Synthesis of an inherently chiral calix[4]arene amino acid and its derivatives: Their application to asymmetric reactions as organocatalysts

Article abstract of DOI:10.1002/ejoc.200801288

The synthesis of an inherently chiral calix[4]arene amino acid as a chiral building block has been achieved in order for subsequent, transformation to various types of inherently chiral calix[4]arenes. The optically pure, inherently chiral calix[4]arene a

Full text of DOI:10.1002/ejoc.200801288

FULL PAPER
DOI: 10.1002/ejoc.200801288
Synthesis of an Inherently Chiral Calix[4]arene Amino Acid and Its
Derivatives: Their Application to Asymmetric Reactions as Organocatalysts
Seiji Shirakawa[a] and Shoichi Shimizu*[a]
Keywords: Calixarenes / Amino acids / Asymmetric catalysis / Michael addition / Phase-transfer catalysis
The synthesis of an inherently chiral calix[4]arene amino
acid as a chiral building block has been achieved in order
for subsequent transformation to various types of inherently
chiral calix[4]arenes. The optically pure, inherently chiral ca-
lix[4]arene amino acids were prepared by the separation of
a diastereomeric mixture of calix[4]arene amino acid deriva-
tives bearing a (R)-BINOL moiety. The separated optically
pure calix[4]arene amino acid derivatives with a (R)-BINOL
moiety were easily transformed to novel inherently chiral ca-
lix[4]arenes containing an amino alcohol structure or a qua-
ternary ammonium moiety. These optically pure chiral ca-
lix[4]arenes were applied to asymmetric reactions as organ-
ocatalysts.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
tionalised inherently chiral calixarenes and separation of
the synthesised chiral calixarenes into optically pure
enantiomers.
Introduction
Optically active amino acids are a biologically significant
class of compounds since they are the basic building blocks
for peptides and proteins and are the biopolymers responsi-
ble for both the structure and function of most living
things.[1] Furthermore, optically active amino acids are used
extensively as chiral building blocks for chiral catalysts and
auxiliaries in modern organic synthesis.[2]
We recently developed a novel and efficient method for
the synthesis and optical resolution of inherently chiral ca-
lix[4]arenes, the latter then being applied to asymmetric re-
actions as organocatalysts.[10,11] Chiral calix[4]arenes have
traditionally been synthesised as racemates and each of the
calixarenes was then resolved into optically pure enantio-
mers. In the course of these studies we became interested in
the design and synthesis of an inherently chiral calix[4]arene
amino acid[12,13] as a chiral building block for subsequent
transformation to various types of inherently chiral calix[4]-
arenes. We herein report the synthesis and optical resolu-
tion of a novel inherently chiral calix[4]arene amino acid 1
Interest in the chemistry of chiral calixarenes has in-
creased in recent years due to their importance in the devel-
opment of new chiral receptors for asymmetric recognition.
This provides a potent tool for understanding the stereo-
chemistry of biochemical systems.[3] Hence, many chiral ca-
lixarenes containing chiral residues at either the wide or the
narrow rim have been prepared for use as chiral receptors[4]
and catalysts.[5] A more challenging and attractive approach
to the introduction of chirality is to make the calixarene
“inherently” chiral by creating an asymmetrical array of
achiral substituents on the calixarene skeleton.[6] For the
past two decades, many inherently chiral calixarenes have
been prepared and some of them have been resolved into
individual enantiomers.[7] In spite of these efforts, only a
few examples of enantiomeric recognition[8] and asymmet-
ric catalysis[9–11] with inherently chiral calixarenes have been
reported. These limited results might arise from difficulties
associated with both the design of a synthetic route to func-
[a] Department of Applied Molecular Chemistry, College of Indus-
trial Technology, Nihon University,
Narashino, Chiba 275-8575, Japan
Fax: +81-47-474-2579
E-mail: s5simizu@cit.nihon-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Figure 1. Inherently chiral calix[4]arene amino acid and its deriva-
tives.
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Inherently Chiral Calix[4]arene Amino Acid and Derivatives
(Figure 1). The optically pure synthetic intermediate of 1 [4]arene amino acid 7 with (R)-BINOL in the presence of
was easily transformed to different types of inherently chiral N,NЈ-dicyclohexylcarbodiimide (DCC) and 4-(dimeth-
calix[4]arenes 2 and 3 in optically pure form (Figure 1). ylamino)pyridine (DMAP) gave the ≈ 1:1 mixture of dia-
Furthermore, the inherently chiral calix[4]arenes were ap- stereomers 10a and 10b. The diastereomeric mixture
plied to asymmetric reactions as organocatalysts.[14]
(0.30 g) of 10a and 10b was loaded onto the preparative
HPLC column and diastereomerically pure 10a (≈ 0.10 g)
and 10b (≈ 0.10 g) were obtained.
Results and Discussion
Synthesis and Optical Resolution of an Inherently Chiral
Calix[4]arene Amino Acid 1
The N-protected calix[4]arene amino acid 9 can be pre-
pared from the already reported proximally p-dibrominated
calix[4]arene dibenzyl ether 4.[15] The process is outlined in
Scheme 1. Treatment of 4 with benzyl bromide in the pres-
ence of NaH gave the proximally p-dibrominated calix[4]-
arene tetrabenzyl ether 5 in the cone conformation as a key
intermediate. The p-dibromocalix[4]arene 5 was trans-
formed into the mono-formylated compound 6 by treat-
ment with 1.1 equiv. of nBuLi and the subsequent addition
of dimethylformamide (DMF). The reductive amination of
the formyl group of 6 with allylamine gave the secondary
amine 7 in 92% yield. Compound 7 was transformed with
allyl bromide to the tertiary amine 8 in 90% yield. Lithia-
tion of the bromine substituent on 8 and trapping of the
resultant anion with CO2 gave the target N-protected ca-
lix[4]arene amino acid 9 as a racemate in 78% yield.
Scheme 2. Resolution of an inherently chiral calix[4]arene amino
acid.
The 1H NMR spectra of diastereomers 10a and 10b, and
the mixture of 10a and 10b are shown in Figure 2. Dia-
stereomers 10a and 10b exhibited differences in their 1H
NMR spectra and a comparison of the spectra with the
diastereomerically pure 10a (Figure 2, a) and 10b (Figure 2,
b), and the mixture (Figure 2, c) clearly indicated that a
perfect separation of diastereomers 10a and 10b was
achieved by preparative HPLC. The diastereomeric purity
of 10a and 10b also was confirmed by means of HPLC
analysis (Figure 3).
The NMR spectra of 10a and 10b provide structural in-
formation. The 1H NMR spectrum of 10a shows four dou-
blets at 4.17, 4.16, 4.00 and 3.98 ppm, corresponding to the
axial protons of the methylene bridges and the 13C NMR
spectrum shows peaks at 31.25, 31.18, 31.05 and 31.02 ppm
for the four pertinent carbons. The values of the 13C NMR
chemical shifts and the 1H and 13C NMR spectroscopic
patterns indicate that 10a is present in the cone conforma-
Scheme 1. Synthesis of N-protected calix[4]arene amino acid 9.
The efficient resolution of an inherently chiral calix[4]- tion[16] and possesses inherent chirality. The NMR spectra
arene amino acid was achieved by preparative high per- of 10b showed a similar situation.
formance liquid chromatography (HPLC) after conversion
Finally, the palladium-catalysed de-N-allylation[17] of 10a
into diastereomeric (R)-BINOL esters 10a and 10b and 10b, followed by hydrolysis with NaOH to remove the
(Scheme 2). Thus, treatment of racemic N-protected calix- BINOL moiety afforded the optically pure calix[4]arene
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S. Shirakawa, S. Shimizu
FULL PAPER
Amino acids (especially -proline) have been utilised as
organocatalysts in various asymmetric reactions including
direct aldol reactions.[20] Therefore, an inherently chiral ca-
lix[4]arene amino acid 1 was applied to the asymmetric di-
rect aldol reaction of acetone. Unfortunately, no catalytic
activity of chiral calix[4]arene 1 was observed presumably
due to low nucleophilicity of the nitrogen on the calix[4]-
arene 1. The improvements in the structure of an inherently
chiral calix[4]arene amino acid that will promote the reac-
tion are now in progress in our laboratory.
Synthesis of Inherently Chiral Calix[4]arenes 2 and 3
Using an efficient synthetic scheme for the inherently chi-
ral calix[4]arene amino acid, the derivatisation of separated
diasteromers 10a and 10b to different types of inherently
chiral calix[4]arenes was examined. The chiral calix[4]arene
2 containing an amino alcohol structure was synthesised by
the reduction of 10a or 10b with LiAlH4 and optically pure
chiral calix[4]arenes (–)-2 and (+)-2 were obtained, respec-
tively, in yields of 81–83% (Scheme 3). These amino alcohol
structures are often present in useful chiral molecules such
as cinchonidine, ephedrine and prolinol. Furthermore, chi-
ral calix[4]arenes containing a quaternary ammonium moi-
ety 3a and 3b were prepared by the N-alkylation of chiral
calix[4]arene 2. The optical rotations of (+)-2 and (–)-2, and
(+)-3 and (–)-3 showed similar values with opposite signs
(Scheme 3) and the circular dichroism (CD) spectra of the
enantiomers of 2 and 3 showed mirror images (Figure 5)
which definitively proved they were a pair of enantiomers.
1
Figure 2. A section of the H NMR spectra of calix[4]arenes 10a
(a) and 10b (b), and mixture of 10a and 10b (c) in CDCl3 at 27 °C.
Figure 3. HPLC chromatographs of 10a (a) and 10b (b), and a
mixture of 10a and 10b (c) [column: SUMICHIRAL OA-4800
(0.46ϫ25 cm), eluent: CHCl3/hexane (80:20), flow rate:
1.0 mLminϪ1].
amino acids (–)298-1 and (+)298-1,[18,19] respectively
(Scheme 2). The circular dichroism (CD) spectra of the
enantiomers of 1 showed perfect mirror images (Figure 4).
Figure 4. CD spectra of the enantiomers of calix[4]arene amino
acid 1 in CHCl3.
Scheme 3. Synthesis of inherently chiral calix[4]arenes 2 and 3.
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Inherently Chiral Calix[4]arene Amino Acid and Derivatives
enantioselectivities were comparable with our previous re-
sults using an inherently chiral calix[4]arene with an ami-
nophenol structure.[10]
Scheme 4. Asymmetric Michael addition reaction of thiophenol ca-
talysed by 2.
Over the past decade, asymmetric phase-transfer cataly-
sis based on the use of chiral quaternary ammonium salts
as catalysts has become a topic of great scientific interest.[22]
The inherently chiral calix[4]arenes 3a and 3b, containing a
quaternary ammonium moiety, were applied to asymmetric
reactions as chiral phase-transfer catalysts. In a preliminary
trial, they were applied to an asymmetric Michael addition
reaction of a glycine derivative (Scheme 5).[23] Thus, the
asymmetric Michael addition of a glycine derivative with
methyl vinyl ketone in toluene with solid Cs2CO3 under the
influence of either (+)-3a or (–)-3a gave the corresponding
α-amino acid derivative 12 in excellent yields with low
enantioselectivities (5% ee). The reaction under the influ-
ence of 3b gave the product 12 in excellent yield with
slightly low selectivity compared with the reaction using 3a.
Asymmetric Michael addition reactions of malonate cata-
lysed by 3a and 3b were also examined under similar reac-
tion conditions (Scheme 6).[24] In the case of Michel ad-
ditions of malonate, catalyst 3b was better than 3a in terms
of enantioselectivity. These results may indicate that the
tuning of the catalyst structure in each reaction is important
Figure 5. CD spectra of enantiomers of calix[4]arenes 2, 3a and 3b
in CHCl3.
Asymmetric Michael Addition Reactions Catalysed by
Inherently Chiral Calix[4]arenes 2 and 3
Scheme 5. Asymmetric Michael addition reaction of a glycine de-
rivative catalysed by 3 under phase-transfer conditions.
The application of inherently chiral calixarenes as chiral
catalysts is a worthy challenge in organic syntheses. How-
ever, quite a limited number of examples of asymmetric ca-
talysis with inherently chiral calixarenes have been re-
ported.[9–11] As an additional example of an inherently chi-
ral calixarene catalyst, chiral calix[4]arene 2 was applied to
the asymmetric Michael addition reaction of thiophenol
which is known to be catalysed by chiral amino alcohols
(Scheme 4).[21] Both enantiomers (+)-2 and (–)-2 promoted
the reaction efficiently and gave a Michael addition product
11 in good yields. The chiral induction of the product was
observed as 15% ee and the configuration of the major en-
Scheme 6. Asymmetric Michael addition reaction of malonate cata-
antiomer was S with (+)-2 and R with (–)-2. The observed lysed by 3 under phase-transfer conditions.
Eur. J. Org. Chem. 2009, 1916–1924
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S. Shirakawa, S. Shimizu
FULL PAPER
128.56, 128.05, 128.03, 127.99, 127.86, 122.60, 115.02, 76.48, 76.28,
for the improvement of enantioselectivity. Although the ob-
served enantioselectivities in the reactions were poor, these
are the first examples of an inherently chiral calixarene be-
ing applied to asymmetric phase-transfer catalysis.[25]
31.21, 31.09, 30.91 ppm. IR: ν = 3061, 3029, 2916, 2866, 1457,
˜
1210, 1190, 977, 750, 697 cm–1. C56H46Br2O4 (942.77): calcd. C
71.34, H 4.92; found C 71.05, H 4.82.
5-Bromo-11-formyl-25,26,27,28-tetrabenzyloxycalix[4]arene [(؎)-6]:
To a solution of 5,11-dibromo-25,26,27,28-tetrabenzyloxycalix[4]-
arene 5 (5.0 mmol) in THF (80 mL), was added nBuLi (5.5 mmol,
1.5  in hexane) at –78 °C under an argon atmosphere and the
mixture was stirred for 15 min at this temperature. Dry dimethyl-
formamide (7.5 mmol) was then added and the mixture was stirred
for 15 min at –78 °C. The reaction mixture was then quenched with
0.1  aqueous HCl (60 mL). After the removal of THF by evapora-
tion, organic materials were extracted with CHCl3 (3ϫ 30 mL). The
organic extracts were washed with water and dried with MgSO4.
Evaporation of solvents and purification of the residue by column
chromatography on silica gel (CHCl3/hexane = 1:2 to 2:1 as eluent)
afforded 6 in 84% yield (3.75 g). 1H NMR (400 MHz, CDCl3): δ
= 9.69 (s, 1 H), 7.09–7.34 (m, 22 H), 6.42–6.70 (m, 8 H), 4.79–5.06
(m, 8 H), 4.27 (d, J = 13.7 Hz, 1 H), 4.21 (d, J = 13.8 Hz, 1 H),
4.12 (d, J = 13.7 Hz, 1 H), 4.05 (d, J = 13.9 Hz, 1 H), 3.04 (d, J =
13.7 Hz, 1 H), 3.02 (d, J = 13.9 Hz, 1 H), 2.88 (d, J = 13.8 Hz, 1
H), 2.83 (d, J = 14.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 191.67, 160.95, 155.38, 155.07, 154.18, 137.44, 137.35, 137.28,
137.03, 136.78, 136.54, 136.48, 136.24, 135.70, 134.96, 134.82,
133.96, 131.09 130.96, 130.51, 130.40, 129.86, 129.57, 129.53,
129.30, 128.73, 128.54, 128.15, 128.07, 128.00, 127.97, 127.91,
127.88, 122.75, 122.43, 115.18, 76.70, 76.53, 76.47, 76.11, 31.24,
Conclusions
In this study, we have described the synthesis of an in-
herently chiral calix[4]arene amino acid as a chiral building
block. The optically pure, inherently chiral calix[4]arene
amino acid 1 was prepared by the separation of a dia-
stereomeric mixture of the calix[4]arene amino acid deriva-
tives 10a and 10b bearing a (R)-BINOL moiety. The sepa-
rated 10a and 10b were easily transformed to different types
of inherently chiral calix[4]arenes 2 and 3 in optically pure
forms. The calix[4]arenes 2 and 3 were applied to asymmet-
ric reactions as chiral base catalysts and as chiral phase-
transfer catalysts. Further improvements in the structure of
chiral calix[4]arenes that will allow more efficient asymmet-
ric catalysis are now in progress in our laboratory.
Experimental Section
General: 1H and 13C NMR spectra were recorded on a Bruker Av-
ance 400 spectrometer in CDCl3. Tetramethylsilane (TMS) served
as the internal standard (δ = 0 ppm) for 1H NMR and CDCl3
served as the internal standard (δ = 77.0 ppm) for 13C NMR spec-
troscopy. IR spectra were measured with a Jasco FTIR-700 spec-
trometer using KBr discs. Circular dichroism (CD) spectra were
measured with a Jasco J-820 spectrometer. Optical rotations were
measured on a Jasco DIP-1000 digital polarimeter. High perform-
ance liquid chromatography (HPLC) was performed on a Hitachi
655 Liquid Chromatograph. Preparative gel-permeation
chromatography (GPC) and preparative HPLC were performed
using a JAI model 908 liquid chromatograph with JAIGEL-1H
31.14, 31.04, 31.01 ppm. IR: ν = 3061, 3029, 2917, 2865, 2725,
˜
1688, 1456, 1191, 977, 748, 698 cm–1. C57H47BrO5·0.1CHCl3
(891.88·0.1CHCl3): calcd. C 75.89, H 5.24; found C 75.81, H 5.10.
5-[(Allylamino)methyl]-11-bromo-25,26,27,28-tetrabenzyloxycalix-
[4]arene [(؎)-7]: To a solution of 6 (4.0 mmol) in a THF (20 mL)
and (15 mL) mixture was added allylamine (20 mmol) at room tem-
perature and the mixture was stirred for 24 h. NaBH4 (4.0 mmol)
was then added and the mixture was stirred for 30 min. The reac-
tion mixture was quenched with sat. aqueous NH4Cl. After the
removal of THF and EtOH by evaporation, organic materials were
extracted with CHCl3 (3ϫ 30 mL). The organic extracts were
washed with water and dried with MgSO4. Evaporation of solvents
and purification of the residue by column chromatography on silica
gel (CHCl3/AcOEt = 1:0 to 0:1 as eluent) afforded 7 in 92% yield
(3.43 g). 1H NMR (400 MHz, CDCl3): δ = 7.12–7.52 (m, 20 H),
6.61–6.74 (m, 6 H), 6.39–6.46 (m, 4 H), 5.89–5.99 (m, 1 H), 5.17–
5.22 (m, 2 H), 4.78–5.00 (m, 8 H), 4.23 (d, J = 13.5 Hz, 1 H), 4.21
(d, J = 13.5 Hz, 1 H), 4.08 (d, J = 13.5 Hz, 1 H), 4.05 (d, J =
13.5 Hz, 1 H), 3.66 (s, 2 H), 3.19 (d, J = 6.2 Hz, 2 H), 2.99 (d, J =
13.7 Hz, 1 H), 2.97 (d, J = 13.7 Hz, 1 H), 2.82 (d, J = 13.6 Hz, 1
H), 2.80 (d, J = 13.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 155.44, 155.03, 154.16, 137.61, 137.38, 137.32, 137.08, 137.02,
136.89, 136.29, 136.06, 135.40, 135.17, 134.52, 134.35, 134.12,
130.54, 130.51, 129.80, 129.78, 129.43, 129.19, 129.15, 128.77,
128.54, 128.15, 128.02, 127.98, 127.94, 127.87, 127.83, 122.55,
122.15, 118.38, 115.02, 76.67, 76.54, 76.14, 76.00, 51.54, 50.15,
and -2H columns with
a SUMICHIRAL OA-4800 column
(2.0ϫ25 cm), respectively. SUMICHIRAL OA-4800 columns were
preactivated by CHCl3 containing 0.2% TFA. Analytical thin-layer
chromatography (TLC) and column chromatography were carried
out on precoated silica gel 60 F254 glass plates (E. Merck) and
with silica gel 60 (spherical 0.040–0.100 mm, Kanto), respectively.
Tetrahydrofuran (THF) was freshly distilled from Na/benzophen-
one.
5,11-Dibromo-25,26,27,28-tetrabenzyloxycalix[4]arene (5): To
a
solution of 5,11-dibromo-25,26-dibenzyloxy-27,28-dihydroxycalix-
[4]arene 4[15] (13.0 mmol) and NaH (130 mmol, 60% dispersion in
paraffin liquid) in CH3CN (300 mL) was added benzyl bromide
(130 mmol) at room temperature. The reaction mixture was stirred
for 2 h at room temperature and then quenched with 1  aqueous
HCl (150 mL). After the removal of CH3CN by evaporation, or-
ganic materials were extracted with CHCl3 (3ϫ 70 mL) and the
organic extracts were dried with MgSO4. Evaporation of solvents
and purification of the residue by column chromatography on silica
gel (CHCl3/hexane = 1:3 to 1:1 as eluent) afforded 5 in 87% yield
(10.7 g). 1H NMR (400 MHz, CDCl3): δ = 7.19–7.30 (m, 20 H),
6.52–6.74 (m, 10 H), 4.83–4.96 (m, 8 H), 4.26 (d, J = 13.7 Hz, 1
H), 4.12 (d, J = 13.7 Hz, 2 H), 3.98 (d, J = 13.8 Hz, 1 H), 3.02 (d,
31.22, 31.08 ppm. IR: ν = 3423, 3061, 3029, 2975, 2916, 2865, 1456,
˜
1211, 1190, 981, 753, 697 cm–1. C60H54BrNO4·0.5CHCl3
(932.98·0.5CHCl3): calcd. C 73.24, H 5.49, N 1.41; found C 73.47,
H 5.45, N 1.45.
5-Bromo-11-[(diallylamino)methyl]-25,26,27,28-tetrabenzyloxycalix-
[4]arene [(؎)-8]: To a mixture of 7 (3.0 mmol), K2CO3 (6.0 mmol)
J = 13.7 Hz, 1 H), 2.87 (d, J = 13.8 Hz, 2 H), 2.70 (d, J = 13.9 Hz, 1 and CH3CN (60 mL) was added allyl bromide (3.3 mmol) and the
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.24, 154.33, 137.77,
mixture was heated at 50 °C for 15 h. The reaction mixture was
137.43, 136.87, 135.29, 134.40, 131.09, 130.44, 129.62, 129.41,
cooled to room temperature and the mixture quenched with water.
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Inherently Chiral Calix[4]arene Amino Acid and Derivatives
After the removal of CH3CN by evaporation, organic materials (first fraction) (≈ 100 mg) and 10b (second fraction) (≈ 100 mg)
were extracted with CHCl3 (3ϫ 30 mL) and the organic extracts
were dried with MgSO4. Evaporation of solvents and purification
of the residue by column chromatography on silica gel (CHCl3/
AcOEt = 30:1 to 15:1 as eluent) afforded 8 in 90% yield (2.63 g).
1H NMR (400 MHz, CDCl3): δ = 7.10–7.38 (m, 20 H), 6.59–6.77
(m, 6 H), 6.34–6.41 (m, 4 H), 5.81–5.90 (m, 2 H), 5.13–5.18 (m, 4
H), 4.80–5.15 (m, 8 H), 4.23 (d, J = 13.6 Hz, 1 H), 4.21 (d, J =
13.5 Hz, 1 H), 4.07 (d, J = 13.5 Hz, 1 H), 4.05 (d, J = 13.5 Hz, 1
H), 3.39 (s, 2 H), 2.94–3.00 (m, 6 H), 2.81 (d, J = 13.7 Hz, 1 H),
2.78 (d, J = 13.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 155.39, 154.96, 154.51, 154.09, 137.68, 137.40, 137.09, 136.96,
136.11, 135.81, 135.23, 134.98, 134.41, 130.53, 130.41, 129.88,
129.70, 129.39, 129.16, 129.05, 128.78, 128.16, 128.15, 128.00,
127.83, 127.80, 122.54, 122.28, 117.70, 115.04, 76.65, 76.56, 76.03,
were obtained. The diastereomeric purity of 10a and 10b was deter-
mined by HPLC analysis.
1
10a: [α]2D5 = +49.3 (c = 1.1, CHCl3). H NMR (400 MHz, CDCl3):
δ = 8.08 (d, J = 8.9 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.78 (d, J
= 8.8 Hz, 2 H), 7.61 (d, J = 8.9 Hz, 1 H), 7.50 (dt, J = 1.5, 7.3 Hz,
1 H), 7.09–7.36 (m, 26 H), 6.90–6.94 (m, 2 H), 6.37–6.59 (m, 6 H),
6.23–6.25 (m, 2 H), 6.12 (br. s, 1 H), 5.66–5.76 (m, 2 H), 4.98–5.06
(m, 8 H), 4.76–4.86 (m, 4 H), 4.17 (d, J = 13.5 Hz, 1 H), 4.16 (d,
J = 13.5 Hz, 1 H), 4.00 (d, J = 13.4 Hz, 1 H), 3.98 (d, J = 13.5 Hz,
1 H), 3.24 (d, J = 13.7 Hz, 1 H), 3.16 (d, J = 13.8 Hz, 1 H), 2.93
(d, J = 13.5 Hz, 1 H + 1 H), 2.77 (d, J = 6.1 Hz, 4 H), 2.68 (d, J
= 13.6 Hz, 1 H), 2.63 (d, J = 13.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.57, 160.04, 155.20, 154.89, 153.95,
151.90, 148.22, 137.59, 137.36, 136.94, 135.93, 135.91, 135.64,
135.60, 135.42, 135.33, 134.52, 134.30, 133.78, 133.75, 133.53,
133.45, 131.84, 130.56, 130.26, 130.00, 129.86, 129.68, 129.60,
129.44, 128.87, 128.69, 128.43, 128.35, 128.24, 128.19, 128.16,
128.04, 128.01, 127.97, 127.95, 127.87, 127.82, 127.75, 127.00,
126.47, 125.81, 124.79, 123.12, 122.61, 122.31, 122.23, 121.95,
118.23, 117.70, 114.28, 76.73, 76.62, 76.04, 75.89, 56.77, 56.20,
56.82, 56.15, 31.26, 31.21, 31.11, 31.08 ppm. IR: ν = 3062, 3029,
˜
2975, 2917, 2867, 2807, 1458, 1211, 1190, 979, 916, 697 cm–1
.
C63H58BrNO4·0.1CHCl3 (973.04·0.1CHCl3): calcd. C 76.95, H
5.94, N 1.42; found C 76.75, H 5.89, N 1.23.
5-Carboxy-11-[(diallylamino)methyl]-25,26,27,28-tetrabenzyloxyca-
lix[4]arene [(؎)-9]: To a solution of 8 (2.0 mmol) in THF (50 mL)
was added nBuLi (3.0 mmol, 1.5  in hexane) at –78 °C under an
argon atmosphere and the mixture was stirred for 15 min at this
temperature. CO2 gas was then bubbled through a needle into the
solution for 15 min at –78 °C. The reaction mixture was quenched
with 0.1  aqueous HCl (40 mL). After removal of THF by evapo-
ration, organic materials were extracted with CHCl3 (3ϫ 20 mL).
The organic extracts were washed with water and dried with
MgSO4. Evaporation of solvents and purification of the residue by
column chromatography on silica gel (CHCl3/MeOH = 40:1 to 10:1
as eluent) afforded 9 in 78% yield (1.46 g). 1H NMR (400 MHz,
CDCl3): δ = 12.03 (br. s, 1 H), 7.19–7.44 (m, 22 H), 6.41–6.73 (m,
8 H), 6.03–6.13 (m, 2 H), 5.39–5.42 (m, 2 H), 5.01–5.15 (m, 6 H),
4.78–4.88 (m, 4 H), 4.23 (d, J = 13.4 Hz, 1 H), 4.18 (d, J = 13.4 Hz,
1 H), 4.16 (d, J = 13.4 Hz, 1 H), 4.10 (d, J = 13.6 Hz, 1 H), 3.83
(d, J = 13.6 Hz, 1 H), 3.76 (d, J = 13.5 Hz, 1 H), 3.01–3.18 (br. m,
2 H), 2.98 (d, J = 13.5 Hz, 1 H), 2.96 (d, J = 14.1 Hz, 1 H), 2.93
(d, J = 14.4 Hz, 1 H), 2.89 (d, J = 14.1 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.85, 159.82, 156.13, 155.11, 155.07,
137.25, 136.99, 136.64, 136.56, 136.40, 136.03, 135.84, 135.32,
135.22, 134.75, 134.04, 131.48, 130.98, 130.73, 130.16, 129.79,
129.75, 129.47, 129.44, 128.72, 128.28, 128.16, 128.14, 128.09,
128.03, 127.92, 127.71, 127.28, 124.61, 124.09, 122.65, 122.23,
31.25, 31.18, 31.05, 31.02 ppm. IR: ν = 3525, 3446, 3060, 3030,
˜
2976, 2918, 2867, 2816, 1730, 1457, 1303, 1211, 1171, 980, 747,
698 cm–1. C84H71NO7·0.1CHCl3 (1206.47·0.1CHCl3): calcd. C
82.91, H 5.87, N 1.15; found C 82.60, H 5.74, N 0.93.
10b: [α]2D3 = +77.3 (c = 0.88, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 8.09 (d, J = 8.9 Hz, 1 H), 7.99 (d, J = 8.2 Hz, 1 H), 7.76–7.80
(m, 2 H), 7.51 (dt, J = 1.1, 7.4 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 1 H),
7.12–7.36 (m, 26 H), 6.89–6.95 (m, 2 H), 6.37–6.61 (m, 6 H), 6.12–
6.19 (m, 2 H), 5.70–5.80 (m, 2 H), 5.48 (br. s, 1 H), 4.91–5.12 (m,
8 H), 4.75–4.87 (m, 4 H), 4.18 (d, J = 13.4 Hz, 1 H), 4.16 (d, J =
13.3 Hz, 1 H), 3.98 (d, J = 13.5 Hz, 1 H), 3.97 (d, J = 13.5 Hz, 1
H), 3.26 (d, J = 13.4 Hz, 1 H), 3.19 (d, J = 13.4 Hz, 1 H), 2.94 (d,
J = 13.6 Hz, 1 H + 1 H), 2.86 (dd, J = 6.3, 13.9 Hz, 2 H), 2.78
(dd, J = 7.1, 13.8 Hz, 2 H), 2.66 (d, J = 13.7 Hz, 1 H), 2.64 (d, J
= 13.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.84,
160.12, 155.23, 154.90, 154.02, 151.79, 148.43, 137.58, 137.35,
136.88, 135.93, 135.58, 135.48, 135.21, 135.16, 134.57, 134.44,
133.75, 133.58, 133.51, 133.34, 131.98, 130.48, 130.36, 130.32,
130.00, 129.61, 129.59, 129.46, 129.40, 129.07, 128.82, 128.68,
128.33, 128.26, 128.19, 128.02, 127.98, 127.95, 127.90, 127.86,
127.76, 127.71, 127.24, 126.54, 125.99, 125.61, 124.62, 123.27,
123.13, 122.27, 122.17, 121.85, 118.30, 117.66, 114.25, 76.69, 76.55,
121.20, 77.03, 76.82, 76.11, 76.01, 53.86, 53.68, 31.17 ppm. IR: ν =
˜
76.17, 75.80, 56.33, 55.87, 31.21, 31.14, 31.05 ppm. IR: ν = 3522,
˜
3422, 3060, 3029, 2920, 2868, 2526, 1703, 1455, 1212, 1189, 979,
763, 698 cm–1. C64H59NO6·0.7CHCl3 (938.16·0.7CHCl3): calcd. C
76.11, H 5.82, N 1.37; found C 76.14, H 5.89, N 1.38.
3446, 3060, 3030, 3006, 2976, 2917, 2867, 2814, 1728, 1457, 1303,
1210, 1171, 979, 763, 747, 698 cm–1. C84H71NO7 (1206.47): calcd.
C 83.62, H 5.93, N 1.16; found C 83.69, H 5.83, N 1.28.
Diastereomers 10a and 10b: To a solution of 9 (2.0 mmol), DCC
(3.0 mmol) and DMAP (1.0 mmol) in CH2Cl2 (30 mL) was added
(R)-BINOL (2.2 mmol) at room temperature and the mixture was
stirred for 6 h. The reaction mixture was filtered through celite and
the filtrate was dried with MgSO4. Evaporation of CH2Cl2 and
purification of the residue by column chromatography on silica gel
(CHCl3/AcOEt = 30:1 to 5:1 as eluent) afforded a ca. 1:1 mixture
of diastereomers 10a and 10b in 92% yield (2.22 g).
5-(Aminomethyl)-11-carboxy-25,26,27,28-tetrabenzyloxycalix[4]-
arene (1): The mixtures of 10a and 10b (0.50 mmol), each with
N,NЈ-dimethylbarbituric acid [NDMBA (2.5 mmol)], Pd(OAc)2
(0.10 mmol) and PPh3 (0.40 mmol) in CH2Cl2 (20 mL) were stirred
for 8 h at 35 °C. After the removal of CH2Cl2 by evaporation, the
solvent was replaced with benzene (20 mL). The benzene solution
was washed with sat. aqueous NaHCO3 (3ϫ 10 mL) and dried with
MgSO4. Evaporation of solvents and purification of the residue by
Resolution of Calix[4]arenes 10a and 10b by Preparative HPLC: column chromatography on silica gel (CHCl3/MeOH = 30:1 to 5:1
Resolution of diastereomers 10a and 10b was carried out by pre-
parative HPLC using a SUMICHIRAL OA-4800 column
(2.0ϫ25 cm) with CHCl3 as the eluent. The diastereomeric mixture
of 10a and 10b (≈ 1:1) (300 mg) was then loaded onto the prepara-
tive column. The CHCl3 solutions of separated diastereomers were
washed with sat. aqueous NaHCO3 and pure calix[4]arenes 10a
as eluent) afforded the de-N-allylated product. The de-N-allylated
product in a THF (5.0 mL) ethanol (3.0 mL) solvent mixture was
treated with 1  aqueous NaOH (1.5 mL) and the mixture was
heated at 60 °C for 6 h. The reaction mixtures were then cooled to
0 °C and neutralised with 1  aqueous HCl (1.6 mL). After removal
of THF and ethanol by evaporation, organic materials were ex-
Eur. J. Org. Chem. 2009, 1916–1924
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1921

S. Shirakawa, S. Shimizu
FULL PAPER
tracted with CHCl3 (3ϫ 10 mL). The organic extracts were washed
with water and dried with MgSO4. Evaporation of solvents and
purification of the residue by column chromatography on silica gel
(CHCl3/MeOH = 15:1 to 3:1 as eluent) afforded (–)298-1 and
(+)298-1 in yields of 43% (0.184 g) and 41% (0.176 g), respectively.
1H NMR (400 MHz, CDCl3): δ = 8.50 (br. s, 3 H), 6.20–7.28 (m,
30 H), 4.69–4.97 (m, 8 H), 3.91–4.17 (m, 6 H), 2.79–2.94 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.16, 159.80, 156.05,
155.33, 154.84, 137.55, 137.40, 137.26, 136.98, 136.61, 136.12,
135.28, 134.98, 134.78, 134.14, 133.83, 130.67, 130.18, 129.69,
129.60, 129.04, 128.84, 128.48, 128.25, 128.09, 127.97, 127.82,
127.76, 127.74, 126.41, 123.79, 122.52, 122.17, 76.59, 76.49, 75.96,
75.32, 63.85, 62.75, 61.00, 31.26, 31.13, 31.04 ppm. IR: ν = 3377,
˜
3060, 3029, 2920, 2866, 1456, 1214, 1190, 1135, 982, 748, 698 cm–1.
C67H66BrNO5·H2O (1045.15·H2O): calcd. C 75.69, H 6.45, N 1.32;
found C 75.75, H 6.32, N 1.29.
5-[(Diallyl-methylammonio)methyl]-11-hydroxymethyl-25,26,27,28-
tetrabenzyloxycalix[4]arene Iodide (3b): Mixtures of (–)-2 and (+)-
2 (0.20 mmol) each with methyl iodide (2.0 mmol) in CH3CN
(5.0 mL) were heated at 80 °C for 8 h. Evaporation of CH3CN and
purification of the residue by column chromatography on silica gel
(CHCl3/MeOH = 20:1 to 5:1 as eluent) afforded (+)-3b ([α]2D7
=
+11.2 [c = 0.93, CHCl3]) and (–)-3b ([α]2D7 = –11.3 [c = 1.1, CHCl3])
1
yields of 98% (0.209 g) and 97% (0.207 g), respectively. H NMR
43.11, 31.15, 31.04, 30.87 ppm. IR: ν = 3398, 3060, 3030, 2974,
˜
(400 MHz, CDCl3): δ = 7.16–7.33 (m, 21 H), 6.96 (d, J = 1.9 Hz,
1 H), 6.92 (dd, J = 1.4, 7.4 Hz, 1 H), 6.86–6.89 (m, 2 H), 6.76 (t,
J = 7.4 Hz, 1 H), 6.51 (d, J = 7.2 Hz, 1 H), 6.36 (t, J = 7.4 Hz, 1
H), 6.32 (dd, J = 1.5, 7.4 Hz, 1 H), 6.20 (d, J = 1.5 Hz, 1 H), 5.57–
5.86 (m, 5 H), 5.36 (d, J = 16.7 Hz, 1 H), 5.15–5.22 (m, 3 H), 5.05
(d, J = 11.8 Hz, 1 H), 4.61–4.76 (m, 5 H), 4.52 (dd, J = 7.0, 12.7 Hz,
1 H), 4.33 (d, J = 12.7 Hz, 1 H), 4.22 (d, J = 12.9 Hz, 1 H), 4.17
(d, J = 13.1 Hz, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 4.00 (d, J =
13.0 Hz, 1 H), 3.97 (d, J = 10.1 Hz, 1 H), 3.90 (dd, J = 7.1, 13.2 Hz,
1 H), 3.80 (t, J = 6.8 Hz, 1 H), 3.70 (dd, J = 6.8, 13.3 Hz, 1 H),
3.18 (dd, J = 6.6, 13.8 Hz, 1 H), 2.95 (d, J = 12.9 Hz, 1 H), 2.92
(d, J = 13.7 Hz, 1 H), 2.89 (d, J = 13.6 Hz, 1 H), 2.75 (dd, J = 7.4,
13.5 Hz, 1 H), 2.68 (d, J = 13.5 Hz, 1 H), 2.18 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.14, 154.83, 154.77, 154.27,
137.51, 137.24, 136.92, 136.78, 136.64, 136.40, 136.03, 135.83,
135.04, 134.88, 133.96, 133.86, 131.17, 130.31, 130.10, 129.51,
129.30, 128.85, 128.54, 128.26, 128.16, 128.03, 127.88, 127.84,
127.76, 127.72, 127.62, 127.07, 124.12, 124.00, 122.61, 122.29,
119.71, 77.59, 77.29, 76.10, 75.09, 63.70, 63.37, 62.33, 61.20, 46.41,
2916, 2868, 2610, 1685, 1602, 1455, 1376, 1281, 1213, 1191, 983,
762, 734, 698 cm–1. C58H51NO6·0.5CHCl3 (858.03·0.5CHCl3):
calcd. C 76.60, H 5.60, N 1.53; found C 76.54, H 5.81, N 1.50.
5-[(Diallylamino)methyl]-11-hydroxymethyl-25,26,27,28-tetrabenzyl-
oxycalix[4]arene (2): To solutions of 10a and 10b (0.50 mmol), each
in THF (15 mL) was LiAlH4 (1.5 mmol) at 0 °C. The mixtures were
warmed to room temperature and stirred for 1 h. The reaction mix-
tures were quenched with 0.2  aqueous HCl (30 mL). After the
removal of THF by evaporation, organic materials were extracted
with CHCl3 (3ϫ 10 mL). The organic extracts were washed with
sat. aqueous NaHCO3 and dried with MgSO4. Evaporation of sol-
vents and purification of the residue by column chromatography
on silica gel (CHCl3/AcOEt = 10:1 to 1:1 as eluent) afforded (–)-2
([α]2D7 = –2.2 [c = 1.1, CHCl3]) and (+)-2 ([α]2D6 = +2.3 [c = 1.1,
CHCl3]) in yields of 83% (0.384 g) and 81% (0.374 g), respectively.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.34 (m, 16 H), 7.11–7.16
(m, 4 H), 6.61–6.72 (m, 5 H), 6.35–6.46 (m, 5 H), 5.78–5.88 (m, 2
H), 5.10–5.15 (m, 4 H), 4.94–5.02 (m, 4 H), 4.82–4.88 (m, 4 H),
4.14–4.21 (m, 6 H), 3.39 (d, J = 13.3 Hz, 1 H), 3.35 (d, J = 13.3 Hz,
1 H), 2.87–2.99 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
155.32, 155.21, 154.76, 154.38, 137.61, 137.57, 137.54, 135.79,
135.76, 135.50, 135.42, 134.76, 134.55, 129.88, 129.35, 129.27,
129.22, 128.39, 128.11, 128.07, 127.86, 127.81, 127.80, 127.72,
127.13, 126.98, 122.18, 121.69, 117.63, 76.59, 75.99, 65.10, 56.99,
31.26, 31.16, 31.02, 30.86 ppm. IR: ν = 3376, 3060, 3029, 2920,
˜
2866, 1458, 1215, 1191, 1136, 982, 766, 748, 699 cm–1.
C65H64INO5·H2O (1066.11·H2O): calcd. C 72.01, H 6.14, N 1.29;
found C 72.09, H 5.73, N 1.25.
Asymmetric Michael Addition Reaction of Thiophenol Catalysed by
Either (+)- or (–)-2 (Scheme 4): To a solution of either (+)- or
(–)-2 (0.015 mmol) and 2-cyclohexen-1-one (0.50 mmol) in toluene
(1.0 mL) was added thiophenol (0.60 mmol) at 0 °C under an argon
atmosphere and the mixture was stirred for 24 h at this tempera-
ture. The reaction was quenched with 0.2  aqueous HCl (2.0 mL)
and the organic materials were extracted with CHCl3 (2ϫ 3.0 mL).
The organic solution was washed with water (5.0 mL) and dried
with MgSO4. Evaporation of solvents and purification of the resi-
due using flash chromatography on silica gel afforded the Michael
addition product 11. The enantioselectivity of the product was de-
termined using chiral HPLC analysis and the absolute configura-
tion was determined by comparison of the observed optical rota-
tion with the reported value.[21]
56.08, 31.27 ppm. IR: ν = 3423, 3062, 3030, 2918, 2865, 1456, 1211,
˜
1190, 1133, 985, 916, 763, 698 cm–1. C64H61NO5 (924.17): calcd. C
83.18, H 6.65, N 1.52; found C 82.95, H 6.59, N 1.47.
5-Hydroxymethyl-11-[(triallylammonio)methyl]-25,26,27,28-tetra-
benzyloxycalix[4]arene Bromide (3a): The mixtures of (–)-2 and (+)-
2 (0.20 mmol) each with allyl bromide (1.0 mmol) in CH3CN
(5.0 mL) were heated at 80 °C for 8 h. Evaporation of CH3CN and
purification of the residue by column chromatography on silica gel
(CHCl3/MeOH = 20:1 to 5:1 as eluent) afforded (+)-3a ([α]2D7
=
+9.9 (c = 1.1, CHCl3)) and (–)-3a ([α]2D8 = –9.9 [c = 1.1, CHCl3])
1
yields of 91% (0.190 g) and 93% (0.194 g), respectively. H NMR
(400 MHz, CDCl3): δ = 7.16–7.32 (m, 20 H), 7.11 (d, J = 1.7 Hz,
1 H), 6.86–6.90 (m, 2 H), 6.82 (dd, J = 1.5, 7.5 Hz, 1 H), 6.78 (d,
J = 1.5 Hz, 1 H), 6.74 (t, J = 7.4 Hz, 1 H), 6.48 (dd, J = 1.6, 7.3 Hz,
1 H), 6.37 (t, J = 7.4 Hz, 1 H), 6.30–6.34 (m, 2 H), 5.82–5.93 (m,
3 H), 5.57 (d, J = 10.4 Hz, 3 H), 5.51 (d, J = 16.8 Hz, 3 H), 5.02–
5.18 (m, 4 H), 4.68–4.77 (m, 4 H), 4.54 (s, 2 H), 4.20 (d, J =
13.0 Hz, 1 H), 4.19 (d, J = 13.2 Hz, 1 H), 4.15 (s, 2 H), 4.06 (d, J
= 13.1 Hz, 1 H), 4.03 (d, J = 13.3 Hz, 1 H), 3.60 (dd, J = 7.0,
13.8 Hz, 3 H), 3.35 (dd, J = 6.9, 13.8 Hz, 3 H), 2.87–2.94 (m, 3 H),
2.74 (d, J = 13.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 156.34, 155.01, 154.93, 154.24, 137.53, 137.27, 137.07, 136.75,
3-(Phenylthio)cyclohexanone (11):[21] 1H NMR (400 MHz, CDCl3):
δ = 7.40–7.43 (m, 2 H), 7.25–7.33 (m, 3 H), 3.39–3.45 (m, 1 H),
2.65–2.70 (m, 1 H), 2.28–2.40 (m, 3 H), 2.10–2.16 (m, 2 H), 1.66–
1.78 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 208.71,
133.15, 132.96, 129.03, 127.74, 47.69, 46.04, 40.83, 31.15,
23.97 ppm. IR: ν = 2946, 1715, 1222, 745, 694 cm–1. MS (EI) m/z
˜
206 [M]+, 110, 97.
Asymmetric Michael Addition Reaction of a Glycine Derivative Cat-
alysed by Either (+)- or (–)-3 (Scheme 5): To a mixture of either
136.51, 136.48, 136.37, 135.72, 135.67, 135.64, 135.20, 134.16, (+)- or (–)-3 (0.010 mmol), tert-butyl glycinate benzophenone
133.88, 133.29, 131.29, 130.23, 130.08, 129.35, 129.28, 128.87, Schiff base (0.10 mmol) and Cs2CO3 (0.30 mmol) in toluene
128.31, 128.17, 128.01, 127.86, 127.83, 127.82, 127.71, 127.51, (0.50 mL) was added methyl vinyl ketone (0.50 mmol) at 0 °C un-
127.47, 127.21, 124.65, 122.48, 122.02, 120.03, 77.43, 77.10, 76.06, der an argon atmosphere and the mixture was stirred for 24 h at
1922
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1916–1924

Inherently Chiral Calix[4]arene Amino Acid and Derivatives
[3]
For representative reviews on calixarenes, see: a) C. D. Gutsche,
Calixarenes, Monographs in Supramolecular Chemistry (Ed.:
J. F. Stoddart), The Royal Society of Chemistry, Cambridge,
UK, 1989; b) Calixarenes: A Versatile Class of Macrocyclic
Compounds, Topics in Inclusion Science 3 (Eds: J. Vicens, V.
Böhmer), Kluwer, Dordrecht, The Netherlands, 1991; c) S.
Shinkai, Tetrahedron 1993, 49, 8933–8968; d) M. Takeshita, S.
Shinkai, Bull. Chem. Soc. Jpn. 1995, 68, 1088–1097; e) V.
Böhmer, Angew. Chem. Int. Ed. Engl. 1995, 34, 713–745; f) A.
Pochini, R. Ungaro, in Comprehensive Supramolecular Chemis-
try (Ed.: F. Vögtle), Pergamon Press, Oxford, UK, 1996, vol.
2, pp. 103–142; g) C. D. Gutsche, Caixarenes Revisited, Mono-
graphs in Supramolecular Chemistry (Ed.: J. F. Stoddart), The
Royal Society of Chemistry, Cambridge, UK, 1998; h) Calixar-
enes in Action (Eds: L. Mandolini, R. Ungaro), Imperial Col-
lege Press, London, UK, 2000; i) Calixarenes (Eds.: Z. Asfari,
V. B öhmer, J. Harrowfield, J. Vicens), Kluwer, Dordrecht, The
Netherlands, 2001; j) N. Morohashi, F. Narumi, N. Iki, T. Hat-
tori, S. Miyano, Chem. Rev. 2006, 106, 5291–5316; k) D. M.
Homden, C. Redshaw, Chem. Rev. 2008, 108, 5086–5130.
this temperature. The reaction was quenched with water (3.0 mL)
and the organic materials were extracted with CHCl3 (2ϫ 3.0 mL).
The organic solution was washed with water (5.0 mL) and dried
with MgSO4. Evaporation of solvents and purification of the resi-
due using flash chromatography on silica gel afforded a Michael
addition product 12. The enantioselectivity of the product was de-
termined using chiral HPLC analysis, and the absolute configura-
tion was determined by comparison of the HPLC retention time
with the reported time.[23]
tert-Butyl 2-(Diphenylmethyleneamino)-5-oxohexanoate (12):[23] 1H
NMR (400 MHz, CDCl3): δ = 7.62–7.65 (m, 2 H), 7.30–7.47 (m, 6
H), 7.15–7.18 (m, 2 H), 3.96 (t, J = 6.1 Hz, 1 H), 2.44–2.58 (m, 2
H), 2.13 (s, 3 H), 2.08–2.20 (m, 2 H), 1.44 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 208.29, 170.92, 170.46, 139.38, 136.38,
130.27, 128.70, 128.57, 128.43, 127.97, 127.64, 81.10, 64.62, 39.80,
29.88, 27.98, 27.64 ppm. IR: ν = 3060, 2977, 2932, 1719, 1151,
˜
699 cm–1.
Asymmetric Michael Addition Reaction of Malonate Catalysed by
Either (+)- or (–)-3 (Scheme 6): To a mixture of either (+)- or (–)-
3 (0.010 mmol), chalcone (0.10 mmol) and Cs2CO3 (0.30 mmol) in
toluene (0.50 mL) was added dibenzyl malonate (0.50 mmol) at
0 °C under an argon atmosphere and the mixture was stirred for
24 h at this temperature. The reaction was quenched with water
(3.0 mL) and the organic materials were extracted with CHCl3 (2ϫ
3.0 mL). The organic solution was washed with water (5.0 mL) and
dried with MgSO4. Evaporation of solvents and purification of the
residue using flash chromatography on silica gel afforded the
Michael addition product 13. The enantioselectivity of the product
was determined using chiral HPLC analysis, and the absolute con-
figuration was determined by comparison of the observed optical
rotation with the reported value.[26]
[4]
a) Y. Kubo, S. Maeda, S. Tokita, M. Kubo, Nature 1996, 382,
522–524; b) E. Pinkhassik, I. Stibor, A. Casnati, R. Ungaro, J.
Org. Chem. 1997, 62, 8654–8659; c) R. K. Castellano, C. Nuck-
olls, J. Rebek Jr., J. Am. Chem. Soc. 1999, 121, 11156–11163;
d) L. J. Prins, F. D. Jong, P. Timmerman, D. N. Reinhoudt, Na-
ture 2000, 408, 181–184; e) B. Botta, D. Subissati, A. Tafi, G.
Della Monache, A. Filippi, M. Speranza, Angew. Chem. Int.
Ed. 2004, 43, 4767–4770; f) Y.-S. Zheng, C. Zhang, Org. Lett.
2004, 6, 1189–1192; g) S. Cherenok, A. Vovk, I. Muravyova,
A. Shivanyuk, V. Kukhar, J. Lipkowski, V. Kalchenko, Org.
Lett. 2006, 8, 549–552; h) C. Bonini, L. Chiummiento, M. Fun-
icello, M. Teresa Lopardo, P. Lupattelli, A. Laurita, A. Cornia,
J. Org. Chem. 2008, 73, 4233–4236.
a) G. Arnott, H. Heaney, R. Hunter, P. C. B. Page, Eur. J. Org.
Chem. 2004, 5126–5134; b) C. Gaeta, M. De Rosa, M. Fruilo,
A. Soriente, P. Neri, Tetrahedron: Asymmetry 2005, 16, 2333–
2340; c) G. Arnott, R. Hunter, Tetrahedron 2006, 62, 992–1000;
d) A. Quintard, U. Darbost, F. Vocanson, S. Pellet-Rostaing,
M. Lemaire, Tetrahedron: Asymmetry 2007, 18, 1926–1933; e)
A. Marson, Z. Freixa, P. C. J. Kamer, P. W. N. M.
van Leeuwen, Eur. J. Inorg. Chem. 2007, 4587–4591.
[5]
Dibenzyl 2-(3-Oxo-1,3-diphenylpropyl)malonate (13):[26] 1H NMR
(400 MHz, CDCl3): δ = 7.80 (d, J = 7.8 Hz, 2 H), 7.50 (t, J =
7.4 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 2 H), 7.13–7.30 (m, 13 H), 7.04–
7.07 (m, 2 H), 5.16 (d, J = 12.2 Hz, 1 H), 5.11 (d, J = 12.2 Hz, 1
H), 4.90 (s, 2 H), 4.22 (dt, J = 9.5, 6.8 Hz, 1 H), 3.95 (d, J = 9.5 Hz,
1 H), 3.44 (d, J = 6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 197.28, 167.94, 167.42, 140.23, 136.63, 135.07, 134.97, 132.96,
128.51, 128.44, 128.38, 128.35, 128.25, 128.17, 128.10, 127.99,
[6]
[7]
a) V. Böhmer, D. Kraft, M. Tabatabai, J. Inclusion Phenom.
Mol. Recognit. Chem. 1994, 19, 17–39; b) H. Otsuka, S. Shin-
kai, Supramol. Sci. 1996, 3, 189–205; c) A. Dalla Cort, L. Man-
dolini, C. Pasquini, L. Schiaffino, New J. Chem. 2004, 28,
1198–1199.
127.13, 67.28, 67.07, 57.46, 42.20, 40.68 ppm. IR: ν = 3060, 3033,
˜
2954, 1744, 1688, 1262, 1165, 1135, 747, 698 cm–1.
a) S. Pappalardo, S. Caccamese, L. Giunta, Tetrahedron Lett.
1991, 32, 7747–7750; b) S. Shinkai, T. Arimura, H. Kawabata,
H. Murakami, K. Iwamoto, J. Chem. Soc. Perkin Trans. 1 1991,
2429–2434; c) K. Iwamoto, H. Shimizu, K. Araki, S. Shinkai,
J. Am. Chem. Soc. 1993, 115, 3997–4006; d) H. Otsuka, S. Shin-
kai, J. Am. Chem. Soc. 1996, 118, 4271–4275; e) T. Jin, K.
Monde, Chem. Commun. 1998, 1357–1358; f) J. K. Browne,
M. A. McKervey, M. Pitarch, J. A. Russell, J. S. Millership,
Tetrahedron Lett. 1998, 39, 1787–1790; g) N. Morohashi, N.
Iki, T. Onodera, C. Kabuto, S. Miyano, Tetrahedron Lett. 2000,
41, 5093–5097; h) S. Caccamese, A. Bottino, F. Cunsolo, S.
Parlato, P. Neri, Tetrahedron: Asymmetry 2000, 11, 3103–3112;
i) D. Hesek, Y. Inoue, M. G. B. Drew, P. D. Beer, G. A. Hem-
bury, H. Ishida, F. Aoki, Org. Lett. 2000, 2, 2237–2240; j) Y.-
D. Cao, J. Luo, Q.-Y. Zheng, C.-F. Chen, M.-X. Wang, Z.-T.
Huang, J. Org. Chem. 2004, 69, 206–208; k) F. Narumi, T. Hat-
tori, W. Yamabuki, C. Kabuto, H. Kameyama, Tetrahedron:
Asymmetry 2005, 16, 793–800; l) R. Miao, Q.-Y. Zheng, C.-F.
Chen, Z.-T. Huang, J. Org. Chem. 2005, 70, 7662–7671; m) V. I.
Boyko, A. Shivanyuk, V. V. Pyrozhenko, R. I. Zubatyuk, O. V.
Shishkin, V. I. Kalchenko, Tetrahedron Lett. 2006, 47, 7775–
7778; n) A. V. Yakovenko, V. I. Boyko, O. Danylyuk, K. Suwin-
ska, J. Lipkowski, V. I. Kalchenko, Org. Lett. 2007, 9, 1183–
1185; o) Z.-X. Xu, C. Zhang, Q.-Y. Zheng, C.-F. Chen, Z.-T.
Supporting Information (see also the footnote on the first page of
this article): 1H NMR and 13C NMR spectra of all new com-
pounds, as well as HPLC chromatographs for Michael addition
products.
Acknowledgments
We thank Yuichi Tanaka and Takafumi Kobari for their assistance
in this study.
[1] a) G. C. Barrett, Chemistry and Biochemistry of the Amino Ac-
ids, Chapman and Hall, London, 1985; b) Amino Acids, Pep-
tides and Proteins, Specialist Periodical Reports, The Royal So-
ciety of Chemistry, London, 1969–1985, vol. 1–16; c) Amino
Acids and Peptides, Specialist Periodical Reports, The Royal
Society of Chemistry, London, 1984–1987, vol. 17–20.
[2] a) J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmet-
ric Synthesis Wiley, New York, 1995; b) A. Mori, H. Abe, S.
Inoue, Appl. Organomet. Chem. 1995, 9, 189–197; c) A. Studer,
Synthesis 1996, 793–815; d) J. L. Vicario, D. Badia, L. Carrillo,
E. Reyes, J. Etxebarria, Curr. Org. Chem. 2005, 9, 219–235.
Eur. J. Org. Chem. 2009, 1916–1924
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1923

S. Shirakawa, S. Shimizu
FULL PAPER
Huang, Org. Lett. 2007, 9, 4447–4450; p) V. I. Boyko, A. V.
Yakovenko, Y. I. Matvieiev, O. I. Kalchenko, O. V. Shishkin,
V. I. Kalchenko, Tetrahedron 2008, 64, 7567–7573; q) F. Na-
rumi, N. Matsumura, N. Sasagawa, K. Natori, T. Kajiwara, T.
Hattori, Tetrahedron: Asymmetry 2008, 19, 1470–1475; r) Z.-
X. Xu, C. Zhang, Y. Yang, C.-F. Chen, Z.-T. Huang, Org. Lett.
2008, 10, 477–479; s) M. Paletta, M. Klaes, B. Neumann, H.-
G. Stammler, S. Grimme, J. Mattay, Eur. J. Org. Chem. 2008,
555–562.
[19]
[20]
The values of optical rotation [α]D of (+)298- and (–)298-1 were
very small (0).
a) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004,
37, 580–591; b) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471–5569; c) H. Kotsuki, H. Ikishima,
A. Okuyama, Heterocycles 2008, 75, 493–529; d) T. Kano, K.
Maruoka, Chem. Commun. 2008, 5465–5473.
a) H. Hiemstra, H. Wynberg, J. Am. Chem. Soc. 1981, 103,
417–430; b) K. Suzuki, A. Ikegami, T. Mukaiyama, Bull.
Chem. Soc. Jpn. 1982, 55, 3277–3282; c) F. Wang, M. Tada,
Agric. Biol. Chem. 1990, 54, 2989–2992; d) M. Ostendorf, S.
van der Neut, F. P. J. T. Rutjes, H. Hiemstra, Eur. J. Org. Chem.
2000, 105–113; e) M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes,
H. Hiemstra, Eur. J. Org. Chem. 2000, 115–124.
For recent reviews on asymmetric phase-transfer catalysis, see:
a) M. J. O’Donnell, Acc. Chem. Res. 2004, 37, 506–517; b) B.
Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518–525; c) T.
Ooi, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222–4266;
d) T. Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656–
5682; e) K. Maruoka, Asymmetric Phase Transfer Catalysis,
Wiley-VCH, Weinheim, 2008.
[21]
[22]
[8] a) K. Araki, K. Inada, S. Shinkai, Angew. Chem. Int. Ed. Engl.
1996, 35, 72–74; b) F. Narumi, T. Hattori, N. Matsumura, T.
Onodera, H. Katagiri, C. Kabuto, H. Kameyama, S. Miyano,
Tetrahedron 2004, 60, 7827–7833; c) J. Luo, Q.-Y. Zheng, C.-F.
Chen, Z.-T. Huang, Tetrahedron 2005, 61, 8517–8528.
[9] Inherently chiral calixarenes containing other chiral residues
were applied to asymmetric reactions as chiral ligands or cata-
lysts, see: a) C. Dieleman, S. Steyer, C. Jeunesse, D. Matt, J.
Chem. Soc., Dalton Trans. 2001, 2508–2517; b) Z.-X. Xu, G.-
K. Li, C.-F. Chen, Z.-T. Huang, Tetrahedron 2008, 64, 8668–
8675.
[10] a) S. Shirakawa, A. Moriyama, S. Shimizu, Org. Lett. 2007, 9,
3117–3119; b) S. Shirakawa, A. Moriyama, S. Shimizu, Eur. J.
Org. Chem. 2008, 5957–5964.
[11] S. Shirakawa, T. Kimura, S. Murata, S. Shimizu, J. Org. Chem.
2009, 74, 1288–1296.
[12] S. Shirakawa, Y. Tanaka, T. Kobari, S. Shimizu, New J. Chem.
2008, 32, 1835–1838.
[13] For the synthesis of achiral calixarene amino acids, see: a) F.
Sansone, L. Baldini, A. Casnati, E. Chierici, G. Faimani, F.
Ugozzoli, R. Ungaro, J. Am. Chem. Soc. 2004, 126, 6204–6205;
b) J.-A. Richard, M. Pamart, N. Hucher, I. Jabin, Tetrahedron
Lett. 2008, 49, 3848–3852.
[23] a) E. J. Corey, M. C. Noe, F. Xu, Tetrahedron Lett. 1998, 39,
5347–5350; b) M. J. O’Donnell, F. Delgado, E. Dominguez, J.
de Blas, W. L. Scott, Tetrahedron: Asymmetry 2001, 12, 821–
828; c) S. Arai, R. Tsuji, A. Nishida, Tetrahedron Lett. 2002,
43, 9535–9537; d) T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sek-
ine, T. Ohshima, M. Shibasaki, Tetrahedron Lett. 2002, 43,
9539–9543; e) B. Lygo, B. Allbutt, E. H. M. Kirton, Tetrahe-
dron Lett. 2005, 46, 4461–4464; f) T. Shibuguchi, H. Mihara, A.
Kuramochi, T. Ohshima, M. Shibasaki, Chem. Asian J. 2007, 2,
794–801.
[24] a) D. Y. Kim, S. C. Huh, S. M. Kim, Tetrahedron Lett. 2001,
42, 6299–6301; b) R. T. Dere, R. R. Pal, P. S. Patil, M. M. Sa-
lunkhe, Tetrahedron Lett. 2003, 44, 5351–5353; c) T. Ooi, D.
Ohara, K. Fukumoto, K. Maruoka, Org. Lett. 2005, 7, 3195–
3197.
[25] Calixarene-based chiral phase-transfer catalyst with chiral resi-
due, see: S. Bozkurt, M. Durmaz, M. Yilmaz, A. Sirit, Tetrahe-
dron: Asymmetry 2008, 19, 618–623.
[14] For representative reviews on organocatalysts, see: a) P. I.
Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138–5175;
b) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–724;
c) A. Berkssel, H. Gröger, Asymmetric OrganocatalysisϪFrom
Biomimetic Concepts to Applications in Asymmetric Synthesis
Wiley-VCH, Weinheim, 2005; d) Enantioselective Organocata-
lysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007; e) S. B.
Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716.
[26] a) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie, W. Duan, W. Wang,
J. Am. Chem. Soc. 2006, 128, 12652–12653; b) M. Agostinho,
S. Kobayashi, J. Am. Chem. Soc. 2008, 130, 2430–2431; c) H.
Naka, N. Kanase, M. Ueno, Y. Kondo, Chem. Eur. J. 2008, 14,
5267–5274.
[15] S. Shimizu, A. Moriyama, K. Kito, Y. Sasaki, J. Org. Chem.
2003, 68, 2187–2194.
[16] C. Jaime, J. de Mendoza, P. Prados, P. M. Nieto, C. Sánchez,
J. Org. Chem. 1991, 56, 3372–3376.
[17] F. Garro-Helion, A. Merzouk, F. Guibé, J. Org. Chem. 1993,
Received: December 27, 2008
Published Online: March 5, 2009
58, 6109–6113.
[18] The signs of (+)- and (–)-1 were assigned from CD spectra at
λmax (298 nm) and indicated as (+)298-1 or (–)298-1, respectively.
1924
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