Reverse Turn and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds

Article abstract of DOI:10.1021/acs.joc.9b01509

Controlling the network of intramolecular interactions encoded by Nα-chiral side chains and the equilibria between cis- and trans-amide junctions in cyclic peptoid architectures constitutes a significant challenge for the construction of stable reverse turn and loop structures. In this contribution, we reveal, with the support of NMR spectroscopy, single-crystal X-ray crystallography and density functional theory calculations, the relevant noncovalent interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic peptoids (as free hosts and host-guest complexes) with strategically positioned N-(S)-(1-phenylethyl)/N-benzyl side chains, and how these interactions influence the backbone topological order. With the help of theoretical models and spectroscopic/diffractometric studies, we disclose new β-turn and loop structures present in α-peptoid-based macrocycles and classify them according φ, ψ, and ω torsion angles. In our endeavor to characterize emergent secondary structures, we solved the solid-state structure of the largest metallated cyclic peptoid ever reported, characterized by an unprecedented alternated cis/trans amide bond linkage. Overall, our results indicate that molecules endowed with different elements of asymmetry (central and conformational) provide new architectural elements of facile atroposelective construction and broad conformational stability as the minimalist scaffold for novel stereodefined peptidomimetic foldamers and topologically biased libraries necessary for future application of peptoids in all fields of science.

Full text of DOI:10.1021/acs.joc.9b01509

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Article
Reverse Turn and Loop Secondary Structures
in Stereodefined Cyclic Peptoid Scaffolds
Assunta D'Amato, Giovanni Pierri, Consiglia Tedesco, Giorgio Della
Sala, Irene IZZO, Chiara Costabile, and Francesco De Riccardis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01509 • Publication Date (Web): 24 Jul 2019
Downloaded from pubs.acs.org on July 25, 2019
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Reverse Turn and Loop Secondary Structures
in Stereodefined Cyclic Peptoid Scaffolds
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Assunta D’Amato, Giovanni Pierri, Consiglia Tedesco, Giorgio Della Sala, Irene Izzo,
Chiara Costabile* and Francesco De Riccardis*
Department of Chemistry and Biology “A. Zambelli”, University of Salerno, Via Giovanni Paolo II, 132,
Fisciano (SA), 84084, Italy
Keywords: Cyclic peptoids • Secondary structure • Peptidomimetics • Host-guest chemistry
ABSTRACT. Controlling the network of intramolecular interactions encoded by N-chiral side chains and
the equilibria between cis- and trans-amide junctions in cyclic peptoid architectures constitutes a significant
challenge for the construction of stable reverse turn and loop structures. In this contribution we reveal, with
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the support of NMR spectroscopy, single crystal X-ray crystallography and DFT calculations, the relevant
noncovalent interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic peptoids (as free hosts and host-
guest complexes) with strategically positioned N-(S)-(1-phenylethyl)/N-benzyl side chains and how these
interactions influence the backbone topological order. With the help of theoretical models and
spectroscopic/diffractometric studies we disclose new -/-turn and loop structures present in -peptoid-
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based macrocycles and classify them according , and torsion angles. In our endeavour to characterize
emergent secondary structures, we solved the solid state structure of the largest metallated cyclic peptoid
ever reported, characterized by an unprecedented alternated cis/trans amide bonds linkage. Overall, our
results indicate that molecules endowed with different elements of asymmetry (central and conformational)
provide new architectural elements of facile atroposelective construction and broad conformational stability
as minimalist scaffold for novel stereodefined peptidomimetic foldamers and topologically biased libraries
necessary for future application of peptoids in all the fields of science.
INTRODUCTION
The control of intramolecular interactions is essential to direct the self-organization of oligomers into
defined spatial arrangements and crucial to expedite the transition toward functionally (bio)active
1
structures. The design of malleable amide-based species represents a direct entry into the construction of
2
stable sequence-directed intelligent architectures and factors affecting the oligomers’ morphology must be
carefully considered. Strategic insertion of bulky/chiral N-side chains,3,4 cyclization, metal ion chelation,
3
5
6
7
8
9
and noncovalent interactions (i.e.: n→* interactions, 1,3-allylic strain, Cα−H···O=C and C−F···O=C
10
interactions) determine the conformation of peptoids (N-substituted glycine oligomers). Zuckermann was
the first to recognize the effects of N-chiral side chains on the helicity of polyproline type I secondary
4
a
2a,3a,4a,11
structures. Further works
confirmed the correlation between side chains stereogenic centers and
helix topological arrangement (S stereogenic centers induce right-handed helices,2c,11 R configurations form
7
e
10c
left-handed spirals). More recently, Cobb and co-workers demonstrated that fluoroalkyl monomers can
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be used to influence the Kcis/trans of peptoid amide bonds and Faure and Taillefumier offered a novel route to
control peptoid amide conformation avoiding aromatic building blocks.4d,e
Despite considerable efforts have been devoted to understand the relationships between structural and
functional capabilities of linear peptoids, no explicit correlation between side chain configuration, backbone
topological order, and conformational stability has ever been established for cyclic peptoids.12
In this communication we report the preparation of trimeric, tetrameric, hexameric, and octameric cyclic
peptoids (and their sodium ion complexes) with strategically positioned N-(S)-(1-phenylethyl)glycine
(Nspe)/N-benzylglycine (Npm) residues and describe, for the first time in the cyclic peptoid field, the
intricate interplay between side chain configuration, backbone conformational isomerism (based on the
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c
13
amide bonds planar chirality), and reverse turn/loop topological attributes (Figure 1).
R
N
O
(
S)
Bn
H
OH R =
,
n
n = 3, 4, 6, 8
Cyclization
R
N
R
N
O
O
H
H
pS
pR
O
O
N
N
n - 1
n - 1
free
hosts
CP1-3/CP'1-3 -/-turns
Na+
Na+
Na+
O
O
O
O
N
N
O
O
R
R
N
N
pS N
N R
p
R
R
metal
complexes
(
hexamer and
octamer cyclic
peptoids)
CPM1,2/CPM'1,2 loops
Figure 1. General plan for the synthesis of N-(S)-(1-phenylethyl)glycine/N-benzylglycine-based cyclic -peptoid oligomers and
their sodium complexes as stereodefined reverse turn or loop structures. Nspe residue evidenced in red.
In our endeavour to analyze and classify new peptoid secondary structures, we report the first solid state
structure of a cyclic octamer peptoid as a sodium complex (showing an unprecedented alternated cis/trans
5
d
amide backbone arrangement), those of three cyclic peptoids containing chiral side chains, and that of a
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unique bicyclic pyrrolopyrazine formed by an unprecedented rearrangement of H-(Nspe )-OH during the
3
cyclization reaction. The additive effects of -chiral aromatic side chains on the conformation of cyclic
peptoids have been examined with the help of Density Functional Theory (DFT) calculations, NMR
spectroscopy, and X-ray crystallography. The analysis of , and torsion angles and the surprising
conformational homogeneity of some macrocyclic peptoids in solution, as free hosts or sodium ion
complexes, showed that weak noncovalent interactions can significantly stabilize secondary structures.
We anticipate that the results presented herein, serve as starting point to better understand the peptoid
folding rules and for the design peptoid-based recognition/catalytic sites.
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RESULTS AND DISCUSSION
Synthesis and Structural Properties of Trimeric Cyclic Peptoid Models. Although cyclic peptoids are
promising biomimetics, strategies to control their topological order are lacking and formation of mixtures of
enantiomorphic or diastereomeric conformational isomers plagues their synthesis and impair their
spectroscopic homogeneity.3b,c A recently reported method to control their geometric attributes utilized the
N-benzyl alanine residue as backbone chiral inducer.7d
With the aim to simplify the oligomers’ synthesis, we selected the classic Nspe residue as possible chiral
inducer and started with the inspection of the simplest possible model prototype: cyclo-(Nspe-Npm
Preliminary DFT studies showed moderate energy difference for the two possible non-equivalent “crown”
conformational isomers cyclo-[(cis, S)Nspe-(cis, S)Npm-(cis, S)Npm)] (1), and cyclo-[(cis, R)Nspe-
(cis, R)Npm-(cis, R)Npm)] (2, E = 1.3 kcal mol in DMSO, Figure 2a). Lower stability of model 2 was
2
).
p
p
p
p
-
1
p
p
attributed to steric clash between methyl group and carbonyl residue (3.03 Å, Figure 2a and c) and the
weaker hydrogen bond between the Cα−H group of the (S)-N-(1-phenylethyl) side chain and the carbonyl
residue14 (2.39 Å, Figure 2b). Model 1 was stabilized by the sterically interresidue beneficial
9
Ph(Me)NC−H/C=O eclipsing, relieving the 1,3-allylic strain (Figure 2c).
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a)
1
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b)
Bn
N
Bn
N
2
.21 Å
2.39 Å
pS
Bn
O
O
pR
Bn
O
O
H  5.47

5.10 H
1
1
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pR
pS
pS
O
O
pR
N
N
N
N
2
1
c)
Hydrogen bond
CH2
CH3
N
O
H
CH3
C-H···O=C
eclipsing
in 1
H C
N
2
O
H
O
Ph
1 = -138.8°
Ph
1 = 87.0°
d)
NC
NC
1
O

O
N


CO(i - 1)
C(i)
Figure 2. a) Minimum energy structures of 1 and 2 and their respective internal energies calculated in DMSO and expressed in
-
1
kcal mol (see SI for atomic coordinates). Hydrogen atoms have been omitted for clarity (except for the CH–CH
residue, in yellow). Atom type: C light grey (yellow for the CH residues of Nspe), N blue, O red. Distances are in Å. b)
Schematic structures of conformational isomers 1 and 2, and key hydrogen bond distances. Nspe residue is colored in red. c)
Newman projections indicating the  in conformational isomer 1 and 2. Evidenced in yellow is the steric clash between methyl
and carbonyl group. d) Dihedral angles definition for a hypothetical residue i:4d,12a,c ω [Cα(i – 1); CO(i – 1); N(i); Cα(i)], φ [CO(i – 1)
[CO(i – 1); N(i); NCα; NCβ].
3
of the Nspe
3
1
;
N
(i); Cα(i); CO(i)], ψ [N(i); Cα(i); CO(i); N(i + 1)], χ
1
Experimentally, high dilution cyclization of linear H-Npm-Nspe-Npm-OH (3), in the presence of HATU,
1
5
yielded the expected “crown” (i.e.: cis-cis-cis; ccc) conformer 1 and 2, in a 70:30 ratio, respectively, as an
1
inseparable mixture of conformational isomers in slow equilibrium on the NMR time scale ( H NMR
analysis, (CD
3
) SO). The structure of the major conformational isomer was attributed to 1 on the basis of
2
the theoretical studies. Further support came from NMR spectroscopy: the downfield shift of the side chain
methine proton chemical shift ( 5.47 ppm) testified for a shorter hydrogen bond in 1 (compared to  5.10
ppm recorded for the same proton in minor atropisomer 2, Figure 2b).
9
The energetically favorable inter-residue Ph(Me)NC−H/C=O eclipsing, implicating a 
1
≈ −130° torsion
angle and due to the S side chain configuration in 1, induced a S amide bond planar chirality. Similar
p
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values of 
oligomer
handed N-(R)-(1-cyclohexylethyl) linear pentamer Nrch
1
(and consequent S/
p
S configurational pairing) have also been evidenced in linear Nspe
8
≈ −120°),2c,11 in the X-ray crystal structure of cyclo-(Nspe
) (
≈ −130°) and in the right-
4c
(

1
9
1
oligomer7e (where an enantiomorphous R/
R
R
5
p
configurational pairing is present). Higher energy conformational isomer 2 showed  ≈ 90° and S/
1
p
0
1
2
3
4
5
6
7
8
9
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2
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1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mismatch.
In oligoamides, turn motifs are the most important secondary structures after helices and -strands. The
2c
folding pattern observed in 1 and 2, typical of trimeric cyclic peptoids, resembles peptide “open”13d -
turns.13b,c The relevant φ and  angles for atropisomer 1 fall within the definition of an inverse -turn (φ =
13c
16
−
79 ± 40°,  = 69 ± 40°), the most common form of -turn. Torsion angles in 2 evoke “classic” -turn
1
6b
(
φ from 70 to 95°,  from −75 to −45°). However, lack of hydrogen bonds between residues and, above
all, the presence of cis amide bonds in cyclic trimeric peptoids require a different classification for these
new turn motifs. We suggest the acronym “CP” (from “Cyclic Peptoid”) to identify these turns, a subscript
number to identify the type and, as in the classic notation, a prime symbol for motifs with opposite torsion
angles (“inverse” turns). According to this new notation, cyclic trimeric peptoid 1 and 2 show CP’
1
and CP
1
type -turns, respectively (Figure 3) with Cα(i)−Cα(i+2) distances shorter than 5.5 Å (as typically expected for
these kind of turns).13d
CP’
1
type
CP
1
type
-turn in 1
-turn in 2

i+1

i+1

i+1
1 1
Figure 3. Perspective drawing of cyclotripeptoid 1 and 2 segment structures folded into inverse CP’ and classic CP -turns in 1
(left) and in 2 (right), respectively. Hydrogen atoms and a fragment of the Nspe (i) residue are omitted for clarity. Atom type: C
light grey, N blue, O red.
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Idealized ,  and  torsion angles values (verified by structural data)2c,5d,7d and those inferred by
theoretical studies, plus Cα(i)−Cα(i+2) distances, have been reported in Table 1.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Central residue dihedral angle values, amide bonds planar chirality and Cα(i)−Cα(i+2) distances for CP’
1 1
- and CP -type-
turns in 1 and 2 
Distance
Cα(i)-Cα(i+2)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

i+1 (planar
chirality)
Compound
Turn type

i+1

i+1
in Å
1
-
CP’
1
2.0 (
0 ( S)
180
p
S)
–99.3
–95
–79
95.9
95
94.2
95
2.97
≤5.5
CP’ a

1
p


≤5.513d
2.96
-
Inverse 
CP
CP a
69
2
-
1
–1.8 (
p
R)
–98.3
–95
–64
≤5.5
1
0 ( R)
p


≤5.513d
-
Classic  
180
75
a
idealized torsion angles values
With the aim to induce the formation of a single conformational isomer, we attempted the synthesis of
prototypes with two and three chiral residues (cyclo-(Nspe -Npm), 4, and cyclo-(Nspe ), 5, Figure 4).
However, cyclization in the usual conditions of linear H-Npm-Nspe -OH (6) and H-Nspe -OH (7), gave
2
3
2
3
rearranged dehydrated congeners 8 and 9, in 25 and 26% yield, respectively, and no trace of the expected 4
Bn
and 5 (Figure 4).17
Ph
O
O
O
O
N
N
O
O
Ph
N
Ph
Ph
N
N
Ph
N
4
5
R1
R
N
4
N
5
3
R =
Ph
Ph
6
2
8
9, R, R =
1
Ph
7
O
1N
R
R =
1
O
Figure 4. Expected (4 and 5) and unexpected (8 and 9) products in the cyclization of linear trimeric H-Npm-Nspe
H-Nspe -OH (7).
2
-OH (6), and
3
The structure of the unprecedented 3,4,5,6-tetrahydro-1H-pyrrolo[2,3-b]pyrazine-2,7-dione heterocyclic
17
nucleus was inferred by accurate analysis of their one- and two-dimensional NMR spectra (see SI). It was
attributed to an exceptional double intramolecular segment coupling linking the oligomers termini to the
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central amide junction via formation of an oxazolonium ion intermediate18,19 (11), N-terminal aminolysis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(from 11 to 12) and pyrrole ring closure (to form hypothetical immonium 14, Scheme 1).
Oxazolonium ion
O
R
R
O
R
N
O
R
HATU
Base
6, 7
HN
HN
N
N
R
OAt
N
R
O
O
O
O
10
11
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
N
R
N
R
R
N
R
N
O
R
N
N
HATU
8
, 9
H
O
N
R
O
N
R
AtO
O
O
N
R
H
H
O
B
B
14
13
12
Scheme 1. Suggested mechanism for the formation of pyrrolopyrazine 8 and 9 from high dilution condensation of H-Npm-Nspe
OH (6) and H-Nspe -OH (7). At = 7-azabenzotriazole; R = benzyl or (S)-N-(1-phenylethyl) side chain.
2
-
3
Formation of bicyclic products starting from linear tripeptoids with three Nspe residues is
thermodynamically reasonable if we compare the free energy of formation of cyclopeptoid 5 (–7.5 kcal mol-
1)
and bicyclic 9 (–15.1 kcal mol , as predicted by DFT calculations) and take into account the entropically
-1
favorable development of two water molecules for the formation of pyrrolopyrazine 9 (instead of one, as in
).
5
Recrystallization trials on a microcrystalline sample of rearranged 9 provided single crystals suitable for X-
ray diffraction. X-ray analysis confirmed the formation of a pyrrolopyrazine nucleus and revealed the
2
0
presence of a hydroxyl group on C3, due to autoxidation processes (15, Figure 5).
HO 3 N 4
5
N
6
2
15
7
O
1 N
O
a)
b)
Figure 5. Structure ORTEP drawing of bicyclic compound 15. Ellipsoids are drawn at 20% probability level. Atom type: C grey,
N blue, O red, H white.
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5
5
5
5
6
The intermolecular hydrogen bonding between C-7 carbonyl oxygen and hydroxyl group (OH∙∙∙O 2.677 Å,
O-H∙∙∙O 169.3°) facilitates the crystallization of 15 giving rise to a left-handed helix through the
crystallographic 2 screw axis parallel to the shortest cell axis (i.e. a axis).
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
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5
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7
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9
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7
8
9
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3
4
5
6
7
8
9
0
Synthesis and Structural Properties of Tetrameric Cyclic Peptoid Models. Cyclic cis-trans-cis-trans
(ctct) tetrapeptoids are gifted minimalist scaffolds for the generation of reverse turn “conformational
templates”.7d,21 DFT studies on tetrapeptoids with a single N-chiral side chain indicated a small energy
difference between the lowest energy cyclo-[(cis,
showing a favorable S/ S configurational pairing due to a reduced allylic strain, 
higher energy cyclo-[(cis,
p
R)Npm-(trans,
p
R)Npm-(cis,
p
S)Nspe-(trans,
p
S)Npm], 16
(
p
1
= -106.4°), and the
p
S)Npm-(trans,
p
S)Npm-(cis,
p
R)Nspe-(trans,
p
R)Npm], 17 (displaying a S/ R
p
-1
configurational mismatch originated by the unfavorable 
1
= 85.6°, E = 1.3 kcal mol , Figure 6).
a)
b)
Bn
2
.17 Å
2.84 Å
O
Bn
N
pR
O
N
pS
N
t
Bn
H
N
c
H
O
pS
Bn
pR
O
pR
O
O
c
t
pS
N
N
N
pS
N
pR
17
O
Bn
1 = -106.4°
1 = 85.6°
O
Bn
16
Figure 6. a) Minimum energy and schematic structures of conformational diastereoisomers 16 and 17 and their respective
-1
internal energies calculated in chloroform and expressed in kcal mol . Hydrogen atoms have been omitted for clarity except for
3 3
the CHCH of the Nspe residue (in yellow). Atom type: C light grey (yellow for the CH residues of Nspe), N blue, O red (see SI
for atomic coordinates). Distances are in Å. b) Schematic structures of conformational diastereoisomers 16 and 17 with, in red,
the Nspe residue; c = cis; t = trans.
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9
1
1
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2
2
2
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2
2
2
2
2
3
3
3
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5
5
5
5
5
5
5
6
Cyclization of the H-Npm
2
-Nspe-Npm-OH linear sequence (18) yielded an inseparable mixture of the
1
expected conformational isomers 16 and 17 in a 85:15 ratio, respectively ( H NMR analysis), in a slow
equilibrium on the NMR time scale. The downfield shift of the side chain methine proton observed for the
…
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
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6
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8
9
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0
major conformational isomer ( 5.92, due to the short C-H O=C distance) confirmed 16 as the most stable
conformer in the mixture. The relatively high values (>5.00 ppm) found for the Ph(Me)C-H protons in both
16 and 17, attested the presence of the N-chiral side chains on cisoid amide bonds.4a,12b
Crystallization trials of cyclooligomers mixture 16/17 afforded single crystals suitable for X-ray diffraction
analysis by dissolution in hot dichloromethane. Structural analysis showed that only the lowest energy
cyclo-oligomer 16 crystallized, confirming the structural hypothesis based on DFT and NMR studies
(
Figure 7).
Figure 7. ORTEP drawing of compound 16. Ellipsoids are drawn at 20% probability level. Atom type: C grey, N blue, O red, H
white.
The secondary structure present in tetrameric cyclopeptoids (Figure 7 and 8) is reminiscent of type VI -
13
turn (characterized by the presence of a cis-proline at the i + 2 residue). However, for the large deviations
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5
5
6
from the canonical values, the turn motifs in 16 and 17 are better described as type CP
formally belonging to non-classified type IV -turns).
It is interesting to note that for the peculiar symmetry properties of the ctct oligoamide framework (which,
2
and CP’ -turns
2
(
2
2
in the absence of a chiral side chain, would show an inversion center), CP
2
and CP’
2
turns are present in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
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2
3
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5
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7
8
9
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
both the halves of tetramers 16 and 17 (blue and black part of each molecule, Figure 8a).
a) CP type turn
CP'2 type turn
2
Bn
N
O
O
i+2
Bn
O
i+2
N
Bn
N
N
O
Bn
N
O
O
Bn
N
Ph
(S)
Ph
(S)
N
N
i+1
i
O
i+1
i
Bn
O
16
17
CP' type turn
CP type turn
2
2
b)
CP
2
-turn in 16
CP’ -turn in 17
2
Figure 8. a) Schematic structures of conformational diastereoisomers depicting type CP
2
and CP’
2
-turns present in 16 and 17.
The arrows point toward the CO→N direction. b) Models of CP and CP’ -turns extracted from the minimum energy structures
2
2
of 16 and 17, respectively. Hydrogen atoms are omitted for clarity. Residue i and i +3 are partially omitted for clarity. Atom type:
C light grey, N blue, O red.

,  and  torsion angles of 16 and 17 are reported in Table 2.2c,5d,7d The table also includes the values of
type VIb -turn (the closest to the CP’
2
turn) and the Cα(i)−Cα(i+3) distances (always shorter than 7.0 Å, as
typically expected for classic -turns).13a
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Table 2. Central residues dihedral angle values, amide bonds planar chirality and Cα(i)−Cα(i+3) distances for type CP
2
and CP’
2
tct
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6

-turns in 16, 17, and 19
Distance

-Turn i+1 (planar
type chirality)
i+2 (planar
chirality)
Compound

i+1

i+1

i+2

i+2
Cα -
(
i)
Cα(i+3) in Å
–
170.7 (
p
S) 118.8 –65.8
–6.6 (
(0.8)
p
R)
93.8
–169.9
2.93
(2.89)
6a
1
1
1
CP
CP
CP
2
2
2
(–169.5) (118.9) (–69.4)
(91.6) (–172.4)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
9a
-
–170.4 (
–170.4 (
p
S) 119.6 –59.2
S) 121.3 –67.4
–13.8 (
–2.7 (
(–13.4)
0 ( R)
5.4 ( S)
(7.2)
p
R)
100.34
93.0
–171.7
–173.0
2.91
p
p
R)
2.93
(
–171.1) (118.4) (–60.0)
180 ( S) 120 –65
70.0 (
(99.6) (–170.8)
(2.87)
b
CP
2
p
p
95
–170
≤ 7
1
p
R) –119.6 65.3
p
–91.0
(–95.1) (171.2)
171.8
2.93
(2.86)
6a
CP’
CP’
CP’
2
2
2
(
170.4) (–121.5) (63.4)
17
169.0 (
69.4 (
p
R) –119.1 64.2
R) –119.0 64.3
7.4 (
5.5 (
p
S)
S)
–95.1
–91.7
170.0
171.5
2.94
1
p
p
2.91
(2.83)
19a
(
171.8) (–120.9) (63.4)
(6.5)
(–93.8) (170.4)
b
-
-
CP’
2
180 (
p
R)
–120
–135
65
0 ( S)
p
–95
–75
170
160
≤ 7
VIb16
180
135
0
≤ 713a
a
in parenthesis data from the X-ray crystal structures
idealized torsion angles values
b
In order to evaluate the effect of multiple substitution of bulky chiral groups on the conformational stability
of tetrameric scaffold, we embarked in the synthesis of cyclo-[(Nspe-Npm) ] and cyclo-(Nspe ).
Preliminary conformational search on cyclo-[(Nspe-Npm) ] and subsequent DFT calculations predicted the
formation of an atropisomer with both the N-(S)-(1-phenylethyl) side chains on cis-amide bonds (i.e.: cyclo-
2
4
2
-1
[(cis,
p
R)Nspe-(trans,
p
R)Npm-(cis,
p
S)Nspe-(trans, S)Npm], 19, E = 0.0 kcal mol ). Bulky chiral side
p
-1
chains on trans positions raised the energy of the hypothetical 20, to E = 3.8 kcal mol (Figure 9a).
Successful experimental head-to-tail cyclization of linear precursor H-Nspe-Npm-Nspe-Npm-OH (21)
1
yielded the asymmetric cyclopeptoid ctct-19 as the only revealed conformational isomer ( H NMR analysis,
Figure 9b). Its structure was confirmed by the relatively high chemical shift values of the non-equivalent
methine protons linked to cis peptoid junctions ( 5.86 and 5.38 ppm)4a,12b and the presence of the two
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2
2
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5
5
5
5
6
benzyl groups on transoid junctions (attested by the small  values detected for the diastereotopic
methylene protons: 0.22 and 0.10 ppm).12b
a)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
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6
7
8
9
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2
3
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5
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9
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2
3
4
5
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7
8
9
0
b) CP2 type turn
Bn
O
O
pR N
t
N
N
N
c
Bn
O
pR
O
O
pS
c
O
O
t
Bn
N
N
N
N
pS
O
Bn
9, >98%, 1H NMR analysis
20
1
Figure 9. a) Minimum energy structures and their respective internal energies calculated in chloroform and expressed in kcal
-1
mol ; distances in black report the favorable hydrogen bonds, in red the unfavorable C-C distance. Hydrogen atoms have been
omitted for clarity except some in the Nspe residue (in yellow). Atom type: C light grey (yellow for the CH
blue, O red (see SI for atomic coordinates). Distances are in Å. b) Schematic structures of conformational isomers 19 and 20
with, in red, the chiral residues. The arrow in 19 (following the CO→N direction) depicts CP type-turn.
3
residues of Nspe), N
2
With the aim to confirm the structural hypothesis based on DFT and NMR studies, we attempted the
crystallization of compound 19. To our delight, recrystallization from a solution of chloroform/toluene (2:1)
afforded single crystals suitable for the X-ray diffraction studies (Figure 10).
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 10. ORTEP drawing of compound 19. Ellipsoids are drawn at 20% probability level. For clarity only one possible
position for disordered atoms is displayed. Atom type: C grey, N blue, O red, H white.
Compound 19 crystallizes in space group P2 with a ctct tetralactam core geometry and overall rectangular
1
shape of the peptoid backbone in agreement with DFT model and NMR studies.
Close proximity of bulky residues (in the case of easily assembled linear H-Nspe -OH, 22) prevented
4
cyclization of the tetrameric oligomer, yielding a complex mixture of inseparable oligopeptoids, instead of
the expected cyclo-(Nspe ), 23.
4
Synthesis and Structural Properties of Hexameric Cyclic Peptoid Models. While trimeric and
‡
-1 2c,23
tetrameric cyclic peptoids display relatively rigid scaffolds (G for the ring inversion > 20 kcal mol ),
hexameric and octameric macrocycles often show multiple isoenergetic conformations in slow equilibrium
‡
-1 2c,d,3,5c,7d,22,24
on the NMR time scale (G ~ 14-16 kcal mol ).
Given the intrinsic instability of larger
cyclohexapeptoids, we decided to probe the conformational stability of three different structures showing a
single, three alternated, and six chiral side chains in the sequence. If, on one side, cyclization of the linear
oligomer with one chiral side chain (H-Npm -Nspe-Npm-OH, 24) induced the formation of cyclooligomer
4
27 as a complex mixture of multiple species in slow equilibrium on the NMR time scale (Figure 11, see
NMR spectra in the SI), head-to-tail condensation of oligomers with multiple N-chiral side chains (H-
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9
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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3
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4
4
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4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(Nspe-Npm)
3
-OH, 25 and H-Nspe
6
-OH, 26) yielded cctcct-28 (or cctcct-29, as a possible alternative
conformational isomer) and cctcct-30 as a major conformationally homogeneous species (Figure 11 and
NMR spectra in the SI).
O
O
27
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
5
O
O
t
c
c
N p
t
Bn
O
N
Bn
Bn
N
pS
Bn
O
N
N
S
N
pR
pS
pR
pR
pR
c
c
O
O
O
O
O
O
pS
c
c
pR
pR
pS
pS
N
N
N
N
c
c
N
t
N
(
S)
t
(S)
O
Bn
Bn
O
28
29
O
t
c
N
N
N
pR
c
pR
pR
O
O
O
O
pS
c
pS
pS
N
c
N
N
t
O
30
Figure 11. Schematic structures of cyclic hexameric peptoids 27-30 with, in red, the Nspe chiral residues.
1
The cctcct arrangement of 28 (or 29) was suggested by the accurate analysis of its H NMR spectrum. The
presence of two N-1-(S)-(1-phenylethyl) and two N-benzyl side chains on cis amide bonds was inferred by
the resonance of the (S)-(1-phenylethyl) Cα−H groups at  5.98/5.74, and the large difference of the benzyl
groups’ diastereotopic protons ( 1.87/1.48 ppm).12b The two remaining chiral and benzyl side chains
were located on the two transoid junctions ( 4.78 for the Cα−H group and  0.35 ppm for the
diastereotopic protons of the benzyl group).12b
Support for the formation of conformer 28 (cyclo-[(cis,
p
R)Npm-(trans,
p
R)Nspe-(cis,
p
R)Npm-(cis, S)Nspe-
p
(trans,
p
S)Npm-(cis,
p
S)Nspe], with the matching cis-(S,
p
S) configurations, evidenced in blue color in Figure
25
-1
1
1) came from DFT calculations (29: E = 3.6 kcal mol , Figure 12). Formation of key hydrogen bonds
…
between side chains methine groups on cis amide bonds and adjacent carbonyl groups (C−H O=C
distance: 2.19 and 2.33 Å, Figure 12) increased the stability of the former structure.
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9
1
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
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4
5
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 12. Minimum energy structures of 28 and 29 and their respective internal energies calculated in chloroform and expressed
-
1
in kcal mol with reported hydrogen bonds as dotted lines (and atomic distances). Hydrogen atoms have been omitted for clarity
except some in the Nspe residue (in yellow). Atom type: C light grey (yellow for the CH residues of Nspe), N light blue, O red
see SI for atomic coordinates). Distances are in Å.
3
(
As revealed by Kirshenbaum and co-workers (studying the solid state structure of cyclo-[(Nme-Npm) ]
3
5
c
model), the cctcct-hexapeptoid backbone is morphologically similar to type I (and III) -turns. However,
the large differences in the torsion angles plus the presence of two cis bonds in the peptoid turn motif,
suggested the use of a different type of classification reported in Figure 13 (CP
torsion angles, CP and CP’ type turn motifs are more similar to the right handed poly-proline I (PPI) helix
(φ = −75°,  = 160°) and the left handed PPI helix (φ = 75°,  = −160°), respectively. The main difference
between CP and CP’ and PPI models is the planar chirality of the amide bond (which is opposite in the
3
and CP’
3
). In terms of
3
3
3
3
peptoid and peptide models, as evidenced in Table 3). It is interesting to note that in larger cyclic peptoids
(with six or more residues), where the ring strain is lower, the  and  torsion angles (φ ≈ 70° and −70° and

≈ 180° and −180°) are similar to those reported for most published peptoid structures.12d
,  and  dihedral angles values and the Cα(i)−Cα(i+3) distances for CP
3
and CP’ -turns for cyclic
3
hexameric peptoids 28 and 30 are reported in Table 3.
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a) CP' type turn
CP type turn
3
3
1
2
3
4
5
6
7
8
9
O
pR
i'+2
i
Bn
N
Bn
N
N
N
pR
pR
i+1
O
O
O
O
i'+1
pS
pS
pS
N
N
i'
i+2
O
Bn
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8
b)
CP
3
-turn
CP’
3
-turn
in 28
in 28
Figure 13. a) Schematic structures of 28 depicting type CP’
towards the CO→N direction. b) Models of type CP’ (left) and CP
8. Hydrogen atoms are omitted for clarity. Atom type: C light grey, N blue, O red.
3
(in black) and CP
3
(in blue) cct -turns with arrows pointing
3
3
(right) cct turns present in the minimum energy structures of
2
Table 3. Central residues dihedral angles values, amide bonds planar chirality and Cα(i)−Cα(i+3) distances for type CP
turns in 28/30 and PPI helix
3 3
and CP’
Distance

-Turn
type/helix

i+1 (planar
chirality)
i+2 (planar
chirality)
Compound

i+1

i+1

i+2

i+2
Cα(i)-Cα(i+3)
in Å
28
CP
CP
3
3
12.4 (
18.4 (
p
p
R)
R)
–74.0
–75.8
–75
176.7
167.6
175
–7.6 (
p
S)
–69.4
–79.1
–75
168.6
–179.2
175
5.35
5.41
≤ 7
3
0a
–0.2 ( S)
p
b
-
-
CP
3
0 (
p
R)
p
0 ( S)
Right handed
PPI helix
-
0 (
p
S)
–75
160
-
-
2
8
CP’
3
3
–16.1 (
p
S)
77.9
75.7
75
–176.4
–174.7
–175
5.7 (
p
R)
R)
74.6
78.6
75
–170.4
–159.9
–175
5.35
5.41
3
0a
CP’
–19.9 ( S)
–2.0 (
p
p
b
-
-
CP’
3
0 (
0 (
p
S)
0 (
p
-
R)
≤ 7
Left handed
PPI helix
p
R)
75
–160
-
-
a
data from X-ray crystal structure
idealized values
b
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The cctcct-peptoid bond arrangement present in cyclooligomer 30 was suggested by the presence of four N-
-(S)-(1-phenylethyl) side chains on cis amide bonds ( 6.05, 5.95, 5.72, and 5.30 for the Cα−H groups) and
1
two N-chiral side chains on trans amide bonds (4.83 and 4.72). It is interesting to note that for its
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
specific symmetry properties, configurational inversion of all the amide bonds gives back the same
structure (i.e.: cyclo-[(cis,
p
R)Nspe-(trans,
p
R)Nspe-(cis,
p
R)Nspe-(cis,
p
S)Nspe-(trans,
p
S)Nspe-(cis, S)Nspe],
p
Figure 11) and therefore just one cctcct-conformational isomer is possible for this macrocyclic species.
Accurate X-ray diffraction studies confirmed the structure and torsion angle values for type CP
3
and CP’
3
turns (Figure 14).26
Figure 14. ORTEP drawing of conformational isomer 30. Ellipsoids are drawn at 20% probability level. Atom type: C grey, N
blue, O red, H white.
Macrocycles 28 and 30 add up to the small group of conformationally stable cyclic hexamer peptoids12a (on
the NMR time scale) and constitute the only known examples of rigid (non-N-arylated and non-complexed)
hexameric cyclopeptoids with stereodefined backbone conformations.
Synthesis and Structural Properties of Octameric Cyclic Models. Cyclic octamer peptoids are the
largest members of the cyclopeptoid family showing homogeneous conformations in solution.2e,3b,c,22,24
With the aim to evaluate the stereoelectronic and topological influence of the N-1-(S)-(1-phenylethyl) side
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chain on this rare class of peptidomimetics, we have synthesized three linear octamer peptoid precursors.
The first one contained a single chiral side chain (H-Npm -Nspe-Npm-OH, 31), the second one showed a
set of paired Nspe /Npm residues matching the ccttcctt amide bond sequence found in most of the
conformationally rigid cyclic octamer peptoids (H-Npm-Nspe
one displayed eight chiral amino acid residues (H-Nspe -OH, 33) in the primary sequence.
While high dilution macrocyclization of 31 and 32, produced conformationally heterogeneous macrocycles
6
2
2
2
c
2
-Npm
2
-Nspe -Npm-OH, 32), and the last
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
3
4 and 35 (Figure 15), cyclization of homooligomer 33 showed the presence of a two-fold symmetric
1
species ( H NMR analysis, C
6
D
5
CD , 62% of the conformational isomers mixture, see SI) with four side
3
chains located on cisoid bonds ( 6.14/5.47 for the Cα−H groups) and four positioned on transoid junctions
(
 4.40/4.22) suggesting the formation of one of the two possible inequivalent C
2
-symmetric22 ccttcctt
conformational isomers 36 or 37.
O
O
O
O
N
N
N
N
2
2
2
7
34
35
O
O
O
O
pS
t
pR
t
c
N
N
N
N
N
pS
N
pR
N p
S
N p
S
N
pR
pR
c
O
O
O
O
O
O
c
O
O
pR
pR
N
N
t
pS
pR
N
pS
N
c
N
t
pS
N
N
pR
pS
O
O
O
O
36
37
C2-symmetry
C2-symmetry
axis
axis
Figure 15. Schematic structures of the synthesized cyclic octameric peptoids 34, 35, and conformational isomer 36 or 37 with, in
red, residues with chiral side chain.
Differently from the lower homologue 30, the concurrent inversion of amide bonds generates two
inequivalent species: conformational isomers 36 and 37. The analysis of the NMR spectra evidenced the
presence of a major species. In order to establish the identity of the most stable conformational isomer,
detailed DFT studies were performed. Multiple unfavourable steric interactions between methyl and
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
carbonyl groups were found in cyclo-{[(cis,
7toE = 2.6 kcal mol-1 (Figure 16) and pointed towards the formation of cyclo-{[(cis,
}, 36.27
p
S)Nspe-(cis,
p
R)Nspe-(trans,
p
R)Nspe-(trans,
p
S)Nspe]
2
},
3
p
R)Nspe-
(cis,
p
S)Nspe-(trans,
p
S)Nspe-(trans,
p
R)Nspe]
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 16. Minimum energy structures of 36 and 37 and their respective internal energies calculated in chloroform and expressed
-
1
in kcal mol . The unfavorable steric interactions present in conformational isomer 37 evidenced in red. Hydrogen atoms have
been omitted for clarity. Atom type: C light grey (yellow for the CH
coordinates). Distances are in Å.
3
residues of Nspe), N light blue, O red (see SI for atomic
2
C -symmetric macrocyclic peptoid 36 shows the same ,  and  dihedral angles in both the -turns
present in the oligomer (φi+1 = −78.8°, i+1 = −173.7°; φi+2 = −69.2°, i+2 = 164.2°), compatible with type
-turn (Figure 17 and Table 4).5c The enantiomorphic type CP’
CP
3
3
-turn (with opposite torsion
angles/amide bonds planar chirality) would be observable in a hypothetical cyclooctamer with N-(R)-(1-
phenylethyl) side chains (i.e.: ent-36).
CP -turn
3
in 36
Figure 17. Model of type CP
3
2
turn in the minimum energy structures of C -symmetric 36. Hydrogen atoms are omitted for
clarity. Atom type: C light grey, N blue, O red.
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3
Table 4. Central residues dihedral angles values, amide bonds planar chirality and Cα(i)−Cα(i+3) distances for type CP cct turn in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
6
Distance
Cα(i)-Cα(i+3)
in Å

i+2 (planar
chirality)
-Turn
type
i+1 (planar
chirality)
Compound

i+1

i+1

i+2

i+2
5.28
3
6
CP
3
–4.8 ( R) –78.8 –173.7
p
–9.1 (
p
S)
–69.2 164.2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Sodium Complexation Studies on Hexameric Cyclic Peptoid Models. Addition of metal ions to
solutions of larger cyclic peptoids promotes the formation of all-trans 1:13b host/guest
complexes.2c,7d,12b,f,22,28
bis(trifluoromethyl)phenyl]borate (NaTFPB) to CDCl
metallated species in slow equilibrium with the respective free hosts on the NMR time scale (see titration
Stepwise
quantitative
additions
of
sodium
tetrakis[3,5-
3
solutions of cyclohexamer 28 and 30 led to
.
+
.
+
experiments in Figures S2 and S3). Formation of all-trans three-fold symmetric [28 Na] and [30 Na]
-1
-1
species (log Kass = 4.4, ∆G° = –6.0 kcal mol , and log Kass = 4.3, ∆G° = –5.9 kcal mol , respectively,
1
calculated by H NMR, 3.0 mM host/guest solutions in CDCl
3
, see SI), was attested by the simplification of
1
the H NMR spectra of the complexes (Figure 18), methine protons upfield shift (quartet signals at  <
5
.01) and low  values for diastereotopic benzyl protons ( < 0.27).
[
30·Na]+
28·Na]+
b)
a)
[
1
.
+
.
+
Figure 18. H NMR spectra of a) [28 Na] and b) [30 Na] complexes as NaTFPB salts in CDCl
3
(600 MHz, 8.0–1.3 ppm
expansion). Water impurity denoted with *.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Metallation of 28, in principle, yields two possible non-equivalent all-trans C
3
-symmetric conformational
.Na]+,
isomers: [cyclo-[(trans,
p
R)Nspe-(trans,
p
S)Npm]
2
.Na]+ and [cyclo-[(trans,
p
S)Nspe-(trans,
p
R)Npm]
2
.
+
.
+
[
28a Na] and [28b Na] , respectively (Figure 19a).
.
+
Theoretical (DFT) studies indicated [28b Na] as the higher energy atropisomer for the repulsive steric
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
interactions between the methyl side chains (in yellow in Figure 19b) and intra-annular methylene groups
-1

E = 14.1 kcal mol ). It is interesting to note that while in cis peptoid junctions, S side chains induce
p
S
amide configurations (as reported for most of the cyclic species as free hosts and for all the studied linear
peptoids), in trans amide bonds this configuration stabilizes
p
R planar chirality.
a)
pS
pR
N
N
pR
pS
N
N
N
pR
O O
N
pS
O O
O
O
pS
O
O
pR
O O
N
O O
N
N
N
pR
pS
R
N pS
N p
C3-symmetry
C3-symmetry
.
+
[28b Na]+
.
[
28a Na]
axis
axis
b)
.
+
.
+
Figure 19. a) Schematic structures of all-trans conformational diastereoisomers [28a Na] /[28b Na] with, in red, the chiral
+
residues (Na as the magenta sphere); b) Minimum energy structures and their respective internal energies calculated in
-
1
chloroform and expressed in kcal mol . Hydrogen atoms have been omitted for clarity except for selected H residues of Nspe (in
yellow). Atom type: C light grey (yellow for the CH
Distances are in Å.
3
of Nspe), N blue, O red, Na magenta (see SI for atomic coordinates).
For symmetry reason, metalation of cyclohomooligomer 30 forms a single all-trans atropisomer: [(cyclo-
+
.
+
[(trans,
p
R)Nspe-(trans,
p
S)Nspe] .
Na] , [30a Na] , illustrated in the minimum energy DFT structure (Figure
2
2
0). Configurational inversion of all the amide bonds, in fact, does not change the structure.
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2
3
4
5
6
7
8
9
a)
b)
pS N
N
N
O O
O O
R
p
O
O
N
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C -symmetry
3
.
+
[
30a Na]
axis
.
+
+
Figure 20. a) Schematic structures of [30a Na] with, in red, the chiral residues (Na as the magenta sphere); b) Minimum energy
structure calculated in chloroform. Hydrogen atoms have been omitted for clarity except for the H residues of Nspe (in yellow).
+
Atom type: C light grey (yellow for the CH
3
residues of Nspe), N light blue, O red, Na magenta (see SI for atomic coordinates).
.
+
.
+
The pleated ttt arrangement present in both [28a Na] and [30a Na] features a loop structure (the distance
between the Cα(i) and the Cα(i+3) is larger than 7.0 Å). We suggest to name this folding, typical of hexameric
metallated cyclic peptoids, as “CPM
1
loop” (Figure 21, M stands for Metal). CPM loop’s torsion angles are
1
similar to the left handed poly-proline II (PPII) helix (φ = −75°,  = 150°). The difference between those
two secondary structures resides in the amide bond planar chirality (as illustrated in Table 5).
The values of ,  and  dihedral angles and the Cα(i)−Cα(i+3) distances in CPM
1
have been reported in
loops (present in the
Table 5. In principle, the use of N-(R)-(1-phenylethyl) side chains would form CPM’
1
.
+
hypothetical ent-[28a Na] ).
CPM loop in
1
.
+
[
28a Na]
.
+
Figure 21. CPM
1
loop present in the minimum energy structures of [28a Na] . Hydrogen atoms are omitted for clarity. Atom
type: C light grey, N blue, O red, Na magenta.
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1 1
Table 5. Central residues dihedral angles values, amide bonds planar chirality and Cα(i)−Cα(i+3) distances for the CPM and CPM’
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
.
+
.
+
loops in [28a Na] /[30a Na] and PPII helix
Distance
Cα(i)-Cα(i+3)
in Å


i+1 (planar
i+2 (planar
chirality)
Compound
Loop type

i+1

i+1

i+1

i+1
chirality)
.
+
+
[28 Na]
CPM
CPM
1
1
174.2 (
176.7 (
p
p
R) –71.5 175.0 –173.5 (
R) –73.1 175.4 –179.2 (
p
p
S) 70.5 –174.5
S) 75.4 –176.1
7.59
7.59
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.
[
30 Na]
-
CPM a
1
180 (
p
R) –70 175
S) –75 150
S)
180 (
-
p
S)
70 –175
>7.0
left handed
PPII helix
-
180 (
180 (
p
-
-
-
.
+
[ent-28 Na] /
[ent-30 Na]
CPM’ a
70 –175 180 (
R) –70 175
.
+
1
p
p
>
7.0
a
idealized torsion angles values
Sodium Complexation Studies on Octameric Cyclic Peptoid Models. Conformationally stable all-trans
metallated species were formed by addition of two equivalents of sodium ions to 35 and 36,3c,22,28 as
suggested by the methine proton chemical shift values of ( < 5.0) and the relatively small  recorded for
the diastereotopic benzyl protons ( < 0.16, Figure 22 and titration experiments in Figures S5 and S6).
Addition of a single equivalent of NaTFPB gave a complex mixture of multiple species in slow equilibrium
on the NMR time scale.
[36·2Na]2+
b)
[
35·2Na]2+
a)
1
.
2+
.
2+
-
3
Figure 22. H NMR spectra of a) [35 2Na] and b) [36 2Na] complexes as NaTFPB salts in CDCl (600 MHz, 8.0–1.0 ppm
expansion).
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1
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9
1
1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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4
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4
4
4
4
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5
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5
5
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5
5
5
5
5
6
The presence of two metallated species in the H NMR spectrum of 35 (Figure 22a) attested the formation
.
2+
.
2+
of two nonequivalent almost isoenergetic conformational isomers [35a 2Na] and [35b 2Na] in a 58:42
ratio (Figure 23). For symmetry reason, only one C -symmetric all-trans species can be formed for the
homooligomeric [36a 2Na] complex (simultaneous inversion of all the amide bonds does not change the
4
.
2+
-1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
structure, Figure 23, log Kass = 6.3, ∆G° = –8.6 kcal mol , calculated by H NMR, 3.0 mM host/6.0 mM
guest solutions in CDCl , see SI).
3
pRN
pS
pS N
pR
N
N
N
pS
N
O
O
O
O
pR
O O
O
O
N
O
O
N
N
O
N
O
pR
O
pS
O
O
O
N
N
N
N
N
N
C2-symmetry
C2-symmetry
axis
axis
.
2+
.
2+
[
35a 2Na]
[35b 2Na]
pRN
N
N
pS
O
O
O
O
N
N
O
O
O
O
N
N
N
C -symmetry
4
axis
.
2+
[
36a 2Na]
.
2+
.
2+
.
2+
+
Figure 23. Schematic structures of [35a 2Na] , [35b 2Na] and [36a 2Na] with chiral residues in red (Na ions as the magenta
sphere).
For the large cavity present in octamer cyclopeptoids, the structures of the complexes can be described as
the average of multiple fluxional conformations in fast equilibrium on NMR time scale (as in the case of the
non-symmetric minimum energy structures calculated for the cyclo-(Nbe
) sodium complexes).22 The
8
dynamic of this process cannot be described by the static structures of theoretical studies.
Another significant consequence of the fast dynamic equilibria of the sodium cation(s) inside the cavity of
cyclic octamer peptoids is the intrinsic difficulty to form single crystals of the metal complexes suitable for
X-ray diffractometric studies.3c,22 After multiple failed attempts to obtain crystals from solutions of 36 as
mono- or disodium complexes, we decided to use the smaller PF -
as the sodium counterion (used in the
6
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2
9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
past by our group to facilitate the crystallization of prolinated cyclic peptoids). Quantitative addition of a
single equivalent of NaPF to the host 36 (in CDCl :CD CN (9:1), Figure 24 and Figure S7) showed the
formation of an unexpected four-fold symmetric species, in slow equilibrium with the free host on the NMR
6
3
3
-1
1
time scale (log Kass = 4.5, ∆G° = –6.2 kcal mol , calculated by H NMR, 3.0 mM host/3.0 mM guest
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solutions).
+
-
[
36·Na] PF
6
1
.
+
-
Figure 24. H NMR spectra showing cyclic peptoid [36 Na] PF
6
in CD
3
CN:CDCl
3
(9:1) (600 MHz, 8.0–1.0 ppm expansion).
The presence of cis and trans amide junctions (in a 1:1 ratio) was deduced by the side chain methine proton
chemical shift values ( 5.94, for the cis amide bond, and 4.76, for the trans amide bond). The two only
possible four-fold symmetric conformational isomers compatible with the spectral data were the C -
4
.
+
-
.
+
-
symmetric ctctctct-[36b Na] PF
6
and ctctctct-[36c Na] PF complexes (Figure 25) reminiscent of the rare
6
peptoid ribbon-like structure,7a the “-helix , or the mixed cis-trans ,-oligopeptoids31 secondary
”30
structures.
O
O
pR
pS
t
N
N
pS N
N
N
N
c
pR
c
t
c
c
O
O
O
O
O
O
N
t
N
t
N
N
t
O
t
O
O
O
O
O
c
c
c
c
N
N
N
N
N
N
t
t
O
O
C -symmetry
C -symmetry
4
4
axis
axis
.
+
.
+
[
36b Na]
[36c Na]
.
+
-
.
+
-
+
Figure 25. Schematic structures of [36b Na] PF
6
and [36cNa] PF
6
conformational isomers (Na ion is the magenta sphere).
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9
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Dissolution of 36 in hot acetonitrile and addition of one equivalent of NaPF afforded single crystals
6
suitable for X-ray analysis. Relevant crystallographic data and structure refinement details are listed in
+
Table S4 (SI). Single crystal X-rays diffraction analysis revealed the formation of a 1:1 Na cyclopeptoid
1
complex with the unprecedented ctctctct peptoid bond sequence detected by H NMR spectroscopy and
structurally similar to complex [36b Na] PF
–.
.
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.
+
–
The tetragonal crystalline unit cell contains two symmetry independent [36b Na(H
2
O)] PF
6
moieties
+
(
Figure 26). Na ions are located on the crystallographic fourfold rotation axes and are hexacoordinated to
four trans carbonyl oxygen atoms of the macrocycle, to one water molecule and one PF -
Interestingly the side chain groups are alternately directed on opposite faces of the macrocycle providing a
fluorine atom.
6
-
.
+
–
pocket where PF
6
ion is located. Moreover, [36b Na(H
2
O)] PF moieties are aligned along the c axis by
6
means of CH∙∙∙OC hydrogen bonds between cis carbonyl groups and aromatic p-hydrogen atoms, forming
channels parallel to the c axis, where acetonitrile molecules are located.
a)
b)
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.
O)] PF6-: a) side view; b) top view. Ellipsoids are drawn at 10% probability level.
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 26. ORTEP drawing of [36b Na(H
2
For clarity hydrogen atoms have been omitted and only one possible disordered PF -
moiety is displayed. Atom type: C grey, N
6
blue, O red, P magenta, F green.
The loop structure evident in the X-ray structure (CPM
2
loop) is exemplified in Figure 27. Table 6 reports
.
O)] PF
-. The use of N-
+
the values of the ,  and  dihedral angles of the solid state complex [36b Na(H
2
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.
O)] PF
-, with an
+
(
R)-(1-phenylethyl) side chains would have formed the hypothetical ent-[36b Na(H
2
6
enantiomorphous CPM’ loop.
2
CPM loop
2
.
+
-
[
36b Na(H
2
O)] PF
6
2 2 6
loop present in the solid state structure of [36b Na(H O)] PF
-. Hydrogen atoms are omitted for
.
+
Figure 27. Model of the CPM
clarity. Atom type: C light grey, N blue, O red, Na magenta.
2 2
Table 6. Central residues dihedral angles values, amide bonds planar chirality and Cα(i)−Cα(i+3) distance for the CPM and CPM’
loops

i+1

i+2 (planar
chirality)
Distance
Loop
type
Compound
(planar
chirality)

i+1

i+1

i+1

i+1
Cα(i)-Cα(i+3) in Å
.
O)]+
[
36b Na(H
2
CPM
CPM a
O)]+ CPM’ a
2
–4.6 ( S) –81.5 –164.1 172.5 (
p
R) –67.7 170.4
7.94
>7.0
>7.0
p
-
2
0 (
0 (
p
S)
–80
–165
180 (
p
R)
S)
–70 170
70 –170
.
ent[36b Na(H
2
2
p
R)
80
165
180 (
p
a
idealized values
.
+
-
The unique bond arrangement of the ctctctct-[36b Na(H
2
O)] PF
6
complex recapitulates the major
structural traits of cyclic peptoid foldamers. In this species, S side chains pair with (cis,
p
S)- and (trans, R)-
p
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amide bonds, metal-dipole electrostatic bonds and Ph(Me)NC−H O=C hydrogen bonds stabilize the
oligoamide scaffold, and torsion angles 
1
≈ −130° optimize the side chain/backbone geometry. Structural
data also confirm that cis- and trans-amide bonds induce similar  and torsion angles values.12e
.
+
The combined sets of conformational preferences emerging in complex [36b Na] proves that understanding
the relationships between sequence and topological order in peptoid foldamers allows prediction of their
secondary structures.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSIONS
Since the first synthesis of peptoids, considerable efforts have been devoted to the generation of stable
folded oligomers. The biological and pharmacological applications of this class of peptidomimetics are, in
fact, strictly dependent on the ability to control their shape and conformational properties. In this
contribution we have examined how the concurrent presence of chiral aromatic residues, head-to-tail
cyclization, and metal chelation are capable of shaping the topological order of three dimensional
oligoamide-based architectures. While stereoelectronic effects in linear peptoid structures induce regular
patterns on oligomers with more than 5 or even 8 residues, in cyclic peptoids it is possible to obtain stable
folding even in trimeric and tetrameric oligomers. Conformational preferences in larger cyclooligoamides
(with six or eight residues) are strictly dependent on the amount and relative position of N-chiral aromatic
side chains and vary remarkably in the presence of chelating cations. Weak intramolecular forces emerging
from adjacent residues, when exalted by covalent constraints induced by cyclization or by efficient ion-
dipole forces, can be used to effectively modulate reverse turn and loop conformations and provide new
ways to design non-repetitive architectures complementing the studies made on helix secondary or higher
order structures.
Ongoing work in our laboratory is focused on applying these design principles to expand the peptoid three-
dimensional chemical space in the frame of the pervading conformational isomerism, the proper conceptual
scheme for future application of peptoids in all the fields of science.
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