Application of the Dakin-West reaction for the synthesis of oxazole-containing dual PPARα/γ agonists

Article abstract of DOI:10.1021/jo026655v

An improved method for the preparation of a series of oxazole-containing dual PPARα/γ agonists is described. A synthetic sequence utilizing a Dakin-West reaction was devised that allows for the introduction of the oxazole ring either late in the synthetic sequence via aminomalonate-derived chemistry or in pivotal SAR intermediates derived from aspartic acid.

Full text of DOI:10.1021/jo026655v

Ap p lica tion of th e Da k in -West Rea ction for th e Syn th esis of
Oxa zole-Con ta in in g Du a l P P ARr/γ Agon ists
Alexander G. Godfrey,* Dawn A. Brooks, Lynne A. Hay, Mary Peters,
J ames R. McCarthy, and David Mitchell
Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285
agg@lilly.com
Received November 4, 2002
An improved method for the preparation of a series of oxazole-containing dual PPARR/γ agonists
is described. A synthetic sequence utilizing a Dakin-West reaction was devised that allows for the
introduction of the oxazole ring either late in the synthetic sequence via aminomalonate-derived
chemistry or in pivotal SAR intermediates derived from aspartic acid.
We have recently disclosed the structure of 1a , a dual
PPARR/γ agonist, and demonstrated the compound’s
preclinical beneficial impact on multiple facets of type 2
diabetes and the associated cardiovascular risk.1 The
peroxisome proliferator activated receptor (PPAR) family
of nuclear hormone receptors has been identified as key
modulators of metabolism since the first member of the
receptor family was cloned a decade ago.2 The profile of
a dual PPARR/γ agonist appears well-suited as a treat-
ment for type 2 diabetes3 because of the insulin-sensitiz-
ing/glucose-controlling potential of PPARγ agonists, the
molecular target of the thiazolidine-2,4-diones (TZDs),4
in combination with the positive lipid- and cholesterol-
modulating activities of PPARR agonists, the molecular
target of the fibrates.5 Herein we describe the develop-
ment of a practical synthesis of 1a and related analogues,
utilizing the Dakin-West reaction6 followed by Robin-
son-Gabriel cyclodehydration7 to install substitution at
the 5-position of the oxazole ring. The versatility of these
historic reactions is further demonstrated using acylated
aspartic acid derivatives to prepare a variety of 2-sub-
stituted oxazole analogues.
Interest in compound 1a led to the development of a
synthetic route amenable to large-scale execution. Previ-
ous preparation of compound 1a , depicted in Scheme 1,
utilized early oxazole ring formation through condensa-
tion of butanedione monooxime with 4-bromobenzalde-
hyde.8 This route allowed preparation of 2-aryl analogues
for structure-activity relationship studies by incorporat-
ing straightforward coupling of tosylates of 5-methyl-2-
aryl-4-oxazolylethanols (5) with 2-(4-hydroxyphenoxy)-
2-methylpropanoic acid ethyl ester. However, the sequence
offers opportunities for process improvement to avoid
several potentially hazardous reagents and intermedi-
ates. These include potassium cyanide, diborane, an
unstable N-oxide intermediate (2), and the explosive
hazard associated with butanedione monooxime.9 In
addition, attempts to expand the SAR by condensation
of the monooxime with certain halogen-substituted aro-
matic aldehydes (particularly o-bromobenzaldehyde) were
unsatisfactory.
(1) (a) Brooks, D. A.; Etgen, G. J .; Rito, C. J .; Shuker, A. J .;
Dominianni, S. J .; Warshawsky, A. M.; Ardecky, A.; Paterniti, J . R.;
Tyhonas, J .; Karanewsky, D. S.; Kauffman, R. F.; Broderick, C. L.;
Oldham, B. A.; Montrose-Rafizadeh, C.; Winneroski, L. L.; Faul, M.
M.; McCarthy, J . R. J . Med. Chem. 2001, 44, 2061. (b) Etgen, G. J .;
Oldham, B. A.; J ohnson, W. T., Broderick, C. L.; Brozinick, J . T.; Bean
J . S.; Bensch, W. R.; Brooks, D. A.; Rito, C. J .; Shuker, A. J .; Kauffman,
R. F. Diabetes 2002, 51, 1083.
(2) (a) Issemann, I.; Green, S. Nature 1990, 347, 645. (b) Mangels-
dorf, D. J .; Evans, R. M. Cell 1995, 83, 841. (c) Willson, T. M.; Brown,
P. J .; Sterbach, D. D.; Henke, B. R. J . Med. Chem. 2000, 43, 527.
(3) Auwerx, J . In Insulin Resistance, Metabolic Disease and Diabetic
Complications: Proceedings of the 7th European Symposium on
Metabolism, Padova, Sept 30-Oct 3, 1998; Elsevier: Amsterdam, 1999,
p 167.
(4) (a) Sohda, T.; Mizuno, K.; Momose, Y.; Ikeda, H.; Fujita, T.;
Meguro, K. J . Med. Chem. 1992, 35, 2617. (b) Hulin, B.; Clark, D. A.;
Goldstein, S. W.; McDermott, R. E.; Dambek, P. J .; Kappeler, W. H.;
Lamphere, C. H.; Lewis, D. M.; Rizzi, J . P. J . Med. Chem. 1992, 35,
1853. (c) Lehmann, J . M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison,
W. O.; Willson, T. M.; Kliewer, S. A. J . Biol. Chem. 1995, 270, 12953.
(d) Nomura, M.; Kinoshita, S.; Satoh, H.; Maeda, T.; Murakami, K.;
Tsunoda, M.; Miyachi, H.; Awano, K. Bioorg. Med. Chem. Lett. 1999,
9, 533.
Resu lts a n d Discu ssion
In reviewing the literature for other methods to
prepare oxazole-ethanols 6, the work of Meguro et al. and
others10 suggested aspartic acid â esters 8 could be
(5) Fruchart, J .-C.; Duriez, P.; Staels, B. Curr. Opin. Lipidol. 1999,
10, 245.
(6) (a) Dakin, H. D.; West, R. J . Biol. Chem. 1928, 91, 745. (b)
Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91.
(7) (a) Robinson, R. J . Chem. Soc. 1909, 95, 2167. (b) Gabriel, S.
Chem. Ber. 1910, 43, 134, 1283.
(8) Goto, Y.; Yamazaki, M.; Hamana, M. Chem. Pharm. Bull. 1971,
19, 2050.
(9) Diacetyl monooxime, CAS [57-71-6], OHS Material Safety Data
Sheet.
10.1021/jo026655v CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/06/2003
J . Org. Chem. 2003, 68, 2623-2632
2623

Godfrey et al.
SCHEME 1. P r ep a r a tion of 1a fr om Bu ta n ed ion e Mon ooxim ea
a
(a) p-Bromobenzaldehyde, HOAc, HCl (74%); (b) POCl3, CHCl3 (72%); (c) KCN, KI, DMF (100%); (d) KOH, 2-methoxyethanol (60%);
(e) BH3-THF; MeOH (72%); (f) PhB(OH)2, Pd(OAc)2, PPh3 (95%); (g) (Ts)2O, Pyr, DMAP (95%); (h) 2-(4-hydroxyphenoxy)-2-methylpropanoic
acid ethyl ester, Cs2CO3, DMF (50%); NaOH, EtOH (68%).
SCHEME 2. Retr osyn th etic An a lysis
SCHEME 3. An a logu es 14 fr om Asp a r tic Acid â Ester s 8a
a
(a) Na2CO3, acetone, H2O, 0 °C; (b) NMM, 2-Cl-4,6-dimethoxy-1,3-5-triazine; (c) acetic anhydride, pyridine, 90 °C; (d) POCl3, DMF,
90 °C or H2SO4, Ac2O, 90 °C; (e) KOH or NaOH, EtOH; (f) BH3-THF; MeOH, 50 °C.
utilized as the starting material to provide 1a and related
analogues. The sequence would involve acylation to
differentiate R1, Dakin-West conversion to the keto-
amide to introduce R2, cyclodehydration to the oxazole
ring, and reduction of the ester side chain. Alternatively,
it was envisioned that the synthesis of 1a and related
analogues from inexpensive aminodiethyl malonate hy-
drochloride 9 was possible via simple acylation to attach
the biphenyl unit, followed by the Sorensen method11 for
amino acid incorporation into the side chain. The result-
ing amino acid could be converted to the keto-amide via
a Dakin-West reaction prior to cyclodehydration to
provide the central oxazole ring. Aspartic acid â esters 8
provided direct access to key oxazol-4-yl ethanol SAR
intermediates with incorporation of a variety of aryl or
alkyl substitution at the 2-position of the oxazole ring.
In the preparation of intermediates related to alcohol 5,
aspartic acid methyl (or benzyl) ester hydrochloride salt
was acylated with the appropriate acid or acid chloride.
Dakin-West conditions (acetic anhydride, pyridine) were
then utilized to install the 5-methyl group (12) prior to
Robinson-Gabriel cyclodehydration to provide oxazole
esters 13 in three steps (Scheme 3).12 Cyclodehydration
(10) (a) Meguro, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.; Kawamat-
su, Y. Chem. Pharm. Bull. 1986, 34, 2840. (b) Hulin, B.; Clark, D. A.;
Goldstein, S. W.; McDermott, R. E.; Dambek, P. J .; Kappeler, W. H.;
Lamphere, C. H.; Lewis, D. M.; Rizzi, J . P. J . Med. Chem. 1992, 35,
1853. (c) Collins, J . L.; Blanchard, S. G.; Boswell. G. E.; Charifson, P.
S.; Cobb, J . E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.;
Lake, D. H.; Leesnitzer, L. M.; Lehmann, J .; Lenhard, J . M.; Orband-
Miller, L. A.; Gray-Nunez, Y.; Parks, D. J .; Plunkett, K. D.; Tong, W.-
Q. J . Med. Chem. 1998, 41, 5037.
(12) The workup could be simplified by conducting the acylation step
in the presence of PVP (4% cross-linked polyvinyl pyridine), which
could be readily removed from the reaction mixture via filtration.
Treatment of the ether-diluted filtrate with concentrated sulfuric acid
(1 equiv) at room temperature for 2 h then provided direct formation
of the oxazole product in yields comparable to the two-step procedure
(40-50% following chromatography).
(11) (a) Sorensen, S. P. L. C. R. Trav. Lab. Carlsberg, Ser. Chim.
1903, 6,1. (b) Sorensen, S. P. L.; Andersen, A. C. Z. Physiol. Chem.
1905, 44, 448. (c) Sorensen, S. P. L. Z. Physiol. Chem. 1908, 56, 236.
2624 J . Org. Chem., Vol. 68, No. 7, 2003

Oxazole-Containing Dual PPARR/ γ Agonists
TABLE 1. Oxa zol-4-yl Acetic Acid Ester P r od u cts 12 a n d 13
a
b
Method A: POCl3, DMF, 90 °C. Method B: H2SO4, Ac2O, 90 °C.
was carried out at 90 °C for 30 min with either phos-
phorus oxychloride in DMF (Method A) or catalytic
sulfuric acid in acetic anhydride (Method B). In our
hands, superior yields were found in this series using
POCl3 for aromatic substrates (13c,d ), whereas aliphatic
substrates generally gave better results with Method B.
Hydrolysis of the ester and reduction of the acid with
borane-THF afforded alcohols 14. Table 1 summarizes
the formation of oxazol-4-yl acetic acid esters 13a -g in
good to excellent yields.
19 in 89% with sodium hydride in DMF. Triester 19 was
converted to crystalline 20 with concentrated HCl and
acylated with 4-biphenylcarbonyl chloride using trieth-
ylamine in N-methylpyrrolidinone to provide 21a . The
material was submitted directly to the Dakin-West
conditions of pyridine and acetic anhydride at 90 °C to
effect conversion of the carboxylic acid to methyl ketone
22a in excellent yield. Cyclodehydration of 22a was
optimized with acetic anhydride and sulfuric acid in
refluxing ethyl acetate to generate the desired product
1a in 87% yield after crystallization from EtOAc/heptane.
This convergent five-step route was found to be scalable
with excellent, reproducible overall yield and was prefer-
able to the aspartic acid route on the basis of cost of
starting materials.
Evaluation of the utility of aminodiethyl malonate
hydrochloride (9) as a starting material began with the
coupling of 9 with 4-biphenylcarbonyl chloride in N-
methylpyrrolidinone and triethylamine as the base to
provide amide 15 in 98% yield. Alkylation of 15 with 16
provided low yields (∼50%) of 17. The expected tri-ester
product was never observed or isolated. When NaOEt
was used as the base in ethanol or DMF, a competing
decarboxylation of 15 provided the glycine derivative 18.
Other bases such as NaH gave similar results. The
competing decarboxylation reaction may be due to dian-
ion formation of the acidic nitrogen proton and could
potentially be avoided by the use of an acetyl-protecting
group to decrease the acidity of this proton.
Compound 20 could be acylated with other acid chlo-
rides including 4-phenylcyclohexylcarbonyl chloride to
provide 21b. Additional 5-position analogues were pre-
pared from the common late-stage intermediate 21a
using n-butyric anhydride and benzoic anhydride (1b,c).
In the preparation of analogues 1b-d , small-scale puri-
fication to remove residual acid was best achieved by
conversion to the methyl ester of 22b-d with diazo-
methane prior to cyclodehydration with phosphorus
oxychloride in DMF. Hydrolysis to 1b-d was straight-
forward with NaOH in EtOH.
Preparation of the 5-trifluoromethyl derivative 1e (eq
2) necessitated modification of the original procedure
since reaction of 21a with TFAA in pyridine led to
complete decomposition of the starting material. Reacting
the primary N-acyl amino acid directly with TFAA is
likely problematic because N-acylation is competitive
with oxazolone formation.
Indeed, alkylation of inexpensive N-acetylaminodi-
methyl malonate with 16, as shown in Scheme 4, yielded
J . Org. Chem, Vol. 68, No. 7, 2003 2625

Godfrey et al.
SCHEME 4. Syn th esis of 1 a n d An a logu es fr om N-Acyla m in od ieth ylm a lon a tea
a
(a) NaH, DMF (89%); (b) conc HCl (78%); (c) 4-biphenylcarbonyl chloride, Et3N, NMP or 4-phenylcyclohexylcarbonyl chloride, Et3N,
CH2Cl2; (d) (RCO)2O, pyridine; (e) H2SO4, Ac2O, EtOAc (Method A) or POCl3, DMF (Method B). bR3 ) H. cR3 ) Me, isolated yield following
conversion to the methyl ester with diazomethane.
SCHEME 5
SCHEME 6. P r ep a r a tion of th e 5-CF 3-Oxa zole An a logu e 1ea
a
(a) NaHB(OAc)3, benzaldehyde (64%); (b) 4-biphenylacetyl chloride, Et3N, CH2Cl2 (100%); (c) NaOH, dioxane; (d) (CF3CO)2O, pyridine;
(e) CH2N2, CH2Cl2 (25%, 3 steps); (f) NaOH, EtOH (98%).
This observation is consistent with those of Kolb and
co-workers,13 who have shown that producing the ox-
azolone a priori and subsequent reaction with TFAA
yields the requisite trifluoromethyl ketone on acid-
catalyzed decarboxylation of the acylated intermediate
(Scheme 5).
The Kawase14 protocol using N-acyl-N-benzyl-R-amino
acids was successfully adopted starting with 23, the
diethyl ester derivative of 20, as shown in Scheme 6.
Treatment of 23 with benzaldehyde under reductive
(14) (a) Kawase, M. Heterocycles 1993, 36, 2441. (b) Kawase, M.;
Miyamae, H.; Kurihara, T. Chem. Pharm. Bull. 1998, 46, 749. (c)
Kawasi, M.; Miyamae, H.; Narita, M.; Kurihara, T. Tetrahedron Lett.
1993, 34, 859. (d) Kawase, M. Tetrahedron Lett. 1994, 35, 149.
(13) Kolb, M.; Barth, J .; Neises, B. Tetrahedron Lett. 1986, 27, 1579.
2626 J . Org. Chem., Vol. 68, No. 7, 2003

Oxazole-Containing Dual PPARR/ γ Agonists
column chromatography (EtOAc/hexanes) to provide 1.16 g
(68% yield) of the desired product as a pale yellow oil. HPLC
amination conditions provided 24 in 64% yield followed
by N-acylation with biphenyl-4-carbonyl chloride to give
25 in quantitative yield. Following hydrolysis to the
diacid, formation of the oxazole is afforded directly on
treatment with trifluoroacetic anhydride in the presence
of pyridine to give 1e. In practice the crude acid product
obtained was further esterfied to facilitate purification
by normal phase chromatography in 25% yield and then
saponified to back to 1e in 98% yield.
1
(>99.9 area%, tR ) 5.8 min at 60% ISO); H NMR (400 MHz,
CDCl3) δ 7.35 (m, 5 H), 6.62 (d, J ) 7.5 Hz, 1 H), 5.12 (s, 2 H),
4.76 (ddd, J ) 8.5, 4.4, 4.3 Hz, 1 H), 3.04 (B of ABX, J BA
)
17.0 Hz, J BX ) 4.8 Hz, 1H), 2.83 (A of ABX, J AB ) 17.0 Hz,
J AX ) 4.4 Hz, 1H), 2.22 (s, 3 H), 2.12 (tt, J ) 11.6, 3.4 Hz, 1
H), 1.77 (m, 5 H), 1.33 (m, 5 H); 13C NMR (100 MHz, CDCl3)
δ 26.06, 27.09, 29.83, 29.90, 35.65, 45.60, 55.11, 55.16, 67.26,
128.53, 128.83, 135.42, 171.49, 175.91, 205.59; MS m/z 332.2
(M + H)+.
In conclusion, the application of the Dakin-West
reaction, coupled with the Robinson-Gabriel reaction,
was applied to develop a practical means to 1a . This
methodology offered several opportunities for process
improvement over the reported procedure and enabled
the multi-kilogram synthesis of 1a . In addition, the
method was useful for the rapid preparation of a wide
variety of 2,4,5-substituted oxazole-containing SAR in-
termediates and products from readily available starting
materials.
3-[(Cycloh ex-1-en eca r bon yl)-a m in o]-4-oxo-p en ta n oic
Acid Ben zyl Ester (12b). The title compound was prepared
by the method described for 12a and obtained as an oil in 58%
yield after normal phase chromatography. HPLC (96.9 area%,
1
tR ) 4.4 min at 60% ISO); H NMR (400 MHz, CDCl3) δ 7.36
(m, 5 H), 6.89 (d, J ) 7.9 Hz, 1 H), 6.64 (m, 1 H), 5.12 (s, 2 H),
4.83 (ddd, J ) 8.5, 4.4, 4.3 Hz, 1 H), 3.07 (B of ABX, J BA
)
17.1 Hz, J BX ) 4.8 Hz, 1H), 2.86 (A of ABX, J AB ) 17.1 Hz,
J AX ) 4.4 Hz, 1H), 2.24 (s, 3 H), 2.19 (m, 3 H), 1.65 (m, 5 H);
13C NMR (100 MHz, CDCl3) δ 205.67, 171.55, 168.13,
135.40, 135.30, 132.53, 128.84, 128.67, 128.54, 67.27, 55.40,
55.32, 35.65, 27.17, 25.90, 24.47, 22.48, 21.86; MS m/z 330.2
(M + H)+.
Exp er im en ta l Section
3-(3-Meth oxy-ben zoylam in o)-4-oxo-pen tan oic Acid Ben -
zyl Ester (12c). The title compound was prepared by the
method described for 12a and obtained as a solid in 91% yield
Gen er a l Meth od s. Commercially available reagents and
solvents were used without further purification unless other-
wise noted. Melting points are uncorrected. For NMR, chemical
shifts are reported in ppm relative to residual nondeuterated
solvent. For analytical HPLC measurements, various isocratic
methods were used as appropriate to achieve optimal resolu-
tion using the indicated percentage of acetonitrile/0.03M
phosphate buffer, such as 40% ISO, 60% ISO, and 80% ISO;
flow rate 1.5 mL/min; column Zorbax SB-C18, 4.6 mm × 250
mm, 5 µm; 220 nm detection. A gradient method was applied
for compound 16 using a 15 min gradient of 40% acetonitrile/
60% 0.1% aqueous trifluouroacetic acid to 80% acetonitrile/
20% 0.1% aqueous trifluouroacetic acid; flow rate 1.0 mL/min;
column Zorbax SB-phenyl, 4.6 mm × 250 mm, 5 µm; 225 nm
detection. Elemental analysis was performed by a microana-
lytical lab, and high-resolution mass spectrometry data was
provided by the Physical Chemistry group of Lilly Research
Laboratories. Organic solutions were dried over magnesium
sulfate unless otherwise specified. Flash column chromatog-
raphy was carried out using silica gel (230-400 mesh) with
EtOAc/hexanes as an eluent. Preparative reversed-phase
separations (C-18 silica columns) were carried out using water/
acetonitrile gradient programs. Diazomethane solution was
prepared as follows: 1-Methyl-3-nitro-1-nitrosoguanidine (1.2
equiv) was slowly added to a stirring mixture of 5.0 N KOH
(1.2 equiv) and ethyl ether (0.14 M) at room temperature. The
biphasic mixture was stirred for an additional 10 min followed
by separation and direct use of the organic phase. Starting
amides 11a -h were prepared by literature methods15 as
described in Supporting Information.
1
after normal phase chromatography. Mp 56-57 °C; H NMR
(300 MHz, DMSO-d6) δ 8.96 (d, J ) 7.7 Hz, 1H), 7.41 (m, 3H),
7.31 (m, 5H), 7.13 (m, 1H), 5.11 (s, 2H), 4.79 (m, 1H), 3.81 (s,
3H), 2.88 (A of ABX, J AB ) 16.1 Hz, J AX ) 4.2 Hz, 1H), 2.86 (B
of ABX, J BA ) 16.1 Hz, J BX ) 2.7 Hz, 1H), 2.14 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 170.43, 166.07, 159.17, 135.96,
134.92, 129.49, 128.28, 127.88, 127.71, 119.54, 117.37, 112.60,
101.93, 90.08, 65.63, 55.72, 55.26, 34.31, 26.34; MS m/z 365.20
(M + H)+.
3-(4-Meth oxy-ben zoylam in o)-4-oxo-pen tan oic Acid Ben -
zyl Ester (12d ). The title compound was prepared by the
method described for 12a and obtained as a solid in 94% yield
after normal phase chromatography. Mp 115 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.82 (d, J ) 7.7 Hz, 1H), 7.84 (d, J ) 8.7
Hz, 2H), 7.32 (m, 5H), 7.02 (d, J ) 8.7 Hz, 2H), 5.11 (s, 2H),
4.77 (m, 1H), 3.82 (s, 3H), 2.87 (A of ABX, J AB ) 16.1 Hz,
J AX ) 4.2 Hz, 1H), 2.85 (B of ABX, J BA ) 16.1 Hz, J BX ) 2.7
Hz, 1H), 2.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 170.49,
165.80, 161.85, 135.97, 129.23, 128.29, 127.87, 127.70, 125.71,
113.54, 92.05, 90.07, 65.60, 55.67, 55.34, 34.40, 26.30; MS m/z
365.20 (M + H)+.
4-Oxo-3-ph en ylacetylam in o-pen tan oic Acid Meth yl Es-
ter (12e). The title compound was prepared by the method
described for 12a and obtained as an oil in 52% yield after
normal phase chromatography. HPLC (>99.9 area%, tR ) 2.1
min at 60% ISO); 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 5 H),
6.61 (d, J ) 7.5 Hz, 1 H), 4.71 (ddd, J ) 8.6, 4.6, 4.4 Hz, 1 H),
3.62 (s, 2 H), 3.61 (s, 3H), 2.95 (B of ABX, J BA ) 16.7 Hz,
J BX ) 4.8 Hz, 1H), 2.74 (A of ABX, J AB ) 16.7 Hz, J AX ) 4.4
Hz, 1H), 2.15 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 204.94,
171.45, 170.57, 134.12, 129.04, 128.88, 127.33, 55.04, 52.08,
43.69, 34.97, 26.70; MS m/z 264.1 (M + H)+.
3-(Cycloh exa n eca r bon yl-a m in o)-4-oxo-p en ta n oic Acid
Ben zyl Ester (12a ). A mixture of 2-(cyclohexanecarbonyl-
amino)-succinic acid 4-benzyl ester 1.72 g, 5.16 mmol), pyridine
(5 mL), and acetic anhydride (3 mL) was heated at 90 °C for
2 h. Excess acid anhydride and pyridine were removed under
reduced pressure, and the residue was then diluted with ether
(150 mL). The organic phase was then washed successively
with 1.0 N HCl (50 mL) and water (50 mL), then dried over
solid sodium chloride, decanted, and concentrated under
reduced pressure to yield an oil. The residue was purified by
4-Oxo-3-(3-p h en yl-p r op ion yla m in o)-p en t a n oic Acid
Meth yl Ester (12f). The title compound was prepared by the
method described for 12a and obtained as an oil in 69% yield
after normal phase chromatography. HPLC (>99.9 area%,
1
tR ) 2.3 min at 60% ISO); H NMR (400 MHz, CDCl3) δ 7.23
(m, 5 H), 6.60 (d, J ) 7.9 Hz, 1 H), 4.71 (ddd, J ) 8.5, 4.4, 4.3
Hz, 1 H), 3.64 (m, 3 H), 2.99 (t, J ) 7.0 Hz, 2 H), 2.93 (B of
(15) (a) Seki, M.; Kubota, H.; Moriya, T.; Yamagishi, M.; Nishimoto,
S.; Matsumoto, K. Y. Chem. Pharm. Bull. 1986, 34, 4516. (b) Hipskind,
P. A.; Howbert, J .; Cho, S.; Cronin, J . S.; Fort, S. L.; Ginah, F. O.;
Hansen, G. J .; Huff, B. E.; Lobb, K. L.; Martinelli, M. J .; Murray, A.
R.; Nixon, J . A.; Staszak, M. A.; Copp, J . D. J . Org. Chem. 1995, 60,
7033.
ABX, J BA ) 17.2 Hz, J BX ) 4.8 Hz, 1H), 2.66 (A of ABX, J AB
)
17.2 Hz, J AX ) 4.4 Hz, 1H), 2.57 (t, J ) 7.0 Hz, 2 H), 2.11 (m,
3 H); 13C NMR (100 MHz, CDCl3) δ 205.59, 172.10, 172.00,
140.49, 128.74, 128.55, 126.52, 55.12, 52.43, 38.57, 35.32,
31.92, 27.00; MS m/z 278.1 (M + H)+.
J . Org. Chem, Vol. 68, No. 7, 2003 2627

Godfrey et al.
4-Oxo-3-(4-ph en yl-bu tyr ylam in o)-pen tan oic Acid Meth -
yl Ester (12g). The title compound was prepared by the
method described for 12a and obtained as an oil in 68% yield
(5-Meth yl-2-p h en eth yl-oxa zol-4-yl)-a cetic Acid Meth yl
Ester (13f). Meth od B. To 4-oxo-3-(3-phenyl-propionylamino)-
pentanoic acid methyl ester (10 g, 36 mmol) and acetic
anhydride (28 mL) was added concentrated H2SO4 (1 mL). The
solution was heated to 90 °C for 30 min and then cooled to
ambient temperature. The reaction was slowly diluted with
DI water (30 mL, potential exotherm). The reaction mixture
was partitioned between CH2Cl2 and water. The organic phase
was washed with DI water, 10% aqueous NaHCO3, brine,
dried, and concentrated to obtain a brown oil. The residue was
purified by column chromatography (35% EtOAc/hexanes) to
provide the desired product (3.25 g) as a pale, yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.72 (s, 3H), 3.47
(s, 2H), 3.08-2.96 (m, 4H), 2.24 (s, 3H); MS m/z 260 (M + H)+.
after normal phase chromatography. HPLC (93.3 area%, tR
)
2.8 min at 60% ISO); 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2
H), 7.19 (m, 3 H), 6.62 (d, J ) 7.91 Hz, 1 H), 4.76 (ddd, J )
8.02, 4.61, 4.50 Hz, 1 H), 3.68 (s, 3 H), 2.99 (B of ABX, J BA
)
16.9 Hz, J BX ) 4.8 Hz, 1H), 2.80 (A of ABX, J AB ) 16.9 Hz,
J AX ) 4.4 Hz, 1H), 2.67 (m, 2 H), 2.26 (m, 2 H), 2.24 (s, 3 H),
2.00 (dt, J ) 14.94, 7.47 Hz, 2 H); 13C NMR (100 MHz, CDCl3)
δ 205.36, 172.66, 172.05, 141.40, 128.67, 128.63, 128.60, 55.33,
52.54, 36.09, 35.49, 27.43, 27.13; MS m/z 292.1 (M + H)+.
(2-Cycloh exyl-5-m eth yl-oxa zol-4-yl)-a cetic Acid Ben zyl
Ester (13a ). Meth od A. Phosphorus oxychloride (22 mL, 0.235
mol, 3.0 equiv) was added dropwise to a solution of 3-(cyclo-
hexanecarbonyl-amino)-4-oxo-pentanoic acid benzyl ester 26.0
g, 0.078 mol) in DMF (330 mL). The mixture was heated to 90
°C for 30 min and then cooled to ambient temperature before
being diluted by the slow addition of DI water (600 mL;
Ca u tion exoth er m ic). The mixture was cooled to ambient
temperature and extracted with MTBE. The combined organic
phases were washed with DI water and brine (150 mL), dried,
and concentrated to obtain 21.1 g (86%) as a brown oil. Further
[5-Meth yl-2-(3-p h en yl-p r op yl)-oxa zol-4-yl]-a cetic Acid
Meth yl Ester (13g). The title compound was prepared by the
method described for 13f and obtained as solid in 81% yield
after reverse phase chromatography. HPLC (99.0 area%, tR
)
4.8 min at 60% ISO); 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2
H), 7.17 (m, 3 H), 3.71 (s, 3 H), 3.46 (s, 2 H), 2.70 (m, 4 H),
2.24 (s, 3 H), 2.07 (m, 2 H); 13C NMR (100 MHz, CDCl3)
δ 170.45, 161.99, 144.46, 141.04, 128.17, 128.03, 127.19,
125.61, 51.96, 35.11, 31.71, 28.57, 27.51, 10.01; MS m/z 274.11
(M + H)+.
1
purification was not necessary. H NMR (400 MHz, CDCl3) δ
2-(2-Cycloh exyl-5-m eth yl-oxa zol-4-yl)-eth a n ol (14a ). (2-
Cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid benzyl ester (54.8
g, 0.174 mol), 2B-3 ethanol (276 mL), DI water (230 mL), and
KOH (23.0 g, 0.349 mol) were stirred at ambient temperature
for 60 min. The reaction mixture was concentrated, diluted
with water (150 mL), and extracted three times with MTBE.
The MTBE layers were discarded. The aqueous layer was
acidified and extracted three times with MTBE. The combined
MTBE layers were washed with brine, dried, and concentrated
to obtain 34.17 g of (2-cyclohexyl-5-methyl-oxazol-4-yl)-acetic
acid.
BH3-THF complex (96 mL, 0.096 mol, 2.3 equiv) was added
dropwise to a solution of (2-cyclohexyl-5-methyl-oxazol-4-yl)-
acetic acid (34.17 g, 0.153 mol) in THF (164 mL). The reaction
mixture was stirred for 3 h and then quenched with MeOH
(130 mL). After stirring overnight at room temperature, the
mixture was heated at 60 °C for 2 h, cooled to ambient
temperature, and concentrated. The residue was dissolved in
CH2Cl2 (185 mL), washed with 1 N NaOH and brine, dried,
and concentrated under reduced pressure to obtain 14a (33.23
g, 91% from 13a ) of a yellow oil. 1H NMR (400 MHz, CDCl3) δ
3.73 (t, J ) 6.8 Hz, 2H), 2.58 (tt, J ) 11.6, 3.6 Hz, 1H), 2.54 (t,
J ) 6.8 Hz, 2H), 2.13 (s, 3H), 1.93-1.89 (m, 2H), 1.74 (dt, J )
12.8, 3.6 Hz, 2H), 1.67-1.62 (m, 1H), 1.41 (qd, J ) 12.0, 3.2
Hz, 1H), 1.33-1.17 (m, 4H); 13C NMR (75 MHz, d6-DMOS) δ
164.37, 142.55, 131.13, 59.96, 36.42, 30.16, 29.16, 25.29, 24.93,
9.52; MS m/z 210.1 (M + H)+, 232.1 (M + H + Na)+. Anal.
Calcd for C12H19NO2: C, 68.88; H, 9.15; N, 6.69. Found: C,
68.56; H, 9.04; N, 6.43.
7.30-7.27 (m, 5H), 5.11 (s, 2H), 3.49 (s, 2H), 2.68 (tt, J ) 11.6,
3.6 Hz, 1H), 2.17 (s, 3H), 2.01-1.97 (m, 2H), 1.76 (dt, J ) 12.8,
3.6 Hz, 2H), 1.68-1.63 (m, 1H), 1.41 (qd, J ) 12.0, 3.2 Hz,
1H), 1.33-1.17 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 169.88,
144.09, 136.06, 128.24, 127.82, 127.55, 127.41, 65.56, 36.31,
31.38, 30.09, 28.57, 25.27, 24.85, 9.48; MS m/z 314.1 (M + H)+.
(2-Cycloh ex-1-en yl-5-m eth yl-oxa zol-4-yl)-a cetic Acid
Ben zyl Ester (13b). The title compound was prepared by the
method described for 13f and obtained as a clear oil in 80%
yield after normal phase chromatography. HPLC (>99.9
area%, tR ) 4.0 min at 80% ISO); 1H NMR (400 MHz, CDCl3)
δ 7.33 (m, 5 H), 6.67 (ddd, J ) 4.06, 2.20, 2.09 Hz, 1 H), 5.15
(s, 2 H), 3.55 (s, 2 H), 2.45 (m, 2 H), 2.25 (s, 3 H), 2.22 (m, 2
H), 1.70 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 169.89, 160.54,
144.22, 135.54, 129.98, 128.24, 128.11, 127.92, 125.81, 66.58,
32.13, 25.42, 24.61, 22.12, 21.85, 10.24.
[2-(3-Meth oxy-ph en yl)-5-m eth yl-oxazol-4-yl]-acetic Acid
Ben zyl Ester (13c). The title compound was prepared by the
method described for 13a and obtained as solid in 98% yield
after normal phase chromatography. Mp 63-64 °C; FTIR
(CHCl3) 3019, 1737, 1555, 1492, 1467, 1204, 1159, 672; 1H
NMR (300 MHz, DMSO-d6) δ 7.51-7.34 (m, 8H), 7.06 (m, 1H),
5.15 (s, 2H), 3.82 (s, 3H), 3.71 (s, 2H), 2.35 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 169.82, 159.55, 158.18, 146.03, 136.02,
130.26, 129.14, 128.33, 128.16, 127.94, 127.76, 117.78, 116.31,
110.10, 65.81, 55.21, 31.38, 9.76; MS m/z 360.1 (M + H)+.
[2-(4-Meth oxy-ph en yl)-5-m eth yl-oxazol-4-yl]-acetic Acid
Ben zyl Ester (13d ). The title compound was prepared by the
method described for 13a and obtained as solid in 84% yield
2-(2-Cycloh ex-1-en yl-5-m eth yl-oxazol-4-yl)-eth an ol (14b).
Hydrolysis of ester 13b by the procedure described for 14a
provided (2-cyclohex-1-enyl-5-methyl-oxazol-4-yl)-acetic acid
(tR ) 2.6 min at 60% ISO), which was reduced by the procedure
described for 14a to provide 14b as a clear oil following normal
phase chromatography (76% for two steps). HPLC (99.1 area%,
after normal phase chromatography. HPLC (99.3 area%, tR
)
3.1 min at 80% ISO); mp 95.5 °C; 1H NMR (400 MHz, CDCl3)
δ 7.92 (d, J ) 8.8 Hz, 2H), 7.36-7.31 (m, 5H), 6.94 (d, J ) 8.8
Hz, 2H), 5.18 (s, 2H), 3.85 (s, 3H), 3.60 (s, 2H), 2.32 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.5, 161.2, 159.8, 145.3, 136.0,
129.2, 128.7, 128.4, 127.9, 120.7, 114.3, 114.2, 67.0, 55.6, 32.4,
10.5; HRMS-ES m/z [M + H]+ calcd for C20H20NO4 338.1385,
found 338.1392. Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68;
N, 4.15. Found: C, 71.25; H, 5.70; N, 4.18.
1
tR ) 3.3 min at 60% ISO); H NMR (400 MHz, CDCl3) δ 6.64
(m, 1 H), 3.82 (t, J ) 5.93 Hz, 2 H), 3.57 (s, 1 H), 2.62 (t, J )
5.71 Hz, 2 H), 2.39 (m, 2 H), 2.22 (s, 3 H), 2.19 (m, 2 H), 1.67
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ 160.55, 142.58, 132.67,
130.10, 125.77, 61.82, 28.16, 25.47, 24.58, 22.15, 21.88, 10.07;
MS m/z 208.04 (M + H)+.
(2-Ben zyl-5-m eth yl-oxa zol-4-yl)-a cetic Acid Meth yl Es-
ter (13e). The title compound was prepared by the method
described for 13f and obtained as solid in 72% yield after
reverse phase chromatography. HPLC (98.0 area%, tR ) 3.2
min at 60% ISO); 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5 H),
4.04 (s, 2 H), 3.72 (s, 3 H), 3.47 (s, 2 H), 2.23 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 170.37, 160.29, 145.21, 135.40, 128.44,
128.30, 127.49, 126.60, 51.96, 34.59, 31.71, 10.04; MS m/z
246.08 (M + H)+.
2-[2-(3-Met h oxy-p h en yl)-5-m et h yl-oxa zol-4-yl]-et h a -
n ol (14c). Hydrolysis of ester 13c by the procedure described
for 14a provided [2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl]-
acetic acid. HPLC (99.1 area%, tR ) 2.3 min at 60% ISO); mp
1
166.1 °C; H NMR (400 MHz, DMSO-d6) δ 7.47 (dt, J ) 8.0,
1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.03 (ddd, J ) 7.6, 2.8, 1.2
Hz, 1H), 3.79 (s, 2H), 3.49 (s, 2H), 2.32 (s, 3H)); 13C NMR (100
2628 J . Org. Chem., Vol. 68, No. 7, 2003

Oxazole-Containing Dual PPARR/ γ Agonists
MHz, CDCl3) δ 172.2, 160.3, 158.7, 146.5, 131.1, 130.8, 129.0,
2-(4-Hyd r oxy-p h en oxy)-2-m eth yl-p r op ion ic Acid Eth yl
Ester (16). A mixture of 2-(4-hydroxy-phenoxy)-2-methyl-
propionic acid ethyl ester (22.42 g, 0.10 mol), 1,2-dibromoeth-
ane (100 mL), potassium carbonate (27.64 g, 0.20 mol), sodium
sulfate (22.4 g), and 2B-3 ethanol (150 mL) was heated at
reflux for 10 h and allowed to cool to room temperature. The
mixture was filtered under vacuum, and the filter cake was
rinsed with 2B-3 ethanol. Concentration of the filtrate under
vacuum gave 33.25 g of oil. Purification by silica gel chroma-
tography (MTBE/heptane eluent) yielded 27.79 g (83.9%) of
118.4, 117.0, 110.7, 55.6, 32.3, 10.3. Anal. Calcd for C13H13
-
NO4: C, 63.15; H, 5.30; N, 5.67. Found: C, 62.89; H, 5.34; N,
5.65).
[2-(3-Methoxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid was
reduced by the procedure described for 14a to provide 14c as
a white solid. HPLC (99.4 area%, tR ) 2.5 min at 60% ISO);
1
mp 70.5 °C; H NMR (400 MHz, CDCl3) δ 7.55 (dd, J ) 6.4,
1.2 Hz, 1H), 7.48 (dd, J ) 2.4, 1.6 Hz, 1H), 7.32 (t, J ) 7.6 Hz,
1H), 6.95 (ddd, J ) 5.6, 2.6, 1.2 Hz, 1H), 3.92 (t, J ) 5.6 Hz,
2H), 3.86 (s, 3H), 3.37 (br s, 1H), 2.71 (t, J ) 5.6 Hz, 2H), 2.31
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 159.6, 144.4,
134.1, 130.0, 128.9, 118.7, 116.6, 110.8, 62.0, 55.6, 28.4, 10.3;
HRMS-FAB m/z [M + H]+ calcd for C13H16NO3 234.1130,
found 234.1127. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48;
N, 6.00. Found: C, 66.50; H, 6.53; N, 5.94.
1
16. HPLC (98.5 area%, tR ) 12.82 min, gradient method); H
NMR (300 MHz, DMSO-d6) δ 6.88-6.77 (m, 4H), 4.25 (t, J )
5.3 Hz, 2H), 4.16 (q, J ) 7.1 Hz, 2H), 3.76 (t, J ) 5.3 Hz, 2H),
1.45 (s, 6H), 1.19 (t, J ) 7.1 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 173.1, 153.3, 148.8, 121.2, 115.2, 79.1, 68.1, 60.8,
31.4, 24.9, 13.8; MS m/z 331.0 (M + H)+.
2-[2-(4-Met h oxy-p h en yl)-5-m et h yl-oxa zol-4-yl]-et h a -
n ol (14d ). Hydrolysis of ester 13d by the procedure described
for 14a provided [2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-
acetic acid (97.7 area%, tR ) 2.3 min at 60% ISO), which was
reduced by the procedure described for 14a to provide 14d as
a white solid (78% for two steps). Mp 78 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.81 (d, J ) 8.8 Hz, 2H), 7.02 (d, J ) 8.8 Hz, 2H),
4.59 (t, J ) 5.7 Hz, 1H), 3.79 (s, 3H), 3.61 (q, J ) 7.0 Hz, 2H),
2.57 (t, J ) 7.0 Hz, 2H), 2.29 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 160.20, 157.89, 143.47, 132.94, 126.81, 119.83,
114.20, 59.93, 55.23, 29.33, 9.89; MS m/z 234.02 (M + H)+.
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found:
C, 66.96; H, 6.49; N, 5.94.
2-(2-Ben zyl-5-m et h yl-oxa zol-4-yl)-et h a n ol (14e). Hy-
drolysis of ester 13e by the procedure described for 14a
provided (2-benzyl-5-methyl-oxazol-4-yl)-acetic acid (>99.9
area%, tR ) 4.0 min at 40% ISO), which was reduced by the
procedure described for 14a to provide 14e as a clear oil
following normal phase chromatography (74% for two steps).
HPLC (>99.9 area%, tR ) 4.1 min at 40% ISO); 1H NMR (400
MHz, CDCl3) δ 7.28 (m, 5 H), 4.02 (s, 2 H), 3.86 (t, J ) 5.71
Hz, 2 H), 3.00 (s, 1 H), 2.64 (t, J ) 5.71 Hz, 2 H), 2.21 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 160.37, 143.86, 135.45, 131.86,
128.51, 128.40, 126.71, 61.51, 34.64, 28.30, 9.98; MS m/z 218.04
(M + H)+.
2-(5-Meth yl-2-p h en eth yl-oxa zol-4-yl)-eth a n ol (14f). (5-
Methyl-2-phenethyl-oxazol-4-yl)-acetic acid methyl ester (8.75
g, 33.8 mmol), in MeOH (120 mL) was treated with 5 N NaOH
(40 mL), and then the solution was warmed to 40 °C. After 40
min, the reaction mixture was concentrated under reduced
pressure, suspended in water, and then acidified to pH ) 1
with 5 N HCl. The mixture was extracted with EtOAc, dried,
and concentrated to provide 5.25 g (63%) of (5-methyl-2-
phenethyl-oxazol-4-yl)-acetic acid as an off-white solid. 1H
NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.52 (s, 2H),
3.06-3.03 (m, 4H), 2.24 (s, 3H).
2-Acetyla m in o-2-{2-[4-(1-eth oxyca r bon yl-1-m eth yl-eth -
oxy)-p h en oxy]-eth yl}-m a lon ic Acid Dieth yl Ester (19). To
diethyl acetamidomalonate (12.0 g, 55.1 mmol) dissolved in
DMF (120 mL) was added NaH (60% dispersion in mineral
oil, 2.44 g, 61.1 mmol) at room temperature. The mixture was
stirred for 90 min at ambient temperature. Then 2-[4-(2-bromo-
ethoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (18.0 g,
54.5 mmol) was added, and the reaction was heated to 70 °C
overnight. The reaction was cooled to room temperature,
diluted with water (150 mL), and extracted with diethyl ether.
The combined organics were washed successively with water
and then brine, dried, and concentrated to a yellow oil. The
oil was triturated with hexanes and dried under vacuum to
1
yield 22.7 g (89% yield) of the title compound. H NMR (300
MHz, DMSO-d6) δ 8.35 (s, 1H), 6.76 (m, 4H), 4.19-4.09 (m,
6H), 3.91 (t, J ) 5.5 Hz, 2H), 2.57 (t, J ) 5.5 Hz, 2H), 1.93 (s,
3H), 1.44 (s, 6H), 1.23-1.11 (m, 9H); 13C NMR (75 MHz,
DMSO-d6) δ 169.2, 167.4, 153.5, 148.4, 121.3, 114.6, 79.1, 64.1,
62.7, 61.5, 60.8, 32.1, 24.8, 22.1, 13.9, 13.7; MS m/z 468.3
(M + H)+, 466.4 (M - H,)-.
2-Am in o-4-[4-(1-ca r b oxy-1-m et h yl-et h oxy)-p h en oxy]-
bu tyr ic Acid Hyd r och lor id e Sa lt (20). Concentrated HCl
(35.0 mL) was added to the triester 19 (13.6 g, 29.3 mmol);
the mixture was heated to reflux for 6 h and then cooled to
room temperature. The mixture was concentrated under
vacuum, and the residue was diluted with acetonitrile (70 mL).
Solids formed at room temperature and were filtered, rinsing
with a small amount of acetonitrile to provide 7.60 g (78%
yield) of the title compound. A second crop was obtained from
1
the filtrate. H NMR (300 MHz, DMSO-d6) δ 8.62 (br s, 3H),
6.83 (m, 4H), 4.09 (m, 2H), 4.00 (m, 1H), 2.27 (q, J ) 6.2 Hz,
2H), 1.43 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 174.9, 170.5,
153.3, 148.9, 120.9, 115.0, 78.8, 63.5, 49.4, 29.6, 24.9; MS m/z
298.3 (M + H)+. Anal. Calcd for C14H20NO6Cl: C, 50.38; H,
6.04; N, 4.20. Found: C, 50.76; H, 6.08; N, 4.49.
2-[(Biph en yl-4-car bon yl)-am in o]-4-[4-(1-car boxy-1-m eth -
yl-eth oxy)-p h en oxy]-bu tyr ic Acid (21a ). Amino diacid 20
(0.203 g, 0.94 mmol) and 4-biphenylcarbonyl chloride (0.316
g, 0.92 mmol) were dissolved in N-methylpyrrolidinone, and
triethylamine (0.52 mL, 3.73 mmol) was added slowly. The
mixture was stirred at room temperature for 2.5 h, diluted
with water, and acidified with 1.0 N HCl. Product was
extracted with EtOAc and dried. Removal of solvent under
vacuum provided 0.403 g (92% yield) of the desired product,
which was used without further purification. The product could
be purified by crystallization from acetonitrile. HPLC (96.9
area%, tR ) 1.8 min at 80% ISO);1H NMR (500 MHz, DMSO-
d6) δ 12.80 (br s, 2H), 8.75 (d, J ) 7.8 Hz, 1H), 7.97 (d, J ) 8.2
Hz, 2H), 7.77 (d, J ) 8.2 Hz, 2H), 7.71 (d, J ) 8.0 Hz, 2H),
7.48 (t, J ) 7.6 Hz, 2H), 7.39 (t, J ) 7.6 Hz, 1H), 6.83 (d, J )
9.2 Hz, 2H), 6.79 (d, J ) 9.2 Hz, 2H), 4.63-4.58 (m, 1H), 4.06-
4.00 (m, 2H), 3.34 (br s, 2H), 2.31-2.26 (m, 1H), 2.23-2.17
(m, 1H), 1.40 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 174.98,
173.40, 166.21, 153.63, 148.78, 142.86, 139.09, 132.66, 128.93,
128.05, 127.97, 126.79, 126.38, 120.92, 114.91, 78.79, 64.61,
(5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid (5.05 g, 20.6
mmol) was reduced by the procedure described for 14a and
purified by column chromatography (500 mL SiO2, 35% EtOAc/
hexanes) to provide 14f (3.99 g, 84%) as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.84 (q, J )
5.6 Hz, 2H), 3.06-2.67 (m, 4H), 2.62 (t, J ) 5.6 Hz, 2H), 2.22
(s, 3H); MS m/z 232.19 (M + H)+, 254.15 (M + H + Na)+.
2-[5-Met h yl-2-(3-p h en yl-p r op yl)-oxa zol-4-yl]-et h a n ol
(14g). Hydrolysis of ester 13g by the procedure described for
14a provided [5-methyl-2-(3-phenyl-propyl)-oxazol-4-yl]-acetic
acid, HPLC (98.5 area%, tR ) 7.6 min at 40% ISO), which was
reduced by the procedure described for 14a to provide 14g as
a clear oil following normal phase chromatography (90% for
1
two steps). HPLC (98.4 area%, tR ) 8.2 min at 40% ISO); H
NMR (400 MHz, CDCl3) δ 7.23 (m, 5 H), 3.85 (t, J ) 5.71 Hz,
2 H), 3.14 (s, 1 H), 2.70 (td, J ) 7.58, 1.98 Hz, 4 H), 2.62 (t,
J ) 5.49 Hz, 2 H), 2.21 (s, 3 H), 2.07 (q, J ) 15.27, 7.58, 7.47
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 161.94, 143.01, 141.04,
131.48, 128.18, 128.06, 125.65, 61.48, 35.14, 28.51, 28.28,
27.48, 9.88.
J . Org. Chem, Vol. 68, No. 7, 2003 2629

Godfrey et al.
49.72, 30.31, 24.89; HRMS-FAB m/z [M + H]+ calcd for C27H28
NO7 478.1866; found 478.1859.
-
(m, 1H), 4.04-3.92 (m, 2H), 2.62-2.54 (m, 1H), 2.31-2.23 (m,
1H), 1.48 (m, 6H); MS m/z 552.3 (M + H)+.
4-[4-(1-Ca r boxy-1-m eth yl-eth oxy)-ph en oxy]-2-[(4-ph en -
yl-cycloh exa n eca r bon yl)-a m in o]-bu tyr ic Acid (21b). To
a mixture of amino diacid 20 (0.600 g, 1.89 mmol) and
triethylamine (0.63 mL, 4.49 mmol) in methylene chloride (4
mL) was slowly added 4-phenyl-cyclohexanecarbonyl chloride
(0.420 g, 1.80 mmol) dissolved in methylene chloride (1 mL).
After 30 min, the reaction mixture was partitioned between
1.0 N HCl (50 mL) and methylene chloride (50 mL). The
organic phase was dried over sodium chloride and concentrated
under reduced pressure to yield 869 mg (100%) of oil that was
carried forward without further purification. HPLC (62.7
area%, tR ) 1.9 min at 80% ISO); 1H NMR (400 MHz, CDCl3)
δ 7.25-7.11 (m, 5H), 6.85 (d, J ) 9.3 Hz, 2H), 6.72 (d, J ) 9.3
Hz, 2H), 6.56 (d, J ) 6.8 Hz, 2H), 4.73-4.68 (m, 1H), 4.11-
3.97 (m, 2H), 2.49-2.42 (m, 2H), 2.37-2.33 (m, 2H), 2.23-
2.08 (m, 2H), 2.02-1.92 (m, 4H), 1.61-1.51 (m, 2H), 1.49 (s,
6H), 1.47-1.41 (m, 2H).
2-(4-{3-[(Biph en yl-4-car bon yl)-am in o]-4-oxo-pen tyloxy}-
p h en oxy)-2-m eth yl-p r op ion ic Acid (22a ). To compound
21a (0.487 g, 1.02 mmol) dissolved in 2.2 mL pyridine was
added 1.8 mL acetic anhydride, and the mixture was heated
to 90 °C for 2 h. After cooling to room temperature the reaction
was quenched with water (2.3 mL). This mixture was heated
to 90 °C for 30 min, cooled to room temperature, and diluted
with water, acidifying with 1.0 N HCl. Product was extracted
with CH2Cl2. The combined organic phases were washed with
brine, dried, and concentrated to a yellow oil. This product can
be crystallized from toluene to provide 22a as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.88 (d, 1H,
J ) 7.3 Hz), 7.99 (d, 2H, J ) 8.4 Hz), 7.80-7.72 (m, 4H), 7.52-
7.38 (m, 3H), 6.82 (m, 4H), 4.59 (m, 1H), 4.02 (m, 2H), 2.29
(m, 1H), 2.17 (s, 3H), 2.11 (m, 1H), 1.42 (s, 6H). MS m/z 476.2
(M + H)+, 474.3 (M - H)-. Anal. Calcd for C28H29NO6: C,
70.72; H, 6.15; N, 2.95. Found: C, 70.90; H, 6.13; N, 2.96.
2-(4-{3-[(Biph en yl-4-car bon yl)-am in o]-4-oxo-h eptyloxy}-
p h en oxy)-2-m eth yl-p r op ion ic Acid Meth yl Ester (22b).
Compound 21a (0.676 g, 1.42 mmol), dissolved in pyridine (2.53
mL, 42.5 mmol), was treated with butyric anhydride (4.45 mL,
26.9 mmol) and heated at 90 °C for 1 h. Upon cooling to room
temperature, 1 N HCl (50 mL) was added, and the mixture
stirred for 1 h. The mixture was then extracted with ethyl
acetate and concentrated under reduced pressure (27.4 area%,
tR ) 2.3 min at 80% ISO). The acid dissolved in ethyl ether
(50 mL) was treated with diazomethane, and then the reaction
mixture was concentrated under reduced pressure and purified
via SiO2 chromatography to yield 535 mg (73%) of 22b as an
oil. HPLC (80.5 area%, tR ) 3.9 min at 80% ISO); 1H NMR
(400 MHz, CDCl3) δ 7.89 (d, J ) 8.3 Hz, 2H), 7.68-7.61 (m,
4H), 7.48-7.37 (m, 3H), 6.80 (t, J ) 8.8 Hz, 2H), 6.71 (t, J )
8.8 Hz, 2H), 4.90 (m, 1H), 4.07-3.97 (m, 1H), 3.77 (s, 3H),
2.78-2.70 (m, 1H) 2.63-2.55 (m, 2 H), 2.42-2.32 (m, 1H)
1.74-1.65 (m, 2H), 1.53 (s, 6H), 0.97 (t, J ) 7.3 Hz, 3H).
2-(4-{3-[(Bip h en yl-4-ca r bon yl)-a m in o]-4-oxo-4-p h en yl-
bu toxy}-p h en oxy)-2-m eth yl-p r op ion ic Acid Meth yl Ester
(22c). Compound 21a (0.500 g, 1.05 mmol), dissolved in
pyridine (3.4 mL, 41.9 mmol, 30 equiv), was treated with
benzoic anhydride (0.711 g, 3.14 mmol, 3 equiv) and heated
at 90 °C for 10 h. The reaction mixture was allowed to cool to
room temperature and then partitioned by addition of 1.0 N
HCl (50 mL) and methylene chloride (50 mL). The organic
phase was dried over sodium chloride and concentrated under
reduced pressure to 1.10 g of oil (85.5 area%, tR ) 2.4 min at
60% ISO). The acid (0.563 g, 1.05 mmol) was dissolved in CH2-
Cl2 (10 mL) and treated with diazomethane. The reaction
mixture was then concentrated under reduced pressure and
purified via silica gel chromatography to yield 422 mg (73%)
of 22c as an oil. HPLC (88.8 area%, tR ) 4.0 min at 80% ISO);
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J ) 8.8 Hz, 2H), 7.89 (d,
J ) 8.8 Hz, 2H), 7.64 (d, J ) 8.8 Hz, 2H), 7.59-7.33 (m, 7 H),
6.73 (d, J ) 9.3 Hz, 2H), 6.64 (d, J ) 9.3 Hz, 2H), 5.94-5.90
2-Meth yl-2-(4-{4-oxo-3-[(4-ph en yl-cycloh exan ecar bon yl)-
a m in o]-p en tyloxy}-p h en oxy)-p r op ion ic Acid Meth yl Es-
ter (22d ). Acid 21b (0.869 g, 1.80 mmol) was dissolved in
pyridine (4.37 mL, 53.9 mmol, 30 equiv), treated with acetic
anhydride (3.22 mL, 34.1 mmol, 19 equiv), and then heated
at 90 °C for 3 h. After cooling to room temperature, the reaction
mixture was treated with 5.0 N NaOH (7.5 mL). The mixture
was partitioned after 10 min between ethyl ether (50 mL) and
water (50 mL). The aqueous layer was then treated with
sufficient 5.0 N HCl to achieve a pH of <3. The mixture was
extracted with methylene chloride, and then the combined
organic phases were dried over sodium chloride and concen-
trated under reduced pressure to an oil (73.1 area%, tR ) 2.2
min at 80% ISO). The acid (0.865 g, 1.80 mmol) was dissolved
in ethyl ether (10 mL) and treated with diazomethane. The
reaction mixture was then concentrated under reduced pres-
sure and purified by silica gel chromatography to yield 368
mg (41%) of 22d as an oil. HPLC (tR ) 2.9 min at 80% ISO);
1H NMR (400 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.17-7.12
(m, 3H), 6.76 (d, J ) 9.3 Hz, 2H), 6.66 (d, J ) 9.3 Hz, 2H),
6.56 (d, J ) 6.3 Hz, 2H), 4.66-4.62 (m, 1H), 3.98-3.93 (m,
1H), 3.86-3.80 (m, 1H), 3.73 (s, 3H), 2.53-2.40 (m, 2H), 2.27
(s, 3H), 2.28-2.15 (m, 2H), 2.01-1.93 (m, 4H), 1.65-1.54 (m,
2H), 1.49 (s, 6H), 1.48-1.40 (m, 2H).
2-{4-[2-(2-Bip h en yl-4-yl-5-m eth yl-oxa zol-4-yl)-eth oxy]-
p h en oxy}-2-m eth yl-p r op ion ic Acid (1a ). Ketone 22a (5.00
g, 10.51 mmol) was dissolved in 40 mL EtOAc. Acetic anhy-
dride (3.22 g, 31.54 mmol) and 95-98% sulfuric acid (0.31 g,
3.16 mmol) in 2.5 mL EtOAc were added, and the mixture was
heated at reflux for 3 h. The reaction mixture was cooled, and
5 N NaOH (12.6 mL, 63 mmol) diluted to 25 mL with water
was added. The reaction was heated at reflux for 30 min and
then cooled to room temperature. The resulting layers were
separated. The organic layer was washed with 1 N HCl and
10% brine, dried (Na2SO4), concentrated in vacuo to 26.5 g,
and stirred overnight at room temperature. The resulting
slurry was diluted with heptane (24 mL) and cooled at 0 °C
for 1 h. Filtration and drying yielded 4.21 g (88% yield) of 1a
in 95% yield as a white solid. Mp 141 -143.5 °C; 1H NMR
(300 MHz, DMSO-d6) δ 7.99 (d, J ) 9.0 Hz, 2H), 7.80 (d, J )
6.0 Hz, 2H), (d, J ) 9.0 Hz, 2H), 7.49 (t, J ) 7.6 Hz, 2H), 7.38
(t, J ) 7.6 Hz, 1H), 6.91-6.79 (m, 4H), 4.17 (t, J ) 6.4 Hz,
2H), 2.92 (t, J ) 6.4 Hz, 2H), 2.36 (s, 3H), 1.44 (s, 6H); 13C
NMR (75 MHz, DMSO-d6) δ 175.0, 158.1, 153.6, 148.8, 145.1,
141.4, 139.1, 132.8, 129.0, 127.9, 127.1, 126.6, 126.0, 121.0,
114.9, 78.9, 66.5, 25.7, 24.9; HRMS-FAB m/z [M + H]+ calcd
for C28H28NO5 458.1967; found 458.1958. Anal. Calcd for
C
28H27NO5: C, 73.51; H, 5.95; N, 3.06. Found: C, 73.81; H,
6.16; N, 3.13.
2-{4-[2-(2-Bip h en yl-4-yl-5-p r op yl-oxa zol-4-yl)-eth oxy]-
p h en oxy}-2-m eth yl-p r op ion ic Acid (1b). Ester 22b (0.514
g, 0.99 mmol) was dissolved in 6 mL of dry DMF followed by
addition of phosphorus oxychloride (0.28 mL, 2.88 mmol, 3
equiv). The mixture was heated at 90 °C for 20 min under a
nitrogen atmosphere, cooled to room temperature and treated
with cold water (10 mL). The mixture was neutralized with
1.0 N sodium hydroxide and partitioned between ethyl ether
(100 mL) and water (50 mL). The aqueous layer was back-
extracted with ethyl ether, and the organic phases were
combined, which were then washed with 5% aqueous LiCl,
dried over NaCl, and concentrated in vacuo to yield an oil,
which was immediately subjected to silica gel chromatography
to yield 484 mg (98%) of an oil. HPLC (tR ) 12.7 min at 80%
1
ISO); H NMR (400 MHz, CDCl3) δ 8.02 (d, J ) 8.3 Hz, 2H),
7.64-7.58 (m, 4H), 7.43-7.33 (m, 3H), 6.78-6.72 (m, 4H), 4.17
(t, J ) 6.3 Hz, 2H), 3.73 (s, 3H), 2.94 (t, J ) 6.3 Hz, 2H), 2.66
(t, J ) 7.3 Hz, 2H), 1.73-1.67 (m, 2H), 1.48 (s, 6H), 0.97 (t,
J ) 7.3 Hz, 3H); MS m/z 500.1 (M + H)+.
2-{4-[2-(2-Biphenyl-4-yl-5-propyl-oxazol-4-yl)-ethoxy]-phe-
noxy}-2-methyl-propionic acid methyl ester (0.484 g, 0.97
2630 J . Org. Chem., Vol. 68, No. 7, 2003

Oxazole-Containing Dual PPARR/ γ Agonists
mmol) was dissolved in ethanol (5 mL) followed by addition of
5.0 N NaOH (2 mL). After 2 h at 50 °C for 2 h, the reaction
mixture was allowed to cool to room temperature and then
partitioned between methylene chloride (50 mL) and 1.0 N HCl
(15 mL). The organic phase was separated, dried over sodium
chloride, and concentrated in vacuo to yield 384 mg (82%) of
1b as a glassy solid. HPLC (97.5 area%, tR ) 6.4 min at 80%
∼13 with 1.0 N NaOH, the layers were separated, and the
aqueous layer was extracted with methylene chloride. The
combined organic phases were dried over sodium chloride and
then concentrated under reduced pressure. The crude product
was purified by silica gel chromatography to yield 24 (492 mg,
64%) as an oil. HPLC (tR ) 2.8 min at 80% ISO); 1H NMR
(400 MHz, CDCl3) δ 7.28-7.18 (m, 5H), 6.79-6.76 (m, 2H),
6.70-6.68 (m, 2 H), 4.22-4.12 (m, 4H), 4.08-4.02 (m, 1H),
3.99-3.91 (m, 1H), 3.83-3.80 (d, J ) 12.7 Hz, 1H), 3.65-3.62
(d, J ) 12.7 Hz, 1H), 3.49-3.47 (m, 1H), 2.17-2.09 (m, 1 H),
2.00-1.92 (m, 1H), 1.49 (s, 6H), 1.26-1.20 (m, 6H).
2-[Ben zyl-(bip h en yl-4-ca r bon yl)-a m in o]-4-[4-(1-eth oxy-
ca r bon yl-1-m eth yl-eth oxy)-p h en oxy]-bu tyr ic Acid Eth yl
Ester (25). Diester 24 (0.490 g, 1.10 mmol) was dissolved in
10 mL of methylene chloride followed by addition of triethyl-
amine (0.31 mL, 2.21 mmol) and biphenyl-4-carbonyl chloride
(0.287 g, 1.33 mmol). After 12 h at room temperature, the
reaction mixture was partitioned between methylene chloride
(50 mL) and 0.1 N HCl (50 mL). The organic phase was dried
over sodium chloride and then concentrated under reduced
pressure to yield 687 mg (100%) of 25 as an oil. HPLC (91.6
area%, tR ) 7.6 min at 80% ISO); 1H NMR (400 MHz, CDCl3)
δ 7.60-7.20 (m, 14H), 6.77-6.46 (m, 4H), 4.91-4.45 (m, 2H),
4.19-3.66 (m, 7H), 2.78-2.12 (m, 2H), 1.49 (s, 6H), 1.25-1.22
(m, 6H).
1
ISO); H NMR (400 MHz, CDCl3) δ 8.01 (d, J ) 8.3 Hz, 2H),
7.63-7.58 (m, 4H), 7.43-7.33 (m, 3H), 6.86 (d, J ) 9.3 Hz,
2H), 6.73 (d, J ) 9.3 Hz, 2H), 4.13 (t, J ) 6.3 Hz, 2H), 2.97 (t,
J ) 6.3 Hz, 2H), 2.66 (t, J ) 7.3 Hz, 2H), 1.73-1.68 (m, 2H),
1.49 (s, 6H), 0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3) δ 13.67,
21.78, 24.90, 26.05, 26.60, 66.95, 80.14, 114.86, 122.36, 126.05,
126.57, 127.01, 127.34, 127.76, 128.82, 132.34, 140.13, 142.77,
147.89, 149.24, 154.97, 159.57, 176.47; HRMS-FAB m/z
[M + H]+ calcd for C30H31NO5 486.2280, found 486.2308.
2-{4-[2-(2-Bip h en yl-4-yl-5-p h en yl-oxa zol-4-yl)-eth oxy]-
p h en oxy}-2-m eth yl-p r op ion ic Acid (1c). Cyclodehydration
of ester 22c (0.422 g, 0.765 mmol) was carried out by the
procedure described for 1b to yield 362 mg (89%) of an oil.
HPLC (88.8 area%, tR ) 13.8 min at 80% ISO); 1H NMR (400
MHz, CDCl3) δ 8.16 (d, J ) 8.8 Hz, 2H), 7.78 (d, J ) 8.8 Hz,
2H), 7.68 (d, J ) 8.8 Hz, 2H), 7.61 (d, J ) 8. Hz, 2H), 7.47-
7.33 (m, 6H), 6.75 (m, 4H), 4.36 (t, J ) 6.8 Hz, 2H), 3.72
(s, 3H), 3.29 (t, J ) 6.8 Hz, 2H), 1.48 (s, 6H).
Hydrolysis of 2-{4-[2-(2-biphenyl-4-yl-5-phenyl-oxazol-4-yl)-
ethoxy]-phenoxy}-2-methyl-propionic acid methyl ester (0.360
g, 0.675 mmol) was carried out by the procedure described for
1b to yield 347 mg (99%) of 1c a glassy solid. HPLC (92.4
area%, tR ) 7.2 min at 80% ISO); 1H NMR (400 MHz, CDCl3)
δ 8.11 (d, J ) 8.8 Hz, 2H), 7.78 (d, J ) 8.8 Hz, 2H), 7.66 (d,
J ) 8.8 Hz, 2H), 7.60 (d, J ) 8.8 Hz, 2H), 7.46-7.34 (m, 6H),
6.87 (d, J ) 9.3 Hz, 2H), 6.76 (d, J ) 9.3 Hz, 2H), 4.32 (t, J )
6.8 Hz, 2H), 3.29 (t, J ) 6.8 Hz, 2H), 1.50 (s, 6H); 13C NMR
(CDCl3) δ 24.88, 27.40, 66.86, 80.32, 115.07, 122.71, 125.70,
126.04, 126.96, 127.11, 127.50, 127.94, 128.37, 128.53, 128.88,
128.92, 133.56, 140.10, 143.31, 147.20, 147.76, 155.14, 159.89,
176.61; HRMS-FAB m/z [M + H]+ calcd for C33H29NO5,
520.2124; found 520.2107.
2-{4-[2-(2-Bip h en yl-4-yl-5-tr iflu or om eth yl-oxa zol-4-yl)-
eth oxy]-p h en oxy}-2-m eth yl-p r op ion ic Acid (1e). Com-
pound 25 (0.687 g, 1.10 mmol) was dissolved in 5 mL of dioxane
followed by addition of 5.0 N NaOH (2.3 mL, 11.6 mmol). The
mixture was heated at 60 °C for 7 h. The reaction mixture
was allowed to cool to room temperature followed by addition
of 1.0 N HCl (12 mL, 12 mmol) and then partitioned by
addition of methylene chloride (50 mL). The organic phase was
separated, dried over sodium chloride, and concentrated under
reduced pressure to yield 690 mg (∼100%) of a glassy solid.
1
HPLC (94.9 area%, tR ) 2.2 min at 80% ISO); H NMR (400
MHz, CDCl3) δ 12.82 (broad s, 2H), 7.70-7.75 (m, 4H), 7.45-
7.17 (m, 10H), 6.75-6.48 (m, 4H), 2.24-2.00 (m, 2H), 1.39 (s,
6H); MS m/z 568.31 (M + H)+.
2-Meth yl-2-(4-{2-[5-m eth yl-2-(4-p h en yl-cycloh exyl)-ox-
a zol-4-yl]-eth oxy}-p h en oxy)-p r op ion ic Acid (1d ). Cyclo-
dehydration of ester 22d (0.422 g, 0.765 mmol) was carried
out by the procedure described for 1b to yield 327 mg (92%) of
an oil. HPLC (97.5 area%, tR ) 7.2 min at 80% ISO); 1H NMR
(400 MHz, CDCl3) δ 7.28-7.13 (m, 5H), 6.77-6.70 (m, 4H),
4.08 (t, J ) 6.8 Hz, 2H), 3.73 (s, 3H), 2.87 (t, J ) 6.8 Hz, 2H),
2.83-2.76 (m, 1H), 2.55-2.47 (m, 1H), 2.22 (s, 3H), 2.17-2.13
(m, 2H), 1.98-1.94 (m, 2H), 1.72-1.62 (m, 2H), 1.56-1.49 (m,
2H), 1.47 (s, 6H).
A sample of 2-[benzyl-(biphenyl-4-carbonyl)-amino]-4-[4-(1-
carboxy-1-methyl-ethoxy)-phenoxy]-butyric acid (0.625 g, 1.10
mmol) was dissolved in 5 mL of toluene followed by addition
of pyridine (0.54 mL, 6.61 mmol, 6 equiv). The reaction mixture
was chilled to 0 °C, and trifluoroacetic anhydride (0.47 mL,
3.30 mmol, 3 equiv) was then added. The reaction mixture was
allowed to stir at room temperature for 12 h followed by
heating at reflux for 9 h. The reaction mixture was then
allowed to cool to room temperature followed by partitioning
between water (50 mL) and methylene chloride (50 mL). The
organic phase was dried over sodium chloride and concentrated
under reduced pressure to yield 563 mg of a glassy solid. The
material was treated with diazomethane and then concen-
trated to an oil under reduced pressure prior to silica gel
chromatography to yield 141 mg (25%) of an oil. HPLC (96.2
area%, tR ) 11.7 min at 80% ISO); 1H NMR (400 MHz, CDCl3)
δ 8.01 (d, J ) 8.3 Hz, 2H), 7.67 (d, J ) 8.3 Hz, 2H), 7.60 (d,
J ) 8.3 Hz, 2H), 7.45-7.41 (m, 2H), 7.37-7.34 (m, 1H), 6.78-
6.73 (m, 4H), 4.22 (t, J ) 6.8 Hz, 2H), 3.72 (s, 3H), 3.14 (t,
J ) 6.8 Hz, 2H), 1.48 (s, 6H); MS m/z 526.3 (M + H)+.
2-{4-[2-(2-Biphenyl-4-yl-5-trifluoromethyl-oxazol-4-yl)-ethoxy]-
phenoxy}-2-methyl-propionic acid methyl ester (141 mg, 0.21
mmol) was dissolved in ethanol (2 mL) followed by addition of
5.0 N NaOH (0.6 mL). After 1 h at 50 °C, the reaction mixture
was cooled to room temperature, acidified with 1.0 N HCl (3
mL), and then extracted with methylene chloride. The organic
phase was dried over sodium chloride and concentrated under
reduced pressure to yield 134 mg (98%, 24% overall) of a glassy
solid. HPLC (>99.9 area%, tR ) 5.8 min at 80% ISO); 1H NMR
(400 MHz, CDCl3) δ 8.08 (d, J ) 8.3 Hz, 2H), 7.67 (d, J ) 8.3
Hz, 2H), 7.60 (d, J ) 8.3 Hz, 2H), 7.45-7.36 (m, 3H), 6.86 (d,
J ) 9.3 Hz, 2H), 6.78 (d, J ) 9.3 Hz, 2H), 4.24 (t, J ) 6.3 Hz,
2H), 3.15 (t, J ) 6.3 Hz, 2H), 1.48 (s, 6H); 13C NMR (CDCl3) δ
Hydrolysis of 2-methyl-2-(4-{2-[5-methyl-2-(4-phenyl-cyclo-
hexyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid methyl es-
ter (0.322 g, 0.67 mmol) was carried out by the procedure
described for 1b to yield 312 mg (100%) of 1d as a glassy solid.
1
HPLC (96.7 area%, tR ) 4.0 min at 80% ISO); H NMR (400
MHz, CDCl3) δ 7.25-7.11 (m, 5H), 6.82 (d, J ) 8.8 Hz, 2H),
6.68 (d, J ) 8.8 Hz, 2H), 4.04 (t, J ) 6.8 Hz, 2H), 2.89-2.76
(m, 3H), 2.54-2.47 (m, 1H), 2.22 (s, 3H), 2.17-2.13 (m, 2H),
1.98-1.95 (m, 2H), 1.72-1.62 (m, 2H), 1.56-1.49 (m, 2H), 1.47
(s, 6H); 13C NMR (CDCl3) δ 10.02, 25.05, 25.41, 30.60, 33.34,
37.05, 43.45, 66.70, 80.01, 114.90, 122.01, 126.17, 126.76,
128.42, 129.29, 145.07, 146.64, 148.36, 154.63, 166.43, 176.48;
HRMS-FAB m/z [M + H]+ calcd for C28H33NO5 464.2437,
found 464.2435.
2-Ben zyla m in o-4-[4-(1-et h oxyca r b on yl-1-m et h yl-et h -
oxy)-p h en oxy]-bu tyr ic Acid Eth yl Ester (24). Amino-4-[4-
(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid eth-
yl ester (0.612 g, 1.73 mmol) and benzaldehyde (220 mg, 2.08
mmol) were dissolved in 10 mL of methylene chloride followed
by addition of sodium triacetoxyborohydride (550 mg, 2.60
mmol). After 4 h at room temperature, the reaction mixture
was partitioned between methylene chloride (50 mL) and 0.1
N HCl (50 mL). The pH of the mixture was then adjusted to
J . Org. Chem, Vol. 68, No. 7, 2003 2631

Godfrey et al.
24.75, 26.55, 29.65, 65.83, 80.39, 115.06, 122.95, 124.72,
127.09, 127.45, 127.52, 128.11, 128.91, 139.78, 140.08, 140.11,
144.32, 147.53, 155.08, 162.07, 176.68; HRMS-FAB m/z
[M + H]+ calcd for C28H24F3NO5, 512.1685; found 512.1709.
their contributions along with the members of the
Physical Chemistry Group, Lilly Research Laboratories,
for providing much of the analytical data.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for intermediates 11a -f and 23 and
the 1H NMR spectra for compounds 11f, 12a ,c,d ,f, 13a ,c,
14d ,f, 21a , 22b-d , 1b-e, and 23-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The authors would like to thank
Professors William Roush, Leo Paquette, Paul Wender,
Peter Wipf, and Marvin Miller for helpful discussions
during the course of this work. Mr. J ames P. Wepsiec
and Mr. Darrell R. Hutchison are also acknowledged for
J O026655V
2632 J . Org. Chem., Vol. 68, No. 7, 2003