Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral oxazolylaniline moieties

Article abstract of DOI:10.1016/j.cclet.2019.07.061

Absolute one-handed chiral quinoline tetramers andoctamers containing different oxazolylanilines at the C-terminus have been synthesized. The absolute one-handed sense and diastereomeric excess values were valued by ¹H NMR. X-ray crystal diffra

Full text of DOI:10.1016/j.cclet.2019.07.061

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Absolute control of helicity at the C-termini in quinoline oligoamide
foldamers by chiral oxazolylaniline moieties
*
Dan Zheng, Chengyuan Yu, Lu Zheng, Yulin Zhan, Hua Jiang
Department of Chemistry, Beijing Normal University, Beijing 100875, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Available online xxx
Absolute one-handed chiral quinoline tetramers andoctamers containing different oxazolylanilines at
the C-terminus have been synthesized. The absolute one-handed sense and diastereomeric excess values
were valued by 1NMR. X-ray crystal diffractionand CD studies reveal that the S-oxazolylaniline always
induces a P-handed helicity and the absolute helicity is driven by the stable three-center hydrogen
bonding between protons in the amide and N atoms in oxazolylaniline and adjacent quinoline ring. CPL
investigations demonstrated that S-CQn-aꢀd are CPL active and its glum values are dependent on its
length. Interestingly, the sizes of the substituents in the chiral centers are different, however, they exert
no effect on the dissymmetric factors gabs and glum of quinoline oligoamide foldamers.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Chiral induction
Helical chirality
Aromatic foldamer
Circularly polarized luminescence
Three-center hydrogen bonding
Helical chirality is unique for the non-existence of stereogenic
centers and has drawn great interests of scientists to build artificial
chiral helix since Pauling first proposed α-helix [1], and Watson
and Crick discovered the double helical structure for DNA [2] in the
early 1950s. To mimic the helical structure of DNA, a number of
artificial folded molecules termed as foldamers have been reported
in the past few decades [3]. Aromatic foldamers bearing helical
conformation driven by non-covalent forces are one of intensively
studied foldamers, which exhibit an equilibrium between the left
(M)- and right (P)- handed enantiomers. Breaking of such
equilibrium by attaching chiral moieties to aromatic foldamers
generates chiral foldamers with a preferred one-handedness [4],
leading to many potential applications in chiral recognition [5],
chiral electrooptical devices and asymmetric catalysis. Although
the inductions of helicity in foldamers can be readily achieved by
appending chiral motifs at the end of foldamers, inserting chiral
unit into the middle of folded sequences, or binding chiral guests in
helical cavities, the elegant examples on quantitative chiral
inductions have been reported in only a few cases [6]. To some
extent, lack of absolute control of helical handedness in chiral
foldamers would greatly limit their applications in dissymmetric
catalysis [7], photocatalysts [8], storage devices [9], and circularly
polarized luminescence (CPL) laser [10].
β-pinene-derived pyridyl moiety at the N-terminus [6c], or locking
the dynamic interconversion between the M- and P-conformers
[11]. Very recently, we have reported the quantitative induction of
one-handed helicity in QOFs by introducing chiral oxazolylanilines
at the C-terminus [12]. These QOFs with absolute one-handedness
exhibited strong CPL signals and high luminescence dissymmetric
factors glum, which display the significant dependence on the
length of QOFs. To further understand the quantitative induction of
one-handed helicity caused by oxazolyanilines, we designed and
synthesized tetrameric and octameric QOFs containing different
residues in oxazolylanilines and explored the effect of the sizes of
the residues on the chiral induction in these QOFs.
Previously, Ivan and co-workers found that the steric effect of
chiral group at the C-terminus of QOFs plays a dominant role in
amplifying the chirality in the case of incomplete chiral inductions,
where the bulkiest group in the chiral center tends to point away
from the helix while the smallest one prefers to point to the helix
[4b]. To explore if the steric effect in the chiral centers would also
influence the chiral induction of QOFs in the case of absolute chiral
inductions, chiral oxazolylanilines with the different residues
ranging from methyl to benzyl substitutes (Fig. 1) were designed.
We expected there is a very stable intramolecular hydrogen bond
network between QOFs and chiral induced group that would
efficiently prevent the rotation of chiral induced groups
and significantly eliminate the effect of the residues in the chiral
induced groups on the chiral inductions. The synthetic routes of
the tetrameric or octameric QOFs containing various chiral
oxazolylaniline motifs were outlined in Scheme 1. First of all,
chiral oxazolylanilines were prepared by treating 2-amino
We have previously achieved the absolute control of helical
sense in quinoline oligoamide foldamers (QOFs) by appending
* Corresponding author.
E-mail address: jiangh@bnu.edu.cn (H. Jiang).
https://doi.org/10.1016/j.cclet.2019.07.061
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: D. Zheng, et al., Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral
oxazolylaniline moieties, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.061

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D. Zheng et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
containing aromatic substituents in S-Q4-b and S-Q4-d, whose
protons appear at 13.03 ppm. The nuanced differences in the
chemical shifts are presumablyattributed to the shielding effect of
aromatic rings in the chiral centers. Additionally, considering that
there maybe the possibility that the proton signals coalesce due to
a fast interconversion between SÀÀP and SÀÀM diastereoisomeric
QOF tetramers at 298 K on the NMR time scale [14], variable low
temperature 1H NMR experiments were carried out. As we
expected, the spectra of all tetramers exhibited single set of peaks
and no split signals was observed even at 183 K (Figs. S5 and S6 in
Supporting inforamtion). The observations support the facts that
chiral inductions of S-Q4-aꢀd are quantitative and the diastereo-
meric excess (de) in each case is ꢁ 99%. As for S-Q8-aꢀd, the
chemical shifts exhibit similar features to those of S-Q4-aꢀd, but
appear in the higher field because of stronger shielding effect of
aromatic rings in octamers. We believe that the absolute
controlling of helicity can be accounted for by the stable hydrogen
bonding network forming between the oxazolylanino group and
quinoline amide.
Fig.1. Parts of the 1H NMR spectra of (a) S-Q4-a, (b) S-Q4-b, (c) S-Q4-c, (d) S-Q4-d, (e)
S-Q8-a, (f) S-Q8-b, (g) S-Q8-c and (h) S-Q8-d in CDCl3 at 298 K.
To further conform the presence of the three-center hydrogen
bonding network mentioned above, the racemates (Æ)S/R-Q4-a
and (Æ)S/R-Q4-b were designed and synthesized. Their crystals
were grown by diffusing hexane into a chloroform concentrated
solution. Both crystal structures of (Æ)S/R-Q4-a and (Æ)S/R-Q4-b
display the formation of a three-center hydrogen bonding network
between the amide hydrogen and N atoms in both oxazolylaniline
and adjacent quinoline ring (Fig. 2), which renders oxazolylanilino
group to adopt a parallel conformation to the adjacent quinoline
rings in the helix. This parallel conformation leads to that the
methyl or phenyl group in chiral center is almost perpendicular to
the helix and points away from the helix to minimize the steric
barrier, while the proton points to the helix. The space groups of
(Æ)S/R-Q4-a and (Æ)S/R-Q4-b are P-1 and P21/n, respectively. More
importantly, XRD data also reveal that one pair of enantiomers co-
crystallize as true racemates in which the S-chiral center always
induces the P helicity, while the R-chiral center always induces the
M helicity (Fig. 2), consistent with our previous reports [4b].
As shown in Fig. 3, the CD spectra of S-Q4-aꢀd featured almost
identical and exhibited positive intense cotton effect at
250–450 nm region originated from quinoline chromophores,
indicating a preferred P-handedness. S-Q4-aꢀd displayed peaks at
Scheme 1. Synthetic route for S-Qn-aꢀd and S-CQn-aꢀd. Reaction conditions:
i. 2-aminobenzonitrile (1.0 equiv.), S-amino alcohols (1.5 equiv.), anhydrous ZnCl2
powder (2.5 equiv.), chlorobenzene, reflux, 36 h; ii. (a) NaOH (2.5 equiv.), THF/
MeOH/H2O (v/v/v = 10:2:1), 40 ꢂC; (b) Oxalyl chloride (2.0 equiv.), DCM, room
temperature, 2 h; (c) S-chiral amines (0.9 equiv.), DIPEA (2.0 equiv.), DCM;
iii. (a) Pd/C (0.1 equiv.), HCOONH4, NH4VO3, EA/EtOH/H2O (v/v/v = 4:1:0.5); 95 ꢂC;
(b) Pivaloyl chloride (1.2 equiv.), DIEPA (2.0 equiv.), DCM, room temperature.
386 nm with De around 93 L
Á
molÀ1 cmÀ1. The absorption dissym-
R)/(eL R) [15], were calculated
metric factors gabs, defined as 2(eL
-e
+e
to be around 0.020 (Table S1 in Supporting information). The CD
spectra of S-Q8-aꢀd also exhibited positive cotton effects at
250ꢀ450 nm region similar to that of S-Q4-aꢀd, but with larger CD
intensity. The gabs values of S-Q8-aꢀd were found in the range from
0.028 to 0.034 (Table S1), which are apparently larger than those of
S-Q4-aꢀd. The enhanced gabs values are beneficial from the
increase on the length of the foldamers. The above results clearly
demonstrate that the central chirality of the oxazolylanilino chiral
motifs has been efficiently transferred into the helicity of the QOFs
without depreciation of chiral information, leading to the
quantitative chiral inductions. The absolute controlling of helicity
is attributed to the stable three-center hydrogen bonding network
between the chiral group and foldamer. We also note that the
substituents in the chiral centers have negligible effect on chiral
inductions, which is completely different from the results observed
in the case of incomplete chiral induction [4b].
benzonitrile and enantiomeric 2-aminoalcohols in anhydrous
chlorobenzene with zinc chloride as catalysts under refluxing
condition according to the reported methods [13]. The compounds
S-Qn-aꢀd were obtained by coupling corresponding quinoline
tetrameric or octameric acids with chiral oxazolylanilines with the
yield of over 80% for tetrameric QOFs and over 60% for octameric
QOFs, respectively.
The 1H NMR spectra of tetramers S-Q4-aꢀd feature a single set
of signals in CDCl3 at 298 K and the sharp signals appearing at
11.5ꢀ13.5 ppm are assignable to the carboxamide protons.
Thereinto, the chemical shifts appearing at 13.0ꢀ13.3 ppm can
be assigned to the amide protons close to the oxazolylanilino
groups according to our previous results [12], which are about
1 ppm lower than those located inside the helix, owing to the
stable three-center hydrogen bonding networks and the weaker
On the other hand, materials with the feature of circularly
polarized emission have attracted growing attention due to its
potential applications in chiroptical or electrooptical devices and
information storage [8b,8c,9a]. In order to shed light on chiral
conformational and three-dimensional information of the lumi-
nescent QOFs in the excited state, CPL active S-CQn-aꢀd were
prepared by simple coupling the pivaloyl protected QOFs acids
effects of
p-p aromatic stackings compared with those formed
between quinoline rings. Furthermore, the signals of the amide
protons close to the oxazolylamine groups containing alkyl
substituents in S-Q4-a and S-Q4-c appear at 13.13 and
13.18 ppm, respectively, which are about 0.1 ppm lower than those
Please cite this article in press as: D. Zheng, et al., Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral
oxazolylaniline moieties, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.061

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3
Fig. 2. The crystal structures of (a) the side and top views of racemic (Æ)S/R-Q4-a and its three-center hydrogen bonding networkand (b) the side and top views of racemic (Æ)
S/R-Q4-b and its three-center hydrogen bonding network. In the both cases, R chiral center always induces a M helix and S chiral center always induced a P helix. The
oxazolylanilino groups were labeled in blue in the top views. The isobutyl groups were deleted for clarity.
Fig. 4. (a) CD and CPL spectra of S-CQ4-aꢀd and S-CQ8-aꢀd; (b) UV–vis and FL
spectra of S-CQ4-aꢀd and S-CQ8-aꢀd (1.0 Â 10À5 mol/L, DCM, 298 K).
Fig. 3. (a). CD spectra of S-Q4-aꢀd and S-Q8-aꢀd (1.0 Â 10À5 mol/L, DCM, 298 K);
(b). UV–vis spectra of S-Q4-aꢀd and S-CQ8-aꢀd (1.0 Â 10À5 mol/L, DCM, 298 K).
the modifications at N-terminal exert no effect on the
absorption dissymmetric factors inthe ground state. The emission
with chiral oxazolylanilines with an overall yield of 64ꢀ86%
(Scheme 1). 1H NMR studies reveal that the spectra of S-CQ4-aꢀd
and S-CQ8-aꢀd feature as single set of signals as its non-
luminescent counterparts S-Qn-aꢀd do, indicative of quantitative
chiral induction for S-CQn-aꢀd.
of S-CQ4-aꢀd landed at the blue region, exhibiting its maximal
emission at around 480 nm. The fluorescence quantum yields were
determined to be about 1.61% using a calibrated integrating sphere
(Table 1). The fluorescent properties of S-CQ4-aꢀd allow us to
investigate the chiral induction at the excited state. As shown in
Fig. 4, the CPL spectra display the bands around 400ꢀ600 nm, in
accordance with that of the fluorescent spectra. Moreover, all
S-configured QOFs exhibit positive CPL signals, indicative of aP
helical sense in each case that is consistent with the observations in
the CD experiments. The emission dissymmetry factors glum were
calculated according to the definition of glum = 2(IL-IR)/(IL+IR) [15a],
Before we set off to evaluate chiral properties of S-CQn-aꢀd in the
excited state, the properties in the ground state of S-CQn-aꢀd were
investigated by CD. As shown in Figs. 3 and 4, it is not surprised to
find that S-CQ4-aꢀd display the P helicity with the absorption
dissymmetric factors gabs almost identical to its non-luminescent
counterparts S-Q4-aꢀd (Table 1 and Table S1), hinting that
Please cite this article in press as: D. Zheng, et al., Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral
oxazolylaniline moieties, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.061

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D. Zheng et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Table 1
The summery of the chiroptical characters of compounds S-CQn-aꢀd.
FF (%)a
Compd.
gabs (10À2
)
glum (10À2
)
<t
> (ns)
kr (107 sÀ1
)
knr (108 sÀ1
)
b
glum
kr
knr
gabs
S-CQ4-a
2.0
1.9
2.2
2.0
3.0
3.1
3.3
3.1
1.5
1.5
1.6
1.5
2.5
2.5
2.8
2.7
0.75
0.79
0.73
0.75
0.83
0.81
0.85
0.87
1.63
1.61
1.68
1.65
8.57
8.87
8.77
7.96
0.76
0.70
0.74
0.79
1.13
1.18
1.11
1.14
2.1
2.3
2.3
2.1
7.6
7.5
7.9
7.0
12.9
14.1
13.3
12.5
8.1
7.7
8.2
8.1
61
61
58
60
11
10
10
12
S-CQ4-bc
S-CQ4-c
S-CQ4-d
S-CQ8-a
S-CQ8-bc
S-CQ8-c
S-CQ8-d
a
FF measured using a calibrated integrating sphere, excitation wavelength, lex = 310 nm, lex = 485 nm.
The radiative rate constant kf and non-radiative rate constant knr were obtained from the equations: kf = FF /<
The results are taken from our previous work [12].
b
c
t
> and knr = (1 - FF)/<t>, respectively.
where IL and IR refer to left- and right-handed circularly polarized
Acknowledgments
light, respectively [15a]. The glum values of S-CQ4-aꢀd are about
0.02, which are almost same (Table 1), implying that the
substituents in the chiral centers exert no effect on the glum values.
The steady-state fluorescence spectra of S-CQ8-aꢀd show blue
shift emission with a maximal peak at 455 nm and the fluorescence
quantum yields were determined to be about 8% (Table 1). The CD
and CPL studies reveal similar chiroptical properties to those of its
short analogs S-CQ4-aꢀd. However, their gabs and glum values were
determined to be about 0.031 and 0.027, respectively, which are
apparently larger than the corresponding values for the short
S-CQ4-aꢀd (Table 1) and those for helically chiral molecules
reported to date [16]. The large glum values are probably attributed
to the increase on the lengths of QOFs. Besides, the ratios of
emission and absorption dissymmetric factors glum/gabs range from
0.73 to 0.79 for S-CQ4-aꢀd and from 0.81 to 0.87 for S-CQ8-aꢀd,
respectively, suggesting that the dissymmetry of these chiral QOFs
is mainly kept in the excited state [16c].
We acknowledge the financial supports from the 973 Program
(No. 2015CB856502) and the National Natural Science Foundation
of China (No. 21672026). We also thank Applied Photophysics for
their generous assistance on CPL measurements.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.07.061.
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Please cite this article in press as: D. Zheng, et al., Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral
oxazolylaniline moieties, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.061