Controlling Helix Sense at N- and C-Termini in Quinoline Oligoamide Foldamers by β-Pinene-Derived Pyridyl Moieties

Article abstract of DOI:10.1021/acs.orglett.7b00510

A series of quinoline oligoamide foldamers bearing a β-pinene-derived pyridyl group at the N-terminus or the C-terminus were synthesized, and the efficiencies of chiral inductions have been evaluated by ¹H NMR and CD spectra. The chiral inductions were quantitative when chiral pyridyl acid was appended at the N-terminus, but were inferior when chiral pyridyl amine was appended at the C-terminus. Unexpectedly, N-oxidation on the pyridine ring at the C-terminus does not notably enhance the chiral induction efficiency in spite of the presence of three-center hydrogen bonds.

Full text of DOI:10.1021/acs.orglett.7b00510

Letter
pubs.acs.org/OrgLett
Controlling Helix Sense at N- and C‑Termini in Quinoline Oligoamide
Foldamers by β‑Pinene-Derived Pyridyl Moieties
Lu Zheng,† Yulin Zhan,† Chengyuan Yu,† Fu Huang,†,‡ Ying Wang,† and Hua Jiang*,†
†Key Laboratory of Radiopharmaceuticals and Key Laboratory of Theoretical and Computational Photochemistry, College of
Chemistry, Beijing Normal University, Beijing 100875, P. R. China
‡Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: A series of quinoline oligoamide foldamers bearing a β-pinene-derived pyridyl group at the N-terminus or the C-
terminus were synthesized, and the efficiencies of chiral inductions have been evaluated by 1H NMR and CD spectra. The chiral
inductions were quantitative when chiral pyridyl acid was appended at the N-terminus, but were inferior when chiral pyridyl
amine was appended at the C-terminus. Unexpectedly, N-oxidation on the pyridine ring at the C-terminus does not notably
enhance the chiral induction efficiency in spite of the presence of three-center hydrogen bonds.
Scheme 1. Structures of Quinoline Oligoamides with Chiral
Inducing Groups at Termini
he one-handed helicity of biomacromolecules, such as
Tproteins and DNA, originating from their chiral monomers,
plays a fundamental role in many biological processes such as
DNA replication, asymmetric catalysis, and chiral transmissions
of biological information. A variety of artificial oligomers termed
as foldamers have been developed for understanding such chiral
conformation in nature over the past two decades.1 A foldamer
consisting of achiral monomers, displaying an interconversion
between the right- and left-handed helicity, is achiral. The
strategies to bias one-handed preference including chiral
inductions,2−9 external stimuli,3b,10−13 and cross-linking14 have
been receiving ever-increasing attention due to potentially
practical uses in chiral sensing, chiral optical devices, and
asymmetric catalysis.15−17 Although a few examples have been
reported on absolute control of one-handed helicity in aromatic
foldamers, absolute control of helix sense at the N- and C-termini
of aromatic peptides still presents a significant challenge.9
We envisioned that absolute control of helix sense could be
achieved when chiral information was efficiently transferred with
high-fidelity from chiral group to achiral foldamer backbone.
Such chiral transfer can be realized by the combination of
hydrogen bonds and steric interaction between chiral group and
foldamer. For this end, oligoamides of 8-amino-2-quinolinecar-
boxylic acid, capable of folding into a helical conformation driven
by a three-center hydrogen bond (Scheme 1), were chosen as
model foldamers for investigating chiral induction because of its
robust folded conformation and efficient synthetic procedures.18
As for chiral induction moieties, we chose chiral β-pinene-
derived pyridyl acid and amine because these chiral groups not
only possess a large steric moiety inherited from the isoprenoid
of β-pinene but also provide a pyridyl moiety able to form
hydrogen bonds with the amide hydrogen (Scheme 1). These
Received: February 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00510
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1HNMR spectra of (+)-NQ8 showed only a single set of signals
in polar solvents (Figure S1), such as DMSO-d6 and pyridine-d5,
indicating that neither chiral induction nor helical stability is
affected by the polarity of solvents.
features will be in favor of chirality transfer from chiral group to
foldamer. We expected that when chiral acid was attached at the
N-termini of quinoline oligoamide foldamers, the amide
hydrogen forms stable three-center hydrogen bonds between
the adjacent quinoline and the chiral moiety (Scheme 1b), which
restrict the rotation of the chiral pyridyl group, leading to a strong
chiral induction. While chiral amine was attached at the C-
terminus of quinoline oligoamide foldamers, there is a two-center
hydrogen bond between the chiral group and the adjacent
quinoline so that a weak chiral induction is anticipated.
Importantly, pyridine N-oxidation19 will provide an extra
hydrogen bond acceptor so as to generate three-center hydrogen
bonds (Scheme 1c), which should also produce a strong chiral
induction.
1
In the case of (+)-NQ4, although H NMR spectrum also
displays only one set of signals (Figure 1a), a complete helical
sense bias is unable to be claimed at this moment because
tetramer shows fast helix handedness inversion on the NMR time
scale in CDCl3 at 25 °C.18a,22 To further clarify the chiral
induction efficiency of chiral pyridyl group in (+)-NQ4, variable-
temperature (VT) NMR experiments were carried out from −80
to 100 °C and revealed only one set of signals detectable in the
whole range of temperatures (Figures S2 and S3), hinting at an
absolute helical sense bias for (+)-NQ4. The VT NMR
experiments further strengthen the argument for diastereomeric
purity of (+)-NQ4 and also imply that the single set of NMR
originates from either M or P diastereomeric (+)-NQ4.
Next, we decided to destroy the three-center hydrogen bond
network by protonation of the pyridine in the chiral group to see
whether the chiral induction could be weakened. The
protonation indeed led to the observation of two sets of new
signals assignable to two diastereomers, as demonstrated by
NMR for (+)-NQ4 and (+)-NQ6 (Figures S4 and S5), implying
an incomplete chiral induction. The two sets of new signals could
be reversely converted to the single set of signals by the
sequential neutralization. Given that the parent foldamer could
not be protonated as shown in the control experiments (Figure
S6), we therefore believe that the protonation takes place in the
chiral group and simultaneously breaks down the hydrogen bond
network, which consequently causes the loss of chiral induction
of helix sense.
1
Here we demonstrate our proof-of-concept design. Our H
NMR and circular dichroism (CD) investigations showed that β-
pinene-derived pyridyl carboxylic acid is able to completely bias
the helical sense of quinoline oligoamide foldamers at the N-
terminus, but β-pinene-derived pyridyl amine is a much inferior
chiral induction group at the C-terminus. Surprisedly, N-
oxidation on the pyridine ring at the C-terminus did not
significantly enhance the chiral induction efficiency.
Chiral β-pinene-derived pyridyl carboxylic acid (+)-5 and
amine (+)-7 have been easily synthesized from its precursor β-
pinene-derived pyridone.20,21 The coupling reaction of (+)-5 and
amino-quinoline dimer via acid chlorides gave dimer (+)-NQ2,
which was saponified and further coupled with the appropriate
quinoline oligomeric amines to generate (+)-NQ4, (+)-NQ5,
(+)-NQ6, and (+)-NQ8 (named for the N-terminus) (Scheme
1). (+)-CQ4, (+)-CQ5, (+)-CQ6, and (+)-CQ8 (named for the
C-terminus) have been synthesized by the coupling of chiral
amine (+)-7 with amino-quinoline oligomers. The structures of
these new compounds were confirmed by 1H NMR, 13C NMR,
and MS spectra (Supporting Information).
The CD spectra of foldamers (+)-NQ4−(+)-NQ8 in DCM
(Figure 2) show strong positive Cotton effects in the absorption
The populations of two diastereomeric M and P helices can be
assessed by a 1H NMR spectrum if a foldamer is long enough to
undergo slow interconversion on the NMR time scale. As shown
in Figure 1, 1H NMR spectra display only one set of signals for
Figure 2. CD spectra of compounds (+)-NQ4 (dark cyan), (+)-NQ5
(blue), (+)-NQ6 (red), and (+)-NQ8 (black) in DCM.
region of the quinoline chromophores (350−420 nm), indicating
a P handedness2 induced by (+)-pinene-derived pyridyl group at
N-terminus. The linear fitting of the Δε of (+)-NQ4−(+)-NQ8
at 383 nm (Figure S12) illustrated that the intensity of the
Cotton effect increased linearly with the growth of the chain
length and that each compound had the same intensity (Δε) per
monomer, strongly suggesting that there is no loss of chiral
induction of helix sense by (+)-pinene-derived pyridyl group at
the N-terminus as the chain of foldamer is lengthened. This
finding is consistent with the case in which the quantitative
helical sense biases were induced by chiral camphanyl group.9a
Finally, the CD signals of (+)-NQ4 and (+)-NQ6 disappeared
upon the protonation and almost recovered to the original state
upon the sequential neutralization (Figure S13). Again, these CD
1
Figure 1. Parts of the 400 MHz H NMR spectra of compounds: (a)
(+)-NQ4; (b) (+)-NQ5; (c) (+)-NQ6; (d) (+)-NQ8 in CDCl3 at 25
°C.
(+)-NQ5, (+)-NQ6, and (+)-NQ8, assignable to either P or M
diastereomers for (+)-NQ5, (+)-NQ6, and (+)-NQ8 because
previous studies showed that pentamer of quinoline oligoamide
foldamer is long enough to undergo slow helix handedness
inversion on the NMR time scale in CDCl3 at 25 °C.9a Therefore,
it is clear that the inductions of the helical sense are absolute in
this solution for these long oligoamides. Additionally, the
B
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Letter
results further support that the protonation damages the fidelity
of the chirality transfer from the chiral group to the achiral
foldamer, and the single set of NMR signals originates from
either diastereomeric pure P or M helix rather than a mixture of
M and P diastereomers with a fortuitous coincidence of all
resonances.
We next examined the chiral induction efficiency of pinene-
derived pyridyl amine at the C-terminus of aromatic peptides.
1
The H NMR spectra of (+)-CQ5, (+)-CQ6, and (+)-CQ8
showed two sets of signals on the NMR time scale in CDCl3 at 25
°C (Figure S7), revealing the existence of two diastereomers in
CDCl3. The de values of (+)-CQ5−(+)-CQ8 were ca. 73% on
the basis of NMR measurements. However, the 1H NMR spectra
showed only single set of signals for (+)-CQ4 at 25 °C in CDCl3.
Given the incomplete chiral inductions in the cases of (+)-CQ5−
(+)-CQ8, this phenomenon is attributed to the fast inversion of
two diastereomers in the solution rather than the existence of
single diastereomer, which was further confirmed by VT NMR
experiments in which the single set of signals of (+)-CQ4
decoalesced into two slowly exchanging constituent peaks when
the temperature was cooled to 0 °C (Figure S8). The de value was
calculated to be about 70%, which remained constant even the
temperature decreased further.
The CD spectra demonstrated that (+)-CQ4−(+)-CQ8 also
prefer a P helical conformation (Figure S14), showing that
pinene-derived pyridyl amine (+)-7 attached at the C-terminus is
also able to induce a P helix but with a smaller amplitude of Δε
values in comparison with pinene-derived pyridyl acid (+)-5
attached at the N-terminus under the same conditions. This can
lead the conclusion that chiral induction at the N-terminus is
more efficient than that at the C-terminus due to the more stable
hydrogen bond network at the N-terminus. This observation is
consistent with the previous study of oligomers of α-amino-
isobutyric acid (Aib), which adopt 310 helix.4b
Figure 3. Parts of the 400 MHz 1H NMR spectra of (a) (+)-CQ8; (b)
(+)-CQ8 in the presence of 8 equiv of m-CPBA in 12 h; (c) (+)-CQ8-P
in the presence of 8 equiv of m-CPBA in 1 day; and (d) (+)-CQ8-P in
CDCl3 at 25 °C.
oxidation on diastereomeric pure (+)-CQ8-P (P helix) under the
same condition. NMR monitoring display that the oxidation of
(+)-CQ8-P was also completed in less than 30 min and the
oxidized product (+)-CQ8−P-O appeared simultaneously.
However, another set of minor signals set to appear over 25
min (Figures 3 and S11), implying that the major P helix of
(+)-CQ8-O is able to partially convert into M helix of (+)-CQ8-
O. Thus, it is not surprised that the final products are almost the
same in the both cases due to interconversion as demonstrated
by NMR and CD spectra (Figures 3 and S16). The de values of
(+)-CQ8 and (+)-CQ8-O were determined to 73% and 80% on
the basis of CD measurements, respectively (Table S1),
indicating that although the oxidation generates an extra
hydrogen acceptor for forming three-center hydrogen bonds, it
poses a slight effect on chiral induction. The chiral induction at
the C-terminus is weaker than that at the N-terminus and may be
attributed to the different stability of three-center hydrogen
bonds at the both termini. Finally, the half-lives of helices for
approach to equilibrium were found to be 223 and 172 min for
(+)-CQ8 and (+)-CQ8-O, respectively (Figures S18 and S19;
Table S2 and S3).
In summary, we have demonstrated controlling helical sense of
quinoline oligoamide foldamers at the N- and C-termini by β-
pinene-derived pyridyl moieties. The present studies reveal that
the chiral inductions were absolute at the N-terminus but
incomplete at the C-terminus, which suggests that chiral
induction is great if a chiral input is applied at the N-terminus
rather than at the C-terminus. Our investigations highlight a
great challenge to obtain absolute helical sense at the C-terminus,
which is an ongoing project in our group.
The previous investigations show that the half-life of helix
inversion of chiral octamer of quinoline oligoamide is long
enough to allow separation of two diastereomers by chromatog-
raphy.2 As expected, the pair of diastereomers of (+)-CQ8
appeared as two distinct spots on TLC at room temperature,
allowing a successful separation of the two diastereomers by
1
regular silica gel chromatography. H NMR spectra of the
diastereomers were recorded just after separation and revealed
that the major diastereomer was pure, but the minor one was not
(Figure S9). An attempt to further purify the minor diastereomer
failed. The major diastereomers progressively convert to the
minor ones, and equilibrium is reached after 1 day at room
temperature (Figure S15). The handedness of the major
diastereomer of (+)-CQ8 is assigned as P helicity according to
CD experiments.2
N-Oxidation was chosen to generate an extra hydrogen bond
acceptor because it should not notably affect the helical structure
of quinoline-derived oligoamides.19 The oxidation of (+)-CQ8
was tested first in the presence of 8 equiv of m-CPBA. NMR
experiments revealed that the oxidation was over in less than 30
min by monitoring the peak of amide hydrogen at 9.17 ppm close
to chiral group and that original two sets of signals disappeared
gradually with simultaneous appearance of two sets of new
signals in low field rather than one set of signals as expected
(Figures 3 and S10), hinting that the chiral induction is not
absolute either. Mass spectrometry show N-oxidation only
occurred on the chiral pyridyl ring (Figure S20) because no
oxidation on quinoline rings was detected in the control
experiments (data not shown). However, we also tested the
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00510.
Experimental procedures, characterization of synthesized
oligomers, and additional data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiangh@bnu.edu.cn.
ORCID
Ying Wang: 0000-0002-7015-7228
Hua Jiang: 0000-0002-9917-2683
C
DOI: 10.1021/acs.orglett.7b00510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) (a) Li, C.; Wang, G.; Yi, H.; Jiang, X.; Li, Z.; Wang, R. Org. Lett.
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Notes
The authors declare no competing financial interest.
(16) (a) Masu, H.; Sakai, M.; Kishikawa, K.; Yamamoto, M.;
Yamaguchi, K.; Kohmoto, S. J. Org. Chem. 2005, 70, 1423. (b) Nagata,
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ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21472015, 21511130061, and 21332008).
̀
(17) (a) Byrne, L.; Sola, J.; Boddaert, T.; Marcelli, T.; Adams, R. W.;
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