Synthesis of new chiral crown ethers containing a (p-methoxyphenoxy)methyl moiety and their chiral recognition ability towards amino acid esters

Article abstract of DOI:10.1016/j.tetasy.2005.05.019

Novel crown ethers 9-13 containing a chiral subunit derived from 3-(p-methoxyphenoxy)propane-1,2-diol 7 were prepared in enantiomerically pure forms. Chiral recognition properties of these receptors towards L- and D-amino acid derivatives were examined by the UV-vis titration method. These receptors exhibit good chiral recognition towards the isomers (up to K_L/K _D = 5.81, ΔΔG₀ = 4.30 kJ mol^-1) in CHCl₃ at 25°C.

Full text of DOI:10.1016/j.tetasy.2005.05.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2119–2124
Synthesis of new chiral crown ethers containing a
(p-methoxyphenoxy)methyl moiety and their chiral
recognition ability towards amino acid esters
Mehmet Karakaplan* and Tarik Aral
University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakır, Turkey
Received 11 April 2004; accepted 11 May 2005
Abstract—Novel crown ethers 9–13 containing a chiral subunit derived from 3-(p-methoxyphenoxy)propane-1,2-diol 7 were pre-
pared in enantiomerically pure forms. Chiral recognition properties of these receptors towards L- and D-amino acid derivatives were
examined by the UV–vis titration method. These receptors exhibit good chiral recognition towards the isomers (up to KL/KD = 5.81,
DDG0 = 4.30 kJ molꢀ1) in CHCl3 at 25 ꢀC.
ꢁ 2005 Published by Elsevier Ltd.
1. Introduction
N-pivot crown ethers having methyl and ethylene side
arms, attached to aromatic p-donors have been re-
ported.8,9 In addition to this, a number of protein struc-
tures, having a flexible side arm, have been described to
demonstrate ammonium cation–p interactions.10 It is
known that the chiral nature of a crown ether, the rigi-
dity of the microenvironment of its cavity and the quality
of the side arm are all expected to play an important role
in enantioselective induction.
The chemistry of crown ethers has developed rapidly in
the years since Pedersen first described their synthesis.1
Over the last two decades, a wide interest in the chemis-
try of chiral crown ethers has been shown. A major
incentive for this research has been the discovery that
chiral recognition and catalytic activity, two important
properties of natural enzymes, can be displayed by these
macrocycles.2 Amino acids are the most important tar-
gets for molecular recognition by artificial host com-
pounds. This is due to their rich chemistry. For this
reason, chemists have been studying host–guest binding
of amino acids as an instrument for manipulation of
their reactivity.
In light of these observations and requirements for novel
types of host molecules to improve enantioselectivity, we
therefore undertook the design and synthesis of a group
of crown ethers replete with donor groups appended to
the macroring as a part of a flexible arm. We report
herein, the synthesis of new chiral crown ethers 9–13
from 3-(p-methoxyphenoxy)propane-1,2-diol 7, which
is also used for precursor of b-blockers. The host–guest
interaction involving these receptors 10–13 and chiral
amino acid derivatives were characterized.
Since Cram et al. reported the use of chiral macrocyclic
ligands in enantiomeric recognition,3 a great number of
chiral artificial receptors have been developed, such as
cyclophanes,4 crown ethers5 and cyclodextrins.6 There
is still a strong requirement for novel types of host mole-
cules in order to improve the enantioselectivity. Evi-
dence has accumulated over the past two decades that
cation–p interactions play an important role in macro-
molecular organization and in molecular recognition.7
Thus, alkali metal cation–p complexes of C-pivot and
2. Results and discussion
2.1. Synthesis
The glycerol unit could be incorporated by the primary
and secondary hydroxyls, which can be used as nucleo-
philes for the formation of the macrocycle rings and side
arm attached via the secondary hydroxyl. Thus, a number
*
Corresponding author. Fax: +90 412 24 88 039; e-mail:
mkkaplan@dicle.edu.tr
0957-4166/$ - see front matter ꢁ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.05.019

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M. Karakaplan, T. Aral / Tetrahedron: Asymmetry 16 (2005) 2119–2124
of side arms can be incorporated quite readily. In this
study, a (p-methoxyphenoxy)methyl flexible side arm
was chosen due to its donor groups, which are
analogous to the structures already reported.8,9 Chiral
subunit diol 7, was prepared from (S)-glycidol, p-meth-
oxyphenol and catalytic amounts of piperidine hydro-
chloride in high yield and enantiopurity according to
our previous report.11 As shown in Scheme 1, building
block diol 8 was prepared according to the procedure
reported.12 First, ethylene glycol was pseudoselectively
monoprotected with 3,4-2H-dihydropyran to give 2-(tetra-
hydropyranyloxy)ethanol and then the remaining free hy-
droxyl group in 2-(tetrahydropyranyloxy)ethanol was
tosylated to obtain 6 in a nearly quantitative yield. The
condensation of 2 equiv of 6 with 7 in the presence of
NaH followed by removal of the THP protection groups,
provided 8 in 69% overall yield, which is the common pre-
cursor of 18-crown-6 ethers 11–13 as shown in Scheme 2.
RO
RO
O
i
ii
ROH
OH
+
+
TsO
OTHP
HO
O
O
OH
HO
OH
8
7
6
OH
O
O
OH
OH
O
O
O
OTs
OTs
iii
iv
+
OH
4
3
Scheme 1. Reagents and conditions: (i) Piperidine hydrochloride, 70–80 ꢀC, 4 h; (ii) NaH, THF then HCl, MeOH; (iii) piperidine hydrochloride; (iv)
TsCl, pyridine, R = –C6H4–p-OMe.
RO
HO
O
OH
O
RO
RO
+
O
O
i
i
O
O
O
n
O
O
O
OTs
TsO
O
n=1,2
9
10
RO
RO
RO
O
O
O
O
O
O
O
O
O
i
O
O
+
i
+
O
O
O
O
O
O
OTs TsO
OH
HO
O
OTs TsO
+
OTs TsO
12
O
O
13
i
O
O
O
O
O
O
OR
11
Scheme 2. Reagents and conditions: (i) NaH, THF, reflux, 56 h.

M. Karakaplan, T. Aral / Tetrahedron: Asymmetry 16 (2005) 2119–2124
2121
The synthesis of crown ether 9 was initiated from the
ring closure of 7 with triethylene glycol di(p-toluenesulfo-
nate) in the presence of NaH in THF under high dilu-
tion conditions to give 9 in 15% yield, which was not
used for host–guest interaction due to its small cavity
size. Receptor 10 was prepared by essentially the same
procedure as that used for the preparation of 9 by using
tetraethylene glycol di(p-toluenesulfonate) to give 10 in
39% yield. The racemic form of this receptor has been
synthesized by similar ways and studied thoroughly for
different purposes such as its biological activity,13 mus-
cle contractility influence14 and binding properties.13,15
The enantiomerically pure chiral building block 8 was
employed simply for the synthesis of 18-membered
ethers 11–13. Thus, treatment of 8 with triethylene gly-
col di(p-toluenesulfonate) as described for 9 gave 11 in
18% yield. In order to investigate the effect of the benzo
unit on the macrocycle ring for the molecular recogni-
tion, which is known to increase the enantioselectivity
of aza-15-crown-5 ether derivatives towards chiral
ammonium cations,16 crown ether 12 was prepared by
the ring closure of 8 with ditosylate 2 in 12% yield.
Ditosylate 4 is an example of ditosylate containing a
naphtho unit for the extended rigidity of macrocycle
13 as seen in Scheme 1. Thus, the ring opening reaction
of ethylene oxide with 2,3-dihydroxynaphthalene and
piperidine hydrochloride as catalyst gave diol 3 accord-
ing to the reported procedure,17 then tosylated 3 gave 4
in overall 50% yield. The ring closure of 8 with 4 gave 13
in 12% yield, which can be easily crystallized from etha-
nol. The structures purposed for these macrocycles are
UV–vis spectroscopy is a convenient and widely used
method for the study of this binding phenomena. When
the receptor absorbs light at different wavelengths in the
free and complexed states, the difference in the UV–vis
spectra is sufficient for the estimation of molecular rec-
ognition thermodynamics. In UV spectroscopic titration
experiments, the addition of a varying concentration of
guest molecules results in a gradual increase or decrease
of characteristic absorption of 1:1 stoichiometry. The
complexation of ammonium cations (G) with chiral
crown ether type molecular (H) is expressed by Eq. 1:
H+G ꢀ HꢁG
ð1Þ
Under the conditions employed herein, chiral amino
acid esters were selected as the guest molecules. The
association constants of the supramolecular system
formed, were calculated according to the modified Ben-
esi–Hilderbrand equation,18 Eq. 2, where [H]0 and [G]0
refer to the total concentration of crown ether and amino
acid ester, respectively, De is the change in molar extinc-
tion co-efficient between the free and complexed crown
ether and DA denotes the absorption change of crown
ether on the addition of amino acid esters.
½Hꢂ ½Gꢂ =DA ¼ 1=KaDe þ ½Gꢂ =De
ð2Þ
0
0
0
For all the guest molecules examined, plots of calculated
[H]0[G]0/DA values as a function of [G]0 values gave
excellent linear relationships, supporting the 1:1 com-
plex formation. The binding constant (Ka) and free
energy changes (ꢀDG0) of these host with guest mole-
cules obtained from usual curve fitting analyses
(R >0.98) of observed absorbance changes are summa-
rized in Table 1. The binding constant Ka of the
complexes of crown ethers 10–13 with amino acid
ester salts was determined by the Benesi–Hilderbrand
equation on the basis of the UV–vis spectrum of the
1
consistent with the data obtained from H NMR, 13C
NMR, IR spectra and elemental analysis.
2.2. Molecular recognition and UV–vis
The main purpose of synthesizing these receptors is to
study their molecular recognition for guest molecules.
Table 1. Binding constants (Ka), the Gibbs free energy changes (ꢀDG0), enantioselectivities KL/KD and ꢀDDG0 calculated from ꢀDG0 for the
complexation of L/D guest with the chiral host 10, 11, 12 and 13 at 241 and 291 nm in CHCl3 at 25 ꢀC
Hosta
Guestb
K (dm3 molꢀ1
)
KL/KD
ꢀDG0 (kJ molꢀ1
27.3
)
cDDG0 (kJ molꢀ1
)
10
L-Ala-OMeÆHCl
D-Ala-OMeÆHCl
L-Phe-OMeÆHCl
D-Phe-OMeÆHCl
6.16 · 104
1.06 · 104
6.00 · 103
5.43 · 103
5.81
1.08
23.00
21.60
21.30
4.30
0.30
11
L-Ala-OMeÆHCl
D-Ala-OMeÆHCl
L-Phe-OMeÆHCl
D-Phe-OMeÆHCl
3.33 · 103
3.80 · 103
3.25 · 103
3.60 · 103
20.10
20.40
20.10
20.30
0.87
0.84
ꢀ0.30
ꢀ0.20
12
L-Ala-OMeÆHCl
D-Ala-OMeÆHCl
L-Phe-OMeÆHCl
D-Phe-OMeÆHCl
2.75 · 103
3.00 · 103
4.25 · 103
3.86 · 103
3.00 · 103
4.14 · 103
3.33 · 103
7.78 · 103
19.60
19.80
20.00
20.50
0.91
1.10
ꢀ0.20
ꢀ0.30
13d
L-Ala-OMeÆHCl
D-Ala-OMeÆHCl
L-Phe-OMeÆHCl
D-Phe-OMeÆHCl
19.80
20.60
20.10
20.20
0.72
0.42
ꢀ1.20
ꢀ2.10
a The concentration of the hosts = 2.00 · 10ꢀ4 mol dmꢀ3
.
b Ala-OMeÆHCl: alanine methyl ester hydrochloride; Phe-OMeÆHCl: phenylalanine methyl ester hydrochloride.
c DDG0 = DG0(L) ꢀ DG0(D).
d 2.00 · 10ꢀ5 mol dmꢀ3
.

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M. Karakaplan, T. Aral / Tetrahedron: Asymmetry 16 (2005) 2119–2124
ity of 13 may also play an important role in enantio-
selective recognition.
Significant results were obtained with receptor 10, which
was found to be the strongest binding constant and the
best enantioselectivity towards ala-OMe hydrochloride.
The binding constants of 10 towards L- and D-ala-
OMe hydrochloride were found to be 6.16 ·
104 dm3 molꢀ1 and 1.06 · 104 dm3 molꢀ1, respectively.
The L-form was 5.81 times more stable than the D-form
of ala-OMe hydrochloride, while receptor 10 had no
enantioselectivity towards phe-OMe hydrochloride
(KD/KL = 1.08). It is known that for enantiomeric recog-
nition, the steric repulsion between the substituent on
the stereogenic centre and the substituent of ammonium
cation,19 cation–p interaction,4d,8,9 is expected to be an
important factor. The enhanced chiral recognition abil-
ity has been suggested to arise from cation–p interaction
and the cavity size of 10 when compared with those of
18-membered rings and small aliphatic side chain of ala-
nine to make favourable recognition ability for receptor
10. These results show that the cavity size, structural
rigidity of hosts, p–p stacking and cation–p interactions
between host and guest, and steric repulsion between the
substituent on the stereogenic centre and on the ammo-
nium cation may be the most important factors for the
enantioselective recognition of amino acid derivatives.
Figure 1. UV–vis spectra of 10 (2 · 10ꢀ4 mol dmꢀ3) in presence of
L-ala-OMeÆHCl in CHCl3 at 25 ꢀC.
complexes in CHCl3 at 25 ꢀC. The typical UV spectral
changes upon addition of L-ala-OMe hydrochloride to
10 are shown in Figure 1 while typical plots are shown
for the complexation of 10 with L-ala-OMe hydrochlo-
ride in Figure 2.
We have shown that crown ethers 10–13 formed com-
plexes of appreciable stability constants towards isomers
of ala-OMe hydrochloride and phe-OMe hydrochloride
(Ka = 2.75 · 103–6.16 · 104 dm3 molꢀ1). It is thought
that the macroring would envelop the cation in a fashion
normally associated with crown ether binding while the
donor groups attached to the flexible side arm would
further solvate the bound cation. The data presented
herein are superior than those obtained with a chiral
cyclophane receptor, which was applied also towards
amino acid derivatives.4d As shown in Table 1, the
crown receptor shows chiral recognition ability for the
amino acid derivatives, while 11 and 12 cannot recog-
nize the chirality of the L- and D-isomer (KL/KD ffi 1).
3. Conclusion
In conclusion, general classes of crown compounds 10–
13 have been prepared in order to investigate hosts capa-
ble of recognizing the chirality of the amino acid deriv-
atives. Moderate enantiomeric recognition of amino
acid esters was achieved with chiral (S)-10 and (S)-13.
We found that receptor 13 exhibits a stronger binding
and better enantioselectivity towards phe-OMe hydro-
chloride (KD/KL = 2.38), whereas receptor 13 has a poor
recognition ability for the ala-OMe hydrochloride (KD/
KL = 1.39). Thus, receptor 13 exhibits stronger binding
and better enantioselectivity for amino acid esters con-
taining an aromatic group than those possessing a small
aliphatic side chain, inferring that the p–p stacking
interaction between the receptor and the aromatic side
chain of amino acid is the principle attractive interaction
involved and that this result is consistent with those
demonstrated previously.4d In addition to this, the rigid-
4. Experimental
4.1. General information
Melting points were determined with a Gallenkamp
Model apparatus with open capillaries. Infrared spectra
were recorded on a Midac-FTIR Model 1700 spectro-
photometer. The UV–vis spectra were measured by
Shimadzu 160 UV spectrophotometer. The Elemental
analyses were obtained with Carlo Erba Model 1108
apparatus. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on Bruker DPX-400
high performance digital FT-NMR spectrometer with
tetramethysilane as the internal standard solu- tions in
deuteriochloroform. J Values are given in hertz. Optical
rotations were recorded using Perkin–Elmer Model 341
polarimeter. All chemicals were of reagent grade unless
otherwise specified. THF was dried (on sodium benzo-
phenone ketyl) and distilled prior to use.
400
300
200
100
0
0
5
10
15
4.2. 1,2-Bis-(2-hydroxyethoxy)benzene 1
[G]o/10-4mol.dm-3
This compound was prepared according to the proce-
dure recorded in the literature17 from catechol (11.0 g,
0.1 mol) diethylamine hydrochloride (as a catalyst) and
Figure 2. Typical plot of [H]0[G]0/DA versus [G]0 for the host–guest
complexation of 11 and L-Ala-OMeÆHCl in CHCl3 at 25 ꢀC.

M. Karakaplan, T. Aral / Tetrahedron: Asymmetry 16 (2005) 2119–2124
2123
ethylene oxide (9.8 mL, 0.2 mol) to give 18.8 g, 95%; mp
81–83 ꢀC.
71.50, 114.98, 121.62, 129.62, 158.54. Anal. Calcd
for C10H14O4: C, 60.60; H, 7.07. Found: C, 60.45; H,
7.10.
4.3. 1,2-Bis-(2-p-tolylsulfonyl ethoxy)benzene 2
4.9. (S)-4-(p-Methoxyphenoxy)methyl-3,6-dioxa-1,8-
octanediol 8
This compound was prepared according to the proce-
dure recorded in the literature17 from 1, 2-bis-(2-
hydroxyethoxy)benzene (26.73 g, 0.135 mol), pyridine
(110 mL) at ꢀ10 ꢀC and p-toluenesulfonylchloride
(51.43 g, 0.27 mol) to give 66 g, 96%; mp 95–95.5 ꢀC.
This compound was synthesized as described above12 by
using (S)-3-(4-methoxyphenoxy)propane-1,2-diol (4.95 g,
0.025 mol) and 1-(tetrahydropyranyloxy)-2-[(p-tolyl-
sulfonyl)oxy]ethane (15 g, 0.05 mol) to give 4.93 g
(69%) of pure product as a colourless viscous oil, which
was purified by silica gel column chromatography [elu-
ent: EtOAc–hexane–EtOH–triethylamine (14/7/2/2)].
4.4. 2,3-Bis-(2-hydroxyethoxy)naphthalene 3
It was synthesized as described by the above method by
using 2,3-dihydroxynaphthalene (16.0 g, 0.1 mol), piper-
idine hydrochloride (as catalyst) and ethylene oxide
(10 mL, 0.2 mol) to give 17.36 g (70%), mp 146–147 ꢀC.
24
1
½aꢂ ¼ þ9.5 (c 0.25, MeOH). H NMR d: 3.12 (br s,
D
2H, OH), 3.62–3.65 (m, 2H), 3.68–3.78 (m, 10H), 3.8–
3.84 (m, 2H), 3.99–4.0 (d, 5.28 Hz, 2H), 6.81–6.86
(m, 4H). IR m: 3413, 3049, 2942, 2873, 1898, 1516,
1460, 1246, 1127, 1058, 894, 831, 756 cmꢀ1. Anal. Calcd
for C14H22O6: C, 59.00; H, 8.00. Found: C, 59.20; H,
7.96.
4.5. 2,3-Bis-[2-(p-tolylsulfonyl)ethoxy]naphthalene 4
This compound was synthesized in the usual manner
using 2,3-bis-(2-hydroxyethoxy)naphthalene (20.0 g, 0.08
mol), pyridine (100 mL) at ꢀ10 ꢀC and p-toluenesulfon-
ylchloride (30.64 g, 0.16 mol) to give 30 g (68.2%);
4.10. 2-[(p-Methoxyphenoxy)methyl]-12-crown-4 9
1
mp 111–112 ꢀC. H NMR d: 2.42 (s, 6H), 4.28–4.31 (q,
To a suspension of 0.886 g (29 mmol 80% in mineral oil)
of NaH in 150 mL of dry THF at 0 ꢀC was added a solu-
tion of 1.30 g (6.56 mmol) of (S)-3-(p-methoxyphen-
oxy)propane-1,2-diol in 250 mL of THF. The reaction
mixture was refluxed for 2 h. After cooling to 0 ꢀC, a
solution of triethylene glycol di-(p-toluenesulfonate)
3 g (6.56 mmol) in 250 mL of THF was slowly added.
The suspension was refluxed for 56 h. The solvent was
evaporated after which 100 mL of water was added to
the residue. The mixture was extracted with CH2Cl2
(4 · 20 mL) and the combined organic layers washed
with 50 mL of water, dried over MgSO4 and the solvent
evaporated. To the solution of crude product in toluene
was added a solution of NaClO4ÆH2O in EtOAc then the
crystallized complex was filtered to give the pure prod-
uct. Free ligand was obtained by the silica gel column
chromatography of complex (eluent: EtOAc–hexane–
4.5 Hz, 2H), 4.43–4.45 (q, 4 Hz, 2H), 7.28–7.38 (m,
8H), 7.62–7.66 (dd, 2H), 7.82–7.85 (m, 4H). IR m:
3063, 2950, 1636, 1602, 1509, 1490, 1463, 1363, 1265,
1189, 1113, 1027, 935, 816, 789, 670, 552 cmꢀ1
.
4.6. Tetra(ethylene glycol)di(p-toluenesulfonate) 5
p-Toluenesulfonylchloride (10.47 g, 55.00 mmol) in
small portions was added to tetra(ethylene glycol) (4.45
g, 25.0 mmol) in 30 mL of distilled pyridine at ꢀ10 ꢀC.
The mixture was kept overnight at 4 ꢀC. Then, the
mixture was extracted with CH2Cl2 (3 · 50 mL). The
organic layer was extracted with 6 M HCl at 0 ꢀC. The
combined organic layers were washed with water
(2 · 25 mL) and saturated NaHCO3 solution and dried
with CaCl2 and the solvent evaporated. Purification by
flash column chromatography (eluent: ethanol–CH2Cl2,
98/2) yielded 10.59 g (84%) of tetraethylene glycol di(p-
toluenesulfonate).
triethylamine, 5/5/1) to yield 0.2 g (15%) as a viscous
30
D
oil. ½aꢂ ¼ ꢀ9.5 (c 5, CHCl3). The spectral data of this
1
complex is as follows: H NMR d: 6.68–6.73 (m, 4H),
3.54–4.01 (m, 20H). 13C NMR d: 154.01, 152.62,
115.22, 114.67, 73.21, 67.14, 66.37, 66.24, 65.89, 65.39,
65.19, 55.71. IR m: 3042, 2924, 2878, 1595, 1509, 1470,
4.7. Synthesis of 1-(tetrahydropyranyloxy)-2-[(p-tolyl-
sulfonyl)oxy]ethane 6
1238, 1100, 1020, 921, 842, 750, 624 cmꢀ1
.
This compound was prepared from ethylene glycol
according to the method reported12 and the crude prod-
uct was purified by silica gel column chromatography
using methanol–dichloromethane (2/98) as eluent to give
pure product.
4.11. (S)-2-[(p-Methoxyphenoxy)methyl]-15-crown-5 10
This compound was prepared in a manner similar to
that described for the preparation of 9 by using diol 7
(1.30 g, 6.56 mmol) and tetraethylene glycol di(p-tolu-
enesulfonate) (3.29 g, 6.56 mmol). The crude product
was purified by column chromatography (eluent:
4.8. (S)-3-(p-Methoxyphenoxy)propane-1,2-diol 7
This compound was prepared by the method described11
from (S)-glycidol (3.7 g, 0.05 mol), p-methoxyphenol
(6.2 g, 0.05 mol) and piperidine hydrochloride (0.3 g,
EtOAc–hexane–triethylamine, 5/5/1) to yield as a vis-
30
D
cous oil 0.91 g (39%) of pure product. ½aꢂ ¼ ꢀ14.5 (c
1
7, CHCl3). H NMR d: 3.64–4.03 (m, 24H); 6.81–6.88
(m, 4H ). 13C NMR d: 153.75, 152.82, 115.34, 114.61,
77.66, 77.58, 77.43, 77.12, 75.86, 70.82, 70.62, 70.58,
70.15, 68.56, 65.42, 55.69. IR m: 3043, 2940, 2874,
1602, 1509, 1463, 1233, 1133, 1041, 941, 829,
2.5 mmol) as a catalyst to give 8.51 g (86%); mp
20
80–82 ꢀC, ½aꢂ ¼ þ10.5 (c 0.5, MeOH). 1H NMR d:
D
3.65–3.77 (m, 7H), 3.93–3.94 (m, 2H), 4.01 (m, 1H),
6.76–6.83 (m, 4H). 13C NMR d: 63.15, 64.16, 69.49,

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M. Karakaplan, T. Aral / Tetrahedron: Asymmetry 16 (2005) 2119–2124
743 cmꢀ1. Anal. Calcd for C18H28O7: C, 60.66; H, 7.92.
Found: C, 60.45; H, 8.05.
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Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997, 95, 3313;
(c) Samu, E.; Huszthy, P.; Somogyi, L.; Hollosi, M.
Tetrahedron: Asymmetry 1999, 10, 2775; (d) Samu, E.;
Huszthy, P.; Horvath, G.; Szo¨llosy, A.; Neszmelyi, A.
Tetrahedron: Asymmetry 1999, 10, 3615; (e) Zhaou, H.;
Hua, W. J. Org. Chem. 2000, 65, 2933.
4.12. (S)-2-[(p-Methoxyphenoxy)methyl]-18-crown-6 11
This compound was prepared in a manner similar to
that described for the preparation of 9 by using diol 8
(1.45 g, 5 mmol) and triethylene glycol di(p-toluenesulf-
onate) (2.8 g, 5 mmol) to give 0.35 g (18%) of 11 as a vis-
cous oil. Crude product was purified by chromatography
30
as described for 10. ½aꢂ ¼ ꢀ8.8 (c 4.66, CHCl3).
D
1H NMR d: 6.71–6.78 (m, 4H), 3.54–3.97 (m, 28H).
13C NMR d: 153.84, 152.99, 115.53, 114.55, 77.82,
77.74, 77.34, 71.31, 70.96, 70.85, 70.83, 70.72, 70.69,
70.65, 70.10, 68.67, 67.90, 55.68. IR m: 3049, 2937,
2871, 1602, 1516, 1470, 1358, 1290, 1238, 1120, 1041,
988, 948, 829, 750 cmꢀ1. Anal. Calcd for C20H32O8: C,
60.0; H, 8.0. Found: C, 59.87; H, 8.20.
4.13. (S)-12-[(4-Methoxyphenoxy)methyl]-2,3-benzo-18-
crown-6 12
This compound was prepared in a manner similar to
that described for the preparation of 9 by using diol
8 (1 g, 3.5 mmol) and 2,3-bis-[2-(p-tolylsulfonyl)eth-
oxy]benzene (1.77 g, 3.5 mmol) to give 0.20 g (12%)
of pure 12 as a viscous oil, whose crude product was
purified by silica gel column chromatography (eluent:
petroleum ether (60–80)–EtOAc–triethylamine, 80/17/
6. For cyclodextrins, see: (a) Maletic, M.; Wennemers, H.;
McDonald, D. Q. Angew. Chem., Int. Ed. 1996, 35, 1490;
(b) Breslow, R.; Yang, Z.; Ching, R.; Trojiandt, G.;
Odobel, F. J. Am. Chem. Soc. 1998, 120, 3536.
7. De Wall, S. L.; Barbour, L. J.; Gokel, G. W. J. Am. Chem.
Soc. 1999, 121, 8405.
8. Meadows, E. S.; De Wall, S. L.; Barbour, L. J.; Gokel, G.
W. J. Am. Chem. Soc. 2001, 123, 3092.
9. Muraoka, M.; Ueda, A.; Zhang, W.; Kida, T.; Nakatsuji,
Y.; Ikeda, I.; Kanehisa, N.; Kai, Y. Tetrahedron Lett.
1998, 39, 9493.
10. Scrutton, N. S.; Raine, A. R. C. Biochem. J. 1996, 319, 1.
11. Karakaplan, M.; Turgut, Y.; Hoßsgoren, H. J. Chem. Res.
2005, 1, 41.
12. Huszthy, P.; Masatoshi, Q.; Bradshaw, J. S.; Zhu, C. Y.;
Wang, T.; Dalley, N. K.; Curtis, J. C.; Izatt, R. M. J. Org.
Chem. 1992, 57, 5383.
30
1
3). ½aꢂ ¼ ꢀ2.7 (c 2, CHCl3). H NMR: d 3.71–3.84
D
(m, 12H), 3.89–4.01 (m, 8H), 4.15–4.20 (m, 4H),
6.78–6.85 (m, 4H), 6.90–6.94 (m, 4H). 13C NMR d:
152.96, 151.94, 149.43, 121.63, 114.31, 113.85, 113.38,
73.80, 71.93, 70.95, 70.42, 70.02, 69.97, 69.88, 69.32,
67.52, 67.34, 66.82, 54.20; IR m: 3069, 2924, 2871,
1615, 1509, 1451, 1233, 1133, 1041, 935, 829,
750 cmꢀ1. Anal. Calcd for C24H32O8: C, 64.0; H, 7.0.
Found: C, 64.38; H, 7.24.
13. Dishong, D. M.; Diamond, C. J.; Cinoman, M. I.; Gokel,
G. W. J. Am. Chem. Soc. 1983, 105, 586.
14. Kolbeck, R. C.; Hendry, L. B.; Bransome, E. D.; Speir,
W. A. Experienta 1984, 40, 727.
4.14. (S)-12-[(4-Methoxyphenoxy)methyl]-2,3-naphtho-
18-crown-6 13
15. (a) Arnold, K. A.; Echegoyen, L.; Gokel, G. W. J. Am.
Chem. Soc. 1987, 103, 3713; (b) Dowidson, R. B.; Izatt, R.
M.; Christensen, J. L.; Schultz, R. A.; Dishang, D. M.;
Gokel, G. W. J. Org. Chem. 1984, 49, 5080; (c) Iheda, I.;
Yamamura, S.; Nahatsuji, Y.; Okahara, M. J. Org. Chem.
1980, 45, 5355.
This compound was prepared in a manner similar to
that described for the preparation of 9 by using diol 8
(1.45 g, 5 mmol) and 2,3-bis-[2-(p-tolylsulfonyl)eth-
oxy]naphthalene 4 (2.72 g, 5 mmol) to give 0.30 g
(12%) of pure 13 as a white solid, whose crude product
was purified by crystallization from ethanol, mp 88–
ˇ
16. Turgut, Y.; Sßahin, E.; Togrul, M.; Hoßsgo¨ren, H. Tetra-
30
1
hedron: Asymmetry 2003, 14, 3815–3818.
ˇ
89 ꢀC. ½aꢂ ¼ ꢀ8.6 (c 3.76, CHCl3). H NMR d: 7.58–
D
17. Topal, G.; Demirel, N.; Togrul, M.; Turgut, Y.; Hoßsgo¨-
7.56 (dd, 2H), 7.16–7.25 (dd, 2H), 7.01–7.02 (d,
2.8 Hz, 2H); 6.60–6.69 (m, 4H), 4.12–4.20 (m, 4H),
3.80–3.94 (m, 8H), 3.59–3.75 (m, 12H). 13C NMR d:
152.74, 151.89, 148.05, 128.25, 125.27, 123.13, 114.39,
113.45, 106.87, 76.92, 70.49, 70.24, 70.05, 69.94, 69.15,
68.45, 67.70, 67.59, 67.34, 54.58. IR m: 3056, 2931,
2884, 1610, 1516, 1457, 1240, 1120, 1060, 941, 823,
743 cmꢀ1. Anal. Calcd for C28H34O8: C, 67.0; H, 6.0.
Found: C, 66.85; H, 6.22.
ren, H. J. Heterocycl. Chem. 2001, 38, 281.
18. (a) Polster, J.; Lachman, H. Spectrometric Titration; VCH:
Weinheim, 1989; (b) Connors, K. A. Binding Constants.
The Measurement of Molecular Complex; Wiley: New
York, 1987; Bennesi, H. A.; Hildebrand, J. H. J. Am.
Chem. Soc. 1949, 71, 2703.
19. Davidson, R. B.; Bradshaw, J. S.; Jones, B. A.; Dalley, N.
K.; Christensen, J. J.; Izatt, R. M.; Morin, F. G.; Grant,
D. M. J. Org. Chem. 1984, 49, 353.