Selection between pinching-type and supramolecular polymer-type complexes by α-cyclodextrin-β-cyclodextrin hetero-dimer and hetero-cinnamamide guest dimers

Article abstract of DOI:10.1021/jo0604686

Novel supramolecular complexes have been prepared from an α-cyclodextrin-β-cyclodextrin heterodimer (α-CD-β-CD hetero-dimer) and hetero-cinnamamide guest dimers, G-t-Boc and G-NH₂, having adamantyl groups in aqueous solutions. On addition of th

Full text of DOI:10.1021/jo0604686

Selection between Pinching-Type and Supramolecular Polymer-Type
Complexes by r-Cyclodextrin-â-Cyclodextrin Hetero-Dimer and
Hetero-Cinnamamide Guest Dimers
Hirokazu Takahashi, Yoshinori Takashima, Hiroyasu Yamaguchi, and Akira Harada*
Department of Macromolecular Science, Graduate School of Science, Osaka UniVersity, Toyonaka,
Osaka 560-0043, Japan
harada@chem.sci.osaka-u.ac.jp
ReceiVed March 4, 2006
Novel supramolecular complexes have been prepared from an R-cyclodextrin-â-cyclodextrin hetero-
dimer (R-CD-â-CD hetero-dimer) and hetero-cinnamamide guest dimers, G-t-Boc and G-NH2, having
adamantyl groups in aqueous solutions. On addition of the competitive guest, the supramolecular structure
formed by a mixture of the R-CD-â-CD hetero-dimer and G-t-Boc was found to be different from that
1
of a mixture of the R-CD-â-CD hetero-dimer and G-NH2 by the H NMR spectroscopy, the ROESY
NMR spectroscopy, and the circular dichroism spectroscopy. The size of the supramolecular complex
from the mixture of the R-CD-â-CD hetero-dimer and G-NH2 is larger than that from the mixture of the
R-CD-â-CD hetero-dimer and G-t-Boc, which was proved by the pulse field gradient spin-echo NMR
and the atomic force microscopy. These results suggest that the mixture of the R-CD-â-CD hetero-
dimer and G-t-Boc formed a pinching-type complex, and the mixture of the R-CD-â-CD hetero-dimer
and G-NH2 formed a supramolecular polymer-type complex.
Introduction
molecule. CD dimers were prepared by some researchers to
increase the association constants with CDs, because association
constants for complexations of appropriate guests with CDs
show 104 M-1, whereas the corresponding values for complex-
ations of substrates with antibody are more than 100 times
larger.4,5 Many researchers are actively working on producing
enzyme models based on CD dimers that strongly bind
appropriate substrates to both CD cavities such as a pinching-
type structure.6,7 Although there are some papers on the
cooperative binding of guests by CD hetero-dimers,8,9 there are
Biological systems offer several excellent examples of
supramolecular polymers including double- and triple-helical
DNA, as well as protein â-sheet and tobacco mosaic virus.1
Microtubles are supramolecular polymers consisting of hetero-
dimers of R-tubulin and â-tubulin with alternating structures.2
Chemists have challenged the formation of supramolecules
based on host-dimers as supramolecular architectures of artificial
assemblies.3 Cyclodextrins (CDs) have been used frequently as
a component of supramolecular complexes. CD dimers, used
for molecular recognition and drug delivery, possess the
structural characteristics to completely encapsulate a guest
(4) (a) Pease, A. R.; Jeppeson, J. O.; Stoddart, J. F.; Lop, Y. I.; Collier,
C. P.; Heath, J. R. Acc. Chem. Res. 2001, 34, 433. (b) Harada, A. Acc.
Chem. Res. 2001, 34, 456. (c) Harada, A.; Kawaguchi, Y.; Hoshino, T. J.
Inclusion Phenom. Macrocyclic Chem. 2001, 41, 115. (d) Miyauchi, M.;
Takashima, Y.; Yamaguchi, H.; Harada, A. J. Am. Chem. Soc. 2005, 127,
2984-2989.
* Corresponding author. Tel.: +81-6-6850-5445. Fax: +81-6-6850-5445.
(1) Aggeli, A.; Bell, M.; Boden, N.; Keen, J. N.; Knowles, P. F.; McLeish,
T. C. B.; Pitkeathly, M.; Radford, S. E. Nature 1997, 386, 259-262.
(2) (a) Amos, L. A.; Baker, T. S. Nature 1979, 279, 607-612. (b)
Luduena, R. F. Mol. Biol. Cell 1993, 4, 445-457. (c) Stullivan, K. F. Annu.
ReV. Cell Biol. 1988, 4, 687-716. (d) Wade, R. H.; Chre¨tien, D. J. Struct.
Biol. 1993, 110, 1-27.
(3) (a) Yamaguchi, N.; Gibson, H. W. Angew. Chem., Int. Ed. 1999, 38,
143. (b) Yamaguchi, N.; Nagvekar, D. S.; Gibson, H. W. Angew. Chem.,
Int. Ed. 1998, 37, 2361. (c) Gibson, H. W.; Yamaguchi, N.; Jones, J. W. J.
Am. Chem. Soc. 2003, 125, 3522.
(5) Mulder, A.; Reinhoudt, D. N. Chem. Commun. 2002, 22, 2734-
2735.
(6) (a) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry;
Springer: Berlin, 1978. (b) Bender, M. L.; Bergeron, R. J.; Komiyama, M.
The Bioorganic Chemistry of Enzymatic Catalysis; Wiley: New York, 1984.
(7) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 317. (b) Zhang, B.;
Breslow, R. J. Am. Chem. Soc. 1997, 119, 1676-1681. (c) Breslow, R.;
Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535-4536.
10.1021/jo0604686 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/02/2006
4878
J. Org. Chem. 2006, 71, 4878-4883

Complexes by R-Cyclodextrin-â-Cyclodextrin Dimers
FIGURE 1. Chemical structures of R-CD-â-CD dimer, G-t-Boc, and
G-NH2 guest dimers.
FIGURE 3. ROESY spectrum of the mixture of the G-t-Boc dimer
and the R-CD-â-CD dimer in D2O at 30 °C.
SCHEME 1
FIGURE 2. 1H NMR spectra of the G-t-Boc dimer (a), the mixture of
the R-CD-â-CD dimer and G-t-Boc in 3 mM (b), and the mixture of
the R-CD-â-CD dimer and G-t-Boc in the presence of 5 equiv of
AdCA in D2O at 30 °C (c).12
by the reaction of 6-amino-R-CD and 6-O-(4-carboxylphenyl-
amide)-â-CD using DCC (dicyclohexyl carbodiimide) and
HOBT (1-hydroxybenzotriazole) in DMF. Hetero-guest dimers,
G-t-Boc and G-NH2 were prepared by aminocinnamate, ami-
nopyridine, and 1-adamantyl bromomethyl ketone. Two kinds
of hetero-guest dimers were prepared: one with an adamantyl
group and tert-butyl group (t-Boc) and the other with an
adamantyl group and both having an amino cinnamate group
as a spacer (Figure 1). The t-Boc group and an amino group
are included in the R-CD cavity, while an adamantyl group is
not included in the R-CD cavity because of the steric hindrance.
Formation of Supramolecular Complexes from R-CD-
â-CD hetero-dimer and hetero-guest dimers. The supra-
molecular complexes from the R-CD-â-CD hetero-dimer with
G-t-Boc or the R-CD-â-CD hetero-dimer with G-NH2 were
expected to form two types, a pinching-type and a supramo-
lecular polymer-type. The NMR spectroscopy was used to reveal
the mode of these supramolecular complexes. Figure 2 shows
the 1H NMR spectra of the mixtrue of the R-CD-â-CD hetero-
dimer and the G-t-Boc guest dimer in D2O. The peaks of phenyl,
pyridinium, and t-Boc protons showed the peak shifts with an
increase in the concentration (Figure 2b and S3). The two-
dimensional ROESY NMR spectrum showed that the peaks of
the cinnamamide protons, adamantane protons, and t-Boc
protons were correlating with inner protons (C(3)-H and
C(5)-H) of CDs (Figure 3), but the correlation peaks between
the peaks of pyridinium protons and inner protons of CDs were
not observed.11 Considering the molecular size of the adamantyl
few on the formation of supramolecular complexes of CD
hetero-dimers with hetero-guest dimers. Previously, we reported
that a CD dimer formed supramolecular polymers with ditopic
guest molecules and did not form a 1:1 inclusion complex.10 In
the present paper, we describe the synthesis of an R-CD-â-
CD hetero-dimer and formation of supramolecular complexes
from the R-CD-â-CD hetero-dimer and hetero-cinnamamide
guest dimers. Our purpose was the construction of a new
supramolecular polymer consisting of the CD hetero-dimer and
hetero-cinnamamide guest dimers. However, we found the
selection between the pinching-type structure and the supramo-
lecular polymer-type structure in these systems, depending on
the combination of an R-CD-â-CD hetero-dimer and a hetero-
cinnamamide guest dimer.
Results and Discussion
Preparation of R-CD-â-CD Hetero-Dimer and Hetero-
Guest Dimers. The R-CD-â-CD hetero-dimer was prepared
(8) (a) Wang, Y.; Ueno, A.; Toda, F. Chem. Lett. 1994, 167-170. (b)
Ikeda, H.; Nishikawa, S.; Takao, J.; Akiike, T.; Yamamoto, Y.; Ueno, A.;
Toda, F. J. Inclusion Phenom. Macrocyclic Chem. 1996, 25, 133-136.
(9) Lock, J. S.; May, B. L.; Clements, P.; Lincoln, S. T.; Easton, C. J.
J. Inclusion Phenom. Macrocyclic Chem. 2004, 50, 13-18.
(10) (a) Hasegawa, Y.; Miyauchi, M.; Takashima, Y.; Yamaguchi, H.;
Harada, A. Macromolecules 2005, 38, 3724-3730. (b) Ohga, K.; Takashima,
Y.; Takahashi, H.; Kawaguchi, Y.; Yamaguchi, H.; Harada, A. Macromol-
ecules 2005, 38, 5897-5904.
J. Org. Chem, Vol. 71, No. 13, 2006 4879

Takahashi et al.
indicative of the formation of the supramolecular complex. The
mixture of R-CD-â-CD dimer, G-t-Boc guest dimer, and AdCA
were thought to form four possible supramolecular complexes
(Scheme S1). These results of one-dimensional (1D) 1H
NMR and ROESY NMR showed that the supramolecular
structure, shown in Scheme 1a, was formed by the mixture of
R-CD-â-CD dimer, G-t-Boc guest dimer, and AdCA.
The mixture of the R-CD-â-CD hetero-dimer and G-NH2
1
showed the same behavior in the H NMR (Figure 4b) and
showed that the peaks of cinnamamide protons and adamantly
protons were correlating with inner protons (C(3)-H and
C(5)-H) of CDs (Figure S6), indicative of the formation of
the inclusion complex. However, upon addition of AdCA to
the solution of the R-CD-â-CD hetero-dimer with G-NH2, the
peak shifts of G-NH2 protons were not observed (Figure 4c).
We supposed that AdCA was not included in the â-CD cavity
or that the conformation of the inclusion complex does not
change on addition of AdCA. The cinnamamide protons and
adamantyl protons were correlating with inner protons (C(3)-H
and C(5)-H) of CDs (Figure S8). Moreover, the ROE correla-
tion between AdCA and inner protons (C(3)-H and C(5)-H)
of CDs was observed. These results of 1D 1H NMR and ROESY
NMR showed that the supramolecular structure from the mixture
of R-CD-â-CD dimer and G-NH2 guest dimer was different
from that from the mixture of R-CD-â-CD dimer, G-t-Boc
guest dimer and AdCA.
FIGURE 4. 1H NMR spectra of the G-NH2 dimer (a), the mixture of
the R-CD-â-CD dimer and G-NH2 in 3 mM (b), and the mixture of
the R-CD-â-CD dimer and G- NH2 on addition of 5 equiv of AdCA
in D2O at 30 °C (c).12
group and the t-Boc group, the t-Boc group is included in the
R-CD cavity, and the adamantyl group is included in the â-CD
cavity, because the adamantyl group is too large to fit the
adamantyl group in the R-CD cavity. These data indicate the
formation of inclusion complexes, but it is difficult to determine
a pinching-type or a supramolecular polymer-type.
The direction of the cinnamamide group in the pinching-type
supramolecular complex is supposed to change on addition of
excessive amounts of the competitive guest, which is included
in the â-CD cavity. The direction of the cinnamamide group in
the supramolecular polymer-type did not change on addition
of excessive amounts of adamantane carboxylic acid (AdCA;
Scheme 1).
When 5 equiv of AdCA, which is strongly bound to the â-CD
cavity, were added to the solution of the R-CD-â-CD hetero-
dimer and G-t-Boc, the peaks of the aromatic protons and the
t-Boc protons showed the peak shifts (Figure 2c and S4). These
results showed that the inclusion complex was dissociated or
that the mode of the inclusion complex changed on addition of
AdCA. The ROE correlation between cinnamamide protons,
adamantly protons, t-Boc protons, AdCA and inner protons
(C(3)-H and C(5)-H) of CDs were observed (Figure S7),
The protons of the cinnamamide group in the mixture of the
R-CD-â-CD hetero-dimer and G-t-Boc showed the peak shifts
1
by addition of AdCA in the H NMR spectroscopy. On the
contrary, the protons of the cinnamamide in the mixture of the
R-CD-â-CD hetero-dimer and G-NH2 did not show any peak
shifts. These mixtures of the R-CD-â-CD hetero-dimer and
guest dimers showed the ROE correlation between the inner
protons of CDs and guest parts. On the basis of these data, we
suppose that the mixture of the R-CD-â-CD hetero-dimer and
G-t-Boc formed the pinching-type complex, and the mixture of
the R-CD-â-CD hetero-dimer and G-NH2 formed the supramo-
lecular polymer-type complex (Scheme 2).
Calculation of the Molecular Sizes of Supramolecular
Complexes. The pulsed field gradient spin-echo NMR was
measured to determine diffusion coefficients of the supramo-
lecular complex between the R-CD-â-CD hetero-dimer and
SCHEME 2
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Complexes by R-Cyclodextrin-â-Cyclodextrin Dimers
FIGURE 5. Concentration dependence of the diffusion coefficient
values (D) of supramolecular polymers formed between the R-CD-
â-CD dimer and the G-t-Boc dimer (filled square) and the R-CD-
â-CD dimer and the G-NH2 dimer (filled circle) in D2O at 30 °C by
NMR.
FIGURE 7. AFM images of a 1:1 mixture of the G-t-Boc dimer and
the R-CD-â-CD dimer (a) and the G-NH2 dimer and the R-CD-
â-CD dimer (b).
from the R-CD-â-CD hetero-dimer and G-t-Boc at 5mM,
indicating that the mixture of the R-CD-â-CD hetero-dimer
and G-NH2 guest dimer formed the supramolecular polymer.
These data support the formation of a pinching-type complex
from the R-CD-â-CD hetero-dimer and G-t-Boc and the
formation of a supramolecular polymer-type complex from the
R-CD-â-CD hetero-dimer and G-NH2 by NMR studies.
Circular Dichroism Spectra. The achiral compounds located
in the CD cavity produce induced circular dichroism signals in
the corresponding transition bands.11,12 To confirm the different
conformations of the complex of the R-CD-â-CD hetero-dimer
with G-t-Boc and that of the R-CD-â-CD hetero-dimer with
G-NH2, their circular dichoism spectra were measured at 25
°C. The mixture of the R-CD-â-CD hetero-dimer and G-t-Boc
showed a negative Cotton band at 240 nm and a negative Cotton
band at 350 nm, while the mixture of the R-CD-â-CD hetero-
dimer and G-NH2 showed a negative Cotton band at 240 nm
and a positive Cotton band at 350 nm in Figure 6. These results
indicate that the location of cinnamamide moiety of G-t-Boc in
the cavity of the R-CD-â-CD hetero-dimer is different from
that of G-NH2.
Direct Observation by Atomic Force Microscopy. To
confirm the nanometer-sized molecular assemblies, the su-
pramolecular dimer or polymer, atomic force microscopy (AFM)
measurements were performed. When the sample was made
from a 1:1 mixture of the R-CD-â-CD hetero-dimer and
G-t-Boc, only a small object that was approximately 20 nm in
overall length could be detected. The size of the small object
from the R-CD-â-CD hetero-dimer and G-t-Boc was as large
as that of the R-CD-â-CD hetero-dimer. However, nanometer-
sized supramolecular wires that were approximately 250 nm in
overall length were observed on the mica substrate (Figure 7).
Conclusion. We studied the preparation of the supramolecular
complex using the R-CD-â-CD hetero-dimer and hetero-guest
dimers. The mixture of the R-CD-â-CD hetero-dimer and
hetero-guest dimers, G-t-Boc and G-NH2, had been expected
to form supramolecular polymers. However, it is concluded that
a 1:1 mixture of the R-CD-â-CD hetero-dimer and G-t-Boc
FIGURE 6. Circular dichroism spectra of the mixture of the
G-t-Boc dimer and the R-CD-â-CD dimer (a) and the mixture of the
G-NH2 dimer and the R-CD-â-CD dimer (b) as a fraction of the
concentration in H2O at 25 °C.
hetero-guest dimers. Figure 5 shows that the apparent diffusion
coefficient (D) of the mixture of the R-CD-â-CD hetero-dimer
and G-t-Boc slightly decreased with an increase in the con-
centration. D of the mixture of the R-CD-â-CD hetero-dimer
and G-t-Boc was comparable to D of the R-CD-â-CD hetero-
dimer, indicative of the formation of the pinching-type com-
plex. However, D of the supramolecular complex from the
R-CD-â-CD hetero-dimer and G-NH2 largely decreased with
an increase in the concentration. The hydrodynamic volume of
the supramolecular complex from the R-CD-â-CD hetero-dimer
and G-NH2 is larger than that of the supramolecular complex
(11) Generally, the cationic compounds are not included in the CD cavity.
Previously, we have studied the formation inclusion complexes between
the viologen polymers and the a-CD. These results indicated that the cationic
groups play a rule in the electron stopper and were not included in the
R-CD caviry. (a) Kawaguchi, Y.; Harada, A. J. Am. Chem. Soc. 2000, 122,
3797-3798. (b) Kawaguchi, Y.; Harada, A. Org. Lett. 2000, 2, 1353-
1356.
(12) Excess amounts of AdCA, which exceeded the limit of the solubility
in D2O, were added to the solution of the mixture of R-CD-â-CD dimer
and G-t-Boc guest dimer.
J. Org. Chem, Vol. 71, No. 13, 2006 4881

Takahashi et al.
SCHEME 3
SCHEME 4
SCHEME 6
SCHEME 5
SCHEME 7
guest dimer forms a pinching-type dimer structure and that a
1:1 mixture of the R-CD-â-CD hetero-dimer and the G-NH2
guest dimer forms a supramolecular polymer-type structure. The
selection of supramolecular complexes is caused by the steric
effect, the association constants, and some interactions such as
the hydrophobic interaction, the hydrogen bond interaction, and
so on. This is the first example of the selection of supramolecular
complexes between a pinching-type complex and a supramo-
lecular polymer-type complex. These results are important from
a viewpoint of not only supramolecular chemistry, but of the
formation of specific structures in biological systems.
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 8.4 (t, 1H,
-CONH-), 8.0 (d, 2H, 2-Ph), 7.9 (d, 2H, 3-Ph), 5.7 (m, 14H,
O(2)H and O(3)H), 4.9 (d, 1H, C(1)′H), 4.8 (m, 6H, C(1)H), 4.2
(m, 4H, O(6)H), 4.15 (m, 1H, O(6)′H), 3.6 (m, 21H, C(3)H, C(5)-
H, and C(6)H), 3.3 (m, 14H, C(2)H and C(4)H). Elem anal. Calcd
for C50H75NO37‚6.0H2O: C, 43.20; H, 6.31; N, 1.01. Found: C,
42.98; H, 6.22; N, 1.24. MALDI-TOF MS (m/z): 1306.4 ([M +
Na]+).
Preparation of R-CD-â-CD Hetero-Dimer (Scheme 6). To a
solution of terephthalamide â-CD (0.12 mg, 0.09 mmol) in 10 mL
of DMF was added the mixture solution of 3-NH2-R-CD, DCC
(0.37 mg, 0.18 mmol), and 1-hydroxylbenzotriazole (24 mg, 0.18
mmol) at 0 °C. After being stirred for an hour, it was allowed to
warm to room temperature and stirred for 3 days. After the
prescribed time, the precipitate, dicyclohexylurea, was removed by
centrifuge. The supernatant solution was poured into 300 mL of
acetone to precipitate the CD compounds. The crude product was
purified by the size exclusion column chromatography on Tosoh
TSKgel R-2500 and R-3000, eluted with water, to give the R-CD-
â-CD hetero-dimer in 17% yield.
Experimental Section
Preparation of Terephthalic Acid Methyl ONSu Ester (Scheme
3). Terephthalic acid monomethyl ester (2.2 g, 12.0 mmol),
dicyclohexyl carbodiimide (DCC; 3.7 g, 18.0 mmol), and N-
hydroxylsuccinimide (2.4 g, 18.0 mmol) were allowed to react in
THF (30 mL) at room temperature. After a day, the precipitate,
dicyclohexylurea, was removed by centrifuge. The supernatant
solution was evaporated to dryness in vacuo. The residue was
dissolved in 30 mL of 2-propanol and recrystallized at 2 °C as a
white crystal in 50% yield.
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 8.30 (b, 1H,
-CONH-), 8.17 (d, 1H, -CONH-), 7.89 (s, 4H, 2,3-Ph), 5.90-
5.19 (m, 26H, O(2)H and O(3)H), 4.93 (m, 1H, C(1)′H), 4.82 (s,
11H, C(1)H), 4.79 (s, 1H, C(1)′′H), 4.67-4.29 (m, 11H, O(6)H),
4.04-3.50 (m, 39H, C(3)H, C(5)H, and C(6)H), 3.47-3.14 (m,
overlaps with HOD, C(2)H and C(4)H). Elem anal. Calcd for C
86H134N2O65‚11.0H2O: C, 42.43; H, 6.46; N, 1.15. Found: C, 42.25;
H, 6.41; N, 1.35. MALDI-TOF MS (m/z): 2252.6 ([M + Na]+).
Preparation of Hetero-Guest Dimers (Scheme 7).
(1) Preparation of tert-Boc-aminocinnamic Acid. p-Amino-
cinnamic acid was dissolved in 20 mL of dioxane and 10 mL of 1
M aq NaOH and stirred at 0 °C for 30 min. To the mixture solution
was added a dioxane (10 mL) solution of (tert-Boc)2O (2.4 g, 11
mmol) at 0 °C and stirred 12 h. The mixture solution was neutralized
by the addition of hydrochloric acid solution (pH 3). The product
was extracted with ethyl acetate, and the separated organic layer
was washed with water three times. The separated organic layer
was dried under sodium sulfate and evaporated under reduced
pressure to give the product (0.61 g) in 23% yield.
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 8.1 (d, 2H, 2-Ph),
8.2 (d, 2H, 3-Ph), 3.9 (s, 3H, Me), 2.9 (s, 4H, ONSu). Elem anal.
Calcd for C13H11NO6: C, 56.32; H, 4.00; N, 5.05. Found: C, 56.10;
H, 3.96; N, 5.23.
Preparation of Methylterephthalamide â-CD (Scheme 4). To
a solution of 6-NH2-â-CD (1.0 g, 0.88 mmol) in 20 mL of DMF
was added terephthalic acid methyl ONSu ester (0.3 g, 1.01 mmol).
The reaction mixture was stirred at room temperature for 36 h.
After the prescribed time, the reaction mixture was poured into
300 mL of acetone to precipitate methylterephthalamide â-CD. The
crude methylterephthalamide â-CD was collected by centrifuge and
washed with acetone to give methylterephthalamide â-CD in 87%
yield.
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 8.4 (t, 1H,
-CONH-), 8.0 (d, 2H, 2-Ph), 7.9 (d, 2H, 3-Ph), 5.7 (m, 14H,
O(2)H and O(3)H), 4.9 (d, 1H, C(1)′H), 4.8 (m, 6H, C(1)H), 4.2
(m, 4H, O(6)H), 4.15 (m, 1H, O(6)′H), 3.92 (s, 3H, Me), 3.6 (m,
21H, C(3)H, C(5)H, and C(6)H), 3.3 (m, 14H, C(2)H, and C(4)H).
Preparation of Terephthalamide â-CD (Scheme 5). Methyl-
terephthalamide â-CD was dissolved in 10 mL of water and added
to 0.2 mL of 1 M NaOH and stirred for an hour. After the prescribed
time, the reaction mixture was neutralized by citric acid and
evaporated to dryness under reduced pressure. The crude product
was purified by column chromatography on DIAION HP-20 (eluted
with water/methanol ) 100/0 to 50/50). The 60/40 (water/methanol)
eluent was concentrated to give terephthalamide â-CD in 88% yield.
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 9.5 (s, 1H,
-CONH-), 7.6 (d, 1H, -CHdCH-), 7.5 (d, 2H, 2-Ph), 7.4 (d,
2H, 3-Ph), 6.38 (d, 1H, -CHdCH-), 1.5 (s, 9H, t-Bu).
(2) Preparation of Boc-aminocinnamamide Pyridine. 4-Ami-
nopyridine (1.20 g, 12.7 mmol) and tert-Boc-aminocinnamic acid
(2.80 g, 10.6 mmol) were allowed to react with DCC (2.19 g, 10.6
mmol) and HOBt (1.43 g, 10.6 mmol) in 30 mL of DMF at 0 °C
4882 J. Org. Chem., Vol. 71, No. 13, 2006

Complexes by R-Cyclodextrin-â-Cyclodextrin Dimers
for an hour. After stirring for an hour, it was allowed to warm to
room temperature and stir for 2 days. After the prescribed time,
the precipitate, dicyclohexylurea, was removed by centrifuge. The
supernatant solution was poured into 300 mL of acetone to
precipitate the crude tert-Boc-aminocinnamamide pyridine. The
product was washed with acetone three times and dissolved in 30
mL of ethyl acetate. The separated organic layer was washed with
water three times and evaporated under reduced pressure to give
the product (2.03 g) in 56% yield.
(4) Preparation of Adamantyl-N-methyl Ketone Aminocin-
namamide Pyridine (G-NH2). Adamantyl-N-methyl ketone Boc-
aminocinnamamide pyridine (G-t-Boc) (66.6 mg, 0.19 mmol) was
dissolved in 20 mL of 6 M HCl and 1,4-dioxane and stirred at
room temperature for an hour. After an hour, the mixture was
evaporated to dryness under reduced pressure, and the crude product
was washed with acetone and diethyl ether three times. The
precipitate was dried in vacuo to give the crude product. The
resulting residue was recrystallized from 2-propanol/water (9/1) at
0 °C in 52% yield (42 mg).
1H NMR (DMSO-d6, 30 °C, 270 MHz): δ 10.5 (s, 1H,
-CONH-Py), 9.55 (s, 1H, -CONH-Ph), 8.4 (d, 2H, Py), 7.4-
7.7 (m, 7H, Ph, Py, -CHdCH-Ph), 6.8 (d, 1H, -CHdCH-),
1.55 (s, 9H, t-Bu). FAB MS (m/z): 340.0 ([M + Na]+).
1H NMR (D2O, 30 °C, 270 MHz): δ 8.30 (d, J ) 7.3 Hz, 2H,
2-Py), 8.11 (d, J ) 7.6 Hz, 2H, 3-Py), 7.78 (d, J ) 15.1 Hz, 1H,
-CHdCH-Ph), 7.71 (d, J ) 8.9 Hz, 2H, 2-Ph), 7.27 (d, J ) 8.6
Hz, 2H, 3-Ph), 6.76 (d, J ) 15.7 Hz, 1H, -CHdCH-Ph), 5.65 (s,
2H, CO-CH2-), 2.00 (b, 3H, adamantane), 1.89 (b, 6H, adaman-
tane), 1.72 (q, 6H, adamantane). Elem anal. Calcd for C26H30
BrN3O2‚0.4H2O: C, 62.00; H, 6.16; N, 8.34. Found: C, 61.97; H,
6.19; N, 8.30. MALDI-TOF MS (m/z): 416.2 ([M - Br]+).
(3) Preparation of Adamantyl-N-methyl Ketone tert-Boc-
aminocinnamamide Pyridine (G-t-Boc). tert-Boc-aminocinnama-
mide pyridine (200 mg, 1.77 mmol) and 1-adamantyl bromomethyl
ketone (455 mg, 1.77 mmol) were allowed to react in acetone (20
mL) at 60 °C for 3 h. After being cooled to room temperature, the
yellow precipitate was collected by filtration and washed with
diethyl ether three times to give the crude product. The resulting
residue was recrystallized from 2-propanol/water (9/1) at 0 °C in
59% yield (181 mg).
Acknowledgment. This work has been partially supported
by Grant in-Aid No. S14103015 for Scientific Research and
has been conducted with financial support from the 21st Century
COE (Center of Excellence) program of the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
1H NMR (D2O, 30 °C, 270 MHz): δ 8.22 (d, J ) 7.8 Hz, 2H,
2-Py), 8.04 (d, J ) 7.7 Hz, 2H, 3-Py), 7.65 (d, J ) 15.1 Hz, 1H,
-CHdCH-Ph), 7.58 (d, J ) 8.4 Hz, 2H, 2-Ph), 7.35 (d, J )
8.4 Hz, 2H, 3-Ph), 6.59 (d, J ) 15.9 Hz, 1H, -CHdCH-Ph),
2.01 (b, 3H, adamantane), 1.85 (b, 6H, adamantane), 1.72 (q,
6H, adamantane), 1.45 (s, 9H, t-Bu). Elem anal. Calcd. for
C31H38BrN3O4‚1.3H2O: C, 60.06; H, 6.60; N, 6.78. Found: C,
59.82; H, 6.25; N, 6.55. FAB MS (m/z): 517.3 ([M - Br]+).
Supporting Information Available: ROESY NMR spectra for
the R-CD-â-CD hetero-dimer and adamantane hetero-cinnamate
guests (G-t-Boc and G-NH2) are shown. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0604686
J. Org. Chem, Vol. 71, No. 13, 2006 4883