An acyclic aminonaphthyridine-based receptor for carbohydrate recognition: Binding studies in competitive solvents

Article abstract of DOI:10.1002/ejoc.200700264

¹H NMR spectroscopic and microcalorimetric titrations revealed that receptor 3b, consisting of three protonated 2-amino-1,8-naphthyridine units, binds N-acetylneuraminic acid (Neu5Ac), the most commonly occurring sialic acid, with high affinity

Full text of DOI:10.1002/ejoc.200700264

FULL PAPER
DOI: 10.1002/ejoc.200700264
An Acyclic Aminonaphthyridine-Based Receptor for Carbohydrate Recognition:
Binding Studies in Competitive Solvents
Monika Mazik*[a] and Hüseyin Cavga[a]
Keywords: Molecular recognition / Receptors / Carbohydrates / Supramolecular chemistry / Hydrogen bonds
1H NMR spectroscopic and microcalorimetric titrations re-
vealed that receptor 3b, consisting of three protonated 2-
amino-1,8-naphthyridine units, binds N-acetylneuraminic ranoside,
to sialic acid-binding proteins. Furthermore, indications for
weak binding of neutral sugars, such as methyl β- -glucopy-
-maltose and -cellobiose were provided by NMR
D
D
D
acid (Neu5Ac), the most commonly occurring sialic acid, with
high affinity in competitive solvents such as water/dimethyl
sulfoxide. Receptor 3b is able to form neutral/charge-rein-
forced hydrogen bonds and ion pairs with Neu5Ac, similar
spectroscopy. Molecular modelling calculations, synthesis
and binding studies in aqueous media are described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
range of biological processes, including different cellular re-
cognition processes.[1a,6] Specificity for Neu5Ac-containing
ligands is expressed by the hemagglutinins of numerous
viruses, notably of influenza (including H5N1 influenza A
viruses[6b]), as well as several others, such as Sendai, New-
castle disease and polyoma viruses.[1a] The design of artifi-
cial receptors for the recognition of Neu5Ac[7,8] may serve
as a basis for the development of new therapeutics or sen-
sors.
Introduction
The biological recognition processes involving neutral
sugars use hydrogen bonding (both neutral and charge-rein-
forced hydrogen bonds), CH-π interactions, metal coordi-
nation and van der Waals forces for sugar binding.[1]
Furthermore, ion pairing and ionic hydrogen bonding fav-
our the binding of ionic sugars, such as sialic acids.[1a,2] The
interactions observed in the crystal structures of protein–
carbohydrate complexes inspire the development of dif-
ferent artificial receptor structures for the recognition of
carbohydrates.[3–5] Our previous studies showed that acyclic
receptors containing two to four recognition units intercon-
nected by a phenyl or biphenyl spacer perform effective re-
cognition of carbohydrates through multiple interac-
tions.[4d–4g,4i,5] As in natural complexes, the combination of
neutral and charge-reinforced hydrogen bonds, as well as
hydrophobic interactions, provides impetus for the binding
of neutral sugars in water.[4f] Both charge-reinforced hydro-
gen bonds and ion pairs seem to be the major driving force
for the association of ionic sugars in competitive media.[4i]
In this study, we focused on the interactions of acyclic
naphthyridine-based receptor 3b with N-acetylneuraminic
acid (for α- and β-anomers, see formulas 4α and 4β) in com-
petitive media like H2O/DMSO or D2O/[D6]DMSO (1:9,
v/v). Additionally, comparative binding studies were carried
out with methyl β--glucopyranoside (6), methyl β--galac-
topyranoside (7), -maltose (8) and -cellobiose (9) (See
Figure 1). N-Acetylneuraminic acid (Neu5Ac) is the most
commonly occurring sialic acid playing a key role in a wide
Figure 1. Structures of sugars investigated in this study.
Results and Discussion
Molecular modelling studies indicated that receptor 3b,
containing three protonated 2-amino-1,8-naphthyridine
units,[9] should be able to form strong complexes with
Neu5Ac through multiple interactions (see Figures 2 and
3a–c), including ion pairing, neutral and charge-reinforced
[a] Institut für Organische Chemie der Technischen Universität
Braunschweig,
Hagenring 30, 38106 Braunschweig
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3633–3638
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3633

M. Mazik, H. Cavga
FULL PAPER
hydrogen bonds and CH–π interactions (in line with the
observations in the complexes formed between the Neu5Ac-
containing ligands and sialic acid binding lectins[1a]). The
above-mentioned noncovalent interactions should provide
impetus for effective binding of Neu5Ac in aqueous media.
Furthermore, the formation of charge-reinforced hydrogen
bonds between the ionic groups of 3b and the hydroxy
groups of neutral sugar molecules (for examples of hydro-
gen bonding motifs, see Figure 2c,d; for examples of en-
ergy-minimised structures of the 1:1 complex between 3b
and β--maltose, see Figure 3d–f) should provide the major
driving force for the complexation of neutral sugars in pro-
tic solvents (the binding of neutral sugars in aqueous media
was expected to be much less effective than that of
Neu5Ac). As in previously described artificial systems,[4d]
the participation of the central phenyl ring of 3b in CH–π
interactions with sugar CHs was expected to provide ad-
ditional stabilisation of the receptor–sugar complexes.
Figure 3. Energy-minimised structure of the (a) 1:2 complex be-
tween N1-protonated 3b and Neu5Ac 4β, (b,c) 1:2 complex between
N8-protonated 3b and Neu5Ac 4β (two different representations),
(d,e) 1:1 complex between N1-protonated 3b and β--maltose (8)
(two different representations), (f) 1:1 complex between N8-proton-
ated 3b and β--maltose (8) (MacroModel V.8.5, OPLS-AA force
field, MCMM, 50000 steps). Colour code: receptor C, blue; recep-
tor N, green; the sugar molecules are highlighted in yellow or
orange.
Figure 2. Examples of neutral/charge-reinforced hydrogen bonds
and ion pairing found by molecular modelling studies in the com-
plexes formed between receptor 3b (N1- or N8-protonated) and
(a,b,e,f) Neu5Ac 4β (Neu5Ac-I/II: two Neu5Ac molecules involved
in the formation of 1:2 receptor–sugar complexes), or (c,d) β--
maltose (8) (1:1 receptor-sugar complexes). MacroModel V.8.5,
OPLS-AA force field, MCMM, 50000 steps.
compound 2 by treatment with 2,6-diaminopyridine.[5a] The
reaction of 2 with 4,4-dimethoxy-2-butanone gave 3a (the
crystal structure of 3a is shown in Figure 4), which was fur-
ther converted into trihydrochloride 3b (see Scheme 1 and
Supporting Information).
1
Protonation of 2-amino-1,8-naphthyridine is feasible at
Comparison of the H and 13C NMR chemical shifts of
both the N-1 and N-8 positions (the protonation on N-1 3a and 3b with those of the pyridine derivatives (α-amino
would produce, for example, the hydrogen-bonding surface and methyl-substituted pyridines, before and after proton-
that is complementary to that of the carboxylate of ation, [D6]DMSO) indicates that in the case of 3b proton-
Neu5Ac, as shown in Figure 2a). According to molecular ation occurs on N-8 rather than on N-1 (for comparison of
1
modelling, both the carboxylate and the acetamido/hydroxy the H and 13C NMR chemical shifts of 3a with those of
groups of Neu5Ac should be able to participate in the bind- 3b, see Figure S1, Supporting Information; for a discussion
ing process. Examples of hydrogen bonding motifs indi- of the pH-dependence of the 13C NMR chemical shifts in
cated by molecular modelling are shown in Figure 2.
the pyridine ring, see ref.[11]).
The synthesis of 3b started from 1,3,5-tris(bromometh-
The interactions of receptor 3b[12,13] and the carbo-
1
yl)-2,4,6-triethylbenzene (1),[10] which was converted into hydrates were investigated by H NMR spectroscopy and
3634
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3633–3638

Acyclic Aminonaphthyridine-Based Receptor for Carbohydrate Recognition
Scheme 1. Reaction conditions: a) CH3CN/THF, K2CO3, 48 h (40%); b) H3PO4, 90 °C, 4 h (23%); c) CH3OH, 10% HCl.
microcalorimetry. The titration experiments were carried 1H NMR Titrations
out by adding increasing amounts of the tetramethylammo-
The complexation between receptor 3b and sugar 5 (used
nium salt of Neu5Ac (5)[14] to a solution of receptor 3b.
as an anomeric mixture; for α- and β-anomer of the tetra-
methylammonium salt of Neu5Ac, see formulas 5α and
5β)[15] in D2O/[D6]DMSO (1:9) was evidenced by several
changes in the NMR spectra (see Figure 5).[16a,16b] The up-
field shifts of the CH2, CH3 and naphthyridine CH protons
of 3b were monitored as a function of sugar concentration
(typical titration curves are shown in Figure 6 and Fig-
ure S2, Supporting Information). The signals for the naphth-
yridine CH protons moved in the range of 0.26–0.61 ppm,
whereas those for the CH2 and CH3 protons shifted in the
range of 0.11–0.20 ppm. The naphthyridine CHs broaden
during the titration and became distinct near saturation,
which occurred after the addition of approx. 2 equiv. of 5.
Both the curve fitting of the titration data[17] and the
mole ratio plots (see Figure S3, Supporting Information)
suggested the existence of 1:1 and 1:2 receptor–sugar com-
plexes in the D2O/[D6]DMSO mixture. The binding con-
Figure 4. Crystal structure of 3a.
Figure 5. Partial 1H NMR spectra (400 MHz; D2O/[D6]DMSO, 1:9) of receptor 3b after the addition of (from bottom to top) 0.00, 0.25,
0.50, 0.76, 1.01, 1.35, 1.68, 2.11, 2.53, 2.95, 3.37, 3.80, 4.22, 4.64 and 5.06 equiv. of 5 ([3b] = 0.78 m). Shown are chemical shifts of the
(a) naphthyridine CH, (b) CH2, and (c) CH3 resonances.
Eur. J. Org. Chem. 2007, 3633–3638
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3635

M. Mazik, H. Cavga
FULL PAPER
Figure 6. Plot of the chemical shifts of the naphthyridine CH (a), CH2 (b), and CH3 (c) resonances of 3b as a function of added 5 in
D2O/[D6]DMSO (1:9). The [receptor]:[sugar] ratio is marked.
stants for 3b·5 were found to be 3880 (Ka1) and 10930 –1 Microcalorimetric Titrations
(Ka2).[16c,16d]
The microcalorimetric titrations (isothermal titration cal-
The interactions between receptor 3b and neutral sugars
orimetry, ITC) were carried out in H2O/DMSO (1:9) at
6–9 in aqueous media are expectedly weaker than those ob-
298 K by use of a Thermometric titration calorimetric sys-
served with anionic sugar 5. The complexation induced
tem(Thermometric, Sweden). The reproducibility of the cal-
shifts observed after the addition of 10 equiv. of methyl β--
orimeter was checked with the complexation of Ba2+ by 18-
glucopyranoside (6), methyl β--galactopyranoside (7), -
crown-6. A solution of the tetramethylammonium salt of
maltose (8) or -cellobiose (9) into the solution of 3b in
Neu5Ac (5) (6–7 m) was titrated into a 0.66–0.90 m solu-
D2O/[D6]DMSO (1:9) were small (in the range of 0.01–
tion of receptor 3b (see, for example, the caption of Fig-
0.04 ppm), indicating weaker binding. It should be noted
ure 8). The data obtained were analysed using the Digitam
that the spectral changes observed after the addition of glu-
4.1 software provided by Thermometric (heat of dilution
copyranoside 6 (∆δ ≈ 0.04 ppm), maltose 8 (see Figure 7)
was corrected).
and cellobiose 9 were more substantial than those observed
in the presence of galactopyranoside 7 (∆δ ≈ 0.01 ppm). In
the case of neutral sugars, the formation of charge-rein-
forced hydrogen bonds between the charged groups of the
receptor and the hydroxy groups of sugar molecules seems
to be the major driving force for receptor–sugar association
in highly competitive media (see also ref.[4f]). In the case of
ionic sugars, both charge-reinforced hydrogen bonds and
ion pairs provide the major driving force for the complex-
ation in aqueous solutions.
Figure 8. ITC Titration of receptor 3b with 5 in H2O/DMSO (1:9)
at 25 °C. (a) Thermogram of the microcalorimetric titration (posi-
tive P values correspond to exothermic processes, negative P values
correspond to endothermic processes). (b) Isotherm for titration of
0.66 m 3b with 10-µL aliquots of 6.12 m 5 (40 injections). The
molar ratio of the sugar to the receptor is given (for the thermo-
dynamic parameters see Table 1).
The best fit of titration data was obtained with the mixed
1:1 and 1:2 receptor–sugar binding model. The binding
constants for 3b·5 were found to be Ka1 = 5860 and Ka2
= 10600 –1 (β2 = 6.23ϫ107 –2)[16d] and are of the same
Figure 7. Partial 1H NMR spectra (400 MHz; D2O/[D6]DMSO,
magnitude as those determined by NMR spectroscopy in
1:9) of receptor 3b before addition of guest (a), and after addition
D2O/[D6]DMSO (1:9) (the β2 values differ by a factor of
of 10 equiv. of (b) methyl β--glucopyranoside (6), (c) -maltose
about 1.4, such differences are typical for the results ob-
tained by these two methods[18]).
(8), and (d) Neu5Ac 5 ([3b] = 1.00 m). Shown are chemical shifts
of the naphthyridine CH resonances of 3b.
3636
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3633–3638

Acyclic Aminonaphthyridine-Based Receptor for Carbohydrate Recognition
Table 1. Results of microcalorimetric titrations of 3b with 5 in H2O/DMSO (1:9) at 25 °C.[a]
[b]
[b]
β1
β2
∆H1
∆H2
T∆S1
T∆S2
Ka1
Ka2
∆H1s
–12.3
∆H2s
T∆S1s
T∆S2s
(∆G)
5.86ϫ103
(–21.5)
(∆G)
1.06ϫ104
(–22.9)
5.86ϫ103
6.23ϫ107
–12.3
1.3
9.2
45.8
13.6
9.2
36.6
[a] In the ligand binding program of Digitam the equilibrium constants (βi) and the reaction enthalpies (∆Hi) for the overall reaction are
determined. β1 = Ka1 (–1); β2 = Ka1Ka2 (–2). ∆His, reaction enthalpies for the stepwise reaction (∆H1s = ∆H1; ∆H2s = ∆H2 – ∆H1). Ka
(–1); ∆G, ∆H and T∆S (kJmol–1). Errors in Ka are less than 10%. Errors in ∆H are less than 5%. [b] See ref.[16d]
The microcalorimetric data revealed that the first step is
The results obtained with 3b serve as a basis for the con-
an exothermic and entropically driven process (see Table 1), struction of new effective and selective artificial receptors
whereas the second step was determined as an endothermic for the recognition of neutral and ionic sugars in aqueous
and entropically favoured binding event (for a discussion media. Syntheses of new aminonaphthyridine-based recep-
of the energetics of protein–carbohydrate interactions, see tors including additional recognition units and different
ref.[19]).
Our previous ITC studies with benzimidazolium- and
spacers are in progress.
aminopyrimidine/guanidinium based receptors, displaying
very high affinity toward Neu5Ac, showed also that the
binding processes based on neutral/ionic hydrogen bonds
and ion pairing in aqueous media are entropically favou-
red.[4i] Our results are in agreement with ITC measurements
carried out by Diederich and coworkers.[20a] These authors
Experimental Section
1,3,5-Tris[(7-methylnaphthyridin-2-yl)aminomethyl]-2,4,6-triethyl-
benzene (3a): 1,3,5-Tris[(6-aminopyridin-2-yl)aminomethyl]-2,4,6-
triethylbenzene (2)[5a] (4.7 g, 8.9 mmol), 4,4-dimethoxy-2-butanone
(26.3 mmol) and H3PO4 (50 mL) were held at 90 °C for 4 h and
then stirred at room temperature for 2 h. The reaction mixture was
reported that the complexation of dicarboxylates by cleft- poured into water (300 mL), neutralised and extracted several times
with chloroform. The collected organic layer was dried with
MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified several times by column chromatog-
raphy (silica gel, CHCl3/CH3OH, 7:1 to 2:1). Yield: 1.3 g (23%). Rf
= 0.89 (silica gel 60 F254 plates, CHCl3/CH3OH, 2:1). M.p. 207–
208 °C. 1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.5 Hz, 9 H),
2.69 (s, 9 H), 2.82 (q, J = 7.5 Hz, 6 H), 4.74 (br. s, 3 H), 4.82 (d, J
= 3.0 Hz, 3 H), 6.58 (d, J = 8.6 Hz, 3 H), 7.04 (d, J = 8.1 Hz, 3
H), 7.72 (d, J = 8.6 Hz, 3 H), 7.79 (d, J = 8.1 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 16.9, 23.1, 25.3, 40.6, 112.1, 115.2,
118.3, 132.9, 136.2, 136.9, 144.5, 156.7, 158.4, 161.3 ppm. HRMS:
calcd. for C42H44N9 674.3719; found 674.3714.
type diamidinium receptors in protic solvents is also entrop-
ically driven.[20a] They concluded that “associations be-
tween strongly solvated organic ions by ion pairing and
ionic H-bonding in protic solvents such as MeOH or H2O
presumably are generally entropically driven”. Further-
more, Berger and Schmidtchen reported that the complex-
2–
ation of the SO4 ion by a bis(guanidinium) receptor in
CD3OD is also strongly entropically driven, with an un-
favourable enthalpic change partially compensating the en-
tropic driving force.[20b]
Trihydrochloride 3b: Compound 3a (0.1 g, 0.148 mmol) was dis-
solved in MeOH (3 mL) and HCl (1 mL, 10%) was added. The
resulting solution was stirred at room temperature for 30 min and
evaporated in vacuo. This procedure was repeated twice to obtain
trihydrochloride 3b. M.p. 237–238 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 1.16 (t, J = 9.9 Hz, 9 H), 2.78–2.82 (s + q, 9 H + 6
H), 4.80 (d, J = 3.5 Hz, 3 H), 7.33 (d, J = 12.1 Hz, 3 H), 7.48 (d,
J = 10.6 Hz, 3 H), 8.15 (d, J = 12.1 Hz, 3 H), 8.61 (d, J = 10.6 Hz,
3 H), 9.08 (br. s, 3 H), 15.29 (br. s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 15.9, 19.5, 22.8, 39.5, 116.1, 116.8, 117.8, 130.7,
Conclusions
Receptor 3b, including protonated 2-amino-1,8-naphth-
yridine subunits, was found to be an efficient receptor for
the recognition of N-acetylneuraminic acid in competitive
media. Furthermore, receptor 3b seems to be able to form
weak complexes with neutral sugar in aqueous media, as
indicated by 1H NMR spectroscopy. As in natural com-
plexes, the charge-reinforced hydrogen bonds and ion pairs
seem to be the major driving force for receptor–Neu5Ac
136.2, 143.7, 149.5, 154.8, 159.5 ppm. ESI-MS: m/z
= 676
[M – 2H]+, 338.6 [M – H]2+, 226.1 [M]3+ (C42H48N93+).
1
association in competitive media. Both the H NMR spec-
CCDC-641444 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
troscopic and the microcalorimetric titrations suggested the
formation of complexes with 1:1 and 1:2 receptor–sugar
binding stoichiometry. In D2O/[D6]DMSO (1:9) the binding
constants Ka1 and Ka2 were found to be 3880 and 10930 –1
(β2 = 4.24ϫ107 –2), respectively. The binding constants
determined on the basis of the ITC measurements in H2O/
DMSO (1:9) amounted to Ka1 = 5860 and Ka2 = 10600 –1
(β2 = 6.23ϫ107 –2). Thus, the β2 values determined by the
two methods are in the range of 107 –2. The microcalori-
metric data revealed that the complexation of 5 by receptor
3b in a H2O/DMSO mixture is an entropically favoured
binding event.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of 2, 1H und 13C NMR spectra of 3a and 3b, further
examples of titration curves, representative mole ratio plots and X-
ray data for compound 3a.
Acknowledgments
Financial support of the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. We thank Prof. Dr. R. Boese and Dipl.-
Eur. J. Org. Chem. 2007, 3633–3638
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3637

M. Mazik, H. Cavga
FULL PAPER
leaven, R. M. Strongin, J. Am. Chem. Soc. 2002, 124, 5000–
5009; e) T. Zhang, E. V. Anslyn, Org. Lett. 2006, 8, 1649–1652.
[8] For examples of reviews on anion recognition, see: a) S. Kubik,
C. Reyheller, S. Stüwe, J. Inclusion Phenom. Macrocyclic Chem.
2005, 52, 137–187; b) R. J. T. Houk, S. L. Tobey, E. V. Anslyn,
Top. Curr. Chem. 2005, 255, 199–229; c) M. D. Best, S. L. To-
bey, E. V. Anslyn, Coord. Chem. Rev. 2003, 240, 3–15; d) R. J.
Fitzmaurice, G. M. Kyne, D. Douheret, J. D. Kilburn, J. Chem.
Soc. Perkin Trans. 1 2002, 841–864; e) J. H. Hartley, T. D.
James, C. J. Ward, J. Chem. Soc. Perkin Trans. 1 2000, 3155–
3184; f) F. P. Schmidtchen, M. Berger, Chem. Rev. 1997, 97,
1609–1646; g) J. Yoon, S. K. Kim, N. J. Singh, K. S. Kim,
Chem. Soc. Rev. 2006, 35, 355–360.
[9] For a discussion of the importance of the protonation of 2-
amino-1,8-naphthyridine unit in a recognition process, see: A.
Kobori, S. Horie, H. Suda, I. Saito, K. Nakatani, J. Am. Chem.
Soc. 2004, 126, 557–562. The facile protonation of 2-amino-
naphthyridine chromophore at pH 7 was found to be responsi-
ble for the high selectivity of a naphthyridine-based sensor to
the cytosine–cytosine mismatch.
Ing. D. Bläser (Institut für Anorganische Chemie der University of
Duisburg-Essen) for performing the X-ray measurements of 3a.
[1]
a) H. Lis, N. Sharon, Lectins, Kluwer Academic Publishers,
Dordrecht, The Netherlands, 2003; b) W. I. Weiss, K. Drick-
amer, Annu. Rev. Biochem. 1996, 65, 441–473; c) H. Lis, N.
Sharon, Chem. Rev. 1998, 98, 637–674; d) F. A. Quiocho, Pure
Appl. Chem. 1989, 61, 1293–1306; e) R. U. Lemieux, Chem.
Soc. Rev. 1989, 18, 347–374.
[2]
[3]
a) P. R. Dormitzer, Z. Y. Sun, G. Wagner, S. C. Harrison,
EMBO J. 2002, 21, 885–897; b) J. N. Varghese, J. McKimm-
Breschkin, J. B. Caldwell, A. A. Kortt, P. M. Colman, Proteins
Struct. Funct. Genet. 1992, 14, 327–332.
For reviews on carbohydrate recognition with artificial recep-
tors, see: a) A. P. Davis, T. D. James in Functional Synthetic
Receptors (Eds.: T. Schrader, A. D. Hamilton), Wiley-VCH,
Weinheim, Germany, 2005, pp. 45–109; b) A. P. Davis, R. S.
Wareham, Angew. Chem. 1999, 111, 3161–3179; Angew. Chem.
Int. Ed. 1999, 38, 2979–2996; c) For a review on boronic acid
based receptors, see: T. D. James, S. Shinkai, Top. Curr. Chem.
2002, 218, 159–200.
[10] K. J. Wallace, R. Hanes, E. Anslyn, J. Morey, K. V. Kilway, J.
Siegel, Synthesis 2005, 2080–2083.
[11] E. Breitmaier, K. H. Spohn, Tetrahedron 1973, 29, 1145–1152.
[12] For complexation of pyranosides in CDCl3 with receptors con-
sisting of CONH(naphthyridine)units, see ref.[5d] and J. Cuntze,
L. Owens, V. Alcázar, P. Seiler, F. Diederich, Helv. Chim. Acta
1995, 78, 367–390.
[4] Some recent examples of receptors operating through nonco-
valent interactions:a) E. Klein, M. P. Crump, A. P. Davis, An-
gew. Chem. 2005, 117, 302–306; Angew. Chem. Int. Ed. 2005,
44, 298–302; b) H. Abe, Y. Aoyagi, M. Inouye, Org. Lett. 2005,
7, 59–61; c) M. G. J. Ten Cate, D. N. Reinhoudt, M. Crego- [13] For examples of other naphthyridine-based receptors for
Calama, J. Org. Chem. 2005, 70, 8443–8453; d) M. Mazik, H.
Cavga, P. G. Jones, J. Am. Chem. Soc. 2005, 127, 9045–9052;
e) M. Mazik, A. König, J. Org. Chem. 2006, 71, 7854–7857; f)
M. Mazik, H. Cavga, J. Org. Chem. 2006, 71, 2957–2963; g)
M. Mazik, M. Kuschel, W. Sicking, Org. Lett. 2006, 8, 855–
858; h) H. Takeharu, M. Nakamura, Y. Fukazawa, Heterocy-
cles 2006, 68, 2477–2482; i) M. Mazik, H. Cavga, J. Org. Chem.
2007, 72, 831–838; j) M. Mazik, A. König, Eur. J. Org. Chem.
2007, 3271–3276.
carbohydrates, see: a) S.-i. Tamaru, M. Yamamoto, S. Shinkai,
A. B. Khasanow, T. W. Bell, Chem. Eur. J. 2001, 7, 5270–5276;
b) J.-M. Fang, S. Selvi, J.-H. Liao, Z. Slanina, Ch. T. Chen, P.-
T. Chou, J. Am. Chem. Soc. 2004, 126, 3559–3566.
[14] Tetralkylammonium ions are commonly used as countercations
in the binding studies of anions. For a recent discussion of the
solvent and countercation effects, see: J. L. Sessler, D. E. Gross,
W.-S. Cho, V. M. Lynch, F. P. Schmidtchen, G. W. Bates, M. E.
Light, P. A. Gale, J. Am. Chem. Soc. 2006, 128, 12281–12288.
[15] For studies on mutarotation of Neu5Ac in water, see: H. Frie-
bolin, P. Kunzelman, M. Supp, R. Brossmer, G. Keilich, D.
Ziegler, Tetrahedron Lett. 1981, 22, 1383–1386.
[16] a) Dilution experiments show that receptor does not self-aggre-
gate in the used concentration range; b) four titrations were
carried out; for each titration 15–20 samples were prepared; c)
errors in Ka are Ͻ10%; d) Ka1 corresponds to the 1:1 associa-
tion constant. Ka2 corresponds to the 1:2 receptor–sugar asso-
ciation constant.
[5] a) M. Mazik, W. Radunz, R. Boese, J. Org. Chem. 2004, 69,
7448–7462; b) M. Mazik, W. Sicking, Tetrahedron Lett. 2004,
45, 3117–3121; c) M. Mazik, W. Radunz, W. Sicking, Org. Lett.
2002, 4, 4579–4582; d) M. Mazik, W. Sicking, Chem. Eur. J.
2001, 7, 664–670; e) M. Mazik, H. Bandmann, W. Sicking, An-
gew. Chem. 2000, 112, 562–565; Angew. Chem. Int. Ed. 2000,
39, 551–554.
[6] a) R. Schauer, A. K. Schukla, C. Schroder, E. Muller, Pure
Appl. Chem. 1984, 56, 907–921; b) K. Shinya, M. Ebina, S.
Yamada, M. Ono, N. Kasai, Y. Kawaoka, Nature 2006, 440,
435–436.
[17] C. S. Wilcox, N. M. Glagovich, Program HOSTEST 5.6, Uni-
versity of Pittsburgh, Pittsburgh, PA, 1994.
[7] For examples of boronic acid based receptors for N-acetylneur-
aminic acid (using covalent interactions for sugar binding), see:
a) H. Otsuka, E. Uchimura, H. Koshino, T. Okano, K. Ka-
taoka, J. Am. Chem. Soc. 2003, 125, 3493–3502; b) K. Djanash-
vili, L. Frullano, J. A. Peters, Chem. Eur. J. 2005, 11, 4010–
4018; c) M. Yamamoto, M. Takeuchi, S. Shinkai, Tetrahedron
1998, 54, 3125–3140; d) M. He, R. J. Johnson, J. O. Escobedo,
P. A. Beck, P. K. K. Kim, N. N. St.Luce, C. J. Davis, P. T.
Lewis, F. R. Fronczek, B. J. Melancon, A. A. Mrse, W. D. Tre-
[18] K. A. Connors in Comprehensive Supramolecular Chemistry
(Eds.: J. L. Atwood, J. E. D. Davis, D. D. MacNicol, F. Vögtle),
Pergamon, Oxford, UK, 1996, vol. 3, p. 233.
[19] E. J. Toone, Curr. Opin. Struct. Biol. 1994, 4, 719–728.
[20] a) F. Diederich, Helv. Chim. Acta 2000, 83, 80–92; b) M. Ber-
ger, F. P. Schmidtchen, Angew. Chem. 1998, 110, 2840–2842;
Angew. Chem. Int. Ed. 1998, 37, 2694–2696.
Received: March 26, 2007
Published Online: June 14, 2007
3638
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3633–3638