Design, synthesis and antimicrobial activity of chiral 2-(substituted- hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.05.028

Chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives were synthesized and their antibacterial activities were evaluated against fungus, Gram-negative and Gram-positive bacteria. In general, these compounds showed in vitro acti

Full text of DOI:10.1016/j.ejmech.2011.05.028

European Journal of Medicinal Chemistry 46 (2011) 3639e3650
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and antimicrobial activity of chiral 2-(substituted-hydroxyl)-
3-(benzo[d]oxazol-5-yl)propanoic acid derivatives
1
1
*
Wei Zhang , Wenlu Liu , Xizhen Jiang, Faqin Jiang, Hao Zhuang, Lei Fu
School of Pharmacy, Shanghai Jiao Tong University, Min Hang District, Dong Chuan Road 800, Shanghai 200240, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives were synthesized and
their antibacterial activities were evaluated against fungus, Gram-negative and Gram-positive bacteria.
In general, these compounds showed in vitro activities against all screened Gram-negative and Gram-
positive bacteria, but poor MIC values for fungus Candida albicans. Remarkably, the (S)-configuration-
substituted phenoxyl side chain on position 2 of propanoic acid exerted excellent antibacterial activity
against all screened bacteria. Preliminary structureeactivity studies revealed that the hydrophobic
substitutes, para-tert-butyl (11r), para-phenyl (11s) and para-benzyloxy (11t) on the phenoxyl side chain
displayed best activities against all Gram-negative and Gram-positive bacteria with MIC values between
Received 30 January 2011
Received in revised form
12 May 2011
Accepted 13 May 2011
Available online 20 May 2011
Keywords:
Antibacterial activity
Benzo[d]oxazole
1.56 and 6.25 mg/mL.
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
aromatic center (A) and substituted acid head (C), respectively
(Fig. 2(I)). Specifically, we introduced an aromatic tie (B) 5-methyl-
2-phenyloxazole to a benzo[d]oxazole central skeleton (A) via
a three carbon aliphatic linker. The resulting structure is coupled
with a chiral (S or R)-2-(substituted-hydroxyl)propanoic acid (C)
where substitutes on the hydroxyl are either an aromatic or
aliphatic groups (Fig. 2(II)).
Since the discovery of penicillin in 1929, antibiotic families have
been greatly expended. The natural and semi-synthetic antibiotics,
and many synthetic compounds have made outstanding contribu-
tions to counter causative organisms for human health. However,
the rising epidemics of multi-drug resistant microbial infections
have become a serious problem in the past few decades. Imminent
development of new antibacterial agents is necessary [1].
2. Chemistry
The antimicrobial activities of benzo[d]oxazole derivatives have
long been established. Benzo[d]oxazoles have drawn considerable
attention over the last few years, and many kinds of antibiotics
containing benzo[d]oxazole fragment have been published [2e7].
Betual and coworkers reported a series of 2,5-disubstitued
benzo[d]oxazoles having potential antimicrobial activities with
the minimum inhibitory concentration (MIC) values around
According to Schemes 1 and 2, compounds 11, 13 and 15,
respectively were synthesized. Specifically, starting from 3-(4-
hydroxyphenyl)propanoic acid 1, compound 2 was prepared from
the nitration and methyl esterification. The nitro group of 2 was
reduced under hydrogen atmosphere with anhydrous 10% Pd/C. The
amino intermediate from 2 was treated directly with methyl
2-chloroacetimidate hydrochloride to give an important skeleton
benzo[d]oxazole 3 in high yield. Heating of 3 and triethyl phosphite
in DMF yielded 4. Via HornereWadswortheEmmons olefination
and PtO2 hydrogenation successively, compound 5 was prepared
from 4 and aldehyde 19. Compound 6 was easily produced from the
hydrolysisof5. The Evansamide (R)-7 was obtained from 6 and(R)-4-
isopropyloxazolidin-2-one [9,10], and similarly, (S)-7 from 6 and
respective (S)-4-isopropyl oxazolidin-2-one. Sequentially, 3-phenyl-
2-(phenylsulfonyl)-1,2-oxaziridine [11,12] made (R)-7 convert to
(R,R)-8 via Davis asymmetric oxidation [13,14], and (S)-7 to (S,S)-8,
respectively. The chiral accessory ((R or S)-4-isopropyloxazolidin-2-
one) was quickly removed with magnesium methoxide [15] to
produce methyl esters (R)-9 and (S)-9. Compounds 10 and 14 were
6.25e100 mg/mL against Gram-positive and Gram-negative bacte-
rial, even fungus [8]. We recognized that the chemical structure of
Betual’s antimicrobial agent (Fig. 1) could be divided into four
moieties: an aromatic tie, a linker, a benzo[d]oxazole skeleton and
a polar head, respectively.
In this communication, we described a novel family of antimi-
crobial agents with a similar functional module arrangement,
which consists of three fragment modules: aromatic tie (B), linker,
* Corresponding author. Tel.: þ86 21 34204791; fax: þ86 021 34204787.
E-mail address: leifu@sjtu.edu.cn (L. Fu).
1
Co-first authors.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.05.028

3640
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
4. Results and discussion
The minimum inhibitory concentration (MIC) assays of the first
five (S)-configuration compounds: aromatic side chain derivatives
(phenyl (11a), pyridin-3-yl (11b), and quinolin-5-yl (11c)); and
aliphatic side chain derivatives (methyl (13a), isopropyl derivative
(13b)) were determined (Table 1). All, but 11b and 13a exhibited
potent antimicrobial activities. The MIC values of 11a and 11c were
at 100 mg/mL against Gram-negative bacteria E. coli, and 25e50 mg/
mL for Gram-positive bacteria S. aureus, MRSA, and B. subtilis. The
aliphatic side chain derivative isopropyl derivative (13b) exerted
antibacterial activity only against Gram-positive bacteria S. aureus,
Fig. 1. 2,5-Disubstituted benzo[d]oxazole as antimicrobial agents.
MRSA, and B. subtilis, at 50 mg/mL. All five compounds displayed no
potentiality in antimycotic assay.
obtained by treating (R)-9 and (S)-9 with a variety of substituted
phenols under Mitsunobu conditions [16]. Preparation of 12, bearing
an alkoxyl group, was obtained from (S)-9 by using alkyl iodide with
Ag2O [17]. After treatment of 10, 12 and 14 with LiOH, the final
carboxylic acids 11, 13 and 15 were afforded.
Synthesis of the aldehyde 19 is shown in Scheme 3. Methyl ester
17 was easily prepared according to the Malamas method [18].
Aldehyde 19 was then afforded quantitatively from LiAlH4 reduc-
tion and the DesseMartin oxidation [19], sequentially.
The above primary results suggested that compounds bearing
aromatic side chain exerted acceptable MIC values against Gram-
negative bacteria and Gram-positive bacteria, but no activity for
fungus. Taking these findings into consideration, we designated the
phenyl derivative (11a) as our lead compound for further modifica-
tion. We attached halogens on ortho-, meta- and para-positions of the
phenoxyl group. The MIC values of4-Br(11g), 2-Br(11h), 3-I (11k) and
4-I (11l) were determined and revealed that the para-position
substitute exerted better antibacterial activity than ortho- and meta-
positions, but no difference on activities when fluorine atom was
attached to the para-(11d) or meta-position (11e). Data in Table 1
revealed that the order of antibacterial activities of the mono-
halogen substitutions was I > Br > Cl > F; and while para-position
was attached with certain electron-withdrawing or-donating groups
such as: CF3 (11m), CN (11n), CH3CO (11o), CH3 (11p) and CH3O (11q),
the general order was: CF3 > CH3 z CH3O > CN > CH3CO.
Previous studies suggested that the hydrophobicity (Log P
value) of agents may alter the antimicrobial activities [22,23].
Analysis of our para-substituted compounds revealed that the
changes in antibacterial activities were generally in parallel with
the orders of their calculated Log P values: I (Log P ¼ 6.86) (11l) >
CF3 (6.43) (11m) > Br (6.33) (11g) > Cl (6.06) (11i) > CH3 (5.99)
(11p) > F (5.66) (11d) > CN (5.54) (11n) > CH3O (5.38) (11q) >
CH3CO (4.82) (11o) as shown in Table 1.
All intermediates and final compounds were characterized by
the NMR and HRMS spectroscopies.
3. Antimicrobial activity evaluations
The minimum inhibitory concentration (MIC) assays of the
newly synthesized compounds were conducted against a fungus
Candida albicans ATCC 10231, Gram-negative bacteria Escherichia
coli ATCC 11303 and Gram-positive bacteria Staphylococcus aureus
ATCC 10832, methicillin-resistant S. aureus ATCC 700699, Bacillus
subtilis ATCC 33712 by using the twofold serial dilution technique
[20,21]. The MIC is defined as the lowest antibiotic concentration
that resulted in visible growth after incubation at 37 ꢀC for 24 h.
Ceftazidime, Cefotaxime, Cefradine, Sodium Penicillin, Miconazole
nitrate, and Ketoconazole were used as control drugs. The antimi-
crobial activity data of the compounds and the control drugs as MIC
We further explored this hydrophobicityeactivity relationship by
introducing multiple halogen atoms as well as substitutes with
higher hydrophobic constants (p) [24,25]. We discovered that
(mg/mL) values are given in Table 1.
multiple halogen-substituted derivatives 11f (Log P ¼ 5.96) and 11j
(Log P ¼ 6.62) were better than their respective mono-halogen-
substituted derivatives 11d (Log P ¼ 5.66) and 11i (Log P ¼ 6.06).
We also demonstrated that more hydrophobic groups, e.g. tert-butyl
(
p
¼ 1.98) (11r), phenyl ( ¼ 1.96) (11s) and benzyloxy (11t) exerted
p
better antibacterial activities in all screened assays. Among them, the
para-tert-butyl (11r) and para-phenyl (11s) derivatives displayed
best activities against Gram-negative bacteria E. coli at 3.12
The para-tert-butyl (11r) and para-benzyloxy derivative (11t) were
active at 1.56 g/mL against Gram-positive bacteria S. aureus and
mg/mL.
m
MRSA, and even better than certain antibiotics studied. Furthermore,
the para-benzyloxy derivative (11t) exerted best activity against
B. subtilis at 1.56 mg/mL, but lower than Cefotaxime and Penicillin.
The hydrophobicityeactivity relationships also apply to the first
five compounds in Table 1, (11a), (11b), (11c), (13a) and (13b),
among which phenyl moiety possesses the better hydrophobicity.
In addition, we found that the (S)-configuration trifluoromethyl
derivative (11m), tert-butyl (11r), phenyl (11s) and benzyloxy (11t)
had displayed two to eightfold higher bioactivity than its respective
(R)-enantiomer 15aed, suggesting chiral center of propanoic acid
may play certain role in the antibacterial activity. Our data also
suggest that the carboxylic acid ending group may be critical in
activity as the corresponding carboxylic ester 10s has shown no
activities for any bacteria.
Fig. 2. Design of novel benzo[d]oxazole antimicrobial agents.

W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
3641
Scheme 1. Synthesis of compounds 11 and 13a. aReagents and conditions: (a) (1) HOAc, HNO3, 15 ꢀC, 30 min, (2) MeOH, H2SO4, reflux, 12 h, 84%; (b) 1) 10% Pd/C, H2, MeOH, 1 h, 2)
ClCH2C(]NH)OCH3$HCl, MeOH, reflux, 1.5 h, 95%; (c) P(OEt)3, DMF, 150 ꢀC, 3 h, 70%; (d) (1) 19, t-BuOK, THF, ꢁ10 ꢀC, 10 min, (2) PtO2$3H2O, MeOH, H2, 1 atm, 12 h, 34%; (e)
LiOH$H2O, EtOH, H2O, 1 h, 98%; (f) 1) pivaloylchloride, Et3N, THF, ꢁ78 ꢀC, 30 min, (2) (R or S)-4-isopropyloxazolidin-2-one, n-BuLi, THF, ꢁ78 ꢀC, 30 min, 70e83%; (g) (1) KHMDS,
THF, ꢁ78 ꢀC, 1 h, (2) 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine, THF, ꢁ78 ꢀC, 4 h, (3) AcOH, THF, ꢁ78 ꢀC, 52e62%; (h) 2.5 M EtMgBr/Ether, MeOH, ꢁ10 ꢀC, 10 min, 71e75%; (i)
Phenols, DIAD, Ph3P, toluene, 0 ꢀC then rt, 12 h, 19e82%; (j) LiOH$H2O, EtOH, H2O, rt, 2 h, 70e90%; (k) Alky-I, Ag2O, CH3CN, 40 ꢀC, 12 h, 36e52%.
5. Conclusions
para-position of phenoxyl moiety deliver the best prominent
antibacterial activities in all screened assays, and were even
better than most positive control antibiotics examined in this
study.
In this manuscript, we reported our synthetic and screening
work, and we plan to expand our library of compounds through
the structural modification of active leads found in this work. We
will conduct structureeactivity relationship (SAR) studies and
provide with a possible mechanism of action for this type of
compounds.
In summary, we have utilized the Evans amide and Davis
asymmetric oxidation to synthesize
(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic
The synthesized compounds showed a broad spectrum of in vitro
activities against Gram-positive bacteria such as S. aureus, MRSA,
B. subtilis, and Gram-negative bacteria E. coli as well.
Furthermore, we have demonstrated that hydrophobic groups,
like tert-butyl (11r), phenyl (11s) and benzyloxy (11t) on the
a
series of chiral 2-
acid.
a
Scheme 2. Synthesis of compounds 15a. Reagents and conditions: (a) Phenols, DIAD, Ph3P, toluene, 0 ꢀC then rt, 12 h, 50e75%; (b) LiOH$H2O, EtOH, H2O, rt, 2 h, 81e93%.

3642
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
Scheme 3. Synthesis of aldehyde 19a. aReagents and conditions: (a) Br2, CHCl3, 0 ꢀC, 2 h, rt, 19 h; (b) benzamide, toluene, reflux, 42% (two steps); (c) LiAlH4, ether, 0 ꢀC, 30 min, 80%;
(d) DesseMartin Periodinane, CH2Cl2, rt, 30 min.
6. Experimental
of standard techniques for the exclusion of moisture. Reactions
were monitored by TLC under 254 nm UV. 1H NMR and 13C NMR
were recorded on either a Brucker 300 MHz Avance DPX or a Bruker
500 MHz Avance DRX instrument. Chemical shifts are reported in
6.1. Chemistry
All commercial chemicals and solvents are grade and were used
without further purification unless otherwise specified. All reac-
tions expect those in aqueous media were carried out with the use
parts per million (d) and coupling constants (J) in hertz (Hz). High
resolution mass spectroscopy was conducted using Micromass LCT
system.
Table 1
In vitro antimicrobial activity of compounds 10, 11, 13 and 15 with the control drugs.
O
N
O
*
R
O
2
O
R1
N
O
Compound
Configuration
R1
R2
MIC (m
g/mL)a,b
E. coli
S. aureus
MRSA
B. subtilis
C. albicans
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
13a
13b
15a
15b
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(S)
Phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
100
>200
200
50
50
25
12.5
50
25
6.25
25
12.5
12.5
200
>200
50
100
3.12
3.12
6.25
>200
200
25
25
12.5
25
>200
200
200
25
0.78
e
25
200
25
25
200
25
25
>200
50
25
25
6.25
6.25
50
12.5
3.12
12.5
6.25
6.25
50
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
e
Pyridin-3-yl
Quinolin-5-yl
4-F-phenyl
12.5
12.5
12.5
3.12
25
6.25
3.12
3.12
1.56
1.56
50
12.5
12.5
6.25
3.12
25
6.25
1.56
1.56
1.56
1.56
50
100
12.5
25
1.56
1.56
1.56
100
50
6.25
12.5
6.25
25
>200
12.5
3.12
50
3-F-phenyl
3,4,5-triflurophenyl
4-Br-phenyl
2-Br-phenyl
4-Cl-phenyl
2,4-Dichorophenyl
3-I-Phenyl
4-I-Phenyl
4-CF3-phenyl
4-CN-phenyl
4-CH3CO-phenyl
4-CH3-phenyl
4-CH3O-phenyl
4-tBu-phenyl
4-Ph-phenyl
4-BnO-phenyl
CH3
100
25
25
>200
50
50
1.56
1.56
1.56
200
50
12.5
12.5
12.5
25
>200
0.78
3.12
25
3.12
e
3.12
3.12
1.56
200
50
12.5
12.5
6.25
12.5
>200
6.25
0.78
50
Isopropyl
4-CF3-phenyl
4-tBu-phenyl
4-Ph-phenyl
4-BnO-phenyl
4-Ph-phenyl
15c
15d
10s
Ceftazidime
Cefotaxime
Cefradine
Sodium penicillin
Miconazole nitrate
Ketoconazole
e
e
3.12
e
<0.39
e
e
1.56
<0.39
e
e
e
e
a
E. colidEscherichia coli, S. aureusdStaphylococcus aureus, MRSAdmethicillin-resistant Staphylococcus aureus, B. subtilisdBacillus subtilis, C. albicansdCandida albicans.
The sign (ꢁ) referred to that compounds not tested.
b

W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
3643
6.1.1. Methyl 3-(4-hydroxy-3-nitrophenyl)propanoate (2)
10 min and quenched with 50 mL saturated NH4Cl aqueous. The
water layer was sequentially extracted with ethyl acetate, washed
with brine and dried with anhydrous Na2SO4. An orange residue
was afforded, and it was stirred with PtO2$3H2O (0.512 g,
1.82 mmol) in 150 mL methanol for 12 h under hydrogen at
1.0 atm. Sequentially, the mixture was filtered. The filtrate was
concentrated and purified over silica gel column eluting with
petroleum ether/ethyl acetate (5:1) to give compound 5 (2.25 g,
34.5%) as a yellow solid; mp: 58e60 ꢀC; 1H NMR (300 MHz, CDCl3)
A mixture of 60% HNO3 (9.83 mL, 0.144 mmol) and acetic acid
(20 mL) was added drop-wise into
a
solution of 3-(4-
hydroxyphenyl)propanoic acid (1) (20.0 g, 0.120 mmol) in acetic
acid (150 mL) at 15 ꢀC over 1.0 h. The resulting mixture was stirred
for 30 min, and then it was poured into cool 300 mL water. The
water layer was extracted with 200 mL CH2Cl2. The organic layer
was washed with brine and dried with anhydrous Na2SO4. The
solvent was removed in vacuum to give a yellow solid 24.6 g. The
crude yellow solid was dissolved in a mixture of MeOH (300 mL)/
H2SO4 (30 mL), and the mixture was heated at reflux for 12 h. The
reaction was cooled to room temperature, and the solvent was
removed. The residue was poured into ice-water and then extracted
with ether (300 mL). The ether layer was washed with brine and
dried over anhydrous Na2SO4. The solvent was removed to give
a solid residue, which was filtered through a short silica gel column
eluting with petroleum ether/ethyl acetate (3:1) to give compound
2 (22.8 g, 84%) as a bright yellow solid; 1H NMR (300 MHz, CDCl3)
d
7.97e7.95 (m, 2H, ArH), 7.46 (s, 1H, ArH), 7.41e7.39 (m, 3H, ArH),
7.35 (d, 1H, ArH, J ¼ 8.4 Hz), 7.10 (d, 1H, ArH, J ¼ 8.4 Hz), 3.66 (s, 3H,
CH3), 3.04 (t, 2H, CH2, J ¼ 7.5 Hz), 2.96 (t, 2H, CH2, J ¼ 7.2 Hz), 2.65
(t, 2H, CH2, J ¼ 7.2 Hz), 2.63 (t, 2H, CH2, J ¼ 6.6 Hz), 2.30 (s, 3H,
CH3), 2.26 (m, 2H, CH2); HRMS-ESIþ: C24H24N2O4 calcd [M þ H]þ
405.1814, found 405.1835.
6.1.5. 3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
oxazol-5-yl)propanoic acid (6)
d
10.47 (s, 1H, OH), 7.93 (d, 1H, ArH, J ¼ 2.4 Hz), 7.44 (dd, 1H, ArH,
An aqueous of LiOH$H2O (1.17 g, 27.8 mmol, 20 mL) was added
to a solution of compound 5 (2.25 g, 5.56 mmol) in 30 mL ethanol at
room temperature. After 1 h stirring, the resulting solution was
concentrated to remove ethanol. The residue water layer was
acidified with 1 N HCl to pH ¼ 3, then extracted with 50 mL CH2Cl2
and the CH2Cl2 layer was dried over anhydrous Na2SO4. The organic
layer was filtered over Celite and the filtrate was concentrated to
give compound 6 (2.11 g, 98%) as a yellow solid; mp: 80e82 ꢀC; 1H
J ¼ 8.4 Hz,1.2 Hz), 7.08 (d,1H, ArH, J ¼ 8.7 Hz), 3.66 (s, 3H, CH3), 2.94
(t, 2H, CH2, J ¼ 7.5 Hz), 2.63 (t, 2H, CH2, J ¼ 7.7 Hz); HRMS-ESIþ:
C10H11NO5 calcd [M þ H]þ 226.0715, found 226.0733.
6.1.2. Methyl3-(2-(chloromethyl)benzo[d]oxazol-5-yl)propanoate(3)
A mixture of methyl 3-(4-hydroxy-3-nitrophenyl)propanoate
(2) (10.0 g, 44.4 mmol) and Pd/C (10%, 2.3 g, 2.22 mmol) was stirred
tempestuously in 150 mL methanol under hydrogen (1.0 atm) for
1.0 h. The solution was filtered. The filtrate was concentrated to give
a white solid, which was mixed with methyl 2-chloroacetimidate
hydrochloride (7.70 g, 53.29 mmol) in 150 mL methanol. The
resulting mixture was heated at reflux for 1.5 h, and then it was
cooled to room temperature and removed solvent in vacuum. The
residue was diluted with 150 mL ethyl acetate. The organic layer
was washed with 50 mL saturated NaHCO3 aqueous, then brine and
dried over anhydrous Na2SO4. The solvent was removed to give
a crude product, which was over silica gel column eluting with
petroleum ether/ethyl acetate (10:1) to give compound 3 (10.7 g,
NMR (300 MHz, DMSO-d6)
d 7.87e7.84 (m, 2H, ArH), 7.51e7.44 (m,
5H, ArH), 7.16 (d, 1H, ArH, J ¼ 8.8 Hz), 2.92 (t, 2H, CH2, J ¼ 6.9 Hz),
2.88 (t, 2H, CH2, J ¼ 6.9 Hz), 2.56 (t, 2H, CH2, J ¼ 6.6 Hz), 2.53 (t, 2H,
CH2, J ¼ 6.8 Hz), 2.28 (s, 3H, ArCH3), 2.09 (qui, 2H, CH2, J ¼ 7.0 Hz,
6.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 173.6, 166.7, 158.3, 148.7,
144.0, 141.0, 137.1, 134.9, 129.9, 128.9, 127.1, 125.3, 124.9, 118.5, 109.9,
35.6, 30.2, 27.0, 25.4, 24.1, 9.7; HRMS-ESIþ: C23H22N2O4 calcd
[M þ H]þ 391.1658, found 391.1667.
6.1.6. (R)-4-Isopropyl-3-(3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)
propyl)benzo[d]oxazol-5-yl)propanoyl)oxazolidin-2-one ((R)-7)
Pivaloyl chloride (0.684 mL, 5.69 mmol) was added, over
30 min, into a mixture of compound 6 (2.117 g, 5.42 mmol) and
triethylamine (0.907 mL, 6.51 mmol) in dry tetrahydrofuran
(50 mL) at ꢁ78 ꢀC. Sequentially, the resulting solution was stirred at
0 ꢀC for 30 min and recooled to ꢁ78 ꢀC. A ꢁ78 ꢀC solution of lithium
(R)-4-isopropyl-2-oxooxazolidin-3-ide (prepared from (R)-4-
isopropyloxazolidin-2-one (0.770 g, 5.96 mmol) and nBuLi
(3.73 mL 1.6 M/hexane, 5.96 mmol) in THF at ꢁ78 ꢀC) was trans-
ferred through a cannula to the mixture above. Then the resulting
mixture was warmed to room temperature. After another 30 min
stirring, the reaction was quenched with a saturated NH4Cl aqueous
(100 mL), and then extracted with ethyl acetate (100 mL). Organic
layer was washed with brine and dried over anhydrous Na2SO4. The
organic solution was concentrated and the residue was over silica
gel column eluting with petroleum ether/ethyl acetate (2:1) to give
compound (R)-7 (2.268 g, 83.4%) as a yellow oil; 1H NMR (300 MHz,
95%) as a colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.54 (s, 1H, ArH),
7.45 (d, 1H, ArH, J ¼ 9.0 Hz), 7.22 (dd, 1H, ArH, J ¼ 8.4 Hz, 1.3 Hz),
4.73 (s, 2H, CH2), 3.65 (s, 3H, CH3), 3.05 (t, 2H, CH2, J ¼ 7.7 Hz), 2.66
(t, 2H, CH2, J ¼ 7.7 Hz); HRMS-ESIþ: C12H12ClNO3 calcd [M þ H]þ
254.0584, found 254.0573.
6.1.3. Methyl 3-(2-((diethoxyphosphoryl)methyl)benzo[d]oxazol-5-
yl)propanoate (4)
Compound
3 (10.0 g, 39.4 mmol) and triethyl phosphite
(13.7 mL, 78.8 mmol) were dissolved in 40 mL DMF and stirred at
150 ꢀC for 3 h. The solvent was removed in vacuum, and then the
residue was purified with silica gel column eluting with petroleum
ether/ethyl acetate (2:1) to give compound 4 (9.78 g, 70%) as an
orange oil; 1H NMR (300 MHz, DMSO-d6)
d 7.56 (d, 1H, ArH,
J ¼ 7.8 Hz), 7.54 (s, 1H, ArH), 7.21 (dd, 1H, ArH, J ¼ 8.4 Hz, 1.5 Hz),
4.05 (m, 4H, 2CH2), 3.79 (s, 1H, CHP ¼ O), 3.71 (s, 1H, CHP ¼ O), 3.54
(s, 3H, CH3), 2.94 (t, 2H, CH2, J ¼ 7.8 Hz), 2.65 (t, 2H, CH2, J ¼ 7.8 Hz),
1.20 (t, 6H, 2CH3, J ¼ 7.1 Hz); HRMS-ESIþ: C16H22NO6P calcd
[M þ H]þ 356.1263, found 356.1255.
CDCl3) d 7.99e7.96 (m, 2H, ArH), 7.50 (s, 1H, ArH), 7.43e7.40 (m, 3H,
ArH), 7.36 (d, 1H, ArH, J ¼ 8.7 Hz), 7.16 (d, 1H, ArH, J ¼ 8.7 Hz),
4.43e4.38 (m, 1H, CH), 4.27e4.16 (m, 2H, CH2), 3.36e3.17 (m, 2H,
CH2), 3.07 (t, 2H, CH2, J ¼ 6.8 Hz), 2.96 (t, 2H, CH2, J ¼ 7.4 Hz), 2.63 (t,
2H, CH2, J ¼ 7.2 Hz), 2.37e2.22 (m, 2H, CH2), 2.30 (s, 3H, CH3), 0.89
(d, 3H, CH3, J ¼ 7.5 Hz), 0.82 (d, 3H, CH3, J ¼ 6.9 Hz); HRMS-ESIþ:
C29H31N3O5 calcd [M þ H]þ 502.2342, found 502.2359.
6.1.4. Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)benzo
[d]oxazol-5-yl)propanoate (5)
A solution of compound 4 (6.47 g, 18.2 mmol) in 40 mL dry
tetrahydrofuran was dropped into a solution of t-BuOK (2.04 g,
18.2 mmol) in 100 mL dry tetrahydrofuran at ꢁ10 ꢀC over 30 min,
and then it was stirred for 30 min at this temperature. To the
above resulting mixture was added a solution of the aldehyde 19
(3.66 g, 18.2 mmol) in 40 mL dry THF. The mixture was stirred for
6.1.7. (S)-4-Isopropyl-3-(3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)
propyl)benzo[d]oxazol-5-yl)propanoyl)oxazolidin-2-one ((S)-7)
Compound (S)-7 (2.040 g, 70%) as a yellow oil; 1H NMR
(300 MHz, CDCl3)
d 7.98e7.96 (m, 2H, ArH), 7.50 (s, 1H, ArH),

3644
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
7.42e7.40 (m, 3H, ArH), 7.35 (d, 1H, ArH, J ¼ 8.4 Hz), 7.16 (d, 1H, ArH,
J ¼ 7.8 Hz), 4.43e4.38 (m, 1H, CH), 4.26e4.16 (m, 2H, CH2),
3.39e3.17 (m, 2H, CH2), 3.07 (t, 2H, CH2, J ¼ 7.0 Hz), 2.96 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.63 (t, 2H, CH2, J ¼ 7.0 Hz), 2.39e2.21 (m, 2H, CH2), 2.30
(s, 3H, CH3), 0.88 (d, 3H, CH3, J ¼ 6.3 Hz), 0.82 (d, 3H, CH3,
J ¼ 6.9 Hz); HRMS-ESIþ: C29H31N3O5 calcd [M þ H]þ 502.2342,
found 502.2362.
6.1.11. (S)-Methyl 2-hydroxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-
yl)propyl)benzo[d]oxazol-5-yl)propanoate ((S)-9)
Compound (S)-9 (0.723 g, 75.2%) as
a white solid; mp:
68e70 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.98e7.94 (m, 2H, ArH), 7.48
(s, 1H, ArH), 7.43e7.35 (m, 4H, ArH), 7.13 (dd, 1H, ArH, J ¼ 8.1 Hz,
1.4 Hz), 4.49e4.46 (m, 1H, CH), 3.77 (s, 3H, CH3), 3.13 (dd, dd, 2H,
CH2, J ¼ ꢁ13.7 Hz, 6.7 Hz, 4.6 Hz), 2.96 (t, 2H, CH2, J ¼ 7.5 Hz), 2.62
(t, 2H, CH2, J ¼ 7.0 Hz), 2.30 (s, 3H, CH3), 2.30e2.23 (m, 2H, CH2);
HRMS-ESIþ: C24H24N2O5 calcd [M þ H]þ 421.1763, found 421.1769.
6.1.8. (R)-3-((R)-2-Hydroxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-
yl)propyl)benzo[d]oxazol-5-yl)propanoyl)-4-isopropyl oxazolidin-
2-one ((R,R)-8)
6.1.12. General synthesis of compounds 10 and 14
A solution of KHMDS (5.43 mL 1.0 M/THF, 5.43 mmol) was
dropped into a solution of compound (R)-7 (2.268 g, 4.52 mmol) in
dry THF (50 mL) at ꢁ78 ꢀC. The mixture was stirred for 1.0 h after
addition of KHMDS. A ꢁ78 ꢀC solution of 3-phenyl-2-(phenyl-
sulfonyl)-1,2-oxaziridine (1.418 g, 4.52 mmol) in 20 mL THF was
transferred into the solution above through a cannula, and then it
was stirred for 4 h. The reaction was quenched with a solution of
acetic acid (2 mL) in 6 mL dry THF at ꢁ78 ꢀC, and then the solvent
was removed in vacuum. The residue was diluted with 100 mL
ethyl acetate, and washed with brine, dried over anhydrous
Na2SO4. The solvent was removed and the crude product was
purified over silica gel column eluting with petroleum ether/ethyl
acetate (2:1) to give compound (R,R)-8 (1.219 g, 52%) as a white
Compound (R)-9/(S)-9 (0.050 g, 0.119 mmol), Ph3P (0.047 g,
0.178 mmol) and phenols (0.178 mmol) were dissolved in 5 mL dry
toluene. A solution of diisopropyl azodicarboxylate (DIAD) (0.036 g,
0.178 mmol) in 1 mL dry toluene was added at 0 ꢀC, and the
resulting solution was stirred for 12 h at room temperature. The
toluene was removed in vacuum, and the residue was purified over
silica column eluting with petroleum ether/ethyl acetate (8:1) to
give compounds 10 and 14.
6.1.12.1. (S)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
benzo[d]oxazol-5-yl)-2-phenoxypropanoate (10a). Compound 10a
(35 mg, 60%) as
7.96e7.94 (m, 2H, ArH), 7.59 (s, 1H, ArH), 7.40e7.35 (m, 4H, ArH),
a
colorless oil; 1H NMR (300 MHz, CDCl3)
d
solid; mp: 35e38 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.98e7.95 (m,
7.25e7.19 (m, 3H, ArH), 6.92 (t, 1H, ArH, J ¼ 7.4 Hz), 6.83e6.80 (m,
2H, ArH), 4.84e4.80 (m, 1H, CH), 3.71 (s, 3H, CH3), 3.33 (d, 2H, CH2,
J ¼ 5.7 Hz), 2.96 (t, 2H, CH2, J ¼ 7.3 Hz), 2.62 (t, 2H, CH2, J ¼ 7.0 Hz),
2.28 (s, 3H, CH3), 2.26e2.21 (m, 2H, CH2); HRMS-ESIþ: C30H28N2O5
calcd [M þ H]þ 496.1998, found 496.1985.
2H, ArH), 7.52 (s, 1H, ArH), 7.42e7.36 (m, 4H, ArH), 7.23e7.20 (d,
1H, ArH, J ¼ 7.5 Hz), 4.39e4.36 (m,1H, CH), 4.32e4.27 (m, 2H, CH2),
3.56 (br, 1H, OH), 3.25 (dd, 1H, CH, J ¼ ꢁ13.8, 4.5), 2.99e2.94 (m,
3H, CH2, CH), 2.62 (t, 2H, CH2, J ¼ 7.3 Hz), 2.44e2.39 (m, 1H, CH),
2.30 (s, 3H, CH3), 2.28 (m, 2H, CH2), 0.91 (d, 3H, CH3, J ¼ 6.9 Hz),
0.87 (d, 3H, CH2, J ¼ 7.2 Hz); HRMS-ESIþ: C29H31N3O6 calcd
[M þ H]þ 518.2291, found 518.2287.
6.1.12.2. (S)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
benzo[d]oxazol-5-yl)-2-(pyridin-3-yloxy)propanoate (10b). Compo-
und 10b (49 mg, 82%) as a transparence oil; 1H NMR (300 MHz,
6.1.9. (S)-3-((R)-2-Hydroxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-
yl)propyl)benzo[d]oxazol-5-yl)propanoyl)-4-isopropyl oxazolidin-
2-one ((S,S)-8)
CDCl3) d 8.28 (s, 2H, ArH), 8.03e7.99 (m, 2H, ArH), 7.63 (s, 1H, ArH),
7.45e7.43 (m, 4H, ArH), 7.32e7.16 (m, 3H, ArH), 4.92e4.88 (m, 1H,
CH), 3.79 (s, 3H, CH3), 3.42 (d, 2H, CH2, J ¼ 6.6 Hz), 3.03 (t, 2H, CH2,
J ¼ 7.5 Hz), 2.68 (t, 2H, CH2, J ¼ 6.9 Hz), 2.35 (s, 3H, CH3), 2.35e2.27
(m, 2H, CH2); HRMS-ESIþ: C29H27N3O5 calcd [M þ H]þ 497.1951,
found 497.1964.
Compound (S,S)-8 (1.341 g, 62.4%)asawhitesolid; mp:36e38 ꢀC;
1H NMR (300 MHz, CDCl3)
d 7.98e7.95 (m, 2H, ArH), 7.51 (s,1H, ArH),
7.43e7.36 (m, 4H, ArH), 7.22 (d, 1H, ArH, J ¼ 8.4 Hz), 4.39e4.35 (m,
1H, CH), 4.32e4.27 (m, 2H, CH2), 3.56 (br, 1H, OH), 3.25 (dd, 1H, CH,
J ¼ ꢁ13.6 Hz, 3.9 Hz), 2.99e2.91 (m, 3H, CH2, CH), 2.62 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.45e2.40(m,1H,CH), 2.30 (s, 3H,CH3), 2.30e2.21 (m, 2H,
CH2), 0.91 (d, 3H, CH3, J ¼ 6.9 Hz), 0.88 (d, 3H, CH3, J ¼ 7.2 Hz); HRMS-
ESIþ: C29H31N3O6 calcd [M þ H]þ 518.2291, found 518.2283.
6.1.12.3. (S)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
benzo[d]oxazol-5-yl)-2-(quinolin-4-yloxy)propanoate (10c). Comp-
ound 10c (13 mg, 19%) as a white solid; mp: 75e77 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
8.73 (d, 1H, ArH, J ¼ 5.4 Hz), 8.33 (d, 1H, ArH,
J ¼ 8.4 Hz), 8.09 (d, 1H, ArH, J ¼ 7.8 Hz), 8.02e7.98 (m, 2H, ArH), 7.76
(t, 1H, ArH, J ¼ 8.2 Hz), 7.71 (s, 1H, ArH), 7.60 (t, 1H, ArH, J ¼ 6.9 Hz),
7.48e7.45 (m, 4H, ArH), 7.33 (d, 1H, ArH, J ¼ 9.0 Hz), 6.60 (d, 1H,
ArH, J ¼ 6.0 Hz), 5.18e5.14 (m, 1H, CH), 3.98 (s, 3H, CH3), 3.58 (d, 2H,
CH2, J ¼ 6.0 Hz), 3.02 (t, 2H, CH2, J ¼ 7.3 Hz), 2.67 (t, 2H, CH2,
J ¼ 7.1 Hz), 2.33 (s, 3H, CH3), 2.33e2.28 (m, 2H, CH2); 13C NMR
6.1.10. (R)-Methyl 2-hydroxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-
yl)propyl)benzo[d]oxazol-5-yl)propanoate ((R)-9)
A 2.5 M EtMgBr/ether solution (3.7 mL, 9.28 mmol) was added
slowly into 30 mL dry MeOH at ꢁ10 ꢀC. After addition of EtMgBr,
a solution of compound (R,R)-8 (1.20 g, 4.64 mmol) in dry MeOH
(15 mL) was added in one portion. The mixture was stirred for
10 min and was quenched with a saturate NH4Cl aqueous (50 mL).
MeOH was removed in vacuum and the residue water layer was
extracted with 50 mL ethyl acetate. Organic layer was dried over
anhydrous Na2SO4. The solvent was concentrated and the crude
product was purified over silica gel column eluting with petroleum
ether/ethyl acetate (3:1) to give compound (R)-9 (0.697 g, 71.5%) as
a sticky colorless oil which solidified at 4 ꢀC; mp: 68e72 ꢀC; 1H
(125 MHz, CDCl3)
d 170.3, 167.7, 160.7, 159.7, 150.8, 150.2, 149.0,
144.0, 141.9, 135.1, 131.8, 130.3, 129.9, 128.8, 128.5, 127.9, 126.4,
126.0, 125.2, 122.1, 121.3, 120.4, 110.5, 101.1, 77.8, 52.8, 39.0, 29.9,
28.0, 26.1, 25.2, 10.3; HRMS-ESIþ: C33H29N3O5 calcd [M þ H]þ
548.2185, found 548.2174.
6.1.12.4. (S)-Methyl 2-(4-fluorophenoxy)-3-(2-(3-(5-methyl-2-pheny-
loxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10d). Compound
10d (28 mg, 46%) as a white sticky oil; 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d 7.98e7.95 (m, 2H, ArH), 7.48e7.47 (d, 1H,
ArH, J ¼ 0.9 Hz), 7.42e7.39 (m, 3H, ArH), 7.36 (d, 1H, ArH, J ¼ 7.8 Hz),
7.13 (dd, 1H, ArH, J ¼ 8.1 Hz, 1.5 Hz), 4.49e4.46 (m, 1H, CH), 3.77 (s,
3H, CH3), 3.13 (dd, dd, 2H, CH2, J ¼ ꢁ13.6 Hz, 6.3 Hz, 4.5 Hz), 2.96 (t,
2H, CH2, J ¼ 7.6 Hz), 2.62 (t, 2H, CH2, J ¼ 7.2 Hz), 2.30 (s, 3H, CH3),
2.30e2.23 (m, 2H, CH2); HRMS-ESIþ: C24H24N2O5 calcd [M þ H]þ
421.1763, found 421.1766.
d 8.11 (m, 2H, ArH), 7.63 (s, 1H, ArH), 7.50 (m, 3H, ArH), 7.43 (d, 1H,
ArH, J ¼ 8.7 Hz), 7.26 (d, 1H, ArH, J ¼ 7.8 Hz), 6.95 (m, 2H, ArH), 6.81
(m, 2H, ArH), 4.82e4.78 (m, 1H, ArH), 3.78 (s, 3H, CH3), 3.37 (d, 2H,
CH2, J ¼ 5.7 Hz), 3.05 (br, 2H, CH2), 2.76 (br, 2H, CH2), 2.38 (s, 3H, CH3),
2.38e2.29 (m, 2H, CH2); HRMS-ESIþ: C30H27FN2O5 calcd [M þ H]þ
515.1982, found 515.1970.

W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
3645
6.1.12.5. (S)-Methyl 2-(3-fluorophenoxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10e). Com-
pound 10e (32 mg, 87%) as a colorless oil; 1H NMR (300 MHz,
6.1.12.11. (S)-Methyl 2-(3-iodophenoxy)-3-(2-(3-(5-methyl-2-phenyl-
oxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10k). Compo-
und 10k (37 mg, 50%) as a colorless oil; mp: 50e52 ꢀC; 1H NMR
CDCl3)
d
8.06 (m, 2H, ArH), 7.63 (s, 1H, ArH), 7.47e7.42 (m, 4H,
(300 MHz, CDCl3) d 8.02e7.97 (m, 2H, ArH), 7.58 (s, 1H, ArH),
ArH), 7.24e7.18 (m, 2H, ArH), 6.72e6.58 (m, 3H, ArH), 4.87e4.83
(m, 1H, CH), 3.78 (s, 3H, CH3), 3.38 (d, 2H, CH2, J ¼ 6.0 Hz), 3.04 (br,
2H, CH3), 2.72 (br, 2H, CH2), 2.36 (s, 3H, CH3), 2.36e2.24 (m, 2H,
CH2); HRMS-ESIþ: C30H27FN2O5 calcd [M þ H]þ 515.1982, found
515.1963.
7.42e7.36 (m, 5H, ArH), 7.21e7.17 (m, 2H, ArH), 6.93 (t, 1H, ArH,
J ¼ 9.6 Hz), 6.78e6.74 (m, 1H, ArH), 4.81e4.76 (m, 1H, CH), 3.73 (s,
3H, CH3), 3.32 (d, 2H, CH2, J ¼ 7.8 Hz), 2.98 (t, 2H, CH2, J ¼ 7.4 Hz),
2.65 (t, 2H, CH2, J ¼ 7.1 Hz), 2.30 (s, 3H, CH3), 2.35e2.22 (m, 2H,
CH2); HRMS-ESIþ: C30H27IN2O5 calcd [M þ H]þ 623.1043, found
623.1032.
6.1.12.6. (S)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
benzo[d]oxazol-5-yl)-2-(3,4,5-trifluorophenoxy)propanoate (10f).
Compound 10f (41 mg, 74%) as a white solid; mp: 55e58 ꢀC; 1H
6.1.12.12. (S)-Methyl 2-(4-iodophenoxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10l). Comp-
ound 10l (58 mg, 80%) as a white solid; mp: 60e63 ꢀC; 1H NMR
NMR (300 MHz, CDCl3)
d 7.99e7.96 (m, 2H, ArH), 7.54 (s, 1H, ArH),
7.42e7.37 (m, 4H, ArH), 7.18 (d, 1H, ArH, J ¼ 8.7 Hz), 6.46e6.41 (m,
2H, ArH), 4.72e4.67 (m, 1H, CH), 3.74 (s, 3H, CH3), 3.31(d, 2H, CH2,
J ¼ 5.4 Hz), 2.98 (t, 2H, CH2, J ¼ 7.7 Hz), 2.65 (t, 2H, CH2, J ¼ 6.6 Hz),
2.31 (s, 3H, CH3), 2.30e2.25 (m, 2H, CH2); HRMS-ESIþ:
C30H25F3N2O5 calcd [M þ H]þ 550.1716, found 550.1724.
(300 MHz, CDCl3) d 7.97e7.93 (m, 2H, ArH), 7.58 (s,1H, ArH), 7.49 (d,
2H, ArH, J ¼ 8.4 Hz), 7.14e7.34 (m, 4H, ArH), 7.19 (d, 1H, ArH,
J ¼ 8.4 Hz), 6.59 (d, 2H, ArH, J ¼ 8.4 Hz), 4.79e4.75 (m, 1H, CH), 3.71
(s, 3H, CH3), 3.32 (d, 2H, CH2, J ¼ 6.0 Hz), 2.97 (t, 2H, CH2, J ¼ 7.2 Hz),
2.64 (t, 2H, CH2, J ¼ 7.4 Hz), 2.29 (s, 3H, CH3), 2.27e2.19 (m, 2H,
CH2); HRMS-ESIþ: C30H27IN2O5 calcd [M þ H]þ 623.1043, found
623.1032.
6.1.12.7. (S)-Methyl 2-(4-bromophenoxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10g). Com-
pound 10g (43 mg, 78%) as a white solid; mp: 45e49 ꢀC; 1H NMR
6.1.12.13. (S)-Methyl
3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
(300 MHz, CDCl3)
d
7.99e7.96 (m, 2H, ArH), 7.57 (s, 1H, ArH),
benzo[d]oxazol-5-yl)-2-(4-(trifluoromethyl)phenoxy)propanoate (10m)
7.42e7.36 (m, 4H, ArH), 7.31 (d, 2H, ArH, J ¼ 8.7 Hz), 7.18 (d, 1H, ArH,
J ¼ 9.0 Hz), 6.70 (d, 2H, ArH, J ¼ 9.6 Hz), 4.79e4.74 (m, 1H, CH), 3.72
(s, 3H, CH3), 3.32 (d, 2H, CH2, J ¼ 6.9 Hz), 2.97 (t, 2H, CH2, J ¼ 7.2 Hz),
2.64 (t, 2H, CH2, J ¼ 7.1 Hz), 2.30 (s, 3H, CH3), 2.30e2.19 (m, 2H,
CH2); HRMS-ESIþ: C30H27BrN2O5 calcd [M þ H]þ 575.1182, found
575.1191.
.Compound 10m (50 mg, 70%) as a pale white solid; mp: 62e65 ꢀC; 1H
NMR (300 MHz, CDCl3) d 8.00e7.99 (m, 2H, ArH), 7.60 (s, 1H, ArH),
7.50 (d, 2H, ArH, J ¼ 8.1 Hz), 7.46e7.39 (m, 4H, ArH), 7.22 (d, 1H,
ArH, J ¼ 8.4 Hz), 6.90 (d, 2H, ArH, J ¼ 8.7 Hz), 4.91e4.87 (m, 1H,
CH), 3.75 (s, 3H, CH3), 3.38 (d, 2H, CH2, J ¼ 6.9 Hz), 3.00 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.67 (t, 2H, CH2, J ¼ 6.9 Hz), 2.32 (s, 3H, CH3), 2.32e2.24
(m, 2H, CH2); HRMS-ESIþ: C31H27F3N2O5 calcd [M þ H]þ 564.1872,
found 564.1885.
6.1.12.8. (S)-Methyl 2-(2-bromophenoxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10h). Com-
pound 10h (54 mg, 80%) as a white solid; mp: 50e54 ꢀC; 1H NMR
6.1.12.14. (S)-Methyl 2-(4-cyanophenoxy)-3-(2-(3-(5-methyl-2-phe-
(300 MHz, CDCl3)
d
7.98e7.95 (m, 2H, ArH), 7.66 (s, 1H, ArH), 7.52
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10n). Com-
(d, 1H, ArH, J ¼ 7.5 Hz), 7.42e7.31 (m, 5H, ArH), 7.15 (t, 1H, ArH,
J ¼ 8.7 Hz), 6.84 (t, 1H, ArH, J ¼ 8.1 Hz), 6.65 (d, 1H, ArH, J ¼ 8.4 Hz),
4.86e4.81 (m, 1H, CH), 3.71 (s, 3H, CH3), 3.41 (d, 2H, CH2, J ¼ 7.0 Hz),
2.97 (t, 2H, CH2, J ¼ 7.5 Hz), 2.63(t, 2H, CH2, J ¼ 7.1 Hz), 2.29 (s, 3H,
CH3), 2.29e2.24 (m, 2H, CH2); HRMS-ESIþ: C30H27BrN2O5 calcd
[M þ H]þ 575.1182, found 575.1188.
pound 10n (44 mg, 71%) as
a
bubble-shaped solid; mp:
8.06e8.05 (m, 2H, ArH),
72e76 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.62 (s, 1H, ArH), 7.59 (d, 2H, ArH, J ¼ 9.0 Hz), 7.48e7.43 (m, 4H,
ArH), 7.25 (d, 1H, ArH, J ¼ 8.4 Hz), 6.92 (d, 2H, ArH, J ¼ 9.3 Hz),
4.95e4.91 (m, 1H, CH), 3.80 (s, 3H, CH3), 3.42 (d, 2H, CH2,
J ¼ 6.3 Hz), 3.04 (t, 2H, CH2, J ¼ 6.8 Hz), 2.72e2.70 (m, 2H, CH2),
2.37 (m, 5H, CH3, CH2); HRMS-ESIþ: C31H27N3O5 calcd [M þ H]þ
522.1029, found 522.1011.
6.1.12.9. (S)-Methyl 2-(4-chlorophenoxy)-3-(2-(3-(5-methyl-2-phenyl-
oxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10i). Compound
10i (51 mg, 80%) as a white solid; mp: 32e34 ꢀC; 1H NMR (300 MHz,
6.1.12.15. (S)-Methyl 2-(4-acetylphenoxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10o). Com-
pound 10o (30 mg, 60%) as a white solid; mp: 67e70 ꢀC; 1H NMR
CDCl3)
d 7.98e7.95 (m, 2H, ArH), 7.57 (s, 1H, ArH), 7.42e7.36 (m, 4H,
ArH), 7.19 (d, 1H, ArH, J ¼ 8.7 Hz), 7.17 (d, 2H, ArH, J ¼ 9.6 Hz), 6.74 (d,
2H, ArH, J ¼ 8.4 Hz), 4.79e4.74 (m, 1H, CH), 3.72 (s, 3H, CH2), 3.32 (d,
2H, CH2, J ¼ 6.6 Hz), 2.98 (t, 2H, CH2, J ¼ 7.5 Hz), 2.63 (t, 2H, CH2,
J ¼ 7.1 Hz), 2.30 (s, 3H, CH3), 2.29e2.24 (m, 2H, CH2); HRMS-ESIþ:
C30H27ClN2O5 calcd [M þ H]þ 531.1687, found 531.1674.
(300 MHz, CDCl3)
d 7.97e7.94 (m, 2H, ArH), 7.86 (d, 2H, ArH,
J ¼ 8.4 Hz), 7.57e7.36 (m, 5H, ArH), 7.20 (d, 1H, ArH, J ¼ 9.6 Hz), 6.85
(d, 2H, ArH, J ¼ 9.3 Hz), 4.92e4.88 (m, 1H, CH), 3.72 (s, 3H, CH3),
3.36 (d, 2H, CH2, J ¼ 6.3 Hz), 2.97 (t, 2H, CH2, J ¼ 7.4 Hz), 2.63 (t, 2H,
CH2, J ¼ 7.1 Hz), 2.51 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.29e2.21 (m,
2H, CH2); HRMS-ESIþ: C37H30N2O6 calcd [M þ H]þ 539.2182, found
539.2192.
6.1.12.10. (S)-Methyl 2-(2,4-dichlorophenoxy)-3-(2-(3-(5-methyl-2-
phenyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10j). Co-
mpound 10j (22 mg, 33%) as a colorless oil; 1H NMR (300 MHz,
CDCl3)
d
7.97e7.94 (m, 2H, ArH), 7.61 (s, 1H, ArH), 7.41e7.36 (m, 4H,
6.1.12.16. (S)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)propyl)
ArH), 7.32 (d, 1H, ArH, J ¼ 2.4 Hz), 7.27 (d, 1H, ArH, J ¼ 9.6 Hz), 7.06
(dd, 1H, ArH, J ¼ 9.0 Hz, 2.4 Hz), 6.61 (d, 1H, ArH, J ¼ 8.4 Hz),
4.81e4.77 (m,1H, CH), 3.71 (s, 3H, CH2), 3.39 (d, 2H, CH2, J ¼ 6.3 Hz),
2.97 (t, 2H, CH2, J ¼ 7.4 Hz), 2.62 (t, 2H, CH2, J ¼ 6.9 Hz), 2.29 (s, 3H,
benzo[d]oxazol-5-yl)-2-(p-tolyloxy)propanoate
10p (34 mg, 60%) as a colorless oil; 1H NMR (300 MHz, CDCl3)
8.02e8.01 (m, 2H, ArH), 7.59 (s, 1H, ArH), 7.48e7.42 (m, 3H, ArH),
7.36 (d, 1H, ArH, J ¼ 7.8 Hz), 7.21 (d, 1H, ArH, J ¼ 10 Hz), 7.01 (d, 2H,
ArH, J ¼ 8.1 Hz), 6.72 (d, 2H, ArH, J ¼ 8.7 Hz), 4.80e4.75 (m, 1H, CH),
3.71 (s, 3H, CH3), 3.31 (d, 2H, CH2, J ¼ 5.4 Hz), 2.97 (t, 2H, CH2,
J ¼ 7.2 Hz), 2.67 (t, 2H, CH2, J ¼ 6.8 Hz), 2.31 (s, 3H, CH3), 2.31e2.23
(m, 2H, CH2), 2.23 (s, 3H, CH3); HRMS-ESIþ: C31H30N2O5 calcd
[M þ H]þ 510.2155, found 510.2166.
(10p). Compound
d
CH3), 2.29e2.24 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3)
d 170.0,
166.8, 158.9, 151.7, 149.6, 143.4, 141.1, 134.5, 131.3, 129.8, 129.2, 128.1,
127.3, 126.9, 126.4, 125.8, 125.4, 124.0, 120.0, 114.6, 109.5, 78.5, 52.0,
38.5, 27.4, 25.4, 24.5, 9.7; HRMS-ESIþ: C30H26Cl2N2O5 calcd
[M þ H]þ 565.1297, found 565.1312.

3646
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
6.1.12.17. (S)-Methyl 2-(4-methoxyphenoxy)-3-(2-(3-(5-methyl-2-ph-
enyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl) propanoate (10q). Com-
pound 10q (25 mg, 40%) as a white sticky oil; 1H NMR (300 MHz,
7.42e7.40 (m, 3H, ArH), 7.36 (d, 1H, ArH, J ¼ 8.4 Hz), 7.14 (d, 1H, ArH,
J ¼ 8.1 Hz), 4.01e3.96 (m,1H, CH), 3.73 (s, 3H, CH3), 3.34 (s, 3H, CH3),
3.17e3.02 (m, 2H, CH2), 2.97 (t, 2H, CH2, J ¼ 7.2 Hz), 2.64 (t, 2H, CH2,
J ¼ 6.9 Hz), 2.30 (s, 3H, CH3), 2.30e2.25 (m, 2H, CH2); 13C NMR
CDCl3) d 8.03e8.01 (m, 2H, ArH), 7.64 (s, 1H, ArH), 7.47e7.42 (m, 4H,
ArH), 7.26 (d,1H, ArH, J ¼ 8.7 Hz), 6.81 (s, 4H, ArH), 4.80e4.76 (m,1H,
CH), 3.77 (s, 6H, 2CH3), 3.36 (d, 2H, CH2, J ¼ 6.0 Hz), 3.03 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.69 (t, 2H, CH2, J ¼ 7.0 Hz), 2.32 (m, 2H, CH2), 2.33 (s, 3H,
CH3); HRMS-ESIþ: C31H30N2O6 calcd [M þ H]þ 527.2182, found
527.2163.
(125 MHz, CDCl3) d 171.9, 166.6, 158.9, 149.3, 143.5, 141.0, 134.3,
132.5,129.3,128.1,125.5,125.4,119.5,109.3, 81.3, 57.9, 51.4, 38.5, 27.4,
25.4, 24.4, 9.7; HRMS-ESIþ: C25H26N2O5 calcd [M þ H]þ 434.1842,
found 434.1855.
6.1.14. (S)-Methyl 2-isopropoxy-3-(2-(3-(5-methyl-2-
6.1.12.18. (S)-Methyl
phenyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10r). Com-
pound 10r (31 mg, 47%) as a colorless oil; H NMR (300 MHz, CDCl3)
2-(4-tert-butylphenoxy)-3-(2-(3-(5-methyl-2-
phenyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (12b)
Compound 12b (20 mg, 36%) as a yellow oil; 1H NMR (300 MHz,
1
CDCl3) d 7.97e7.95 (m, 2H, ArH), 7.52 (s, 1H, ArH), 7.41e7.39 (m, 3H,
d
7.98e7.95 (m, 2H, ArH), 7.58 (s,1H, ArH), 7.42e7.39 (m, 3H, ArH), 7.36
ArH), 7.35 (d, 1H, ArH, J ¼ 8.4 Hz), 7.16 (d, 1H, ArH, J ¼ 7.8 Hz),
4.10e4.06 (m, 1H, CH), 3.71 (s, 3H, CH3), 3.48 (q, 1H, CH, J ¼ 6.0 Hz),
3.06 (dd, dd, 2H, CH2, J ¼ ꢁ13.5 Hz, 4.2 Hz, 4.5 Hz), 2.97 (t, 2H, CH2,
J ¼ 7.3 Hz), 2.63 (t, 2H, CH2, J ¼ 6.9 Hz), 2.29 (s, 3H, CH3), 2.29e2.18
(m, 2H, CH2), 1.13 (d, 3H, CH3, J ¼ 6.0 Hz), 0.91 (d, 3H, CH3,
(d, 1H, ArH, J ¼ 8.4 Hz), 7.24 (d, 1H, ArH, J ¼ 6.9 Hz), 7.22 (d, 2H, ArH,
J ¼ 8.7 Hz), 6.74 (d, 2H, ArH, J ¼ 9.3 Hz), 4.80e4.75 (m, 1H, CH), 3.73 (s,
3H, CH3), 3.31 (d, 2H, CH, J ¼ 5.1 Hz), 2.96 (t, 2H, CH2, J ¼ 7.4 Hz), 2.62 (t,
2H, CH2, J ¼ 7.2 Hz), 2.31e2.22 (m, 2H, CH2), 2.29 (s, 3H, CH3), 1.24 (s,
9H, 3CH3); HRMS-ESIþ: C34H36N2O5 calcd [M þ H]þ 553.2702, found
553.2710.
J ¼ 6.3 Hz); 13C NMR (125 MHz, CDCl3)
d 173.5, 167.2, 159.6, 149.9,
144.0, 141.6, 135.2, 133.7, 129.8, 128.8, 128.0, 126.2, 126.1, 120.4,
109.8, 78.5, 72.7, 52.1, 39.8, 28.1, 26.1, 25.1, 22.7, 21.5, 10.3; HRMS-
ESIþ: C27H30N2O5 calcd [M þ H]þ 463.2233, found 463.2217.
6.1.12.19. (S)-Methyl 2-(biphenyl-4-yloxy)-3-(2-(3-(5-methyl-2-phe-
nyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate
(10s). Compound 10s (35 mg, 51%) as a white solid; mp: 60e65 ꢀC;
6.1.15. General synthesis of compounds 11, 13 and 15
1H NMR (300 MHz, CDCl3)
d
8.00e7.99 (m, 2H, ArH), 7.61 (s, 1H,
Compounds 10, 12 and 14 (0.05 mmol) were dissolved in 1 mL
ethanol, and then the aqueous of LiOH$H2O (0.25 mmol, 1 mL) was
added. The mixture was stirred for 2 h at room temperature. The
ethanol was removed in vacuum. The water residue was acidified
with 1 N HCl to pH ¼ 4, and extracted with ethyl acetate (5 mL).
Organic layer was dried over anhydrous Na2SO4. The solvent was
concentrated, and the crude product was purified over silica
column eluting with 90% CH2Cl2/10% MeOH to give final
compounds 11, 13 and 15.
ArH), 7.50e7.36 (m, 9H, ArH), 7.30e7.22 (m, 3H, ArH), 6.89 (d, 2H,
ArH, J ¼ 8.4 Hz), 4.88e4.84 (m, 1H, CH), 3.75 (s, 3H, CH3), 3.36 (d,
2H, CH2, J ¼ 5.4 Hz), 2.98 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.30 (m,
5H, CH3, CH2); HRMS-ESIþ: C36H32N2O5 calcd [M þ H]þ 573.2389,
found 573.2370.
6.1.12.20. (S)-Methyl 2-(4-(benzyloxy)phenoxy)-3-(2-(3-(5-methyl-2-
phenyloxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (10t). Co-
mpound 10t (16 mg, 22%) as a colorless oil; 1H NMR (300 MHz,
CDCl3)
d
7.98e7.94 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.42e7.29 (m, 9H,
6.1.15.1. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
ArH), 7.21 (d,1H, ArH, J ¼ 8.7 Hz), 6.82 (d, 2H, ArH, J ¼ 9.0 Hz), 6.74 (d,
2H, ArH, J ¼ 9.3 Hz), 4.96 (s, 2H, CH2), 4.74e4.70 (m, 1H, CH), 3.72 (s,
3H, CH3), 3.30 (d, 2H, CH2, J ¼ 6.6 Hz), 2.98 (t, 2H, CH2, J ¼ 7.4 Hz),
2.63 (t, 2H, CH2, J ¼ 7.2 Hz), 2.31e2.24 (m, 5H, CH3, CH2); 13C NMR
oxazol-5-yl)-2-phenoxypropanoic acid (11a). Compound 11a
(15 mg, 60%) as sticky oil; 1H NMR (300 MHz, DMSO-d6)
d 7.87e7.84
(m, 2H, ArH), 7.59 (s,1H, ArH), 7.52 (d,1H, ArH, J ¼ 8.1 Hz), 7.45e7.44
(m, 3H, ArH), 7.26 (d,1H, J ¼ 8.4 Hz), 7.20 (t, 2H, ArH, J ¼ 7.8 Hz), 6.87
(t,1H, ArH, J ¼ 7.2 Hz), 6.80 (d, 2H, ArH, J ¼ 8.1 Hz), 4.96e4.92 (m,1H,
CH), 3.32e3.22 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.3 Hz), 2.55 (t, 2H,
CH2, J ¼ 6.9 Hz), 2.27 (s, 3H, CH3), 2.11e2.06 (m, 2H, CH2); 13C NMR
(125 MHz, CDCl3) d 171.2, 166.7, 153.3, 151.5, 149.5, 143.4, 141.1, 136.6,
134.5, 132.0, 129.2, 128.1, 128.0, 127.4, 127.3, 126.9, 125.5, 125.4, 119.8,
116.1, 115.3, 109.5, 78.6, 70.0, 51.8, 38.6, 27.4, 25.5, 24.5, 9.68; HRMS-
ESIþ: C37H35N2O6 calcd [M þ H]þ 603.2495, found 603.2480.
(125 MHz, DMSO-d6)
d 171.5, 166.2, 157.5, 155.1, 147.2, 143.1, 141.9,
138.1, 137.1, 130.9, 130.1, 129.9, 129.5, 129.0, 128.1, 127.5, 125.0, 121.3,
117.1, 119.3, 109.2, 77.1, 37.0, 27.2, 25.1, 24.0, 9.7; HRMS-ESIꢁ:
C29H26N2O5 calcd [M ꢁ H]ꢁ 481.1763, found 481.1755.
6.1.12.21. (R)-Methyl 3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)pro-
pyl)benzo[d]oxazol-5-yl)-2-(4-(trifluoromethyl)phenoxy)propano-
ate (14a). Compound 14a (40 mg, 60%) as a pale white solid; mp:
72e74 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.98e7.96 (m, 2H, ArH),
6.1.15.2. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
oxazol-5-yl)-2-(pyridin-3-yloxy) propanoic acid (11b). Compound
11b (22 mg, 90%) as a yellow solid; mp: 48e52 ꢀC; 1H NMR
7.58 (s, 1H, ArH), 7.48 (d, 2H, ArH, J ¼ 8.7 Hz), 7.42e7.37 (m, 4H,
ArH), 7.20 (d, 1H, ArH, J ¼ 7.2 Hz), 6.88 (d, 2H, ArH, J ¼ 8.4 Hz),
4.89e4.84 (m, 1H, CH), 3.73 (s, 3H, CH3), 3.35 (d, 2H, CH2,
J ¼ 6.3 Hz), 2.98 (t, 2H, CH2, J ¼ 7.2 Hz), 2.64 (t, 2H, CH2, J ¼ 6.4 Hz),
2.30 (s, 3H, CH3), 2.30e2.25 (m, 2H, CH2); HRMS-ESIþ:
C31H27F3N2O5 calcd [M þ H]þ 564.1872, found 564.1889.
(300 MHz, DMSO-d6) d 8.20 (s, 1H, ArH), 8.12 (s, 1H, ArH), 7.87e7.84
(m, 2H, ArH), 7.61 (s, 1H, ArH), 7.52 (d, 1H, ArH, J ¼ 8.1 Hz),
7.46e7.44 (m, 3H, ArH), 7.28e7.27 (m, 3H, ArH), 5.18e5.14(m, 1H,
CH), 3.29 (dd, dd, 2H, CH2, J ¼ ꢁ14.1 Hz, 8.4 Hz, 4.2 Hz), 2.93 (t, 2H,
CH2, J ¼ 7.2 Hz), 2.55 (t, 2H, CH2, J ¼ 7.1 Hz), 2.27 (s, 2H, CH3), 2.10
(qui, 2H, CH2, J ¼ 7.2 Hz, 7.1 Hz); 13C NMR (125 MHz, DMSO-d6)
6.1.13. (S)-Methyl 2-methoxy-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl)propanoate (12a)
d
171.3, 166.9, 158.3, 154.0, 149.1, 144.0, 142.0, 141.0, 138.0, 135.3,
Under nitrogen atmosphere, iodomethane (0.075 mL,1.19 mmol)
was added, through syringe, into a mixture of compound (S)-9
(0.050 g, 0.119 mmol) and Ag2O (0.041 g, 0.178 mmol) in dry aceto-
nitrile (2 mL). The resulting mixturewas stirredat 45 ꢀC for 12 h. The
solution was filtered and the filtrate was concentrated. The residue
was purified with silica column eluting with petroleum ether/ethyl
acetate (3:1) to give compound 12a (27 mg, 52%) as a colorless oil; 1H
134.9,132.7,129.9,128.9,127.2,126.0,125.3,124.1,121.7,119.8,109.9,
76.8, 37.6, 27.0, 25.4, 21.0, 9.7; HRMS-ESIꢁ: C28H25N3O5 calcd
[M ꢁ H]ꢁ 482.1716, found 482.1724.
6.1.15.3. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
oxazol-5-yl)-2-(quinolin-4-yloxy) propanoic acid (11c). Compound
11c (24 mg, 90%) as sticky oil; 1H NMR (300 MHz, DMSO-d6)
NMR (300 MHz, CDCl3)
d
7.98e7.96 (m, 2H, ArH), 7.50 (s, 1H, ArH),
d
8.93e8.91 (d,1H, ArH, J ¼ 6.0 Hz), 8.30 (d,1H, ArH, J ¼ 8.1 Hz), 8.08

W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
3647
(d, 1H, ArH, J ¼ 8.4 Hz), 7.94 (t, 1H, ArH, J ¼ 7.5 Hz), 7.88e7.85 (m,
2H, ArH), 7.78e7.73 (m, 2H, ArH), 7.58 (d, 1H, ArH, J ¼ 8.1 Hz),
7.48e7.46 (m, 3H, ArH), 7.40 (d,1H, ArH, J ¼ 8.4 Hz), 7.21 (d,1H, ArH,
J ¼ 5.7 Hz), 5.68 (m, 1H, CH), 3.59e3.44 (m, 2H, CH2), 2.94 (t, 2H,
CH2, J ¼ 7.2 Hz), 2.56 (t, 2H, CH2, J ¼ 6.9 Hz), 2.27 (s, 3H, CH3),
6.1.15.8. (S)-2-(2-Bromophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11h). Compound
11h (23 mg, 81%) as a white solid; mp: 57e60 ꢀC; 1H NMR (300 MHz,
DMSO-d6)
d 7.87e7.85 (m, 2H, ArH), 7.67 (s, 1H, ArH), 7.54e7.45 (m,
5H, ArH), 7.33 (d, 1H, ArH, J ¼ 6.6 Hz), 7.24 (t, 1H, ArH, J ¼ 7.2 Hz),
6.87e6.81 (m, 2H, ArH), 5.07e5.04 (m, 1H, CH), 3.38e3.26 (m, 2H,
CH2), 2.93 (t, 2H, CH2, J ¼ 6.8 Hz), 2.56 (t, 2H, CH2, J ¼ 7.4 Hz), 2.28 (s,
3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.2 Hz, 7.2 Hz); 13C NMR (125 MHz,
2.14e2.07 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6)
d 170.3,
167.4, 158.7, 149.7, 144.5, 141.5, 137.5, 135.8, 135.4, 132.8, 131.1, 130.0,
129.4, 126.6, 125.8, 122.7, 120.7, 120.4, 110.5, 103.1, 78.2, 37.7, 27.5,
25.9, 24.8, 22.5, 10.2; HRMS-ESIꢁ: C32H27N3O5 calcd [M ꢁ H]ꢁ
532.1872, found 532.1879.
DMSO-d6) d 170.9, 166.8, 158.3, 149.1, 144.0, 140.9, 137.0, 134.9, 133.1,
132.5, 130.6, 129.9, 128.9, 128.7, 127.1, 126.3, 125.4, 122.3, 120.2, 113.6,
110.9,109.7, 76.9, 37.8, 27.0, 25.4, 24.1, 9.7; HRMS-ESIꢁ: C29H25BrN2O5
calcd [M ꢁ H]ꢁ 559.0869, found 559.0861.
6.1.15.4. (S)-2-(4-Fluorophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (11d). Compound
11d (22 mg, 87%) as an off-white solid; mp: 58e60 ꢀC; 1H NMR
6.1.15.9. (S)-2-(4-Chlorophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11i). Compound 11i
(20 mg, 80%) as a white solid; mp: 157e162 ꢀC; 1H NMR (300 MHz,
(300 MHz, DMSO-d6) d 7.88e7.85 (m, 2H, ArH), 7.59 (s,1H, ArH), 7.52
(d, 1H, ArH, J ¼ 8.7 Hz), 7.47e7.45 (m, 3H, ArH), 7.26 (d, 1H, ArH,
J ¼ 8.7 Hz), 7.04 (t, 2H, ArH, J ¼ 9.0 Hz), 6.85e6.81 (m, 2H, ArH),
4.96e4.92 (m, 1H, CH), 3.32e3.17 (m, 2H, CH2), 2.93 (t, 2H, CH2,
J ¼ 7.2 Hz), 2.56 (t, 2H, CH2, J ¼ 7.2 Hz), 2.28 (s, 3H, CH3), 2.17 (qui,
DMSO-d6)
d 7.88e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.52 (d, 1H,
ArH, J ¼ 8.1 Hz), 7.46e7.44 (m, 3H, ArH), 7.26 (d, 3H, ArH, J ¼ 8.1 Hz),
6.85 (d, 2H, ArH, J ¼ 8.7 Hz), 5.02e4.98 (m, 1H, CH), 3.25 (dd, dd, 2H,
J ¼ ꢁ14.1 Hz, 8.7 Hz, 5.1 Hz), 2.93 (t, 2H, CH2, J ¼ 7.2 Hz), 2.56 (t, 2H,
CH2, J ¼ 7.1 Hz), 2.28 (s, 3H, CH3), 2.94 (qui, 2H, CH2, J ¼ 7.0 Hz,
2H, J ¼ 7.2 Hz, 7.1 Hz); 13C NMR (125 MHz, DMSO-d6)
d 171.6, 166.9,
158.3, 157.6, 155.7, 153.8, 149.1, 144.0, 140.9, 137.0, 134.9, 132.8, 130.7,
129.9, 128.9, 127.7, 127.2, 126.0, 125.4, 119.8, 116.3, 115.9, 115.7, 109.9,
77.1, 37.8, 27.0, 25.4, 24.1, 9.7; HRMS-ESIꢁ: C29H25FN2O5 calcd
[M ꢁ H]ꢁ 499.1669, found 499.1683.
7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 171.8, 167.3, 158.8, 156.8,
149.6,144.5,141.4, 135.4,133.2,130.4, 129.6, 129.4, 127.6, 126.4, 125.8,
125.2, 120.2, 117.1, 110.3, 77.1, 38.2, 27.5, 25.9, 24.6, 10.2; HRMS-ESIꢁ:
C29H25ClN2O5 calcd [M ꢁ H]ꢁ 515.1374, found 515.1387.
6.1.15.5. (S)-2-(3-Fluorophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11e). Compound 11e
6.1.15.10. (S)-2-(2,4-Dichlorophenoxy)-3-(2-(3-(5-methyl-2-pheny-
loxazol-4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11j). Com-
pound 11j (22 mg, 80%) as a white solid; mp: 148e150 ꢀC; 1H NMR
(21 mg, 88%) as sticky oil; 1H NMR (300 MHz, DMSO-d6)
d 7.89e7.87
(m, 2H, ArH), 7.61 (s, 1H, ArH), 7.54 (d, 1H, ArH, J ¼ 8.4 Hz),
7.48e7.46 (m, 3H, ArH), 7.30e7.22 (m, 2H, ArH), 6.76e6.69 (m, 3H,
ArH), 5.10e5.06 (m, 1H, CH), 3.35e3.20 (m, 2H, CH2), 2.95 (t, 2H,
CH2, J ¼ 7.8 Hz), 2.58 (t, 2H, CH2, J ¼ 7.2 Hz), 2.29 (s, 3H, CH3),
(300 MHz, DMSO-d6)
d 7.88e7.85 (m, 2H, ArH), 7.63 (s, 1H, ArH),
7.54e7.45 (m, 5H, ArH), 7.31e7.26 (m, 2H, ArH), 6.95 (d, 1H, ArH,
J ¼ 8.4 Hz), 5.14e5.10 (m, 1H, CH), 3.31 (dd, dd, 2H, CH2,
J ¼ ꢁ14.5 Hz, 8.0 Hz, 4.8 Hz), 2.93 (t, 2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H,
CH2, J ¼ 7.4 Hz), 2.28 (s, 3H, CH3), 2.09 (qui, 2H, CH2, J ¼ 6.9 Hz,
2.16e2.09 (m, 2H, CH3); 13C NMR (125 MHz, DMSO-d6)
d 171.4,
166.9, 158.3, 157.6, 154.7, 149.0, 144.1, 140.9, 137.7, 134.9, 132.9, 130.7,
129.9, 128.9, 127.1, 126.0, 125.4, 119.7, 115.9, 109.8, 76.7, 37.7, 27.0,
25.4, 24.2, 9.7; HRMS-ESIꢁ: C29H25FN2O5 calcd [M ꢁ H]ꢁ 499.1669,
found 499.1687.
7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 170.7, 166.9, 158.3, 152.0,
149.2, 144.0, 140.9, 137.1, 134.9, 132.5, 130.7, 129.9, 129.4, 128.9,
127.8, 127.6, 127.1, 126.2, 125.4, 124.8, 122.5, 120.1, 115.1, 109.8, 77.0,
37.7, 27.0, 25.5, 24.1, 9.7; HRMS-ESIꢁ: C29H24Cl2N2O5 calcd [M ꢁ H]ꢁ
549.0984, found 549.0965.
6.1.15.6. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
oxazol-5-yl)-2-(3,4,5-trifluorophenoxy) propanoic acid (11f).
Compound 11f (23 mg, 87%) as a white solid; mp: 182e186 ꢀC; 1H
6.1.15.11. (S)-2-(3-Iodophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11k). Compound
11k (26 mg, 85%) as a white solid; mp: 70e75 ꢀC; 1H NMR
NMR (300 MHz, DMSO-d6)
d 7.87e7.85 (m, 2H, ArH), 7.58 (s, 1H,
ArH), 7.54e7.51 (d, 1H, ArH, J ¼ 9.0 Hz), 7.47e7.45 (m, 3H, ArH), 7.25
(d, 1H, ArH, J ¼ 9.0 Hz), 6.90 (dd, 2H, ArH, J ¼ 9.9 Hz), 5.19e5.15 (m,
1H, CH), 3.35e3.28 (m, 1H, CH2), 3.20 (dd, 1H, CH2, J ¼ ꢁ14.1 Hz,
8.1 Hz), 2.93 (t, 2H, CH2, J ¼ 7.5 Hz), 2.56 (t, 2H, CH2, J ¼ 6.9 Hz), 2.28
(s, 3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.1 Hz, 7.2 Hz); 13C NMR
(300 MHz, DMSO-d6) d 7.89e7.87 (m, 2H, ArH), 7.61 (s,1H, ArH), 7.53
(d, 1H, ArH, J ¼ 8.1 Hz), 7.48e7.47 (m, 3H, ArH), 7.29e7.25 (m, 2H,
ArH), 7.19 (s,1H, ArH), 7.02 (t,1H, ArH, J ¼ 8.0 Hz), 6.88e6.85 (m,1H,
ArH), 5.03 (m, 1H, CH), 3.38e3.17 (m, 2H, CH2), 2.95 (t, 2H, CH2,
J ¼ 7.5 Hz), 2.58 (t, 2H, CH2, J ¼ 6.9 Hz), 2.30 (s, 3H, CH3), 2.14e2.10
(125 MHz, DMSO-d6)
d 170.9, 166.9, 158.3, 149.1, 144.0, 141.0, 137.0,
135.3, 134.9, 132.6, 130.6, 129.9, 128.9, 127.6, 127.2, 126.7, 125.9,
125.4, 123.3, 119.8, 115.5, 109.9, 100.5, 77.2, 37.0, 25.5, 24.2, 9.7;
HRMS-ESIꢁ: C29H23F3N2O5 calcd [M ꢁ H]ꢁ 535.1481, found
535.1496.
(m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6)
d 171.3, 166.8, 158.3,
149.1,144.0,140.9,134.9,132.9,131.2,129.9,128.9,127.1,126.0,125.3,
123.5, 119.7, 114.6, 109.8, 94.8, 76.6, 37.8, 27.0, 25.4, 24.1, 9.7; HRMS-
ESIꢁ: C29H24IN2O5 calcd [M ꢁ H]ꢁ 607.0730, found 607.0719.
6.1.15.7. (S)-2-(4-Bromophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (11g). Compound 11g
(22 mg, 80%) as a white solid; mp: 158e162 ꢀC; 1H NMR (300 MHz,
6.1.15.12. (S)-2-(4-Iodophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11l). Compound
11l (25 mg, 80%) as a white solid; mp: 152e154 ꢀC; 1H NMR
DMSO-d6)
d
7.87e7.85 (m, 2H, ArH), 7.58 (s,1H, ArH), 7.52 (d,1H, ArH,
(300 MHz, DMSO-d6) d 7.88e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH),
J ¼ 8.4 Hz), 7.46e7.44 (m, 3H, ArH), 7.38 (d, 2H, ArH, J ¼ 9.0 Hz), 7.25
(d, 1H, ArH, J ¼ 7.5 Hz), 6.80 (d, 2H, ArH, J ¼ 9.0 Hz), 5.01e4.97 (m, 1H,
CH), 3.28e3.17 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.1 Hz), 2.56 (t, 2H,
CH2, J ¼ 7.4 Hz), 2.27 (s, 3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.3 Hz, 7.1 Hz);
7.52 (d, 3H, ArH, J ¼ 8.4 Hz), 7.46e7.45 (m, 3H, ArH), 7.25 (d, 1H,
ArH, J ¼ 8.1 Hz), 6.67 (d, 2H, ArH, J ¼ 8.4 Hz), 4.50e4.96 (m, 1H, CH),
3.27e3.17 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.2 Hz), 2.56 (t, 2H, CH2,
J ¼ 6.9 Hz), 2.28 (s, 3H CH3), 2.10 (qui, 2H, CH2, J ¼ 7.2 Hz, 7.2 Hz);
13C NMR (125 MHz, DMSO-d6)
d
171.3,166.8, 158.3,156.8,149.1, 144.0,
13C NMR (125 MHz, DMSO-d6)
d 171.4, 166.9, 158.3, 149.1, 144.0,
140.9, 134.9, 132.7, 132.0, 129.9, 128.9, 127.1, 126.0, 125.3, 119.8, 117.1,
112.4, 109.9, 76.6, 37.7, 27.0, 25.4, 24.1, 9.7; HRMS-ESIꢁ: C29H25BrN2O5
calcd [M ꢁ H]ꢁ 559.0869, found 559.0855.
140.9, 137.9, 137.0, 134.9, 132.8, 130.6, 129.9, 128.9, 127.1, 126.0,
125.3, 119.7, 117.6, 109.8, 83.6, 76.4, 37.7, 27.0, 25.4, 24.1, 9.7; HRMS-
ESIꢁ: C29H24IN2O5 calcd [M ꢁ H]ꢁ 607.0730, found 607.0715.

3648
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
6.1.15.13. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo[d]
oxazol-5-yl)-2-(4-(trifluoromethyl)phenoxy)propanoicacid(11m). Co-
mpound 11m (24 mg, 88%) as a white solid; mp: 160e164 ꢀC; 1H
6.1.15.18. (S)-2-(4-tert-Butylphenoxy)-3-(2-(3-(5-methyl-2-phenyl-
oxazol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (11r). Com-
pound 11r (24 mg, 90%) as a white solid; mp: 50e54 ꢀC; 1H NMR
NMR (300 MHz, DMSO-d6)
d
7.88e7.87 (m, 2H, ArH), 7.62e7.58 (m,
(300 MHz, DMSO-d6) d 7.87e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH),
3H, ArH), 7.54 (d, 1H, ArH, J ¼ 8.1 Hz), 7.48e7.47 (m, 3H, ArH), 7.29 (d,
1H, ArH, J ¼ 8.1 Hz), 7.03 (d, 2H, ArH, J ¼ 9.3 Hz), 5.17e5.12 (m, 1H,
CH), 3.30 (dd, dd, 2H, CH2, J ¼ ꢁ13.8 Hz, 7.8 Hz, 3.0 Hz), 2.95 (t, 2H,
CH2, J ¼ 7.7 Hz), 2.58 (t, 2H, CH2, J ¼ 6.8 Hz), 2.30 (s, 3H, CH3),
7.52 (d,1H, ArH, J ¼ 8.1 Hz), 7.46e7.44 (m, 3H, ArH), 7.26 (d,1H, ArH,
J ¼ 9.3 Hz), 7.20 (d, 2H, ArH, J ¼ 8.7 Hz), 6.72 (d, 2H, ArH, J ¼ 8.4 Hz),
4.90e4.86 (m, 1H, CH), 3.25e3.16 (m, 2H, CH2), 2.92 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.55 (t, 2H, CH2, J ¼ 7.4 Hz), 2.27 (s, 3H, CH3), 2.10 (qui,
2H, CH2, J ¼ 7.1 Hz, 7.0 Hz), 1.18 (s, 9H, 3CH3); 13C NMR (125 MHz,
2.14e2.09 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6)
d 172.1, 166.9,
159.9, 158.3, 149.1, 144.0, 141.0, 135.9, 132.7, 129.3, 129.0, 128.9, 128.1,
126.9, 125.3, 119.8, 115.3, 109.9, 76.9, 37.6, 27.1, 25.5, 24.2, 9.8; HRMS-
ESIꢁ: C30H25F3N2O5 calcd [M ꢁ H]ꢁ 549.1637, found 549.1617.
DMSO-d6) d 172.4, 161.4, 158.7, 144.3, 143.7, 137.5, 135.7, 131.1, 130.4,
129.5, 128.1, 127.7, 126.5, 125.8, 123.6, 116.0, 114.7, 77.3, 38.1, 35.5,
34.2, 31.7, 25.1, 24.7, 10.2; HRMS-ESIꢁ: C33H33N2O6 calcd [M ꢁ H]ꢁ
537.2389, found 537.2378.
6.1.15.14. (S)-2-(4-Cyanophenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (11n). Compound 11n
(21 mg, 85%) as a white solid; mp: 155e160 ꢀC; 1H NMR (300 MHz,
6.1.15.19. (S)-2-(Biphenyl-4-yloxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (11s). Compound 11s
(25 mg, 89%) as a white solid; mp: 88e92 ꢀC; 1H NMR (300 MHz,
DMSO-d6)
d
7.87e7.84 (m, 2H, ArH), 7.70(d, 2H, ArH, J ¼ 9.3 Hz), 7.63 (s,
1H,ArH),7.58(d,1H,ArH,J ¼ 9.0 Hz),7.55e7.45(m,3H,ArH),7.27(d,1H,
ArH, J ¼ 8.1 Hz), 7.00 (d, 2H, ArH, J ¼ 9.3 Hz), 5.22e5.18 (m, 1H, CH),
3.37e3.22 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H, CH2,
DMSO-d6) d 7.86e7.84 (m, 2H, ArH), 7.61 (s, 1H, ArH), 7.55e7.51 (m,
5H, ArH), 7.46e7.44 (m, 3H, ArH), 7.41e7.36 (m, 2H, ArH), 7.30e7.26
(m, 2H, ArH), 6.91 (d, 2H, ArH, J ¼ 8.7 Hz), 5.05e5.00 (m, 1H, CH),
3.34e3.26 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H, CH2,
J ¼ 6.9 Hz), 2.27 (s, 3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.1 Hz, 7.2 Hz); 13
C
NMR(125 MHz, DMSO-d6)
d
170.9,166.9,160.9,158.3,149.1,144.0,141.0,
J ¼ 7.1 Hz), 2.27 (s, 3H, CH3), 2.09 (qui, 2H, CH2, J ¼ 7.5 Hz, 7.3 Hz); 13
C
134.9, 134.1, 132.5, 131.5, 131.4, 129.9, 128.9, 128.7, 128.6, 127.1, 126.0,
125.3, 119.8, 118.9, 115.8, 109.9, 103.3, 76.3, 37.5, 27.0, 25.4, 24.1, 9.7;
HRMS-ESIꢁ: C30H25N3O5 calcd [M ꢁ H]ꢁ 506.1716, found 506.1702.
NMR (125 MHz, DMSO-d6) d 171.7, 158.2, 157.2, 143.9, 139.6, 137.1,
135.3, 133.1, 130.6, 129.9, 129.0, 128.8, 127.7, 127.2, 126.7, 126.1, 125.4,
115.3, 76.8, 37.5, 24.6, 24.3, 9.8; HRMS-ESIꢁ: C35H30N2O5 calcd
[M ꢁ H]ꢁ 557.2076, found 557.2088.
6.1.15.15. (S)-2-(4-Acetylphenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11o). Compound 11o
(18 mg, 71%) as a yellow solid; mp: 65e68 ꢀC; 1H NMR (300 MHz,
6.1.15.20. (S)-2-(4-(Benzyloxy)phenoxy)-3-(2-(3-(5-methyl-2-phenyl-
oxazol-4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11t).
Compound 11t (24 mg, 85%) as a white solid; mp: 96e98 ꢀC; 1H NMR
DMSO-d6)
d
7.87e7.85 (m, 2H, ArH), 7.80 (d, 2H, ArH, J ¼ 8.4 Hz), 7.59
(s, 1H, ArH), 7.50 (d, 1H, ArH, J ¼ 8.7 Hz), 7.46e7.45 (m, 3H, ArH), 7.26
(d, 1H, ArH, J ¼ 8.1 Hz), 6.88 (d, 2H, ArH, J ¼ 8.7 Hz), 4.91 (m, 1H, CH),
3.25 (dd, dd, 2H, CH2, J ¼ ꢁ14.4 Hz, 8.7 Hz, 3.6 Hz), 2.92 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.55 (t, 2H, CH2, J ¼ 7.1 Hz), 2.48 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 2.09 (qui, 2H, CH2, J ¼ 6.9 Hz,7.2 Hz); 13CNMR(125 MHz, DMSO-
(300 MHz, DMSO-d6) d 7.88e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.51
(d, 1H, ArH, J ¼ 8.1 Hz), 7.47e7.45 (m, 3H, ArH), 7.38e7.24 (m, 6H,
ArH), 6.85 (d, 2H, ArH, J ¼ 8.7 Hz), 6.73 (d, 2H, ArH, J ¼ 9.3 Hz), 4.97
(s, 2H, CH2), 4.84e4.79 (m, 1H, CH), 3.28e3.13 (m, 2H, CH2), 2.93 (t,
2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H, CH2, J ¼ 7.1 Hz), 2.28 (s, 3H, CH3), 2.10
(qui, 2H, CH2, J ¼ 7.2 Hz, 7.0 Hz); 13C NMR (125 MHz, DMSO-d6)
d6)
d 196.1, 166.8, 161.9, 158.3, 149.0, 144.0, 140.9, 137.0, 134.9, 131.5,
131.4, 130.7, 130.2, 129.9, 129.7, 128.9, 128.8, 128.7, 127.1, 125.9, 125.3,
119.7, 114.6, 109.8, 77.5, 38.0, 27.0, 26.3, 25.4, 24.1, 9.7; HRMS-ESIꢁ:
C31H28N2O6 calcd [M ꢁ H]ꢁ 523.1869, found 523.1855.
d 172.2,158.4,152.7,151.7,146.6,144.1,137.0,135.0,130.7,130.0,129.0,
128.4, 127.7, 127.5, 127.2, 126.9, 125.7, 125.4, 116.0, 115.6, 77.6, 69.6,
48.6, 35.0, 30.2, 24.6, 18.9, 9.6; HRMS-ESIꢁ: C35H30N2O6 calcd
[M ꢁ H]ꢁ 573.2026, found 573.2007.
6.1.15.16. (S)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo
[d]oxazol-5-yl)-2-(p-tolyloxy) propanoic acid (11p). Compound 11p
6.1.15.21. (S)-2-Methoxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)pr-
opyl)benzo[d]oxazol-5-yl)propanoic acid (13a). Compound 13a
(18 mg, 85%) as a yellow sticky oil; 1H NMR (300 MHz, DMSO-d6)
(19 mg, 80%) as a sticky oil; 1H NMR (300 MHz, DMSO-d6)
d 7.89e7.87
(m, 2H, ArH), 7.60 (s, 1H, ArH), 7.53 (d, 1H, ArH, J ¼ 8.1 Hz), 7.48e7.46
(m, 3H, ArH), 7.27 (d,1H, ArH, J ¼ 8.1 Hz), 7.02 (d, 2H, ArH, J ¼ 8.7 Hz),
6.72 (d, 2H, ArH, J ¼ 8.4 Hz), 4.89 (m,1H, CH), 3.25e3.18 (m, 2H, CH2),
2.95 (t, 2H, CH2, J ¼ 7.4 Hz), 2.58 (t, 2H, CH2, J ¼ 7.5 Hz), 2.30 (s, 3H,
CH3), 2.18 (s, 3H, CH3), 2.14e2.09 (m, 2H, CH2); 13C NMR (125 MHz,
d
7.88e7.85 (m, 2H, ArH), 7.51e7.45 (m, 5H, ArH), 7.16 (dd, 1H, ArH,
J ¼ 8.4 Hz, 2.1 Hz), 3.97e3.93 (m, 1H, CH), 3.21 (s, 3H, CH3), 3.05 (dd,
1H, CH2, J ¼ ꢁ13.8 Hz, 4.2 Hz), 2.99e2.91 (m, 3H, CH2, CH2), 2.57 (t,
2H, CH2, J ¼ 7.2 Hz), 2.29 (s, 3H, CH3), 2.11 (qui, 2H, CH2, J ¼ 7.2 Hz,
DMSO-d6)
d
172.1, 162.9, 158.7, 144.1, 143.7, 137.5, 135.7, 131.1, 130.4,
7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 173.2, 167.2, 158.8, 149.4,
129.1, 128.0, 127.2, 126.1, 125.5, 123.6, 116.0, 114.7, 78.1, 37.2, 25.1, 24.7,
21.2, 9.8; HRMS-ESIꢁ: C30H27N2O5 calcd [M ꢁ H]ꢁ 495.1920, found
495.1937.
144.5,141.3,137.5,135.4,133.9,131.1,130.4,129.4,127.6,126.3, 125.8,
120.0, 110.2, 81.1, 57.7, 38.4, 27.5, 25.9, 24.6, 10.2; HRMS-ESIꢁ:
C24H24N2O5 calcd [M ꢁ H]ꢁ 419.1607, found 419.1629.
6.1.15.17. (S)-2-(4-Methoxyphenoxy)-3-(2-(3-(5-methyl-2-phenyloxazol-
6.1.15.22. (S)-2-Isopropoxy-3-(2-(3-(5-methyl-2-phenyloxazol-4-yl)
propyl)benzo[d]oxazol-5-yl) propanoic acid (13b). Compound 13b
(16 mg, 70%) as a yellow sticky oil; 1H NMR (300 MHz, DMSO-d6)
4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (11q). Compound 11q
(20 mg, 80%) as
7.88e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.52 (d, 1H, ArH,
a
sticky oil; 1H NMR (300 MHz, DMSO-d6)
d
d 7.89e7.86 (m, 2H, ArH), 7.51e7.45 (m, 5H, ArH), 7.17 (d, 1H, ArH,
J ¼ 8.4 Hz), 7.47e7.45 (m, 3H, ArH), 7.26 (d, 1H, ArH, J ¼ 8.1 Hz),
6.80e6.73 (m, 4H, ArH), 4.85e4.81 (m, 1H, CH), 3.30 (s, 3H, CH3),
3.24e3.19 (m, 2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H, CH2,
J ¼ 8.4 Hz), 4.09e4.05 (m, 1H, CH), 3.47 (qui, 1H, CH, J ¼ 6.2 Hz,
6.3 Hz), 3.05e2.85 (m, 4H, CH2, CH2), 2.57 (t, 2H, CH2, J ¼ 7.1 Hz),
2.48 (s, 3H, CH3), 2.12 (qui, 2H, CH2, J ¼ 7.1 Hz, 7.2 Hz), 1.02 (d, 3H,
CH3, J ¼ 5.4 Hz), 0.84 (d, 3H, CH3, J ¼ 6.3 Hz); 13C NMR (125 MHz,
J ¼ 7.5 Hz), 2.28 (s, 3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.0 Hz, 7.2 Hz); 13
C
NMR (125 MHz, DMSO-d6)
d
171.9, 166.8, 158.3, 153.7, 151.5, 149.1,
DMSO-d6) d 173.5, 166.7, 158.3, 148.9, 144.0, 140.8, 137.0, 134.9,
144.0, 140.9, 137.0, 134.9, 133.0, 130.7, 129.9, 128.9, 127.2, 125.9, 125.4,
119.8, 116.0, 114.5, 109.9, 77.5, 55.3, 37.9, 27.0, 25.5, 24.1, 9.7; HRMS-
ESIꢁ: C30H27N2O5 calcd [M ꢁ H]ꢁ 511.1869, found 511.1855.
133.7, 130.6, 129.9, 128.9, 127.1, 125.9, 125.4, 119.7, 109.6, 77.0, 70.9,
38.6, 27.0, 25.4, 24.1, 22.6, 21.2, 9.7; HRMS-ESIꢁ: C26H28N2O5 calcd
[M ꢁ H]ꢁ 447.1920, found 447.1901.

W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
3649
6.1.15.23. (R)-3-(2-(3-(5-Methyl-2-phenyloxazol-4-yl)propyl)benzo
[d]oxazol-5-yl)-2-(4-(trifluoromethyl)phenoxy)propanoic acid (15a).
Compound 15a (22 mg, 81%) as a white solid; mp: 162e164 ꢀC; 1H
6.1.17. Methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (17)
The crude compound 16 (25.0 g) and benzamide (25.0 g,
0.206 mol) was dissolved in 500 mL toluene, and it was heated at
reflux with Dean and Stark apparatus overnight. After cooling, the
reaction solution was filtered and concentrated. The residue was
purified over silica gel column eluting with petroleum ether/ethyl
acetate (from 10:1 to 3:1) to give compound 17 (20.0 g, 42%) as
NMR (300 MHz, DMSO-d6)
d 7.87e7.84 (m, 2H, ArH), 7.60 (s, 2H,
ArH), 7.57 (s, 1H, ArH), 7.52 (d, 1H, ArH, J ¼ 8.1 Hz), 7.46e7.44 (m, 3H,
ArH), 7.27 (dd, 1H, ArH, J ¼ 8.7 Hz, 1.5 Hz), 7.01 (d, 2H, ArH,
J ¼ 8.7 Hz), 5.17e5.13 (m,1H, CH), 3.30 (dd, dd, 2H, CH2, J ¼ ꢁ14.1 Hz,
8.1 Hz, 3.9 Hz), 2.93 (t, 2H, CH2, J ¼ 7.4 Hz), 2.56 (t, 2H, CH2,
J ¼ 6.9 Hz), 2.27 (s, 3H, CH3), 2.10 (qui, 2H, CH2, J ¼ 7.2 Hz, 7.2 Hz);
a colorless oil; 1H NMR (300 MHz, CDCl3)
d 8.00e7.98 (m, 2H, ArH),
7.42e7.40 (m, 3H, ArH), 3.73 (s, 3H, CH3), 3.58 (s, 2H, CH2), 2.362(s,
13C NMR (125 MHz, DMSO-d6)
d 171.1, 166.9, 160.3, 158.3, 149.1,
3H, CH3); MS (ESI m/z): 254 (M þ H)þ.
144.0, 141.0, 134.9, 132.7, 129.9, 128.9, 127.1, 126.9, 126.0,125.3, 119.8,
115.3, 109.9, 76.4, 37.6, 27.0, 25.4, 24.1, 9.7; HRMS-ESIꢁ:
C30H25F3N2O5 calcd [M ꢁ H]ꢁ 549.1637, found 549.1617.
6.1.18. 2-(5-Methyl-2-phenyloxazol-4-yl)ethanol (18)
A solution of compound 17 (18.0 g, 77.8 mmol) in 100 mL dry
ether was dropped into a suspension of LiAlH4 (2.95 g, 77.8 mmol)
in 250 mL dry ether at 0 ꢀC. The mixture was stirred for 30 min at
this temperature, and then quenched with 5 mL water. The ether
solution was dried over anhydrous Na2SO4 and filtered. The solvent
was removed to give compound 18 (12.64 g, 80%) as a white solid;
6.1.15.24. (R)-2-(4-tert-Butylphenoxy)-3-(2-(3-(5-methyl-2-phenyloxa-
zol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (15b). Compound
15b (25 mg, 93%) as a white solid; mp: 53e56 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 7.87e7.85 (m, 2H, ArH), 7.58 (s, 1H, ArH), 7.51 (d, 1H, ArH,
J ¼ 8.1 Hz), 7.45e7.44 (m, 3H, ArH), 7.26 (d, 1H, ArH, J ¼ 8.4 Hz), 7.20
(d, 2H, ArH, J ¼ 8.4 Hz), 6.71 (d, 2H, ArH, J ¼ 8.1 Hz), 4.90e4.86 (m, 1H,
CH), 3.25e3.20 (m, 2H, CH2), 2.92 (t, 2H, CH2, J ¼ 6.9 Hz), 2.55 (t, 2H,
CH2, J ¼ 6.9 Hz), 2.27 (s, 3H, CH3), 2.10e2.06 (m, 2H, CH2), 1.17 (s, 9H,
1H NMR (300 MHz, CDCl3)
d 7.99e7.96 (m, 2H, ArH), 7.43e7.41 (m,
3H, ArH), 3.93 (t, 2H, CH2, J ¼ 5.8 Hz), 2.72 (t, 2H, CH2, J ¼ 5.4 Hz),
2.33 (s, 3H, CH3); MS (ESI m/z): 226 (M þ Na)þ.
3CH3); 13C NMR (125 MHz, DMSO-d6)
d
171.9, 166.8, 158.3, 155.3,149.1,
6.1.19. 2-(5-Methyl-2-phenyloxazol-4-yl)acetaldehyde (19)
144.0, 143.3, 140.9, 134.9, 133.0, 129.9, 128.9, 127.1, 126.0, 125.9, 125.4,
119.7, 114.2, 109.8, 76.6, 37.9, 33.7, 31.2, 27.0, 25.5, 24.1, 9.8; HRMS-
ESIꢁ: C33H33N2O6 calcd [M ꢁ H]ꢁ 537.2389, found 537.2385.
To a suspension solution of DesseMartin periodiane (4.3 g,
10.13 mmol) in dichloromethane (100 mL), was added a solution of
compound 18 (1.716 g, 8.44 mmol) in dichloromethane (20 mL) at
room temperature. After stirring for 30 min, the reaction was
quenched with 50 mL saturated Na2S2O3 aqueous. The organic layer
was separated and the water layer was extracted with 20 mL
dichloromethane for one time, then the organic layer was
combined and dried over anhydrous Na2SO4. The solvent was
concentrated to give crude aldehyde 19 (1.6 g) as a yellow sticky oil,
which was used to next step without further purifications.
6.1.15.25. (R)-2-(Biphenyl-4-yloxy)-3-(2-(3-(5-methyl-2-phenyloxa-
zol-4-yl)propyl)benzo[d]oxazol-5-yl)propanoic acid (15c). Comp-
ound 15c (23 mg, 85%) as a white solid; mp: 89e91 ꢀC; 1H NMR
(300 MHz, DMSO-d6)
d 7.86e7.84 (m, 2H, ArH), 7.62 (s, 1H, ArH),
7.55e7.50 (m, 5H, ArH), 7.46e7.44 (m, 3H, ArH), 7.41e7.35 (m, 2H,
ArH), 7.30e7.26 (m, 2H, ArH), 6.91 (d, 2H, ArH, J ¼ 8.7 Hz),
5.05e5.00 (m, 1H, CH), 3.33e3.26 (m, 2H, CH2), 2.93 (t, 2H, CH2,
J ¼ 7.4 Hz), 2.56 (t, 2H, CH2, J ¼ 7.0 Hz), 2.27 (s, 3H, CH3), 2.09 (qui,
2H, CH2, J ¼ 7.2 Hz, 7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d
171.7,
6.2. In vitro antimicrobial activity assays
166.8,158.3, 157.2, 149.1, 144.0,141.0,139.7,134.9, 133.1, 132.9, 129.9,
128.8, 127.7, 127.1, 126.8, 126.1, 126.0, 125.4, 119.8, 115.3, 109.9, 76.6,
37.9, 27.1, 25.5, 24.1, 9.7; HRMS-ESIꢁ: C35H30N2O5 calcd [M ꢁ H]ꢁ
557.2076, found 557.2080.
According to the standards of Nation Committee for Clinical
Laboratory [17,18], we adopted 96-well microtitre broth dilution
method to determinate minimum inhibitory concentration (MIC).
All the compounds were tested for their in vitro growth inhibitory
activity against different bacteria and a fungus C. albicans. The
origin of bacterial strains was S. aureus, MRSA, B. subtilis as Gram-
positive and E. coli as Gram-negative bacteria.
6.1.15.26. (R)-2-(4-(Benzyloxy)phenoxy)-3-(2-(3-(5-methyl-2-phenyl-
oxazol-4-yl)propyl)benzo[d]oxazol-5-yl) propanoic acid (15d).
Compound 15d (25 mg, 88%) as a white solid; mp: 95e98 ꢀC; 1H
NMR (300 MHz, DMSO-d6)
d
7.88e7.85 (m, 2H, ArH), 7.58 (s, 1H,
All the compounds and control drugs were dissolved in DMSO
(4 mg/mL), and then diluted with MuellereHinton broth bacteria
(105 CFU/mL) or Sabouraud dextrose broth fungus (104 CFU/mL) to
the sample concentration (4 mg/mL). Using the multipipettor,
ArH), 7.52 (d, 1H, ArH, J ¼ 8.1 Hz), 7.46e7.44 (m, 3H, ArH), 7.38e7.24
(m, 6H, ArH), 6.85 (d, 2H, ArH, J ¼ 9.0 Hz), 6.73 (d, 2H, ArH,
J ¼ 9.3 Hz), 4.96 (s, 2H, CH2), 4.86e4.82 (m, 1H, CH), 3.29e3.19 (m,
2H, CH2), 2.93 (t, 2H, CH2, J ¼ 7.2 Hz), 2.56 (t, 2H, CH2, J ¼ 7.2 Hz), 2.27
(s, 3H, CH3), 2.09 (qui, 2H, CH2, J ¼ 7.4 Hz, 7.4 Hz); 13C NMR (125 MHz,
dispense 10
column 2. Dispense 100
column 2 to column 12 and another 100
100 L into column 2. Using the multipipettor set at 100
compound solution into the wells in column 2 by sucking up and
down 6e8 times. Withdraw 100 L from column 2 and add this to
column 3. This makes column 3 a twofold dilution of column 2. Mix
up and down 6e8 times. Transfer 100 L to column 4. Repeat the
procedure down to column 11 only and discard 100 L from column
11. The final concentrations from columns 2 to 11 were 200, 100, 50,
25, 12.5, 6.25, 3.12, 1.56, 0.78 and 0.39 g/mL. Pipette 100 L of
m
L of a 4 mg/mL compound solution into the wells in
L of the broth bacteria or fungus into
L dispense bacteria into
L, mix the
m
DMSO-d6)
d
171.9, 166.8, 158.3, 152.7, 151.6, 149.1, 144.0, 140.9, 137.2,
m
134.9, 133.0, 129.9, 128.9, 128.3, 127.6, 127.1, 125.9, 125.3, 119.7, 116.0,
115.5, 109.8, 77.3, 69.5, 37.9, 27.0, 25.4, 24.1, 9.7; HRMS-ESIꢁ:
C35H30N2O6 calcd [M ꢁ H]ꢁ 573.2026, found 573.2021.
m
m
m
6.1.16. Methyl 4-bromo-3-oxopentanoate (16)
m
According to the Malamas method, a solution of bromide
(5.9 mL, 0.115 mol) in 20 mL CHCl3 was added to a solution of
methyl 3-oxopentanoate (15.0 g, 0.115 mol) in 150 mL CHCl3 over
2 h at 0 ꢀC. Being stirred overnight at room temperature, air was
bubbled through the reaction for 1.0 h to remove hydrogen
bromide. The resulting solution was directly dried with anhy-
drous Na2SO4. The solvent was concentrated to give yellow
oil 16 (25.0 g), which was used to next step without further
purification.
m
m
m
sterile medium into column 1, and the column 12 as control groups.
After incubation for 24 h at 37 ꢀC, we streaked the bacterial culture
on plates to check their clarity. MIC values were taken as the lowest
concentration of drug that made the well clean. In order to ensure
that the solvent DMSO had no effect on bacterial growth, a control
test was also performed containing inoculated broth supplemented

3650
W. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3639e3650
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with only DMSO at the same dilutions used in our experiments and
found inactive in culture medium.
Acknowledgements
We thank the National Comprehensive Technology Platforms for
Innovative Drug R&D, 2009ZX09301-007 for the financial support.
We thank Professor Fengsheng Zhao (Shanghai Jiao Tong Univer-
sity) for the biological support of this research. We also thank JW&Y
(Shanghai) PharmLab Co., Ltd. for the supplies of all substituted
phenols.
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