An inherently chiral calix[4]crown carboxylic acid in the 1,2-alternate conformation

Article abstract of DOI:10.1007/s10847-012-0111-2

For better understanding of the structure/property relationship of inherently chiral calixarenes in the 1,2-alternate conformation, we designed and synthesized an inherently chiral calix[4]crown-4 carboxylic acid 1,2-alternate conformer. Resolution of the racemates was effected by condensation with (S)-BINOL as a chiral auxiliary and separation of the resultant diastereomers via preparative TLC plates, followed by hydrolysis of the isolated diastereomers to afford enantiopure antipodes of the title compound. Preliminary property study revealed that the title compound has the ability to enantioselectively discriminate 2-phenylglycinol by ¹H NMR spectroscopy.

Full text of DOI:10.1007/s10847-012-0111-2

J Incl Phenom Macrocycl Chem (2012) 74:277–284
DOI 10.1007/s10847-012-0111-2
ORIGINAL ARTICLE
An inherently chiral calix[4]crown carboxylic acid in the
1,2-alternate conformation
•
Yu-Xiang Xia Hao-Hui Zhou Jiao Shi
•
•
•
Si-Zhe Li Min Zhang Jun Luo Guang-Ya Xiang
•
•
Received: 21 October 2011 / Accepted: 8 January 2012 / Published online: 3 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract For better understanding of the structure/prop-
erty relationship of inherently chiral calixarenes in the
1,2-alternate conformation, we designed and synthesized
an inherently chiral calix[4]crown-4 carboxylic acid
1,2-alternate conformer. Resolution of the racemates was
effected by condensation with (S)-BINOL as a chiral
auxiliary and separation of the resultant diastereomers via
preparative TLC plates, followed by hydrolysis of the
isolated diastereomers to afford enantiopure antipodes of
the title compound. Preliminary property study revealed
that the title compound has the ability to enantioselectively
prospect of application. The two major structural features
of calixarenes, namely, the readiness of modification and
the richness of stereochemistry provide an excellent
opportunity of generating calixarene-based chiral species.
At molecular level, a calixarene could be chiral by virtue of
incorporating chiral subunit(s) into its skeleton, in which
case the chirality is owing to local chiral element(s) such as
a chiral center [1–7] and a chiral axis [8, 9]. Alternatively,
a calixarene could be endowed with ‘‘inherent chirality’’,
which is based on the asymmetric arrangement of achiral
subunit(s) on its skeleton [10–18]. It is this stereochemical
appeal that stimulates chemists to study the structures and
functions of inherently chiral calixarenes.
1
discriminate 2-phenylglycinol by H NMR spectroscopy.
Keywords Inherently chiral Á Calix[4]arene Á
1,2-Alternate Á Resolution Á Chiral recognition
The past decade has witnessed concrete advances in
inherently chiral calixarenes. As regards synthesis, efficient
resolution of racemates has become most widely used to
obtain enantiopure enantiomers [19–29]. A few efforts have
also been made on the asymmetric synthesis of inherently
chiral calixarenes [30–37], with an impressive example
recently reported by Arnott et al. [38, 39] demonstrating high
enantiomeric excesses of no less than 92%. Accompanied
with the development of synthetic methodologies, increasing
attempts have been made on the applications of enantiopure
inherently chiral calixarenes. Encouraging (but not satis-
factory) results have been obtained, which to some extent
reflected the crucial role that could be played by inherent
chirality in chiral recognition [19–21, 30], and asymmetric
catalysis [21–24, 31, 32, 40, 41].
Introduction
The study of functionalized chiral calixarenes is attractive
to researchers because of its theoretical significance and
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-012-0111-2) contains supplementary
material, which is available to authorized users.
Y.-X. Xia Á J. Shi Á S.-Z. Li Á M. Zhang Á J. Luo (&) Á
G.-Y. Xiang
Tongji School of Pharmacy, Huazhong University of Science
and Technology, Wuhan 430030, China
e-mail: lawdream1975@163.com
Attainment of structural/functional diversity as well as
establishment of structure/function relationship is one of
the central topics of calixarene chemistry. So far, though
inherently chiral calix[4]arenes with diverse substitution
patterns (wide and/or narrow rim, meta-position) have
emerged, most of them are based on cone, partial cone and
1,3-alternate conformers. The scarcity of synthesis of
H.-H. Zhou (&)
Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College,
Beijing 100050, China
e-mail: sd4885760@hotmail.com
123

278
J Incl Phenom Macrocycl Chem (2012) 74:277–284
inherently chiral calix[4]arene 1,2-alternate conformers
[28, 42, 43] and the vacancy of resolution and property
study have aroused our attention. To gain deeper insight
into inherently chiral calix[4]arene 1,2-alternate conform-
ers, we designed the target molecule 4 (Fig. 1) on the basis
of the following considerations: (i) the use of two trieth-
ylene glycolic bridges may lead to a rigid 1,2-alternate
conformation in acceptable yield [44, 45]; (ii) the carboxyl
attached on the calixarene is an advantageous site for
optical resolution; (iii) the crown ether moiety, the car-
boxyl and the inverted aromatic rings, as potential recog-
nition sites, are convergent and may form a chiral
environment suitable for enantioselective recognition.
both antipodes of inherently chiral calix[4]arene 1,2-alter-
nate conformers (-)-4 and (?)-4, respectively.
Spectroscopic data are consistent with the given struc-
tures of all new compounds and herein only representative
1
data were detailed. In the H NMR spectrum of ( )-3, the
proton signals attributable to the methylene bridges con-
necting two syn aromatic rings appear at 4.51/3.36 ppm (a
pair of doublets, J = 12.4 Hz) and 4.26/3.15 ppm (a pair of
doublets, J = 12.4 Hz), while the proton signals attributable
to the methylene bridges connecting two anti aromatic rings
appear at 3.97/3.86 ppm (a pair of doublets, J = 16.0 Hz)
and 3.90 ppm (a singlet). Several multiplets (3.1–2.4 ppm)
assignable to the protons of the crown ether moiety undergo
dramaticdown-field shift, indicatingthe existence of astrong
shield effect imposed by the opposite aromatic rings. The
conformation information was also supported by the 13C
NMR spectrum, where the two signals appearing at 38.7/
38.4 ppm and that appearing at 28.8/28.4 ppm correspond to
the methylene bridge carbons connecting two anti and two
syn aromatic rings, respectively. The NMR spectra of ( )-4
revealed similar structure features with that of ( )-3 (see
Supplementary material).
Results and discussion
The synthetic pathway is depicted in Scheme 1. Selective
modification of one of the two phenol units of
1,2-calix[4]monocrown-4 1 [25] via the Gross formylation
afforded the monoformylated product 2 as a cone con-
former in 32% yield. In this step, inherent chirality was
generated in the calix[4]monocrown-4 skeleton. To lock
the conformation into a 1,2-alternate one, 2 was further
reacted with triethylene glycol ditosylate in the presence of
t-BuOK in toluene to furnish the inherently chiral
calix[4]biscrown aldehyde 1,2-alternate conformer 3 as
racemates in 41% yield. Subsequent oxidation converted
( )-3 into the title compound ( )-4 in 44% yield. In an
attempt to optically resolve racemates 4 using the attached
carboxyl as a resolution site, (S)-BINOL proved to be a
most efficient chiral auxiliary compared with (S)-a-phen-
ylethylamine and (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol
(Pirkle’s reagent). By condensation of ( )-4 with (S)-BI-
NOL in the presence of DCC and DMAP, a pair of dia-
stereomers were formed in ca. 1:1 ratio (based on the
integral intensity of the phenoxy hydrogens of the BINOL
Slow crystallization of ( )-3 (from CH2Cl2/C2H5OH)
and ( )-4 (from CH2Cl2/CH3CN) resulted in single crys-
tals suitable for X-ray diffraction studies, which unam-
biguously confirmed their 1,2-alternate conformations [46]
(Fig. 2). The four methylene bridge carbons in each
structure form a plane which could serve as a reference
plane (E) to define the detailed structures of 1,2-alternate
conformers (Table 1). Thus, in the solid states, 3 and 4
share such common structural features that the crown ether
moiety connecting rings A and B orients almost face to
face with the inverted aromatic benzene ring D, while the
inverted ring C tilts away from the chiral cavity formed by
the crown ether moiety and rings A and B.
The 1H NMR spectra of the separated diastereomers 5-1
and 5-2 are shown in Fig. 3. The signals of the BINOL
protons and aromatic protons of the calix[4]arene
(8.15–6.75 ppm), as well as the signals of the methylene
protons of the crown ether moiety (3.25–2.35 ppm) which
are shielded by the facing aromatic rings show distinct dif-
ferences in splitting patterns and chemical shifts, reflecting
the structural differences of the diastereomeric pair. The
signal of hydroxyl proton of 5-1 appears at 6.38 ppm, while
that of 5-2 appears at 6.64 ppm. This could be advanta-
geously used to assess the diastereomeric purity of each
diastereomer. Base on the above observations, it is reason-
able to assume that the introduction of the bulky axially
chiral BINOL unit in close proximity to the inherently chiral
calix[4]arene units via covalent bonds favors the structural
differentiation of the resultant diastereomers.
1
moiety in the H NMR spectrum of the crude diastereo-
meric mixture), which were separated by preparative TLC
in yield of 10% for 5-1 (the less polar component) and 14%
for 5-2, respectively. Hydrolysis of 5-1 and 5-2 afforded
To investigate the recognition ability of the calix[4]-
crown acid 1,2-alternate conformer 4, which contains a
Fig. 1 The structure of the inherently chiral calix[4]arene 1,2-
alternate conformer 4
123

J Incl Phenom Macrocycl Chem (2012) 74:277–284
279
Fig. 2 Crystal structures of
compounds 3 (left) and 4 (right).
Hydrogen atoms are omitted for
clarity
Scheme 1 Synthesis and
optical resolution of 4
Table 1 The interplanar angles of the phenolic rings (A, B, C, and D) with the reference plane (E) containing the four methylene bridge carbons
Compound
Interplanar angle
A/E
B/E
C/E
D/E
A/B
B/C
C/D
D/A
3
4
98.8
123.8
130.9
141.7
133.2
88.5
96.7
84.6
78.2
65.1
61.3
89.7
79.8
85.5
79.1
101.8
123

280
J Incl Phenom Macrocycl Chem (2012) 74:277–284
Fig. 3 A comparison of partial
1H NMR spectra of 5-1 and 5-2
(CDCl3, 25 °C)
carboxyl group and a crown ether unit, we chose chiral
amines and aminoalcohols as guests because acid–base
interaction and crown ether-primary ammonium cation
interaction are popular in molecular recognition. We first
guest is the major cause of the recognition event. The
recognition is most likely to occur at the rim where the
crown ether moiety and the carboxyl are convergent
because it has been known that the neighboring crown
ether moiety may help stabilize the ammonium cation
(which is positioned around the carboxylate) through
additional hydrogen bond between the –NH3? group of the
guest and the oxygen atom of the crown ether moiety [47].
The coexistence of the hydroxyl and benzene ring in
2-phenylglycinol as a discriminately recognizable guest
implies that maybe hydrogen bonding and p-concerned
interaction are key to the enantioselectivity of the recog-
nition event.
1
measured the H NMR spectra of ( )-4 in the presence of
ten equivalents of enantiopure amine or aminoalcohols.
The complexation is a fast process on the NMR time-scale,
because a single set of time-averaged signals were
observed for both free and complexed species of the host
and guest. In the presence of (R)-1-phenylethylamine, L-2-
amino-1-propanol, L-leucinol and L-phenylalaninol as
guests, the signals of the host generally demonstrated dis-
cernible changes. Particularly, the signals of the aromatic
protons ortho to the carboxyl and the axial methylene
bridge protons undergo slight up-field shifts. However,
nearly no clear splitting was observed (see Supplementary
material). This phenomenon suggested that in these cases
there is a non-selective interaction between the host and
guest, which is believed to be the acid–base interaction.
In contrast, in the presence of ten equivalents of (S)-2-
phenylglycinol, the signals of the host exhibit obvious
splitting in regions of 8.0–7.8 ppm (aromatic protons ortho
to the carboxyl), 4.5–4.1 ppm (axial methylene bridge pro-
tons) and 1.37–1.32 ppm (tert-butyl) (Fig. 4), indicating the
diastereomeric properties of the complexed species. This
Conclusion
We have synthesized an inherently chiral calix[4]crown
carboxylic acid in the 1,2-alternate conformation. NMR
spectra and crystallographic data provided the structural
details of the 1,2-alternate conformer. The success of res-
olution by use of (S)-BINOL was attributed to the differ-
ential interactions existing between the BINOL unit and the
inherently chiral calix[4]arene units with different config-
urations in the diastereomers. NMR experiments showed
that the title compound could interact enantioselectively
with 2-phenylglycinol. The enantioselectivity of the rec-
ognition event was thought to be associated with hydrogen
bonding and p-concerned interaction. We wish this work
may attract more attention to the study of inherently chiral
calix[4]arenes in the 1,2-alternate conformation.
1
prompted us to measure the H NMR spectra of (-)-4 and
(?)-4 (5 mM) in the presence of (S)-2-phenylglycinol (10
equiv), respectively. The results showed that the chemical
shift differences between the diastereomeric host–guest
complexes are large enough (Dd = 0.02–0.06 ppm for ArH
and axial ArCH2Ar) (Table 2). Accordingly, enantiopure
calix[4]crown acid 1,2-alternate conformer 4 could be used
as a chiral solvating agent for enantioselectively discrimi-
nating (S)-phenylglycinol by 1H NMR spectroscopy.
Experimental
By analysis of the structures of the host and guests, as
well as the host–guest complexation behavior, we could
deduce that the acid–base interaction between the host and
Melting points were measured on a Beijing Taike X-5
apparatus and uncorrected. NMR spectra were recorded on
123

J Incl Phenom Macrocycl Chem (2012) 74:277–284
281
Fig. 4 A comparison of the
1
partial H NMR spectra
(400 MHz, CDCl3, 25 °C)
of (a) ( )-4, (b) ( )-4 in the
presence of (S)-2-
phenylglycinol (10 equiv),
(c) (-)-4 (5 mM) in the
presence of (S)-2-
phenylglycinol (10 equiv), and
(d) (?)-4 (5 mM) in the
presence of (S)-2-
phenylglycinol (10 equiv)
1
Table 2 Selected chemical shifts in the H NMR spectra (400 MHz,
CDCl3, 25 °C) of (-)-4 and (?)-4 (5 mM) in the presence of (S)-2-
phenylglycinol (10 equiv)
0 °C for 2.5 h. Water (50 mL) was added and the reaction
mixture was stirred for another 1 h. The organic layer was
separated and washed with water (25 mL) and dried over
MgSO4. Column chromatography (SiO2, petroleum ether/
ethyl acetate = 9/2) gave ( )-2 as a white solid in 32% yield
(0.41 g). Mp 192–194 °C (CH2Cl2/CH3OH). 1H NMR
(400 MHz, CDCl3) d 9.73 (s, 1H), 9.72 (s, 1H), 9.37 (s, 1H),
7.59 (d, 1H, J = 2.0 Hz), 7.56 (d, 1H, J = 2.0 Hz), 7.24 (d,
1H, J = 2.4 Hz), 7.09–7.01 (m, 3H), 7.00 (d, 1H, J =
2.4 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.69 (t, 1H, J = 7.6 Hz),
4.63 (d, 1H, J = 12.0 Hz), 4.50–4.43 (m, 1H), 4.45 (d, 1H,
J = 13.6 Hz), 4.36 (d, 1H, J = 12.8 Hz), 4.34–4.30 (m,
1H), 4.25–4.10 (m, 7H), 4.14 (d, 1H, J = 13.6 Hz),
4.00–3.85 (m, 3H), 3.48 (d, 1H, J = 14.0 Hz), 3.46 (d, 1H,
J = 13.6 Hz), 3.44 (d, 1H, J = 13.6 Hzr), 3.40 (d, 1H,
J = 12.4 Hz), 1.21 (s, 9H), 1.12 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 191.20, 159.20, 151.64, 150.74, 150.51, 148.13,
146.96, 135.10, 133.73, 132.31, 131.67, 131.09, 130.73,
130.52, 129.45, 129.28, 128.98, 128.91, 128.70, 126.93,
126.33, 126.14, 125.82, 121.30, 76.10, 75.83, 72.85, 70.97,
70.52, 69.77, 34.37, 34.25, 32.95, 32.30, 31.76, 31.51, 31.42,
29.97. ESI–MS m/z 701.4 [M ? Na?].
1H NMR
signals
d[(-)-4]
d[(?)-4]
Ddc
ArHa
7.98 (d)
7.87 (d)
4.45 (d)
4.21 (d)
7.92 (d)
7.82 (d)
4.43 (d)
4.25 (d)
0.06
0.05
0.02
-0.04
ArCH2Arb
a
The aromatic hydrogens ortho to the carboxyl
b
The axial hydrogens of the methylene bridges connecting two syn
aromatic rings
c
Dd = d[(-)-4] - d[(?)-4]
a Bruker Av-400 spectrometer with CDCl3 as a solvent and
TMS as an internal standard. ESI–MS spectra were recor-
ded on an LCD Deca XP mass spectrometer. Optical
rotation was measured on a Perkin Elmer-341LC polar-
imeter. Preparative TLC was self-made in our laboratory.
Toluene was freshly distilled from Na-benzophenone prior
to use. Compound 1 was synthesized according to the lit-
erature [25].
Compound ( )-2
Compound ( )-3
To a solution of 1 (1.2 g, 1.84 mmol) and Cl2CHOCH3 (445
lL, 4.60 mmol) in CH2Cl2 (50 mL) at 0 °C was added SnCl4
(1.97 mL, 18.4 mmol). The reaction mixture was stirred at
To a solution of ( )-2 (0.74 mmol, 500 mg) in dry toluene
(100 mL) was added t-BuOK (0.21 g, 1.87 mmol) and the
reaction mixture was stirred at 70 °C under N2 for 1 h.
123

282
J Incl Phenom Macrocycl Chem (2012) 74:277–284
Triethylene glycol ditosylate (0.41 g, 0.99 mmol) was
added and the reaction mixture was stirred at 70 °C under
N2 for 2 days. After removal of the solvent under reduced
pressure, the residue was partitioned between water
(50 mL) and CH2Cl2 (50 mL). The water layer was
extracted with CH2Cl2 (20 mL). The combined organic
layer was dried over anhydrous MgSO4. Column chroma-
tography (SiO2, petroleum ether/ethyl acetate = 4/1)
afforded ( )-3 as a white solid in 41% yield (0.24 g). Mp
208–211 °C (CH2Cl2/C2H5OH). 1H NMR (400 MHz,
CDCl3) d 9.93 (s, 1H), 7.71 (d, 1H, J = 2.0 Hz), 7.69 (d,
1H, J = 2.0 Hz), 7.28–7.23 (m, 3H), 7.08–6.96 (m, 4H),
4.51 (d, 1H, J = 12.4 Hz), 4.26 (d, 1H, J = 12.4 Hz), 3.97
(d, 1H, J = 16.0 Hz), 3.90 (s, 2H, ArCH2Ar), 3.86 (d, 1H,
J = 16.0 Hz), 3.76–3.56 (m, 10H), 3.48–3.28 (m, 8H),
3.26 (d, 1H, J = 12.8 Hz), 3.21–3.15 (m, 2H), 3.15 (d, 1H,
J = 12.4 Hz), 3.09–3.05 (m, 1H), 2.92–2.86 (m, 1H),
2.63–2.58 (m, 1H), 2.47–2.41 (m, 1H), 1.34 (s, 9H), 1.33
(s, 9H). 13C NMR (100 MHz, CDCl3) d 192.38, 161.45,
156.29, 153.36, 153.00, 145.21, 145.03, 135.95, 135.01,
134.80, 134.54, 134.34, 133.02, 132.52, 131.61, 131.50,
131.38, 130.25, 129.46, 128.90, 126.47, 125.91, 125.43,
125.37, 122.99, 71.68, 71.35, 71.07, 70.94, 69.59, 69.57,
68.98, 68.81, 68.75, 68.41, 68.30, 67.91, 38.65, 38.45,
34.26, 34.24, 31.87, 31.86, 28.79, 28.40. ESI–MS
m/z 815.4 [M ? Na?].
134.71, 134.40, 134.36, 134.07, 132.78, 131.78, 131.72,
131.44, 131.40, 129.21, 128.91, 126.24, 125.76, 125.30,
125.22, 123.21, 122.89, 71.39, 71.30, 70.93, 70.78, 69.63,
69.41, 68.76, 68.65, 68.63, 68.33, 68.30, 67.83, 38.55,
38.32, 34.11, 31.75, 31.73, 28.70, 28.28. ESI–MS
m/z 831.5 [M ? Na?].
Chemical resolution of ( )-4
To a solution of ( )-4 (200 mg, 0.24 mmol) was added
DCC (76 mg, 0.37 mmol), DMAP (6 mg, 0.049 mmol)
and (S)-BINOL (82 mg, 0.287 mmol). The reaction mix-
ture was stirred at room temperature for 1 day. After fil-
tration, the solvent was removed under reduced pressure.
To the residue was added ethyl acetate (3 mL) and the
precipitate was removed by filtration. After removal of the
solvent of the filtrate under reduced pressure, the residue
was subjected to column chromatography (SiO2, petroleum
ether/ethyl acetate = 4/1) to afford the diastereomeric
mixture 5-1 and 5-2 as a white solid. The diastereomeric
mixture was subjected to preparative TLC (SiO2, CHCl3/
acetone = 40/1) to give the isolated 5-1 (the less polar
diastereomer) and 5-2 as white solids in yield of 10%
(26 mg) and 14% (36 mg), respectively. 5-1: Mp
1
179–184 °C. [a]2D5 = -24.2 (c = 4.68 mg/mL, THF). H
NMR (400 MHz, CDCl3) d 8.07 (d, 1H, J = 8.8 Hz), 7.98
(d, 1H, J = 8.0 Hz), 7.82–7.81 (m, 2H), 7.71–7.69 (m,
2H), 7.51–7.41 (m, 1H), 7.37 (d, 1H, J = 2.0 Hz),
7.34–7.28 (m, 4H), 7.24–7.21 (m, 3H), 7.15–7.06 (m, 3H),
7.00 (d, 1H, J = 2.4 Hz), 6.96 (d, 1H, J = 2.0 Hz), 6.93
(t, 1H, J = 7.6 Hz), 6.38 (s, 1H), 4.37 (d, 1H,
J = 12.4 Hz), 4.25 (d, 1H, J = 12.4 Hz), 3.87 (s, 2H),
3.74–3.27 (m, 20H), 3.21–3.10 (m, 2H), 3.15 (d, 1H,
J = 12.4 Hz), 3.06 (d, 1H, J = 12.8 Hz), 2.96–2.92
(m, 1H), 2.86–2.81 (m, 1H), 2.74–2.69 (m, 1H), 2.61–2.56
(m, 1H), 1.32 (s, 18H). 13C NMR (100 MHz, CDCl3) d
166.15, 160.73, 155.87, 152.92, 152.80, 152.20, 148.17,
145.03, 144.94, 135.22, 134.60, 134.43, 134.21, 134.03,
133.63, 133.40, 133.23, 132.42, 131.92, 131.43, 131.28,
131.20, 129.99, 129.88, 129.30, 128.91, 128.89, 128.22,
127.99, 127.01, 126.57, 126.03, 125.89, 125.81, 125.25,
125.23, 125.05, 123.47, 123.29, 122.92, 122.63, 122.38,
118.27, 114.47, 70.54, 70.43, 70.14, 70.01, 69.78, 69.54,
69.27, 68.51, 68.27, 68.17, 68.02, 38.51, 38.14, 34.11,
34.09, 31.71, 28.70, 27.92. ESI–MS m/z 1099.6
[M ? Na?]. 5-2: Mp 177–179 °C. [a]2D5 = ? 29.4
Compound ( )-4
To a solution of ( )-3 (0.2 g, 0.25 mmol) in CH2Cl2
(50 mL) and acetone (50 mL) was added a solution of
NH2SO3H (73 mg, 0.75 mmol) and NaClO2 (79 mg,
0.88 mmol) in water (2.25 mL). The reaction mixture was
stirred at room temperature for 1 h. Another batch of
NH2SO3H (37 mg, 0.38 mmol) and NaClO2 (40 mg,
0.44 mmol) in water (1.2 mL) was added and the reaction
mixture was stirred at room temperature for another 1 h.
After the complete consumption of ( )-3 (TLC monitor),
the solvent was removed under reduced pressure. The
residue was partitioned between 10% aqueous HCl
(50 mL) and CH2Cl2 (50 mL). The aqueous layer was
extracted with CH2Cl2 (20 mL). The combined organic
layer was dried over MgSO4. Recrystallization (CH2Cl2/
CH3CN) furnished ( )-4 as a white solid in 44% yield
(89 mg). Mp 203–206 °C (CH2Cl2/CH3CN). 1H NMR
(400 MHz, CDCl3) d 7.96 (d, 1H, J = 2.0 Hz), 7.89 (d,
1H, J = 2.0 Hz), 7.32–6.98 (m, 7H), 4.49 (d, 1H,
J = 12.4 Hz), 4.29 (d, 1H, J = 12.4 Hz), 3.97–3.35 (m,
22H), 3.25 (d, 1H, J = 12.8 Hz), 3.21–3.17 (m, 2H), 3.16
(d, 1H, J = 12.8 Hz), 3.14–3.08 (m, 1H), 2.97–2.91 (m,
1H), 2.69–2.60 (m, 1H), 2.53–2.47 (m, 1H), 1.34 (s, 9H),
1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) d 170.84,
160.50, 156.13, 153.26, 152.89, 145.01, 144.81, 135.21,
1
(c = 9.40 mg/mL, THF). H NMR (400 MHz, CDCl3) d
8.06 (d, 1H, J = 9.2 Hz), 7.97 (d, 1H, J = 7.2 Hz), 7.95
(d, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 9.2 Hz), 7.92 (d, 1H,
J = 8.0 Hz), 7.51–7.44 (m, 3H), 7.36–7.26 (m, 4H),
7.24–7.18 (m, 3H), 7.15 (d, 1H, J = 8.4 Hz), 7.10 (d, 1H,
J = 7.2 Hz), 7.01–6.98 (m, 2H), 6.77 (d, 1H, J = 6.8 Hz),
6.64 (s, 1H), 4.32 (d, 1H, J = 12.8 Hz), 4.22 (d, 1H,
123

J Incl Phenom Macrocycl Chem (2012) 74:277–284
283
6. Gopalsamuthiram, V., Predeus, A.V., Huang, R.H., Wulff, W.D.:
Optically active calixarenes conduced by methylene substitution.
J. Am. Chem. Soc. 131, 18018–18019 (2009)
7. Fulton, D.A., Stoddart, J.F.: Neoglycoconjugates based on
cyclodextrins and calixarenes. Bioconj Chem. 12, 655–672
J = 12.4 Hz), 3.90 (s, 2H), 3.74–3.28 (m, 20H), 3.20–3.07
(m, 3H), 3.13 (d, 1H, J = 12.8 Hz), 3.03 (d, 1H,
J = 12.4 Hz), 2.97–2.89 (m, 1H), 2.62–2.56 (m, 1H),
2.43–2.37 (m, 1H), 1.33 (s, 9H), 1.31 (s, 9H). 13C NMR
(100 MHz, CDCl3) d 166.18, 160.13, 156.07, 153.11,
152.68, 152.39, 147.92, 145.13, 144.80, 135.05, 134.76,
134.26, 134.20, 134.03, 133.93, 133.66, 132.60, 131.96,
131.83, 131.61, 131.43, 130.27, 130.08, 129.08, 128.81,
128.24, 128.01, 126.90, 126.42, 126.26, 126.17, 125.80,
125.74, 125.23, 125.20, 125.14, 123.48, 123.25, 123.15,
123.11, 122.37, 118.39, 114.00, 71.22, 71.18, 70.99, 70.73,
69.28, 68.76, 68.66, 68.48, 68.41, 68.24, 67.75, 67.11, 38.48,
38.07, 34.09, 31.72, 31.71, 28.66, 28.19. ESI–MS m/z 1099.6
[M ? Na?]. Compounds (-)-4 and (?)-4 were produced by
hydrolysisof 5-1 and 5-2, respectively under basic condition:
To a solution of 5-1 or 5-2 (36 mg, 0.033 mmol) in THF
(2 mL) was added a solution of NaOH (13 mg, 10 equiv) in
water (2 mL) and the reaction mixture was stirred under
reflux overnight. After removal of the solvent, the residue
was partitioned between aqueous HCl (10%, 10 mL) and
CH2Cl2 (2 9 10 mL). The combined organic layer was
dried over MgSO4. Column chromatography (SiO2, petro-
leum ether/ethyl acetate = 8/1 to 1/1) afforded (-)-4 or
(?)-4 as a white solid in ca. 60% yield. The NMR spectra and
ESI–MS spectra of (-)-4 and (?)-4 are identical with that of
(–)-4. Enantiopure (-)-4 and (?)-4 have identical melting
points of 178-180 °C. The specific rotation of (-)-4 and
(?)-4 are [a]2D5 = -41.3 (c = 4.34 mg/mL, THF) and
[a]2D5 = ? 47.6 (c = 3.93 mg/mL, THF), respectively.
(2001)
8. Bitter, I., Koszegi, E., Grun, A., Bako, P., Pal, K., Grofcsik, A.,
´
}
¨
´
´
´
´
Kubinyi, M., Balazs, B., Toth, G.: Synthesis of chiral 1,3-
calix[4](crown-6) ethers as potential mediators for asymmetric
recognition processes. Tetrahedron Asymmetry 14, 1025–1035
(2003)
9. Liu, S., Sandoval, C.A.: Evaluation of calix[4]arene-based chiral
diphosphite ligands in Rh-catalyzed asymmetric hydrogenation of
simple dehydroamino acid derivatives. J. Mol. Catal. A 325,
65–72 (2010)
¨
10. Bohmer, V., Kraft, D., Tabatabai, M.: Inherently chiral calixa-
renes. J. Incl. Phenom. Mol. Recognit. Chem. 19, 17–39 (1994)
11. Otsuka, H., Shinkai, S.: Stereochemical control of calixarenes
useful as rigid and conformationally diversiform platforms for
molecular design. Supramol. Sci. 3, 189–205 (1996)
¨
12. Vysotsky, M., Schmidt, C., Bohmer, V.: Chirality in calixarenes
and calixarene assemblies. In: Gokel, G.W. (ed.) Adv. Supramol.
Chem., vol. 7, pp. 139–233. JAI Press, Stanford (2000)
13. Cort, A.D., Mandolini, L., Pasquini, C., Schiaffino, L.: ‘‘Inherent
chirality’’ and curvature. New J. Chem. 28, 1198–1199 (2004)
14. Cherenok, S., Dutasta, J.-P., Kalchenko, V.: Phosphorus-con-
taining chiral macrocycles. Curr. Org. Chem. 10, 2307–2331
(2006)
15. Mclldowie, M.J., Mocerino, M., Ogden, M.I.: A brief review of
Cn-symmetric calixarenes and resorcinarenes. Supramol. Chem.
22, 13–39 (2010)
16. Szumna, A.: Inherently chiral concave molecules—from syn-
thesis to applications. Chem. Soc. Rev. 39, 4274–4285 (2010)
17. Li, S.-Y., Xu, Y.-W., Liu, J.-M., Su, C.-Y.: Inherently chiral
calixarenes: synthesis, optical resolution, chiral recognition and
asymmetric catalysis. Int. J. Mol. Sci. 12, 429–455 (2011)
18. Zheng, Y.-S., Luo, J.: Inherently chiral calixarenes: a decade’s
review. J. Incl. Phenom. Macrocycl. Chem. 71, 35–56 (2011)
19. Luo, J., Zheng, Q.-Y., Chen, C.-F., Huang, Z.-T.: Facile synthesis
and optical resolution of inherently chiral fluorescent calix[4]-
crowns: enantioselective recognition towards chiral leucinol.
Tetrahedron 61, 8517–8528 (2005)
Acknowledgments We are grateful to National Natural Science
Foundation of China (No. 20902029) for financial support and Ana-
lytical and Testing Center of Huazhong University of Science and
Technology for measurement service.
20. Shirakawa, S., Moriyama, A., Shimizu, S.: Design of a novel
inherently chiral calix[4]arene for chiral molecular recognition.
Org. Lett. 9, 3117–3119 (2007)
21. Shirakawa, S., Shimizu, S.: Synthesis of an inherently chiral
calix[4]arene amino acid and its derivatives: their application to
asymmetric reactions as organocatalysts. Eur. J. Org. Chem.
2009, 1916–1924 (2009)
22. Shirakawa, S., Moriyama, A., Shimizu, S.: Synthesis, optical
resolution and enantiomeric recognition ability of novel, inher-
ently chiral calix[4]arenes: trial application to asymmetric reac-
tions as organocatalysts. Eur. J. Org. Chem. 2008, 5957–5964
(2008)
23. Shirakawa, S., Kimura, T., Murata, S., Shimizu, S.: Synthesis and
resolution of a multifunctional inherently chiral calix[4]arene
with an ABCD substitution pattern at the wide rim: the effect of a
multifunctional structure in the organocatalyst on enantioselec-
tivity in asymmetric reactions. J. Org. Chem. 74, 1288–1296
(2009)
24. Shirakawa, S., Shimizu, S.: Improved design of inherently chiral
calix[4]arenes as organocatalysts. New J. Chem. 34, 1217–1222
(2010)
References
1. Sansone, F., Barboso, S., Casnati, A., Sciotto, D., Ungaro, R.: A
new chiral rigid cone water soluble peptidocalix[4]arene and its
inclusion complexes with a-amino acids and aromatic ammonium
cations. Tetrahedron Lett. 40, 4741–4744 (1999)
´
2. Rincon, A.M., Prados, P., de Mendoza, J.: A calix[4]arene urei-
dopeptide dimer self-assembled through two superposed hydro-
gen bond arrays. J. Am. Chem. Soc. 123, 3493–3498 (2001)
3. Zheng, Y.S., Zhang, C.: Exceptional chiral recognition of race-
mic carboxylic acids by calix[4]arenes bearing optically pure ab-
amino alcohol groups. Org. Lett. 6, 1189–1192 (2004)
4. Bonini, C., Chiummiento, L., Funicello, M., Lopardo, M.T.,
Lupattelli, P., Laurita, A., Cornia, A.: Novel chiral calix[4]arenes
by direct asymmetric epoxidation reaction. J. Org. Chem. 73,
4233–4236 (2008)
5. Demirtas, H.N., Bozkurt, S., Durmaz, M., Yilmaz, M., Sirit, A.:
Chiral calix[4]azacrowns for enantiomeric recognition of amino
acid derivatives. Tetrahedron 65, 3014–3018 (2009)
25. Cao, Y.-D., Luo, J., Zheng, Q.-Y., Chen, C.-F., Wang, M.-X.,
Huang, Z.-T.: Preparation of both antipodes of enantiopure
123

284
J Incl Phenom Macrocycl Chem (2012) 74:277–284
inherently chiral calix[4]crowns. J. Org. Chem. 69, 206–208
(2004)
26. Luo, J., Zheng, Q.-Y., Chen, C.-F., Huang, Z.-T.: Synthesis and
optical resolution of a series of inherently chiral calix[4]crowns
with cone and partial cone conformations. Chem. Eur. J. 11,
5917–5928 (2005)
27. Li, S.-Y., Zheng, Q.-Y., Chen, C.-F., Huang, Z.-T.: Preparation of
enantiopure inherently chiral calix[5]arenes. Tetrahedron Asym-
metry 16, 641–645 (2005)
28. Narumi, F., Hattori, T., Yamabuki, W., Kabuto, C., Kameyama,
H.: Resolution of inherently chiral anti-O,O’-dialkylated
calix[4]arenes and determination of their absolute stereochem-
istries by CD and X-ray methods. Tetrahedron Asymmetry 16,
793–800 (2005)
37. Xu, Z.-X., Zhang, C., Yang, Y., Chen, C.-F., Huang, Z.-T.:
Effective nonenzymatic kinetic resolution of racemic m-nitro-
substituted inherently chiral aminocalix[4]arenes. Org. Lett. 10,
477–479 (2008)
38. Herbert, S.A., Arnott, G.E.: An asymmetric ortholithiation
approach to inherently chiral calix[4]arenes. Org. Lett. 11,
4986–4989 (2009)
39. Herbert, S.A., Arnott, G.E.: Synthesis of inherently chiral
calix[4]arenes: stereocontrol through ligand choice. Org. Lett. 12,
4600–4603 (2010)
40. Dieleman, C., Steyer, S., Jeunesse, C., Matt, D.: Diphosphines
based on an inherently chiral calix[4]arene scaffold: synthesis and
use in enantioselective catalysis. J. Chem. Soc. Dalton Trans. 30,
2508–2517 (2001)
29. Miao, R., Zheng, Q.-Y., Chen, C.-F., Huang, Z.-T.: Efficient
syntheses and resolutions of inherently chiral calix[4]quinolines
in the cone and partial-cone conformation. J. Org. Chem. 70,
7662–7671 (2005)
41. Amato, M.E., Ballistreri, F.P., Papparlardo, A., Tomaselli, G.A.,
Toscano, R.M., Williams, D.J.: Novel chiral (salen)MnIII com-
plexes containing a calix[4]arene unit as catalysts for enantiose-
lective epoxidation reactions of (Z)-aryl alkenes. Eur. J. Org.
Chem. 2005, 3562–3570 (2005)
42. Shimizu, S., Moriyama, A., Kito, K., Sasaki, Y.: Selective syn-
thesis and isolation of all possible conformational isomers of
proximally para-disubstituted calix[4]arene. J. Org. Chem. 68,
2187–2194 (2003)
43. Narumi, F., Yamabuki, W., Hattori, T., Kameyama, H., Miyano,
S.: Synthesis and optical resolution of an anti-O, O’-dialkylated
calix[4]arene. Chem. Lett. 32, 320–321 (2003)
44. Ferguson, G., Lough, A.J., Notti, A., Pappalardo, S., Parisi, M.F.,
Petringa, A.: 1,2-Bridged calix[4]arene monocrowns and biscr-
owns in the 1,2-alternate conformation. J. Org. Chem. 63,
9703–9710 (1998)
45. Arduini, A., Domiano, L., Pochini, A., Secchi, A., Ungaro, R.,
Ugozzoli, F., Struck, O., Verboom, W., Reinhoudt, D.N.: Syn-
thesis of 1,2-bridged calix[4]arene-biscrowns in the 1,2-alternate
conformation. Tetrahedron 53, 3767–3776 (1997)
46. Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 848950 and 848951)
47. Narumi, F., Hattori, T., Matsumura, N., Onodera, T., Katagiri, H.,
Kabuto, C., Kameyama, H., Miyano, S.: Synthesis of an inher-
ently chiral O, O’-bridged thiacalix[4]crowncarboxylic acid and
its application to a chiral solvating agent. Tetrahedron 60,
7827–7833 (2004)
30. Boyko, V.I., Yakovenko, A.V., Matvieiev, Yu.I., Kalchenko,
O.I., Shishkin, O.V., Shishkina, S.V., Kalchenko, V.I.: Regio-
and stereoselective 1(S)-camphor sulfonylation of mono-
alkoxycalix[4]arenes. Tetrahedron 64, 7567–7573 (2008)
31. Xu, Z.-X., Li, G.-K., Chen, C.-F., Huang, Z.-T.: Inherently chiral
calix[4]arene-based bifunctional organocatalysts for enantiose-
lective aldol reactions. Tetrahedron 64, 8668–8675 (2008)
32. Xu, Z.-X., Zhang, C., Huang, Z.-T., Chen, C.-F.: Efficient syn-
thesis and resolution of meta-substituted inherently chiral amin-
ocalix[4]arene derivatives. Chin. Sci. Bull. 55, 2859–2869 (2010)
33. Yakovenko, V., Boyko, V.I., Danylyuk, O., Suwinska, K., Lip-
kowski, J., Kalchenko, V.I.: Diastereoselective lower rim (1S)-
camphor sulfonylation as the shortest way to the inherently chiral
calix[4]arene. Org. Lett. 9, 1183–1185 (2007)
34. Boyko, V.I., Shivanyuk, A., Pyrozhenko, V.V., Zubatyuk, R.I.,
Shishikin, O.V., Kalchenko, V.I.: A stereoselective synthesis of
asymmetrically substituted calix[4]arene carbamates. Tetrahe-
dron Lett. 47, 7775–7778 (2006)
35. Kliachyna, M.A., Yesypenko, O.A., Pirozhenko, V.V., Shishkina,
S.V., Shishkin, O.V., Boyko, V.I., Kalchenko, V.I.: Synthesis,
optical resolution and absolute configuration of inherently chiral
calixarene carboxylic acids. Tetrahedron 65, 7085–7091 (2009)
36. Xu, Z.-X., Zhang, C., Zheng, Q.-Y., Chen, C.-F., Huang, Z.-T.: A
new approach to enantiopure inherently chiral calix[4]arenes:
determination of their absolute configurations. Org. Lett. 9,
4447–4450 (2007)
123