Chiral calix[4]azacrowns for enantiomeric recognition of amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2009.01.087

In this study the synthesis of novel chiral calix[4]azacrown derivatives has been reported. The enantioselectivity of chiral receptors was investigated by using UV-vis spectroscopy. All the chiral calix[4]arene derivatives exhibited certain chiral recogni

Full text of DOI:10.1016/j.tet.2009.01.087

Tetrahedron 65 (2009) 3014–3018
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Chiral calix[4]azacrowns for enantiomeric recognition of amino acid derivatives
*
Havva Nur Demirtas, Selahattin Bozkurt, Mustafa Durmaz, Mustafa Yilmaz, Abdulkadir Sirit
Department of Chemistry, Selçuk University, 42099 Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study the synthesis of novel chiral calix[4]azacrown derivatives has been reported. The enan-
tioselectivity of chiral receptors was investigated by using UV–vis spectroscopy. All the chiral calix[4]-
arene derivatives exhibited certain chiral recognition toward the enantiomers of phenylalanine
(Phe-OMe$HCl) and alanine methyl ester hydrochlorides (Ala-OMe$HCl). As a chiral receptor, the fur-
Received 25 September 2008
Received in revised form 5 January 2009
Accepted 22 January 2009
Available online 29 January 2009
furyl-armed calix[4]azacrown ether 7 has the best enantiomeric discriminating ability for a-amino acid
ester hydrochlorides (up to KL/KD¼2.08, DDG0¼ꢀ1.82 kJ molꢀ1) in CHCl3. The enantiomeric recognition
abilities for guests are also discussed from a thermodynamic point of view.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
preparation, separation, and analysis of enantiomers. In this regard,
investigations conducted on the synthesis and chiral recognition
Molecular recognition is a fundamental property of various
natural systems, based on the ability of a molecular receptor to
form a complex preferentially with one of the enantiomers of
a chiral molecule by noncovalent interaction such as hydrogen
bonding, electrostatic interaction, and hydrophobic interaction.1
Therefore, the chemical or biological activity of a compound often
depends upon its stereochemistry in living organisms.
Amino acids and their derivatives are chiral organic molecules
involved in a wide variety of biological processes, and also play an
important role in the area of design and preparation of pharma-
ceuticals, as they are part of the synthesis process in the production
of drug intermediates and protein-based drugs. Therefore the study
of the enantiomeric recognition of these compounds is of particular
significance for understanding the interactions between biological
molecules and design of asymmetric catalysis systems, new phar-
maceutical agents,2 and separation materials.3
The rational design of receptors with chiral recognition ability
for chiral amino acids is still receiving considerable attention, al-
though numerous chiral macrocyclic receptors have been de-
veloped for amines, amino acids, and related compounds.4
Among the several types of synthetic receptors for recognition,
calixarenes offer a number of advantages in terms of their selec-
tivity and efficiency of binding.5,6 One of the most frequently used
strategies for introducing chiral recognition ability into calixarenes
is anchoring chiral subunits at either the lower or the upper rims of
the calixarene macrocyclic ring. Chiral receptors that are based on
the calixarene platform may have potential applications in the
properties of chiral calix[4]arene derivatives have attracted con-
siderable attention.7
In recent years, we have reported the synthesis of novel chiral
calix[4]arenes containing various functionalities including crown8
and azacrown ethers,9 amides,10 Schiff bases,11 and quaternary
ammonium salts12 as well as their catalytic activities and enan-
tiomeric recognition properties toward chiral amines, carboxylic
acids, and amino acid derivatives. In the present study, we report
the synthesis of novel calix[4]arene derivatives bearing a chiral
azacrown-5 moiety at the lower rim and their recognition abilities
for
a-amino acid methyl esters by a UV–vis titration method in
CHCl3.
2. Results and discussion
2.1. Design and synthesis of calix[4]arene based receptors
Calix[4]azacrowns containing a calix[4]arene platform and an
azacrown unit in their framework have received much attention
because of their special structures and good complexing properties
toward anions and cations.13 In a recent study, we reported that the
furfuryl-armed calix[4]azacrown ethers exhibited different chiral
R
Ph
Methanol
R
N
NH2
+
70 °C, 5h
O
OH
OH
R = Benzyl or furfuryl
1: R= Benzyl
2: R= Furfuryl
* Corresponding author. Tel.: þ90 332 3238220/5405; fax: þ90 332 3238225.
E-mail address: asirit42@yahoo.com (A. Sirit).
Scheme 1. Preparation of amino diols 1 (85%) and 2 (86%).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.087

H.N. Demirtas et al. / Tetrahedron 65 (2009) 3014–3018
3015
O
O
N
N
R
R
O
O
O
OR'
OR'
OR'
O
O
O
O
O
O
OR'
OR'
OR'
i
ii
5: R' = H
6: R' = Me
3: R = Br, R' = H
R' = Me
7: R' = H
8: R' = Me
4: R = OTs,
Scheme 2. (i) and (ii) Chiral amino diol 1 or 2, NaH, DMF, reflux (5, 42%; 6, 54%).
recognition abilities toward the enantiomers of racemic mandelic
acid and dibenzoyltartaric acid. These nitrogen binding sites, at-
tached to the calix[4]arene platform could also serve as chiral re-
ceptors for the enantioselective recognition of amino acid methyl
esters. For the desired goal, p-tert-butylcalix[4]arene derivatives 3
and 4 were chosen as the precursors, and the synthetic route is
shown in Schemes 1 and 2 for the synthesis of furfuryl- and benzyl-
armed chiral calix[4]azacrown ethers.
Upon addition of (D)-Ala-OMe$HCl to the CHCl3 solution con-
taining chiral receptor 8 (2.0ꢁ10ꢀ4 mol dmꢀ3, 25 ꢂC), the absor-
bance of 8 at 246 nm decreased and the one at 282 nm increased,
with an isobestic point at 272 nm (Fig. 1). A similar spectral change
was observed when other receptors were used as hosts and was
believed to be due to hydrogen bonding and p–p stacking.
With the assumption of a 1:1 stoichiometry, the complexation of
amino acid derivatives (G) with chiral calix[4]arene (H) is expressed
by Eq. 1.
Thus, following the literature procedure,14a,b starting materials 1
and 2 were prepared by the ring opening of the (R)-styrene oxide
with furfuryl- and benzylamine in high yields, respectively. The
benzyl-armed calix[4]azacrowns obtained in 42 and 54% yields by
the reaction of the p-tert-butylcalix[4]arene derivatives 3 or 4 with
chiral amino diol 1 in DMF.
K
H þ G % H$G
(1)
Under the conditions employed, the concentration of calix[4]-
arene derivatives (2.0ꢁ10ꢀ4 mol dmꢀ3) is much smaller than that of
amino acid derivatives, i.e., [H]0ꢃ[G]0. Therefore, the stability
constant of the supramolecular system formed can be calculated
according to the modified Hildebrand–Benesi equation,19 Eq. 2,
where [G]0 denotes the total concentration of amino acid, [H]0 re-
fers to the total concentration of calix[4]arene derivative, D3 is the
difference between the molar extinction coefficient for the free and
The products were characterized by a combination of 1H NMR,
13C NMR, FABMS, IR, and elemental analysis. The conformational
characteristics of calix[4]arenes were conveniently estimated by
way of the splitting pattern of the ArCH2Ar methylene protons in
the 1H and 13C NMR spectroscopy.15 1H and 13C NMR data showed
that newly synthesized chiral p-tert-butylcalix[4]arene derivatives
5 and 6 are in a cone conformation.
complexed calix[4]arene derivative, and DA denotes the changes in
the absorption of the modified calix[4]arene on adding amino acid
derivatives.
2.2. UV spectral titrations
1=
D
A ¼ 1=KD3½Hꢄ0½Gꢄ0þ1=D3½Hꢄ0
(2)
It is well known that calix[n]arene derivatives act as receptors
for ammonium cations through their aromatic cone cavity.16 Cal-
For all guest molecules examined, plots of calculated 1/
values as a function of 1/[G]0 values give good straight lines, sup-
porting the 1:1 complex formation. Typical plots are shown for the
complexation of compound 8 with (D)-alanine methyl ester in
D
A
ix[n]arenes exhibit a special ability for cation–
to their preorganized aromatic rings. We have now extended these
studies to the enantioselective recognition of -amino acid methyl
p
17 interactions due
a
ester hydrochlorides by the chiral calix[4]azacrown derivatives 5–8.
The binding constants (K) of inclusion complexes of above-
mentioned chiral calix[4]arene receptors with amino acid methyl
esters were determined on the basis of the differential UV spec-
trometry in chloroform.18
Figure 2.
-4.00
-8.00
1.20
1.00
0.80
0.60
0.40
0.20
0.00
-12.00
-16.00
200
220
240
260
Wavelength (nm)
280
300
320
0
250
500
1/G
750
1000
Figure 1. UV–vis spectra of 8 (2.0ꢁ10ꢀ4 mol dmꢀ3) in the presence of (D)-Ala-OMe$HCl
(1.0–9.0ꢁ10ꢀ3 mol dmꢀ3) in chloroform solution at 25 ꢂC.
Figure 2. Typical Benesi–Hildebrand plot of 1/
DA versus 1/[G]0.

3016
H.N. Demirtas et al. / Tetrahedron 65 (2009) 3014–3018
The free-energy change (DG) for inclusion complexes formed by
chiral calix[4]azacrown derivatives and guest amino acid de-
rivatives is calculated from the equilibrium constant K by Eq. 3 and
is related to
0.12
0.08
0.04
0
D
G ¼ ꢀRTln K
(3)
and to the enthalpic and entropic changes (
DH and
D
S) through the
Gibbs–Helmholtz equation, Eq. 4. Combining Eqs. 3 and 4, we ob-
tain Eq. 5, which describes the temperature dependence of K. Thus,
plots of the ln K values as a function of the inverse of temperature
gave good linear relationships for working temperature range
(Fig. 4).
D
G ¼
D
H ꢀ T
D
S
(4)
0
0.2
0.4
0.6
0.8
1
[H]/([H]+[G])
Figure 3. Job plot of 8 with (D)-Ala-OMe$HCl. The total concentration of the host and
ln K ¼ ꢀ
D
H=RT þ
D
S=R
(5)
guest is 3.0ꢁ10ꢀ4 mol dmꢀ3
.
The association constants (K), the free-energy change (DDG0)
calculated from the slope and the intercept, and the thermody-
namic parameters are summarized in Table 1, along with the
enantioselectivity KL/KD for the complexation of
esters by these hosts.
As can be recognized readily from Table 1, all the values of the
enthalpy changes
Hꢂ) and the entropy changes Sꢂ) of
the resulting complexes are positive. These results indicate that the
complexation of calix[4]arenes (6–8) with -amino acid methyl
In order to verify the 1:1 complexation, we used a Job plot ex-
periment. Figure 3 illustrates that the 8-( )-Ala-OMe$HCl complex
D
D/L-amino acid
concentration approaches maximum when the molar fraction of
[H]/([H]þ[G]) is 0.5, suggesting that host 8 forms a 1:1 complex
with (D)-Ala-OMe$HCl.
(
D
(D
a
esters examined is driven predominantly by the favorable entropic
change, typically showing large positive entropy changes
5.72
5.68
5.64
5.60
(
D
Sꢂ¼54.66–103.27 J molꢀ1) and somewhat smaller positive en-
thalpy changes (
tion for the complexation of the large entropy-driven is that both
D
Hꢂ¼1.44–19.06 kJ molꢀ1). One possible explana-
dissociated a-amino acid methyl esters and free calix[4]arene de-
rivatives are heavily solvated by hydrogen-bonding interactions.
From the data shown in Table 1, all hosts have greater K values
toward the enantiomers of Phe-OMe than Ala-OMe, a non-aromatic
analog of Phe-OMe. This may be due to the fact that the chiral
calix[4]azacrowns with an aromatic group attached to the nitrogen
of the macrocyclic ring could have
p–p interactions with that of
Phe-OMe as an additional binding force. As a result, stronger
binding was realized in all cases.
UV–vis spectroscopic studies indicate that chiral selectors 5 and
7 show strong binding and good recognition ability for the enan-
tiomers of phenylalanine (Phe-OMe$HCl) and alanine methyl ester
hydrochlorides (Ala-OMe$HCl).
3.20
3.24
3.28
3.32
3.36
3.40
3.44
(1/T)x103 K-1
Figure 4. The plot of ln K versus 1/T for the host–guest complexation of 8 and (D)-Ala-
OMe$HCl in CHCl3.
Table 1
Binding constants (K), enantioselectivities (KL/KD), and thermodynamic parameters for the complexation of L/D C
-amino acid esters with the chiral receptors 5–8 in CHCl3 at 25 ꢂ
Entry
Host
Guesta
-Phe-OMe$HCl
-Phe-OMe$HCl
-Ala-OMe$HCl
-Ala-OMe$HCl
-Phe-OMe$HCl
-Phe-OMe$HCl
-Ala-OMe$HCl
-Ala-OMe$HCl
-Phe-OMe$HCl
-Phe-OMe$HCl
-Ala-OMe$HCl
-Ala-OMe$HCl
-Phe-OMe$HCl
-Phe-OMe$HCl
-Ala-OMe$HCl
-Ala-OMe$HCl
Kꢁ103 (Mꢀ1
)
KL/KD
ꢀ
D
G (kJ molꢀ1
)
ꢀ
DDGb
D
H (kJ molꢀ1
)
DDHc
D
S (J molꢀ1
)
DDSd
1
2
3
4
5
6
7
8
5
5
5
5
6
6
6
6
7
7
7
7
8
8
8
8
D
0.583ꢅ0.026
1.049ꢅ0.090
0.315ꢅ0.024
0.356ꢅ0.027
0.310ꢅ0.012
0.395ꢅ0.028
0.109ꢅ0.008
0.111 ꢅ0.021
0.809ꢅ0.044
1.684ꢅ0.130
0.419ꢅ0.017
0.532ꢅ0.014
0.342ꢅ0.007
0.480ꢅ0.020
0.284ꢅ0.014
0.311ꢅ0.009
1.80
15.78ꢅ0.16
17.23ꢅ0.21
14.25ꢅ0.26
14.55ꢅ0.36
14.21ꢅ0.14
14.81ꢅ0.12
11.62ꢅ0.20
11.71ꢅ1.20
16.59ꢅ0.14
18.41ꢅ0.06
14.96ꢅ0.03
15.55ꢅ0.04
14.46ꢅ0.07
15.30ꢅ0.10
14.01ꢅ0.29
14.22ꢅ0.21
1.45
0.30
0.60
0.09
1.82
0.59
0.84
0.22
6.25ꢅ0.16
7.95ꢅ0.21
7.23ꢅ0.26
10.72ꢅ0.36
4.96ꢅ0.14
8.60ꢅ0.12
16.08ꢅ0.20
19.06ꢅ1.20
4.21ꢅ0.14
4.47ꢅ0.06
1.44ꢅ0.03
2.33ꢅ0.04
1.83ꢅ0.07
3.22ꢅ0.10
5.82ꢅ0.29
8.25ꢅ0.21
1.70
73.92ꢅ0.55
84.47ꢅ0.71
72.08ꢅ0.85
84.80ꢅ1.21
64.32ꢅ0.47
78.57ꢅ0.39
92.96ꢅ0.67
103.27ꢅ3.99
69.81ꢅ0.45
76.79ꢅ0.20
55.04ꢅ0.09
60.01ꢅ0.15
54.66ꢅ0.22
62.16ꢅ0.32
66.52ꢅ0.96
75.42ꢅ0.69
10.55
12.72
14.25
10.31
6.98
L
D
1.13
1.28
1.02
2.08
1.27
1.40
1.09
3.50
3.65
2.98
0.26
0.89
1.39
2.43
L
D
L
D
L
9
D
10
11
12
13
14
15
16
L
D
4.97
L
D
7.49
L
D
8.89
L
a
Phe-OMe$HCl: phenylalanine methyl ester hydrochloride; Ala-OMe$HCl: alanine methyl ester hydrochloride.
b
c
DDG¼
D
D
D
GLꢀ
D
GD.
HD.
DDH¼
HLꢀD
d
DDS¼
SLꢀDSD.

H.N. Demirtas et al. / Tetrahedron 65 (2009) 3014–3018
3017
NH2.HCl
OMe
O
N
..
OMe
O
O
O
NH2. HCl
NH+3
D-phenylalanine methylester hydrochloride
D-alanine methylester hydrochloride
O
O
NH2.HCl
OMe
O
O
O
O
H
O
OMe
HO
NH2. HCl
O
L-phenylalanine methylester hydrochloride
L-alanine methylester hydrochloride
Figure 6. Chemical structures of guests employed.
Figure 5. Proposed recognition mode of chiral calix[4]arene 5 toward a chiral amino
acid methyl ester.
spectra were recorded at room temperature on a Varian 400 MHz
spectrometer in CDCl3. IR spectra were obtained on a Perkin–Elmer
1605 FTIR spectrometer using KBr pellets. Optical rotations were
measured on an Atago AP-100 digital polarimeter. The HPLC mea-
surements were carried out on Agilent 1100 equipment connected
with a Zorbax RX-C18 column. Elemental analyses were performed
using a Leco CHNS-932 analyzer. FABMS spectra were taken on
a Varian MAT 312 spectrometer.
Analytical TLC was performed using Merck prepared plates
(silica gel 60 F254 on aluminum). Flash chromatography separations
were performed on a Merck silica gel 60 (230–400 mesh). All re-
actions, unless otherwise noted, were conducted under a nitrogen
atmosphere. All starting materials and reagents used were of
standard analytical grade from Fluka, Merck, and Aldrich and used
without further purification. Toluene was distilled from CaH2 and
stored over sodium wire. Other commercial grade solvents were
distilled and then stored over molecular sieves. The drying agent
employed was anhydrous MgSO4.
Table 1 also shows the enantiomeric discrimination of a pair of
a
-amino acid ester hydrochlorides, characterized by the value of
KD/KL, which are 1.13–2.08 or DDG0 of ꢀ0.30 to ꢀ1.82 kJ molꢀ1 for
chiral calix[4]arene receptors 5 and 7. It was found that chiral host 5
gave stronger binding and better recognition ability for amino acid
esters containing an aromatic group than for those possessing an
aliphatic group, whereas receptor 7 exhibits the strongest binding
and the best enantioselectivity for Phe-OMe$HCl, affording KL/KD of
1.27–2.08 or the DDG0 of ꢀ0.59 to ꢀ1.82 kJ molꢀ1. This is pre-
sumably due to multiple hydrogen bonding and
p–p stacking in-
teractions between the receptor and the aromatic side chain of
amino acid.
The results revealed that the D/L-enantioselectivities are highly
sensitive to the furan ring and phenolic-OH of the chiral receptors
and shape of the substituted group in amino acid esters. The steric
hindrance between the ammonium cation and aromatic moieties
around the stereogenic centers of the host may also play an im-
portant role in chiral recognition and is expected to be minimized
Analytical grade
purchased from Aldrich and employed without further purification
as guest molecules for the experiments, i.e., -alanine methyl ester
hydrochloride ( -Ala-OMe), -alanine methyl ester hydrochloride
-Ala-OMe), -phenylalanine methyl ester hydrochloride ( -PheO-
-phenylalanine methyl ester hydrochloride ( -Phe-OMe)
a-amino acid methyl ester hydrochlorides were
L
L
D
for the
ester hydrochlorides form more favorable complexes with the
chiral selectors than the -isomers (Fig. 5).
The complexation of chiral calix[4]azacrowns with
esters possibly occurs through interaction of the nitrogen atom in
the azacrown loop and the quaternary ammonium cation in the
L-isomer in all cases. Therefore, the L-isomers of amino acid
(D
L
L
Me), and
(Fig. 6).
D
D
D
a
-amino acid
a
-
4.2. Syntheses
amino acid esters. Noncovalent interactions between the guests
and hydrogen bonding sites defined by ethylene oxygens, furan
oxygen, and phenolic oxygen contribute to the stabilization of these
Compounds 1, 3, and 4 were prepared according to previously
described methods.14a,20 The synthesis of 2, 7, and 8 has been al-
ready described by us.14b
complexes as well as p–p interactions.
3. Conclusion
4.2.1. General procedure for the synthesis of compounds 5 and 6
To a suspension of NaH (60% in mineral oil) (0.14 g, 3.56 mmol)
in DMF (3 mL) was added a solution of 1 (0.31 g, 0.89 mmol) in DMF
(5 mL) dropwise at 0 ꢂC under nitrogen atmosphere. The mixture
was stirred at room temperature for 2 h. Then 3 or 4 (0.89 mmol) in
DMF (20 mL) was added slowly to the mixture. The mixture was
stirred at room temperature for 2 days. DMF extract was evaporated
and water (10 mL) added to the remaining residue. The mixture
was extracted with CH2Cl2 (3ꢁ10 mL) and combined organic phase
dried over MgSO4. The solvent was evaporated and the crude
product was obtained.
In conclusion, novel calix[4]azacrown ethers were synthesized
by the reaction of dibromo or ditosyl derivatives of p-tert-butyl-
calix[4]arene with a chiral diol. The enantioselective recognition of
these receptors has been studied by UV–vis spectroscopy. Chiral
selectors 5 and 7 show strong binding and some chiral recognition
ability for the enantiomers of phenylalanine and alanine methyl
ester hydrochlorides. The results indicate that the multiple hydro-
gen bonding, steric hindrance, structural rigidity or flexibility, and
p–p stacking between the aromatic groups may be responsible for
the enantiomeric recognition.
4.2.1.1. N-Benzyl-5,11,17,23-tetra-tert-butyl-25,27-dihydroxy-26,28-
(40R,80R-diphenyl-60-aza-30,90,-dioxaundecane)-dioxycalix[4]arene (5).
The crude product was purified by flash chromatography on silica
4. Experimental section
4.1. General
gel (EtOAc/hexane 1:15) to afford 5 as a white solid. Yield 42%;
25
white crystal; mp 124–127 ꢂC; [
a]
D
þ24 (c 1, CHCl3). IR (KBr):
Melting points were determined on an Electrothermal 9100
apparatus in a sealed capillary and are uncorrected. 1H and 13C NMR
3364, 3022, 2960, 2865, 1478, 1460, 1360, 1204, 1023, 871,
702 cmꢀ1 1H NMR (400 MHz, CDCl3):
(ppm) 7.32–6.96 (m, 21H,
;
d

3018
H.N. Demirtas et al. / Tetrahedron 65 (2009) 3014–3018
ArH and ArOH), 6.70–6.66 (m, 4H, ArH), 4.45 (d, 2H, J¼12.9 Hz,
ArCH2Ar), 4.36 (d, 2H, J¼13.1 Hz, ArCH2Ar), 4.21 (t, 2H, J¼5.7 Hz,
–OCHPh), 3.98–3.88 (m, 4H, –OCH2CH2), 3.66–3.58 (m, 2H,
PhCH2N), 3.54–3.43 (m, 4H, –OCH2CH2), 3.26 (d, 4H, J¼13.1 Hz,
ArCH2Ar), 3.10 (dd, 2H, J1¼5.9 Hz, J2¼5.7 Hz, –CHCH2N), 2.98 (dd,
2H, J1¼5.6 Hz, J2¼5.6 Hz, –CHCH2N), 1.27 (s, 18H, C(CH3)3), 0.83 (s,
Acknowledgements
This work was supported by the Scientific and Technical Re-
search Council of Turkey (TUBITAK–106T091) and Research Foun-
dation of Selçuk University (BAP–06401067).
18H, C(CH3)3); 13C NMR (100 MHz, CDCl3):
d (ppm) 150.1, 149.1,
References and notes
145.5, 140.8, 139.9, 131.5, 131.4, 127.4, 127.2, 127.0, 126.9, 126.8,
126.7, 124.4, 124.3, 124.0, 75.7, 74.2, 65.9, 60.5, 32.8, 30.8, 30.4,
30.0, 28.7; FABMS m/z: (1071.29) [MþNa]þ. Anal. Calcd for
C71H85NO6 (1048.44): C, 81.34%; H, 8.17%; N, 1.34%. Found: C,
81.94%; H, 8.29%; N, 1.28%.
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4.2.1.2. N-Benzyl-5,11,17,23-tetra-tert-butyl-25,27-dimethoxy-26,28-
(40R,80R-diphenyl-60-aza-30,90,-dioxaundecane)-dioxycalix[4]arene (6).
The crude product was purified by flash chromatography on silica
3. Chromatographic Separations Based on Molecular Recognition; Jinno, K., Ed.;
VCH: Weinheim, 1996.
gel (EtOAc/hexane 1:20) to afford 6 as a white solid. Yield 54%;
25
4. (a) Fitzmaurice, R. J.; Kyne, G. M.; Douheret, D.; Kilburn, J. D. J. Chem. Soc., Perkin
Trans. 1 2002, 841–864; (b) You, J.-S.; Yu, X.-Q.; Zhang, G.-L.; Xiang, Q.-X.; Lan,
J.-B.; Xie, R.-G. Chem. Commun. 2001, 1816–1817; (c) Diederich, F. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 362–386; (d) Meyer, E. A.; Castellano, R. K.; Diederich, F.
Angew. Chem., Int. Ed. 2003, 42, 1210–1250; (e) Hof, F.; Craig, S. L.; Nuckolls, C.;
Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41, 1488–1508; (f) Casnati, A.; Sansone,
F.; Ungaro, R. Acc. Chem. Res. 2003, 36, 246–254; (g) de Namor, A. F. D.; Clev-
erley, R. M.; Zapata-Ormachea, M. L. Chem. Rev. 1998, 98, 2495–2525.
5. (a) Vicens, J.; Bo¨hmer, V. Calixarenes: A Versatile Class of Macrocyclic Compounds;
Kluwer: Boston, MA, 1991; (b) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34,
713–745.
white crystal; mp 115–120 ꢂC; [
a]
D
ꢀ2.5 (c 0.8, CHCl3). IR (KBr):
3024, 2957, 2868, 1482, 1456, 1362, 1202, 1025, 870, 699 cmꢀ1
;
1H
NMR (400 MHz, CDCl3): (ppm) 7.34–7.28 (m, 19H, ArH), 6.90–
d
6.75 (m, 4H, ArH), 4.43 (d, 2H, J¼13.1 Hz, ArCH2Ar), 4.25 (d, 2H,
J¼13.0 Hz, ArCH2Ar), 4.22 (t, 2H, J¼5.7 Hz, –OCHPh), 3.99 (br, 6H,
–OCH3), 3.78 (br, 4H, –OCH2CH2), 3.68–3.62 (m, 2H, PhCH2N),
3.54–3.47 (m, 4H, –OCH2CH2), 3.22 (d, 4H, J¼12.9 Hz, ArCH2Ar),
3.07 (dd, 2H, J1¼5.8 Hz, J2¼5.9 Hz, –CHCH2N), 2.85 (dd, 2H,
J1¼5.5 Hz, J2¼5.6 Hz, –CHCH2N), 1.23 (s, 18H, C(CH3)3), 0.85 (s, 18H,
6. Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713–1734.
C(CH3)3); 13C NMR (100 MHz, CDCl3):
d (ppm) 152.4, 150.9, 147.6,
7. (a) Tuntulani, T.; Thavornyutikarn, P.; Poompradub, S.; Jaiboon, N.; Ruang-
pornvisuti, V.; Chaichit, N.; Asfari, Z.; Vicens, J. Tetrahedron 2002, 58, 10277–
10285; (b) Diamond, D.; McKervey, M. A. Chem. Soc. Rev. 1996, 25, 15–24; (c)
Kim, S. K.; Lee, S. H.; Lee, J. Y.; Lee, J. Y.; Bartsch, R. A.; Kim, J. S. J. Am. Chem. Soc.
2004, 126, 16499–16506.
8. Karakucuk, A.; Durmaz, M.; Sirit, A.; Yilmaz, M.; Demir, A. S. Tetrahedron:
Asymmetry 2006, 17, 1963–1968.
9. (a) Sirit, A.; Karakucuk, A.; Memon, S.; Kocabas, E.; Yilmaz, M. Tetrahedron:
Asymmetry 2004, 15, 3595–3600; (b) Sirit, A.; Kocabas, E.; Memon, S.; Kar-
akucuk, A.; Yilmaz, M. Supramol. Chem. 2005, 17, 251–256.
142.4, 138.7, 132.5, 132.1, 128.6, 128.1, 127.9, 127.6, 127.1, 126.9,
125.3, 124.9, 124.3, 76.2, 75.4, 66.5, 61.2, 33.2, 31.2, 30.7, 30.4, 29.2,
22.9; FABMS m/z: (1099.37) [MþNa]þ. Anal. Calcd for C73H89NO6
(1076.49): C, 81.45%; H, 8.33%; N, 1.30%. Found: C, 81.89%; H,
8.54%; N, 1.24%.
10. (a) Kocabas, E.; Karakucuk, A.; Sirit, A.; Yilmaz, M. Tetrahedron: Asymmetry
2006, 17, 1514–1520; (b) Kocabas, E.; Durmaz, M.; Alpaydin, S.; Sirit, A.; Yilmaz,
M. Chirality 2008, 20, 26–34.
4.3. UV–vis spectral measurement
11. (a) Durmaz, M.; Alpaydin, S.; Sirit, A.; Yilmaz, M. Tetrahedron: Asymmetry 2006,
17, 2322–2327; (b) Durmaz, M.; Alpaydin, S.; Sirit, A.; Yilmaz, M. Tetrahedron:
Asymmetry 2007, 18, 900–905.
12. Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron: Asymmetry 2008, 19,
618–623.
13. (a) Oueslati, I.; Thue´ry, P.; Shkurenko, O.; Suwinska, K.; Harrowfield, J. M.; Abidi,
R.; Vicens, J. Tetrahedron 2007, 63, 62–70; (b) Queslati, I. Tetrahedron 2007, 63,
10840–10851; (c) Banthia, S.; Samanta, A. Org. Biomol. Chem. 2005, 3, 1428–
1434; (d) Kim, J. S.; Shon, O. J.; Ko, J. W.; Cho, M. H.; Yu, I. Y., II; Vicens, J. J. Org.
Chem. 2000, 65, 2386–2392.
14. (a) Prabagaran, N.; Abraham, S.; Sundararajan, G. ARKIVOC 2002, 7, 212–226; (b)
Demirtas, H. N.; Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron:
Asymmetry 2008, 19, 2020–2025.
The recognition abilities of chiral calix[4]arenes with amino acid
derivatives were determined on the basis of the differential UV
spectrometry in chloroform. The UV–vis spectra were measured at
20, 25, and 30 ꢂC with a thermostated cell compartment by Shi-
madzu 160 UV spectrometer. The same concentrations of guest
solution were added to the sample cell and reference cell (light
path¼1 cm). The association constants were determined at 246 nm.
The concentration of the hosts is 2.0ꢁ10ꢀ4 mol dmꢀ3 with the
concentration of added guest increasing between 1.0 and
9.0ꢁ10ꢀ3 mol dmꢀ3
.
15. (a) Gutsche, C. D. Acc. Chem. Res. 1983, 16, 161–170; (b) Gutsche, C. D. In
Calixarenes Revisited; Stoddart, J. F., Ed.; The Royal Society of Chemistry:
Cambridge, 1998.
4.4. Evaluation of the stoichiometric ratio of the host–guest
complex (Job plots)
16. (a) Mutihac, L.; Buschmann, H.-J.; Tudorescu, A.; Mutihac, R. J. Inclusion Phenom.
Macrocyclic Chem. 2003, 47, 123–128; (b) Mutihac, L.; Buschmann, H.-J.; Muti-
hac, R.-C.; Schollmeyer, E. J. Inclusion Phenom. Macrocyclic Chem. 2005, 51, 1–10.
17. (a) Arnecke, R.; Bo¨hmer, V.; Cacciapaglia, R.; Cort, A. D.; Mandolini, L. Tetrahe-
dron 1997, 53, 4901–4908; (b) Meadows, E. S.; De Wall, S. L.; Barbour, L. J.;
Gokel, G. W. J. Am. Chem. Soc. 2001, 123, 3092–3107.
The stoichiometry of the complex between chiral hosts 5–8 and
enantiomers of amino acid methyl esters was determined by
a continuous-variation plot (Job plot).21 Stock solutions of hosts
(7.5 mM) and guests (3 mM) in CHCl3 were prepared. In ten 2.5-mL
flasks, a portion of the host and guest solutions was added in such
a way that their ratio changed from 0 to 1, keeping the total volume
to 2.5 mL and the total concentration to 0.3 mM. The UV–vis spectra
for each sample were measured by spectrometer.
18. (a) Ogasahara, K.; Hirose, K.; Tobe, Y.; Naemura, K. J. Chem. Soc., Perkin Trans. 1
´
1997, 3227–3236; (b) Mohammed-Ziegler, I.; Poor, B.; Kubinyi, M.; Grofcsik, A.;
Gru¨ n, A.; Bitter, I. J. Mol. Struct. 2003, 650, 39–44.
19. Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703–2707.
20. (a) Li, Z.-T.; Ji, G.-Z.; Zhao, C.-X.; Yuan, S.-D.; Ding, H.; Huang, C.; Du, A.-L.; Wei,
M. J. Org. Chem. 1999, 64, 3572–3584; (b) Kerdpaiboon, N.; Tomapatanaget, B.;
Chailapakul, O.; Tuntulani, T. J. Org. Chem. 2005, 70, 4797–4804.
21. Job, P. Ann. Chim. (Paris) 1928, 9, 113–203.