Synthesis of an inherently chiral O,O′-bridged thiacalix[4] crowncarboxylic acid and its application to a chiral solvating agent

Article abstract of DOI:10.1016/j.tet.2004.06.074

Treatment of readily available O,O′-1,1,3,3-tetraisopropyldisiloxane- 1,3-diyl-bridged p-tert-butylthiacalix[4]arene (1) with tri(ethylene glycol) di-p-tosylate and subsequent desilylation gave O,O′-bridged thiacalix[4]crown 3 in an excellent yield. Mono-O-alkylation of 3 with ethyl bromoacetate, followed by optical resolution by chiral HPLC, and subsequent hydrolysis of the ester moiety gave inherently chiral O,O′-bridged thiacalix[4]crowncarboxylic acid (+)-6, which clearly discriminated enantiomeric primary amines, as well as amino esters, by ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2004.06.074

Tetrahedron 60 (2004) 7827–7833
Synthesis of an inherently chiral O,O0-bridged
thiacalix[4]crowncarboxylic acid and its application to a chiral
solvating agent
b
b
b
b
Fumitaka Narumi,a Tetsutaro Hattori, Nobuji Matsumura, Toru Onodera, Hiroshi Katagiri,
,
,
*
*
Chizuko Kabuto,c Hiroshi Kameyamaa and Sotaro Miyanob
aDepartment of Basic Sciences, School of Science and Engineering, Ishinomaki Senshu University, 1 Shinmito, Minamisakai,
Ishinomaki 986-8580, Japan
bDepartment of Environmental Studies, Graduate School of Environmental Studies, Tohoku University, Aramaki-Aoba 07, Aoba-ku,
Sendai 980-8579, Japan
cDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
Received 9 June 2004; revised 15 June 2004; accepted 15 June 2004
Available online 28 July 2004
Abstract—Treatment of readily available O,O0-1,1,3,3-tetraisopropyldisiloxane-1,3-diyl-bridged p-tert-butylthiacalix[4]arene (1) with
tri(ethylene glycol) di-p-tosylate and subsequent desilylation gave O,O0-bridged thiacalix[4]crown 3 in an excellent yield. Mono-O-
alkylation of 3 with ethyl bromoacetate, followed by optical resolution by chiral HPLC, and subsequent hydrolysis of the ester moiety gave
inherently chiral O,O0-bridged thiacalix[4]crowncarboxylic acid (þ)-6, which clearly discriminated enantiomeric primary amines, as well as
1
amino esters, by H NMR spectroscopy.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives by introducing an achiral substituent at one of the
two remaining hydroxy groups.8 In this respect, it should be
noted that in spite of the considerable efforts which had been
paid to the preparation of inherently chiral calixarenes,8,9 their
chiral recognition abilities have yet to be improved except a
recentreportbyMattetal. dealing with anapplication tochiral
ligands for asymmetric catalysis.10 This is in sharp contrast to
the fact that another type of chiral calixarenes prepared by
introducing chiral substituents at the lower rim through the
phenolic oxygens have enjoyed many successful applications
to chromogenic receptors,11 additives in capillary electro-
phoresis,12 chiral stationary phases for GC and HPLC,13 chiral
solvating agents for NMR,14 and so on.15 Herein, we report
facile synthesis of inherently chiral O,O0-bridged thiacalix[4]-
crowncarboxylic acid 6 and its chiral recognition ability as a
chiral solvating agent in discriminating enantiomeric amines,
Calix[n]crowns which are composed of two kinds of receptor
elements, a calix[n]arene1 and a crown ether,2 have attracted
muchinterestashostcompoundsinthehopeforimproving the
binding ability as well as selectivity to a particular guest
speciessuchasanorganicmolecule3 oralkalimetalion4 bythe
synergic effects of the two receptor elements arranged in a
defined three-dimensional alignment. In these endeavors,
O,O00-bridged calix[4]crowns, in which a calix[4]arene is
linked at the distal phenolic oxygens with a poly(oxyethylene)
chain, have been employed as a molecular scaffold, while only
little attention has been paid toward the proximally O,O0-
bridged analogs.5 This is partly due to the difficulty in
preparing the latter type of compounds in substantial
quantities. In previous papers, we reported an efficient method
for a net proximal dialkylation of calix[4]arenes0at the lower
rim via the dialkylation of readily available O,O -disiloxane-
diyl-bridged calix[4]arenes (e.g., 1) and subsequent desilyl-
ation,6 which could be advantageously utilized for the
synthesis of O,O0-bridged thiacalix[4]crowns.7 It is readily
conceivable that O,O0-bridged calix[4]crowns having only
one symmetry plane are desymmetrized to inherently chiral
1
as well as amino esters, by H NMR spectroscopy. Also
reported is the absolute stereochemistry of acid 6 determined
by an X-ray crystallographic analysis.
2. Results and discussion
2.1. Synthesis of inherently chiral O,O0-bridged
thiacalix[4]crowncarboxylic acid (1)-6
Keywords: Calixarene; Calixcrown; Inherently chiral; Chiral recognition.
*
Corresponding authors. Tel.: þ81-225-22-7716; fax: þ81-225-22-7746
(F.N.); e-mail addresses: fnarumi@isenshu-u.ac.jp;
hattori@orgsynth.che.tohoku.ac.jp
O,O0-Bridged thiacalix[4]crown 3 was prepared according
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.074

7828
F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
to our previously reported procedure (Scheme 1). Thus,
treatment of O,O0-disiloxane-1,3-diyl-bridged thiacalix[4]-
arene 16 with tri(ethylene glycol) di-p-tosylate in the
presence of Cs2CO3 in THF gave O00,O000-bridged thia-
calix[4]crown 2 in high yield, which was desilylated with
tetrabutylammonium fluoride to liberate diol 3. Subsequent
monoalkylation of 3 with ethyl bromoacetate in the
presence of Na2CO3 in THF gave two stereoisomers 4 and
5, originated from the syn and anti conformations of the
ethoxycarbonylmethyl and crown moieties with respect to
be optically resolved by chiral HPLC on a preparative scale
to give several 100-mg yields of both the enantiomers
(.99% ee) (Fig. 1). Subsequent alkaline hydrolysis of one
enantiomer (þ)-4 gave enantiomerically pure acid (þ)-6
(Scheme 2).
1
the mean plane defined by the calix ring. The H NMR
spectrum of the major isomer 4 showed two doublets (each
1H) for the methylene protons of the OCH2CvO moiety at
4.71 and 4.87 ppm, while one of the corresponding signals
(4.05 and 4.87 ppm) of the minor isomer 5 resonated at a
higher field owing to the shielding effects by the facing
benzene rings. This indicates that compound 5 adopts a
partial cone or 1,2-alternate conformation with the anti
arrangement of the ethoxycarbonylmethyl and crown
moieties and that the relative configuration of the two
substituents in compound 4 can consequently be assigned to
syn. This assignment was unambiguously confirmed by an
X-ray crystallographic analysis of acid 6 prepared from
Figure 1. HPLC chromatogram of compound (^)-4. Column: Daicel
Chiralpak AD (4.6 mm i.d.£250 mm); mobile phase: hexane–2-propanol
(98:2); flow rate: 0.5 ml min21
.
1
compound 4 (vide infra). Although the unsymmetrical H
NMR resonance pattern of compound 4 gave no information
about the conformation of the free p-tert-butylphenol
residue, it is conceivable that this compound adopted a
cone conformation in the solution by virtue of possible
intramolecular hydrogen bond of the hydroxyl proton to the
nearby oxygen atoms at the lower rim. Compound 4 could
Scheme 2.
2.2. Chiral recognition ability of acid (1)-6
Measurement of the enantiomeric composition of a chiral
compound with the aid of a chiral solvating agent in NMR
spectroscopy is a classical but convenient and reliable way
based on the transient diastereomeric interactions between
the chiral compound and the agent.16,17 With the desired
acid in hand, we next examined its chiral recognition ability
as a chiral solvating agent in discriminating enantiomeric
amines as well as amino esters. Figure 2 shows the 1H NMR
spectra of 1-phenylethylamine in the presence or absence of
acid (þ)-6. The methyl signal of the racemic amine
resonating at 1.39 ppm as a doublet (a) shifted to downfield
with splitting into two doublets (b) upon addition of
1.0 mol equiv. of acid (þ)-6, while the broad NH2 signal
centered at 1.52 ppm (a) shifted to 8.0–9.0 ppm (not
shown), indicating the formation of diastereomeric
ammonium salts. One diastereomer, which showed the
methyl signal at the lower field, was assigned to the (S)-
ammonium salt by comparison of the chemical shift value
with that of the sample prepared from the (S)-amine and
acid (þ)-6 (c). The results of enantiodiscrimination of
amines, as well as amino esters are listed in Table 1. The
Scheme 1.

F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
7829
Table 1. Chiral recognition ability of acid (þ)-6 in discriminating
enantiomeric amines and amino esters by 1H NMR spectroscopy in
CDCl3 at 22 8C
Entry
Analyte
dH(Free)a dH(S)a dH(R)a DdH(S–R)b
1
1.393
1.560
1.856 1.733
2.006 1.863
0.123
0.143
2
3
4
1.052
0.886
1.493 1.415
1.070, 1.031c
0.078
(0.039)
5
1.154
1.403, 1.401c
(0.002)
6
7
8
1.373
3.727
3.724
1.606 1.619 20.013
3.676 3.752 20.076
3.700 3.673
0.027
Figure 2. 500 MHz 1H NMR spectra of 10 mM 1-phenylethylamine in
CDCl3 in the presence or absence of 1.0 mol equiv. of acid (þ)-6. (a) (^)-
1-Phenylethylamine; (b) (^)-1-phenylethylamine in the presence of acid
(þ)-6; (c) (S)-1-phenylethylamine in the presence of acid (þ)-6.
9
3.706
3.722
3.721 3.697
3.686 3.682
0.024
0.004
10
methyl signals of an enantiomeric pair of primary amines
were clearly differentiated from each other (entries 1–4),
including the cases of sec-butylamine and 2-methylbutyl-
amine (entries 3 and 4) where the difference in the steric
bulk of the two alkyl substituents attached to the asymmetric
carbon center is rather subtle; in both cases it required
differentiation between methyl and ethyl group and
furthermore, in the latter case the chiral carbon was
separated from the amino nitrogen by a methylene group.
It is noteworthy that the methyl signal of an (S)-ammonium
salt shifted to a lower field than that of the (R)-counterpart in
every case (entries 1–3). Although secondary and tertiary
amines could also be discriminated by acid (þ)-6 (entries 5
and 6), the chemical shift difference between the dia-
stereomeric salts DdH(S–R) was insufficient for quantitative
analysis. In the case of amino acid methyl esters, chiral
discrimination could be advantageously carried out by using
the intense singlet signal of the ester methyl moiety (entries
7–11). Consequently, baseline separation of the methyl
signals were achieved for each amino ester except the case
of the phenylalanine derivative (entry 10) although the
DdH(S–R) values are relatively small as compared to those
for primary amines.
11
3.717
3.645 3.665 20.020
a
Chemical shift values of the methyl protons specified in italics in the
presence [dH(S) and dH(R)] or absence [dH(Free)] of 1.0 mol equiv. of
acid (þ)-6.
b
c
DdH(S–R)¼dH(S)2dH(R).
The signals are not assigned to the (S)- and (R)-isomers.
2.3. Determination of the absolute stereochemistry of
acid (1)-6 by X-ray crystallographic analysis and
consideration of the chiral discrimination mechanism
The ammonium salt prepared from acid (þ)-6 and (S)-1-
phenylethylamine was crystallized from methanol–water to
give colorless plates, one of which was subjected to X-ray
crystallographic analysis (Fig. 3). The absolute stereo-
chemistry of acid (þ)-6 could be determined to be S by
using the (S)-1-phenylethyl moiety as an internal
reference.18 It can be seen that the 1-phenylethylammonium
cation is associated with the deprotonated (þ)-6 by three

7830
F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
Figure 5. A steric model for the chiral discrimination of (S)- and (R)-1-
phenylethylamine by acid (þ)-6.
critical role for the salt formation. On the other hand, the
difference in the chemical shifts of the methyl protons
between the diastereomeric salts is ascribed to the disposi-
tions of three substituents bonded to the asymmetric carbon
center (Fig. 5). Molecular model inspections suggest that the
bulkiest substituent should orient as far apart as possible
from the crown and carboxylato moieties to minimize steric
repulsion. This forces the methyl group of the (R)-
ammonium salt to face against the crown ring to be the
more strongly affected by its electronic effects, showing the
1H NMR signal at a higher field than that of the (S)-
counterpart.21 In the case of the secondary and tertiary
amines, the bulkiness of the ammonium center seemingly
makes it difficult to form such a well-arranged ammonium
salt, resulting in the insufficient separation of the methyl
signals. If the chiral discrimination model depicted in
Figure 5 were applicable to amino esters where the bulkiest
substituent directs apart from the crown and carboxylato
moieties, an (S)-amino ester having a substituent bulkier
than the ester moiety at the asymmetric carbon center should
show the methyl signal at a higher field than the (R)-
counterpart because the relevant methoxycarbonyl group
will locate near to the polyoxyethylene chain. However,
inspection of the results shown in Table 1 indicates that the
simple steric model based on apparent bulk of the
substituents cannot be applied to the methyl esters (entries
7–11), indicating participation of stereoelectronic effect of
the polar ester function.
Figure 3. X-ray structure of the ammonium salt between acid (þ)-6 and
(S)-1-phenylethylamine. Dotted lines indicate hydrogen bonds.
hydrogen bonds between the ammonio group and three
oxygen atoms, that is, the carboxylato oxygen, the phenolic
hydroxy oxygen and one of the four oxygens of the crown
moiety, the distance from the nitrogen to these oxygens
˚
being 2.703, 2.901, and 2.886 A, respectively. It should be
noted that the phenyl group of the ammonium ion is
arranged to turn away from the crown and carboxylato
moieties to avoid steric repulsion.
A Job plot between (S)-1-phenylethylamine and acid (þ)-6
revealed that the stoichiometry of the ammonium salt in
CDCl3 was the same as that in the crystals (amine:acid¼1:1)
(Fig. 4).20 In the 13C NMR spectrum of a diastereomeric
mixture of 1-phenylethylammonium salts, the asymmetric
carbon centers of the (S)- and (R)-1-phenylethyl moieties
resonated in the close vicinity [DdC(S–R)¼0.098 ppm],
while the methyl signals appeared considerably apart from
each other [DdC(S–R)¼0.441 ppm]. This suggests that the
asymmetric carbons are located at a nearly same position in
both the diastereomeric salts, because the electrostatic
interaction between the carboxylate anion and ammonium
cation assisted with three intramolecular hydrogen bonds as
were found in the X-ray structure (Fig. 3) should play a
3. Conclusion
We have shown here 0an efficient method for the synthesis of
optically active O,O -bridged thiacalix[4]crowncarboxylic
acid (þ)-6. The absolute stereochemistry was determined by
an X-ray crystallographic analysis. The compound could
discriminate enantiomeric amines as well as amino acid
1
methyl esters by H NMR spectroscopy.
4. Experimental
4.1. General
Melting points (mps) were taken using a Mitamura Riken
MP-P apparatus. Samples for the mp measurement were
routinely recrystallized from chloroform–methanol, unless
Figure 4. Job plot for the titration of (S)-1-phenylethylamine with acid (þ)-
6 in CDCl3.

F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
7831
otherwise noted. Optical rotations were measured on a
JASCO DIP-1000 polarimeter and [a]D values are given in
units of 1021 deg cm2 g21. Microanalyses were carried out
in the Microanalytical Laboratory of the Institute of
Multidisciplinary Research for Advanced Materials,
Tohoku University. IR spectra were recorded on a JEOL
JIR-3510 spectrophotometer. 1H and 13C NMR spectra were
recorded on a Bruker DPX-400 or DRX-500 spectrometer
using tetramethylsilane (1H NMR) or chloroform (13C
NMR) as an internal standard and CDCl3 as a solvent. Mass
4.2.3. syn- and anti-5,11,17,23-Tetra-tert-butyl-25-
ethoxycarbonylmethoxy-26-hydroxy-27,28-(1,4,7,10-
tetraoxadecane-1,10-diyl)thiacalix[4]arene (4 and 5). To
a solution of calix[4]crown 3 (835 mg, 1.00 mmol) in THF
(20 ml) were added Na2CO3 (106 mg, 1.10 mmol) and ethyl
bromoacetate (1.67 g, 9.96 mmol) and the mixture was
heated at reflux with stirring for 48 h. After cooling, the
mixture was quenched with 2 M HCl and extracted with
chloroform. The extract was washed with water, dried
(MgSO4) and evaporated. The residue was purified by
column chromatography on silica gel with hexane–ethyl
acetate (4:1) as an eluent to give ester 4 (562 mg, 61%) and
5 (42.3 mg, 5%) as colorless powders. Ester 4: mp 104–
106 8C (Found: C, 65.2; H, 7.0; S, 14.0. Calcd for
C50H64O8S4: C, 65.2; H, 7.0; S, 13.9%); nmax (KBr)/cm21
1765 (CO); dH (400 MHz) 0.62 [9H, s, C(CH3)3], 1.04 [9H,
s, C(CH3)3], 1.31 (3H, t, J¼7.1 Hz, OCH2CH3), 1.32 [18H,
s, C(CH3)3£2], 3.80–4.51 (12H, m, OCH2CH2O£3), 4.26
(2H, q, J¼7.1 Hz, OCH2CH3), 4.71 (1H, d, J¼16.3 Hz,
OCH2CO), 4.87 (1H, d, J¼16.3 Hz, OCH2CO), 6.57 (1H, d,
J¼2.4 Hz, ArH), 6.63 (1H, d, J¼2.4 Hz, ArH), 7.29 (1H, d,
J¼1.9 Hz, ArH), 7.31 (1H, d, J¼2.5 Hz, ArH), 7.59 (1H, d,
J¼2.5 Hz, ArH), 7.65 (1H, d, J¼2.5 Hz, ArH), 7.68 (1H, d,
J¼2.5 Hz, ArH), 7.71 (1H, d, J¼2.5 Hz, ArH) and 8.02 (1H,
s, OH); FAB-MS m/z 921 [(Mþ1)þ]. Ester 5: dH (400 MHz)
1.00 (3H, t, J¼7.2 Hz, OCH2CH3), 1.23 [9H, s, C(CH3)3],
1.31 [9H, s, C(CH3)3], 1.32 [9H, s, C(CH3)3], 1.36 [9H, s,
C(CH3)3], 2.67–4.09 (12H, m, OCH2CH2O), 3.98 (2H, q,
J¼6.8 Hz, OCH2CH3), 4.05 (1H, d, J¼15.1 Hz, OCH2CO),
4.87 (1H, d, J¼15.1 Hz, OCH2CO), 7.42 (1H, d, J¼2.4 Hz,
ArH), 7.43 (1H, d, J¼2.4 Hz, ArH), 7.46 (1H, d, J¼2.4 Hz,
ArH), 7.54 (1H, d, J¼2.5 Hz, ArH), 7.59 (1H, d, J¼2.5 Hz,
ArH), 7.64 (1H, d, J¼2.5 Hz, ArH), 7.65 (1H, d, J¼2.5 Hz,
ArH), 7.77 (1H, d, J¼2.5 Hz, ArH) and 7.91 (1H, s, OH).
spectra were measured on
a JEOL JMS-DX602
spectrometer. Silica gel columns were prepared by use of
Merck silica gel 60 (63–200 mm). THF was distilled from
sodium diphenylketyl just before use. Compound 1 was
prepared as reported previously.6 Other materials were used
as purchased.
4.2. Synthesis of acid (1)-6
4.2.1. 5,11,17,23-Tetra-tert-butyl-25,26-(2,2,4,4-tetra-
isopropyl-1,3,5-trioxa-2,4-disilapentane-1,5-diyl)-27,28-
(1,4,7,10-tetraoxadecane-1,10-diyl)thiacalix[4]arene (2).
To a solution of O,O0-disiloxane-bridged thiacalix[4]arene 1
(482 mg, 500 mmol) in THF (50 ml) were added Cs2CO3
(489 mg, 1.50 mmol) and tri(ethylene glycol) di-p-tosylate
(275 mg, 600 mmol). After heating at reflux with stirring for
30 h, the mixture was cooled to 0 8C and quenched with 2 M
HCl. The mixture was extracted with chloroform and the
extract was washed with water, dried (MgSO4) and
evaporated. The residue was purified by column chroma-
tography on silica gel with hexane–ethyl acetate (10:1) as
an eluent to give disiloxane-bridged thiacalix[4]crown 2
(451 mg, 84%) as a colorless powder, mp 319–321 8C
(Found: C, 64.5; H, 7.85; S, 11.6. Calcd for C58H84O7S4Si2:
C, 64.6; H, 7.9; S, 11.9%); dH (400 MHz) 0.43 (6H, d,
J¼7.4 Hz, CHCH3£2), 0.76 (6H, d, J¼7.5 Hz, CHCH3£2),
0.80–0.92 [2H, m, CH(CH3)2£2], 1.02 (6H, d, J¼7.5 Hz,
CHCH3£2), 1.06 (6H, d, J¼7.4 Hz, CHCH3£2), 1.15–1.24
[2H, m, CH(CH3)2£2], 1.28 [18H, s, C(CH3)3£2], 1.35
[18H, s, C(CH3)3£2], 2.64–2.73 (2H, m, OCH2), 3.28–3.60
(6H, m, OCH2£3), 3.73–3.82 (4H, m, OCH2£2), 7.32 (2H,
d, J¼2.4 Hz, ArH£2), 7.55 (2H, d, J¼2.4 Hz, ArH£2), 7.57
(2H, d, J¼2.5 Hz, ArH£2) and 7.78 (2H, d, J¼2.5 Hz,
ArH£2); FAB-MS m/z 1076 (Mþ).
4.2.4. Optical resolution of compound 4. Racemic ester 4
was subjected to optical resolution by chiral HPLC [column:
Daicel CHIRALPAK AD, 20 mm i.d.£25 cm; mobile
phase:hexane-2-propanol (98:2); flow rate: 6.0 ml min21].
A solution of racemic 4 (20 mg) in hexane (500 ml) was
injected into the column per one operation and three
fractions were collected. Enantiomerically pure (þ)- and
(2)-4 (.99% ee) were recovered in 37 and 24% yields from
the first and third fractions, respectively. Ester (þ)-4:
[a]2D6¼þ9.0 (c 0.50, ethanol). Ester (2)-4: [a]2D6¼29.0 (c
0.50, ethanol).
4.2.2. 5,11,17,23-Tetra-tert-butyl-25,26-dihydroxy-27,28-
(1,4,7,10-tetraoxadecane-1,10-diyl)thiacalix[4]arene (3).
To a solution of disiloxane-bridged thiacalix[4]crown 2
(323 mg, 300 mmol) in THF (15 ml) was added a 1.0 M
solution of tetrabutylammonium fluoride in THF (300 ml,
300 mmol). The mixture was stirred at room temperature for
1 h and quenched with 2 M HCl. The mixture was extracted
with chloroform and the extract was washed with water,
dried (MgSO4) and evaporated. The residue was purified by
column chromatography on silica gel with hexane–ethyl
acetate (3:1) as an eluent to give calix[4]crown 3 (240 mg,
96%) as a colorless powder, mp 132–134 8C (Found: C,
65.9; H, 7.05; S, 15.6. Calcd for C46H58O6S4: C, 66.15; H,
7.00; S, 15.4%); dH (400 MHz) 1.04 [18H, s, C(CH3)3£2],
1.23 [18H, s, C(CH3)3£2], 3.28–4.65 (12H, m, OCH2CH2-
O£3), 7.36 (4H, br, ArH£4), 7.55 (2H, d, J¼2.5 Hz,
ArH£2), 7.58 (2H, d, J¼2.5 Hz, ArH£2) and 8.87 (2H, s,
OH£2); FAB-MS m/z 835 [(Mþ1)þ].
4.2.5. syn-5,11,17,23-Tetra-tert-butyl-25-hydroxy-26-
hydroxycarbonylmethoxy-27,28-(1,4,7,10-tetraoxa-
decane-1,10-diyl)thiacalix[4]arene (1)-6. A mixture of
ester (þ)-4 (340 mg, 369 mmol), 5.5 M KOH (2.0 ml) and
ethanol (15 ml) was heated at reflux with stirring for 48 h.
After cooling, the mixture was quenched with 2 M HCl and
extracted with chloroform. The extract was washed with
water, dried (MgSO4) and evaporated. The residue was
purified by recrystallization from methanol to give acid (þ)-
6 as a colorless powder (326 mg, 99%); mp 145–147 8C
(Found: C, 64.3; H, 6.8; S, 14.5. Calcd for C48H60O8S4: C,
64.5; H, 6.8; S, 14.4%); [a]2D7¼þ14.5 (c 1.05, chloroform);
nmax (KBr)/cm21 1722 (CO); dH (400 MHz) 1.03 [9H, s,
C(CH3)3], 1.04 [9H, s, C(CH3)3], 1.18 [9H, s, C(CH3)3],
1.22 [9H, s, C(CH3)3], 3.81–4.59 (12H, m, OCH2CH2O£3),
4.55 (1H, d, J¼16.2 Hz, OCH2CO), 5.53 (1H, d, J¼16.2 Hz,

7832
F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
OCH2CO), 7.30 (1H, d, J¼2.5 Hz, ArH), 7.31 (2H, br,
ArH), 7.34 (1H, d, J¼2.5 Hz, ArH), 7.50 (1H, d, J¼3.3 Hz,
ArH), 7.51 (1H, d, J¼2.5 Hz, ArH), 7.57 (1H, d, J¼2.5 Hz,
ArH), 7.60 (1H, d, J¼2.5 Hz, ArH) and 8.35 (1H, s, OH);
FAB-MS m/z 893 [(Mþ1)þ].
Research on Priority Areas (No. 14044009) from the
Ministry of Education and Technology, Japan.
References and notes
1
4.3. General procedure for the H NMR shift
experiments
1. For general overview of the calixarene chemistry, see:
(a) Gutsche, C. D. Calixarenes Revisited, Monographs in
Supramolecular Chemistry; Stoddart, J. F., Ed.; The Royal
The sample containing an amine was prepared by mixing a
20.0 mM solution of acid (þ)-6 (0.25 ml) in CDCl3 with a
20.0 mM solution of an appropriate amine (0.25 ml) in
CDCl3. The sample containing an amino ester was similarly
prepared from two 40.0 mM solutions of acid (þ)-6 and an
amino ester (0.25 ml each). These samples, together with
the solutions of the amine (10.0 mM) and amino ester
(20.0 mM) in CDCl3, were analyzed by 1H NMR
spectroscopy (500 MHz) at 22 8C.
¨
Society: Cambridge, 1998; Vol. 6. (b) Asfari, Z.; Bohmer, V.;
Harrowfield, J.; Vicens, J. Calixarenes 2001; Kluwer
Academic: Dordrecht, 2001.
¨
2. Vogtle, F. Supramolecular Chemistry: An Introduction;
Wiley: New York, 1991.
3. (a) Reichwein, A. M.; Verboom, W.; Harkema, S.; Spek, A. L.;
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Tetrahedron 1997, 53, 10345–10356. (d) Pappalardo, S.;
Parisi, M. F. Tetrahedron Lett. 1996, 37, 1493–1496.
4. (a) Ungaro, R.; Casnati, A.; Ugozzoli, F.; Pochini, A.; Dozol,
J.-F.; Hill, C.; Rouquette, H. Angew. Chem., Int. Ed. Engl.
1994, 33, 1506–1509. (b) Asfari, Z.; Bressot, C.; Vicens, J.;
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1103–1109. (d) Lamare, V.; Dozol, J.-F.; Fuangswasdi, S.;
4.4. Determination of the stoichiometry of the salt
between acid (1)-6 and (S)-1-phenylethylamine
Two 10.0 mM solutions of acid (þ)-6 and (S)-1-phenyl-
ethylamine in CDCl3 were mixed in the following volume
ratios; 10:0, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8 and 0:10. These
samples were analyzed by 1H NMR spectroscopy
(500 MHz) at 22 8C. The chemical shift value of the methyl
protons of the amine (dobs) was converted to the chemical
shift change (Dd) as follows: Dd¼dobs2damine, where damine
is the chemical shift value in the absence of acid (þ)-6.
Finally [G]/([H]þ[G])£Dd was plotted against [G]/
([H]þ[G]), where [G] is the total concentration of the
amine and [H] is that of acid (þ)-6.
´
Arnaud-Neu, F.; Thuery, P.; Nierlich, M.; Asfari, Z.; Vicens, J.
J. Chem. Soc., Perkin Trans. 2 1999, 271–284. (e) Kim, J. S.;
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M. H.; Kim, E. T.; Ra, D. Y. J. Chem. Soc., Perkin Trans. 2
´
1999, 837–846. (f) Guillon, J.; Leger, J. M.; Sonnet, P.; Jarry,
4.5. X-ray analysis of the salt between acid (1)-6 and (S)-
1-phenylethylamine
C.; Robba, M. J. Org. Chem. 2000, 65, 8283–8289.
5. (a) Yamamoto, H.; Sasaki, T.; Shinkai, S. Chem. Lett. 1994,
469–472. (b) Arduini, A.; McGregor, W. M.; Paganuzzi, D.;
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1997, 53, 3767–3776. (d) Mathieu, A.; Asfari, Z.; Vicens, J.
Tetrahedron Lett. 2002, 43, 1225–1229.
Data were collected on a Rigaku/MSC Mercury CCD
˚
diffractometer using Mo Ka radiation (l¼0.71069 A). The
calculation was performed using the software package
TeXsan (v. 1.11).22 The structure was solved by the direct
methods with SIR9223 and refined by full-matrix least
squares methods with SHELXL-97.24 All non-hydrogen
atoms were refined anisotropically. Crystal data and
refinement statistics are as follows: C57H81NO14S4,
6. (a) Narumi, F.; Morohashi, N.; Matsumura, N.; Iki, N.;
Kameyama, H.; Miyano, S. Tetrahedron Lett. 2002, 43,
621–625. (b) Narumi, F.; Hattori, T.; Morohashi, N.;
Matsumura, N.; Yamabuki, W.; Kameyama, H.; Miyano, S.
Org. Biomol. Chem. 2004, 890–898.
M¼1132.51, monoclinic, a¼15.459(4), b¼14.821(3), c¼
3
˚
˚
15.978(4) A, b¼113.416(3)8, V¼3359(1) A , T¼223(2) K,
space group P21, Z¼2, m (Mo Ka)¼0.197 mm21, 42641
reflections measured, 12887 unique (Rint¼0.058). Final
R1¼0.077 for 9856 data [I.2s(I)] and wR2¼0.214 for all
data, GOF¼1.047. The absolute stereochemistry of acid
(þ)-6 was assigned to be S by using the (S)-1-phenylethyl
moiety as an internal reference. The details of the crystal
data have been deposited with Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC
238754.
7. Narumi, F.; Matsumura, N.; Morohashi, N.; Kameyama, H.;
Miyano, S. J. Chem. Soc., Perkin Trans. 1 2002, 1843–1844.
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A.; Pappalardo, S.; Parisi, M. F.; Principato, G. Tetrahedron
1999, 55, 5505–5514. (c) Cao, Y.-D.; Luo, J.; Zheng, Q.-Y.;
Chen, C.-F.; Wang, M.-X.; Huang, Z.-T. J. Org. Chem. 2004,
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Chem. Soc. 1993, 115, 3997–4006. (b) Ferguson, G.;
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M. J. Org. Chem. 1994, 59, 42–53. (c) Jin, T. Chem. Commun.
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Acknowledgements
This work was supported in part by the Proposal-Based New
Industry Creative Type Technology R and D Promotion
Program from NEDO and a Grant-in-Aid for Scientific

F. Narumi et al. / Tetrahedron 60 (2004) 7827–7833
7833
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18. In this paper, the absolute stereochemistry is denoted by
applying the R and S designation for planar chirality.19 Thus,
in acid (þ)-6, the three phenolic oxygen atoms are fixed on the
same side of the mean plane defined by the calixarene, one of
which is chosen as a ‘pilot atom’. According to the sequence
rule, this is the oxygen which resides opposite to the hydroxy
group. The sequence-rule-preferred path within the mean
plane from the aromatic carbon attached to this oxygen toward
that attached to the carboxymethoxy group traces counter-
clockwise tracks, which is denoted as S.
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