Parallel and antiparallel triple helices of naphthyridine oligoamides

Article abstract of DOI:10.1002/anie.200906401

Three, no less and no more, Is the number of naphthyridine oligoamide strands that intertwine to form a unique and robust triple helix architecture. The formation of either a parallel or antiparallel arrangement of the helical strands is governed by factors such as the polarity of the solvent (see picture). (Figure Presented)

Full text of DOI:10.1002/anie.200906401

Communications
DOI: 10.1002/anie.200906401
Helical Structures
Parallel and Antiparallel Triple Helices of Naphthyridine
Oligoamides**
Yann Ferrand, Amol M. Kendhale, Joachim Garric, Brice Kauffmann, and Ivan Huc*
The hybridization of organic strands into double helices is a
common structural pattern of biopolymers. In recent years, a
number of synthetic oligomers and polymers have also been
reported to form stable double helices[1] following original
strand–strand recognition motifs as, for example: aromatic
oligoamides based on pyridine[2] or fluoroquinoline rings;[3]
oligoresorcinols;[4] ethynylhelicene oligomers;[5] m-terphenyl
backbone oligomers exploiting amidinium–carboxylate salt
bridges;[6] and alternate sequences of aromatic hydrogen-
bond donors and acceptors.[7] However, the occurrence of
triple helices formed from the direct recognition of three
organic strands is much less common.[8] Natural triple helices
include those of collagen,[9] nucleic acids,[10] and some
polysaccharides,[11] but aside from nucleic acid analogues
(e.g. PNA),[12] artificial triple helices have not been described
to date. Herein, we report the serendipitous discovery of
stable parallel and antiparallel triple helices formed by 1,8-
naphthyridine oligoamides (Scheme 1). We found that these
oligomers can spontaneously assemble in triply stranded
structures in solution at the exclusion of any other species and
thus emerge as a robust and unprecedented triplex motif.
We and others have embarked on a systematic program
aiming at exploring the structures and functions of folded
aromatic oligoamides[1,13] driven by the hypothesis that the
chemical space offered by these foldamers may be as vast as
that of their aliphatic counterparts, namely a-peptides and
their homologues. We have reported on sequences comprised
of pyridine,[2] quinoline,[14] 8-fluoroquinoline,[3] and pyrido-
quinoline[15] monomers, as well as combinations thereof,[15,16]
and their ability to form a variety of single-helical and double-
helical architectures. Our interest for 1,8-naphthyridine
stemmed from its ability to serve as a hydrogen-bonding
unit in molecular recognition and large self-assemblies,[17] and
as a potential precursor of hollow helices.[18] We thus designed
and prepared tetrameric oligomer 1, which is composed of
four
2-amino-5-isobutoxy-1,8-naphthyridine-7-carboxylic
acid units. The synthesis of amidonaphthyridine derivatives
is notoriously tedious owing to the poor solubility and weak
reactivity of aminonaphthyridine precursors as well as the
relative instability of amide functions.[19] As shown in the
Supporting Information, these difficulties could be overcome,
and a new protected naphthyridine amino acid monomer was
prepared in four steps from 2,6-diaminopyridine on a 30 g
scale without any chromatographic purification (Scheme S1).
Key synthetic steps consisted of the addition of an amino-
pyridine onto dimethylacetylene dicarboxylate, thermal cyc-
lization of the resulting fumarate into a naphthyridone, and
the introduction of the isobutoxy side chains under Mitsu-
nobu conditions. Isobutoxy groups provided excellent solu-
bility of the monomers and oligomers in organic media as well
as high crystallinity. Amine and acid functions were protected
as tert-butyl carbamate and benzyl esters, respectively.
Oligomer synthesis was performed through selective depro-
tections and couplings using coupling agents (e.g. 1-benzo-
triazolyloxytris(pyrollidino)phosphonium hexafluorophos-
phate) to yield naphthyridine tetramer 1.
Scheme 1. Hybridization of three single-helical strands into a triple
helix through a springlike extension. Triple helices may adopt parallel
(bottom right) or antiparallel (top right) configurations. The balls at
the end of each strand discriminate the strand ends and symbolize the
strand polarity.
[*] Dr. Y. Ferrand, Dr. A. M. Kendhale, Dr. J. Garric, Dr. I. Huc
Universitꢀ de Bordeaux—CNRS UMR5248
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
Fax: (+33)5-4000-2215
E-mail: i.huc@iecb.u-bordeaux.fr
B. Kauffmann
Universitꢀ de Bordeaux—CNRS UMS3033—INSERM US001
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
[**] This work was supported by the CNRS, the University of Bordeaux I,
the French Ministry of Research and Education (predoctoral
fellowship to J.G.), and an ANR grant (NT09_478591).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906401.
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The new naphthyridine oligomer was expected to adopt a
helical conformation stabilized by conjugation between
amide and aryl units, intramolecular hydrogen bonding, and
electrostatic repulsions between amide oxygen and endocy-
clic nitrogen atoms, as for other aromatic oligoamide
foldamers.[13] Additionally, the helix cavity in 1 was expected
to be larger than of the related 8-fluoroquinoline oligoa-
mides,[3] whose cavities are partly filled with fluorine atoms.
These predictions were validated by the solid-state structure
of 1 obtained by X-ray diffraction analysis of single crystals
grown from a pyridine/hexane mixture. In this structure,
tetramer 1 adopts a single-helical conformation spanning just
over one turn and with a helix pitch of 3.5 ꢀ (Figure 1a). The
helix cavity has a diameter of 5 ꢀ and accommodates an
included pyridine solvent molecule (not shown). The single-
helical conformation also appears to prevail in solution in
pyridine, a solvent known to disfavor hybridization of
aromatic oligoamides.[20] The presence of a single set of
sharp 1H NMR signals, the low-field resonance of amide
protons (d > 12 ppm; Figure 2b), and the absence of a
diastereotopic motif of the side chains and benzylic methyl-
ene protons are consistent with a single helix that rapidly
inverts its handedness.[21] Cooling the sample or increasing the
concentration (Figure S1 and S2) only led to slight variations
in chemical shift, suggesting a poor ability of 1 to aggregate in
this solvent.
Two different crystal types of 1 were also obtained in two
separate batches of a chloroform/pyridine/hexane ternary
solvent mixture. Crystallographic analysis revealed two dis-
tinct and unprecedented triple-helical structures. The first
triplex displays a parallel orientation of the three strands
(Figure 1b); three tert-butyloxycarbonyl groups protrude at
one extremity and the three benzyl ester groups at the other.
This triplex has a perfect C3 symmetry axis coinciding with the
helix axis. In the second triplex, one strand is oriented
antiparallel to the two others, and the helix has no symmetry
element. The two structures are almost superimposable
except for the one strand that has inverted its orientation.
Interstrand interactions consist of extensive p–p contacts
between both sides of each strand with its neighbors. Triplex
formation requires a springlike extension of each strand from
its single-helical conformation to reach a triple helical pitch of
around 10.5 ꢀ. This extension is accommodated by an
increase of the twist angle between adjacent naphthyridine
rings in each strand up to an average 268 (see
Table S1 in the Supporting Information). The
triplex cavities are slightly narrower (4.3 ꢀ)
than that of the single helix as a result of the
springlike extension.
Solution studies carried out in CDCl3 and
CD3CN supported the prevalence of a mixture
of the parallel and antiparallel triplexes in both
media, at the exclusion of any other species
(Figure 2c,d). In particular, no duplex was
found, unlike in many other aromatic oligoa-
mides.[2,3] Evidence in support of this conclu-
sion is as follows: 1) ESI mass spectra showed
the almost exclusive presence of a trimer (1)3
(Figure S7). 2) 1H NMR spectra feature two
sets of signals corresponding to one species
having a single strand as its smallest asymmet-
ric unit (three distinct amide resonances), and
to another species having three strands as its
smallest asymmetric unit (nine distinct amide
resonances). This latter pattern strongly sup-
ports the presence of the antiparallel triplex,
whereas the former might arise from a variety
of species. 3) NMR spectra measured in
CD3CN/CDCl3 mixtures show chemical shift
variations and reveal that the two species with
high and low symmetry are the same in the two
solvents (Figure S6). 4) 1H DOSY experiments
of 1 in CD3CN show that the two sets of signals
belong to species having the same diffusion
Figure 1. Side views and top views in cylindrical and CPK representations of crystal
structures of 1 determined by X-ray diffraction of three independent crystals: a) 1 as a
single helix; b) (1)3 as parallel triple helix; c) (1)3 as an antiparallel triple helix. Atoms in
(a) are color coded as follows: carbon gray, hydrogen white, nitrogen blue, oxygen red.
In (b) and (c), each strand of the triplex is color coded in red, blue, and gray. The
terminal phenyl groups are shown in gold to highlight the relative orientation of the
strands in the triplexes. Included solvent molecules and isobutoxy residues are omitted
for clarity.
coefficient, that is, the same size (Figure S8).
5) Dilution studies showed no change between
the proportion of the two species, suggesting
identical molecularities. 6) Unlike in pyridine
(Figure 2b), signals of the side-chain benzylic
methylene protons in CDCl3 and CD3CN show
diastereotopic patterns (Figure 2c,d).[21]
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Communications
line did not form any triplex but only duplex
and poorly stable quadruplex structures.[3]
A
potential factor that can make any triple helix a
less likely architecture is that it requires at least
two adjacent strands to adopt a parallel ori-
entation (Scheme 1). Triple helices may thus not
be favored by strongly polar sequences possess-
ing a large macrodipole. We propose that the
very structure of naphthyridine rings is crucial
to triplex formation because, although naph-
thyridines possess a large dipole, these dipoles
are oriented in planes perpendicular to the
triple helix axis of 1 and thus do not contribute
to the helix macrodipole. In contrast, 8-fluoro-
quinoline oligoamides contribute to the helix
macrodipole and only antiparallel arrange-
ments are observed in their multiple helices,
de facto excluding triply stranded structures.
In summary, we have characterized a unique
and robust artificial triple helix architecture.
The principles governing these assemblies may
allow the design of multistranded structures
with even higher multiplicity resembling pro-
tein b-barrel architectures, for example, upon
further increasing the monomer size and helix
diameter.
Figure 2. Excerpts of 1H NMR spectra at 298 K of: a) 2 (5 mm) in CDCl3; b) 1 (5 mm)
in [D5]pyridine; c) 1 (5 mm) in CDCl3; d) 1 (5 mm) in CD3CN. Signals of the triplex in
*
*
parallel and antiparallel configurations are marked with open ( ) and filled circles ( ),
^
respectively. Methylene protons of benzyl ester groups are indicated by diamonds ( ).
The water peak in pyridine appears at around d=5.1 ppm. A few aromatic signals are
marked with a star.
Received: November 13, 2009
Published online: February 4, 2010
Diluting CD3CN or CDCl3 solutions of 1 down to 0.1 mm
did not give any sign of new lower molecularity species (e.g.
single or double helices). These experiments provided a
minimal estimate of the constant of formation of (1)3 as
Keywords: helical structures · hybridization ·
.
structure elucidation · supramolecular chemistry ·
X-ray diffraction
K
trim > 108 L2 molÀ2. Considerable broadening of NMR signals
occurred upon heating the solution or adding pyridine,
suggesting a faster exchange of the two triplexes and
presumably the emergence of single helices. In CD3CN, the
molar ratio between parallel and antiparallel triplexes is
15:85, reflecting a deviation from a statistical distribution
(i.e., equal stability) of the two species, in favor of the
antiparallel triplex. Interestingly, this ratio is almost reversed
in chloroform (75:25), revealing a strong bias in favor of the
parallel triplex.[22]
These findings bring up two questions. What factors favor
the triplex structure of 1 to such a dramatic extent, and why
are triplex structures rare in general and had never been
observed in other aromatic oligoamide foldamers? It was
demonstrated that the hybridization of multistranded helical
oligoamides is an enthalpically driven process that reflects a
balance between strong attractive interstrand p–p interac-
tions and a very unfavorable springlike extension of single
helical monomers to accommodate the other strand(s)
(Scheme 1).[15b] It was also shown that the energy cost of
springlike extension is much lower for helices with large
diameters because it can be achieved with smaller twist angles
of aryl–amide bonds than in helices with small diameters.[3,15]
The emergence of (1)3 is in agreement with these observa-
tions: a larger diameter permits an easy springlike extension
and the reciprocal intercalation of not two but three strands.
Nevertheless, oligomers related to 1 based on 8-fluoroquino-
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[20] See reference [15b] for another example. This behavior is
presumably due to very favorable interactions between aromatic
strands and the solvent, which competes with intermolecular
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[21] The P and M enantiomers of a multiple helix are expected to
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triple helix in CDCl3. Acetonitrile has a larger dipole moment
than chloroform and might have been expected to stabilize the
triple helix better. However, the C3 symmetry of chloroform
molecules may provide an interface more suited to solvate the C3
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