ChemInform Abstract: Foldamers Containing γ-Amino Acid Residues or Their Analogues: Structural Features and Applications

Abstract

Over the past 20 years, the field of foldamers has rapidly increased. Many β-peptides have already been described and shown interesting properties. γ-Peptides have more recently emerged but seem to be very interesting as well. In this review, we will cover every peptidomimetic oligomer that contains a γ-amino acid or an analogue and presents a structural feature. It includes γ-peptides but also hybrid α-γ peptides, β-γ peptides and analogues such as oligoureas or aminoxy acids. We will present the biological properties of these oligomers.

Full text

REVIEW ARTICLE
Foldamers containing c-amino acid residues or their analogues:
structural features and applications
Francelin Bouille
`re •Sophie The
´tiot-Laurent •
Cyrille Kouklovsky •Vale
´rie Alezra
Received: 19 January 2011 / Accepted: 18 March 2011 / Published online: 1 April 2011
ÓSpringer-Verlag 2011
Abstract Over the past 20 years, the field of foldamers
has rapidly increased. Many b-peptides have already been
described and shown interesting properties. c-Peptides
have more recently emerged but seem to be very interesting
as well. In this review, we will cover every peptidomimetic
oligomer that contains a c-amino acid or an analogue and
presents a structural feature. It includes c-peptides but also
hybrid a–cpeptides, b–cpeptides and analogues such as
oligoureas or aminoxy acids. We will present the biological
properties of these oligomers.
Keywords Gamma-amino acid Gamma-peptide 
Foldamer Hybrid peptide Secondary structure
Introduction
Proteins are essential biomacromolecules that participate in
almost every process within cells. As their function is
related to their structure, a great effort has been made to
gain deeper insights into the determination of their struc-
tures and in the processes of folding. A part of this chal-
lenging problem is to build new small oligomers that adopt
a well-defined conformation in solution. A new field of
research, the foldamers, has emerged during the last
20 years. The term foldamer was proposed by Gellman in
1996 to describe ‘‘any polymer with strong tendency to
adopt a specific compact conformation’’ (Appella et al.
1996; Gellman 1998). Later on, Moore proposed the fol-
lowing narrower definition: ‘‘any oligomer that folds into a
conformationally ordered state in solution, the structures of
which are stabilized by a collection of noncovalent inter-
actions between nonadjacent monomer units’’ (Hill et al.
2001). This definition covers both ‘‘single-stranded folda-
mers that only fold and multiple-stranded foldamers that
both associate and fold’’. This definition seems to be a little
restrictive for several reasons. First, many efforts have been
devoted to determine the structures of synthetic oligomers
in the solid state. Second, by specifying ‘‘noncovalent
interactions’’, the definition obviously excludes the poly-
proline helices or their mimics, and it seems that this type of
structure also contributes (as well as the other helices,
sheets and turns) to the secondary structures adopted by
proteins. Therefore, we will prefer the following shorter
definition: ‘‘any oligomer that folds in a conformationally
ordered state’’, and we will present oligomers that are fol-
ded in the solid state (even though a structure in solution is
not always clearly demonstrated), and also oligomers that
tend to adopt extended structures similar to polyprolines.
In this review, we will cover every peptidomimetic
oligomer (excluding abiotic oligomers containing an aro-
matic ring in the skeleton or nucleotidomimetic oligomers)
that contains a c-amino acid or an analogue of a c-amino
acid. By analogue, we mean a compound in which the
nitrogen atom is separated from the carbonyl group by
three atoms (including, for instance, the oligoureas and the
b-aminoxy acids). We will also describe some cyclic
oligomers that both fold and above all associate. We will
present the structures observed for homogeneous and het-
erogeneous oligomers and their analogues before describ-
ing the biological properties and applications of these
foldamers. Several reviews have covered some parts of
F. Bouille
`re S. The
´tiot-Laurent C. Kouklovsky 
V. Alezra (&)
Universite
´Paris-Sud, CNRS, Laboratoire de Chimie des
Proce
´de
´s et Substances Naturelles, ICMMO, UMR 8182,
Ba
ˆt 410, 91405 Orsay, France
e-mail: valerie.alezra@u-psud.fr
URL: http://www.icmmo.u-psud.fr
123
Amino Acids (2011) 41:687–707
DOI 10.1007/s00726-011-0893-3

this subject (Goodman et al. 2007; Hecht and Huc 2007;
Seebach et al. 2004a,b,2006; Stigers et al. 1999; Vasudev
et al. 2011) and we will focus mostly on work published
since Moore’s review in 2001.
Homogeneous oligomers containing c-amino acids
After three decades of studies on homogeneous oligomers
containing b-amino acids, molecules based on c-amino
acids were investigated. Although this homologation
reduces (for an oligomer of the same length) the number of
potential hydrogen bonds, the c-peptides have shown their
capability to adopt various stable conformations, such as
helices, sheets and turn.
In 1998, Seebach and Hannessian reported simulta-
neously that homogeneous oligomers containing mono-
substituted c-amino acids can form stable helical
conformations in solution. Seebach synthesized hexamer 1
and performed extensive 2D-NMR studies in pyridine-d
5
(Hintermann et al. 1998). Many NOEs were extracted from
the ROESY spectra and used as distance restraints in a
simulated annealing protocol. The secondary structure
obtained was a right-handed helix stabilized by H-bonds
between the carbonyl group of residue iand the NH group
of residue (i?3) (Fig. 1). Moreover, the same NOEs were
also present in CD
3
OH, although a smaller dispersion of
chemical shifts was observed. Thus, this 14 helix, pos-
sessing the same screw sense and polarity as the a-helix of
a-peptides, is also populated in CD
3
OH.
Hanessian et al. (1998) also described the same 14 helices
(helices with C
14
pseudocycles) for compounds 2,3and 4.In
these cases, a tetramer is sufficient to observe the helix for-
mation (Fig. 1). The structure determination was achieved
through 2D-NMR studies in pyridine-d
5
(NOE-derived dis-
tances and coupling constant-derived dihedral angles were
included in a restrained molecular dynamics simulated
annealing protocol). Moreover, for peptides 2and 3, tem-
perature-dependence experiments, as well as DMSO-d
6
titration experiments confirmed this conformation.
Hofmann later performed calculations on unsubstituted
and monosubstituted c-peptides (with one methyl group on
the a-, b-orc-position), employing ab initio MO theory at
various levels of approximation (Baldauf et al. 2003,
2005). He showed that the observed 14-helix conformation
and the 9-helix were the most stable conformations. He
also claimed that for unsubstituted and monosubstituted
c-peptides, mixed helices could also be observed (Baldauf
et al. 2004). In these cases, the most stable helices are the
22/24 and the 14/12 helices. The hydrogen bonds are ori-
ented alternately in opposite directions leading to a small
helix dipole (Fig. 2). These mixed helices should then be
favored in less polar media.
As predicted by Hofmann, a 9 helix has been observed
in other monosubstituted c-peptides. In fact, Kunwar
showed that tetramer 5and hexamer 6[alternating a
C-linked carbo-c
4
-amino acid and c-aminobutyric acid
(GABA)] form a 9 helix in CDCl
3
(Fig. 3). To determine
this conformation, extensive NMR studies were performed
(including NOESY, ROESY, DMSO-d
6
titration experi-
ments) and the resulting data were used to achieve
restrained MD calculations (Sharma et al. 2006a).
On the contrary, monosubstituted hexamers 7and 8
(Fig. 4) showed limited dispersion of the chemical shifts,
probably indicating the absence of secondary structure in
solution (Seebach et al. 2002).
Disubstituted c-peptides have also been investigated.
Balaram, for instance, synthesized many peptides incor-
porating the quaternary achiral Gabapentin residue (Gpn;
Fig. 5), in homogeneous and heterogeneous peptides (see
below). He thus obtained a crystallographic structure of
dimer 9(Boc-Gpn-Gpn-NHMe) and tetramer 10 (Boc-
Gpn-Gpn-Gpn-Gpn-NHMe). The tetramer formed a 9 helix
stabilized by three hydrogen bonds. For dimer 9, he also
identified a conformation stabilized by two C
9
hydrogen
bonds between the C=O moiety of residue iand the NH
group of the residue (i?2). Nevertheless, in that case, the
backbone torsion angles are different and the folded con-
formation is a C
9
ribbon (Vasudev et al. 2005). The same
C
9
hydrogen bond around the Gpn residue (i?1), between
the C=O moiety of residue iand the NH group of the
residue (i?2), was also observed in the crystallographic
structures of other small oligomers regardless of the
other residue: Boc-Gpn-Aib-OH, Piv-Pro-Gpn-Val-OMe,
P
1
N
H
H
NN
H
H
NOP
2
O
O
O
O
n
2 n = 1 P
1
= Boc P
2
= TMSE (tetramer)
3 n = 2 P
1
= Boc P
2
= Bn (hexamer)
4 n = 1 P
1
= H P
2
= Bn (octamer, TFA salt)
HN
H
H
NN
H
O
O
O
1
H
NN
H
H
NOH
O
O
O
Fig. 1 c
4
-peptides forming 14
helices (H-bond i?3?iare
shown with curved arrows).
TMSE trimethylsilylethyl
688 F. Bouille
`re et al.
123

Boc-Gpn-Gpn-Leu-OMe, Boc-Ac
6
c-Gpn-OH [Ac
6
c stands
for 1-(aminomethyl)cyclohexaneacetic acid], and Boc-Val-
Pro-Gpn-OH (Vasudev et al. 2007).
Disubstituted c
2,4
-amino acids have also been used for
c-peptide elaboration. This additional substitution reduces
the number of accessible conformations for the backbone.
In fact, only two of the nine possible conformers for a
c-residue do not possess unfavorable syn-pentane interac-
tions (Fig. 7). Thus, Hanessian synthesized tetramers 11,
13 and hexamer 12 and concluded that they all adopt a
right-handed 14-helix conformation in pyridine-d
5
. Struc-
tures of compounds 11 and 12 were determined using a
restrained molecular dynamics simulated annealing proto-
col (temperature-dependence experiments and DMSO-d
6
titration experiments were also performed, Hanessian et al.
1998) and for compound 13, long-range NOE data and
temperature-dependence experiments corroborate the same
14-helix formation (Hannessian et al. 1999). On the con-
trary, hexamer 14, which possesses the opposite relative
configuration, presents no helical conformation (Fig. 6).
This behavior has been rationalized by Seebach and
Hoffmann (Hoffmann et al. 1999; Hoffmann 2000; Brenner
and Seebach 2001a). In fact, a disubstituted c
2,4
-amino
acid Acan adopt a conformation found in the 14 helix
(conformation II), whereas for compound B, this type of
conformation is destabilized by a syn-pentane repulsive
interaction (conformation V). Compound Bshould be able to
adopt a turn conformation (conformations III and IV; Fig. 7).
In fact, a turn conformation has been identified by
Hanessian and Seebach. Tetrapeptide 15 forms a reverse
turn in pyridine-d
5
, as suggested by NOE data and deute-
rium exchange (Hanessian et al. 1999). Crystallographic
structures of heterochiral dipeptides 16 and 17 clearly
indicate the same conformation (Fig. 8; Brenner and
Seebach 2001a), which should be retained in solution (for
compound 16, an NOE was observed between NH group of
the terminal methylamide group and H–C(c) of residue 1,
and between H–C(c) of residue 1 and H–C(a) of residue 2
in CD
3
OH), according to ROESY analysis.
Other disubstituted c-peptides possessing a hydroxyl
moiety have been synthesized, although only the CD
spectra of these peptides (18–22; Fig. 9) were studied in
acetonitrile, MeOH and water. As no specific CD pattern in
the field of c-peptide can be related to a secondary struc-
ture, no firm conclusion can be drawn, but the fact that
modifications of the CD curves are observed when
changing the solvent may suggest the presence of a pre-
ferred secondary structure (Brenner and Seebach 2001b).
Trisubstituted c
2,3,4
-peptides have also been studied
(Seebach et al. 2001,2002). Peptides 23 and 24 possess the
same 2,4-relative configuration as compounds 11–13, and
they also form a 14 helix (the opposite 2,4-absolute con-
figuration of 23 and 24 led in this case to a left-handed
N
H
H
NN
H
H
N
O
O
O
O
N
H
H
NN
H
H
NN
H
H
N
O
O
O
O
O
O
14-helix (i+3 i)
9-helix (i+2 i)
C
14
(i+3 i)
C
12
(i i+2)
C
22
(i i+3)
C
24
(i+5 i)
Fig. 2 H-bonding in 14 helix or
9 helix (top) and in mixed
helices: 14/12 helix or 24/22
helix (bottom)
tBuO H
NN
H
H
NN
H
OMe
O
O
O
O
O
O
OO
MeO
nO
OO
MeO 5 n =1 (tetramer)
6 n=2 (hexamer)
Fig. 3 9 helix of tetramer 5and hexamer 6(all NH, except NH(1),
participate in H-bonding)
H
H
NN
H
H
NOH
O
O
O
CF
3
CO
2
H
2
7
H
H
NN
H
H
NOH
O
O
O
CF
3
CO
2
H
2
8
Fig. 4 No secondary structure
for monosubstituted hexamers 7
(c
3
-peptide) and 8(c
2
-peptide)
CO
2
HH
2
N
Gpn
H
2
NCO
2
H
Ac
6
c
Fig. 5 Structures of Gpn (c
3,3
-amino acid) and of Ac
6
c residues
Foldamers containing c-amino acid residues or their analogues 689
123

helix, compare Figs. 6and 10). This means that a supple-
mentary substitution is compatible with this type of sec-
ondary structure, there are no steric interferences. To
determine this helical structure, the authors obtained a
crystallographic structure of tetrapeptide 23, and they
performed extensive NMR studies of hexapeptide 24 in
CD
3
OH (including temperature-dependence and H/D
exchange experiments). Introduction of the extracted NOEs
and the dihedral angles derived from coupling constants
into a restrained molecular dynamics simulated annealing
protocol led to the same helical conformation, with a good
superposition of the two secondary structures.
Other conformations are also accessible with c-peptides
containing cyclic monomers. For instance, Royo has
synthesized a family of c-peptides based on cis-c-amino-L-
proline (Farrera-Sinfreu et al. 2004). Among these
peptides, compound 26 was investigated by NMR spec-
troscopy. A C
9
ribbon in H
2
O has been postulated on the
basis of NOE connectivities (Fig. 11).
AC
7
bend-ribbon has also been observed for homochiral
and heterochiral tartrate-derived peptidesin benzene-d
6
(Fig. 12). For compounds 27 and 29, DMSO-d
6
titration
experiments were performed and showed the formation of
a hydrogen bond between the amide NH group and the
carbonyl group of the same residue (in the first residue, this
is not true, probably because an ester is a poorer hydrogen-
bond acceptor than an amide). This structure was consistent
with the observed NOE correlations and with the downfield
shift of the chemical shifts of the amide NH in the
1
HNMR
tBuO H
NN
H
O
O
OR
R
OP
11 n = 2, R = Me, P = Bn
12 n = 3, R = Me, P = Bn
13 n = 2, R = CH
2
-CH=CH-Ph(E), P = Me
n
tBuO H
NN
H
H
NOTMSE
O
O
O
O
14
2
Fig. 6 Structures of
c
2,4
-peptides
HR
2
H
H
R
3
H
N
O
H
NH
R
3
H
H
H
R
2
HN
O
R
4
R
2
R
3
R
1
H
R
3
R
1
HN
R
2
H
H
COR
4
HNHR
1
H
R
2
H
H
H
R
3
COR
4
syn-pentane interaction
A (like)
HN
O
R
4
R
2
R
3
R
1
B (unlike)
H
COR
4
R
1
HN
R
2
H
H
R
3
HNHR
1
H
R
2
H
H
H
COR
4
R
3
NHR
1
R
3
R
2
H
H
H
H
COR
4
III
III IV V
N
OH
H
O
14-helix
Fig. 7 Conformations of
c
2,4
-amino acids and schematic
presentation of the
14-membered H-bonded rings
R N
H
H
NN
H
O
O
OBn
16 R = Me
17 R = OtBu
tBuO H
NN
H
O
O
O
OTMSE
2
Ph
Ph
15
Fig. 8 Structures of c
2,4
-peptides forming a turn conformation with a
C
14
hydrogen bond
tBuO N
H
H
NN
H
O
O
O
O
OH OH
OH
OBn
n
18 n = 1
19 n = 2
R
1
N
H
H
NN
H
O
O
O
OR
2
n
20 n = 1 R
1
= Boc R
2
= Bn
21 n = 2 R
1
= Boc R
2
= Bn
22 n = 2 R
1
= R
2
= H (TFA salt)
OH
OH
OH
Fig. 9 Structures of c
2,4
- and
c
3,4
-peptides with a hydroxyl
moiety
R
1
H
NN
H
O
O
OR
2
23 n = 2, R
1
= Boc, R
2
= Bn
24 n = 3, R
1
= R
2
= H (TFA salt)
n
Fig. 10 Structures of c
2,3,4
-peptides: left-handed 14 helix
690 F. Bouille
`re et al.
123

spectrum (Kothari et al. 2007). The same pattern was
observed for compounds 28 and 30.
The same type of intraresidue H-bonding has been
postulated for the sugar derivative oligomers 31 and 32
(Fig. 13). For dimer 31, a crystallographic structure
revealed a seven-membered ring hydrogen-bonded c-turn
like structure, and for tetramer 32, a similar high d
NH
(observed in benzene-d
6
) suggested the same type of
structure (Edwards et al. 2006). Oligomers with the
opposite configuration for the ether substituent showed no
secondary structure. Nevertheless, no further study was
described for these compounds.
Cyclopropane c-peptides have also been studied by
Smith. These authors initially synthesized a trimer 33 that
adopts an infinite parallel sheet structure in the solid state
(Qureshi and Smith 2006). The crystallographic structure
shows the formation of a bifurcated hydrogen-bonding
pattern: the carbonyl oxygen interacts both with the amide
NH group and one CH of the cyclopropane ring (Fig. 14).
Subsequently, they use this property to build a hairpin
conformation with the help of a nonpeptidic reverse turn
(Jones et al. 2008). For compounds 34 and 35, which are
diastereomers, several cross-strand NOE correlations were
observed in CDCl
3
. Variable-temperature and DMSO-d
6
titration experiments were also performed and all these
data were indicative of the formation of a hairpin. For
compound 35, a longer extended sheetlike conformation is
populated.
The propensity of trans-3-ACPC (trans-3-aminocyclo-
pentanecarboxylic acid) to form a parallel sheet secondary
structure was studied (Woll et al. 2001). Molecules 36,37
and 38 (Fig. 15) composed of trans-3-ACPC and D-prolyl-
(1,1-dimethyl)-1,2-diaminoethyl units were prepared.
Crystal structures of 36 and 37 show that both molecules
adopt the hairpin conformation in the solid state. The
conformation of compound 37 was confirmed by 2D NMR
spectroscopy in CD
2
Cl
2
. Molecule 38 was synthesized to
see if the parallel sheet secondary structure could propagate
out from the loop. Analysis by 2D NMR in pyridine-d
5
showed unambiguous evidence of a hairpin conformation,
in which the parallel c-peptide sheet involves the four
trans-3-ACPC residues.
Table 1summarizes the conformations stabilized by
hydrogen bonds that are observed in the c-peptide family.
In the a-peptide family, the polyproline helical confor-
mation, stable without any hydrogen bonds, is also present.
In the field of b-orc-peptides, conformations that are
stable without hydrogen bonds are rarely observed. In
2000, Guarna described the synthesis of c-oligomers
composed of (1R,7R)-3-aza-6,8-dioxabicyclo[3.2.1]-
octane-7-carboxylic acid, which can be considered either as
ac-amino acid or as a d-amino acid (BTG, 39, Machetti
et al. 2000). The di-, tri- and tetrapeptides 40–42 were
studied by NMR and circular dichroism (Fig. 16). The
latter spectroscopy, when performed in methanol, showed a
positive band (at ca. 210–215 nm), the intensity of which
increases with the chain length, indicating an additive
contribution of each unit to the ellipticity. This band is
preliminary evidence that oligomers composed of BTG can
form secondary structures without any hydrogen bonds.
N
H
N
O
O
NH
2
R6
R = H, , alkyl
25
N
O
N
O
N
O
H
H
N
O
O
N
O
N
O
N
H
H
N
O
O
N
O
N
O
N
H
H
N
O
N
O
HH
26
O
R'
Fig. 11 Oligomers of
cis-c-amino-L-proline
OO
OH
N
OO
ON
3
iPrO
OO
OH
N
OO
OH
N
iPrO
OO
OH
N
OO
ON
3
nn
27 n = 3
28 n = 5
29 n = 1
30 n = 2
C
7
C
7
C
7
Fig. 12 Oligomers forming a
C
7
bend-ribbon
O
H
N
PO
OO
N
3
PO
O
iPrO
n
31 n = 1 (P = OTBDPS)
32 n = 3 (P = OTBDPS)
Fig. 13 Sugar derivative oligomers
Foldamers containing c-amino acid residues or their analogues 691
123

Heterogeneous oligomers containing c-amino acids
Heterogeneous peptides (alternating with a-orb-residues)
considerably increase the number of possible oligomers
compared to oligomers composed only of c-residues. If one
considers b- and c-amino acids, homogeneous backbones
generate b- and c-peptides, respectively. The heterogeneous
approach allows different combinations, often with the
natural a-amino acids, such as a–c–a–c–a,a–a–c–a–a–c,
N
3
O
N
N
O
O
O
H
H
H
H
H
N
3
O
N
N
O
O
O
H
H
H
H
H
33
CF
3
O
N
N
H
O
N
H
O
N
3
H
H
O
N
O
H
N
3
H
H
H
CF
3
O
N
N
H
O
N
H
O
N
3
H
H
O
N
O
H
N
3
H
H
H
34 35
Fig. 14 Hairpin and parallel
sheet based on cyclopropane
c-amino acids
N
H
R'
O
N
ONH
O
H
N
O
H
N
R
O
n
36, n=1, R=R'=OtBu
37, n=1, R=R'=CH
2
Ph
38, n=2, R=CH
2
Ph, R'=tBu
Fig. 15 Hairpin and parallel sheet based on trans-3-ACPC
Table 1 Conformations
observed in the c-peptide family
RMD restrained molecular
dynamics-simulated annealing
protocol
Peptides Analysis References Conformation
1NMR (Pyr-d
5
), RMD Hintermann et al. (1998) 14 helix
2,3,4NMR (Pyr-d
5
), RMD Hanessian et al. (1998) 14 helix
5,6NMR (CDCl
3
), RMD Sharma et al. (2006a) 9 helix
Boc-(Gpn)
2
-NHMe 9X-ray Vasudev et al. (2005) 9 ribbon
Boc-(Gpn)
4
-NHMe 10 X-ray Vasudev et al. (2005) 9 helix
11,12 NMR (Pyr-d
5
), RMD Hanessian et al. (1998) 14 helix
13 NMR (Pyr-d
5
) Hannessian et al. (1999) 14 helix
15 NMR (Pyr-d
5
) Hannessian et al. (1999) Reverse turn
16 X-ray, NMR (CD
3
OH) Brenner and Seebach (2001a) Reverse turn
17 X-ray Brenner and Seebach (2001a) Reverse turn
23 X-ray Seebach et al. (2001,2002) 14 helix
24 NMR (CD
3
OH), RMD Seebach et al. (2001,2002) 14 helix
26 NMR (H
2
O) Farrera-Sinfreu et al. (2004)C
9
ribbon
27–30 NMR (benzene-d
6
) Kothari et al. (2007)C
7
ribbon
31 X-ray Edwards et al. (2006)C
7
turn
32 NMR (benzene-d
6
) Edwards et al. (2006)C
7
turn
33 X-ray Qureshi and Smith (2006) Parallel sheet
34,35 NMR (CDCl
3
) Jones et al. (2008) Hairpin
36 X-ray Woll et al. (2001) Hairpin
37 X-ray, NMR (CD
2
Cl
2
) Woll et al. (2001) Hairpin
38 NMR (Pyr-d
5
) Woll et al. (2001) Hairpin
692 F. Bouille
`re et al.
123

c–c–a–c–c–a,a–a–c–cto name just a few. Several
groups have thus studied the conformational analysis of
a/c-peptides and b/c-peptides.
a/chybrid peptides
Introduction of a a-residue in a c-peptide induces modifi-
cation of the possible conformations. Concerning the
helical accessible conformations, Hofmann performed
calculations on unsubstituted hybrid a/c-peptides (octa-
mers), employing ab initio MO theory at various levels of
approximation (Baldauf et al. 2006). He showed that the
most stable conformations were the 12-helix conformation
and the mixed 12/10 or 18/20 helices (Fig. 17). With a
smaller helix dipole, these mixed helices are favored in less
polar media.
The 12 helix and the mixed 12/10 helix were observed
in several hybrid peptides. For instance, Balaram synthe-
sized many different a/chybrid peptides using the con-
strained c-residue Gpn (Fig. 5; Vasudev et al. 2009) and
observed these helical conformations. The C
12
/C
10
mixed
hydrogen-bonding pattern was reported in the tetrapeptide
Boc-Leu-Gpn-Leu-Aib-OMe 43 crystal structure, com-
posed of three a-amino acids and Gpn (Vasudev et al.
2008). In the Gpn residue, the gem-dialkyl unit limits the
torsion angles about the Cc–Cband Cb–Cabonds to ±60°.
The folded conformation of 43 is stabilized by two intra-
molecular hydrogen bonds: a 12-membered ring is
observed between the Boc C=O group and Leu(3) NH
groups, while a 10-membered ring is observed between the
Gpn(2) NH and Leu(3) C=O groups. The C
12
hydrogen-
bonding pattern was also observed in the tetrapeptides
Boc-Aib-Gpn-Aib-Gpn-OMe 44 (Ananda et al. 2005) and
Boc-Aib-Gpn-Aib-Gpn-NHMe 45 (Chatterjee et al. 2008b)
in the solid state and in chloroform solution. In that case,
two successive C
12
hydrogen-bonded turns [between the
Boc C=O group and Gpn(2) N–H group and Aib(1) C=O
group and Gpn(4) N–H group] generate a 12 helix. On the
contrary, the tetrapeptide Boc-Gpn-Aib-Gpn-Aib-OMe 46
shows (crystallographic structure) two C
7
hydrogen bonds
across the Gpn residue, which can be seen as an expansion
of the C
5
-helix observed in a-peptides (Vasudev et al.
2007).
The 12 helix was also reported in longer peptides in the
solid state and in solution. Recently, the octapeptide Boc-
(Gpn-Aib)
3
-Gpn-Aib-OMe 47 (composed of a succession
of Aib and Gpn residues) revealed a continuous 12 helix
over the Aib(2)–Aib(6) segment (Chatterjee et al. 2009).
The four Aib residues adopt a helical conformation with
the sole exception that the terminal residue has the opposite
hand. In addition, the N- and C-terminal Gpn residues have
a 9-membered hydrogen-bonded ring. The authors also
noted the evidence of this 12 helix in longer peptides
composed of a succession of Aib- and Gpn-residues (see
peptides 48 and 49; Table 2).
The hybrid acaaca peptide, Boc-Leu-Gpn-Aib-Leu-
Gpn-Aib-OMe 50, reveals a continuous helical conforma-
tion in crystals stabilized by three intramolecular C
12
hydrogen bonds and one C
10
hydrogen bond across the
central aa residues (Fig. 18; Chatterjee et al. 2008a). This
mixed hydrogen-bonding pattern is an extension of the 3
10
conformation found in the a-peptides.
In the pentamer aacaa 51(Boc-Ala-Aib-Gpn-Aib-Ala-
OMe) possessing only one Gpn residue, a 12 helix is still
observed in the crystallographic structure (Vasudev et al.
2007).
N
O
R
CO
2
R'
O
39
δ-amino acid
γ-amino acid
N
O
Bn O
O
N
O
O
O
N
O
CO
2
Me
O
n
40 n=0 (dimer)
41 n=1 (trimer)
42 n=2 (tetramer)
Fig. 16 Oligomers based on
BTG
C12 (i+3 i)
C10 (i i+1) C18 (i i+3)
C20 (i+5 i)
N
H
H
NN
H
H
NN
H
H
N
O
O
O
O
O
N
H
NH2
O
O
O
H
N
O
N
H
H
NN
H
H
NN
H
H
N
O
O
O
O
O
N
H
NH2
O
O
O
H
N
O
12-helix (i+3 i)
12-helix (i+3 i)
Fig. 17 H-bonding in 12 helix
(top) and in mixed helices:
12/10 helix or 18/20 helix
(bottom)
Foldamers containing c-amino acid residues or their analogues 693
123

In Gellman’s group, a constrained cyclohexyl derivative
was used as the c-amino acid. Linking of this c-residue and
a-residues generated tetra- and hexapeptides 52 and 53,
respectively (Fig. 19). Both adopted a 12-helical confor-
mation, as revealed in the crystal structures and by NMR
spectroscopy (Guo et al. 2009). In each case, the maximum
number of C=O(i)–H–N(i?3) H bonds is formed.
Sharma synthesized a family of a/c-peptides (compounds
54–57) derived from dipeptide repeats with alternating
arrays of L-Ala and c-Caa
(m)
(C-linked carbo-c-amino acid
from D-mannose, 58; Fig. 20) and found mixed 12/10-
helical conformations for all these compounds by NMR
spectroscopy (linked with a restrained molecular dynamics
simulated annealing protocol) and CD spectroscopy (Shar-
ma et al. 2006b).
A hybrid sequence composed of bbbbabacaca residues
[with b=C-linked carbo b-amino acids =bCaa 59 (both
configuration at Cb), a=Ala, c=C-linked carbo c-amino
acids =cCaa 60; Fig. 20] was prepared and consisted of
three different foldamer classes: the 12/10 helices of
b-peptides and a/c-hybrid peptides and the 11/9 helix of
a/b-hybrid peptides (Sharma et al. 2009). In this peptide
61, all amide protons [except NH(1) and NH(10)] partici-
pate in hydrogen bonding, as suggested by the Ddvalues in
the solvent titration studies and also by their low field
dvalues. The authors showed that the 12/10- and 11/9-
helical pattern of the first seven residues was identical to
that observed in the corresponding bbbbaba peptide. Then,
the 11/9 helix smoothly changes into the 12/10 helix of the
alternating c- and a-residues (Fig. 21).
Table 2summarizes the helical conformations stabilized
by hydrogen bonds that are observed in the a/c-peptide
family.
The c-amino acids have also been used to build hairpin
or sheets either by being the turn inducer or by being
present in the strands.
Crystallographic studies of Boc-Leu-Phe-Val-Aib-Gpn-
Leu-Phe-Val-OMe (62; Fig. 22) reveal an almost perfect
b-hairpin structure stabilized by four cross-strand hydrogen
bonds between the two Leu-Phe-Val tripeptide segments
with the Aib-Gpn segment, forming a nonhelical C
12
turn
(Chatterjee et al. 2009). Peptide 62 was also studied in
solution, both in methanol and in chloroform. In both
solvents, the observation of the interstrand NOEs is con-
sistent with the hairpin conformation similar to that
observed in crystals.
It should be noted that crystal structures of dipeptides
63–67 (see Table 3) revealed C
7
or C
9
hydrogen bonds,
which is adequate to generate an antiparallel sheet (Arav-
inda et al. 2003; Vasudev et al. 2007). The
D
Pro-Gpn-based
turn can generate the b-hairpin conformation of peptide
Boc-Leu-Phe-Val-
D
Pro-Gpn-Leu-Phe-Val-OMe 68,as
observed by NMR spectroscopy in methanol according to
key NOE contacts (Rai et al. 2007).
This 12-membered pattern has also been observed when
c-aminobutyric acid (named either cAbu or GABA) is
used (Maji et al. 2002). Authors observed in peptides
Table 2 Helices observed in the a/c-peptide family
Peptide Analysis Reference Helix
Boc-Leu-Gpn-Leu-Aib-OMe 43 X-ray, NMR (CDCl
3
) Vasudev et al. (2008) 12/10
Boc-Aib-Gpn-Aib-Gpn-OMe 44 X-ray, energy minimization Ananda et al. (2005)12
Boc-Aib-Gpn-Aib-Gpn-NHMe 45 X-ray, NMR (CDCl
3
) Chatterjee et al. (2008b)12
Boc-Gpn-Aib-Gpn-Aib-OMe 46 X-ray Vasudev et al. (2007)C
7
Boc-(GpnAib)
3
-Gpn-Aib-OMe 47 X-ray, NMR (CDCl
3
), energy minimization Chatterjee et al. (2009)12?C
9
Boc-(AibGpn)
3
-Aib-Gpn-Aib-OMe 48 NMR (CDCl
3
) Chatterjee et al. (2008b)12
Boc-(AibGpn)
3
-Aib-Gpn-Leu-OMe 49 NMR (CDCl
3
) Chatterjee et al. (2008b)12
Boc-Leu-Gpn-Aib-Leu-Gpn-Aib-OMe 50 X-ray, NMR (CDCl
3
) Chatterjee et al. (2008a)12?C
10
Boc-Ala-Aib-Gpn-Aib-Ala-OMe 51 X-ray Vasudev et al. (2007)12
52 X-ray Guo et al. (2009)12
53 X-ray, NMR (CDCl
3
) Guo et al. (2009)12
Boc-Ala-cCaa
(m)
-OMe 54, Boc-(Ala-cCaa
(m)
)
2
-OMe 55,
Boc-(Ala-cCaa
(m)
)
3
-OMe 56,
NMR (CDCl
3
), RMD Sharma et al. (2006b) 12/10
Boc-(cCaa
(m)
-Ala-)
3
-OMe 57
Boc-bCaa
4
-Ala-bCaa-Ala-(cCaa-Ala)
2
-OMe 61 NMR (CDCl
3
) Sharma et al. 2009 12/10
RMD restrained molecular dynamics simulated annealing protocol
N
HO
H
N
O
N
HO
H
N
O
N
HO
H
NOMe
O
(H
3
C)
3
CO
O
C
12
C
12
C
12
50
C
10
Fig. 18 Structure of peptide 50 with hydrogen bonds
694 F. Bouille
`re et al.
123

Boc-cAbu-Aib-Ala-OMe (69) and Boc-cAbu-Aib-Ala-Aib-
OMe (70) unusual turns composed of 12-membered
hydrogen-bonded rings involving the C=O group from the
Boc-group and Ala(3) NH group in crystals and in solution.
The contiguous location of cAbu and Aib is essential for
this conformation (Fig. 23). The crystallographic structure
of peptide Boc-Pro-cAbu-OH 71 reveals a folded confor-
mation stabilized by a C–HO hydrogen bond involving
one of the a-methylene hydrogen atoms of the cAbu resi-
due and the C=O group of the Boc group (Fig. 23), char-
acteristic of a b-turn mimetic structure (Sengupta et al.
2006). Curiously, for the same compound 71, smaller
hydrogen-bonded rings (C
5
and C
6
) have also been
observed in the crystallographic structure by another group
(Kumar et al. 2010).
In 2002, Guarna used derivatives of BTG such as
compounds 72 and 73 (Fig. 24) and a-amino acids in the
synthesis of hybrid peptides Ac-Val-Ala-6-endo-BTL-Val-
Gly-OMe (74) and Ac-Val-Ala-6-endo-BtL-Val-Gly-OMe
(75), respectively (Trabocchi et al. 2002,2006). The con-
formations of the corresponding peptides were studied by
NMR (CDCl
3
), IR, and molecular modeling. For peptide
74, all the NMR analyses provided evidence of a stable
b-hairpinlike conformation, which was confirmed by IR
and modeling calculations. For peptide 75, the absence of
any cross-strand NOE peaks suggested that the oligomer
folded in an open turn probably because of the steric hin-
drance of the half-chair conformation of the six-membered
ring moving the two strands apart from each other.
Ab-hairpin conformation in peptide Boc-Leu-Val-
cAbu-Val-
D
Pro-Gly-Leu-cAbu-Val-Val-OMe (76) was
observed (Roy et al. 2006). In this case, the turn is induced
by the
D
Pro-Gly residues and the c-amino acids that are
present in the strands (a situation which is similar to pep-
tides in Figs. 14,15). Although
1
H NMR studies in
methanol support the formation of the nucleating turn,
evidence for cross-strand registry was not detected.
H
N
O
tBuO
O
H
N
Ph
O
N
HN
H
OPh
O
O
H
N
OO
H
N
O
N
HN
H
OH
N
O O
OBn
N
H
O
tBuO
52
53
Fig. 19 12 helix of peptides 52
and 53
OO
O
MeO
H2N
O
OH
γ−Caa(m)-residue 58
O
H2NOH
β−Caa-residue 59
OO
OMe
O
(R) or (S) at Cβ
O
H2N
γ−Caa-residue 60
OO
OMe
OH
O
Fig. 20 Structures of b-orc-amino acids used as monomers
O
H
N
tBuO
O
OO
H
3
CO
H
N
OO
OO
H
3
CO
H
N
OO
OO
H
3
CO
H
N
OO
OO
H
3
CO
H
N
O
O
N
H
O
N
H
O
H
3
CO
OO
O
H
N
O
OO
H
3
CO
N
H
O
O
H
N
O
OO
H
3
CO
N
H
O
O
OMe
C
12
C
12
C
12
C
12
C
11
C
10
C
10
C
10
C
9
C
9
61
Fig. 21 Structure of peptide 61 with hydrogen bonds
N
OH
N
O
HN
N
H
O
N
O
62
O
NOMe
N
H
NBoc
O
O
OBn
Bn
HH
H H
Fig. 22 Hairpin structure of compound 62 induced by the Aib-Gpn
residues
Foldamers containing c-amino acid residues or their analogues 695
123

However, single crystal X-ray diffraction studies revealed a
b-hairpin conformation for both molecules in the crystal-
lographic asymmetric unit, stabilized by four cross-strand
hydrogen bonds. The directions of the cross-strand
NHC=O hydrogen bonds alternate in the same manner as
in hairpin turns containing a-amino acids in the strands
(Fig. 25). The crystal packing has the same features as the
packing for an all-a-hairpin peptide except that the a-sheet
stacks in 76 have a V-shaped tilt contrasting with the flat
arrangement in all a-peptides.
Table 3summarizes the hairpin and turn conformations
stabilized by hydrogen bonds that are observed in the
a/c-peptide family.
The features of (2S,10R,3R,4R)-3,4-(aminomethan-
o)prolinol (c-Amp
a
) and (2R,10S,3S,4S)-3,4-(aminomet-
hano)prolinol (c-Amp
b
) were investigated in the synthesis
of alternating a/c-amino acid sequences (Brackmann et al.
2006). The peptide folding of compounds 77–80 (Fig. 26)
was examined by CD in water and methanol, and it was
shown that the dichroic properties of these oligomers are
independent of the solvent. These properties are consistent
with c-Amp residues inducing two different preferred
conformations.
An extended sheet has also been observed by Wipf using
ac-amino acid containing a cyclopropane ring. Compound
81 adopts an extended b-sheet conformation in the solid
state, crystallizing as an antiparallel dimer (Fig. 27; Wipf
and Stephenson 2005). It is noteworthy that for this com-
pound, as for compound 33, the dihedral angles in the
c-amino acid cyclopropane residue are of the same order of
magnitude (all greater than 135°). Thus, both compounds
adopt similar geometries dictated by the cyclopropane ring.
Cyclic peptides have also been investigated by the group
of Granja (Table 4).
Oligomers composed of (1R,3S)-3-aminocyclopentane-
carboxylic acid (L-c-Acp, 82; Fig. 28)or(1R,3S)-3-amino-
cyclohexanecarboxylic acid (L-c-Ach, 83; Fig. 28) or their
enantiomers as c-amino acid residues mixed with a-amino
acids have largely been synthesized in order to study
the properties of these artificial nanotubular materials
Table 3 Hairpin and turn observed in the a/c-peptide family
Peptide Analysis Reference Member in the loop
Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-
Val-OMe 62
X-ray, NMR (MeOH, CDCl
3
),
energy minimization
Chatterjee et al. (2009)12
Piv-Pro-Gpn-OH 63 X-ray, energy minimization Aravinda et al. (2003) 10 and 9
Boc-Gly-Gpn-OH 64 X-ray, energy minimization Aravinda et al. (2003)7
Boc-Aib-Gpn-OH 65 X-ray, energy minimization Aravinda et al. (2003)9
Boc-Aib-Gpn-OMe 66 X-ray, energy minimization Aravinda et al. (2003)7
Boc-Ac
6
c-Gpn-OMe 67 X-ray Vasudev et al. (2007)7
68 NMR (CD
3
OH) Rai et al. (2007)12
Boc-cAbu-Aib-Ala-OMe 69 X-ray, NMR (CDCl
3
) Maji et al. (2002)12
Boc-cAbu-Aib-Ala-Aib-OMe 70 X-ray, NMR (CDCl
3
) Maji et al. (2002) 12 and 10
Boc-Pro-cAbu-OH 71 X-ray Sengupta et al. (2006)10
Boc-Pro-cAbu-OH 71 X-ray, IR Kumar et al. (2010) 5 and 6
74 NMR (CDCl
3
), energy minimization Trabocchi et al. (2002)13
76 X-ray, NMR (MeOH Roy et al. (2006)10
tBuO
H
N
O
O
N
H
O
H
N
MeO
O
69
tBuO
H
N
O
O
N
H
O
H
N
N
H
O
70
MeO
O
N
OO
tBu
HHN
OH
71
C
10
O
OH
HC
6
C
5
Fig. 23 Turns observed for
peptides containing the cAbu
residue
N
O
R
CO
2
H
O
72 6-endo-BTL
N
O
R
CO
2
H
O
73 6-endo-BtL
Fig. 24 Structures of 6-endo-BTL and 6-endo-BtL
696 F. Bouille
`re et al.
123

(Brea et al. 2009; Garcia-Fandino et al. 2009; Reiriz et al.
2009a). The formation of self-assembling peptide nano-
tubes (SPNs) can exist with the sole all-trans-conformation
for the amide bonds (Amorin et al. 2003; Brea et al. 2005).
In fact, for peptide 84, crystallographic and NMR analyses
in polar and apolar solvents (CCl
4
, CDCl
3
, MeOH, DMSO)
reflect a high degree of symmetry and the all-trans con-
formation required for the flatness of the ring (Amorin
et al. 2003). Results observed confirmed the a–adimer-
ization of flat, antiparallel rings by means of a b-sheet-like
array. Moreover, such dimers can stack to form nanotubes
(Fig. 28; Amorin et al. 2005a).
The same group showed that methylation of either
c-residues (86–89)ora-residues (90) has no effect on the
dimerization of the flat rings but prevents the self-assembly
of the nanotube (Brea et al. 2005; Amorin et al. 2005b).
Even the heterodimerization between 86 and 85 or 87 and
90 was observed by NMR and X-ray analysis (Brea et al.
2005). Such heterodimers were used to prepare a bio-
inspired nanohybrid dimer system, in which the first
cyclopeptide composed of D-c-Acp, D-Leu and decorated
with a fullerene as an electron acceptor is coupled by a
b-sheet-like hydrogen-bond system to a second one com-
posed of D-c-Acp, D-Phe and substituted by an electron
donor {2-[9-(1,3-dithiol-2-ylidene)antracen-10(9H)-ylidene]-
1,3-dithiole} (Brea et al. 2007; Reiriz et al. 2009a).
A new class of cyclic-peptide foldamers, composed of
three a-amino acids and one L-c-Acp (or Ach), was
developed (91–95; Amorin et al. 2008). The authors
observed that these peptides can either remain as flat rings
that dimerize through arrays of hydrogen bonds of the
antiparallel b-sheet type (91–92), or fold into twisted
double c-turns, associating in nonpolar solvents to form
helical supramolecular structures (93–95), depending on
their backbone N-methylation patterns and on the medium.
The same authors prepared cyclic peptides by mixing
D-NMe-c-Acp residues with Leu and Tyr as a-amino acids
and a C2-modified c-amino acid, namely 4-amino-3-
hydroxytetrahydrofuran-2-carboxylic acid [c-Ahf-OH (97);
Fig. 28]. The resulting cyclic peptide 96 can form self-
assembling nanotubes, the cavity properties of which can
be modulated by the hydroxyl group of residue 97 (Reiriz
et al. 2009b).
b/chybrid peptides
b/c-Peptides have only recently emerged in the literature
(an early example was described by Karle et al. 1997),
probably because of the lower availability of the b-amino
acids compared to a-amino acids. These oligomers are
nevertheless of particular interest because the backbone of
ab/c-dipeptide possesses the same number of atoms as an
a-tripeptide.
Hofmann performed calculations on unsubstituted
hybrid b/c-peptides (octamers) (Baldauf et al. 2006). He
showed that the most stable conformations were the 11- or
13-helix conformation and the mixed 11/13 or 20/22 heli-
ces. As previously stated, these mixed helices are favored
in less polar media (Fig. 29). These authors also compared
the 13 helix of the hybrid b/c-peptides to the secondary
structure of the native a-peptides, because a hybrid b/c-
dipeptide has the same number of atoms as an a-tripeptide.
It appears that there are important similarities between
these two structures in terms of geometry (good
N
H
OH
N
O
N
H
OH
N
O
OMe
O
HN O
N
OH
N
O
N
H
OH
N
O
N
H
Boc
i
Pr
i
Bu
Pri
i
Bu
i
Pr
i
Pr
76
Fig. 25 Hairpin of peptide 76
N
H
NH
H
N
O
O
H
N
O
N
HO
NH
2
OH
Fmoc
n
γ-Amp
b
γ-Amp
a
N
H
NH
H
N
O
O
H
N
O
N
HO
NH
2
OH
Fmoc
nn=2 (77)
n=3 (78)
n=2 (79)
n=3 (80)
oo
Fig. 26 Structure of
a/c-peptides based on c-Amp
a
and c-Amp
b
Ph
H
N
O
CO
2
Me
Ph
NH
O
BnO
81
H
N
O
MeO
2
C
Ph
HN
Ph
O
OBn
Fig. 27 Extended sheet of dipeptide 81
Foldamers containing c-amino acid residues or their analogues 697
123

superimposition of the two helices), hydrogen bonds and
helix dipole orientation.
In order to study these conformations, Kunwar prepared
three b/c-peptides composed of C-linked carbo-b- and
c-amino acids of D-xylose named (S)-b-Caa (59; Fig. 20)
and c-Caa (60; Fig. 20), respectively (Sharma et al. 2006b).
These b/c-peptides {Boc-[(S)-b-Caa-c-Caa]
2
-OMe (98),
Boc-[(S)-b-Caa-c-Caa]
2
-b-Caa-OMe (99) and Boc-[(S)-b-
Caa-c-Caa]
3
-OMe (100)} were analyzed by NMR (CDCl
3
)
and circular dichroism. For the tetrapeptide 98, determi-
nation of NOEs and coupling constants provided evidence
for a 11/13 helix, with an 11/13/11 H-bonded arrangement.
Table 4 Structures of the cyclic peptides
Cyclic peptide Analysis Reference Conformation
(L-c-Acp-D-Ala)
3
84
(L-c-Ach-D-Phe)
3
85
X-ray, NMR (CCl
4
, CDCl
3
,
MeOH, DMSO)
Amorin et al. (2003)b-Sheet like
(L-NMe-c-Acp-D-Leu)
3
86
(L-NMe-c-Acp-D-Phe)
3
87
X-ray, NMR (CCl
4
, CDCl
3
,
MeOH, DMSO)
Brea et al. (2005)b-Sheet like
(D-Phe-L-NMe-c-Ach)
2
88 NMR (CCl
4
, CDCl
3
,
MeOH, DMSO), IR
Amorin et al. (2005b)b-Sheet like
(L-Leu-D-NMe-c-Acp)
2
89 X-ray, NMR (CCl
4
, CDCl
3
,
MeOH, DMSO, IR
Amorin et al. (2005b)b-Sheet like
(L-NMe-Ala-D-c-Ach)
2
90 NMR (CCl
4
, CDCl
3
, MeOH,
DMSO), IR
Amorin et al. (2005b)b-Sheet like
(L-Ser(Bn)-D-NMe-c-Ach-L-Phe-D-Ala)
2
91
(L-c-Ach-D-Ala-L-Ser(Bn)-D-NMe-Ala)
2
92
X-ray, NMR (CDCl
3
), IR Amorin et al. (2008)b-Sheet like
(L-c-Ach-D-Phe-L-NMe-Ala-D-Phe)
2
93
(L-c-Ach-D-NMe-Ala-L-Ser(Bn)-D-Ala)
2
94
(L-Ser(Bn)-D-c-Ach-L-Phe-D-NMe-Ala)
2
95
X-ray, NMR (CDCl
3
), IR Amorin et al. (2008) Twist, double
reverse turn
(L-c-Acp-L-Leu-c-Ahf-OH-L-Phe) 96 NMR (CDCl
3
), Reiriz et al. (2009b)b-Sheet like
H2N
O
OH
n
n=0 L-γ-Acp (L-82)
n=1 L-γ-Ach (L-83)
O
HO2C
HO NH2
γ-Ahf-OH (97)
N
O
N
H O
N
H
O
N
O
N
O
N
O
H
H
H
H
N
O
N
O
H
HN
O
N
O
N
O
H
N
H
OH
H
N
O
N
H O
N
H
O
N
O
N
O
N
O
H
H
H
H
N
O
N
O
H
HN
O
N
O
N
O
H
N
H
OH
H
γ−γ
α−α
Fig. 28 Structures of the
c-amino acids used for
cyclopeptides and
representation of nanotubes
with hydrogen bond network
(amino acid side chains have
been omitted for clarity)
698 F. Bouille
`re et al.
123

Similar observations were made for the pentapeptide 99
and hexapeptide 100 supporting a 11/13-mixed helix with
an 11/13/11 H-bonding pattern (Fig. 30). Restrained
molecular dynamics were performed for peptides 98 and 99
and showed 2.7 residues per turn, a 2.2 A
˚rise per residue
and a pitch of 5.9 A
˚.
The use of a Gpn residue allowed Vasudev to observe
and to characterize two C
13
turns in the solid state for the
hybrid sequences Boc-bLeu-Gpn-Val-OMe (101) and Boc-
bPhe-Gpn-Phe-OMe (102) (Vasudev et al. 2007). In both
cases, a C
13
hydrogen bond between the Boc C=O group
and the Val/Phe NH groups is observed (Fig. 31). In pep-
tide 102, an additional hydrogen bond between the Gpn(2)
NH group and the Phe(3) C=O group is observed in the
Gpn-Phe segment. This corresponds to a C
10
hydrogen
bond with reversal directionality.
Gellman’s group studied the formation of the left-
handed b/c-peptide 13 helix (Guo et al. 2010). Three peptides
composed of c-residues (a aminocyclohexanecarboxylic
acid derivative) and of b-residues [(R,R)-2-aminocyclo-
pentanecarboxylic acid trans-2-ACPC] were prepared
(compounds 103–105; Fig. 32). Both peptides 103 and 104
revealed a 13-atom H-bonded ring in the solid state. In 103,
the 13-membered ring involves the NH group of the second
ACPC residue and the C=O group of the N-terminal Boc
group. In 104, the three C=O(i)–H–N(i?3) H-bonds are
formed. Parameters determined from these crystals are
consistent with the predictions for the 13-helical confor-
mations from Hofmann (Baldauf et al. 2006). Peptide 105
gave no high-quality crystals. Nevertheless, 2D
1
HNMR
spectroscopy in pyridine-d
5
supported a 13-helix confor-
mation. These 13-helical conformations are similar to the
a-helix formed by pure a-residues: both have 5.4 A
˚rise per
turn and have similar radii (2.5 vs. 2.3 A
˚).
Table 5summarizes the conformations stabilized by
hydrogen bonds that are observed in the b/c-peptide family.
Araghi used these similarities to mimic a-helical turns in
proteins by introducing a b/c-pattern (Araghi et al. 2010;
Araghi and Koksch 2011). They showed that a heptad of
a-amino acids in a protein motif, comprising three 13-atom
H-bonded turns of the helix, could be substituted by a
pentad repeat of alternating b- and c-amino acids with
retention of the helix dipole and of the quaternary structure
(CD spectra and molecular models).
H
NH
NN
HN
H
H
NH
NN
HN
H
NH
2
O O
O O
O O
O O
O
H
NH
NN
HN
H
H
NH
NN
HN
H
NH
2
O O
O O
O O
O O
O
11-helix (i i+1)
13-helix (i+3 i)
C
11
(i i+1)
C
13
(i+3 i)
C
20
(i i+3)
C
22
(i+5 i)
Fig. 29 H-bonding in 11 helix
and 13 helix (top) and in mixed
helices: 11/13 helix or 20/22
helix (bottom)
O
H
N
tBuO
O
H
N
O
N
H
O
N
H
OH
N
O
OO
O O
OO OO
OO OO
MeO
OMe OMe
MeO
C
11
C
11
C
13
100
O
OO
MeO
H
N
O
O
OO
MeO
OMe
C
13
C
11
Fig. 30 11/13 helix
conformation of hexapeptide
100
N
H
H
N
O
C
13
O
OMe
101
O
N
H
iPr
t
BuO
O
N
H
H
N
O
C
13
O
OMe
102
O
Ph
N
H
t
BuO
OPh
C
10
Fig. 31 b/cHybrid peptides
with Gpn
Foldamers containing c-amino acid residues or their analogues 699
123

Foldamers containing analogue of c-amino acids
One of the first pieces of work demonstrating that chain
molecules based on c-amino acids form defined secondary
structure was reported by Schreiber and Clardy (Hagihara
et al. 1992). The authors studied protein-like substances
in which the repeating unit is a c-amino acid with an
a,b-unsaturation (vinylogous c-peptides). To restrict the
conformational space of the c-amino acid backbone, an
a-methyl substituent was initially examined. For this
substitution pattern, allylic strain (A
1,3
) was expected to
drive the c-hydrogen to lie in the amide plane, and would
favor sheetlike conformations. The crystal structures of
dipeptide 106 revealed that this conformational prefer-
ence, and a two-stranded, antiparallel sheet was observed
in the crystal packing. However, the a-methyl substituent
seemed to prevent higher ordered sheets with longer
oligomers.
Removal of the a-methyl substituent resulted in vinyl-
ogous c-peptides that are organized in long stacks of
parallel sheets. To favor antiparallel alignment, a Pro-Gly
dipeptide turn was inserted in two vinylogous c-amino
acids (Fig. 33;107).
1
H NMR studies in solution revealed
the existence of intramolecular hydrogen bonds involving
N and C termini. Finally, a tetrapeptide incorporating a
vinylogous c-amino acid, a Pro-Gly turn and a c
2,3
-amino
acid showed an helical conformation stabilized by 10- and
12-membered H-bonded rings (Fig. 33;108).
Employing ab initio MO theory, Hofmann and co-
workers have investigated the folding propensities of the
vinylogous c-peptides by the introduction of an (E)-double
bond between the Caand the Cbatoms of the c-amino acid
constituents (Baldauf et al. 2003). This strategy seems to be
an interesting idea to avoid the formation of smaller
pseudocycles and to favor helices with larger ones. Con-
formational analysis showed that structures with nearest-
neighbor H-bonds like C
7
,C
9
and also C
12
cannot be
formed with a,b-unsaturation. In this case, the most stable
conformations proved to be the 19 and 22 helices at HF and
DFT levels of ab initio theory.
H
N
O
N
H
tBuO
OEt O
H
N
N
H
OEt OBn
O
103
C
13
C
8
H
N
O
N
H
tBuO
OEt O
H
N
N
H
OEt
104
C
13
C
13
O
NH OBr
C
13
H
N
O
N
H
tBuO
OEt O
H
N
N
H
OEt
O
H
N
O
N
HEt
O
OBn
105
Fig. 32 13 helix based on
alternating band c-cyclic
residues
Table 5 Conformations stabilized by hydrogen bond observed in the b/c-peptide family
Peptide Analysis Reference Conformation
Boc-[(S)-b-Caa-c-Caa]
2
-OMe 98
Boc-[(S)-b-Caa-c-Caa]
2
-b-Caa-OMe 99
Boc-[(S)-b-Caa-c-Caa]
3
-OMe 100
NMR (CDCl
3
), CD
(MeOH), RMD
Sharma et al. (2006b)
Sharma et al. (2006b)
Sharma et al. (2006b)
11/13 helix
11/13 helix
11/13 helix
Boc-bLeu-Gpn-Val-OMe 101 X-ray Vasudev et al. (2007)C
13
-turn
Boc-bPhe-Gpn-Phe-OMe 102 X-ray Vasudev et al. (2007)C
13
?C
10
Boc-(ACPC-Achc)
2
-OBn 103 X-ray Guo et al. (2010) 13 helix ?C
8
Boc-(ACPC-Achc)
2
-ACPC-OBnBr 104 X-ray Guo et al. (2010) 13 helix
Boc-(ACPC-Achc)
3
-OBn 105 NMR (Py-d
5
) Guo et al. (2010) 13 helix
RMD restrained molecular dynamics simulated annealing protocol
700 F. Bouille
`re et al.
123

In 2003, Chakraborty and Kunwar (2003) produced
series of penta- and hexapeptides containing the E-vinyl-
ogous prolines 109 and 110. They postulated that since
E-vinylogous prolines are known to stabilize a cis amide
bond with the preceding amino acid, such dipeptides might
lead to intramolecularly hydrogen-bonded structures when
incorporated in the middle of a sequence. As expected,
detailed NMR spectroscopy and MD simulation analysis of
the major conformer of hexapeptide 111 in CDCl
3
revealed
ab-hairpin like structure with a well-defined 12-membered
H-bonded ring (Fig. 34).
The authors emphasized the similarity between the
observed structure and a type VI b-turn (supported by the
average u,wangles of central residues).
Grison and et al. (2005) have also studied the insertion
of various cis-ortrans-vinylogous residues in short chain
peptides using X-ray diffraction in the solid state and
1
H
NMR and IR spectroscopy in solution. Experimental
studies showed that the structural consequences greatly
depend on the stereochemistry of the vinylogous residue.
The cis-vinylogous fragment promotes a folded confor-
mation with an intramolecular NH to CO hydrogen bond
closing a C
9
pseudocycle (named ‘‘cis-vinylog turn’’).
Compounds containing a trans-vinylog fragment accom-
modated completely different conformations, revealing an
open structure and no intramolecular interaction. Further
investigation was realized on a cis–cis-divinylog dipeptide
and experimental data clearly indicated two consecutive
cis-vinylog turns. Therefore, the authors claimed that an
oligo cis-vinylog should adopt a helical structure with
consecutive cis-vinylog turns.
Among the wide variety of unnatural peptidomimetic
oligomers, oligoureas can be considered as promising
foldamer candidates. In pioneering studies, the Nowick
group studied the synthesis of di- and tri-urea derivatives to
produce compounds that mimic the structures and hydro-
gen-bonding patterns of protein b-sheets (Nowick et al.
1992,1995a). IR and NMR studies revealed that these
derivatives are intramolecularly hydrogen bonded and thus
suitable for forming rigidified scaffolds (see compound
112). They next produced compounds such as 113
(Fig. 35), in which a diurea molecular scaffold juxtaposes
two dipeptide strands, giving rise to artificial b-sheet-like
structures (Nowick et al. 1995b). To create even more
robust artificial b-sheets, the Nowick group has also
investigated incorporation of a b-strand mimic (derived of
5-amino-2-methoxybenzoı
¨c acid) (Nowick et al. 1996,
1997; Smith et al. 1997).
Although N,N0-linked oligoureas have been readily
accessible by solid-phase synthesis since 1995 (Burgess
and Linthicum 1995; Burgess et al. 1997), their confor-
mational preferences and their folding propensities were
only clearly elucidated in 2002 by the Guichard group
(Semetey et al. 2002a; Hemmerlin et al. 2002). In the
beginning, they postulated that the substitution of NH for
C(a)inc-amino acid residues could stabilize the 14-helical
fold by fixing the wdihedral angle close to 170°–180°.In
fact, in pyridine-d
5
solution, N,N0-linked heptaureas con-
taining proteinogenic side chains adopt a well-defined
right-handed 12/14 helix, sharing some features with the
c
4
-peptide 14 helix. Nevertheless, the structure of heptau-
rea displayed a more complicated hydrogen-bonding pat-
tern characterized by the presence of both C
12
and C
14
pseudocycles as shown below (Fig. 36).
CD spectra recorded in methanol also exhibit a strong
positive band at 203 nm suggesting the presence of a
defined secondary structure. However, extensive NMR
conformational investigations on N,N0-linked oligoureas in
N
H
Me
O
OMe
O
O
106
2
N
H
N
O
Me
MeO
NH
CO
N
O
Me
Me
H
N
O
OtBu
N
H
O
O
MeO
NH
CO
N
O
Me
Me
H
N
O
OtBu
OMe
107 108
C
10
C
12
Fig. 33 Schematic structures of
vinylogous peptides. Hairpin
conformation of 107 and helical
secondary structure of 108 with
10- and 12-membered
H-bonded rings
N
H
CO2H
N
H
Me
CO2H
N
O
O
N
H
N
H
O
H
N
O
O
O
H
N
O
N
HO
O
109 110
111
Fig. 34 Structures of
E-vinylogous prolines 109 and
110. Schematic representation
of b-hairpin structure of 111
with indicated hydrogen bonds
Foldamers containing c-amino acid residues or their analogues 701
123

protic solvents revealed that the 12/14-helical fold co-
exists with other folding conformations with various pro-
portions of urea cis–trans rotamers (Violette et al. 2005).
The ability of enantiopure N,N0-linked oligoureas of vari-
ous lengths to adopt stable helix conformations was also
supported by accurate NMR restrained simulated annealing
protocol (Guichard et al. 2008) and X-ray diffraction
studies (Fischer et al. 2010). Interestingly, crystallographic
data highlight the fact that only four acyclic residues are
sufficient to promote complete helix formation with all
complementary H-bonding sites being satisfied.
Otherwise, macrocyclic N,N0-linked oligoureas such as
114 can represent versatile building blocks for the con-
struction of H-bonded nanostructures (Semetey et al.
2002b).
Enantiopure cyclo-N,N0-linked oligoureas can generate
robust hydrogen-bonded polar nanotubes in which all urea
groups point in the same direction. The dimensions of the
cavity in these systems can be controlled by variation of the
number of repeat units in the ring (triurea 114 or tetraurea
115; Fig. 37; Fischer and Guichard 2010.
As previously stated for N,N0-linked oligoureas,
replacing carbon atoms in a c-peptide backbone by het-
eroatoms represents a promising opportunity to design new
foldamers. b-Aminoxy acids are compounds in which an
oxygen atom has replaced the c-carbon atom of c-amino
acids. Compared to the classical peptide backbone, the
‘‘amidoxy’’ bond induces stiffening of the backbone
through the lone pair electron repulsion, which stabilizes
the secondary structure.
Several investigations, including FT-IR and NMR
spectroscopy in CDCl
3
, as well as X-ray diffraction studies,
have been carried by the group of Yang (Li and Yang
2006) on small b-aminoxy peptides with different substi-
tution patterns (Fig. 38).
These studies revealed a clear preference for a nine-
membered ring hydrogen bond between the carbonyl -
Raygroup of residue (i-1) and the NH group of residue
(i?1). The so-called ‘‘bN–O turn’’ was further stabilized
by another six-membered ring hydrogen bond between the
NO group of residue iand the NH group of residue (i?1).
Nevertheless, slightly different features have been
elucidated for ‘‘bN–O turn’’ conformations depending on
substitution patterns. In small b
2,2
-aminoxy peptides, the
N–O bond was positioned anti to the Ca–Cbin the solid
state and in CDCl
3
solution (Yang et al. 2002). Regarding
diamides of b
3
-aminoxy acids, the conformation of these
two bonds can be anti or gauche depending on the sizes
of their side chains (Yang et al. 2004a). For cyclic b
2,3
-
aminoxy acids, conformation seems to be independent of
the ring size of the side chains with an anti arrangement
N
O
HN RPh
N
O
HN R
N
O
N
H
R
CN
nN
O
N
H
Ph
N
O
N
H
NC
R
Val
O
H
N
R
Ala
O
N
H
R
Phe
O
H
N
R
Leu
O
N
H
112 113
Fig. 35 Triurea molecular scaffold 112, artificial b-sheet 113
H
NN
H
O
N
H
H
N
O
H
NN
HN
H
OH
N
O
C12
C14
Fig. 36 Schematic representation of the hydrogen-bonding pattern as
found in the helix of N,N0-linked heptaurea
NH
NH
NH
N
H
HN
HN
HN
H
N
O
O
O
O
n
114 n = 1
115 n = 0
Fig. 37 Structures of macrocyclic oligoureas 114 and 115 forming
H-bonded self-assemblies
OOH
H
2
N
RR'
O
OOH
H
2
N
OR O
OH
O
H
2
NOOH
H
2
N
OR
R'
1
2
3
β
2,2
-aminoxy acid β
3
-aminoxy acid cyclic β
2,3
-aminoxy acid acyclic
β
2,3
-aminoxy acid
O
HN
ON
H
β N--O turn
O
Fig. 38 General formula of
different subclasses of
b-aminoxy acids. Schematic
representation of the ‘‘bN–O
turn’’
702 F. Bouille
`re et al.
123

around the Cb–O bond (Yang et al. 2004b). Finally, in
acyclic b
2,3
-aminoxy peptides with a syn configuration the
N–O bond is gauche to the Ca–Cbbonds in both solution
and the solid state. In the acyclic b
2,3
-aminoxy peptides
with an anti configuration, an extended strand is found
in the solid state, and several conformations including
non-hydrogen-bonded and intramolecular hydrogen-bon-
ded states are present simultaneously in nonpolar solvents
(Zhang et al. 2010).
Biological properties and applications
Foldamers derived from c-peptides and analogues show
several potential applications, although they have received
less attention than those derived from b-peptides. First,
c-peptides display exceptional stability toward proteolytic
enzymes: a set of c
2
,c
3
,c
4
and c
2,3,4
peptides 116–119
known to adopt an helical conformation were tested with
15 proteolytic enzymes (Fig. 39): no degradation was
observed after 48 h, whereas common a-peptides were
degraded after 15 min (Frackenpohl et al. 2001).
Some small c-peptides have been shown to mimic the
b-turn of biologically active peptides. For example, the
N-acyl c-dipeptide 120, the conformation of which has
been confirmed by NMR spectroscopy (Fig. 40), shows
submicromolar affinity for several human somatostatin
receptors (Seebach et al. 2003).
N
H
H
NN
H
H
NN
H
H
NOR
2
O
O
O
O
O
O
R
1
N
H
H
NN
H
H
NN
H
H
N
O
O
O
O
O
OMe
O
Boc
N
H
H
NN
H
H
NN
H
OH
H
2
N
O
O
O
O
O
O
N
H
H
N
N
H
Boc
O
O
OBn
O
116a: R
1
= Boc, R
2
= Bn
116b: R
1
=R
2
=H
117
118
119
Fig. 39 c-Peptides tested for
stability toward proteolitic
enzymes
OMe
H
NN
H
OH
N
O
Me
R
4
N R
1
N
R
2
R
3
H
N
O
N
R
2
R
3
O
Me
NR
1
O
NMe
R
4
H
H
120
R
1
= H, Mes; R
2
, R
3
= H, Bn; R
4
= H, Me
Fig. 40 b-Turn mimic
c-peptides with affinity for
human somatostatin receptor
H
N
NH
O
N
H
NH
O
NH
2
O
N
NH
O
N
HN
O
O
O
O
H
2
121
Fig. 41 c/e-Hybrid peptide as oligonucleotide analogues
Foldamers containing c-amino acid residues or their analogues 703
123

c-Peptides or c/e-hybrid peptides have been used as
backbones for the design of oligonucleotide analogues
(Roviello et al. 2010). These compounds have been proven
to bind to DNA or RNA and are promising substrates for
biotechnological applications (Fig. 41). Nevertheless, their
structural features have not yet been elucidated.
The cell penetrating ability of natural or synthetic pep-
tides is an important issue for therapeutic applications. This
ability is enabled either by the presence of cationic charges
(at least 6) or the presence of hydrophobic residues.
A series of N-functionalized hexamers of cis-c-aminopro-
line (see Fig. 11) have been synthesized and have proven
capacity for cellular uptake (Fig. 42; Farrera-Sinfreu et al.
2005).
The self-assembly of cyclic peptides as nanotubes is an
important feature which may find several applications in
the field of biosensors or selective transporter systems
(Brea et al. 2010; Bong et al. 2001). The cyclic hybrid a/c-
peptide 125 has been shown to form nanotubes in several
solvent systems (Fig. 43). These nanotubes possess a
hydrophobic inner cavity, which allows the inclusion of
nonpolar compounds such as chloroform (Garcia-Fandino
et al. 2009).
Antibacterial peptides are helical peptides that contain
alternating hydrophobic and cationic side chains. Since
these peptides are prone to enzymatic degradation, hydro-
lysis-resistant analogues have been designed: the oligourea
127 (isosteric to a c-peptide; Fig. 44) can mimic the helix
conformation of the parent peptide and exhibits antimi-
crobial properties (Violette et al. 2006). Incorporation of
c-aminoacids into the sequence (as for 126) results in
conformational modifications as well as a decrease in the
antimicrobial activity (Claudon et al. 2010).
N
H
N
Ac
O
NH
2
H
6
N
H
N
H
O
NH
2
H
6
R
N
H
N
O
NH
2
H
6
H
2
N
NH
2
122
123
R= H, Me, (CH
2
)
2
Ph, iC
5
H
11
124
Fig. 42 c-Peptides derived
from cis-c-aminoproline
HN
NH
H
N
HN
N
H
NH
O
O
O
O
O
O
125
Fig. 43 Hybrid a/c-
cyclopeptide that forms
nanotubes in solution
N
HN
H
H
NN
HN
H
H
NH
NN
H
H
NH
NN
HN
H
H
NH
N
O
O
O
O
O
O
O
O
NH
2
O
NH
3+
NH
NH
3+
NH
NH
3+
N
HN
H
H
NH
NN
HN
H
H
NH
NN
HN
H
H
NH
NN
HN
H
H
NH
N
O
O
O
O
O
O
O
O
NH
2
O
NH
3+
NH
NH
3+
NH
NH
3+
126
127
Fig. 44 Antibacterial oligourea
and mixed oligourea/c
4
-peptide
foldamers
704 F. Bouille
`re et al.
123

Conclusion
The field of foldamers is still growing. After several years
of extensive studies on b-peptides, many foldamers con-
taining c-amino acids or analogues have been described so
far and have shown interesting properties. It is noteworthy
that going from a-peptides to b- and c-peptides, helices of
increasing stability are obtained (in the c-peptide family,
helices have been observed with oligomers as short as four
residues). Moreover, c
4
-peptide helices have the same
screw sense and macrodipole as a-peptide helices, whereas
b
3
-peptide helices have the opposite. Compared to b-pep-
tides, introduction of a supplementary carbon in the
backbone can be a source of structural diversity. Incorpo-
ration of c-amino acid residues in hybrid a/c-orb/c-pep-
tides is widening the accessible conformations, leading for
the 13 helix of the hybrid b/c-peptides to a good mimicry
of the a-peptide helix. Thus, the easy structuration of
c-peptides, and their high stability and diversity are
important assets in the foldamer domain.
All the different types of secondary structures have been
observed, ranging from helices, to sheets, turns and
extended structures, although there is a lack of good
mimics of the polyproline helix conformation. It is likely
that other new structural features or properties will emerge
by the development of original amino acid building blocks.
Potentially interesting results can be expected in the field of
wider helices, as they were predicted by Hofmann to be
very stable.
Acknowledgments This research was supported by the Ministe
`re de
la Recherche et de l’enseignement supe
´rieur (doctoral grant to F.B.)
and by ANR (Agence Nationale de la Recherche; ANR Grant no.
ANR-08-JCJC0099, financial support for S.T.-L.). The authors thank
Dr. Susannah Coote for assistance with the English language editing
of the manuscript.
Conflict of interest The authors declare that they have no conflict
of interest.
References
Amorin M, Castedo L, Granja JR (2003) New cyclic peptide
assemblies with hydrophobic cavities: the structural and ther-
modynamic basis of a new class of peptide nanotubes. J Am
Chem Soc 125:2844–2845
Amorin M, Castedo L, Granja JR (2005a) Self-assembled peptide
tubelets with 7A
˚pores. Chem Eur J 11:6543–6551
Amorin M, Brea RJ, Castedo L, Granja JR (2005b) The smallest a,c-
peptide nanotubulet segments: cyclic a,c-tetrapeptide dimers.
Org Lett 7:4681–4684
Amorin M, Castedo L, Granja JR (2008) Folding control in cyclic
peptides through N-methylation pattern selection: formation of
antiparallel b-sheet dimers, double reverse turns and supramo-
lecular helices by 3a,ccyclic peptides. Chem Eur J
14:2100–2111
Ananda K, Vasudev PG, Sengupta A, Poopathi Raja KM, Shamala N,
Balaram P (2005) Polypeptide helices in hybrid peptide
sequence. J Am Chem Soc 127:16668–16674
Appella DH, Christianson LA, Karle IL, Powell DR, Gellman SH
(1996) b-Peptide foldamers: robust helix formation in a new
family of b-amino acid oligomers. J Am Chem Soc
118:13071–13072
Araghi RR, Koksch B (2011) A helix-forming abc-chimeric peptide
with catalytic activity: a hybrid peptide ligase. Chem Commun
47:3544–3546
Araghi RR, Ja
¨ckel C, Co
¨lfen H, Salwiczek M, Vo
¨lkel A, Wagner SC,
Wieczorek S, Baldauf C, Koksch B (2010) Ab/cmotif to mimic
a-helical turns in proteins. Chem Bio Chem 11:335–339
Aravinda S, Ananda K, Shamala N, Balaram P (2003) a–cHybrid
peptides that contain the conformationally constrained gabapen-
tin residue: characterization of mimetics of chain reversals.
Chem Eur J 9:4789–4795
Baldauf C, Gu
¨nther R, Hofmann H-J (2003) Helix formation and
folding in c-peptides and their vinylogues. Helv Chim Acta
86:2573–2588
Baldauf C, Gu
¨nther R, Hofmann H-J (2004) Mixed helices—a general
folding pattern in homologous peptides? Angew Chem Int Ed
43:1594–1597
Baldauf C, Gu
¨nther R, Hofmann H-J (2005) Side-chain control of
folding of the homologous a-, b-, and c-peptides into ‘‘mixed’’
helices (b-helices). Biopolymers (Pept Sci) 80:675–687
Baldauf C, Gu
¨nther R, Hofmann H-J (2006) Helix formation in a,
c- and b/c-hybrid peptides: theoretical insights into mimicry of
a- and b-peptides. J Org Chem 71:1200–1208
Bong DT, Clark TD, Granja JR, Ghadiri MR (2001) Self-assembling
organic nanotubes. Angew Chem Int Ed 40:988–1011
Brackmann F, Colombo N, Cabrele C, de Meijere A (2006) An
improved synthesis of 3,4-(aminomethano)proline and its incor-
poration into small oligopeptides. Eur J Org Chem 4440–4450
Brea RJ, Amorin M, Castedo L, Granja JR (2005) Methyl-blocked
dimeric a-c-peptide nanotube segments: formation of a peptide
heterodimer through backbone-backbone interactions. Angew
Chem Int Ed 44:5710–5713
Brea RJ, Castedo L, Granja JR, Herranz MA, Sanchez L, Martin N,
Seitz W, Guldi DM (2007) Electron transfer in Me-blocked
heterodimeric a-c-peptide nanotubular donor-acceptor hybrids.
Proc Natl Acad Soc USA 104:5291–5294
Brea RJ, Reiriz C, Granja JR (2009) Towards functional bionano-
materials based on self-assembling cyclic peptide nanotubes.
Chem Soc Rev 39:1448–1456
Brea RJ, Reiriz C, Granja JR (2010) Towards functional bionanom-
aterials based on self-assembling cyclic peptide nanotubes.
Chem Soc Rev 39:1448–1456
Brenner M, Seebach D (2001a) Design, synthesis, NMR-solution and
X-ray crystal structure of N-acyl-c-dipeptide amides that form a
bII0-type turn. Helv Chim Acta 84:2155–2166
Brenner M, Seebach D (2001b) Synthesis and CD spectra in MeCN,
MeOH, and H
2
Oofc-oligopeptides with hydroxyl groups on the
backbone. Helv Chim Acta 84:1181–1189
Burgess K, Linthicum DS (1995) Solid-phase syntheses of unnatural
biopolymers containing repeating urea units. Angew Chem Int
Ed Engl 34:907–908
Burgess K, Ibarzo J, Linthicum DS, Russell DH, Shin H, Shitangkoon
A, Totani R, Zhang AJ (1997) Solid phase syntheses of
oligoureas. J Am Chem Soc 119:1556–1564
Chakraborty TK, Ghosh A, Kiran Kumar S, Kunwar AC (2003)
Nucleation of b-hairpin structures with cis amide bonds in
E-vinylogous proline-containing peptides. J Org Chem 68:6459–
6462
Chatterjee S, Vasudev PG, Raghotama S, Shamala N, Balaram P
(2008a) Solid state and solution conformations of a hybrid
Foldamers containing c-amino acid residues or their analogues 705
123

acaaca hexapeptide. Characterization of a backbone expanded
analog of the a-polypeptide 3
10
-Helix. Biopolymers 90:759–767
Chatterjee S, Vasudev PG, Ananda A, Raghotama S, Shamala N,
Balaram P (2008b) Multipleconformationnal states in crystals
and in solution in ac hybrid peptides. Fragility of the C
12
helix in
short sequences. J Org Chem 73:6595–6606
Chatterjee S, Vasudev PG, Raghotama S, Ramakrishnan C, Shamala
N, Balaram P (2009) Expanding the b-turn in ac hybrid
sequences: 12 atom hydrogen bonded helical and hairpin turns.
J Am Chem Soc 131:5956–5965
Claudon P, Violette A, Lamour K, Decossas M, Fournel S, Heurtault
B, Godet J, Me
´ly Y, Jamart-Gre
´goire B, Averlant-Petit M-C,
Briand J-P, Duportail J, Monteil H, Guichard G (2010)
Consequences of isostructural main-chain modifications for the
design of antimicrobial foldamers: helical mimics of host-
defence peptides based on a heterogeneous amide/urea back-
bone. Angew Chem Int Ed 49:333–336
Edwards AA, Sanjayan GJ, Hachisu S, Tranter GE, Fleet GW (2006)
A novel series of oligomers from 4-aminomethyl-tetrahydro-
furan-2-carboxylates with 2,4-cis and 2,4-trans stereochemistry.
Tetrahedron 62:7718–7725
Farrera-Sinfreu J, Zaccaro L, Vidal D, Salvatella X, Giralt E, Pons M,
Albericio F, Royo M (2004) A new class of foldamers based on
cis-c-amino-L-proline. J Am Chem Soc 126:6048–6057
Farrera-Sinfreu J, Giralt E, Castel S, Albericio F, Royo M (2005)
Cell-penetrating cis-c-amino-L-proline-derived peptides. J Am
Chem Soc 127:9459–9468
Fischer L, Guichard G (2010) Folding and self-assembly of aromatic
and aliphatic urea oligomers: towards connecting structure and
function. Org Biomol Chem 8:3101–3117
Fischer L, Claudon P, Pendem N, Miclet E, Didierjean C, Ennifar E,
Guichard G (2010) The canonical helix of urea oligomers at
atomic resolution: insights into folding-induced axial organiza-
tion. Angew Chem Int Ed 49:1067–1070
Frackenpohl J, Arvidsson PI, Schreiber JV, Seebach D (2001)
Theoutstanding biological stability of b- and c-peptides toward
proteolytic enzymes: an in vitro investigation with fifteen
peptides. Chem Bio Chem 2:445–455
Garcia-Fandino R, Granja JR, D’Abramo M, Orozco M (2009)
Theoretical characterization of the dynamical behavior and
transport properties of a,c-peptide nanotubes in solution. J Am
Chem Soc 131:15678–15686
Gellman SH (1998) Foldamer: a manifesto. Acc Chem Res
31:173–180
Goodman CM, Choi S, Shandler S, DeGrado WF (2007) Foldamers as
versatile frameworks for the design and evolution of function.
Nat Chem Biol 3:252–262
Grison C, Coutrot P, Gene
`ve S, Didierjean C, Marraud M (2005)
Structural investigation of ‘‘cis’’ and ‘‘trans’’ vinylogous peptides:
cis-vinylog turn in folded cis-vinylogous peptides, an excellent
mimic of the natural b-turn. J Org Chem 70:10753–10764
Guichard G, Violette A, Chassaing G, Miclet E (2008) Solution
structure determination of oligoureas using methylene spin state
selective NMR at
13
C natural abundance. Magn Reson Chem
46:918–924
Guo L, Almeida AM, Zhang W, Guzei IA, Parker BK, Gellman SH
(2009) Stereospecific synthesis of conformationally constrained
c-amino acids: new foldamer building blocks that support helical
secondary structure. J Am Chem Soc 131:16018–16020
Guo L, Almeida AM, Zhang W, Reidenbach AG, Choi SH, Guzei IA,
Gellman SH (2010) Helix formation in preorganized b/c-peptide
foldamers: hydrogen-bond analogy to the a-helix without
a-amino acid residues. J Am Chem Soc 132:7868–7869
Hagihara M, Anthony NJ, Stout TJ, Clardy J, Schreiber SL (1992)
Vinylogous polypeptides: an alternative peptide backbone. J Am
Chem Soc 114:6568–6570
Hanessian S, Luo X, Schaum R, Michnick S (1998) Design of
secondary structures in unnatural peptides: stable helical c-tetra-,
hexa-, and octapeptides and consequences of a-substitution.
J Am Chem Soc 120:8569–8570
Hannessian S, Luo X, Schaum R (1999) Synthesis and folding
preferences of c-amino acid oligopeptides: stereochemical
control in the formation of a reverse turn and a helix.
Tetrahedron Lett 40:4925–4929
Hecht S, Huc I (2007) Foldamers: structure properties and applica-
tions. Wiley-VCH Verlag, Weinheim
Hemmerlin C, Marraud M, Rognan D, Graff R, Semetey V, Briand
JP, Guichard G (2002) Helix-forming oligoureas: temperature-
dependent NMR, structure determination, and circular dichroı
¨sm
of a nonamer with functionalized side chains. Helv Chim Acta
85:3692–3711
Hill DJ, Mio MJ, Prince RB, Hughes TS, Moore JS (2001) A field
guide to foldamers. Chem Rev 101:3893–4011
Hintermann T, Gademann K, Jaun B, Seebach D (1998) c-Peptides
forming more stable secondary structures than a-peptides:
synthesis and helical NMR-solution structure of the c-hexapep-
tide analog of H-(Val-Ala-Leu)
2
-OH. Helv Chim Acta
81:983–1002
Hoffmann RW (2000) Conformation design of open chain com-
pounds. Angew Chem Int Ed 39:2054–2070
Hoffmann RW, Lazaro MA, Caturla F, Framery E (1999) Confor-
mational analysis of (R,S)-4-amido-2, 4-dimethyl-butyric acid
derivatives. Tetrahedron Lett 40:5983–5986
Jones CR, Qureshi MKN, Truscott FR, Hsu STD, Morrison AJ,
Smith MD (2008) A nonpeptidic reverse turn that promotes
parallel sheet structure stabilized by C–HO hydrogen bonds
in cyclopropane c-peptides. Angew Chem Int Ed 47:7099–
7102
Karle IL, Pramanik A, Banerjee A, Bhattacharjya S, Balaram P
(1997) x-Amino acids in peptide design. Crystal structures and
solution conformations of peptide helices containing a b-alanyl-
c-aminobutyryl segment. J Am Chem Soc 119:9087–9095
Kothari A, Qureshi MKN, Beck EM, Smith MD (2007) Bend-ribbon
forming c-peptides. Chem Commun 2814–2816
Kumar N, Venugopalan P, Kishore R (2010) Rapid communication
crystallography observed folded topology of an unsubstituted
c-aminobutyric acid incorporated in a model peptide: importance
of a C–HO interaction. Biopolymers 93:927–931
Li X, Yang D (2006) Peptides of aminoxy acids as foldamers. Chem
Commun 3367–3379
Machetti F, Ferrali A, Menchi G, Occhiato EG, Guarna A (2000)
Oligomers of enantiopure bicyclic c/d-amino acids (BTAa). 1.
Synthesis and conformationnal analysis of 3-aza-6, 8-dioxabi-
cyclo[3.2.1]octane-7-carboxylic acid oligomers (PolyBTG). Org
Lett 2:3987–3990
Maji SK, Banerjee R, Razak DVA, Fun HK, Banerjee A (2002)
Peptide design using x-amino acids: unusual turn sequences
nucleated by an N-terminal single c-aminobutyric acid residue in
short model peptides. J Org Chem 67:633–639
Nowick JS, Powell NA, Martinez EJ, Smith EM, Noronha G (1992)
Molecular scaffolds. 1. Intramolecular hydrogen bonding in a
family of di- and triureas. J Org Chem 57:3763–3765
Nowick JS, Abdi M, Bellamo KA, Love JA, Martinez EJ, Noronha G,
Smith EM, Ziller JW (1995a) Molecular scaffolds. 2. Intramo-
lecular hydrogen bonding in 1,2-diaminoethane diureas. J Am
Chem Soc 117:89–99
Nowick JS, Smith EM, Noronha G (1995b) Molecular scaffolds. 3.
An artificial parallel b-sheet. J Org Chem 60:7386–7387
Nowick JS, Holmes DL, Mackin G, Noronha G, Shaka AJ, Smith EM
(1996) Anartificial b-sheet comprising a molecular scaffold, a
b-strand mimic and a peptide strand. J Am Chem Soc
118:2764–2765
706 F. Bouille
`re et al.
123

Nowick JS, Pairish M, Lee IQ, Holmes DL, Ziller JW (1997) An
extended b-strand mimic for a larger artificial b-sheet. J Am
Chem Soc 119:5413–5424
Qureshi MKN, Smith MD (2006) Parallel sheet structure in cyclo-
propane c-peptides stabilized by C–HO hydrogen bonds. Chem
Commun 5006–5008
Rai R, Vasudev PG, Ananda K, Raghotama S, Shamala N, Karle IL,
Balaram P (2007) Hybrid peptides: expanding the bturn in
peptide hairpins by the insertion of b-, c-, and d-residues. Chem
Eur J 13:5917–5926
Reiriz C, Brea RJ, Arranz R, Carrascosa JL, Garibotti A, Manning B,
Valpuesta JM, Eritja R, Castedo L, Granja JR (2009a) a,
c-Peptide nanotube templating of one-dimensional parallel
fullerene arrangements. J Am Chem Soc 131:11335–11337
Reiriz C, Amorin M, Garcia-Fandino R, Castedo L, Granja JR
(2009b) a,c-Cyclic peptide ensembles with a hydroxylated
cavity. Org Biol Chem 7:4358–4361
Roviello GN, Musumeci D, Pedone C, Bucci EM (2010) Synthesis,
characterization and hybridation studies of an alternate nucleo-e/
c-peptide: complexes formation with natural nucleic acids.
Amino Acids 38:103–111
Roy RS, Gopi HN, Raghothama S, Karle IL, Balaram P (2006) Hybrid
peptide hairpins containing a- and x-amino acids: conformation-
nal analysis of decapeptides with unsubstituted b-, c-, and
d-residues at positions 3 and 8. Chem Eur J 12:3295–3302
Seebach D, Brenner M, Rueping M, Schweizer B, Jaun B (2001)
Preparation and determination of X-ray-crystal and NMR-
solution structures of c
2,3,4
-peptides. Chem Commun 207–208
Seebach D, Brenner M, Rueping M, Jaun B (2002) c2-, c3, and c2, 3,
4-amino acids, coupling to c-hexapeptides: CD spectra, NMR
solution and X-ray crystal structures of c-peptides. Chem Eur J
8:573–584
Seebach D, Schaeffer L, Brenner M, Hoyer D (2003) Design and
synthesis of c-dipeptide derivatives with submicromolar affini-
ties for human somatostatin receptors. Angew Chem Int Ed
42:776–778
Seebach D, Kimmerlin T, Sebesta R, Campo MA, Beck AK (2004a)
How we drifted into peptide chemistry and where we have
arrived at. Tetrahedron 60:7455–7466
Seebach D, Beck AK, Bierbaum DJ (2004b) The world of b- and
c-peptides comprised of homologated proteinogenic amino acids
and other components. Chem Biodiv 1:1111–1239
Seebach D, Hook DF, Gla
¨ttli A (2006) Helices and secondary
structures of b- and c-peptides. Biopolymers (Pept Sci) 84:23–37
Semetey V, Rognan D, Hemmerlin C, Graff R, Briand JP, Marraud
M, Guichard G (2002a) Stable helical secondary structure in
short chain N,N0-linked oligoureas bearing proteinogenic side
chains. Angew Chem Int Ed 41:1893–1895
Semetey V, Didierjean C, Briand JP, Aubry A, Guichard G (2002b)
Self-assembling organic nanotubes from enantiopure cyclo-N,N0-
linked oligoureas: design, synthesis, and crystal structure.
Angew Chem Int Ed 41:1895–1898
Sengupta A, Aravinda S, Shamala N, Poopathi Raja KM, Balaram P
(2006) Structural studies of model peptides containing b-, c-,
d-amino acids. Org Biomol Chem 4:4214–4222
Sharma GVM, Jayaprakash P, Narsimulu K, Ravi Sankar A, Ravinder
Reddy K, Radha Krishna K, Kunwar AC (2006a) A left-handed
9-helix in c-peptides: synthesis and conformational studies of
oligomers with dipeptide repeats of C-linked carbo-c
4
-amino
acids and c-aminobutyric acid. Angew Chem Int Ed
45:2944–2947
Sharma GVM, Jadhav VB, Ramakrishna KVS, Jayaprakash P,
Narsimulu K, Subash V, Kunvar AC (2006b) 12/10- and
11/13-mixed helices in a/c- and b/c-hybrid peptides containing
C-linked carbo c-amino acids with alternating a- and b-amino
acids. J Am Chem Soc 128:14657–14668
Sharma GVM, Chandramouli N, Choudhary M, Nagendar P, Rama-
krishna KVS, Kunwar AC, Schramm P, Hofmann H-S (2009)
Hybrid helices: motifs for secondary structure scaffolds in
foldamers. J Am Chem Soc 131:17335–17344
Smith EM, Holmes DL, Shaka AJ, Nowick JS (1997) Anartificial
antiparallel b-sheet containing a new peptidomimetic template.
J Org Chem 62:7906–7907
Stigers KD, Soth MJ, Nowick JS (1999) Designed molecules that fold
to mimic protein secondary structures. Curr Opin Chem Biol
3:714–723
Trabocchi A, Occhiato EG, Potenza D, Guarna A (2002) Synthesis
and conformational analysis of small peptides containing
6-endo-BT(t)L scaffolds as reverse turn mimetics. J Org Chem
67:7483–7492
Trabocchi A, Menchi G, Guarna F, Machetti F, Scarpi D, Guarna A
(2006) Design, synthesis and applications of 3-aza-6,8-dioxabi-
cyclo[3.2.1]octane-based scaffolds for peptidomimetics chemis-
try. Synlett 331–353
Vasudev PG, Shamala N, Anando K, Balaram P (2005) C
9
helices and
ribbons in c-peptides: crystal structures of Gabapentin oligomers.
Angew Chem Int Ed 44:4972–4975
Vasudev PG, Ananda K, Chatterjee S, Aravinda S, Shamala N,
Balaram P (2007) Hybrid peptide design. Hydrogen bonded
conformations in peptides containing the stereochemically
constrained c-amino acid residue, Gabapentin. J Am Chem Soc
129:4039–4048
Vasudev PG, Chatterjee S, Ananda K, Shamala N, Balaram P (2008)
Hybrid ac polypeptides: structural characterization of a C12/C10
helix with alternating hydrogen-bond polarity. Angew Chem Int
Ed 47:6430–6432
Vasudev PG, Chatterjee S, Shamala N, Balaram P (2009) Gabapentin:
astereochemically constrained camino acid residue in hybrid
peptide design. Acc Chem Res 42:1628–1638 (and cited
references)
Vasudev PG, Chatterjee S, Shamala N, Balaram P (2011) Structural
chemistry of peptides containing backbone expanded amino
acids residues: conformational features of b,cand hybrid
peptides. Chem Rev 111:657–687
Violette A, Averlant-Petit MC, Semetey V, Hemmerlin C, Casimir R,
Graff R, Marraud M, Briand JP, Rognan D, Guichard G (2005)
N,N0-Linked oligoureas as foldamers: chain length requirements
for helix formation in protic solvent investigated by circular
dichroı
¨sm, NMR spectroscopy, and molecular dynamics. J Am
Chem Soc 127:2156–2164
Violette A, Fournel S, Lamour K, Chaloin O, Frisch B, Briand JP,
Monteil H, Guichard G (2006) Mimicking helical antibacterial
peptides with nonpeptidic folding oligomers. Chem Biol
13:531–538
Wipf P, Stephenson CRJ (2005) Three-component synthesis of a,b-
cyclopropyl-c-amino acid. Org Lett 7:1137–1140
Woll MG, Lai JR, Guzei IA, Taylor SJC, Smith MEB, Gellman SH
(2001) Parallel sheet secondary structure in c-peptides. J Am
Chem Soc 123:11077–11078
Yang D, Zhang YH, Zhu NY (2002) b2,2-Aminoxy acids: anew
building block for turns and helices. J Am Chem Soc
124:9966–9967
Yang D, Zhang YH, Li B, Zhang DW, Chan JCY, Zhu NY, Luo SW,
Wu YD (2004a) Effect of side chains on turns and helices in
peptides of b
3
-aminoxy acids. J Am Chem Soc 126:6956–6966
Yang D, Zhang DW, Hao Y, Zhu NY, Luo SW, Wu YD (2004b)
b2,3-Cyclic aminoxy acids: rigid and ring-size-independent
building blocks of foldamers. Angew Chem Int Ed
43:6719–6722
Zhang Y-H, Song K, Zhu NY, Yang D (2010) The effect of backbone
stereochemistry on the folding of acyclic b2,3-aminoxy peptides.
Chem Eur J 16:577–587
Foldamers containing c-amino acid residues or their analogues 707
123