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 enantioselectivity in asymmetric reactions

Article abstract of DOI:10.1021/jo8024412

An efficient synthetic route to inherently chiral calix[4]arenes with an ABCD substitution pattern at the wide rim in the cone conformation was developed for the first time. For the synthesis of inherently chiral ABCD-type calix[4]arenes, first 5,11-dibro

Full text of DOI:10.1021/jo8024412

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
Enantioselectivity in Asymmetric Reactions
Seiji Shirakawa, Tomohiro Kimura, Shun-ichi Murata, and Shoichi Shimizu*
Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon UniVersity,
Narashino, Chiba, 275-8575, Japan
s5simizu@cit.nihon-u.ac.jp
ReceiVed NoVember 2, 2008
An efficient synthetic route to inherently chiral calix[4]arenes with an ABCD substitution pattern at the
wide rim in the cone conformation was developed for the first time. For the synthesis of inherently chiral
ABCD-type calix[4]arenes, first 5,11-dibromo-17-(3,5-dimethylphenyl)-25,26,27,28-tetrapropoxycalix[4]arene
(9) was prepared as a key intermediate. Then, functionalization of the calix[4]arene 9 was examined, and
highly regioselective monofunctionalization was achieved via selective monolithiation of bromo groups.
Various multifunctionalized inherently chiral ABCD-type calix[4]arenes can be synthesized by using
this method; thus, the synthesis of inherently chiral phosphine and carboxylic acid derivatives of ABCD-
type calix[4]arene was demonstrated. In addition, the aminophenol derivative 1b of an ABCD-type
calix[4]arene with a 3,5-dimethylphenyl group at the wide rim was synthesized and resolved into optically
pure enantiomers. The chiral calix[4]arene 1b was used as an organocatalyst in asymmetric Michael
addition reactions of thiophenols. The effect of the 3,5-dimethylphenyl group at the wide rim of
calix[4]arene 1b on enantioselectivity was examined, and a positive effect of the 3,5-dimethylphenyl
group was observed.
Introduction
array of achiral substituents on the calixarene skeleton.4 Over
the past two decades, many inherently chiral calixarenes have
been prepared, and some of them have been resolved into
individual enantiomers.5 In spite of these efforts, only a few
Calixarenes have been widely used as three-dimensional
molecular platforms for the design of artificial molecular
receptors, owing to the ready availability of cheap starting
materials and the facile modification of the calixarene structure
at the wide and narrow rims.1
The chemistry of chiral calixarenes has received increasing
interest in recent years, as it is important to the development of
new chiral receptors for asymmetric recognition and provides
potent tools for understanding the stereochemistry of biochemi-
cal systems. Hence, many chiral calixarenes containing chiral
residues at either the wide or the narrow rim have been prepared
as chiral receptors2 and catalysts.3 A more challenging and
attractive approach to the introduction of chirality is to make
the calixarene “inherently” chiral by creating an unsymmetrical
(1) For representative reviews on calixarenes, see: (a) Calixarenes: A Versatile
Class of Macrocyclic Compounds; Topics in Inclusion Science 3; Vicens, J.,
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Tetrahedron 1993, 49, 8933–8968. (c) Takeshita, M.; Shinkai, S. Bull. Chem.
Soc. Jpn. 1995, 68, 1088–1097. (d) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713–745. (e) Pochini, A.; Ungaro, R. In ComprehensiVe Supramo-
lecular Chemistry; Vo¨gtle, F., Ed.; Pergamon Press: Oxford, UK, 1996; Vol. 2,
pp 103-142. (f) Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97, 1713–1734. (g)
Gutsche, C. D. Caixarenes ReVisited; Monographs in Supramolecular Chemistry;
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J., Vicens, J., Eds.;Kluwer: Dordrecht, The Netherlands, 2001. (j) Morohashi,
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* Corresponding author. Phone: +81 47-474-2568. Fax: +81 47-474-2579.
1288 J. Org. Chem. 2009, 74, 1288–1296
10.1021/jo8024412 CCC: $40.75 2009 American Chemical Society
Published on Web 12/19/2008

Multifunctional Inherently Chiral Calix[4]arene
examples of enantiomeric recognition6 and asymmetric catalysis7
with inherently chiral calixarenes have been reported. These
limited results might arise from difficulties associated with both
the design of a synthetic route to functionalized inherently chiral
calixarenes and separation of the chiral products into optically
pure enantiomers.
Recently, we developed an efficient method for the synthesis
and optical resolution of a novel inherently chiral calix[4]arene
1a with dual functionalities (Figure 1).8 The chiral calix[4]arene
1a possesses amino and hydroxy groups, which are involved
in molecular recognition at proximal positions on the wide rim
(ABCC substitution pattern). Also, the conformation of the chiral
calix[4]arene 1a was fixed in the cone conformation, which
provides a specific chiral environment. The enantiomeric
recognition ability of the chiral calix[4]arene 1a was examined,
FIGURE 1. Functionalized inherently chiral calix[4]arenes 1.
and we found that the chiral calix[4]arene 1a could be used as
an organocatalyst9 in asymmetric Michael addition reactions of
thiophenols10 with high catalytic efficiency. Unfortunately, the
observed enantioselectivity of the products was poor. For the
design of a more effective chiral catalyst, we introduced
additional substituent on the wide rim. Ultimately, we designed
an inherently chiral ABCD-type calix[4]arene 1b containing a
3,5-dimethylphenyl group as a sterically bulky substituent
(Figure 1). Such an inherently chiral wide rim ABCD-type
calix[4]arene is very rare,11 and to the best of our knowledge,
the synthesis of an ABCD-substituted calix[4]arene with control
of the conformation has never been reported. Herein, we wish
to report the development of an efficient synthetic route to the
inherently chiral wide rim ABCD-type calix[4]arene fixed in a
cone conformation, and the beneficial effects of the multifunc-
tional structure on its enantioselectivity as an organocatalyst in
asymmetric Michael addition reactions.
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Results and Discussion
Synthesis of Key Intermediate 9 for the Synthesis of
Inherently Chiral Calix[4]arenes with an ABCD Substi-
tution Pattern at the Wide Rim. For the synthesis of inherently
chiral ABCD-substituted calix[4]arenes in the cone conforma-
tion, we synthesized 5,11-dibromo-17-(3,5-dimethylphenyl)-
25,26,27,28-tetrapropoxycalix[4]arene (9) as a key intermediate.
The calix[4]arene 9 can be prepared from the already reported
calix[4]arene dibenzyl ether 2,12 as outlined in Scheme 1. For
the regioselective introduction of bromo and 3,5-dimethylphenyl
groups onto the wide rim, first, a 3,5-dimethylphenyl group was
introduced onto the calix[4]arene. Thus, one of the proximal
dihydroxy groups of 2 was selectively transformed to a mono-
O-alkylated product 3 by treatment with propyl bromide in the
presence of Na2CO3 as a base. Use of Na2CO3 as the base was
a key factor in the selective mono-O-alkylation of 2.12 The para
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Shirakawa et al.
SCHEME 1. Synthesis of Calix[4]arene 9 as a Key
Intermediate
SCHEME 2. Regioselective Formylation of 9
SCHEME 3. Confirmation of the Lithiated Position for
Selective Functionalization
position of the free phenolic ring of tri-O-alkylated calix[4]arene
3 was selectively brominated to afford 4. After O-propylation
of 4, the tetraalkoxycalix[4]arene 5 was treated with n-BuLi
and the resulting lithiation compound was transformed to the
boronate by treatment with B(OMe)3. Then, the 3,5-dimeth-
ylphenyl group was installed by using a Suzuki-Miyaura
coupling reaction13 between the boronate of calix[4]arene and
1-iodo-3,5-dimethylbenzene to afford the calix[4]arene 6. The
selective dealkylation of the benzyl groups at the narrow rim
of 6 was performed by treatment with 2.3 equiv of trimethylsilyl
iodide to afford the dialkoxycalix[4]arene 7. After regioselective
dibromination on the para positions of the free phenolic rings
in calix[4]arene 7, the resulting dibromo calix[4]arene 8 was
O-alkylated with propyl iodide in the presence of NaH to yield
the desired calix[4]arene 9 fixed in the cone conformation.
Regioselective Functionalization of the Calix[4]arene 9.
Next, we focused on the regioselective functionalization of the
proximally disubstituted bromo groups of the calix[4]arene 9.
For the synthesis of calix[4]arene 1b, monoformylation of 9
was performed as follows. The calix[4]arene 9 was treated with
1.1 equiv of n-BuLi and, subsequently, with N,N-dimethylfor-
mamide. As a result of regioselective lithiation, the monoformy-
lated calix[4]arene 10 was obtained in 79% yield (Scheme 2).
The position of the formyl group in 10 was confirmed by
treatment with aqueous HCl after lithiation (Scheme 3). We
knew that if the bromine-lithium exchange reaction occurred
selectively at the distal position of the 3,5-dimethylphenyl group,
then the inherently chiral calix[4]arene 11 would be obtained
as the result of protonation by aqueous HCl. On the other hand,
we knew that if the reaction occurred at the proximal position
of the 3,5-dimethylphenyl group, the achiral calix[4]arene 12
would be obtained. After the monolithiation of 9 shown in
1
Scheme 3, H and 13C NMR analyses of the obtained product
clearly indicated that the product possessed an inherent chirality
derived from product 11. Thus, the H NMR spectrum of 11
1
showed a set of four AB systems for methylene bridges of
calix[4]arene, at 4.48, 4.46, 4.43, and 4.40 ppm for axial protons
and at 3.22, 3.17, 3.15, and 3.10 ppm for equatrial protons. The
13C NMR spectrum showed peaks at 31.11, 30.99, 30.97, and
30.84 ppm for the four pertinent carbons. The 1H and 13C NMR
spectra observed exhibited patterns characteristic of inherently
chiral calix[4]arenes in a cone conformation.14 The origin of
regioselectivity for the lithiation of 9 is presumably due to the
steric hindrance of the 3,5-dimethylphenyl group.
Other regioselective functionalization was also possible by
using the present method (Scheme 4). After monolithiation of
9, the resulting lithiated compound was treated with either
chlorodiphenylphosphine or CO2, and gave either the corre-
sponding phosphine15,16 or the carboxylic acid derivatives 13
and 14. This synthetic procedure offers an efficient method for
the synthesis of various inherently chiral wide rim ABCD-type
calix[4]arenes.
Synthesis and Optical Resolution of a Multifunctional
Inherently Chiral Calix[4]arene 1b. Synthesis of the inherently
(14) Jaime, C.; de Mendoza, J.; Prados, P.; Nieto, P. M.; Sa´nchez, C. J. Org.
Chem. 1991, 56, 3372–3376.
(15) For reviews on phosphine-substituted calixarenes, see: (a) Wieser, C.;
Dieleman, C. B.; Matt, D. Coord. Chem. ReV. 1997, 165, 93–161. (b) Harvey,
P. D. Coord. Chem. ReV. 2002, 233-234, 289–309. (c) Jeunesse, C.; Armspach,
D.; Matt, D. Chem. Commun. 2005, 5603–5614.
(16) For wide rim phosphine-substituted calixarenes, see: (a) Hamada, F.;
Fukugaki, T.; Murai, K.; William, G.; Atwood, J. L. J. Incl. Phenom. 1991, 10,
57–61. (b) Wieser-Jeunesse, C.; Matt, D.; De Cian, A. Angew. Chem., Int. Ed.
1998, 37, 2861–2864. (c) Shimizu, S.; Shirakawa, S.; Sasaki, Y.; Hirai, C. Angew.
Chem., Int. Ed. 2000, 39, 1256–1259. (d) Shirakawa, S.; Shimizu, S.; Sasaki,
Y. New J. Chem. 2001, 25, 777–779. (e) Ve´zina, M.; Gagnon, J.; Villeneuve,
K.; Drouin, M.; Harvey, P. D. Organometallics 2001, 20, 273–281. (f) Takenaka,
K.; Obora, Y.; Hong Jang, L.; Tsuji, Y. Organometallics 2002, 21, 1158–1166.
(g) Lejeune, M.; Se´meril, D.; Jeunesse, C.; Matt, D.; Peruch, F.; Lutz, P. J.;
Ricard, L. Chem. Eur. J. 2004, 10, 5354–5360.
(13) For reviews on Suzuki-Miyaura coupling reactions, see: (a) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147–168.
1290 J. Org. Chem. Vol. 74, No. 3, 2009

Multifunctional Inherently Chiral Calix[4]arene
SCHEME 6. Optical Resolution of Inherently Chiral
Calix[4]arene 1b
FIGURE 2. HPLC chromatograms of 17a (a), 17b (b), and a mixture
of 17a and 17b (c) [column: SUMICHIRAL OA-2000 (0.46 cm × 25
cm); eluent: CHCl3; flow rate: 1.0 mL/min].
SCHEME 4. Other Examples of Regioselective
Functionalization
SCHEME 5. Synthesis of Inherently Chiral Calix[4]arene
1b
a ∼1:1 mixture of the diastereomers 17a and 17b. The
diastereomeric mixture (200 mg) of 17a and 17b was loaded
onto the preparative HPLC column, and diastereomerically pure
17a (∼65 mg) and 17b (∼35 mg) were obtained.
In the 1H NMR spectra of diastereomers 17a and 17b (Figure
S1, Suporting Information), there was a significant difference
in the chemical shift of the protons next to the sulfonyl group.
The protons of SO2CH2 in the camphorsulfonyl moieties showed
a set of two doublets for 17a (3.66, 2.94 ppm) and 17b (3.61,
3.03 ppm). Comparison of the spectra for the diastereomerically
pure 17a and 17b and their mixture clearly indicates that perfect
separation of the diastereomers 17a and 17b was achieved by
using preparative HPLC. The diastereomeric purity of 17a and
17b was also confirmed with HPLC analyses (Figure 2).
Finally, hydrolysis of 17a and 17b with NaOH for removal
of the camphorsulfonyl group afforded the optically pure
calix[4]arenes (+)-1b and (-)-1b, respectively (Scheme 6). The
optical rotations for (+)-1b and (-)-1b showed similar values
with opposite signs, and the circular dichroism (CD) spectra of
the enantiomers of 1b showed mirror images (Figure 3), which
proved they were indeed a pair of enantiomers. This is the first
example of the separation of enantiomers of an inherently chiral
calix[4]arene with an ABCD substitution pattern at the wide
rim.
chiral calix[4]arene 1b was achieved from 10 in a manner similar
to the previously described synthesis of 1a (Scheme 5).8 Thus,
the reductive amination of the formyl group of 10 with
n-butylamine gave the secondary amine 15 in 95% yield.
Compound 15 was transformed with n-butyl bromide to the
tertiary amine 16 in 89% yield. Lithiation of the bromine
substituent on 16 and the trapping of the resulting anion with
B(OMe)3 gave the corresponding boronate. The boronate was
oxidized by H2O2 with use of a one-pot method, giving the target
calix[4]arene 1b as racemates in 69% yield.17
The efficient resolution of inherently chiral calix[4]arene 1b
could be achieved by preparative HPLC after conversion into
the diastereomeric (1S)-camphorsulfonyl esters 17a and 17b
(Scheme 6). Thus, treatment of racemic calix[4]arene 1b with
(1S)-10-camphorsulfonyl chloride in the presence of NaH gave
Asymmetric Michael Addition Reactions Catalyzed by
an Inherently Chiral Calix[4]arene 1b. Previously, we have
reported that the use of a wide rim ABCC-type chiral
calix[4]arene 1a18 as an organocatalyst efficiently promoted the
Michael addition reaction of thiophenol with low enantioselec-
tivity (15% ee, Scheme 7).8 Although the observed enantiose-
lectivity of the product was low, it was noteworthy that, for the
(17) The target calix[4]arene (()-1b was prepared from 2 in 12 steps and
14% overall yield.
(18) The signs of (-)-1a were assigned from the CD spectrum at λmax (295
nm). For the CD spectrum of (-)-1a, see ref 8.
J. Org. Chem. Vol. 74, No. 3, 2009 1291

Shirakawa et al.
TABLE 1. Catalytic Asymmetric Michael Addition Reactions of
2-Cyclohexen-1-one Catalyzed by (+)-1b
entry
R
% yielda
% eeb (config)c
1
2
3
4
5
6
Ph
>99(18a)
97(18b)
97(18c)
96(18d)
>99(18e)
18 (18f)
31(R)
22(R)
25(R)
24(R)
16(R)
∼0
2-naphthyl
4-t-BuC6H4
4-MeOC6H4
4-ClC6H4
PhCH2
a Isolated yield. b Determined by HPLC. c Determined by comparison
with the literature values of optical rotations.10
SCHEME 8. Catalytic Asymmetric Michael Addition
Reactions of Thiophenol Catalyzed by (+)-1b
FIGURE 3. CD spectra of enantiomers of an inherently chiral
calix[4]arene 1b in CHCl3.
SCHEME 7. Effect of Catalyst Structure in the Michael
Addition Reaction
face. So, this hypothesis indicates the direction that design of
more efficient inherently chiral calixarene catalysts should take.
The results of the Michael addition reactions of 2-cyclohexen-
1-one catalyzed by calix[4]arene (+)-1b are summarized in
Table 1. Various substituted thiophenols could be applied to
the reaction system, to give the product in excellent yields with
low to moderate enantioselectivities (entry 1-5). When alkyl
thiols, such as benzyl mercaptan, were used, the product was
obtained in low yield with low enantioselectivity (entry 6).
Furthermore, this reaction system could be applied to other
cyclic and acyclic enones (Scheme 8). Substituted cyclohex-
enone gave the product 19a with a degree of enantioselectivity
comparable to that observed for the reaction of 2-cyclohexen-
1-one. Other cyclic enones with different ring sizes gave the
products 19b and 19c in lower enantioselectivities. The reaction
of chalcone, which is an acyclic enone, afforded the product
19d in excellent yield with moderate enantioselectivity.
first time, an inherently chiral calixarene with no chiral residue
was successfully used in asymmetric catalysis. For the improve-
ment of enantioselectivity, we employed an ABCD-type chiral
calix[4]arene 1b containing a 3,5-dimethylphenyl group at the
wide rim for a Michael addition reaction of thiophenol.
Pleasingly, a positive effect of the additional 3,5-dimethylphenyl
group was observed and the product 18a was obtained in 31%
ee with excellent yield (Scheme 7). In addition, the chiral
calix[4]arene 1c,19 which is masked with a methyl group on
the hydroxy group, was tested as a catalyst in the reaction. The
catalyst 1c promoted the Michael addition reaction moderately
with almost no enantioselectivity. These results clearly indicate
that both the amino and hydroxy groups of catalyst 1b are
important for both reactivity and selectivity in the Michael
addition reaction of thiophenols. Although the details of the
mechanism of the asymmetric Michael addition reaction are not
yet clear, it is expected that the amino group of catalyst 1b
activates thiophenol and forms the ammonium thiolate complex,
and that the hydroxy group of catalyst 1b activates cyclohex-
enone via a hydrogen bond between the carbonyl group of the
substrate and the hydroxy group of the catalyst.10 Moreover,
the 3,5-dimethylphenyl group of catalyst 1b may selectively
block the one of the enantio-face of cyclohexenone, and the
thiolate anion attacks to the cyclohexenone from the opposite
Conclusions
In the present study, we developed an efficient synthetic route
to new inherently chiral calix[4]arenes with an ABCD substitu-
tion pattern at the wide rim in the cone conformation. The
synthetic method shows potential for the synthesis of inherently
chiral ABCD-type calix[4]arenes. For instance, the inherently
chiral calix[4]arene 1b containing both a 3,5-dimethylphenyl
group and an aminophenol structure was synthesized and
resolved into optically pure enantiomers. The effect of the 3,5-
dimethylphenyl group of 1b in the asymmetric Michael addition
reactions was examined, and a positive effect on enantioselec-
tivity was observed. The asymmetric induction observed for the
Michael addition reaction was still moderate. However, we
believe that this result indicates the direction that the design of
more efficient inherently chiral calixarene catalysts should take.
(19) The signs of (+)-1c were assigned from the CD spectrum at λmax (300
nm). For the CD spectrum of (+)-1c, see the Supporting Information, Figure
S2.
1292 J. Org. Chem. Vol. 74, No. 3, 2009

Multifunctional Inherently Chiral Calix[4]arene
129.7, 129.0, 128.8, 128.3, 128.1, 127.90, 127.85, 127.81, 127.79,
127.77, 122.5, 122.4, 122.1, 114.7, 76.7, 76.6, 76.5, 76.1, 31.11,
31.08, 30.9, 23.21, 23.16, 10.4, 10.1 ppm; IR 3060, 3032, 2963,
Experimental Section
25,26-Dibenzyloxy-27-hydroxy-28-propoxycalix[4]arene [(()-
3]. To a mixture of 25,26-dibenzyloxy-27,28-dihydroxycalix-
[4]arene12 (20 mmol) and Na2CO3 (600 mmol) in DMF (150 mL)
was added n-propyl bromide (300 mmol), and the mixture was
heated at 80 °C for 15 h. The reaction mixture was cooled to room
temperature, and was then quenched with water. After the removal
of solvents by distillation, the organic materials were dissolved in
CHCl3 (150 mL). The organic solution was washed with H2O, and
dried over MgSO4. Evaporation of solvents and purification of the
residue by column chromatography on silica gel (CHCl3/hexane )
3/2 as eluent) afforded 3 in 87% yield: 1H NMR (400 MHz, CDCl3)
δ 7.17-7.38 (m, 10H), 7.04-7.13 (m, 4H), 6.91 (t, J ) 7.4 Hz,
1H), 6.75 (t, J ) 7.4 Hz, 1H), 6.36-6.49 (m, 6H), 5.46 (s, 1H),
5.13 (d, J ) 11.9 Hz, 1H), 5.09 (d, J ) 11.9 Hz, 1H), 4.72 (d, J )
11.6 Hz, 1H), 4.68 (d, J ) 11.6 Hz, 1H), 4.39 (d, J ) 13.8 Hz,
1H), 4.35 (d, J ) 13.7 Hz, 1H), 4.30 (d, J ) 13.1 Hz, 1H), 4.08
(d, J ) 13.1 Hz, 1H), 3.63-3.72 (m, 2H), 3.32 (d, J ) 13.7 Hz,
1H), 3.16 (d, J ) 13.2 Hz, 1H), 3.12 (d, J ) 13.7 Hz, 1H), 2.94
(d, J ) 13.2 Hz, 1H), 1.64-1.84 (m, 2H), 0.98 (t, J ) 7.4 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 155.4, 154.2, 153.9, 153.4,
137.6, 137.4, 136.9, 133.6, 133.5, 133.1, 132.7, 131.0, 130.6, 130.2,
129.1, 128.9, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.91,
127.85, 127.60, 127.59, 123.3, 123.1, 119.2, 77.6, 77.4, 75.8, 31.2,
31.1, 31.0, 23.1, 10.6 ppm; IR 3526, 3063, 3030, 2963, 2920, 2874,
1459, 1249, 1200, 1089, 967, 762, 700 cm-1. Anal. Calcd for
C45H42O4: C, 83.56; H, 6.54. Found: C, 83.18; H, 6.66.
25,26-Dibenzyloxy-5-bromo-28-hydroxy-27-propoxycalix[4]-
arene [(()-4]. To a solution of 3 (12 mmol) in 2-butanone (180
mL) was added N-bromosuccinimide (12.6 mmol), and the yellow
solution was stirred at room temperature for 24 h. After evaporation
of the solvent, trituration of the solid residue with MeOH gave 4
in 95% yield: 1H NMR (400 MHz, CDCl3) δ 7.16-7.38 (m, 12H),
7.12 (dd, J ) 1.5, 7.4 Hz, 1H), 7.06 (dd, J ) 1.5, 7.5 Hz, 1H),
6.92 (t, J ) 7.4 Hz, 1H), 6.44-6.50 (m, 6H), 5.59 (s, 1H), 5.11 (d,
J ) 11.8 Hz, 1H), 5.07 (d, J ) 11.8 Hz, 1H), 4.68 (s, 2H), 4.34 (d,
J ) 13.7 Hz, 1H), 4.28 (d, J ) 13.0 Hz, 1H), 4.25 (d, J ) 13.4
Hz, 1H), 4.07 (d, J ) 13.1 Hz, 1H), 3.59-3.71 (m, 2H), 3.26 (d,
J ) 13.7 Hz, 1H), 3.16 (d, J ) 13.2 Hz, 1H), 3.02 (d, J ) 13.7
Hz, 1H), 2.95 (d, J ) 13.2 Hz, 1H), 1.65-1.80 (m, 2H), 0.97 (t, J
) 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 155.3, 154.1,
153.7, 152.6, 137.5, 137.15, 137.09, 136.7, 133.7, 133.6, 132.9,
132.4, 132.2, 131.8, 130.7, 130.6, 130.1, 129.1, 128.9, 128.7,
128.36, 128.35, 128.30, 128.0, 127.9, 127.8, 127.6, 123.5, 123.2,
111.0, 77.7, 77.5, 75.8, 31.1, 30.9, 30.7, 23.0, 10.6 ppm; IR 3524,
3064, 3030, 2963, 2922, 2875, 1458, 1250, 1200, 1087, 966, 763,
699 cm-1. Anal. Calcd for C45H41BrO4: C, 74.48; H, 5.69. Found:
C, 74.56; H, 5.49.
25,26-Dibenzyloxy-5-bromo-27,28-dipropoxycalix[4]arene [(()-
5]. To a mixture of 4 (15 mmol) and NaH (45 mmol, 60%
dispersion in paraffin liquid) in DMF (150 mL) was added n-propyl
bromide (45 mmol), and the reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with 1 N HCl aq
(30 mL). After the removal of solvents by distillation, the organic
materials were dissolved in CHCl3 (150 mL). The organic solution
was washed with H2O, and dried over MgSO4. Evaporation of
solvents and purification of the residue by column chromatography
on silica gel (CHCl3/hexane ) 1/1 as eluent) afforded 5 in 89%
yield: 1H NMR (400 MHz, CDCl3) δ 7.17-7.40 (m, 10H),
6.70-6.81 (m, 6H), 6.61 (t, J ) 7.5 Hz, 1H), 6.45-6.48 (m, 2H),
6.36-6.41 (m, 2H), 4.93 (d, J ) 11.9 Hz, 1H), 4.89 (d, J ) 11.8
Hz, 1H), 4.83 (s, 2H), 4.40 (d, J ) 13.5 Hz, 1H + 1H), 4.18 (d, J
) 13.5 Hz, 1H), 4.16 (d, J ) 13.5 Hz, 1H), 3.89-3.98 (m, 2H),
3.70-3.76 (m, 2H), 3.10 (d, J ) 13.6 Hz, 1H + 1H), 2.98 (d, J )
13.5 Hz, 1H), 2.95 (d, J ) 13.6 Hz, 1H), 1.78-1.95 (m, 4H), 0.97
(t, J ) 7.4 Hz, 3H), 0.88 (t, J ) 7.5 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 156.9, 155.4, 155.2, 155.0, 137.8, 137.6, 136.9,
136.7, 136.2, 135.9, 135.3, 135.1, 134.51, 134.48, 130.45, 130.38,
2874, 1457, 1248, 1209, 1193, 1084, 1005, 974, 766, 756, 698 cm-1
.
Anal. Calcd for C48H47BrO4: C, 75.09; H, 6.17. Found: C, 74.79;
H, 6.07.
25,26-Dibenzyloxy-5-(3,5-dimethylphenyl)-27,28-di-
propoxycalix[4]arene [(()-6]. To a solution of 5 (10 mmol) in
THF (70 mL) was added n-BuLi (13 mmol, 1.5 M in hexane) at
-78 °C under argon atmosphere, and the mixture was stirred for
30 min at this temperature. B(OMe)3 (20 mmol) was then added,
and the mixture was stirred for 1 h at -78 °C. The mixture was
then warmed to room temperature and stirred for an additional 1 h.
The reaction was quenched with 1 N HCl aq (30 mL). After removal
of THF by evaporation, the organic materials were extracted with
CHCl3 (2 × 50 mL). The organic solution was washed with water
and dried over MgSO4. The solvent was evaporated to obtain the
crude boronic acid derivative. To a mixture of the crude boronic
acid, 1-iodo-3,5-dimethylbenzene (20 mmol), and Pd(PPh3)4 (0.40
mmol) in benzene (150 mL) was added 2 M Na2CO3 aq (50 mL).
The reaction mixture was refluxed for 20 h under argon atmosphere.
After completion of the reaction, the reaction mixture was extracted
with CHCl3 (2 × 50 mL). The organic solution was washed with
water and dried over MgSO4. Evaporation of solvents and purifica-
tion of the residue by silica gel column chromatography (CHCl3/
1
hexane ) 2/3 as eluent) afforded 6 in 83% yield: H NMR (400
MHz, CDCl3) δ 7.23-7.34 (m, 10H), 6.88-6.90 (m, 3H),
6.76-6.78 (m, 2H), 6.50-6.67 (m, 8H), 6.41 (t, J ) 7.5 Hz, 1H),
4.87-4.91 (m, 4H), 4.49 (d, J ) 13.4 Hz, 1H), 4.37 (d, J ) 13.4
Hz, 1H), 4.36 (d, J ) 13.4 Hz, 1H), 4.15 (d, J ) 13.4 Hz, 1H),
3.85-3.91 (m, 4H), 3.20 (d, J ) 13.5 Hz, 1H), 3.10 (d, J ) 13.6
Hz, 1H), 3.06 (d, J ) 13.6 Hz, 1H), 2.94 (d, J ) 13.5 Hz, 1H),
2.33 (s, 6H), 1.88-1.97 (m, 4H), 0.96 (t, J ) 7.4 Hz, 3H), 0.95 (t,
J ) 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.5, 156.1,
155.3, 141.6, 137.90, 137.87, 137.7, 135.4, 135.28, 135.26, 135.23,
135.10, 135.08, 135.07, 135.05, 129.5, 129.4, 128.32, 128.26,
128.22, 128.1, 127.95, 127.94, 127.86, 127.75, 127.03, 127.00,
125.0, 122.3, 122.0, 76.7, 76.6, 76.4, 31.25, 31.22, 31.14, 31.12,
23.33, 23.28, 21.4, 10.34, 10.31 ppm; IR 3062, 3036, 2962, 2916,
2874, 1458, 1213, 1192, 1005, 968, 759, 698 cm-1. Anal. Calcd
for C56H56O4: C, 84.81; H, 7.12. Found: C, 84.52; H, 7.02.
5-(3,5-Dimethylphenyl)-25,26-dihydroxy-27,28-dipropoxy-
calix[4]arene [(()-7]. To a solution of 6 (10 mmol) in CHCl3 (80
mL) was added dropwise trimethylsilyl iodide (23 mmol) under
argon atmosphere. The mixture was stirred for 48 h at 45 °C and
then the reaction was quenched with water (20 mL). The organic
materials were extracted with CHCl3 (2 × 50 mL). The combined
organic solution was washed with 2 M Na2SO3 aq and water. The
solution was dried over MgSO4, and the solvent was evaporated.
The resulting residue was purified by column chromatography on
silica gel (CHCl3/hexane ) 3/2 as eluent) to obtain (()-7 in 81%
1
yield: H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.92 (s, 1H),
7.26 (d, J ) 2.2 Hz, 1H), 7.17 (d, J ) 2.2 Hz, 1H), 7.08 (dd, J )
1.5, 7.6 Hz, 1H), 6.91-7.03 (m, 8H), 6.77 (t, J ) 7.6 Hz, 1H),
6.63 (t, J ) 7.5 Hz, 1H), 6.62 (t, J ) 7.5 Hz, 1H), 4.58 (d, J )
12.4 Hz, 1H), 4.38 (d, J ) 12.4 Hz, 1H), 4.36 (d, J ) 13.4 Hz,
1H), 4.35 (d, J ) 12.4 Hz, 1H), 4.04-4.18 (m, 2H), 3.86-3.97
(m, 2H), 3.46 (d, J ) 12.8 Hz, 1H + 1H), 3.39 (d, J ) 12.8 Hz,
1H), 3.36 (d, J ) 13.4 Hz, 1H), 2.32 (s, 6H), 2.08-2.21 (m, 4H),
1.17 (t, J ) 7.4 Hz, 3H + 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 153.7, 153.0, 151.6, 151.1, 141.0, 138.1, 138.0, 135.2, 134.45,
134.37, 134.2, 129.6, 129.40, 129.37, 129.33, 129.1, 128.9, 128.8,
128.7, 128.3, 128.14, 128.08, 127.9, 125.1, 124.8, 120.9, 120.5,
78.5, 78.4, 32.4, 31.96, 31.93, 30.3, 23.5, 23.4, 21.5, 10.5, 10.4
ppm; IR 3322, 3024, 2965, 2931, 2876, 1465, 1387, 1219, 1096,
988, 846, 753 cm-1. Anal. Calcd for C42H44O4: C, 82.32; H, 7.24.
Found: C, 82.20; H, 7.18.
5,11-Dibromo-17-(3,5-dimethylphenyl)-27,28-dihydroxy-25,26-
dipropoxycalix[4]arene [(()-8]. To a solution of 7 (7.5 mmol) in
J. Org. Chem. Vol. 74, No. 3, 2009 1293

Shirakawa et al.
CHCl3 (300 mL) was added dropwise a solution of Br2 (15 mmol)
in CHCl3 (50 mL) at -20 °C. After complete addition of the Br2
solution, the reaction was quenched with sat. Na2SO3 aq (20 mL).
The organic materials were extracted with CHCl3 (2 × 50 mL).
The organic solution was washed with H2O and dried over MgSO4.
Evaporation of solvents and purification of the residue by column
chromatography on silica gel (CHCl3/hexane ) 2/3 as eluent)
J ) 12.9 Hz, 1H), 3.21 (d, J ) 13.2 Hz, 1H), 3.16 (d, J ) 13.7
Hz, 1H), 2.39 (s, 6H), 1.85-1.97 (m, 8H), 1.08 (t, J ) 7.4 Hz,
3H), 1.07 (t, J ) 7.4 Hz, 3H), 0.93 (t, J ) 7.4 Hz, 3H + 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 191.5, 163.4, 156.9, 155.5, 154.8,
140.8, 138.1, 137.4, 136.5, 136.4, 135.5, 135.2, 135.1, 133.9, 132.7,
130.9, 130.8, 130.21, 130.17, 128.3, 128.1, 127.6, 127.5, 127.1,
124.8, 122.6, 115.1, 77.0, 76.91, 76.85, 76.7, 31.1, 30.99, 30.97,
30.8, 23.4, 23.3, 23.2, 23.1, 21.4, 10.63, 10.56, 9.96, 9.94 ppm; IR
2962, 2923, 2874, 1691, 1458, 1196, 1126, 1003, 964 cm-1. Anal.
Calcd for C49H55BrO5: C, 73.21; H, 6.90. Found: C, 73.30; H,
6.37.20
1
afforded 8 in 90% yield: H NMR (400 MHz, CDCl3) δ 8.96 (s,
1H), 8.81 (s, 1H), 7.30 (d, J ) 2.2 Hz, 1H), 7.12-7.16 (m, 4H),
7.06-7.08 (m, 2H), 7.02 (s, 2H), 6.94-6.99 (m, 2H), 6.83 (t, J )
7.6 Hz, 1H), 4.54 (d, J ) 12.4 Hz, 1H), 4.32 (d, J ) 13.5 Hz, 1H),
4.31 (d, J ) 12.9 Hz, 1H), 4.28 (d, J ) 13.2 Hz, 1H), 4.04-4.18
(m, 2H), 3.86-3.95 (m, 2H), 3.48 (d, J ) 12.5 Hz, 1H), 3.42 (d,
J ) 13.2 Hz, 1H), 3.36 (d, J ) 13.0 Hz, 1H), 3.23 (d, J ) 13.5
Hz, 1H), 2.35 (s, 6H), 2.07-2.19 (m, 4H), 1.16 (t, J ) 7.4 Hz, 3H
+ 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.3, 152.6, 150.8,
150.3, 140.6, 138.4, 138.1, 135.0, 134.4, 133.3, 133.1, 131.6, 131.4,
131.3, 131.1, 130.83, 130.75, 130.69, 130.4, 129.3, 129.1, 128.8,
128.2, 128.0, 125.1, 125.0, 112.4, 112.0, 78.54, 78.47, 32.1, 31.7,
31.3, 30.1, 23.3, 23.2, 21.4, 10.35, 10.25 ppm; IR 3312, 2977, 2931,
2876, 1476, 1387, 1266, 1219, 989, 847 cm-1. Anal. Calcd for
C42H42Br2O4 ·0.4CHCl3: C, 62.26; H, 5.18. Found: C, 62.20; H,
5.11.
5-Bromo-11-(3,5-dimethylphenyl)-25,26,27,28-tetrapropoxy-
calix[4]arene [(()-11]. To a solution of 9 (0.50 mmol) in THF
(10 mL) was added n-BuLi (0.55 mmol, 1.5 M in hexane) at -78
°C under argon atmosphere, and the mixture was stirred for 20
min at this temperature. The reaction was quenched with 0.2 N
HCl aq (10 mL). After removal of THF by evaporation, organic
materials were extracted with CHCl3 (2 × 10 mL). The organic
solution was washed with water and dried over MgSO4. Evaporation
of solvents and purification of the residue with silica gel column
chromatography (CHCl3/hexane ) 1/10 to 1/3 as eluent) afforded
11 in 77% yield: 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 2H), 7.02
(d, J ) 2.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1H), 6.94 (s, 1H), 6.80
(d, J ) 7.4 Hz, 1H), 6.75 (d, J ) 6.3 Hz, 1H), 6.58-6.64 (m, 2H),
6.54 (d, J ) 2.3 Hz, 1H), 6.49 (d, J ) 2.2 Hz, 1H), 6.46 (d, J )
7.4 Hz, 1H), 6.41 (d, J ) 7.0 Hz, 1H), 4.48 (d, J ) 13.4 Hz, 1H),
4.46 (d, J ) 13.4 Hz, 1H), 4.43 (d, J ) 13.4 Hz, 1H), 4.40 (d, J )
13.4 Hz, 1H), 3.75-3.94 (m, 8H), 3.22 (d, J ) 13.5 Hz, 1H), 3.17
(d, J ) 13.5 Hz, 1H), 3.15 (d, J ) 13.5 Hz, 1H), 3.10 (d, J ) 13.5
Hz, 1H), 2.37 (s, 6H), 1.85-1.96 (m, 8H), 1.04 (t, J ) 7.4 Hz,
3H), 1.03 (t, J ) 7.4 Hz, 3H), 0.95 (t, J ) 7.4 Hz, 3H), 0.94 (t, J
) 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.0, 156.6,
156.0, 155.3, 141.3, 137.9, 136.8, 136.7, 136.1, 136.0, 135.1, 134.9,
134.3, 134.2, 130.5, 130.4, 128.7, 128.2, 128.1, 127.9, 127.8, 127.5,
126.9, 125.0, 122.2, 122.1, 114.7, 76.8, 76.7, 76.6, 31.1, 30.99,
30.97, 30.8, 23.3, 23.2, 23.13, 23.10, 21.4, 10.52, 10.45, 10.1 ppm;
IR 2961, 2930, 2873, 1456, 1195, 1006, 965, 762 cm-1. Anal. Calcd
for C48H55BrO4 ·0.2CHCl3: C, 72.41; H, 6.93. Found: C, 72.66; H,
6.97.
11-Bromo-5-(3,5-dimethylphenyl)-17-diphenylphosphino-
25,26,27,28-tetrapropoxycalix[4]arene [(()-13]. To a solution of
9 (0.50 mmol) in THF (10 mL) was added n-BuLi (0.55 mmol,
1.5 M in hexane) at -78 °C under argon atmosphere and the
mixture was stirred for 20 min at this temperature. A solution of
chlorodiphenylphosphine (1.0 mmol) in THF (3 mL) was then added
to the reaction mixture, and the mixture was stirred for 0.5 h at
-78 °C. The reaction mixture was then warmed to room temper-
ature and stirred for an additional 1 h. The reaction was quenched
with sat. NH4Cl aq (10 mL). After removal of THF by evaporation,
the organic materials were extracted with CHCl3 (2 × 10 mL).
The organic solution was washed with water and dried over MgSO4.
Evaporation of solvents and purification of the residueby column
chromatography on silica gel (CHCl3/hexane ) 1/2 as eluent)
afforded 13 in 79% yield: 1H NMR (400 MHz, CDCl3) δ 7.27-7.40
(m, 14H), 7.09 (dd, J ) 1.8, 7.9 Hz, 1H), 6.96-6.99 (m, 2H), 6.52
(t, J ) 7.6 Hz, 1H), 6.26 (d, J ) 2.3 Hz, 1H), 6.22 (d, J ) 7.4 Hz,
1H), 6.19 (d, J ) 2.3 Hz, 1H), 6.10 (d, J ) 7.1 Hz, 1H), 4.48 (d,
J ) 13.5 Hz, 1H), 4.42 (d, J ) 13.6 Hz, 1H + 1H), 4.36 (d, J )
13.4 Hz, 1H), 3.94-4.07 (m, 4H), 3.58-3.73 (m, 4H), 3.24 (d, J
) 13.6 Hz, 1H), 3.15 (d, J ) 13.6 Hz, 1H), 3.09 (d, J ) 13.4 Hz,
1H), 3.01 (d, J ) 13.5 Hz, 1H), 2.41 (s, 6H), 1.79-1.99 (m, 8H),
1.09 (t, J ) 7.0 Hz, 3H), 1.07 (t, J ) 7.0 Hz, 3H), 0.89 (t, J ) 7.4
Hz, 3H), 0.88 (t, J ) 7.4 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 158.8, 157.4, 155.2, 154.5, 141.0, 138.2, 137.6, 137.5,
137.2, 136.7, 136.6, 136.2, 135.9, 135.5, 135.4, 135.2, 135.0, 134.5,
134.3, 133.5, 133.32, 133.26, 132.9, 130.4, 130.1, 128.6, 128.5,
5,11-Dibromo-17-(3,5-dimethylphenyl)-25,26,27,28-tetra-
propoxycalix[4]arene [(()-9]. To a mixture of 8 (7.0 mmol)
and NaH (105 mmol, 60% dispersion in paraffin liquid) in DMF
(150 mL) was added n-propyl iodide (105 mmol) at 0 °C, and the
reaction mixture was stirred at 0 °C for 24 h. The reaction was
quenched with 1 N HCl aq (30 mL). After the removal of solvents
by distillation, the organic materials were dissolved in CHCl3 (300
mL). The organic solution was washed with H2O and dried over
MgSO4. Evaporation of solvents and purification of the residue with
silica gel column chromatography (CHCl3/hexane ) 2/5 as eluent)
afforded 9 in 69% yield: 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J
) 2.1 Hz, 1H), 7.17 (s, 2H), 7.15 (d, J ) 2.1 Hz, 1H), 7.10 (d, J
) 2.3 Hz, 1H), 7.05 (d, J ) 2.3 Hz, 1H), 6.95 (s, 1H), 6.57 (t, J
) 7.6 Hz, 1H), 6.42 (d, J ) 2.3 Hz, 1H), 6.34-6.36 (m, 2H), 6.29
(d, J ) 7.5 Hz, 1H), 4.48 (d, J ) 13.4 Hz, 1H), 4.42 (d, J ) 13.5
Hz, 1H + 1H), 4.36 (d, J ) 13.5 Hz, 1H), 3.86-4.01 (m, 4H),
3.67-3.79 (m, 4H), 3.23 (d, J ) 13.5 Hz, 1H), 3.16 (d, J ) 12.7
Hz, 1H), 3.12 (d, J ) 12.9 Hz, 1H), 3.05 (d, J ) 13.6 Hz, 1H),
2.39 (s, 6H), 1.83-1.97 (m, 8H), 1.07 (t, J ) 7.3 Hz, 3H), 1.06 (t,
J ) 7.3 Hz, 3H), 0.92 (t, J ) 7.4 Hz, 3H), 0.91 (t, J ) 7.4 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 157.0, 156.7, 155.5, 154.8,
141.0, 138.7, 138.0, 137.7, 136.5, 136.3, 135.5, 135.4, 135.2, 133.8,
132.9, 131.6, 130.9, 130.7, 130.2, 128.3, 128.0, 127.8, 127.5, 127.2,
125.0, 122.5, 115.1, 114.4, 77.0, 76.8, 76.72, 76.68, 31.2, 31.1,
30.9, 30.7, 23.4, 23.3, 23.1, 23.0, 21.5, 10.7, 10.6, 10.0, 9.9 ppm;
IR 2963, 2935, 2875, 1457, 1196, 1004, 965, 847 cm-1. Anal. Calcd
for C48H54Br2O4: C, 67.45; H, 6.37. Found: C, 67.28; H, 6.36.
11-Bromo-5-(3,5-dimethylphenyl)-17-formyl-25,26,27,28-
tetrapropoxycalix[4]arene [(()-10]. To a solution of 9 (5.0 mmol)
in THF (70 mL) was added n-BuLi (5.5 mmol, 1.5 M in hexane)
at -78 °C under argon atmosphere and the mixture was stirred for
20 min at this temperature. Dry N,N-dimethylformamide (7.5 mmol)
was then added, and the mixture was stirred for 15 min at -78 °C.
The reaction was quenched with 0.2 N HCl aq (40 mL). After
removal of THF by evaporation, the organic materials were
extracted with CHCl3 (2 × 50 mL). The organic solution was
washed with water and dried over MgSO4. Evaporation of solvents
and purification of the residue with silica gel column chromatog-
raphy (CHCl3/hexane ) 1/2 to 2/1 as eluent) afforded 10 in 79%
yield: 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.51 (d, J ) 1.8
Hz, 1H), 7.46 (d, J ) 1.8 Hz, 1H), 7.18 (d, J ) 2.1 Hz, 1H),
7.11-7.13 (m, 3H), 6.96 (s, 1H), 6.57 (t, J ) 7.6 Hz, 1H), 6.43 (d,
J ) 2.3 Hz, 1H), 6.36 (d, J ) 6.9 Hz, 1H), 6.33 (d, J ) 2.2 Hz,
1H), 6.26 (d, J ) 7.4 Hz, 1H), 4.51 (d, J ) 13.6 Hz, 1H), 4.48 (d,
J ) 13.9 Hz, 1H), 4.45 (d, J ) 14.0 Hz, 1H), 4.43 (d, J ) 13.5
Hz, 1H), 3.69-4.12 (m, 8H), 3.29 (d, J ) 13.7 Hz, 1H), 3.24 (d,
(20) A formylated calix[4]arene 10 was somewhat unstable compared with
other calixarenes.
1294 J. Org. Chem. Vol. 74, No. 3, 2009

Multifunctional Inherently Chiral Calix[4]arene
128.44, 128.39, 127.8, 127.5, 127.4, 127.2, 124.9, 122.4, 115.0,
77.0, 76.8, 76.7, 76.5, 31.2, 31.1, 30.9, 30.8, 23.5, 23.4, 23.1, 23.0,
21.5, 10.8, 10.7, 9.9, 9.8 ppm; 31P NMR (162 MHz, CDCl3) δ -6.3
and was then quenched with water. After the removal of CH3CN
by evaporation, the organic materials were extracted with CHCl3
(2 × 50 mL), and the organic solution was dried over MgSO4.
Evaporation of solvents and purification of the residue from column
chromatography on silica gel (CHCl3/AcOEt ) 20/1 to 10/1 as
(s) ppm; IR 3017, 2969, 2927, 2878, 1738, 1456, 1374, 1217 cm-1
.
Anal. Calcd for C60H64BrO4P: C, 75.06; H, 6.72. Found: C, 74.80;
H, 6.83.
1
eluent) afforded 16 in 89% yield: H NMR (400 MHz, CDCl3) δ
11-Bromo-5-carboxy-17-(3,5-dimethylphenyl)-25,26,27,28-
tetrapropoxycalix[4]arene [(()-14]. To a solution of 9 (0.50
mmol) in THF (10 mL) was added n-BuLi (0.55 mmol, 1.5 M in
hexane) at -78 °C under argon atmosphere and the mixture was
stirred for 20 min at this temperature. Then, CO2 gas was bubbled
via a needle for 15 min at -78 °C. The reaction was quenched
with 0.2 N HCl aq (10 mL). After removal of THF by evaporation,
organic materials were extracted with CHCl3 (2 × 10 mL). The
organic solution was washed with water and dried over MgSO4.
Evaporation of solvents and purification of the residue with silica
gel column chromatography (CHCl3/AcOEt ) 20/1 to 5/1 as eluent)
afforded 14 in 72% yield: 1H NMR (400 MHz, CDCl3) δ 7.87 (d,
J ) 2.0 Hz, 1H), 7.81 (d, J ) 2.0 Hz, 1H), 7.30 (d, J ) 2.2 Hz,
1H), 7.22-7.24 (m, 3H), 6.96 (s, 1H), 6.53 (t, J ) 7.6 Hz, 1H),
6.32 (d, J ) 2.3 Hz, 1H), 6.24-6.27 (m, 2H), 6.19 (d, J ) 7.5 Hz,
1H), 4.50 (d, J ) 13.6 Hz, 1H), 4.49 (d, J ) 13.4 Hz, 1H), 4.44
(d, J ) 13.4 Hz, 1H), 4.43 (d, J ) 13.4 Hz, 1H), 3.95-4.16 (m,
4H), 3.67-3.77 (m, 4H), 3.30 (d, J ) 13.7 Hz, 1H), 3.25 (d, J )
13.2 Hz, 1H), 3.21 (d, J ) 13.4 Hz, 1H), 3.17 (d, J ) 13.7 Hz,
1H), 2.40 (s, 6H), 1.83-1.99 (m, 8H), 1.11 (t, J ) 6.7 Hz, 3H),
1.09 (t, J ) 6.7 Hz, 3H), 0.91 (t, J ) 7.5 Hz, 3H), 0.90 (t, J ) 7.5
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.3, 163.1, 157.3,
155.3, 154.6, 140.8, 138.2, 137.1, 137.0, 136.2, 136.0, 135.1, 135.0,
133.4, 132.6, 131.5, 130.9, 130.6, 130.2, 128.4, 127.9, 127.8, 127.5,
127.2, 124.8, 122.7, 122.6, 115.2, 77.0, 76.9, 76.8, 76.7, 31.2, 31.0,
30.9, 23.5, 23.4, 23.2, 23.0, 21.5, 10.8, 10.7, 9.9 ppm; IR 2963,
2931, 2876, 1681, 1459, 1426, 1307, 1210, 1003, 964 cm-1. Anal.
Calcd for C49H55BrO6: C, 71.78; H, 6.76. Found: C, 71.64; H, 6.60.
11-Bromo-5-(N-butylaminomethyl)-17-(3,5-dimethylphenyl)-
25,26,27,28-tetrapropoxycalix[4]arene [(()-15]. To a solution of
10 (4.0 mmol) in a mixture of THF (30 mL) and EtOH (20 mL)
was added n-butylamine (20 mmol) at room temperature, and the
mixture was stirred for 12 h. NaBH4 (4.0 mmol) was then added,
and the mixture was stirred for 30 min. The reaction was quenched
with sat. NH4Cl aq. After removal of THF and ethanol by
evaporation, the organic materials were extracted with CHCl3 (2
× 50 mL). The organic solution was washed with water and dried
over MgSO4. Evaporation of solvents and purification of the residue
with silica gel column chromatography (CHCl3/MeOH ) 20/1 to
7.22-7.27 (m, 4H), 7.00 (s, 1H), 6.96 (s, 1H), 6.94 (s, 1H), 6.49
(dt, J ) 2.5, 7.6 Hz, 1H), 6.18-6.30 (m, 4H), 4.49 (d, J ) 13.4
Hz, 1H), 4.44 (d, J ) 13.4 Hz, 1H), 4.43 (d, J ) 13.4 Hz, 1H),
4.38 (d, J ) 13.4 Hz, 1H), 3.88-4.05 (m, 4H), 3.66-3.74 (m,
4H), 3.44 (s, 2H), 3.23 (d, J ) 13.5 Hz, 1H), 3.16 (d, J ) 13.4 Hz,
1H), 3.14 (d, J ) 13.5 Hz, 1H), 3.08 (d, J ) 13.4 Hz, 1H), 2.43 (t,
J ) 7.5 Hz, 4H), 2.40 (s, 6H), 1.82-1.98 (m, 8H), 1.43-1.49 (m,
4H), 1.26-1.36 (m, 4H), 1.05-1.11 (m, 6H), 0.87-0.93 (m, 12H)
ppm; 13C NMR (100 MHz, CDCl3) δ 157.3, 156.6, 155.3, 154.6,
140.9, 138.1, 137.0, 136.3, 136.1, 135.94, 135.85, 135.3, 134.7,
133.5, 133.3, 130.3, 130.1, 129.9, 129.3, 128.3, 127.6, 127.4, 127.0,
124.8, 122.3, 114.9, 76.9, 76.7, 76.54, 76.53, 58.1, 53.5, 31.2, 31.0,
30.9, 30.8, 29.0, 23.5, 23.3, 23.0, 21.4, 20.7, 14.1, 10.75, 10.67,
9.90, 9.86 ppm; IR 2958, 2930, 2872, 1456, 1220, 1195, 1006,
965 cm-1. Anal. Calcd for C57H74BrNO4 ·H2O: C, 73.21; H, 8.19;
N, 1.50. Found: C, 73.58; H, 8.08; N, 1.35.
5-(N,N-Dibutylaminomethyl)-17-(3,5-dimethylphenyl)-11-hy-
droxy-25,26,27,28-tetrapropoxycalix[4]arene [(()-1b]. To a solu-
tion of 16 (3.0 mmol) in THF (60 mL) was added sec-BuLi (4.5
mmol, 1.0 M in hexane) at -78 °C under argon atmosphere, and
the mixture was stirred for 45 min at this temperature. B(OMe)3
(6.6 mmol) was then added, and the mixture was stirred for 30
min at -78 °C. To the resulting reaction mixture was added 30%
H2O2 aq (10 mL) and 3 N NaOH aq (10 mL), then the mixture
was warmed to room temperature. After being stirred for 1 h at
room temperature, the reaction was quenched with 0.5 M Na2S2O3
aq (70 mL) and the mixture was stirred for 30 min. After removal
of THF by evaporation, organic materials were extracted with
CHCl3 (2 × 50 mL). The organic solution was washed with 0.1 N
HCl aq and sat. NaHCO3 aq. The solution was dried over MgSO4,
and the solvent was evaporated. The resulting residue was purified
by using silica gel column chromatography (CHCl3/AcOEt ) 3/1
1
to 1/2 as eluent) to obtain (()-1b in 69% yield: H NMR (400
MHz, CDCl3) δ 7.18-7.21 (m, 4H, Ar-H), 6.89-6.94 (m, 3H, Ar-
H), 6.40 (t, J ) 7.5 Hz, 1H, Ar-H), 6.25-6.33 (m, 2H, Ar-H),
5.73-5.75 (m, 2H, Ar-H), 4.49 (d, J ) 13.3 Hz, 1H, ArCH2Ar),
4.45 (d, J ) 13.2 Hz, 1H, ArCH2Ar), 4.43 (d, J ) 13.3 Hz, 1H,
ArCH2Ar), 4.38 (d, J ) 13.2 Hz, 1H, ArCH2Ar), 3.92-3.99 (m,
4H, OCH2CH2), 3.65-3.76 (m, 4H, OCH2CH2), 3.41 (s, 2H,
ArCH2N), 3.21 (d, J ) 13.4 Hz, 1H, ArCH2Ar), 3.13 (d, J ) 13.4
Hz, 1H, ArCH2Ar), 3.12 (d, J ) 13.4 Hz, 1H, ArCH2Ar), 3.05 (d,
J ) 13.4 Hz, 1H, ArCH2Ar), 2.38 (s, 6H, ArCH3), 2.35-2.42 (m,
4H, NCH2CH2), 1.84-1.99 (m, 8H, OCH2CH2CH3), 1.41-1.48 (m,
4H, NCH2CH2CH2), 1.23-1.32 (m, 4H, NCH2CH2CH2CH3),
1.04-1.10 (m, 6H, NCH2CH2CH2CH3), 0.87-0.93 (m, 12H,
OCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3) δ 157.3, 156.7,
155.6, 150.2, 149.5, 141.0, 138.0, 136.6, 136.4, 136.0, 135.9, 134.7,
134.54, 134.49, 133.8, 133.7, 129.7, 129.6, 128.2, 127.7, 127.5,
127.2, 127.1, 124.8, 121.8, 114.3, 114.2, 76.9, 76.8, 76.6, 76.5,
57.9, 53.2, 31.2, 31.1, 31.0, 30.9, 28.5, 23.42, 23.37, 23.04, 23.02,
21.5, 20.7, 14.1, 10.71, 10.69, 10.0, 9.9 ppm; IR 3399, 2959, 2930,
2872, 1463, 1217, 1008 cm-1. Anal. Calcd for C57H75NO5 ·H2O:
C, 78.49; H, 8.90; N, 1.61. Found: C, 78.58; H, 8.91; N, 1.42.
Diastereomers 17a and 17b. To a mixture of (()-1b (1.5 mmol)
and NaH (4.5 mmol, 60% dispersion in paraffin liquid) in a mixture
of THF (20 mL) and DMF (2 mL) was added (1S)-10-camphor-
sulfonyl chloride (4.5 mmol) at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 6 h. The reaction was
quenched with sat. NH4Cl aq (20 mL). After the removal of solvents
by evaporation, the organic materials were extracted with CHCl3
(2 × 20 mL) and the organic solution was dried over MgSO4.
Evaporation of solvents and purification of the residue by using
1
10/1 as eluent) afforded 15 in 95% yield: H NMR (400 MHz,
CDCl3) δ 7.21 (d, J ) 2.0 Hz, 1H), 7.17 (s, 2H), 7.15 (d, J ) 2.0
Hz, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 6.53 (t, J ) 7.6
Hz, 1H), 6.38 (d, J ) 2.1 Hz, 1H), 6.30-6.34 (m, 2H), 6.26 (d, J
) 7.4 Hz, 1H), 4.48 (d, J ) 13.4 Hz, 1H), 4.44 (d, J ) 13.4 Hz,
1H), 4.43 (d, J ) 13.4 Hz, 1H), 4.38 (d, J ) 13.4 Hz, 1H),
3.86-4.02 (m, 4H), 3.69-3.76 (m, 4H), 3.61 (s, 2H), 3.23 (d, J )
13.5 Hz, 1H), 3.15 (d, J ) 13.5 Hz, 1H), 3.14 (d, J ) 13.5 Hz,
1H), 3.08 (d, J ) 13.5 Hz, 1H), 2.58 (t, J ) 7.3 Hz, 2H), 2.39 (s,
6H), 1.83-1.98 (m, 8H), 1.46-1.54 (m, 2H), 1.31-1.40 (m, 2H),
1.08 (t, J ) 7.3 Hz, 3H), 1.06 (t, J ) 7.3 Hz, 3H), 0.88-0.94 (m,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.1, 156.5, 155.5,
154.8, 140.9, 138.0, 136.7, 136.4, 136.2, 136.1, 135.7, 135.4, 134.8,
133.7, 133.6, 133.4, 130.3, 130.2, 128.9, 128.3, 127.59, 127.56,
127.0, 124.8, 122.3, 114.8, 76.9, 76.7, 76.6, 76.5, 53.6, 48.9, 32.0,
31.1, 31.0, 30.9, 30.8, 23.4, 23.3, 23.03, 23.00, 21.5, 20.5, 14.0,
10.7, 10.6, 9.9 ppm; IR 3424, 2960, 2926, 2873, 1456, 1221, 1195,
1006, 965 cm-1. Anal. Calcd for C53H66BrNO4 ·H2O: C, 72.42; H,
7.80; N, 1.59. Found: C, 72.68; H, 7.73; N, 1.64.
11-Bromo-5-(N,N-dibutylaminomethyl)-17-(3,5-dimethylphe-
nyl)-25,26,27,28-tetrapropoxycalix[4]arene [(()-16]. To a mixture
of 15 (4.0 mmol) and K2CO3 (8.0 mmol) in CH3CN (80 mL) was
added n-butyl bromide (12 mmol), and the mixture was refluxed
for 12 h. The reaction mixture was cooled to room temperature
J. Org. Chem. Vol. 74, No. 3, 2009 1295

Shirakawa et al.
silica gel column chromatography (CHCl3/AcOEt ) 5/1 to 1/1 as
eluent) afforded a ∼1:1 mixture of diastereomers 17a and 17b in
95% yield.
of solvents and purification of the residue with silica gel column
chromatography (CHCl3/AcOEt ) 2/1 to 1/1 as eluent) afforded
29
29
(+)-1b ([R]D +3.6 (c 0.90, CHCl3)) or (-)-1b ([R]D -3.7 (c
Resolution of Calix[4]arenes 17a and 17b. Resolution of
diastereomers 17a and 17b was carried out by preparative HPLC,
using a SUMICHIRAL OA-2000 column (2.0 cm × 25 cm) with
CHCl3 as the eluent. The diastereomeric mixture of 17a and 17b
(∼1:1) (200 mg) was loaded onto the preparative column. The
CHCl3 solutions of the separated diastereomers were washed with
sat. NaHCO3 aq and pure calix[4]arenes 17a (first fraction) (∼65
mg) and 17b (second fraction) (∼35 mg) were obtained, respec-
tively. The diastereomeric purity of the calix[4]arene 17a and 17b
was determined with HPLC.
1.4, CHCl3)) in 95% and 92% yields, respectively.
5-(N,N-Dibutylaminomethyl)-17-(3,5-dimethylphenyl)-11-meth-
oxy-25,26,27,28-tetrapropoxycalix[4]arene [(+)-1c]. To a mixture
of (+)-1b (0.20 mmol) and NaH (0.60 mmol, 60% dispersion in
paraffin liquid) in a mixture of THF (5 mL) and DMF (0.5 mL)
was added methyl iodide (0.60 mmol) at 0 °C. The reaction mixture
was warmed to room temperature and stirred for 2 h. The reaction
was quenched with sat. NH4Cl aq (5 mL). After the removal of
solvents by evaporation, the organic materials were extracted with
CHCl3 (2 × 5 mL) and the organic solution was dried over MgSO4.
Evaporation of solvents and purification of the residue with silica
gel column chromatography (CHCl3/AcOEt ) 5/1 to 2/1 as eluent)
17a: [R]28D +16.1 (c 0.96, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.19-7.23 (m, 4H), 6.89-7.00 (m, 3H), 6.39 (t, J ) 7.2 Hz,
1H), 6.10-6.28 (m, 4H), 4.48 (d, J ) 13.4 Hz, 1H), 4.46 (d, J )
14.4 Hz, 1H), 4.43 (d, J ) 14.1 Hz, 1H), 4.42 (d, J ) 13.4 Hz,
1H), 3.87-4.03 (m, 4H), 3.72-3.76 (m, 4H), 3.66 (d, J ) 15.4
Hz, 1H), 3.44-3.52 (m, 2H), 3.23 (d, J ) 13.5 Hz, 1H), 3.21 (d,
J ) 13.5 Hz, 1H), 3.16 (d, J ) 13.4 Hz, 1H), 3.14 (d, J ) 13.4
Hz, 1H), 2.94 (d, J ) 15.4 Hz, 1H), 2.39-2.49 (m, 4H), 2.38 (s,
6H), 2.22-2.30 (m, 2H), 1.85-2.01 (m, 10H), 1.42-1.65 (m, 6H),
1.23-1.35 (m, 5H), 1.06-1.10 (m, 9H), 0.85-0.94 (m, 12H), 0.82
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 214.0, 157.1, 156.7,
155.4, 154.5, 143.3, 140.7, 137.9, 136.6, 136.3, 135.7, 135.4, 135.1,
134.5, 133.8, 133.4, 130.1, 129.5, 128.2, 127.6, 127.4, 127.2, 127.1,
124.7, 122.0, 121.2, 120.8, 76.9, 76.7, 76.6, 76.4, 57.9, 53.1, 47.7,
46.1, 42.5, 41.9, 31.0, 30.92, 30.89, 28.4, 26.5, 24.6, 23.35, 23.29,
23.0, 22.9, 21.4, 20.5, 20.0, 19.6, 14.0, 10.61, 10.55, 9.9 ppm; IR
2959, 2932, 2873, 1748, 1458, 1373, 1220, 1204, 1174, 1007, 982,
966 cm-1. Anal. Calcd for C67H89NO8S·H2O: C, 74.06; H, 8.44;
N, 1.29. Found: C, 74.00; H, 8.23; N, 1.22.
afforded the (+)-1c19 in 62% yield: H NMR (400 MHz, CDCl3)
1
δ 7.06-7.10 (m, 4H), 6.87-6.92 (m, 3H), 6.44-6.52 (m, 3H),
5.96-6.03 (m, 2H), 4.49 (d, J ) 13.1 Hz, 1H), 4.46 (d, J ) 13.0
Hz, 1H), 4.45 (d, J ) 13.0 Hz, 1H), 4.42 (d, J ) 13.4 Hz, 1H),
3.73-3.92 (m, 8H), 3.53 (s, 2H), 3.45 (s, 3H), 3.21 (d, J ) 14.2
Hz, 1H), 3.18 (d, J ) 14.5 Hz, 1H), 3.16 (d, J ) 13.6 Hz, 1H),
3.13 (d, J ) 13.6 Hz, 1H), 2.45 (t, J ) 7.8 Hz, 4H), 2.36 (s, 6H),
1.87-1.99 (m, 8H), 1.50-1.59 (m, 4H), 1.20-1.31 (m, 4H), 1.04
(t, J ) 7.4 Hz, 3H), 1.03 (t, J ) 7.4 Hz, 3H), 0.89-0.98 (m, 12H)
ppm; 13C NMR (100 MHz, CDCl3) δ 157.4, 156.8, 156.0, 154.0,
150.0, 140.6, 137.9, 136.0, 135.93, 135.88, 135.7, 135.0, 134.9,
134.4, 134.2, 134.1, 130.3, 128.2, 127.9, 127.7, 126.7, 126.6, 124.4,
121.9, 113.0, 112.8, 76.74, 76.69, 76.68, 56.6, 54.9, 52.1, 31.3,
31.11, 31.05, 30.8, 26.6, 23.24, 23.17, 23.08, 21.4, 20.3, 13.8, 10.44,
10.42, 10.1 ppm; IR 2959, 2932, 2873, 1604, 1463, 1210, 1059,
1007, 966 cm-1. Anal. Calcd for C58H77NO5 ·0.4CHCl3: C, 76.61;
H, 8.48; N, 1.53. Found: C, 76.33; H, 8.61; N, 1.64.
17b: [R]28D +3.8 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.12-7.16 (m, 4H), 6.84-6.96 (m, 3H), 6.02-6.56 (m, 5H), 4.48
(d, J ) 13.4 Hz, 1H), 4.47 (d, J ) 14.5 Hz, 1H), 4.43 (d, J ) 13.4
Hz, 1H + 1H), 3.87-3.97 (m, 4H), 3.73-3.77 (m, 4H), 3.61 (d, J
) 15.0 Hz, 1H), 3.41-3.52 (m, 2H), 3.22 (d, J ) 13.5 Hz, 1H),
3.20 (d, J ) 13.3 Hz, 1H), 3.18 (d, J ) 13.4 Hz, 1H), 3.15 (d, J )
13.3 Hz, 1H), 3.03 (d, J ) 15.1 Hz, 1H), 2.37 (s, 6H), 2.33-2.53
(m, 6H), 1.86-2.08 (m, 10H), 1.23-1.58 (m, 11H), 1.04-1.08 (m,
9H), 0.89-0.95 (m, 12H), 0.85 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 214.1, 156.9, 155.7, 154.7, 143.4, 140.6, 138.0, 136.3,
135.9, 135.0, 134.6, 134.0, 129.8, 128.3, 127.7, 127.3, 126.8, 124.6,
122.1, 121.2, 120.8, 76.9, 76.73, 76.67, 76.58, 58.0, 53.2, 47.8,
46.8, 42.8, 42.4, 31.15, 31.12, 30.9, 29.7, 26.7, 24.9, 23.4, 23.3,
23.0, 21.4, 20.5, 20.0, 19.7, 13.9, 10.6, 10.5, 10.0 ppm; IR 2959,
2931, 2873, 1749, 1461, 1374, 1220, 1174, 1006, 966 cm-1; Anal.
Calcd for C67H89NO8S·H2O: C, 74.06; H, 8.44; N, 1.29. Found:
C, 74.33; H, 8.26; N, 1.52.
General Procedure for the Catalytic Asymmetric Michael
Addition Reactions Catalyzed by (+)-1b. To a solution of (+)-
1b (0.0050 mmol) and thiophenol (0.60 mmol) in toluene (1 mL)
was added 2-cyclohexen-1-one (0.50 mmol) at 20 °C under argon
atmosphere, and the mixture was stirred for 24 h at this temperature.
The reaction was quenched with 0.2 N HCl aq (2 mL), and the
organic materials were extracted with CHCl3 (2 × 3 mL). The
organic solution was washed with water (5 mL) and dried over
MgSO4. Evaporation of solvents and purification of the residue with
flash chromatography on silica gel afforded a Michael addition
product. The enantioselectivity of the product was determined by
using chiral HPLC analysis, and the absolute configuration was
determined by comparison of the observed optical rotation with
the reported values.10
Acknowledgment. We thank Yuichi Tanaka for his assistance
Hydrolysis of 17a and 17b to Obtain (+)-1b and (-)-1b.
Calixarene 17a or 17b (0.20 mmol) in a mixture of THF (5 mL)
and EtOH (5 mL) was refluxed with 3 M NaOH aq (1.5 mL) for
10 h. The reaction mixture was cooled to 0 °C, and the reaction
was then quenched with 1 N HCl aq (6 mL). After the removal of
solvents by evaporation, the organic materials were extracted with
CHCl3 (2 × 10 mL). The organic solution was washed with 0.1 N
HCl aq and sat. NaHCO3 aq, then dried over MgSO4. Evaporation
with this study.
Supporting Information Available: Copies of 1H NMR and
13C NMR for calixarenes, characterization data, and HPLC
chromatograms for Michael addition products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8024412
1296 J. Org. Chem. Vol. 74, No. 3, 2009