Aromatic δ-peptides

Article abstract of DOI:10.1021/ja029887k

Oligoamides of 8-amino-2-carboxy-quinoline adopt a very stable helical conformation characterized in solution by ¹H NMR and in the solid state by single-crystal X-ray diffraction. The helix comprises only 2.5 units per turn, which represents th

Full text of DOI:10.1021/ja029887k

Published on Web 03/04/2003
Aromatic δ-Peptides
Hua Jiang,† Jean-Michel Le´ger,‡ and Ivan Huc*,†
Institut Europe´en de Chimie et Biologie, 16 aV. Pey Berland, 33607 Pessac Cedex, France, and Laboratoire de
Pharmacochimie, 146 rue Le´o Saignat, 33076 Bordeaux, France
Received December 23, 2002; E-mail: ivan.huc@iecb-polytechnique.u-bordeaux.fr
Scheme 1. Synthesis of Quinoline Monomer 1 and Structure of
Aliphatic â-, γ-, and δ-homologues of R-peptides adopt helical
Oligomers 2-8a
or linear conformations mimicking the structures and potentially
the functions of their natural counterparts.1,2 Oligoamides of
aromatic amines and acids can also fold into well-defined structures
that may prove useful in the field of peptidomimetics.1,3-5 Yet, these
compounds have been less studied despite the fact that their
conformations are often more predictable than those of their
aliphatic analogues. The predictability of the folding of an oligo-
meric molecule is largely increased when stabilizing intramolecular
interactions (e.g., hydrogen bonds) take place between consecutive
units, because it allows the extrapolation of the conformation of
short strands to longer ones. Following this principle, we have
a (a) Dimethylacetylene dicarboxylate, MeOH, room temperature; (b)
diphenyl ether, reflux; (c) BuOH, DEAD, PPh3, THF, room temperature.
designed and now report on the helix formed by oligomers of a
new quinoline-derived δ-amino acid.
i
Oligoamides of some meta-substituted pyridine- and benzene-
derived amines and acids have been shown to fold into crescent
and helical structures.3,4 In principle, a meta substitution defines
an orientation of 120° between substituents and should lead to 6
units per turn in these bent conformations. In practice, intramo-
lecular hydrogen bonding has an effect on the bending of the
strands, and helices of meta-substituted aromatic oligoamides
comprise from 4.5 to 8 units per turn, which remains larger than
the 2-4 units per turn encountered in helices of aliphatic R, â,
and γ peptides. We speculated that aromatic oligoamides with
substituents oriented at 60° (for example, ortho substituents) may
be more bent and give rise to helices with approximately 3 units
per turn. Quinoline monomer 1 was designed for this purpose. Its
nitro and ester groups can respectively be reduced to an amine and
saponified to an acid, oriented at ∼60° (Scheme 1). In oligomers
of 1, intramolecular hydrogen bonding between the amide hydrogen
and both adjacent quinoline nitrogens is expected to stabilize a bent
shape, eventually giving rise to a helix for strands as short as a
trimer.
Quinoline 1 was prepared in only three steps: addition of
2-nitroaniline to dimethyl acetylenedicarboxylate, thermal closure
of the pyridine ring, and formation of the alkyl-aryl ether using
isobutanol under Mitsunobu conditions (Scheme 1).6 This latter step
should allow the facile introduction of numerous groups other than
isobutyl in position 4 of the quinoline. Such groups, which mimic
peptide side chains, are expected to diverge from the helix and
control its physical properties (solubility, amphiphilicity, recognition
motifs). A segment doubling strategy7 involving selective depro-
tections and couplings via acid chlorides was then adopted to yield
dimer 2, tetramer 4, and octamer 8 in a convergent manner.
The 1H NMR spectra of 2-8 in CDCl3 are sharp (Figure 1) and
show no indication of hybridization into double helices or other
types of aggregates, as was observed for pyridine-derived oligo-
amides.8 The signals are spread over a large range of chemical shifts
despite the repetive nature of the sequences, suggesting different
environments of each units. Amide protons are deshielded at 10-
12.5 ppm, as is expected for a hydrogen-bonded structure. Increas-
ing strand length results in a strong shielding of aromatic, amide,
and ester protons that can be attributed to tight contacts between
aromatic rings. For example, the signal of the ester CH3 shifts from
4.23 ppm in 2 to 2.99 ppm in 8 (Figure 1), and the singlets assigned
to the protons in position 3 of the quinoline are found between
7.63 and 8.01 ppm in 2, and between 6.12 and 7.04 ppm in 8.
Upon adding chiral shift reagent Eu(hfc)3 to a CDCl3 solution
1
of 8, amide, aromatic, and ester H NMR signals split into two
signals of equal intensities, suggesting that this compound exists
as a mixture of enantiomers and that stereoselective interactions
with Eu(hfc)3 do not induce an enantiomeric excess. This is also
supported by the pattern of the signals of the OCH2 groups at 3.4-
4.4 ppm. In the absence of Eu(hfc)3, these signals appear as sharp
doublets in 2 and as diastereotopic motifs in 8. For tetramer 4,
three OCH2 doublets are seen along with a broad signal, and
diastereotopic splitting is observed only at low temperature (-20°).
This compound adopts a chiral conformation as well, but its
inversion is faster. For comparison, inversion of 8 is slow even at
high temperatures in polar solvents. For example, no coalescence
is observed at 120° in d6-DMSO (!), suggesting an exceptionally
stable chiral conformation.
All of these data are consistent with helical structures of 4 and
8 inverting slowly on the NMR time scale. ROESY experiments
on 8 show correlations between protons in position 3 of the
quinolines and protons in positions 5 and 7. We expect that these
correlations will give direct evidence of a helical structure in
solution, but we have failed in assigning these signals unambigu-
ously to the corresponding quinoline rings in the sequence.
Meanwhile, we were able to characterize the structure of 8 in the
solid state through single-crystal X-ray diffraction (Figure 2).9 It
shows a helix extending to more than three turns very similar to
the helix predicted by molecular modeling (MM3 in MacroModel).
The pitch of 8 is identical to the pitch of other helical aromatic
oligoamides and corresponds to the thickness of one aromatic ring
† Institut Europe´en de Chimie et Biologie.
‡ Laboratoire de Pharmacochimie.
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J. AM. CHEM. SOC. 2003, 125, 3448-3449
10.1021/ja029887k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
1
Figure 1. Part of the H 400 MHz NMR spectra of (a) 2, (b) 4, and (c) 8 in CDCl3.
quinoline amino acid, which adopt remarkably stable helical
conformations. Future developments include the preparation of
longer oligomers with water-soluble and amphiphilic properties.
Acknowledgment. We acknowledge support by the CNRS, the
University of Bordeaux I, the University of Bordeaux II, and the
Ministe`re de la Recherche (postdoctoral fellowship to H.J.).
Supporting Information Available: Crystallographic data in CIF
format. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
Figure 2. Side view and top view of the structure of 8 in the crystal.
Included solvent molecules, hydrogens, and isobutyl chains have been
omitted for clarity.
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(3.4 Å).3-5 The inner rim of the helix accomplishes approximately
one turn every 15 main chain atoms and adopts a conformation
similar to that of a pentaaza-15-crown-5 macrocycle, with alternat-
ing amido and pyrido nitrogens. Thus, almost exactly 5 units are
required for two helical turns (equivalent to 30 atoms of the inner
rim), which corresponds to the highest curvature reached by helical
aromatic oligoamides until now. Consequently, helices of quinoline-
derived 4-8 also have the largest length per number of units: the
helix of octamer 8 is about 13 Å long, as compared to 6.8 Å for
octamers of pyridine oligoamides.3 The amido protons fill the helix
hollow and completely prevent penetration of solvent molecules.
As expected, they are all involved in two hydrogen bonds with the
adjacent quinoline nitrogens that set the orientation of the amido
and quinoline moieties (Scheme 1). The relative inclination of
consecutive units can be estimated from the torsion angles between
the N(1)-C(2) bond of a quinoline and the C(8)-C(9) of the next
quinoline which range from 159.2 to 169.5°. The isobutyl chains
adopt various conformations. On the contrary, the core of the helix
has a very regular structure, illustrated by almost constant distances
between the oxygens in position 4 of the quinolines (from 11.87 to
11.93 Å). Bending is even along the strand and does not depend
on the central or terminal position of the units, or the conformation
of the side chain or interactions associated with crystal packing.
In summary, we have presented a new class of aromatic
foldamers based on an easily accessible and functionalizable
(3) Singha, N. C.; Sathyanarayana, D. N. J. Mol. Struct.1997, 403, 123-
135. Berl, V.; Huc, I.; Khoury, R. G; Lehn, J.-M. Chem.-Eur. J. 2001, 7,
2798-2809. Huc, I.; Maurizot, V.; Gornitzka, H.; Le´ger, J.-M. Chem.
Commun. 2002, 578-579.
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(6) All new compounds were characterized by 1H and 13C NMR and HRMS,
and several of them were characterized by X-ray diffraction. Experimental
details will be published elsewhere.
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(9) Crystal data for 8: crystallization solvent/precipitant chlorobenzene/hexane,
monoclinic, space group C2/c, color yellow, a ) 46.711(2), b ) 18.829(2),
c ) 30.085(2) Å, â ) 96.79(2)°, T ) 296(2) K, Z ) 8, GOF ) 0.997.
The final R indices were R1 (I > 2σ(I)) ) 0.1373, wR2 (all data) ) 0.5130.
The poor quality of this structure is due to weak diffraction intensity and
strong disorganization of isobutyl side chains and included solvent
molecules. However, all atoms belonging to the backbone of the helix
were accurately located (equivalent isotropic displacement parameters of
0.11 Å2 or less).
JA029887K
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J. AM. CHEM. SOC. VOL. 125, NO. 12, 2003 3449