Sequential Chiral Induction and Regulator-Assisted Chiral Memory of Pillar[5]arenes

Article abstract of DOI:10.1002/anie.202010050

Chirality transfer is widely observed in life processes, and many artificial chiral transfer systems have been developed. In these systems, chiral information is transferred from chiral inducers to chiral acceptors by a direct chiral induction process and a direct chiral memorization process. We have developed ternary nondirect chiral transfer systems based on pillar[5]arenes, in which a third factor was introduced as a regulator. The planar chirality of an acceptor was induced and memorized by a chiral inducer with precise control by a regulator. In the chiral induction period, the feed sequence of the chiral inducer and regulator affected the chiral induction behavior of the chiral acceptor. The chiral memory ability of the acceptor was substantially improved by the combined action of the chiral inducer and regulator.

Full text of DOI:10.1002/anie.202010050

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Accepted Article
Title: Sequential Chiral Induction and Regulator-assisted Chiral
Memory of Pillar[5]arenes
Authors: Shixin Fa, Kouichi Egami, Keisuke Adachi, Kenichi Kato, and
Tomoki Ogoshi
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Sequential Chiral Induction and Regulator-assisted Chiral
Memory of Pillar[5]arenes
Shixin Fa,[a] Kouichi Egami,[a] Keisuke Adachi,[a] Kenichi Kato,[a] and Tomoki Ogoshi*[a],[b]
[a]
Dr. S. Fa, Mr. K. Egami, Mr. K. Adachi, Dr. K. Kato, Prof. T. Ogoshi
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering
Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
E-mail: ogoshi@sbchem.kyoto-u.ac.jp
[b]
Prof. T. Ogoshi
WPI Nano Life Science Institute (WPI-NanoLSI)
Kanazawa University
Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Chirality transfer is widely observed in life processes, and
many artificial chiral transfer systems have been developed. In these
systems, chiral information is transferred from chiral inducers to
chiral acceptors by a direct chiral induction process and a direct
chiral memorization process. Herein we developed ternary nondirect
chiral transfer systems based on pillar[5]arenes, in which a third
factor was introduced as a regulator. The planar chirality of an
acceptor was induced and memorized by a chiral inducer with
precise control by a =regulator. In the chiral induction period, the
feed sequence of the chiral inducer and regulator affected the chiral
induction behavior of the chiral acceptor. The chiral memory ability of
the acceptor was substantially improved by the combined action of
the chiral inducer and regulator.
and one-dimensional aggregates[9] via multi-component
strategies have been investigated. However, the planar chiral
transfer of macrocyclic molecules using a multi-component
strategy has not been reported.
Pillar[n]arenes are cylindrical macrocyclic host molecules with
rims that are easy to functionalize.[14] Pillar[n]arenes possess
two planar chiral isomers (i.e., pR and pS), which interconvert
between each other via oxygen-through-the-annulus-rotation
(Figure 1a).[14,15] This rotation of pillar[n]arenes can be
suppressed by guest complexation[16] or modification of the rim
substituent groups.[17] In the current study, we used rim-
differentiated pillar[5]arene 1[18] as a chiral acceptor, and its
chirality is induced by chiral amine 2 as a chiral inducer (Figure
1b) in direct chiral transfer. However, this system possesses
poor chiral memory ability (Figure 1c). Therefore, we introduce
linear guest molecule 3 as a regulator (Figure 1b) to provide a
ternary system that displays nondirect chiral transfer (Figure 1d).
In the chiral induction period of the ternary system, the feed
sequence of 2 and 3 to the solution of 1 strongly affects the
chiral induction efficiency. This sequential effect has not been
observed in binary chiral transfer systems. Moreover, the chiral
memory ability of 1 is markedly improved by the combined
action of 2 and 3.
First, direct chiral transfer without a regulator was conducted in
solvents to induce chirality of 1a by addition of chiral amines
(Figure S1). Chloroform and 1-cyclohexylethyl amine 2 were the
best solvent and chiral amine, respectively, because of their
suitable sizes. The planar chirality of 1a was induced by forming
supramolecular diastereomers with R-2 and S-2 as was
evidenced by the Cotton effect observed in the circular
dichroism (CD) spectrum of the mixture of 1a and 2 (Figures
2a).[17b,19] The diastereomeric excess (de) was ca. 11% (Figure
S3). By adding mixtures of R-2 and S-2 with various ratios and
keeping the total amount of amine constant, the induced CD
intensity of 1a showed an approximately linear relationship with
the enantiomeric excess (ee) of 2 (Figure S4). The real-time CD
signal of 1a with R-2 decreased and then inverted upon addition
of S-2 (Figures 2b and S5). By replacing the R-2 interacting with
1a with 100 equiv. of achiral isoamylamine, the positive CD
signal of 1a decayed very fast. The half life period was only 40
min (Figure S6). These results suggest that 1a possesses high
chiral induction ability and no chiral memory ability in the direct
chiral transfer system, which was caused by the oxygen-
Chirality transfer is widely observed in life processes,[1] and has
been successfully used to develop chiroptical sensors[2] and
asymmetric syntheses.[3] Chirality transfer involves the induction
and memorization of chirality in acceptors through noncovalent
interactions with chiral inducers.[4] Systems capable of chiral
memory have been developed, including discrete small
molecules,[4a,5]
mechanically
interlocked
molecular
architectures,[6] polymers,[4b,7] self-assembled helical one-
dimensional stacks,[8] nanotubes,[9] cages,[10] molecular
imprinting materials,[11] and gels.[12] Most of the reported systems
are binary, with the chirality of acceptors being directly induced
by chiral inducers and the induced chiral information being
directly memorized upon removal of the chiral inducers (i.e.,
direct chiral transfer). Kinetic stabilization of acceptors by steric
hindrance
or
through
interactions
such
as
metal
coordination[1d,8a,b,13] is needed to achieve chiral memory in these
systems.
Nature frequently regulates life processes and expresses
variable functions in one simple system through the synergistic
interactions of multiple components. For instance, only the
regions of a DNA molecule influenced by gene-regulatory
proteins are transcribed and expressed in cells. As a result,
specific proteins are synthesized under the guidance of gene-
regulatory proteins. Inspired by this natural behavior, subtly
regulating the chiral induction and memory processes within a
single system via the synergistic interactions of multiple
components (i.e., nondirect chiral transfer) is an interesting
target for chiral transfer systems.[5a,8d,9] For example, memory of
axial chirality of a porphyrin dimer[5a] and helicity of polymers[8d]
1
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through-the-annulus rotation enabled by the low steric bulk of
the n-butyl rim substituents (Figure 1c).
Figure 1. (a) Planar chirality of pillar[5]arene 1. (b) Chiral inducer and regulator. Rational design of (c) direct and (d) nondirect chiral transfer systems.
In this ternary system, the feed sequence of R-2 and 3 to the
solution of 1a was found to strongly influence the chiral induction
efficiency (Figure 1d). We initially considered Path A, which
involved induction first. The planar chirality of 1a was
successfully induced with 5 equiv. of R-2. Further addition of 850
equiv. of 3 increased both the ultraviolet–visible (UV-vis)
absorption and CD intensities of 1a (Figures 3a and S8). The de
value increased to 13% (Figure S7) . In Path B, complexation
was conducted first. In this case, after addition of 3 to form
complex with 1a, further addition of R-2 failed to induce the
planar chirality of 1a at 20 oC (red curve in Figure 3b). It is
possible that the initial addition of 3 inhibited the free rotation of
1a because of guest inclusion. Consequently, the planar chiral
Figure 2. (a) CD and UV-vis spectra of 1a (0.1 mM) upon addition of R-2 and
induction by addition of R-2 was prevented at room temperature.
Heating this second sample at 50 C for 10 min resulted in an
intense CD signal at 308 nm (blue line in Figure 3b). We believe
S-2 at 20 oC. The inset of (a) shows Δε at 308 nm recorded with different
o
equivalents of chiral amine 2. (b) Real-time CD changes of a mixture of 1a (0.1
mM) and R-2 (5 equiv.) upon addition of S-2 (0–10 equiv.).
that heating caused guest molecule 3 to dissociate from the
cavity of 1a and then the 2 present induced the selective rotation
of 1a (mechanistic details are shown in Figures S9-S10). The
induction of the CD signal became slower as the temperature
was decreased (Figure S11). Fitting the Eyring plots at various
temperatures revealed that the Gibbs free energy of activation
Guest complexation is an effective method to suppress the
rotation of pillar[n]arenes.[16] Guest complexation may slow the
racemization between the two isomers of 1a, which would
improve its chiral memory ability. Thus, 1,4-dibromobutane 3, an
o
(Δ‡G at 25 C) of chiral induction of 1a in the presence of 850
ideal guest for the cavity of pillar[5]arenes (with the association
equiv. of 3 was 95.4 kJ mol−1 (Figure S12).[21] After heating, the
constant K > 103 M−1),[14c,18b,20] was introduced as a third factor.
2
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sequential effect of 2 and 3 was erased; both solutions showed
almost the same CD intensity (Figures 3a and 3b).
To evaluate the real chiral memory ability of 1a, 100 equiv. of
achiral isoamylamine was used to completely replace R-2
interacting with 1a (Figure S23). The half life period of 1a with
4250 equiv. of 3 reached 5 days, whereas it was only 40 min for
the binary system (Figure 4b).
Because of its longer alkyl chains on one rim than is the case for
1a, the rotation barrier of 1b (Figure 1a) was higher than that of
1a and its free rotation was slower (see Figures S13–S19 for
details of chiral induction of 1b).[17a] For instance, the de value of
1b with 4250 equiv. of 3 increased to 31% (Figure S16). This
resulted in 1b possessing better chiral memory ability than that
of 1a (see Figures S22, S24 and S25 for details of chiral
memory of 1b). The half life period of 1b with 4250 equiv. of 3
reached 23 days when R-2 was completely replaced by
isoamylamine. Overall, the chiral memory ability of both 1a and
1b was markedly improved by the combined action of the 2 and
3 (Table S1).
Figure 3. CD and UV-vis spectra of 1a (0.1 mM) upon addition of R-2 and 3 by
(a) path A and (b) path B at 20 oC.
Different from binary chiral transfer systems, the input of the
additional factor (i.e., 3) was essential to help regulate the chiral
memory ability of 1 in ternary chiral transfer systems. Other
guest molecules of pillar[5]arenes also regulated the chiral
induction and chiral memory abilities of 1, providing a convenient
method to increase the diversity of these systems (Figure
S26).[14c]
The chiral memory ability of the ternary system of 1a + R-2 (5
equiv.) + 3 (850 equiv.) was investigated initially by chiral
inversion experiments via the real-time CD changes upon
addition of S-2. Negligible decrease was observed of the signal
intensity after the addition of 10 equiv. of S-2 (Figure S20). This
result suggested that the induced planar chirality of 1a was
successfully memorized. Fitting the time-dependent CD decay in
Figure 4a (light blue line) revealed that its half life period was 6.8
h.[10d,22] In contrast, the half life period upon adding the same
amount of S-2 to the binary system was too short to be
determined (Figure 2b and dashed line in Figure 4a), illustrating
that the chiral memory ability of 1a was improved in the ternary
system compared with that in the binary system. One advantage
of the ternary chiral transfer system is that the chiral memory
ability could be easily regulated by varying the charge of the
chiral regulator. By increasing the amount of 3 to 4250 equiv.,
the half life period increased to 20.4 h upon adding 10 equiv. of
S-2 (dark blue line in Figure 4a and details in Figure S21).
Figure 5. Temperature dependence of (a) planar chiral induction and (b)
inversion of 1a (0.1 mM) with 3 (850 equiv.) caused by addition of 2 and
alternating heating at 40 oC and cooling at 20 oC.
Based on the kinetic trapping properties of the nondirect ternary
chiral transfer system of 1a, the temperature-dependent planar
chirality induction and inversion of 1a were subtly demonstrated
(Figure 5). At 20 °C, 1a with 850 equiv. of 3 showed negligible
CD signal after addition of 5 equiv. of R-2 or S-2 because of the
kinetic trapping at this temperature. Upon heating the solution to
Figure 4. CD changes of 1a (0.1 mM) with R-2 (5 equiv.) and various
concentrations of 3 recorded at 308 nm after addition of (a) S-2 (10 equiv.)
and (b) isoamylamine (100 equiv.).
o
40 C, the rotation barrier was crossed and the planar chirality
induction occurred. Positive and negative CD signals at 308 nm
were observed in the presence of R-2 and S-2, respectively
o
(Figure 5a). However, cooling the solution to 20 C fixed the CD
3
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level. In another demonstration, after inducing the planar
chirality of 1a by adding 1.5 equiv. of R-2 in the presence of 3,
8.5 equiv. of S-2 was added to the system (Figure 5b). The initial
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of 1a inverted to negative because of the excess amount of S-2.
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stage by alternately heating and cooling the sample.
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In conclusion, based on rim-differentiated pillar[5]arene 1, chiral
amine 2, and guest molecule 3, we developed well-controlled
planar chiral induction and memory systems. In these systems,
2 induced planar chirality, while 3 worked as a regulator to
control the memorization of planar chirality. The two-component
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Acknowledgements
This work was supported by JSPS KAKENHI JP18H04510 and
JP19H00909, JST CREST (JPMJCR18R3), and the World
Premier International Research Center Initiative (WPI), MEXT,
Japan.
[19] The electrostatic interaction was confirmed by 1H NMR, see Figure S2 in
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Keywords: chirality • host-guest systems • macrocycles •
noncovalent interactions • pillar[n]arenes
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Entry for the Table of Contents
The planar chirality of an acceptor was induced and memorized by a chiral inducer with precise control by a regulator.
5
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