Inherently chiral biscalix[4]arenes: Design and syntheses

Article abstract of DOI:10.1021/jo9023792

(Chemical Equation Presented) Inherently chiral biscalix[4]arenes have been designed and synthesized by covalently assembling two calix[4]arene building blocks in a 1,3-position linking with 1,2-position pattern at the lower rims via two triethylene glycol bridges.

Full text of DOI:10.1021/jo9023792

pubs.acs.org/joc
fragments to the calix skeleton by reacting calix[4]arene
Inherently Chiral Biscalix[4]arenes: Design and
Syntheses
with corresponding chiral electrophiles under basic condi-
tions.1 A newly developed and intriguing method utilizes
a direct asymmetric reaction on properly functionalized
calixarene to produce chiral calix[4]arenes.2 The second stra-
tegy creates “inherent chirality”, a phenomenon that is related
to the presence of molecular curvature,3 by the asymmetric
array of achiral substituent(s) onto the nonplanar 3-dimen-
sional calix skeleton. Generating inherent chirality without
using chiral reagents results in a racemic mixture of both
enantiomers, which could be optically resolved through chiral
HPLC4 or by chemical resolution method5 in some cases.
Stereoselective approaches to inherently chiral calix[4]arenes
have also been developed recently.6 So far, there have been
examples of inherently chiral calix[4]arenes with diversified
substitution patterns (upper and/or lower rim, meta-posi-
tion5e,g,j,6c,d,7) and conformations (cone, partial cone,4e,5c-5e
1,2-alternate,8 and 1,3-alternate9), all of which were based on
one calix platform. The versatility of calixarene provides
much room for the design of calix-based hosts of more
sophisticated structures and, hopefully, superior properties.
Conceptually, the marriage of inherent chirality and biscalix-
arene gives birth to inherently chiral biscalixarene, whose
merits may include (i) spacious chiral environment; (ii)
possible synergistic effect of the two calix cavities, and (iii)
more deployable binding sites compared with monocalix-
based inherently chiral entity. Herein we report on the design
and syntheses of inherently chiral biscalix[4]arenes.
Jun Luo, Li-Ching Shen, and Wen-Sheng Chung*
Department of Applied Chemistry, National Chiao-Tung
University, Hsinchu 30050, Taiwan, Republic of China
wschung@cc.nctu.edu.tw
Received July 20, 2009
Inherently chiral biscalix[4]arenes have been designed and
synthesized by covalently assembling two calix[4]arene
building blocks in a 1,3-position linking with 1,2-position
pattern at the lower rims via two triethylene glycol bridges
The design of singly bridged inherently chiral biscalix-
[4]arene seems rather straightforward. The strategy is to treat
one calix unit as the parent and the other calix unit as one of
the substituents which form an asymmetric array on the
skeleton of the parent calixarene. However, the orientation
of the two calix components may be undefined due to the free
rotation along the bridging covalent single bond (eq 1). Such
The study of chiral calixarenes is a robust and lasting
development stage in calixarene chemistry, for the prospect
of obtaining efficient calix-based chiral sensors and cata-
lysts.1-7 Generally, two strategies have been applied to
endowing parent calix[4]arene with chirality. The first strat-
egy introduces stereogenic center(s) directly onto the calix
platform. In this regard, the relatively simple and most
widely used method involves anchoring various chiral
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S.; Kubo, M. Nature 1996, 382, 522. (b) Zheng, Y.-S.; Zhang, C. Org. Lett.
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464 J. Org. Chem. 2010, 75, 464–467
Published on Web 12/16/2009
DOI: 10.1021/jo9023792
r
2009 American Chemical Society

Luo et al.
JOCNote
a disadvantage could be circumvented by covalently con-
necting two calix units with two bridges. There are three
patterns to link two calix[4]arene building blocks as cone
conformers via two identical bridges at the lower rims to
form a doubly bridged biscalix[4]arene: (i) 1,3-position link-
ing with 1,3-position, (ii) 1,2-position linking with 1,2-posi-
tion, and (iii) 1,3-position linking with 1,2-pisition (eq 2). In
the first scenario, where two bridges link the two calix units
distally, it would be difficult to generate inherent chirality
due to the C2v symmetry plane that always exists. The second
scenario, where two bridges link the two calix units proxi-
mally, may result in a mixture of syn and anti isomers. By
contrast, the third scenario, where two bridges connect the
two calix units distally at one rim and proximally at the
other, allows both simpler products and further modification
for creation of inherent chirality at the lower rims and
therefore is the strategy of choice.
SCHEME 1. Syntheses of Inherently Chiral Biscalix[4]arenes
The synthetic pathway of the doubly bridged inherently
chiral biscalix[4]arenes is depicted in Scheme 1. 25,27-Dipro-
poxy-26,28-dihydroxy-p-tert-butylcalix[4]arene 110 was
treated with 1-tosyl-10-(tetrahydropyran-2-yl)-1,4,7,10-
tetraoxadecane11 in the presence of NaH to afford the
tetra-O-alkylated intermediate, the THP protecting groups
of which were subsequently removed with TsOH H2O to
3
give the diol compound 2 in 81% yield for the two steps.
Tosylation of 2 afforded 3 as building block I in 90% yield.
Reacting 3 with 25,26-dibenzyloxy-27,28-dihydroxy-p-tert-
butylcalix[4]arene,12 which served as building block II, in
the presence of t-BuOK in toluene at 70 °C furnished
biscalix[4]arenes 4 and 5 as a mixture of two conformational
isomers (the less polar cone-1,2-alternate conformer and the
more polar cone-cone conformer) in a ratio of ca. 1.5:1. In an
attempt to debenzylate 4 and 5 respectively, trimethylsilyl
bromide (TMSBr) proved to be a relatively more efficient
reagent compared with Pd/C-catalyzed hydrogenation or
AlCl3. In the case of 4, reaction with TMSBr (2.0 equiv) in
(10) Iwamoto, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4955.
(11) Asakawa, M.; Ashton, P. R.; Balzani, V.; Boyd, S. E.; Credi, A.;
Mattersteig, G.; Menzer, S.; Montalti, M.; Raymo, F. M.; Ruffilli, C.;
Stoddart, J. F.; Venturi, M.; Williams, D. J. Eur. J. Org. Chem. 1999, 985.
(12) Groenen, L. C.; Ruel, B. H. M.; Casnati, A.; Timmerman, P.;
Verboom, W.; Harkema, S.; Pochini, A.; Ungaro, P.; Reinhoudt, D. N.
Tetrahedron Lett. 1991, 32, 2675.
CHCl3 at room temperature for 45 min led to 6 as a major
product in 72% yield, which was suggested by ESI-MS m/z
1723.2 [MþNaþ] as the monodebenzylated compound and
therefore is an inherently chiral biscalix[4]arene. In principle,
J. Org. Chem. Vol. 75, No. 2, 2010 465

Luo et al.
JOCNote
the free phenolic hydroxyl in 6 might pass the annulus by
rotation, leading to two possible conformers (the cone-
partial cone and the cone-1,2-alternate conformers as indi-
cated in Scheme 1). However, NMR spectra (CDCl3, 25 °C)
suggested that a simple compound was formed as could be
seen from the two sextets (1.95 and 1.82 ppm, J = 7.5 Hz) for
1
the ArOCH2CH2CH3 protons in the H NMR spectrum as
well as two sets of signals (23.50, 23.38, 10.73, and 10.58 ppm)
for the ArOCH2CH2CH3 carbons in the 13C NMR spectrum.
For the moment, there has been no absolute evidence for the
unambiguous determination of the structure of 6. By exten-
sion of the reaction time (2.5 h) and increase of the amounts of
TMSBr (4.0 equiv), we obtained the fully debenzylated pro-
duct 7 in 18% yield along with other complicated side
products. By contrast, it was easier to fully debenzylate the
cone-cone conformer 5. When 5 was subjected to TMSBr
(2.0 equiv) in CHCl3 at room temperature for 40 min, 7 was
formed in 67% yield. The structure of 7 was confirmed by its
spectroscopic data (see the Experimental Section). Notably, in
FIGURE 1. 1H NMR spectrum (300 MHz, 25 °C) of inherently
chiral biscalix[4]arene (()-9 in CDCl3.
1
and 6.66 ppm (1H each, J = 2.7 Hz), and 6.54 and 6.53 ppm
(1H each, J = 2.7 Hz) are attributable to the aromatic pro-
tons of the 1,2-bridged calix unit. The singlet appearing at
5.76 ppm corresponds to the phenolic hydroxyl proton. In
the region of 3.41-3.14 ppm, six doublets at 3.33, 3.31, 3.30,
3.24, 3.18, and 3.16 ppm (1H, 1H, 1H, 1H, 3H, 1H, J = ca.
13.0 Hz) are assignable to the eight equatorial protons of the
ArCH2Ar methylene groups. The two triplets appearing at
1.12 (3H, J = 7.5 Hz) and 0.98 ppm (3H, J = 7.5 Hz) corres-
pond to the methyl protons of the two sets of propyl groups.
In the 13C NMR spectrum of 9, the carbon signal arising
from ArCH2Ar methylene groups at around 31.0 ppm is
consistent with its cone-cone conformation. As a proof of
the inherent chirality, 1H NMR spectra of compounds (()-
9-11 were measured in the presence of excess (S)-(þ)-2,2,2-
trifluoro-1-(9-anthryl)ethanol (Pirkle’s reagent) and several
signals showed obvious splitting in all cases, presumably due
to the formation of the diastereomeric complexes.
Atthe currentstage, attempts toopticallyresolve inherently
chiral biscalix[4]arene carboxylic acid racemates (()-11 by
chemical resolution method with chiral auxiliaries such as (S)-
BINOL and (R)-1-phenylethylamine (in the presence of DCC
and DMAP in CH2Cl2) failed. In both cases, the reaction was
quite slow (presumably due to the steric hindrance of 11) and
the diastereomers formed appeared as one spot on the ana-
lytic TLC plate. However, optical resolution of (()-11 was
achieved by semi-preparative HPLC with a CHIRACEL
OD-H column. The CD spectra of the separated enantiomers
showed mirror images of each other (Figure 2).
its H NMR spectrum, the singlet appearing at 8.70 ppm
corresponds to the phenolic hydroxy groups. As expected, the
triplets appearing at 1.10 and 1.00 ppm correspond to the
methyl protons of the two propyl groups, which is also
consistent with the two groups of signals for the propyl
carbons in the 13C NMR spectrum.
The tedious protection-deprotection procedure and low
yields prompted us to seek direct access to compound 7,
which is a useful achiral precursor for the construction of
inherently chiral biscalix[4]arenes. Previous literatures13
have adequately proven that t-BuOK as a base in toluene
generally favors the formation of proximally substituted
calixbiscrowns as a mixture of cone and 1,2-alt conformers
upon treatment of either parent calix[4]arene with 2 equiv of
polyethylene glycol ditosylates or calix[4]monocrown with 1
equiv of polyethylene glycol ditosylates. Enlightened by this,
we treated p-tert-butylcalix[4]arene (as building block II)
with 1 equiv of calix[4]arene ditosylate 3 (building block I) in
the presence of t-BuOK in toluene and obtained the proxi-
mally linked product 7 in yield up to 34%. Further mono-
alkylation of 7 with suitable electrophiles (BnBr and ethyl
bromoacetate) in the presence of Cs2CO3 in DMF furnished
corresponding inherently chiral biscalix[4]arene derivatives
8 and 9 as racemates, respectively. Alkylation of the remain-
ing phenolic hydroxyl of 8 by reaction with ethyl bromoace-
tate in the presence of NaH in CH3CN provided compound
10, which was further converted into corresponding car-
boxylic acidderivative 11byhydrolysis under basic condition.
As expected, the NMR spectra of all the inherently chiral
biscalix[4]arenes are quite complicated due to the complex
splitting patterns and overlapping of the signals. Still, some
details of the structural features are discernible. For exam-
In summary, we have offered an approach to inherently
chiral biscalix[4]arenes, which were covalently assembled by
two calix[4]arene building blocks in a 1,3-position linking
with 1,2-position pattern at the lower rims via two triethylene
glycol bridges. The achiral intermediate 7, which has only
one symmetry plane, may provide an excellent platform for
the construction of inherently chiral biscalix[4]arene deriva-
tives.
1
ple, in the H NMR spectrum of 9 (Figure 1), the signals
arising from the aromatic rings of the two calix moieties
appear in the region of 7.18-6.49 ppm, where two singlets at
7.16 (4H) and 6.49 ppm (4H) are attributable to the aromatic
protons of the 1,3-bridged calix unit and the four pairs of
doublets at 7.17 and 7.16 ppm (1H each, J = 2.7 Hz, partly
overlapped), 7.12 and 7.09 ppm (1H each, J = 2.7 Hz), 6.67
Experimental Section
Reaction of Compound 3 (Building Block I) with p-tert-
Butylcalix[4]arene (Building Block II) for the Preparation of
Biscalix[4]arenes 7. To a suspension of p-tert-butylcalix[4]arene
(1.00 g, 1.54 mmol) in toluene (200 mL) was added t-BuOK
(13) (a) Arduini, A.; Domiano, L.; Pochini, A.; Secchi, A.; Ungaro, R.;
Ugozzoli, F.; Struck, O.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1997,
53, 3767. (b) Ferguson, G.; Lough, A. J.; Notti, A.; Pappalardo, S.; Parisi,
M. F.; Petringa, A. J. Org. Chem. 1998, 63, 9703.
466 J. Org. Chem. Vol. 75, No. 2, 2010

Luo et al.
JOCNote
J = 12.6 Hz), 3.12 (d, 4H, J=12.6 Hz), 3.10 (d, 1H, J = 12.6
Hz), 1.98 (sextet, 2H, J = 7.5 Hz), 1.88 (sextet, 2H, J = 7.5 Hz),
1.333 (s, 27H), 1.327 (s, 9H), 1.07 (t, 2H, J = 7.5 Hz), 0.91 (t, 2H,
J = 7.5 Hz), 0.83 (s, 9H), 0.811 (s, 9H), 0.807 (s, 18H); 13C NMR
(CDCl3, 125 MHz) δ 154.7, 154.4, 153.8, 152.4, 151.4, 151.1,
150.7, 145.8, 145.5, 145.4, 145.1, 145.0, 144.0, 143.9, 141.5,
137.5, 135.9, 135.8, 135.6, 135.5, 132.6, 132.2, 131.88, 131.86,
131.84, 131.77, 131.65, 129.4, 129.1, 129.0, 128.5, 128.0, 125.8,
125.53, 125.49, 125.4, 125.1, 125.00, 124.95, 124.92, 124.86,
124.8, 124.5, 124.44, 124.42, 78.2, 77.74, 77.72, 75.0, 72.2,
71.8, 71.3, 71.1, 70.8, 70.5, 70.23, 70.17, 70.0, 69.44, 69.36,
34.11, 34.07, 33.9, 33.67, 33.65, 33.6, 31.8, 31.73, 31.71, 31.7,
31.5, 31.3, 31.13, 31.08, 31.0, 30.9, 23.6, 23.4, 10.8, 10.6; FAB-
MS m/z 1723 [M þ Naþ]. Anal. Calcd for C113H150O12: C 79.82,
H 8.89. Found: C 79.41, H 8.79.
FIGURE 2. The CD spectra of the enantiomers of inherently chiral
biscalix[4]arene 11 in CHCl3 at 25 °C. The black solid line and the
red dotted line denote the (þ)-11 and (-)-11 which were separated
by chiral HPLC.
Alkylation of (()-8 for the Preparation of Compound (()-10.
To a stirred mixture of (()-8 (500 mg, 0.294 mmol), NaH (118
mg, 2.94 mmol) in THF (15 mL), and CH3CN (40 mL) was
added ethyl bromoacetate (327 μL, 2.94 mmol) at room tem-
perature. Then the reaction mixture was heated at 70 °C for 1 d.
After removal of the solvent under reduced pressure, CH2Cl2 (50
mL) was added. The solid residue was removed by passing
through a thin layer of Celite. The organic filtrate was evapo-
rated and the residue was purified by column chromatography
(SiO2, hexane/ethyl acetate = 15:1) to furnish compound 10 as a
white solid in 90% yield. Mp 149.0-151.4 °C (CH2Cl2/CH3-
CN); 1H NMR (CDCl3, 300 MHz) δ 7.55-7.34 (m, 5H), 7.12 (s,
4H), 6.95 (s, 4H), 6.63 (s, 4H), 6.46 (s, 4H), 4.93 (d, 1H, J = 10.8
Hz), 4.85 (d, 1H, J = 10.8 Hz), 4.82 (d, 1H, J = 16.5 Hz), 4.76
(d, 1H, J = 12.6 Hz), 4.68 (d, 1H, J = 16.5 Hz), 4.60 (d, 1H, J =
13.2 Hz), 4.56 (d, 1H, J = 12.9 Hz), 4.44-3.60 (m, 33H),
3.57-3.38 (m, 2H), 3.19-3.06 (m, 8H), 2.04-1.83 (m, 4H),
1.35 (s, 9H), 1.34 (s, 9H), 1.28 (t, 3H, J = 7.2 Hz), 1.21 (s, 18H),
1.06 (t, 3H, J = 7.5 Hz), 0.97 (s, 18H), 0.94 (t, 3H, J = 7.5 Hz),
0.83 (s, 18H); 13C NMR (CDCl3, 75 MHz) δ 170.7, 154.6,
154.5, 153.8, 153.6, 152.7, 152.6, 152.4, 145.1, 145.0, 144.6,
144.5, 144.0, 143.9, 138.2, 135.54, 135.49, 135.0, 134.6, 134.3,
134.0, 133.3, 133.0, 132.8, 132.7, 131.87, 131.86, 131.8, 129.7,
128.2, 127.9, 125.6, 125.5, 125.4, 125.3, 125.1, 125.0, 124.8,
124.5, 124.4, 77.74, 77.69, 73.6, 72.3, 72.1, 72.0, 71.04,
71.02, 70.9, 70.6, 70.43, 70.35, 70.0, 69.6, 60.3, 34.1, 33.9, 33.7,
33.6, 31.7, 31.64, 31.55, 31.5, 31.4, 31.3, 31.1, 31.0, 30.9, 30.8,
23.53, 23.46, 14.2, 10.7, 10.6; FAB-MS m/z 1809 [M þ Naþ].
Anal. Calcd for C117H156O14: C 78.66, H 8.80. Found: C 78.53,
H 8.94.
(862 mg, 5.0 equiv) and the reaction mixture was stirred at 70 °C
for 1 h. Then 3 (2.21 g, 1.1 equiv) was added and the reaction
mixture was stirred at 70 °C for 1 d. After removal of the solvent
under reduced pressure, the residue was partitioned between
H2O (80 mL) and CH2Cl2 (2 ꢀ 80 mL). The combined organic
layer was dried over MgSO4 and evaporated. The residue was
purified by column chromatography (SiO2, hexane/AcOEt =
20/1) to give 7 as a white solid in 34% yield. Mp 189.1-192.8 °C;
1H NMR (CDCl3, 300 MHz) δ 8.70 (s, 2H), 7.13 (s, 4H), 7.01 (d,
2H, J = 2.4 Hz), 6.96 (s, 2H), 6.95 (s, 2H), 6.92 (d, 2H, J = 2.4
Hz), 6.48 (s, 2H), 6.47 (s, 2H), 4.59 (d, 1H, J = 12.6 Hz),
4.44-3.86 (m, 31H), 3.71 (q, 4H, J = 7.8 Hz), 3.34 (d, 4H, J =
13.2 Hz), 3.16 (d, 2H, J = 12.6 Hz), 3.15 (d, 2H, J = 12.6 Hz),
2.07-1.90 (m, 4H), 1.35 (s, 18H), 1.22 (s, 18H), 1.11 (s, 18H),
1.10 (t, 3H, J = 7.5 Hz), 1.00 (t, 3H, J = 7.5 Hz), 0.85 (s, 9H),
0.84 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 154.3, 152.3, 151.7,
148.9, 146.2, 145.1, 144.0, 143.9, 142.1, 135.49, 135.46, 133.7,
133.4, 131.9, 131.8, 128.6, 127.8, 125.9, 125.47, 125.45, 125.13,
125.06, 124.4, 77.7, 77.6, 74.8, 71.9, 70.8, 70.6, 70.4, 69.6, 34.1,
34.0, 33.8, 33.5, 31.9, 31.7, 31.5, 31.2, 31.1, 31.0, 30.9, 23.6, 23.5,
10.8, 10.7; ESI-MS m/z 1633.2 [M þ Naþ]. Anal. Calcd for
C
106H144O12: C 79.06, H 9.01. Found: C 78.97, H 8.86.
Reaction of 7 with Electrophiles. General Procedure for the
Preparation of Inherently Chiral Biscalix[4]arenes. A stirred
mixture of 7 (869 mg, 0.54 mmol), electrophile (1.2 equiv), and
Cs2CO3 (211 mg, 0.65 mmol) in DMF (60 mL) was heated at
70 °C for 12 h. The solvent was evaporated under reduced
pressure. The residue was partitioned between 1% HCl (50 mL)
and CH2Cl2 (2 ꢀ 50 mL). The combined organic layer was dried
over MgSO4. The crude product was further purified by column
chromatography to give inherently chiral biscalix[4]arene 8 or 9
as a white solid. (()-8: Benzyl bromide (77 μL, 0.65 mmol) was
used as the electrophile in the reaction. Column chromato-
graphy (SiO2, hexane/AcOEt=15/1). Yield 83%. Mp 165.5-
Acknowledgment. We are grateful to the National Science
Council (NSC) and the MOE ATU program of the Ministry
of Education, Taiwan, ROC for financial support.
1
Supporting Information Available: Experimental proce-
dures for compounds 2, 3, 4, 5, 6, 9, and 11; 1H and 13C NMR
spectra of all the new compounds; partial 1H NMR spectra of
(()-9-11 in the absence and presence of Pirkle’s reagent; HPLC
chromatogram of 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
168.5 °C (CH2Cl2/C2H5OH); H NMR (CDCl3, 300 MHz) δ
7.61-7.33 (m, 5H), 7.13 (s, 2H), 7.11 (s, 2H), 7.10 (s, 2H), 7.07 (s,
2H), 6.54 (s, 2H), 6.51 (s, 2H), 6.43 (s, 4H), 5.53 (s, 1H), 4.86 (d,
1H, J = 11.1 Hz), 4.80 (d, 1H, J = 11.1 Hz), 4.52 (d, 1H, J =
12.9 Hz), 4.41 (d, 1H, J = 13.5 Hz), 4.39-3.58 (m, 33H),
3.35-3.25 (m, 4H), 3.18 (d, 1H, J = 12.6 Hz), 3.16 (d, 1H,
J. Org. Chem. Vol. 75, No. 2, 2010 467