Evidence of nanotubular self-organization in solution and solid states of heterochiral cyclo 1:1 [/-N α-Bn-hydrazino]mers series

Article abstract of DOI:10.1021/jo502684g

The cyclization of heterochiral 1:1 [α/α-N^α-Bn-hydrazino]mers leads to the corresponding cyclotetramer and cyclohexamer 3 and 4. X-ray crystallographic analysis of 3 unveils its ability to self-assemble into nanotubular structures. Further expe

Full text of DOI:10.1021/jo502684g

Article
pubs.acs.org/joc
Evidence of Nanotubular Self-Organization in Solution and Solid
States of Heterochiral Cyclo 1:1 [α/α‑Nα‑Bn-hydrazino]mers Series
Ralph-Olivier Moussodia,† Samir Acherar,*,† Eugenie Romero,† Claude Didierjean,‡
́
and Brigitte Jamart-Gregoire*,†
†Laboratoire de Chimie Physique Macromolec
́
́
ulaire (LCPM), Universite
́
de Lorraine-CNRS, UMR 7375, 1 rue Grandville, BP 20451,
54001 Nancy cedex, France
‡Laboratoire de Crystallographie, Res
́
onance Magnet
́
ique et Model
́
isations (CRM2), Universite
́
de Lorraine-CNRS, UMR 7036,
Faculte
́
des Sciences et Technologies, BP 20239, 54506 Vandœuvre-les
̀
-Nancy cedex, France
S
* Supporting Information
ABSTRACT: The cyclization of heterochiral 1:1 [α/α-Nα-Bn-hydrazino]mers leads to the corresponding cyclotetramer and
cyclohexamer 3 and 4. X-ray crystallographic analysis of 3 unveils its ability to self-assemble into nanotubular structures. Further
experiments conducted in the solid state through SEM analyses demonstrate the capability of 3 and 4 to form aerogels consisting
of a network of nontwisted fibers, thus confirming the presence of self-organization within this series of mixed-hydrazinopeptides.
Subsequent FTIR and NMR studies demonstrate the presence of an equilibrium between monomeric (intramolecular H-bonds)
and nanotubular (intermolecular H-bonds) forms in solution. This equilibrium can be modified by varying the solvent.
angles, would form closed rings capable of stacking through
backbone−backbone H-bonding, leading to a contiguous sheet
structure. However, Ghadiri and co-workers were the first to
assemble cyclic peptide into a nanotube in 1993, which they
achieved by controlled acidification of a pH-responsive
octapeptide.7
INTRODUCTION
■
The organization of shape-persistent peptidic macrocycles into
supramolecular structures has gained considerable interest
because of the modularity of their surface and internal
diameter, which can be tuned by the choice of the individual
subunits and the length of the amino acid chain. These
noteworthy features make them good candidates for potential
applications in nanomedicine, biotechnologies, and material
science.1−3
Hassall was the first to envision the formation of theses
tubular assemblies, called nanotubes, through the self-assembly
of cyclic subunits by noncovalent processes (e.g., H-bonding,
aromatic stacking) in 1972.4 He suggested that cyclic tetramers
of alternating α- and β-amino acids would assemble through
backbone−backbone H-bonding to form hollow cylindrical
structures. This prediction was only partially validated in 1974
by a crystallographic analysis of the tetrapeptide cyclo[−(L-
Ser(OtBu)-β-Ala-Gly-β-Asp(OMe))−].5 Indeed, the peptides
were shown to organize as rings that stacked above one another
in the crystal cell. However, only two of the four amide groups
engaged in the expected inter-subunit H-bonds. During the
same year, within the context of a theoretical analysis of peptide
sequences, De Santis et al.6 concluded that peptides comprising
an even number of alternating D- and L-amino acid residues,
which display conformationally equivalent β-type dihedral
More recently, the concept of peptidic nanotubes has been
extended to cyclic pseudopeptides containing β-amino
acids,8−11 alternating α- and β-amino acids (14-membered
ring),5 vinylogous δ-amino acids (18-membered ring),12 and
oligoureas.13,14 Among these pseudopeptidic macrocycles, a
new class has been highlighted: the hydrazinopeptides. These
pseudopeptides differ from regular peptides through the
replacement of the amide bond by a hydrazide bond, extending
the concept of β-peptides (Figure 1a).15,16 Thanks to the
presence of a supplementary nitrogen, these α-hydrazinopep-
tides offer a wide variety of possible structure modifications and
novel types of secondary structure.
Le Grel and co-workers recently demonstrated that aza-β3-
cyclopeptides (i.e. hydrazinoglycine oligomers) could be
obtained from the corresponding linear oligomers.17,18 X-ray
crystallographic and NMR analyses showed that the cyclic aza-
Received: November 27, 2014
Published: March 3, 2015
© 2015 American Chemical Society
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Scheme 1. General Stepwise Strategy for Macrocyclization of
3 and 4
Figure 1. Bis-nitrogenated compounds: (a) hydrazino acid and (b)
autostructuration of a heterochiral 1:1 [α/α-Nα-Bn-hydrazino]
tetramer into γ-turns and hydrazinoturns.
β3 scaffold, as its linear precursors, is structured by a fully
cooperative intramolecular H-bonding network. This is in sharp
contrast to the nanotubular assemblies observed for β-
cyclotetrapeptides, which rely on intermolecular H-bond-
ing.10,19
Moreover, we have shown previously that heterochiral linear
pseudopeptides composed by the alternation of α-amino acids
and α-hydrazino acids can fold in solution via a succession of γ-
turns and hydrazinoturns (Figure 1b).20 This structuration is
similar to the one observed by Yang and co-workers for mixed
1:1 [α/α-aminoxy]mers, which indeed alternate γ-turns and
N−O turns.21,22
We expect these specific conformational features to enhance
macrocyclization greatly. Therefore, we propose to synthesize
the corresponding macrocyclic derivatives and to evaluate their
propensities to form tubular assemblies.
In comparison with the rich knowledge that has been
gathered on the propensity of nanotubes to self-assemble in the
solid state, less is known concerning their behavior in solution.
Herein we report and compare the conformational behavior of
heterochiral cyclo 1:1 [α/α-Nα-Bn-hydrazino]mers in the solid
state, in solution, and in the gel.
RESULTS AND DISCUSSION
■
The general stepwise strategy used to synthesize the
heterochiral cyclo 1:1 [α/α-Nα-Bn-hydrazino]mers 3 and 4 is
described in Scheme 1. Linear heterochiral tetramer 1 and
hexamer 2, respectively, were obtained by a coupling reaction
using conditions described previously.20,23 The corresponding
macrocycles 3 and 4 were obtained from the deprotected
precursors by reaction with an excess of HBTU in DCM/DMF
at 1 mM. They were isolated with very high purity in yields of
over 35%. These yields are lower than those obtained for the
cyclization of aza-β3-peptides (over 70%) performed by Le
Grel’s group.17,18 Such a discrepancy may at first be considered
rather surprising because the conformations of the aza-β3-
peptides and the α/α-hydrazinopeptides likely rely on similar
hydrazinoturn conformations.20,24,25 It should be noted,
however, that the lack of a chiral asymmetric carbon Cα
confers a specific conformational flexibility to aza-β3-peptides,
a specific feature that likely plays a role in the greater efficiency
of the macrocyclization.
Figure 2. View of the nanotubular organization of 3 in the crystal state
(X-ray): (a) side view; (b) view from the top. The intermolecular H-
bonds are marked as dashed lines. The H atoms, except those of the
NH groups, have been omitted for clarity.
collapsed and the substituents adopt pseudoequatorial posi-
tions. Moreover, all of the Nα atoms have a pyramidal
conformation with the R configuration as Cα atoms of D-
leucine residues. Thus, their side chains and the mean plane of
the ring are practically coplanar and allow tight packing of the
molecules into nanotubes. The 14-membered macrocycle
shows an all-trans conformation, as observed in most crystal
structures of α,β-cyclotetrapeptides (α,β-CTPs) described in
Single crystals of 3 suitable for X-ray crystallographic analysis
were grown by slow evaporation from a CH3CN/EtOH
solution (see pp S9 and S10 in the Supporting Information).
Tetracycle 3 crystallized in the space group C2 with four half-
molecules in the asymmetric unit (i.e. eight molecules in the
unit cell). All of independent molecules exhibited the same C2-
symmetric conformation in which the central hole of the ring is
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1
Figure 3. (a, b) Concentration-dependent H NMR (300 MHz) chemical shifts in CDCl3 (from 10−2 to 10−5 M) of (a) 3 and (b) 4. (c−f) IR
spectra in CHCl3 of (c, d) 3 (from 10−2 M to 5.10−5 M) and (e, f) 4 (from 10−2 M to 10−4 M).
the literature.5,26 In addition, the carbonyl groups, alternatively
up and down, are oriented along the C2 symmetry axis of the
ring. Analysis of the α-CTP or α,β-CTP structures deposited in
the Cambridge Structural Database (version 5.34) revealed that
one-half or less of the carbonyl groups are oriented along the
ring axis. In our case, the alignments of the carbonyl groups
allow self-assembly of the molecules in a straight line. Indeed,
each CO group is involved in a bifurcated H-bond with one
N−H and one Cα−H group. This tight packing is similar to that
observed in cyclotetraurea peptides, where each bifurcated H-
bond involves in this case both N−H groups of the urea
bond.13 Finally, the nanotubular rods are held together by
CH−π and Van Der Walls interactions.
pseudoequatorially from the exterior walls of the so-formed
nanotubes. The crystal structure revealed that the molecule
exists in a C2-symmetric conformation in which the central hole
of the peptide ring is collapsed and not large enough to
accommodate water and small ions (Figure 2).10,19 In contrast,
the conformation adopted by the cyclo α-Nα-Bn-aza-β3
tetramer in the solid state is quite different.18 The latter
assumes a monomeric form where all of the N−H and CO
bonds are involved in strong intramolecular hydrazinoturns. No
tubular structure was observed. This result demonstrates that
the presence of α-amino acid units in the cycle contributes to
decreasing the strength of the intramolecular H-bonds and
allows intermolecular interactions between NH and CO
groups.
In the solid state, the amide N−H and CO bonds are
aligned parallel to the tube length while the side chains project
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Figure 4. Temperature-dependent spectra of 3 in the gel state (toluene-d8, c = 8.6 × 10−3 M): (a) 1H NMR (300 MHz) spectra (from 5 to 95 °C);
(b, c) FTIR spectra of 3 in CHCl3 (from 25 to 95 °C).
Unfortunately, the X-ray structure of 4 could not be solved
because of the poor quality of the crystals.
bonded hydrazidic ones. Furthermore, these wavenumbers
were constant with varying concentrations of 3 in CHCl3,
confirming the exclusive presence of intramolecular H-bonding
contacts.
Concentration-dependent NMR and FTIR studies of 3
performed in CDCl3 and CHCl3, respectively, demonstrated
that the nanotubular structure is not maintained in these
solvents. A single signal could be detected for both hydrazidic
and both amidic NHs, located at 7.7 and 8.1 ppm, respectively.
This result was in agreement with a C2-symmetric con-
formation. The high values of these chemical shifts seemed also
to indicate that all of the NH protons were involved in a H-
bonding network. In addition, these chemical shifts were not
affected by a variation of the concentration (Figure 3a),
demonstrating the absence of intermolecular H-bonds. 2D
NMR analyses (see p S4 in the Supporting Information) led us
to detect two types of intramolecular H-bond networks: a
hydrazinoturn involving amidic NH and hydrazidic CO and a γ-
turn involving hydrazidic NH and amidic CO (see Figure 1).
The intramolecular H-bonding network was further con-
firmed by FTIR measurements in CHCl3 (Figure 3c,d). The
N−H stretching band of 3 was below 3400 cm−1, centered at
3296 cm−1. This observation suggested the existence of a H-
bonding network in which all of the NH protons were
involved.27 In the CO area, two bands were detected at 1650
and 1701 cm−1, assigned respectively to bonded amidic CO and
Similar to what was observed for compound 3, 1H NMR and
FTIR experiments in CDCl3 and CHCl3 demonstrated that
compound 4 did not self-assemble in CHCl3 and that all of the
NH protons were involved in an intramolecular H-bonding
network (Figure 3b,e,f). Thus, we can conclude that compound
4 did not adopt a tubular structure in solution.
When a small amount of 3 was refluxed and cooled in
toluene or dodecane, the formation of a thermoreversible
physical organogel was observed. Thermoreversible physical
organogels are the consequence of self-assembly of molecules
into fibers that trap the solvent by forming a three-dimensional
network through noncovalent cross-linked interactions.28 The
sol to gel transition can be monitored by measuring the elastic
modulus (storage modulus G′) and viscous modulus (loss
modulus G″) at a certain frequency as a function of
temperature. The rheogram on p S5 in the Supporting
Information shows the viscous (G″) and elastic (G′) response
behavior of 3 in toluene-d8 solution at the critical gelation
concentration (8.6 × 10−3 M) as a function of temperature.
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Figure 5. Representation of the equilibrium between intramolecular (solution state) and intermolecular (gel state) H-bonds of 3 in toluene-d8. The
H atoms, except those of the NH groups, have been omitted for clarity.
Figure 6. SEM images of aerogels obtained from organogels of (a) 3 in toluene (external diameters of the fibers were measured to be around 220
nm) and (b) 4 in cyclohexane (external diameters of the fibers were measured to be around 150 nm).
This graph shows the gel formation point of 3 (the intersection
of the G′ and G″ curves) at around 62 °C.
signals, we can conclude that the bands located at 1657 and
1707 cm−1 corresponded to intramolecular H-bonded amidic
and hydrazidic CO, respectively, and those located at 1647 and
1687 cm−1 to intermolecular H-bonded amidic and hydrazidic
CO, respectively.
To gain further insight into these phenomena, the behavior
of 3 in toluene-d8 was then investigated using temperature-
dependent FTIR and NMR spectroscopy from 25 °C (gel
state) to 95 °C (solution state) (Figure 4). FTIR measurements
at 25 °C showed the presence of two N−H stretching bands
characteristic of H-bonded NH groups located respectively at
3310 and 3263 cm−1. Heating the toluene-d8 gel of 3 from 5 to
95 °C led to a gradual collapse of the H-bonded NH in favor of
one band located at 3293 cm−1, as shown in Figure 4b. This
observation could be interpreted as the consequence of the
disruption of the intermolecular H-bonding network respon-
sible for the gel formation. This wavenumber was close to the
one obtained in CHCl3 and was characteristic of an
intramolecular H-bonded NH (Figure 4b). Studies of the
CO stretching bands gave rise to the same conclusion. Four
H-bonded CO, located at 1647, 1658, 1687, and 1707 cm−1
(see the deconvolution spectra on p S7 in the Supporting
Information), could be observed in the gel state (red, Figure
4c). Heating the solution led to the collapse of the bands
located at 1647 and 1687 cm−1 in favor of the peaks located at
1657 and 1707 cm−1. The shape of the spectra recorded at high
temperatures was very similar to the one obtained for 3 in
CHCl3. In agreement with the results obtained for the NH
In most of the cases reported in the literature, the gelator
NMR signals completely disappear in the gel state but are
present in the liquid state.29 This observation can be explained
by the fact that the gel fiber can be considered as a crystal of the
gelator in which the molecular motion is very limited and the
solvent molecules are excluded from the fibers. Therefore, the
1
disappearance of the H NMR peaks is considered to be one
criterion for “dry gels”. In our case, the lower the temperature,
1
the lower the visible part of the molecule in the H NMR
spectrum (Figure 4a). However, peaks were always detected,
even at 5 °C. This result suggests that some of the gelator
molecules still kept good thermal mobility in the fibers.28,30
The chemical shifts of the gelator signals were unchanged when
the temperature was varied, demonstrating that the free and
aggregate species were separated.31
1
The H NMR spectra of the gel in toluene-d8 displayed
signals that were quite different from the ones obtained in
CDCl3 at the same temperature. In the gel state (from 5 to 50
°C), several signals could be observed for hydrazidic and amidic
NHs around 7.9 and 8.4 ppm, respectively. A coalescence
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Figure 7. Comparison of the ATR-FTIR spectra in the crystal and xerogel states for (a) 3 and (b) 4.
phenomenon occurred when the temperature reached 50 °C.
We and others had already observed this phenomenon and
concluded that the NMR-visible part of the gel could be
composed of monomers but also of incipient precursors
corresponding to small associated species.28a,32 Over 55 °C, the
gel turned into a solution, and its spectrum looked like the one
obtained in CDCl3, with the presence of a unique set of signals
for amidic and hydrazidic NHs. Heating the gel finally led to
total molecular dissociation.
nanotubular structure in the gel state was also demonstrated by
powder X-ray diffraction (XRD) analysis. The XRD data for the
aerogel of 3 exhibited a stacking pattern that was very similar to
the one observed in the crystal structure, indicating that the
molecules in the gel state adopted a similar packing mode
(nanotubular structure) as in the crystal structure (Figure 8).
Interestingly, an organogel of 4 could be obtained only in
cyclohexane and was transformed into the corresponding
aerogel. SEM analysis confirmed also the presence of
All of these observations are in agreement with the presence
of a slow equilibrium between monomeric and nanotubular
forms in the gel state (Figure 5). These nanotubes could be
associated through π−π stacking interactions between the
aromatic segments in the gel.
The removal of all of the solvent using a supercritical CO2
drying process led to the formation of the corresponding
aerogel33 (see p S11 in the Supporting Information). SEM
analysis performed on this dried material confirmed the
presence of nontwisted fibers (Figure 6a). The diameter of
these fibers was evaluated to be around 220 nm.
Comparison of the ATR-FTIR spectra of the xerogel
(obtained by slow evaporation of the organogel state in air)
and the crystal showed the presence of two N−H stretching
bands located at 3263 and 3310 cm−1 and two small CO
stretching bands at 1647 and 1687 cm−1 (Figure 7a). In
agreement with the previous results, small bands located at
1657 cm−1 (see the deconvolution spectra on p S8 in the
Supporting Information) and 1707 cm−1 could also be detected
in the xerogel, both corresponding to intramolecular CO H-
bonds. The similarity between these spectra led us to conclude
that the same nanotubular structure exists in the crystal and the
xerogel and by deduction in the organogel. The presence of a
Figure 8. XRD patterns of the aerogel of 3 (red) and the theoretical
profile calculated from its crystallographic data (blue). The powder
XRD measurement was performed using a diffractometer equipped
with a Cu tube and a Ge(111) incident-beam monochromator (λ =
1.5406 A). Data collection was carried out over the scattering angle
(θ) range of 3−55° in steps of 0.0167° over 15 h.
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Figure 9. Temperature-dependent IR spectra from 25 to 95 °C of 4 in the gel state (cyclohexane, c = 8.6 × 10−3 M).
Reactions were monitored by thin-layer chromatography (TLC)
using aluminum-backed silica gel plates. TLC spots were viewed under
UV light or/and by heating the plate after treatment with a staining
solution of phosphomolybdic acid. Chromatography was carried out
on silica gel (0.04−0.063 μm). All yields were calculated from pure
isolated products.
nontwisted fibers (Figure 6b). In the case of compound 4, the
diameter of the fibers (150 nm) was smaller than that observed
for compound 3 (220 nm). As shown in Figure 9, FTIR spectra
recorded for the organogel of 4 in cyclohexane at different
temperatures demonstrated that heating the cyclohexane
organogel from 25 to 95 °C led to a gradual collapse of the
NH bands located at 3332 and 3248 cm−1 in favor of one
located at 3221 cm−1. This last band was located much closer to
those obtained in CHCl3 and should correspond to the
signature of nonassembled molecules. Moreover, comparison of
the ATR-FTIR spectra of the xerogel and the crystal
demonstrated the same IR signature for the two states (Figure
7b). All of these results led us to conclude that compound 4
was self-assembled in the same manner in the gel and in the
crystal state.
1H and 13C NMR spectra were recorded on a 300 MHz
spectrometer. Chemical shifts (δ) are given in parts per million
relative to tetramethylsilane (TMS), and coupling constants (J) are
given in hertz. The spectra were recorded in CDCl3 solvent at room
1
temperature. TMS served as an internal standard (δ = 0 ppm) for H
NMR, and CDCl3 was used as an internal standard (δ = 77.0 ppm) for
13C NMR. Multiplicities are reported as follows: s = singlet, d =
doublet, q = quartet, m = multiplet, br = broad, Ar. = aromatic. IR
spectra were recorded over 256 scans. Electrospray ionization mass
spectrometry (ESI-MS) was performed on a ToF-Q HR spectrometer.
HRMS spectra were obtained by the ESI method. All melting points
(mp) were measured and are uncorrected.
General Ester Deprotection Procedure. To a solution of methyl
ester-protected 1 or 2 (1.0 equiv, 22 mmol) in MeOH (80 mL) was
added a solution of 1 N NaOH (2.0 equiv, 44 mmol) at 0 °C. The
mixture was vigorously stirred for 3−6 h at room temperature until
reaction completion (as monitored by TLC). After evaporation of
MeOH, the aqueous layer was washed with cyclohexane (2 × 10 mL).
The aqueous phase was cooled to 0 °C and acidified with 1 N HCl to
pH 1 and extracted with EtOAc (3 × 20 mL). The residue was dried
over MgSO4, filtered, and evaporated in vacuo to give the
corresponding carboxylic acid, which was used without further
purification.
CONCLUSION
■
The present work emphasizes the synthesis of new mixed cyclic
1:1 [α/α-Nα-Bn-hydrazino]mers and their ability to adopt two
types of self-assembly in solution, the solid state, and the gel
phase. While 3 and 4 fold into an intramolecular H-bonding
network through alternate γ-turns and hydrazinoturns in the
same way as their linear counterparts in chloroform, they are
also able to self-assemble into an intermolecular H-bond
network to form thermoreversible physical organogels. This
self-assembly occurs in specific solvents, namely, toluene and
cyclohexane for 3 and 4, respectively. Removal of the solvent by
a supercritical CO2 process gives access to the corresponding
aerogels, which reveal the existence of nontwisted fibers
through SEM analysis. The intermolecular H-bonding network
responsible for the gel formation seems to arise from
nanotubular self-organization, as demonstrated by the X-ray
crystallographic structure of 3. It is noteworthy that for 3, the
xerogel, the organogel, and the crystal present the same IR
signature and XRD pattern, thus confirming that nanotubes
also exist in solution and in the gel. Therefore, since obtaining
an organogel in cyclohexane for compound 4 is in agreement
with the presence of self-organization, we expect nanotube
formation within the molecules.
General Boc Deprotection and Macrocyclization Proce-
dures. To a stirred solution of a Boc-protected compound (1.0
equiv, 9 mmol) in DCM was added a portion of TFA representing
two-thirds of the quantity of DCM added. The mixture was stirred
overnight without any control by TLC. The solution was concentrated
under vacuum, and the excess of TFA was coevaporated with MeOH
and Et2O, affording the corresponding trifluoroacetate salt compound
as a white foam in quantitative yield. The crude residue was dissolved
in DCM, and DIPEA was added (4.0 equiv, 36 mmol). The solution
was added dropwise into a solution of HBTU (1.0 equiv, 9 mmol) in
DCM (the concentration was almost 1 mM in the mixture). This slow
addition ran during 7 h, and then the reaction mixture was stirred at
room temperature under nitrogen for 2 days. The volume was reduced
to around 100 mL, and the solution was washed successively with 1 N
HCl (2 × 20 mL), saturated NaHCO3 (2 × 20 mL), H2O (2 × 20
mL), and brine (2 × 20 mL) and finally dried over MgSO4 and
evaporated in vacuo to give 3 or 4 as a white solid. The resulting crude
material was purified and characterized as reported below.
EXPERIMENTAL SECTION
■
General. Unless otherwise stated, all chemicals were purchased as
the highest purity commercially available and were used without
further purification. Dry DCM was obtained by distillation over P2O5
under an argon atmosphere, MeOH was purchased in anhydrous form,
and other reagent-grade solvents were used as received.
Heterochiral Cyclotetramer [L-Leucine-Nα-benzyl-D-hydrazi-
noalanine]2 (3). White powder (2.08 g, 40%). Purified by
precipitation with Et2O/MeOH. Characterization data: mp 327 °C;
1H NMR (300 MHz, CDCl3, 10 mM) δ 0.75 (d, J = 6.3 Hz, 6H, 2 δ-
CH3 Leu), 0.78 (d, J = 6.3 Hz, 6H, 2 δ-CH3 Leu), 1.32 (d, J = 6.9 Hz,
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6H, 2 β-CH3 Ala), 1.33−1.50 (m, 4H, 2 γ-CH Leu, 1 β-CH2 Leu),
1.58−1.82 (m, 2H, 1 β-CH2 Leu), 3.42 (q, J = 6.9 Hz, 2H, 2 α-CH
Ala), 3.76 (d, J = 12.3 Hz, 2H, CH2 Nα-Bn), 3.84 (d, J = 12.3 Hz, 2H,
CH2 Nα-Bn), 4.10 (dd, J = 16.2 and 7.2 Hz, 2H, 2 α-CH Leu), 7.16−
7.28 (m, 6H, Ar.), 7.30−7.38 (m, 4H, Ar.), 7.70 (s, 2H, 2 hydrazidic
NHs), 8.14 (d, J = 9.3 Hz, 2H, 2 amidic NHs); 13C NMR (75 MHz,
CDCl3) δ 6.7 (2 β-CH3 Ala), 23.2 (4 δ-CH3 Leu), 25.4 (2 γ-CH Leu),
37.3 (2 β-CH2 Leu), 49.6 (2 α-CH Leu), 59.4 (2 α-CH Ala), 60.7 (2
CH2, Nα-Bn), 128.7 (2 CH Ar.), 129.2 (4 CH Ar.), 130.0 (4 CH Ar.),
136.6 (2 C Ar.), 170.9 (2 CO hydrazide), 173.5 (2 CO amide);
HRMS (ESI) calcd for C32H46N6O4 [M + Na]+ m/z 601.3478, found
601.3473.
(10) Seebach, D.; Matthews, J. L.; Meden, A.; Wessels, T.;
Baerlocher, C.; McCusker, L. B. Helv. Chim. Acta 1997, 80, 173.
(11) Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew. Chem.,
Int. Ed. 1999, 38, 1223.
(12) Gauthier, D.; Baillargeon, P.; Drouin, M.; Dory, Y. L. Angew.
Chem., Int. Ed. 2001, 40, 4635.
(13) Semetey, V.; Didierjean, C.; Briand, J.-P.; Aubry, A.; Guichard,
G. Angew. Chem., Int. Ed. 2002, 41, 1895.
(14) Fischer, L.; Decossas, M.; Briand, J.-P.; Didierjean, C.; Guichard,
G. Angew. Chem., Int. Ed. 2009, 48, 1625.
(15) Gunther, R.; Hofmann, H.-J. J. Am. Chem. Soc. 2001, 123, 247.
̈
(16) Lelais, G.; Seebach, D. Helv. Chim. Acta 2003, 86, 4152.
Heterochiral Cyclohexamer [L-Leucine-Nα-benzyl-D-hydrazi-
noalanine]3 (4). White powder (3.13 g, 35%). Purified by flash
chromatography with EtOAc/MeOH = 95:5. Characterization data:
(17) Le Grel, P.; Salaun, A.; Potel, M.; Le Grel, B.; Lassagne, F. J.
̈
Org. Chem. 2006, 71, 5638.
(18) Salaun, A.; Mocquet, C.; Perochon, R.; Lecorgne, A.; Le Grel,
̈
1
mp 163 °C; H NMR (300 MHz, CDCl3, 10 mM) δ 0.80 (d, J = 6.3
B.; Potel, M.; Le Grel, P. J. Org. Chem. 2008, 73, 8579.
(19) Clark, T. D.; Buehler, L. K.; Ghadiri, M. R. J. Am. Chem. Soc.
1998, 120, 651.
Hz, 9H, 3 δ-CH3 Leu), 0.87 (d, J = 7.2 Hz, 9H, 3 δ-CH3 Leu), 1.13 (d,
J = 7.2 Hz, 9H, 3 β-CH3 Ala), 1.51−1.69 (m, 9H, 3 γ-CH Leu, 3 β-
CH2 Leu), 3.43 (q, J = 7.2 Hz, 3H, 3 α-CH Ala), 3.82−3.99 (m, 9H, 3
CH2 Nα-Bn, 3 α-CH Leu), 7.18−7.39 (m, 15H, Ar.), 8.38 (s, 3H, 3
hydrazidic NHs), 9.37 (br d, J = 5.4 Hz, 3H, 3 amidic NHs); 13C NMR
(75 MHz, CDCl3) δ 12.3 (3 β-CH3 Ala), 22.7 (3 δ-CH3 Leu), 23.6 (3
δ-CH3 Leu), 25.2 (3 γ-CH Leu), 37.6 (3 β-CH2 Leu), 50.8 (3 α-CH
Leu), 60.9 (3 CH2 Nα-Bn), 62.4 (3 α-CH Ala), 128.6 (3 CH Ar.),
129.1 (6 CH Ar.), 129.9 (6 CH Ar.), 136.7 (3 C Ar.), 173.0 (3 CO
hydrazide), 175.6 (3 CO amide); HRMS (ESI) calcd for
C48H69N9O6 [M + Na]+ m/z 890.5269, found 890.5263.
(20) (a) Acherar, S.; Salaun, A.; Le Grel, P.; Le Grel, B.; Jamart-
̈
Greg
Acherar, S.; Bordessa, A.; Vanderesse, R.; Jamart-Greg
Tetrahedron 2012, 68, 4682.
́
oire, B. Eur. J. Org. Chem. 2013, 5603. (b) Moussodia, R.-O.;
́
oire, B.
(21) Yang, D.; Ng, F.-F.; Li, Z.-J.; Wu, Y.-D.; Chan, K. W. K.; Wang,
D.-P. J. Am. Chem. Soc. 1996, 118, 9794.
(22) Yang, D.; Li, W.; Qu, J.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem. Soc.
2003, 125, 13018.
(23) Acherar, S.; Jamart-Greg
6377.
́
oire, B. Tetrahedron Lett. 2009, 50,
ASSOCIATED CONTENT
* Supporting Information
(24) Salaun, A.; Potel, M.; Roisnel, T.; Gall, P.; Le Grel, P. J. Org.
̈
■
Chem. 2005, 70, 6499.
S
Copies of 1H and 13C NMR spectroscopic data for compounds
3 and 4, portion of the 2D NOESY NMR spectroscopic data
and rheological data for compound 3, IR and ATR-FTIR
spectra (deconvolution) for compound 3 in the gel state
(solution and xerogel, respectively), crystallographic data (CIF)
for compound 3, and method of aerogel preparation. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(25) Salaun, A.; Favre, A.; Le Grel, B.; Potel, M.; Le Grel, P. J. Org.
̈
Chem. 2006, 71, 150.
(26) (a) Hass, K.; Ponikwar, W.; Noth, H.; Beck, W. Angew. Chem.,
̈
Int. Ed. 1998, 37, 1086. (b) Di Blasio, B.; Lombardi, A.; D’Auria, G.;
Saviano, M.; Isernia, C.; Maglio, O.; Pedone, L.; Pavone, V.
Biopolymers 1993, 33, 621.
(27) Formaggio, F.; Crisma, M.; Toniolo, C.; Broxterman, Q. B.;
Kaptein, B.; Corbier, C.; Saviano, M.; Palladino, P.; Benedetti, E.
Macromolecules 2003, 36, 8164.
(28) (a) Allix, F.; Curcio, P.; Pham, Q. N.; Pickaert, G.; Jamart-
́
Gregoire, B. Langmuir 2010, 26, 16818. (b) Van Esch, J. H. Langmuir
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Samir.Acherar@univ-lorraine.fr.
*E-mail: Brigitte.Jamart@univ-lorraine.fr.
■
2009, 25, 8392. (c) Hanabusa, K.; Yamada, M.; Kimura, M.; Shirai, H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1949.
(29) Cassin, G.; De Costa, C.; Van Duynhoven, J. P. M.; Agterof, W.
G. M. Langmuir 1998, 14, 5757.
(30) (a) Sakurai, K.; Jeong, Y.; Koumoto, K.; Friggeri, A.; Gronwald,
O.; Sakurai, S.; Okamoto, S.; Inoue, K.; Shinkai, S. Langmuir 2003, 19,
8211. (b) Wang, R.; Geiger, C.; Chen, L.; Swanson, B.; Whitten, D. G.
J. Am. Chem. Soc. 2000, 122, 2399. (c) Geiger, C.; Stanescu, M.; Chen,
L.; Whitten, D. G. Langmuir 1999, 15, 2241.
(31) Escuder, B.; Llusar, M.; Miravet, J.-F. J. Org. Chem. 2006, 71,
7747.
(32) Duncan, D. C.; Whitten, D. G. Langmuir 2000, 16, 6445.
(33) Placin, F.; Desvergne, J.-P.; Cansell, F. J. Mater. Chem. 2000, 10,
2147.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge O. Fabre for running NMR
experiments and E. Wenger for performing XRD experiments.
■
REFERENCES
■
(1) Duncan, R.; Gaspar, R. Mol. Pharmaceutics 2011, 8, 2101.
(2) Lin, Y.; Taylor, S.; Li, H.; Fernando, K. A. S.; Qu, L.; Wang, W.;
Gu, L.; Zhou, B.; Sun, Y.-P. J. Mater. Chem. 2004, 14, 527.
(3) Martin, C. R.; Kohli, P. Nat. Rev. Drug Discovery 2003, 2, 2.
(4) Hassall, C. H. Chem. Biol. Pept., Proc. Am. Pept. Symp. 3rd 1972,
153.
(5) Karle, I. L.; Handa, B. K.; Hassall, C. H. Acta Crystallogr. 1975,
B31, 555.
(6) De Santis, P.; Morosetti, S.; Rizzo, R. Macromolecules 1974, 7, 52.
(7) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324.
(8) Jagannadh, B.; Reddy, M. S.; Rao, C. L.; Prabhakar, A.; Jagadeesh,
B.; Chandrasekhar, S. Chem. Commun. 2006, 4847.
(9) Fujimura, F.; Hirata, T.; Morita, T.; Kimura, S.; Horikawa, Y.;
Sugiyama, J. Biomacromolecules 2006, 7, 2394.
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DOI: 10.1021/jo502684g
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