Chiral Overpass Induction in Dynamic Helical Polymers Bearing Pendant Groups with Two Chiral Centers

Article abstract of DOI:10.1002/anie.201915213

The dynamic behavior of helical polymers bearing pendant groups with two chiral centers was studied. Controlled conformational changes at the chiral units placed either closer to or further away from the main chain promote different helical structures. Al

Full text of DOI:10.1002/anie.201915213

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Chiral Overpass-Induction in Dynamic Helical Polymers Bearing
Pendant Groups with Two Chiral Centers
Authors: Felix Freire, Esteban Suárez-Picado, Emilio Quiñoá, and
Ricardo Riguera
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915213
Angew. Chem. 10.1002/ange.201915213
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10.1002/anie.201915213
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chiral Overpass-Induction in Dynamic Helical Polymers Bearing
Pendant Groups with Two Chiral Centers
Esteban Suárez-Picado, Emilio Quiñoá, Ricardo Riguera and Félix Freire*
Centro Singular de investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Departamento de Química Orgánica
Universidade de Santiago de Compostela
E-15782 Santiago de Compostela, Spain
felix.freire@usc.es
Abstract: The dynamic behaviour of helical polymers bearing
pendants with two chiral centers was studied. Controlled
conformational changes at the chiral units placed either closer or
further to the main chain promote different helical structures.
Although the first residue is usually responsible for commanding a
specific helicity (P or M), herein it was found that the second chiral
center is also able to induce a preferred helical sense when is
located spatially closer to the main chain, thereby cancelling the
order from the first chiral moiety. This result is achieved through
proper coordination with a metal cation. As proof of concept, PPAs
that bear one and two chiral amino acid units of different sizes and
configuration combinations (L/D alanine and L/D phenylalanine) as
pendants were evaluated. In total, ten polymers were studied. This
result constitutes the first report of axial control from the remote
stereocenter in polymers bearing complex stereopendants.
acids residues are antiperiplanar (anti, ap) oriented, placing the
first chiral center closer to the polyene backbone, while the other
chiral centers are placed further away. This fact clearly explains
how the first chiral center of a peptide sequence commands the
helical sense in multi-chiral PPAs (Figure 1). [27, 28]
residue
2
residue
1
syn
anti
H
R1
O
O
H
N
R1
O
N
N
H
O
R2
a)
N
R2
O
O
H
O
O
anti
anti
O
O
syn
R2
R2
O
O
syn
O
N
syn
O
N
O
H
H
R1
N
H
R1
N
H
parallel β-sheet
b)
parallel β-sheet
R1 commands the
helical sense
R1 commands the
helical sense
H
N
R1
O
O
O
O
H
N
R1
O
O
O
O
Introduction
N
O
O
N
O
O
O
O
R2
H
H
R1
O
O
R2
H
H
R1
In helical polymers, the helicity sense of the backbone is
determined by the chirality of the pendant.[1-15] Thus, for a certain
helical polymer, P or M helical senses can be obtained switching
the R/S absolute configuration of the asymmetric center.
In the case of dynamic helical polymers, the helical sense
control can be obtained by external stimuli[1-16], which can alter
the conformational composition of the pendant group, and as a
result, producing changes in both helical sense and elongation
of the scaffold. This stimuli-responsive behaviour of dynamic
helical polymers has attracted the attention of the scientific
community during the last years due to the potential applications
of these materials in fields such as sensors,[7-9] chiroptical
switches,[10-12] chiral stationary phases[16] or chiral catalysts,[17-22]
among other applications.
N
N
N
H
N
H
R2
R2
anti
(L)
anti
(L)
anti
(D)
anti
(D)
M helix
P helix
rotation at the first
chiral residue
Is there a
chiral conflict
between the units?
c)
helix inversion
O
R2
O
O
R2
O
syn
(D)
O
N
H
O
anti
(D)
NH
O
R1
N
H
N
H
R1
(D)
syn
turn
R1 commands the
helical sense
(D)
2 chiral centers close to the backbone
In literature, it is found that helical polymers bearing pendant
groups with more than one chiral center, the helical sense of the
polymer is governed by the chiral moiety closer to the helical
backbone.[23-25] These studies unravel an important relationship
between the orientation of the different substituents at the
pendant group and the helical sense adopted by the helical
polymer.
In this work we want to deepen the study of the dynamic
behavior of helical polymers bearing more than one chiral
residue. Specifically, we want to explore how conformational
changes at the chiral residues placed closer or further to the
main chain affect the helical sense of the polymer.
Poly(phenylacetylene)s (PPAs) bearing amino acid or peptide
residues as substituents generally adopt helical structures
stabilized by hydrogen bonds between neighboring pendants —
nth and (n+2)th or nth and (n+3)th— adopting a b-sheet like
orientation.[25, 26] In such a case, the amide groups of the amino
Figure 1. Conceptual representation of: (a) possible conformational changes
at residue 1 and residue 2, (b) a b-sheet arrangement between pendants and
(c) expected helical structural effects by the presence of different conformers
at residue 1 in a PPA bearing a dipeptide pendant group.
Interestingly, other structural motifs different than b-sheets are
also found in literature related to PPAs bearing peptides with a
31]
single chiral residue as pendants.[30,
Thus, “turns” can be
obtained due to rotation of the dihedral angle between amide
residues, and a synperiplanar (syn, sp) conformation between
33]
carbonyl groups is also possible.[32,
These conformational
changes towards different structural motifs are usually produced
by changes in the polarity of the solvent [9, 34] or by the addition of
external stimuli such as metal ions and are accompanied always
with changes in the helical structure of the polymer (elongation
and/or helical sense).[35-41]
1
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10.1002/anie.201915213
Angewandte Chemie International Edition
RESEARCH ARTICLE
CD studies of poly-(1-3) —containing single alanine (poly-1) or
dialanine as pendants [i.e. poly-(2-3)], where the first alanine is
always introduced in the L configuration, while the second one is
introduced in either L or D absolute configuration— show similar
CD traces in CHCl3 and DMF, (M and P helices, respectively),
even though the absolute configuration of the second alanine
residue differs in poly-2 and poly-3. These results suggest that
the chirality of the second alanine does not play a role in the
helical induction of the PPA, and moreover, the anti/syn
equilibrium found in PPAs bearing a single amino acid as
pendants can be extrapolated to a dialanine system (Figure 3a-
c).
Results and Discussion
Herein, we want to study the helical sense control in PPAs
bearing a chiral dipeptide pendant group with conformational
changes in the two chiral residues.
To perform these studies, two different amino acids capped at
the
C termini with a methyl ester group —alanine and
phenylalanine— were chosen due to their different size. Alanine
(Ala) is the smallest natural chiral amino acid, while
phenylalanine (Phe) contains a large side chain (benzyl group).
In our design, PPAs containing a single amino acid are
necessary as control —poly-(L)-Ala-OMe, (poly-1), and poly-(L)-
41]
Phe-OMe, (poly-6)—.[39,
In addition, eight PPAs bearing
CHCl3
DMF
dipeptides with different diastereomeric relationship are needed
—poly-(L,L)-Ala-Ala-OMe, (poly-2); poly-(L,D)-Ala-Ala-OMe,
(poly-3); poly-(L,L)-Ala-Phe-OMe, (poly-4); poly-(L,D)-Ala-Phe-
OMe, (poly-5); poly-(L,L)-Phe-Ala-OMe, (poly-7); poly-(L,D)-Phe-
Ala-OMe, (poly-8); poly-(L,L)-Phe-Phe-OMe, (poly-9); poly-(L,D)-
Phe-Phe-OMe, (poly-10)— to analyze how configuration and
size of the different amino acids affect the helical structure of the
PPA (Figure 2).
Ala commands the
helical sense
Ala commands the
helical sense
a)
Me
O
O
O
O
O
O
O
N
O
O
Me
N
H
Me
H
N
H
O
O
O
N
Me
anti
H
M helix
P helix
syn
The first residue
commands the
helical sense
O
a)
The first residue
commands the
helical sense
b)
O
H
N
H
O
Me
O
O
O
O
O
O
O
O
N
N
O
N
O
O
N
H
Me
O
H
No effect
O
O
N
Me
Me
O
H
Me
O
H
N
O
H
H
N
O
N
H
m-(L)-Ala-OMe (1)
O
Me
m-(L)-Phe-OMe (6)
Me
N
H
Me
O
O
O
O
No effect
anti
(L)
H
N
H
N
M helix
N
H
O
N
H
O
syn
P helix
O
O
c)
d)
30
poly-(L,L)-Ala-Ala-OMe / Co2+
poly-(L,D)-Ala-Ala-OMe / Co2+
poly-(L,D)-Ala-Ala-OMe
poly-(L,L)-Ala-Ala-OMe
poly-(L)-Ala-OMe
30
m-(L,L)-Ala-Ala-OMe (2)
m-(L,L)-Phe-Ala-OMe (7)
O
O
15
0
15
0
O
O
H
N
DMF
P
H
N
P
N
H
O
Co2+
N
H
O
O
O
M
M
m-(L,D)-Ala-Ala-OMe (3)
-15
-30
-45
-15
-30
-45
m-(L,D)-Phe-Ala-OMe (8)
CHCl3
poly-(L,L)-Ala-Ala-OMe
poly-(L,D)-Ala-Ala-OMe
poly-(L)-Ala-OMe
O
O
H
N
poly-(L,L)-Ala-Ala-OMe
poly-(L,D)-Ala-Ala-OMe
O
O
H
N
N
H
O
N
H
O
O
O
m-(L,L)-Ala-Phe-OMe (4)
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
m-(L,L)-Phe-Phe-OMe (9)
O
O
H
N
e)
f)
30
15
O
O
H
N
poly-(L,L)-Ala-Ala-OMe /Li+
N
H
O
15
N
H
O
O
Li+
O
m-(L,D)-Ala-Phe-OMe (5)
P
0
-15
-30
m-(L,D)-Phe-Phe-OMe (10)
0
M
M
b)
O
R
O
R
O
H
N
O
-15
-30
-45
H
N
H
H
N
H
O
O
O
R
poly-(L,L)-Ala-Ala-OMe
n
n
poly-(L,D)-Ala-Ala-OMe /Li+
poly-(L,D)-Ala-Ala-OMe
Figure 2. (a) Monomer structures (1-10). (b) General PPA structures.
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
Thus, monomers (1-10) were prepared using peptide synthesis
in solution and polymerized with [Rh(nbd)Cl]2 as catalyst (nbd =
2,5-norbornadiene), affording PPAs [poly-(1-10)] in good yields
(»90 %) and with a high content of the cis configuration of the
double bonds (see SI for full details).
Figure 3. (a) Syn/anti conformational composition of poly-1 in DMF and CHCl3.
(b) Syn/anti conformational composition of poly-(2-3). (c) CD spectra of poly-
(1-3) in DMF and CHCl3. (d) Helical inversion in a CHCl3 solution of poly-(2-3)
by complexation with Co2+. CD spectra of (e) poly-2 and (f) poly-3 in CHCl3
before and after the addition of LiClO4 (50 mg/mL). [Concn = 0.3 mg/mL].
2
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10.1002/anie.201915213
Angewandte Chemie International Edition
RESEARCH ARTICLE
Next, we proceed to study the dynamic helical properties of
these PPAs both in the presence and absence of cations as
external stimuli. So, several metal ions dissolved in MeOH (50
mg/mL) were added to the polymer solution (0.3 mg/mL). It was
found that Co2+ can invert the helical structure of poly-(2-3) in
CHCl3 due to an anti to syn shift of the conformational
composition of the first residue of alanine produced by chelation
with the metal ion (Figure 3d). [38] On the other hand, the addition
of Li+ produces different results in poly-2 and poly-3, depending
on the absolute configuration of the alanine residue placed at
the remote position (second residue). Thus, while a helical
inversion is obtained in poly-2 by the addition of Li+, poly-3 is not
able to invert its helical structure, decreasing only its folding into
a left-handed helical structure (Figure 3e, f).
In literature, we found that Li+ can interact simultaneously with
more than three different oxygen atoms in dipeptide/Li+
complexes. [42-44] Thus, a tripodal coordination of the metal ion to
the dipeptide pendant can explain the abnormal effect observed
when Li+ is added. The formation of such a tripodal complex can
force the two amino acid residues to adopt a syn conformation
between carbonyls. This new spatial arrangement places the
side chain of the alanine closer to the backbone and therefore
affecting the helical sense of the PPA.
second residue, we suggest that one of the Co2+ must chelate
the two amide groups, inducing therefore a syn conformation at
residue 1, while another Co2+ coordinates the ester group
leaving the residue 2 in anti-conformation. As a result, by using
Co2+, the conformation stabilized at the dipeptide pendant group
is analogous to the one obtained when the polymer is dissolved
in polar solvents. The result in both cases is the adoption of a P
helix (Figure 4c, d and Figures S30, S31, S32).
Next, we decided to explore the role of the size of the
substituents in the helical induction of a PPA bearing a dipeptide
as pendant group. Thus, CD spectra of poly-(4-5) —[poly-(L,L)-
Ala-Phe-OMe, (poly-4); poly-(L,D)-Ala-Phe-OMe, (poly-5)]—
were measured in different solvents. Interestingly, we could
observe that in polar solvents (i.e., DMF), poly-(4-5) behave in
the same way as poly-(1-3), which indicates that the first alanine,
in a syn conformation, is the one that governs the helical sense
(Figure 2a). Unexpectedly, when the same experiments were
carried out in CHCl3, CD spectra showed that these dipeptides
do not behave as the previous ones —poly-(1-3)—. The ICD
signals of poly-(4-5) in the vinyl region (»370 nm) are weak,
suggesting the presence of different conformations in equilibrium
at the pendants (Figure 5a, b).
b)
a)
Thus, while in poly-2/Li+ —poly-(L,L)-Ala-Ala-OMe/Li+— the
methyls of first and second residues of alanine are oriented in
the same direction, and therefore induce an analogous helix, in
poly-3/Li+ —poly-(L,D)-Ala-Ala-OMe/Li+— they are oriented in
opposite directions. So, while the first residue induces a P helix,
the second one induces an M helical structure, obtaining a
combination of the two effects within the polymer chain, which
results in a slight excess of an M helical structure in the polymer
metal complex. The coordination of lithium atoms to the three
different carbonyl groups was further confirmed by IR (Figure 4a,
b and Figures S39-40).
30
15
poly-(L)-Ala-OMe
CHCl3
poly-(L,L)-Ala-Phe-OMe
poly-(L,D)-Ala-Phe-OMe
15
0
P
M
-15
-30
-45
0
poly-(L,D)-Ala-Phe-OMe
poly-(L,L)-Ala-Phe-OMe
poly-(L)-Ala-OMe
DMF
-15
250 300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
poly-(L,D)-Ala-Ala-OMe / Li+
a) poly-(L,L)-Ala-Ala-OMe / Li+
b)
residue 2 - M helix
c)
d)
poly-(L,D)-Ala-Phe-OMe / Co2+
poly-(L,L)-Ala-Phe-OMe / Co2+
Tripodal
coordination
Tripodal
coordination
O
O
M helix
15
P
15
Li+
Me
Li+
O
Me
O
N
N
O
same spatial
arrangement of
side chains
O
H
opposite spatial
arrangement of
side chains
O
H
Me
N
P
Me
N
0
H
H
0
M
residue 1 and 2
commands P helix
residue 1 - P helix
P helix
P helix
-15
poly-(L,D)-Ala-Ala-OMe / Co2+
poly-(L,D)-Ala-Phe-OMe
-15
poly-(L,L)-Ala-Phe-OMe
c) poly-(L,L)-Ala-Ala-OMe / Co2+
d)
O
O
Co2+
Me
300 350 400 450 500
Wavelength [nm]
Co2+
Me
300 350 400 450 500
Wavelength [nm]
Co2+
Co2+
O
O
HN
HN
O
anti
anti
O
O
N
N
residue 2
(too far from
main chain)
Me
residue 2
(too far from
main chain)
Me
Figure 5. (a) CD spectra of poly-1 and poly-(4-5) in DMF and (b) CHCl3. (c-d)
CD spectra of poly-(4-5) before and after the addition of Co(ClO4)2. [Concn=
0.3 mg/ mL].
H
H
syn
syn
residue 1 - P helix
residue 1 - P helix
Figure 4. Suggested structures for: (a) poly-2/Li+, (b) poly-3/Li+, (c) poly-2/Co2+
and (d) poly-3 /Co2+
Addition of metal ions as external stimuli reveals very interesting
structural effects in the polymer. The addition of Co(ClO4)2 into a
CHCl3 solution of poly-(4-5) induces the formation of a P helix, in
a similar way to the poly-(1-3)/Co2+ complexes, and suggesting
an analogous mechanism (Figure 5c, d).
Interestingly, when LiClO4 is added to a CHCl3 solution of poly-
(4-5), a dual effect is observed controlled by the presence of a
cosolvent (MeOH) (Figure 6a, b). In the presence of a small
.
In the case of poly-(2-3)/Co2+complexes, IR studies indicate that
Co2+ interacts with three carbonyl groups (Table S5, ESI). To
explain the helical inversion in both helical polymer metal
complexes, without influence of the absolute configuration of the
3
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10.1002/anie.201915213
Angewandte Chemie International Edition
RESEARCH ARTICLE
amount of MeOH (5 equiv per monomeric repeating unit equiv),
an M helical structure is generated in poly-4 and poly-5,
suggesting the induction of an ap conformation at the pendant
group, similar to the one obtained for poly-(2-3) in low polar
solvents, and where the chirality of the second residue does not
play a role in the helical induction. 7Li-NMR experiments indicate
that the anti conformation is stabilized by the formation of a
cation-p interaction (Figure 6c-h).[37, 40, 45] Ulterior additions of
methanol (> 225 equiv) disrupt the cation-p interaction. The
coordination mode of the Li+ towards the pendant group changes
to a tripodal coordination in a similar way as the one described
In a new design, we switched positions between alanine and
phenylalanine residues at the dipeptide pendant. These new
PPAs —[poly-(L,L)-Phe-Ala-OMe (poly-7); poly-(L,D)-Phe-Ala-
OMe, (poly-8)]— allowed exploring how the size of the different
substituents affect both the helical structure and the dynamic
behaviour of the PPAs. In previous systems —poly-(4-5)—, the
largest amino acid residue was placed in a remote position
(second residue), being now, in this new design, closer to the
polyene scaffold (as first residue).
CD studies of poly-6 —(poly-(L)-Phe-OMe) used as control—
and poly-(7-8) in polar and low-polar solvents show that when a
second amino acid —in this case alanine— is coupled to a
phenylalanine residue, the helical folding of the PPA is almost
lost. This fact is due to the presence of several conformations in
equilibrium at the dipeptide pendant (Figures 7a, b).
previously for poly-(2-3)/Li+
.
poly-(L,D)-Ala-Phe-OMe / Li+
15
poly-(L,L)-Ala-Phe-OMe / Li+
b)
a)
poly-4/ Li+/MeOH
15
b)
a)
poly-5
P
P
poly-(L)-Phe-OMe
CHCl3
40
20
0
20
0
-15
-30
0
-15
-30
poly-4
P
M
M
0
poly-5/ Li+/MeOH
poly-5/Li+
M
-20
-40
-60
-80
poly-4/Li+
DMF
poly-(L,D)-Phe-Ala-OMe
poly-(L,L)-Phe-Ala-OMe
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
-20
poly-(L,L)-Phe-Ala-OMe
poly-(L,D)-Phe-Ala-OMe
poly-(L)-Phe-OMe
c)
Li+
O
Li+
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
Li+
O
H
N
Me
O
O
Li+
d)
c)
15
MeOH
poly-(L,L)-Phe-Ala-OMe
poly-(L,D)-Phe-Ala-OMe
N
O
poly-(L,L)-Phe-Ala-OMe
poly-(L,D)-Phe-Ala-OMe
N
H
O
O
H
O
Me
N
Li+
CHCl3
H
0
0
residue 1and 2
commands P helix
M helix
anti
anti
poly-4
P helix
Δδ= 3.64
ppm
Δδ= 0.55
ppm
7 Li
CHCl3
d)
e)
7 Li
-15
-30
M
M
-15
poly-(L,L)-Phe-Ala-OMe / Li+
poly-(L,D)-Phe-Ala-OMe / Li+
poly-(L,L)-Phe-Ala-OMe / Co2+
poly-(L,D)-Phe-Ala-OMe / Co2+
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
residue 2
commands
M helix
f)
O
Li+
e)
Li+
Li+
O
Li+
H
N
Me
O
O
Li+
Li+
N
O
MeOH
Li+
H
N
O
O
O
H
N
H
O
O
Me
N
N
O
O
H
Li+
H
Me
Li+
residue 1
commands P helix
poly-5
anti
anti
Δδ= 0.50
ppm
poly-(7-8)
M helix
Δδ= 3.77
ppm
anti
anti
g)
h)
7 Li
7 Li
Δδ= 3.81
ppm
Δδ= 3.64
ppm
f)
g)
7 Li
7 Li
poly-7 / Li+
poly-8 / Li+
Figure 6. (a) CD spectra of poly-4 and (b) poly-5 in CHCl3 before and after the
addition of LiClO4. (c) Suggested structures for poly-4/Li+ and 7Li-NMR
experiments before (d) and after (e) disruption of the cation-p interaction by
addition of MeOH. (f) Suggested structures for poly-5/Li+ and 7Li-NMR
experiments before (g) and after (h) disruption of the cation-p interaction by
addition of MeOH. [Concn= 0.3 mg/ mL].
Figure 7. (a) CD spectra of poly-7 and poly-8 in DMF and (b) CHCl3. (c) CD
spectra of poly-(7-8) in CHCl3 before and after the addition of LiClO4 and (d)
Co(ClO4)2. (e) Suggested structures for poly-7/Li+ and poly-8/Li+ (f) 7Li-NMR
spectra confirming the cation-p interaction in poly-7 and (g) poly-8.
4
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10.1002/anie.201915213
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RESEARCH ARTICLE
Next, we decided to stabilize a conformation at the dipeptide
fragment by adding metal ions and to induce a single-handed
helix in the polymer. We found that Li+ can only stabilize the anti-
(L,D)-Phe-Phe-OMe/Ba2+ adopts
a P helix. These results
demonstrate that the chiral order commanded by a chiral residue
directly linked to the backbone can be surpassed by another
chiral center in a spatially closer position to the polyene main
chain. This is a very interesting phenomenon in dynamic helical
polymers that can have potential applications in fields such as
sensing, chiral stationary phases or asymmetric synthesis,
among others.
conformation at the pendant group through cation- interactions,
p
although no evidence of tripodal syn conformation was obtained
by titration of the poly-(7-8)/Li+ complexes with methanol (Figure
7c, e-g and Figures S35a, S36a). Moreover, other metal ions
such as Co2+ —that induces in the previous cases a syn
conformation of the alanine residue— cannot form a similar
complex when phenylalanine is occupying that position. In
addition, the metal ion interaction only occurs for poly-8,
indicating that in this case the absolute configuration of the
second chiral center does play a role in the PPA interaction with
metal ions (Figure 7d and Figures S35d, S36d).
Finally, we decided to study a PPA bearing a diphenylalanine
dipeptide as pendant group to complete the PPA dipeptide
series [poly-(L,L)-Phe-Phe-OMe (poly-9); poly-(L,D)-Phe-Phe-
OMe, (poly-10)]. In this case, CD studies in polar and low polar
solvents show again that these PPAs are highly dynamic. In
CHCl3, a CD signal is obtained in both cases at 280 nm
corresponding to the pendant chirality but not to a PPA helical
structure. On the other hand, in polar solvents the presence of
an excess of a left-handed helix is observed (Figure 8a).
Addition of LiClO4 to a CHCl3 solution of poly-(9-10) produces a
similar response to poly-(7-8)/Li+ complex, the induction of M
helix due to the presence of all anti conformations at the
15
a)
b)
poly-(L,D)-Phe-Phe-OMe
poly-(L,L)-Phe-Phe-OMe
CHCl3
poly-(L,D)-Phe-Phe-OMe
poly-(L,L)-Phe-Phe-OMe
15
0
CHCl3
0
-15
-30
DMF
M
-15
-30
poly-(L,L)-Phe-Phe-OMe / Li+
poly-(L,D)-Phe-Phe-OMe / Li+
poly-(L,D)-Phe-Phe-OMe
poly-(L,L)-Phe-Phe-OMe
300 350 400 450 500
Wavelength [nm]
300 350 400 450 500
Wavelength [nm]
c)
d)
poly-(L,D)-Phe-Phe-OMe / Ba2+
15
0
Li+
CHCl3
P
Li+
H
O
O
N
N
O
pendants, in this case stabilized by cation-
p
interactions as
O
H
M
determined by 7Li-NMR (Figure 8b, c and Figures S45, S46).
Other metals such as Co2+, that interacts better with the PPA
when alanine is the first residue of the dipeptide in poly-(2-5),
are not able to produce any responses in poly-(9-10). This
outcome indicates that formation of the syn conformer in bulky
amino acids is less favored (Figures S37, S38).
Li+
-15
-30
poly-(L,L)-Phe-Phe-OMe / Ba2+
poly-(L,D)-Phe-Phe-OMe
M helix
anti
anti
poly-(9-10)/Li+
poly-(L,L)-Phe-Phe-OMe
300 350 400 450 500
nm
A remarkable and unexpected result was obtained when Ba2+
was added as external stimulus. In this case, the two PPAs poly-
(9-10) induce opposite helical senses when interact with this
metal ion (Figure 8d). This result indicates that the residue that
governs the helical sense is residue 2, the one placed at the
remote position. IR studies indicate that the metal ion
coordinates only residue 2, the one that governs the helical
sense (Figures S47, S48). This fact is probably due to the larger
size of the metal ion.
Chiral Overpass-Induction by the Phe
placed in a closer spatial position to the backbone
f)
e)
O
O
O
O
N
H
N
H
O
Ba2+
O
O
Ba2+
O
N
N
H
H
To have an effective helical induction from a remote chiral center,
surpassing the chiral information from the closest chiral center, it
is necessary for the dipeptide pendant to adopt a bent structure.
By doing this, the second amino acid is placed spatially closer to
the polyene backbone. Therefore, a reasonable mechanism of
helical induction in these systems is shown in Figure 8e, f.
P helix
M helix
poly-(L,L)-Phe-Phe-OMe / Ba2+
poly-(L,D)-Phe-Phe-OMe / Ba2+
Figure 8. (a) CD spectra of poly-(9) and poly-(10) in DMF and CHCl3. (b) CD
spectra of poly-(9-10) before and after the addition of LiClO4 and (c) Ba(ClO4)2.
(d) Suggested structures for poly-(L,L)-Phe-Phe-OMe/Li+ and poly-(L,D)-Phe-
Phe-OMe/Li+. (e) Suggested structures for poly-(L,L)-Phe-Phe-OMe/Ba2+ and
(f) poly-(L,D)-Phe-Phe-OMe/Ba2+ showing the chiral overpass-induction
phenomena.
Conclusion
We have demonstrated that PPAs bearing pendant groups with
more than one chiral center adopt a helical sense induced by the
chiral center placed in a closer spatial position to the polyene
backbone. This center does not have to be coincident with the
first chiral residue in the sequence of the pendant. We have
prepared PPAs bearing diphenylalanine dipeptide pendants
whose helical sense, when interacting with Ba2+, is governed by
the chirality of the phenylalanine located in the remote position.
So, poly-(L,L)-Phe-Phe-OMe/Ba2+ adopts an M helix, while poly-
Acknowledgements
Financial support from MINECO (CTQ2014-61470-EXP,
CTQ2015-70519-P), Xunta de Galicia (ED431C 2018/30, Centro
singular de investigación de Galicia accreditation 2016-2019,
ED431G/09) and the European Regional Development Fund
(ERDF) is gratefully acknowledged. E. S. P. is grateful to MEC
for a FPU predoctoral fellowship.
5
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10.1002/anie.201915213
Angewandte Chemie International Edition
RESEARCH ARTICLE
[33] Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. Small, 2019, 15,
1970070.
Keywords: cation-p • circular dichroism • chirality • chiral
overpass-induction
•
helical polymers
•
helical sense
•
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6
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Angewandte Chemie International Edition
RESEARCH ARTICLE
TOC
2
2
comands the helical sense
comands the helical sense
2
2
1
1
closer in
the sequence
No induction of helicity
closer in
the sequence
No induction of helicity
M helix
P helix
7
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