Enantioselective transport of amino acids as their potassium and sodium salts by optically active diaza-18-crown-6 ethers having arene sidearms

Article abstract of DOI:10.1016/j.tetasy.2004.06.007

The enantioselective transport of amino acids as their sodium and potassium salts has been investigated by optically active diaza crown ethers. The reversed enantioselectivity of chiral crown ether 1 was observed.

Full text of DOI:10.1016/j.tetasy.2004.06.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2045–2049
Enantioselective transport of amino acids as their potassium and
sodium salts by optically active diaza-18-crown-6 ethers having
arene sidearms
*
€
Nadir Demirel, Yasemin Bulut and Halil Hoßsgoren
Department of Chemistry, Faculty of Science, University of Dicle, 21280 Diyarbakır, Turkey
Received 7 May 2004; accepted 7 June 2004
Available online
Abstract—The enantioselective transport of amino acids as their sodium and potassium salts has been investigated by optically
active diaza crown ethers. The reversed enantioselectivity of chiral crown ether 1 was observed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
presence of a flexible sidearm with an electron donor site
is well known to enhance the binding ability of the li-
gand by participation of this additional donor group in
the complexation, providing a three dimensional cavity.
Amino acids are important bioactive substances. A
study on transport selectivity and kinetics of amino
acids through the liquid membrane would be helpful for
separation and in understanding the transport process
of amino acids through the cell membrane. Supramo-
lecular systems for transporting biologically active
agents (e.g., drug delivery, amino acids purification, etc.)
have been singled out as one of the more promising for
science and industry.1–3 Selective membrane transport
presents the basic functional features of supramolecular
chemistry and is induced by the selective binding of
substrate by the receptor in the membrane phase. So far,
a lot of work has been carried out for designing and
synthesizing new receptor molecules incorporating bi-
naphthyl, sugars, tartaric acid,4;5 steroids,6 amino acids7
etc. The chiral nature of crown ether, the rigidity of
micro-environment of its cavity and the quality of the
sidearm are all expected to play an important role in
enantioselective induction. Aza crown ethers8;9 with a
sidearm attached to the nitrogen atom in the macrocy-
clic ring may enhance and regulate the cation binding
properties as well as the lipophilicity. Lariat ethers or
armed crown ethers, which have heteroatom containing
podand arms, are known to have highly lipophilic
character and a unique guest specificity via macro-ring-
sidearm cooperativity. For some lariat ethers, the
The first enantioselective transport of Z-amino acid
(Z ¼ benzyloxycarbonyl) and dipeptide Kþ carboxylates
through a bulky chloroform membrane was reported by
Gokel et al.10
Pietraszkiewicz et al. have also reported transport and
liquid–liquid extraction of amino acids in their zwitter-
ionic form, or as their potassium and sodium salts by
using an 18-crown-6 incorporating a 2-naphthalene
unit.11 de Mendoza et al. reported the enantioselective
transport of amino acids by guanidinium receptors.12
We have previously13 reported the enantioselective
transport and liquid–liquid extraction of amino acids as
their sodium and potassium salts by optically active
crown ethers. Herein we have altered the aliphatic
sidearms with aromatic crown ethers in order to inves-
tigate the effect of sidearms. Gokel et al.14 has previously
reported the importance of arene sidearms on the
complexation of crown ether.
2. Results and discussion
Table 1 shows a set of transport experiments (Fig. 1) for
phenylglycine, phenylalanine and tryptophan as their
potassium and sodium salts, respectively. Sodium
phenylglycinates, sodium -phenylalaninates and so-
dium -tryptophanates are better recognized than their
D-
D
* Corresponding author. Tel.: +90-412-2488-550; fax: +90-412-2488-
039; e-mail: demireln@dicle.edu.tr
L
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.007

2046
N. Demirel et al. / Tetrahedron: Asymmetry 15 (2004) 2045–2049
potassium salts. Taking into account the transport
experiments for macrocycle 1, it is clear that the flux of
11
10
9
L
L
D
the
This indicates that the
transported. In the case of the potassium salt, the situ-
ation is reversed. For PhAla, selectivity for -enantio-
mer over its -form is observed for the sodium salt,
whereas the selectivity of -enantiomer over its
enantiomer is seen for the potassium salt. With trypto-
phan, the fluxes were higher for -tryptophan in the case
of sodium salt and -tryptophan for potassium salt. The
highest selectivity of a -enantiomer over its -enan-
D
-PhGlyNa is higher than for
L-PhGlyNa (Fig. 2).
D
-enantiomer is more easily
8
L
D
7
D
D
6
D
L
D
L
L
5
D
L
D-
4
L
3
L
2
D
1
D
L
0
tiomer was observed in the case of potassium salt. For
macrocycle 2, the situation for PhGlyNa was reversed
PhGlyNa PhGlyK PhAlaNa PhAlaK TrpNa
TrpK
Figure 2. Bar plots of fluxes of amino acids as their sodium and
potassium salts for 1.
(Fig. 3). The selectivity of the
enantiomer was observed for each salt. For PhAla, the
selectivity for the -enantiomer over its -form was
L-enantiomer over its D-
L
D
observed for sodium salt. However, the selectivity was
not observed for potassium salt. With tryptophan, the
highest selectivity of a L-enantiomer over its D-enan-
20
L
18
tiomer was observed in the case of sodium salt.
16
L D
14
12
10
8
D
L
L
D
D
Table 1. Transport through liquid membrane data
106 · Transport
aT
Amino acid
L
6
rates/mol hÀ1
L
D
4
D
1
2
1
2
2
L
-PhyGlyNa
-PhyGlyNa
-PhyGlyK
-PhyGlyK
-PhAlaNa
-PhAlaNa
-PhAlaK
-PhAlaK
-TrpNa
-TrpNa
-TrpK
-TrpK
0.50
0.55
0.99
0.50
0.70
0.88
0.96
0.53
0.51
0.41
0.32
0.68
1.10
0.90
1.15
1.13
1.74
0.99
1.35
1.34
0.60
0.34
0.35
0.24
1.10b
1.22a
1.02a
1.76a
1.00
0
D
PhGlyNa PhGlyK PhAlaNa PhAlaK
TrpNa
TrpK
L
1.98a
1.26b
1.81a
1.24a
2.12b
D
Figure 3. Bar plots of fluxes of amino acids as their sodium and
potassium salts for 2.
L
D
L
D
1.77a
1.46a
amino acids with the chiral barriers on sidearm of
macrocycle. In general, the highest selectivity was ob-
served in the case of tryptophanNa (
macrocycle 2 (Fig. 5) and tryptophanK (
L
D
L
L
/D
) in the case of
) in the case
D
D/L
of macrocycle 1. This could be the result of strong steric
interactions of the indolic group relative to the phenyl
one with chiral barriers on the sidearm. These results are
consistent with our previous ones.13 The most interest-
ing result was that a reversed selectivity within the same
amino acid enantiomer was observed for macrocycle 1
(Fig. 4). This indicated the influence of the cation in-
volved. The effect of the cation involved in the transport
is probably dependent on the structure of the crown
ether employed. It is known that variations in Naþ/Kþ
selectivity are primarily due to the degree of interaction
of the pendant arm with Naþ and Kþ. Gokel et al. used
lariat ether receptor systems to obtain clear evidence for
cation-p interactions between Naþ or Kþ and benzene,
phenol and indole.16–18 The complex of Kþ with lariat
ether is the most remarkable owing to its previously
reported apical-p interaction.19 In our system, substi-
tuting the arene unit on the macro-ring may probable
changed the conformation of the crown ether. The
macro-ring-sidearm in our system probably led to the
formation of apical-p interactions with Kþ.
Estimated error <12%.
a aT: Ratio of fluxes (
b aT: Ratio of fluxes (
L
/
D
).
).
D/L
(c)
(a)
(b)
Figure 1. Transport apparatus and detailed experimental conditions:
(a) feed phase (5 mL): amino acids 10À2 M and 10À2 M NaOH or
KOH; (b) organic phase (10 mL): chloroform; carrier: 1 and 2 10À3 M;
(c) receiving phase (5 mL): pure water.
Taking into account the employed host systems, the
observed enantioselectivity could be attributed to the
different interaction modes of some functional groups of
Ion pair20 receptors to date have been based on hydro-
gen bonding, positively charged or Lewis acidic groups

N. Demirel et al. / Tetrahedron: Asymmetry 15 (2004) 2045–2049
2047
10À1 deg cm2 gÀ1. We have previously described the
molecular recognition of some -amino acids as their
PhGly
PhAla
Trp
L
2.5
2
sodium and potassium salts by UV–vis titration method
earlier.15 Transport experiments were performed with
amino acids sodium and potassium salts. Transport
experiments were repeated three times for each run with
the estimated error being <12%.
1.5
1
0.5
0
3.2. Transport experiments
RCOONa
RCOOK
The transport experiments (Fig. 1) were run at 25 ꢁC in a
custom-made U-shaped glass apparatus of 25 mm
diameter for 72 h. The bulk liquid membrane consisted
of 10 mL of chloroform containing the crown ethers
(Scheme 1) at a concentration of 10À3 M. The membrane
was stirred magnetically at 200 rpm. The source phase
(5 mL) contained the amino acid salt at a concentration
of 10À2 M and at pH 10.5. The receiving phase was pure
water. Blank tests indicated that transport of amino
acids was negligible. The concentration of amino acids
salts in the receiving phase and the water phase were
assessed by UV. The initial transport rates measured for
different amino acids salts are shown in Table 1.
Figure 4. Enantiomeric differentiation of salts of amino acids during
transport for 1.
PhGly
PhAla
Trp
2
1.5
1
0.5
0
RCOONa
RCOOK
3.3. N,N0-Di-(R)-(+)-1-phenylethyl-7,16-diaza-1,4,10,13-
tetraoxa-2,3-benzo-cyclooctadec-2-ene 1
Figure 5. Enantiomeric differentiation of salts of amino acids during
transport for 2.
To a mixture of tripropylamine (14.3 g, 100 mmol) in
xylene (500 mL), 1,2-bis-(2-p-tolylsulfonylethoxy)-benz-
ene (5.06 g, 10 mmol) and 1,10-di-(R)-(+)-1-phenylethyl-
4,7-dioxa-1,10-diazadecane15 (3.56 g, 10 mmol) were
added simultaneously. The mixture was stirred for
2 days at 120 ꢁC. The mixture was then cooled to rt and
the xylene evaporated. The concentrated crude product
was washed with hot water, extracted with CHCl3
(3 · 50 mL) and dried over Na2SO4. The chloroform was
then evaporated and the residue purified by column
chromatography (200 mesh Si-gel, ethyl acetate–petro-
to coordinates the anion crown moieties to bind the
cation. These types of host molecules often exhibit
cooperative and allosteric effects, whereby the associa-
tion of one ion alters the binding affinity of the coun-
terion.21 This cooperative behaviour can be positive or
negative depending on whether the binding affinity is
enhanced or reduced, respectively. Cooperative behav-
iour can result from several factors, such as through-
bond or through-space electrostatic interactions be-
tween bound ions, or conformational changes induced
by binding. In general the higher transport rates of
macrocycle 2 can be explained in terms of cooperative
behaviour (Table 1).
leum ether–triethylamine 17:80:3) to afford 1 (2.80 g) in
20
D
54% yield as a yellow oil. ½aŠ ¼ +27.4 (c 0.05, CH2Cl2),
IR m: 3068, 3029, 2974, 2926, 2872, 1597, 1496, 1441,
1371, 1348, 1325, 1261, 1215, 1112, 1053, 1029, 776, 745,
1
699; H NMR d: 1.17–1.19 (d, J 6.70, 6H, CH3), 2.68–
2.72 (m, 4H, ArOCH2CH2N), 2.84–2.87 (t, J 6.28, 4H,
NCH2), 3.31–3.37 (m, 8H, OCH2, ArOCH2), 3.66–3.68
(q, J 6.69, 2H, CHN), 3.76–3.81 (m, 4H, OCH2CH2O),
6.54–6.65 (m, 4H, Ar-H), 7.00–7.19 (m, 10H, Ar-H); 13C
NMR d: 17.69, 50.35, 51.37, 61.70, 69.03, 71.06, 71.62,
113.63, 121.23, 127.21, 128.11, 128.61, 145.05, 149.35.
Anal. Calcd for C32H42N2O4: C, 74.09; H, 8.16; N, 5.40.
Found: C, 74.12; H, 8.12; N, 5.46.
3. Experimental
3.1. General information
All chemicals were grade reagent unless otherwise
specified. Melting points were determined with a GAL-
LENKAMP Model apparatus with open capillaries.
Infrared spectra were recorded on a MIDAC-FTIR
Model 1700 spectrophotometer. The elemental analyses
were obtained with CARLO-ERBA Model 1108 appa-
3.4. N,N0-Di-(R)-(+)-1-phenylethyl-1,7,10,16-tetraoxa-
4,13-diaza-cyclooctadecane 2
ratus. H (400 MHz) and 13C (100 MHz) NMR spectra
1
were recorded on a Bruker DPX-400 high performance
digital FT-NMR spectrometer, with tetramethylsilane
as the internal standard for solutions in deuteriochlo-
roform. J values are given in hertz. Optical rotations
were recorded using an ATAGO DR Model 21949
To a mixture of tripropylamine (14.3 g, 100 mmol) in
xylene (500 mL), triethylene glycol ditosylate (4.58 g,
10 mmol) and 1,10-di-(R)-(+)-1-phenylethyl-4,7-dioxa-
1,10-diazadecane15 (3.56 g, 10 mmol) were added simul-
taneously. The mixture was stirred for 2 days at 120 ꢁC.
polarimeter, and ½aŠ
values are in units of
D

2048
N. Demirel et al. / Tetrahedron: Asymmetry 15 (2004) 2045–2049
H3C
(R)
H
N
O
O
O
O
a
N
(R)
H3C
H
(R)
OTs
+
H
H
NH
H3C
O
O
CH3
(R)
O
O
NH2
2
OTs
b
NH
H3C
H
(R)
H
(R)
H3C
N
O
O
O
O
N
(R)
H
CH3
1
Scheme 1. Reagents and conditions: (a) tripropyl amine (10 equiv), triethylene glycol ditosylate, xylene, 120 ꢁC, 48 h; (b) tripropyl amine (10 equiv),
1,2-bis-(2-p-tolylsulfonylethoxy) benzene, xylene, 120 ꢁC, 48 h.
3. Seel, C.; Galan, A.; de Mendoza, J. In Top. Curr. Chem.;
Weber, E., Ed.; 1995; pp 102–132.
4. Lehn, J.-M. Chemia Supramolekurna; ICHF PAN: War-
saw, 1993.
5. Stoddart, J. F.; Chiral Top. Stereochem. 1987, 17, 207.
6. Gokel, G. W. In Crown Ethers and Cryptands, Mono-
graphs in Supramolecular Chemistry; Stoddart, J. F., Ed.;
The Royal Society of Chemistry: Cambridge, England,
1991.
The mixture was then cooled to rt and xylene evapo-
rated. The concentrated crude product was washed with
hot water to remove tripropylamine salt, extracted with
CHCl3 (3 · 50 mL) and dried over Na2SO4. The chlo-
roform was then evaporated and the residue purified by
column chromatography (200 mesh Si-gel, ethyl acetate–
petroleum ether–triethylamine 17:80:3) to afford 2
20
D
(2.25 g) in 48% yield as a yellow oil. ½aŠ ¼ +19.2 (c 0.05,
CH2Cl2), IR m: 3091, 3053, 3029, 2972, 2931, 2869, 1605,
1478, 1455, 1376, 1352, 1298, 1201, 1121, 1067, 1034,
980, 911, 833, 770, 731, 708; 1H NMR d: 1.38–1.40 (d, J
6.76, 6H, CH3), 2.78–2.86 (m, 8H, NCH2), 3.56–3.61 (m,
16H, OCH2CH2O, OCH2), 3.86–3.88 (q, J 6.72, 2H,
NCH), 7.23–7.40 (m, 10H, Ar-H); 13C NMR d: 17.65,
51.24, 61.48, 71.15, 71.38, 127.09, 128.10, 128.48,
144.81. Anal. Calcd for C28H42N2O4: C, 71.46; H, 8.99;
N, 5.95. Found: C, 71.38; H, 8.76; N, 5.87.
€
7. Joly, J.-P.; Schroder, G. Tetrahedron Lett. 1997, 38, 8197–
8198.
8. Chadwick, D. J.; Cliffe, I. A.; Sutherland, I. O. J. Chem.
Soc., Chem. Commun. 1981, 992–994.
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G. W. J. Chem. Soc., Chem. Commun. 1990, 1726–
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11. Pietraszkiewicz, M.; Kozbial, M.; Pietraszkiewicz, O.
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Santamaria, S.; Gago, F.; Prados, P.; de Mendoza, C. J.
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Acknowledgements
This work was supported by University of Dicle under
€
grant no. DUAPK-03-FF-93.
€
13. Demirel, N.; Bulut, Y.; Hoßsgoren, H. Chirality 2004, 16,
347–350.
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