Recognition properties of receptors based on dimesitylmethane-derived core: Di- vs. monosaccharide preference

Article abstract of DOI:10.1039/b901173k

Dimesitylmethane-derived receptors 12 and 13, incorporating four heterocyclic recognition groups capable of serving as hydrogen bonding sites, were designed to recognize disaccharides. It has been shown by ¹H NMR and fluorescence spectroscopic

Full text of DOI:10.1039/b901173k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Recognition properties of receptors based on dimesitylmethane-derived core:
Di- vs. monosaccharide preference†
Monika Mazik* and Arno C. Buthe
Received 20th January 2009, Accepted 2nd March 2009
First published as an Advance Article on the web 23rd March 2009
DOI: 10.1039/b901173k
Dimesitylmethane-derived receptors 12 and 13, incorporating four heterocyclic recognition groups
capable of serving as hydrogen bonding sites, were designed to recognize disaccharides. It has been
shown by 1H NMR and fluorescence spectroscopic titrations that compounds 12 and 13 display high
binding affinities toward a- and b-maltoside, as well as strong di- vs monosaccharide preference in
organic media. Both hydrogen-bonding and interactions of the sugar CH’s with the phenyl rings of the
receptor contribute to the stabilisation of the receptor–sugar complexes, as indicated by experimental
data and molecular modeling calculations.
R = H) was able to form 1 : 1 complexes with disaccharides, such as
octyl b-maltoside 1a (K11 = 11000 M-1 in CD3CN/CD3OD, 88 : 12
v/v), whereas the smaller monosaccharides were not significantly
bound.6a,b The four phosphodiester groups of the receptor con-
verge towards the binding cavity, which is complementary in size
to one disaccharide, and provide efficient bidentate ionic hydrogen
bond acceptor sites. The incorporation of two methyl carboxylate
groups into the receptor structure (Fig. 2a, R = CO2CH3) further
enhanced the disaccharide binding affinity by additional hydrogen
bonding interactions.6b
The potential of biphenyl- and terphenyl-based macrocyclic
receptors for the recognition of mono- and oligosaccharides has
been explored by Davis et al. (see, for example Fig. 2b).3g,3h,6c The
receptors were designed to provide both apolar and polar contacts
to a sugar molecule. A terphenyl-based macrotricycle was shown
to be an effective receptor for the all-equatorial octyl b-cellobioside
2a (see Fig. 3).6c In contrast, the biphenyl-based macrotetracyclic
receptor, shown in Fig. 2b, complexed the dodecyl b-maltoside 1b
more strongly (K11 = 780 M-1 in CHCl3/CH3OH, 75 : 25) than the
octyl b-cellobioside 2a (K11 = 310 M-1).3g More recently, a water-
soluble meta-terphenyl-based tetracyclic receptor was developed
to target all-equatorial disaccharides such as cellobiose.3h The
receptor showedgood affinities (for example, methylb-cellobioside
2b was bound with K11 ~ 900 M-1) and remarkable selectivities for
its chosen substrate in aqueous solutions.
Introduction
The selective recognition of carbohydrates with artificial receptors
employing noncovalent interactions remains a challenging goal of
artificial receptor chemistry.1–4 Subtle variations in the sugar struc-
tures and the three-dimensional arrangement of their functionality
make carbohydrates complicated targets for such recognition;
particularly, the neutral carbohydrates are especially challenging
substrates to recognize.1–3 The design of carbohydrate receptors is
often inspired by the binding motifs found in the crystal structures
of protein–carbohydrate complexes5 (for example, see Fig. 1). In
particular, many representatives of hydrogen bonding receptors
have been prepared and studied. Most of the described binding
studies involve the complexation of monosaccharides, whereas the
oligosaccharides have received far less attention.6–8 Although some
receptors show interesting oligo- vs. monosaccharides preference,
the selective recognition of oligosaccharides by receptors using
noncovalent interactions is still rare.6
Cyclic porphyrin–cryptand conjugates were investigated as
receptors for mono-, di- and trisaccharides by Schmidtchen et al.
The cyclic receptors showed selective binding of saccharides
in water solution, revealing a trend increasing from mono- to
trisaccharide.6d
Our studies showed that acyclic receptors 6–93i,3q,9b based on
a trimethyl- or triethylbenzene scaffold10 (see Fig. 4) are able to
recognise both mono- and disaccharides, with a strong preference
for the disaccharides. In contrast, the symmetrical receptor 10,
incorporating three heterocyclic groups capable of serving as
hydrogen bonding sites, was shown to be able to form strong
complexes with both mono- and disaccharides3q,9b (see Table 1).
Comparison of the binding properties of 10 with those of the
receptors 6–9 reveals that the replacement of heterocyclic groups
by phenyl-based recognition units results in a substantial drop in
Fig.
1
Examples of hydrogen bonds in the complexes of (a)
D-galactose-binding protein with D-glucose, and (b) L-arabinose-binding
protein with L-arabinose.5b
Diederich et al. had shown that optically active, 1,1¢-binaphthyl-
derived cyclophane receptor with a preorganized central cavity
lined with four anionic phosphodiester groups (see Fig. 2a,
Institut fu¨r Organische Chemie der Technischen Universita¨t Braunschweig,
Hagenring 30, 38106, Braunschweig, Germany. E-mail: m.mazik@tu-bs.de
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 12, 13, 15 and 16. See DOI: 10.1039/b901173k
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(K11 ~1 ¥ 105 M-1). In the case of receptor 7, both glucose units
of the disaccharide 1b or 3 have the possibility to interact with
four phenyl rings of the receptor (three oxime-substituted phenyl
rings and the central phenyl ring); these interactions seem to be
responsible for the 1 : 1 binding stoichiometry, similar to the
complex between maltose binding protein (MBP) and maltose.
Quiocho et al. pointed out that “the maltose is wedged between
four aromatic side chains and the resulting stacking of these aro-
matic residues on the faces of the glucosyl units provides a majority
of the van der Waals contacts in the complex”.5f In the case of MBP
the aromatic residues involve three indol rings (from Trp 62, Trp
230, and Trp 340) and hydroxyphenyl ring (from Tyr 155).5f
Di- vs. monosaccharide preference in the recognition of carbo-
hydrates was also observed for the acyclic biphenyl-based receptor
11, which was designed to recognise disaccharides.3b Molecular
modeling calculations indicated that a 3,3¢,5,5¢-tetrasubstituted-
biphenyl scaffold12 should provide a cavity of the correct shape
and size for disaccharide encapsulation.
The aim of this work was to explore the potential of
dimesitylmethane-based receptors 12 and 13 (see Fig. 5), in-
corporating four 2-aminopyridine units capable of serving as
hydrogen bonding sites, in the recognition of neutral sugar
molecules. It should be noted that 2-aminopyridine group pro-
vides an excellent structural motif for binding carbohydrates,
associated with the ability to form cooperative and bidentate
hydrogen bonds with the sugar OH groups, as shown by our
previously binding studies with different receptor molecules.9 2-
aminopyridine units can be regarded as analogues of natural
recognition groups, namely as heterocyclic analogues of the as-
paragine/glutamine primary amide side chains (see Fig. 1; see also
ref. 13).
To compare the binding properties of receptors 12 and 1314
with the properties of previously published receptors, the dodecyl
b-D-maltoside (1b), dodecyl a-D-maltoside (3), and octyl b-D-
glucopyranoside (4) were selected as substrates. The interactions of
the receptors and carbohydrates were investigated by 1H NMR and
fluorescence spectroscopy in organic media. The 1H NMR binding
titration data were analyzed using the Hostest 5.6 program.15
The fluorescence binding titration data were analyzed using the
Hyperquad 2006 program.16 Stoichiometry of the receptor–sugar
complexes was determined by mole ratio plots17 and by the curve-
fitting analysis of the titration data.
Fig. 2 Structure of (a) the 1,1¢-binaphthyl-derived cyclophane receptor
of Diederich et al. (R = H or CO2CH3, OBn = Benzyloxy group)6a,b and
(b) the biphenyl-based macrotetracyclic receptor of Davis et al.3h
Results and discussion
Synthesis of the receptors
The synthetic route for 12 and 13 is shown in Scheme 1. Four
bromomethyl groups were appended to dimesithylmethane (14)
over two steps leading to 3,3¢,5,5¢-tetrabromomethyl-2,2¢,4,4¢,6,6¢-
hexamethyldiphenylmethane (16).18 The reaction of 16 with
2-amino-6-methylpyridine (17) or 2-amino-4,6-dimethylpyridine
(18) provided the compounds 12 and 13, respectively (see
Scheme 1).
Fig. 3 Structures of sugar molecules.
the binding affinity towards monosaccharides (the binding affinity
for monosaccharides, such as 4 and 5, decreases with decreasing
the number of the heterocyclic recognition groups attached to the
central phenyl ring). In contrast, the incorporation of suitable
substituted phenyl groups into the 2,4,6-trialkylbenzene scaffold
provides receptors capable of forming strong complexes with
disaccharides. The symmetrical oxime-based receptor 7,3i,11 for
example, is able to form strong 1 : 1 complexes with dodecyl
b-D- and a-D-maltoside, 1b and 3, in chloroform solutions
Binding studies
Dodecyl b-D-maltoside (1b) and dodecyl a-D-maltoside (3) are
poorly soluble in CDCl3, but could be solubilized in this solvent in
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Table 1 Association constantsa,b for receptors 12 and 13 and sugars 1b, 3 and 4 as well as for the previously studied receptors 7–11 and sugars 1b and 4c
11/M-1
K21 or K12e/M-1
b21 or b12f/M-2
Methodg
d
Receptor–sugar complex
Solvent
K
h
12·1b
CDCl3
CHCl3
1% DMSO/CHCl3
CHCl3
1% DMSO/CHCl3
CDCl3
CHCl3
CDCl3
1% DMSO-d6/CDCl3
CDCl3
CDCl3
CDCl3
CHCl3
CDCl3
CHCl3
CDCl3
CDCl3
CDCl3
CHCl3
>100 000 (K21
)
NMR
5.76 ¥ 107 (K21
1.61 ¥ 107 (K21
)
)
Fluorescence
Fluorescence
Fluorescence
Fluorescence
NMR
Fluorescence
NMR
NMR
NMR
NMR
NMR
Fluorescence
NMR
Fluorescence
NMR
NMR
NMR
Fluorescence
NMR
Fluorescence
NMR
14 600
12·3
12·4
13·1b
10 300
260
350
630 (K12
840 (K12
)
)
1.63 ¥ 105
2.94 ¥ 105
h
>100 000 (K21
)
)
19 800
h
13·3
13·4
7·1b
>100 000 (K21
270
100 500
98 900
170
371 200
2050
560 (K12
)
1.51 ¥ 105
7·4
1730 (K12
7950 (K21
)
)
2.94 ¥ 105
2.95 ¥ 109
1.48 ¥ 106
8·1b
8·4
720 (K12
>100 000 (K21
180 (K12
42 300 (K21
)
h
h
9·1b
9·4
)
)
1830
130 700
48 630
54 920
)
3.29 ¥ 105
5.52 ¥ 109
6.42 ¥ 107
8.07 ¥ 107
10·1b
10·4
)
CDCl3
CHCl3
CDCl3
CDCl3
1320 (K12
1470 (K12
)
)
11·1b
>100 000 (K21
11·4
8800
300 (K12
)
2.64 ¥ 106
NMR
d
a Average Ka values from multiple titrations. b Errors in Ka are less than 10%. c According to the references 3b,3i,3q, and 9b. K21 corresponds to 2 : 1
g
receptor–sugar association constant. e
K
12 corresponds to 1 : 2 receptor–sugar association constant. f b21 = K11
K
21, b12 = K11K12
.
1H NMR spectroscopic
titrations (CDCl3 and DMSO-d6/CDCl3, 1 : 99 v/v) or fluorescence titrations (CHCl3 and DMSO/CHCl3, 1 : 99 v/v. h The best fit of the titration data
was obtained with the “pure” 2 : 1 receptor–substrate binding model (see ref. 15b).
Fig. 4 Structures of the previously studied receptors 6–11.3b,3i,3q,9b
the presence of the receptor 12 or 13, indicating favourable inter-
actions between the binding partners (similar solubility behaviour
of the disaccharides 1b and 3 was observed in the presence of the
previously described receptors 6–9). Thus, the receptor in CDCl3
was titrated with a solution of maltoside dissolved in the same
receptor solution. In addition, 1H NMR titration experiments with
the disaccharides were performed in DMSO-d6/CDCl3 mixtures.
The 1H NMR titrations with b-glucopyranoside 4 were carried out
by adding increasing amounts of the sugar to a CDCl3 solution of
the receptor 12 or 13. The complexation between 12 or 13 and the
saccharides 1b, 3 and 4 was evidenced by several changes in the
NMR spectra (for examples, see Fig. 6 and 7).
During the titrations of both of the receptors with the
disaccharide 1b or 3 in CDCl3 the signal due to the amine
NH of 12 and 13 moved downfield by about 0.25–0.30 ppm
indicating the participation of the NH groups in the formation
of intermolecular hydrogen bonds. It should be noted that the
addition of only 0.5 equivalent of sugar 1b or 3 led to practically
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Scheme 1 Reaction conditions: (a) CH2O, HBr, CH3COOH, (b) CH2O, HBr, ZnCl2, CH3COOH, (c) 4.4 equiv of 2-amino-6-methylpyridine (17) or
2-amino-4,6-dimethylpyridne (18), CH3CN/THF, K2CO3.
Fig. 5 Structures of receptors investigated in this study.
complete complexation of the receptors 12 and 13 (see Fig. 6a
and 7a). Furthermore, the H NMR spectra showed changes in
consistent with 1 : 1 receptor–sugar binding; the binding constant
for 13·1b was determined to be 19 800 M-1.
1
the chemical shifts of the CH3, CH2 and CH resonances of the
receptors (up- and downfield shifts in the range of 0.03–0.05 ppm).
The best fit of the titration data for 12·1b, 12·3, 13·1b, and 13·3 was
obtained with the 2 : 1 receptor–sugar binding model15b (typical
titration plot is shown in Fig. 7a); however, the binding constants
were too large to be accurately determined by 1H NMR titrations
in CDCl3 (K21 > 100 000 M-1, see Table 1).19,20 The formation of
complexes with 2 : 1 receptor–maltoside binding stoichiometry
was further supported by the mole ratio plots.
According to molecular modeling calculations the 2 : 1 receptor-
maltoside complexes are stabilized by several hydrogen bonds as
well as interactions of sugar CHs with the phenyl groups of both
of the receptor molecules. The two receptor molecules almost
completely enclose the sugar (for example, see Fig. 8a), leading
to involvement of sugar OH groups and the ring-O in interactions
with the two receptor molecules (OH ◊ ◊ ◊ N-pyr, HO ◊ ◊ ◊ HN, and
ring-O ◊ ◊ ◊ HN hydrogen bonds, see Table 2). The sugar OH groups
are engaged in the formation of cooperative hydrogen bonds
resulting from the simultaneous participation of a sugar OH as
donor and acceptor of hydrogen bonds (similar to interactions
in protein–carbohydrate complexes5). Examples of noncovalent
interactions indicated by molecular modeling calculations for the
complex formed between receptor 13 and the disaccharide 1b are
given in Fig. 9 and Table 2.
The interactions between the receptor 12 and the disaccharide
1b or 3 could also be analysed on the base of fluorescence
titrations (the binding properties of the receptor 13 could not
be analysed on the base of fluorescence spectroscopy).21 The
fluorescence titration experiments were carried out by adding
increasing amounts of the sugar 1b or 3 (both disaccharides
are soluble in CHCl3 in the concentration range required for
fluorescence titrations) to a CHCl3 solution of the receptor 12
(for example, see Fig. 10a). The best fit of the titration data at
360 nm was obtained with the 2 : 1 receptor–sugar binding model,
in agreement with the 1H NMR binding studies; the binding
constant for 12·1b was found to be 5.76 ¥ 107 M-1, whereas
that for 12·3 amounted to 1.61 ¥ 107 M-1. The spectral changes
observed during the titrations of 12 with 1b or 3 in the presence
of DMSO (DMSO/CHCl3, 1 : 99 v/v) were less substantial
than those observed during the titrations in pure chloroform and
were consistent with 1 : 1 receptor–sugar binding; the binding
constant for 12·1b was determined to be 14 600 M-1, that for 12·3
amounted to 10 300 M-1. Thus, the addition of dimethyl sulfoxide
caused both the change of the binding model and a substantial
drop in the binding affinity, as indicated by 1H NMR titrations.
1H NMR titrations of 12 or 13 with the glucopyranoside
4 in CDCl3 indicated much weaker interactions of the both
receptors with the monosaccharide than those with the disac-
charides. Whereas after the addition of about 0.5 equivalent of
the disaccharide 1b or 3 almost no more change was observed
in the chemical shift of the receptor signals, the addition of
more than 5 equivalents of monosaccharide 4 was necessary to
achieve the saturation. During the titrations of 12 and 13 with
Studies performed with the receptor 13 and b-maltoside 1b in
DMSO-d6/CDCl3 mixture (1 : 99 v/v) revealed that the affinity
of 13 for the disaccharide 1b significantly decreases as solvent
polarity increases. The motions of the signals observed during
the titrations of 13 with 1b in the presence of DMSO-d6 were
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of the CH3, CH2, and CH protons shifted up- or downfield in the
range of 0.02–0.10 ppm. The curve fitting of the titration data
suggested the existence of 1 : 1 and 1 : 2 receptor–monosaccharide
complexes in the chloroform solution (typical titration curve is
shown in Fig. 7b). A calculated structure of the 1 : 2 receptor–
sugar complex formed between receptor 13 and b-glucopyranoside
4 is shown in Fig. 8b (MacroModel V.8.5, OPLS-AA force field,
MCMM, 50 000 steps). The binding constants for 12·4 were found
to be 260 (K11) and 630 (K12) M-1, whereas those for 13·4 amounted
to 270 (K11) and 560 (K12) M-1.19c
Interactions between receptor 12 and b-glucopyranoside 4 could
also be detected by fluorescence (fluorescence intensity increased
with increasing monosaccharide concentration); however, the
spectral changes observed during the fluorescence titrations with
glucopyranoside 4 were less substantial than those observed
during the titrations with disaccharides 1b and 3 (for example,
see Fig. 10b). The analysis of the titration data (at 360 nm)
confirmed the “mixed” 1 : 1 and 1 : 2 receptor–glucopyranoside
binding model; the binding constants determined on the base
of fluorescence titrations in CHCl3 were comparable with those
determined on the base of the NMR spectroscopic titrations in
CDCl3 (see Table 1).
Comparison of the binding properties of 12 and 13 with those
of the receptors 6–9 and 11 (see Table 1) reveals similar tendency
to the formation of relative weak 1 : 1 and 1 : 2 receptor–sugar
complexes with the monosaccharide 4 (in contrast to the symmet-
rical aminopyridine-based receptor 10, which has been established
as a powerful receptor for b-glucopyranoside 4; see Table 1).
Conclusion
As part of our program aimed at the development of selective
carbohydrate receptors using noncovalent interactions, we have
prepared dimesitylmethane-based receptors 12 and 13, which
were expected to prefer disaccharides. The compounds 12 and 13
consist of four heterocyclic recognition groups capable of serving
as hydrogen bonding sites. According to molecular modeling
calculations, the hydrogen bonding interactions are complemented
by CH-p interactions between the sugar CH’s and the phenyl
rings of the receptor 12 or 13 (see Table 2).22,23 The phenyl rings
provide additional apolar contacts to a saccharide, similar to
sugar-binding proteins,5 which commonly place aromatic surfaces
against patches of sugar CH groups.
Fig. 6 (a) Partial 1H NMR spectra (400 MHz, CDCl3) of 13 after addition
of (from bottom to top) 0.00–2.28 equiv of a-maltoside 3 ([13] = 1.02 mM).
(b) Partial 1H NMR spectra of 13 after addition of (from bottom to top)
0.00–13.16 equiv of b-glucoside 4 ([13] = 0.93 mM).
the monosaccharide 4 the signal due to the amine NH of 12 and
13 moved downfield by about 0.9 ppm (after the addition of ~9
equivalents of sugar, as illustrated in Fig. 6b), whereas the signals
Fig. 7 Plot of the observed (+) and calculated (–) chemical shifts of the NH resonances of 13 (1.02 mM) as a function of added b-maltoside 1b (a) or
b-glucopyranoside 4 (b) The [receptor] : [sugar] ratio is marked.
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It has been shown by 1H NMR and fluorescence spectroscopic
titrations that compounds 12 and 13 display high binding affinity
toward b- and a-maltoside, 1b and 3, as well as strong di-
vs monosaccharide preference in organic media (similar to the
previously described receptors 6–9 and 11). The curve fitting of all
titration data suggested the existence of very strong 2 : 1 receptor–
disaccharide complexes in chloroform solutions (K21 > 105 M-1,
see Table 1).15b,19c The addition of dimethyl sulfoxide caused both
the change of the binding model and a substantial drop in the
binding affinity. The curve fitting of the titration data obtained in
the presence of DMSO or DMSO-d6 indicated the formation of
complexes with 1 : 1 receptor–disaccharide stoichiometry with K11
of 104 M-1 (see Table 1).
As expected, relative low binding constants were obtained on
titrating the compounds 12 or 13 with b-glucopyranoside 4. The
binding studies indicated the formation of complexes with 1 : 1
and 1 : 2 receptor–monosaccharide stoichiometry with K11 and
K12 in the range of 102 M-1 in chloroform (see Table 1). Both 1H
NMR and fluorescence titrations clearly showed that the receptor–
monosaccharide complexes are much less stable than those formed
with the disaccharides 1b and 3.
Receptors 12 and 13 are thus representatives of a new series of
acyclic carbohydrate-binding receptors displaying an interesting
di- vs. monosaccharide preference. The acyclic architecture is
notably easy to prepare and especially suitable for systematic
variations; such synthetic receptors provide valuable model sys-
tems to study the basic molecular features of carbohydrate recog-
nition. Syntheses of new receptors based on dimesitylmethane-
derived core and incorporating different recognition groups are in
progress.
Experimental section
Analytical TLC was carried out on silica gel 60 F254 plates.
Melting points are uncorrected. Dimesitylmethane (14), dodecyl
b-D-maltoside (1b), dodecyl a-D-maltoside (3), and octyl b-D-
glucopyranoside (4) are commercially available. 1H NMR and
fluorescence titration experiments were carried out similar to those
described in the supplementary information of ref. 3q.
3,3¢-Bisbromomethyl-2,2¢,4,4¢,6,6¢-hexamethyldiphenylmethane
(15)
Fig. 8 Energy-minimized structure of the 2 : 1 receptor–sugar complex
formed between receptor 13 and b-maltoside 1b (a) and 1 : 2 receptor–sugar
complex between receptor 13 and b-glucoside 4 (b). MacroModel V.8.5,
OPLS-AA force field, MCMM, 50 000 steps. Color code: receptor C, blue;
receptor N, green; sugar molecule, yellow or orange.
Dimesitylmethane (14) (2 g, 0.008 mmol) was combined with
glacial acetic acid (30 mL) and paraformaldehyde (1.44 g,
0.048 mol). This mixture was heated to ~80 ◦C, at which time
Table 2 Examples of noncovalent interactions indicated by molecular modeling calculationsa for the 2 : 1 receptor–sugar complex formed between
receptor 13 and sugar 1b
Receptor–substrate complex
Noncovalent interactionsb,c
13·1b
(I) pyridine-N ◊ ◊ ◊ HO-4 (g2); (I) NH ◊ ◊ ◊ OH-3 (g2); (I) pyridine-N ◊ ◊ ◊ HO-6 (g2);
(I) NH ◊ ◊ ◊ O-ring (g2); (I) NH ◊ ◊ ◊ OH-3 (g1); (I) pyridine-N ◊ ◊ ◊ HO-6 (g1);
(I) NH ◊ ◊ ◊ OH-6 (g1); (II) pyridine-N ◊ ◊ ◊ HO-3 (g2); (II) NH ◊ ◊ ◊ OH-4 (g2);
(II) NH ◊ ◊ ◊ OH-6 (g2); (g2) 2-OH ◊ ◊ ◊ OH-3 (g1);
2 : 1 receptor–sugar complexb
(I) phenyl ◊ ◊ ◊ HO-2 (g2); (I) phenyl ◊ ◊ ◊ HC-2 (g1);
(II) phenyl ◊ ◊ ◊ HC-3 (g1); (I) pyridine-CH3 ◊ ◊ ◊ O-ring (g1)
a MacroModel V.8.5, OPLS-AA force field, MCMM, 50 000 steps. b I and II: two receptors in the 2 : 1 receptor–sugar complex; c g1 and g2: the glucose units
of 1b (for labeling see Fig. 3).
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Fig. 9 Examples of hydrogen-bonding motifs found by molecular modeling studies in the 2 : 1 complex between receptor 13 and maltoside 1b
(MacroModel V.8.5, OPLS-AA force field, MCMM, 50 000 steps).
solution,◦and again with water. Yield 96% (3.36 g, 0.078 mol). Mp
132–133 C. 1H-NMR (400 MHz, CDCl3): d = 2.09 (s, 6H), 2.10
(s, 6H), 2.36 (s, 6H), 4.05 (s, 2H), 4.55 (s, 4H), 6.82 (s, 2H). 13C-
NMR (100 MHz, CDCl3): d = 15.83, 19.21, 21.22, 30.87, 32.22,
130.90, 132.21, 134.86, 136.44, 136.60, 137.46. HR-MS calcd for
C21H26Br2 438.03764; found: 438.03748. Rf = 0.83 (toluene/ethyl
acetate, 1 : 1 v/v).
3,3¢,5,5¢-Tetrabromomethyl-2,2¢,4,4¢,6,6¢-hexamethyl-
diphenylmethane (16)
Paraform-aldehyde (0.86 g, 0.0288 mol) was combined with 40 mL
of glacial acetic acid, and then zinc(II) bromide (0.60 g, 0.0026 mol)
and 3 mL of a 33% hydrobromic acid–acetic acid solution were
added. This suspension was heated to 100 ◦C for 0.5 h (at this
time a clear solution was formed), and then 3,3¢-bisbromomethyl-
2,2¢,4,4¢,6,6¢-hexamethylbiphenylmethane
(15)
(1.05
g,
0.0024 mol) was added (in portions). This solution was
heated to 100 ◦C for 8 h. Afterwards the mixture was cooled to the
room temperature, and the resulting precipitate was filtrated. The
solid was washed with water, potassium carbonate solution, and
again with water. Yield 79% (1.19 g, 1.90 mmol). Mp 171–172 ◦C.
1H-NMR (400 MHz, CDCl3) d = 2.14 (s, 12H), 2.45 (s, 6H),
4.17 (s, 2H), 4.55 (s, 8H). 13C-NMR (100 MHz, CDCl3) d =
15.19, 16.65, 30.88, 33.11, 132.95, 134.94, 137.16, 137.76. HR-MS
calcd for C23H28Br4 619.89190; found: 619.89232. Rf = 0.95
(toluene/ethyl acetate, 1 : 1 v/v).
3,3¢,5,5¢-Tetrakis[(6-methylpyridin-2-yl)aminomethyl]-
2,2¢,4,4¢,6,6¢-hexamethyl-biphenylmethane (12)
A
mixture of 3,3¢,5,5¢-tetrabromomethyl-2,2¢,4,4¢,6,6¢-hexa-
Fig. 10 Fluorescence titration of receptor 12 with a-maltoside 3 (a)
and b-glucopyranoside 4 (b) in CHCl3; [12] = 8.51 ¥ 10-5 and 9.57 ¥
10-5 M; Equiv of 3 = 0.00–4.03; Equiv of 4 = 0.00–18.69. Excitation
wavelength 324 nm. Fluorescence intensity increased with increasing sugar
concentration.
methylbiphenylmethane (16) (0.50 g, 0.80 mmol), 2-amino-
6-methyl-pyridine (0.45 g, 4.16 mmol) and K2CO3 (1.50 g,
10.86 mmol) in CH3CN/THF (1 : 1 v/v; 40 mL) was stirred
at room temperature for 72 h (the solution was monitored by
TLC). After filtration and evaporation of solvents, the crude
product was purified by column chromatography (aluminium
oxide, chloroform/diethyl◦ether, 2 : 3 v/v). Yield 56% (0.33 g,
30 mL of a 33% hydrobromic acid–acetic acid solution was
added. The mixture was heated until a clear solution was formed.
Afterwards the reaction mixture was stirred allowing the mixture
to cool to room temperature. The solid precipitating from the
solution was filtered, washed with water, potassium carbonate
1
0.45 mmol). Mp 115–116 C. H-NMR (400 MHz, CDCl3) d =
2.13 (s, 12H), 2.38 (s, 18H), 4.18 (s, 2H), 4.22 (t, 4H, J = 4.28 Hz),
4.33 (d, 8H, J = 4.3 Hz), 6.26 (d, 4H, J = 8.3 Hz), 6.46 (d, 4H,
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J = 7.3 Hz), 7.36 (m, 4H). 13C-NMR (100 MHz, CDCl3) d = 15.84,
16.83, 24.36, 33.41, 42.04, 102.77, 112.28, 133.41, 134.61, 135.98,
137.56, 137.87, 157.06, 158.17. HR-MS (ESI) calcd for C47H57N8
733.47007; found: 733.46974. Rf = 0.60 (chloroform/diethyl ether,
2 : 3 v/v).
James and S. Shinkai, Top. Curr. Chem., 2002, 218, 159–200; (b) T. D.
James, K. R. A. S. Sandanayake and S. Shinkai, Angew. Chem., 1996,
108, 2038–2050; T. D. James, K. R. A. S. Sandanayake and S. Shinkai,
Angew. Chem., Int. Ed., 1996, 35, 1910–1922; (c) S. Striegler, Curr. Org.
Chem., 2003, 7, 81–102; (d) J. H. Hartley, T. D. James and C. J. Ward,
J. Chem. Soc. Perkin Trans. 1, 2000, 3155–3184.
5 (a) H. Lis, and N. Sharon, Lectins, Kluwer Academic Publishers:
Dordrecht, The Netherlands, 2003; (b) F. A. Quiocho, Pure. Appl.
Chem., 1989, 61, 1293–1306; (c) W. I. Weiss and K. Drickamer, Annu.
Rev. Biochem., 1996, 65, 441–473; (d) R. U. Lemieux, Chem. Soc. Rev.,
1989, 18, 347–374; (e) H. Lis and N. Sharon, Chem. Rev., 1998, 98,
637–674; (f) S. P. Spurlino, G.-Y. Lu and F. A. Quiocho, J. Biol. Chem,
1991, 266, 5202–5219.
3,3¢,5,5¢-Tetrakis[(4,6-dimethylpyridin-2-yl)aminomethyl]-
2,2¢,4,4¢,6,6¢-hexamethyl-biphenylmethane (13)
A
mixture of 3,3¢,5,5¢-tetrabromomethyl-2,2¢,4,4¢,6,6¢-hexa-
methylbiphenylmethane (16) (0.50 g, 0.80 mmol), 2-amino-4,6-
dimethyl-pyridine (0.47 g, 3.85 mmol) and K2CO3 (1.50 g,
10.86 mmol) in CH3CN/THF (1 : 1 v/v; 60 mL) was stirred
at room temperature for 72 h (the solution was monitored by
TLC). After filtration and evaporation of solvents, the crude
product was purified by column chromatography (aluminium
oxide, chloroform/diethyl ether, 2 : 3 v/v). Yield 50% (0.32 g,
0.40 mmol). Mp 145–146 ◦C. 1H-NMR (400 MHz, THF-d8): d =
2.11 (s, 12H), 2.16 (s, 12H), 2.25 (s, 12H), 2.51 (s, 6H), 4.22 (s,
2H), 4.40 (d, J = 4.3 Hz, 8 H), 5.06 (t, J = 4.3 Hz, 4H), 6.05
(s, 4H), 6.20 (s, 4H). 13C-NMR (100 MHz, THF-d8): d = 15.90,
16.88, 20.90, 24.34. 34.17, 42.10, 105.09, 113.07, 135.01, 135.31,
136.33, 138.01, 147.93, 156.81, 159.63. HR-MS calcd for C51H64N8
788.52242; found: 788.52249. Rf = 0.57 (chloroform/diethyl ether,
2 : 3 v/v).
6 (a) For examples of selective oligosaccharide binding by receptors using
noncovalent interactions, see references 3b, 3g–i, 3q, and: U. Neidlein
and F. Diederich, Chem. Commun., 1996, 1493–1494; (b) A. S. Droz,
U. Neidlein, S. Anderson, P. Seiler and F. Diederich, Helv. Chim. Acta.,
2001, 84, 2243–2289; (c) G. Lecollinet, A. P. Dominey, T. Velasco and
A. P. Davis, Angew. Chem., Int. Ed., 2002, 41, 4093–4096(Angew. Chem.
2002, 114, 4267–4270); (d) V. Kra´l, O. Rusin and F. P. Schmidtchen,
Org. Lett., 2001, 3, 873–876; (e) O. Rusin, K. Lang and V. Kra´l, Chem.–
Eur. J., 2002, 8, 655–663; (f) R. D. Hubbard, S. R. Horner and B. L.
Miller, J. Am. Chem. Soc., 2001, 123, 5810–5811; (g) For other receptors
with interesting oligosaccharide binding properties, see references 3c,
3r, and: J. Billing, H. Grundberg and U. J. Nilsson, Supramol. Chem,
2002, 14, 367–372; (h) J. Otsuki, K. Kobayashi, H. Toi and Y. Aoyama,
Tetrahedron Lett., 1993, 34, 1945–1948; (i) Y.-Q. Chen, X.-Z. Wang,
X.-B. Shao, J.-L. Hou, X.-Z. Chen, X.-K. Jiang and Z.-T. Li, Tetra-
hedron, 2004, 60, 10253–10260; (j) For complexation studies between
anions and carbohydrate models, including di- and monosaccharides,
see: H.-J. Schneider, L. Tianjun and N. Lomadze, Chem. Commun.,
2004, 2436–2437; (k) J. M. Cotero´n, F. Hacket and H.-J. Schneider,
J. Org. Chem., 1996, 61, 1429–1435.
Acknowledgements
7 (a) A number of studies have demonstrated that artificial multi-
valent carbohydrate ligands possess high affinities for specific
carbohydrate-binding proteins. For examples of such oligosaccharide-
based ligands, see: T. K. Dam and C. F. Brewer, Chem. Rev., 2002,
102, 387–429; (b) T. K. Lindhorst, Top. Curr. Chem., 2002, 218, 201–
235.
We thank Prof. C. S. Wilcox for giving access to the HOSTEST
program.
8 For examples of oligosaccharide-based model systems for studying
carbohydrate-carbohydrate interactions, see: J. Rojo, J. C. Morales and
S. Penade´s, Top. Curr. Chem., 2002, 218, 45–92.
9 (a) M. Mazik, H. Cavga and P. G. Jones, J. Am. Chem. Soc., 2005, 127,
9045–9052; (b) M. Mazik, W. Radunz and R. Boese, J. Org. Chem.,
2004, 69, 7448–7462; (c) M. Mazik and W. Sicking, Tetrahedron Lett.,
2004, 45, 3117–3121; (d) M. Mazik, W. Radunz and W. Sicking, Org.
Lett., 2002, 4, 4579–4582; (e) M. Mazik and W. Sicking, Chem.–Eur. J.,
2001, 7, 664–670; (f) M. Mazik, H. Bandmann and W. Sicking, Angew.
Chem., Int. Ed., 2000, 39, 551–554.
10 It should be also noted that triethylbenzene scaffold has been exten-
sively used for the construction of receptors for cations and anions, as
well as boronic-acid based receptors. For a review, see: G. Hennrich
and E. V. Anslyn, Chem.–Eur. J., 2002, 8, 2219–2224.
11 (a) Oximes have received far less attention in supramolecular chemistry
than other compounds such as carboxylic acids and amides. For some
examples, see: M. Mazik, D. Bla¨ser and R. Boese, J. Org. Chem., 2005,
70, 9115–9122; (b) M. Mazik, D. Bla¨ser and Boese, Tetrahedron, 1999,
55, 7835–7840; (c) M. Mazik, D. Bla¨ser and R. Boese, Tetrahedron
Lett., 1999, 40, 4783–4786; (d) M. Mazik, D. Bla¨ser and R. Boese,
Chem.–Eur. J., 2000, 6, 2865–2873; (e) C. B. Aakero¨y, A. M. Beatty
and D. S. Leinen, CrystEngComm., 2000, 27, 1–6; (f) E. A. Bruton, L.
Brammer, F. C. Pigge, C. B. Aakero¨y and D. S. Leinen, New. J. Chem.,
2003, 1084–1094; (g) A. W. Marsman, E. D. Leussink, J. W. Zwikker,
L. W. Jenneskens, W. J. J. Smeets, N. Veldman and A. L. Spek,
Chem. Mater., 1999, 11, 1484; (h) A. W. Marsman, C. A. van Walree,
R. W. A. Havenith, L. W. Jenneskens, M. Lutz, A. L. Spek, E. T. G.
Lutz and J. H. van der Maas, J. Chem. Soc. Perkin Trans 2, 2000,
501.
12 (a) In the area of sugar recognition the biphenyl-unit has mostly
been used as a building block for macrocyclic receptors. Particularly
interesting biphenyl-based macrocyclic architecture was designed by
Davis and co-workers. The recognition properties of a series of tricyclic
oligoamides have been explored in organic solvents, in two-phase
systems, and in water (see references 12a–d). A related macrotricyclic
receptor featuring two 1,1¢-biphenyl platforms linked by amide bridges
References
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4 (a) Another strategy, which has been employed for the design of
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bonding interactions; this strategy relies on the reversible formation of
covalent bonds from diol units and boronic acid. For reviews, see: T. D.
2070 | Org. Biomol. Chem., 2009, 7, 2063–2071
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was designed by molecular modeling by Diederich and coworkers (see
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Diederich, Helv. Chim. Acta., 2003, 86, 548–562.
Liu, H. Sakamoto, and K. Kimura, in Comprehensive Supramolecular
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18 Compounds 15 and 16 were also characterized by X-ray crystallogra-
phy; the binding motifs found in the crystal structures of 15 and 16 will
be published soon.
19 (a) Dilution experiments showed that receptors do not self-aggregate
in the used concentration range. For each system at least three 1H
NMR titrations were carried out; for each titration 15–20 samples
were prepared; (b) Error in a single Ka estimation was <10%. (c) K11
corresponds to the 1 : 1 association constant; K21 corresponds to the
2 : 1 receptor-sugar association constant; K12 corresponds to the 1 : 2
13 Anslyn an co-workers have exploited the 2-aminopyridine unit for
binding of cyclohexane diols and triols. The authors used this unit
to mimic the hydrogen-bonding motifs formed by the asparagine side
chain in the complexes of arabinose-binding protein with monosaccha-
rides. See:C. Y. Huang, L. A. Cabell and E. V. Anslyn, J. Am. Chem.
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14 The second methyl group at the 4-position of the pyridine ring should
favorably increase the basicity of the pyridine moiety, see: A. R. Ka-
tritzky, A. F. Pozharski, Handbook of Heterocyclic ChemistryPergamon:
Amsterdam, The Netherlands, 2000, p. 178.
receptor-sugar association constant; b21 = K11 x K21; b12 = K11 x K12
.
20 For a review discussing the limitations of the NMR method, see:L.
Fielding, Tetrahedron, 2000, 56, 6151–6170.
21 (a) For each system at least two fluorescence titrations were carried out;
for each titration 15–20 samples were prepared; (b) Error in a single Ka
estimation was < 10%.
15 (a) C. S. Wilcox, and N. M. Glagovich, Program HOSTEST 5.6Uni-
versity of Pittsburgh: Pittsburgh, PA, 1994; (b) Hostest program is
designed to fit data to different binding models, which include both
“pure” binding models, taking into consideration the formation of only
one type of complex in solution (1 : 1, 1 : 2 or 2 : 1 receptor-substrate
complex), and “mixed” binding models containing more than one type
of complex in solution (for example, 1 : 1 and 1 : 2 or 1 : 1 and 2 : 1
receptor-substrate binding stoichiometry).
22 (a) For some discussions on the importance of carbohydrate-aromatic
interactions, see: G. Terraneo, D. Potenza, A. Canales, J. Jime´nez-
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17 (a) H.-J. Schneider, and A. Yatsimirsky, Principles and Methods in
Supramolecular Chemistry Jon Wiley & Sons, Chichester,2000; (b) H.
Tsukube, H. Furuta, A. Odani, Y. Takeda, Y. Kudo, Y. Inoue, Y.
23 For examples of CH-p interactions in the crystal structures of the
complexes formed between artificial receptors and carbohydrates, see
reference 9a.
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The Royal Society of Chemistry 2009
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©