Chiral calix[4]arenes bearing aminonaphthol moieties as membrane carriers for amino acid methyl esters and mandelic acid

Article abstract of DOI:10.1016/j.tetasy.2011.04.019

Chiral calix[4]arene derivatives functionalized at the lower rim with chiral aminonaphthol units have been prepared. The structures of these receptors were characterized by a combination of ¹H NMR, ¹³C NMR, FTIR and elemental analysi

Full text of DOI:10.1016/j.tetasy.2011.04.019

Tetrahedron: Asymmetry 22 (2011) 791–796
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral calix[4]arenes bearing aminonaphthol moieties as membrane carriers
for amino acid methyl esters and mandelic acid
Mustafa Durmaz a, Selahattin Bozkurt a, Hayriye Nevin Naziroglu b, Mustafa Yilmaz a, Abdulkadir Sirit a,
⇑
a Department of Chemistry, Selçuk University, 42099 Meram, Konya, Turkey
b Department of Chemistry, Karamanoglu Mehmetbey University, 70100 Karaman, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 March 2011
Accepted 28 April 2011
Chiral calix[4]arene derivatives functionalized at the lower rim with chiral aminonaphthol units have
been prepared. The structures of these receptors were characterized by a combination of 1H NMR, 13C
NMR, FTIR and elemental analysis. The transport of amino acid derivatives (phenylglycine, phenylalanine
and tryptophan methyl ester hydrochlorides) and mandelic acid were studied through a bulk liquid
membrane in the presence of chiral calix[4]arene derivatives. The transport rate and enantioselectivity
of the amino acid esters studied depended mainly upon the structure of the chiral receptors. The influ-
ence of calixarene and amino acid ester structures upon transport through a liquid membrane is dis-
cussed. The receptors with hydrogen bonding sites and aromatic groups showed considerable higher
transport rates and stereoselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives,5 crown ethers,6 chiral complexes of transition metals,7
carriers with porphyrin or sapphyrin rings,8 macrocyclic pseudo-
Chirality is a fundamental property of biomolecules,1 and is of
central importance in modern drug discovery and development.
Living organisms are composed of chiral biological materials, and
they interact with each stereoisomer of a racemic drug, as well
as metabolize each enantiomer by way of a separate pathway to
produce different pharmacological activities. Therefore, one ste-
reoisomer may produce the desired therapeutic activities, while
the other may be inactive or produce harmful effects. Recognizing
the importance of chiral effects, regulatory agencies, such as the US
Food and Drug Administration, issued a guideline that pharmaceu-
tical companies are required to evaluate the effects of individual
enantiomers and to verify the enantiomeric purity of chiral drugs
that are produced. Therefore, there is a great interest in obtaining
those compounds with the required enantiopurity, which can be
produced from natural sources, by asymmetric synthesis including
catalysis and stereoselective enzyme transformation, or by sepa-
rating racemic or non-racemic mixtures.2 Chiral separation still re-
mains the most popular approach because it is relatively
inexpensive, simple to carry out, easy to scale-up and has a reason-
ably low time cost.3
peptides,9 chiral phosphoric acid esters,10 guanidine derivatives
of sterols,11 or cinchonidine12 have been reported as membrane
carriers. Although calixarene derivatives have been used as mem-
brane carriers for anions,13 cations14 and neutral organic mole-
cules,15 only a few calix[4]arene derivatives have been used for
the enantioselective transport of chiral compounds.16 The intro-
duction of chiral substituents into the calixarene macrocyclic ring
either by attaching chiral units at one of the calix rims, or by syn-
thesizing ‘inherently’ chiral derivatives could, in turn, lead to chi-
rality of the artificial receptors.17,18 Thus, chiral calix[4]arene
derivatives obtained in this way might be good candidates as
membrane carriers for the separation of chiral compounds.
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 design and preparation of pharmaceuti-
cals, as they are part of the synthesis process in the production
of drug intermediates and protein-based drugs. Therefore, a study
on the enantiomeric recognition of amino acids is of particular sig-
nificance for understanding the transport process of these com-
pounds through the cell membrane, the design of asymmetric
catalysis systems, new pharmaceutical agents,19 and separation
materials.20
Amongst the various accessible techniques, membrane-based
separation that includes the solvent extraction and stripping pro-
cesses in a single step, has a great potential for the separation of
racemic mixtures. In the literature, cyclodextrins,4 tartaric acid
In a continuation of our work on the synthesis of chiral recep-
tors equipped with various functionalities including azacrown
ethers,21 Schiff bases,22 and quaternary ammonium salts23 as well
as their catalytic activities and enantiomeric recognition properties
toward chiral amines,24 carboxylic acids,25 and amino acid
⇑
Corresponding author. Tel.: +90 332 3238220/5822; fax: +90 332 3238225.
E-mail address: asirit@selcuk.edu.tr (A. Sirit).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.019

792
M. Durmaz et al. / Tetrahedron: Asymmetry 22 (2011) 791–796
derivatives,26 we herein report the synthesis of novel chiral recep-
tors as organic carriers for the transport of mandelic acid and ami-
no acid esters through a bulk liquid membrane.
while reaction steps leading to 2 and 3 are described for the first
time.
Following the strategy outlined in Scheme 1, compounds 2–7
were prepared by coupling of the aminonaphthols with the ca-
lix[4]arene dibromide 1 in DMF with anhydrous K2CO3 at room
temperature and led to the formation of the chiral calix[4]arene
derivatives in moderate to good yields. The products were charac-
terized by a combination of 1H NMR, 13C NMR, FTIR and elemental
analysis.
2. Results and discussion
2.1. Design and synthesis of the new hosts
The main goal of this work was the development of novel ca-
lix[4]arene derivatives bearing aminonaphthol moieties as chiral
carriers capable of selectively separating mandelic acid and amino
acid methyl esters through a bulk liquid membrane. For the desired
goal, dibromo calix[4]arene 1 was chosen as the starting material,
and the synthetic route is shown in Scheme 1. Compounds 4–7
were prepared according to the previously published procedures,27
2.2. Liquid membrane transport of amino acid methyl esters
and mandelic acid
With the enantiomerically pure calix[4]arene derivatives bear-
ing aminonaphthol moieties in hand, we next studied the transport
Br
O
N
N
O
N
O
+
O
O
O
O
OHOH
OHOH
3
4
N
i
OH
Ph
Ph
NH
O
HN
O
Br
O
Br
Ph
Ph
NH
OH
NH
OH
HN
O
HN
NH
O
HO
OH
OH
O
i
i
O
O
O
OH
OH
OH
OH
O
1
2
5
N
NH
OH
OH
i
i
O
HN
O
N
NH
O
N
O
O
O
O
O
OH OH
OH OH
7
6
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, rt.

M. Durmaz et al. / Tetrahedron: Asymmetry 22 (2011) 791–796
793
ability of these receptors as enantioselective carriers for mandelic
acid and aromatic amino acid methyl esters (Fig. 1) across liquid
membranes.
The transport experiments were carried out using a U-shaped
glass tube. The transport apparatus and detailed experimental
conditions are shown in Figure 2. As the fluxes obtained from
the U-tube systems are hard to reproduce due to the many factors
influencing transport rates, experiments were performed in all
cases at least three times under strictly similar conditions. Errors
could be estimated as <10%.
In order to determine the concentration of the transported
guests, the corresponding samples were periodically withdrawn
from the aqueous receiving phases in each experiment and the
changes in concentrations of the analytes were measured
spectrophotometrically.
Figure 2. Transport apparatus and detailed experimental conditions. (a) Source
phase (5 mL): amino acid methyl esters hydrochloride (pH 5.5) or mandelic acid
(pH 2.0) (2 ꢁ 10ꢂ4 or 7 ꢁ 10ꢂ3 M). (b) Organic membrane phase (10 mL): CHCl3;
carrier: chiral calix[4]arene derivatives 2–7 (2 ꢁ 10ꢂ4 M). (c) Receiving phase
(5 mL): pure water (pH 1.5 for amino acid methyl ester hydrochlorides and pH 8.0
for mandelic acid).
The flux (J) of each enantiomer was calculated by:28
V
rDCr
J ¼
ð1Þ
At
where t is the time over which the concentration difference,
D
Cr, is
measured in the receiving phase, Vr the receiving volume and A is
the effective membrane area. This is the flux from the start of the
experiment until time t.
The enantioselectivity was calculated in terms of the flux ratio
(a), and corresponds to the flux of the one enantiomer with respect
to the other enantiomer
JD
JL
a
¼
ð2Þ
For the initial studies, phenylalanine methyl ester hydrochlo-
ride (PhAlaOMeꢀHCl) was assayed for its enantiomeric transport
with chiral receptors 2–7 in order to evaluate the conditions for
the enantiomeric separation by the liquid membrane system and
the transport experiments were carried out under the following
conditions.29 The source phase contains 5 mL of amino acid ester
aqueous solution at pH 5.5 in one arm, while the aqueous receiving
phase, 5 mL (pH 1.5) is present in the other arm. The membrane
phase, 10 mL of chiral calix[4]arenes of 2.0 ꢁ 10ꢂ4 M in chloroform
was introduced in the tube. The aqueous and organic phases were
stirred at 300 rpm at room temperature for 24 h.
Figure 3. Bar plots of fluxes of PhAlaOMeꢀHCl for hosts 2–7.
Chiral macrocyclic carriers 2 and 7 showed a much higher
transport rate for the enantiomers of PhAlaOMeꢀHCl when com-
pared with other receptors 3–6, whereas calix[4]arene derivative
2 exhibited the best enantioselectivity for PhAlaOMeꢀHCl, affording
KD/KL of 2.05 (Fig. 3). Furthermore, it is clear that compared with
compound 3, chiral carrier 4, which contains an extra aminonaph-
thol unit, showed a better transport rate and enantioselectivity.
In the case of phenylglycine methyl ester (PhGlyOMeꢀHCl), when
compared with PhAlaOMeꢀHCl, it lacks a methylene spacer between
the amine group and the aromatic ring, its transport rate is the
highest amongst the amino acid methyl esters studied which can
Figure 4. Bar plots of fluxes of PhGlyOMeꢀHCl for hosts 2–7.
also observed for hosts 4 and 5, but the highest and reverse selectiv-
ity was found with the host 2 (Fig. 4).
be interpreted as a favourable
p
–
p
interaction between the phenyl
As can be seen from Table 1 and Figure 5, the transport rates
for tryptophan methyl ester (TrpOMeꢀHCl) enantiomers were sig-
nificantly lower than in case of other amino acid esters. The same
group in PhGlyOMeꢀHCl and the aromatic moieties in the carriers as
well as hydrogen bonding. A relatively higher L/D selectivity was
O
OH
O
O
OH
OCH3
OCH3
OCH3
HN
NH2
·HCl
O
NH2
·HCl
NH2
·HCl
·HCl
DL-Mandelic acid
DL-Tryptophan methyl ester
hydrochloride
DL-Phenylalanine methyl ester
hydrochloride
DL-Phenylglycine methyl ester
hydrochloride
Figure 1. Chemical structures of the guests investigated.

794
M. Durmaz et al. / Tetrahedron: Asymmetry 22 (2011) 791–796
Table 1
Transport data through liquid membranea,b,c
D
-Trp-
L-Trp-
D
-PhAla
L
-PhAla
D
-PhGly
L
-PhGly
D
-Mandelic
L-Mandelic
OMeꢀHCl
OMeꢀHCl
OMeꢀHCl OMeꢀHCl
J24 ꢁ 10ꢂ9
OMeꢀHCl OMeꢀHCl
J24 ꢁ 10ꢂ9
acid
acid
Host
J24 ꢁ 10ꢂ9
aT
aT
aT
J24 ꢁ 10ꢂ9 (mol mꢂ2 sꢂ1
)
aT
(mol mꢂ2 sꢂ1
)
(mol mꢂ2 sꢂ1
)
(mol mꢂ2 sꢂ1
)
2
3
4
5
6
7
17.04
5.53
6.06
6.17
5.57
6.26
5.54
5.68
9.04
9.96
6.42
11.51
3.08 (D) 350.13
1.03 (L) 118.69
1.49 (L) 154.94
1.62 (L) 150.94
1.15 (L) 127.08
1.84 (L) 285.50
170.68
125.14
181.90
196.61
145.01
342.14
2.05 (D) 370.52
1.05 (L) 134.56
1.17 (L) 200.48
1.30 (L) 222.41
1.14 (L) 228.99
1.08 (L) 216.22
199.06
148.36
313.75
312.59
260.60
256.21
1.86 (D) 16.30
6.95
2.35 (D)
1.09 (L)
1.48 (L)
1.76 (L)
1.22 (L)
2.11 (L)
1.10 (L)
1.56 (L)
1.41 (L)
1.14 (L)
1.18 (L)
5.85
6.36
11.67
13.06
8.37
7.90
7.42
6.84
5.75
12.12
a
Estimated errors are <10%.
J24 = Flux of transported amino acid methyl esters or mandelic acid after 24 h (mol mꢂ2 sꢂ1);
b
a
T = ratio of fluxes: higher/lower flux; TrpOMeꢀHCl = Tryptophan methyl
ester hydrochloride; PhAlaOMeꢀHCl = Phenylalanine methyl ester hydrochloride; PhGlyOMeꢀHCl = Phenylglycine methyl ester hydrochloride.
c
D or L indicates the preferential form of the enantiomers.
sequence of carriers transport efficiency towards PhAlaOMeꢀHCl,
2 > 7 > 5 > 4 > 6 > 3, was found in the case of TrpOMeꢀHCl.
Amongst the amino acid esters investigated, the highest enanti-
oselectivities were observed for TrpOMeꢀHCl with chiral calix[4]-
arene derivatives.
by the fact that the chiral pendant groups of the calix[4]arene
readily fixed the mandelic acid of the same chirality to form
hydrogen-bonded aggregates as previously reported.30
All macrocyclic carriers showed a much higher transport rate
for the enantiomers of PhGlyOMeꢀHCl and PhAlaOMeꢀHCl than
the enantiomers of TrpOMeꢀHCl and mandelic acid, indicating
that there may be a stronger interaction between carrier and
PhGlyOMeꢀHCl and PhAlaOMeꢀHCl induced by hydrogen bonds,
The facilitated transport of mandelic acid through a liquid
membrane was also studied in the presence of chiral calix[4]ar-
ene derivatives. Liquid membrane experiments were carried out
using a source phase containing 5 mL of aqueous mandelic acid
solution at pH 2 and the aqueous receiving phase (5 mL) at pH
8. The membrane phase, 10 mL of chiral calix[4]arenes of
2.0 ꢁ 10ꢂ4 M in chloroform was introduced in the tube. The aque-
ous and organic phases were stirred at 300 rpm at room temper-
ature for 24 h. The experimental data of the transport shown in
Table 1 and Figure 6 indicated that chiral hosts 2 and 7 gave a
stronger binding and a better recognition ability for mandelic
acid, whereas receptor 2 exhibits the best enantioselectivity,
affording a KD/KL value of 2.35. These results can be explained
charge transfer as well as
p–p interaction. Taking into account
the transport experiments, the L-enantiomer form had a higher
flux than that of the D-form in all cases investigated, except in
the case of host 2, which enantioselectively transported the
D-
amino acid esters over the -antipodes. In most cases, the enanti-
L
oselectivity increased linearly during the first 90 min, after which
time a decrease in enantioselectivity was observed. This is prob-
ably due to the loss of the protonated chiral carrier from the
membrane phase to the aqueous solution leading to reduced
enantioselectivities and lower fluxes due to facilitated trans-
port.28a The results indicated that the structure of the calixarene
is one of the most important parameters for the recognition of
amino acid esters. Comparing the chiral carriers, it was found that
compound 2 showed the best transport ability and enantioselec-
tivity for each amino acid ester, affording KD/KL values of 1.86–
3.08. The formation of hydrogen bonds between the amino group
and the binding sites of the macrocycle, as well as the
p–p inter-
action takes important role in the transport ability and enantiose-
lectivity. Meanwhile, chiral carrier 3, which bears only one
aminonaphthol unit in its platform forms much weaker com-
plexes with all amino acid esters and mandelic acid and can
hardly discriminate between the L- or D-isomers. This could be
related to the weak interactions of those substituents with the
amino acid ester molecule. Moreover, the carrier is quite flexible
and might readily change conformations.
Figure 5. Bar plots of fluxes of TrpOMeꢀHCl for hosts 2–7.
3. Conclusion
In conclusion, novel chiral calix[4]arene derivatives bearing
aminonaphthol moieties have been developed as enantioselective
carriers for the transport of aromatic amino acid esters and man-
delic acid. The receptors exhibited different transport abilities and
enantioselectivities towards the enantiomers of guests. Chiral
macrocyclic carriers 2 and 7 showed much higher transport rate
and the best enantioselectivity for amino acid esters and man-
delic acid and could be used for the separation of the guests stud-
ied. The results indicate that multiple hydrogen bonding, steric
hindrance, structural rigidity or flexibility and
p–p stacking be-
tween the aromatic groups may be responsible for the enantio-
meric recognition.
Figure 6. Bar plots of fluxes of mandelic acid for hosts 2–7.

M. Durmaz et al. / Tetrahedron: Asymmetry 22 (2011) 791–796
795
1.30 (s, 18H, C(CH3)3), 1.77 (br, 4H, CH2), 2.37–2.43 (m, 2H,
NCH2), 2.63–2.68 (m, 4H, NCH2 + CH2), 3.34–3.39 (m, 4H, ArCH2Ar),
3.76 (t, 2H, J = 6.5 Hz, OCH2), 4.01–4.15 (m, 4H, CH2), 4.31–4.37 (m,
6H, ArCH2Ar + OCH2), 4.67–4.77 (m, 2H, CH2Br), 5.66 (s, 1H, NCH),
6.88–6.91 (m, 4H, ArH), 7.07–7.11 (m, 6H, ArH), 7.21–7.23 (m, 2H,
ArH), 7.28–7.32 (m, 1H, ArH), 7.42–7.45 (m, 1H, ArH), 7.66–7.75
(m, 6H, ArH + ArOH), 9.37 (d, 1H, J = 8.8 Hz, ArH); 13C NMR
(100 MHz, CDCl3): d (ppm): 23.9, 30.4, 30.5, 30.9, 31.3, 31.9, 32.1,
32.2, 33.5, 33.7, 34.0, 34.2, 54.0, 66.3, 66.5, 72.5, 73.2, 73.5,
114.7, 123.5, 125.1, 125.4, 125.5, 125.9, 126.0, 126.2, 126.7,
127.4, 127.8, 127.9, 128.1, 128.2, 128.3, 129.1, 129.5, 129.7,
132.9, 133.0, 133.2, 141.8, 141.9, 144.3, 147.4, 147.5, 149.4,
149.5, 149.7, 150.8, 150.9, 153.8. Anal. Calcd for C71H86BrNO5
(1113.35): C, 76.59; H, 7.79; N, 1.26. Found: C, 76.82; H, 7.44; N,
1.16.
4. Experimental section
4.1. General
Melting points were determined on an Electrothermal 9100
apparatus in a sealed capillary. 1H and 13C NMR spectra were re-
corded at room temperature on a Varian 400 MHz spectrometer
in CDCl3. IR spectra were obtained on a Perkin Elmer Spectrum
100 FTIR spectrometer using KBr pellets. UV/vis spectra were mea-
sured with a Perkin Elmer Lambda 25 spectrometer. Optical rota-
tions were measured on an Atago AP-100 digital polarimeter. The
HPLC measurements were carried out on Agilent 1100 equipment
connected with a Zorbax RX-C18 column. Elemental analyses were
performed using a Leco CHNS-932 analyzer. An Orion 2 Star pH
Benchtop pH meter was used for the pH measurements.
Analytical TLC was performed using Merck prepared plates (Sil-
ica Gel 60 F254 on aluminium). Flash chromatography separations
were performed on a Merck Silica Gel 60 (230–400 Mesh). All reac-
tions, unless otherwise noted, were conducted under a nitrogen
atmosphere. All starting materials and reagents used were of stan-
dard 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. All aqueous solutions were pre-
pared with deionized water that had been passed through a Milli-
pore milli-Q Plus water purification system.
4.3. Analytical procedure
4.3.1. Transport experiments
Transport experiments were run at 25 °C in the custom-made,
U-type glass tube for 24 h (Fig. 1). The bulk liquid membrane con-
sisted of 10 mL of chloroform containing the chiral calixarene
derivatives 2–7 at a concentration of 2 ꢁ 10ꢂ4 M. The membrane
phase was stirred magnetically at 300 rpm. The source phase con-
tains 5 mL of aqueous solution of amino acid methyl ester (the con-
centrations ranged between 2.0 ꢁ 10ꢂ4–7.0 ꢁ 10ꢂ3 M, depending
on the amino acid methyl ester) at pH 5.5 present in one arm (left
in Fig. 2) whereas the aqueous receiving phase, 10 mL (pH 1.5) is
present in the other arm (right in Fig. 2). For mandelic acid the con-
centration was 2.0 ꢁ 10ꢂ4 and the pH of the source and receiving
phases was 2.0 and 8.0, respectively. Blank tests indicated that
the transport of guests was negligible. The concentration of the
guests in the receiving phase and the source phase was assessed
by using a UV spectrophotometer.
4.2. Syntheses
4.2.1. General procedure for the synthesis of compound 2 and 3
Compounds 2 and 3 were synthesized using a modified proce-
dure originally reported by Zhang et al.31 To a suspension of appro-
priate aminonaphthol (1 mmol) and K2CO3 1.38 g (10 mmol) in dry
DMF (15 mL) was added dropwise a solution of p-t-butylca-
lix[4]arene 1,3-dibromide derivative 1 (0.5 or 1.0 mmol) in dry
DMF (15 mL). The mixture was stirred at room temperature for
48 h. Then it was poured into water (50 mL) and extracted with
toluene (10 mL ꢁ 3), washed with water (10 mL) and brine
(10 mL). The organic phase was dried over MgSO4, filtered, evapo-
rated and purified by flash chromatography.
Acknowledgements
This work was supported by the Scientific and Technical Re-
search Council of Turkey (TUBITAK–109T167) and Research Foun-
dation of Selçuk University (BAP–10101005). The provision of PhD
studentship to M.D. by TUBITAK-BIDEB is gratefully acknowledged.
4.2.1.1. 25,27-Bis[1,10-(S,1S,10S)-1,3-phenylenebis(((S)-1-phenyl-
References
ethylamino)methylene)-dinaphthalen-2-yloxy)propoxy]-26,28-
1. (a) Beckett, A. H. Biochem. Soc. Trans. 1991, 19, 443–446; (b) Hof, F.; Craig, S. L.;
Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41, 1488–1508; (c)
Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008, 108, 1–73.
2. (a)Enzyme Catalysis in Organic Synthesis: A Comprehensive Handbook; Drauz, K.,
Waldmann, H., Eds.; VCH: Weinheim, 1995; Vols. I & II, (b) Maximini, A.;
Chmiel, H.; Holdik, H.; Maier, N. W. J. Membr. Sci. 2006, 276, 221–231.
3. Xie, R.; Chu, L.-Y.; Deng, J.-G. Chem. Soc. Rev. 2008, 37, 1243–1263.
4. (a) Armstrong, D. W.; Ward, T. J.; Armstrong, R. D.; Beesley, T. E. Science 1986,
232, 1132–1135; (b) Ferreira, Q.; Coelhoso, I. M.; Ramalhete, N.; Marques, H. M.
C. Sep. Sci. Technol. 2006, 41, 3553–3568; (c) Wang, H.-D.; Chu, L.-Y.; Song, H.;
Yang, J.-P.; Xie, R.; Yang, M. J. Membr. Sci. 2007, 297, 262–270.
5. Abe, Y.; Shoji, T.; Kobayashi, M.; Qing, W.; Asai, N.; Nishizawa, H. Chem. Pharm.
Bull. 1995, 43, 262–265.
6. (a) Newcomb, M.; Toner, J. L.; Helgeson, R. C.; Cram, D. J. J. Am. Chem. Soc. 1979,
101, 4941–4947; (b) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem.
1981, 46, 393–406; (c) Pietraszkiewicz, M.; Kozbial, M.; Pietraszkiewicz, O. J.
Membr. Sci. 1998, 138, 109–113; (d) Aydin, I.; Aral, T.; Karakaplan, M.;
Hosgoren, H. Tetrahedron: Asymmetry 2009, 20, 179–183.
7. (a) Tsukube, H.; Shinoida, S.; Uenishi, J.; Kanatani, T.; Itoh, H.; Shiode, M.;
Iwachido, T.; Yonemitsu, O. Inorg. Chem. 1998, 37, 1585–1591; (b) Verkuijl, B. J.
V.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2009, 74, 6526–
6533.
dihydroxy-5,11,17,23-tetra(tert-butyl)calix[4]arene 2.
Yield
84%; mp 195–198 °C; ½a D25
ꢃ
¼ þ42:0 (c 1, CHCl3); IR (cmꢂ1): 3342,
2954, 1623, 1597, 1485, 1237, 743, 701. 1H NMR (CDCl3): d
(ppm) 1.17 (s, 18H, C(CH3)3), 1.21 (d, 6H, J = 6.5 Hz, CHCH3), 1.34
(s, 18H, C(CH3)3), 1.90–2.16 (br, 4H, OCH2CH2CH2O), 3.45 (d, 4H,
J = 12.9 Hz, ArCH2Ar), 3.52–3.60 (m, 2H, OCH2), 3.92–4.14 (m, 6H,
ArCH2Ar + OCH2), 4.18–4.52 (m, 4H, OCH2), 4.65–4.80 (m, 2H,
CHCH3), 5.66 (s, 2H, NHCH), 7.02–7.34 (m, 26H, ArH), 7.62–7.94
(m, 8H, ArH), 8.30–8.50 (br, 2H, ArOH); 13C NMR (CDCl3) d
(ppm): 25.6, 30.4, 31.4, 31.5, 31.9, 32.0, 34.2, 34.4, 55.8, 73.6,
116.3, 116.4, 116.5, 123.5, 125.5, 125.6, 125.7, 126.1, 126.2,
127.3, 128.3, 128.5, 128.7, 133.0, 133.2, 133.4, 133.5, 133.6,
133.8, 142.0, 144.5, 144.6, 146.5, 147.7, 149.4, 149.7, 151.0,
155.1. Anal. Calcd for C94H104N2O6 (1356.79): C, 83.15; H, 7.72;
N, 2.06. Found: C, 83.46; H, 7.51; N, 2.01.
4.2.1.2. 25-[(1-((R)-(-Pyrrolidinylbenzyl))naphthalen-2-yloxy)-
8. Sessler, J. L.; Andrievsky, A. Chem. Eur. J. 1998, 4, 159–167.
9. Miyake, H.; Yamashita, T.; Kojima, Y.; Tsukube, H. Tetrahedron Lett. 1995, 36,
7669–7672.
propoxy]-27-(3-bromo-propoxy)-26,28-dihydroxy-5,11,17,23-
tetra(tert-butyl)-calix[4]arene 3.
Yield 15%; mp 155–158 °C;
´
10. (a) Dzygiel, P.; Wieczorek, P.; Jonsson, J.; Milewska, M.; Kafarski, P. Tetrahedron
½
a 2D5
ꢃ
¼ ꢂ22:0 (c 2, CHCl3); IR (cmꢂ1): 3353, 2957, 2869, 1623, 1484,
1999, 55, 9923–9932; (b) Dz´ygiel, P.; Wieczorek, P.; Kafarski, P. J. Sep. Sci. 2003,
26, 1050–1056.
1238, 752, 699; 1H NMR (CDCl3): d (ppm) 1.09 (d, 18H, C(CH3)3),

796
M. Durmaz et al. / Tetrahedron: Asymmetry 22 (2011) 791–796
11. (a) Baragana, B.; Blackburn, A. G.; Breccia, P.; Davis, A. P.; de Mendoza, J.;
Padron-Carrillo, J. M.; Prados, P.; Riedner, J.; de Vries, J. G. Chem. Eur. J. 2002, 8,
2931–2936; (b) Urban, C.; Schmuck, C. Chem. Eur. J. 2010, 16, 9502–9510; (c)
Breccia, P.; Van Gool, M.; Perez-Fernandez, R.; Martin-Santamaria, S.; Gago, F.;
Prados, P.; de Mendoza, J. J. Am. Chem. Soc. 2003, 125, 8270–8284.
12. (a) Stella, D.; Calzado, J. A.; Girelli, A. M.; Canepari, S.; Bucci, R.; Palet, C.;
Valiente, M. J. Sep. Sci. 2002, 25, 229–238; (b) Canepari, S.; Girelli, A. M.; Mattei,
E.; Tosti, D. J. Braz. Chem. Soc. 2009, 20, 429–436.
19. The Design of Drugs to Macromolecular Targets; Beddell, C. R., Ed.; Wiley:
Chichester, UK, 1992.
20. Chromatographic Separations Based on Molecular Recognition; Jinno, K., Ed.; VCH:
Weinheim, 1996.
21. Demirtas, H. N.; Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron:
Asymmetry 2008, 19, 2020–2025.
22. Durmaz, M.; Alpaydin, S.; Sirit, A.; Yilmaz, M. Tetrahedron: Asymmetry 2006, 17,
2322–2327.
13. Alpaydin, S.; Saf, A. O.; Bozkurt, S.; Sirit, A. Desalination, in press. doi: 10.1016/
j.desal.2011.02.048.
23. Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron: Asymmetry 2008, 19,
618–623.
14. (a) Ludwig, R. Fresenius J. Anal. Chem. 2000, 367, 103–128; (b) Iqbal, K. S. J.;
Cragg, P. J. Dalton Trans. 2007, 26–32.
24. Kocabas, E.; Durmaz, M.; Alpaydin, S.; Yilmaz, M.; Sirit, A. Chirality 2008, 20,
26–34.
15. (a) Oshima, T.; Suetsugu, A.; Baba, Y.; Shikaze, Y.; Ohto, K.; Inoue, K. J. Membr. Sci.
2008, 307, 284–291; (b) Mutihac, L. Anal. Lett. 2010, 43, 1355–1366; (c) Mutihac,
L.; Mutihac, R. J. Inclusion Phenom. Macrocycl. Chem. 2007, 59, 177–181.
16. (a) Okada, Y.; Kasai, Y.; Nishimura, J. Tetrahedron Lett. 1995, 36, 555–558; (b)
Oshima, T.; Inoue, K.; Furusaki, S.; Goto, M. J. Membr. Sci. 2003, 217, 87–97.
17. (a) Ikeda, A.; Nagasaki, T.; Shinkai, S. J. Phys. Org. Chem. 1992, 5, 699–710; (b)
Iwamoto, K.; Shimizu, H.; Araki, K.; Shinkai, S. J. Am. Chem. Soc. 1993, 115,
3997–4006; (c) Nagasaki, T.; Fujishima, H.; Shinkai, S. Chem. Lett. 1994, 989–
992; (d) Dondoni, A.; Marra, A.; Sherrmann, M.-C.; Casnati, A.; Sansone, F.;
Ungaro, R. Chem. Eur. J. 1997, 3, 1774–1782; (e) Sansone, F.; Barboso, S.;
Casnati, A.; Fabbi, M.; Pochini, A.; Ugozzoli, F.; Ungaro, E. Eur. J. Org. Chem.
1998, 1998, 897–905; (f) Sansone, F.; Barboso, S.; Casnati, A.; Sciotto, D.;
Ungaro, E. Tetrahedron Lett. 1999, 40, 4741–4744.
25. (a) Naziroglu, H. N.; Durmaz, M.; Bozkurt, S.; Sirit, A. Chirality 2011, 22, 541–
549; (b) Bozkurt, S.; Durmaz, M.; Naziroglu, H. N.; Yilmaz, M.; Sirit, A.
Tetrahedron: Asymmetry 2011, 22, 541–549.
26. Demirtas, H. N.; Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron 2009,
65, 3014–3018.
27. Durmaz, M.; Yilmaz, A.; Sirit, A. Org. Biomol. Chem. 2011, 9, 571–580.
28. (a) Jiao, F.; Chen, X.; Hu, W.; Yang, L.; Huang, K. J. Braz. Chem. Soc. 2007, 18,
804–809; (b) Krieg, H. M.; Lotter, J.; Keizer, K.; Breytenbach, J. C. J. Membr. Sci.
2000, 167, 33–45; (c) Raizada, P.; Vyas, V.; Sharma, U. Indian J. Chem. Tech.
2011, 18, 21–28.
29. Kim, L.; Hamdi, A.; Stancu, A. D.; Souane, R.; Mutihac, L.; Vicens, J. J. Inclusion
Phenom. Macrocycl. Chem. 2010, 66, 55–59.
30. Zinic, M.; Frkanec, L.; Skaric, V.; Trafton, J.; Gokel, G. W. J. Chem. Soc., Chem.
Commun. 1990, 1726–1728.
31. (a) Ma, F.; Ai, L.; Shen, X.; Zhang, C. Org. Lett. 2007, 9, 125–127; (b) Ma, F.; Shen,
X.; Ming, X.; Wang, J.; Ou-Yang, J.; Zhang, C. Tetrahedron: Asymmetry 2008, 19,
1576–1586.
18. (a) Castellano, R. K.; Nuckolls, C.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 11156–
11163; (b) Lazzarotto, M.; Nachtigall, F. F.; Vencato, I.; Nome, F. J. Chem. Soc.,
Perkin Trans. 2 1998, 995–998; (c) Ito, K.; Noike, M.; Kida, A.; Ohba, Y. J. Org. Chem.
2002, 67, 7519–7522; (d) Sirit, A.; Yilmaz, M. Turk. J. Chem. 2009, 33, 159–200.