Helical oligomers of thiazole-based γ-amino acids: Synthesis and structural studies

Article abstract of DOI:10.1002/anie.201302106

9-Helix: 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) were synthesized as new γ-amino acid building blocks. The structures of various ATC oligomers were analyzed in solution by CD and NMR spectroscopy and in the solid state by X-ray crystallography. The ATC sequences adopted a well-defined 9-helix structure in the solid state and in aprotic and protic organic solvents as well as in aqueous solution. Copyright

Full text of DOI:10.1002/anie.201302106

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DOI: 10.1002/anie.201302106
Foldamers
Helical Oligomers of Thiazole-Based g-Amino Acids: Synthesis and
Structural Studies**
Loꢀc Mathieu, Baptiste Legrand, Cheng Deng, Lubomir Vezenkov, Emmanuel Wenger,
Claude Didierjean, Muriel Amblard, Marie-Christine Averlant-Petit, Nicolas Masurier,
Vincent Lisowski, Jean Martinez, and Ludovic T. Maillard*
Peptides and proteins are molecular devices that can adopt
specific folded and organized structures for performing
diverse functions in living systems. The formation of such
tertiary and quaternary structures arises from the assembly of
stable secondary structures such as helices, sheets, and turns.
The ability of synthetic oligomers of b- and g-amino acids to
adopt protein-like secondary structures is of great interest to
develop helical mimics with functional properties.[1] Incorpo-
ration of constrained cyclic building blocks reducing the
backbone flexibility has permitted to improve the stability of
the folding and to substantially enlarge the helical foldamer
realms. According to the results obtained with b-peptides,[2] g-
amino acids were expected to be valuable to design new
scaffolds.[3] Nevertheless, to date, only few g-subunits are
available owing to the difficulty to access stereochemically
pure species, and only few g-oligomer secondary structures
have been described.[4] The first helical fold of g-peptides,
independently reported by the research groups of Hanes-
sian[5] and Seebach,[6] was a helix stabilized by 14-membered
pseudo-rings. Sheets,[7] ribbons,[8] or helices[9] stabilized by C7
or C9 hydrogen-bonded pseudocycles were obtained later by
using constrained cyclic g-amino acid building blocks. Addi-
tionally, while the conformational control is crucial for
biological function, the access to foldamers bearing a wide
variety of side chains and being soluble under physiological
conditions is essential to purchase biological applications.
However, the combination of these three criteria remains
challenging.[10]
In this context, we report herein the design of 4-amino-
(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) 1 as new g-
building blocks (Scheme 1). These highly constrained mono-
mers were built around a thiazole ring to limit conformational
flexibility around 08 about the aC–bC bond. We proposed
a fast and robust synthetic pathway for the formation of
Scheme 1. Thiazole-based g-amino acid building blocks and oligomeric
derivatives. Fmoc=9-fluorenylmethoxycarbonyl, Boc=tert-butoxycar-
bonyl.
[*] L. Mathieu,[+] Dr. B. Legrand,[+] Dr. L. Vezenkov, Dr. M. Amblard,
Dr. N. Masurier, Prof. V. Lisowski, Prof. J. Martinez, Dr. L. T. Maillard
Institut des Biomolꢀcules Max Mousseron, UMR 5247, CNRS
Universitꢀs Montpellier I et II
ATCs, thereby giving opportunity of a straightforward mod-
ulation of the two substitution positions while controlling the
stereochemistry at the g-carbon atom. We characterized the
structures of various ATC oligomers in solution by CD and
NMR spectroscopy and in the solid state by X-ray crystallog-
raphy. Significantly, the ATC sequences adopted a well-
defined 9-helix structure in the solid state and in aprotic and
protic organic solvents as well as in aqueous solution.
Our synthetic approach to access ATCs is described in
Scheme 2. We started from N-Fmoc-protected a-amino acids
to access benzyl b-ketoesters 4. Although the cross-Claisen
condensation is a well-known reaction to access b-ketoesters,
successful results were only achieved when sterically non-
hindered esters like ethyl or benzyl acetate were used.[11]
Additionally, the required basic conditions are usually not
compatible with Fmoc protection.[11a] Thus, we turned our
attention toward another straightforward reaction: the Lewis
UFR des Sciences Pharmaceutiques et Biologiques
15 Avenue Charles Flahault, 34093 Montpellier Cedex 5 (France)
E-mail: ludovic.maillard@univ-montp1.fr
C. Deng, Dr. M.-C. Averlant-Petit
Laboratoire de Chimie-Physique Macromolꢀculaire
LCPM-UMR 7568 CNRS Universitꢀ de Lorraine
1 rue Grandville, 54001 Nancy Cedex 1 (France)
E. Wenger, Dr. C. Didierjean
Laboratoire de Cristallographie, Rꢀsonance Magnꢀtique et Modꢀ-
lisation, UMR 7063 CNRS Universitꢀ de Lorraine
Boulevard des Aiguillettes, 54506 Vandoeuvre-lꢁs-Nancy Cedex
(France)
[+] These authors contributed equally to the work.
[**] We thank the IBMM, the CNRS, and the University of Montpellier
1 for financial support and the University of Lorraine for NMR and
XRD facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302106.
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Scheme 2. Synthesis of a) N-Fmoc protected g-amino acids and b) oligomers 2, 3a, 3b. AA=a-amino acid; BOP=benzotriazol-1-yloxy-tris-
(dimethylamino)phosphonium hexafluorophosphate, NMM=N-methylmorpholine, EDC=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydro-
chloride, HOBT=1-hydroxybenzotriazole.
acid catalyzed C–H insertion of a diazoacetate on aldehydes.
The N-Fmoc-protected a-amino acids were converted into
Weinreb amides. Reduction with LiAlH4 led to the corre-
sponding aldehydes, which were promptly condensed with
benzyl diazoacetate in CH2Cl2 in the presence of a catalytic
amount of tin(II) chloride to yield the orthogonally protected
b-ketoesters 4. Effective monohalogenations were performed
with sulfuryl chloride,[12] then the a-chloro-b-ketoesters 5
were engaged without any further purification in a Hantzsch
cyclization with a thioamide or thiourea to lead to the
thiazole-based g-amino benzylesters 6. Because racemization
is a major issue when aminoaldehyde intermediates are used,
the enantiomeric excess was ascertained by determination of
edge, Mann and Kessler reported the unique example of
(hetero)aromatic-based g-amino acids in which the ring is an
oxazole.[14] Included into a small peptide, such a building
block acts as a C9 turn inducer.
Four g-peptides, 2, 3a, 3b, and 3c of different lengths (2, 4,
and 6 monomers) were first synthesized through an Fmoc/
OBn strategy (Scheme 2b). The peptides exhibited a high
solubility in chloroform but were poorly soluble in polar
solvents. Hence, assuming that the introduction of lateral
chains containing amine groups could greatly improve the
solubility in polar solvents, we synthesized g-peptides 3d, 3e,
and 3 f from building blocks 6c and 6d (see the Supporting
Information).
NMR-spectroscopic analyses of 2, 3a, and 3b were
conducted in CDCl3. The water-soluble compounds 3d, 3e,
and 3 f were studied in CD3OH and H2O/D2O (9:1, pH 6.5).
In all cases, the NMR signals were well dispersed and nearly
all 1H, 13C and 15N resonances could be assigned by combining
15N-HSQC and 13C-HSQC at 15N and 13C natural abundance
(Tables S1–S18 in the Supporting Information). The sequen-
tial assignment was based on the strong NH(i)/gCH(iꢁ1)
NOE correlations on the ROESY/NOESY spectra. In
addition, characteristic weak NHi/dCH(iꢁ1) and gCH(i)/
dCH(i+1) sequential NOE connectivities were observed
along the backbones. Similar NOE sets were obtained for
dimers 2 and 3d, for tetramers 3a and 3e, and for hexamers
3b and 3 f (Figure 1, Tables S20–22). The 14-helical fold
typical for g-peptides could be excluded at this stage, since no
20
the optical rotation of both enantiomers (S)-6a (½aꢀD ¼ + 4.98
20
(c = 1.95, CHCl3)) and (R)-6a (½aꢀD ¼ꢁ4.98 (c = 2.08, CHCl3))
and by using HPLC on a chiral stationary phase (see
Figure S11 in the Supporting Information). The rate of
racemization was 2% when the synthesis was performed on
a 1 g scale (37% yield on the overall sequence). Starting from
a set of N-protected amino acids and thioamides, the synthetic
pathway provided a highly versatile and flexible method for
the introduction of different substitution patterns either on
the g-carbon atom of the backbone or at position 2 of the
thiazole core (Scheme 2a). Ab initio calculations from Hof-
mann and co-workers[13] suggested that oligomers of Z-
vinylogous g-amino acids would favor two stable helical
conformers with seven- and nine-membered hydrogen-
bonded pseudocycles. On the other hand and to our knowl-
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tively, when the capping groups are omitted. The tetramer 3a
and the hexamer 3b exhibited tight right-handed 9-helix
…
=
structures stabilized by C O(i) HN(i+2) hydrogen bonds.
Notably only two residues were necessary to initiate the
folding into C9 hydrogen-bonded pseudocycles as observed on
dimer 2. The hydrogen-bonding patterns were homogenous
along the entire sequences in a forward direction, from N to
C. The average values of the dihedral angles for the ATC helix
were f= ꢁ76 ꢂ 168, q = 128 ꢂ 128, z = ꢁ6 ꢂ 58, and y =
ꢁ28 ꢂ 68 (Table 1). Only small distortions were observed on
the y angles of the C-terminal residues of each oligomer.
Table 1: Average backbone torsion angles for g-peptides adopting 9-
helical fold. The y angles of the last residue of the NMR and XRD
structures were omitted.
f
q
z
y
Balaram’s oligomers[9b]
Kunwar’s oligomers[9a]
Predicted Z-vinylogous
g-oligomers[13]
1098
1258
ꢁ79.88
ꢁ638
ꢁ688
122.88
ꢁ778
ꢁ658
888
978
ꢁ46.58
0.18
ATC oligomers
Average NMR values:
2, 3a, 3b
3d, 3e, 3 f
Figure 1. Superimposition of the NH/gCH region of the TOCSY (in
dark) and ROESY (in light) spectra of a) 3b recorded in CDCl3, b,c) 3 f
recorded in CD3OH and H2O/D2O, pH 6.5 at 2–10 mm. Typical strong
sequential NOE correlations of HN(i)/gCH(iꢁ1) are annotated. 1H
chemical shifts on both axes are given in ppm. HG corresponds to
gCH. d) Typical interresidue NOE pattern along the 3b and the 3 f
hexamers.
ꢁ76ꢂ168 128ꢂ128 ꢁ6ꢂ58 ꢁ28ꢂ68
ꢁ72ꢂ338 114ꢂ298 ꢁ5ꢂ68 ꢁ23ꢂ118
XRD structure of 3c
ꢁ78ꢂ38
127ꢂ148
0ꢂ38 ꢁ41ꢂ48
Importantly, we were able to crystallize the tetramer 3c by
solvent diffusion of diisopropyl ether into a solution of the
oligomer in toluene. Low-resolution X-ray diffraction data
were sufficient to show that ATC g-peptides adopt the same
helical structure in solid state and solution (Figure 2a,b). All
amide groups of the molecule form inter- or intrahelix
hydrogen bonds (Figure S7). The typical average dihedral
angles were comparable to those measured in NMR-spectro-
scopic experiments (f= ꢁ78 ꢂ 38, q = 127 ꢂ 148, z = 0 ꢂ 38
and y = ꢁ41 ꢂ 48, Table 1) with a notable deviation of the C-
terminal y torsion angle (y = ꢁ1658), which allowed the
packing of the molecules into infinite chains in the crystal.
Simulations of Hofmann and co-workers predicted that Z-
vinylogous g-oligomers could adopt a helical fold with nine-
membered hydrogen-bonded pseudocycles with close torsion
angles (f= ꢁ79.88, q = 122.88, z = 0.18, y = ꢁ46.58).[13] By
comparison, the C9 hydrogen-bonded helices reported by the
research groups of Balaram and Kunwar have values of f=
1098, q = ꢁ638, z = ꢁ778, y = 888 and f= 1258, q = ꢁ688, z =
ꢁ658, y = 978, respectively.[9] Considering the global shape of
the ATC oligomers, the edifice appeared to be close to a C3-
symmetric helix with three residues to achieve a complete
rotation with a pitch of 11.8 ꢀ. This helix had a rise-per-
residue of 3.9 ꢀ and exhibited six substitution patterns per
turn, which were distributed around a 608 angle all along the
axis (Figure 2c). We then solved the NMR solution structures
of the compounds 3d, 3e, and 3 f in water (pH 6.5) by using
12, 49, and 72 constraints, respectively, with the generalized
Born solvation model[18] in AMBER (Figure 3a and S5,
Table 1). As expected, since similar NOE sets were obtained
for the water-soluble series (Tables S20–22), comparable
typical (i, i + 2), (i, i + 3) medium-range NOEs were
detected.[15] Whatever the length of the oligomers and the
nature of the solvent, all the amide protons exhibited
remarkable downfield chemical shifts, for example, from
9.18 ppm for dimer 2 (Table S1) to 10.67 ppm for hexamer 3b
in CDCl3 (Table S5). As a comparison, Kunwar and co-
workers previously described a 9-helix for a g-peptide
oligomer in which amide resonances were found between
6.92 and 7.60 ppm in CDCl3.[9a] This marked unshielding of
the amide protons could be attributed to a highly stable
hydrogen-bonding pattern and/or to a ring-current effect of
the thiazole heterocycle. In addition, 3J(NH,gCH) values
smaller than 6 Hz (5.4 ꢂ 0.4 Hz) were typical of f values
around ꢁ608 (Table S19). Taken together, these data were
strong evidence of a well-organized system in solution for all
compounds whatever the solvent considered.
The ATC monomers were parameterized using the
Antechamber package[16] starting from the X-ray crystal
structure of 6b, which exhibited an extended conformation
with dihedral angles f= ꢁ1268, q = 1588, z = ꢁ48 and y =
1808 (Figure S6 and Table S25). NOEs were used as restraints
for calculations on the structure in solution determined by
NMR spectroscopy by using a simulated annealing protocol
with AMBER 10.[17] The solution structures of 2, 3a, and 3b in
CDCl3 were solved by using 39, 87, and 124 unambiguous
restraint distances, respectively. Figure S5 depicts a super-
imposition of the 20 lowest-energy structures calculated for
each compound. The root-mean-square deviation (RMSD)
values for the backbone are 0.11 ꢀ, 0.48 ꢀ, 0.63 ꢀ, respec-
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Figure 3. a) Overlay of the 20 lowest-energy structures of hexamer 3 f
calculated from NMR data in water, pH 6.5. Lateral chains are omitted
for clarity. b) CD spectra of 3d (g), 3e (a), and 3 f (c) at
200 mm in MeOH (green) and water, pH 6.5 (blue). [q]res =molar
ellipticity per residue.
This study thus presents the design of a new family of ring-
constrained g-amino acids and the identification of a novel
right-handed 9-helix structure in g-peptides. These features
g
resulted from the planar conformation of the C-bC-aC-C(O)
torsion angle imposed by the thiazole heterocycle. Moreover,
we demonstrate that ATC oligomers display a high stability in
organic and in aqueous media, which is of particular
importance for applications in medicinal chemistry. The fast
and highly robust synthetic pathway ensures the access to
a wide diversity of enantiopure ATCs, thereby giving a real
opportunity to straightforwardly modulate the physicochem-
ical properties of the oligomers and to drive molecular
recognition.
Figure 2. a) Orthogonal and axial views of the crystal structure of the
tetramer 3c.[19] b) Superimposition of the 20 lowest-energy NMR
structures of 3a (in orange) with the XRD structure of 3c (in purple).
Nonamide protons and capping groups are omitted for clarity. c) Axial
projection of the ATC oligomers. d) Characteristic hydrogen-bond net-
work of oligomer 3b.
Received: March 13, 2013
Published online: April 25, 2013
structures were calculated showing that the ATC oligomers
remarkably conserved their unique fold even in water.
The far-UV CD spectra for 3d, 3e, 3 f were then recorded
in methanol and water (pH 6.5) between 190 and 300 nm
(Figure 3b). The CD signatures of the hexamer 3 f shared
similar global shapes in methanol and in water. We observed
two minima at 195 and 231 nm and 195 and 226 nm in
methanol and water, respectively, and a strong maximum
around 263 nm. The two minima were assigned to the p–p*
and n–p* transitions of the amide chromophore, respectively,
while the maximum could be attributed to the thiazole core.
The classical blue shift observed for the n–p* transition in
aqueous solution is certainly a result of stronger solute–
solvent hydrogen-bond interactions and/or the higher water
polarizability. The first NV1 p–p* transition minimum was
weaker in water, but no significant wavelenght shift was
detected. Interestingly, the intensity of the maximum dra-
matically increased with the oligomer size from two to six
residues to reach a molar ellipticity value per residue of
82700 degcm2 dmolꢁ1 in methanol and 74000 degcm2 dmolꢁ1
in water for 3 f, thus suggesting an increased stability with
length. Some differences were observed for tetramer 3e, since
a third weak minimum appeared at 211 nm, and for dimer 3d
for which the first minimum was red-shifted at 200–205 nm in
all solvents.
Keywords: conformation analysis · foldamers ·
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helical structures · peptidomimetics · g-peptides
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