Cyclic hexapeptide of D,L-α-aminoxy acids as a selective receptor for chloride ion

Article abstract of DOI:10.1021/ja027073y

Cyclic hexapeptide 2, prepared from linear hexapeptide 1 of alternating D- and L-α-aminoxy acids, was found to adopt a C₃ symmetric and bracelet-like conformation with consecutive eight-membered-ring hydrogen bonds (N-O turns) in nonpolar solve

Full text of DOI:10.1021/ja027073y

Published on Web 09/25/2002
Cyclic Hexapeptide of D,L-r-Aminoxy Acids as a Selective Receptor for
Chloride Ion
Dan Yang,*,† Jin Qu,† Wei Li,† Yu-Hui Zhang,† Yi Ren,‡ De-Ping Wang,‡ and Yun-Dong Wu*,‡
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong, China, and Department of
Chemistry, The Hong Kong UniVersity of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
Received May 28, 2002
In recent years, significant effort has been devoted to the
investigation of the functions of foldamers, that is, oligomers of
unnatural building blocks that fold into defined secondary struc-
tures.1 For example, oligomers of â-amino acids (â-peptides) with
significant antimicrobial activities have been reported.2 Cyclic
peptides composed of D,L-R-amino acids or â3-amino acids have
been discovered to self-assemble into nanotubes and function as
transmembrane ion channels.3 These works inspired us to inves-
tigate R-aminoxy acids, a class of unnatural amino acids, for their
potential functions. Our previous work demonstrated that, as a
backbone analogue of â-amino acids, R-aminoxy acids represented
a new class of foldamers. They can induce an eight-membered-
ring intramolecular hydrogen bond (the N-O turn)4 between
adjacent residues when incorporated into peptides, and oligomers
of D-R-aminoxy acids can form right-handed 1.88 helical conforma-
tions in nonpolar solvents.5 Here we report that cyclic hexapeptide
of D,L-R-aminoxy acids can function as a selective receptor for
chloride ion.
A conformational search of model cyclic hexapeptide 3 (with
all methyl side chains) resulted in 3a as the global minimum (Figure
1).6 The backbone of 3a folds into consecutive N-O turns with
strong hydrogen bonds (d(H‚‚‚O) ) 2.05 Å, N-H‚‚‚O ) 140°)
and adopts a C3 symmetric and bracelet-like conformation, in
agreement with the fact that 2 only gave two sets of amide NH
peaks in its 1H NMR spectra. All R-protons of aminoxy acid
residues point inward, and the side chains point outward with those
of D-aminoxy acids on one face of the bracelet and those of
L-aminoxy acids on the other face. It is therefore conjectured that
2 has a polar interior and a nonpolar exterior. This is supported by
the fact that 2 has excellent solubility in nonpolar organic solvents
such as dichloromethane, diethyl ether, and benzene. The preferred
conformation of 3 is reminiscent of that of cyclodepsipeptide
valinomycin, a natural ionophore with a high selectivity for K+
ion.8 By forming consecutive 10-membered-ring intramolecular
hydrogen bonds, valinomycin also has a bracelet-like conformation
in nonpolar solvents.8
Given its bracelet-like conformation and small pore size (d )
3.22 Å from calculated structure of 3a), 2 is expected to bind small
ions. Its carbonyl groups may coordinate with cations, whereas the
amide NHs may form intermolecular hydrogen bonds with anions.
Thus, both cations and anions were screened for possible com-
plexation with 2 by using 1H NMR titration and ESI-MS methods.
Interestingly, 2 was found to bind halide ions9-11 but not alkali
metal ions.12
Linear hexapeptide 1 of alternating D- and L-R-aminoxy acids
was prepared following our previously developed convergent
1
synthetic scheme.5a The NMR study in CDCl3 showed that the
1
Figure 2 shows the amide proton region of H NMR spectra of
chemical shifts of all amide NHs of 1 were rather downfield (10.6-
11.5 ppm) and independent of concentrations,6 indicating that they
were intramolecularly hydrogen bonded with consecutive N-O
turns. Hexapeptide 1 was then deprotected at both ends and treated
with PyAOP7 to give cyclic hexapeptide 2 in 35% yield. In the 1H
NMR spectra of 2 in CDCl3,6 only two sets of sharp peaks
originating from the two aminoxy acid residues were observed. The
downfield signals of amide NHs of 2 (at 11.90 and 11.84 ppm)
were almost unchanged in the concentration range of 0.5-200 mM,
characteristic of intramolecular hydrogen bonds. This was also
corroborated by the fact that the N-H stretch frequency of 2
appeared at a lower wavenumber (3182 cm-1 at 1 mM in CH2Cl2)
than that of a typical non-hydrogen-bonded aminoxy amide N-H
(3400-3380 cm-1). Furthermore, it was found that in non-
hydrogen-bonding solvents, the NOE pattern6 of 2 was in ac-
cordance with those of N-O turns: strong NOE between NHi and
CRHi but weaker NOE between NHi+1 and CRHi.4b,5a Therefore, 2
should adopt cyclic conformations with consecutive N-O turns.
free 2 and the 1:1 mixture of 2 with Cl-, F-, and Br-, respec-
tively, at -30 °C in CDCl3. The two singlets at about 12 ppm
corresponded to the amide NHs of free 2, and the two singlets at
about 11 ppm were assigned to amide NHs of halide-bound 2.
Clearly, the selectivity of 2 for halide ions follows the order of
Cl- . F- . Br-.
In the ESI-MS spectra (-ve mode) of a 1:1 or a 1:2 mixture of
2 and Ph4PCl, only two peaks (m/z 876.5 and m/z 911.9) were
observed, corresponding to free 2 and the 1:1 complex of 2 and
Cl-, respectively. The abundance of 2‚Cl- complex was also much
higher than that of free 2.6
The association constants Ka for complexes 2‚Cl- and 2‚F-
were then calculated to be 11880 and 30 M-1, respectively, at 298
K using the van’t Hoff plots of Ka values obtained from low temper-
1
ature H NMR experiments.6 Considering the pore size of 3a and
the diameters of halides, we found that Cl- (d ) 3.34 Å) is more
suitable than F- (d ) 2.38 Å) and Br- (d ) 3.64 Å) for binding
2.13 However, the hydrogen-bonding ability of halides follows the
sequence of F- > Cl- > Br-. Our experimental results suggested
that the selectivity of 2 for halides is mainly governed by the size
complementarity rather than the hydrogen-bonding strength.
* To whom correspondence should be addressed. E-mail: (D.Y.) yangdan@
hku.hk; (Y.-D.W.) chydwu@ust.hk.
† The University of Hong Kong.
‡ The Hong Kong University of Science and Technology.
9
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J. AM. CHEM. SOC. 2002, 124, 12410-12411
10.1021/ja027073y CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
and Hong Kong Research Grants Council. Croucher Foundation
is acknowledged for Senior Research Fellowships (to D.Y. and
Y.-D.W.). D.Y. thanks Bristol-Myers Squibb for the Unrestricted
Grants in Synthetic Organic Chemistry.
Supporting Information Available: Synthetic scheme and char-
acterization data of 1 and 2; 1H NMR studies of 1 and 2; 1H NMR and
ESI-MS spectra of mixtures of 2 and Ph4PCl; determination of the
association constants for 2‚Cl- and 2‚F- complexes; calculation
procedures and the calculated energies and coordinates of 3a and 3‚Cl-
complex (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 1. HF/6-31G* optimized lowest-energy conformation of model
cyclic hexapeptide 3.
References
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Figure 2. The amide NH region of overlaid 1H NMR spectra of free 2
and the 1:1 mixture of 2 with (n-Bu)4NF, Ph4PCl, and Ph4PBr, respectively
(3 mM in CDCl3 at -30 °C).
Figure 3. The HF/6-31G* optimized lowest-energy conformation of 3‚
Cl-: top view (left) and side view (right).
The solution conformation of 2‚Cl- complex was then investi-
gated using 1H NMR techniques. In CD2Cl2, only one set of sharp
peaks was found in the 1H NMR spectrum of a 1:2 mixture of 2 (6
1
mM) and Ph4PCl at room temperature.6 The H NMR spectrum
also indicated that 2‚Cl- complex still adopted a C3 symmetrical
conformation. The HMBC spectrum revealed that amide NHs of
OLeu and OPhe switched their positions in the 1H NMR spectrum
after 2 was complexed with Cl-. The ROESY spectrum exhibited
a different NOE pattern (medium NOEs between NHi and CRHi
and also medium NOEs between CRHi and NHi+1) as compared
with that of free 2 under the same condition, indicating that the
conformation of 2‚Cl- was quite different from the bracelet-like
conformation.
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(6) See the Supporting Information.
(7) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205-
The HF/6-31G* optimized6 lowest-energy conformation of 3‚Cl-
complex is shown in Figure 3. Upon Cl- ion binding, the original
bracelet-like conformation 3a turns into a rather flat conformation
with all of the amide NHs pointing inward. The Cl- ion at the
center of 3 is hydrogen bonded to six NHs simultaneously. The
calculated H‚‚‚Cl distance and N-Η‚‚‚Cl angle are 2.40 Å and
154°, respectively. The distance between NHi and CRHi is 3.19 Å,
whereas that between CRHi and NHi+1 is 3.40 Å, matching well
with the observed NOEs for 2‚Cl- complex in solution.
In conclusion, we found that cyclic hexapeptide 2 consisting of
alternating D,L-R-aminoxy acids adopted the highly symmetrical
bracelet-like conformation, which is quite different from those of
cyclic D,L-R-peptides and â3-peptides but similar to that of
valinomycin. In contrast to valinomycin that binds cations selec-
tively, 2 showed affinities for halides with high selectivity for Cl-
ion in nonpolar solvents. The discovery of a novel chloride receptor
may open up new opportunities in the molecular design of selective
chloride sensors and transporters.
208.
(8) (a) Ovchinnikov, Yu. A.; Ivanov, V. T. Tetrahedron 1974, 30, 1871-
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442.
-
(9) No binding was detected for other anions such as HCO3-, HSO4-, H2PO4
,
HPO42-, NO2-, and N3-. 2 showed weak affinity to NO3 (Ka ) 5 M-1
-
at 298 K).
(10) For reviews on anion receptors, see: (a) Sessler, J. L.; Davis, J. M. Acc.
Chem. Res. 2001, 34, 989-997. (b) Beer, P. D.; Gale, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 486-516. (c) Snowden, T. S.; Anslyn, E. V. Curr.
Opin. Chem. Biol. 1999, 3, 740-746.
(11) For recent examples of cyclic receptors for anions, see: (a) Bucher, C.;
Zimmerman, R. S.; Lynch, V.; Kral, V.; Sessler, J. L. J. Am. Chem. Soc.
2001, 123, 2099-2100. (b) Bucher, C.; Zimmerman, R. S.; Lynch, V.;
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Sci. U.S.A. 2002, 99, 5127-5132. (f) Camiolo, S.; Gale, P. A. Chem.
Commun. 2000, 1129-1130.
(12) Our conformational search revealed that 2 was quite rigid with only a
limited number of conformations. The anion-binding conformation was
found to be the second most stable one, whereas the cation-binding
conformation was much higher in energy.
(13) Cotton, F. A.; Wilkinson, G. AdVanced Inorganic Chemistry, 5th ed.; John
Wiley & Sons: New York, 1988; p 545.
Acknowledgment. This work was supported by The University
of Hong Kong, Hong Kong University of Science and Technology,
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