Synthesis of chiral monoaza-15-crown-5 ethers from a chiral amino alcohol and enantiomeric recognition of potassium and sodium salts of amino acids

Article abstract of DOI:10.1016/j.tetasy.2005.07.002

The enantiomeric recognition of chiral monoaza-crown ethers for amino acids as their sodium and potassium salts has been investigated by UV-vis. The highest discrimination was observed for TrpK (d/l = 6.47). The reversed enantioselectivity of chiral monoaza-crown ether II was observed for TrpK.

Full text of DOI:10.1016/j.tetasy.2005.07.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2771–2777
Synthesis of chiral monoaza-15-crown-5 ethers from a chiral
amino alcohol and enantiomeric recognition of potassium
and sodium salts of amino acids
Mahmut Togrul,a,* Muzaffer Askinb and Halil Hosgorena
aDepartment of Chemistry, Faculty of Science, University of Dicle, 21280 Diyarbakır, Turkey
bDepartment of Physics, Faculty of Science, University of Dicle, 21280 Diyarbakır, Turkey
Received 17 June 2005; accepted 4 July 2005
Available online 2 August 2005
Abstract—The enantiomeric recognition of chiral monoaza-crown ethers for amino acids as their sodium and potassium salts has
been investigated by UV–vis. The highest discrimination was observed for TrpK (D/L = 6.47). The reversed enantioselectivity of
chiral monoaza-crown ether II was observed for TrpK.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
complexes with a variety of molecules present various
types of interaction modes.8
Molecular and enantiomeric recognition phenomena
play an important role in a variety of physical, chemical,
and biological processes. Examples include the determi-
nation of concentrations, separation of enantiomers,
catalysis reactions, and the incorporation of single enan-
tiomeric forms of amino acids, organic ammonium salts,
and in biochemical pathways.1 Crown ethers, first intro-
duced in 1967 by Pedersen,2,3 are macrocyclic poly-
ethers, which are able to form stable and selective
complexes with alkali, alkaline-earth, and primary
ammonium cations. Following this discovery, chemists
realized that chiral derivatives of these molecules could
serve as models for the study of chiral recognition in
enzymatic and other reactions. Since Cram et al. pub-
lished their pioneering studies on the use of chiral mac-
rocyclic ligands for enantiomeric recognition,4 a large
number of chiral macrocycles have been synthesized
and studied.5–7
Among the various types of compounds studied, such as
derivatized amino acids and cyclodextrins, proteins, and
carbohydrates, chiral crown ethers have been recognized
as the most successful selectors used in LC chiral sta-
tionary phases for the resolution of primary amine con-
taining compounds.9 It has been predicted that chiral
macrocyclic compounds will play a major role in future
enantiomeric separations.10
Bako et al. synthesized a number of monoaza-15-crown-
5 ethers from monosaccharides, such as glucose, galac-
tose, and mannitol. They found that most of them can
be used as catalysts in asymmetric reactions, such as
Michael additions and Darzens condensations.11 The
chiral nature of the crown ether, the rigidity of the micro-
environment of its cavity, and the quality of the side
arm, are all expected to play important roles. Azacrown
ethers with a side arm attached to the nitrogen of the
macrocyclic ring may enhance and regulate the
cation-binding properties, as well as lipophilicity.
Crown ethers are known to have a highly lipophilic
character and unique guest selectivity via the macroring
side arm.12
The study of enantiomeric recognition of amines and
protonated amines is of great significance since these
compounds are basic building blocks for biological mole-
cules. Amino acids are major components of proteins in
natural living systems and their versatile abilities to form
There has been continuing interest for the molecular rec-
ognition of amino acids derivatives by NMR, UV–vis,
extraction and transport experiment.13–16 Until today,
marvelous host–guest combinations systems, which
*
Corresponding author. Tel.: +90 412 2488550; fax: +90 412
2488039; e-mail: mtogrul@dicle.edu.tr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.002

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M. Togrul et al. / Tetrahedron: Asymmetry 16 (2005) 2771–2777
show high degrees of chiral recognition, have been
developed and their recognition mechanism has been
gradually made clear as same combined effects of
charge-dipole, hydrogen bonding, hydrophobic, and
p–p interaction and steric complementarity etc.17
catalyst was used, at mild temperature gave 5 in high
yield. In the reaction, two catalysts were used, diethylene
amine hydrochloride, and piperidine hydrochloride, but
the yield of product was similar.19 The conversion of
(R)-2-amino-1-butanol 1 to N-benzyl aminoalcohol
derivatives 2 was carried out by our previous method.20
The conversion of 2 to 3 was carried out at ꢀ20 ꢁC, as
shown in Scheme 1. Chiral macrocycles I and II were
prepared in the 65% and 69% yields, respectively, as
shown in Scheme 2. After the cyclization reaction,
sodium perchlorate (NaClO4ÆH2O) was added to crude
product, and the macrocycles obtained as NaClO4ÆH2O
complexes. The free ligand was recovered by column
chromatograph. The structure of the free ligand was
determined by NMR and X-ray analysis.20
Recently, our interest has concerned monoaza-crown
ethers from (R)-(ꢀ)-2-amino-1-butanol, which is widely
used in the production of the antituberculostatic ethem-
butol and is inexpensive.18 The interaction of these
chiral macrocycles with potassium and sodium salts of
amino acids helps us to understand the binding pheno-
mena and their catalytic effects on chiral recognition.
Herein, to the enantioselective recognition capabilities
of chiral monoaza-15-crown ethers toward potassium
and sodium salts of amino acids are compared by
UV–vis spectroscopy.
2.2. UV–vis
UV–vis spectroscopy is a convenient and widely used
method for the study of binding phenomena.21 When
the receptor (or substrate) absorbs light at different
wavelengths in the free and complexed states, the differ-
ences in ultraviolet spectrophotometry may be enough
for the estimation of molecular and enantiomeric recog-
nition. The binding constants (Ka) of the inclusion com-
plexes of monoaza-15-crown-5 ethers with amino acids
2. Results and discussion
2.1. Synthesis
The versatile building block for crown ether synthesis
was prepared as shown in Scheme 1. A single step reac-
tion of catechol with ethylene oxide in the presence of a
HO
HO
i
ii
H
HO
H
NH
H
NH2
N
OH
1
2
3
OH
OH
O
O
OTs
OTs
O
O
OH
OH
iv
iii
4
6
5
Scheme 1. Reagents and conditions: (i) PhCH2CI, Na2CO3, 110 ꢁC; (ii) ethylene oxide, MeOH, ꢀ20 ꢁC; (iii) ethylene oxide, MeOH, 40 ꢁC; (iv) TsCl,
pyridine, ꢀ10 ꢁC.
O
O
OTs
N
O
O
O
6
O
OTs
II
HO
H
N
OH
O
O
OTs
N
O
3
7
O
O
O
OTs
I
Scheme 2. Reagents and conditions: NaH, THF, reflux, 5 days.

M. Togrul et al. / Tetrahedron: Asymmetry 16 (2005) 2771–2777
2773
potassium and sodium salts were determined on the
30
25
20
15
10
5
y = 0.2805x + 1.5727
R2 = 0.9952
basis of the differential absorption spectra. UV spec-
trometry was measured in a solution of CH3CN (HPLC
grade)–H2O (50:2, differential absorption spectra were
obtained directly using the instrument according to its
normal procedures. The quartz cells were kept at a
constant temperature (25 0.1 ꢁC) with a thermostated
cell compartment.
In the UV spectroscopic titration experiments, the addi-
tion of varying concentrations of amino acid salts
(guest) molecules resulted in either a gradual increase
or decrease of characteristic absorptions of the host
molecules. With the assumption of a 1:1 stoichiometry,
the complexation of amino acid salts (G) with chiral
macrocycles (H) is expressed by Eq. 1:
0
0
20
40
60
80
[G]0/10-5 mol.dm-3
Figure 2. Typical plot of [H]oꢁ[G]o/DA versus [G]o for the host–guest
complexation of II and L-PhAlaNa salt in CH3CN–H2O (50:2).
H þ G¡H ꢁ G
ð1Þ
ð2Þ
lem of the amino acid salts arises. Macrocycle II gives
good absorbance in CHCl3 at 242 and 276 nm but in
CH3CN–H2O mixture (50:2) just one absorbance at
242.3 nm was observed.
½Hꢂo ꢁ ½Gꢂo=DA ¼ 1=KaDe þ ½Gꢂo=De
Under the conditions employed, the concentration of
the host (1.01 · 10ꢀ5 mol dmꢀ3) is much lower that of
amino acid salts, that is [H]o ꢃ [G]o. Therefore, the
binding constant of the supramolecular system formed
can be calculated according to modified Hildebrand–
Benesi equation,22 Eq. 2, where [H]o represents the total
concentration of host; [G]o denotes the total concentra-
tion of guest amino acid salts; De is the difference
between the molar extinction coefficient for the free
and complexed chiral monoaza-15crown-5 ether; DA
denotes the changes in the absorption of the host on
adding aminoacid salts. For all the guest molecules
examined, plots of calculated [H]oꢁ[G]o/DA values as a
function of [G]o values gave an excellent linear relation-
ship (R > 0.9952) supporting the 1:1 complex function.
The typical UV spectral changes upon the addition of
L-PhAlaNa salt to II are shown in Figure 1, while a
typical plot is shown for the complexation of compound
host II with guest L-PhAlaNa in Figure 2.
The binding constant (Ka) and the free-energy changes
(DGo) of this host with guest molecules obtained from
usual curve fitting analyses (R >0.9952) of observed Ka
values and ꢀDGo changes are summarized in Table 1,
along with enantioselectivity KD/KL or DDGo calculated
from ꢀDGo for the complexation of D/L-amino acid
potassium and sodium salts by this host. The amino acid
may interact in different ways to form stable complexes.
In a neutral solution, the amino acid may be complexed
in its neutral form (coordination of the amino group and
hydrogen bonding of the acid part), or more generally,
in its zwiterionic form for which thermodynamic studies
have been undertaken, complexation being weak; in
acidic medium the amino acid is bound through the
ammonium ion. In the basic medium it was complexed
through the carboxylate function.23 It should therefore
be equally true that the variation of guest structure will
also effect the extent of enantiomeric recognition dis-
played by a given ligand and stability of the complex
formed between the guest and the given ligand (Scheme
3). Ion pair24 receptors to date have been based on
The properties of macrocycle I deserve special interest.
Macrocycle I did not give any absorbance in a mixture
of CH3CN–H2O, but gave good absorbance in CHCl3
at 241.7 nm. However in this case, the solubility prob-
Figure 1. UV–vis spectra of II (1.01 · 10ꢀ5 mol dmꢀ3) in the presence of L-PhAlaNa salt (2.5 · 10ꢀ5–8.1 · 10ꢀ4 mol dmꢀ3) in CH3CN–H2O (50:2).

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M. Togrul et al. / Tetrahedron: Asymmetry 16 (2005) 2771–2777
Table 1. Binding constants (Ka), free-energy changes (ꢀDGo), enantioselectivities KL/KD and DDGo calculated from ꢀDGo, for complexation for 1:1
of L/D-amino acids potassium and sodium salts with chiral host II in CH3CN–H2O at 25 ꢁCa
Entry
Host
Guestb
Ka (dm3 molꢀ1
)
KD/KL
ꢀDGo (kJ molꢀ1
23.83
26.76
24.28
24.66
)
DDGo (kJ molꢀ1 c
)
1
2
3
4
II
II
II
II
L-PhAlaNa
D-PhAlaNa
L-PhAlaK
D-PhAlaK
(1.5 0.040) · 104
(4.9 0.038) · 104
(1.8 0.042) · 104
(2.1 0.048) · 104
3.27
2.93
1.17
0.38
5
6
7
8
II
II
II
II
L-PhGlyNa
D-PhGlyNa
L-PhGlyK
D-PhGlyK
(2.0 0.051) · 104
(5.5 0.033) · 104
(1.8 0.036) · 104
(2.8 0.040) · 104
2.75
1.56
24.54
27.05
24.28
25.38
2.51
1.10
9
II
II
II
II
L-TrpNa
D-TrpNa
L-TrpK
D-TrpK
(1.7 0.041) · 103
(1.9 0.055) · 103
(1.7 0.048) · 103
(1.1 0.04) · 104
1.12
6.47
18.43
18.71
18.43
23.06
0.28
4.63
10
11
12
a Concentration of the receptor (1.01 · 10ꢀ5 M).
b PhAlaNa(K): phenylalanine sodium or potassium salts, PhGlyNa(K): phenylglycine sodium or potassium salts, TrpNa(K): tryptophan sodium or
potassium salts.
c DDGo: ꢀ(DGo( )ꢀDGo( )).
L
D
60
50
40
30
20
10
0
NH2
R
H2N
O
R
L
O
O
D
O
O
O
O
O
N
N
Na
Na
O
O
O
O
Scheme 3. The enantiomeric recognition mode of amino acid sodium
or potassium salts by host II.
Figure 3. Bar plot of enantioselective recognition of L,D-PhAla,
PhGly, and tryptophan Na or K salts for II.
hydrogen bonding. Positively charged or Lewis acid
groups coordinate the anion crown moieties to bind
the cation. These types of host molecules generally exhi-
bit cooperative and allosteric effects, whereby the associ-
ation of one ion alters the binding affinity of the
counterion. This cooperative behavior can be positive
or negative depending on whether the binding affinity
is enhanced or reduced, respectively. Cooperative
behavior can result from several factors, such as
through-space or through-space electrostatic interac-
tions between ions or conformational changes induced
by binding.
PhAla
PhGly
Trp
7
6
5
4
3
2
1
0
RCOONa
RCOOK
Table 1 shows the binding constant (Ka) and the free
energy changes ꢀDGo for phenylalanine, phenylglycine,
and tryptophan as their sodium and potassium salts,
respectively. The experimental result shows that the D-
enantiomer of PhAlaNa, PhAlaK, PhGlyNa, PhGlyK,
TrpNa, TrpK were better recognized than their L-enan-
tiomer (Fig. 3). Although both enantiomers of PhAl-
aNa, PhAlaK, PhGlyNa, and PhGlyK give more
stable complexes than TrpNa and TrpK; the highest dis-
crimination was observed for TrpK (Fig. 4).
Figure 4. Enantiomeric differentiation of salts of amino acid by
macrocycle II.
This could be the result of strong steric interactions of
the indolic group relative to the phenyl one with an
arene unit on the macrocycle. The effect of the cation
involved in the enantiomeric recognition is probably
dependent on the structure of the crown ether employed.
It is well known that variations in Na+/K+ selectivity
are primarily due to the degree of interaction of the pen-
dant arm with Na+ and K+. Gokel et al. used a lariat
ether receptor system to obtain clear evidence for cat-
ion–p interactions between Na+ or K+ and benzene,
phenol, and indole.25 The complex of K+ with lariat
ether is the most remarkable owing to its previously
Taking into account the host employed, the observed
enantioselectivity could be attributed to the different
modes of some functional groups of amino acids with
the chiral macrocycle. In general, the highest discrimina-
tion was observed with TrpK D/L for the macrocycle.

M. Togrul et al. / Tetrahedron: Asymmetry 16 (2005) 2771–2777
2775
reported apical–p interaction.26 In our system, substitut-
ing the arene unit on the macroring could probably lead
to formation of apical–p interactions with K+. This
result was observed in the case of TrpK. In general,
the observed chiral discrimination can be achieved by
the repulsive noncovalent steric interaction with the
chiral barrier on the ring, side arm of macrocycle and
the functional groups of the amino acids.
the mixture was cooled and CHCl3 (100 mL) was added
to the mixture and refluxed for 1 h. The CHCl3 layer
was separated from the solid phase. The remaining solid
was then re-extracted with CHCl3 (3 · 25 mL).The com-
bined CHCl3 layers were dried over Na2SO4 and evapo-
rated. The product was distilled at reduced pressure to
20
give 33 g (94%), ½aꢂD ¼ ꢀ25.6 (c 0.08, EtOH). Bp 98–
100 ꢁC/0.1 mmHg, mp 71–72 ꢁC. Mw 179 g (found: C,
73.67; H, 9.63; N, 7.74; C11H17NO requires: C, 73.70;
H, 9.56; N, 7.80); IR (KBr): 3287, 3076, 2931, 2836,
1
3. Experimental
1467, 1361, 1068 cmꢀ1; H NMR (CDCl3): d 0.98 (3H,
t, J = 7.48 Hz), 1.48–1.63 (2H, m), 2.64–2.68 (1H, m),
3.38–3.85 (2H, ddd), 3.75–3.85 (2H, dd), 7.29–7.39
(5H, m); 13C NMR (CDCl3): d 10.73, 24.64, 51.48,
60.21, 63.05, 127.45, 128.86, 140.83.
3.1. General remarks
All chemicals were reagent grade unless otherwise spec-
ified. Amino acid was purchased from Fluka chemical
company. Silica gel 60 (Merck, 0.040–0.063 mm) and sil-
ica gel/TLC-cards (F254) were used for flash column
chromatography and TLC. Melting points were deter-
mined with a Gallenkamp Model apparatus with open
capillaries. Infrared spectra were recorded on a MID-
AC-FTIR Model 1700 spectrophotometer. Elemental
analyses were obtained with a Carlo-Erba 1108 model
apparatus. Optical rotations were taken on a Perkin–
3.2.4. (R)-(ꢀ)-N-Benzyl-4-hydroxymethyl-3-azahexane-
1-ol 3. A solution of 47 g (260 mmol) of 2 in 100 mL
of methanol was cooled to ꢀ20 ꢁC in a 250 mL flask.
11.52 g (260 mmol) of ethylene oxide in 50 mL of meth-
anol was added to the solution dropwise at the same
temperature. After addition the mixture was stirred for
12 h at ꢀ20 ꢁC and then for 24 h at +4 ꢁC. The mixture
was kept for one day at room temperature. Methanol
was then evaporated in vacuo. The product was purified
by distillation under reduced pressure at 155 ꢁC/
Elmer 341 model polarimeter. H (400 MHz) and 13C
1
(100 MHz) NMR spectra were recorded on a Bruker
DPX-400 High Performance Digital FT-NMR Spec-
trometer. Refraction indexes were measured using an
Atago Abbe refractometer.
0.1 mmHg to give 56 g (94%) of 2. g2i 0 ¼ 1.524;
20
½aꢂD ¼ ꢀ14.9 (c 0.08, EtOH). Mw 223 g (found: C,
66.76; H, 9.04; N, 6.08, C13H21NO2 requires: C, 66.90;
H, 9.07; N, 6.00); IR (neat film): 3368, 3085, 3061,
3026, 2957, 2876, 1602, 1494, 1453, 1372, 1115, 1054,
3.2. Absorption spectra measurements
729, 698 cmꢀ1 1H NMR (CDCl3): d 0.93 (3H, t,
;
The abilities of crown ethers to coordinate to amino acid
salts were investigated using UV spectroscopic titra-
tion.21 The UV–vis spectra were measured at
25 0.1 ꢁC with a thermostated cell compartment with
a Shimadzu 160 UV spectrometer. The same concentra-
tion of guest solution was added to the sample cell and
reference cell. The maximum wavelength is 242.3 nm for
2. CH3CN–H2O (50:2) was used as the solvent. The con-
centration of the hosts was 1.01 · 10ꢀ5 mol dmꢀ3 with
an increasing concentration of the added guest.
J = 7.47 Hz), 1.22–1.29 (1H, m), 1.60–1.67 (1H, m),
2.59–2.64 (1H, dt), 2.71–2.85, (2H, m), 3.41 (2H, t,
J = 10.28), 3.45–3.56 (2H, ddd), 3.62–3.84 (4H, dd),
7.22–7.37 (5H, m); 13C NMR (CDCl3): d 12.23, 19.72,
51.87, 55.32, 60.52, 61.90, 63.41, 127.41, 128.76,
129.16, 140.52.
3.2.5.
(R)-(ꢀ)-2-Ethyl-N-benzyl-4,7,10,13-tetraoxa-1-
azacyclopentadecane I. To a solution of NaH (80% in
mineral oil) 3.57 g (120 mmol) in dry THF (100 mL) in
an N2 atmosphere, (R)-(ꢀ)-N-benzyl-4-hydroxymethyl-
3-azahexzan-1-ol 3 6.62 g (30 mmol) in THF (100 mL)
was added slowly at 0 ꢁC. The mixture was heated
slowly to 30–40 ꢁC. The mixture was then kept at this
temperature for 1.5 h. Then triethylene glycol ditosylate
7 14.95 g (33 mmol) in THF (200 mL) was added slowly
to the mixture. The mixture was stirred at 80 ꢁC for
5 days. THF extract was evaporated and water
(50 mL) added to the remaining residue. The organic
phase was extracted with CHCI3 (3 · 50 mL) and the
combined organic phase dried over MgSO4 and evapo-
rated. The product was dissolved in ethyl acetate
(5 mL) and NaClO4H2O 4.20 g (30 mmol) in ethyl ace-
tate (5 mL) was added. The product was recrystallized
3.2.1. 1,2-Bis-(2-hydroxy ethoxy)benzene 5. This com-
pound was prepared according to the procedure
recorded in the literature19 from catechol (11.0 g,
100 mmol) diethylamine hydrochloride (as a catalyst)
and ethylene oxide (9.8 mL, 200 mmol) to give 18.8 g,
95%; mp 81–83 ꢁC.
3.2.2. 1,2-Bis-(2-p-tolylsulfonylethoxy)benzene 7. This
compound was prepared according to the procedure
recorded in the literature19 from 1,2-bis-(2-hydroxy
ethoxy)benzene 5 (26.73 g, 135 mmol), pyridine (110
mL) at ꢀ10 ꢁC and p-toluenesulfonylchloride (51.43 g,
270 mmol) to give 66 g, 96%; mp 95–95.5 ꢁC.
from ethyl acetate to yield 9.20 g (65%), mp 132–
3.2.3. (R)-(ꢀ)-N-Benzyl-2-amino-1-butanol 2. (R)-(ꢀ)-
Amino-1-butanol 1 (71.2 g, 0.8 mol), benzyl chloride
(25.3 g, 0.2 mol) and Na2CO3 (20 g, 0.18 mol) were
placed in a 250 mL two-necked round bottomed flask
equipped with an addition Dean Stark apparatus. The
mixture was stirred at 100 ꢁC for 8 h under dry N2. Then
20
133 ꢁC. ½aꢂD ¼ ꢀ28.8 (c 0.04, EtOH). Mw 459.5 g
(found: C, 49.57; H, 6.74; N, 3.05, C19H31NO4ÆNaClO4
requires: C, 49.62; H, 6.75; N, 2.98). IR (KBr): 3478,
3062, 3027, 1479, 1454, 1246, 1121, 741 cmꢀ1 1H
.
NMR (CDCl3): d 0.86 (3H, t, J = 7.21 Hz); 1.16 (1H,

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M. Togrul et al. / Tetrahedron: Asymmetry 16 (2005) 2771–2777
10. Armstrong, D. W.; Zhou, Y.-W. J. Liquid Chromatogr.
1994, 17, 1695.
br s); 1.56 (1H, br s); 2.80–4.10 (21H, m); 7.25–7.35 (5H,
m). 13C NMR (CDCl3): d 12.05, 17.92, 68.51, 68.76,
68.96, 69.91, 127.31, 128.78, 128.94. The free
ligand was recovered by passing the complex through
a column on basic AI2O3. Triethyl amine–ethyl acetate–
petroleum ether [(40–60), 3:30:67, respectively] as oil.
´
´
11. Bako, P.; To¨ke, L. J. Incl. Phenom. 1995, 23, 195; Bako,
P.; Kiss, T.; To¨ke, L. Tetrahedron Lett. 1997, 38, 7259;
´
Bako, P.; Vizvardi, K.; Toppet, S.; Eycken, der E. V.;
Hoornaert, G. J.; To¨ke, L. Tetrahedron 1998, 54, 14975;
´
Bako, P.; Novak, T.; Ludanyi, K.; Peter, B.; To¨ke, L.;
Keglevich, G. Tetrahedron: Asymmetry 1999, 10, 2373;
´
´
Bako, P.; Czinege, E.; Bako, T.; Czugler, M.; To¨ke, L.
3.2.6. (R)-(ꢀ)-2-Ethyl-N-benzyl-4,7,10,13-tetraoxa-8,9-
´
Tetrahedron: Asymmetry 1999, 10, 4539; Bako, P.; Bajor,
Z.; To¨ke, L. J. Chem. Soc., Perkin Trans. 1 1999, 3651;
benzo-1-azacyclopentadec-8-ene II. To
a
solution
of NaH (80% in mineral oil) 3.57 g (120 mmol) in dry
´
´
Bako, P.; Bako, T.; Bisztray, K.; Szo¨llo¨sy, A.; Nagy, K.;
THF (100 mL) under a N2 atmosphere, (R)-(ꢀ)-N-
To¨ke, L. J. Incl. Phenom. Macrocycl. Chem. 2001, 39, 247;
Novak, T.; Bako, P.; Keglevich, G.; Dobo, A.; Vekey, K.;
benzyl-4-hydroxymethyl-3-azahexzan-1-ol
3
6.62 g
´
´
(30 mmol) in THF (100 mL) was added slowly at 0 ꢁC.
The mixture was heated slowly to 30–40 ꢁC. The mixture
was then kept at this temperature for 1.5 h. 1,2-Bis-(2-p-
tolylsulfonylethoxy)benzene 6 (16.7 g, 33 mmol) in THF
(100 mL) was added dropwise to the mixture in 2 h. The
mixture was stirred at 80 ꢁC for 5 days. THF extract was
evaporated and water (50 mL) added to the remaining
residue. The organic phase was extracted with CHCl3
(3 · 50 mL) and the combined organic phase dried using
MgSO4 and evaporated. The product was dissolved in
ethyl acetate (5 mL) and NaClO4ÆH2O 4.20 g (30 mmol)
in ethyl acetate (5 mL) was then added. The product was
To¨ke, L. J. Incl. Phenom. Macrocycl. Chem. 2001, 40, 207;
´
´
Bako, T.; Bako, P.; Szo¨llo¨sy, A.; Czugler, M.; Keglevich,
´
G.; To¨ke, L. Tetrahedron: Asymmetry 2002, 13, 203; Bako,
´
T.; Bako, P.; Keglevich, A. G.; Batheri, N.; Czugler, M.;
Tatai, J.; Novak, T.; Parlagh, G.; To¨ke, L. Tetrahedron:
Asymmetry 2003, 14, 1917.
12. Gokel, G. W. Chem. Soc. Rev. 1992, 21, 39.
13. Samu, E.; Huszthy, P.; Horvath, G.; Szo¨llosy, A.;
Neszmelyi, A. Tetrahedron: Asymmetry 1999, 10, 3615;
Izatt, R. M.; Wang, T.; Hathaway, J. K.; Zhang, X. X.;
Curtis, J. C.; Bradshaw, J. S.; Zhu, C. Y. J. Incl. Phenom.
Macrocycl. Chem. 1994, 17, 157.
14. Pietraszkiewicz, M.; Kozbial, M.; Pietraszkiewicz, O. J.
Membr. Sci. 1998, 138, 109; Togrul, M.; Turgut, Y.;
Hosgoren, H. Chirality 2004, 16, 351; Turgut, Y.; Sahin,
E.; Togrul, M.; Hosgoren, H. Tetrahedron: Asymmetry
2004, 15, 1583; Demirel, N.; Bulut, Y. Tetrahedron:
Asymmetry 2003, 14, 2633; Demirel, N.; Bulut, Y.;
Hosgoren, H. Tetrahedron: Asymmetry 2004, 15,
2045.
recrystallized from ethyl acetate to yield 10.50 g (69%),
20
mp 152–154 ꢁC. ½aꢂD ¼ ꢀ2.2 (c 0.04, EtOH). Mw
507.5 g (found: C, 54.45; H, 6.18; N, 2.72, C23H31NO4-
NaClO4 requires: C, 54.38; H, 6.10; N, 2.75); IR (KBr):
3061, 3024, 2968, 2876, 1593, 1503, 1455, 1250, 1199,
1117, 1028, 928, 748, 702, 623 cmꢀ1; 1H NMR (CDCl3):
d 0.94 (3H, t, J = 7.32 Hz), 1.63 (1H, br s), 1.56 (1H, br
s), 2.86–4.31 (17H, m), 6.75–7.31 (9H, m); 13C NMR
(CDCl3): d 12.51, 18.23, 66.79, 68.30, 68.67, 70.75,
113.02, 122.45, 127.55, 128.77, 129.36, 147.13.
15. Peng, X.-B.; Huang, J.-W.; Li, T.; Ji, L.-N. Inorg. Chim.
Acta 2000, 305, 111; Demirel, N.; Bulut, Y.; Hosgoren, H.
Chirality 2004, 16, 347.
16. Chen, X.; Du, D.-M.; Hua, W.-T. Tetrahedron: Asymme-
try 2003, 14, 999.
17. For example, see: (a) Vo¨gtle, F.; Weber, E. In The
Chemistry of Ethers, Crown Ethers, Hydroxyl Groups and
their Sulphur Analogues. Part 1; Patai, S., Ed.; John Wiley:
New York, 1980, Chapter 2, pp 59–156; (b) Weber, E.;
Vo¨gtle, F. In Host Guest Complex Chemistry I; Vo¨gtle, F.,
Ed.; Springer: Berlin, 1981, Chapter 1, pp 1–41; (c) Cram,
D. J.; Trueblood, K. N. In Host Guest Complex Chemistry
1; Vo¨gtle, F., Ed.; Springer: Berlin, 1981, Chapter 2, pp
43–106.
Acknowledgement
This work was supported by the University of
¨
Dicle under grant no. DUAPK-04-FF-56.
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