A highly efficient synthesis of antiobestic ligand GW501516 for the peroxisome proliferator-activated receptor δ through in situ protection of the phenol group by reaction with a Grignard reagent

Article abstract of DOI:10.1016/j.tetlet.2005.07.145

A new synthesis of an agonist for the peroxisome proliferator-activated receptor δ (PPARδ) GW501516 as a potential antiobesity drug is described. The synthetic route involves the in situ protection of the phenol group with a Grignard reagent and a regio-controlled one-pot reaction for the formation of a sulfide bond as the key step. Starting from commercially available 4-iodo-2-methylphenol, this approach affords GW501516 with an overall yield of 87%.

Full text of DOI:10.1016/j.tetlet.2005.07.145

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6683–6686
A highly efficient synthesis of antiobestic ligand GW501516
for the peroxisome proliferator-activated receptor d through
in situ protection of the phenol group by reaction
with a Grignard reagent
Jungyeob Ham and Heonjoong Kang*
Marine Biotechnology Laboratory and Research Institute of Oceanography, School of Earth and Environmental
Sciences and Center for Marine Natural Products and Drug Discovery, Seoul National University, NS-80, Seoul 151-747, Korea
Received 28 June 2005; accepted 27 July 2005
Available online 15 August 2005
Abstract—A new synthesis of an agonist for the peroxisome proliferator-activated receptor d (PPARd) GW501516 as a potential
antiobesity drug is described. The synthetic route involves the in situ protection of the phenol group with a Grignard reagent
and a regio-controlled one-pot reaction for the formation of a sulfide bond as the key step. Starting from commercially available
4-iodo-2-methylphenol, this approach affords GW501516 with an overall yield of 87%.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Obesity is a devastating medical condition, which is
associated with type II diabetes, hyperlipidemia, cardio-
vascular disease, and hypertension.1 Many medical
strategies have been devised to treat obesity, such as
the manipulation of food intake centrally or peripher-
ally, blocking of fat absorption by inhibition of a pan-
creatic lipase, modulation of fat metabolism, and
control of adaptive thermogenesis.2 Although, very suc-
cessful in the market, the drugs currently available are
either facing serious problems such as unpleasant side
effects and even patient deaths, or their efficacies are
modest: a 5–10% loss of initial body weight in less than
50% of patients.3 Stimulation of thermogenesis (the regu-
lated production of heat) has thus long been pursued to
treat obesity.4 Recently, the uncoupling of oxidative
phosphorylation through uncoupling proteins (UCPs)
has become an attractive process in the development
of antiobesity drugs.5 Direct control of UCPs has be-
come a promising strategy to treat obesity in humans.
We have identified that PPARd is a key regulator of
UCPs in peripheral tissue in collaboration with EvansÕ
group at the Salk Institute.6 Targeted activation of
PPARd in adipocytes and muscles in combination with
a chemical tool GW501516 showed that it selectively
activates genes responsible for fatty acid oxidation and
energy uncoupling and causes an adaptive muscle switch
and an increase in mitochondrial biogenesis.6,7 These
findings suggest that PPARd serves as a widespread regu-
lator of fat burning and as a key transcriptional factor
regulating muscle fiber plasticity. Overall PPARd is a
novel target for developing drugs to treat obesity and
its associated diseases.8
Recently, the research group of GlaxoSmithKline
discovered GW501516 (1) to be the most effective and
selective ligand for PPARd over the other PPAR
subtypes through structure-based drug design and com-
binatorial chemistry (Fig. 1).9 Treatment for two
months with a PPARd-selective agonist GW501516 of
mice on a high-fat diet (35%) showed that the treated
mice gained much less body weight and fat mass
O
O
OH
S
S
F3C
N
Keywords: PPARd; Antiobestic drug; GW501516; Grignard reagent;
One-pot synthesis; Sulfide.
GW501516 (1)
*
Figure 1. Chemical structure of GW501516 as a PPARd synthetic
Corresponding author. Tel.: +82 2 880 5730; fax: +82 2 883 9289;
agonist.
e-mail: hjkang@snu.ac.kr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.145

6684
J. Ham, H. Kang / Tetrahedron Letters 46 (2005) 6683–6686
(one-third) than controls.7 Therefore, compound 1 is an
indispensable tool in efforts to reveal the underlying
biology of ubiquitously expressed PPARd and a poten-
tial drug in the treatment of obesity and its associated
disorders, such as type II diabetes10 and atherosclerosis.11
result, we were able to obtain the desired compound 3
at 42% and 96% yields (entries 4 and 5), respectively.
Concerning the reactivity of halide on 2 (entries 5–7),
4-iodo- and 4-bromo-2-methylphenols were good start-
ing materials for the preparation of the targeted sulfide
compound (3), while 4-chloro-2-methylphenol did not
undergo lithium–halogen exchange at all under the same
conditions used for the other starting materials.
The synthesis of 1 and its derivatives was first reported
by the GlaxoSmithKline group, and involved the cou-
pling of thiazole chloride with aryl thiol prepared from
o-cresol in more than eight steps with an overall yield
of 7%.9a Later on Wei and Kozikowski reported a
more efficient method for the synthesis of 1 with a
78% overall yield.12 Although this method shows an
improvement in both the number of synthetic steps
and the overall yield, there are still a few limitations in
the production of 1.
Based on the results of the model reactions, we were able
to prepare the intermediate sulfide 8 at 91% yields, from
4-iodo-2-methylphenol as a starting material, via a one-
pot reaction that included the in situ protection of phe-
nol with isopropylmagnesium chloride, lithium–halogen
exchange by tert-butyllithium, thiolate formation, and
quenching the resultant thiolate with chloromethyl thia-
zole 79b (Scheme 1).
For example, it is still difficult to prepare 4-mercapto-2-
methylphenol from o-cresol, which can easily form a
disulfide under oxidative and low pH conditions, or with
free radicals, causing a lower overall yield. Thus, a much
simpler, safer, and more efficient synthesis of 1 is in
demand. Herein, we wish to report a simple preparation
of 1 through in situ protection of the phenol group by
reaction with a Grignard reagent and through an exten-
sion of the one-pot methodology used for alkyl aryl sul-
fides published in a previous report.13
The starting material 2 is commercially available or eas-
ily prepared from o-cresol by general methods.14
Although we could not detect the intermediates 4–6 di-
rectly during the reaction, we could infer their formation
from the target compound 8 (68–91%).15 Quenching
each step—from phenol protection, lithium–halogen
exchange to thiolate formation—with water or mild acid
yielded the desired compounds 2, 9, and 10, respectively,
thus proving the formation of the reaction intermediates
4–6.
We first attempted to find the reaction conditions for the
preparation of 4-benzylsulfanyl-2-methylphenol (3)
through a one-pot reaction without any special steps
to protect the phenol group on the starting material
(Table 1). First, we tried n-butyllithium (2.0 equiv)13
and tert-butyllithium (2.0–3.0 equiv) for in situ protec-
tion of the phenol and for lithium–halogen exchange.
However, these reactions produced low yields (entries
1–3), and so were hardly applicable for the synthesis
of the intermediate compound 8. However, Grignard re-
agent (1.0 equiv), used instead of n- or tert-butyllithium,
proved effective at in situ protection of the phenol group
(1.0 equiv) from reaction at room temperature. As a
We found that the in situ protecting group (–OMgCl,
from PrMgCl on the starting material 2) was free from
lithium–halogen exchange and lithium thiolate forma-
tion. In addition, the nucleophilicity of sulfur anion in
i
OH
X
OMgCl
OH
X
MgCl
H2O
2
4
2
9
X
(X = Br, I)
t-BuLi
OMgCl
OH
H2O
5
Table 1. Optimization of the one-pot reaction for compound 3a
Li
i) A / THF / r.t
OH
ii) -78oC / B
OH
sulfur
iii) sulfur
iv) benzyl bromide
S
X
2
3
OMgCl
6
OH
SH
H3O+
Entry
X
A (equiv)
B (equiv)
% Yieldb
10
1
2
3
4c
5
6
7
I
I
I
I
I
None
None
None
iPrMgCl (1)
iPrMgCl (1)
iPrMgCl (1)
iPrMgCl (1)
n-BuLi (2)
t-BuLi (2)
t-BuLi (3)
n-BuLi (1)
t-BuLi (2)
t-BuLi (2)
t-BuLi (2)
33
Trace
26
42
96
73
S Li
S
N
Cl
F3C
7
OH
Br
Cl
No reaction
S
S
X = I
X = Br
91%
68%
F3C
a All reactions were performed using 4-halo-2-methylphenol
(0.5 mmol), sulfur (1.0 equiv), and benzyl bromide (1.0 equiv).
b Yields were given for isolated products and average values of tri-
flicate reactions.
c 4-Butylsulfanyl-2-methylphenol as a side product was obtained in
36% yields.
8
N
Scheme 1. Reagents and conditions: (i) 4-halo-2-methylphenol
(5.0 mmol), isopropylmagnesium chloride (1.0 equiv), THF, 0 ꢁC,
10 min; (ii) tert-butyllithium (2.0 equiv), À78 ꢁC, 0.5 h; (iii) sulfur
powder, THF, À78 to 0 ꢁC, 0.5 h; (iv) compound 7, THF, 0 ꢁC, 0.5 h.

J. Ham, H. Kang / Tetrahedron Letters 46 (2005) 6683–6686
6685
References and notes
8
a
b
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gelman, B. M. Nature 2000, 404, 652–660.
Yield = 98%
O
O
O
OEt
OH
S
S
F3C
11
N
Yield = 98%
O
S
S
F3C
N
GW 501516 (1)
Scheme 2. Reagents and conditions: (a) ethyl bromoacetate, K2CO3,
aq DMSO, 50 ꢁC, 1 h; (b) 3 N NaOH, aq EtOH, rt, 0.5 h, then 1 N
HCl.
the intermediate 6 was found to be much higher than
that of oxygen anion toward chloromethyl thiazole 7.
Although 4-mercapto-2-methylphenol (10) was obtained
more easily and with better yields (93%)16 by our meth-
od than by any other known method,12 compound 10
was readily converted into its disulfide under oxidative
and acidic conditions or with free radicals. Thus, we
chose a one-pot synthesis of compound 8 instead of
using a step-by-step process, which gave the target com-
pound at good yields.
5. (a) Harper, J. A.; Dickinson, K.; Brand, M. D. Obesity
Rev. 2001, 2, 255–265; (b) Giordano, A.; Centemeri, C.;
Zingaretti, M. C.; Cinti, S. Int. J. Obesity 2002, 26, 354–
360.
6. Wang, Y.-X.; Lee, C.-H.; Tiep, S.; Yu, R. T.; Ham, J.;
Kang, H.; Evans, R. M. Cell 2003, 113, 159–170.
7. Wang, Y.-X.; Zhang, C.-L.; Yu, R. T.; Cho, H. K.;
Nelson, M. C.; Bayuga-Ocampo, C. R.; Ham, J.; Kang,
H.; Evans, R. M. PLoS Biology 2004, 2, 1532–1539.
8. (a) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke,
B. R. J. Med. Chem. 2000, 43, 527–550; (b) Berger, J.;
Moller, D. E. Annu. Rev. Med. 2002, 53, 409–435; (c) Lee,
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Subjects 2003, 1633, 43–50; (e) Luquet, S.; Lopez-Soriano,
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M.; Grimaldi, P. A. FASEB J. 2003, 17, 2299–2301; (f)
Akiyama, T. E.; Lambert, G.; Nicol, C. J.; Matsusue, K.;
Peters, J. M.; Brewer, H.; Bryan, Jr.; Gonzalez, F. J. J.
Biol. Chem. 2004, 279, 20874–20881; (g) Luquet, S.;
Lopez-Soriano, J.; Holst, D.; Gaudel, C.; Jehl-Pietri, C.;
Fredenrich, A.; Grimaldi, P. A. Biochimie 2004, 86, 833–
837.
9. (a) Oliver, W. R., Jr.; Shenk, J. L.; Snaith, M. R.; Russell,
C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.;
Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu,
H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.;
Willson, T. M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
5306–5311; (b) Sznaidman, M. L.; Haffner, C. D.; Malo-
ney, P. R.; Fivush, A.; Chao, E.; Goreham, D.; Sierra, M.
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In the second step, treatment of 8 with K2CO3 and ethyl
bromoacetate in 5% aqueous DMSO at 50 ꢁC for 1 h
gave the ester 11 with a 98% yield (Scheme 2).17 In pre-
vious reports, the compound 8 was reacted with the
same reagents in THF or CH3CN for 16 h or 5 h.9b,12
However, our synthesis enabled the reaction time to be
reduced to 1 h when a 5% aqueous DMSO with mild
heating was used.
As the final step, the saponification of ester 11 with 3 N
NaOH afforded the target compound 1 at a 98% yield
(Scheme 2).18
In conclusion, we have developed a simple route for the
synthesis of an antiobestic ligand GW501516 for
PPARd (1) from commercially available 4-iodo- or
4-bromo-2-methylphenol (2). Our method has accom-
plished the synthesis of 1 in 87% overall yields. More-
over, the in situ protection of phenol with a Grignard
reagent and the regio-controlled one-pot synthesis of
the central sulfide is a very useful protocol for the prep-
aration of other pharmaceutical drugs that include the
alkyl aryl sulfides.
10. Tanaka, T.; Yamamoto, J.; Iwasaki, S.; Asaba, H.;
Hamura, H.; Ikeda, Y.; Watanabe, M.; Magoori, K.;
Ioka, R. X.; Tachibana, K.; Watanabe, Y.; Uchiyama, Y.;
Sumi, K.; Iguchi, H.; Ito, S.; Doi, T.; Hamakubo, T.;
Naito, M.; Auxerx, J.; Yanagisawa, M.; Kodama, T.;
Sakai, J. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15924–
15929.
Acknowledgments
11. Lee, C.-H.; Chawla, A.; Urbiztondo, N.; Lio, D.; Boisvert,
W. A.; Evans, R. M. Science 2003, 302, 453–457.
12. Wei, Z.-L.; Kozikowski, A. P. J. Org. Chem. 2003, 68,
9116–9118.
13. Ham, J.; Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236–
3239.
J.H. was supported by the BK21 program, Ministry of
Education and Human Resources, Korea. This work
was supported by a grant from the MarineBio 21 Pro-
gram, Ministry of Maritime Affairs and Fisheries,
Korea.

6686
J. Ham, H. Kang / Tetrahedron Letters 46 (2005) 6683–6686
14. (a) Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55,
5287–5291; (b) Bora, U.; Bose, G.; Chaudhuri, M. K.;
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Lett. 2000, 2, 247–249.
chromatography on silica gel with hexane/ethyl acetate (3/
1, v/v) to obtain 10 as a white solid (1.4 g, 93%). 1H NMR
(300 MHz, CDCl3) d 7.11 (d, 1H, J = 1.8 Hz), 7.05 (dd,
1H, J = 8.2, 1.8 Hz), 6.66 (d, 1H, J = 8.2 Hz), 4.68 (s, 1H),
3.33 (s, 1H), 2.20 (s, 3H). 13C NMR (75.5 MHz, CDCl3) d
153.1, 134.2, 130.4, 124.9, 119.6, 116.1, 15.9. CIMS m/z
141 [M+H]+.
15. For the synthesis of 4-{{2-[4-(trifluoromethyl)phenyl]-4-
methylthiazol-5-yl}methylthio}-2-methylphenol 8: To a
solution of 4-iodo-2-methylphenol (2) (1.17 g, 5.0 mmol)
in THF (50 mL) was added isopropylmagnesium chloride
(2.5 mL, 2.0 M in THF solution, 5.0 mmol) at 0 ꢁC and
the mixture was stirred for 10 min under N2 atmosphere.
After the mixture was cooled to À78 ꢁC, tert-butyllithium
(5.88 mL, 1.7 M solution in pentane, 10.0 mmol) was
introduced dropwise and stirred for 0.5 h at the same
temperature. A solution of sulfur (160 mg, 5.0 mmol) in
THF (5 mL) was slowly added and then the reaction
mixture warmed to room temperature for 0.5 h. After the
mixture was cooled to 0 ꢁC again, a solution of 7 (1.46 g,
5.0 mmol) in THF (5 mL) was added and stirred at room
temperature for additional 0.5 h. The reaction was moni-
tored by thin-layer chromatography. After the reaction
was completed, it was quenched with aqueous NH4Cl
(40 mL). The organic layer was separated and then the
aqueous layer was extracted with ethyl acetate (2 · 25 mL).
The combined extract was washed with water, dried over
anhydrous MgSO4, filtered, and evaporated under reduced
pressure to give the crude product. The crude compound
was purified by column chromatography on silica gel with
hexane–ethyl acetate (3/1, v/v) to obtain 7 as an ivory solid
17. For the synthesis of ethyl 2-{4-{{2-[4-(trifluoro-
methyl)phenyl]-4-methylthiazol-5-yl}methylthio}-2-meth-
ylphenoxy}acetate 11: To a solution of 8 (1.2 g, 3.0 mmol)
in 5% aqueous DMSO (25 mL) was added K2CO3
(622 mg, 4.5 mmol), followed by ethyl bromoacetate
(2.02 mL, 3.6 mmol) at room temperature. The reaction
mixture was warmed to 50 ꢁC and then vigorously stirred
for 1 h. After the reaction was completed, the mixture was
poured into water (30 mL) and extracted with ethyl
acetate (3 · 35 mL). The combined extract was washed
with water, dried over anhydrous MgSO4, filtered, and
evaporated under reduced pressure to give the crude
product. The crude compound was purified by column
chromatography on silica gel with hexane/ethyl acetate (v/
v = 5/1) to obtain 11 as an ivory solid (1.4 g, 98%). 1H
NMR (300 MHz, CDCl3) d 7.97 (d, 2H, J = 8.1 Hz), 7.65
(d, 2H, J = 8.3 Hz), 7.21 (d, 1H, J = 2.0 Hz), 7.12 (dd, 1H,
J = 8.4, 2.0 Hz), 6.59 (d, 1H, J = 8.4 Hz), 4.61 (s, 2H),
4.24 (q, 2H, J = 7.1 Hz), 4.11 (s, 2H), 2.24 (s, 3H), 2.21 (s,
3H), 1.28 (t, 3H, J = 7.1 Hz). 13C NMR (75.5 MHz,
CDCl3) d 169.1, 163.5, 156.8, 151.8, 137.2, 136.5, 132.5,
131.6 (q, J = 32.8 Hz), 131.1, 128.8, 126.8, 126.2 (q,
J = 3.9 Hz), 125.7, 124.3 (q, J = 272.3 Hz) 111.9, 65.9,
61.7, 32.9, 16.5, 15.2, 14.5. HREIMS m/z 481.0993 (calcd
for C23H22F3NO3S2, 481.0993).
1
(1.62 g, 91%). H NMR (300 MHz, CDCl3) d 7.96 (d, 2H,
J = 8.1 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.18 (d, 1H, J =
1.5 Hz), 7.03 (dd, 1H, J = 8.2, 2.0 Hz), 6.63 (d, 1H,
J = 8.2 Hz), 5.48 (br s, 1H), 4.08 (s, 2H), 2.19 (s, 3H),
2.14 (s, 3H). 13C NMR (75.5 MHz, CDCl3) d 164.1, 155.6,
151.6, 137.5, 136.8, 133.6, 131.9 (q, J = 32.6 Hz), 131.8,
126.9, 126.3 (q, J = 3.7 Hz), 125.9, 124.3 (q, J = 272.3 Hz),
123.8, 115.6, 33.2, 16.2, 14.7. HREIMS m/z 395.0622
(calcd for C19H16F3NOS2: 395.0625).
18. For the synthesis of 2-{4-{{2-[4-(trifluoromethyl)phenyl]-
4-methylthiazol-5-yl}methylthio}-2-methylphenoxy}acetic
acid 1: To a solution of 11 (1.0 g, 2.1 mmol) in ethyl
alcohol (40 mL) was slowly added 3 N NaOH (1.1 mL) at
room temperature. After the reaction mixture was stirred
for 0.5 h to complete the reaction, the reaction mixture
was acidified with 1 N HCl to pH 2–3 and ethyl alcohol
was removed. The residue was dissolved into ethyl acetate
(60 mL) and washed with brine (2 · 30 mL), dried over
MgSO4, and evaporated under reduced pressure to give
the crude product. The crude compound was purified by
LH-20 column chromatography with methyl alcohol to
16. Certification of 4-mercapto-2-methylphenol 10: To a
solution of 4-iodo-2-methylphenol (2) (234 mg, 1.0 mmol)
in THF (15 mL) was added isopropylmagnesium chloride
(0.5 mL, 2.0 M in THF solution, 1.0 mmol) at 0 ꢁC and
the mixture was stirred for 10 min under N2 atmosphere.
After the mixture was cooled to À78 ꢁC, tert-butyllithium
(1.18 mL, 1.7 M solution in pentane, 2.0 mmol) was
introduced dropwise and stirred for 0.5 h at the same
temperature. A solution of sulfur (32 mg, 1.0 mmol) in
THF (1.5 mL) was slowly added and then the reaction
mixture warmed to room temperature for 1 h. After that,
the reaction mixture was quenched with aqueous NH4Cl
(10 mL) and then acidified with 1 N HCl. The mixture was
extracted with ethyl acetate (3 · 20 mL). The combined
extract was dried over anhydrous MgSO4, filtered, and
evaporated under reduced pressure to give the crude
product. The crude compound was purified by column
1
obtain GW501516 (1) as a white solid (932 mg, 98%). H
NMR (300 MHz, CDCl3) d 8,98 (br s, 1H), 7.93 (d, 2H,
J = 8.1 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.21 (d, 1H, J =
1.6 Hz), 7.10 (dd, 1H, J = 8.4, 2.1 Hz), 6.61 (d, 1H,
J = 8.5 Hz), 4.66 (s, 2H), 4.09 (s, 2H), 2.22 (s, 3H), 2.14 (s,
3H). 13C NMR (75.5 MHz, CDCl3) d 173.2, 164.1, 156.6,
151.6, 136.8, 136.7, 132.6, 131.9 (q, J = 32.8 Hz), 131.4,
128.8, 126.9, 126.3 (q, J = 3.8 Hz), 125.8, 124.3 (q,
J = 272.2 Hz), 111.9, 65.5, 32.8, 16.5, 14.9. HREIMS
m/z 453.0679 (calcd for C21H18F3NO3S2: 453.0680).