.92. Methyl (3S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-yloxy]phenyl}-3-ethoxypropanoate (28d)
In the same manner as the preparation of 19k using 27 and (1R)-indan-1-ol, the title compound was obtained as colorless oil (110
mg, 55%). 1H NMR (400 MHz, CDCl3) δ 1.19 (3H, t, J = 7.2 Hz), 2.21-2.29 (1H, m), 2.56-2.65 (2H, m), 2.86 (1H, dd, J = 8.8, 15.2
Hz), 2.96 (1H, ddd, J = 5.6, 8.8, 16.0 Hz), 3.18 (1H, ddd, J = 5.6, 8.8, 16.0 Hz), 3.35-3.48 (2H, m), 3.72 (s, 3H), 4.75 (1H, dd, J =
4.4, 8.8 Hz), 5.79 (1H, dd, J = 4.8, 6.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.26-7.35 (5H, m), 7.46 (1H, d, J = 7.6 Hz).
5.1.93. Methyl (3S)-3-{4-[(1R)-2,3-dihydro-1H-inden-1-yloxy]phenyl}-3-ethoxypropanoic acid (28e)
In the same manner as the preparation of 19k using 27 and (1S)-indan-1-ol, the title compound was obtained as colorless oil (110
mg, 55%). 1H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 2.14-2.22 (1H, m), 2.50-2.58 (2H, m), 2.79 (1H, dd, J = 9.2, 15.2
Hz), 2.90 (1H, ddd, J = 6.0, 8.8, 16.0 Hz), 3.11 (1H, ddd, J = 5.6, 9.2, 16.4 Hz), 3.29-3.39 (2H, m), 3.65 (s, 3H), 4.68 (1H, dd, J =
4.8, 9.2 Hz), 5.72 (1H, dd, J = 4.4, 6.8 Hz), 6.95 (2H, d, J = 6,4 Hz), 7.20-7.28 (5H, m), 7.40 (1H, d, J = 7.6 Hz).
5.1.94. Methyl (3S)-3-ethoxy-3-{4-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yloxy]phenyl}propanoate (28f)
In the same manner as the preparation of 19k using 27(1S)-tetralin-1-ol, the title compound was obtained as colorless oil (96mg,
54%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 6.0 Hz), 1.74-1.80 (1H, m), 1.98-2.02 (2H, m), 2.11-2.15 (1H, m), 2.56 (1H,
dd, J = 4.0, 12.0 Hz), 2.72-2.82 (2H, m), 2.88 (1H, dt, J = 1.2, 4.4 Hz), 3.29-3.41 (2H, m), 3.66 (3H, s), 4.68 (1H, dd, J = 3.6, 6.8
Hz), 5.34 (1H, d, J = 3.6 Hz), 6.97 (2H, d, J = 11.2 Hz), 7.12-7.26 (5H, m), 7.36 (1H, d, J = 6.0 Hz).
5.1.95. Methyl (3S)-3-[4-(2,3-Dihydro-1H-inden-2-yloxy)phenyl]-3-ethoxypropanoate (28g)
In the same manner as the preparation of 19k using 27 and indan-2-ol, the title compound was obtained as yellow oil (103 mg,
68%). 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 2.58 (1H, dd, J = 4.7, 15.3 Hz), 2.82 (1H, dd, J = 8.9, 15.2 Hz), 3.20
(2H, dd, J = 2.7, 16.4 Hz), 3.31-3.41 (4H, m), 3.68 (3H, s), 4.70 (1H, dd, J = 5.1, 9.0 Hz), 5.14-5.19 (1H, m), 6.88 (2H, d, J = 8.6
Hz), 7.19 (1H, d, J = 5.9 Hz), 7.20 (1H, d, J = 5.5 Hz), 7.24-7.26 (4H, m).
5.1.96. Methyl (3S)-3-[4-(6,7-dihydro-5H-cyclopenta[]pyridin-5-yloxy)phenyl]-3-ethoxypropanoate(28h)
In the same manner as the preparation of 19k using 27 and 6,7-dihydro-5H- cyclopenta[]pyridin-5-ol, the title compound was
1
obtained as colorless oil (71 mg, 47%). H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 2.18-2.26 (1H, m), 2.55 (1H, dd, J =
4.8, 15.2 Hz), 2.59-2.66 (1H, m), 2.80 (1H, dd, J = 8.8, 15.2 Hz), 3.02 (1H, ddd, J = 6.4, 9.2, 16.8 Hz), 3.22 (1H, ddd, J = 5.2, 9.2,
16.8 Hz), 3.28-3.39 (2H, m), 3.63 (3H, s), 4.68 (1H, dd, J = 4.8, 8.8 Hz), 5.75 (1H, t, J = 5.2 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.12 (1H,
dd, J = 5.2, 7.6 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.0 Hz), 8.50 (1H, dd, J = 1.6, 4.4 Hz).
5.1.97. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate (28j)
In the same manner as the preparation of 19k using 27 and (1S)-4-methylindan-1-ol, the title compound was obtained as
colorless oil (105 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 2.14-2.22 (1H, m), 2.27 (3H, s), 2.55 (2H, dd J

= 4.8, 15.2 Hz), 2.76-2.85 (2H, m), 3.02 (1H, ddd, J = 5.6, 8.8, 15.6 Hz), 3.27-3.39 (2H, m), 3.65 (3H, s), 4.67 (1H, dd, J = 4.8, 9.2
Hz), 5.72 (1H, dd, J = 4.0, 6.8 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.09-7.16 (2H, m), 7.22-7.26 (3H, m).
5.1.98. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-4-ethyl-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate (28k)
In the same manner as the preparation of 19k using 27 and (1S)-4-ethylindan-1-ol, the title compound was obtained as colorless
1
oil (140 mg, 57%). H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 1.20 (3H, t, J = 7.2 Hz), 2.14-2.22 (1H, m), 2.49-2.64
(4H, m), 2.76-2.88 (2H, m), 3.06 (1H, ddd, J = 5.6, 9.2, 16 Hz), 3.29-3.39 (2H, m), 3.65 (3H, s), 4.68 (1H, dd, J = 4.8, 9.2 Hz), 5.72
(1H, dd, J = 4.4, 6.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.12-7.25 (5H, m).
5.1.99. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-4-(propan-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate (28l)
In the same manner as the preparation of 19k using 27 and (1S)-4-isopropylindan-1-ol, the title compound was obtained as
1
colorless oil (152 mg, 44%). H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.2 Hz), 1.22 (6H, d, J = 7.2 Hz), 2.14-2.21 (m, 1H),
2.49-2.57 (2H, m), 2.79 (1H, dd, J = 8.8, 14.8 Hz), 2.88 (1H, ddd, J = .5.4, 8.4, 16.0 Hz), 3.03-2.96 (1H, m), 3.10 (1H, ddd, J = 5.6,
8.8, 16.0 Hz), 3.29-3.39 (2H, m), 3.65 (3H, s), 4.68 (1H, dd, J = 5.2, 9.6 Hz), 5.71 (1H, dd, J = 4.0, 6.8 Hz), 6.95 (2H, d, J = 8.4 Hz),
7.19-7.25 (5H, m).
5.1.100. Methyl (3S)-3-ethoxy-3-{4-[(4-methoxy--2,3-dihydro-1H-inden-1-yl)oxy]phenyl}propanoate (28n)
In the same manner as the preparation of 19k using 27 and 4-methoxyindan-1-ol, the title compound was obtained as a white
solid (87 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 6.8 Hz), 2.15-2.25(1H, m), 2.51-2.59 (2H, m), 2.78-2.89 (2H, m),
3.05 (1H, ddd, J = 5.2, 8.4, 16.4 Hz), 3.29-3.42 (2H, m), 3.67 (3H, s), 3.84 (3H, s), 4.69 (1H, dd, J = 4.8, 8.8 Hz), 5.33 (1H, dd, J =
4.8, 6.8 Hz), 6.80 (1H, d, J = 7.6 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J = 8 Hz), 7.21-7.26 (3H, m).
5.1.101. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-4-ethoxy-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate (28o)
In the same manner as the preparation of 19k using 27 and (1S)-4-ethoxyindan-1-ol, the title compound was obtained as colorless
oil (79 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, t, J = 6.4 Hz), 1.41 (3H, t, J = 6.8 Hz), 2.14-2.22 (1H, m), 2.56 (1H, dd,
J = 5.2, 15.6 Hz), 2.78-2.89 (2H, m), 3.06 (1H, ddd, J = 4.8, 9.2, 16.0 Hz), 3.31-3.40 (2H, m), 3.67 (3H, s), 4.07 (2H, q, J = 6.8 Hz),
4.69 (1H, dd, J = 4.8, 8.8 Hz), 5.73 (1H, dd, J = 4.8, 6.0 Hz), 6.78 (1H, d, J = 7.6 Hz), 6.96 (2H, d, J = 9.2 Hz), 7.00 (1H, d, J = 7.6
Hz), 7.18-7.26 (3H, m).
5.1.102. Methyl (3S)-3-(4-{[(1R)-4-chloro-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)-3-ethoxypropanoate (28p)
In the same manner as the preparation of 19k using 27 and (1S)-4-chloroindan-1-ol, the title compound was obtained as colorless
oil (151 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, t, J = 6.8 Hz), 2.17-2.54 (1H, m), 2.54-2.63 (2H, m), 2.81 (1H, dd, J =
8.8, 15.2 Hz), 2.95 (1H, ddd, J = 5.2, 8.8, 16.4 Hz), 3.16 (1H, ddd, J = 4.8, 8.8, 16.8 Hz), 3.31-3.40 (2H, m), 3.67 (3H, s), 4.70 (1H,
dd, J = 5.2, 9.6 Hz), 5.76 (1H, dd, J = 4.0, 6.4 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.19 (1H, t, J = 7.6 Hz), 7.24-7.30 (4H, m).
5.1.103. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate (28q)
In the same manner as the preparation of 19k using 27 and (1S)-4-(trifluoromethoxy)indan-1-ol, the title compound was obtained
as colorless oil (141 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J = 7.6 Hz), 2.17-2.45 (1H, m), 2.52-2.63 (2H, m), 2.79
(1H, dd, J = 8.8, 15.2 Hz), 2.94 (1H, ddd, J = 6.0, 8.8, 16.4 Hz), 3.15 (1H, ddd, J = 5.2, 8.8, 16.4 Hz), 3.30-3.39 (2H, m), 3.65 (3H,
s), 4.68 (1H, dd, J = 4.8, 8.8 Hz), 5.74 (1H, dd, J = 4.4, 6.4 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.28-7.23 (3H,
m), 7.33 (1H, d, J = 7.2 Hz).
5.1.104. Methyl (3S)-3-ethoxy-3-(4-{[(1R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoate(28s)
In the same manner as the preparation of 19k using 27 and (1S)-5-(trifluoromethyl)indan-1-ol, the title compound was obtained
as colorless oil (39 mg, 54%). 1H NMR (500 MHz, CDCl3) δ 1.18 (3H, t, J = 7.0 Hz), 2.25-2.32 (1H, m), 2.61 (1H, dd, J = 4.5, 15.0
Hz), 2.64-2.70 (1H, m), 2.86 (1H, dd, J = 9.0, 15.5 Hz), 3.01 (1H, ddd, J = 6.5, 8.5, 15.5 Hz), 3.21 (1H, ddd, J = 5.5, 9.0, 16.0 Hz),
3.35-3.40 (2H, m), 3.72 (3H, s), 4.75 (1H, dd, J = 5.0, 9.0 Hz), 5.80 (1H, t, J = 5.5 Hz), 7.01 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 9.0
Hz), 7.53-7.56 (2H, br), 7.59 (1H, s).
5.1.105. Methyl (3S)-3-ethoxy-3-(4-{[(3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl]oxy}phenyl)propanoate (28t)
In the same manner as the preparation of 19k using 27 and (3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-ol, the title
compound was obtained as colorless oil (50 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 1.16 (3H, t, J = 7.0 Hz), 2.58 (1H, dd, J = 5.1,
15.3 Hz), 2.82 (1H, dd, J = 9.0, 15.3 Hz), 3.33-3.42 (2H, m), 3.69 (3H, s), 4.71 (1H, dd, J = 5.1, 9.0 Hz), 4.76 (1H, dd, J = 2.7, 11.0
Hz), 4.83 (1H, dd, J = 6.7, 11.0 Hz), 5.92 (1H, dd, J = 2.7, 6.7 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.02 (1H, t, J = 7.4 Hz), 7.30 (2H, d, J
= 8.6 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.56 (1H, t, J = 7.4 Hz).

5.1.106. (3S)-3-Ethoxy-3-(4-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}phenyl)propanoic acid (29b)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (107 mg, 87%). H NMR (400
MHz, CDCl3) δ 1.16 (3H, t, J = 6.8 Hz), 2.41 (1H, dd, J = 4.4, 15.6 Hz), 2.82 (1H, dd, J = 9.2, 15.2 Hz), 3.32-3.44 (2H, m), 4.67
(1H, dd, J = 4.4, 9.6 Hz), 5.03 (2H, s), 6.94 (2H, d, J = 8.8 Hz), 7.19-7.27 (3H, m), 7.60 (1H, brs), 7.66 (1H, d, J = 6.4 Hz). HRMS
(ESI): m/z calcd. for C19H18F4O4 [M-H]-: 385.1141; found: 385.1048.
5.1.107. (3S)-3-Ethoxy-3-(4-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}phenyl)propanoic acid (29c)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (137 mg, 85%). H NMR (400
MHz, CDCl3) δ 1.15 (3H, t, J = 6.8 Hz), 2.59 (1H, dd, J = 4.0, 15.6 Hz), 2.80 (1H, dd, J = 9.2, 15.6 Hz), 3.31-3.42 (2H, m), 4.65
(1H, dd, J = 4.4, 9.6 Hz), 5.01 (2H, s), 6.91 (2H, d, J = 8.4 Hz), 7.17-7.31 (5H, m). HRMS (ESI): m/z calcd. for C19H18F4O5 [M-H]-:
401.1090; found: 401.0995.
5.1.108. (3S)-3-{4-[(1S)-2,3-Dihydro-1H-inden-1-yloxy]phenyl}-3-ethoxypropanoic acid (29d)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (31 mg, 42%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 2.14-2.22 (1H, m), 2.50-2.57 (1H, m), 2.62 (1H, dd, J = 4.0. 16.0 Hz), 2.83 (1H, dd, J = 9.8,
16.0 Hz), 2.90 (1H, ddd, J = 6.4, 8.8, 14.8 Hz), 3.12 (1H, ddd, J = 5.2, 8.0, 14.8 Hz), 3.35-3.46 (2H, m), 4.66 (1H, dd, J = 4.0, 9.6
Hz), 5.73 (1H, dd J = 4.0, 6.4 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.23-7.29 (5H, m), 7.40 (1H, d, J = 7.6 Hz). LCMS (ESI) m/z 325 (M-
H)-.
5.1.109. (3S)-3-{4-[(1R)-2,3-Dihydro-1H-inden-1-yloxy]phenyl}-3-ethoxypropanoic acid (29e)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (32 mg, 43%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.2 Hz), 2.14-2.21 (1H, m), 2.50-2.58 (1H, m), 2.62 (1H, dd, J = 4.0. 15.6 Hz), 2.82 (1H, dd, J = 9.8,
16.0 Hz), 2.90 (1H, ddd, J = 6.0, 8.8, 14.8 Hz), 3.12 (1H, ddd, J = 5.2, 8.4, 16.0 Hz), 3.35-3.46 (2H, m), 4.66 (1H, dd, J = 4.0, 9.6
Hz), 5.73 (1H, dd J = 4.4, 6.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.21-7.29 (5H, m), 7.40 (1H, d, J = 7.2 Hz). LCMS (ESI) m/z 325 (M-
H)-.
5.1.110. (3S)-3-Ethoxy-3-{4-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yloxy]phenyl}propanoic acid (29f)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (40 mg, 54%). H NMR (500
MHz, CDCl3) δ 1.21 (3H, t, J = 7.1 Hz), 1.75-1.84 (1H, m), 1.97-2.07 (2H, m), 2.12-2.21 (1H, m), 2.66 (1H, dd, J = 3.9, 16.0 Hz),
2.73-2.82 (1H, m), 2.86 (1H, dd, J = 9.8, 16.0 Hz), 2.87-2.95 (1H, m), 3.38-3.52 (2H, m), 4.69 (1H, dd, J = 3.9, 9.8 Hz), 5.38 (1H,
dd J = 4.1, 4.1 Hz), 7.02 (2H, d, J = 8.3 Hz), 7.14-7.22 (2H, m), 7.24 (1H, dd, J = 1.5, 7.4 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.36 (1H,
dd, J = 1.0, 7.3 Hz). LCMS (ESI) m/z 339 (M-H)-.
5.1.111. (3S)-3-[4-(2,3-Dihydro-1H-inden-2-yloxy)phenyl]-3-ethoxypropanoic acid (29g)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (88 mg, 92%). H NMR (400
MHz, CDCl3) δ 1.18 (3H, t, J = 7.0 Hz), 2.64 (1H, dd, J = 4.3, 16.0 Hz), 2.85 (1H, dd, J = 9.4, 16.0 Hz), 3.21 (2H, dd, J = 2.7, 17.0
Hz), 3.33-3.44 (4H, m), 4.69 (1H, dd, J = 4.3, 9.4 Hz), 5.14-5.19 (1H, m), 6.89 (2H, d, J = 8.6 Hz), 7.18-7.26 (6H, m). LCMS (ESI)
m/z 325 (M-H)-.
5.1.112. (3S)-3-[4-(6,7-Dihydro-5H-cyclopenta[]pyridin-5-yloxy)phenyl]-3-ethoxypropanoic acid (29h)
1
In the same manner as the preparation of 11b, the title compound was obtained as colorless oil (51 mg, 75%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.2 Hz), 2.18-2.28 (1H, m), 2.63 (2H, dd, J = 4.0, 15.2 Hz), 2.87 (1H, dd, J = 8.8, 15.6 Hz), 2.98-
3.08 (1H, m), 3.17-3.26 (1H, m), 3.34-3.43 (2H, m), 4.74 (1H, dd, J = 4.8, 8.8 Hz), 5.76 (1H, dd, J = 4.8, 6.8 Hz), 6.95 (2H, d, J =
8.0 Hz), 7.19 (1H, dd, J = 4.8, 7.6 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.74 (1H, d, J = 7.6 Hz), 8.51-8.53 (1H, m). LCMS (ESI) m/z 326
(M-H)-.
5.1.113. (3S)-3-Ethoxy-3-(4-{[(1R)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29j)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (27 mg, 27%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.1 Hz), 2.17-2.26 (1H, m), 2.30 (3H, s), 2.52-2.61 (1H, m), 2.65 (1H, dd, J = 4.3, 15.6 Hz), 2.81-
2.89 (2H, m), 3.06 (1H, ddd, J = 5.5, 8.6, 14.5 Hz), 3.36-3.49 (2H, m), 4.71 (1H, dd, J = 4.3, 9.4 Hz), 5.77 (1H, dd, J = 3.9, 6.6 Hz),
6.99 (2H, d, J = 8.6 Hz), 7.14 (1H, d, J = 7.4 Hz), 7.18 (1H, dd, J = 7.4, 7.4 Hz), 7.26-7.28 (3H, m). HRMS (ESI): m/z calcd. for
C21H24O4 [M-H]-: 339.1675; found: 339.1581.
5.1.114. (3S)-3-Ethoxy-3-(4-{[(1R)-4-ethyl-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29k)

1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (218 mg, 95%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.4 Hz), 2.18-2.26 (1H, m), 2.53-2.60 (1H, m), 2.62-2.67 (3H, m), 2.86 (1H,
dd, J = 9.4, 15.7 Hz), 2.87-2.92 (1H, m), 3.10 (1H, ddd, J = 5.5, 8.6, 14.4 Hz), 3.35-3.49 (2H, m), 4.71 (1H, dd, J = 4.3, 9.4 Hz),
5.76 (1H, dd, J = 3.9, 6.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 7.17 (1H, d, J = 7.0 Hz), 7.23 (1H, dd, J = 7.5, 7.5 Hz), 7.26-7.29 (3H, m).
HRMS (ESI): m/z calcd. for C22H26O4 [M-H]-: 353.1831; found: 353.1767.
5.1.115. (3S)-3-Ethoxy-3-(4-{[(1R)-4-(propan-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29l).
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (164 mg, 100%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 1.23 (6H, dd, J = 5.6, 12.0 Hz), 2.14-2.22 (1H, m), 2.49-2.58 (1H, m), 2.62 (1H, dd, J = 4.0,
15.6 Hz), 2.82 (1H, dd, J = 9.6, 15.6 Hz), 2.86-2.93 (1H, m), 2.97-3.03 (1H, m), 3.06-3.14 (1H, m), 3.35-3.46 (2H, m), 4.66 (1H, dd,
J = 4.0, 9.6 Hz), 5.72 (1H, dd, J = 4.0, 6.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.19-7.25 (5H, m). HRMS (ESI): m/z calcd. for C23H28O4
[M-H]-: 367.1988; found: 367.1923.
5.1.116. (3S)-3-Ethoxy-3-{4-[(4-methoxy-2,3-dihydro-1H-inden-1-yl)oxy]phenyl}propanoic acid (29n)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (66 mg, 79%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.1 Hz), 2.21 (1H, ddd, J = 4.6, 8.9, 17.9 Hz), 2.53-2.60 (1H, m), 2.66 (1H, dd, J = 4.3, 15.7 Hz),
2.83-2.91(2H, m), 3.09 (1H, ddd, J = 5.5, 9.0, 16.5 Hz), 3.35-3.48 (2H, m), 3.86 (3H, s), 4.71 (1H, dd, J = 4.0, 9.4 Hz), 5.76 (1H, t,
J = 4.6 Hz), 6.82 (1H, d, J = 7.8 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 7.9 Hz), 7.23-7.29 (3H, m). LCMS (ESI) m/z 355
(M-H)-.
5.1.117. (3S)-3-Ethoxy-3-(4-{[(1R)-4-ethoxy-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29o)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (57 mg, 75%). H NMR (400
MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 1.39 (3H, t, J = 6.8 Hz), 2.12-2.20 (1H, m), 2.49-2.58 (1H, m), 2.61 (1H, dd, J = 4.0, 15.6
Hz), 2.79-2.88 (2H, m), 3.05 (1H, ddd, J = 5.6, 8.4, 16.4 Hz), 3.33-3.48 (2H, m), 4.05 (2H, q, J = 6.8 Hz), 4.65 (1H, dd, J = 4.0, 9.6
Hz), 5.72 (1H, dd, J = 4.4, 6.8 Hz), 6.77 (1H, d, J = 8.4 Hz), 6.95-7.00 (3H, m), 7.17-7.24 (3H, m). LCMS (ESI) m/z 369 (M-H)-.
5.1.118. (3S)-3-(4-{[(1R)-4-Chloro-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)-3-ethoxypropanoic acid (29p)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (130 mg, 89%). H NMR (500
MHz, CDCl3) δ 1.21 (3H, t, J = 7.1 Hz), 2.19-2.27 (1H, m), 2.56-2.65 (1H, m), 2.65 (1H, dd, J = 3.9, 15.6 Hz), 2.86 (1H, dd, J = 9.5,
15.6 Hz), 2.94-3.01 (1H, m), 3.14-3.21 (1H, m), 3.37-3.50 (2H, m), 4.70 (1H, dd, J = 3.9, 9.5 Hz), 5.78 (1H, dd, J = 4.1, 6.6 Hz),
6.98 (2H, d, J = 8.8 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.25-7.34 (4H, m). HRMS (ESI): m/z calcd. for C20H21ClO4 [M-H]-: 359.1128;
found: 359.1059.
5.1.119. (3S)-3-Ethoxy-3-(4-{[(1R)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29q)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (135 mg, 99%). H NMR (400
MHz, CDCl3) δ 1.21 (3H, t, J = 7.0 Hz), 2.20-2.29 (1H, m), 2.66 (1H, dd, J = 4.0, 15.8 Hz), 2.58-2.69 (1H, m), 2.86 (1H, dd, J = 9.6,
15.8 Hz), 2.94-3.04 (1H, m), 3.15-3.25 (1H, m), 3.38-3.52 (2H, m), 4.71 (1H, dd, J = 4.0, 9.6 Hz), 5.79 (1H, dd, J = 4.5, 6.9 Hz),
7.00 (2H, d, J = 8.6 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.27-7.34 (1H, m), 7.38 (1H, d, J = 7.4 Hz). HRMS
(ESI): m/z calcd. for C21H21F3O5 [M-H]-: 409.1341; found: 409.1265.
5.1.120. (3S)-3-ethoxy-3-(4-{[(1R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (29s)
1
In the same manner as the preparation of 11b, the title compound was obtained as a white solid (30 mg, 80%). H NMR (400
MHz, CDCl3) δ 1.19 (3H, t, J = 7.2 Hz), 2.20-2.28 (1H, m), 2.58-2.60 (2H, m), 2.84 (1H, dd, J = 9.6, 15.6 Hz), 2.93-3.00 (1H, m),
3.17 (1H, ddd, J = 5.6, 9.2, 16.8 Hz), 3.36-3.49 (2H, m), 4.69 (1H, dd, J = 4.0, 9.6 Hz), 5.75 (1H, t, J = 6.0 Hz), 6.98 (2H, d, J = 8.4
Hz), 7.27 (2H, d, J = 8.4 Hz), 7.50 (2H, br), 7.54 (1H, s). HRMS (ESI): m/z calcd. for C21H21F3O4 [M-H]-: 393.1392; found:
393.1325.
5.1.121. (3S)-3-Ethoxy-3-(4-{[(3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl]oxy}phenyl)propanoic acid (29t)
1
In the same manner as the preparation of 11b, the title compound was obtained as colorless oil (32 mg, 66%). H NMR (400
MHz, CDCl3) δ 1.20 (3H, t, J = 7.3 Hz), 2.63 (1H, dd, J = 4.4, 15.6 Hz), 2.85 (1H, dd, J = 9.3, 15.6 Hz), 3.37-3.47 (2H, m), 4.70
(1H, dd, J = 4.4, 9.3 Hz), 4.75 (1H, dd, J = 2.9, 10.7 Hz), 4.83 (1H, dd, J = 6.4, 10.7 Hz), 5.92-5.94 (1H, m), 6.91 (2H, d, J = 8.8
Hz), 7.03 (1H, t, J = 7.3 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.55 (1H, t, J = 7.3 Hz), 7.57 (1H, t, J = 7.3 Hz). HRMS (ESI): m/z calcd. for
C20H19F3O5 [M-H]-: 395.1185; found: 395.1100.
5.1.122. (3S)-3-Ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)-3-propanoic acid (29r)
The detailed procedure was described in the supporting information. The titled compound was obtained as a white solid (1.30 g,
79%). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.1 Hz), 2.22-2.31 (1H, m), 2.59-2.70 (1H, m), 2.66 (1H, dd, J = 4.1, 15.8 Hz),

2.86 (1H, dd, J = 9.7, 15.8 Hz), 3.07-3.17 (1H, m), 3.27-3.37 (1H, m), 3.38-3.53 (2H, m), 4.71 (1H, dd, J = 4.1, 9.7 Hz), 5.77 (1H,
dd, J = 4.5, 6.9 Hz), 7.00 (2H, d, J = 9.0 Hz), 7.30 (2H, d, J = 9.0 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.61 (1H, d,
J = 7.8 Hz). 13C NMR (100MHz, CDCl3,) δ 176.5, 158.0, 143.8, 141.9, 133.4, 128.9, 127.9, 127.2, 127.0 (q, J = 32 Hz), 125.8 (q, J
= 4.8 Hz), 124.3 (q, J = 273 Hz), 115.8, 80.8, 77.4, 64.3, 43.4, 32.0, 29.1, 15.1. IR (KBr pellet) 2975, 2936, 1710, 1608, 1584, 1510,
1460, 1328, 1312, 1242, 1231, 1210, 1165, 1123, 1108, 1038, 966, 838, 794 cm-1. Anal. calcd for C21H21F3O4 : C, 63.95; H, 5.37; F,
14.45; found: C, 63.93; H, 5.38; F, 14.66. MS (FAB) m/z 433 (M+K)+. HRMS (ESI): m/z calcd. for C21H21F3O4 [M-H]-: 393.1392;
found: 393.1313. mp 111 °C. []D -54.820o (c 1.002, CH3CN). The purity of compound 29r (S,R)-isomer was confirmed as over
95% by a chiral HPLC. HPLC condition: CHRALCEL OJ-RH 4.6 mmID x 150 mmL x 2 column by isocratic elution: 20 mM
H3PO4-KH2PO4aq. (pH 2.2-2.3)/MeOH/CH3CN=30/60/10 (v/v) at a flow rate of 0.3 mL/min, with UV detection at 220 nm, at
column temperature of 25 °C. Retention time: 29r (S,R)-isomer : 118.8 min, (S,S)-isomer : 92.3 min, (R,R)-isomer : 111.1 min,
(R,S)-isomer : 131.9 min.
5.1.123 (3S)-3-Ethoxy-3-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)propanoic acid (29a)
1
In the same manner as the preparation of 29r, the title compound was obtained as a white solid (2.17 g, 88%). H NMR (500
MHz, CDCl3) δ 1.19 (3H, t, J = 7.3 Hz), 2.63 (1H, dd, J = 4.4, 16.1 Hz), 2.83 (1H, dd, J = 9.8, 16.1 Hz), 3.36-3.47 (2H, m), 4.68
(1H, dd, J = 4.4, 9.8 Hz), 5.13 (2H, s), 6.96 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J =
8.3 Hz). HRMS (ESI): m/z calcd. for C19H19F3O4 [M-H]-: 367.1235; found: 367.1161.
5.1.124. (3S)-3-(4-{[(1R)-4-Cyclopropyl-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)-3-ethoxypropanoic acid (29m)
1
In the same manner as the preparation of 29r, the title compound was obtained as a white solid (186 mg, 90%). H NMR (400
MHz, CDCl3) δ 0.67-0.73 (2H, m), 0.92-0.99 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.86-1.94 (1H, m), 2.20-2.29 (1H, m), 2.54-2.65 (1H,
m), 2.66 (1H, dd, J = 3.8, 16.0 Hz), 2.86 (1H, dd, J = 9.6, 16.0 Hz), 2.97-3.06 (1H, m), 3.17-3.27 (1H, m), 3.36-3.53 (2H, m), 4.70
(1H, dd, J = 3.8, 9.6 Hz), 5.77 (1H, dd, J = 4.1, 6.9 Hz), 6.88 (1H, d, J = 7.5 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.19 (1H, t, J = 7.5 Hz),
7.28 (2H, d, J = 8.6 Hz), 7.23-7.31 (1H, m). HRMS (ESI): m/z calcd. for C23H26O4 [M-H]-: 365.1831; found: 365.1749.
5.1.125. (3S)-3-Ethoxy-3-{4-[(7-methyl-1,2-benzoxazol-3-yl)oxy]phenyl}propanoic acid (29i)
Title compound was obtained as colorless oil (104 mg, 85%). The detailed procedure was described in the supporting
information. 1H NMR (400 MHz, CDCl3) δ 1.15 (3H, t, J = 7.0 Hz), 2.49 (3H, s), 2.63 (1H, dd, J = 4.4, 15.6 Hz), 2.83 (1H, dd, J =
9.2, 16.0 Hz), 3.34-3.44 (2H, m), 4.75 (1H, dd, J = 4.4, 9.6 Hz), 7.16 (1H, t, J = 7.4 Hz), 7.30-7.39 (6H, m). LCMS (ESI) m/z 340
(M-H)-.
5.1.126. (1S)-1-(6-Chloropyridin-3-yl)propane-1,3-diol (31)
To a solution of 30 (12.0 g, 84.8 mmol) in DMF (90.0 mL), (R)-,-bis[3,5-bis(trifluoromethyl)phenyl]-4-pyrrolidinemethanol
(4.45 g, 8.47 mmol), acetaldehyde (19.0 mL, 339 mmol) were added and stirred at room temperature for 24 h. Acetaldehyde (19.0
mL, 339 mmol) was added again, and stirred at room temperature for another 24 h. The reaction mixture was cooled to -20 °C, then
pored into diethyl ether. Water was added and followed by extraction with diethyl ether. The organic layer was washed with water,
and dried over Na2SO4, and filtered. The solvent was distilled off, and the residue was dissolved in THF (50.0 mL) and cooled to -
40 °C. After NaBH4 (3.30 g, 87.2 mmol) was added, MeOH (2.0 mL) was added dropwise to the solution. The reaction mixture was
stirred under N2 atmosphere at -40 °C for 1 h. To the reaction solution, saturated NH4Cl aq. was added, and followed by extraction
with AcOEt. The organic layer was washed with brine, and dried over Na2SO4 and filtered. After the solvent was distilled off under
reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane : methanol = 100:0 : 0 to 90:10
(v/v)) to obtain 31 as pale yellow oil (5.25 g, 33%, 94% ee). HPLC condition: CHIRALPAK IC 4.6 mmID x 250 mmL column by
isocratic elution: hexane/2-propanol = 75/25 (v/v) at a flow rate of 1.0 mL/min, with UV detection at 220 nm, at column
1
temperature of 25°C]. Retention time: major product 31 (S) 6.39 min, minor product (R) 6.79 min. H NMR (500 MHz, CDCl3) δ
1.90-2.04 (2H, m), 2.28 (1H, m), 3.55 (1H, m), 3.88-3.97 (2H, m), 5.04 (1H, ddd, J = 2.9, 3.4, 8.8 Hz), 7.33 (1H, d, J = 8.3 Hz),
7.72 (1H, dd, J = 2.4, 8.3 Hz), 8.37 (1H, d, J = 2.4 Hz).
5.1.127. (1S)-1-(6-Chloropyridine-3-yl)-3-[(triisopropylsilyl)oxy]propan-1-ol (32)
To a solution of 31 (5.00 g, 26.6 mmol) in DMF (30.0 mL), imidazole 2.36 g, 34.7 mmol) and TIPSCl (6.00 mL, 28.0 mmol)
were added at 0 °C, and stirred at r.t. for 16 h. To the reaction solution, saturated NH4Cl aq. was added, and followed by extraction
with diethyl ether. The organic layer was washed with brine, then dried over anhydrous sodium sulfate and filtered. The solvent was
distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to
80:20 (v/v)), and the title compound was abstained as colorless oil (7.60 g, 83%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.20 (21H, m),
1.87-2.02 (2H, m), 4.00-4.07 (2H, m), 4.38 (1H, d, J = 2.3 Hz), 5.05 (1H, ddd, J = 2.3, 3.1, 8.6 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.74
(1H, dd, J = 2.3, 8.2 Hz), 8.37 (1H, d, J = 2.3 Hz).
5.1.128. 2-Chloro-5-{(1S)-1-ethoxy-3-[(triisopropylsilyl)oxy]propyl}pyridine (33)

To a solution of 32 (7.60 g, 22.1 mmol) and EtI (3.60 mL, 45.0 mmol) in DMF (30.0 mL) cooled to 0 oC, NaH (63% in mineral
oil, 1.36 g, 34.0 mmol) was added, and stirred for 16 h at room temperature. Saturated NH4Cl aq. was added to the reaction mixture,
and followed by extraction with diethyl ether. The organic layer was washed with brine, and dried over Na2SO4. After filtration, the
solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt =
1
100:0 to 90:10 (v/v)) to give the title compound was obtained as colorless oil (7.96 g, 97%). H NMR (500 MHz, CDCl3) δ 1.04-
1.12 (21H, m), 1.17 (3H, t, J = 6.8 Hz), 1.75 (1H, m), 2.00 (1H, m), 3.35 (2H, q, J = 6.8 Hz), 3.62 (1H, m), 3.87 (1H, ddd, J = 4.4,
7.8, 10.3 Hz), 4.55 (1H, dd, J = 4.9, 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.63 (1H, dd, J = 2.4, 8.3 Hz), 8.32 (1H, d, J = 2.4 Hz).
5.1.129.
5-[(1S)-1-Ethoxy-3-{[(triisopropylsilyl)oxy]propyl}-2-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-
1yl]oxy}pyridine (34a)
To a solution of 33 (1.42 g, 3.81 mmol) in toluene (60 mL), (1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol22 (2.31 g, 11.4
mmol), KOH (1.28 g, 22.9 mmol) and 18-crown-6 (202 mg, 0.762 mmol) were added, and stirred at 110 °C for 5 h. The reaction
mixture was poured into water and organic material was extracted with AcOEt. The organic layer was washed with brine, then dried
over Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column
1
chromatography (hexane:AcOEt = 100:0 to 70:30 (v/v)) to give 34a as colorless oil (1.65 g, 80%). H NMR (400 MHz, CDCl3) δ
1.02-1.08 (21H, m), 1.16 (3H, td, J = 0.8, 6.8 Hz), 1.70-1.81 (1H, m), 1.94-2.01 (1H, m), 2.11-2.26 (1H, m), 2.63-2.72 (1H, m),
3.04-3.12 (1H, m), 3.26-3.39 (2H, m), 3.62 (2H, m), 3.83-3.88 (1H, m), 4.48 (1H, dd, J = 5.2, 8.4 Hz), 6.52 (1H, dd, J = 4.4, 6.8 Hz),
6.71 (1H, d, J = 8.8 Hz), 7.29 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 6.4 Hz), 7.56 (1H, dd, J = 2.0, 8.4 Hz), 7.64 (1H, d, J = 7.2 Hz),
8.10 (1H, d, J = 2.4 Hz).
5.1.130.
5-[(1S)-1-Ethoxy-3-{[(triisopropylsilyl)oxy]propyl}-2-{[(3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-
yl]oxy}pyridine (34b)
In the same manner for the preparation of 34a using 33 and (3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-ol22 the title
1
compound was obtained as colorless oil (783 mg, 91%). H NMR (400 MHz, CDCl3) δ 1.07 (21H, m), 1.16 (3H, t, J = 7.2 Hz),
1.73-1.78 (1H, m), 1.98-2.05 (1H, m), 3.30-3.38 (2H, m), 3.59-3.64 (1H, m), 3.82-3.88 (1H, m), 4.49 (1H, dd, J = 5.2, 8.0 Hz), 4.71
(1H, dd, J = 2.8, 10.8 Hz), 4.90 (1H, dd, J = 6.8, 11.2 Hz), 6.56 (1H, dd, J = 2.8, 6.8 Hz), 6.72 (1H, d, J = 8.4 Hz), 6.98 (1H, t, J =
7.6 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 2.4, 8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 8.07 (1H, d, J = 2.4 Hz).
5.1.131. (3S)-3-Ethoxy-3-(6-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}pyridin-3-yl)propanoic acid (35a)
To a solution of 34a (1.65 g, 3.07 mmol) in THF (20.0 mL), a 1.0 M tetra-n-butylammonium fluoride THF solution (5.0 mL, 5.0
mmol) was added thereto at 0 °C, and stirred for 2 h at room temperature. Water was added to the reaction mixture, the organic
material was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4. After filtration, the solvent was
distilled off under reduced pressure. The resulting residue was roughly purified by silica gel column chromatography
(hexane:AcOEt = 100:0 to 35:65 (v/v)), and obtained colorless oil (670 mg).
To a solution of the obtained colorless oil (670 mg) in acetonitrile (14.0 mL), a phosphate buffer (pH 6.8, 14.0 mL), 2,2,6,6-
tetramethylpiperidine N-oxyl (27.0 mg, 0.176 mmol), sodium chlorite (80% purity, 398 mg, 3.52 mmol), and an aqueous solution of
sodium hypochlorite (effective chlorine concentration: 5%) (0.34 mL, 0.176 mmol) were sequentially added at 0 °C, and stirred at
10 °C for 2 h. To the reaction mixture, 2 N NaOH (2.1 mL, 4.2 mmol) was added to adjust pH 8-9. An aqueous solution of Na2SO3
(531 mg, 4.22 mmol, 5.0 mL) was added and stirred 1 h. To the mixture, 1 N HCl was added to adjust pH 3. The organic material
was extracted with AcOEt, washed by brine, and then dried over Na2SO4. After filtration, the solvent was distilled off under reduced
pressure. The residue was purified by silica gel column chromatography (hexane:AcOEt = 100:0 to 0:100 (v/v)) to give 35a as a
1
white solid (213 mg, 31%). H NMR (500 MHz, CDCl3) δ 1.23 (3H, t, J = 7.0 Hz), 2.23-2.29 (1H, m), 2.69 (1H, dd, J = 5.0, 16.0
Hz), 2.69-2.76 (1H, m), 2.93 (1H, dd, J = 9.5, 16.5 Hz), 3.10-3.16 (1H, m), 3.31-3.37 (1H, m), 3.46 (2H, qd, J = 2.5, 7.1 Hz), 4.76
(1H, dd, J = 4.5, 9.0 Hz), 6.55 (1H, dd, J = 4.5, 7.5 Hz), 6.79 (1H, d, J = 8.0 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 7.5 Hz),
7.64 (1H, dd, J = 2.5, 8.0 Hz), 7.68 (1H, d, J = 7.5 Hz), 8.19 (1H, d, J = 2.0 Hz). HRMS (ESI): m/z calcd. for C20H20F3NO4 [M-H]-:
394.1344; found: 394.1264.
5.1.132. (3S)-3-Ethoxy-3-(6-{[(3S)-7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl]oxy}pyridine-3-yl)propanoic acid (35b)
1
In the same manner for the preparation of 35a, the title compound was obtained as colorless oil (329 mg, 78%). H NMR (500
MHz, CDCl3) δ 1.22 (3H, t, J = 7.3 Hz), 2.68 (1H, dd, J = 5.0, 16.0 Hz), 2.93 (1H, dd, J = 9.5, 16.0 Hz), 3.45 (2H, q, J = 7.0 Hz),
4.74-4.78 (2H, m), 4.94 (1H, dd, J = 7.0, 11.0 Hz), 6.60 (1H, dd, J = 3.0, 7.0 Hz), 6.80 (1H, d, J = 8.5 Hz), 7.04 (1H, dd, J = 7.5, 7.5
Hz), 7.56 (1H, d, J = 8.0 Hz), 7.66 (1H, dd, J = 2.5, 8.5 Hz, 2H), 7.71 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 2.0 Hz). HRMS (ESI):
m/z calcd. for C19H18F3NO5 [M-H]-: 396.1137; found: 396.1062.
5.2 Biological assays
5.2.1. The procedure of in vitro assay
Calcium flux assay in GPR40-transfected CHO cells (FLIPR assay)

The CHO cells stably expressing human and rat GPR40 receptors (1×103 cells/well) were seeded into a 384-well plate (Corning)
1 day before the assay (37 °C, 5% CO2). After removal of the culture media, the cells were incubated with 40 μL/well of Calcium3
Dye (FLIPR Calcium Assay Kit #R8108, Molecular Devices, LLC. Sunnyvale, CA, USA), which was diluted to 1/20 by Hanks-
HEPES buffer (20 mM HEPES, 2.5 mM Probenecid, in Hanks Balanced Salt Solution, pH7.4) at 37 °C for 60 min. Compounds at
50 μM were dissolved in DMSO and diluted to the desired concentration with Hanks-HEPES buffer and 10 μL of each solution was
added to the cells. Fluorescence output was measured using a fluorometric imaging plate reader 3 (FLIPR3) (Molecular Devices,
LLC.). EC50 values were estimated by sigmoid fitting using Prism (GraphPad Software, San Diego, CA, USA). The EC50 values for
GPR40s of each compound were normalized by the averaged EC50 values of 3-{4-[(2’,6’-dimethylbiphenyl-3-
yl)methoxy]phenyl}propanoic acid23 known as a GPR40 agonist (hGPR40: 6.7 nM, rGPR40: 17.7 nM).
5.2.2 The procedure of in vivo assay
SD rat intravenous glucose tolerance test
All experimental procedures were performed in accordance with the in-house guidelines of the Institutional Animal Care and Use
Committee of Daiichi Sankyo Co., Ltd. 7-week-old male Sprague Dawley rats (control and 29r (0.3 mg/kg) : n = 7, 29r
(0.03mg/kg) : n= 6, purchased from Charles River Japan, Inc.) were fasted for 6 h before the experiments.
Rats were orally administered vehicle (0.5% methylcellulose) or 29r (0.03 or 0.3 mg/kg) 60 min before intravenous injection in
the tail vein with 1 mL/kg of saline or 0.5 g/kg (1 mL/kg) glucose for the euglycemic or the hyperglycemic conditions, respectively.
Blood samples were collected via the tail vein 5 min after intravenous injection. The plasma insulin levels were measured with
Ultrasensitive Rat insulin measurement kits (Morinaga Institute of Biological Science, Inc.). The plasma glucose levels were
measured with and Glucoroder-GXT (A and T Corporation).
Statistical analyses were performed using SAS software package version 8.2. The plasma insulin levels of 0.03 and 0.3 mg/kg
29r treated groups were compared by Dunnett test. Significant difference (P < 0.05) is represented (*).
5.3 Pharmacokinetics
The pharmacokinetics of compounds 1, 29a, 29r were determined in fasting F344 rats. Compound 1 and 29a were administered
intravenously in a saline solution (contains dimethylacetamide and Tween 80) or by oral gavage in 0.5% methylcellulose.
Compound 29r was prepared for oral and intravenous administrations as a solution of [1% Lutrol/100 mmol/L Tris solution (pH
10.4)] and [0.2% Lutrol/10 mmol/L Tris buffer (pH 8.2)/5% mannitol], respectively. Following dosing, blood samples were taken
over 24 h with 9 time points (1, 29a) or 48 h with 12 time points (29r). Plasma concentrations were measured by HPLC/MS/MS.
PK parameters were calculated from non-compartmental analysis of the plasma concentration-time curves.
5.4 Molecular modeling
Compound 29r conformations were generated using program Ligprep24 and used for induced-fit docking24 in the crystal structure
of GPR40 receptor (Protein Data Bank: 4PHU)18.
Acknowledgments
References and notes
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Supplementary Material
Supplementary data (experimental detailes and characterization data for compounds 23, 29i, 29r) associated with this article can
be found, in the online version, at http://..............

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Optimization of 3- aryl-3-ethoxypropanoic
acids and discovery of the potent GPR40
agonist DS-1558
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Rieko Takano *,a, Masao Yoshida a, Masahiro Inoue b, Takeshi Honda c, Ryutaro Nakashima d, Koji Matsumoto d,
Tatsuya Yano d, Tsuneaki Ogata e, Nobuaki Watanabef, Masakazu Hirouchi f, Takako Kimura g and Narihiro
Toda *,c
Z; C > N
n; 1 > 2
X; C > O
n
*
S > R
*
R > S
Y; O > NH >> amide
R; CF3> Cl> R> OR