The synthesis of GW710936X to support the development of potent PPARγ agonists

Article abstract of DOI:10.1016/S0040-4020(01)00743-8

(2S)-[(2-Benzoyl-4-hydroxy-phenyl)amino]-3-{4-[2-(5-methyl-2-phenyloxazol-4- yl)ethoxy]phenyl}propanoic acid has been synthesised from N-Cbz-L-tyrosine methyl ester utilising a copper(I) catalysed N-arylation as the key coupling step. The synthetic route

Full text of DOI:10.1016/S0040-4020(01)00743-8

TETRAHEDRON
Pergamon
Tetrahedron 57 "2001) 7765±7770
The synthesis of GW710936X to support the development of
potent PPARg agonists
²
Dominic J. Reynolds and Stephen A. Hermitagep
GlaxoSmithKline Research and Development, Chemical Development Division, Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire SG1 2NY, UK
Received 14 May 2001; revised 14 June 2001; accepted 12 July 2001
AbstractÐ"2S)-["2-Benzoyl-4-hydroxy-phenyl)amino]-3-{4-[2-"5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid has been
synthesised from N-Cbz-l-tyrosine methyl ester utilising a copper"I) catalysed N-arylation as the key coupling step. The synthetic route
was designed to be convergent and to facilitate ease of isolation of the unstable product that had proven to be unobtainable by concentration
of extracts from biological assays. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Inspection of the structure of 2 identi®ed oxazole ethanol 3,4
tyrosine derivative 4 and unsymmetrical benzophenone 5 as
suitable, readily available starting materials that would
permit a convergent synthesis "Scheme 1). The key features
of the plan involve: "i) a copper"I) catalysed N-arylation of
the amino acid moiety to attach 5, the lipophilic portion of
the molecule and "ii) the ®nal ¯uoride mediated deprotec-
tion of the phenol with a view towards avoiding any
potential degradation problems.
N-"2-Benzoylphenyl)-l-tyrosine derivatives form a novel
and potent class of antihyperglycemics that were discovered
and optimised from a l-tyrosine-derived screening hit using
in vitro assays of peroxisome proliferator-activated receptor
g "PPARg) activity.1±3 In particular, compound 1 was
shown to have antidiabetic activity when dosed orally to
rodent models of Type 2 diabetes1 "Fig. 1).
During the course of our effort towards developing
molecules with a greater therapeutic ef®cacy in treating
Type
2
diabetes, the synthesis of compound 2,
GW710936X, was required with the primary objectives of
providing suf®cient material to: "i) elucidate its PPARg
activity and "ii) to serve as an authentic standard for stability
and disposition studies.
Scheme 1. Synthetic plan for 2.
2. Results and discussion
Figure 1.
The synthesis commenced with the preparation of the
unsymmetrical benzophenone 5. Starting with 2-bromo-5-
methoxy-benzoic acid methyl ester 6, a two step procedure
involving Weinreb amide formation followed by the addi-
tion of phenyl magnesium chloride was envisaged to afford
7. However treatment of 6 with N,O-dimethylhydroxyl-
amine hydrochloride and isopropyl magnesium chloride in
Keywords: N-arylation; copper; catalysis.
Corresponding author. Tel.: 144-1438-763-658; fax: 144-1438-764-
p
869; e-mail: sah45573@gsk.com
Present address: Department of Chemistry and Chemical Biology,
²
Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Tel.: 11-617-495-2949.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020"01)00743-8

7766
D. J. Reynolds, S. A. Hermitage / Tetrahedron 57 -2001) 7765±7770
ammonium iodide cleaved the methyl substituent to give
the corresponding phenol "Scheme 3).7 Subsequent reaction
of the crude phenol with 2-"trimethylsilyl)ethoxymethyl-
chloride "SEMCl) in the presence of diisopropylethylamine
afforded 5 in 70% yield over two steps.8 At this stage of the
synthesis a trial copper"I) catalysed coupling reaction with a
commercially available amino acid was attempted, accord-
ing to the protocol of Ma et al.9 Thus treatment of 5 and
O-benzyl-l-tyrosine with copper"I) iodide and potassium
carbonate in DMF at 908C afforded after 3 days, the
N-arylated amino acid in 50% yield after chromatography.
For ease of characterisation the carboxylic acid was
protected as the 2-"trimethylsilyl)ethanol "TMSE) ester 10
in 71% yield by treatment with TMSE, catalytic DMAP and
dicyclohexylcarbodiimide "DCC).10
Scheme 2. Reagents and conditions. "1) MeNH"OMe)´HCl, iPrMgCl, THF,
1 h, 2308C "9/8, 4:1); "2) MeNH"OMe)´HCl, PhMgCl, THF, 1 h, 258C; "3)
PhMgCl, THF, 5 h, 210!258C "89%, 2 steps).
Following the preparation of 10, which has the carboxylic
acid protected and the two phenol moieties differentiated, an
alternative route involving debenzylation, Mitsunobu
coupling with oxazole ethanol 3 and then ¯uoride mediated
deprotection to afford 2 was considered. However, initial
attempts at the removal of the benzyl ether by hydrogena-
tion using catalytic palladium on carbon failed due to
competing exhaustive reduction of the ketone to afford 11
"Scheme 4). Thus this approach was abandoned in favour of
pursuing a shorter, more convergent strategy.
THF at 2308C according to the procedure of Williams et al.
afforded large amounts of the debrominated Weinreb amide
8 resulting from halogen metal exchange with the aryl
bromide "Scheme 2).5,6 This problem could be avoided by
using phenyl magnesium chloride to act as the base in the
formation of 9 which, following aqueous washing to remove
the excess N,O-dimethylhydroxylamine, underwent
a
second reaction with the same Grignard reagent to afford
the desired phenyl ketone 7 in 89% yield over two steps. It is
worth noting that an attempted `one pot' transformation
delivered inferior yields of 7Ðpresumably due to the
competitive addition of the reactive magnesium amide
species to the Weinreb amide intermediate 8.5 This problem
was exacerbated by the requirement of excess "1.5 equiv.)
N,O-dimethylhydroxylamine hydrochloride in order to
obtain complete conversion of the methyl ester into 7.
With evidence that the N-arylation seemed feasible, the
prior coupling of the oxazole ethanol 3 with the amino
acid 4 was investigated. Commencing with N-Cbz-l-
tyrosine methyl ester 4, Mitsunobu reaction with 3
using diisopropylazodicarboxylate "DIAD) and triphenyl-
phosphine in toluene at 458C afforded the coupled product
"Scheme 5).11 Subsequent hydrogenation of the Cbz group
using catalytic palladium on carbon followed by saponi®ca-
tion of the methyl ester with aqueous sodium hydroxide
afforded, after acidi®cation, the amino acid derivative 12
in an unoptimised 55% yield over 3 steps.
With 7 in hand, it was deemed prudent to exchange the
methyl ether for a more labile protecting group, which
requires removal at the end of the synthesis. Thus treatment
of 7 with boron trichloride in the presence of tetrabutyl-
The key coupling reaction proceeded by reaction of 12 and 5
using the conditions previously adopted, which, after
4 days, afforded N-arylated product 13 in a disappointing
38% yield after chromatography. The lower yield
obtained on changing the amino acid component may be a
result of the greatly reduced solubility of 12 as compared to
O-benzyl-l-tyrosine. However, the reaction was deemed
capable of generating suf®cient material in order to serve
the primary purpose of the synthesis. Initial attempts at
removing the SEM group using mild conditions such as
treatment with TBAF in THF at re¯ux proved unsuccessful.
Scheme 3. Reagents and conditions. "1) BCl3, nBu4NI, CH2Cl2, 14 h,
i
278!258C; "2) SEMCl, Pr2NEt, CH2Cl2, 18 h, 258C "70%, 2 steps); "3)
O-benzyl-l-tyrosine, K2CO3, cat. CuI, DMF, 72 h, 908C "50%); "4) DCC,
DMAP, TMSE, EtOAc, 18 h, 258C "71%).
Scheme 4. Reagents and conditions. "1) Pd/C "10%), EtOH, 258C "65%).

D. J. Reynolds, S. A. Hermitage / Tetrahedron 57 -2001) 7765±7770
7767
accomplished starting from a homochiral l-tyrosine deriva-
tive, using a copper"I) catalysed N-arylation as the key bond
forming reaction. Despite the low yielding coupling step,
the synthesis has permitted the generation and isolation of
suf®cient amounts of an unstable compound in order to meet
the requirements for further elucidation of its PPARg
activity.
4. General experimental section
Proton and carbon NMR were recorded on a Bruker
DPX400 spectrometer. Infrared spectra were recorded on
a Nicolet 20SXC FTIR spectrophotometer and mass spectra
run on Micromass Q-TOF, hybrid quadropole time-of-¯ight
MS 2/1ve ion electrospray instrument. Reagents and
solvents were obtained from commercial suppliers and
used as supplied.
5. Experimental
5.1. Data for compounds
5.1.1. .2-Bromo-5-methoxy-phenyl)-phenyl-methanone
7. Phenyl magnesium chloride "2 M in THF, 220 mL,
0.44 mol) was added dropwise to a slurry of the methyl
ester 6 "35.5 g, 0.15 mol) and N,O-dimethylhydroxylamine
hydrochloride "21.5 g, 0.22 mol) in THF "300 mL) at
2108C. After stirring for 1 h at 258C, the reaction was
quenched by the addition of 20% ammonium chloride solu-
tion "200 mL). The organic phase was separated and washed
with water "200 mL), brine "200 mL), dried "Na2SO4) and
concentrated in vacuo to afford the Weinreb amide 9
"39.2 g, 0.14 mol) as a solid which was used without further
puri®cation. m/z "C10H13BrNO3) [MH]1 274 and 276
"100%).
Scheme 5. Reagents and conditions. "1) DIAD, 3, PPh3, 4, toluene, 30 min,
458C "68%); "2) Pd/C "20%), EtOH, 15 h, 258C; "3) MeCN/NaOH "aq), 1 h,
508C "84%, 2 steps); "4) K2CO3, cat. CuI, 5 DMF, 96 h, 908C "38%); "5)
TBAF´3H2O, DMPU, 2 h, 1108C "68%).
However, a simple solvent change to N,N0-dimethylpropyl-
eneurea "DMPU) saw a dramatic increase in rate with
complete deprotection being observed within 2 h at 1108C.
It is worth noting that DMPU served as an adequate replace-
ment for the highly carcinogenic HMPA which is normally
the solvent of choice for this transformation.12 Isolation and
puri®cation by ¯ash column chromatography afforded 2 "in
68% yield). The product was found to decompose rapidly in
solution,13 although storage under nitrogen at 2208C was
suf®cient to maintain purity, once concentration in vacuo
had been achieved.
Phenyl magnesium chloride "2 M in THF, 300 mL,
0.60 mol) was added dropwise to a solution of the crude
Weinreb amide 9 "39.2 g, 0.14 mol) in THF "250 mL) at
2108C. The resulting solution was warmed to room
temperature, stirred for 5 h, then quenched by the dropwise
addition of aqueous hydrochloric acid "1N, 550 mL), taking
care to keep the reaction temperature below 358C. After
cooling to room temperature, the organic layer was sepa-
rated, dried "Na2SO4) and concentrated in vacuo to afford
the phenyl ketone 7 "37.4 g, 89%) as a pale brown oil which
was used without further puri®cation. Rf 0.37 "iso-hexane/
Disappointingly, closer analysis of the isolated product 2
using chiral HPLC14 revealed that partial epimerisation of
the a-amino acid carbon had occurred to afford a 2.3:1 ratio
of enantiomers. The cause of this erosion of e.e. is currently
unknown, although Ma et al. carried out a thorough analysis
of the N-arylated products afforded by their copper iodide
promoted coupling reaction, demonstrating no loss of
stereochemical integrity.9 This allows speculation that the
®nal TBAF/DMPU mediated deprotection may be respon-
sible for the observed results. Fortunately, the use of
preparative chiral HPLC allowed the isolation of a suf®cient
quantity of material to support the subsequent biological
studies. As a result no further synthetic investigations
have been undertaken to establish the cause of the
epimerisation.
1
diethyl ether, 8:1); H NMR "CDCl3, 250 MHz) dH 7.85±
7.81 "2H, m, Ar), 7.63±7.56 "1H, m, Ar), 7.52±7.43 "3H, m,
Ar), 6.92±6.86 "2H, m, Ar) and 3.79 "3H, s, OCH3); 13C
NMR "CDCl3, 62.5 MHz) dC 196.0 "CvO), 159.2 "ipso
C±O), 141.8, 136.3, 134.4, 134.2, 130.7, 129.1, 117.8,
114.6, 110.1 "9£Ar) and 56.1 "OCH3); nmax "®lm, cm21
)
1673 "CvO), 1594, 1570, 1468 and 1450 "Ar); m/z
291.0009, C14H1279BrO2 [MH]1 requires 291.0021; m/z
Low Res: 291 and 293 "[MH]1, 100%).
5.1.2.
.2-Bromo-5-.2-trimethylsilylethoxy)-methoxy-
3. Conclusions
phenyl)phenylmethanone 5. Boron trichloride "1 M in
dichloromethane, 100 mL, 100 mmol) was added dropwise
over 15 min to a solution of phenyl ketone 7 "11.6 g,
In summary, a short and convergent synthesis of 2 has been

7768
D. J. Reynolds, S. A. Hermitage / Tetrahedron 57 -2001) 7765±7770
40 mmol) and tetrabutylammonium iodide "35.4 g,
96 mmol) in dichloromethane "200 mL) at 2788C. After
warming to room temperature, the reaction was stirred for
14 h, then ice/water ",200 mL) was added and the resulting
mixture stirred vigorously for 1 h. Saturated sodium
bicarbonate solution "200 mL) was then added, the aqueous
phase separated and re-extracted with dichloromethane
"2£200 mL). The combined organic phase was dried
"MgSO4) and concentrated in vacuo to afford a pale
brown oil ",11.0 g) which was used in the subsequent
step without further puri®cation.
the fully protected adduct 10 "0.58 g, 71%) as a bright
yellow oil. Rf 0.30 "iso-hexane/ethyl acetate "8:1); 1H
NMR "CDCl3, 400 MHz) dH 8.55 "1H, d, Jˆ7.5 Hz, NH),
7.65 "2H, dd, Jˆ8.5, 1.5 Hz, Ar), 7.54±7.33 "8H, m, Ar),
7.28±7.22 "3H, m, Ar), 7.16 "1H, dd, Jˆ9.0, 3.0 Hz, Ar),
6.93 "2H, m, Ar), 6.64 "1H, d, Jˆ9.0 Hz, Ar), 5.04 "4H, s,
ArCH2O and OCH2OAr), 4.33 "1H, q, Jˆ7.0 Hz, CHN),
4.26±4.14 "2H, m, CO2CH2CH2Si), 3.70 "2H, t, Jˆ8.0 Hz,
CH2OCH2), 3.22 "1H, dd, Jˆ13.5, 6.0 Hz, CHHCHN), 3.11
"1H, dd, Jˆ13.5, 7.5 Hz, CHHCHN), 0.99±0.87 "4H, m,
2£SiCH2), 0.04 "9H, s, Si"CH3)3) and 0.00 "9H, s,
Si"CH3)3); 13C NMR "CDCl3, 100 MHz) dC 200.0 "CvO),
174.4 "OCvO), 159.3, 148.2, 147.5, 141.5, 138.5, 132.5,
131.8, 130.6, 130.4, 130.0, 129.5, 129.4, 128.9, 126.6,
124.6, 120.0, 116.3, 114.5 "18£Ar), 95.7 "OCH2OAr),
71.4 "CO2CH2), 67.3 "CH2OCH2O), 65.0 "ArCH2O), 60.0
"CHN), 39.6 "CH2CHN), 19.5 "SiCH2), 18.8 "SiCH2), 0.00
"Si"CH3)3) and 20.08 "Si"CH3)3); nmax "®lm, cm21) 3321
"N±H), 1739 "OCvO), 1632 "CvO), 1611, 1577, 1511 and
1453 "Ar); m/z 698.3315 C40H52NO6Si2 requires [MH]1
698.3333.
SEMCl "7.1 mL, 40 mmol) was added dropwise to a
solution of crude phenol ",40 mmol) and diisopropylethyl-
amine "13.9 mL, 80 mmol) in dichloromethane "200 mL) at
room temperature. After stirring for 18 h, saturated sodium
bicarbonate solution "200 mL) was added and the mixture
extracted with diethyl ether "2£200 mL). The combined
organic phase was dried "MgSO4) and concentrated in
vacuo. Puri®cation by ¯ash column chromatography eluting
with iso-hexane/diethyl ether "8:1) afforded the SEM acetal
5 "11.3 g, 70%) as a pale brown oil. Rf 0.42 "iso-hexane/
1
diethyl ether, 8:1); H NMR "CDCl3, 250 MHz) dH 7.86±
5.1.4. .2S)-[.2-Benzoyl-4-.2-trimethylsilylethoxy)methoxy-
phenyl)amino]-3-.4-hydroxyphenyl) propionic acid
2-trimethylsilylethyl ester 11. A solution of 10 "83 mg,
0.12 mmol) in ethanol "1 mL) was added to a suspension
of 5% palladium on carbon "moist, 10 mg) in ethanol "2 mL)
under an atmosphere of hydrogen. After stirring for 3 h the
catalyst was removed by ®ltration through Celitew and the
®ltrate was concentrated in vacuo. Puri®cation by ¯ash
column chromatography eluting with iso-hexane/ethyl
acetate "4:1) afforded phenol 11 "46 mg, 65%) as an oil.
7.83 "2H, m, Ar), 7.65±7.59 "1H, m, Ar), 7.55±7.45 "3H, m,
Ar), 7.09±7.04 "2H, m, Ar), 5.22 "2H, s, OCH2O), 3.75 "2H,
t, Jˆ8.0 Hz, CH2CH2O), 0.94 "2H, t, Jˆ8.0 Hz, CH2CH2O)
and 0.00 "9H, s, Si"CH3)3); 13C NMR "CDCl3, 62.5 MHz) dC
196.9 "CvO), 158.1 "ipso C±O), 142.9, 137.4, 135.4,
135.2, 131.7, 130.1, 120.6, 118.3, 112.2 "9£Ar), 94.5
"OCH2O), 68.0 "CH2CH2O), 27.1 "CH2CH2O) and 0.00
"Si"CH3)3); nmax "®lm, cm21) 1676 "CvO), 1595, 1567,
1467 and 1450 "Ar); m/z 407.0661, C19H2479BrO3Si
[MH]1 requires 407.0678; m/z Low Res: 424 and 426
"[MNH4]1, 100%).
1
Rf 0.14 "iso-hexane/ethyl acetate "8:1); H NMR "CDCl3,
250 MHz) dH 7.29±7.09 "5H, m, Ar), 6.87±6.81 "3H, m,
Ar), 6.75 "1H, d, Jˆ3.0 Hz, Ar), 6.62 "2H, d, Jˆ8.5 Hz, Ar),
6.47 "1H, d, Jˆ8.5 Hz, Ar), 5.16 "1H, br s, NH), 5.09 "2H, s,
OCH2OAr), 4.18±3.98 "3H, m, CHN and CO2CH2CH2Si),
3.80 "2H, s, ArCH2Ar), 3.72 "2H, t, Jˆ8.5 Hz, CH2OCH2),
2.92±2.87 "2H, m, CH2CHN), 0.96±0.81 "4H, m,
2£SiCH2), 0.00 "9H, s, Si"CH3)3) and 20.02 "9H, s,
Si"CH3)3); 13C NMR "CDCl3, 62.5 MHz) dC 175.2
"OCvO), 155.9, 151.3, 141.1, 140.5, 131.8, 130.1, 130.0,
129.8, 128.7, 127.7, 121.5, 116.8, 116.7, 113.8, "14£Ar),
95.3 "OCH2OAr), 67.2 "CH2OCH2O), 64.8 "CO2CH2),
59.9 "CHN), 39.2 "CH2CHN), 27.1 "ArCH2Ar), 19.4
"SiCH2), 18.7 "SiCH2), 0.00 "Si"CH3)3) and 20.15
"Si"CH3)3); m/z "C33H48NO5Si2) [MH]1 594 "100%).
5.1.3. .2S)-[.2-Benzoyl-4-.2-trimethylsilylethoxy)methoxy-
phenyl)amino]-3-.4-benzyloxyphenyl) propionic acid
2-trimethylsilylethyl ester 10. DMF "4.5 mL) was added
to a mixture of O-benzyl-l-tyrosine "0.67 g, 2.40 mmol),
aryl halide 5 "1.00 g, 2.40 mmol), potassium carbonate
"0.51 g, 3.70 mmol) and copper iodide "0.05 g,
0.24 mmol) under nitrogen. The reaction mixture was
heated at 908C for 72 h, then cooled to room temperature,
diluted with ethyl acetate "50 mL) and water "30 mL) and
acidi®ed to pH 3 by the addition of 2 M aqueous hydro-
chloric acid. The aqueous layer was separated and extracted
with ethyl acetate "2£20 mL), then the combined organic
phase was washed with 10% lithium chloride solution
"3£30 mL), dried "MgSO4) and concentrated in vacuo. Puri-
®cation by ¯ash column chromatography eluting with ethyl
acetate/iso-hexane "1:3!1:1) along with ,0.1% acetic acid
afforded arylamine "0.72 g, 50%) as a yellow oil.
5.1.5. .2S)-2-Amino-3-{4-[2-.5-methyl-2-phenyloxazol-4-
yl)-ethoxy]phenyl}propionic acid 12. A solution of DIAD
"3.30 mL, 16.8 mmol) in toluene "3 mL) was added drop-
wise to a solution of N-Cbz-l-tyrosine methyl ester 4
"4.44 g, 13.4 mmol), oxazole ethanol
3
"3.00 g,
DCC "0.24 g, 1.17 mmol) was added portionwise to a solu-
tion of carboxylic acid "0.71 g, 1.17 mmol), DMAP "15 mg,
0.12 mmol) and 2-trimethylsilylethanol "0.14 g, 1.17 mmol)
in ethyl acetate "2.5 mL) at room temperature. After stirring
for 18 h, the precipitate was removed by ®ltration and
washed with ethyl acetate "30 mL). The organic phase
was washed with 20% ammonium chloride solution
"20 mL), brine "20 mL), dried "MgSO4) and concentrated
in vacuo. Puri®cation by ¯ash column chromatography
eluting with iso-hexane/ethyl acetate "10:1!8:1) afforded
14.8 mmol) and triphenylphosphine "4.41 g, 16.8 mmol) in
toluene "30 mL). After complete addition the reaction was
heated at 458C for 30 min, then cooled to room temperature
and concentrated in vacuo. Puri®cation by ¯ash column
chromatography eluting with dichloromethane/methanol
"98:2) afforded oxazole amino acid "4.70 g, 68%) as a
foam. Rf 0.67 "dichloromethane/methanol, 95:5); m/z
"C30H31N2O6) [MH]1 515 "100%).
A solution of oxazole amino acid "4.70 g, 9.14 mmol) in

D. J. Reynolds, S. A. Hermitage / Tetrahedron 57 -2001) 7765±7770
7769
ethanol "50 mL) was added to 5% palladium on carbon
"1 g). The reaction was then placed under a hydrogen
atmosphere and stirred for 15 h at room temperature.
After purging the reaction vessel with nitrogen, the catalyst
was removed by ®ltration through Celitew and washed with
ethanol "100 mL). Concentration in vacuo afforded the
crude amine as a gum. m/z "C22H25N2O4) [MH]1 381
"100%).
"CH2CH2OAr), 18.8 "CH2Si), 9.73 "CCH3), 0.01
"Si"CH3)3); nmax "nujol mull, cm21) 3253 "N±H), 2500
"br, CO2H), 1725 "OCvO), 1631 "CvO), 1610, 1576,
1533, and 1510 "Ar); m/z 693.2994, C40H45N2O7Si [MH]1
requires 693.2996; m/z Low Res: 693 "[MH]1, 90%), 322
"100%).
5.1.7. .2S)-[.2-Benzoyl-4-hydroxyphenyl)amino]-3-{4-[2-
.5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl} propionic
acid 2. TBAF´3H2O "1.4 g, 3.6 mmol) was added in one
portion to a solution of the SEM acetal 13 "1.0 g,
1.4 mmol) in DMPU "10 mL). After stirring for 2 h at
1108C, the reaction was cooled to room temperature, diluted
with ethyl acetate "100 mL), washed with 10% citric acid
solution "3£60 mL), water "3£60 mL), dried "MgSO4), and
concentrated in vacuo. Puri®cation by ¯ash column chro-
matography eluting with ethyl acetate/iso-hexane "2:1, 2
column lengths) followed by acidi®cation of the eluent
[ethyl acetate/iso-hexane "2:1) along with 0.1% acetic
acid] afforded the metabolite 2 "0.55 g, 68%) as an orange
foam which was stored under nitrogen at 2208C. Rf 0.42
Aqueous sodium hydroxide "2.5 M, 15 mL) was added to
solution of the crude amine in acetonitrile "15 mL) and the
mixture heated at 508C for 1 h. After cooling to 08C, the
solution was acidi®ed to pH 8 by the dropwise addition of
aqueous hydrochloric acid "2 M, ,20 mL). The precipitate
was collected by ®ltration, washed with ice cold water then
dried in a vacuum oven at 608C for 16 h to afford oxazole
amino acid 4 "2.80 g, 84%) as a white solid. 1H NMR "D2O/
DCl, 400 MHz) dH 7.72 "2H, d, Jˆ8.0 Hz, Ar), 7.47 "1H, t,
Jˆ7.5 Hz, Ar), 7.36 "2H, m, Ar), 6.95 "2H, d, Jˆ8.5 Hz,
Ar), 6.72 "2H, Jˆ8.5 Hz, Ar), 4.07 "2H, t, Jˆ6.0 Hz,
CH2OAr), 4.02 "1H, Jˆ6.5 Hz, CHNH2), 2.97±2.83 "4H,
m, CH2CH2OAr and ArCH2CHN) and 2.20 "3H, s, Me);
13C NMR "D2O/DCl, 400 MHz) dC 171.4 "CO2H), 157.6,
135.0, 131.0, 130.0, 127.6, 126.0, 125.7, 120.3, 115.7
"9£Ar), 65.8 "CH2OAr), 54.2 "CHN), 34.9 "CH2CHN),
22.9 "CH2CH2OAr) and 9.6 "CH3); nmax "nujol mull,
cm21) 2570 "NH31), 1601 "CO22), 1555, 1513, 1486 and
1462 "Ar); m/z 367.1651, C21H23N2O4 [MH]1 requires
367.1658; m/z Low Res: 367 "[MH]1, 100%).
1
"ethyl acetate/iso-hexane, 2:1 plus 0.1% acetic acid); H
NMR "d6-DMSO, 400 MHz) dH 12.84 "1H, br s, CO2H),
8.82 "1H, s, OH), 8.11 "1H, br s, NH), 7.92 "2H, dd,
Jˆ8.0, 2.0 Hz, Ar), 7.66±7.49 "8H, m, Ar), 7.12 "2H, d,
Jˆ8.5 Hz, Ar), 6.98 "1H, dd, Jˆ9.0, 2.5 Hz, Ar), 6.83±
6.81 "3H, m, Ar), 6.74 "1H, d, Jˆ9.0 Hz, Ar), 4.45±4.40
"1H, br s, CHN), 4.15 "2H, t, Jˆ6.5 Hz, CH2OAr), 3.12 "1H,
dd, Jˆ14.0, 5.5 Hz, ArCHH), 3.00 "1H, dd, Jˆ14.0, 6.5 Hz,
ArCHH), 2.90 "2H, t, Jˆ6.5 Hz, CH2CH2OAr) and 2.33
"3H, s, CCH3). 13C NMR "d6-DMSO, 100 MHz) dC 198.1
"CvO), 174.0 "CO2H), 158.7, 157.4, 146.7 145.4, 143.8,
140.2, 133.0, 131.3, 130.7, 130.4, 129.4, 129.1, 128.9,
128.6, 127.5, 125.8, 124.2, 119.4, 118.4, 114.6, 114.3
"21£Ar), 66.4 "CH2OAr), 57.1 "CHN), 37.0 "CH2CHN),
5.1.6. .2S)-[.2-Benzoyl-4-.2-trimethylsilylethoxy)methoxy-
phenyl)amino]-3-{4-[2-.5-methyl-2-phenyloxazol-4-yl)-
ethoxy]phenyl} propionic acid 13. DMF "20 mL) was
added to a mixture of oxazole amino acid 4 "2.50 g,
6.80 mmol), aryl halide 5 "2.77 g, 6.80 mmol), potassium
carbonate "1.42 g, 10.3 mmol) and copper iodide "0.13 g,
0.68 mmol) under nitrogen. The reaction mixture was
heated at 908C for 94 h, then cooled to room temperature,
diluted with ethyl acetate "30 mL) and water "15 mL) and
acidi®ed to pH 3 by the addition of 2 M aqueous hydro-
chloric acid. The aqueous layer was separated and extracted
with ethyl acetate "2£20 mL), then the combined organic
phase was washed with 10% lithium chloride solution
"3£30 mL), dried "MgSO4) and concentrated in vacuo. Puri-
®cation by ¯ash column chromatography eluting with ethyl
acetate/iso-hexane "1:3!1:1) along with ,0.1% acetic acid
afforded arylamine 12 "1.80 g, 38%) as an orange foam. 1H
NMR "d6-DMSO, 400 MHz) dH 13.02 "1H, br s, CO2H),
8.35 "1H, d, Jˆ8.0 Hz, NH), 8.00±7.98 "2H, m, Ar),
7.69±7.56 "8H, m, Ar), 7.28 "1H, dd, Jˆ9.0, 3.0 Hz, Ar),
7.18 "2H, d, Jˆ8.5 Hz, Ar), 7.14 "1H, d, Jˆ3.0 Hz, Ar),
6.91±6.87 "3H, m, Ar), 5.08 "2H, s, OCH2O), 4.60±4.55
"1H, m, CHN), 4.26 "2H, t, Jˆ6.5 Hz, CH2OAr), 3.67
"2H, t, Jˆ8.0 Hz, SiCH2CH2), 3.21 "1H, dd, Jˆ14.0,
5.5 Hz, ArCHH), 3.09 "1H, dd, Jˆ14.0, 6.5 Hz, ArCHH),
2.96 "2H, t, Jˆ6.5 Hz, CH2CH2OAr), 2.40 "3H, s, CH3),
0.87 "2H, t, Jˆ8.0 Hz, SiCH2) and 0.00 "9H, s, Si"CH3)3);
13C NMR "d6-DMSO, 100 MHz) dC 199.0 "CvO), 174.7
"CO2H), 159.8 "ipso C±O), 158.5 "ipso C±O), 147.4, 146.8,
146.7, 146.5, 140.9, 134.1, 132.7, 131.8, 131.4, 130.5,
130.2, 130.0, 129.6, 128.6, 126.9, 123.3, 119.0, 115.7,
115.2 "19£Ar), 95.0 "OCH2O), 67.5 "CH2OAr), 66.4
"SiCH2CH2), 57.9 "CHN), 37.9 "CH2CHN), 27.0
25.9 "CH2CH2OAr) and 10.2 "CH3); nmax "®lm, cm21
)
3330 "OH and NH), 1714 "OCvO), 1633 "CvO), 1611,
1552, and 1511 "Ar); m/z 563.2166, C34H31N2O6 [MH]1
requires 563.2182; m/z Low Res: 563 "[MH]1, 12%), 322
"100%).
Acknowledgements
We are grateful to Hong Lu of the Division of Drug
Metabolism and Pharmacokinetics for performing the
HPLC and stability studies.
References
1. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown,
K. K.; Cobb, J. E.; Collins, J. L.; Harrington, Jr., W. W.;
Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.;
Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Orband-
Miller, L. A.; Miller, J. F.; Mook, Jr., R. A.; Noble, S. A.;
Oliver, Jr., W.; Parks, D. J.; Plunket, K. D. et al., J. Med.
Chem. 1998, 41, 5020±5036.
2. 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.;

7770
D. J. Reynolds, S. A. Hermitage / Tetrahedron 57 -2001) 7765±7770
Plunkett, K. D.; Tong, W.-Q. J. Med. Chem. 1998, 41, 5037±
5054.
8. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21,
3343±3346.
3. Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.;
Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.;
Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.;
Oliver, Jr., W.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket,
K. D.; Tong, W.-Q. J. Med. Chem. 1998, 41, 5055±5069.
4. Hulin, B.; Clark, D. A.; Goldstein, S. W.; McDermott, R. E.;
Dambeck, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis,
D. M.; Rizzi, J. P. J. Med. Chem. 1992, 35, 1853±1864.
5. Williams, M. J.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36,
5461±5464.
9. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459±12467.
10. Bourne, G. T.; Horwell, D. C.; Pritchard, M. C. Tetrahedron
1991, 47, 4763±4774.
11. Hughes, D. L. Org. React. 1992, 42, 335.
12. Kocienski, P. J. Thieme Foundations of Organic Chemistry
Series; Enders, D., Noyori, R., Trost, B. M., Eds.; Thieme:
Stuttgart, 1994; pp 80±82.
13. In an aqueous/organic solution 2 was found to decompose
with a half-life of approximately 7 h. In dry acetonitrile at
2208C under nitrogen it appears stable for at least 2 days.
14. Chiral HPLC was carried out using a Chiralcel OD-R "0.46 cm
i.d.£0.25 cm) eluting with acetonitrile/water "3:1, containing
1% formic acid).
Â
6. Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.;
È
Rottlander, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618±
4634.
7. Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.;
Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org Chem.
1999, 64, 9719±9721.