and phosphate affinity independently and the ratio of the
corresponding stability constants then provided informa-
tion about binding preferences. Such studies usually do
not yield direct evidence of whether binding of one anion
could indeed be achieved in the presence of an excess of the
competing anion, however. Here, we introduce cyclopep-
quite reaching the maximum number of 12 hydrogen
bonds ideal for coordination of sulfate.8 A seam of
NH OdC hydrogen bonds between the ammonium
3 3 3
groups and the carbonyl groups of the β-alanine residues
causes additional stabilization of the complex.
Receptor 1 3HCl was obtained by reacting a parent
3
tide-based receptor 1 whose hydrochloride salt 1 3HCl
possesses appreciable sulfate affinity in water. Impor-
tantly, 1 3HCl binds to sulfate anions even in phosphate
cyclopeptide containing (4R)-4-aminoproline subunits
with Z-protected β-alanine pentafluorophenyl ester fol-
lowed by hydrogenation of the product in the presence of 3
equiv of HCl (see Supporting Information). The (4R)-4-
aminoproline subunits in the cyclopeptide originally derive
from hydroxyproline. Since natural hydroxyproline also
has the R-configuration at C-4, substitution of the hydro-
xyl group by an amino group required two steps, each
causing inversion of configuration at C-4.
3
3
buffer, hence in the presence of anions of similar structure
but with a different degree of protonation, clearly demon-
strating the high sulfate selectivity of this receptor.
Qualitative information about the interaction of 1 3HCl
3
with sulfate anions was obtained from ESI mass spectro-
metric and 1H NMR spectroscopic studies. For ESI mass
spectrometry a 1 mM solution of 1 3HCl in methanol/
3
water, 1:1 (v/v) adjusted to pH 4.8 by 40 mM acetate buffer
was used to ensure complete protonation of the receptor.
Mass spectra of this solution showed peaks of monoproto-
nated 1 [1 þ H]þ and the corresponding sodium adduct
[1 þ Na]þ in the positive mode and of the chloride adduct
[1þ Cl]ꢀ in the negative mode as the major species. Addition
of 1 equiv of Na2SO4 caused the appearance of peaks that
could be assigned to cations containing a single sulfate anion
([1 þ 3H þ SO4]þ, [1 þ 2H þ Na þ SO4]þ, [1 þ H þ 2Na þ
SO4]þ) (see Supporting Information). No peaks were found,
also not in the negative mode, correlating to ions with more
than one sulfate anion. Thus, the spectra support the
Receptor 1 is based on the anion-binding cyclic hexa-
peptide with L-proline and 6-aminopicolinic acid subunits
described by us.6 The proline subunits contain appended
β-alanine residues whose ammonium groups were ex-
pected to impart water solubility in addition to directly
contributing to anion binding by Coulomb attraction and
hydrogen bonding. Indeed, molecular modeling7 indicated
that the triprotonated form of 1 should be well suited to
interact with fully deprotonated tetrahedral oxoanions
suchassulfate. The graphical abstractshowsthe calculated
assumption that sulfate ions bind to 1 3HCl in a 1:1 fashion.
The NMR spectrum of a 1 mM solution of 1 3HCl in
3
structure of the sulfate complex of 1 3Hþ. It is evident that
3
3
aqueous acetate buffer at pH 4.8 (40 mM CD3COOD/
CD3COONa in D2O) and the spectrum obtained after the
addition of 2 equiv of Na2SO4 are depicted in Figure 1.
These spectra show that the presence of the salt causes a
downfield shift of the proline H(R) signal. According to
previous investigations this shift is a characteristic effect
of the interactions of our cyclopeptides with anions.6
three oxygen atoms of the sulfate anion can form hydrogen
bonds to the NH groups along the cyclopeptide ring. The
same oxygen atoms also form hydrogen bonds to the
ammonium groups, each of which forming an additional
hydrogen bond to the fourth sulfate oxygen atom. Thus,
the substrate is bound by altogether 9 hydrogen bonds not
ꢀ~
´
(5) (a) Beer, P. D.; Cadman, J.; Lloris, J. M.; Martınez-Manez, R.;
Padilla, M. E.; Pardo, T.; Smith, D. K.; Soto, J. J. Chem. Soc., Dalton Trans.
1999, 127–133. (b) Prohens, R.; Martorell, G.; Ballester, P.; Costa, A.
Chem. Commun. 2001, 1456–1457. (c) Arranz, P.; Bencini, A.; Bianchi,
A.; Diaz, P.; Garcıa-Espana, E.; Giorgi, C.; Luis, S. V.; Querol, M.;
´
~
~
Valtancoli, B. J. Chem. Soc., Perkin Trans. 2 2001, 1765–1770. (d) Pina,
ꢁ
M. N.; Soberats, B.; Rotger, C.; Ballester, P.; Deya, P. M.; Costa, A.
New J. Chem. 2008, 32, 1919–1923. (e) Mateus, P.; Delgado, R.;
~
ꢀ
Brandao, P.; Felix, V. J. Org. Chem. 2009, 74, 8638–8646. (f) Mateus,
~
ꢀ
P.; Delgado, R.; Brandao, P.; Carvalho, S.; Felix, V. Org. Biomol. Chem.
2009, 7, 4661–4673. (g) Jia, C.; Wu, B.; Li, S.; Yang, Z.; Zhao, Q.; Liang,
J.-J.; Li, Q.-S.; Yang, X.-J. Chem. Commun. 2010, 46, 5376–5378. (h)
Kim, J.; Juwarker, H.; Liu, X.; Lah, M. S.; Jeong, K.-S. Chem. Commun.
~
2010, 764–766. (i) Delgado-Pinar, E.; Rotger, C.; Costa, A.; Pina, M. N.;
ꢀ
ꢀ
~
Jimenez, H. R.; Alarcon, J.; Garcıa-Espana, E. Chem. Commun. 2012,
´
48, 2609–2611. (j) Young, P. G.; Jolliffe, K. A. Org. Biomol. Chem. 2012,
10, 2664–2672. (k) Huang, X.; Wu, B.; Jia, C.; Hay, B. P.; Li, M.; Yang,
X.-J. Chem.;Eur. J. 2013, 19, 9034–9041.
(6) (a) Kubik, S.; Goddard, R.; Kirchner, R.; Nolting, D.; Seidel, J.
Angew. Chem. 2001, 113, 2722–2725. Angew. Chem., Int. Ed. 2001, 40,
2648–2651. (b) Kubik, S.; Goddard, R. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 5127–5132.
Figure 1. 1H NMR spectrum of a 1 mM solution of 1 in D2O
containing 40 mM CD3CO2D/CD3CO2Na (pD 4.8) (a) and of a
respective solution containing additional 2 equiv of Na2SO4 (b).
(7) For structural optmization DFT/B3LYP/6-31G* calculations
were performed using Spartan 10 for Mac (Wavefunction, Inc.). The
conformation of the cyclopeptide was based on the crystal structure of
the unsubstituted parent compound.6a
(8) Hay, B. P.; Firman, T. K.; Moyer, B. A. J. Am. Chem. Soc. 2005,
127, 1810–1819.
Org. Lett., Vol. 15, No. 24, 2013
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