Amphipathic helices from aromatic amino acid oligomers

Article abstract of DOI:10.1021/jo0603577

Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally occurring molecules while at the same time introducing new structures and properties. In particular, oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived amino acids having either hydrophobic or cationic side chains are described. Their structures were characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in protic solvents, including MeOH and H ₂O. The introduction of polar proteinogenic side chains to these foldamers, as described here for the first time, promises to provide possibilities for the biological applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to their importance in a variety of biological processes, and the unique structure and properties of the quinoline-derived oligoamides may allow new structure-activity relationships to be developed.

Full text of DOI:10.1021/jo0603577

VOLUME 71, NUMBER 21
OCTOBER 13, 2006
© Copyright 2006 by the American Chemical Society
Amphipathic Helices from Aromatic Amino Acid Oligomers
Elizabeth R. Gillies,† Christel Dolain,† Jean-Michel Le´ger,‡ and Ivan Huc*,†
Institut Europe´en de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac Cedex, France, and
Laboratoire de Pharmacochimie, 146 rue Le´o Saignat, 33076 Bordeaux, France
i.huc@iecb.u-bordeaux.fr.
ReceiVed February 21, 2006
Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally
occurring molecules while at the same time introducing new structures and properties. In particular,
oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and
stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived
amino acids having either hydrophobic or cationic side chains are described. Their structures were
characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of
these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in
protic solvents, including MeOH and H2O. The introduction of polar proteinogenic side chains to these
foldamers, as described here for the first time, promises to provide possibilities for the biological
applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to
their importance in a variety of biological processes, and the unique structure and properties of the
quinoline-derived oligoamides may allow new structure-activity relationships to be developed.
Introduction
achievable with synthetic systems does not yet approach that
of natural systems, some potential advantages of the synthetic
oligomers include resistance to enzymatic degradation and
access to the vast array of functional groups available to
synthetic chemists.
Inspired by nature’s ability to create a vast array of macro-
molecular structures and functions from a relatively limited set
of monomers arranged in linear sequences, there is significant
interest in the development of synthetic oligomers that fold into
stable, well-defined conformations. These molecules, commonly
referred to as “foldamers” promise to provide new scaffolds
for a wide range of biological and materials science applica-
tions.1 While the degree of structural and functional complexity
Helices are a key structural motif in natural biopolymers, such
as proteins and DNA, and are also the most extensively
investigated foldamer architecture. Thus far, a wide variety of
synthetic oligomers ranging from â-peptides2-7 and pep-
† Institut Europe´en de Chimie et Biologie.
‡ Laboratoire de Pharmacochimie.
(1) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
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10.1021/jo0603577 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/09/2006
J. Org. Chem. 2006, 71, 7931-7939
7931

Gillies et al.
toids8-12 to aromatic oligoamides13-19 and poly(m-phenylene
ethynylene)20 have been demonstrated to fold into helical
structures. While the vast majority of reports on helical
foldamers still deal with their design, synthesis, and structural
characterization, some biological studies have recently been
reported describing the promising therapeutic potential of this
class of molecules, particularly â-peptides2,21-28 and peptoids.29-32
In our group, we have been focusing on aromatic oligoamides
that fold into helical conformations due to hydrogen bonds
between the protons of the amide functionality and the endocy-
clic nitrogens of the adjacent aromatic rings, repulsive electro-
static interactions between these nitrogen atoms and the amide
oxygens, and additional stabilization by aromatic interactions
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no chiral building blocks are involved. In addition, their helical
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acid remain folded at 120 °C in DMSO.18,34 Thus far, helices
based on aromatic amino acid monomers have not yet been
functionalized with polar peptide-like side chains for biological
applications, but their unique structures and properties relative
to R-peptides and aliphatic synthetic analogues may provide new
opportunities for structure-activity relationships in biological
systems and for the development of therapeutics. For example,
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is often dependent on the side-chain functionality and oligomer
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oligomers already possess well-defined and stable conformations
similar to those of longer oligomers. Thus, a property of a folded
oligomer may be directly related to the presence or absence of
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7932 J. Org. Chem., Vol. 71, No. 21, 2006

Amphipathic Helices from Aromatic Amino Acid Oligomers
FIGURE 1. Design of a facially amphipathic quinoline-derived helical
oligoamide having 2.5 units per turn. Hydrophilic residues are
represented in light gray and hydrophobic residues are represented in
dark gray.
FIGURE 2. Retrosynthetic analysis of two amphipathic quinoline
decamers: one having a larger hydrophobic face (above) and another
having a larger hydrophilic face (below). Both sequences can be
prepared from two monomers and a single dimer. Hydrophilic residues
are shaded in light gray while hydrophobic residues are shaded in dark
gray.
structure on their efficacy and mechanism of action still exist.
Here we report a novel series of amphipathic helices composed
of quinoline-derived amino acids. The introduction of peptide-
like side chains to these oligomers provides the first possibility
for the evaluation of this class of foldamers in biological
applications.
prepare both the series of helices having the larger hydrophobic
face and the series having the larger hydrophilic face. As shown
in Figure 2, retrosynthetic analysis of the proposed amphipathic
sequences reveals that an amphipathic decamer can be dissected
into two identical pentamers, while the pentamer can ultimately
be dissected into two identical dimers and a monomer. The
constituting dimer is the same in both series of helices, while
the monomer completing the pentamer is different in each case.
Thus, the first step in the synthesis was to prepare significant
quantities of the requisite monomer and dimer building blocks.
A trifluoroacetamide protecting group was chosen for the
pendant amine group of the hydrophilic monomer, because
experience in our group has shown that the preparation of
quinoline oligomers generally requires the activation of the
monomer or oligomer acids to acid chlorides. As this has been
accomplished in our group by heating the acids in refluxing
thionyl chloride, it is desirable to use a protecting group that is
very resistant to acid. Thus, the quinolone 155 was converted to
the protected hydrophilic monomer 2, by introduction of the
trifluoroacetamide-protected aminopropoxy side chain under
Mitsunobu conditions, as shown in Scheme 1. Monomer 2 could
then be reduced to the corresponding amine 3 by hydrogenation
of the nitro group and subsequently coupled with the previously
reported quinoline acid 4,34 following the acid’s activation with
thionyl chloride, to provide the dimer 5 (Scheme 2), the structure
of which was confirmed by single-crystal X-ray crystallography
(see Supporting Information). The preparation of key intermedi-
ate 5 is described in the Experimental Section on a 1.5-g scale,
but synthetic procedures could easily be scaled up, all the more
easily as none of them involve chromatographic purification.
With the required dimer in hand, one possible approach to
the pentamer was to couple two dimers to form a tetramer then
add the fifth monomer. One drawback to this approach is that
we have found that the activation of quinoline acids is frequently
Results and Discussion
Design. On the basis of data from X-ray crystallography18,34
and solution NMR,54 we have previously determined that as a
result of hydrogen bonding between the amide protons and the
nitrogens of adjacent aromatic rings, as well as aromatic
interactions, quinoline-derived oligoamides fold into helices
having close to 2.5 residues per turn, where residue i is placed
above residue i + 5. Therefore, looking end-on down the helix,
as illustrated in Figure 1, it was possible to design two simple
amphipathic analogues of these helices: one having a larger
hydrophobic face and the other having a larger hydrophilic face.
The simplest versions of these analogues require only two
different quinoline monomers. A quinoline monomer having an
isobutoxy side chain was selected as the hydrophobic monomer,
a mimic of leucine, while a monomer having an aminopropoxy
side chain was chosen as the hydrophilic monomer, a mimic of
lysine. The amino group is expected to be protonated and, thus,
positively charged at neutral physiological pH. A cationic face
is a common feature of biomimetic amphipathic helices exhibit-
ing biological activity.21-25,27,51-53
Synthesis. While oligomers of quinoline monomers bearing
isobutoxy side chains had previously been prepared in our group,
the preparation of the proposed oligomers consisting of two
different monomers required a new synthetic approach. Because
quinoline oligoamides are currently prepared using solution
chemistry,34 it is desirable to use the most convergent approach
possible, using the minimum number of building blocks to
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1985, 28, 298-302.
J. Org. Chem, Vol. 71, No. 21, 2006 7933

Gillies et al.
SCHEME 1
impurity consist of four residues, making purification difficult
by chromatography or cystrallization. Therefore, the 3 + 2
strategy toward the pentamer was explored. The dimer 5 was
reduced to the corresponding amine 6 and was coupled with 4
to form the trimer 7, as illustrated in Scheme 3. The ester group
of 7 was selectively saponified using LiOH in 10:1 DMF/H2O
at 0 °C to provide the acid 8. The base-sensitive trifluoroac-
etamide protecting group remained intact under these relatively
mild conditions. The trimer acid was then activated to the acid
chloride in thionyl chloride and coupled with the amine 6 to
form the pentamer 9.
While the most convergent approach to the decamer would
involve the coupling of two pentamers, it was not possible to
obtain the desired pentamer acid. As the length of the oligomers
increases, folding appears to make the saponification of the
terminal ester group more difficult. Thus, under the conditions
required for the ester hydrolysis, the trifluoroacetamide groups
were also cleaved. However, the decamer can be prepared by
adding first dimer, then trimer to the pentamer amine 10. The
dimer 5 can be converted to the acid 11 using LiOH in 10:1
DMF/H2O at 0 °C, but activation to the corresponding acid
chloride using thionyl chloride is not possible due to the poor
solubility of 11 in thionyl chloride. Prolonged heating of 11 in
thionyl chloride leads to eventual dissolution and acid chloride
formation, but this is accompanied by the formation of
significant quantities of byproducts involving chlorination of
the quinoline aromatic ring. Standard peptide coupling agents
such as HBTU/HOBT, PyBOP, PyClOP, PyBrOP, and HCTU
were surveyed but did not lead to efficient coupling. Fortunately,
it was found that the dimer 5 could be efficiently activated to
the corresponding acid chloride under mild conditions using the
Ghosez reagent (1-chloro-N,N,2-trimethylpropenylamine).57 While
this reagent has typically been used for activation to acid
SCHEME 2 a
a Note that all amide functions are trans in the folded oligomers, but for
the purpose of structure clarity, they are shown as cis conformers in the
schemes.
accompanied by the formation of a small amount of the
symmetrical anhydride,56 which is resistant to coupling or
hydrolysis due to folding. In the case of coupling two dimers
to form the tetramer, both the desired product and the anhydride
SCHEME 3
SCHEME 4
7934 J. Org. Chem., Vol. 71, No. 21, 2006

Amphipathic Helices from Aromatic Amino Acid Oligomers
SCHEME 5
TABLE 1. Quinoline Side-Chain Identities in the Amphipathic
Helical Targetsa
SCHEME 6
compound number
residue numberb
15
16
17
18
19
20
1
2
3
4
5
o
o
i
o
i
o
i
o
o
i
o
o
i
o
i
i
o
i
o
i
o
i
i
o
i
i
o
i
o
i
6
7
8
o
i
o
o
i
o
i
i
o
i
9
10
o
i
o
i
chlorides in nonpolar solvents, such as dichloromethane, in
which 11 is not soluble, we found that the activation of 11 can
be performed efficiently in N,N-dimethylacetamide (DMAc).
The success of the Ghosez reagent in the activation of quinoline
oligomer acids is an important synthetic step as the mild,
nonacidic conditions that it requires should allow for the
incorporation of a wide range of quinoline amino acids, having
functional side chains with a variety of protecting groups,
including the widely used BOC group. Thus, coupling of the
pentamer amine 10 with 11 provides the heptamer 12, as shown
in Scheme 4, while the subsequent reduction to the amine 13
and coupling with 8 gives the decamer 14 (Scheme 5).
The final step in the preparation of the target amphipathic
helices was removal of the trifluoroacetamide protecting groups.
In this transformation, it is desirable to either completely
saponify the terminal ester group or leave it completely intact.
As described above, this ester becomes increasingly resistant
to saponification as oligomer length increases. After surveying
various conditions, it was found that using aqueous ammonium
hydroxide in dioxane/methanol made it possible to selectively
hydrolyze the trifluoroacetamides of pentamer 9, heptamer 12,
and decamer 14, leaving the esters intact to provide the
corresponding amphipathic helical oligomers 15, 16, and 17.
An example showing the conversion of pentamer 9 to 15 is
given in Scheme 6. These targets belong to the target series
having a larger hydrophobic face. The amphipathic helices
having a larger hydrophilic than hydrophobic face were prepared
by an analogous strategy (see Supporting Information), provid-
ing the pentamer 18, heptamer 19, and decamer 20. The general
structures of each target amphipathic helix are given in Table
1.
a Methyl ester and nitro end groups are conserved, as shown in Scheme
6. i ) -O(CH2)3NH2 (hydrophilic side chain), o ) -OCH2CH(CH3)2
(hydrophobic side chain). b Residues are numbered starting from the nitro
terminus.
TABLE 2. Crystallographic Parameters for the Structures
Determined
5
12
14
formula
C
30H28F3N5O8
C102H94F9N17O20 C145H134F12N24O27
(C3H7NO)3 (CH3OH)7 (H2O)2
2268.23 3133.09
FW (g mol-1
)
643.57
dimensions (mm) 0.20 × 0.15 × 0.15 0.15 × 0.20 × 25 0.20 × 0.15 × 0.10
color
yellow
monoclinic
P21/c
8.568(3)
36.381(7)
9.457(6)
90
98.27(2)
90
2917(2)
1.465
163(2)
Cu KR
1.541 78
4.86 to 72.49
33 260
5117
yellow
triclinic
P1
yellow
triclinic
P1
cryst syst
space group
a (Å)
b (Å)
c (Å)
10.6083(4)
21.8311(5)
24.3418(11)
86.317(4)
89.074(4)
83.529(3)
5589.6(4)
1.348
153(2)
Cu KR
1.541 78
6.38 to 72.75
57 436
17.0458(3)
21.4658(3)
21.6536(5)
89.712(2)
78.770(2)
80.944(2)
7671.8(2)
1.356
153(2)
Cu KR
1.541 78
6.35 to 58.93
82 569
R (°)
â (°)
γ (°)
volume (Å3)
F (g cm-3
temp (K)
radiation
λ (Å)
)
θ measured (°)
refl. measured
refl. unique
GOF
19 772
1.063
18 982
1.066
1.124
R1 (I > 2σ(I))
wR2 (all data)
0.0573
0.1926
0.1427
0.5164
0.1136
0.4387
were characterized in the solid state by single-crystal X-ray
diffraction (Table 2). As observed for the previously prepared
quinoline dimer having two isobutoxy side chains, 5 assumes a
crescent-shaped conformation, where the aromatic, amide, and
Structure Characterization. The structures of the dimer 5
(see Supporting Information), heptamer 12, and decamer 14
J. Org. Chem, Vol. 71, No. 21, 2006 7935

Gillies et al.
protons shift upfield as a result of shielding by nearby aromatic
rings. In addition, for oligomers of pentamer length and longer,
the signals from the OCH2 groups of the side chains appear as
diastereotopic motifs, indicative of chiral conformations that
undergo inversion slowly on the NMR time scale.
NMR studies were also previously performed to demonstrate
the high helical stability of a quinoline oligoamide octamer in
DMSO, even at 120 °C. These results suggested that it might
be possible to obtain stable helices, even in protic solvents such
as MeOH and H2O. However, solubility limitations due to the
hydrophobicity of the side chains did not permit these studies.
The introduction of the hydrophilic aminopropoxy side chains
in the amphipathic helices reported here provided the possibility
for the evaluation of helical stability in protic solvents.
1
Therefore, H NMR spectra of the amphipathic pentamer 18
with its sidearms as free bases (unprotonated) were obtained in
CDCl3 with increasing percentages of CD3OD. In pure CDCl3,
the peaks are somewhat broad, indicative of nonspecific
aggregation arising from their amphipathic structures and
possible partial protonation of the amines by residual acid from
the chloroform. The addition of only 5% CD3OD produces sharp
peaks, likely a result of the solvation of the hydrophilic side
chains. As the percentage of CD3OD is increased to 90%, no
dramatic changes are observed in the spectrum. Diastereotopic
motifs are still observed for the OCH2 groups of the side chains,
indicating that the molecules are still in a chiral conformation.
Remarkably, even at high concentrations of CD3OD, exchange
of the amide protons with deuterium is slow, and the rate is
different for each proton. For example, after approximately 1
h, one of the amide protons is completely exchanged, while
another amide proton is 80% unexchanged. This is indicative
of different chemical environments for each amide proton in
the folded helices. Poor solubility of the amphipathic quinoline
oligomers prohibits their structural evaluation in 100% CD3-
OD, but overall, it appears that methanol does not lead to helix
destabilization when the sidearms are not protonated.
FIGURE 3. Crystal structures of 12 (a and b) and 14 (c and d).
Included solvent molecules and hydrogens of the side chains and
aromatic rings have been omitted for clarity. In (a) and (c), the views
are nearly parallel to the planes of the aromatic rings, while in (b) and
(d), the views are nearly parallel to the helix axis.
ester moieties are nearly coplanar. The amide proton is hydrogen
bonded to the two nitrogens of the quinoline rings, while the
carbonyl of the amide and ester groups are pointing away from
the quinoline nitrogens. The crystal structures confirm that 12
and 14 fold into helices in the solid state with close to 2.5 units
per turn, as expected. The amido protons are hydrogen bonded
to adjacent quinoline nitrogens and they fill the helix hollow,
preventing the penetration of solvent molecules. Most impor-
tantly, as shown in Figure 3, these solid-state structures verify
our design principles by illustrating that the hydrophobic
isobutoxy side chains diverge from one face of the helix and
the protected aminopropoxy side chains diverge from the other
face. Specifically, the top view of the structure of decamer 14
(Figure 3d) clearly shows that the 10 residues protrude from
the helix along only five directions. To the best of our
knowledge, these are the first examples of X-ray crystal
structures of nonalpha peptidic amphipathic helices or their
precursors. In alpha peptides, amphipathic helices are often
associated with the formation of bundles. However, no well-
defined discrete assembly of helices could be identified in the
crystal structures of 12 and 14.
Since our first reports of quinoline oligoamide foldamers,
detailed NMR studies have been carried out to verify that the
solution structures of these molecules correspond to those
observed in the solid state.54 Key features of the 1H NMR spectra
(in CDCl3) of the oligomers reported here correspond well with
those of the previously reported oligomers. For example, the
signals assignable to the amido protons are spread over a
remarkably large range of chemical shifts, suggesting different
chemical environments for each unit, and they are shifted
relatively far downfield (10.5-12.2 ppm), consistent with the
hydrogen-bonded structures. As the lengths of the oligomers
increase, signals from the amide, aromatic, and ester CH3
Experiments were also performed on the fully protonated form
of pentamer 18. While the hydrochloride salts of the amphipathic
helices reported here are not soluble in 100% water at the
concentrations required for NMR, the hydrochloride salt of
pentamer 18 was dissolved in DMSO-d6, and D2O was gradually
added. As shown in Figure 4, the peaks in pure DMSO-d6 are
somewhat broad and are sharpened upon the addition of D2O.
At higher concentrations of D2O (≈50%), the peaks again begin
to slightly broaden, indicating aggregation in water presumably
a result of the hydrophobic side chains. Consistent with this
hypothesis, the peaks sharpen again upon diluting the sample
while keeping the concentration of D2O constant. At a D2O
concentration of 80%, the highest concentration investigated,
the helical conformation appears to be retained, as indicated
by the diastereotopic motifs from the OCH2 groups of the side
chains. In addition, as the solvent is gradually changed from
pure DMSO-d6 to 80/20 D2O/DMSO-d6, signals from the amide
protons shift farther upfield by approximately 0.5 ppm, and
exchange of all amide protons with deuterium is very slow.
Various aromatic protons on the quinoline ring also shift upfield
(∆δ ≈ 0.5), and the signal from the CH3 group of the terminal
methyl ester gradually shifts from 3.2 to 2.8 ppm.
In contrast, when the amphipathic decamer 20 is dissolved
in DMSO-d6 and D2O is gradually added up to 80%, no
significant upfield shifts of the signals of the analogous protons
on this molecule are observed. This suggests that the upfield
(56) Dolain, C.; Le´ger, J.-M.; Delsuc, N.; Gornitzka, H.; Huc, I. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 16146-16151.
(57) Ghosez, L.; Haveaux, B.; Viehe, H. G. Angew. Chem., Int. Ed. Engl.
1969, 8, 454-455.
7936 J. Org. Chem., Vol. 71, No. 21, 2006

Amphipathic Helices from Aromatic Amino Acid Oligomers
1
FIGURE 4. Part of the H NMR (400 MHz) spectrum of 18 in DMSO-d6, with increasing amounts of D2O added: (a) pure DMSO-d6, (b) 10%
D2O, (c) 30% D2O, (d) 50% D2O, and (e) 80% D2O. Chemical shift values are given in ppm.
shifts observed for the pentamer are due to increased shielding
by the aromatic rings as the helical conformation becomes more
stable. Changes are not observed for the decamer because this
molecule, in contrast to the pentamer, already adopts a highly
stable helical conformation in pure DMSO, and the signals for
the amide, aromatic, and ester OCH3 protons are already at
similar chemical shifts to the signals observed for the pentamer
18 at high D2O concentrations. Thus, it appears that the helices
are even more stable in water than in organic solvents! The
formation of stable helices in water is noteworthy for oligoamide
foldamers, particularly for short oligomers such as the pentamer
investigated here. However, it is not unreasonable considering
that, in addition to hydrogen bonding, these quinoline oligomers
are favored to fold into helices as a result of aromatic
interactions between the quinoline rings, which should become
stronger in protic solvents as solvophobic terms dominate. Such
solvent effects have previously been observed for foldamers
based on aromatic units, where aromatic stacking is promoted
by solvophobic interactions.20,58,59 An additional feature of our
quinoline oligomers that may contribute to their high stability
in a variety of solvents is the fact that the helix hollow is
inaccessible to solvent molecules, thus protecting the hydrogen-
bonding motif from competing interactions with polar solvent
molecules.
Conclusions
Here we reported the synthesis of a new series of amphipathic
helices based on quinoline oligoamides having hydrophilic
aminopropoxy side chains on one face and hydrophobic
isopropoxy groups on the other face. Relative to previously
investigated amphipathic helices, we believe that these molecules
provide exceptional helical stability and rigidity as a result of
their aromatic structures. This helical stability was demonstrated
even for an oligomer as short as a pentamer, which spans two
helical turns, in 80/20 D2O/DMSO-d6. The introduction of
peptide-like side chains as described here opens the possibility
for the first biological evaluations of aromatic oligoamide
foldamers, and it is hoped that their unique structures and
properties will provide new structure-activity relationships. As
amphipathic helices are implicated in a wide variety of biological
processes ranging from cholesterol transport to membrane
disruption, these molecules are versatile initial targets. The
application of our amphipathic helical quinoline oligoamides
in several therapeutic areas is currently being explored. Future
work will additionally focus on synthetic methods for the
incorporation of a variety of peptide-like side chains and for
improving the solubility of the helices in pure water.60
Experimental Section
Monomer 2. The quinolone 155 (8.0 g, 32 mmol, 1.0 equiv),
triphenylphosphine (PPh3; 9.3 g, 35 mmol, 1.1 equiv) and hydroxy-
(58) Lokey, R. S.; Iverson, B. L. Nature 1995, 375, 303-305.
(59) Sindkhedkar, M. D.; Mulla, H. R.; Worth, M. A.; Cammers-
Goodwin, A. Tetrahedron 2001, 57, 2991-2996.
(60) For an example of a short folded oligomer in water, see: Formaggio,
F.; Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman, Q. B.;
Kamphuis, J.; Toniolo, C. Chem.sEur. J. 2000, 6, 4498-4504.
J. Org. Chem, Vol. 71, No. 21, 2006 7937

Gillies et al.
propyltrifluoroacetamide61 (6.1 g, 35 mmol, 1.1 equiv) were
combined under argon and then partially dissolved in dry THF (80
mL). The reaction mixture was cooled to 0 °C, and then diisopro-
pylazodicarboxylate (DIAD; 7.2 mL, 35 mmol, 1.1 equiv) was
added. The reaction mixture was stirred at 0 °C for 30 min and
then was allowed to come to room temperature and stirred
overnight. The reaction progress was monitored by TLC (90/10
toluene/EtOAc) and, when necessary, an additional 0.15 equiv of
PPh3 and DIAD were added. The reaction mixture was stirred for
an additional night. The reaction mixture was evaporated, and the
product was recrystallized from 150 mL of 3/1 MeOH/CHCl3 to
provide 9.2 g (71% yield) of 2 as pale brown crystals: mp 188.8-
added, and the reaction mixture was stirred at 0 °C overnight. An
additional 2.0 equiv of LiOH‚H2O was added, and the reaction
mixture was stirred for another 24 h at 0 °C. The reaction mixture
was acidified with 1 M HCl and then diluted with H2O at room
temperature. The resulting precipitate was filtered off and then
purified by silica gel chromatography using 90/10 CH2Cl2/EtOAc
to elute a small amount of starting material, followed by 98/2 CH2-
Cl2/MeOH to elute the product, providing 0.59 g (91% yield) of 8
as a yellow solid. IR (CHCl3 solution) νmax: 3310, 1739, 1695,
1
1670, 1590, 1565, 1527, 1509 cm-1. H NMR (DMSO-d6, 400
MHz): δ 1.15 (d, 6H, J ) 6.8 Hz), 1.19 (d, 6H, J ) 6.8 Hz),
2.10-2.15 (m, 2H), 2.28-2.34 (m, 2H), 3.50-3.55 (m, 2H), 4.14
(t, 2H, J ) 5.6 Hz), 4.29 (d, 2H, J ) 6.4 Hz), 4.33 (d, 2H, J ) 6.4
Hz), 6.69 (s, 1H), 7.55 (t, 1H, J ) 7.8 Hz), 7.64 (d, 1H, J ) 7.8
Hz), 7.74 (t, 1H, J ) 8.0 Hz), 7.80 (s, 1H), 7.83 (s, 1H), 7.86 (d,
1H, J ) 8.3 Hz), 8.04 (d, 1H, J ) 8.3 Hz), 8.46 (d, 1H, J ) 8.3
Hz), 8.88 (d, 1H, J ) 7.3 Hz), 8.96 (d, 1H, J ) 7.8 Hz), 9.63 (t,
1H, J ) 4.4 Hz), 11.94 (s, 1H), 12.12 (s, 1H), 12.48 (br s, 1H).
13C NMR (2/1 CDCl3/CD3OD, 100 MHz): δ 18.8, 27.95, 27.99,
28.05, 36.7, 66.2, 75.1, 75.5, 98.8, 99.4, 99.8, 116.0, 116.8, 118.1,
121.6, 122.2, 123.4, 124.5, 125.5, 127.3, 127.4, 128.2, 134.0, 134.6,
138.7, 138.8, 139.2, 145.4, 145.6, 150.3, 154.0, 162.1, 162.9, 163.0,
163.6, 164.6. MS calcd [M + H]+ (C43H41N7O10F3), 872.2867;
found (TOF MS ES+), 872.2864.
1
190.2 °C. IR (CHCl3 solution) νmax: 1732, 1540 cm-1. H NMR
(DMSO-d6, 400 MHz): δ 2.11-2.19 (m, 2H), 3.47-3.52 (m, 2H),
3.96 (s, 3H), 4.23 (t, 2H, J ) 5.4 Hz), 7.64 (s, 1H), 7.83 (t, 1H, J
) 7.9 Hz), 8.34 (d, 1H, J ) 7.6 Hz), 8.43 (d, 1H, J ) 8.6 Hz),
9.53-9.60 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 28.5, 37.1,
55.9, 67.9, 103.4, 116.8 (q, J ) 288 Hz), 123.1, 125.3, 126.4, 127.8,
139.6, 149.1, 151.7, 157.2 (q, J ) 36 Hz), 163.0, 165.7. MS calcd
[M + H]+ (C16H15N3O6F3), 402.0913; found (TOF MS ES+),
402.0905.
Monomer Amine 3 and General Procedure for the Nitro
Group Reduction. Compound 2 (2.0 g, 5.0 mmol) was dissolved
in 400 mL of EtOAc, and 200 mg of 10 wt % Pd/C was added.
The reaction was stirred under a hydrogen atmosphere overnight.
Progress was monitored by TLC and NMR, and an additional 10
wt % of Pd/C was added if necessary to complete the reaction.
Upon completion, the catalyst was removed by filtration over Celite,
and the filtrate was evaporated to provide 1.9 g (99% yield) of the
amine 3 as a yellow solid. IR (CHCl3 solution) νmax: 3427, 1726,
1645, 1546, 1509 cm-1. 1H NMR (DMSO-d6, 400 MHz): δ 2.08-
2.14 (m, 2H), 3.42-3.46 (m, 2H), 3.95 (s, 3H), 4.32 (t, 3H, J )
5.6 Hz), 6.03 (s, 1H), 6.94 (d, 1H, J ) 7.3 Hz), 7.29 (d, 1H, J )
8.3 Hz), 7.38 (t, 1H, J ) 8.0 Hz), 7.45 (s, 1H), 9.46-9.60 (m,
1H). 13C NMR (DMSO-d6, 100 MHz): δ 28.7, 37.2, 53.4, 66.9,
101.5, 107.9, 110.7, 116.8 (q, J ) 288 Hz), 123.1, 129.9, 138.0,
145.9, 146.9, 157.2 (q, J ) 36 Hz), 162.5, 166.4. MS calcd [M +
H]+ (C16H17N3O4F3), 372.1171; found (TOF MS ES+), 372.1176.
Dimer 5 and General Procedure for Coupling Using Thionyl
Chloride Activation. The acid 4 (0.86 g, 3.0 mmol, 1.0 equiv)
was heated at reflux in SOCl2 (11 mL, 150 mmol, 50 equiv) for 15
min and then cooled in an ice bath, and the excess SOCl2 was
removed in vacuo to provide the corresponding acid chloride. To
a suspension of amine 3 (0.88 g, 2.4 mmol, 0.8 equiv) in dry CH2-
Cl2 (20 mL) and diisopropylethylamine (DIEA; 1.0 mL, 5.9 mmol,
2.0 equiv) was added the acid chloride in CH2Cl2 via cannula. The
reaction mixture was stirred at room temperature overnight, resulting
in complete dissolution of the amine. The solvent was evaporated,
and the product was purified by recrystallization from CHCl3/MeOH
to provide 1.4 g (92% yield) of the dimer 5 as pale brown crystals:
mp 212.2-213.7 °C. IR (CHCl3 solution) νmax: 3435, 1720, 1639,
Heptamer 12 and General Procedure for Coupling Using
1-Chloro-N,N,2-trimethylpropenylamine. The dimer acid 11 (60
mg, 93 µmol, 1.0 equiv) was dissolved in anhydrous DMAc (2
mL) under an argon atmosphere and 1-chloro-N,N,2-trimethylpro-
penylamine (62 mg, 460 µmol, 5.0 equiv) was added. The reaction
mixture was stirred at room temperature overnight, and then the
DMAc and excess reagent was evaporated in vacuo to provide the
corresponding acid chloride. To a solution of the amine 10 (100
mg, 70 µmol, 0.75 equiv) in dry CH2Cl2 (3 mL) containing DIEA
(160 µL, 930 µmol, 10 equiv) was added the acid chloride in dry
CH2Cl2 via cannula. The reaction mixture was stirred at room
temperature overnight, and then the solvent was evaporated. The
product was purified by silica gel chromatography using a gradient
from 80/20 to 65/35 toluene/EtOAc to provide 100 mg (70% yield)
of 12 as a yellow solid. IR (CHCl3 solution) νmax: 3426, 1720,
1
1677, 1608, 1539 cm-1. H NMR (CDCl3, 400 MHz): δ 1.07-
1.37 (m, 24H), 2.16-2.36 (m, 10H), 3.07 (s, 3H), 3.74-4.04 (m,
11H), 4.09-4.17 (m, 5H), 4.22-4.30 (m, 1H), 4.34-4.42 (m, 2H),
4.50-4.57 (m, 1H), 6.39 (s, 1H), 6.52 (s, 1H), 6.53 (s, 1H), 6.57
(s, 1H), 7.05 (s, 1H), 7.08-7.13 (m, 2H), 7.17-7.28 (m, 4H), 7.35-
7.47 (m, 5H), 7.58-7.65 (m, 3H), 7.72 (d, 1H, J ) 8.3 Hz), 7.81
(d, 1H, J ) 7.8 Hz), 7.85 (d, 1H, J ) 8.3 Hz), 7.94-7.98 (m, 1H),
8.00-8.03 (m, 2H), 8.08 (d, 1H, J ) 7.8 Hz), 8.13 (d, 1H, J ) 7.3
Hz), 8.19 (d, 2H, J ) 7.8 Hz), 8.40 (d, 1H, J ) 7.8 Hz), 11.05 (s,
1H), 11.21 (s, 1H), 11.24 (s, 1H), 11.35 (s, 1H), 11.39 (s, 1H),
11.65 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 19.3, 19.36, 19.40,
19.48, 19.54, 19.6, 19.7, 27.9, 28.2, 28.27, 28.31, 28.4, 28.7, 29.8,
37.0, 37.5, 39.3, 52.2, 65.8, 66.4, 68.1, 75.1, 75.47, 75.5, 75.7, 97.6,
97.7, 98.5, 98.6, 99.1, 100.0, 100.1, 115.6, 115.9, 116.0, 116.11
(q, J ) 288 Hz), 116.16 (q, J ) 288 Hz), 116.23, 116.40 (q, J )
288 Hz), 116.41, 116.7, 117.0, 117.2, 117.2, 121.3, 121.4, 121.7,
122.0, 122.3, 122.6, 123.8, 124.1, 125.9, 126.0, 126.3, 126.9, 127.0,
128.1, 128.2, 132.66, 132.72, 133.2, 133.5, 133.86, 133.94, 137.56,
137.62, 137.8, 138.1, 138.4, 138.7, 138.9, 144.7, 144.8, 148.7,
148.9, 149.2, 150.0, 153.1, 157.7 (q, J ) 36 Hz), 157.9 (q, J ) 37
Hz), 158.0 (q, J ) 36 Hz), 159.7, 160.1, 160.2, 160.7, 160.8, 161.0,
162.45, 162.53, 162.9, 163.0, 163.1, 163.2, 164.4. MS calcd [M +
H]+ (C102H95N17O20F9), 2048.6796; found (TOF MS ES+),
2048.6523.
1
1520 cm-1. H NMR (DMSO-d6, 400 MHz): δ 1.06 (d, 6H, J )
6.6 Hz), 2.10-2.19 (m, 3H), 3.44-3.52 (m, 2H), 4.09 (s, 3H), 4.13
(d, 2H, J ) 6.4 Hz), 4.37 (t, 2H, J ) 5.5 Hz), 7.53 (s, 1H), 7.65
(t, 1H, J ) 8.0 Hz), 7.74 (s, 1H), 7.79 (t, 1H, J ) 7.9 Hz), 7.85 (d,
1H, J ) 8.0 Hz), 8.37-8.40 (m, 2H), 8.93 (d, 1H, J ) 7.6 Hz),
9.56 (t, 1H, J ) 5.1 Hz), 11.51 (s, 1H). 13C NMR (DMSO-d6, 100
MHz): δ 19.7, 28.4, 28.6, 37.2, 54.0, 67.3, 76.0, 101.0, 102.3, 116.8
(q, J ) 288 Hz), 117.0, 118.5, 122.2, 123.2, 126.5, 126.9, 127.5,
128.7, 135.1, 138.9, 139.2, 148.2, 149.1, 153.7, 157.2 (q, J ) 36
Hz), 162.4, 162.8, 163.6, 167.0. MS calcd [M + H]+ (C30H29N5O8F3),
644.1968; found (TOF MS ES+), 644.1938.
Trimer Acid 8 and General Procedure for Saponification
Using LiOH. The trimer 7 (0.65 g, 0.73 mmol, 1.0 equiv.) was
dissolved in DMF (14 mL), and the solution was cooled to 0 °C.
LiOH‚H2O (62 mg, 1.5 mmol, 2.0 equiv) in H2O (1.4 mL) was
Pentamer 15 and General Procedure for the Removal of the
Trifluoroacetamide Protecting Groups. The pentamer 9 (50 mg,
34 µmol) was dissolved in 5.0 mL of dioxane, and 7.5 mL of
methanol was added, followed by 2.5 mL of 28% w/w aqueous
NH3. The reaction mixture was stirred at room temperature for 72
h, adding an additional 2.5 mL of aqueous NH3 after the first 24 h
(61) Svirskaya, P. I.; Leznoff, C. C.; Steinman, M. J. Org. Chem. 1987,
52, 1362-1364.
7938 J. Org. Chem., Vol. 71, No. 21, 2006

Amphipathic Helices from Aromatic Amino Acid Oligomers
and an additional 2 mL of dioxane after 48 h to ensure that
everything was soluble. The reaction mixture was then diluted with
CH2Cl2, extracted with water, dried with MgSO4, and evaporated
generator with monochromatized Cu KR radiation (1.541 78 Å).
The data collection, unit cell refinement, and data reduction were
performed using the CrystalClear software package. The positions
of non-H atoms were determined by the program SHELXS 87, and
the position of the H atoms were deduced from coordinates of the
non-H atoms and confirmed by Fourier synthesis. H atoms were
included for structure factor calculations but not refined.
to give 43 mg (99% yield) of 15 as a yellow solid. IR (solution)
1
ν
max: 3313, 1683, 1530 cm-1. H NMR (CDCl3, 400 MHz): δ
1.21-1.31 (m, 18H), 2.10-2.17 (m, 4H), 2.32-2.37 (m, 1H),
2.47-2.53 (m, 2H), 3.07-3.17 (m, 4H), 3.20 (s, 3H), 3.92-3.95
(m, 2H), 4.13-4.21 (m, 4H), 4.24-4.31 (m, 2H), 4.37-4.39 (m,
2H), 6.60 (s, 1H), 6.28 (s, 1H), 6.87 (s, 1H), 7.31-7.41 (m, 3H),
7.47-7.50 (m, 3H), 7.60 (d, 1H, J ) 8.6 Hz), 7.64 (d, 1H, J ) 8.1
Hz), 7.82 (d, 1H, J ) 8.6 Hz), 7.94 (d, 1H, J ) 8.3 Hz), 8.03 (d,
1H, J ) 8.3 Hz), 8.10 (d, 1H, J ) 8.6 Hz), 8.17-8.21 (m, 2H),
8.44-8.47 (m, 2H), 8.55 (d, 1H, J ) 6.8 Hz), 11.5 (s, 1H), 11.7
(s, 1H), 11.8 (s, 1H), 11.9 (s, 1H). 13C NMR (CDCl3, 100 MHz):
δ 19.48, 19.54, 19.58, 19.64, 28.4, 28.5, 29.9, 32.6, 32.7, 39.16,
39.24, 52.2, 66.9, 67.1, 75.4, 75.6, 75.9, 97.4, 98.2, 99.8, 100.5,
115.5, 116.5, 116.6, 116.8, 117.1, 117.3, 117.4, 121.8, 121.9, 122.2,
122.6, 124.1, 124.5, 126.1, 126.7, 126.9, 127.5, 127.9, 128.1,
133.75, 133.85, 134.2, 134.4, 138.2, 138.5, 138.6, 139.2, 139.2,
145.32, 145.34, 149.29, 149.39, 150.6, 153.7, 160.7, 161.0, 161.4,
162.1, 162.3, 163.1, 163.1, 163.3, 163.5, 164.1. MS calcd [M +
H]+ (C69H71N12O13), 1275.5265; found (TOF MS ES+), 1275.5242.
X-ray Crystallography. Single crystals of dimer 5, heptamer
12, and decamer 14 were mounted on a Rigaku R-Axis Rapid
diffractometer equipped with a MM007 micro focus rotating anode
Acknowledgment. This work was supported by the Euro-
pean Commission (Marie Curie Postdoctoral Fellowship to
E.R.G.), by the CNRS, the university Bordeaux 1, the university
Victor Segalen Bordeaux 2, and by the Conseil Re´gional
d’Aquitaine. We thank Katell Bathany for mass spectroscopy
data. The cover art was adapted from Katsushika Hokusai’s
work entitled “The Great Wave at Kanagawa” (from a Series
of Thirty-six Views of Mount Fuji), ca. 1830-32, Metropolitan
Musem of Art, New York.
Supporting Information Available: Complete synthesis details,
characterization data and NMR spectra of all products, crystal-
lographic data in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0603577
J. Org. Chem, Vol. 71, No. 21, 2006 7939