Synthesis of novel C2-symmetric chiral crown ethers and investigation of their enantiomeric recognition properties

Article abstract of DOI:10.1016/j.tetasy.2009.09.010

A series of new C₂-symmetric chiral aza crown ether macrocycles 1-4 have been synthesized from (S)-3-aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These new macrocycles have be

Full text of DOI:10.1016/j.tetasy.2009.09.010

Tetrahedron: Asymmetry 20 (2009) 2293–2298
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of novel C2-symmetric chiral crown ethers and investigation
of their enantiomeric recognition properties
*
Yilmaz Turgut , Tarik Aral, Halil Hosgoren
University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakır, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new C2-symmetric chiral aza crown ether macrocycles 1–4 have been synthesized from (S)-3-
aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester
derivatives. These new macrocycles have been shown to be strong complexing agents for primary organic
Received 4 August 2009
Accepted 10 September 2009
Available online 14 October 2009
ammonium salts (with K up to 176.93 Mꢀ1 and
D
G° up to 12.81 kJ molꢀ1) by 1H NMR titration. These
-enantiomer of phenylalanine methyl
ester hydrochloride with KD/KL up to 6.87 in CDCl3 with 0.25% CD3OD.
Ó 2009 Elsevier Ltd. All rights reserved.
macrocyclic host exhibited enantioselective bonding toward the
D
1. Introduction
into the macrocyclic skeleton increases the stability of complexes
with ammonium ion and amine and amino acid salts.10 However,
among a large series of chiral crown ethers, aza crown ethers have
been studied to the least extent.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 ex-
pected to play an important role. Azacrown ethers with a side arm
attached to the nitrogen atom in the macrocyclic ring may enhance
and regulate cation binding properties, as well as the lipophilicity.
Crown ethers with heteroatom-containing podand arms are known
to have a highly lipophilic character and a unique guest selectivity
via macroring-side arm cooperativity.12,13
It is known that the symmetry of the macrocyclic ring is crucial
for enantiomeric recognition, therefore we focused on the synthesis
of C2-symmetric chiral crown ethers derived from amino alcohols.
Our interest has been focused on the enantiomeric recognition of
amino acids utilizing a synthetic chiral crown ether. We recently
studied the enantiomeric recognition of chiral ammonium salts by
an aza crown ether.14 Herein, we report the synthesis of a new
C2-symmetric chiral receptor 18-crown-6 derivatives and their
Chiral crown ethers are among the most efficient enantioselec-
tive receptors for amines, amino acids, and their derivatives.1
Therefore, they can be used as catalysts in asymmetric reactions,
enantioselective sensors, and models of biological systems.2,3 In
1970s the first synthetic chiral crown ethers were prepared by
Cram et al.4 These enantiomerically pure macrocyclic molecules
showed significant enantiomeric recognition toward protonated
chiral amines and amino acid esters.5 Since the pioneering work
of Cram and co-workers a large number of different chiral crown
ethers have been synthesized and studied for enantiomeric recog-
nition toward protonated chiral primary amines, amino acids, and
their derivatives.6,7,1,8,9 The study of the enantioselective recogni-
tion of protonated chiral primary amines, amino acids, and their
derivatives is of great significance since these compounds are basic
building blocks of important biomolecules1 and useful in develop-
ing new methods for asymmetric (synthesized) chromatographic
resolution of enantiomers.1
Effective enantiomeric recognition requires that a chiral macro-
cyclic receptor be capable of forming sufficiently stable complexes
with substrate enantiomers and that a chiral barrier be present,
which reduces the stability of one of the diastereoisomeric com-
plexes thus formed.
enantiomeric recognition of different
hydrochlorides -PheAlaOMe, -PheAlaOMe,
-ValOMe) by 1H NMR titration method in CDCl3 with 0.25% CD3OD.
a-amino acid methyl ester
(D
L
D-ValOMe, and
L
In other words, the enantiodifferentiating properties of chiral
crown ethers are determined by the stability of complexes with
chiral substrates and by the nature of the chiral fragment in the
macroring. The complexing power of chiral crown ethers depends
on a number of factors, including the nature of the donor groups in
the macroring. In many cases, the introduction of nitrogen atoms
2. Results and discussion
2.1. Synthesis
Initially, phenol and (S)-glycidol were transformed into diol 1b,
which was tosylated to generate 2b. Compounds 2a and 2b were
reacted with excess (S)-
in yields of 65% and 63%, respectively (Scheme 1).
a-phenyl ethylamine to obtain 4a and 4b
* Corresponding author. Tel.: +90 412 2488550; fax: +90 412 2488300.
E-mail address: yturgut@dicle.edu.tr (Y. Turgut).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.010

2294
Y. Turgut et al. / Tetrahedron: Asymmetry 20 (2009) 2293–2298
OH
R
R
R
i
ii
Ar-OH
+
+
O
HO
HO
OH
OTs
iv
TsO
OTs
1
2
3
Ar
N
R
R
iii
Ar
N
+
+
OTs
Ar
Ar
NH2
HO
TsO
OTs
HO
N
H
OH HO
4
(S,S)-3
Ar
R:
a: -CH3,
b: -CH2OAr
Ar
N
N
ArO
OAr
OH HO
(S,S)-4
Scheme 1. Reagents and conditions: (i) piperidine hydrochloride, 75 °C; (ii) tosyl chloride, dichloromethane: pyridine, ꢀ25 °C, and (iii, iv) Na2CO3, 14 h, 120 °C.
The C2-symmetric chiral amino alcohols (S,S)-3 and (S,S)-4 were
synthesized from the ditosylate with excess 4a and 4b in the pres-
ence of Na2CO3 in yields of 46% and 48%, respectively.
Chiral C2-symmetric crowns 1–4 were synthesized for the enan-
tiomeric recognition of a-amino acid methyl ester hydrochlorides.
The syntheses of the designed chiral crown ethers 1–4 are summa-
rized in Schemes 2 and 3, respectively. Cyclization of the appropri-
ate ditosylate with (S,S)-3 and (S,S)-4 using NaH as a base in dry
and freshly prepared THF afforded 3 and 4.
agents. Crown ethers, which usually involve compounds with an
18-crown-6 unit, are known for their ability to bond to protonated
primary ammonium cations16 via a three-point (tripod) hydrogen
bond interaction. Studies on the binding of amino acid carboxyl-
ates by multiple hydrogen bonding receptors have gained increas-
ing importance in recent years. Examples of chiral recognition
involving chiral 18-crown-6 type ligands and chiral primary
ammonium cations have already been shown by us and others.17,18
The association constants of the supramolecular systems
formed were calculated according to the modified Benesi–Hilde-
brand equation.19 All the binding constants of the complexes were
obtained by the non-linear least-squares method on the basis of
the 1H NMR spectra data using the same methyl peak of the chiral
guest.20
2.2. Enantiomeric recognition by 1H NMR of host–guest
complexes
NMR spectroscopy is one of the most common methods em-
ployed for the analysis of chiral compounds.15 Enantiomerically
pure derivatizing reagents can be used to prepare diastereomeric
compounds that have differences in their NMR spectra. Alterna-
tively, enantiomerically pure or enriched compounds can be used
as chiral solvating agents to form diastereomeric complexes that
associate through non-covalent interactions.
The enantiomeric recognition for the hydrogen chloride salts of
D
-, L-PheAlaOMe, D-, L-ValOMe by chiral crown ethers 1–4 have
been characterized by 1H NMR titration method. Figure 2 shows
the spectroscopic changes of the 1H NMR methine proton signals
of
D
- and
L
-phenylalanine methyl ester hydrochloride (5.6 mM) in
(2.23–
the absence and presence of chiral crown ethers
4
The NMR titration method has proven to be effective in deter-
mining the bonding constant value for chiral crown ether-chiral
ammonium cation interaction, especially for systems in which
both host and guest molecules contain aromatic groups. The
advantage of the 1H NMR method are that the experiment can be
carried out in a wide variety of solvents and that useful structural
information can often be obtained.
17.8 mM) in CDCl3 with 0.25% CD3OD at 298 K. Before adding
any host, the methine proton of guest showed one triplet peak at
around 4.35 ppm. When the host and guest interact in a solution
forming a 1:1 complex, this singlet peak was shifted downfield.
The binding constant of the complex was obtained using these
peaks.
As shown in Table 1 and Figure 2, all amino acid methyl ester
hydrochlorides form a stable complex with chiral crown ethers
1–4. The association constants of the chiral crown ether 1 with
Crown ethers are important families of cavity compounds that
have found rather widespread application as chiral NMR solvating
Ar
Ar
Ar
Ar
Ar
N
N
N
N
N
O
O
O
O
Ar
N
O
O
O
O
+
+
O
O
O
O
OTs
TsO
OTs
TsO
OH
HO
(S,S)-3
1
2
Scheme 2. Synthesis of chiral crown macrocycles. Reagents and conditions: (1) NaH/THF, reflux, 2 h; (2) ditosylate/THF, 50 h.

Y. Turgut et al. / Tetrahedron: Asymmetry 20 (2009) 2293–2298
2295
Ar
Ar
Ar
N
O
N
N
O
N
OAr
ArO
TsO
O
O
O
O
Ar
N
N
O
O
+
+
O
O
O
O
TsO
ArO
OAr
OAr
ArO
OH HO
Ar
OTs TsO
Ar
3
4
(S,S)-4
Scheme 3. Synthesis of chiral crown macrocycles. Reagents and conditions: (1) NaH/THF, reflux, 2 h; (2) ditosylate/THF, 50 h.
found that the highest enantioselectivity can be obtained when
the host contains a benzo unit on the ring of the chiral macrocycles
0.5
0.4
0.3
0.2
0.1
0.0
as seen in 3. From Table 1, host 3, the
D
-form of PheAlaOMe is 6.87
times more stable than the
L
-form (KD/KL = 6.87 and ꢀ G° =
D
12.81 kJ molꢀ1). These results demonstrate that the substituent
on the stereogenic center plays a very important role on the chiral
recognition. It is also known that for enantiomeric recognition, the
steric repulsion between the substituent on the stereogenic center
(e.g., alkyl-group) and the substituent of the amino acid ester has
been found to be an important factor.21 The high enantioselectivity
of the macrocycles might be due to its pseudo 18-crown-6 frame
work, which seems to provide a good environment for noncovalent
0.0
0.5
1.0
[H]/[H]+[G]
Figure 1. Job Plots for
D
-ValOMeꢁHCI and host 4.
interactions (e.g., ion pairing, hydrogen bonding, cation–
p interac-
tion and aromatic face-to-face or/and edge interaction). On
p–p
the
and 25.45, respectively, The
the -form (KD/KL = 1.37), as shown in Table 1. In the same way,
crown 2 exhibited chiral recognition toward the enantiomers of a
PheAlaOMe salt by forming a complex with the -form of the guest,
which was 2.27 times more stable than that formed with the
-form and ꢀ
G° = 9.61 kJ molꢀ1
Host 1 differed from 3 in that the methyl substituent on 1 is re-
placed by an aryloxy group in 3. From our earlier study;14 it was
D
- and
L
-enantiomers of PheAlaOMe were found to be 34.82
the other hand, the macrocyclic 4 exhibits stronger binding and
better enantioselectivity for the amino acid esters containing an
aliphatic group than for those possessing an aromatic group. This
result can be explained by the bulkiness of the valine group com-
pared to the phenylalanine group of the amino acids.
D-form is 1.37 times more stable than
L
D
As shown in Table 1, steric repulsion will give one of the possi-
L
D
.
ble explanations of the
hydrochlorides higher binding constant as compared to that of
the -series. Even though it is quite difficult to extract any clear
D-form of all amino acid methyl ester
L
Figure 2. 1H NMR spectral changes of chiral crown ether 4 in the presence of phenyl alanine methyl ester hydrochloride (methine signal) in CDCl3 with 0.25% CD3OD.

2296
Y. Turgut et al. / Tetrahedron: Asymmetry 20 (2009) 2293–2298
Table 1
4.2. Syntheses
Binding constants (Ka), the Gibbs free energy changes (ꢀDG°) and enantioselectivites
KD/KL for the complexation of D-/L-guest with the hosts (1–4) in CDCl3 with 0.25%
4.2.1. (S)-(+)-2-Hydroxypropyl p-toluenesulfonate 2a
CD3OD
To a stirred solution of (S)-2-propanediol (5.18 g, 68.06 mmol) in
dichloromethane/pyridine (10:10 V/V) at ꢀ25 °C under argon was
added dropwise p-toluenesulfonylchloride (12.97 g, 68.06 mmol)
dissolved in 10 mL CH2Cl2 over a period of 2 h. The mixture was stir-
red at ꢀ25 °C for 4 h and then rt for 2 h. After the reaction was com-
pleted, 150 mL of CH2Cl2 were added and the mixture was shaken
successively with ice-cold water, 1 M 40 mL aqueous HCl, 75 mL
water, saturatedNaHCO3, and water, respectively. The organic phase
was dried with MgSO4 and filtered and the solvent was removed un-
der reduced pressure. The residue was purified by chromatography
over silicagel usingtoluene/EtOAc(5/1) to give 2a (9 g, 58%)as white
Host
1
Guest
-PheAlaOMeꢁHCI
-PheAlaOMeꢁHCI
-ValOMeꢁHCI
-ValOMeꢁHCI
-PheAlaOMeꢁHCI
-PheAlaOMeꢁHCI
-ValOMeꢁHCI
-ValOMeꢁHCI
-PheAlaOMeꢁHCI
-PheAlaOMeꢁHCI
-ValOMeꢁHCI
-ValOMeꢁHCI
-PheAlaOMeꢁHCI
-PheAlaOMeꢁHCI
-ValOMeꢁHCI
-ValOMeꢁHCI
Ka (dm3 molꢀ1
)
KD/KL
ꢀD )
G° (kJ molꢀ1
D
34.82 0.012
25.45 0.021
0.50 0.039
6.43 0.008
48.44 0.014
21.38 0.028
4.80 0.031
8.30 0.007
176.93 0.016
25.76 0.018
9.04 0.038
2.66 0.018
46.19 0.019
21.71 0.022
36.48 0.014
6.06 0.017
1.37
8.78 0.018
8.01 0.018
7.47 0.032
6.92 0.018
9.61 0.014
7.58 0.011
7.95 0.030
7.20 0.008
12.81 0.018
8.04 0.019
9.64 0.030
8.63 0.020
9.49 0.020
7.62 0.021
12.17 0.012
6.87 0.016
L
D
1.45
2.27
1.36
6.87
1.50
2.13
8.50
L
2
3
4
D
L
D
L
D
L
D
crystals. Mp 33–35 °C (lit.23 34–35 °C), ½a D25
ꢂ
ꢀ 12:05 (c 1, CHCl3). 1H
L
D
NMR (CDCI3): d (ppm) 1.17 (d, 3H, J = 7.2 Hz), 2.12 (s, 1H), 2.47 (s,
3H), 3.84–3.89 (m, 1H), 3.99–4.08 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz),
7.82 (d, 2H, J = 8.0 Hz).
L
D
L
4.2.2. (S)-1-(p-Toluenesulfonate)-3-phenoxy-2-propanole 2b
To a stirred solution of (S)-3-phenoxypropane-1,2-diol24 (5.00 g,
29 mmol) in dichloromethane/pyridine (10:10 V/V) at ꢀ25 °C un-
der argon was added dropwise p-toluenesulfonylchloride (5.67 g,
29 mmol) dissolved in 20 mL of CH2Cl2 over a period of 2 h. The
mixture was stirred at ꢀ25 °C for 4 h and then kept at rt for 2 h.
After the reaction was completed, 150 mL of CH2Cl2 were added
and the mixture was shaken successively with ice-cold water,
1 M of 40 mL aqueous HCl, 75 mL of water, saturated NaHCO3,
and water. The organic phase was dried with MgSO4 and filtered,
and the solvent was removed under reduced pressure. The residue
was purified by chromatography over silica gel using toluene/
EtOAc (5/1) to give 2b (7 g, 75%) as white crystals. Mp: 83–84 °C
reason for this trend, the hydrogen bonding of the ammonium cat-
ion of the guest with the oxygen and nitrogen of the macrocycle
could play important roles in enantiomeric recognition. Therefore,
the hydrogen bonding between the host and the guests may lead to
the formation of the complex, while steric interaction contributes
to enantiomeric recognition. In general, a N–Hꢁ ꢁ ꢁN hydrogen bond
is stronger than a N–Hꢁ ꢁ ꢁO bond.22 Thus, the typical tripod hydro-
gen bond involving nitrogen on the macrocycle and two alternate
oxygen atoms of the macrocycle and three hydrogen atoms of
the ammonium cation is possible.
½
a 2D5
ꢂ
¼ ꢀ10:0 (c 1, MeOH); 1H NMR (CDCl3): d (ppm) 2.50 (s, 3H),
3. Conclusions
4.16 (d, 2H, J = 4.9 Hz), 4.23–4.29 (m, 3H), 6.94 (d, 2H, J = 9.6 Hz),
7.35 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz), 8.20 (d, 2H,
J = 7.8 Hz); 13C NMR (CDCl3): d (ppm) 21.54, 68.00, 68.80, 69.80,
114.64, 125.84, 127.94, 129.98, 132.85, 142.33, 145.30, 163.00.
Anal. Calcd for C16H18SO5: C, 59.63; H, 5.59; S, 9.94. Found: C,
59.64; H, 5.60; S, 7.01.
In conclusion, we have developed a series of new C2-symmetric
chiral amino alcohol and crown macrocycles 1–4 and their enan-
tiomeric recognition properties toward D- and L-amino acid methyl
ester hydrochlorides using NMR titration have been studied.
Crown macrocycle 3 exhibited the highest enantioselectivity to-
ward
to 6.87. The structure–binding relationship studies showed that
the interaction between the phenyl group of the ammonium
D-phenylalanine methyl ester hydrochloride with KD/KL equal
4.2.3. (S)-1-[N-(S)-
a-Phenyl ethyl]amino-2-propanole 4a
p–p
(S)- -Phenylethylamine (18.97 g, 156.52 mmol), (S)-(+)-2-hydroxy-
a
guest and benzo unit and aryloxy subunit of the macrocycle host
is important for high enantioselectivity.
propyl p-toluenesulfonate (9 g, 39.13 mmol) and Na2CO3 (4.77 g,
45.00 mmol) were stirred at 110 °C for 12 h under argon. The mixture
was cooled after which 100 mL of CHCl3 were added to the mixture
and refluxed for 2 h. The organic phase was separated from the solid
phase. The remaining solid was re-extracted with CHCl3 (3 ꢃ 50 mL).
The combined CHCl3 layers were dried with Na2SO4 and the organic
4. Experimental
4.1. Reagents and general methods
All chemicals were reagent grade unless otherwise specified. (S)-
phase was removed under reduced pressure. The excess (S)-a-phenyl
ethylamine was distilled at 90–95 °C/1 mmHg and the product was
a-Phenyl ethylamine was purchased from Fluka. The D- and L-ami-
distilled at 140–141 °C/1 mmHg to give 4a (4.52 g, 65%) as an oil.
a 3D4
ꢂ
¼ þ25:4 (c 1, CHCl3); 1H NMR (CDCl3): d (ppm) 1.10 (d, 3H,
no acid methyl ester hydrochlorides were obtained from Aldrich
Chemical Co. Silica Gel 60 (Merck, 0.040–0.063 mm) and silica
gel/TLC-cards (F254) were used for flash column chromatography
and TLC. All reactions were carried out under an N2 atmosphere
with a dry solvent under anhydrous conditions, unless otherwise
noted. Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none ketyl immediately prior to use and methylene chloride
(CH2CI2) was dried from calcium hydride. Melting points were
determined with a Gallenkamp Model apparatus with open capil-
laries. Elemental analyses were performed with a Carlo-Erba 1108
model apparatus. Optical rotations were taken on a Perkin Elmer
341 model polarimeter. 1H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded on a Bruker DPX-400 High Performance Dig-
ital FT-NMR Spectrometer. The chemical shifts (d) and coupling
constants (J) are expressed in parts per million and hertz.
½
J = 4 Hz), 1.40 (d, 3H, J = 4 Hz), 2.26 (q, 1H, J = 4.0 Hz), 2.52 (br s, 2H),
2.47 (q, 1H, J = 8.0 Hz), 3.82 (q, 2H, J = 4.0 Hz), 7.25 (m, 5H). 13C NMR
(CDCl3): d (ppm) 20.41, 24.46, 54.40, 57.68, 65.79, 126.54, 129.09,
128.56, 144.98. Anal. Calcd for C11H17NO: C, 73.74; H, 9.49; N, 7.82.
Found: C, 74.00; H, 9.70; N, 7.80.
4.2.4. (S)-1-[N-(S)-a-Phenyl ethyl]amino-3-phenoxy-2-
propanole 4b
(S)-a-Phenylethylamine (3.75 g, 31.05 mmol), (S)-1-(p-toluene-
sulfonate)-3-phenoxy-2-propanole 2b (2.00 g, 6.21 mmol) and
Na2CO3 (0.65 g, 6.13 mmol) were stirred at 110 °C for 12 h under
argon. Then the mixture was cooled and 50 mL CHCl3 was added
to the mixture and refluxed for 2 h. The organic phase was sepa-
rated from the solid phase. The remaining solid was re-extracted

Y. Turgut et al. / Tetrahedron: Asymmetry 20 (2009) 2293–2298
2297
with CHCl3 (3 ꢃ 25 mL). The combined CHCl3 layers were dried
in 50 mL of THF was added dropwise. The resulting mixture was
stirred at 0 °C for 30 min and then refluxed for 50 h. After the reac-
tion was complete, the solvent was removed. The residue was ta-
with Na2SO4 and organic phase was removed under reduced pres-
sure. The excess (S)-a-phenylethylamine was distilled at 90–95 °C/
1 mmHg and the residue was purified by chromatography over sil-
ken up in
a
mixture of ice-water (50 mL) and CH2Cl2
ica gel using EtOAc/n-hexane/Et3N (7/5/1) to give 4b (1.00 g, 63%)
(3 ꢃ 100 mL). The resulting mixture was mixed well and separated.
The combined organic phase was dried over MgSO4, filtered, and
the solvent evaporated. The crude product was purified by chroma-
tography on silica gel (eluent: petroleum ether/EtOAc/Et3N: 90/10/
as a yellow oil. ½a D34
ꢂ
¼ þ35:4 (c 1.68, CHCl3); IR:
m 3326, 3058, 3031,
2967, 2929, 2877, 1741, 1606, 1587, 1490, 1452, 1375, 1297, 1247,
1170, 1085, 1047, 881, 815, 752, 694 cmꢀ1 1H NMR (CDCl3): d
.
(ppm) 1.44 (d, 3H, J = 7.0 Hz), 2.63 (br s, 2H, NH ve OH) 2.73 (m,
2H), 3.83 (q, 1H, J = 7.0 Hz) 3.97 (m, 3H), 6.95 (m, 3H), 7.39 (m,
10H). 13C NMR (CDCl3): d (ppm) 24.23, 50.12, 58.74, 68.95, 70.61,
115.65, 121.07, 126.69, 127.15, 128.61, 129.53, 145.15, 158.72.
Anal. Calcd for C17H21NO2: C, 75.27; H, 7.75; N, 5.16. Found: C,
75.25; H, 7.59; N, 5.18.
5) to give 1 (120 mg, 20%) as an oil. ½a D30
ꢂ
¼ þ41 (c 2.5, CHCl3) 1H
NMR (CDCl3): d (ppm) 0.98 (d, 6H, J = 6.0 Hz), 1.31 (d, 6H,
J = 6.8 Hz), 2.34–2.38 (dd, 2H, J = 8.0 Hz), 2.57–2.61 (m, 4H), 2.72
(q, 2H, J = 8.0 Hz), 3.51 (q, 2H, J = 8.0 Hz), 3.66–3.80 (m, 14H),
7.28–7.31 (m, 10H). 13C NMR (CDCl3): d (ppm) 15.90, 18.19,
51.55, 56.94, 60.33, 68.21, 71.00, 71.30, 75.47, 126.54, 127.92,
128.34, 144.37. Anal. Calcd for C30H46N2O4: C, 72.29; H, 4.60; N,
5.62. Found: C, 72.40; H, 4.65; N, 3.50.
4.2.5. (2S,9S)-4,7-[N-(S)-a-Phenyl ethyl]diaza-2,9-decanediol
(S,S)-3
(S)-1-[N-(S)-a-Phenyl ethyl] amino-2-propanole (9 g, 50.28 mmol),
4.2.8. (6S,17S)-1,4-[N-(S)-a-Phenylethyl]-diaza-6,17-dimethyl-
ethylene glycol ditosylate (3.10 g, 8.38 mmol), and Na2CO3 (1.5 g,
14.15 mmol) were stirred at 120 °C for 14 h under Argon. Then the
mixture was cooled and 100 mL CHCl3 was added to the mixture
and refluxed for 2 h. The organic phase was separated from the so-
lid phase. The remaining solid was re-extracted with CHCl3
(3 ꢃ 50 mL). The combined CHCl3 layers were dried with Na2SO4
and the organic phase was removed under reduced pressure. The
11,12-benzo-7,10,13,19-tetraoxacyclooctadec-11-ene 2
Macrocycle 2 was prepared as described above for macrocycle 1
starting from (S,S)-3 (400 mg, 1.04 mmol) and 1,2-bis-(2-p-tolylsul-
phonyl ethoxy)benzene (527 mg, 1.04 mmol). The crude product
was purified by chromatography on silica gel (eluent: petroleum
ether/EtOAc/Et3N: 67/30/3) to give 2 (120 mg, 22%) as an oil.
½
a 3D0
ꢂ
¼ þ85 (c 2.5, CHCl3) 1H NMR (CDCI3): d (ppm) 1.04 (d, 6H,
excess (S)-1-[N-(S)-a-phenyl ethyl] amino-2-propanole was dis-
J = 5.6 Hz), 1.30 (d, 6H, J = 6.4 Hz), 2.19–2.26 (m, 2H), [AB system: a
part of A 2.39, 1H, J = 5.59 Hz; a part of B: 2.44, J = 7.60, 1H], [AB sys-
tem: a part of A: 2.52, 1H, J = 7.60 Hz; a part of B: 2.53, 1H, J = 12.80),
2.66 (dd, 2H, J = 5.2 Hz and J = 8.0 Hz), 3.40 (q, 2H, J = 6.00 Hz), 3.74–
3.86 (m, 6H), 4.11 (t, 4H, J = 4.00 Hz), 6.97–7.07 (m, 6H), 7.20–7.30
(m, 8H), 13C NMR (CDCl3): d (ppm) 14.80, 18.43, 50.52, 56.88,
59.59, 67.34, 68.97, 75.77, 115.05, 119.27, 121.42, 124.28, 127.88,
144.18, 149.72. Anal. Calcd for C34H46N2O4: C, 74.72; H, 8.42; N,
5.13. Found: C, 74.96; H, 8.64; N, 5.14.
tilled at 140–141 °C/1 mmHg. The residue was purified by chroma-
tography over silica gel using EtOAc/hexane/Et3N (10/30/2) to give
(S,S)-3 (1.50 g, 46.00%) as a yellow oil. ½a D25
¼ ꢀ72:9 (c 3.4, CHCl3).
ꢂ
1H NMR (CDCl3): d (ppm) 1.12 (d, 6H, J = 8.0 Hz), 1.48 (d, 6H,
J = 8.0 Hz), 2.24 (t, 4H, J = 12.0 Hz), 2.43 (q, 2H, J = 4.0 Hz), 2.71–
2.76 (m, 2H), 3.76–3.80 (m, 4H). 3.76–3.80 (m, 4H), 4.78 (br s,
2H), 7.18–7.37 8 m, 10H). 13C NMR (CDCl3): d (ppm) 18.67, 20.25,
48.70, 58.56, 59.48, 63.57, 127.24, 128.18, 141.08. Anal. Calcd for
C24H36O2N2: C, 75.00; H, 9.37; N, 7.29. Found: C, 75.20; H, 9.45;
N, 7.18.
4.2.9. (6S,17S)-1,4-[N-(S)-a-Phenylethyl]-diaza-6,17-
diphenoxymethyl-7,10,13,19-tetraoxacyclooctadecane 3
Macrocycle 3 was prepared as described above for macrocycle 1
starting from (S,S)-4 (500 mg, 0.88 mmol) and triethyleneglycol
ditosylate (403 mg, 0.88 mmol). The crude product was purified
by chromatography on silica gel (eluent: petroleum ether/EtOAc/
4.2.6. (1S,8S)-3,6-[N-(S)-
diphenoxymethyl-1,8-decanediol (S,S)-4
(S)-1-[N-(S)- -Phenyl ethyl]amino-3-phenoxy–2-propanole 4b
a-Phenyl ethyl]diaza-1,8-
a
(5.60 g, 20.6 mmol), dibromoethane (1.29 g, 6.90 mmol) and
Na2CO3 (1.00 g, 9.40 mmol) were stirred at 120 °C for 14 h under
argon. Then the mixture was cooled and 100 mL of CHCl3 were
added to the mixture and refluxed for 2 h. The organic phase was
separated from the solid phase. The remaining solid was re-ex-
tracted with CHCl3 (3 ꢃ 50 mL). The combined CHCl3 layers were
dried with Na2SO4 and the organic phase was removed under re-
duced pressure. The residue was purified by chromatography over
silica gel using EtOAc/petroleum ether/Et3N (2/12/1) to give (S,S)-4
triethylamine: 25/5/3) to give 3 (150 mg, 25%) as oil. ½a D32
¼ þ87
ꢂ
(c 1, CHCl3); 1H NMR (CDCI3): d (ppm) 1.30 (d, 6H, J = 2.4 Hz),
2.50–2.55 (m, 6H), 2.59–2.64 (m, 1H), 2.92–2.97 (m, 1H), 3.64–
3.84 (m, 16H), 3.39–4.11 (m, 4H), 6.90–6.98 (m, 5H), 7.21–7.32
(m, 15H). 13C NMR (CDCl3): d (ppm) 16.84, 50.60, 53.03, 60.15,
68.91, 69.88, 70.83, 70.92, 71.34, 114.62, 120.65, 126.74, 127.89,
128.01, 129.38, 143.15, 158.94. Anal. Calcd for C42H54N2O6: C,
73.90; H, 7.92; N, 4.11. Found: C, 73.98; H, 8.05; N, 4.20.
(1.90 g, 48.71%) as a yellow oil. ½a D34
ꢂ
¼ ꢀ40:5 (c 0.74, CHCl3); IR:
m
3411, 3070, 3031, 2973, 2935, 2877, 1741, 1697, 1600, 1496, 1452,
4.2.10. (6S,17S)-1,4-[N-(S)-a-Phenylethyl]-diaza-6,17-
diphenoxymethyl-11,12-benzo-7,10,13,19-
1380, 1303, 1247, 1182, 1047, 912, 881, 823, 757 cmꢀ1
;
1H NMR
(CDCl3): d (ppm) 1.40 (d, 6H, J = 6.9 Hz), 2.51–2.65 (m, 5H), 2.77–
2.84 (m, 3H), 3.83–4.07 (m, 8H), 6.93–7.00 (m, 5H), 7.30–7.33
(m, 15H). 13C NMR (CDCI3): d (ppm) 13.92, 49.76, 53.59, 59.43,
67.63, 70.10, 114.67, 120.92, 127.73, 128.20, 128.33, 129.50,
142.20, 158.88. Anal. Calcd for C36H44O4N2: C, 76.05; H, 7.75; N,
4.93. Found: C, 76.10; H, 7.85; N, 4.98.
tetraoxacyclooctadec-11-ene 4
Macrocycle 4 was prepared as described above for macrocycle 1
starting from (S,S)-4 (500 mg, 0.88 mmol) and 1,2-bis-(2-p-tolylsul-
phonyl ethoxy)benzene (445 mg, 0.88 mmol). The crude product
was purified by chromatography on silica gel (eluent: petroleum
(40–60 °C) ether/EtOAc/Et3N: 25/5/3) to give 4 (130 mg, 20%).
½
a 3D0
ꢂ
¼ þ89 (c 2.5, CHCl3) 1H NMR (CDCl3): d (ppm) 1.33 (d, 6H, J =
4.2.7. (6S,17S)-1,4-[N-(S)-
a-Phenylethyl]-diaza-6,17-dimethyl-
6.8 Hz), 2.67–2.78 (m, 6H), 2.86 (d, 2H, J = 11.6 Hz), 3.77–3.84 (m,
4H), 3.88–3.98 (m, 4H), 4.09–4.19 (m, 8H), 6.79 (d, 4H, J = 8.4 Hz),
6.92–6.96 (m, 6H), 7.22–7.29 (m, 14H). 13C NMR (CDCl3): d (ppm)
15.87, 51.89, 52.68, 60.54, 69.06, 69.79, 78.70, 93.36, 113.99,
114.51, 120.51, 121.31, 126.75, 127.93, 128.02, 129.28, 143.92,
149.20, 158.85. Anal. Calcd for C46H54N2O6: C, 75.62; H, 7.39; N,
3.84. Found: C, 76.05; H, 7.40; N, 3.98.
7,10,13,19-tetraoxacyclooctadecane 1
To a well-stirred suspension of NaH (80 mg, 98%) in 50 mL of
dry THF was added dropwise under argon at 0 °C (S,S)-3 (400 mg,
1.04 mmol) dissolved in 50 mL of THF. The mixture was stirred at
rt for 1 h and at reflux temperature for 2 h. The reaction mixture
was cooled to 0 °C and ditosylate (447 mg, 1.04 mmol) dissolved

2298
Y. Turgut et al. / Tetrahedron: Asymmetry 20 (2009) 2293–2298
5. Kyba, E. P.; Timko, J. M.; Kaplan, L. J.; de Jong, F.; Gokel, G. W.; Cram, D. J. J. Am.
4.3. NMR experiments
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The stoichiometric of the complex between host-guest was
determined by a continuous variation plot (Job’s plot) according
to a method described in the literature.20 Equimolar amounts of
host and guest compounds were dissolved in CDCl3 with 0.25%
CD3OD. These solutions were distributed among ten NMR tubes,
with the molar fraction host and guest in the resulting solutions in-
creased or decreased from 0.1 to 0.9. The Job plots of 4 with
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D-Val-
D
that host 4 and the guests formed 1:1 instantaneous complexes.
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4.3.2. NMR titrations
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ten NMR tubes. The first tube was sealed only as guest. The host
solution was added in increasing amounts to the NMR tubes, so
that solutions with the following relative amounts of host versus
guest compound.25 The concentration of the guest was constant
(5.6 mM) with the increasing concentration of the added host.
Acknowledgements
18. Turgut, Y.; Demirel, N.; Hosgoren, H. J. Inclusion Phenom. Macrocyclic Chem.
2006, 54, 29.
We thank The Scientific and Technological Research Council of
Turkey for their financial support (Project No. 107 T 079). We also
thank Dr. Murat Kizil for various assistances.
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