The shortest hydrogen bond occurs in the seven-membered
ring of the glutamic acid derivative 2c, which explains the
largest downfield shift of the NH signal upon deprotonation
in this peptide. The intramolecular hydrogen bonds in the
peripheral substituents reduce the flexibility of 2a-c and
stabilize certain orientations of the carboxylate groups. Both
effects could contribute to receptor selectivity, but overall
peptides 2a-c should still be flexible enough to adapt to
the steric demand of different guest molecules.
glucosides as potential guests, saccharides that are insoluble
in pure chloroform.
Even in this competitive solvent mixture, interactions
between the cyclopeptides and carbohydrates are still detect-
able as illustrated by the effects of, e.g., 2c on prominent
signals of R-D-methylglucopyranoside in the 1H NMR
spectrum (Figure 2). Again, a small upfield shift of the signal
In the 1H NMR spectra of 2a-c in CDCl3, the signals of
all peptide protons are significantly broadened, indicating
either a slow conformational equilibrium or intermolecular
association. We still carried out initial investigations on the
monosaccharide affinity of the peptides in this solvent. A
comparison of the 1H NMR spectrum of an equimolar
mixture of R-D-octylglucopyranoside and 2c with the spectra
of the individual components at the same concentration
clearly revealed an interaction of the cyclopeptide with the
sugar. Most importantly, the prominent doublet of the
anomeric proton of the glucoside is slightly but reproducibly
shifted upfield in the presence of 2c (ca. -0.015 ppm). Such
upfield shifts are usually observed when guest molecules are
included into a receptor cavity that is lined by aromatic
subunits,7 and we believe that they also indicate complex
formation in the present case. No influence of sugar binding
on the spectrum of 2c could be detected. However, the signals
of the tetra-n-butylammonium protons are also shifted upfield
upon complex formation. This effect is strongest for the
R-CH2 protons of the cation and decreases with increasing
distance of the protons from the ammonium nitrogen. It is
reasonable to assume that in CDCl3 the anionic receptor and
the quaternary ammonium ion form a close ion pair with
the R-CH2 protons of the cation located in close proximity,
possibly even hydrogen bonded to the receptor carboxylate
groups. Hydrogen bonding capabilities of methylene groups
adjacent to ammonium centers have in fact been demon-
strated in solution and in the solid state.8 Such hydrogen
bonding would lead to a downfield shift of the R-CH2 protons
in the 1H NMR spectrum of 2c, and the upfield shift that is
observed when the guest is added therefore illustrates the
dissociation of the cation-carboxylate ion pair that precedes
sugar binding.
Figure 2. 1H NMR spectra of 2c (a), R-D-methylglucopyranoside
(c), and a 1:1 mixture of both compounds (b) in 4% CD3OD/CDCl3
(c ) 1 mM, 25 °C).
of the anomeric proton can be observed, the upfield shift of
the resonance of the sugar OCH3 group is significantly larger,
however.
Receptor 2c (and also the other two peptides) thus binds
monosaccharides in the presence of a ca. 10 000-fold excess
of methanol molecules that compete in binding to the
carboxylate groups. A Job plot furthermore revealed a
defined 1:1 stoichiometry for the complex between 2c and
R-D-methylglucopyranoside.9 This indicates that the monosac-
charide is included into the peptide cavity upon complex
formation where it can interact with all three carboxylate
groups simultaneously. Linear analogues of 2c such as the
hexapeptide 3 and the dipeptide 4 lack the preorganization
of the cyclic derivative, and their interaction with monosac-
charides is thus less specific. In the case of 4, the interaction
is in fact too weak to be determined quantitatively (∆δ <
0.001 ppm for the sugar protons), and in the case of 3, a
A competition between cation and glucoside complicates
the complex equilibrium in CDCl3, and we therefore tried
to suppress the interaction of the ammonium cation with the
peptides by increasing the polarity of the solvent. Indeed,
no significant interactions between the ammonium ions and
the carboxylate groups of the peptides were detected in
CDCl3 containing 4% CD3OD. This solvent mixture has the
additional advantages that the receptor signals in the 1H NMR
spectra become sharper, and it is possible to use methyl
(7) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303-1324.
Lhota´k, P.; Shinkai, S. J. Phys. Org. Chem. 1997, 10, 273-285.
(8) Reetz, M. T.; Hu¨tte, S.; Goddard, R. J. Am. Chem. Soc. 1993, 115,
9339-9340. Deakyne, C. A.; Meot-Ner (Mautner), M. J. Am. Chem. Soc.
1999, 121, 1546-1557. Houk, K. N.; Menzer, S.; Newton, S. P.; Raymo,
F. M.; Stoddart, J. F., Williams, D. J. J. Am. Chem. Soc. 1999, 121, 1479-
1487. Cousins, G. R. L.; Furlan, R. L. E., Ng, Y.-F., Redman, J. E., Sanders,
J. K. M. Angew. Chem., Int. Ed. Engl. 2001, 40, 423-428.
(9) We determined a 1:1 complex stoichiometry also for other receptor/
monosaccharide combinations, e.g., 2b and â-D-methylglucopyranoside. In
addition, the excellent agreement of the saturation curves obtained
experimentally in our NMR titrations with the ones calculated on the basis
of 1:1 complex formation indicates that this stoichiometry holds for all
complexes investigated (see Supporting Information).
Org. Lett., Vol. 3, No. 17, 2001
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