Asymmetric Transformation Driven by Confinement and Self-Release in Single-Layered Porous Nanosheets

Article abstract of DOI:10.1002/anie.202010809

Reported here is the use of single-layered, chiral porous sheets with induced pore chirality for repeatable asymmetric transformations and self-separation without the need for chiral catalysts or chiral auxiliaries. The asymmetric induction is driven by chiral fixation of absorbed achiral substrates inside the chiral pores for transformation into enantiopure products with enantioselectivities of greater than 99 % ee. When the conversion is completed, the products are spontaneously separated out of the pores, enabling the porous sheets to perform repeated cycles of converting achiral substrates into chiral products for release without compromising pore performance. Confinement of achiral substrates into two-dimensional chiral porous materials provides access to a highly efficient alternative to current asymmetric synthesis methodologies.

Full text of DOI:10.1002/anie.202010809

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Accepted Article
Title: Asymmetric Transformation Driven by Confinement and Self-
Release in Single-Layered Porous Nanosheet
Authors: Bo Sun, Bowen Shen, Akio Urushima, Xin Liu, Xiaopeng
Feng, Eiji Yashima, and Myongsoo Lee
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Asymmetric Transformation Driven by Confinement and Self-
Release in Single-Layered Porous Nanosheet
[a]
[b]
[c]
[a]
[a]
[c]
Bo Sun, Bowen Shen, Akio Urushima, Xin Liu, Xiaopeng Feng, Eiji Yashima, and Myongsoo
Lee*[b]
[a]
[b]
[c]
Dr. B. Sun, Dr. X. Liu, X. Feng
State Key Laboratory for Supramolecular Strucuture and Materials
College of Chemistry, Jilin University
Changchun 130012, China
E-mail:
Dr. B. Shen, Prof. M. Lee
Department of Chemistry
Fudan University
Shanghai 200438, China
Email: mslee@fudan.edu.cn
A. Urushima, Prof. E. Yashima
Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering
Nagoya University
Nagoya 464-8603, Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: Asymmetric transformation requires the use of chiral
catalysts which is hampered by energy intensive processes such as
high cost, inefficient recycle, and tedious separation. Here we report
the use of single-layered, chiral porous sheets with induced pore
chirality for repeatable asymmetric transformation and self-separation
without the need of chiral catalysts or chiral auxiliaries. The
asymmetric induction is driven by chiral fixation of absorbed achiral
substrates inside the chiral pores to transform into enantiopure
products with enantioselectivity of greater than 99% ee. When the
conversion is completed, the products are spontaneously separated
out of the pores, enabling the porous sheets to perform repeated
cycles of converting achiral substrates to release as chiral products
without compromising pore performance, thereby confining achiral
substrates into 2-D chiral porous materials provides access to a highly
efficient alternative to current asymmetric synthesis methodologies.
substrates to the chiral spaces to induce a fixed spatial orientation
for exposure of their preferential face to a reagent, because all the
pores maintain the structural integrity of individual pores without
pore blocks and pore to pore connections caused by layer
[14-19]
stackings.
Thus, the precise confinement of achiral
substrates inside the chiral cavities of the 2-D pore assembly
would lead to highly efficient asymmetric transformations.
Results and Discussion
Construction of single-layered porous nanosheets with
induced chiral pores. To explore the asymmetric induction in
chemical transformations purely by confining achiral substrates to
a chiral space, we used a single-layered porous sheet assembly
containing only achiral building blocks in which the chiral
environment of the pores is induced by a memory effect using a
chiral template, (S)- or (R)-2,2’-dimethoxy- 1,1’binaphthyl (BD)
(Figure 1a).[ The homochiral porous sheet structures form from
the self-assembly of an achiral macrocycle amphiphile, 1 (Figure
1a and Figures S1, S2), thereby a lack of chiral moieties in its
assembly. The primary pore structure of the sheets consists of a
paired macrocycle dimer with opposing dendritic chains at the
aromatic basal planes. Our earlier study showed that the aromatic
plane of 1 adopts a non-planar conformation which leads the
paired aromatic macrocycles to be rotationally offset from each
other with a certain twist angle.[ In the absence of the chiral
template, a twist stack of the non-planar macrocycle generates a
racemic mixture of P- and M-stacked pores in methanol, resulting
in circular dichroism (CD)-silent, racemic sheet structures (Figure
2a). In contrast, the self-assembly in the presence of a chiral
template generates homochiral porous sheet structures (Figure
2a and Figure S3). When 1 equivalent of (S)-BD as a chiral
template was added to the methanol solution of 1, the solution
exhibited a near maximum CD signal in the absorption range
associated with the aromatic macrocycle of 1 (Figures 2b and 2c
and Figure S4), indicating that the chiral guest drives the stacked
macrocycle dimers to adopt the twisted conformation with a
clockwise rotation because the strong hydrophobic and π-π
interactions between the macrocycle dimer and the chiral guest
lead the chiral information to transfer into the dimeric pore, giving
Introduction
20]
Asymmetric induction in chemical transformations has enormous
impact on the advancement of nanotechnology and drug
discovery.[
1,2]
However, the use of chiral catalysts suffers from
energy intensive processes such as high cost, difficult recovery,
and laborious separations. Although the confinement in chiral
spaces can render reactions enantioselective without the help of
chiral catalysts, it is hampered by a lack of generality and
insufficient enantiomeric purity.[
3-6]
The self-assembly of pore
19]
units into an extended nanostructure can offer a necessary
condition for chiral transformations under confinement.[
Nevertheless, most of the porous nanostructures are far from the
7-11]
internal cavities with chiral environments required to guide precise
asymmetric fixation for clean chiral transformation.[
12-14]
Here we
report that chiral porous nanosheets are able to perform clean
asymmetric transformation (>99% ee) of absorbed achiral
substrates without the use of chiral catalysts or chiral auxiliaries.
When the conversion is completed, the products are
spontaneously separated out of the nanosheets, enabling the
sheets to perform repeated cycles of converting achiral substrates
to release as chiral products.
We envisioned that a single layer porous structure with uniformly
discrete cavities would precisely confine all entrapped achiral
1
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Angewandte Chemie International Edition
10.1002/anie.202010809
RESEARCH ARTICLE
rise to a P-stacked chiral superstructure.[19] After removal of the
chiral template by centrifugation (Figure 2d and Figure S5), the
global homochiral packing can be trapped, revealing a chiral
memory
to high rotational restriction in the stacked dimer of the non-planar
macrocycle. The twist angle of the chiral dimer was measured to
be 30o using 2D-NMR with rotating frame nuclear Overhauser
effect (ROE) (Figures S9 and S10). After removal of the chiral
guest, cryogenic transmission electron microscopy (cryo-TEM)
showed that isolated sheet objects, in lateral dimensions ranging
from submicro- to several micrometers are retained, indicating
that the sheets are robust and free existence in bulk solution
(
Figure 2f). TEM experiments with cast films revealed flat 2-D
structures (Figure 2g), consistent with the cryo-TEM results.
Atomic force microscopy (AFM) analysis showed that the sheets
are very flat and uniform with a thickness of 3.0 nm (Figure 2h).
Considering the molecular size of 1, this thickness implies that the
primary structure consists of 2 molecules in which the aromatic
macrocycles face one another (Figure 1a). This was further
confirmed by topochemical polymerization of the sheet solution,
which produced a pure dimer with a lack of any higher-molecular-
weight fractions (Figure S11). This result demonstrates that the
dimeric chiral pores created by a chiral memory effect laterally
associate into
a single-layered homochiral porous sheet
structures. The porous sheets derived from (R)-BD exhibit
opposite CD signals with a perfect mirror image relationship
(
Figures 2a and 2e), indicating that the chirality of the template is
transferred to the self-assembly of the macrocycles.
Chiral reduction in the homochiral porous nanosheets. We
envisioned that the pores with a chiral cavity can entrap prochiral
ketone substrates with a fixed spatial orientation in a confined
chiral space.[
9,23]
The preferred spatial orientation of one face over
the other toward a nucleophile would lead to the asymmetric
transformation of achiral molecules. To corroborate the capability
of the homochiral porous sheets for enantioselective
transformation of achiral molecules, 4-acetylbiphenyl (S1) was
selected as
experiments showed that one pore includes
a
prochiral substrate (Figure 3a). Titration
substrate
2
molecules with 96% uptake of the pores (Figures S12 and S13).
It is worth noting that the CD signal of the sheets remains
unchanged even after inclusion of the substrate (Figure S14),
demonstrating that the dimeric macrocycle with a chiral cavity
retains a fixed conformation, even with guest inclusion. 2-Acetyl-
6-methoxynaphthalene (S2), similar size to S1, can be also
entrapped by the porous sheet with 96% uptake. In great contrast,
the sheets do not exhibit any apparent inclusion activity for the
smaller aromatic derivatives such as 4-t-butyl acetophenone (S3)
and 4-methoxy acetophenone (S4), indicative of size selectivity
(
Figure S12).
To corroborate the fixed chiral orientation of the prochiral
substrates inside the chiral cavities, vibrational CD (VCD)
experiments were performed with S1. When the substrate is
entrapped inside the hollow cavities of the sheets with P-stacked
pores (Figure 3b and Figures S15-S17), the VCD spectrum
Figure 1. Homochiral porous nanosheet for asymmetric transformation and
self-separation. (a) Molecular structure of host amphiphile 1 and guest (S)-
or (R)-2,2’-dimethoxy-1,1’binaphthyl (BD). The pore chirality of the dimers
is induced by memory effect of (S)-BD (P-stacked pore) and (R)-BD (M-
stacked pore), respectively, which laterally assemble into a ~3 nm thick 2-
D porous sheet structure in MeOH. (b) A homochiral porous sheet as a
chiral transformer that changes achiral substrates to self-release as chiral
products. (c) Fixation-driven chiral transformation of the hydride reduction
of a ketone and the chiral macrocyclization of a linear substrate in the
presence of triflic acid inside the chiral pores of the 2-D homochiral porous
sheets at room temperature in MeOH.
showed a negative signal in the carbonyl stretching IR region at
-1
1
680 cm (Figure 3c and Figure S18), demonstrating that the
pores entrap the prochiral substrate to fix a preferential chiral
conformer. The enantiomeric sheets based on M-stacked pores
lead to a mirror-imaged VCD signal, indicating that the pore
chirality communicates with the prochiral substrate to fit into the
chiral environment. The fixed spatial orientation of prochiral
ketones would allow preferential exposure of one face over the
opposite face of the carbonyl group to a nucleophile for an
enantioselective reaction (Figure 3d). To corroborate the
asymmetric induction in chemical transformation, we added
effect.[21,22] This was confirmed by CD measurements after
4
NaBH to the methanol solution of 1 based on P-stacked pores
containing S1 at room temperature. Remarkably, the homochiral
porous sheets perform quantitative reduction of the ketone
substrate within 50 min at room temperature to yield a pure one
enantiomer with enantiomeric excess (ee) of >99% (Figure 4a and
complete removal of the chiral guest, which showed that the CD
intensity remains unchanged (Figure 2e and Figures S6 and S7).
Importantly, the induced chirality of the porous sheet structures is
very stable, as illustrated by retaining the CD intensity for at least
several months (Figure S8). This stability in chirality is attributed
2
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RESEARCH ARTICLE
Figure S19). Molecular dynamics (MD) calculations showed that
the phenyl group of S1 in 1P adopts clockwise rotation with
Figure 2. The homochiral porous nanosheets induced by chiral memory and their structural characterization. (a) CD spectra of 1 (91 μM)—(S)-BD (91
μM) (red solid line), 1 (91 μM)—(R)-BD (91 μM) (dark blue solid line), 1 (91 μM) (black dashed line) and (S)-BD (91 μM) (light blue solid line) in methanol
solution. (b) CD spectra of 1 (91 μM) with different equivalents of (S)-BD in methanol solution. (c) CD intensity at 306 nm of 1 with different equivalents
1
of (S)-BD. Trend lines from (S)-BD indicate the formation of a 2/1 inclusion complex with chiral pores. (d) Partial H-NMR spectra of 1 (2.74 mM) with
(
4 8
S)-BD (2.74 mM) and after remove (S)-BD (2.74 mM) by centrifugation in methanol-d /THF-d (3:2 vol/vol). The proton peaks associated with (S)-BD
disappear after centrifugation, indicative of the complete removal of (S)-BD from 1P. (e) CD spectra of 1P (91 μM) and 1M (91 μM) after removal of (S)-
BD and (R)-BD, respectively. (f and g) Cryo-TEM image (f) and negatively-stained TEM image (g) of 1P (91 μM) in methanol solution. (h) AFM height
image of sheets on mica. The sample film was dropcasted from 1P (91 μM) in methanol solution. The cross-sectional profiles (top) is taken along the
white line.
ketone substrate is converted into a more polar hydroxyl product
(
Figure 4b). After removal of the released products using a
respect to a carbonyl axis, generating less hindered si face than
re face, thereby producing the (R)-alcohol (Figure S20), which
explains the observed enantioselectivity. For a control experiment,
we performed an identical reduction of S1 in the absence of the
porous sheets (Figure S21). The reaction yielded only a racemic
product as expected, indicating that the confinement of the ketone
substrate inside the chiral space induces highly efficient
asymmetric conversion. S2 based on a naphthalene group also
undergoes nearly perfect asymmetric conversion in an identical
reaction condition (Figures S22 and S23). Notably, when the
reduction is completed, both the chiral products are
spontaneously released out of the porous materials because the
Sephadex column, analytical high-performance liquid
chromatography (HPLC) measurements of the solutions showed
a complete lack of the substrate and product, demonstrating that
reduction leads the substrates to spontaneously release out of the
internal cavities, which was further confirmed by NMR (Figure 4c
and Figures S24 and S25) and fluorescence measurements
(
Figure S26). The self-release of the enantiomeric product allows
the porous sheets to perform consecutive cycles of binding
carbonyl substrates to release as enantiomeric products without
compromising the pore performance in both uptake capacity and
asymmetric conversion (Figure 4d and Figures S19 and S27).
3
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RESEARCH ARTICLE
Chiral macrocyclization under confinement in porous sheets.
We considered that the concept of asymmetric induction under
confinement can be extended to perform enantioselective
macrocyclization which is a crucial step for drug discovery and
nanomedicine.[ To date, however, it remains an enormous
challenge because of additional requirement for a linear precursor
24]
to
adopt
an
entropically
disfavored,
pre-organized
[
25]
conformation.
As result, the traditional synthetic
a
methodologies for asymmetric macrocyclization are still far from
perfect.[ One approach to overcome this difficulty is to entrap a
26]
linear precursor inside a uniformly discrete chiral space.[
27,28]
Our
Figure 4. Asymmetric reduction of prochiral aromatic ketones inside
homochiral pores. (a) Time-dependent HPLC conversion of S1 (91 μM)
with 1P (91 μM) in the presence of NaBH in methanol solution. Inset:
4
HPLC spectra of S1 reduction in the presence and absence of 1P in
methanol solution. (b) Time-dependent substrate amount remaining in the
homochiral porous nanosheets of 1P in the presence (orange) and
absence (violet) of NaBH
(
4
. (c) Time-dependent 1D NOE spectra from 1P
2.74 mM)—S1 (2.74 mM) in the presence of NaBH in methanol- d /THF-
peak) induced NOE
). The induced NOE correlations of H —H
4
4
8 c
d (3:2, vol/vol). Irradiation at 7.666—7.692 ppm (H
peaks at 7.624—7.643 ppm (H
3
c
3
gradually disappear with time, indicative of the self-release of P1 from
pores. (d) Time-dependent HPLC conversions of S1 (91 μM) with 1P (91
μM) in the presence of NaBH with repeated cycles.
4
Figure 3. Fixed chiral orientation of prochiral substrates inside chiral
cavities. (a) Chemical structure of prochiral ketone guests S1-S4. (b) 1D
NOE spectrum from 1P (2.74 mM)—S1 (2.74 mM) in methanol-d
3:2, vol/vol). Irradiation at 7.849 ppm (H peak) induced NOE peaks at
.790-7.806 ppm. (c) VCD and IR spectra of 1M—S1 (red line) and 1P—
4 8
/THF-d
(
7
g
induction, a linear substrate based on an α,β-unsaturated
carbonyl group and an indole moiety (S5-6) was selected because
its estimated size in a folded conformation is compatible with the
internal cavity (Figure 5a and Figures S28 and S29). Titration
experiments showed that each pore is occupied by a single S5-6
molecule with greater than 98% uptake (Figure 6b and Figures
S30 and S31), indicative of near perfect fit between the internal
cavity and the substrate with a folded conformation. Considering
S1 (blue line) in the presence of S1 (1 equivalent) recorded as KBr pellets
after normalization of the peak intensities. The induced VCD peak at 1679
-1
cm shows complete mirror image, indicative chiral conformer formed of
S1 in 1M and 1P. (d) Schematic representation of the fixed chiral
conformer and mechanism of asymmetric reduction of S1 in P pore.
2-D porous sheets with uniformly discrete internal cavities are well
that the end parts of S5-6 are functionalized for a Michael
fit for a linear precursor to adopt a folded conformation, a
favorable shape for cyclization. Moreover, the chiral environment
of the pores is able to provide asymmetric induction in cyclization
because the chiral information of the pore interior can be
[29]
reaction,
the entrapment of the substrate inside the chiral
confined space would promote asymmetric cyclization by
adopting a spirally-folded conformation, which was confirmed by
CD measurements and dynamic simulations (Figures 5b-5d and
Figure S32). Moreover, sequestering the substrate would prevent
any possible intermolecular processes producing undesired linear
oligomers. To corroborate the asymmetric cyclization inside the
chiral cavities, we added a catalytic amount of triflic acid (1 mol%
relative to S5-6) to the methanol solution of 1 containing S5-6 at
room temperature.[ Remarkably, the 2-D porous sheets perform
transferred into
a linear precursor through stereoselective
couplings. To explore the capability of the porous nanosheets for
asymmetric macrocyclization and the generality of the chiral
30]
4
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RESEARCH ARTICLE
Figure 5. Folded conformation of linear substrates inside confined
homochiral pores. (a) Chemical structure of hydrophobic linear substrate
S5-6 for Michael reaction. 1D NOE spectra from 1P (2.74 mM)—S5-6 (1.37
Figure 6. Enantioselective macrocyclization inside homochiral pores. (a)
Time-dependent HPLC conversion of S5-6 (46 μM) with triflic acid (0.46
μM) for cyclization in the presence of 1P (91 μM) in methanol solution. (b)
Uptake, conversion and enantioselectivity of cyclization from 1P (91 μM)
and 1M (91 μM) with different guest molecules. (c) Time-dependent
substrate amount remaining in the homochiral porous nanosheets of 1P in
the presence (orange) and absence (violet) of triflic acid. (d) Time-
dependent HPLC conversions of S5-6 (46 μM) with 1P in the presence of
triflic acid (0.46 μM) with repeated cycles.
mM) in methanol-d
4
/THF-d
peak) induced NOE peaks at 7.692 ppm and 7.596 ppm. Irradiation at
.048—7.053 ppm (H11 peak) induced NOE peaks at 6.988—7.011 ppm,
8
(3:2, vol/vol). Irradiation at 7.662—7.688 ppm
(H
c
7
indicative formation of the folded structure between unsaturated carbonyl
segment and indole moiety of S5-6. (b) CD spectra of 1P (91 μM)—S5-6
(46 μM) (red line), 1M (91 μM)—S5-6 (46 μM) (blue line) in methanol
solution. The wavelength range shaded by green color corresponds to the
substrates. (c) Top and side views of MD simulation of S5-6 trapped in 1P.
(d) Schematic representation of the fixed chiral conformer of S5-6 in 1P.
Notably, when the conversion is completed, the macrocycle
product is spontaneously released out of the porous materials
without applying any external forces such as shaking and stirring
clean macrocyclization of the linear substrate preventing
undesired oligomerization. Upon addition of triflic acid, a single
additional peak corresponding to a macrocycle product was
identified in analytical HPLC of which the intensity increases
gradually at the expense of S5-6 and then levels-off at 6 hr (Figure
(
Figure 6c and Figures S39 and S40). After removal of the
macrocycle product by simple Sephadex filtrations, analytical
HPLC measurements of the solution showed a complete lack of
the cyclic product, demonstrating that converting into
a
6a and Figure S33), demonstrating that the reaction inside a
macrocycle leads the substrate to spontaneously release out of
the internal pores. This is in sharp contrast to the linear substrate
which resides inside the pore during this period of time without
any noticeable release (Figure 6c). The spontaneous release
could be attributed to the size mismatch of the substrate with the
fixed internal cavity by changing into a cyclic topology because
macrocycle structures possess smaller hydrodynamic volumes in
comparison to their linear counterparts as a consequence of a
confined space yields pure macrocycle product with
a
stoichiometric conversion, while preventing the formation of
undesired linear oligomers. Notably, the cyclization proceeds with
highly efficient asymmetric transformation to yield an enantiopure
macrocycle (>99% ee), as traced by analytical HPLC using a
chiral column (Figure 6b and Figure S34). The obtained profile
shows only a single peak associated with the pure enantiomer of
the macrocycle without any noticeable trace associated with the
other enantiomer, demonstrating that the cyclization inside the
fixed chiral space gives rise to precise asymmetric induction. For
a control experiment with the identical Michael reaction of S5-6 in
the absence of the porous sheets showed that the reaction
yielded only mixture products with low conversion of less than
[31]
conformational constraint of cyclic chains.
Considering the spontaneous release of the macrocycle product,
the porous nanosheet solution is able to perform a new cycle of
binding substrates to convert into macrocycles and then release.
Indeed, upon subsequent addition of S5-6 into the solution after
removal of the cyclic product, a new cycle of the substrate
conversion undergoes without compromising the pore
performance in both uptake and conversion efficiency (Figure 6d).
The subsequent cycles showed that the porous sheet structures
repeatedly perform full conversion with high optical purity of ~99%
27 % (Figure S34), demonstrating that the inclusion of the open
chains inside the confined chiral space is essential, not only for
quantitative cyclization, but also for perfect asymmetric
tarnsformation. The linear substrate based on a heptyl chain (S5-
7
), similar size to S5-6, can be also entrapped by the porous sheet
with 97 % uptake, generating enantiopure macrocycle (Figure 6b
and Figure S35). In great contrast, the sheets are unable to
perform chiral macrocyclization for the other linear substrates
such as S5-4, S5-5, and S5-8 that are not fit into the pore (Figure
S36), indicating that the pores are remarkably size selective and
very stereospecific. This is further supported by precise control of
enantiomeric excess (ee%) using different ratios of 1P and 1M
ee and complete release up to
3 cycles (Figure S41),
demonstrating that the pores are highly stable without
deterioration in their performance even after many cycles of
binding the substrate for asymmetric conversion.
(
Figures S37 and S38).
5
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Keywords: 2D porous sheet • induced pore chirality • chiral
confinement • chiral conversion • self-release
Detailed experimental procedures, compound characterizations,
supporting data and movies are present in the Supporting
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[
Our results demonstrate that homochiral porous sheet structures
can perform highly efficient asymmetric conversion purely by
confining achiral substrates to the chiral cavities without the use
of chiral moieties or catalysts. Moreover, the near perfect
chemical transformation of the substrates allows the porous
nanosheet structures to spontaneously release as enantiopure
products, thus enabling the regenerated porous sheets to carry
out repeated cycles of binding achiral substrates to release as
chiral products without deterioration in pore performance.
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as a product. We anticipate that such a purely geometric
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into chiral molecule foundry for diverse asymmetric conversions
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This work was supported by the National Natural Science
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6
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Angewandte Chemie International Edition
10.1002/anie.202010809
RESEARCH ARTICLE
Entry for the Table of Contents
Insert graphic for Table of Contents here.
We construct single layer, homochiral porous sheet with induced pore chirality. The porous sheets perform repeatable asymmetric
transformation of absorbed achiral substrates without the help of chiral catalysts or chiral auxiliaries. The porous sheets allow diverse
asymmetric transformation including chiral reduction and chiral macrocyclization with a highly size selective and stereospecific way.
7
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