Molecular recognition of ω-amino acids by thiazolobenzocrown receptors: A GABA-selective ionophore

Article abstract of DOI:10.1080/10610278.2012.726731

Three new thiazolobenzocrown (TBC) ethers conjugated with picolinic acid, benzoic acid and pyridylmethyl were synthesised and their binding properties towards amino acids were assessed by ¹H NMR titration and isothermal titration calorimety (ITC). The TBC-picolinic acid conjugate (4) showed a pronounced selectivity towards GABA by the ¹H NMR titration, and the association constant for GABA had the largest value determined by ITC. The association constant of 4 for GABA was about 19 times higher than that of glycine.

Full text of DOI:10.1080/10610278.2012.726731

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Supramolecular Chemistry
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Molecular recognition of ω-amino acids by
thiazolobenzocrown receptors: a GABA-selective
ionophore
Young Rae Yi a , Ki-Soo Kim a , Aasif Helal a & Hong-Seok Kim a
a Department of Applied Chemistry , Kyungpook National University , Daegu , 702-701 ,
Republic of Korea
Published online: 02 Oct 2012.
To cite this article: Young Rae Yi , Ki-Soo Kim , Aasif Helal & Hong-Seok Kim (2013) Molecular recognition of ω-amino
acids by thiazolobenzocrown receptors: a GABA-selective ionophore, Supramolecular Chemistry, 25:1, 16-23, DOI:
10.1080/10610278.2012.726731
To link to this article: http://dx.doi.org/10.1080/10610278.2012.726731
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Supramolecular Chemistry
Vol. 25, No. 1, January 2013, 16–23
Molecular recognition of v-amino acids by thiazolobenzocrown receptors:
a GABA-selective ionophore
Young Rae Yi, Ki-Soo Kim, Aasif Helal and Hong-Seok Kim*
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
(Received 5 May 2012; final version received 28 August 2012)
Three new thiazolobenzocrown (TBC) ethers conjugated with picolinic acid, benzoic acid and pyridylmethyl were
1
synthesised and their binding properties towards amino acids were assessed by H NMR titration and isothermal titration
calorimety (ITC). The TBC-picolinic acid conjugate (4) showed a pronounced selectivity towards GABA by the 1H NMR
titration, and the association constant for GABA had the largest value determined by ITC. The association constant of 4 for
GABA was about 19 times higher than that of glycine.
Keywords: thiazolobenzocrown ether; picolinic acid; selective recognition; GABA; amino acid
1. Introduction
suitably preorganised scaffold that holds them in close
proximity, but not so close that the sites interact. In most of
the studies reported so far, crown ethers have been chosen as
ammonium binding sites (12–16), and quaternary
ammonium (12–14), guanidinium (15–17), urea (17) or
metals (18, 19) have been used as carboxylate binding sites.
g-Aminobutyric acid (GABA), as one of two main
inhibitory neurotransmitters, plays an important role in the
mammalian central nervous system (20). The concen-
tration of GABA in the brain is estimated to be
approximately 1000 times that of the levels of classical
monoamine neurotransmitters. More than one-third of the
neurons in the brain use GABA for synaptic communi-
cation and the concentration of brain GABA essentially
controls the mental and, to a large extent, the physical
health of humans. It affects ionotropic and metabotropic
receptors and altered GABAergic neurotransmission has
been implicated in major neurological and psychiatric
disorders such as anxiety and stress disorders, musculos-
keletal and pain disorders, insomnia and sleep disorders,
addiction and drug-withdrawal syndromes, epilepsy and
seizures, brain ischaemia, mood disorders, schizophrenia,
anaesthesia, liver diseases and hepatic encephalopathy,
cognition, learning and memory disorders, premenstrual
and other hormonal disorders and Alzheimer’s disease
(21). However, direct measurement of GABA concen-
trations in the brain faces several significant challenges, as
it is difficult to detect GABA through an enzymatic
reaction. In light of the ubiquitous importance of GABA to
our health, the development of GABA receptors is of great
therapeutic interest (22).
The development of artificial receptors for selective
recognition of biologically interesting species has attracted
attention because of their applications as molecular
probes. Amino acids are the most important targets for
molecular recognition by artificial host compounds. This is
due to their relevance in the biological world and their rich
biomimetic chemistry (1). For this reason, chemists have
been studying host–guest binding of amino acids as an
instrument for the manipulation of their reactivity (2).
There have been several amino acid receptors reported
based on crown ethers and heterocrown ethers (3), redox-
active ferrocene unit (4), binaphthyl crown ether (5),
calixarene (6), sapphyrin-lasalocid conjugates (7), macro-
bicyclic receptors (8) and macrocyclic metal complexes
such as metalloporphyrins (9).
Recognition of amino acids by artificial receptors is
limited due to the hydrophilic character of amino acids. In
order to recognise the zwitterionic form of an amino acid
effectively, simultaneous binding of ammonium and
carboxylate groups is required.
Moreover, the electronic densities of carboxylate and
ammonium groups are greatly affected by their mutual
vicinity, causing the binding forces between the comp-
lementary groups and the receptor to be less effective for
complexation (10). Thus, for the selective recognition of
amino acids, convergent heteroditopic receptors that contain
two different binding sites connected by a linker and capable
of a simultaneous coordination with ammonium and
carboxylate groups are required (11). However, the design
of a convergent heteroditopic receptor is quite a challenge
because the ion-binding sites have to be incorporated into a
It is presumed that macrocyclic polyethers having
two conformational features such as crown ether-type
*Corresponding author. Email: kimhs@knu.ac.kr
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2013 Taylor & Francis
http://dx.doi.org/10.1080/10610278.2012.726731
http://www.tandfonline.com

Supramolecular Chemistry
17
S
S
N
N
N
O
O
Cl
Cl
O
O
O
O
X
i
2: X = NHBoc
3: X = NH2
4, 5, 6
ii
N
iii, iv, v
1
S
S
Scheme 1. (i) N-Boc-dopamine, NaI, K2CO3, butanone; (ii) CF3CO2H, CH2Cl2; (iii) picolinic acid, DIC, HOBt, CH2Cl2; (iv) benzoic
acid, DCC, HOBt, CH2Cl2; (v) 2-(bromomethyl)pyridine, TEA, CH2Cl2.
compounds with right cavity size for NHþ4 and those
containing symmetrically positioned heterocylic units in
the structure may exhibit enhanced NHþ4 selectivity. It was
reasoned that NHþ4 may be nested in or perched on the
cavity of a cyclic polyether and bound tightly via balanced
hydrogen bonding to the ligand donor atoms of the
heterocylic units (23). Thus, crown ethers that contain
thiazole moieties have been reported to exhibit high
ammonium (23), silver (24) and mercury ion selectivity
(25). In this work, we used a dibenzo-18-crown-6 ether
containing thiazole ring as an ammonium ion binding site,
and for the first time, we used a conjugated picolinic amide
as a carboxylate ion binding site. The new receptor, 4, was
synthesized, as shown in Scheme 1, and its binding affinity
towards several amino acids, GABA and dipeptide
was evaluated and compared with that of 5, which has no
pyridine moiety, and 6, which has no amide bond (Figure 1).
(4) and thiazolobenzocrown-benzoic acid conjugate (TBC-
BAC) (5) with a 64 and 78% yield, respectively. The
structure of TBC-PAC was confirmed by spectroscopic and
analytical data. For instance, the 1H NMR spectrum showed
pyridine protons at d 8.52, 8.05, 8.0 and 7.62, thiazole
protons at d 7.72 and 7.71, a broad amide proton at d 8.29,
and three sets of methylene protons at d 5.24, 5.02 and 4.99,
respectively. In addition, TBC-PAC receptor exhibited a
characteristic amide absorption band at 1654 cm21 in the IR
spectrum. Similar structural assignments were made for
TBC-BAC (5) and TBC-PMC (6), and the structure was the
same as the proposed one.
An initial NMR screening of the binding affinities of 4
and its derivative 5 towards GABA showed a pronounced
dependence of the association constant (Ka) on the nature of
the aromatic group. In order to determine the selective
binding ability of 4 towards an amino acid, we studied the
1H NMR spectral changes caused by the addition of an
amino acid to aqueous DMSO (3:7) solution containing the
receptor. The 1H NMR titration spectrum of the receptor 4
with GABA shows an interesting trend in their chemical
shifts as the molar ratios of the ligand to NHþ4 increase
from 0 to 1 (Figure 2). When 4 was mixed with 1 equiv. of
GABA, the proton signals of CONH (H4), ThzCH2O
groups (H5), thiazolyl-H (H6) and pyridine-H1 nearest to
the nitrogen (H1) in 4 moved downfield. The proton signal
of N-H and pyridine-H1 clearly underwent a downfield shift
from 8.26 to 8.43 ppm and from 8.58 to 8.66 ppm,
respectively, due to the hydrogen bonding between the
carboxylate anion and the amide N-H and acidic pyridine-
H1, which also indicates that the acidic proton of pyridine
acts as a binding site of this heteroditopic receptor.
2. Results and discussion
The synthesis of receptors 4–6 was carried out as shown
in Scheme 1. Thecyclisation of1 with N-Boc-dopamine (26,
27) in the presence of sodium iodide and K2CO3 resulted in
2 with a 72% yield, which was subsequently deprotected
with trifluoroacetic acid resulting in free amine 3 with a 70%
yield. This compound was converted into receptors 4–6 by
coupling with the corresponding acid and 2-pyridylmethyl
bromide. The reaction of 3 with picolinic acid and benzoic
acid in the presence of 1,3-diisopropylcarbodiimide (DIC)
and/or 1,3-dicyclohexylcarbodiimide (DCC), and 1-hydro-
xybenzotriazole (HOBT) in dichloromethane provided
thiazolobenzocrown-picolinic acid conjugate (TBC-PAC)
S
O
O
S
N
N
4: R =
5: R =
6: R =
N
O
N
N
O
O
O
O
NHR
O
O
O
H
O
H
N
H
O
2
N
N
-
H
O
N
C
S
S
Figure 1. Structures of conjugates 4–6 and proposed structure of the complex for conjugate 4 with the amino acid.

18
Y.R. Yi et al.
6a
S
1
4
H
N
7
5a
2
N
N
N
O
O
3
O
O
O
5b
S
6b
1
Figure 2. Partial H NMR (400 MHz) titration spectra of 4 (4.5 £ 1023 M) with GABA in D2O–DMSOd6 (3:7) at 258C.
The proton signals of the crown ether moiety also exhibited
significant complexation-induced shifts. The methylene
protons and the thiazolyl-H peaks showed downfield shifts
from 4.93 to 5.03 ppm and from 7.68 to 7.80 ppm,
respectively, due to the electrostatic interaction between
the ether oxygen and thiazole ring nitrogen with NHþ4 upon
addition of 1 equiv. of GABA. These results indicated that 4
acts as a convergent heteroditopic receptor for GABA
In order to gain insight into the characteristics of the
interactions between GABA and 4, molecular modelling
studies were conducted using SPARTAN 04 (Figure 4).
The energy-minimised diagram shows that the ammonium
ion forms hydrogen bonds disposed in a three-fold
symmetry pattern with the thiazole nitrogen (a ¼ 2.49 and
˚
b ¼ 2.37 A) and the ether oxygen (c ¼ 1.90, d ¼ 2.80,
˚
e ¼ 2.94 and f ¼ 2.55 A) (29).
1
through hydrogen bonding. From the H NMR titration
The carboxylate anion, on the other hand, formed
hydrogen bonds with the amide N-H (g ¼ 1.90 and
using the nonlinear curve-fitting program WinEQNMR
(28), the association constant (Ka) of 4 with GABA
was calculated to be 3190 M21. A Job plot of 4 with GABA
indicated that 4 formed a 1:1 complex with GABA
(Figure 3).
˚
˚
h ¼ 3.08 A) and the acidic pyridine-H1 (i ¼ 3.52 A).
Moreover, a conformational change occurred as a result
of complex formation; the dihedral angles Cbenzo-O-Cmet
Cmet changed from 1218 to 1108, thus making the
-

Supramolecular Chemistry
19
Time (min)
20
0
10
30
40
1.8E-04
1.5E-04
1.2E-04
9.0E-05
6.0E-05
0.0
–0.1
–0.2
–0.3
3.0E-05
0
–0.4
0
0.2
0.4
0.6
0.8
1.0
Mole fraction
0.00
–0.02
–0.04
–0.06
–0.08
–0.10
–0.12
–0.14
–0.16
Figure 3. A Job plot of 4 with GABA in D2O–DMSOd6 (3:7) at
258C.
ammonium ion of GABA the ideal guest in the 18-crown-6
˚
cavity (,1.42 A). Thus, the optimised structure of the 4–
GABA complex suggests that the design of the new
heteroditopic receptor system is capable of the simul-
taneous coordination of both anionic and cationic groups
of the guest species. In order to establish the thermodyn-
amic characterisation of the complexation, isothermal
titration calorimetry (ITC) experiments of the receptors
with GABA and other amino acids were carried out in
DMSO:H2O (7:3) at 258C. ITC significantly showed one
association constant throughout the titration of 4 with
GABA (Figure 5). However, the association constant
0.0
0.5
1.0
1.5
Molar ratio
Figure 5. Isothermal calorimetric titration of 4 (1 mM) with
GABA (20 mM) in H2O–DMSO (3:7) at 258C.
Figure 4. Energy minimised structure of the 4–GABA complex as predicted by Hartree–Fock 3-21G calculations.

20
Y.R. Yi et al.
Table 1. Association constants (M21) and thermodynamic
values from ITC for the complexation of amino acids with
receptors.a
arginine, glutamine and Gly–Gly with a longer-chain
length had lower association constants with 4 compared
with GABA. In the case of receptors 5 and 6, the absence
of the acidic pyridine-H1 and amide NH, respectively,
weakened the formation of the hydrogen bond between the
carboxylate anion of GABA and the receptors, conse-
quently lowering the association constants. A decrease in
the association constant of 4 with 5-APA and 6-AHA
compared with GABA indicated that the proper orien-
tations of the ammonium and carboxylate anion are
necessary to ideally poise the binding site of the receptor.
Receptor
Guest
Ka
DH
DS
4
Gly
115
158
440
82
22.28 £ 103
26.04 £ 103
25.64 £ 103
22.94 £ 103
24.10 £ 103
21.61 £ 104
21.31 £ 105
26.10 £ 104
22.09 £ 104
21.32 £ 103
22.05 £ 104
8.47
–10.2
27.17
20.96
26.68
2290
2418
2187
2674
215.2
222.2
L-Alanine
Glutamine
Arginine
b-Alanine
Gly–Gly
GABA
39
1300
2220
1400
1250
19
5-APAb
6-AHAc
GABA
5
6
GABA
291
3. Experimental section
a Determined in H2O–DMSO (3:7) at 258C, [H]o ¼ 1.0 £ 1023 M,
3.1 General methods
[G]o ¼ 2.0 £ 1022 M.
General experimental procedures for melting points, FT-
IR spectra, mass spectra and elemental analyses have been
described previously (23b). 1H and 13C NMR spectra were
recorded on a Bruker AM-400 Spectrometer with TMS as
an internal standard. 1H NMR titrations were run at 45 mM
concentrations, with addition of a 0.25 M amino acid
solution. ITC measurements were performed using an
Omega titration microcalorimeter. A 15 mM solution of
amino acid in 40 times (5 mL injection) was added to a
1 mM receptor solution (1.8 mL) in a calorimetric cell.
Flash column chromatography was performed with Merck
silica gel 60 (70–230 mesh). All reactions were carried out
under an atmosphere of argon. The solution was washed
with brines and dried over anhydrous sodium sulphate.
1,3-Dichloroacetone, trifluoroacetic acid, picolinic acid,
benzoic acid, 2-(bromomethyl)pyridine, DIC, DCC and
HOBT hydrate were purchased from Aldrich Co. and used
as received. 1,2-Bis(thioamidomethyloxy)benzene and N-
Boc-dopamine were prepared with a procedure described
in the literature (23, 26).
b 5-Aminopentanoic acid.
c 6-Aminohexanoic acid.
obtained for 4 with GABA at 508C was four times less than
that observed at 258C. This might be due to the improper
orientation of GABA towards the proper binding site at
high temperature. These results suggested that the addition
of GABA forms a 1:1 complex with 4 regardless of how
much the concentration of GABA is increased.
A similar kindof binding mode was obtained for all other
amino acids. Moreover, the complexation of all the amino
acids with the receptors was enthalpystabilised (since all DH
values are negative; Table 1). The enthalpy change DH
was obtained directly from the calorimetric experiments,
whereas the entropy change DS was calculated according
to the formula: DG8 ¼ 2RT ln K ¼ DH 2 TDS. Other
thermodynamic parameters derived from the calorimetric
measurements are summarised in Table 1. The association
constant of 4 with GABA obtained from the ITC data was
2220M21. Thecontrolcompounds5and6withGABAhada
lower association constant (Table 1). Thus, the covalently
connected heteroditopic receptor 4 is a superior GABA
receptor capable of binding a carboxylate and an ammonium
ion simultaneously in a cooperative fashion through the
interaction with hydrogen bonding.
3.1.1 Synthesis of 1,2-bis[2(4-chloromethyl)thiazolyl]-
methyloxybenzene (1)
A mixture of 1,2-bis(thioamidomethyloxy)benzene (1.00 g,
3.90 mmol) and 1,3-dichloroacetone (1.00 g, 8.58 mmol) in
benzene (70 mL) was refluxed for 20 h with the Dean–Stark
column to remove water. After the solvent was removed, it
was extracted with dichloromethane, dried and concen-
trated. The residue was purified by column chromatography
(elution with EtOAc–hexane 1:4) to yield 1.32 g of 1
(84%). TLC Rf 0.48 (EtOAc–hexane 1:1); m.p. 1168C
Importantly, the geometry of ditopic receptors must be
optimised so that the anion and cation binding sites are
located within appropriate proximity to one another to
enhance this interaction; incorrect orientation could lead to
the ion pair associating outside of the receptor, or with the
solvent. That is why the terminal NH2-to-COOH distance
of the amino acids is necessary for their proper fixation
onto the receptor molecule, so that the carboxylate group–
amide NH and pyridine-H1 and ammonium group–crown
cavity interactions can occur simultaneously. Thus, the
better the fixation of the amino acid onto the receptor
molecule, the higher the stability of the resulting 1:1
adduct. From Table 1, glycine (Gly), L-alanine, phenyl-
alanine and b-alanine due to their short-chain length and
1
(CH2Cl2–hexane); H NMR (CDCl3) d 7.30 (s, 2H, Thz-
H), 6.97 (m, 4H, Ph), 5.39 (s, 4H, OCH2THz), 4.75 (s, 4H,
CH2Cl); 13C NMR (CDCl3) d 168.7, 152.3, 148.4, 123.2,
118.7, 115.9, 69.1, 41.1; MS (relative intensity) m/z 401
(Mþ, 2), 292 (13), 254 (18), 146 (100%); Anal. Calcd for
C16H14Cl2N2O2S2: C, 47.88; H, 3.52; N, 6.98; S, 15.98.
Found: C, 47.98; H, 3.59; N, 6.94; S, 16.25.

Supramolecular Chemistry
21
3.1.2 Synthesis of TBC-ethylamine-t-Boc (2)
room temperature for 30 min. A solution of 3 (200 mg,
0.41 mmol) in dichloromethane (5 mL) was added to the
resulting mixture, and stirred for 12 h. The mixture was
extracted with dichloromethane, washed, dried and
concentrated to dryness. The residue was purified by
flash chromatography (elution with EtOAc 100%) to yield
158 mg of 4 (64%). TLC Rf 0.10 (100% EtOAc);
m.p. 165–1678C (CH2Cl2–hexane); IR (KBr) 3446,
2924, 2358, 2235, 2119, 1654, 1508, 1244, 1030, 1009,
825; 1H NMR (CDCl3) d 8.52 (d, J ¼ 8.0 Hz, 1H, Py), 8.29
(bd, J ¼ 4.5 Hz, 1H, NHCO), 8.04(d, J ¼ 7.5 Hz, 1H, Py),
8.00 (dd, J ¼ 7.5, 1.5 Hz, 1H, Py), 7.72 (s, 1H, Thz-H),
7.71 (s, 1H, Thz-H), 7.60 (td, J ¼ 7.0, 5.5 Hz, 1H, Py),
7.20 (dd, J ¼ 5.5, 5.0 Hz, 2H, Ar), 7.06 (m, 2H, Ar), 7.04
(s, 1H, Ar), 6.87 (d, J ¼ 8.0 Hz, 1H, Ar), 5.24 (s, 4H,
OCH2Thz), 5.02 (s, 2H, ThzCH2O), 4.99 (s, 2H,
ThzCH2O), 3.63 (t, J ¼ 7.0 Hz, 2H, CH2CH2NH), 2.88
(t, J ¼ 7.0 Hz, 2H, CH2CH2NH); 13C NMR (CDCl3) d
166.2, 166.0, 164.3, 152.9, 152.6, 149.9, 149.8, 149.5,
149.4, 148.4, 148.1, 138.4, 133.9, 126.7, 123.8, 123.8,
122.9, 122.9, 118.5, 118.2, 118.1, 118.0, 117.5, 69.4, 69.3,
68.8, 68.4, 41.2, 35.7; Anal. Calcd for C30H26N4O5S2: C,
61.42; H, 4.47; N, 9.55; S, 10.93. Found: C, 61.31; H, 4.73;
N, 9.30; S, 10.52.
A mixture of N-Boc-dopamine (1.00 g, 3.95 mmol), K2CO3
(1.20 g, 8.69 mmol) and NaI (1.30 g, 8.69 mmol) in
butanone (100 mL) was heated at 608C for 1 h, and then a
solution of 1 (1.74 g, 4.33 mmol) in butanone (10 mL) was
added to the resulting mixture and heated for 6 h. After the
solvent was removed, it was extracted with dichloro-
methane, washed, dried and concentrated. The residue was
purified by chromatography (EtOAc–hexane 1:1) to yield
1.65 g of 2 (72%). TLC Rf 0.43 (EtOAc–hexane 2:1);
m.p. 164–1668C (CH2Cl2–hexane); IR (KBr) 3430, 2346,
2257, 2129, 1649, 1050, 1026. 1002 cm21 1H NMR
;
(CDCl3) d 7.79 (s, 2H, ThzH), 7.29–7.16 (m, 2H, Ph),
7.04–6.97 (m, 4H, Ph), 6.76 (m, 1H, Ph), 5.26 (s, 4H,
OCH2Thz), 5.05 (s, 2H, ThzCH2O), 5.02 (s, 2H, ThzCH2-
O), 3.17 (s, 2H, PhCH2CH2NHCO), 2.67 (t, J ¼ 7.5 Hz, 2H,
PhCH2CH2NHCO), 1.38 (s, 9H, -OC(CH3)3); 13C NMR
(CDCl3) d 163.9, 163.8, 155.9, 152.6, 152.5, 148.1, 148.0,
146.7, 132.6, 122.1, 121.1, 120.9, 120.8, 114.6, 114.0,
113.4, 77.8, 66.1, 65.8, 35.4, 28.7; MS (relative intensity,
%) m/z 581 (Mþ, 14), 189 (100); Anal. Calcd for
C29H33N3O6S2: C, 59.67; H, 5.70; N, 7.20; S, 10.99.
Found: C, 59.78; H, 5.44; N, 7.13; S, 11.07.
3.1.3 Synthesis of TBC-ethylamine (3)
A solution of 2 (1.00 g, 1.72 mmol) in dichloromethane
(50 mL) was reacted with trifluoroacetic acid (2.91 g,
25.80 mmol) at room temperature for 12 h. The mixture
was neutralised with 1 N sodium hydroxide solution,
extracted with dichloromethane, washed, dried and
crystallised in a freezer to yield 580 mg of 3 as white
solid (70%). TLC Rf 0.13 (CH2Cl2–MeOH–NH4OH
16:5:1); m.p. 171–1738C (CH2Cl2); IR (KBr) 3426, 3074,
2930, 1687, 1507, 1246, 1201, 1121, 1022, 799; 1H NMR
(DMSO-d6) d 7.92 (bs, 2H, CH2CH2NH2), 7.84 (s, 1H,
Thz-H), 7.83 (s, 1H, Thz-H), 7.19–7.16 (m, 2H, Ph),
7.08–6.98 (m, 2H, Ph), 7.05 (d, J ¼ 8.1 Hz, Ph), 7.01 (bs,
1H, Ph), 6.78 (d, J ¼ 8.1 Hz, 1H, Ph), 5.28 (s, 2H, OCH2-
Thz), 5.27 (s, 2H, OCH2Thz), 5.07 (s, 2H, ThzCH2O), 5.03
(s, 2H, ThzCH2O), 3.07 (t, J ¼ 8.4 Hz, 2H, CH2CH2NH2),
2.82 (t, J ¼ 8.4 Hz, 2H, CH2CH2NH2); 13C NMR (CDCl3)
d 164.0, 151.9, 147.7, 147.5, 146.6, 129.9, 121.5, 120.7,
113.8, 65.5 (OC H2Thz), 65.1 (ThzC H2O), 40.6 (CH2-
C H2NH2), 32.6 (C H2CH2NH2); Anal. Calcd for
C24H23N3O4S2: C, 59.86; H, 4.81; N, 8.73; S, 13.32.
Found: C, 59.91; H, 4.60; N, 8.88; S, 13.75.
3.1.5 Synthesis of TBC-benzoic acid conjugate (TBC-
BAC, 5)
A mixture of benzoic acid (100 mg, 0.82 mmol), DIC
(0.13 mL, 1.89 mmol), HOBT hydrate (190 mg, 1.4 mmol)
and diisopropylethylamine (1.48 mL, 8.07 mmol) in
dichloromethane (50 mL) was stirred at room temperature
for 30 min. A solution of 3 (410 mg, 0.80 mmol) in
dichloromethane (5 mL) was added to the resulting
mixture, and refluxed for 12 h. The mixture was extracted
with dichloromethane, washed with brine and dried. The
residue was purified by flash chromatography (elution with
EtOAc 100%) to yield 374 mg of 5 (78%). TLC Rf 0.40
(100% EtOAc); m.p. 117–1188C (CH2Cl2–hexane); IR
(KBr) 3430, 2255, 2128, 1652, 1050, 1026, 1004 cm21; 1H
NMR (CDCl3) d 7.69 (s, 1H, Thz-H), 7.67 (s, 1H, Thz-H),
7.37 (m, 2H, Ph), 7.30 (m, 2H, Ar), 7.22 (d, J ¼ 6.0 Hz,
2H), 7–7.30 (m, 3H), 7.22 (d, J ¼ 6.0 Hz, 1H), 6.99 (m,
2H, Ar), 6.94 (d, J ¼ 8.0 Hz, 1H), 6.87 (s, 1H, Ar), 6.79 (d,
J ¼ 8.0 Hz, 1H, Ar), 6.40 (bs, 1H, NHCO), 5.23 (s, 2H,
OCH2Thz), 5.23 (s, 2H, OCH2Thz), 5.02 (s, 2H,
ThzCH2O), 5.00 (s, 2H, ThzCH2O), 3.64 (t, J ¼ 6.5 Hz,
2H, PhCH2CH2), 2.84 (t, J ¼ 6.5 Hz, 2H, PhCH2CH2); 13
C
NMR (CDCl3) d 167.9, 167.3, 167.1, 161.6, 151.7, 151.6,
149.8, 149.3, 134.9, 134.4, 131.8, 128.9, 127.3, 124.2,
124.1, 123.4, 119.0, 118.8, 118.3, 118.2, 117.3, 69.1, 68.3,
67.8, 41.6, 35.5; Anal. Calcd for C31H27N3O5S2: C, 63.57;
H, 4.65; N, 7.11; S, 10.95. Found: C, 63.37; H, 4.86; N,
7.10; S, 11.26.
3.1.4 Synthesis of TBC-picolinic acid conjugate (TBC-
PAC, 4)
A mixture of picolinic acid (115 mg, 0.92 mmol), DIC
(0.15 mL, 0.92 mmol) and HOBT hydrate (135 mg,
0.92 mmol) in dichloromethane (15 mL) was stirred at

22
Y.R. Yi et al.
S.; Kim, S.-G.; Choi, S.M.; Rhee, Y.M.; Ahn, K.H. Org.
Lett. 2010, 12, 4228–4231.
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3.1.6 Synthesis of TBC-2-pyridylmethyl conjugate (TBC-
PMC, 6)
A mixture of 3 (200 mg, 0.42 mmol), Et3N (0.3 mL,
2.1 mmol) and 2-(bromomethyl)pyridine hydrobromide
(160 mg, 0.63 mmol) in dry dichloromethane (20 mL) was
stirred at room temperature for 10 h. The mixture was
extracted with dichloromethane, washed and dried. The
residue was purified by flash chromatography (elution with
EtOAc 100%) to yield 146 mg of 6 (61%). TLC Rf 0.05
(100% EtOAc); m.p. 128–1308C (CH2Cl2–hexane); IR
(KBr) 3430, 2255, 2128, 1652, 1050, 1026, 1004 cm21; 1H
NMR (CDCl3) d 8.64 (d, J ¼ 5.0 Hz, 1H, Py), 7.90 (ddd,
J ¼ 8.0, 7.5, 1.6 Hz, 1H, Py), 7.78 (d, J ¼ 8.0 Hz, 1H, Py),
7.40 (m, 1H, Py), 7.26 (s, 1H, Thz-H), 7.23 (s, 1H, Thz-H),
6.88 (m, 2H, Ar), 6.80 (d, J ¼ 7.5 Hz, 1H, Ar) 6.72 (m,
3H), 6.50 (s, 1H), 5.35 (bs, 1H, NHCO), 5.13 (s, 4H,
OCH2Thz), 5.03 (s, 2H, ThzCH2O), 5.02 (s, 2H,
ThzCH2O), 4.04 (m, 2H, NHCH2Py), 3.29 (m, 2H,
PhCH2CH2), 2.67 (t, J ¼ 7.0 Hz, 2H, PhCH2CH2); 13C
NMR (CDCl3) d 169.6, 169.3, 157.8, 157.6, 156.2, 150.0,
149.8, 148.7, 147.0, 146.9, 136.2, 132.0, 124.2, 122.2,
122.0, 120.9, 115.3, 115.3, 115.0, 114.8, 113.0, 112.8,
70.2, 70.0, 48.2, 36.5; Anal. Calcd for C30H28N4O4S2: C,
62.92; H, 4.93; N, 9.78; S, 11.20. Found: C, 62.57; H, 4.81;
N, 9.80; S, 11.56.
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We have reported that a new heteroditopic receptor,
compound 4, recognises zwitterionic amino acids such as
GABA in polar protic solvents. Compound 4 shows
selectivity towards GABA compared with similar amino
acids based on the spacer length and orientation. The
receptor uses thiazolobenzocrown ether for ammonium
binding and amide NH with a pyridine-H1 for carboxylate
anion binding simultaneously in a cooperative fashion.
Acknowledgements
This study was supported by the Korea Research Foundation
grant (KRF-2001-C060400-DP0332) and the NRF grant funded
by the MEST in Korea (NRF-2010-0010070). The Research
Institute of Industrial Technology at the Kyungpook National
University also supported A.H.
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