Molecular recognition of N -acetylneuraminic acid by acyclic pyridinium- and quinolinium-based receptors in aqueous media: Recognition through combination of cationic and neutral recognition sites

Article abstract of DOI:10.1021/jo301966z

Compounds 5b-8b and 10b, and 11b, containing a triethylbenzene scaffold substituted with both neutral and cationic recognition sites, were shown to be effective receptors for N-acetylneuraminic acid (NeuAc), the most common occurring sialic acid, in highly competitive solvents. These compounds were established to be more powerful receptors for NeuAc than the symmetrical pyridinium- and quinolinium-based compounds 9b and 12b in aqueous media. As in natural protein-sialic acid complexes, the combination of neutral/charge- reinforced hydrogen bonds, ion pairs, CH-π, and van der Waals interactions seems to be responsible for the effective binding of this naturally widespread anionic carbohydrate in aqueous media.

Full text of DOI:10.1021/jo301966z

Article
pubs.acs.org/joc
Molecular Recognition of N‑Acetylneuraminic Acid by Acyclic
Pyridinium- and Quinolinium-Based Receptors in Aqueous Media:
Recognition through Combination of Cationic and Neutral
Recognition Sites
Christoph Geffert, Matthias Kuschel, and Monika Mazik*
Institut fur Organische Chemie der Technischen Universitat Freiberg, Leipziger Strasse 29, 09596 Freiberg, Germany;
̈
̈
S
* Supporting Information
ABSTRACT: Compounds 5b−8b and 10b, and 11b,
containing a triethylbenzene scaffold substituted with both
neutral and cationic recognition sites, were shown to be
effective receptors for N-acetylneuraminic acid (NeuAc), the
most common occurring sialic acid, in highly competitive
solvents. These compounds were established to be more
powerful receptors for NeuAc than the symmetrical
pyridinium- and quinolinium-based compounds 9b and 12b
in aqueous media. As in natural protein−sialic acid complexes,
the combination of neutral/charge-reinforced hydrogen bonds, ion pairs, CH−π, and van der Waals interactions seems to be
responsible for the effective binding of this naturally widespread anionic carbohydrate in aqueous media.
INTRODUCTION
■
N-Acetylneuraminic acid (NeuAc; the most common occurring
sialic acid) and NeuAc-containing ligands play a key role in a
wide range of biological processes.1,2 As the terminal sugar of
cell surface glycoproteins, NeuAc is known to participate in
carbohydrate−protein interactions that mediate recognition
phenomena. NeuAc is frequently used as a recognition unit by
proteins of numerous viruses, such as influenza, Sendai,
Newcastle disease, and polyoma viruses. This naturally
widespread carbohydrate is furthermore known to be overex-
pressed on the cell surface of tumor cells. The biological
recognition processes involving sialoglycoconjugates use both
neutral and charge-reinforced hydrogen bonds, as well as ion
pairing for sugar binding;2 some examples of these interactions
are shown in Figure 1. The natural binding motifs have inspired
the design of artificial receptors for the recognition of
NeuAc,3−5 which may serve as a basis for the development of
new therapeutics or agents for the detection of bound and free
NeuAc (for a recent discussion on the importance of the
detection of free sialic acid in biological samples, see ref 6).
Our previous studies showed that acyclic molecules of types I
and II (see Figure 2) are able to complex neutral and/or ionic
carbohydrates in organic and aqueous media.3a,b,7,8 The acyclic
scaffold facilitates many synthetic modifications of the receptor
structure, providing a base for systematic studies. Such studies
showed the suitability of the aminopyridine, aminopyrimidine,
aminonaphthyridine, indole, imidazole, benzimidazole, pyrrole,
guanidinium, carboxylate, crown ether, hydroxy, amide, and
oxime based groups as recognition groups for carbohydrates.
Mimicking the binding motifs observed in the crystal structures
of protein−carbohydrate complexes, by using natural recog-
Figure 1. Examples of neutral (a) and charge-reinforced (b, c)
hydrogen bonds as well as ion pairing (d) in the crystal structures
formed between NeuAc-containing ligands (red units) and different
proteins (black units): (a) NeuAc(α2-3)Galβ4Glc and polyoma virus;
(b, c) methyl α-sialoside and rhesus rotavirus hemagglutinin; (d)
NeuAc and influenza neuraminidase complex.2
nition groups or their analogues, was shown to be a powerful
strategy for the design of effective and selective carbohydrate
receptors. Depending on the nature of the recognition groups
and the mode of their connection with the aromatic platform, a
wide range of receptors with different binding properties could
be obtained. Among these acyclic compounds, the compounds
1−3 (see Figure 3), consisting of neutral and cationic
recognition units appended to a triethylbenzene core, were
Received: September 26, 2012
© XXXX American Chemical Society
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Figure 2. Examples of acyclic carbohydrate receptors (see refs 3a,b and 7).
Figure 3. Structures of the previously described receptors 1−3 and of N-acetylneuraminic acid (4a; 4b and 4c represent the salts used for the
binding studies).
−
Figure 4. Structures of the prepared pyridinium and quinolinium based compounds 5−12 (Br− and PF6 salts).
shown to be effective receptors for N-acetylneuraminic acid3a,b
(for a recognition of Neu5Ac with receptors containing a
diphenylmethane or biphenyl core, see ref 3c). The studies
indicated that a combination of cationic and neutral recognition
groups provides powerful receptors for the recognition of
anionic sugars in aqueous media.
The aim of the present study was to evaluate the potential of
compounds containing pyridinium or quinolinium groups as
cationic binding sites in the complexation of carbohydrates. As
the first representatives of this group we have prepared
compounds 5−8, 10, and 11 (see Figure 4), incorporating one
or two cationic units and aminopyridine groups as neutral
recognition sites. In our previous studies the aminopyridine
group was established as a valuable building block for
carbohydrate receptors9 and was used as a heterocyclic
analogue of the primary amide group of the Asn/Gln side
chain. Compounds 5−8, 10, and 11, incorporating both
cationic and neutral recognition sites, were expected to
participate in the formation of both neutral and charge-
reinforced hydrogen bonds as well as ion pairs with the anionic
B
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a
Scheme 1
a
Reaction conditions: (a) 5 equiv of 19, CH2Cl2, reflux, 48 h (46%); (b) 9 equiv of NaPF6, MeOH, room temperature (40%); (c) 6 equiv of 17,
CH2Cl2, reflux, 8 h (89%); (d) 9 equiv of NaPF6, MeOH, room temperature (50%); (e) 2 equiv of 2-amino-4,6-dimethylpyridine (14), CH3CN/
THF, K2CO3, room temperature, 3 days (20% 15, 30% 16); (f) 2.5 equiv of 19, CH2Cl2, reflux, 24 h (33%); (g) 6 equiv of NaPF6, MeOH, room
temperature (75%); (h) 2 equiv of 17 or 18, CH2Cl2, reflux, 8 h (63% 7a; 25% 8a); (i) 6 equiv of NaPF6, MeOH, room temperature (53% 7b, 65%
8b); (j) 1 equiv of 19, CH2Cl2, reflux, 16 h (45%); (k) 3 equiv of NaPF6, MeOH, room temperature (80%); (l) 1 equiv of 17 or 18, CH2Cl2, reflux,
8 h in the case of 17 and 12 h in the case of 18 (41% 5a, 47% 6a); (m) 3 equiv of NaPF6, MeOH, room temperature (81% 5b, 78% 6b).
sugar. The participation of the central phenyl ring of 5−8, 10,
and 11 in interactions with sugar CHs10,11 was expected to
provide additional stabilization of the receptor−sugar com-
plexes. The binding properties of these compounds (used as
PF6− salts 5b−8b, 10b, and 11b) were compared with those of
the symmetrical pyridinium and quinolinium based compounds
9b and 12b. It should be noted that symmetrical
triethylbenzene based compounds containing pyridinium or
quinolinium groups as cationic recognition sites have been used
by Steed12 as receptors for anions, such as halides, nitrate, and
acetate. Developments in the molecular recognition of anions
by acyclic and macrocyclic pyridinium based receptors have
recently been reviewed by Kilah and Beer.13 In the area of sugar
recognition by receptors employing noncovalent interactions,
the potential of pyridinium and guinolinium based receptors
has not been evaluated.
titrations. In the case of the symmetrical molecules 9b and 12b,
additional tests were carried out in CD3CN (Neu5Ac was used
as the tetrabutylammonium salt 4c).14
The interactions between the binding partners were analyzed
by titrations in which the concentration of the receptor was
held constant and that of the anionic sugar was varied, as well as
by inverse titrations in which the concentration of the sugar was
held constant (for examples, see the Supporting Information).
The stoichiometry of the receptor−sugar complexes was
determined by mole ratio plots15 and by the curve-fitting
analysis of the titration data.
The complexation between the receptors 5b−8b, 10b, and
11b and NeuAc (used as mixture of anomers)16 was evidenced
by several changes in the NMR spectra; examples are given in
1
Figure 6. The H NMR titration data were analyzed using the
EQNMR program;17 the binding constants are summarized in
Table 1.
RESULTS AND DISCUSSION
■
−
In a 1/9 (v/v) D2O/DMSO-d6 mixture the interactions
between the binding partners are too strong to be accurately
analyzed by the NMR method; the analysis of the titration data
indicated the formation of very strong 2/1 receptor−sugar
complexes (K21 > 100000 M−1; for an energy-minimized
structure of a 2/1 receptor−sugar complex, see Figure 5).
The syntheses of compounds 5−12 (Br− and PF6 salts) are
summarized in Scheme 1 and described in the Experimental
Section. The binding properties of 5b−8b, 10b, and 11b
toward N-acetylneuraminic acid (used as the tetramethylam-
monium salt 4b) were analyzed in mixtures of D2O and
DMSO-d6 (1/9, 1/5, and 1/2.5 v/v) by 1H NMR spectroscopic
C
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a b
,
quinolinium groups, proved to be too strong to be followed
quantitatively (K21 > 100000 M−1).18 In the case of 10b,
incorporating one quinolinium group, the interactions between
Table 1. Examples of Association Constants for the
Tested Receptors and Neu5Ac (Used as Salt 4b or 4c)
K11
β21 = K11K21
(M−2
e
the binding partners are also strong (K11 = 4240 and K21 =
receptor
solvent
(M−1
)
K21 (M−1
)
)
43500 M−1) but less effective as for 11b·4b. The addition of
0.65 equiv of 4b leads to practically complete complexation of
the receptor 10b, whereas in the case of 11b the saturation
occurs before the addition of 0.5 equiv of 4b.
f
5b
1/9 (v/v) D O/
f
>100000
c2
DMSO-d6
c
1/5 D2O/DMSO-d6
3750
43050
1.61 × 108
1.13 × 106
c
c
1/2.5 D2O/DMSO-d6
6330
180
c
f
As the solvent polarity increases, the magnitude of the
complexation-induced chemical shifts decreases and the
addition of more 4b is necessary to reach the saturation (for
example, see parts a and b of Figure 6). When going from 1/5
to 1/2.5 (v/v) mixture of D2O and DMSO-d6, the 2/1
receptor−sugar complexes become much less stable, but the
1/1 binding is markedly improved; examples of association
constants for 5b·4b, 7b·4b, and 11b·4b are given in Table 1.
Thus, the compounds containing both neutral and cationic
recognition sites are able to complex 4b even in the presence of
about 30% D2O.
7b
9b
1/9 D2O/DMSO-d6
f
>100000
c
1/5 D2O/DMSO-d6
2540
61200
1.55 × 108
1.99 × 107
1/2.5 D2O/DMSO-d6
7680
2600
c
1/5 D2O/DMSO-d6
h
h
d
CD3CN
g
g
c
10b
11b
1/5 D2O/DMSO-d6
4240
43500
1.84 × 108
1.94 × 106
c
f
1/5 D2O/DMSO-d6
f
>100000
c
1/2.5 D2O/DMSO-d6
4220
460
h
c
12b
1/5 D2O/DMSO-d6
h
g
d
CD3CN
g
5/95 (v/v) D2O/
h
h
d
CD3CN
In the case of the symmetrical compounds 9b and 12b,
possessing only cationic recognition sites, the interactions with
4b in aqueous media were shown to be significantly weaker
than those observed for the other receptors. For example, the
complexation induced chemical shifts observed during the
titrations of 9b/12b with 4b in a 1/5 mixture of D2O and
DMSO-d6 are too small to be used for the determination of the
binding constants. In addition, no significant shifts of N-
acetylneuraminic acid signals (used as tetramethylammonium
salt 4b) were observed during the titrations of 4b with the
pyridinium-based compound 9b (inverse titrations). These
results are in contrast with those of the inverse titrations of 4b
with receptor 7b, containing both aminopyridine- and
pyridinium-based recognition sites.
a
b
Average Ka values from multiple 1H NMR titrations. Errors in Ka are
c
d
e
less than 15%. Neu5Ac used as salt 4b. Neu5Ac used as salt 4c. K21
corresponds to 2/1 receptor-sugar association constant. Binding
f
constants too large to be accurately determined by NMR titrations.
g
h
Precipitate. Complexation-induced shifts too small to be used for the
determination of the binding constants.
As the solvent polarity decreases, the interactions of the
symmetrical pyridinium- and quinolinium-based compounds
with N-acetylneuraminic acid (used as salts 4b and 4c) become
expectedly more strong. Experiments in CD3CN indicated
effective binding of 4c by 9b and 12b, but precipitation of a
solid, which was identified as a receptor−sugar complex,
prevented the analysis of the binding constants in this solvent
1
by H NMR spectroscopic titrations. In a mixture of CD3CN
1
and D2O (95/5 v/v) the H NMR titrations could be carried
Figure 5. Energy-minimized structure of the 2/1 complex formed
between 5b and Neu5Ac (MacroModel V.9.8, OPLS_2001 force field,
MCMM, 50000 steps). Color code: receptor N, blue; receptor C, gray;
the sugar molecule is highlighted in yellow.
out; however, the complexation-induced shifts were too small
to be used for the determination of the binding constants. The
results obtained with 9b and 12b in D2O/DMSO-d6 and D2O/
CD3CN mixtures indicate that aqueous media are too
competitive for 9b and 12b to bind Neu5Ac effectively. Similar
observations (strong binding in CD3CN and almost no binding
in water) have recently been described by Steed et al. for the
complexation of halides by a triethylbenzene-based anion
receptor incorporating three quinolinium groups as recognition
sites.12e
In a more competitive solvent, such as a 1/5 D2O/DMSO-d6
mixture, the binding of 4b by 5b−7b, 10b, and 11b was also
shown to be very effective. The curve fitting of the titration data
indicated the existence of 1/1 and 2/1 receptor−sugar
complexes in the used medium. The binding constants for
the 2/1 receptor−sugar complexes were determined to be
significantly higher than those for the 1/1 binding. During the
titration of 7b, incorporating two pyridinium units, with 4b the
saturation occurred after the addition of about 0.50 equiv of 4b
(see Figures 6 and 7), indicating strong binding and the
formation of 2/1 receptor−sugar complexes under the titration
conditions. In the case of 5b and 6b the saturation was reached
after the addition of about 0.60 equiv of 4b.
CONCLUSION
■
Nature’s use of both neutral and cationic recognition groups,
such as primary amide (Asn, Gln), hydroxyl (Ser), or
quanidinium groups (Arg), to bind anionic carbohydrates has
inspired the design of the receptors 5b−8b, 10b, and 11b,
which contain both cationic (pyridinium or quinolinium
groups) and neutral (aminopyridine) binding groups. These
compounds were expected to bind N-acetylneuraminic acid, the
most naturally abundant sialic acid, by a combination of
neutral/charge-reinforced hydrogen bonds, ion pairs, CH−π,
In the same medium (1/5 D2O/DMSO-d6 mixture), the
formation of strong 2/1 receptor−sugar complexes was also
indicated by the titrations of quinolinium-based receptors 10b
and 11b with 4b. Binding of 4b by 11b, consisting of two
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Figure 6. (a) Partial 1H NMR spectra (400 MHz) of receptor 7b ([7b] = 0.59 mM) after addition of 0.00−1.52 equiv of 4b in D2O/DMSO-d6 1/5
(v/v). (b) Partial 1H NMR spectra of receptor 7b ([7b] = 0.82 mM) after addition of 0.00−1.71 equiv of 4b in D2O/DMSO-d6 1/2.5 (v/v). Shown
are chemical shifts of the pyridine CH3 signals of 7b.
media, such as acetonitrile, indicated the effective binding of
Neu5Ac by 9b/12b.
In summary, pyridinium and quinolinium groups were shown
to be useful building blocks for the construction of receptor
molecules for anionic carbohydrates. As in natural complexes,
the combination of cationic and neutral recognition groups in
5b−8b, 10b, and 11b seems to be responsible for effective
binding of NeuAc in highly competitive media; the binding
properties of compounds 5−12 have now been analyzed in
more detail (detailed analysis of the different interactions
contributing to complex stability). Interesting complexation
properties are expected for compounds of types 20−25, in
which pyridinium/quinolinium or imidazolium units are
combined with such neutral recognition groups as imidazole,
indole, pyrrole, and 8-hydroxyquinoline (see Figure 8); the
syntheses of these compounds and the analysis of their binding
properties are in progress.
Figure 7. Mole ratio plot: titration of receptor 7b with 4b in D2O/
DMSO-d6 1/5 (v/v) (analysis of the complexation-induced shift of the
CH2 signal of 7b).
and van der Waals interactions. 1H NMR spectroscopic
titrations indicated that compounds 5b−8b, 10b, and 11b are
able to bind NeuAc (used as the salt 4b or 4c) even in the
presence of 30% D2O. Thus, compounds 5b−8b, 10b, and 11b
combine ease of synthesis and the ability to complex NeuAc in
highly competitive aqueous media. In contrast, D2O-containing
media were shown to be too competitive for compounds 9b
and 12b, containing only cationic recognition sites, to bind
Neu5Ac effectively. As expected, experiments in less polar
EXPERIMENTAL SECTION
■
Analytical TLC was carried out on silica gel 60 F254 plates; column
chromatography was carried out on silica gel. Melting points are
uncorrected. Binding studies are described in the Supporting
Information.
1-[(3-Methylpyridinium-1-yl)methyl]-3,5-bis[((4,6-dimethyl-
pyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Bromide
(5a). 1-(Bromomethyl)-3,5-bis[((4,6-dimethylpyridin-2-yl)amino)-
methyl]-2,4,6-triethylbenzene (16; 0.35 g, 0.67 mmol) and 3-
methylpyridine (0.065 mL, 0.67 mmol) were dissolved in dry
Figure 8. Further examples of acyclic receptors containing neutral and cationic recognition sites.
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dichloromethane (35 mL), and the resulting mixture was refluxed for 8
h. The solvent was removed under reduced pressure, and the crude
product was purified via column chromatography (chloroform/
methanol 7/1 (v/v) → 3/1 (v/v)). Yield: 41%. Mp: 157−158 °C.
1H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 7.6 Hz, 6H), 1.28 (t, J =
7.6 Hz, 3H), 2.25 (s, 6H), 2.42 (s, 6H), 2.68 (s, 3H), 2.75 (q, J = 7.6
Hz, 4H), 2.80 (q, J = 7.6 Hz, 2H), 4.48 (s, 4H), 6.17 (s, 2H), 6.34 (s,
2H), 6.40 (s, 2H), 8.04 (m, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.90 (s,
1H), 9.69 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 16.1, 16.3,
18.6, 21.1, 22.3, 23.0, 23.5, 40.5, 58.1, 105.2, 113.6, 124.1, 128.1, 133.2,
139.5, 140.8, 143.5, 145.09, 145.3, 147.4, 150.9, 152.8, 156.1 ppm. HR-
MS (ESI): calcd for C35H46BrN5 268.69103 [M+ + H+], 536.37477
[M+]; found 268.69110, 536.37476. Rf = 0.10 (chloroform/methanol
7/1 v/v).
methyl]-2,4,6-triethylbenzene (15; 0.244 g, 0.52 mmol) and 3-
methylpyridine (17; 0.10 mL, 1.025 mmol) were dissolved in dry
dichloromethane (15 mL), and the resulting mixture was refluxed for 8
h. The solvent was evaporated, and the crude product was purified via
column chromatography (chloroform/methanol 7/1 (v/v) → 3/1 (v/
v)). Yield: 63%. Mp: 183−184 °C. 1H NMR (400 MHz, DMSO-d6): δ
0.83 (t, J = 7.3 Hz, 3H), 1.06 (t, J = 7,3 Hz, 6H), 2.36 (s, 3H), 2.17 (s,
3H), 2.47 (q, J = 7,3 Hz, 2H), 2.57 (s, 3H), 2.66 (q, J = 7.3 Hz, 4H),
4.50 (s, 2H), 5.98 (s, 4H), 6.40 (s, 1H), 6.60 (s, 1H), 8.02 (m, 2H),
8.46 (m, 2H), 8.86 (s, 2H), 8.99 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ 15.5, 15.9, 18.0, 20.8, 23.1, 40.1, 57.1, 104.0, 111.6, 125.0,
127.5, 137.5, 139.9, 142.0, 144.9, 145.1, 147.1 ppm. HR-MS (ESI):
calcd for C34H44Br2N4 254.17775 [M2+], 587.27439 [M2+ + Br−];
found 254.17818, 587.27506. Rf = 0.10 (chloroform/methanol 7/1 (v/
v)).
1-[(3-Methylpyridinium-1-yl)methyl]-3,5-bis[((4,6-dimethyl-
pyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Hexafluoro-
phosphate (5b). To a solution of 5a (145 mg, 0.24 mmol) in
methanol (10 mL) was added a solution of NaPF6 (119 mg, 0.71
mmol) in methanol (2 mL), and the resulting mixture was stirred at
room temperature for 48 h. Afterward, the solvent was evaporated and
the crude product was purified via column chromatography (chloro-
1,3-Bis[(3-methylpyridinium-1-yl)methyl]-5-[((4,6-dimethyl-
pyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Hexafluoro-
phosphate (7b). A solution of NaPF6 (360 mg, 2.14 mmol) in
methanol (5 mL) was added to a solution of 7a (220 mg, 0.357 mmol)
in dry methanol (10 mL), and the resulting mixture was stirred at
room temperature for 48 h. The precipitated product was filtered,
washed several times with methanol, and dried under reduced
pressure; 7b was obtained as a white powder. Yield: 53%. Mp: 181−
1
form/methanol 7/1 (v/v)). Yield: 81%. Mp: 115−116 °C. H NMR
(600 MHz, DMSO-d6): δ 0.80 (t, J = 7.3 Hz, 6H), 0.94 (t, J = 7.2 Hz,
3H), 2.15 (s, 6H), 2.26 (s, 6 H), 2.55 (s, 3H), 2.64 (q, J = 6,2 Hz, 4H),
2.69 (q, J = 6.2 Hz, 2H), 3.40 (br. s, 2 H), 4.41 (s, 4H), 5.94 (s, 2H),
6.20 (s, 2H), 6.30 (s, 2H), 8.04 (t, J = 7.0 Hz, 1H), 8.50 (d, J = 7.7 Hz,
1H), 8.54 (m, 1H), 8.90 (s, 1H) ppm. 13C NMR (150 MHz, DMSO-
d6): δ 16.0, 16.1, 17.9, 20.5, 22.8, 22.9, 39.2, 57.4, 105.1, 112.5, 125.3,
127.5, 134.2, 138.8, 140.6, 143.5, 144.6, 146.1, 146.2, 147.2, 155.9,
157.9 ppm. HR-MS (ESI): calcd for C35H46F6N5P 536.37477 [M+],
682.34677 [M+ + PF6− + H+]; found 536.37550, 682.34899. Rf = 0.24
(chloroform/methanol 7/1 (v/v)).
1
182 °C. H NMR (600 MHz, DMSO-d6): δ 0.70 (t, J = 7.3 Hz, 3H),
0.94 (t, J = 7.3 Hz, 6H), 2.15 (s, 3H), 2.26 (s, 3H), 2.55 (q, J = 7,3 Hz,
2H), 2.64 (s, 6 H), 2.70 (q, J = 7.3 Hz, 4H), 4.41 (s, 2H), 5.94 (s, 4
H), 6.20 (s, 1H), 6.30 (s, 1H), 8.04 (t, J = 5.6 Hz, 2H), 8.50 (m, 2H),
8.54 (s, 2H), 8.90 (s, 2H) ppm. 13C NMR (150 MHz, DMSO-d6): δ
15.5, 17.9, 20.6, 23.1, 23.3, 39.3, 57.2, 104.6, 112.7, 126.6, 127.6, 135.7,
138.9, 139.1, 140.6, 143.6, 146.5, 148.0, 155.3, 157.7 ppm. HR-MS
(ESI): calcd for C34H44F12N4P2: 254.17775 [M2+], 327.16376 [M2+
+
−
PF6− + H+], 653.32023 [M2+ + PF6 ], 799.29224 [M2+ + 2PF6− + H+]
; found 254.17808, 327.16393, 653.32089, 799.29304. Rf = 0.15
(chloroform/methanol 7/1 (v/v)).
1-[(2-Amino-5-methylpyridinium-1-yl)methyl]-3,5-bis[((4,6-
dimethylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene
Bromide (6a). 1-(Bromomethyl)-3,5-bis[((4,6-dimethylpyridin-2-yl)-
amino)methyl]-2,4,6-triethylbenzene (16; 1.020 g, 1.95 mmol) and 2-
amino-5-methylpyridine (18; 0.211 mg, 1.95 mmol) were dissolved in
dry dichloromethane (50 mL), and the resulting mixture was refluxed
for 8 h. The solvent was removed under reduced pressure, and the
crude product was purified via column chromatography (chloroform/
1,3-Bis[(2-amino-5-methylpyridinium-1-yl)methyl]-5-[((4,6-
dimethylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene
Bromide (8a). 1,3-Bis-(bromomethyl)-5-[((4,6-dimethylpyridin-2-
yl)amino)methyl]-2,4,6-triethylbenzene (15; 0.600 g, 1.24 mmol)
and 2-amino-5-methylpyridine (18; 0.310 mg, 2.45 mmol) were
dissolved in dry dichloromethane (20 mL), and the resulting mixture
was refluxed for 12 h. The solvent was evaporated and the crude
product was purified via column chromatography (chloroform/
methanol 7/1 (v/v) → 3/1 (v/v)). Yield: 25%. Mp: 218−219 °C.
1H NMR (400 MHz, DMSO-d6): δ 1.06 (t, J = 3.2 Hz, 3H), 1.21 (t, J
1
methanol 7/1 (v/v)). Yield: 47%. Mp: 163−164 °C. H NMR (400
MHz, CDCl3): δ 1.26 (t, J = 7.5 Hz, 3 H), 1.27 (t, J = 7.4 Hz, 6 H),
2.27 (s, 6H), 2.14 (s, 3H), 2.36 (s, 6H), 2.79 (q, J = 7.4 Hz, 6H), 4.38
(s, 4H), 4.80 (br. s, 2H), 5.44 (s, 2H), 6.18 (s, 2H), 6.37 (s, 2H), 6.77
(s, 1H), 7.46 (m, 1H), 7.85 (d, J = 9.0 Hz, 1H), 9.12 (s, 2H) ppm. 13C
NMR (100 MHz, CDCl3): δ 16.1, 16.6, 17.9, 21.2, 23.1, 23.4, 23.6,
40.5, 52.3, 103.7, 114.1, 116.1, 123.0, 125.1, 131.3, 133.6, 142.9, 145.2,
146.6, 150.2, 153.6, 155.3, 157.3 ppm. HR-MS (ESI): calcd for
C35H47BrN6 276.19675 [M+ + H+], 551.38567 [M+]; found
276.19649, 551.38571. Rf = 0.35 (chloroform/methanol 7/1 (v/v)).
1-[(2-Amino-5-methylpyridinium-1-yl)methyl]-3,5-bis[((4,6-
dimethylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene
Hexafluorophosphate (6b). To a solution of 6a (110 mg, 0.174
mmol) in methanol (7 mL) was added a solution of NaPF6 (88 mg,
0.522 mmol) in methanol (2 mL). The resulting mixture was stirred at
room temperature for 48 h, the solvent was removed through rotary
evaporation, and the crude product was purified via column
chromatography (chloroform/methanol 3/1 (v/v)). Yield: 78%. Mp:
= 7.3 Hz, 6H), 2.22 (s, 6H), 2.12 (m, 2H), 2.24 (s, 3H), 2.45 (s, 3H),
2.67 (m, 4H), 4.54 (s, 2H), 5.12 (s, 4H), 6.54 (s, 1H), 6.90 (s, 1H),
7.39 (d, J = 9.0 Hz, 2H), 7.75 (dd, J = 9.0/1.6 Hz, 2H), 8.70 (s, 4H)
ppm. 13C NMR (100 MHz, DMSO-d6): δ 14.9, 15.9, 16.9, 19.5, 21.1,
22.9, 23.2, 40.4, 49.7, 113.4, 114.5, 123.1, 125.7, 132.3, 144.2, 145.8,
148.1, 153.1 ppm. HR-MS (ESI): calcd for C34H46Br2N6 269.18865
[M2+], found 269.18940. Rf = 0.10 (chloroform/methanol 7/1 (v/v)).
1,3-Bis[(2-amino-5-methylpyridinium-1-yl)methyl]-5-[((4,6-
dimethylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene
Hexafluorophosphate (8b). To a solution of 8a (140 mg, 0.201
mmol) in methanol (8 mL) was added a solution of NaPF6 (119 mg,
0.706 mmol) in methanol (4 mL). The resulting mixture was stirred at
room temperature for 48 h, the solvent was removed through rotary
evaporation, and the crude product was purified via column
chromatography (chloroform−methanol 3/1 (v/v)). Yield: 65%.
1
145 °C. H NMR (600 MHz, DMSO-d6): δ 1.07 (t, J = 7.3 Hz, 3H),
1.23 (t, J = 7.3 Hz, 6H), 2.11 (s, 3H), 2.14 (s, 6H), 2.29 (s, 6H), 2.58
(m, 6H), 2.79 (q, J = 7.3 Hz, 6H), 4.45 (s, 4H), 5.12 (s, 2H), 6.25 (s,
2H), 6.30 (s, 2H), 6.93 (s, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.80 (m,
1H), 8.62 (s, 2H) ppm. 13C NMR (150 MHz, CDCl3): δ 15.9, 16.2,
16.9, 20.2, 22.8, 39.2, 49.2, 105.1, 112.4, 114.7, 122.4, 124.7, 132.3,
134.4, 143.9, 144.2, 145.8, 147.2, 153.0, 155.2, 157.9 ppm. HR-MS
1
Mp: 152−153 °C. H NMR (600 MHz, MeOD-d4): δ 1.11 (t, J =
7.1 Hz, 3 H), 1.27 (t, J = 7.6 Hz, 6H), 2.18 (s, 6H), 2.37 (m, 2H), 2.40
(s, 3H), 2.53 (s, 3H), 2.72 (m, 4H), 4.81 (s, 2H), 5.23 (s, 4H), 6.69 (s,
1H), 6.89 (s, 1H), 7.13 (s, 2H), 7.15 (d, J = 6.1 Hz, 2H), 7.76 (dd, J =
9.1/1.8 Hz, 2H) ppm. 13C NMR (150 MHz, MeOD-d4): δ 15.3, 15.9,
17.4, 18.9, 21.9, 24.4, 24.7, 26.5, 41.8, 50.6, 115.9, 116.1, 125.7, 127.9,
133.6, 133.6, 145.8, 147.8, 148.7, 150.4, 153.9, 155.0 ppm. HR-MS
−
(ESI): calcd for C35H47F6N6P 551.38567 [M+], 697.35040 [M+ + PF6
+ H+]; found 551.38570, 697.35077. Rf = 0.10 (chloroform/methanol
7/1 (v/v)).
(ESI): calcd for C34H46F12N6P2 269.18865 [M2+], 683.34203 [M2+
+
1,3-Bis[(3-methylpyridinium-1-yl)methyl]-5-[((4,6-dimethyl-
pyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Bromide
(7a). 1,3-Bis-(bromomethyl)-5-[((4,6-dimethylpyridin-2-yl)amino)-
−
−
PF6 ] 829.31458 [M2+ + 2PF6 + H+], found 269.18970, 683.34410,
829.31521. Rf = 0.10 (chloroform/methanol 7/1 (v/v)).
F
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The Journal of Organic Chemistry
Article
1,3,5-Tris[(3-methylpyridinium-1-yl)methyl]-2,4,6-triethyl-
benzene Bromide (9a). 3-Methylpyridine (17; 0.132 mL, 1.362
mmol) and 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (13; 0.100
g, 0.227 mmol) were dissolved in dry dichloromethane (50 mL), and
the mixture was refluxed for 24 h. Afterward, the resulting precipitate
was filtered, washed several times with dichloromethane, and dried
under reduced pressure; 9a was obtained as a white powder. Yield:
89%. Mp: 208−209 °C. 1H NMR (400 MHz, D2O): δ 0.93 (t, J = 7.6
Hz, 9H), 2.60 (s, 9H), 2.72 (q, J = 7.4 Hz, 6H), 6.08 (s, 6H), 8.00 (t, J
= 6.2 Hz, 3H), 8.46 (d, J = 8.3 Hz, 3H), 8.54 (d, J = 6.1 Hz, 3H), 8.72
(s, 3H) ppm. 13C NMR (100 MHz, D2O): δ 16.9, 20.7, 26.8, 60.6,
130.8, 130.9, 143.2, 143.5, 145.9, 149.9, 153.4 ppm. HR-MS (ESI):
calcd for C33H42Br3N3 160.11208 [M3+], found 160.10580.
1,3,5-Tris[(3-methylpyridinium-1-yl)methyl]-2,4,6-triethyl-
benzene Hexafluorophosphate (9b). A solution of NaPF6 (420
mg, 2.502 mmol) in methanol (5 mL) was added to a solution of 9a
(200 mg, 0.278 mmol) in dry methanol (30 mL), and the resulting
mixture was stirred at room temperature for 48 h. The precipitated
product was filtered, washed several times with methanol, and dried
under reduced pressure; 9b was obtained as a white powder. Yield:
50%. Mp: 309−310 °C. 1H NMR (400 MHz, DMSO-d6): δ 0.70 (t, J
= 7.4 Hz, 9H), 2.54 (s, 9H), 2.66 (q, J = 7.0 Hz, 6H), 5.97 (s, 6H),
8.04 (dd, J = 7.8/6.2 Hz, 3 H), 8.50 (d, J = 8.0 Hz, 3H), 8.59 (d, J =
6.1 Hz, 3H), 8.72 (s, 3H) ppm. 13C NMR (100 MHz, DMSO): δ 14.7,
17.9, 23.5, 57.1, 127.7, 128.1, 139.1, 140.9, 143.7, 146.5, 149.8 ppm.
HR-MS (ESI): calcd for C33H42F18N3P3 160.11208 [M3+], 312.65048
[M3+ + PF6−], 770.26569 [M3+ + 2PF6−]; found 160.11216,
312.65057, 770.26564.
was removed through rotary evaporation, and the crude product was
purified via column chromatography (chloroform/methanol 3/1 (v/
1
v)). Yield: 33%. Mp: 170−171 °C. H NMR (400 MHz, CDCl3): δ
1.23 (m, 9 H), 2.12 (s, 3H), 2.29 (m, 4H), 2.56 (s, 3H), 2.86 (m, 2H),
2.99 (s, 6H), 4.75 (s, 2H), 6.19 (s, 1H), 6.30 (s, 4H), 6.33 (s, 1H),
7.96 (m, 2H), 8.23 (dd, J = 8.3/1.0 Hz, 2H), 8.31 (ddd, J = 8.7/7.1/
1.3 Hz, 2H), 8.75 (s, 2H), 9.47 (s, 2H), 9.53 (d, J = 8.7 Hz, 2H) ppm.
13C NMR (100 MHz, CDCl3): δ 15.2, 15.7, 16.1, 20.1, 21.1, 24.3, 25.1,
55.7, 65.8, 113.2, 119.2, 124.9, 130.5, 134.8, 135.7, 137.2, 146.5, 146.9,
147.4, 150.0 ppm. HR-MS (ESI): calcd for C42H48Br2N4 304.19340
[M2+], 687.35069 [M2+ + Br−], found 304.19352, 687.30560. Rf = 0.52
(chloroform/methanol 3/1 (v/v)).
1,3-Bis[(3-methylquinolinium-1-yl)methyl]-5-[((4,6-dime-
thylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Hexa-
fluorophosphate (11b). To a solution of 11a (0.085g, 0.11
mmol) in methanol (15 mL) was added a solution of NaPF6 (111
mg, 0.658 mmol) in methanol (5 mL), and the resulting mixture was
stirred at room temperature for 48 h. The precipitated product was
filtered, washed several times with methanol, and dried under reduced
pressure. The solvent of the remaining solution was removed through
rotary evaporation, and the crude product was purified via column
chromatography (chloroform/methanol 3/1 (v/v)). Yield: 75%. Mp:
1
204−205 °C. H NMR (400 MHz, DMSO-d6): δ 1.07 (m, 3H), 1.30
(t, J = 7.3 Hz, 6H), 2.26 (s, 6H), 2.43 (m, 4H), 2.69 (s, 6H), 3.35 (m,
2H), 4.60 (s, 2H), 6.19 (s, 4H), 6.59 (s, 1H), 6.85 (s, 1H), 8.12 (m,
2H), 8.35 (td, J = 8.5/4.2 Hz, 3 H), 8.44 (d, J = 8.2 Hz, 2H), 8.72 (s,
2H), 9.06 (d, 2 H, J = 9.1 Hz, 2H), 9.15 (s, 2H) ppm. 13C NMR (100
MHz, DMSO-d6): δ 15.3, 15.6, 18.6, 23.3, 23.4, 27.8, 40.1, 53.7, 118.5,
126.0, 129.5, 129.9, 130.2, 132.8, 134.8, 137.3, 142.6, 145.9, 146.8,
149.1 ppm. HR-MS (ESI): calcd for C42H48F12N4P2 304.19340 [M2+],
1-[(3-Methylquinolinium-1-yl)methyl]-3,5-bis[((4,6-dime-
thylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Bromide
(10a). 1-(Bromomethyl)-3,5-bis[((4,6-dimethylpyridin-2-yl)amino)-
methyl]-2,4,6-triethylbenzene (16; 0.400 g, 0.75 mmol) and 3-
methylquinoline (19; 0.105 mL, 0.77 mmol) were dissolved in dry
dichloromethane (30 mL) and heated at reflux for 16 h. The solvent
was removed through rotary evaporation, and the crude product was
purified via column chromatography (chloroform−methanol 5/1 (v/
−
753.35153 [M2+ + PF6 ]; found 304.19345, 753.35126. Rf = 0.60
(chloroform/methanol 3/1 (v/v)).
1,3,5-Tris[(3-methylquinolinium-1-yl)methyl]-2,4,6-triethyl-
benzene Bromide (12a). 3-Methylchinoline (19; 0.304 mL, 2.270
mmol) and 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (13; 0.200
g, 0.454 mmol) were dissolved in dry dichloromethane (20 mL), and
the resulting mixture was refluxed for 48 h. Afterward the mixture was
concentrated to a volume of 5 mL and diethyl ether (5 mL) was
added. The resulting yellow precipitate was filtered and washed several
times with diethyl ether; 12a was obtained as a yellow powder. Yield:
46%. Mp: 143−144 °C. 1H NMR (400 MHz, CDCl3/MeOD-d4 10/1
(v/v)): δ 1.17 (m, 9H), 2.57 (m, 6H), 2.93 (s, 9H), 6.36 (s, 6H), 8.04
(m, 3H), 8.31 (m, 9H), 8.83 (s, 3H), 9.05 (d, J = 9.0 Hz, 3H) ppm.
13C NMR (100 MHz, CDCl3/MeOD-d4 10/1 (v/v)): δ 15.3, 19.1,
1
v)). Yield: 45%. Mp: 134−135 °C. H NMR (300 MHz, CDCl3): δ
1.23 (t, J = 7.7 Hz, 6H), 1.31 (t, J = 7.5 Hz, 3H), 2.19 (s, 6H), 2.44 (s,
6H), 2.53 (m, 4H), 2.86 (q, J = 7.5 Hz, 2H), 2.87 (s, 3H), 4.59 (d; J =
3.5 Hz, 4 H), 6.17 (s, 2H), 6.27 (s, 2H), 6.47 (s, 2H), 8.00 (m, 1H),
8.27 (m, 1H), 8.29 (m, 1H), 8.74 (s, 1H), 8.92 (s, 1H), 9.04 (d, J = 8.9
Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 16.5, 16.7, 20.1, 21.1,
23.2, 24.0, 29.7, 40.9, 55.4, 106.2, 113.5, 118.5, 122.7, 129.7, 130.1,
130.6, 134.2, 134.7, 135.6, 137.1, 141.3, 145.3, 146.4, 146.9, 148.9,
157.1, 157.2 ppm. HR-MS (ESI): calcd for C39H48BrN5 293.69885
[M+ + H+], 586.39042 [M+]; found 293.69889, 586.39017. Rf = 0.22
(chloroform/methanol 5/1 (v/v)).
24.8, 54.9, 118.3, 127.7, 129.7, 129.9, 130.5, 134.2, 135.6, 136.9,
146.73, 150.9 ppm.
1,3,5-Tris[(3-methylquinolinium-1-yl)methyl]-2,4,6-triethyl-
benzene Hexafluorophosphate (12b). To a solution of 12a (135
mg, 0.155 mmol) in methanol (10 mL) was added a solution of NaPF6
(235 mg, 1.396 mmol) in methanol (5 mL). The resulting mixture was
stirred at room temperature for 48 h. The precipitated product was
filtered, washed several times with methanol, and dried under reduced
pressure; 12b was obtained as a white powder. Yield: 40%. Mp: 207−
1-[(3-Methylquinolinium-1-yl)methyl]-3,5-bis[(4,6-dimethyl-
pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene Hexafluoro-
phosphate (10b). A solution of NaPF6 (183 mg, 0.476 mmol) in
methanol (5 mL) was added to a solution of 10a (0.110 mg, 0.165
mmol) in methanol (30 mL), and the resulting mixture was stirred at
room temperature for 48 h. The solvent was then evaporated, and the
crude product was purified via column chromatography (chloroform/
1
1
208 °C. H NMR (400 MHz, DMSO-d6): δ 1.12, (m, 9H), 2.46 (m,
methanol 3/1 (v/v)). Yield: 80%. Mp: 124−125 °C. H NMR (300
6H), 2.63 (s, 9H), 6.26 (s, 6H), 8.12 (m, 3H), 8.36 (m, 6H), 8.45 (dd,
J = 8.3/1.1 Hz, 3H) 9.00 (m, 3H), 9.17 (s, 3H) ppm. 13C NMR (100
MHz, DMSO-d6): δ 15.0, 18.5, 24.1, 54.5, 118.7, 127.7, 129.4, 130.0,
130.3, 132.6, 134.9, 137.1, 146.5, 146.7, 150.9 ppm.
MHz, CDCl3): δ 1.17 (t, J = 7.5 Hz, 6H), 1.30 (t, J = 7.4 Hz, 3H), 2.19
(s, 6H), 2.36 (s, 6H), 2.53 (m, 4H), 2.61 (s, 3H), 2.85 (q, J = 7.5 Hz,
2H), 4.48 (d; J = 3.8 Hz, 4H), 4.98 (s, 2 H), 6.04 (s, 2H), 6.32 (s, 2H),
6.36 (s, 2H), 7.97 (m, 1H), 8.25 (m, 3H), 8.73 (m, 2H) ppm. 13C
NMR (75 MHz, CDCl3): δ 15.8, 16.3, 18.7, 20.9, 23.1, 23.3, 40.1, 54.1,
105.3, 113.9, 117.6, 123.1, 129.9, 130.3, 130.8, 133.7, 134.7, 136.1,
137.3, 145.3, 145.4, 147.1, 148.5, 149.8, 154.9, 157.4 ppm. HR-MS
(ESI): calcd for C39H48F6N5P: 293.69885 [M+ + H+], 586.39042
[M+], 732.36243 [M++PF6−+H+], found 293.69896, 586.39037,
732.36236. Rf = 0.41 (chloroform/methanol 3/1 (v/v)).
Binding Studies. The 1H NMR titrations were carried out in
D2O/DMSO-d6 and D2O/CD3CN mixtures at 25 °C. The titration
data were analyzed by nonlinear regression analysis, using the program
EQNMR. Dilution experiments show that the receptors do not self-
aggregate in the concentration range used. Stock solutions in a D2O/
DMSO-d6 or D2O/CD3CN mixture were prepared for the receptor
and the anionic sugar (used as the tetramethylammonium or
tetrabutylammonium salt). These solutions and the corresponding
solvent were combined in such a manner that the concentration of the
receptor was kept constant and that of N-acetylneuraminic acid was
varied (in the case of inverse titrations the concentration of the anionic
sugar was kept constant and that of the receptor was varied). For each
1,3-Bis[(3-methylquinolinium-1-yl)methyl]-5-[((4,6-dime-
thylpyridin-2-yl)amino)methyl]-2,4,6-triethylbenzene Bromide
(11a). 1,3-Bis(bromomethyl)-5-[((4,6-dimethylpyridin-2-yl)amino)-
methyl]-2,4,6-triethylbenzene (15; 0.360 g, 0.75 mmol) and 3-
methylquinoline (19; 0.25 mL, 1.88 mmol) were dissolved in dry
dichloromethane (40 mL) and heated at reflux for 24 h. The solvent
G
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The Journal of Organic Chemistry
Article
titration 15−20 samples were prepared (the probes were equilibrated
Chem. 2011, 9, 2319−2326. (c) Mazik, M.; Sonnenberg, C. J. Org.
Chem. 2010, 75, 6416−6423. (d) Mazik, M.; Hartmann, A. Beilstein J.
Org. Chem. 2010, 6, 9. (e) Mazik, M.; Hartmann, A.; Jones, P. G.
Chem. Eur. J. 2009, 15, 9147−9159. (f) Mazik, M.; Hartmann, A.;
Jones, P. G. Eur. J. Org. Chem. 2010, 458−463. (g) Mazik, M.;
Hartmann, A. J. Org. Chem. 2008, 73, 7444−7450. (h) Mazik, M.;
Buthe, A. C. Org. Biomol. Chem. 2008, 6, 1558−1568. (i) Mazik, M.;
Kuschel, M. Chem. Eur. J. 2008, 14, 2405−2419. (j) Mazik, M.;
Kuschel, M. Eur. J. Org. Chem. 2008, 1517−1526. (k) Mazik, M.;
Buthe, A. C. J. Org. Chem. 2007, 72, 8319−8326. (l) Mazik, M.; Cavga,
H. J. Org. Chem. 2006, 71, 2957−2963. (m) Mazik, M.; Kuschel, M.;
Sicking, W. Org. Lett. 2006, 8, 855−858. (n) Mazik, M.; Cavga, H.;
Jones, P. G. J. Am. Chem. Soc. 2005, 127, 9045−9052. (o) Mazik, M.;
Radunz, W.; Boese, R. J. Org. Chem. 2004, 69, 7448−7462. (p) Mazik,
M.; Sicking, W. Tetrahedron Lett. 2004, 45, 3117−3121. (q) Mazik,
M.; Radunz, W.; Sicking, W. Org. Lett. 2002, 4, 4579−4582. (r) Mazik,
M.; Sicking, W. Chem. Eur. J. 2001, 7, 664−670. (s) Mazik, M.;
Bandmann, H.; Sicking, W. Angew. Chem., Int. Ed. 2000, 39, 551−554.
(8) For examples of acyclic receptors with a biphenyl or
diphenylmethane scaffold, see ref 3c and: (a) Mazik, M.; Buthe, A.
1
at room temperature) and the H NMR spectra were recorded. For
1
each receptor−sugar system at least three H NMR titrations were
carried out; examples are given in Tables S1−S7 (see the Supporting
Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables and figures giving a description of the binding studies
1
and H and 13C NMR spectra of 5b−12b. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: monika.mazik@chemie.tu-freiberg.de. Tel:
03731392389; Fax: 03731393170.
■
Notes
The authors declare no competing financial interest.
C. Org. Biomol. Chem. 2009, 7, 2063−2071. (b) Mazik, M.; Konig, A. J.
̈
ACKNOWLEDGMENTS
This work was supported by the Deutsche Forschungsgemein-
schaft.
■
Org. Chem. 2006, 71, 7854−7857.
(9) (a) 2-Aminopyridines provide an excellent structural motif for
binding carbohydrates, associated with the ability to form cooperative
and bidentate hydrogen bonds with the sugar OH groups.7n,o,q (b)
For binding of cyclohexane diols and triols with compounds
incorporating 2-aminopyridine units, see: Huang, C. Y; Cabell, L. A;
Anslyn, E. V. J. Am. Chem. Soc. 1994, 116, 2778−2792.
REFERENCES
■
(1) (a) Carbohydrate Recognition: Biological Problems, Methods and
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Rojas-Aguilar, A.; Diaz, D.; Jimenez-Barbero, J.; Cuevas, G. J. Am.
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