Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor α and γ dual agonists

Article abstract of DOI:10.1021/jm8003416

In an effort to develop dual PPARα/γ activators with improved therapeutic efficacy, a series of diaryl α-ethoxy propanoic acid compounds comprising two aryl groups linked by rigid oxime ether or isoxazoline ring were designed and synthesized and their biological activities were examined. Most of the compounds possessing an oxime ether linker were more potent PPARγ activators than the lead PPARα/γ dual agonist, tesaglitazar in vitro. Compound 18, one of the derivatives with an oxime ether linker, was found to selectively transactivate PPARγ (EC₅₀ = 0.028 μM) over PPARα (EC₅₀ = 7.22 μM) in vitro and lower blood glucose in db/db mice more than muraglitazar after oral treatment for 11 days.

Full text of DOI:10.1021/jm8003416

6318
J. Med. Chem. 2008, 51, 6318–6333
Design, Synthesis, and Biological Evaluation of Novel Constrained meta-Substituted Phenyl
Propanoic Acids as Peroxisome Proliferator-Activated Receptor r and γ Dual Agonists
Young-Ger Suh,*,† Nam-Jung Kim,† Bon-Woong Koo,† Kwang-Ok Lee,† Sung-Hyun Moon,† Dong-Hyung Shin,†
Jong-Wha Jung,† Seung-Mann Paek,† Dong-Jo Chang,† Funan Li,† Hyun-Jin Kang,‡ Tuong Vy Thi Le,‡ Yu Na Chae,§
Chang Yell Shin,§ Mi-Kyung Kim,§ Joong In Lim,§ Jae-Sang Ryu,| and Hyun-Ju Park*,‡
College of Pharmacy, Seoul National UniVersity, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea, College of Pharmacy,
Sungkyunkwan UniVersity, Suwon 440-746, South Korea, Research Center, Dong-A Pharmaceutical Co., Ltd., 47-5, Sanggal-dong, Giheung-gu,
Yongin, Gyeonggi-do 449-905, South Korea, College of Pharmacy, Ewha Womans UniVersity, Seoul 120-750, South Korea
ReceiVed March 26, 2008
In an effort to develop dual PPARR/γ activators with improved therapeutic efficacy, a series of diaryl R-ethoxy
propanoic acid compounds comprising two aryl groups linked by rigid oxime ether or isoxazoline ring were
designed and synthesized and their biological activities were examined. Most of the compounds possessing
an oxime ether linker were more potent PPARγ activators than the lead PPARR/γ dual agonist, tesaglitazar
in vitro. Compound 18, one of the derivatives with an oxime ether linker, was found to selectively transactivate
PPARγ (EC50 ) 0.028 µM) over PPARR (EC50 ) 7.22 µM) in vitro and lower blood glucose in db/db mice
more than muraglitazar after oral treatment for 11 days.
Introduction
The selective PPARR agonist fenofibrate, which acts by
weakly modulating PPARR (EC50) 20-30 µM), is known to
effectively lower serum triglyceride and free fatty acid levels.
In addition, fenofibrate has excellent tolerability in humans; in
particular, it induced no significant adverse effects in T2D
patients on long-term therapy.7 On the other hand, PPARγ
agonists have been proven to be clinically effective at reducing
high plasma glucose levels in T2D, although some PPARγ
agonists induce edema and body-weight gain, which are clinical
disadvantages in T2D patients.8 To improve blood glucose
lowering and reduce weight gain, it has been suggested that
compounds with marginal PPARR affinity but with selective
PPARγ-modulating activity provide a possible solution.9
PPARR/γ agonists usually possess essential pharmacophoric
elements,2,10 i.e., an acidic group attached to a central flat
aromatic ring, a linker, and a large hydrophobic group (see
Figure 1). On the other hand, dual PPARR/γ agonists possess
a flexible alkyl ether linkage, which allows the molecule to adopt
a bioactive U-shaped conformation that well fits into the arms
of T- or Y-shaped PPAR active sites.11 Furthermore, in recently
reported studies, highly selective and active PPARR/γ dual
agonists with nanomolar to picomolar EC50 values were obtained
by replacing the alkyl ether central linker with a rigid linker
composed of an alkenyl, alkynyl, or indole ring.12
In the present study, we undertook the design, synthesis, and
biological evaluation of a novel series of dual PPARR/γ agonists
to identify ligands with improved in vivo efficacy. The PPARR/γ
dual agonist tesaglitazar was selected as the chemical lead, and
accordingly, analogous compounds (Table 1) were designed and
analyzed in terms of their binding modes by docking analysis.
In terms of molecular design strategy, the R-(S)-ethoxy pro-
panoic acid moiety of tesaglitazar was retained as an acidic head
group and the chemical modifications made centered on linker
rigidity and hydrophobic moiety type. Oxime ether (a bioisostere
of alkene) and isoxazoline ring (a bioisostere of amide) were
selected as potential rigid linker units. Phenyl and substituted
phenyl groups were utilized as hydrophobic moieties. Com-
parisons of binding energy scores and binding modes identified
the meta-substituted aryl structures (scaffolds E and F in Table
1) as the best candidate scaffolds. By varying substituent X in
Peroxisome proliferator-activated receptors (PPARsa) regulate
the lipid and glucose metabolism. PPARR agonists mainly
improve dyslipidemia and PPARγ agonists improve insulin
resistance.1 Many synthetic dual PPARR/γ agonists have been
developed to treat type 2 diabetes (T2D) and metabolic
syndrome and have been shown to be beneficial as compared
with selective PPARR or PPARγ agonists because they improve
lipid and glucose homeostasis.2 However, the adverse toxicity
profiles of dual PPARR/γ activators have raised critical safety
issues, which have caused developmental programs to be
discontinued.3
Studies of the mechanisms responsible for these toxicities
have not proved clearly whether these side effects identified
are target- or compound-related,4 and therefore we believe that
the identification of a dual PPARR/γ agonist with a better
pharmacological profile could provide a suitable therapeutic
option in T2D. For example, the clinical development of
tesaglitazar (a dual PPARR/γ agonist) was discontinued in 2006
due to potential kidney toxicity.3a Nevertheless, recent clinical
investigations undertaken to fully define the beneficial effects
of tesaglitazar revealed that it improves the atherogenic dys-
lipidemia associated with insulin resistance5 and improves
glycemic control and dyslipidemia when used as an add-on
therapy in T2D patients that show poor response to existing
sulfonylurea therapy.6 We believe that these results support the
relevance of further research into PPARR/γ dual agonists for
the treatment of T2D, given that the safety issues are properly
addressed.
* To whom correspondence should be addressed. For Y.-G.S.: phone,
82-2-880-7875; fax, 82-2-888-0649; E-mail, ygsuh@snu.ac.kr. For H.-J.P.:
phone, 82-31-290-7719; fax, 82-31-292-8800; E-mail, hyunju85@skku.edu.
†
College of Pharmacy, Seoul National University.
College of Pharmacy, Sungkyunkwan University.
Dong-A Research Institute.
College of Pharmacy, Ewha Womans University.
‡
§
|
a Abbreviations: PPAR, peroxisome proliferator-activated receptor; T2D,
type 2 diabetes; HOBT, 1-hydroxybenzotriazole; TFAA, trifluoroacetic
anhydride; DEAD; diethyl azodicarboxylate; PTSA, p-toluenesulfonic acid.
10.1021/jm8003416 CCC: $40.75
2008 American Chemical Society
Published on Web 10/01/2008

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6319
Figure 1. Designs of PPARR/γ Dual Agonists.
the phenyl ring, a series of compounds were synthesized (Figure
1) and subsequently their biological activities were examined.
PPARR and γ agonistic activities were determined using in vitro
PPARR/γ-GAL4 cotransfection reporter assays, and in vivo
antihyperglycemic activities were also measured for several
selected compounds. In particular, compound 18 (Table 4),
which possesses an oxime linker, was identified as PPARR/γ
dual agonist that more effectively lowers blood glucose level
than muraglitazar in vivo.
The racemic isoxazoline analogues were conveniently syn-
thesized, as outlined in Scheme 5. Commercially available
isophthalaldehyde (51) was converted to 53 by Wittig olefination
and acetal formation. Hydrogenation and deprotection of 53 gave
the aldehyde 55, which was then transformed to oxime 56, a
precursor of [3 + 2] cycloaddition, by condensation with
hydroxylamine salt. The cycloaddition of the oxime 56 with
substituted styrene derivatives afforded various isoxazoline
analogues 57. As shown in Scheme 6, these analogues were
further transformed into the diasteromeric mixtures of isoxazo-
line analogues containing optically pure (R)- or (S)-ethoxy
propanoic acid using the resolution protocol used for oxime ether
analogues, as depicted in Schemes 1 and 2.
Isoxazole analogues were also synthesized from oxime 56,
which is commonly used to prepare isoxazoline analogues
(Scheme 7). Cycloaddition of oxime with phenylacetylenes
afforded isoxazole analogue,17 which was then subjected to ester
hydrolysis. This analogue was then transformed into the optically
pure (R)- or (S)-isoxazole analogues using a resolution protocol
analogous to that used for oxime ether analogues, as depicted
in Schemes 1 and 2.
The absolute configuration of isoxazoline analogue was also
confirmed by comparing the specific rotation of the compound
45b transformed from optically pure isoxazole analogue with
that of intermediate 45a, prepared as described in Scheme 2.
Isoxazoline analogue 62 was transformed to intermediate 45b
via ethyl ester formation followed by retroaldol condensation
using molybdenum catalyst18 (Scheme 8).
In Vitro Test. The in vitro receptor transactivation activities
of the synthesized compounds were determined,2a and results
are summarized in Tables, 2 and 3. Generally analogues
containing (S)-ethoxy propanoic acid had higher activities than
analogues containing (R)-ethoxy propanoic acid on both PPARR
and PPARγ (Table 2). Most of the active compounds displayed
higher potency at PPARγ than PPARR. Noticeably, most of
analogues possessing an oxime ether linker were more potent
PPARγ activators than the lead PPARR/γ dual agonist, (S)-
tesaglitazar (Table 3).
Results and Discussion
Chemistry. Oxime ether analogues were expediently syn-
thesized via a common intermediate, as outlined in Scheme 1.
The key intermediate was synthesized from commercially
available 3-acetylbenzonitrile (4). Sequential nitrile reduction
to the aldehyde by DIBAL-H, and Wittig olefination gave 7.
Saturation of the double bond of 7 with hydrogen on Pd/C,
removal of ketal, followed by hydrolysis, resulted in the racemic
acid 10, which was transformed into the optically pure amides
via (R)-2-phenylglycinol coupling. Separation of the resulting
two diastereomers, amide hydrolysis, and esterification afforded
methyl esters 14 and 30, respectively (Scheme 2). These
intermediates were readily converted into various oxime ether
analogues (16-29 and 32-41) by condensation with diverse
hydroxyl amines followed by ester hydrolysis (Scheme 2).
The absolute configurations of these oxime ether analogues
were confirmed by comparing the specific rotations of compound
44b transformed from intermediate 45a with that of 44a
prepared from known intermediate 42, as described in Scheme
3. Known intermediate 42, which could be prepared by
enzymatic resolution14 or using a synthetic approach,2e was
readily converted to 44a by triflation, followed by deoxygenation
using Pd (II). Compound 44b was prepared from compound
45a by Baeyer-Villiger oxidation,15 ester hydrolysis, and the
deoxygenation protocol described above.
Some of the alkylhydroxylamines, used to prepare 15 and
31 in Scheme 2, were not commercially available and were
prepared using the method described in Scheme 4. The reduction
of commercially available substituted benzaldehydes to alcohols
followed by the Mitsunobu reaction16 afforded alkylhydroxy-
lamines 50, which were subsequently subjected to imide
hydrolysis using hydrazine.
The results shown in Table 2 reveal the effects of the
configuration of the acidic portion and of the conformational
rigidity of the linker unit on activity. We prepared analogues
containing isoxazoline or isoxazole linker instead of oxime

6320 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
Table 1. Comparison of Calculated Binding Energy Scores for PPARR versus PPARγa
a * ) Gold score13 for the best docked conformation of each compound obtained using the FlexX docking.
ethers, and an ethoxy propanoic acid moiety of each analogue
was prepared in the R and S configurations. Modulation of the
conformational rigidity of the linking portion significantly
affected PPARγ activity but only marginally affected PPARR
activity. Moreover, when the linker unit was too rigid, PPARR
and γ activities decreased. Replacement of the oxime ether
with an isoxazole ring resulted in 30-fold decrease in PPARγ
agonistic activity. Although the configuration at the ethoxy
propanoic acid moiety dramatically affected agonistic activity,
the rigidity of the linker unit was also found to have a substantial
effect on PPAR activity. These present results obtained agreed
well with the docking results shown in Table 1, in which lowest
energy scores were obtained by docking oxime ether analogues
into both PPARR and γ.
stituents (X) on the phenyl ring (Table 3) and examined their
transactivation activities.
For oxime ether derivatives, the presence of an electron
withdrawing group X at the para-position, such as halogen (Cl,
Br, or I) or trifluoromethyl, improved PPARγ agonistic activity,
whereas only iodine increased PPARR activity. In particular,
the 4-chloro analogue 18 not only exhibited greatest PPARγ
activity (EC50 ) 28 nM) but also exhibited 260 times higher
selectivity for PPARγ over PPARR. In contrast, the activities
of analogues with an electron donating group decreased both
at PPARR and γ. These results suggest that electronic effects
of substituent groups influence the charge distribution in the
hydrophobic tail group and the interaction between the drug
and the PPARR/γ receptor cavities. We also examined whether
the position of the chloro group on the phenyl ring affected the
activity of 18 (see the Supporting Information Table S1) and
found that at the ortho- and meta-positions, the introduction of
On the basis of in vitro transactivation assay results shown
in Table 2, 16 and 60 were selected as primary leads for further
optimization. We prepared derivatives with various para sub-

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6321
Scheme 1. Synthesis of the Chiral Intermediate Amidea
a Reagents and conditions: (a) (CH2OH)2, PTSA, benzene, reflux; (b) DIBAL-H, CH2Cl2, -40 °C; (c) 11, tetramethylguanidine, CH2Cl2, 0 °C f rt; (d)
10% Pd/C, H2, MeOH, rt; (e) 2N HCl, THF; (f) LiOH, H2O/MeOH/THF, rt; (g) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diisopropylethylamine, HOBT, (R)-(-)-2-phenylglycinol, CH2Cl2, rt.
chlorine slightly improved PPARR/γ activity but that para-
positioned chlorine provided the greatest selectivity for PPARγ.
In the case of isoxazoline analogues, the compound lacking
para-substituent (60) showed rather high activity, indicating that
the presence of a substituent on the phenyl ring in the
hydrophobic region is not crucial for the interaction with
PPARR/γ. We also examined the effect of the length of the
linker between the isoxazoline and phenyl rings on activity (see
Supporting Information Table S2). Methylene and ethylene
linkages in this region decreased the interaction with PPARR/
γ, indicating that direct bonding between isoxazoline and the
hydrophobic portion provides optimal size for binding.
Oxime ether analogues had higher transactivation activities
than isoxazoline analogues. When we compared the potencies
of the two most potent analogues, it was found that the oxime
ether 18 induced 10-fold more PPARγ activity than the
isoxazoline 60 but that 18 induced about 2-fold less PPARR
activity than 60.
Docking analysis was used to investigate binding between
18 and 60 and the ligand binding domains of PPARγ and
PPARR. As illustrated in Figure 2 (left), both 18 and 60 well-
fitted the X-ray disposition of tesaglitazar in the bent cavity of
PPARγ, which concurred with their highly selective interactions
with PPARγ. Compounds 18 and 60 also well-fitted the
tesaglitazar-binding pocket of PPARR. However, the binding
positions of their hydrophobic moieties differed from that of
tesaglitazar (Figure 2, right). Compound 60 adopts a U-shaped
binding conformation, and its hydrophobic phenyl ring protrudes
deeper into the inner hydrophobic pocket of PPARR, whereas
the chloro-substituted phenyl group of 18 interacts with the
upper portion of the hydrophobic pocket.
excellent PPARγ activity in vitro. To determine whether these
compounds have beneficial effects in a diabetes model, we
evaluated the preliminary in vivo antihyperglycemic activities
of several compounds in db/db mice for 5 days. This model
serves as an obese model of T2D that is characterized by severe
insulin resistance and marked hypertriglyceridemia; in vivo
antihyperglycemic activities of the compounds examined are
summarized in the Supporting Information Table S3. Of the
compounds tested for 5 days, the oxime ether analogues 17 and
18 displayed potent antihyperglycemic activities and caused less
weight gain side effect than muraglitazar. Therefore, we
conducted a chronic 11-day study on 17 and 18 to confirm their
desirable in vivo activities compared with muraglitazar and the
results are summarized in Table 4. The oral administration of
17 and 18 significantly reduced blood glucose levels: 71% and
76% at 3 mg/kg, respectively. The blood-glucose reducing effect
of 18 was more effective than muraglitazar, while that of 17
was similar to muraglitazar in vivo considering error values.
Their effects on body weight gain, a well-known side effect of
PPAR agonists,19 were similar to muraglitazar after an 11-day
treatment.
Conclusion
To identify dual PPARR/γ agonists with more beneficial
biological activities than known dual agonists, we designed and
prepared tesaglitazar analogues containing rigid oxime ether and
isoxazoline ring linkers. The structure-activity relationships
obtained by in vitro PPARR/γ transactivation assays allowed us
to identify several oxime ether compounds with marginal PPARR
activities and higher PPARγ activities than that induced by
In Vivo Test. In the present study, we identified dual
PPARR/γ agonists that induce marginal PPARR activity but

6322 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
Scheme 2. Synthesis of Oxime Ether Analogues by Condensationa
a Reagents and conditions: (a) c-H2SO4, dioxane/H2O, reflux; (b) TMSCl, MeOH, reflux; (c) various hydroxylamines, pyridine, reflux; (d) LiOH, H2O/
MeOH/THF, rt.
Scheme 3. Confirmation of the Absolute Configurations of the Oxime Ether Analoguesa
a Reagents and conditions: (a) Tf2O, Et3N, CH2Cl2, rt; (b) Pd(OAc)2, Ph3P, Et3N, HCO2H, DMF, 60 °C; (c) TFAA, sodium percarbonate, CH2Cl2, rt; (d)
TMSCl, EtOH, reflux.
purification. Tetrahydrofuran and Et2O were distilled from sodium
benzophenone ketyl. Dichloromethane, triethylamine, acetonitrile,
and pyridine were freshly distilled from calcium hydride. All
solvents used for routine product isolation and chromatography were
of reagent grade and glass distilled. Reaction flasks were dried at
100 °C before use, and air and moisture sensitive reactions were
tesaglitazar. In particular, compounds, 18 were found to reduce
blood glucose levels more than muraglitazar at 3 mg/kg oral dose.
Experimental Section
Chemistry. Unless noted otherwise, all starting materials and
reagents were obtained commercially and were used without further

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6323
Scheme 4. Synthesis of O-Alkylhydroxylamine Analoguesa
a Reagents and conditions: (a) NaBH4, MeOH, 0°C f rt; (b) DEAD, N-hydroxyphthalimide, PPh3, THF, 0 °C f rt; (c) NH2NH2, CH3CN, rt.
Scheme 5. Synthesis of Isoxazoline Analoguesa
a Reagents and conditions: (a) 11, tetramethylguanidine, CH2Cl2, 0 °C f rt; (b) (CH2OH)2, PTSA, benzene, reflux; (c) 10% Pd/C, H2, THF, rt; (d) 2N
HCl, THF, rt; (e) hydroxylamine HCl, pyridine, reflux; (f) various styrene derivatives, NaOCl, CH2Cl2, rt.
performed under argon. Flash column chromatography was per-
formed using silica gel 60 (230-400 mesh, Merck) with the
indicated solvents. Thin-layer chromatography was performed using
0.25 mm silica gel plates (Merck). Optical rotations were measured
using a JASCO DIP-1000 digital polarimeter at ambient temperature
using 100 nm cells of 2 mL capacity. Infrared spectra were recorded
on a Perkin-Elmer 1710 FT-IR spectrometer. Mass spectra were
obtained using a VG Trio-2 GC-MS instrument, and high resolution
mass spectra were obtained using a JEOL JMS-AX 505WA unit.
1H and 13C NMR spectra were recorded on either a JEOL JNM-
GCX 400 or JEOL JNM-LA 300 spectrometer in deuteriochloro-
form (CDCl3). Chemical shifts are expressed in parts per million
(ppm, δ) downfield from tetramethylsilane and are referenced to
for 3 h. The reaction mixture was then quenched with MeOH (0.5
mL) and acidified with 2N HCl to pH 3. The mixture was then
warmed to ambient temperature, stirred for 1 h, and diluted with
CH2Cl2. The organic layer was washed with Rochelle’s solution
and brine, dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography (EtOAc:
n-hexane ) 1: 10) afforded 2.07 g (85%) of 6 as colorless oil. 1H
NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 7.99 (t, 1H, J ) 1.7
Hz), 7.81 (td, 1H, J ) 1.5, 7.6 Hz), 7.74 (td, 1H, J ) 1.5, 7.7 Hz),
7.50 (t, 1H, J ) 7.7 Hz), 4.08-4.03 (m, 2H), 3.78-3.74 (m, 2H),
1.65 (s, 3H). LRMS (FAB) m/z 193 (M + H+).
Ethyl 2-ethoxy-3-(3-(2-methyl-1, 3-dioxolan-2-yl)phenyl)acry-
late (7). Tetramethylguanidine (10.0 mL, 79.8 mmol) was added
dropwise at 0 °C to a solution of 6 (10.2 g, 53.2 mmol) in CH2Cl2
(100 mL) containing (1,2-diethoxy-2-oxoethyl)triphenylphospho-
nium chloride (27.4 g, 63.8 mmol). The mixture was then warmed
to ambient temperature and stirred for 12 h. The organic layer was
diluted with CH2Cl2, then washed with NaHCO3 solution and brine,
dried over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography (EtOAc: n-hexane
) 1: 5) afforded 15.0 g (92%) of 7 as colorless oil. 1H NMR (E/Z
mixture of isomers, 300 MHz, CDCl3) δ 7.89 (bs, 1H), 7.73-7.71
(m, 1H), 7.50-7.30 (m, 2H), 6.98 (s, 1H), 4.28 (q, 2H, J ) 7.1
Hz), 4.05-3.96 (m, 4H), 3.78-3.73 (m, 2H), 1.64 (s, 1H), 1.38 (t,
3H, J ) 7.1 Hz), 1.35 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 307
(M + H+).
1
the deuterated solvent (CHCl3). H NMR data are reported in the
order: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet, and/or multiple resonance, numbers of
protons, and coupling constants in hertz (Hz).
3-(2-Methyl-1,3-dioxolan-2-yl)benzonitrile (5). To a solution of
3-acetylbenzonitrile (4) (2 g, 13.8 mmol) in benzene (50 mL) were
added p-toluenesulfonic acid (PTSA) (263 mg, 1.38 mmol) and
ethylene glycol (1.54 mL, 27.6 mmol). The reaction mixture was
then refluxed in a Dean & Stark apparatus for 3 h, cooled to room
temperature, concentrated in vacuo, and diluted with EtOAc. The
organic layer was washed with water and NaHCO3 solution, dried
over MgSO4, filtered, and then concentrated in vacuo. Purification
of the residue by flash column chromatography (EtOAc: n-hexane
1
) 1:5) afforded 2.46 g (94%) of 5 as colorless oil. H NMR (300
Ethyl 2-ethoxy-3-(3-(2-methyl-1, 3-dioxolan-2-yl)phenyl)pro-
panoate (8). A catalytic amount of Pd on carbon under H2 was
added to a solution of 7 (15.0 g, 48.8 mmol) in MeOH (100 mL)
and stirred for 13 h. The reaction mixture was then diluted with
EtOAc, filtered using a celite pad, and concentrated in vacuo.
Purification of the residue by flash column chromatography (EtOAc:
n-hexane ) 1: 5) afforded 15.0 g (99%) of 8 as a colorless oil. 1H
NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.24 (t, 1H, J )
MHz, CDCl3) δ 7.77 (t, 1H, J ) 1.6 Hz), 7.70 (td, 1H, J ) 1.6,
7.9 Hz), 7.57 (td, 1H, J ) 1.5, 7.7 Hz), 7.43 (t, 1H, J ) 7.8 Hz),
4.07-4.02 (m, 2H), 3.76-3.71 (m, 2H), 1.61 (s, 3H). LRMS (FAB)
m/z 190 (M + H+).
3-(2-Methyl-1,3-dioxolan-2-yl)benzaldehyde (6). DIBAL-H (1 M
solution in toluene, 19.0 mL) was added dropwise at -40 °C to a
solution of 5 (2.40 g, 12.7 mmol) in CH2Cl2 (45 mL), and stirred

6324 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
Scheme 6. Synthesis of Diastereomeric Isoxazoline Analogues Containing Optically Pure Ethoxy Propanoic acid Moietya
a Reagents and conditions: (a) LiOH, H2O, MeOH, THF, rt; (b) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diisopropylethylamine,
HOBT, (R)-(-)-2-phenylglycinol, CH2Cl2, rt; (c) c-H2SO4, dioxane/H2O, reflux; (d) TMSCl, MeOH, reflux; (e) LiOH, H2O/MeOH/THF.
Scheme 7. Synthesis of Isoxazole Analoguesa
a Reagents and conditions: (a) phenylacetylene, NaOCl, CH2Cl2, rt; (b) LiOH, H2O/MeOH/THF, rt; (c) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride, diisopropylethylamine, HOBT, (R)-(-)-2-phenylglycinol, CH2Cl2, rt; (d) c-H2SO4, dioxane/H2O, reflux; (e) TMSCl, MeOH, reflux; (f) LiOH,
H2O/MeOH/THF.
7.6 Hz), 7.17-7.15 (m, 2H), 4.15 (q, 2H, J ) 7.2 Hz), 4.03-3.98
(m, 3H), 3.76-3.73 (m, 2H), 3.61-3.57 (m, 1H), 3.34-3.30 (m,
1H), 3.00 (d, 2H, J ) 6.8 Hz), 1.62 (s, 3H), 1.21 (t, 3H, J ) 7.2
Hz), 1.13 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 309 (M + H+).
Ethyl 3-(3-acetylphenyl)-2-ethoxypropanoate (9). 2N HCl (40.8
mL) was added to a solution of 8 in THF (80 mL). The reaction
mixture was then refluxed for 3 h, cooled to room temperature,
and NaHCO3 was added to quench the reaction. The mixture was
then concentrated in vacuo, diluted with EtOAc, and the organic
layer so obtained was washed with water, dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue by
flash column chromatography (EtOAc: n-hexane ) 1: 5) afforded
10.54 g (82%) of 9 as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.84-7.80 (m, 2H), 7.45 (d, 1H, J ) 7.5 Hz), 7.37 (t, 1H, J )

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6325
Scheme 8. Confirmation of the Absolute Configurations of Isoxazoline Analoguesa
a Reagents and conditions: (a) TMSCl, EtOH, reflux; (b) Mo(CO)6, CH3CN/H2O, reflux.
1
7.5 Hz), 4.17 (q, 2H, J ) 7.1 Hz), 4.00 (dd, 1H, J ) 7.8, 5.4 Hz),
3.66-3.56 (m, 1H), 3.36-3.26 (m, 1H), 3.11-2.98 (m, 2H), 2.58
(s, 1H), 1.22 (t, 3H, J ) 7.1 Hz), 1.13 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 265 (M + H+).
1:5) afforded 2.37 g (73%) of 9 as a colorless oil. H NMR (300
MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.45-7.34 (m, 2H), 4.02 (dd,
1H, J ) 7.9, 5.1 Hz), 3.71 (s, 3H), 3.65-3.55 (m, 1H), 3.35-3.25
(m, 1H), 3.11-2.98 (m, 2H), 2.58 (s, 3H), 1.13 (t, 3H, J ) 7.0
Hz). LRMS (FAB) m/z 251 (M + H+).
3-(3-Acetylphenyl)-2-ethoxypropanoic Acid (10). LiOH·H2O
(970 mg, 23.2 mmol) was added to a solution of 9 (2.04 g, 7.72
mmol) in THF/H2O/MeOH (3:1:1, 50 mL) and then stirred for 12 h
at ambient temperature. The reaction was quenched with 2N HCl,
and diluted with EtOAc. The organic layer so obtained was washed
with H2O, dried over MgSO4, filtered, and concentrated in vacuo
to afford 1.81 g (99%) of 10 as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.85-7.81 (m, 2H), 7.47-7.36 (m, 2H), 4.09 (dd, 1H, J
) 7.9, 4.2 Hz), 3.67-3.57 (m, 1H), 3.46-3.36 (m, 1H), 3.18 (dd,
1H, J ) 14.1, 4.2 Hz), 3.06 (dd, 1H, J ) 14.1, 7.9 Hz), 2.59 (s,
3H), 1.15 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 237 (M + H+).
(2(S)-3-(3-Acetylphenyl)-2-ethoxy-N-((R)-2-hydroxy-1-phenyleth-
yl)propanamide (12) and (2(R)-3-(3-acetylphenyl)-2-ethoxy-N-((R)-
2-hydroxy-1-phenylethyl)propanamide (13). To a solution of 10
(9.97 g, 42.2 mmol) in CH2Cl2 (120 mL) at ambient temperature
were added; N-(3-dimethylaminoproryl)-N′-ethylcarbodiimide hy-
drochloride (EDCI) (8.90 g, 46.4 mmol), (R)-(-)-2-phenylgycinol
(6.37 g, 46.4 mmol), and HOBT (6.27 g, 46.4 mmol). Finally,
diisopropylethylamine (8.09 mL, 46.4 mmol) was added dropwise
at 0 °C. The reaction mixture was then stirred for 12 h at ambient
temperature, quenched with saturated NH4Cl solution, and diluted
with CH2Cl2. The organic layer so obtained was washed with H2O,
dried over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography (EtOAc: n-hexane
) 2: 1) afforded 4.60 g (31%) of 12 as a colorless oil and 4.26 g
(28%) of 13 as a white solid.
(R)-Methyl 3-(3-acetylphenyl)-2-ethoxypropanoate (30). c-H2SO4
(5 mL) was added dropwise to a solution of 13 (4.26 g, 12.0 mmol)
in 1,4-dioxane: H2O (10: 1, 55 mL). The reaction mixture was then
refluxed for 8 h, cooled to room temperature, diluted with EtOAc,
and the organic layer so obtained was washed with H2O, dried over
MgSO4, filtered, and concentrated in vacuo to afford 3.68 g of a
brown oil. To a solution of this acid in MeOH (50 mL), TMSCl
(4.56 mL, 35.9 mmol) was then added dropwise. The reaction
mixture was refluxed for 8 h, cooled to room temperature, and the
reaction was quenched with NaHCO3. The mix was then concen-
trated in vacuo, diluted with EtOAc, and the organic layer so
obtained was washed with water, dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash column
chromatography (EtOAc:n-hexane ) 1:5) afforded 2.16 g (72%)
1
of 9 as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.83-7.80
(m, 2H), 7.45-7.34 (m, 2H), 4.02 (dd, 1H, J ) 7.9, 5.1 Hz), 3.71
(s, 3H), 3.65-3.55 (m, 1H), 3.35-3.25 (m, 1H), 3.11-2.98 (m,
2H), 2.58 (s, 3H), 1.13 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 251
(M + H+).
Representative Procedure for the Synthesis of Compounds
16-29 and 32-41: The Preparation of (S)-3-(3-((E)-1-Benzyloxy-
iminoethyl)phenyl)-2-ethoxypropanoic Acid (16). O-Benzylhy-
droxylamine·HCl (25 mg, 0.16 mmol) was added to a solution of
14 (33 mg, 0.13 mmol) in pyridine (3 mL). The reaction mixture
was refluxed for 5 h, cooled to room temperature, concentrated in
vacuo, and diluted with EtOAc. The organic layer so obtained, was
washed with H2O, dried over MgSO4, filtered, and concentrated in
vacuo. Purification of the residue by flash column chromatography
(EtOAc:n-hexane ) 1:5) afforded 34 mg (72%) of ester as colorless
oil. LiOH ·H2O (970 mg, 23.2 mmol) was then added to prepared
ester (102 mg, 0.28 mmol) in THF/H2O/MeOH (3:1:1, 10 mL) and
stirred for 12 h at ambient temperature. The reaction was then
quenched with 2N HCl, and diluted with EtOAc, and the organic
layer so obtained was washed with H2O, dried over MgSO4, filtered,
and concentrated in vacuo to afford 94 mg (99%) of 16 as a
12: 1H NMR (300 MHz, CDCl3) δ 7.85-7.82 (m, 2H),
7.47-7.06 (m, 7H), 5.00-4.94 (m, 1H), 4.00 (dd, 1H, J ) 6.6, 4.0
Hz), 3.73-3.63 (m, 2H), 3.48 (q, 2H, J ) 6.9 Hz), 3.21 (dd, 1H,
J ) 14.1, 3.8 Hz), 3.06 (dd, 1H, J ) 13.9, 6.6 Hz), 2.59 (s, 3H),
1.11 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 356 (M + H+).
13: 1H NMR (300 MHz, CDCl3) δ 7.80-7.75 (m, 2H),
7.39-7.17 (m, 5H), 7.02-6.99 (m, 2H), 5.01-4.96 (m, 1H), 4.04
(dd, 1H, J ) 6.6, 3.9 Hz), 3.83 (d, 2H, J ) 5.0 Hz), 3.63-3.48
(m, 2H), 3.16 (dd, 1H, J ) 14.1, 3.8 Hz), 3.00 (dd, 1H, J ) 14.1,
6.8 Hz), 2.46 (s, 3H), 1.18 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z
356 (M + H+).
1
colorless oil. H NMR (300 MHz, CDCl3) δ 7.53-7.50 (m, 2H),
(S)-Methyl 3-(3-acetylphenyl)-2-ethoxypropanoate (14). c-H2SO4
(5 mL) was added dropwise to a solution of 12 (4.60 g, 13.0 mmol)
in 1,4-dioxane:H2O (10:1, 55 mL). The reaction mixture was
refluxed for 8 h, cooled to room temperature, diluted with EtOAc,
and the organic layer so obtained was washed with H2O, dried over
MgSO4, filtered, and concentrated in vacuo to afford 3.92 g of a
brown oil. To a solution of this prepared acid in MeOH (50 mL),
TMSCl (4.93 mL, 38.85 mmol) was added dropwise and the
resulting mixture was refluxed for 8 h and then cooled to room
temperature. NaHCO3 was then added to quench the reaction. The
reaction mix was then concentrated in vacuo, diluted with EtOAc,
and the organic layer so obtained was washed with water, dried
over MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography (EtOAc:n-hexane )
7.42-7.21 (m, 7H), 5.22 (s, 2H), 4.08 (dd, 1H, J ) 7.9, 4.0 Hz),
3.62-3.52 (m, 1H), 3.47-3.37 (m, 1H), 3.15 (dd, 1H, J ) 14.1,
4.0 Hz), 2.99 (dd, 1H, J ) 14.1, 7.9 Hz), 2.24 (s, 3H), 1.14 (t, 3H,
J ) 7.1 Hz). LRMS (FAB) m/z 342 (M + H+). HRMS (FAB)
calcd for C20H24NO4 (M + H+), 342.1705; found, 342.1708.
(S)-3-(3-((E)-1-(4-Fluorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (17). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.51-7.49 (m, 2H), 7.39-7.21 (m, 4H), 7.06-7.00 (m, 2H), 5.17
(s, 2H), 4.08 (dd, 1H, J ) 7.9, 4.0 Hz), 3.63-3.53 (m, 1H),
3.47-3.37 (m, 1H), 3.14 (dd, 1H, J ) 14.1, 4.0 Hz), 3.00 (dd, 1H,
J ) 14.2, 8.0 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J ) 7.1 Hz). LRMS
(FAB) m/z 360 (M + H+). HRMS (FAB) calcd for C20H23FNO4
(M + H+), 360.1611; found, 360.1621.

6326 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
Table 2. In Vitro Transactivation Assay Results Showing the Effects of Linker Structure and Configuration of the Acidic Portion on Agonistic Activity
a EC50 values were calculated by logistic 4-parametric equation using the mean values of its intrinsic activation obtained from more than three independent
experiments. b Relative maximum efficacies to the percentage of the standards.
(S)-3-(3-((E)-1-(4-Chlorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (18). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.51-7.47 (m, 2H), 7.35-7.22 (m, 6H), 5.18 (s, 2H), 4.07
(dd, 1H, J ) 8.1, 4.0 Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m,
1H), 3.14 (dd, 1H, J ) 14.1, 4.0 Hz), 3.00 (dd, 1H, J ) 14.1,
8.0 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB)
m/z 376 (M + H+). HRMS (FAB) calcd for C20H23ClNO4 (M
+ H+), 376.1316; found, 376.1309.
(dd, 1H, J ) 7.9, 4.0 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m,
1H), 3.14 (dd, 1H, J ) 14.0, 4.1 Hz), 3.00 (dd, 1H, J ) 14.1,
7.9 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB)
m/z 420 (M + H+). HRMS (FAB) calcd for C20H24BrNO4 (M
+ H+), 420.0810; found, 420.0815.
(S)-3-(3-((E)-1-(4-Iodobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (20). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.68-7.65 (m, 2H), 7.51-7.48 (m, 2H), 7.34-7.22 (m, 2H),
7.15-7.12 (m, 2H), 5.15 (s, 2H), 4.06 (dd, 1H, J ) 7.9, 4.0
Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.13 (dd, 1H, J )
13.9, 4.0 Hz), 2.99 (dd, 1H, J ) 14.1, 7.9 Hz), 2.23 (s, 3H),
(S)-3-(3-((E)-1-(4-Bromobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (19). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.50-7.45 (m, 4H), 7.30-7.21 (m, 4H), 5.16 (s, 2H), 4.07

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6327
Table 3. Transactivation Assay Results of Oxime Ether Compounds on Human PPAR R/γ
a EC50 values were calculated by logistic 4-parametric equation using the mean values of its intrinsic activation obtained from more than three independent
experiments. b Relative maximum efficacies to the percentage of the standards.
1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 468 (M + H+).
HRMS (FAB) calcd for C20H24INO4 (M + H+), 468.0672; found
468.0662.
(S)-3-(3-((E)-1-(4-Trifluoromethylbenzyloxyimino)ethyl)phenyl)-
2-ethoxypropanoic Acid (21). Colorless oil. H NMR (300 MHz,
CDCl3) δ 7.61-7.48 (m, 6H), 7.31-7.22 (m, 2H), 5.27 (s, 2H), 4.07
1

6328 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
Figure 2. Binding dispositions of 18 (magenta) and 60 (yellow) in the PPARγ (left) and PPARR (right) binding pockets as compared with that
of tesaglitazar (gray). Solvent-accessible protein surfaces are colored by lipophilicity potential. The color code is shown on the left: lipophilicity
increases from blue (hydrophilic) to brown (lipophilic).
Table 4. Antihyperglycemic Activities and Weight Gain in db/db Mice (In Vivo Data after an 11-Day Study)
% inhibition of blood glucose
weight gain (g) vs day 1
day 7
compd ID
lean
db/db control
Muraglitazar
17
dose (mg/kg)
day 4
day 7
day 11
day 4
day 11
0.6 ( 0.1
0.6 ( 0.6
2.0 ( 0.6
1.9 ( 0.6
2.1 ( 1.0
1.9 ( 0.2
2.5 ( 0.4a
0.4 ( 0.2
1.0 ( 0.7
3.6 ( 0.7a
3.6 ( 0.6a
3.6 ( 1.0
3.7 ( 0.4a
3.7 ( 0.3a
0.9 ( 0.3
2.4 ( 0.8
6.3 ( 0.9a
5.6 ( 0.8a
5.6 ( 1.0a
6.0 ( 0.5a
5.3 ( 0.5a
0 ( 14
53 ( 2a
39 ( 13
64 ( 1a
63 ( 2a
61 ( 4a
0 ( 9
0 ( 10
68 ( 2a
68 ( 2a
71 ( 5a
71 ( 1a
76 ( 1a
3
0.3
3
0.3
3
67 ( 1a
58 ( 4a
73 ( 1a
60 ( 7a
73 ( 1a
18
a P < 0.05 vs db/db control. Data are expressed as mean ( SEM.
(dd, 1H, J ) 7.9, 4.0 Hz), 3.62-3.52 (m, 1H), 3.46-3.36 (m, 1H),
3.14 (dd, 1H, J ) 14.1, 4.0 Hz), 3.00 (dd, 1H, J ) 14.1, 7.9 Hz), 2.26
(s, 3H), 1.13 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 410 (M + H+).
HRMS (FAB) calcd for C21H22F3NO4 (M + H+), 410.1579; found,
410.1575.
4.08 (dd, 1H, J ) 8.1, 4.0 Hz), 3.63-3.53 (m, 1H), 3.47-3.37 (m,
1H), 3.15 (dd, 1H, J ) 14.2, 3.9 Hz), 2.99 (dd, 1H, J ) 14.0, 8.0
Hz), 2.24 (s, 3H), 1.31 (s, 9H), 1.15 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 398 (M + H+). HRMS (FAB) calcd for C24H31NO4 (M
+ H+), 398.2331; found, 398.2318.
(S)-3-(3-((E)-1-(4-Hydroxybenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (22). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.51-7.49 (m, 2H), 7.31-7.19 (m, 4H), 6.82-6.79 (m, 2H), 5.13 (s,
2H), 4.08 (dd, 1H, J ) 7.9, 4.0 Hz), 3.63-3.53 (m, 1H), 3.47-3.37
(m, 1H), 3.14 (dd, 1H, J ) 13.9, 4.0 Hz), 3.00 (dd, 1H, J ) 14.0, 8.0
Hz), 2.21 (s, 3H), 1.15 (t, 3H, J ) 7.04 Hz). LRMS (FAB) m/z 358
(M + H+). HRMS (FAB) calcd for C20H23NO5 (M + H+), 358.1654;
found, 358.1644.
(S)-3-(3-((E)-1-Phenethyloxyiminoethyl)phenyl)-2-ethoxypro-
panoic Acid (26). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.52-7.50 (m, 2H), 7.31-7.18 (m, 6H), 4.39 (t, 2H, J ) 7.0 Hz),
4.08 (dd, 1H, J ) 8.0, 4.0 Hz), 3.64-3.54 (m, 1H), 3.48-3.38 (m,
1H), 3.16 (dd, 1H, J ) 14.2, 3.9 Hz), 3.06-2.97 (m, 3H), 2.19 (s,
3H), 1.16 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 356 (M + H+).
HRMS (FAB) calcd for C21H25NO4 (M + H+), 356.1862; found,
356.1856.
(S)-3-(3-((E)-1-(4-Methanesulfonyloxybenzyloxyimino)ethyl)phenyl)-
1
2-ethoxypropanoic Acid (23). Colorless oil. H NMR (300 MHz,
(S)-3-(3-((E)-1-(3-Phenylpropoxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (27). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.53-7.50 (m, 2H), 7.31-7.14 (m, 6H), 4.20 (t, 2H, J ) 6.5
Hz), 4.08 (dd, 1H, J ) 7.9, 4.0 Hz), 3.63-3.53 (m, 1H), 3.47-3.37
(m, 1H), 3.15 (dd, 1H, J ) 14.1, 4.0 Hz), 3.00 (dd, 1H, J ) 14.0,
8.0 Hz), 2.73 (t, 2H, J ) 7.8 Hz), 2.22 (s, 3H), 2.09-1.99 (m,
2H), 1.15 (t, 3H, J ) 6.96 Hz). LRMS (FAB) m/z 370 (M + H+).
HRMS (FAB) calcd for C22H27NO4 (M + H+), 370.2018; found,
370.2024.
CDCl3) δ 7.51-7.43 (m, 4H), 7.30-7.22 (m, 4H), 5.21 (s, 2H),
4.07 (dd, 1H, J ) 7.7, 4.2 Hz), 3.63-3.53 (m, 1H), 3.46-3.36 (m,
1H), 3.17-3.11 (m, 4H), 3.00 (dd, 1H, J ) 14.1, 7.9 Hz), 2.24 (s,
3H), 1.14 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 436 (M + H+).
HRMS (FAB) calcd for C21H25NO7S (M + H+), 436.1430; found,
436.1418.
(S)-3-(3-((E)-1-(4-Methoxybenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (24). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.52-7.50 (m, 2H), 7.36-7.21 (m, 4H), 6.90-6.87 (m, 2H), 5.15
(s, 2H), 4.08 (dd, 1H, J ) 8.1, 4.0 Hz), 3.79 (s, 3H), 3.63-3.53
(m, 1H), 3.46-3.36 (m, 1H), 3.14 (dd, 1H, J ) 14.1, 4.0 Hz), 3.00
(dd, 1H, J ) 14.1, 8.0 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J ) 7.0 Hz).
LRMS (FAB) m/z 372 (M + H+). HRMS (FAB) calcd for
C21H25NO5 (M + H+), 372.1811; found, 372.1815.
(S)-3-(3-((E)-1-(2-Chlorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (28). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.53-7.50 (m, 2H), 7.46-7.43 (m, 1H), 7.38-7.21 (m, 5H), 5.34
(s, 2H), 4.08 (dd, 1H, J ) 7.9, 4.0 Hz), 3.60-3.52 (m, 1H),
3.47-3.39 (m, 1H), 3.15 (dd, 1H, J ) 14.3, 4.0 Hz), 2.99 (dd, 1H,
J ) 14.1, 7.9 Hz), 2.28 (s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 376 (M + H+). HRMS (FAB) calcd for C20H23ClNO4
(M + H+), 376.1316; found, 376.1309.
(S)-3-(3-((E)-1-(4-(tert-Butylbenzyloxyimino)ethyl)phenyl)-2-
ethoxypropanoic Acid (25). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.54-7.50 (m, 2H), 7.40-7.22 (m, 6H), 5.20 (s, 2H),

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6329
(S)-3-(3-((E)-1-(3-Chlorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (29). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.51-7.48 (m, 2H), 7.38 (m, 1H), 7.31-7.24 (m, 5H), 5.18 (s,
2H), 4.07 (dd, 1H, J ) 7.8, 4.1 Hz), 3.60-3.55 (m, 1H), 3.45-3.39
(m, 1H), 3.14 (dd, 1H, J ) 13.8, 3.8 Hz), 3.00 (dd, 1H, J ) 14.4,
7.8 Hz), 2.25 (s, 3H), 1.14 (t, 3H, J ) 7.05 Hz). LRMS (FAB) m/z
376 (M + H+). HRMS (FAB) calcd for C20H23ClNO4 (M + H+),
376.1316; found, 376.1305.
(R)-3-(3-((E)-1-(4-Methoxybenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (40). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.53-7.50 (m, 2H), 7.36-7.25 (m, 4H), 6.90-6.87 (m, 2H), 5.15
(s, 2H), 4.09-4.05 (m, 1H), 3.79 (s, 3H), 3.64-3.54 (m, 1H),
3.46-3.36 (m, 1H), 3.14 (dd, 1H, J ) 13.9, 3.8 Hz), 3.00 (dd, 1H,
J ) 14.1, 8.1 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 372 (M + H+). HRMS (FAB) calcd for C21H25NO5 (M
+ H+), 372.1811; found, 372.1815.
(R)-3-(3-((E)-1-(4-(tert-Butylbenzyloxyimino)ethyl)phenyl)-2-
ethoxypropanoic Acid (41). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.54-7.51 (m, 2H), 7.40-7.26 (m, 6H), 5.20 (s, 2H),
4.09 (dd, 1H, J ) 7.8, 4.0 Hz), 3.60-3.52 (m, 1H), 3.50-3.41 (m,
1H), 3.16 (dd, 1H, J ) 13.9, 3.8 Hz), 3.00 (dd, 1H, J ) 14.1, 7.9
Hz), 2.24 (s, 3H), 1.31 (s, 9H), 1.15 (t, 3H, J ) 6.96 Hz). LRMS
(FAB) m/z 398 (M + H+). HRMS (FAB) calcd for C24H31NO4 (M
+ H+), 398.2331; found, 398.2318.
(R)-3-(3-((E)-1-Benzyloxyiminoethyl)phenyl)-2-ethoxypropano-
ic Acid (32). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.53-7.50 (m, 2H), 7.42-7.25 (m, 7H), 5.22 (s, 2H), 4.07 (dd,
1H, J ) 8.1, 4.0 Hz), 3.64-3.54 (m, 1H), 3.45-3.35 (m, 1H), 3.14
(dd, 1H, J ) 14.1, 4.0 Hz), 3.00 (dd, 1H, J ) 14.0, 8.1 Hz), 2.24
(s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 342 (M +
H+). HRMS (FAB) calcd for C20H24NO4 (M + H+), 342.1705;
found, 342.1709.
4-((S)-2-(Ethoxycarbonyl)-2-ethoxyethyl)phenyltrifluo-
romethanesulfonate (43). To a solution of (S)-ethyl 2-ethoxy-3-
(4-hydroxyphenyl)propanoate(42)14 (94 mg, 0.394 mmol) in CH2Cl2
(10 mL) at 0 °C were added triethylamine (0.22 mL, 1.58 mmol)
and triflic anhydride (Tf2O) (dropwise 0.1 mL, 0.591 mmol). The
mixture was warmed to ambient temperature and stirred for several
hours until the starting material had been fully consumed as verified
by TLC (EtOAc:n-hexane ) 1:2). The reaction was then quenched
with H2O and CH2Cl2. The organic layer so obtained was washed
with H2O, dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography (EtOAc:
n-hexane ) 1:5) afforded 118 mg (81%) of 43 as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 7.33-7.29 (m, 2H), 7.20-7.16 (m,
2H), 4.15 (q, 2H, J ) 7.1 Hz), 3.97 (dd, 1H, J ) 7.6, 5.7 Hz),
3.7-3.6 (m, 1H), 3.37-3.27 (m, 1H), 3.05-2.99 (m, 2H), 1.20 (t,
3H, J ) 6.8 Hz), 1.13 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 371
(M + H+).
(R)-3-(3-((E)-1-(4-Fluorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (33). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.52-7.48 (m, 2H), 7.39-7.22 (m, 4H), 7.06-7.00 (m, 2H), 5.17
(s, 2H), 4.07 (dd, 1H, J ) 8.1, 4.0 Hz), 3.64-3.54 (m, 1H),
3.45-3.35 (m, 1H), 3.14 (dd, 1H, J ) 14.0, 4.1 Hz), 3.00 (dd, 1H,
J ) 14.1, 8.1 Hz), 2.23 (s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 360 (M + H+). HRMS (FAB) calcd for C20H23FNO4
(M + H+), 360.1611; found, 360.1614.
(R)-3-(3-((E)-1-(4-Chlorobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (34). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.51-7.48 (m, 2H), 7.35-7.25 (m, 6H), 5.18 (s, 2H), 4.07 (dd,
1H, J ) 7.8, 3.9 Hz), 3.61-3.53 (m, 1H), 3.46-3.38 (m, 1H), 3.14
(dd, 1H, J ) 14.1, 4.2 Hz), 3.00 (dd, 1H, J ) 14.1, 7.9 Hz), 2.23
(s, 3H), 1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 376 (M +
H+). HRMS (FAB) calcd for C20H23ClNO4 (M + H+), 376.1316;
found, 376.1305.
(R)-3-(3-((E)-1-(4-Bromobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (35). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.50-7.45 (m, 4H), 7.30-7.25 (m, 4H), 5.16 (s, 2H), 4.08 (dd,
1H, J ) 7.8, 4.1 Hz), 3.60-3.52 (m, 1H), 3.47-3.39 (m, 1H), 3.15
(dd, 1H, J ) 14.1, 3.8 Hz), 3.00 (dd, 1H, J ) 14.1, 7.9 Hz), 2.23
(s, 3H), 1.14 (t, 3H, J ) 7.1 Hz). LRMS (FAB) m/z 420 (M +
H+). HRMS (FAB) calcd for C20H24BrNO4 (M + H+), 420.0810;
found, 420.0810.
(R)-3-(3-((E)-1-(4-Iodobenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (36). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.68-7.13 (m, 8H), 5.15 (s, 2H), 4.09 (m, 1H), 3.57 (m, 1H),
3.43 (m, 1H), 3.16-3.13 (m, 1H), 3.00 (m, 1H), 2.23 (s, 3H), 1.14
(t, 3H, J ) 6.50 Hz). LRMS (FAB) m/z 468 (M + H+). HRMS
(FAB) calcd for C20H24INO4 (M + H+), 468.0672; found, 468.0662.
(S)-Ethyl-2-ethoxy-3-phenylpropanoate (44a). To a solution of
43 (118 mg, 0.319 mmol), triphenylphosphine (20 mg, cat), and
Pd(OAc)2 (18 mg, cat) in anhydrous DMF (2 mL) were added
triethylamine (0.14 mL, 0.957 mmol) and formic acid (0.04 mL,
0.957 mmol). The mixture was then warmed to 60 °C, stirred for
several hours until the starting material had been fully consumed
(confirmed by TLC (EtOAc:n-hexane ) 1:5)). The reaction mixture
was then quenched with brine and Et2O. The organic layer so
obtained, was washed with H2O, dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash column
chromatography (EtOAc:n-hexane ) 1:10) afforded 13 mg (42%)
of 44 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.30-7.17
(m, 5H), 7.20-7.16 (m, 2H), 4.15 (dd, 2H, J ) 7.1, 7.0 Hz), 3.99
(dd, 1H, J ) 7.1, 6.4 Hz), 3.63-3.53 (m, 1H), 3.38-3.28 (m, 1H),
3.00-2.98 (m, 2H), 1.20 (t, 3H, J ) 7.1 Hz), 1.14 (t, 3H, J ) 7.0
(R)-3-(3-((E)-1-(4-Trifluoromethylbenzyloxyimino)ethyl)phenyl)-
1
25
Hz). LRMS (FAB) m/z 223 (M + H+). [R]D ) -22.75 (c 0.44,
2-ethoxypropanoic Acid (37). Colorless oil. H NMR (300 MHz,
CDCl3) δ 7.61-7.48 (m, 6H), 7.30-7.22 (m, 2H), 5.26 (s, 2H),
4.07 (dd, 1H, J ) 8.0, 4.1 Hz), 3.63-3.53 (m, 1H), 3.45-3.35 (m,
1H), 3.13 (dd, 1H, J ) 14.1, 4.0 Hz), 2.99 (dd, 1H, J ) 14.2, 8.0
Hz), 2.26 (s, 3H), 1.13 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 410
(M + H+). HRMS (FAB) calcd for C21H22F3NO4 (M + H+),
410.1579; found, 410.1575.
(R)-3-(3-((E)-1-(4-Hydroxybenzyloxyimino)ethyl)phenyl)-2-ethox-
ypropanoic Acid (38). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.52-7.49 (m, 2H), 7.31-7.20 (m, 4H), 6.82-6.79 (m, 2H), 5.13
(s, 2H), 4.08 (dd, 1H, J ) 7.98, 3.93 Hz), 3.60-3.52 (m, 1H),
3.48-3.38 (m, 1H), 3.15 (dd, 1H, J ) 14.1, 3.9 Hz), 3.00 (dd, 1H,
J ) 14.0, 7.8 Hz), 2.21 (s, 3H), 1.15 (t, 3H, J ) 7.0 Hz). LRMS
(FAB) m/z 358 (M + H+). HRMS (FAB) calcd for C20H23NO5 (M
+ H+), 358.1654; found, 358.1651.
MeOH).
(S)-Ethyl 2-ethoxy-3-(3-hydroxyphenyl)-2-ethoxypropanoate (46).
To a solution of (S)-ethyl 3-(3-acetoxyphenyl)-2-ethoxypropanoate
45a (281 mg, 1.06 mmol), which was prepared from 14 by
transesterification using TMSCl and EtOH mentioned below, in
CH2Cl2 (25 mL) were added sodium percarbonate (2.50 mg, 15.95
mmol) and trifluoroacetic anhydride (0.6 mL, 4.25 mmol). The
mixture was then stirred for several hours at ambient temperature
until the starting material had been fully consumed (confirmed by
TLC (EtOAc:n-hexane ) 1:2)). The reaction mixture was then
quenched with H2O and CH2Cl2 was added. The organic layer so
obtained, was washed with H2O, dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash column
chromatography (EtOAc:n-hexane ) 1:2) afforded 140 mg (47%)
of ester as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.85-6.93
(m, 4H), 4.15 (dd, 2H, J ) 7.1, 7.0 Hz), 3.98 (dd, 1H, J ) 7.5, 5.9
Hz), 3.64-3.54 (m, 1H), 3.38-3.28 (m, 1H), 3.06-2.97 (m, 2H),
2.27 (s, 2H), 1.20 (t, 3H, J ) 7.1 Hz), 1.14 (t, 3H, J ) 7.0 Hz).
LRMS (FAB) m/z 281 (M + H+).
(R)-3-(3-((E)-1-(4-Methanesulfonyloxybenzyloxyimino)ethyl)phenyl)-
1
2-ethoxypropanoic Acid (39). Colorless oil. H NMR (300 MHz,
CDCl3) δ 7.51-7.43 (m, 4H), 7.31-7.22 (m, 4H), 5.21 (s, 2H),
4.07 (dd, 1H, J ) 7.7, 4.0 Hz), 3.61-3.55 (m, 1H), 3.45-3.40 (m,
1H), 3.17-3.13 (m, 4H), 3.00 (dd, 1H, J ) 14.1, 7.7 Hz), 2.24 (s,
3H), 1.14 (t, 3H, J ) 6.9 Hz). LRMS (FAB) m/z 436 (M + H+).
HRMS (FAB) calcd for C21H25NO7S (M + H+), 436.1430; found,
436.1418.
TMSCl (0.2 mL, 1.58 mmol) was added to a solution of provided
ester (140 mg, 0.525 mmol) in EtOH (10 mL), and stirred for several
hours at 80 °C until the starting material had been fully consumed

6330 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
(confirmed by TLC (EtOAc:n-hexane ) 1:2)). The reaction mixture
was the concentrated in vacuo and purification of this residue by
flash column chromatography (EtOAc:n-hexane ) 1:2) afforded
95 mg (81%) of 46 as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.16-7.10 (m, 1H), 6.80-6.67 (m, 3H), 4.82 (s, 1H), 4.16 (q,
2H, J ) 7.1 Hz), 3.99 (dd, 1H, J ) 7.2, 6.0 Hz), 3.64-3.54 (m,
1H), 3.40-3.30 (m, 1H), 2.95-2.93 (m, 2H), 1.21 (t, 3H, J ) 7.1
Hz), 1.15 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 239 (M + H+).
(S)-Ethyl 2-ethoxy-3-phenylpropanoate (44b). Compound 44b
was prepared (24% yield for a 2-stage process) from 46 using the
procedure described for compound 44a. 1H NMR (300 MHz,
CDCl3) δ 7.30-7.17 (m, 5H), 7.20-7.16 (m, 2H), 4.15 (dd, 2H, J
) 7.1, 7.0 Hz), 3.99 (dd, 1H, J ) 7.1, 6.4 Hz), 3.63-3.53 (m,
1H), 3.38-3.28 (m, 1H), 3.00-2.98 (m, 2H), 1.20 (t, 3H, J ) 7.1
Hz), 1.14 (t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 223 (M + H+).
CDCl3) δ 9.98 (s, 1H), 7.76-7.73 (m, 2H), 7.53-7.41 (m, 2H),
4.16 (q, 2H, J ) 7.0 Hz), 4.04-3.99 (m, 1H), 3.67-3.57 (m, 1H),
3.37-3.27 (m, 1H), 3.13-3.01 (m, 2H), 1.22 (t, 3H, J ) 7.0 Hz),
1.13 (t, 3H, J ) 7.0 Hz).
Ethyl 2-Ethoxy-3-(3-benzaldehyde-(E)-oxime)propanoate (56).
Hydroxylamine HCl (1.01 g, 14.6 mmol) was added to a solution
of 55 (3.04 g, 12.2 mmol) in pyridine (25 mL). The mixture was
refluxed for 5 h, cooled to room temperature, and concentrated in
vacuo. EtOAc was then added, and the organic layer so obtained
was washed with H2O, dried over MgSO4, filtered, and concentrated
in vacuo. Purification of the residue by flash column chromatog-
raphy (EtOAc:n-hexane ) 1:5) afforded 3.14 g (97%) of 56 as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.96
-7.42 (m, 2H), 7.32-7.27 (m, 1H), 4.15 (q, 2H, J ) 7.0 Hz),
4.02-3.97 (m, 1H), 3.65-3.55 (m, 1H), 3.37-3.27 (m, 1H),
3.07-2.94 (m, 2H), 1.20 (t, 3H, J ) 7.0 Hz), 1.13 (t, 3H, J ) 7.0
Hz). LRMS (FAB) m/z 266 (M + H+).
Representative Procedure for the Synthesis of 57a-k: The
Preparation of Ethyl-2-ethoxy-3-(3-(5-phenyl-4,5-dihydroisoxazole-
3-yl)phenyl)propanoate (57a). NaOCl (10-13% solution, 2 mL)
was added to a solution of 56 (879 mg, 3.31 mmol) and styrene
(0.42 mL, 3.64 mL) in CH2Cl2 (25 mL). The mixture was stirred
for 2 h at ambient temperature and then CH2Cl2 was added. The
organic layer so obtained was washed with water, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash column chromatography (EtOAc:n-hexane ) 1:5)
afforded 1.00 g (82%) of 57a as a colorless oil. 1H NMR (300
MHz, CDCl3) δ 7.59-7.52 (m, 2H), 7.39-7.29 (m, 7H), 5.72 (dd,
1H, J ) 10.9, 8.2 Hz), 4.16 (q, 2H, J ) 7.0 Hz), 3.99 (dd, 1H, J
) 7.3, 5.7 Hz), 3.76 (ddd, 1H, J ) 16.7, 11.0, 0.9 Hz), 3.65-3.55
(m, 1H), 3.36-3.26 (m, 2H), 3.07-2.94 (m, 2H), 1.22 (t, 3H, J )
7.1 Hz), 1.16 (dt, 3H, J ) 2.73, 6.96 Hz). LRMS (FAB) m/z 368
(M + H+).
25
[R]D ) -22.87 (c 0.44, MeOH).
Ethyl 2-Ethoxy-3-(3-formylphenyl)acrylate (52). Tetrameth-
ylguanidine (4.01 mL, 32.0 mmol) was added dropwise to a solution
of commercially available isophthalaldehyde 51 (2.86 g, 21.3 mmol)
in CH2Cl2 (100 mL) and (1,2-diethoxy-2-oxoethyl)triphenylphos-
phonium chloride 11 (8.23 g, 19.2 mmol) at 0 °C. The mixture
was warmed to ambient temperature and then stirred for several
hours until the starting material had been fully consumed (verified
by TLC (EtOAc:n-hexane ) 1:2)). After adding CH2Cl2, the organic
layer so obtained, was washed with saturated NH4Cl and brine,
dried over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography (EtOAc:n-hexane
1
) 1:5) afforded 4.03 g (85%) of 52 as a colorless oil. H NMR
(300 MHz, CDCl3) δ 10.01 (s, 1H), 8.29 (s, 1H), 8.01 (d, 1H, J )
7.7 Hz), 7.81 (d, 1H, J ) 7.5 Hz), 7.51 (t, 1H, J ) 7.7 Hz), 6.98
(s, 1H), 4.30 (q, 2H, J ) 7.1 Hz), 4.05 (q, 2H, J ) 6.9 Hz), 1.37
(t, 3H, J ) 7.0 Hz), 1.37 (t, 3H, J ) 7.0 Hz).
Ethyl 3-(3-(1,3-Dioxolan-2-yl)phenyl)-2-ethoxyacrylate (53). To
a solution of 52 (4.03 g, 16.2 mmol) in benzene (50 mL) were
added p-toluenesulfonic acid (PTSA) (308 mg, 1.62 mmol) and
ethylene glycol (1.81 mL, 32.5 mmol). The reaction mixture was
then refluxed in a Dean & Stark apparatus for several hours until
the starting material had been fully consumed (verified by TLC
(EtOAc:n-hexane ) 1:2)). The mixture was then cooled to room
temperature and concentrated in vacuo, and EtOAc was added. The
organic layer so obtained, was washed with H2O and NaHCO3
solution, dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography (EtOAc:
n-hexane ) 1:5) afforded 4.75 g (100%) of 53 as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.80-7.76 (m, 1H),
7.42-7.33 (m, 2H), 6.98 (s, 1H), 4.28 (q, 2H, J ) 7.1 Hz),
4.16-4.00 (m, 4H), 3.98 (q, 2H, J ) 7.1 Hz), 1.35 (t, 3H, J ) 7.0
Hz), 1.35 (t, 3H, J ) 7.0 Hz).
Ethyl 3-(3-(1,3-Dioxolan-2-yl)phenyl)-2-ethoxypropanoate (54).
A catalytic amount of Pd on carbon was added to a solution of 53
(4.75 g, 48.8 mmol) in THF (35 mL) under H2, and stirred for
several hours at ambient temperature until the starting material had
been fully consumed (verified by TLC (EtOAc:n-hexane ) 1:2)).
EtOAc was then added, and the mixture was filtered using a Celite
pad and concentrated in vacuo. Purification of the residue by flash
column chromatography (EtOAc:n-hexane ) 1:5) afforded 4.74 g
(99%) of 54 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.76-7.73 (m, 1H), 7.53-7.41 (m, 1H), 7.35-7.18 (m, 2H), 5.77
(s, 1H), 4.20-3.96 (m, 6H), 3.72 (s, 1H), 3.64-3.53 (m, 1H),
3.35-3.25 (m, 1H), 3.09-2.94 (m, 2H), 1.20 (t, 3H, J ) 7.0 Hz),
1.13 (t, 3H, J ) 7.0 Hz).
Representative Procedure for the Synthesis of 58a-k and
59a-k: The Preparation (S)-3-(3-(5-Benzyl-4,5-dihydroisoxazole-
3-yl)phenyl)-ethoxy-N-((S)-2-hydroxy-1-phenylethyl) propanamide
(58a) and (R)-3-(3-(5-benzyl-4,5-dihydroisoxazole-3-yl)phenyl)-
ethoxy-N-((S)-2-hydroxy-1-phenylethyl)propanamide (59a). To a
solution of 57 (920 mg, 2.71 mmol) in CH2Cl2 (25 mL) at ambient
temperature were added 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide hydrochloride, diisopropylethylamine (572 mg, 2.98 mmol),
(R)-(-)-2-phenylgycinol (409 mg, 2.98 mmol), and HOBT (403
mg, 2.98 mmol). The mixture was then cooled to 0 °C and
diisopropylethylamine (0.52 mL, 2.98 mmol) was added dropwise.
The reaction mixture was then stirred for 18 h at ambient
temperature and quenched with brine. CH2Cl2 was then added, and
the organic layer so obtained was washed with H2O, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash column chromatography (EtOAc:n-hexane ) 1:1)
afforded 482 mg (39%) of 58a as a colorless oil and 461 mg (37%)
of 59a also as a colorless oil.
58a: 1H NMR (300 MHz, CDCl3) δ 7.59-7.56 (m, 2H),
7.40-7.26 (m, 9H), 7.17-7.15 (m, 2H), 7.05 (d, 1H, J ) 7.1 Hz),
5.73 (dd, 1H, J ) 11.0, 8.3 Hz), 5.00-4.93 (m, 1H), 4.01 (dd, 1H,
J ) 6.0, 4.1 Hz), 3.84-3.75 (m, 1H), 3.71-3.61 (m, 2H), 3.49 (q,
2H, J ) 7.0 Hz), 3.40-3.28 (m, 1H), 3.18 (dd, 1H, J ) 14.1, 2.9
Hz), 3.05 (dd, 1H, J ) 14.2, 6.1 Hz), 1.16 (dt, 3H, J ) 0.7, 7.0
Hz). LRMS (FAB) m/z 459 (M + H+).
1
59a: H NMR (300 MHz, CDCl3) δ 7.60-7.01 (m, 14H), 5.69
(m, 1H), 4.98 (m, 1H), 4.04 (m, 1H), 3.83-3.82 (m, 2H), 3.66-3.45
(m, 3H), 3.24-3.10 (m, 2H), 2.99 (m, 1H), 3.02 (dd, 1H, J ) 14.4,
7.7 Hz), 1.18 (dt, 3H, J ) 3.8, 7.0 Hz). LRMS (FAB) m/z 459 (M
+ H+).
Ethyl 2-Ethoxy-3-(3-formylphenyl)propanoate (55). 2N HCl (5
mL) was added to a solution of 54 (4.78 g, 16.3 mmol) in THF
(25 mL). The mixture was then refluxed for several hours until the
starting material had been fully consumed (verified by TLC (EtOAc:
n-hexane ) 1:2)), then cooled to room temperature, quenched with
NaHCO3, and concentrated in vacuo. EtOAc was then added and
the organic layer so obtained was washed with H2O, dried over
MgSO4, filtered, then concentrated in vacuo. Purification of the
residue by flash column chromatography (EtOAc:n-hexane ) 1:5)
afforded 3.04 g (75%) of 55 as a colorless oil. 1H NMR (300 MHz,
Representative Procedure for the Synthesis of Compounds
60-81: Preparation of (2(S)-2-Ethoxy-3-(3-(5-phenyl-4,5-dihy-
droisoxazole-3-yl)phenyl)propanoic Acid (60). c-H2SO4 (4 mL) was
added dropwise to a solution of 58 (482 mg, 1.05 mmol) in 1,4-
dioxane:H2O (15:4, 19 mL). The mixture was then refluxed for
6 h, cooled to room temperature, and concentrated in vacuo. EtOAc
was added and the organic layer was washed with H2O, dried over
MgSO4, filtered, and concentrated in vacuo to afford 537 mg of 60

Constrained Meta-Substituted Phenyl Propanoic Acids
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6331
as a crude oil. To a solution of provided acid (537 mg) in MeOH
(15 mL), TMSCl (0.6 mL, 4.75 mmol) was added dropwise. The
reaction mixture was then refluxed for 2 h, cooled to room
temperature, quenched with NaHCO3, and concentrated in vacuo.
EtOAc was then added and the organic layer so obtained was
washed with H2O, dried over MgSO4, filtered, and concentrated in
vacuo. Purification of the residue by flash column chromatography
(EtOAc:n-hexane ) 1:5) afforded 323 mg (87% yield for the two
steps) of ester as a colorless oil. LiOH ·H2O (75 mg, 1.78 mmol)
was then added to a solution of (2S)-ethyl 2-ethoxy-3-(3-(5-phenyl-
4,5-dihydroisoxazol-3-yl)phenyl)propanoate (314 mg, 0.89 mmol)
in THF/H2O/MeOH (15:3:7, 25 mL) and stirred for 5 h at ambient
temperature. The reaction was quenched with 2N-HCl and con-
centrated in vacuo. EtOAc was then added and the organic layer
so obtained was washed with H2O, dried over MgSO4, filtered, and
concentrated in vacuo to afford 302 mg (100%) of 60 as a yellow
oil. 1H NMR (300 MHz, CDCl3) δ 7.60-7.53 (m, 2H), 7.37-7.28
(m, 7H), 5.72 (dd, 1H, J ) 10.8, 8.3 Hz), 4.08 (dd, 1H, J ) 7.70,
4.2 Hz), 3.76 (dd, 1H, J ) 16.7, 11.0 Hz), 3.66-3.56 (m, 1H),
3.47-3.40 (m, 1H), 3.32 (dd, 1H, J ) 16.7, 8.2 Hz), 3.14 (dd, 1H,
J ) 14.1, 4.2 Hz), 3.01 (dd, 1H, J ) 14.0, 7.8 Hz), 1.15 (dt, 3H,
J ) 2.2, 7.0 Hz). LRMS (FAB) m/z 340 (M + H+). HRMS (FAB)
calcd for C20H21NO4 (M + H+), 340.1549; found, 340.1553.
(S)-2-Ethoxy-3-(3-(5-(4-fluorophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (61). Colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.59-7.52 (m, 2H), 7.37-7.28 (m, 4H), 7.08-7.00 (m,
2H), 5.70 (dd, 1H, J ) 10.9, 8.3 Hz), 4.08 (dd, 1H, J ) 7.8, 4.3
Hz), 3.75 (dd, 1H, J ) 16.7, 10.8 Hz), 3.66-3.56 (m, 1H),
3.48-3.38 (m, 1H), 3.28 (dd, 1H, J ) 16.7, 8.2 Hz), 3.14 (dd, 1H,
J ) 14.1, 4.2 Hz), 3.02 (dd, 1H, J ) 14.0, 7.8 Hz), 1.15 (dt, 3H,
J ) 2.2, 7.0 Hz). LRMS (FAB) m/z 358 (M + H+). HRMS (FAB)
calcd for C20H20FNO4 (M + H+), 358.1455; found, 358.1445.
(S)-2-Ethoxy-3-(3-(5-(4-chlorophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (62). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.57-7.52 (m, 2H), 7.35-7.29 (m, 6H), 5.70 (dd, 1H, J
) 11.0, 8.1 Hz), 4.09 (dd, 1H, J ) 7.4, 4.3 Hz), 3.76 (dd, 1H, J )
16.7, 11.0 Hz), 3.65-3.55 (m, 1H), 3.51-3.43 (m, 1H), 3.27 (dd,
1H, J ) 16.7, 8.2 Hz), 3.15 (dd, 1H, J ) 14.1, 4.2 Hz), 3.02 (dd,
1H, J ) 14.1, 7.5 Hz), 1.16 (dt, 3H, J ) 2.0, 7.0 Hz). LRMS (FAB)
m/z 374 (M + H+). HRMS (FAB) calcd for C20H20ClNO4 (M +
H+), 374.1159; found, 374.1167.
2H), 7.36-7.27 (m, 4H), 5.74 (dd, 1H, J ) 10.8, 7.7 Hz), 4.09
(dd, 1H, J ) 7.4, 4.1 Hz), 3.79 (dd, 1H, J ) 16.7, 11.0 Hz),
3.66-3.56 (m, 1H), 3.50-3.40 (m, 1H), 3.29 (dd, 1H, J ) 16.7,
7.9 Hz), 3.18-3.13 (m, 4H), 3.02 (dd, 1H, J ) 14.2, 7.4 Hz), 1.16
(dt, 3H, J ) 1.8, 7.0 Hz). LRMS (FAB) m/z 434 (M + H+). HRMS
(FAB) calcd for C21H23NO7S (M + H+), 434.1273; found,
434.1276.
(S)-2-Ethoxy-3-(3-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (67). Colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.59-7.54 (m, 2H), 7.36-7.28 (m, 4H), 6.90-6.87 (m,
2H), 5.67 (dd, 1H, J ) 10.7, 8.7 Hz), 4.09 (dd, 1H, J ) 7.6, 4.3
Hz), 3.79 (s, 3H), 3.70 (dd, 1H, J ) 16.6, 10.9 Hz), 3.65-3.55
(m, 1H), 3.51-3.43 (m, 1H), 3.30 (dd, 1H, J ) 16.7, 8.6 Hz), 3.15
(dd, 1H, J ) 14.1, 4.2 Hz), 3.02 (dd, 1H, J ) 14.2, 7.6 Hz), 1.16
(dt, 3H, J ) 1.4, 7.0 Hz). LRMS (FAB) m/z 370 (M + H+). HRMS
(FAB) calcd for C21H23NO5 (M + H+), 370.1654; found, 370.1653.
(S)-2-Ethoxy-3-(3-(5-(4-(tert-butylphenyl)-4,5-dihydroisoxazol-
3-yl)phenyl)propanoic Acid (68). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.59-7.54 (m, 2H), 7.40-7.24 (m, 6H), 5.70 (dd, 1H, J
) 10.8, 8.4 Hz), 4.10 (dd, 1H, J ) 7.5, 4.2 Hz), 3.72 (dd, 1H, J )
16.6, 10.9 Hz), 3.62-3.44 (m, 2H), 3.33 (dd, 1H, J ) 16.7, 8.4
Hz), 3.16 (dd, 1H, J ) 14.0, 4.3 Hz), 3.02 (dd, 1H, J ) 14.0, 7.4
Hz), 1.30 (s, 9H), 1.16 (dt, 3H, J ) 1.5, 7.0 Hz). LRMS (FAB)
m/z 396 (M + H+). HRMS (FAB) calcd for C24H29NO4 (M + H+),
396.2175; found, 396.2185.
(S)-3-(3-(5-Benzyl-4,5-dihydroisoxazol-3-yl)phenyl)-2-ethoxypro-
panoic Acid (69). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.52-7.49 (m, 2H), 7.34-7.24 (m, 7H), 4.98 (m, 1H), 4.08-4.07
(m, 1H), 3.61-3.56 (m, 1H), 3.47-3.44 (m, 1H), 3.29 (dd, 1H, J
) 16.7, 10.3 Hz), 3.20-3.12 (m, 2H), 3.07-2.99 (m, 2H), 2.87
(dd, 1H, J ) 13.7, 7.3 Hz), 1.15 (t, 3H, J ) 7.0 Hz). LRMS (FAB)
m/z 354 (M + H+). HRMS (FAB) calcd for C21H23NO4 (M + H+),
354.1705; found, 354.1710.
(S)-2-Ethoxy-3-(3-(4,5-dihydro-5-phenethylisoxazol-3-yl)phenyl-
1
)propanoic Acid (70). Colorless oil. H NMR (300 MHz, CDCl3)
δ 7.55-7.51 (m, 2H), 7.34-7.19 (m, 7H), 4.72 (m, 1H), 4.09 (dd,
1H, J ) 7.8, 4.1 Hz), 3.63-3.55 (m, 1H), 3.47-3.33 (m, 2H), 3.15
(dd, 1H, J ) 14.0, 3.9 Hz), 3.05-2.91 (m, 2H), 2.83-2.74 (m,
2H), 2.11-2.08 (m, 1H), 1.92 (m, 1H), 1.16 (t, 3H, J ) 7.1 Hz).
LRMS (FAB) m/z 368 (M + H+). HRMS (FAB) calcd for
C22H25NO4 (M + H+), 368.1862; found, 368.1855.
(S)-2-Ethoxy-3-(3-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (63). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.56-7.47 (m, 4H), 7.36-7.27 (m, 4H), 5.68 (dd, 1H, J
) 11.0, 8.1 Hz), 4.10 (dd, 1H, J ) 7.3, 4.2 Hz), 3.76 (dd, 1H, J )
16.8, 11.1 Hz), 3.62-3.48 (m, 2H), 3.26 (dd, 1H, J ) 16.6, 8.2
Hz), 3.16 (dd, 1H, J ) 14.3, 4.05 Hz), 3.02 (dd, 1H, J ) 14.2, 7.2
Hz), 1.17 (dt, 3H, J ) 1.9, 7.0 Hz). LRMS (FAB) m/z 418 (M +
H+). HRMS (FAB) calcd for C20H20BrNO4 (M + H+), 418.0654;
found, 418.0643.
(R)-2-Ethoxy-3-(3-(4,5-dihydro-5-phenylisoxazole-3-yl)phenyl-
1
)propanoic Acid (71). Colorless oil. H NMR (300 MHz, CDCl3)
δ 7.60-7.53 (m, 2H), 7.38-7.31 (m, 7H), 5.73 (dd, 1H, J ) 10.8,
8.3 Hz), 4.09 (dd, 1H, J ) 7.9, 4.2 Hz), 3.76 (dd, 1H, J ) 16.7,
11.0 Hz), 3.66-3.56 (m, 1H), 3.48-3.38 (m, 1H), 3.32 (dd, 1H, J
) 16.7, 8.2 Hz), 3.15 (dd, 1H, J ) 14.1, 4.0 Hz), 3.01 (dd, 1H, J
) 14.2, 7.8 Hz), 1.15 (dt, 3H, J ) 2.1, 7.0 Hz). LRMS (FAB) m/z
340 (M + H+). HRMS (FAB) calcd for C20H21NO4 (M + H+),
340.1549; found, 340.1554.
(S)-2-Ethoxy-3-(3-(5-(4-iodophenyl)-4,5-dihydroisoxazol-3-yl)phe-
nyl)propanoic Acid (64). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.70-7.67 (m, 2H), 7.57-7.51 (m, 2H), 7.35-7.28 (m, 2H),
7.13-7.11 (m, 2H), 5.67 (dd, 1H, J ) 10.9, 8.0 Hz), 4.09 (dd, 1H,
J ) 7.5, 4.4 Hz), 3.76 (dd, 1H, J ) 16.5, 11.0 Hz), 3.65-3.55 (m,
1H), 3.48-3.42 (m, 1H), 3.26 (dd, 1H, J ) 16.7, 8.0 Hz), 3.15
(dd, 1H, J ) 14.0, 4.3 Hz), 3.02 (dd, 1H, J ) 14.0, 7.6 Hz), 1.16
(dt, 3H, J ) 2.1, 7.1 Hz). LRMS (FAB) m/z 466 (M + H+). HRMS
(FAB) calcd for C20H20INO4 (M + H+), 466.0515; found, 466.0517.
(S)-2-Ethoxy-3-(3-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (65). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.58-7.53 (m, 2H), 7.35-7.22 (m, 4H), 6.82-6.80 (m,
2H), 5.65 (dd, 1H, J ) 10.8, 8.4 Hz), 4.08 (dd, 1H, J ) 7.7, 4.0
Hz), 3.70 (dd, 1H, J ) 16.7, 10.8 Hz), 3.65-3.55 (m, 1H),
3.48-3.38 (m, 1H), 3.29 (dd, 1H, J ) 16.8, 8.4 Hz), 3.14 (dd, 1H,
J ) 14.0, 4.5 Hz), 3.01 (dd, 1H, J ) 14.2, 7.6 Hz), 1.16 (dt, 3H,
J ) 1.2, 7.1 Hz). LRMS (FAB) m/z 356 (M + H+). HRMS (FAB)
calcd for C20H21NO5 (M + H+), 356.1498; found, 356.1508.
(S)-2-Ethoxy-3-(3-(5-(4-methanesulfonyloxyphenyl)-4,5-dihy-
droisoxazol-3-yl)phenyl)propanoic Acid (66). Colorless oil. 1H
NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 2H), 7.45-7.42 (m,
(R)-2-Ethoxy-3-(3-(5-(4-fluorophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (72). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.58-7.53 (m, 6H), 7.37-7.28 (m, 4H), 7.08-7.01 (m,
2H), 5.70 (dd, 1H, J ) 10.9, 8.34 Hz), 4.08 (dd, 1H, J ) 7.61,
4.31 Hz), 3.75 (dd, 1H, J ) 16.7, 10.8 Hz), 3.66-3.56 (m, 1H),
3.49-3.38 (m, 1H), 3.28 (dd, 1H, J ) 16.6, 8.3 Hz), 3.14 (dd, 1H,
J ) 14.0, 4.3 Hz), 3.02 (dd, 1H, J ) 14.0, 7.6 Hz), 1.16 (dt, 3H,
J ) 2.2, 7.0 Hz). LRMS (FAB) m/z 358 (M + H+). HRMS (FAB)
calcd for C20H20FNO4 (M + H+), 358.1455; found, 358.1445.
(R)-2-Ethoxy-3-(3-(5-(4-chlorophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (73). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.56-7.52 (m, 2H), 7.36-7.30 (m, 6H), 5.70 (dd, 1H, J
) 10.9, 8.0 Hz), 4.10 (dd, 1H, J ) 7.5, 4.2 Hz), 3.76 (dd, 1H, J )
16.6, 11.1 Hz), 3.63-3.55 (m, 1H), 3.49-3.44 (m, 1H), 3.27 (dd,
1H, J ) 16.8, 8.2 Hz), 3.15 (dd, 1H, J ) 14.0, 4.3 Hz), 3.02 (dd,
1H, J ) 14.1, 7.3 Hz), 1.16 (dt, 3H, J ) 2.0, 7.0 Hz). LRMS (FAB)
m/z 374 (M + H+). HRMS (FAB) calcd for C20H20ClNO4 (M +
H+), 374.1159; found, 374.1169.
(R)-2-Ethoxy-3-(3-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (74). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.57-7.47 (m, 4H), 7.36-7.27 (m, 4H), 5.68 (dd, 1H, J

6332 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Suh et al.
) 11.0, 8.1 Hz), 4.10 (dd, 1H, J ) 7.4, 4.3 Hz), 3.76 (dd, 1H, J )
16.7, 11.0 Hz), 3.65-3.55 (m, 1H), 3.51-3.43 (m, 1H), 3.26 (dd,
1H, J ) 16.7, 8.2 Hz), 3.15 (dd, 1H, J ) 14.1, 4.2 Hz), 3.02 (dd,
1H, J ) 14.0, 7.4 Hz), 1.16 (dt, 3H, J ) 2.1, 7.0 Hz). LRMS (FAB)
m/z 418 (M + H+). HRMS (FAB) calcd for C20H20BrNO4 (M +
H+), 418.0654; found, 418.0646.
3.68-3.54 (m, 1H), 3.49-3.39 (m, 1H), 3.23-3.03 (m, 2H), 1.16
(t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 338 (M + H+). HRMS
(FAB) calcd for C20H19NO4 (M + H+), 338.1392; found, 338.1382.
(R)-2-Ethoxy-3-(3-(5-phenylisoxazole-3-yl)phenyl)propanoic Acid
1
(85). Colorless oil. H NMR (300 MHz, CDCl3): 7.84-7.72 (m,
4H), 7.51-7.33 (m, 5H), 6.83-6.82 (m, 1H), 4.14-4.06 (m, 1H),
3.67-3.57 (m, 1H), 3.51-3.29 (m, 1H), 3.24-3.03 (m, 2H), 1.17
(t, 3H, J ) 7.0 Hz). LRMS (FAB) m/z 338 (M + H+). HRMS
(FAB) calcd for C20H19NO4 (M + H+), 338.1392; found, 338.1404.
(2(S)-Ethyl-3-(3-(5-(4-chlorophenyl)-4,5-dihydroisoxazol-3-yl)phe-
nyl)-2-ethoxy Propanoate (86). TMSCl (0.3 mL, 2.29 mmol) was
added dropwise to a solution of (S)-2-ethoxy-3-(3-(5-(4-chlorophe-
nyl)-4,5-dihydroisoxazol-3-yl)phenyl) propanoic acid 62 (285 mg,
0.76 mmol) in EtOH (20 mL). The reaction mixture was refluxed
for 15 h, cooled to room temperature, quenched with NaHCO3,
and concentrated in vacuo. EtOAc was then added, and the organic
layer so obtained was washed with H2O, dried over MgSO4, filtered,
and concentrated in vacuo. Purification of the residue by flash
column chromatography (EtOAc:n-hexane ) 1:5) afforded 273 mg
(89%) of 86 as a colorless oil.
(R)-2-Ethoxy-3-(3-(5-(4-iodophenyl)-4,5-dihydroisoxazol-3-yl)phe-
nyl)propanoic Acid (75). Colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.70-7.67 (m, 2H), 7.57-7.51 (m, 2H), 7.35-7.28 (m, 2H),
7.13-7.11 (m, 2H), 5.66 (dd, 1H, J ) 11.0, 8.1 Hz), 4.09 (dd, 1H,
J ) 7.5, 4.2 Hz), 3.76 (dd, 1H, J ) 16.7, 11.0 Hz), 3.65-3.55 (m,
1H), 3.50-3.42 (m, 1H), 3.26 (dd, 1H, J ) 16.7, 8.0 Hz), 3.14
(dd, 1H, J ) 14.2, 4.3 Hz), 3.02 (dd, 1H, J ) 14.2, 7.4 Hz), 1.16
(dt, 3H, J ) 2.1, 7.0 Hz). LRMS (FAB) m/z 466 (M + H+). HRMS
(FAB) calcd for C20H20INO4 (M + H+), 466.0515; found, 466.0524.
(R)-2-Ethoxy-3-(3-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (76). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.58-7.53 (m, 2H), 7.35-7.22 (m, 4H), 6.83-6.80 (m,
2H), 5.65 (dd, 1H, J ) 10.7, 8.7 Hz), 4.09 (dd, 1H, J ) 7.5, 4.4
Hz), 3.70 (dd, 1H, J ) 16.8, 10.9 Hz), 3.65-3.55 (m, 1H),
3.49-3.41 (m, 1H), 3.29 (dd, 1H, J ) 16.8, 8.5 Hz), 3.14 (dd, 1H,
J ) 14.0, 4.1 Hz), 3.02 (dd, 1H, J ) 13.8, 7.6 Hz), 1.16 (dt, 3H,
J ) 1.1, 7.0 Hz). LRMS (FAB) m/z 356 (M + H+). HRMS (FAB)
calcd for C20H21NO5 (M + H+), 356.1498; found, 356.1508.
(R)-2-Ethoxy-3-(3-(5-(4-methanesulfonyloxyphenyl)-4,5-dihy-
droisoxazol-3-yl)phenyl)propanoic Acid (77). Colorless oil. 1H
NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 2H), 7.45-7.42 (m,
2H), 7.36-7.27 (m, 4H), 5.74 (dd, 1H, J ) 10.8, 7.9 Hz), 4.09
(dd, 1H, J ) 7.4, 4.1 Hz), 3.79 (dd, 1H, J ) 16.7, 11.0 Hz),
3.66-3.56 (m, 1H), 3.51-3.41 (m, 1H), 3.29 (dd, 1H, J ) 16.7,
7.9 Hz), 3.18-3.13 (m, 4H), 3.02 (dd, 1H, J ) 14.2, 7.4 Hz), 1.16
(dt, 3H, J ) 1.7, 7.0 Hz). LRMS (FAB) m/z 434 (M + H+). HRMS
(FAB) calcd for C21H23NO7S (M + H+), 434.1273; found,
434.1279.
(R)-2-Ethoxy-3-(3-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-
yl)phenyl)propanoic Acid (78). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.59-7.54 (m, 2H), 7.36-7.29 (m, 4H), 6.91-6.87 (m,
2H), 5.67 (dd, 1H, J ) 10.9, 8.7 Hz), 4.09 (dd, 1H, J ) 7.6, 4.3
Hz), 3.79 (s, 3H), 3.70 (dd, 1H, J ) 16.7, 10.8 Hz), 3.66-3.55
(m, 1H), 3.50-3.40 (m, 1H), 3.30 (dd, 1H, J ) 16.7, 8.6 Hz), 3.15
(dd, 1H, J ) 14.1, 4.2 Hz), 3.02 (dd, 1H, J ) 14.2, 7.6 Hz), 1.16
(dt, 3H, J ) 1.4, 7.0 Hz). LRMS (FAB) m/z 370 (M + H+). HRMS
(FAB) calcd for C21H23NO5 (M + H+), 370.1654; found, 370.1653.
(R)-2-Ethoxy-3-(3-(5-(4-(tert-butylphenyl)-4,5-dihydroisoxazol-
3-yl)phenyl)propanoic Acid (79). Colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.59-7.54 (m, 2H), 7.40-7.27 (m, 6H), 5.70 (dd, 1H, J
) 10.8, 8.6 Hz), 4.10 (dd, 1H, J ) 7.5, 4.2 Hz), 3.72 (dd, 1H, J )
16.6, 10.9 Hz), 3.65-3.44 (m, 2H), 3.33 (dd, 1H, J ) 16.7, 8.6
Hz), 3.16 (dd, 1H, J ) 14.0, 4.1 Hz), 3.02 (dd, 1H, J ) 14.0, 7.4
Hz), 1.30 (s, 9H), 1.16 (dt, 3H, J ) 1.6, 7.0 Hz). LRMS (FAB)
m/z 396 (M + H+). HRMS (FAB) calcd for C24H29NO4 (M + H+),
396.2175; found, 396.2185.
(S)-Methyl 3-(3-acetylphenyl)-2-ethoxypropanoate (45b). Mo-
(CO)6 (88 mg, 0.33 mmol) was added to a solution of 86 (133 mg,
0.33 mmol) in CH3CN/H2O (100:1, 5 mL). The reaction mixture
was refluxed for 14 h, cooled to room temperature, concentrated,
and EtOAc was added. The mixture was then filtered using a celite
pad and concentrated in vacuo. The residue so obtained, was purified
by flash column chromatography (EtOAc:n-hexane ) 1:5) to afford
44 mg (51%) of 14 as a colorless oil.
Biology. In Vitro Transactivation Assay. PPAR transactivation
assays were conducted as previously described.2a,e The ligand
binding domains (LBD) of human PPARR and PPARγ receptors
were fused to the DNA binding domain (DBD) of the yeast
transcription factor Gal4. Briefly, CV-1 cells were transiently
transfected with an expression vector for the respective PPAR
chimera and with a reporter construct containing five copies of the
Gal4DNA binding site and with pRL-TK as a control vector
(Promega). Test compounds were dissolved in DMSO and diluted
1:1000 in media. Cells were treated with test compounds at seven
concentrations ranging from 0.03 to 100 µM for 24 h and then
subjected to a dual luciferase assay using Dual-Glo luciferase
reagent (Promega). EC50values were calculated by nonlinear
regression using SigmaPlot 4.0 (SPSS).
In Vivo Assay. Male obese db/db mice and lean control C57BL/6
mice were obtained from Japan SLC (Shizuoka, Japan). All mice
were provided with a standard diet and tap water ad libitum. All
mice (n ) 6) were 12 weeks old when drug administration started.
Each compound was administered orally for 11 days. At the end
of the treatment period (4, 7, and 11-day), body weights were
measured, blood samples were collected, and then blood glucose
levels were measured using AccuChek Active (Roche, Germany).
Molecular Docking. The designed derivatives, including all
hydrogen atoms, were built and minimized using Gasteiger-Hu¨ckel
charge and Tripos force field in the SYBYL software suite.13 Docking
analysis was conducted using the FlexX algorithm to examine the
binding modes of the designed derivatives at the active sites of PPARR
and PPARγ. The crystal structures of PPARR and PPARγ compexed
with tesaglitazar11 were used in this study (pdb entry ) 1I7G and
1I7I, respectively). The COOH group of tesaglitazar and the designed
derivatives are bound by PPARR and PPARγ in the form of a
carboxylate anion. Thus, COOH groups were calculated in an anionic
form, which in situ shares its negative charge with two oxygens. The
active sites in PPARR and PPARγ were defined as a collection of
protein residues enclosed within a 6.5Å radius sphere centered by
bound tesaglitazar. The energy-minimized structure of tesaglitazar was
initially docked into PPARR and PPARγ to determine how well the
FlexX algorithm reproduces the experimentally determined binding
conformation of tesaglitazar at the active sites. A superpositioning of
docked tesaglitazar onto crystallographic dispositions of the PPARR
and PPARγ active sites yielded root-mean-square (rms) deviations of
1.59 Å and 1.22 Å, respectively, revealing that FlexX successfully
reproduced the binding conformations of PPARR and PPARγ. To
(R)-3-(3-(5-Benzyl-4,5-dihydroisoxazol-3-yl)phenyl)-2-ethoxypro-
panoic Acid (80). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.52-7.49 (m, 2H), 7.33-7.24 (m, 7H), 5.00-4.98 (m, 1H),
4.10-4.06 (m, 1H), 3.62-3.56 (m, 1H), 3.47-3.41 (m, 1H), 3.29
(dd, 1H, J ) 16.7, 10.3 Hz), 3.19-3.11 (m, 2H), 3.07-2.99 (m,
2H), 2.87 (dd, 1H, J ) 13.8, 7.2 Hz), 1.15 (t, 3H, J ) 7.1 Hz).
LRMS (FAB) m/z 354 (M + H+). HRMS (FAB) calcd for
C20H24NO4 (M + H+), 354.1705; found, 354.1710.
(R)-2-Ethoxy-3-(3-(4,5-dihydro-5-phenethylisoxazol-3-yl)phenyl-
1
)propanoic Acid (81). Colorless oil. H NMR (300 MHz, CDCl3)
δ 7.55-7.51 (m, 2H), 7.35-7.16 (m, 7H), 4.75-4.70 (m, 1H), 4.09
(dd, 1H, J ) 7.7, 4.2 Hz), 3.65-3.55 (m, 1H), 3.47-3.33 (m, 2H),
3.15 (dd, 1H, J ) 14.1, 4.2 Hz), 3.05-2.91 (m, 2H), 2.83-2.74
(m, 2H), 2.16-2.03 (m, 1H), 1.97-1.92 (m, 1H), 1.16 (t, 3H, J )
7.0 Hz). LRMS (FAB) m/z 368 (M + H+). HRMS (FAB) calcd
for C22H25NO4 (M + H+), 368.1862; found, 368.1857.
(S)-2-Ethoxy-3-(3-(5-phenylisoxazole-3-yl)phenyl)propanoic Acid
1
(84). Colorless oil. H NMR (300 MHz, CDCl3) δ 7.84-7.72 (m,
4H), 7.51-7.33 (m, 5H), 6.81 (s, 1H), 4.14-4.06 (m, 1H),

Constrained Meta-Substituted Phenyl Propanoic Acids
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calculate binding affinities between the designed derivatives and
PPARR or PPARγ, we used a consensus scoring program that
integrates multiple well-known scoring functions, i.e., a GOLD-like
function, a DOCK-like function, ChemScore, a PMF function, and
FlexX. In docking/scoring outputs, conformers with high GOLD-scores
(obtained using hydrogen bonding, complex, and internal energies)
were analyzed and compared with tesaglitazar cocrystallized in the
PPARR and PPARγ active site.
Acknowledgment. This research was supported by the grant
from R&D Center for Antidiabetic Drugs, by Ministry of Health
& Welfare, Republic of Korea (A020600), the Korea Research
Foundation Grant funded by the Korean Government (MOE-
HRD) (KRF-2006-511-E00059), and the grant from the Center
for Bioactive Molecular Hybrids, Yonsei University.
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Supporting Information Available: Information on the in vitro
transactivation assays on additional oxime ether and isoxazoline
analogues, in vivo antihyperglycemic activities of several com-
pounds in db/db mice, and HRMS and HPLC data for the target
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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