Regioselective synthesis of 3-aryl-5-(1H-indole-3-carbonyl)-4-hydroxyfuroic acids as potential insulin receptor activators

Article abstract of DOI:10.1016/j.tetlet.2006.08.076

3-Methoxy-4-aryl-furan-2,5-dicarboxylic acid (8) is selectively converted into its C-5 methylester (6) by treatment with methyl chloroformate followed by decarboxylation in one flask. Acylation of the resulting half ester with a 7-substituted indole was p

Full text of DOI:10.1016/j.tetlet.2006.08.076

Tetrahedron Letters 47 (2006) 7579–7582
Regioselective synthesis of
3-aryl-5-(1H-indole-3-carbonyl)-4-hydroxyfuroic acids
as potential insulin receptor activators
Shan-Yen Chou,* Shieh-Shung Tom Chen, Ching-Hui Chen and Lien-Shange Chang
Development Center For Biotechnology, No. 101, Lane 169, Kangning St., XiZhi City, Taipei County 221, Taiwan, ROC
Received 16 March 2006; revised 21 August 2006; accepted 22 August 2006
Abstract—3-Methoxy-4-aryl-furan-2,5-dicarboxylic acid (8) is selectively converted into its C-5 methylester (6) by treatment with
methyl chloroformate followed by decarboxylation in one flask. Acylation of the resulting half ester with a 7-substituted indole
was performed under mild conditions to afford 3-aryl-5-(1H-indole-3-carbonyl)-4-methoxy-2-furoic acid (11). The synthetic utility
of the resulting furoic acids as a skeleton in the synthesis of potential insulin receptor activators is established.
Ó 2006 Elsevier Ltd. All rights reserved.
Various approaches to develop an oral drug for the
H
N
treatment of non-insulin dependent diabetes mellitus
O
(NIDDM) have been developed in recent years.1 Insulin
HO
receptor (IR) activators are fascinating because it is the
primary interaction site relating to signal transduction
of blood sugar metabolism. A dihydroxyquinone deriv-
ative, asterriquinone, discovered at Merck Co., has been
identified as a potent and selective insulin receptor acti-
vator.2 Further modification of the dihydroxyquinone
derivative has led to a series of structurally related and
simplified analogs.2 More recently, a series of asterriqui-
none bioconversion products, 4-hydroxy-2-furoic acids,
have been identified (Fig. 1).3 They are active in the
insulin receptor activation assay and had a significant
glucose-lowering effect in an in vivo experiment con-
ducted in db/db mice. However, the structure of
4-hydroxy-2-furoic acids is complicated, and has left a
room for structure modification to develop simplified
molecules possessing comparable activity. Preliminary
biological data from Merck revealed that the activation
of insulin receptor tyrosine kinase activity of 4-hydroxy-
2-furoic acids depends critically on the terminal hydr-
oxyl group of the C-70 side chain on the C-5 indole ring.3
Better activity is expected if a linear hydroxylalkyl chain
mimics the C-70 side chain of the lead molecule. Hence,
the initial goal of this study is to synthesize various sim-
plified analogs of the lead molecule, in which the C-3
H
OH
biotransformation
N
O
2'
4
HOOC
N
H
3
O
5
OH
HN
7'
O
asterriquinone
R1
R2
R1 = CH3, R2 = CH3
R1 = CH2OH, R2 = CH3
R1 = CH3, R2 = CH2OH
4-hydroxy-2-furoic acids
Figure 1. Biotransformation of asterriquinone.
and C-5 substituents are replaced with aryl and C-70
hydroxyalkyl, and/or C-70 carboxylalkyl substituents,
respectively (Fig. 2).
The initial retroanalysis of furanindoles is shown in
Figure 3.
Target A was planned to be prepared by the acylation
of the half ester C with a C-70 substituted indole B. Half
ester C was planned to be prepared by selective hydro-
lysis of 3-methoxy-4-aryl-furan-2,5-dicarboxylic acid
dimethyl ester D. The methyl ether was selected as a
protecting group, because of its stability to both acidic
and basic conditions in the subsequent steps. We
selected compound 6 as the model molecule to explore
*
Corresponding author. Tel.: +886 2 2695 6933; fax: +886 2 2695
7474; e-mail: sychou@mail.dcb.org.tw
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.076

7580
S.-Y. Chou et al. / Tetrahedron Letters 47 (2006) 7579–7582
i
H
N
O
O
MeO2C
RO
R = H, 3
CO2Me
C6H5
MeO2C
CO2Me
+
C6H5C(O)CO2Me
HOOC
3
1
2
HOOC
O
5
3
Ar
OH
O
5
analogs design
HN
7'
OH
O
ii
R = Me, 4
HN
O
R1
R2
R
iii
O
O
3
MeO2C
5 CO2H
4
HO2C
5 CO2Me
4
7'
2
2
+
R1 = CH3, R2 = CH3
R1 = CH2OH, R2 = H
1 = CH3, R2 = CH2OH
3
MeO
C6H5
MeO
C6H5
R
Ar = phenyl, R = hydroxyalkyl
or carboxylalkyl
5
6
(undesired)
CO2Me
OTf
4-hydroxy-2-furoic acids
5/6 ~ 4 : 1 molar ratio
iv
O
Figure 2. Rational design of 4-hydroxy-2-furoic acid derivatives as
potential insulin receptor activators.
4
MeO2C
O
MeO2C
CO2Me
iv'
MeO
7
RO
4a -4d
Ar
HOOC
2
a. Ar = (3-formyl-4-methoxy)phenyl
b. Ar = 3-(formyl)phenyl
c. Ar = 4-(formyl)phenyl
3
O
OH
5
4
d. Ar = (3,4,5-trimethoxy)phenyl
HN
n 7'
O
X = OH or CO2H
n = 0-3
Scheme 1. Preparation of diester 4 and half esters 5 and 6. Reagents
and conditions: (i) t-BuOK, benzene, reflux; (ii) MeI, K2CO3, DMF,
45.0% (two steps); (iii) LiOH (ꢀ100 mol %), MeOH, H2O, 95.0%; (iv)
C6H5B(OH)2 (1.2 equiv), Na2CO3 (3.0 equiv), PdCl2(PPh3)2, DMF,
90 °C, 80.4% and (iv0) ArB(OH)2 (1.2 equiv), Na2CO3 (3.0 equiv),
PdCl2 (PPh3)2, DMF, 90 °C, 55.5–74.3%.
A
X
MeOOC
O
MeOOC
5
5
Ar
Ar
4
4
HN
n 7'
O
2
OMe), the electron density around the acidic proton is
higher than that of C-2 carboxylic acid for resonance ef-
fect; moreover, the acidic proton is locked intramolecu-
larly by the 3-OMe group. Therefore, the C-2 carboxylic
acid should be relatively less easily deprotonated and
thus less easily acylated in comparison with C-5 carbox-
ylic acid during treatment with methyl chloroformate
and a weak base, such as triethylamine. Precedent
showed that mixed anhydride might undergo decarbox-
ylation into ester in the presence of tertiary amines.5
Accordingly, we proposed that the desired half ester 6
could be selectively prepared from 8 by the mixed anhy-
dride method.
OMe
OMe
+
2
3
3
HO
MeO
O
O
X
B
C
D
Figure 3. Retroanalysis of 4-hydroxy-furoic acid derivatives.
the synthetic pathway of half ester C (Scheme 1). The
furan skeleton, 3-methoxy-4-phenyl-furoic 2,5-dicarb-
oxylic acid dimethyl ester 4, was prepared by adding a
mixture of dimethyl diglycolate 1 and arylglyoxalate 2
(1.5:2 molar ratio) to a refluxing suspension of t-BuOK
(2.7 M equiv vs dimethyl diglycolate, prepared from
potassium and equal molar amounts of t-BuOH) in
refluxing benzene, and the resulting 3 was immediately
protected by methylation to provide 4 without isolation.
A related synthetic method of 3 and a synthetic useful
mixed ester has been described recently.4
O
i
ii
O
5 CO2H
4
C6H5
O
MeO2C
MeO
CO2Me
C6H5
2
O
H
3
O
Me
Alternatively, 4 and various nuclear substituted ana-
logues (4a–d) can be prepared by the palladium-cata-
lyzed cross-coupling of the self-prepared triflate 7 with
a commercial boronic acid in good yield. Our next effort
is to selectively hydrolyze the less hindered C-2 ester of
4, and then acylating that site to introduce the indole
ring. However, the resonance-stabilizing effect of the 3-
OMe group was most probably responsible for the
reluctance of C-2 ester hydrolysis, despite the fact that
the C-2 ester was less hindered than the C-5 ester. The
undesired isomer 5 was formed as a major product (5/
6 ꢀ 4:1 molar ratio). Given the resonance effect of the
3-OMe group, this work suggests that the desired half
ester 6 can be prepared by the selective methylation of
the corresponding diacid 8. Since the C-2 carboxylic acid
of 8 is conjugated with an electron-donating group (3-
4
8
3.78 ppm
O
O
O
OMe
HO
MeO
C6H5
6 (major)
O
O
O
O
O
OMe
+
Et3NH
2 O
MeO
C6H5
3.92 ppm
MeO
O
O
O
OH
C6H5
5 (minor)
MeO
Scheme 2. Regioselective synthesis of 6: Reagents and conditions: (i)
OHꢁ, MeOH, H2O, 90.0% and (ii) ClCO2Me, NEt3, then DMAP
(cat.), 59.0% (6/5 = 4.8:1 molar ratio).

S.-Y. Chou et al. / Tetrahedron Letters 47 (2006) 7579–7582
7581
The route to the desired half ester 6 is achieved regio-
iii
iv
i
selectively from the furoic dimethyl ester 4 (Scheme 2).
Hydrolysis of 4 provided diacid 8. Upon treatment of
8 with 1.0–2.5 M equiv of weak base, such as triethyl-
amine, and methyl chloroformate, the kinetic C-5 carb-
oxylate is preferentially acylated to yield an unstable
mixed anhydride, which is then decarboxylated into
the half ester 6 in the presence of a catalytic amount
of tertiary amine, such as DMAP. We proposed that
even a small amount of methanol formed by decarb-
oxylation of the mixed anhydride could catalyze the
formation of methylester. The regiochemistry is eluci-
dated by 1H NMR, the methyl ester protons of the
desired isomer exhibit an upper chemical shift than that
of the undesired isomer for the shielding effect of the
aryl ring. The presented approach is employed to
prepare related half esters from the respective diacids
with a similar regio-selectivity (Table 1).
N
N
H
ii
H
3
2
AcO
AcO
MeO2C
v
iv
N
H
N
N
H
vi
H
4
HO
4
O
H
vii
ii
iii
iv
N
H
N
H
4
5
MeO2C
AcO
Scheme 3. Preparation of the C-7 substituted indoles: Reagents and
conditions: (i) (MeO)2P(O)CH2CO2Me, NaH, DME, 92.3%; (ii) H2,
Pd–C; ꢀ95.0%; (iii) NaBH4, MeOH, THF, reflux, 65.3–75.3%; (iv)
Ac2O, NEt3, CHCl3, ꢀ90.0%; (v) (C6H5)3P@CH(CH2)3OTHP, 65.4%;
(vi) H3O+, 50.3% and (vii) (MeO)2P(O)CH2CH@CHCO2Me, NaH,
THF, 85.3%.
The 7-substituted indole intermediates were prepared
from 7-formyl indole by a variety of chain extension
reactions; such as by the Wittig reaction, which involves
condensation with ylids, or Horner–Emmons reaction,
hydrophilic groups (e.g., OH or CO2H) were prepared
(Scheme 3).
The synthetic route of 3-aryl-5-(1H-indole-3-carbonyl)-
4-hydroxy-2-furoic acids 11 is illustrated in Scheme 4.
which
involves
condensation
with
trimethyl-
phosphonoacetate. Various linear carbon chains with
Table 1. Selective methylation of 8
X
X
X
X
HO2C
MeO
CO2H
Ar
HO2C
MeO
CO2Me
MeO2C
MeO
CO2H
MeO2C
MeO
CO2Me
Ar
i
+
+
ii
Ar
Ar
8
6
5
4
Entry
X
Ar
NEt3 (M equiv)
ClCO2Me
(M equiv)
Recovery of
8 (%)
Isolated yield
of 4 (%)
Isolated yield of
5 and 6a (%)
Selectivity
6:5b
1
2
3
O
O
O
1.0
1.5
2.0
1.0
1.0
1.0
20.7
8.0
10.6
12.6
17.7
50.7
59.0
45.7
1.9:1
4.8:1
4.1:1
10.6
4
5
6
O
O
O
1.5
1.5
1.5
1.0
1.0
1.0
7.5
9.6
7.0
20.2
11.6
19.8
44.0
59.7
45.7
6.3:1
2.2:1
3.8:1
OMe
SMe
7
O
1.5
1.0
9.1
22.1
40.1
3.5:1
N
Me
O
8
9
O
O
1.5
1.5
1.0
1.0
9.3
18.5
17.7
46.8
45.7
3.7:1
2.5:1
S
Me
10.7
10
11
S
S
1.5
2.0
1.0
1.0
9.7
9.8
14.8
14.5
54.7
52.9
3.2:1
3.7:1
12
S
2.5
1.0
4.5
8.6
71.5
2.4:1
Reagents and conditions: (i) ClCO2Me, CH2Cl2, NEt3, 0 °C and (ii) DMAP (cat.), 0 °C to rt.
a For typical procedure, see Supplementary data.
b Determined by HPLC analysis.

7582
S.-Y. Chou et al. / Tetrahedron Letters 47 (2006) 7579–7582
O
the mixed anhydride method, allowing various aryl
groups to be introduced into the furan ring with the de-
sired regiochemistry. Additionally, both the acylation of
the desired half ester 6 and the demethylation of the
resulting furan indole intermediate 9 can be conducted
under mild conditions. This study also proposed a mod-
el for synthesizing a novel furandiindole skeleton in
which the aryl group (Ar) could be replaced with an in-
dole ring.
i
O
O
CO2Me
C6H5
HO2C
MeO
CO2Me
C6H5
O
Me
ii
N
H
R
6
9
N
H
R
R = -(CH2)n-X
O
n = 3-5, X = OAc
or CO2Me
O
O
O
CO2Me
C6H5
CO2H
C6H5
iv
iii
HO
N
HO
N
H
Acknowledgment
H
R
R'
10
11
R' = -(CH2)n-X'
The authors would like to thank the Ministry of Eco-
nomic Affairs, Taiwan, R.O.C., for financially support-
ing this research.
n = 3-5, X' = OH
or CO2H
Scheme 4. Synthesis of 11. Reagents and conditions: (i) oxalyl
chloride, CH2Cl2, DMAP (cat.); (ii) Et2AlCl, CHCl3, ꢁ10 °C–rt,
60.5–65.3% (two steps); (iii) BCl3, CH2Cl2, 85.5–90.5% and (iv) OHꢁ,
70.0–75.0%.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.08.076.
The acylation of half ester 6 with 7-substituted indoles
was performed under mild conditions, using dialkyl
aluminium chloride as the catalyst.6,7 The acylation
intermediates 9 were deprotected under mild reaction
conditions using excessive amounts of boron trichloride
(ꢀ2–20 M equiv) to give 4-hydroxyfurans 10 in good
yields. Conversion of compounds 6–10 could also be
accomplished in one flask without isolation of interme-
diate 9. Finally, the hydrolysis of the furan ester and
the deprotection of the indole C-7 side chain were
performed simultaneously to provide target molecules
11.
References and notes
1. Ross, S. A.; Gulve, E. A.; Wang, M. Chem. Rev. 2004, 104,
1255–1282, and references cited therein.
2. Liu, K.; Xu, L.; Szalkowski, D.; Li, Z.; Ding, V.; Kwei, G.;
Huskey, S.; Moller, D. E.; Heck, J. V.; Zhang, B.; Jones, A.
B. J. Med. Chem. 2000, 43, 3487–3494.
3. Chen, S. S.; Zhang, B.; and Li, X. U.S. Patent 6,596,760,
2003.
4. Tse, B.; Jones, A. B. Tetrahedron Lett. 2001, 42, 6429–6431.
5. Johnson, D. A. J. Am. Chem. Soc. 1953, 75, 3636–3637.
6. Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.;
Yoshino, H. Org. Lett. 2000, 2, 1485.
7. Notably, the complete removal of superfluous oxalyl
chloride before acylation is key to the success of this step,
for typical procedure see Supplementary data.
8. Efficacies of compounds on cell-based insulin receptor
tyrosine kinase activity will be reported elsewhere.
In conclusion, this study presented a methodology
for synthesizing 3-aryl-5-(1H-indole-3-carbonyl)-4-hydr-
oxy-2-furoic acids.8 The core structure, 3-methoxy-4-
aryl-2,5-furanoic dicarboxylic dimethyl ester, can be
prepared by either condensation or metal-catalyzed
cross coupling reaction. Regioselective esterification of
3-methoxy-4-aryl-2,5-furanoic acid was conducted by