D3h-Symmetrical Shape-Persistent Macrocycles Consisting of Pyridine–Acetylene–Phenol Conjugates as an Efficient Host Architecture for Saccharide Recognition

Article abstract of DOI:10.1002/chem.201603987

Hexagonal shape-persistent macrocycles (SPMs) consisting of three pyridine and three phenol rings linked with acetylene bonds were developed as a preorganized host for saccharide recognition by push–pull-type hydrogen bonding. Three tert-butyl or 2,4,6-tr

Full text of DOI:10.1002/chem.201603987

A Journal of
Accepted Article
Title: D3h-Symmetrical Shape-Persistent Macrocycles Consisting of
Pyridine-Acetylene-Phenol Conjugates as a Highly Efficient Host
Architecture for Saccharide Recognition
Authors: Hajime Abe, Tetsuhiro Yoneda, Yuki Ohishi, and Masahiko
Inouye
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Chemistry - A European Journal
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FULL PAPER
D -Symmetrical Shape-Persistent Macrocycles Consisting of
3h
Pyridine–Acetylene–Phenol Conjugates as an Efficient Host
Architecture for Saccharide Recognition
[
a]
Hajime Abe,* Tetsuhiro Yoneda, Yuki Ohishi, and Masahiko Inouye*
[
9]
Abstract: Hexagonal shape-persistent macrocycles (SPMs)
consisted of three pyridine and three phenol rings linked with
acetylene bonds were developed as a preorganized host for
saccharide recognition by push-pull-type hydrogen bonding. Three
tert-butyl or 2,4,6-triisopropylphenyl substituents were introduced on
the host to suppress self-aggregation by steric hindrance. In spite of
hydrogen-bonding
donor-acceptor
alternative.
Taking
advantage of the precise enthalpic gain arising from the push-
pull hydrogen bonds, the oligomer 1a strongly recognized
various saccharides to form a chiral helical complex in an
induced-fit manner (Figure 1). However, the work is not yet
satisfactory because entropic loss remains to be minimized,
particularly that resulted from the conformational freeze of the
oligomers during the complexation.
a
the simple architecture, association constants K of the host with
6
−1
alkyl glycoside guests reached the order of 10 M on the basis of
UV-vis titration experiments. This glycoside recognition was much
stronger than that in the cases of acyclic equivalent hosts because
of the entropic advantage brought by pre-organization of the
hydrogen-bonding sites. Solid-liquid extraction and liquid-liquid
transport through a liquid membrane were demonstrated by using
native saccharides, and much preference to mannose was observed.
R'
R''
N
I
O
H
H
O
R
TBS
n
Introduction
1a: n = 6
Shape-persistent macrocycles (SPMs) have attracted interests
for their keen-edged structural, spectroscopic, and interactive
properties originated from the well-defined rigid conformation.
1b: n = 3
[1]
Typically, self-aggregation of discotic SPMs has been studied to
make columnar, fibril, and liquid crystalline nanostructures. From
the viewpoint of host-guest chemistry, the center hole within a
SPM framework seems to be attractive because the shape of
the hole is also defined. Thus, if functional groups were located
inside the framework, their positions must be highly
Figure 1. Pyridine–acetylene–phenol oligomers 1a,b and an alcohol guest
associated by push-pull hydrogen bonding. TBS = tert-butyldimethylsilyl.
Now, we planned to study SPM hosts 2 and 3 consisted of
the pyridine–acetylene–phenol conjugate as a highly efficient
[
2−4]
[10,11]
predictable.
In some cases, such architecture would realize
host architecture for saccharide recognition (Figure 2).
Their
pre-organization of the functional groups to strongly recognize
guest molecules fitted in the hole.
We have been developing host molecules consisting of
hydrogen-bonding acceptor and donor units for interacting with
the hydroxy groups of saccharides in a push-pull fashion. In this
hexagonal framework has rigidity and D3h symmetry reasonable
for the mono-saccharide recognition in the hole with pre-
organized hydrogen-bonding donors and acceptors. These
structural aspects certainly guarantee entropic advantages
during the recognition of saccharides, compared with the
previous acyclic oligomers. Bulky groups were introduced in the
peripherals of both the SPMs to avoid self-association. Actually
[
2h,3−6]
context,
a
pyridine–acetylene–(1H)-4-pyridone motif was
selected and proved to be efficient for saccharide
[
4c,7,8]
recognition.
The acetylene spacer kept the distance
a
less bulky analogue
4
suffered from concentration
between the acceptor and the donor to grip a hydroxy group,
avoiding intramolecular interaction. On the other hand, the
oligomers possessing the repeating units were also found to
dependence due to self-association (see below). The octyloxy
groups were used for increasing the solubility. Herein we
describe the preparation, properties, and saccharide recognition
ability of the hosts, especially of 3 in detail. We also investigated
not only usual binding experiments in a solution phase but also
solid-liquid extraction and liquid-liquid hexose transport through
a liquid membrane for 3.
intermolecularly
self-dimerize
through
Very recently, we newly introduced
pyridine–acetylene–phenol unit as a hard to self-dimerize,
pyridone-pyridinol
[
7]
tautomerization.
a
[a]
Dr. H. Abe, Mr. T. Yoneda, Dr. Y. Ohishi, Prof. Dr. M. Inouye
Graduate School of Pharmaceutical Sciences, University of Toyama
Sugitani 2630, Toyama 930-0194 (Japan)
Fax: (+81)76-434-5049
E-mail: abeh@pha.u-toyama.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
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R
The tert-butyl groups for 2 and 2,4,6-triisopropylphenyl (Tip)
groups for 3 were expected to hinder the self-aggregation
through stacking of the large π-plane. Starting from 4-tert-
butylphenol, 2 was obtained by repeating Sonogashira reaction.
The details of the synthetic procedure were described in
A
n-C H
C H17-n
8
17
8
O
O
OH
1
N
N
Supporting Information. The concentration dependence of the H
−
3
−4
NMR chemical shifts ([2] = 9.5 × 10 to 1.5 × 10 M) was
1
observed, and the association constant (Kdim = (1.7 ± 0.6) × 10
−
1
M ) was found to be much small (Figures S3 and S4 in
Supporting Information). In UV-vis measurements, no
meaningful deviation from Beer's law was seen under the
OH
HO
R
R
−4
concentration of [2] ≤ 2.0 × 10 M (Figures S5 and S6 in
N
Supporting Information), so that 2 certainly exists as a monomer
below the concentration.
The SPM host 3 with bulkier substituents was prepared by
the synthetic procedures shown in Scheme 1. Commercially
OC H17-n
8
2
3
4
: R = t-Bu
i-Pr
available
2-bromo-1,3,5-triisopropylbenzene
(TipBr)
was
coupled with 4-methoxybenzeneboronic acid (5) by Suzuki-
Miyaura coupling to give diaryl 6. After removal of the methyl
group, phenol 7 was subjected to iodination followed by
protection of the hydroxy group to afford 9. The use of MOM
groups was necessary to protect the phenolic hydroxy groups
from the undesirable cyclization to benzofuran. Sonogashira
coupling of 9 with (trimethylsilyl)acetylene (TMSA) and treatment
with tetrabutylammonium fluoride (TBAF) gave 11, one of phenol
building blocks. On the other hand, 9 was coupled with 2-methyl-
: R =
i-Pr (Tip)
i-Pr
: R = n-pentyl
B
3
-butyn-2-ol and (tert-butyldimethylsilyl)acetylene (TBSA)
subsequently by two-step Sonogashira reactions to give hetero-
diprotected diyne 13. The liberation of acetone from 13 with
base gave monoprotected diyne 14, another phenol building
block. Sonogashira reaction using 11 and an excess amount of
[
7]
2
,6-diiodo-4-(octyloxy)pyridine (15) yielded diiodide trimer "I-
pyridine-(MOM-phenol)-pyridine-I" 16, while diyne trimer
ethynyl-(MOM-phenol)-pyridine-(MOM-phenyl)-ethynyl" 18 was
obtained by Sonogashira reaction of 15 with two equivalents of
4, followed by the treatment with TBAF. The trimer precursors
"
1
Figure 2. (A) Pyridine–acetylene–phenol SPM hosts 2, 3, and 4. Steric
hindrance was introduced on 2 and 3, and 4 is a less bulky preliminary
analogue. (B) A conceptual illustration for structure of 3. A ball, a ring, and
three crescent-shaped plates represent a glycoside guest, a SPM center, and
a steric hindrance, respectively.
16 and 18 were subjected to final Sonogashira reaction to afford
macrocyclized product 3-MOM, and the MOM groups were
removed by TFA to furnish 3 as a yellow solid.
The MOM protons of 3-MOM were much deshielded after
the macrocyclization, compared with the precursors 16 and 18.
1
The H NMR signals of the methylene and methyl groups of 16
Results and Discussion
appeared at δ 5.51 and 3.76 ppm, respectively, and after the
cyclization to 3-MOM, they appeared at δ 5.73 and 4.05 ppm,
respectively. This anisotropy would be due to a field effect from
the oxygen atoms of the MOM groups stuffed into the hole. In
the cases of 2-MOM and 4-MOM, similar anisotropy effects were
observed.
In a preliminary study, the less bulky SPM 4 was investigated as
a prototype, prior to 2 and 3 possessing steric hindrance. The
preparation and characteristics of 4 were described in the
Supporting Information. The H NMR chemical shifts for 4 were
found to depend on the concentration, and the association
1
The product 3 is well soluble to common organic solvents
such as CH Cl , CHCl , and AcOEt. Owing to the steric
2 2 3
constant assuming dimerization Kdim was estimated to be (2.1 ±
3
−1
1.1) × 10
M
from the titration curve (Figures S1 and S2 in
hindrance, self-association could be completely suppressed, so
that concentration dependence was not observed. Absorbance
Supporting Information). The strong self-association would be
[
4a,b]
due to π-stacking of the planar framework
and would disturb
2 2
of 3 at 282 nm in CH Cl was linearly dependent on the molar
the study of saccharide recognition. So we decided to introduce
steric hindrance to avoid self-association in order to
quantitatively evaluate the host ability of the pyridine–acetylene–
phenol SPM framework.
−
3
−7
concentration [3] from 1.0 × 10 to 6.8 × 10 M (Figures S7 and
S8 in Supporting Information). In addition, no meaningful change
1
occurred for H NMR chemical shifts in CDCl
1
3
even at a range of
−
2
−4
.4 × 10 to 2.1 × 10 M (Figure S9 in Supporting Information).
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Chemistry - A European Journal
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FULL PAPER
OR1
OR2
R3
OMOM
R3
OMe
TipBr, Pd(OAc)2,
KI, H O ,
PdCl (PPh ) , CuI,
2 3 2
TMSA, K CO
2 3
2
2
I
I
SPhos, K PO , toluene
H SO
3
4
2
4
97%
97%
THF, i-Pr NH
2
97%
B(OH)2
Tip
Tip
Tip
MOMCl,
5
1
2
3
BBr3,
6: R = Me i-Pr NEt,
8: R = H
TBAF,
10: R = TMS
2
CH Cl2
CH Cl
97%
H O, THF
2
2
2
2
1
2
3
96%
7: R = H
9: R = MOM
91%
11: R = H
HO
OMOM
R4
OMOM
TBS
Pd(PPh ) , CuI,
I TBSA, Pd(PPh3)4,
CuI, K CO
3
4
K CO
2
3
2
3
9
+ H
OH
THF, i-Pr NH
THF, i-Pr NH
2
2
66%
Tip
89%
Tip
4
12
13: R = CMe OH
2
Pd(PPh ) ,
NaOH, toluene
84%
3
4
Tip
CuI, K CO ,
4
2
3
1
4: R = H
THF, i-Pr NH
2
11
65% C H -n
n-C H
8 17
8
17
O
O
excess
OMOM
Pd(PPh ) , CuI,
3
4
OC H -n
N
N
8
17
K CO , THF, i-Pr NH
TFA, CH Cl
16
2
3
2
Tip
2
2
3
I
I
22%
C H -n
100%
R5
R5
I
N
I
n-C H
8 17
8
17
15
O
O
OMOM
N
N
OMOM
MOMO
14
3
-MOM
Pd(PPh ) ,
3
4
Tip
Tip
CuI, K CO ,
2
3
N
MOMO
THF, i-Pr2
NH
OMOM
Tip
Tip
OC H -n
N
8
17
5
TBAF,
17: R = TBS
H O, THF
7% (2 steps)
2
5
8
18: R = H
OC H -n
8
17
Scheme 1. Synthesis of SPM host 3. Tip
=
2,4,6-triisopropylphenyl, SPhos
=
2-(dicyclohexylphosphino)-2',6'-dimethoxybiphenyl, TMSA =
(
trimethylsilyl)acetylene, TBAF = tetrabutylammonium fluoride, TBSA = (tert-butyldimethylsilyl)acetylene, TFA = trifluoroacetic acid.
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HO
HO
HO
HO
HO
of oct-β-Glc was found to move upfield, thus the influence of the
host-guest interaction extended all along the complex.
O
O
OC H17-n
8
HO
To quantitatively study the saccharide recognition ability of 3,
titration experiments were carried out by the addition of several
OH
HO
OC H17-n
8
oct-β-Glc
−
6
oct-α-Glc
kinds of octyl glycosides (Figure 3) to a solution of 3 (3.0 × 10
M) in 1,2-dichloroethane (DCE) by UV-vis spectroscopy (Figure
A). According to the addition of oct-β-Glc, red shift of the
5
HO OH
O
HO
OH
O
HO
HO
HO
absorption band around 360 nm and hypochromism around 282
nm occurred in 3. When absorbance at 375 nm was plotted
against the molar concentration of the guest glycosides, the
isotherms were well fitted with theoretical curves assuming 1:1
OC H17-n
8
OC H17-n
8
OH
oct-β-Man
oct-β-Gal
HO
HO
HO
a
binding, and the association constants K was found to be (5.0 ±
O
6
−1
2.2) × 10 M (Figure 5B).
OH
O
OH
O
The additive effects of glycoside guests were also
investigated by fluorescence spectroscopy. Figure 5C shows the
changes of the fluorescence spectrum of a solution of 3 (3.0 ×
HO
O
HO
OC12H25-n
OC H17-n
HO
8
HO
−
6
OH
10 M) in DCE by the addition of oct-β-Glc. The emissive band
around 400 nm largely weakened during the titration (Figure 5D)
possibly because the association yielded many vibratable
hydrogen bonds that caused the increased nonradiative decay
process.
OH
β-maltoside
oct-β-Fru
Figure 3. Alkyl glycoside guests applied in this research.
1
Figure 4. H NMR spectra of (top) oct-β-Glc, (middle) a mixture of 3 and oct-
β-Glc, and (bottom) 3. Triangle indicate the terminal methyl protons of the
−
3
−3
octyl chains of oct-β-Glc. Conditions: 3 (3.0 × 10 M), oct-β-Glc (3.0 × 10
M), CDCl
3
, 23 °C, 300 MHz.
Figure 5. Results of titration experiment of 3 with oct-β-Glc. (A) Changes of
UV-vis spectrum of 3. (B) Titration curve of absorbance at 375 nm. The line is
6
−1
fitted curve assuming 1:1 binding, K = 5.0 × 10 M . (C) Changes of
a
−
6
−
6
fluorescent spectrum. Conditions: 3 (3.0 × 10 M), oct-β-Glc (0 to 9.0 × 10
M), DCE, 25 °C, path length = 10 mm. (D) Titration curve of fluorescence at
Association of 3 with octyl β-
Figure 3) was qualitatively studied on H NMR experiments
D
-glucopyranoside (oct-β-Glc,
6
−1
1
a
387 nm. The line is fitted curve assuming 1:1 binding, K = 3.5 × 10 M .
(
Figure 4). When the spectrum of a mixed solution of 3 and oct-
−
3
β-Glc ([3] = [oct-β-Glc] = 3.0 × 10 M) was compared to each
1
−3
−3
H NMR spectrum of 3 (3.0 × 10 M) and oct-β-Glc (3.0 × 10
3
M) in CDCl , it was found that the signals of C-H protons of the
pyranoside moiety in oct-β-Glc moved downfield by association
with 3. The signals of the O-H protons could not be specified in
the spectrum of the host-guest mixture because of overlapping
with the C-H signals and significant broadening. Interestingly,
even the signal of the terminal methyl protons of the octyl group
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Chemistry - A European Journal
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FULL PAPER
and S16 in Supporting Information). Association of 3 and oct-β-
−
1
Glc gave rise to the free-energy change of −37 ~ −38 kJmol ,
Table 1. Association Constants K
Glycoside Guests
a
of SPM Hosts 1a,b, 2, and 3 with
meaning that the one pair of the pyridine−phenol conjugate
played a role in the stabilization of more than 10 kJmol on the
[
a]
−1
average. Moreover, the entropic loss was much smaller in the
case of 3 compared with 1b, while the enthalpic gain is similar
between them. This suggests that the strong host ability of 3 is
secured by rigidity of the framework and pre-organization of the
hydrogen-bonding sites.
[
b]
−1
Host
Guest
K
a
/ M
Procedure / UV-vis
Fluorescence
[
c]
6
6
6
6
6
5
6
7
3
6
6
3
oct-α-Glc
(4.6 ± 1.5) × 10
(5.0 ± 2.2) × 10
(1.7 ± 0.5) × 10
(2.0 ± 1.3) × 10
(1.3 ± 0.3) × 10
(8.5 ± 2.3) × 10
(1.7 ± 0.5) × 10
(1.5 ± 0.4) × 10
(5.3 ± 0.2) × 10
(3.8 ± 3.2) × 10
oct-β-Glc
oct-β-Gal
(3.5 ± 1.4) × 10
Table 2. Thermodynamic parameters of association of hosts 3 and 1b with
oct-β-Glc.
[
d]
6
6
5
6
7
3
oct-β-Man
(5.2 ± 1.1) × 10
(1.5 ± 0.6) × 10
(4.5 ± 2.2) × 10
(1.4 ± 0.9) × 10
(3.4 ± 0.4) × 10
(7.0 ± 0.1) × 10
[
c]
[c]
ΔG
/
−
ΔH /
ΔS /
TΔS /
oct-β-Fru
Host
Guest
1
−1
−1
−1
−1
kJmol
kJmol
JK mol
kJmol
β-maltoside
oct-β-Glc
oct-β-Glc
oct-β-Glc
[
a]
3
oct-β-Glc
oct-β-Glc
−38
−21
−46
−50
−27
−97
−8
2
[b]
1
b
−29
[
e]
1a
−
6
−6
[
a] Conditions: [3] = 3.0 × 10 M, [oct-β-Glc] = 0 to 9.0 × 10 M, DCE, 15, 20,
−5
[
f]
25, and 30 °C, path length = 10 mm. [b] Conditions: [1b] = 1.0 × 10 M, [oct-
1b
−3
β-Glc] = 0 to 3.8 × 10 M, DCE, 15, 20, 25, and 30 °C, path length = 10 mm.
The titration curves and van't Hoff plots were shown in Figures S15 and S16 in
Supporting Information. [c] T = 298 K.
−
6
−6
[
a] Conditions: [3] = 3.0 × 10 , [guest] = 0 to 9.0 × 10 M, DCE, 25 °C, path
length = 10 mm. The changes of spectra and titration curves were shown in
Figure 5 and Figures S10−S14 and S17−18 in Supporting Information. [b]
Association constants were obtained by curve-fitting analyses assuming 1:1
binding for the change of absorbance at λmax and fluorescence intensity at
−
6
−5
F
max. [c] [3] = 5.0 × 10 M, [oct-α-Glc] = 0 to 1.5 × 10 M, CH Cl2, 25 °C,
2
−
6
−5
path length = 10 mm. [d] [3] = 5.0 × 10 , [oct-β-Man] = 0 to 2.5 × 10 M,
DCE 25 °C, path length = 10 mm. [e] From reference 9a. [f] [1b] = 1.0 ×
Association constant between tert-butyl groups-substituted 2
,
6
−1
−
5
−3
and oct-β-Glc could be obtained as K
titration (Figure S18 in Supporting Information). This value was a
little smaller than the K between 3 and oct-β-Glc, possibly
a
= 1.7 × 10 M by UV-vis
10
, [oct-β-Glc] = 0 to 3.8 × 10 M, DCE, 25 °C, path length = 10 mm.
a
because of the positive interaction between the octyl group of
oct-β-Glc and the triisopropylphenyl groups of 3 as suggested in
1
the above H NMR analyses (Figure 4). The less bulky host 4
1
also showed affinity with oct-β-Glc qualitatively in H NMR
measurements (Figure S19 in Supporting Information), however,
The results using a series of glycosides (Figure 3) as a guest
were summarized in Table 1. Various glycosides showed high K
values with 3. These values exceed those for the
corresponding acyclic hexameric analogue 1b (K
a
the strong self-association of
measurements.
4
prevented quantitative
K
a
3
a
= 5.3 × 10
−
1
Solid-liquid extraction experiments were performed by using
native hexose insoluble in apolar organic solvents. A solution of
M
with oct-β-Glc), and compete with those for acyclic
7
−1
[9a]
dodecameric 1a (K
a
= 1.5 × 10
M
with oct-β-Glc).
This
−
4
−6
3
(5.0 × 10 M, 1.5 × 10 mol) in CDCl
3
(3.0 mL) was shaken
means that the recognition efficiency could be improved by the
SPM framework. During these studies, no meaningful Cotton
effect appeared at the absorptive wavelength of 3. The structure
of 3 would be so rigid that the glycoside guests did not induce
chirality detectable by CD analyses. Therefore, above-
mentioned spectral changes caused by the glycoside addition
are most likely to be due to hydrogen bonding at the pyridine
and phenol rings and not to distortion of the rigid macrocyclic π-
framework.
with powdery -glucose for 10 h at room temperature, and the
D
mixture was filtered through a membrane filter to remove
1
insoluble residue. The H NMR spectrum of the filtrate showed
broad signals at a range of 3~6 ppm, which was supposed to be
those of glucose (Figure S20A in Supporting Information). The
amount of the extracted glucose was determined by back-
extraction with D
2
O followed by the addition of sodium 3-
(
trimethylsilyl)propane-1-sulfonate (DSS) as an internal
reference (Figure S20B in Supporting Information). The molar
concentration of glucose extracted in the filtrate was reckoned at
The thermodynamic study was carried out about the
recognition of oct-β-Glc by the cyclic hexamer 3 and the acyclic
counterpart 1b in order to evaluate the advantage of the pre-
−
6
1
.9 × 10 mol, 1.3 equiv to the applied host 3. When absorption
spectrum of the filtrate after the extraction was compared to that
of a solution of 3 in DCE, hypochromism was observed in ε
values at the bands around 282 and 348 nm (Figure S21 in
Supporting Information). When the filtrate was subjected to a
a
organization in 3. The association constants K of these cyclic
and acyclic hosts with oct-β-Glc were collected at 15, 20, 25,
and 30 °C in DCE, and the thermodynamic parameters were
calculated from the van't Hoff plots (Table 2, and Figures S15
−
7
dilution experiment to [3] = 9.8 × 10 M, the plot of absorbance
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Chemistry - A European Journal
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FULL PAPER
at 282 nm against [3] did not deviate from linearity probably
because the association of 3 with native glucose was too strong
to dissociate in DCE (Figure S22 in Supporting Information).
at the bottom of the CDCl
3
phase, and gently stirred for seven
days at room temperature. The amounts of transported hexoses
1
were determined by H NMR measurement of the resulting
−
4
D
-Mannose was also extracted (6.5 × 10 M, 1.3 equiv to 3)
receiving D
experiment, 1.8 × 10 mol of
mannose were transported. The membrane liquid phase can be
recycled with replacing source and receiving D O phases (Table
3). In each cycle, -mannose was transported more than
glucose, and the selectivity for -glucose: -mannose was
approximately 1:4. The control experiments in the absence of 3
showed no hexose transport. -Maltose could not be transported
2
O phase with DSS as an internal reference. In one
−
4
−5
−5
from a solid phase to a solution of 3 (5.0 × 10 M) in CDCl
3
,
D-glucose and 5.8 × 10 mol of D-
while -maltose could not. The difference probably resulted from
D
the size of the saccharides: the hole of 3 was not enough large
to accommodate disaccharide. Interestingly, when a mixture of
2
D
D-
D
-glucose and
D
-mannose (1:1) was applied to the solid-liquid
-mannose was selectively extracted.
Figure 6 showed the H NMR spectrum of the D O layer after
back-extraction from the CDCl filtrate of the mixture. Observed
D
D
extraction experiment,
D
1
2
D
3
by 3 as well as the case of solid-liquid extraction because of the
were the signals of anomeric protons of α- and β-mannose, and
were not those of α- and β-glucose. On the other hand, in
homogeneous conditions, host 3 bound with oct-β-Glc to oct-β-
Man comparably as shown in Table 1. This difference of
selectivity would be caused by the substituent at 1-position of
the guests, which might affect on the binding manner, and/or
caused by the stablity of solid glucose. In general glucose is less
size mismatch..
[
12]
soluble to polar media than mannose.
Figure 7. An apparatus for hexose transport through a membrane filter.
Table 3. Results of transport experiments by recycling a liquid membrane
[
a]
phase.
[
d]
Hexose transported
Ratio
24:76
18:82
24:76
Cycle
1
−5
−5
D
-Glucose / 10 mol
D
-Mannose / 10 mol
1
.8
5.8
[
b]
4.4
4.0
20
13
2
[
c]
3
[
a] The apparatus and the procedure of the experiment were described in
Figure 7 and the text. [b] After cycle 1, the D O phases were removed and
the liquid membrane phase was washed with D O and brought to the cycle
2. [c] After cycle 2, the D O phases were removed and the liquid membrane
2
2
1
2
Figure 6. H NMR spectra of (top)
D
-glucose in D
O layer back-extracted from the filtrate after solid-liquid
extraction experiment for a mixture of -glucose and -mannose. Extraction
procedure: a mixture of 3 (5.0 × 10 M), -glucose (10 mg), and -mannose
10 mg) in CDCl (2.0 mL) was stirred for 10 h at room temperature and
filtered through a membrane filter. The filtrate was subjected to back-extraction
2
O, (middle) D-mannose in
1
phase was brought to the cycle 3 without washing. [d] Evaluated with
NMR spectra using DSS as an internal reference.
H
2 2
D O, and (bottom) a D
D
D
−
4
D
D
(
3
1
2
with a D O (2.0 mL) layer, which was brought to H NMR measurement.
Conditions for NMR measurements: 24 °C, 400 MHz. Letters α and β indicate
anomeric C-H protons and dots indicate spinning side bands..
Conclusions
Transport experiment of hexoses through a liquid membrane
was executed with a U-tube apparatus. For a typical procedure,
In summary, we developed hexagonal SPM hosts consisted of
three pyridine and three phenol rings linked with acetylene
bonds. To inhibit self-aggregation of the host, bulky 2,4,6-
triisopropylphenyl groups were introduced on the phenol rings as
steric hindrance. The macrocyclic hosts efficiently recognized
alkyl hexosides such as glucoside and mannoside. The
a source D
mannose (each of 4.0 × 10 mol) and a receiving D
phase were laid on a liquid membrane CDCl (5.0 mL) phase
with 3 (5.0 × 10 M) as shown in Figure 7. A stirring bar was set
2
O (2.0 mL) phase with a mixture of
D
-glucose and
D-
−
3
2
O (2.0 mL)
3
−
4
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Chemistry - A European Journal
10.1002/chem.201603987
FULL PAPER
thermodynamic study revealed that the main advantage of the
macrocyclic host is an entropic factor in comparison with the
host of acyclic analogue. Native glucose and mannose could be
recognized by the macrocyclic host in heterogeneous conditions.
Solid-liquid extraction and liquid membrane experiments showed
the preference for mannose to glucose. Maltose and maltoside
were not or only weakly recognized by the macrocyclic host
because of the size-mismatch of the host with the disaccharide.
We confirmed the advantages of SPM structure for designing
host molecules and the thermodynamic differences between
macrocyclic and helical host structures. The investigation of
size-sensitive molecular recognition using other classes of
compounds than saccharides are underway.
100 MHz): δ 154.0, 147.7, 146.9, 136.6, 133.2, 130.9, 120.5, 114.8, 34.2,
3
1
3
0.2, 24.2, 24.1; IR (KBr): ν 3266 (br), 2965, 2930, 2868, 1515, 1459,
436 cm ; HRMS (ESI-TOF): m/z calcd for C21H28NaO [M + Na ]:
19.2038; found: 319.2047.
−
1
+
4
-Hydroxy-3,5-diiodo-2',4',6'-triisopropyldiphenyl (8)
To a solution of 7 (11 g, 37 mmol) in MeOH (300 mL) were added
subsequently H SO (11 g, 110 mmol), KI (18 g, 110 mmol), and H
30% aqueous solution, 12 mL, 150 mmol) at 0 °C. The mixture was
stirred for 40 h at room temperature, treated with aq NaHSO (0.2 M, 300
mL), and extracted with CHCl3 (150 mL). The organic layer was washed
with H O (100 mL), dried over Na SO , and concentrated with a rotary
2
4
2 2
O
(
3
2
2
4
evaporator to give 8 (20 g, 97%) as a colorless solid. This product was
1
found to be highly pure by H NMR and brought to the next step without
further purification. For analyses, it could be purified by silica gel column
1
chromatography (eluent: hexane/AcOEt = 10:1). M.p. 209−211 °C;
NMR (CDCl
septet, J = 6.7 Hz, 1 H), 2.59 (septet, J = 6.9 Hz, 2 H), 1.28 (d, J = 6.8
H
Experimental Section
3
, 400 MHz): δ 7.52 (s, 2 H), 7.02 (s, 2 H), 5.75 (s, 1 H), 2.91
(
1
13
13
General. H and C NMR spectra were collected on Varian GEMINI300
and JEOL ECX400 spectrometers by using tetramethylsilane (TMS) as
an internal reference. ESI-HRMS analyses were carried out on a JEOL
JMS-T100LC mass spectrometer by using MeOH solutions of the
analytes. IR, UV-vis, and fluorescence spectra were measured by
JASCO spectrometers FT/IR-460 plus, V-560, and FP-6500, respectively.
Melting points were measured on a Yanaco MP-500D apparatus and not
corrected. All reactions were carried out under an argon atmosphere.
THF was freshly distilled from sodium benzophenone ketyl before use.
Intermediate 4-octyloxy-2,6-diiodopyridine (15) was prepared by the
Hz, 6 H), 1.09 (d, J = 6.8 Hz, 12 H); C NMR (CDCl , 100 MHz): δ 152.1,
3
148.7, 146.8, 140.2, 137.0, 133.6, 120.7, 81.8, 34.3, 30.3, 24.13, 24.06;
−1
IR (KBr): ν 3459, 2957, 2925, 2865, 1459, 1445 cm ; HRMS (ESI-TOF):
+
m/z calcd for C21
27 2
H I O [M + H ]: 549.0151; found: 549.0176.
3
,5-Diiodo-4-(methoxymethoxy)-2',4',6'-triisopropyldiphenyl (9)
To a solution of 8 (20 g, 36 mmol) and MOMCl (15 g, 180 mmol) in
CH Cl (200 mL) was added i-Pr NEt (19 g, 140 mmol) at 0 °C. The
2
2
2
mixture was stirred for 30 min at that temperature and allowed to room
temperature. The resulting reaction mixture was neutralized with
[7]
procedure we previously reported.
saturated aq NaHCO
was dried over Na SO
(21 g, 97%) as a colorless solid. This product was found to be highly
3
(100 mL) and washed with brine. The organic layer
2
,4,6-Triisopropyl-4'-methoxydiphenyl (6)
2
4
and concentrated with a rotary evaporator to give
9
1
To a mixture of Pd(OAc)
mmol) in toluene (200 mL) were added K
methoxyphenylboronic acid (5, 9.1 g, 60 mmol), and 2-bromo-1,3,5-
triisopropylbenzene (11 g, 40 mmol). The mixture was stirred under reflux
for 13 h, allowed to room temperature, and filtered through a Florisil bed.
The filtrate was concentrated with a rotary evaporator and subjected to
2
(90 mg, 0.40 mmol) and SPhos (330 mg, 0.80
PO (13 g, 80 mmol), 4-
pure by H NMR and brought to the next step without further purification.
For analyses, it could be purified by silica gel column chromatography
3
4
1
(eluent: CH Cl ). M.p. 229−232 °C; H NMR (CDCl , 400 MHz): δ 7.64 (s,
2
2
3
2 H), 7.02 (s, 2 H), 5.23 (s, 2 H), 3.80 (s, 3 H), 2.91 (septet, J = 6.9 Hz, 1
H), 2.55 (septet, J = 6.9 Hz, 2 H), 1.28 (d, J = 7.2 Hz, 6 H), 1.09 (d, J =
13
6.8 Hz, 12 H); C NMR (CDCl , 100 MHz): δ 155.0, 148.8, 146.5, 141.1,
3
silica gel column chromatography (eluent: CHCl
give 6 (12 g, 97%) as a colorless solid. M.p. 105−107 °C; H NMR
CDCl , 400 MHz): δ 7.09 (d, J = 8.4 Hz, 2 H), 7.04 (s, 2 H), 6.93 (d, J =
.8 Hz, 2 H), 3.86 (s, 3 H), 2.94 (septet, J = 7.0 Hz, 1 H), 2.64 (septet, J
3
/hexane = 1:10 to 1:5) to
140.9, 133.4, 120.7, 100.2, 90.8, 58.9, 34.3, 30.3, 24.2, 24.0; IR (KBr): ν
1
−1
2958, 2923, 2865, 1462, 1432 cm ; HRMS (ESI-TOF): m/z calcd for
+
(
8
=
3
C23H
I NaO [M + H ]: 615.0233; found: 615.0246.
30 2
13
7.0 Hz, 2 H), 1.30 (d, J = 6.8 Hz, 6 H), 1.08 (d, J = 7.2 Hz, 12 H);
, 100 MHz): δ 158.1, 147.7, 146.9, 136.7, 132.9, 130.7,
20.5, 113.3, 55.2, 34.2, 30.2, 24.2, 24.1; IR (KBr): ν 2956, 2867, 2831,
515, 1467 cm ; HRMS (ESI-TOF): m/z calcd for C22H31O [M + H ]:
11.2375; found: 311.2378.
C
4
-(Methoxymethoxy)-3,5-bis(trimethylsilylethynyl)-2',4',6'-
NMR (CDCl
3
triisopropyldiphenyl (10)
1
1
3
−1
+
A mixture of THF (200 mL) and i-Pr
2
NH (200 mL) was bubbled with argon
CO (4.7 g, 34 mmol),
(5.0 g, 8.4 mmol),
trimethylsilyl)acetylene (TMSA, 5.0 g, 51 mmol), and CuI (32 mg, 0.17
for 30 min, and to this mixture were added K
PdCl (PPh (0.59 g, 0.84 mmol),
2
3
2
3
)
2
9
4
-Hydroxy-2',4',6'-triisopropyldiphenyl (7)
(
mmol) at room temperature. The reaction mixture was stirred for 30 min
at room temperature and additionally stirred for 16 h under reflux. The
resulting mixture was filtered through a Florisil bed, concentrated with a
rotary evaporator, and subjected to silica gel column chromatography
(eluent: hexane/CHCl3 = 20:1 to 5:1) to give 10 (4.4 g, 97%) as a yellow
BBr
CH
temperature with stirring for 5 h and quenched by the addition of
saturated aq NaHCO (50 mL). The organic layer was washed with brine,
dried over Na SO , and concentrated with a rotary evaporator to give 7
11 g, 96%) as a colorless solid. This product was found to be highly pure
3
(19 g, 77 mmol) was added to a solution of 6 (12 g, 39 mmol) in
Cl (75 mL) at −80 °C. This solution was allowed to room
2
2
3
1
2
4
solid. M.p. 163−165 °C; H NMR (CDCl , 400 MHz): δ 7.23 (s, 2 H), 7.02
3
(
(s, 2 H), 5.43 (s, 2 H), 3.75 (s, 3 H), 2.91 (septet, J = 6.9 Hz, 1 H), 2.59
1
by H NMR and brought to the next step without further purification. For
(septet, J = 6.9 Hz, 2 H), 1.28 (d, J = 6.8 Hz, 6 H), 1.09 (d, J = 6.8 Hz, 12
13
analyses, it could be purified by silica gel column chromatography
H), 0.23 (s, 18 H); C NMR (CDCl , 100 MHz): δ 158.6, 148.4, 146.7,
3
1
(
eluent: hexane/AcOEt = 10:1). M.p. 173−175 °C; H NMR (CDCl
3
, 400
136.4, 135.5, 134.6, 120.6, 117.3, 101.1, 99.2, 99.0, 57.7, 34.3, 30.2,
−1
MHz): δ 7.04 (s, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H),
24.3, 24.1, −0.18; IR (KBr): ν 2959, 2927, 2868, 2156, 1456, 1436 cm ;
+
4
1
.74 (s, 1 H), 2.93 (septet, J = 7.0 Hz, 1 H), 2.64 (septet, J = 6.9 Hz, 2 H),
2 2
HRMS (ESI-TOF): m/z calcd for C33H49O Si [M + H ]: 533.3271; found:
13
.30 (d, J = 7.2 Hz, 6 H), 1.07 (d, J = 6.8 Hz, 12 H); C NMR (CDCl
3
,
533.3257.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201603987
FULL PAPER
3
,5-Diethynyl-4-(methoxymethoxy)-2',4',6'-triisopropyldiphenyl (11)
3-((tert-Butyldimethylsilyl)ethynyl)-5-ethynyl-4-(methoxymethoxy)-
2
',4',6'-triisopropyldiphenyl (14)
To a mixture of 10 (1.5 g, 2.8 mmol), THF (72 mL), and H
was added Bu NF (TBAF, 1.0 M in THF, 8.4 mL, 8.4 mmol) at 0 °C, and
this mixture was allowed to room temperature with stirring for 50 min.
The resulting mixture was washed with brine, dried over Na SO
concentrated with a rotary evaporator, and subjected to silica gel column
chromatography to give 11 (1.0 g, 91%) as a colorless solid. M.p.
2
O (1.0 mL)
4
A solution of 13 (1.7 g, 3.0 mmol) in toluene (200 mL) was heated to
120 °C using a Dean-Stark apparatus. Keeping that temperature, ground
NaOH (0.18 g, 4.4 mmol) was added to this solution, which was stirred
for 1 h, and ground NaOH (0.088 g, 2.2 mmol) was added again to the
solution. The reaction mixture was additionally stirred for 30 min at
120 °C and filtered after cooling to room temperature. The filtrate was
concentrated with a rotary evaporator and subjected to silica gel column
2
4
,
1
1
5
2
99−202 °C; H NMR (CDCl
3
, 400 MHz): δ 7.29 (s, 2 H), 7.03 (s, 2 H),
.44 (s, 2 H), 3.73 (s, 3 H), 3.28 (s, 2 H), 2.92 (septet, J = 6.9 Hz, 1 H),
.57 (septet, J = 6.9 Hz, 2 H), 1.29 (d, J = 6.8 Hz, 6 H), 1.09 (d, J = 6.4
Hz, 12 H); C NMR (CDCl
chromatography (eluent: hexane/AcOEt = 70:1) to give 14 (1.2 g, 84%)
13
1
3
, 100 MHz): δ 153.7, 148.5, 146.7, 139.1,
as a yellow solid. M.p. 102−106 °C; H NMR (CDCl
3
, 400 MHz): δ
1
2
36.6, 136.0, 134.4, 120.7, 116.5, 99.4, 81.8, 79.8, 64.6, 57.8, 34.3, 30.2,
7.28−7.26 (m, 2 H), 7.04 (s, 2 H), 5.45 (s, 2 H), 3.73 (s, 3 H), 3.25 (s, 1
H), 2.92 (septet, J = 6.8 Hz, 1 H), 2.66−2.55 (m, 2 H), 1.29 (d, J = 7.2 Hz,
6 H), 1.11−1.08 (m, 12 H), 0.98 (s, 9 H), 0.17 (s, 6 H) (A small amount of
−1
4.2, 24.1; IR (KBr): ν 3268, 2961, 2926, 2869, 1464, 1436 cm ; HRMS
+
(
2
ESI-TOF): m/z calcd for C27H32NaO [M + Na ]: 411.2300; found:
13
4
11.2317.
impurity was observed); C NMR (CDCl
1
8
3
, 100 MHz): δ 160.7, 150.6,
48.8, 138.2, 137.6, 122.8, 122.7, 119.4, 118.6, 103.6, 101.3, 100.0,
3.6, 59.9, 36.4, 32.3, 28.2, 26.4, 26.35, 26.28, 26.2, 18.8, −2.6 (A small
3
2
-(3-Hydroxy-3-methyl-1-butynyl)-5-iodo-4-(methoxymethoxy)-
',4',6'-triisopropyldiphenyl (12)
amount of impurity was observed); IR (KBr): ν 3270, 2960, 2928, 2866,
−
1
2
+
153, 1464, 1435 cm ; HRMS (ESI-TOF): m/z calcd for C30
H
38NaO
3
[M
+
Na ]: 525.3165; found: 525.3164.
A mixture of THF (300 mL) and i-Pr
for 30 min, and to this mixture were added 9 (15 g, 25 mmol), K
g, 100 mmol), Pd(PPh (2.9 g, 2.5 mmol), CuI (96 mg, 0.51 mmol), and
-methyl-3-butyn-2-ol (1.5 g, 18 mmol). The reaction mixture was stirred
2
NH (300 mL) was bubbled with argon
2
CO (14
3
I-pyridine-(MOM-phenol)-pyridine-I Trimer 16
3 4
)
3
for 30 min at room temperature and then additionally stirred for 14 h
under reflux. The resulting mixture was filtered through a Florisil bed,
concentrated with a rotary evaporator, and subjected to silica gel column
A mixture of THF (37 mL) and i-Pr
2
NH (37 mL) was bubbled with argon
for 30 min, and to this mixture were added 2,6-diiodo-4-
[7]
(octyloxy)pyridine (15, 2.5 g, 5.3 mmol), Pd(PPh
3 4
) (0.52 g, 0.45 mmol),
chromatography (eluent: hexane/CHCl
6%) as a reddish brown solid. M.p. 45−47 °C; H NMR (CDCl
MHz): δ 7.60 (d, J = 1.6 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.03 (s, 2 H),
3
= 2:1 to CHCl
3
) to give 12 (6.4 g,
K
2
CO (0.49 g, 3.6 mmol), and 11 (0.35 g, 0.89 mmol). The reaction
3
1
6
3
, 400
mixture was stirred for 16 h under reflux and filtered through a Florisil bed.
The filtrate was concentrated with a rotary evaporator and subjected to
silica gel column chromatography (eluent: hexane/AcOEt = 40:1 to 5:1) to
give recovered 15 and product 16 (0.61 g, 65%) as a yellow oil. H NMR
3
(CDCl , 400 MHz): δ 7.37 (s, 2 H), 7.21 (d, J = 2.0 Hz, 2 H), 7.04 (s, 2 H),
6.99 (d, J = 2.4 Hz, 2 H), 5.51 (s, 2 H), 3.98 (t, J = 6.6 Hz, 4 H), 3.76 (s, 3
H), 2.93 (septet, J = 7.0 Hz, 1 H), 2.58 (septet, J = 6.8 Hz, 2 H),
1.82−1.75 (m, 4 H), 1.45−1.29 (m, 26 H), 1.09 (d, J = 6.8 Hz, 12 H), 0.89
5
.36 (s, 2 H), 3.77 (s, 3 H), 2.92 (septet, J = 6.9 Hz, 1 H), 2.57 (septet, J
1
=
6.8 Hz, 2 H), 2.43 (s, 1 H), 1.28 (d, J = 6.8 Hz, 6 H), 1.11−1.08 (m, 12
13
H); C NMR (CDCl
3
, 100 MHz): δ 156.4, 148.6, 146.5, 140.8, 138.3,
35.0, 134.1, 120.6, 116.2, 99.5, 99.0, 91.7, 78.2, 65.6, 58.5, 34.3, 31.2,
0.2, 24.19, 24.16, 24.0; IR (KBr): ν 3420 (br), 2960, 2925, 2867, 1457,
436 cm ; HRMS (ESI-TOF): m/z calcd for C28H37INaO [M + Na ]:
3
71.1685; found: 571.1709.
1
3
1
5
−1
+
13
(t, J = 6.6 Hz, 6 H); C NMR (CDCl
3
, 100 MHz): δ 165.0, 158.6, 148.5,
46.6, 144.2, 136.9, 136.0, 134.2, 120.61, 120.59, 117.9, 116.5, 114.1,
9.7, 91.8, 86.1, 68.7, 58.0, 34.3, 31.7, 30.3, 29.2, 29.1, 28.7, 25.8, 24.2,
1
9
2
3
4
-((tert-Butyldimethylsilyl)ethynyl)-5-(3-hydroxy-3-methyl-1-butynyl)-
-(methoxymethoxy)-2',4',6'-triisopropyldiphenyl (13)
−1
4.0, 22.6, 14.1; IR (KBr): ν 2958, 2926, 2854, 2219, 1576, 1533 cm
;
+
69 2 2 4
HRMS (ESI-TOF): m/z calcd for C53H I N O [M + H ]: 1051.3347;
found: 1051.3321.
A mixture of THF (50 mL) and i-Pr
for 30 min, and to this mixture were added subsequently K
6 mmol), Pd(PPh (0.37 g, 0.32 mmol), a solution of 12 (3.5 g, 6.4
2
NH (60 mL) was bubbled with argon
2
CO (3.6 g,
3
TBSA-(MOM-phenol)-pyridine-(MOM-phenol)-TBSA Trimer 17
2
3 4
)
mmol) in THF (10 mL), CuI (25 mg, 0.13 mmol), and (tert-
butyldimethylsilyl)acetylene (TBSA, 3.6 g, 26 mmol). The reaction
mixture was stirred for 30 min at room temperature and additionally
stirred for 13 h under reflux. The resulting mixture was filtered through a
Florisil bed, concentrated with a rotary evaporator, and subjected to silica
A mixture of THF (100 mL) and i-Pr
for 30 min, and to this mixture were added 15 (0.31 g, 0.68 mmol),
Pd(PPh (79 mg, 0.068 mmol), K CO (0.38 g, 2.7 mmol), CuI (2.6 mg,
2
NH (100 mL) was bubbled with argon
3
)
4
2
3
0.014 mmol), and 14 (1.4 g, 2.7 mmol). The reaction mixture was stirred
gel column chromatography (eluent: hexane/CHCl
3
= 1:1) to give 13 (3.2
g, 89%) as a yellow solid. M.p. 62-65 °C; H NMR (CDCl , 400 MHz): δ
.23 (d, J = 2.4 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 7.03 (s, 2 H), 5.43 (s,
for 30 min at room temperature and additionally stirred for 13 h under
reflux. The resulting mixture was filtered through a Florisil bed,
concentrated with a rotary evaporator, and subjected to silica gel column
1
3
7
2
2
0
H), 3.75 (s, 3 H), 2.92 (septet, J = 6.9 Hz, 1 H), 2.59 (septet, J = 6.7 Hz,
H), 1.28 (d, J = 7.2 Hz, 6 H), 1.09 (d, J = 7.2 Hz, 12 H), 0.98 (s, 9 H),
chromatography (eluent: hexane/AcOEt = 50:1 to 20:1) to give 17 (0.81 g,
1
87%) as a colorless solid. M.p. 88−90 °C; H NMR (CDCl
3
, 400 MHz): δ
13
.17 (s, 6 H) (A small amount of impurity was observed); C NMR
, 100 MHz): δ 157.8, 148.4, 146.7, 146.4, 136.4, 135.5, 135.1,
7.33 (d, J = 1.6 Hz, 2 H), 7.28 (d, J = 2.4 Hz, 2 H), 7.03 (s, 4 H), 6.99 (s,
2 H), 5.50 (s, 4 H), 4.01 (t, J = 6.4 Hz, 2 H), 3.75 (s, 6 H), 2.92 (septet, J
= 6.9 Hz, 2 H), 2.60 (septet, J = 6.8 Hz, 4 H), 1.82−1.78 (m, 2 H),
1.46−1.41 (m, 2 H), 1.37−1.26 (m, 20 H), 1.10−1.07 (m, 24 H), 0.98 (s,
(CDCl
3
1
3
34.7, 120.6, 117.3, 116.8, 101.7, 99.1, 98.2, 97.6, 78.5, 65.7, 57.8, 34.3,
1.3, 30.22, 30.19, 26.1, 24.3, 24.24, 24.21, 24.19, 24.1, 16.7, −4.68; IR
−1
(
KBr): ν 3446 (br), 2959, 2930, 2859, 2155, 2115, 1456, 1436 cm
;
18 H), 0.89 (t, J = 6.2 Hz, 3 H), 0.17 (s, 6 H) (A small amount of impurity
+
13
HRMS (ESI-TOF): m/z calcd for C36
H
52NaO
3
Si [M + Na ]: 583.3583;
3
was observed); C NMR (CDCl , 100 MHz): δ 158.4, 146.7, 144.7, 136.5,
found: 583.3606.
136.4, 135.3, 134.5, 130.9, 120.6, 117.3, 116.6, 113.3, 101.5, 99.3, 97.9,
9
2
2.4, 85.4, 57.9, 34.3, 31.8, 30.2, 29.2, 26.1, 26.0, 25.9, 24.3, 24.2, 24.1,
2.6, 16.7, 14.1, −4.7; IR (KBr): ν 2958, 2928, 2858, 2218, 2156, 1581,
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−
1
1
550, 1456 cm ; HRMS (ESI-TOF): m/z calcd for C79
H
110NO
5
Si
2
[M +
120.5, 112.7, 109.5, 93.3, 68.5, 34.3, 31.7, 30.3, 29.7, 29.24, 29.19,
+
H ]: 1208.7923; found: 1208.7955.
Ethynyl-(MOM-phenol)-pyridine-(MOM-phenol)-ethynyl Trimer 18
To a mixture of 17 (0.70 g, 0.58 mmol), THF (80 mL), and H O (1.0 mL)
29.16, 28.7, 25.8, 24.4, 24.2, 24.1, 22.6, 14.1; IR (KBr): ν 3446 (br), 2959,
−
1
2
926, 2867, 2217, 1583, 1550, 1464 cm ; HRMS (ESI-TOF): m/z calcd
+
135 3 6
for C114H N O [M + H ]: 1644.0435; found: 1644.0462.
2
was added TBAF (1.0 M in THF, 1.2 mL, 1.2 mmol) at 0 °C, and this
mixture was stirred for 30 min at 0 °C, allowed to room temperature, and
additionally stirred for 2.5 h at room temperature. The resulting mixture
was quenched with brine and extracted with AcOEt (50 mL × 2). The
Acknowledgements
The authors thank Mr. Hisao Kawasumi for preliminary study of
these host molecules. This work was supported by JSPS
Kakenhi Grant Number JP24350066.
combined AcOEt layer was dried over Na
rotary evaporator, and subjected to silica gel column chromatography
eluent: hexane/AcOEt = 20:1) to give 18 (0.57 g, 100%) as a pale yellow
2 4
SO , concentrated with a
(
1
solid. M.p. 77−80 °C; H NMR (CDCl
H), 7.30 (d, J = 2.4 Hz, 2 H), 7.03 (s, 4 H), 6.99 (s, 2 H), 5.49 (s, 4 H),
.02 (t, J = 6.6 Hz, 2 H), 3.75 (s, 6 H), 3.28 (s, 2 H), 2.92 (septet, J = 7.0
Hz, 2 H), 2.58 (septet, J = 6.9 Hz, 4 H), 1.82−1.78 (m, 2 H), 1.48−1.41 (m,
H), 1.38−1.27 (m, 20 H), 1.09−1.07 (m, 24 H), 0.89 (t, J = 7.0 Hz, 3 H)
3
, 400 MHz): δ 7.36 (d, J = 2.0 Hz, 2
Keywords: Host-guest systems • Macrocycles • Glycosides •
Hydrogen bonds •Shape-persistent macrocycles
4
[1]
Recent reviews and accounts for shape-persistent acetylenic
2
13
macrocycles: a) K. S. Merry, Š. M. Ognjen, Org. Biomol. Chem. 2015,
(
A small amount of t-BuMe
2 3
SiOH was observed); C NMR (CDCl , 100
13, 7841–7845; b) M. Iyoda, H. Shimizu, Chem. Soc. Rev. 2015, 44,
6411−6424; c) B. Gong, Z. Shao, Acc. Chem. Res. 2013, 46,
2856−2866; d) M. Iyoda, J. Yamakawa, M. J. Rahman, Angew. Chem.
MHz): δ 165.3, 158.7, 148.5, 146.6, 144.6, 136.7, 136.3, 135.7, 134.3,
1
2
20.6, 116.6, 113.4, 99.5, 92.6, 85.2, 81.8, 79.8, 57.9, 34.3, 31.8, 30.2,
9.23, 29.18, 28.8, 25.9, 24.24, 24.19, 24.0, 22.6, 14.1 (A small amount
Int. Ed. 2011, 50, 10522−10553; Angew. Chem. 2011, 123,
10708−10740; e) K. Tahara,S. B. Lei, J. Adisoejoso, S. De Feyter, Y.
Tobe, Chem. Commun. 2010, 46, 8507−8525; f) W. Zhang, J. S. Moore,
Angew. Chem. Int. Ed. 2006, 45, 4416−4439; Angew. Chem. 2006, 118,
of t-BuMe
2
SiOH was observed); IR (KBr): ν 3275, 2960, 2926, 2869,
−1
2
220, 1581, 1550, 1458 cm
;
HRMS (ESI-TOF): m/z calcd for
+
67 5
C H82NO [M + H ]: 980.6193; found: 980.6144.
4
524−4548; g) S. Höger, In Acetylene Chemistry (Eds. F. Diederich, P.
3
-MOM
J. Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, 2005, pp. 428−452.
h) S. Höger, Angew. Chem. Int. Ed. 2005, 44, 3806−3808; Angew.
Chem. 2005, 117, 3872−3875; i) S. Höger, Chem. Eur. J. 2004, 10,
A mixture of THF (270 mL) and i-Pr
for 30 min. To this mixture were added K
Pd(PPh (12 mg, 0.010 mmol), and 16 (0.11 mg, 0.10 mmol), and the
mixture was stirred for 10 h at room temperature. After the addition of CuI
0.38 mg, 0.0020 mmol), a solution of 18 (0.10 g, 0.10 mmol) in THF (40
2
NH (310 mL) was bubbled with argon
2
CO (56 mg, 0.41 mmol),
3
1320–1329; j) D. H. Zhao, J. S. Moore, Chem. Commun. 2003,
3 4
)
807−818.
[
2]
Examples of host-guest association within the shape-persistent
(
macrocyclic structures: a) C. Yu, Y. Jin, W. Zhang, Chem. Rec. 2015,
mL) was added to the mixture dropwise during 1.5 h. The reaction
mixture was stirred for 14 h under reflux, filtered through a Florisil bed,
concentrated with a rotary evaporator, and subjected to silica gel column
chromatography (eluent: hexane/CHCl
chromatography (Shodex K-2001 and Shimadzu Shim-pack K-2002,
eluent: CHCl ) to give 3-MOM (40 mg, 22%) as a yellow solid. M.p.
15, 97−106; b) J. Cai, J. L. Sessler, Chem. Soc. Rev. 2014, 43,
6
198−6213; c) D. Xiao, D. Zhang, B. Chen, D. Xie, Y. Xiang, X. Li, W.
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Belyakov, O. Daugulis, S. E. Wheeler, O. Š. Miljanic, Chem. Eur. J.
3
= 2:1) and gel permeation
2015, 21, 2750−2754; e) H. Youzhou, X. Min, G. Rongzhao, L. Xiaowei,
3
1
L. Fengxue, W. Xuedan, X. Dingguo, Z. Huaqiang, Y. Lihua, Angew.
Chem. Int. Ed. 2014, 53, 11834−11839; Angew. Chem. 2014, 126,
1
6
48−150 °C; H NMR (CDCl
.94 (s, 6 H), 5.73 (s, 6 H), 4.05 (s, 9 H), 4.00 (t, J = 6.6 Hz, 6 H), 2.94
3
, 400 MHz): δ 7.37 (s, 6 H), 7.06 (s, 6 H),
1
2028−12033; f) Y. Hosokawa, T. Kawase, M. Oda, Chem. Commun.
(
septet, J = 6.9 Hz, 3 H), 2.67 (septet, J = 7.0 Hz, 6 H), 1.80−1.74 (m, 6
2001, 1948−1949; g) Y. Tobe, N. Utsumi, A. Nagano, K. Naemura,
H), 1.44−1.40 (m, 6 H), 1.40−1.25 (m, 42 H), 1.13 (d, J = 6.4 Hz, 36 H),
Angew. Chem. Int. Ed. 1998, 37, 1285−1287; Angew. Chem. 1998, 110,
13
0
1
6
2
3
.87 (t, J = 6.8 Hz, 9 H); C NMR (CDCl , 100 MHz): δ 165.0, 160.0,
48.5, 146.8, 144.7, 135.5, 134.6, 120.6, 117.0, 112.9, 100.2, 93.2, 84.8,
8.4, 58.6, 34.3, 31.8, 30.3, 29.21, 29.18, 28.8, 25.8, 24.3, 24.10, 24.07,
2.6, 14.1; IR (KBr): ν 2958, 2925, 2866, 2220, 1582, 1550, 1457 cm
1347–1349; h) D. L. Morrison, S. Höger, Chem. Commun. 1996,
2313−2314.
[
3]
4]
Saccharide recognition by SPM hosts consisted of butadiyne-
binaphthylene macrocycles: a) A. Bahr, A. S. Droz, M. Puntener, U.
Neidlein, S. Anderson, P. Seiler, F. Diederich, Helv. Chim. Acta 1998,
−1
;
+
147 3 9
HRMS (ESI-TOF): m/z calcd for C120H N O [M + H ]: 1776.1275;
found: 1776.1249.
8
1, 1931−1963; b) S. Anderson, U. Neidlein, V. Gramlich, F. Diederich,
Angew. Chem. Int. Ed. Engl. 1995, 34, 1596−1600; Angew. Chem.
995, 107, 1722–1725.
3
1
[
Polycyclic cyclophanes have been investigated as efficient hosts for
hexose and hexosyl recognition: a) P. Rios, T. S. Carter, T. J.
Mooibroek, M. P. Crump, M. Lisbjerg, M. Pittelkow, N. T. Supekar, G. J.
Boons, A. P. Davis, Angew. Chem. Int. Ed. 2016, 55, 3387−3392;
Angew. Chem. 2016, 128, 3448−3453; b) C. Ke, H. Destecroix, M. P.
Crump, A. P. Davis, Nat. Chem. 2012, 4, 718–723; c) B.
Sookcharoenpinyo, E. Klein, Y. Ferrand, D. B. Walker, P. R.
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2012, 51, 4586–4590; Angew. Chem. 2012, 124, 4664–4668; d) G.
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To a solution of 3-MOM (0.18 mg, 0.10 mmol) in CH
added trifluoroacetic acid (TFA, 3.5 mL) at 0 °C. The mixture was stirred
for 2 h at that temperature, then neutralized with saturated aq NaHCO
washed with brine, and dried over Na SO . The organic layer was
concentrated with a rotary evaporator and subjected to silica gel column
chromatography (eluent: hexane/CHCl = 1:2) to afford 3 (165 mg, 100%)
2 2
Cl (70 mL) was
3
,
2
4
3
1
as a yellow solid. M.p. 230 °C (dec); H NMR (CDCl
s, 6 H), 7.06 (s, 6 H), 6.95 (s, 6 H), 4.02 (t, J = 6.4 Hz, 6 H), 2.94 (septet,
J = 6.8 Hz, 3 H), 2.72 (septet, J = 6.9 Hz, 6 H), 1.83−1.74 (m, 6 H),
.45−1.26 (m, 48 H), 1.13 (d, J = 6.8 Hz, 36 H), 0.87 (t, J = 6.6 Hz, 9 H);
3
, 400 MHz): δ 7.31
(
1
13
C NMR (CDCl , 100 MHz): δ 165.4, 148.3, 147.0, 144.2, 135.4, 135.0,
3
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Klein, N. P. Barwell, M. P. Crump, J. Jiménez-Barbero, C. Vicent, G.-J.
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211−4217. See also references 8g, 8h, 8j.
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[
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Entry for the Table of Contents
FULL PAPER
Grasp
Hexose:
D3h-Symmetrical
Hajime Abe,* Tetsuhiro Yoneda, Yuki
Ohishi, and Masahiko Inouye*
shape-persistent macrocycles (SPMs)
were developed as a synthetic host for
saccharide recognition. They con-
sisted of phenol−acetylene−pyridine
structure, and steric hindrance was
introduced on them to prevent self-
aggregation. Strong affinity for alkyl
hexosides such as glucoside and
mannoside was shown in organic
solvent. In addition, solid-liquid
extraction and liquid-liquid transport of
native hexoses could be performed.
Page No. – Page No.
D
3h-Symmetrical Shape-Persistent
Macrocycles Consisting of Pyridine–
Acetylene–Phenol Conjugates as an
Efficient Host Architecture for
Saccharide Recognition
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