Microwave-assisted synthes is of novel chiral receptors derived from deoxycholic acid and their molecular recognition properties

Article abstract of DOI:10.1246/cl.140701

Under microwave irradiation (MWI), novel chiral receptors derived from deoxycholic acid were synthesized by using deoxycholic acid methyl ester as the spacer, and arylhydrazine and amino acids as the arm. Selective recognition properties of these receptors for aromatic amines and D/L-amino acids have been investigated by UV-vis spectral titration and ¹H NMR spectral study. The results indicate this type of receptors can form a 1:1 supramolecular complex with an aromatic amine and a 1:2 supramolecular complex with D/L-tryptophan.

Full text of DOI:10.1246/cl.140701

CL-140701
Received: July 25, 2014 | Accepted: August 25, 2014 | Web Released: September 2, 2014
Microwave-assisted Synthesis of Novel Chiral Receptors Derived from Deoxycholic Acid
and Their Molecular Recognition Properties
Ying Ye,1,2 Yourui Suo,* Fang Yang, and Lijuan Han1,2
1
1,2
1
Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001, P. R. China
2
University of the Chinese Academy of Sciences, Beijing 100049, P. R. China
(
E-mail: yrsuo@nwipb.cas.cn)
COOH
COOCH3
CONHNH2
OCH3
Under microwave irradiation (MWI), novel chiral receptors
derived from deoxycholic acid were synthesized by using
deoxycholic acid methyl ester as the spacer, and arylhydrazine
and amino acids as the arm. Selective recognition properties of
these receptors for aromatic amines and D/L-amino acids have
been investigated by UV­vis spectral titration and 1H NMR
spectral study. The results indicate this type of receptors can
form a 1:1 supramolecular complex with an aromatic amine and
a 1:2 supramolecular complex with D/L-tryptophan.
OCH3
OCH3
i
ii
1
COOH
COOCH3
iii
iv
OH
OH
OH
OH
3
2
COOCH3
COOCH3
v
OH
OH
O
O
O
NH
NH
C
Using artificial receptors to build bionic enzyme models has
exhibited potential applications in the fields of biomimetic
catalysis, drug synthesis, chiral separation, molecular devices,
biosensors, and so on;1 synthesis and molecular recognition
properties of different types of artificial receptors have also
O
Cl
O
5
4
OCH3
­4
5
­8
COOCH3
COOCH3
become the focus of modern bioorganic chemistry research.
O
NH
vi
O
vii
O
O
Bile acids, because of their rigid structures and asymmetric
features, have been widely used as ideal building blocks for the
construction of molecular tweezers.9 Since it is well known
that biological activity and chemical properties of organic
species are highly dependent on stereochemistry, great efforts
Cl
O
O
O
O
COOCH3
R
H
NH
NH
C
NH
,10
NH
C
O
6
O
7a–7h
OCH3
OCH3
have been made to design and synthesize chiral receptors for
enantioselective recognition of chiral organic species.11­13
7a
R = CH(CH3)2
7b R = CH2CH(CH3)2
7d R = CH2CH2SCH3
7
c
R = CH3
Moreover, with the development of “green chemistry” in
recent years, microwave-assisted techniques have become
increasingly important in the field of organic synthesis not only
because of the advantage of minimal use of organic solvents, but
also because of reduced reaction times, fewer by-products, and
7e
R = CH2Ph
7f
R = Ph
7
g
R = H2
C
OH
7h R = H2C
N
H
Scheme 1. The synthetic route of molecular tweezers 7a­7h.
Reagents and conditions: (i) CH3OH, H2SO4; (ii) N2H4¢H2O; (iii)
CH3I, K2CO3, THF, MWI; (iv) triphosgene, CH2Cl2, pyridine, MWI;
(v) pyridine, K CO , intermediate 1, MWI; (vi) triphosgene, CH Cl ,
pyridine, MWI; (vii) L-amino acid methyl esters hydrochloride,
pyridine, MWI.
1
4,15
a simplified work under microwave irradiation (MWI).
In
this paper, we report an efficient microwave-assisted method
to synthesize novel chiral unsymmetrical arylhydrazide-type
molecular tweezers based on deoxycholic acid. In this type of
receptor structure, three NH groups can be found, which can
form hydrogen bonds with substrates in the molecular recog-
nition process. The binding ability of this kind of molecular
tweezers for recognition of substrates, which also possess the
NH group, such as aromatic amines and D/L-amino acids,
has been investigated; some target molecular tweezers showed
interesting enantioselective recognition of D/L-amino acids,
which have never been reported.
2
3
2
2
highest when irradiating microwave at 450 W for 10 min. Then,
the L-amino acid methyl ester hydrochloride and anhydrous
pyridine were added to compound 6, and the mixture was
irradiated continually for 8­10 min at 300 W. TLC was used
to monitor the reaction progress until it was complete. Target
molecular tweezers 7a­7h (yield 85%­90%) were obtained and
were purified furthermore by column chromatography on silica
gel H with dichloromethane/acetone as the eluent.
A series of experiments were carried out to make a better
comparison between MWI and conventional heating in the
synthesis of intermediate 5 and compounds 7a­7h. The results
are shown in Table 1.
Molecular tweezers 7a­7h were synthesized through seven
steps (Scheme 1). Intermediate 1 was prepared following a
1
6
reported procedure; then, deoxycholic acid (2) was methylated
to methyl ester 3 (yield 87%) by using methyl iodide, followed
by treatment with triphosgene to give compound 4. After
microwave irradiating in K2CO3 with intermediate 1 (yield 85%)
and anhydrous pyridine, compound 5 (yield 91%) was synthe-
sized, which subsequently reacted with triphosgene to give
compound 6. We found that the yield of compound 5 was
The supports remarkably affect the yields of the products.
It was found that when using silica gel H and neutral Al2O3 as
the support and microwave irradiating for 10 min, only a small
amount of compound 5 was obtained, while using K2CO3 as the
1812 | Chem. Lett. 2014, 43, 1812–1814 | doi:10.1246/cl.140701
© 2014 The Chemical Society of Japan

Table 1. Synthetic comparison of intermediate 5 and compounds 7a­
26
24
22
20
7
h between microwave irradiation and conventional heating
Conventional method Microwave method
18
Compd.
tc/tmwa
16
14
12
10
8
6
4
2
0
t/min
Yield/%
t/min
Yield/%
5
2880
2100
2100
2400
2100
2280
2340
2400
2400
75
68
52
65
58
70
68
63
42
10
20
18
20
20
19
18
18
19
91
89
86
87
86
90
89
87
85
288
105
117
120
105
120
130
133
126
7a
7b
7
c
0
5000
10000
15000
20000
25000
7d
(
1/[G]0)/mol L–1
7
e
7f
Figure 2. Typical plot of 1/¦A versus 1/[G]0 for the inclusion
complex of molecular tweezer 7e with p-methoxyaniline in CHCl3 at
25 °C.
7g
7h
atc, conventional method time; tmw, microwave method time.
Table 2. Association constants (Ka) and Gibbs free energy changes
0
(
¦G ) for the inclusion complexes of p-methoxyaniline with
molecular tweezers 7a, 7e, 7g, and 7h in CHCl3 at 25 °C
¹
1
¹¦G0/kJ mol¹1
Host Guest
Ka/L mol
7
a
e
aniline
874.29
39.29
16.78
9.10
o-methoxyaniline
m-methoxyaniline
p-methoxyaniline
aniline
o-methoxyaniline
m-methoxyaniline
p-methoxyaniline
aniline
o-methoxyaniline
m-methoxyaniline
p-methoxyaniline
aniline
o-methoxyaniline
m-methoxyaniline
p-methoxyaniline
620.73
714.48
2242.54
592.87
687.20
332.20
366.82
813.30
834.91
279.29
1697.09
661.54
389.61
488.55
15.93
16.28
19.12
15.82
16.19
14.38
14.63
16.67
16.66
13.95
18.42
16.09
14.78
15.34
7
Wavelength/nm
¹
4
7g
Figure 1. UV­vis spectral changes of compound 7e (1 © 10
¹1
¹4
¹4
mol L ) in the presence of p-methoxyaniline: (a) 0, (b) 0.4 © 10
,
,
¹
4
¹4
¹4
(
(
c) 0.8 © 10 , (d) 1.2 © 10 , (e) 1.6 © 10 , (f) 2.0 © 10
¹
4
¹4
¹4
¹4
g) 2.4 © 10 , (h) 2.8 © 10 , (i) 3.2 © 10 , and (j) 3.6 © 10
¹1
mol L with ­max at 242 nm.
7
h
support and under the same microwave condition, the yield of
intermediate 5 reached 91%.
UV­vis spectral titration was used to investigate the
recognition abilities of compound 7a, 7e, 7g, and 7h for aniline,
p-methoxyaniline, m-methoxyaniline, o-methoxyaniline, D/L-
tryptophan, D/L-histidine, and D/L-tyrosine by monitoring the
¹
4
absorbance changes. When p-methoxyaniline (0­3.6 © 10
¹1
mol L ) was added to the solution of compound 7e (1 ©
¹
4
¹1
10
mol L ) in CHCl3, the absorbance band at 242 nm
decreased regularly. The UV­vis plot of 7e for p-methoxyaniline
is shown in Figure 1. The titration data were analyzed by using
the Hildebrand­Benesi equation. The plots of 1/[G]0 versus
1
/¦A gave a straight line (Figure 2), which showed that
Wavelength/nm
compound 7e could form a complex with p-methoxyaniline
and the supramolecular complex consisted of 1:1 host and guest
¹3
¹3
¹3
Figure 3. UV­vis spectral changes of compound 7e: (a) 1.5 © 10
,
,
,
¹3
¹3
¹3
molecules. The association constants (K ) were calculated
(b) 1.0 © 10¹ , (c) 0.8 © 10 , (d) 0.6 © 10 , (e) 0.5 © 10
a
(f) 0.4 © 10 3, (g) 0.3 © 10 , (h) 0.2 © 10 , (i) 0.15 © 10
¹3 ¹3
according to the intercept and the slope of the line. Job’s plots
also indicated the 1:1 complex formation when aniline, p-
methoxyaniline, m-methoxyaniline, and o-methoxyaniline were
added to the solution of 7a, 7e, 7g, and 7h, respectively.
¹
3
¹3
¹1
(
j) 0.12 © 10 , and (k) 0.1 © 10 mol L
in the presence of
¹3
¹1
L-tryptophan (1 © 10 mol L ) with ­max at 288­304 nm.
0
Association constants (Ka) and free energy change (¹¦G ) for
(Figure 3) and the plots of 1/[G]0 versus 1/¦A gave a curve.
Both Job’s plots and the plots of molar ratio versus absorbance
indicated the formation of a 1:2 supramolecular complex
(Figure 4); the association constants (Ka) were obtained from
the nonlinear curve fitting of A versus CR/CM. The association
constants (K ) and K /K for the inclusion complexes of 7a,
the inclusion complexes of 7a, 7e, 7g, and 7h with aniline,
p-methoxyaniline, m-methoxyaniline, and o-methoxyaniline are
listed in Table 2. Interestingly, when different volumes of the
guest D/L-tryptophan solution was added into defined amounts
of hosts 7a, 7e, 7g, and 7h, though the UV absorbance of the
hosts decreased, the absorption peak shape became narrow
a
D
L
7e, 7g, and 7h with D/L-tryptophan are displayed in Table 3.
Chem. Lett. 2014, 43, 1812–1814 | doi:10.1246/cl.140701
© 2014 The Chemical Society of Japan | 1813

0
.60
A0 0.55
0.50
ring and the amide NH attached to the 3α-moiety of deoxycholic
acid methyl ester. Moreover, other three sharp signals were
found at 5.23, 4.91, and 4.67 ppm, which belong to the amide
NH attached to the 12α-moiety of deoxycholic acid methyl ester,
CH in the 12β-moiety, and CH in the 3β-moiety, respectively.
Upon addition of 1.0 equiv of L-tryptophan, the amide NH
attached to the phenyl ring and the amide NH attached to the 3α-
moiety of deoxycholic acid methyl ester were downfield shifted
to 0.18 and 0.95 ppm, while the amide NH attached to the 12α-
moiety of deoxycholic acid methyl ester, CH in the 12β-moiety,
and CH in the 3β-moiety were upfield shifted to 0.55, 0.37,
and 0.39 ppm, respectively. What’s more, all the protons of
the phenyl rings were downfield shifted in varying degrees
A
0
0
0
0
0
0
0
0
0
.40
.35
.30
.25
.20
.15
.10
.05
.00
0
0
0
0
0
0
.45
.40
.35
.30
.25
.20
-0.05
-
0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1
[
7e]/([7e]+[L-Trp.])
0
.0
0.5
1.0
1.5
2.0
n
C
/C
M
R
(
Figure 5b), which showed that the π­π stacking interactions
Figure 4. Job’s plot and typical plot of A versus CR/CM for the
inclusion complex of molecular tweezer 7e with L-tryptophan in
DMSO at 25 °C, CR: the concentration of molecular tweezer 7e;
CM: the concentration of L-tryptophan.
also contributed to the recognition process. When the added L-
tryptophan was increased up to 2.0 equiv, the signal of the amide
NH attached to the 3α-moiety of deoxycholic acid methyl ester
significantly broadened and weakened (Figure 5c). The change
of chemical shift indicated that both the amide NH and phenyl
rings of compound 7e should bind with L-tryptophan.
Table 3. Association constants (Ka) for the inclusion complexes of
D/L-tryptophan with molecular tweezers 7a, 7e, 7g, and 7h in DMSO
at 25 °C
In conclusion, novel chiral unsymmetrical arylhydrazide-
type molecular tweezers based on deoxycholic acid were
developed and the receptors showed remarkable selectivity and
affinity for D/L-tryptophan and aromatic amines. It might lead to
potential applications in analysis and separation of chiral amino
acids and aromatic amines, or in transport of amino acid drugs
and aromatic amine drugs.
Host
Guest
Ka/L mol 1
¹
KD/KL
7
7
7
7
a
D-tryptophan
L-tryptophan
D-tryptophan
L-tryptophan
D-tryptophan
L-tryptophan
D-tryptophan
L-tryptophan
48849.34
11074.15
15451.57
5466.05
23549.89
13656.81
91768.81
31665.74
4.41
e
2.83
1.72
2.90
g
h
The project is supported by the Fundamental Research
Funds of the National Spark Program (No. 2011GA870007).
We also thank Prof. Z. G. Zhao and Miss. M. Liu for their kind
suggestion and discussion.
Supporting Information is available electronically on J-STAGE.
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Figure 5. Portion of H NMR spectra of compound 7e in DMSO-d6
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(
3
118.
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As shown in Table 3, these receptors showed good chiral
recognition for D-tryptophan; the maximum KD/KL of com-
pound 7a was 4.41 for D/L-tryptophan. However, when different
amounts of guests D/L-histidine and D/L-tyrosine were added
into defined amounts of hosts 7a, 7e, 7g, and 7h, the UV
absorbance showed almost no change. The result clearly
indicated that receptors 7a, 7e, 7g, and 7h selectively bind
D/L-tryptophan.
8
9
1
0 Y. Cheng, D. M. Ho, C. R. Gottlieb, D. Kahne, M. A. Bruck,
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1
1
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by H NMR spectroscopy (see the Supporting Information). For
example, as shown in Figure 5a, free compound 7e displayed
two sharp signals in the downfield region at 9.56 and 8.17 ppm,
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1
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1814 | Chem. Lett. 2014, 43, 1812–1814 | doi:10.1246/cl.140701
© 2014 The Chemical Society of Japan