Induced helix of 2-(2-aminophenoxy)alkanoic acid oligomers as a δ-peptidomimetic foldamer

Article abstract of DOI:10.1016/j.tetlet.2008.05.003

Peptidomimetic foldamers were synthesized by oligomerizing derivatives of the δ-amino acid analogue, 2-(2-aminophenoxy)alkanoic acid. Single-crystal analysis of the tetramer reveals a 2₁-helical secondary structure stabilized by hydrogen bonding and the coiled stacking of aromatic rings. The M-helicity of 2-aminophenoxyacetic acid oligomers was induced by the incorporation of only a single chiral carbon of the N-terminal (R)-2-(2-nitrophenoxy)propionamide moiety. The solution state CD spectra demonstrated that the resulting helix induced a substantial Cotton effect. The secondary structure was further characterized by IR and NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2008.05.003

Tetrahedron Letters 49 (2008) 4430–4433
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Tetrahedron Letters
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Induced helix of 2-(2-aminophenoxy)alkanoic acid oligomers as a
d-peptidomimetic foldamer
*
*
Motohiro Akazome , Yuichi Ishii, Tatsuya Nireki, Katsuyuki Ogura
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Peptidomimetic foldamers were synthesized by oligomerizing derivatives of the d-amino acid analogue,
2-(2-aminophenoxy)alkanoic acid. Single-crystal analysis of the tetramer reveals a 21-helical secondary
structure stabilized by hydrogen bonding and the coiled stacking of aromatic rings. The M-helicity of
2-aminophenoxyacetic acid oligomers was induced by the incorporation of only a single chiral carbon
of the N-terminal (R)-2-(2-nitrophenoxy)propionamide moiety. The solution state CD spectra demon-
strated that the resulting helix induced a substantial Cotton effect. The secondary structure was further
characterized by IR and NMR spectroscopy.
Received 25 March 2008
Revised 1 May 2008
Accepted 2 May 2008
Available online 6 May 2008
Keywords:
Foldamers
d-Amino acid
Helical structure
Hydrogen bonding
Ó 2008 Elsevier Ltd. All rights reserved.
The term ‘foldamer’ has been abundantly used in the field of
supramolecular chemistry and refers to any functional oligomer
that folds into a conformationally ordered state by noncovalent
bonds.1 A focus of foldamer research has been to design peptidem-
imetic oligomers to form helices that are stabilized by the forma-
tion of hydrogen bonds.2,3 Along with b- and c-amino acids,4
various d-amino acids such as quinoline-derived oligoamides,5
cyclohexylether amino acids,6 carbohydrate d-amino acids,7 and
2-aminomethyl-phenyl-acetic acids8 have been used as the repeat-
ing subunits of foldamers. In this context, we were interested in
the oligomers of 2-aminophenoxyacetic acid that is regarded as a
conformationally fixed analogue of d-amino acid (Scheme 1). Here
we report that the oligomers of 2-aminophenoxyacetic acid and its
a-methyl derivative form a hybrid type of chiral helical foldamer
combining both an aromatic and an aliphatic backbone.9
Scheme 1. 2-Aminophenoxyactetic acid as d-amino acid analogue.
Our design relies on the formation of two five-membered
hydrogen bonded motifs (A and B) to stabilize the structure
(Scheme 2). A systematic survey of the Cambridge Structural Data-
base10 has indicated that motifs such as A and B have a respective
79.2% and 73.2% probability of forming intramolecular hydrogen
bonds. The combination of both motifs A and B into a 2-amino-
phenoxyacetic acid oligomer will result in the formation of a
three-centered hydrogen bond, where the hydrogen of the amide
group binds to both of the neighboring ether oxygen atoms. In
other words, the ether oxygen acts as an acceptor of two amide
hydrogens to form a chelated (or bifurcated) hydrogen bond. If
the three-centered and the bifurcated hydrogen bonding elements
Scheme 2. Folding of compound 13 by two motifs of hydrogen bonding.
are sequentially repeated to form a concave network, a new type of
helical foldamer should be formed.
The methods for synthesizing the oligomers (4, 6, and 8) are
summarized in Scheme 3. Although standard peptide synthesis
* Corresponding authors. Tel.: +81 43 290 3369; fax: +81 43 290 3401.
E-mail address: akazome@faculty.chiba-u.jp (M. Akazome).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.003

M. Akazome et al. / Tetrahedron Letters 49 (2008) 4430–4433
4431
Scheme 3. Synthetic routes to compounds 10–13.
requires the protection of the amino acid prior to coupling, we
have developed a route which bypasses the protection of the ami-
no group: we employed a nitro group as a synthetic precursor of
the amino group. Since nitro group is tolerant to the coupling
reaction of a carboxyl acid with an amine, we transformed it into
the amino group after the coupling reaction. The starting materials
are commercially available 2-nitrophenoxyacetic acid (1) and
chiral (R)-2-(2-nitrophenoxy)propionic acid (9) that can be
prepared by the Mitsunobu reaction11 of (S)-lactic acid and 2-nitro-
phenol. The achiral oligomer (4) was synthesized from 1 by
coupling with 2-methoxyaniline (2) and subsequent reduction.
For the coupling reaction, we utilized standard conditions using
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) and
1-hydroxy-1H-benztriazole (HOBt).12 The resulting 4 is the starting
material for the preparation of 6, which is the synthetic precursor
of 8. A series of compounds (10–13) was synthesized by repeating
these steps.
In Figure 1, the CD spectra of compound 12 in methanol, dichloro-
methane, and cyclohexane are shown. Among these solvents,
methanol affords the weakest Cotton effect presumably because
the solvent competes with hydrogen bonding which stabilizes
the folded structure. In cyclohexane, inclusion of a single N-termi-
nal chiral carbon of the trimer induced a strong Cotton effect in the
CD spectrum, which suggesting the helical induction and main
chain propagation.
Thus, we measured the CD spectra of compounds (10–13) in
either cyclohexane or a mixture of cyclohexane and dichlorometh-
ane (19:1) (when required by limited solubility in cyclohexane)
(Fig. 2). The Cotton effect observed in the CD spectra of compound
12 showed a strong induced Cotton effect, whereas with the
shorter oligomers 10 and 11 it was not as pronounced. Surpris-
ingly, the longest oligomer 13 displayed a slightly weaker CD sig-
nal than that of 12 in the same solvent. However, the molar
absorptivity of 13 was comparable to the compound 12 in inten-
In order to characterize the folding of the compounds (10–13)
in a solution, their circular dichroism (CD) spectra were measured.
Figure 1. Solvent effect on CD (top) and UV (bottom) spectra of 12 (3.0 Â 10À5 M).
Figure 2. CD (top) and UV (bottom) spectra of 10–13 (3.0 Â 10À5 M).

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M. Akazome et al. / Tetrahedron Letters 49 (2008) 4430–4433
sity, suggesting a. hypochromic effect caused by the stacking of the
benzene rings. As CD essentially explores the anisotropy of a com-
pound’s UV spectra, hypochromic effects should carry over into the
CD, thereby leading us to conclude that a more direct method was
required to determine the structure. Single-crystal X-ray analysis
of compound 13 (vide infra) confirmed the stacking of the benzene
rings. Similar hypochromism has been demonstrated in the DNA
duplex13 and also artificial foldamers14 with stacked aromatic
rings.
The CD spectra of these oligomers demonstrate that a single
chiral center at the N-terminus can induce helical structure
through an extended oligomer. However, it is difficult to estimate
the degree of formation of the helix in solution. For example, as
mentioned above, solvent can interrupt the hydrogen bond net-
work to destabilize the helical state of 12. Fortunately, single-crys-
tal X-ray analysis could be performed to reveal that the solid state
structure of compound 13 folds itself into 21-helical conformation
(Fig. 3).15 Clearly, the chirality of the (R)-2-(2-nitrophenoxy)propi-
onamide moiety induces M-helicity, which is similar to the P-helix
per the original design. The intermolecular hydrogen bonds are
summarized in Table 1. In addition to two motifs A and B, one oxy-
gen atom of the terminal nitro group forms an additional hydrogen
bond to the network.
It is noteworthy that the benzene–benzene interactions form a
‘parallel stacked and displaced’ structure in the helical structure16
with the ring center-ring center distances of 5.05, 5.10, and 5.15 Å,
respectively (Fig. 4). This stacking geometry would not only stabi-
lize the folding structure to some extent and but would also lead to
the hypochromic effect observed in a case of 13 in Figure 2. Similar
aromatic interactions are observed in natural proteins17 as well as
artificial supramolecular aggregates.18
It is significant that a single chiral carbon can induce an M-heli-
cal structure to propagate through multiple achiral residues.5c,19
Also significant is that the 21-helical structure of the 2-(2-amino-
phenoxy)alkanoic acid oligomer will project its side chains in good
alignment (4.67, 5.16, and 5.19 Å compared to 5.4 Å) with that of
the distance between side chains exhibited by an a-peptidic 3.61
helix in natural proteins (Fig. 4).4a
(a-helix) common to natural
L
-amino acid-based peptides.
Solid-state IR spectra showed an amide H–N peak at 3399 cmÀ1
and CO 1685 cmÀ1. Even in the solution (5 mM in CHCl3), both IR
As shown in schematic drawing in Figure 3b, hydrogen bonding
plays an important role in folding the chain. As predicted, two
hydrogen bonding motifs (A and B) combine to form the alternat-
ing three-centered and bifurcated hydrogen bonding network as
bands of compound 13 are located at 3401 cmÀ1 and 1685 cmÀ1
,
respectively, which are consistent with those of a solid state. These
Table 1
Intramolecular hydrogen bonding of compound 13a
H-bonding
r/Å
h/°
93.8
101.0
101.3
93.9
d/Å
N2–H2Á Á ÁO5
N3–H3Á Á ÁO7
N4–H4Á Á ÁO9
N5–H5Á Á ÁO11
2.50
2.27
2.29
2.34
2.62
2.59
2.60
2.56
H-bonding
r/Å
h/°
d/Å
N2–H2Á Á ÁO3
N3–H3Á Á ÁO5
N4–H4Á Á ÁO7
N5–H5Á Á ÁO9
2.30
2.26
2.27
2.31
106.3
110.1
109.4
105.8
2.68
2.70
2.69
2.69
H-bonding
r/Å
h/°
d/Å
N2–H2Á Á ÁO1
2.50
162.1
3.35
a
Hydrogen atoms were placed in calculated positions (N–H bond: 0.88Å)
Figure 3. Crystal structure of 13 (only backbone atoms are shown as capped sticks):
(a) top view; (b) schematic drawing of intramolecular hydrogen bonds; (c) side
view.
Figure 4. Crystal structure of 13: distances between centroids (green balls) of
benzene rings and distances between peptidemimetic a-carbons (orange).

M. Akazome et al. / Tetrahedron Letters 49 (2008) 4430–4433
4433
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4.75) have geminal coupling (J = 15 Hz). However, no geminal cou-
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In summary, we have prepared a new class of foldamers based
on peptidomimetics of d-amino acids stabilized by a complex
hydrogen bonded network. These foldamers will provide a type
of structured artificial peptides with possible applications to
biochemistry and drug design. Our ongoing research is focused
on further characterizing the structure and properties of these
novel foldamers in detail.
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Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Re-
search (C) (No. 18550117) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
15. Crystal data for 13: Crystallization, C40H37N5O11, Mr = 763.75, colorless plate,
crystal size 0.31 Â 0.10 Â 0.06 mm3, orthorhombic, space group P212121,
a = 9.7196(8), b = 13.5602(11), and c = 27.374(2) Å, V = 3607.9(5) Å3,
Supplementary data
T = 173 K, Z = 4, Dc = 1.406 g cmÀ3
, , k = 0.71073 Å, 16882
l = 0.104 mmÀ1
reflections collected, 6159 (Rint = 0.0481) independent reflections, 508 refined
parameters, R1 (I > 2r(I)) = 0.0495, wR2 (all data) = 0.1235. CCDC-682493.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.003.
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