Chiral calix[4]arenes bearing amino alcohol functionality as membrane carriers for transport of chiral amino acid methylesters and mandelic acid

Article abstract of DOI:10.1002/chir.21034

Novel chiral calix[4]arene derivatives bearing amino alcohol moieties at the lower rim have been synthesized from the reaction of p-tert-butylcalix[4] arene diester with various amino alcohols. The transport of amino acid esters (phenylglycine, phenylalanine, and tryptophan methyl esters hydrochloride) and mandelic acid were studied through chloroform bulk liquid membrane system using chiral calix[4]arenes 15-20. All these receptors have been found to act as carriers for transport of aromatic amino acid methylesters and mandelic acid from the aqueous source phase to the aqueous receiving phase. The influence of calixarene and guest structures upon transport through liquid membrane is discussed.

Full text of DOI:10.1002/chir.21034

CHIRALITY 24:129–136 (2012)
Chiral Calix[4]arenes Bearing Amino Alcohol Functionality as
Membrane Carriers for Transport of Chiral Amino Acid Methylesters
and Mandelic Acid
*
SELAHATTIN BOZKURT, MUSTAFA YILMAZ, AND ABDULKADIR SIRIT
Department of Chemistry, Selc¸uk University, 42099 Konya, Turkey
ABSTRACT
Novel chiral calix[4]arene derivatives bearing amino alcohol moieties at the
lower rim have been synthesized from the reaction of p-tert-butylcalix[4]arene diester with vari-
ous amino alcohols. The transport of amino acid esters (phenylglycine, phenylalanine, and tryp-
tophan methyl esters hydrochloride) and mandelic acid were studied through chloroform bulk
liquid membrane system using chiral calix[4]arenes 15–20. All these receptors have been
found to act as carriers for transport of aromatic amino acid methylesters and mandelic acid
from the aqueous source phase to the aqueous receiving phase. The influence of calixarene and
guest structures upon transport through liquid membrane is discussed. Chirality 24:129–136,
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2012.
2011 Wiley Periodicals, Inc.
KEY WORDS: chiral calix[4]arene; bulk liquid membrane; amino acid methyl esters; mandelic
acid; transport rate
INTRODUCTION
In the literature, various types of chiral receptors bearing
cyclodextrins (CDs),18–20 tartaric acid derivatives,21 crown
ethers,22–24 chiral complexes of transition metals,25 carriers
with porphyrin or sapphyrin rings,26 macrocyclic pseudopep-
tides,27 chiral phosphoric acids esters,28,29 guanidine deriva-
tives of sterols,30,31 or cinchonidine,32 have been reported on
the chiral separation of amino acids. Although many calixar-
ene derivatives have been synthesized as membrane carriers
for anions,33 cations,34,35 and neutral molecules,36–38 only a
few investigations39 have been reported for chiral guests.
Our recent studies in this field were mainly dedicated to
synthesis of novel chiral receptors containing various func-
tionalities including azacrown ethers,40 aminonaphthol deriv-
atives,41,42 and amines43 as well as their extraction abilities
and enantiomeric recognition properties toward chiral car-
boxylic acids and amino acid derivatives, we herein report
the synthesis of novel calix[4]arene derivatives bearing chi-
ral amino alcohol moieties at the lower rim and their poten-
tial applications as carriers in transport of amino acids
through bulk liquid membrane.
The production and availability of enantiomerically pure
compounds is of great importance for the pharmaceutical
industry.1,2 As most drug effects are due to interactions with
chiral biological materials, each stereoisomer of a chiral drug
usually exhibit different pharmacological activities due to the
stereoselectivity of enzymatic reactions and other biological
processes.3 Therefore, only one enantiomer contribute to its
pharmacodynamic behavior, while the other shows no or a
much weaker effect or harmful effects.4 Regulatory agencies
such as the U.S. Food and Drug Administration, issued a
mandate requiring pharmaceutical companies to evaluate the
effects of individual enantiomers and to verify the enantio-
meric purity of chiral drugs that are produced.5,6 Further-
more, even if a drug is to be marketed as a single enan-
tiomer, the pharmaceutical properties and toxicity must be
established for both enantiomers.7,8 Such regulations have
greatly encouraged and stimulated the production and sale
of single-enantiomer drugs.
A variety of methods are available to obtain enantiopure
compounds, for example, from natural sources, fermentation,
or asymmetric synthesis, or by resolution of racemates.9–11
Despite the advances in asymmetric synthesis of pure
enantiomers, the separation of racemates is still the most im-
portant industrial approach for the preparation of enantio-
merically pure compounds. Extractive separation of liquid
membrane is widely used in chiral separation process12–16
due to their cost effectiveness, low energy demand, set-up
simplicity, and the possibility to be used in continuous mode.
Amino acids are important naturally occurring compounds
assembling into polypeptides with a wide range of vital
biological functions and useful building blocks in the produc-
tion of drug intermediates and protein-based drugs. The
complexation and transport of racemic mixtures with chiral
receptors has been pointed out as a smooth method for
enantiomeric resolution, because it requires low concentra-
tions of the receptor, which can be recovered at the end of
the process.17
MATERIALS AND METHODS
General
Melting points were determined on an Electrothermal 9100 apparatus
in a sealed capillary. 1H and 13C NMR spectra were recorded at room
temperature on a Varian 400 MHz spectrometer in CDCl3. Infrared (IR)
spectra were obtained on a Perkin Elmer Fourier transform infrared
(FTIR) spectrum-100 FTIR spectrometer using KBr pellets. Ultraviolet-
visible (UV-Vis) spectra were measured with a Perkin Elmer Lambda 25
spectrometer. Optical rotations were measured on an Atago AP-100
Contract grant sponsor: Scientific and Technical Research Council of Turkey;
Contract grant number: TUBITAK-109T167.
Contract grant sponsor: Research Foundation of Selc¸uk University;
Contract grant number: BAP-10101019.
*Correspondence to: Abdulkadir Sirit, Department of Chemistry, Selc¸uk
University, 42099 Meram/Konya, Turkey. E-mail: asirit@selcuk.edu.tr
Received for publication 30 June 2011; Accepted 8 September 2011
DOI: 10.1002/chir.21034
Published online 19 December 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley Periodicals, Inc.

130
BOZKURT ET AL.
digital polarimeter. Elemental analyses were performed using a Leco
CHNS-932 analyzer.
3.5 Hz, 1H, NH2CH2CH (AB spin system)), 2.20 (bs, 4H, NH2 and OH),
1.35 (d, J 5 6.6 Hz, 3H, NHCHCH3); 13C NMR (100 MHz, CDCl3) dC
(ppm) 145.2, 128.8, 127.3, 126.8, 70.0, 58.2, 51.0, 45.4, 24.5; Anal. Calcd
for C11H18N2O (194.14): C, 68.01%; H, 9.34%; N, 14.42%; Found C, 68.07%;
H, 9.35%; N, 14.45%.
Analytical thin layer chromatography (TLC) was performed using
Merck prepared plates (silica gel 60 F254 on aluminum). Flash chromatogra-
phy separations were performed on a Merck Silica Gel 60 (230–400 mesh).
All reactions, unless otherwise noted, were conducted under a nitrogen
atmosphere. All starting materials and reagents used were of standard ana-
lytical grade from Fluka, Merck and Aldrich and used without further purifi-
cation. 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 used was anhydrous MgSO4.
(2S)-1-amino-3-[[(1R)-2-hydroxy-1-phenyl-
ethyl]amino]propan-2-ol (9)
Viscous yellow oil; yield 91%; a2D5 5 1 20.74 (c 1.88, CHCl3). IR (KBr):
3093 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 7.30–7.05 (m, 5H,
;
ArH), 3.74–3.48 (m, 4H, CHAr and CHOH and CHCH2OH), 2.77–2.20
(m, 4H, NH2CH2CH and NHCH2CH), 1.97 (bs, 5H, NH2 and NH and
OH and OH); 13C NMR (100 MHz, CDCl3) dC (ppm) 138.6, 128.7, 127.8,
127.1, 73.9, 65.2, 64.9, 50.6, 45.9; Anal. Calcd for C11H18N2O2 (210.14): C,
62.83%; H, 8.63%; N, 13.32%; Found C, 62.88%; H, 8.64%; N, 13.35%.
Syntheses
The synthesis of 2–5 has been already described by us.44
General Procedure for the Synthesis of Compounds
6 and 7
((2R)-2-[[(2S)-3-amino-2-hydroxy-propyl]amino]butan-1-ol
(10)
To
a cooled solution of (R)-(-)-N-(2,3-epoxypropyl)phthalimide 1
Viscous yellow oil; yield 76%; a2D5 5 219.34 (c 0.93, CHCl3). IR (KBr):
(102 mg, 0.50 mmol) in 10 ml of 2-propanol, amine, or amino alcohol
(0.6 mmol, 1.2 eq) in 10 ml of 2-propanol was added at 08C and stirred
for 1 h. It was then refluxed for 8 h. After the completion of the reaction,
the solvent was removed under reduced pressure, and the crude product
was purified by flash chromatography on silica gel (CHCl3/MeOH 1:20
as eluent) to afford 6–7 as solids.
3088 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 3.78–3.62 (m, 1H,
;
CHOH), 3.58- 3.48 (m, 3H, NHCH and CHCH2OH), 2.77–2.55 (m, 4H,
NH2CH2CH and NHCH2CH), 1.74 (bs, 5H, NH2 and OH and OH and
NH), 1.53–1.37 (m, 2H, CHCH2CH3), 0.90 (t,
J 5 7.3 Hz, 3H,
CHCH2CH3); 13C NMR (100 MHz, CDCl3) dC (ppm) 74.1, 64.2, 62.8,
51.4, 47.8, 22.1, 10.9; Anal. Calcd for C7H18N2O2 (162.14): C, 51.82%; H,
11.18%; N, 17.27%; Found C, 51.83%; H, 11.18%; N, 17.30%.
2-[(2R)-2-hydroxy-3-indoline-1-yl-propyl]isoindoline-
1,3-dione (6)
((1R,2S)-1-[[(2S)-3-amino-2-hydroxy-propyl]amino]indan-
2-ol (11)
Yellow solid; yield 64%; mp: 105–1088C; a2D5 5 1 23.5 (c 1.53, CHCl3).
IR (KBr): 3460, 1764, 1698, 1605 cm21 1H NMR (400 MHz, CDCl3): dH
;
Viscous yellow oil; yield 73%; a2D5 5 1 24.56 (c 1.14, CHCl3). IR (KBr):
(ppm) 7.90–7.85 (m, 2H, ArH), 7.76–7.71 (m, 2H, ArH), 7.10–7.05 (m,
2H, ArH), 6.70 (t, J 5 7.4 Hz, 1H, ArH), 6.56 (d, J 5 7.8 Hz, 1H, ArH),
4.24-4.18 (m, 1H, OHCH), 3.90 (d, J 5 5.9 Hz, 2H, NCH2CH), 3.51 (q,
J 5 8.6 Hz, 1H, NCH2), 3.35 (q, J 5 8.6 Hz, 1H, NCH2), 3.18-3.08 (m, 2H,
NCH2CH), 3.02–2.98 (m, 2H, NCH2CH2), 2.79 (d, J 5 4.1 Hz, 1H, OH);
13C NMR (100 MHz, CDCl3) dC (ppm) 168.9, 152.7, 134.3, 132.2, 130.1,
127.6, 124.8, 123.7, 118.9, 107.8, 68.5, 55.4, 55.2, 42.4, 29.0; Anal. Calcd
for C19H18N2O3 (322.31): C, 70.82%; H, 5.63%; N, 8.72%; Found C, 70.86%;
H, 5.66%; N, 8.79%.
3095 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 7.14–7.05 (m, 4H,
;
ArH), 4.20–3.95 (m, 4H, NHCHAr, CHCHOH and CHOH), 2.92–2.73 (m,
4H, NH2CH2CH and NHCH2CH), 2.49–2.21 (m, 2H, CH2 ), 2.05 (bs, 4H,
NH2, NH and OH); 13C NMR (100 MHz, CDCl3) dC (ppm) 143.8, 139.7,
128.1, 126.4, 126.4, 124.5, 74.7, 74.2, 72.6, 50.9, 47.4, 37.6; Anal. Calcd for
C12H18N2O2 (222.28): C, 64.84%; H, 8.16%; N, 12.60%; Found C, 64.89%;
H, 8.16%; N, 12.63%.
((2S)-1-amino-3-indolin-1-yl-propan-2-ol (12)
2-[(2R)-3-(dibenzylamino)-2-hydroxy-propyl]isoindoline-
1,3-dione (7)
Viscous yellow oil; yield 92%; a2D5 5 1 24.85 (c 1.69, CHCl3). IR (KBr):
3086 cm21 1H NMR (400 MHz,CDCl3): dH (ppm) 6.98 (m, 2H, ArH),
;
White solid; yield 84%; mp: 142–1448C; a2D5 5 1 19.7 (c 1.32, CHCl3).
6.60 (t, J 5 7.4 Hz, 1H, ArH), 6.44 (d, J 5 7.8 Hz, 1H, ArH), 3.76 (sep,
J 5 4.11, 3.66 Hz, 1H, CHOH), 3.40 (q, J 5 8.4 Hz, 1H, NCH2CH2), 3.22
(q, J 5 8.7 Hz, 1H, NCH2CH2), 3.06 (dd, J 5 5.7, 7.8 Hz, 1H, NCH2CH2),
2.94–2.78 (m, 3H, NCH2CH2 and CHCH2NH2), 2.70–2.50 (m, 5H,
CHCH2NH2 and NH2 and CHCH2N and OH); 13C NMR (100 MHz,
CDCl3) dC (ppm) 153.7, 129.8, 126.8, 125.4, 121.7, 106.9, 70.2, 63.4, 56.8,
47.5, 28.9; Anal. Calcd for C11H16N2O (192.26): C, 68.72%; H, 8.39%; N,
14.57%; Found C, 68.81%; H, 8.40%; N, 14.59%.
IR (KBr): 3468, 1771, 1704, 1613 cm21 1H NMR (400 MHz, CDCl3): dH
;
(ppm) 7.75 (dd, J 5 3.1, 5.5 Hz, 2H, ArH), 7.62 (dd, J 5 3.1, 5.5 Hz, 2H,
ArH), 7.26–7.11 (m, 10H, ArH), 3.99–3.93 (m, 1H, NCH2CHOH), 3.69–
3.63 (m, 3H, NCH2CH and NCH2Ar), 3.55 (dd, J 5 7.3, 14.1 Hz, 1H,
NCH2CH), 3.43 (d, J 5 13.3 Hz, 2H, NCH2Ar), 2.49 (d, J 5 6.6 Hz, 2H,
CHCH2N), 2.25–2.19 (m, 1H, OH); 13C NMR (100 MHz, CDCl3) dC (ppm
168.7, 139.3, 132.4, 130.5, 128.4, 127.9, 127.2, 123.7, 66.4, 61.5, 58.9, 55.2,
45.9; Anal. Calcd for C25H24N2O3 (400.18): C, 74.98%; H, 6.04%; N, 7.00%;
Found C, 75.06%; H, 6.05%; N, 7.03%.
(2S)-1-amino-3-(dibenzylamino)propan-2-ol (13)
Viscous yellow oil; yield 89%; a2D5 5 1 44.66 (c 1.03, CHCl3). IR (KBr):
General Procedure for the Synthesis of Compounds 8–13
3092 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 7.38–7.07 (m, 10H,
;
To a solution of 2–7 (1.0 mmol) in ethanol (10 ml) was added
N2H4.H2O (0.5 ml), and the mixture was refluxed for 8 h. After the com-
pletion of the reaction, the solvent was removed under reduced pressure
and residue was dissolved in CHCl3 (15 ml) and washed with saturated
aq NaHCO3 (2 3 5 ml). The aqueous layer was extracted three times
with CHCl3, and the combined organic solutions were evaporated to
obtain 8–13, as yellow oils.
ArH), 3.77–3.56 (m, 3H, CHOH and CH2Ar), 3.41 (d, J 5 13.4 Hz, 2H,
CH2Ar), 2.63 (dd, J 5 3.6, 12.9 Hz, 1H, CHCH2), 2.53–2.33 (m, 3H,
CHCH2 and NH2CH2CH), 2.10 (bs, 3H, OH and NH2); 13C NMR (100
MHz, CDCl3) dC (ppm) 138.9, 129.2, 128.6, 127.5, 68.9, 59.0, 57.0, 45.7;
Anal. Calcd for C17H22N2O (270.37): C, 75.52%; H, 8.20%; N, 10.36%;
Found C, 75.63%; H, 8.21%; N, 10.41%.
General Procedure for the Synthesis of Compounds 15–20
(2S)-1-amino-3-[[(1S)-1-phenylethyl]amino]propan-
2-ol (8)
An appropriate primary amine (20.0 mmol) was dissolved in 1:2 tolu-
ene/MeOH mixture (30 ml) and added dropwise to a solution of
5,11,17,23-tetra-tert-butyl-25,27-diethoxycarbonylmethoxy-26,28-dihydrox-
ycalix[4]arene 14 (328 mg, 0.4 mmol) in 10 ml toluene with continuous
stirring at room temperature for about 30 min. Then, the reaction mix-
ture was refluxed, and the reactions were monitored by TLC. After the
substrate had been consumed, the solvent was evaporated under
Viscous yellow oil; yield 84%; a2D5 5 222.23 (c 1.44, CHCl3). IR (KBr):
3091 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 7.34–7.20 (m, 5H,
;
ArH), 3.75 (q, J 5 6.6 Hz, 1H, CH3CH), 3.60 (ddd, J 5 11.9, 7.4 Hz,
3.6 Hz, 1H, CHOH), 2.71 (dd, J 5 11.9, 3.5 Hz, 1H, NH2CH2CH (AB spin
system)), 2.58 (dd, J 5 12.7, 3.7 Hz, 2H, NHCH2CH), 2.35 (dd, J 5 11.9,
Chirality DOI 10.1002/chir

CHIRAL CALIX[4]ARENES BEARING AMINO ALCOHOL
131
reduced pressure, and the residue was triturated with MeOH to give a
crude product. The crude products were purified by flash chromatogra-
phy (SiO2, CHCl3/MeOH 15:1) and recrystallized from CHCl3/MeOH.
CHOH), 4.14 (dd, J 5 12.3, 5.1 Hz, 4H, ArCH2Ar), 3.91–3.86 (m, 2H,
CHOH), 3.81 (d, J 5 6.1 Hz, 2H, CHNH), 3.49–3.30 (m, 14H, ArCH2Ar
and CONHCH2CH and NH and OH), 2.92–2.82 (m, 8H, CHCH2NHCH
and CHCHCH2), 1.17 (s, 18H, CCH3), 0.94 (s, 18H, CCH3); 13C NMR
(100 MHz,CDCl3) dC (ppm) 170.2, 149.6, 148.5, 143.5, 142.2, 140.9,
132.5, 132.4, 128.2, 127.6, 127.0, 126.5, 126.3, 125.9, 125.8, 125.6, 124.6,
75.0, 72.1, 70.1, 66.5, 52.0, 44.1, 39.8, 34.1, 32.4, 31.8, 31.1; Anal. Calcd
for C72H92N4O10 (1173.52): C, 73.69%; H, 7.90%; N, 4.77%; Found C,
73.74%; H, 7.91%; N, 4.80%.
25,27-Bis(N-[-[(2R)-2-hydroxy-3-[[(1S)-1-
phenylethyl]amino]propyl]asetamide))-26,28-dihydroxy-
5,11,17,23-tetra(tert-butyl)calix[4]arene (15)
Reaction mixture was refluxed for 3 days. White solid; yield 62%; mp:
104–1078C; a2D5 5 238.5 (c 1.35, CHCl3). IR (KBr): 3325, 2962, 1666
cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 9.01 (t, J 5 5.5 Hz, 2H,
;
25,27-Bis(N-[[(2S)-2-hydroxy-3-indolin-1-yl-
propyl]asetamide))-26,28-dihydroxy-5,11,17,23-tetra(tert-
butyl)calix[4]arene (19)
NH), 7.66 (s, 2H, OH), 7.29–7.19 (m, 10H, ArH), 7.10 (s, 4H, ArH), 6.90
(s, 4H, ArH), 4.61 (d, J 5 15.0 Hz, 2H, OCH2CO), 4.50 (d, J 5 14.9 Hz,
2H, OCH2CO), 4.14 (dd, J 5 13.3, 6.3 Hz, 4H, ArCH2Ar), 3.84 (sep,
J 53.8, 7.5 Hz, 2H, CHOH), 3.63 (q, J 5 6.6 Hz, 2H, CH3CH), 3.52–3.37
(m, 8H, ArCH2Ar and CONHCH2CH), 3.05 (bs, 4H, NH and OH), 2.60
(dd, J 5 8.4, 3.9 Hz, 2H, CHCH2NHCH), 2.44 (dd, J 5 7.9, 4.0 Hz, 2H,
CHCH2NHCH and NHCH2CH), 1.32 (d, J 5 6.7 Hz, 6H, CH3CH), 1.29
(s, 18H, CCH3), 1.03 (s, 18H, CCH3); 13C NMR (100 MHz, CDCl3) dC
(ppm) 169.7, 149.7, 149.6, 148.6, 145.2, 143.4, 132.5, 132.4, 128.7, 127.6,
127.5, 127.2, 126.8, 126.5, 126.3, 125.9, 125.8, 75.0, 69.4, 58.1, 50.7, 44.0,
32.4, 34.3, 31.9, 31.2, 24.4; Anal. Calcd for C70H92N4O8 (1117.51): C,
75.22%; H, 8.33%; N, 5.04%; Found C, 75.28%; H, 8.34%; N, 5.09%.
Reaction mixture was refluxed for 4 days. White solid; yield 71%; mp:
118–1218C; a2D5 5 1 45.1 (c 0.93, CHCl3). IR (KBr): 3332, 2955,
1659 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 9.05 (t, J 5 5.5 Hz,
;
2H, NH), 7.64 (s, 2H, OH), 7.01 (s, 4H, ArH), 6.97 (d, J 5 7.2 Hz, 2H,
ArH), 6.91 (t, J 5 7.9 Hz, 2H, ArH), 6.83 (s, 4H, ArH), 6.59 (t, J 5
7.4 Hz, 2H, ArH), 6.35 (d, J 5 7.9 Hz, 2H, ArH), 4.50 (dd, J 5 2.9, 5.1 Hz,
4H, OCH2CO), 4.09 (d, J 5 13.3 Hz, 4H, ArCH2Ar), 4.04–3.98 (m, 2H,
CHOH), 3.67 (qd, J 5 2.9, 5.1 Hz, 2H, NHCH2CH), 3.42 (qd, J 5 2.4, 5.7
Hz, 2H, NCH2CH2), 3.36–3.30 (m, 6H, NHCH2CH and NCH2CH and
NCH2CH2), 3.14 (q, J 5 8.8 Hz, 2H, NCH2CH), 3.08 (dd, J 5 7.7, 6.0 Hz,
2H, ArCH2Ar), 2.99 (dd, J 5 4.9, 8.6 Hz, 2H, ArCH2Ar), 2.85 (t, J 5
8.2 Hz, 4H, NCH2CH2Ph), 1.55 ( bs, 2H, OH), 1.20 (s, 18H, CCH3), 0.96
(s, 18H, CCH3); 13C NMR (100 MHz, CDCl3) dC (ppm) 169.4, 152.8,
149.6, 149.5, 148.6, 143.4, 132.5, 130.1, 127.6, 127.5, 126.5, 126.4, 125.9,
125.8, 124.7, 118.5, 107.6, 75.1, 69.4, 55.0, 54.9, 43.9, 32.4, 34.3, 31.8,
31.2, 29.0; Anal. Calcd for C70H88N4O8 (1113.47): C, 75.51%; H, 7.97%; N,
5.03%; Found C, 75.56%; H, 7.98%; N, 5.05%.
25,27-Bis(N-[[(2R)-2-hydroxy-3-[[(1R)-2-hydroxy-
1-phenylethyl]amino]propyl]asetamide))-26,28-dihydroxy-
5,11,17,23-tetra(tert-butyl)calix[4]arene (16)
Reaction mixture was refluxed for 4 days. White solid; yield 69%; mp:
110–1138C; a2D5 5 1 29.75 (c 1.21, CHCl3). IR (KBr): 3319, 2959,
1657 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 9.26 (t, J 5 5.1 Hz,
;
2H, NH), 7.74 (s, 2H, OH), 7.40-7.20 (m, 10H, ArH), 7.11–7.09 (m, 4H,
ArH), 6.92–6.89 (m, 4H, ArH), 4.74 (d, J 5 15.3 Hz, 2H, OCH2CO), 4.49
(d, J 5 15.0 Hz, 2H, OCH2CO), 4.17 (dd, J 5 13.1, 6.8 Hz, 4H, ArCH2Ar),
3.94 (sep, J 5 6.1, 5.7, 4.7 Hz, 2H, NHCHCH2OH), 3.78–3.36 (m, 14H,
OHCH and CONHCH2CH and CHCH2NHCH and ArCH2Ar), 3.20–2.95
(m, 6H, NH and CHOH and CH2OH), 2.60 (d, J 5 5.7 Hz, 4H,
CHCH2OH), 1.28 (s, 18H, CCH3), 1.03 (s, 18H, CCH3); 13C NMR
(100 MHz, CDCl3) dC (ppm) 170.3, 149.7, 149.6, 148.5, 143.5, 140.3,
132.6, 132.5, 128.9, 127.8, 127.7, 127.4, 126.8, 126.6, 126.3, 125.9, 125.7,
75.0, 69.1, 67.4, 64.6, 50.2, 44.1, 34.4, 32.4, 31.9, 31.2; Anal. Calcd for
25,27-Bis(N-[[(2S)-3-(dibenzoylamino)-2-hydroxy-
propyl]asetamide))-26,28-dihydroxy-5,11,17,23-tetra(tert-
butyl)calix[4]arene (20)
Reaction mixture was refluxed for 3 days. White solid; yield 76%; mp:
165–1688C; a2D5 5 1 19.4 (c 1.44, CHCl3). IR (KBr): 3336, 2953,
1665 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 8.95 (t, J 5 5.4 Hz,
;
2H, NH), 7.58 (s, 2H, OH), 7.39–7.17 (m, 20H, ArH), 7.08 (s, 4H, ArH),
6.88 (s, 4H, ArH), 4.48 (dd, J 5 15.0, 34.9 Hz, 4H, OCH2CO), 4.22–4.00
(m, 4H, ArCH2Ar), 3.98–3.86 (m, 2H, CHOH), 3.61 (d, J 5 13.6 Hz, 4H,
NCH2Ar), 3.53 (ddd, J 5 3.6, 5.1, 13.6 Hz, 2H, CHCH2NH), 3.47–3.39
(m, 6H, NCH2Ar and CHOH), 3.38–3.27 (m, 6H, CHCH2NH and
ArCH2Ar), 2.71–2.40 (m, 4H, CHCH2N), 1.28 (s, 18H, CCH3), 1.03 (s,
18H, CCH3); 13C NMR (100 MHz, CDCl3) dC (ppm) 169.4, 149.8, 149.6,
148.4, 143.2, 138.8, 132.5, 132.4, 129.2, 128.6, 127.6, 127.4, 127.3, 126.4,
126.3, 125.8, 125.7, 67.7, 58.5, 57.4, 43.9, 34.3, 34.1, 32.4, 32.2, 31.9, 31.2,
14.4; Anal. Calcd for C82H100N4O8 (1269.69): C, 77.61%; H, 7.93%; N,
4.41%; Found C, 77.64%; H, 7.94%; N, 4.45%.
C70H92N4O10 (1149.50): C, 73.14%; H, 8.07%; N, 4.87%; Found C, 73.19%;
H, 8.08%; N, 4.91%.
25,27-Bis(N-[[(2R)-2-hydroxy-3-[[(1R)-1-
(hydroxymethyl)propyl]amino]propyl]asetamide))-26,28-
dihydroxy-5,11,17,23-tetra(tert-butyl)calix[4]arene (17)
Reaction mixture was refluxed for 4 days. White solid; yield 58%; mp:
175–1788C; a2D5 5 1 64.9 (c 1.17, CHCl3). IR (KBr): 3350, 2956, 1650
cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 8.62 (t, J 5 5.2 Hz; 2H,
;
NH), 7.81 (s, 2H, ArOH), 7.07–6.99 (m, 4H, ArH), 6.72 (s, 4H, ArH),
4.56–4.43 (m, 4H, OCH2CO), 4.32–4.16 (m, 6H, ArCH2Ar, CHOH), 3.93
(dd, J 5 12.3, 17.8 Hz, 2H, NHCH), 3.76–3.63 (m, 4H, CH2OH), 3.36–
2.99 (m, 16H, NHCH2 and NHCH2 and ArCH2Ar and CH2CH3), 2.12–
2.02 (m, 6H, NH and OH and OH), 1.28 (s, 18H, CCH3), 0.97 (t, J 5
8.0 Hz, 6H, CH2CH3), 0.92 (s, 18H, CCH3); 13C NMR (100 MHz, CDCl3)
dC (ppm) 169.4, 151.4, 150.6, 143.0, 142.7, 126.7, 126.2, 125.9, 125.7,
125.9, 124.2, 75.9, 70.2, 64.6, 50.9, 44.3, 34.7, 34.5, 32.5, 31.7, 31.4, 31.1,
21.3; Anal. Calcd for C62H92N4O10 (1053.41): C, 70.69%; H, 8.80%; N,
5.32%; Found C, 70.75%; H, 8.82%; N, 5.35%.
RESULTS AND DISCUSSION
Design and Synthesis of the New Hosts
Amino alcohols are known to be very useful substances in
the total synthesis of a variety of natural products, being
widely used in asymmetric synthesis, as building elements
for heterocycles, and used as reagents or catalytic agents in
organic chemistry. It was expected that chiral calix[4]arene
derivatives bearing both an amino group and a hydroxyl
group can be used as membrane carriers for the enantiose-
lective transport of chiral amino acids and mandelic acid. To
the best of our knowledge, there are few examples45,46 of chi-
ral calixarenes known to date as enantioselective carriers in
transport of amino acid esters and mandelic acid through
bulk liquid membrane.
25,27-Bis(N-[[(2R)-2-hydroxy-3-[[(1R,2S)-2-
hydroxyindan-1-yl]amino]propyl]asetamide))-26,28-
dihydroxy-5,11,17,23-tetra(tert-butyl)calix[4]arene (18)
Reaction mixture was refluxed for 3 days. White solid; yield 52%; mp:
175–1788C; a2D5 5 1 25.4 (c 1.73, CHCl3). IR (KBr): 3346, 2956,
1664 cm21 1H NMR (400 MHz, CDCl3): dH (ppm) 9.04 (t, J 5 4.9 Hz,
;
To achieve the desired goal, p-tert-butylcalix[4]arene die-
ster 14 was chosen as the precursor, and the synthetic route
is shown in Scheme 1 and 2 for the synthesis of chiral
2H, NH), 7.58 (s, 2H, OH), 7.22–7.19 (m, 2H, ArH), 7.18–7.09 (m, 6H,
ArH), 7.00–6.97 (m, 4H, ArH), 6.81 (s, 4H, ArH), 4.56 (d, J 5 15.1 Hz,
2H, OCH2CO), 4.47 (d, J 5 15.0 Hz, 2H, OCH2CO), 4.28–4.25 (m, 2H,
Chirality DOI 10.1002/chir

132
BOZKURT ET AL.
characterized by a combination of H NMR, 13C NMR, FTIR,
and elemental analysis. With an efficient synthetic scheme
for the synthesis of chiral calix[4]arenes in hand, we turned
our attention to their transport abilities of these receptors as
enantioselective carriers toward mandelic acid and aromatic
amino acid esters through liquid membranes. To take
advantage of both amine and alcohol group in these calix[4]-
arene derivatives, the enantiomers of phenylglycine
(PhGlyOMe.HCl), phenylalanine (PheOMe.HCl) and trypto-
phan methyl ester hydrochloride (TrpOMe.HCl) and man-
delic acid (MA) were chosen as guest molecules.
1
Scheme 1. (i) Appropriate chiral amine or amino alcohol, 2-propanol,
reflux, 64%–84% (ii) NH2NH2.H2O, ethanol, reflux.
calix[4]arene derivatives 15–20. Thus, following the litera-
ture procedure,44 chiral subunits 8–13 were readily
prepared by the regioselective ring opening of the (R)-N-(2,3-
epoxypropyl)phthalimide with (S)-phenyl ethylamine, (R)-2-
phenyl glycinol, (R)-2-amino-1-butanol, (1R, 2S)-cis-1-amino-2-
indanol, indoline and dibenzylamine and subsequent
cleavage of chiral phthalimides 8–13 with hydrazine hydrate
by refluxing in ethanol.
Then, coupling of the amino alcohols 8–13 with the cal-
ix[4]arene diester by refluxing in toluene/MeOH (1:1) mix-
ture led to the formation of the chiral calix[4]arene deriva-
tives 15–20 in moderate to good yields. The products were
Liquid Membrane Transport of Amino Acid Methyl Esters
and Mandelic Acid
Facilitated transport studies were performed at room tem-
perature in a U-type glass tube, consisting of a chloroform
phase separating two aqueous sources and receiving
phases. The transport apparatus and detailed experimental
conditions are shown in Figure 1. The experiments were
performed in all cases at least twice under strict similar
conditions due to the many factors influencing transport
Scheme 2. (i) Chiral b hydroxy amine 8–13, MeOH/toluene (1:1), reflux, 52%–76%.
Chirality DOI 10.1002/chir

CHIRAL CALIX[4]ARENES BEARING AMINO ALCOHOL
133
The enantioselectivity was calculated in terms of the flux
ratio (a), corresponds to the flux of the one enantiomer with
respect to the other enantiomer.
JD
a ¼
ð2Þ
JL
To determine the concentration of transported guests, cor-
responding samples were periodically withdrawn from the
aqueous receiving phases in each experiment and the
amounts of amino acid esters were measured by UV-Vis
spectroscopy (Fig. 2).
Transport data shown in Table 1 and Figure 3, indicate
that chiral carriers 15–20 showed relatively good transport
abilities for the enantiomers of PhGlyOMe.HCl. The trans-
port sequence of PhGlyOMe.HCl has been found that
the order of carriers is 20 > 16 > 18 > 15 > 19 > 17.
The enantiomer designated
L form had a relatively
higher flux in all cases investigated. This means that chiral
carriers preferentially recognize L-PhGlyOMe.HCl relating to
D-enantiomer. The highest L/D selectivity was observed
with hosts 19 and 20, affording KL/KD of 1.74 and 2.05,
respectively.
As can be seen from Table 1, all macrocyclic carriers
showed significantly lower transport rates for the enantiom-
ers of tryptophan methyl ester hydrochloride than other
amino acid esters. The flux of D-tryptophan ester was found
to be higher than that of the L-enantiomer in each case,
except in the case of host 17, which enantioselectively trans-
port L-enantiomer over D-antipode (Fig. 4). The highest
enantioselectivity was found with the host 16, affording KD/
KL of 3.29.
Among all the amino acid esters studied, phenylalanine
showed the highest transport efficiency with chiral calix[4]-
arene derivatives. This can attributed to the favorable p-p
interaction between the phenyl group in PheOMe.HCl and
the aromatic moieties in carriers as well as hydrophobicity
and hydrogen bonding. With macrocycles 15, 17, and 18,
the fluxes of D-PheOMe.HCl were found to be higher than
that of the L-enantiomer, but the highest and reverse selec-
tivities were found with the host 16, 19, and 20, affording
KL/KD of 1.32, 3.18, and 1.61 respectively (Fig. 5).
The facilitated transport of mandelic acid through a liquid
membrane was also studied in the presence of chiral calix[4]-
arene derivatives. The feed phase contains 5 ml of aqueous
mandelic acid solution at pH 5 2 present in one arm whereas
the aqueous receiving phase, 5 ml (pH 5 8) is present in the
other arm. The membrane phase, 10 ml of chiral calix[4]ar-
enes of 2.0 3 1024 M in chloroform was introduced in the
tube. The aqueous and organic phases were stirred at 300
rpm at room temperature for 24 h. The experimental data of
Fig. 1. Transport apparatus and detailed experimental conditions. (a)
Source phase (5 ml): amino acid methyl esters hydrochloride (pH 5 5.5) or
mandelic acid (pH 5 2.0) (2 3 1024 or 7 3 1023 M). (b) Organic carrier
phase (10 ml): CHCl3; carrier: chiral calix[4]arene derivatives (15–20) (2 3
1024 M). (c) Receiving phase (5 ml): pure water (pH 5 1.5 for amino acid
methyl esters hydrochloride and pH 5 8.0 for mandelic acid).
rates and enantioselectivities. The estimated errors (<10%)
are consistent with those reported in the literature.47 A blank
experiment using the organic solvent without the carrier
indicated that the enantioselectivity of amino acids was
negligible. The feed phase was an aqueous solution (5 ml)
of amino acid methyl ester hydrochloride 2.0 3 1024 or
7.0 3 1023 M at pH 5 5.5 value obtained by adding HCl or
LiOH. The receiving phase was a solution (5 ml) of HCl
(pH 5 1.5). The membrane phase, 10 ml of chiral calix[4]
arenes of 2.0 3 1024 M in chloroform was introduced in the
tube.48 The membrane phase was stirred at 300 rpm by a
magnetic stirrer.
The flux (J) of each enantiomer was calculated by:49–51
VrDCr
At
J ¼
ð1Þ
where t is the time over which the concentration difference,
DCr, is measured in the receiving phase, Vr the receiving vol-
ume, and A is the effective membrane area. This is the flux
from the start of the experiment till time t.
Fig. 2. Chemical structures of the guests studied. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

134
BOZKURT ET AL.
Fig. 3. Bar plots of fluxes of PhGly-OMe for hosts 15–20. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
the transport shown in Table 1 and Figure 6 indicated that
the fluxes of both enantiomers were relatively low when com-
pared with the amino acid esters investigated. All chiral car-
riers displayed similar enantioselectivity and preferentially
transported the D-enantiomers.
It is clear that, the fluxes of both enantimers linearly
increased and the enantioselectivity reached a maximum
during the first 90 min of transport experiments. After this
time, the fluxes and the enantioselectivities decreased down.
This is probably due to the loss of chiral carrier from the liq-
uid membrane leading to reduced enantioselectivities and
lower fluxes as reported.
From the results shown in Table 1, it can be concluded
that the structure of calixarene derivative is one of the most
important factor for recognition of amino acid esters. The chi-
ral carriers 15–20 are broadly similar in that all contain
hydrogen bonding sites defined by carbonyl oxygen, amide
nitrogen, and hydroxy groups at roughly similar positions
with respect to the phenoxy oxygen, chiral and achiral end
groups capable of additional hydrogen bonding (secondary
and tertiary amine or hydroxy group), and alkyl or aryl
groups. With macrocycle 17, the lowest transport rates and
Fig. 4. Bar plots of fluxes of Trp-OMe for hosts 15–20. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. Bar plots of fluxes of PheOMe for hosts 15–20. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

CHIRAL CALIX[4]ARENES BEARING AMINO ALCOHOL
135
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Chirality DOI 10.1002/chir