Catalytic Enantioselective Synthesis and Switchable Chiroptical Property of Inherently Chiral Macrocycles

Article abstract of DOI:10.1021/jacs.0c05369

We report herein a strategy to construct enantiopure inherently chiral macrocycles, ABCD-type heteracalix[4]aromatics, through a catalytic enantioselective intramolecular C-N bond forming reaction. A chiral ligand-palladium complex was found to efficiently induce the inherent chirality of molecules during the macrocyclization process with ee values up to >99%. The resulting ABCD-type heteracalix[4]aromatics displayed excellent and pH-triggered switchable electronic circular dichroism and circularly polarized luminescence properties.

Full text of DOI:10.1021/jacs.0c05369

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Communication
Catalytic Enantioselective Synthesis and Switchable
Chiroptical Property of Inherently Chiral Macrocycles
Shuo Tong, Jiang-Tao Li, Dong-Dong Liang, Yan-E Zhang, Qi-
Yun Feng, Xin Zhang, Jieping Zhu, and Mei-Xiang Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05369 • Publication Date (Web): 12 Aug 2020
Downloaded from pubs.acs.org on August 12, 2020
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Catalytic Enantioselective Synthesis and Switchable Chiroptical
Property of Inherently Chiral Macrocycles
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Shuo Tong1*, Jiang-Tao Li1, Dong-Dong Liang1, Yan-E Zhang1, Qi-Yun Feng1, Xin Zhang,1 Jieping
Zhu2, Mei-Xiang Wang1*
1MOE Key Laboratory of Bioorganic Phosphorous and Chemical Biology, Department of Chemistry, Tsinghua University,
Beijing, 100084, China.
2Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Poltechnique Fédérale
de Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland.
ABSTRACT: We report herein
a strategy to construct enantiopure inherently chiral macrocycles, ABCD-type
heteracalix[4]aromatics, through a catalytic enantioselective intramolecular C-N bond forming reaction. A chiral ligand-palladium
complex was found to efficiently induce the inherent chirality of molecules during macrocyclization process with ee values up
to >99%. The resulting ABCD-type heteracalix[4]aromatics displayed excellent and pH-triggered switchable electronic circular
dichroism and circularly polarized luminescence properties.
Molecular chirality defines the non-superimposability of
three-dimensional molecules onto their mirror images. Since
enantiomers often display drastically different effects on
biological systems, there has been continuous research interest
in the synthesis of enantiopure small organic molecules1 to meet
the demand of the discovery and the development of chiral
drugs2. On the other hand, small chiral molecules provide
unique platforms for the fabrication of chiral functional
materials and devises. However, this fascinating aspect of small
molecular chirality remains largely unexplored3. One of the
current focuses of the study is the chiroptical properties such as
circularly polarized luminescence (CPL) of enantiomerically
enriched or pure small molecules4 and molecular assemblies5.
macrocycles from other well-known central, axial, planar and
helical molecules. It is noteworthy that while synthesis and
application of conventional types of chiral molecules have
reached a highly sophisticated level1, catalytic synthesis of
enantiomerically pure inherently chiral molecules remains a
formidable challenge. Resolution of racemic samples using
analytic HPLC with columns coated with chiral stationary
phase is the most frequently way so far to obtain a tiny amount
of enantiomers8. There were only two attempts to synthesize
inherently chiral macrocycles by means of enantioselective
catalysis. In the presence of cross-linked crystals of Aspergillus
niger lipase, a tris(O-2-hydroxyethyl)-substituted calixarene
derivative underwent mono acetylation to afford an enantiopure
macrocycle in 19% yield9. The other example was a
Pd(dba)2/(R)-SEGPHOS-catalyzed
intramolecular
cross
coupling reaction which produced an azacalix[4]arene product
in 78% yield with 35% ee10. The inaccessibility of inherently
chiral macrocycles has unfortunately hampered the
investigation of the chiroptical properties such as CPL activity
of this class of chiral molecules11.
We report herein the first catalytic enantioselective
synthesis and switchable electronic circular dichroism (ECD)
and CPL properties of ABCD-type heteracalix[4]aromatics.
Heteracalix[4]aromatics are
a unique type of synthetic
macrocycles widely used in molecular recognition, fabrication
of sophisticated (supra)molecular architectures12,13, and the
Figure 1. Schematic presentation of mirror image of inherently chiral
macrocycles and a strategy of catalytic asymmetric synthesis
exploration of high valent organocopper chemistry14-16
.
Evidently, assembly of four different aromatic rings into
heteracalix[4]aromatics would generate novel inherently chiral
macrocycles (ABCD-type, Figure 1). The facile catalytic
synthesis of enantiomerically pure heteracalix[4]aromatics
would significantly expand applications of this already-useful
type of host molecules. More importantly, comprehension of
correlation between inherent chirality and chiroptical properties
will open an avenue to new chiral science and technology. It
should be noted that inherently chiral heteracalix[4]aromatics
do not necessarily contain four completely different aromatic
Molecular chirality is classified generally into point, axial,
planar, and helical chirality based on stereogenic elements. In
1994, Böhmer6,7 coined inherently chiral calixarenes to describe
calixarenes devoid of any symmetry elements except a C1
asymmetry axis (Figure 1). In other words, ring opening of an
inherently chiral calixarene macrocyclic structure leads to an
achiral linear molecule. The term of inherent chirality has now
been accepted by macrocyclic and supramolecular chemistry
community to differentiate a special collection of chiral
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subunits6,7. Even the AABB-type macrocycles such as the
Table 1. Catalytic enantioselective synthesis of 6.
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proximally dechlorinated 1,3-alternate tetraazapyrimidine is
resolvable into a pair of enantiomers17. To showcase the
potential of fragment coupling strategy to create diverse
inherently chiral structures, and also to construct the inherently
chiral cavity surrounded by aromatic rings of different
electronic
features,
we
concentrated
on
tetraazacalix[4]aromatics which contain benzene, pyridine,
pyrimidine and triazine rings. We envisioned the use of a chiral
ligand in Pd-catalyzed intramolecular Caryl-N bond forming
reaction18,19 would induce the inherent chirality. In other word,
the transfer or the expression of chirality of a homochiral
catalyst or a ligand to a macrocyclic skeleton was expected
during macrocyclization process (Figure 1).
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Scheme 1. Reaction design and optimized reaction conditions.
[a]5 (0.1 mmol), Pd(OAc)2 (30 mol%), (R,Sp)-L (60 mol%), NaOtBu (3
equiv.), dioxane/toluene (v/v = 1/2, c 3.3 mM), reflux; [b]Pd2(dba)3 was used
as a catalyst; [c](S,Rp)-L was used as a chiral ligand.
As a prelude of enantioselective catalysis, we examined
the synthesis of racemic tetraazacalix[4]aromatics (+/-)-6 by
ABCD-type macrocycles were resolved into a pair of
enantiomers by chiral HPLC (Supporting Information). The
outcomes also showed clearly that removal of a sterically bulky
group from either upper or lower rim position of benzene ring,
macrocycles 6n and 6o became very fluxional conformationally.
Even in the case of 6m, a methyl group on the benzene ring
appeared not large enough to prevent racemization of the
inherently chiral macrocycle.
means of
a fragment coupling strategy (Scheme 1).
Condensation between 2,6-dibromopyridine 1a and 4,6-
di(methylamino)pyrimidine 2 afforded 4-methylamino-6-((6-
bromopyridin-2-yl)(methyl)amino)pyrimidine
3a.
The
resulting AB segment 3a underwent facile nucleophilic
aromatic substitution with cyanuric chloride to form
intermediate 4a, which, without isolation and purification,
reacted consecutively with 2-(benzyloxy)-5-(tert-butyl)-N1,N3-
dimethylbenzene-1,3-diamine and methylamine to produce an
ABCD-type linear tetramer 5a efficiently in an overall yield of
97%. Pleasingly, Pd(OAc)2/dppp-catalyzed intramolecular
Buchwald-Hartwig reaction20 furnished 16-membered
macrocycle 6a in 56% yield. The method was found very
To develop a synthetic method for enantiopure inherently
chiral heteracalixaromatics, we commenced with Pd-catalyzed
cyclization reaction of linear tetramer 5a using a chiral ligand.
Gratefully, after screening only a handful of chiral ligands,
(R,Sp)-JOSIPHOS (L) stood out as the best one to afford
macrocycle 6a with >99% ee albeit in a low yield. The reaction
conditions were optimized (Supporting Information) and both a
good yield (44%) and outstanding enantioselectivity (>99% ee)
general, and
a
number of racemic ABCD-type
tetraazacalix[4]aromatics 6b-o were synthesized successfully
(Scheme 1). Substantiated by spectroscopic data and single-
crystal X-ray structure of 6b (Supporting Information), 6 adopt
1,3-altenate conformation. Encouragingly, except for 6m-o, all
were achieved when the reaction was refluxed in
a
dioxane/toluene mixture (1:2 v/v) in the presence of Pd(OAc)2
(0.3 equiv.), L (0.6 equiv.), and NaOtBu (3 equiv.) (Scheme 1).
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The catalytic enantioselective reaction provided a very general
(Ric)-6h’ were fluorescent, giving a broad emission band
centered at 479 nm upon excitation at 310 nm. Notably, (Sic)-6h
and (Ric)-6h’ showed strong CPL activity with emission
maxima consistent with those observed in their fluorescent
spectra. Upon UV irradiation at 310 nm in acetonitrile for
instance, (Sic)-6h and (Ric)-6h’ gave complementary CPL
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method for the synthesis of diverse inherently chiral
tetraazacalix[4]aromatics 6 (Table 1). The substrates 5b-c,
which contained the palladium-coordinating cyano group21,
were transformed equally efficiently into the inherently chiral
products 6b-c. When the benzyl group at the lower rim was
replaced by n-propyl, the least alkyl group able to inhibit the
flip of para-t-butylphenyl ether subunit around the annulus of
macrocyclic ring22, macrocycles 6d-e were obtained similarly
with 97% and >99% ees, respectively. Notably, the same
catalytic system was found to tolerate the amino group on the
pyridine nucleus, however with decreased enantioselectivity of
87% ee (6h). The use of a combination of Pd2(dba)3 (15 mol%)
with L (60 mol%) as a catalyst further improved the yield of 6h
to 60% with >99% ee (Supporting Information). Under the
modified catalysis, a number of macrocycles (6g-l), which
contained an enhanced Lewis basic pyridine moiety23 such as
N,N-dimethylamino, 1-pyrrolidinyl and 1-piperidinyl were
prepared in good yields with excellent enantiomeric purity. The
method also enabled the construction of inherently chiral
spectra with large luminescence dissymmetry values of |glum
|
= 2×10-3 at 500 nm. The same signs of ECD and CPL spectra
observed indicated no significant difference between the
ground-state and excited-state conformations.
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Figure 2. Computed transition states TS-1 and TS-2.
tetrazacalix[4]aromatics
which
bear
different
N,N-
dialkylamino substituents including a 4-morpholinyl group (6k)
on the triazine subunit. The absolute configuration was assigned
based on the molecular structure of (Sic)-6h, which was
determined unambiguously with single-crystal X-ray
diffraction experiment (Table 1). Conceivably, macrocyclic
compound (Ric)-6h’, the enantiomer of (Sic)-6h, was
synthesized in 56% yield with >99% ee using ent-L as ligand.
Noteworthily, heating an o-dichlorobenzene solution of
enantioenriched 6h at 150 oC for 20 h did not cause
racemization, indicating the high stability of its inherent
chirality or 1,3-altenate conformation due to the steric effect of
bulky substituents on benzene unit (Supporting Information).
The extraordinarily high-level induction of inherent
chirality by a chiral JOSIPHOS-ligated palladium complex was
unprecedented and intriguing. To have a deeper insight into the
chirality expression from a chiral catalyst to inherently chiral
macrocycles, we conducted DFT calculations at the M06/6-
311+g(d,p)/SDD//M06/6-31g(d)/SDD level of theory. Two
pairs of probable transition states (Figures 2 and S53) of the
Buchwald-Hartwig amination leading to a pair of enantiomers
were computed according to literature.24 The calculations
indicated that the activation free energy of the transition state
(TS-1) leading to the major enantiomer was the lowest
compared to that of others. This was in agreement with the
excellent enantioselectivities observed in the experiments.
Analysis of the transition states also revealed the origin of the
enantiocontrol. In TS-2 which leads to Ric enantiomer, two
cyclohexyl groups on phosphine experience substantial steric
repulsion with pyridine ring and the N-Me group, respectively.
By contrast, the repulsion between the cyclohexyl ring and the
N-Me group in TS-1 is reduced. More importantly, there is non-
covalent C-H···π attraction between the C-H bond of a
cyclohexyl group and pyridine ring. It is therefore the favorable
C-H···π interaction and reduced steric repulsion between
substituents on ligand and fragments of substrate that lower the
activation energy of TS-1 and consequently lead to high
enantioselectivity.
Figure 3. ECD (top left, 2×10-5 M), CPL (top right, 1×10-4 M, λex = 310
nm), UV/vis (bottom left, 1×10-5 M), and fluorescence (bottom right, 1×10-
6
M, λex = 310 nm) spectra of (Sic)-6h and (Ric)-6h’ in the absence and
presence of CF3CO2H (10 equiv) in CH3CN.
All products were able to undergo regiospecific
protonation on the nitrogen atom of the pyridine subunit
because of its highest basicity among aza-arenes within
macrocycle (Supporting Information). Surprisingly, titration of
(Sic)-6h and (Ric)-6h’ with CF3CO2H led to the complete
inversion of all Cotton effects. While the bond at 268 nm was
blue-shifted to 252 nm, two weak absorption bands between
284 and 300 nm were emerged to give a strong peak at 298 nm.
It was remarkable that the switching effect was also observed in
CPL spectra. As a consequence of the interaction of (Sic)-6h and
(Ric)-6h’ with CF3CO2H, for instance, the CPL emission band
was reversed entirely with the concomitant hypsochromic shift
from 500 nm to 450 nm (Figure 3). Slightly decreased |glum
|
value (1×10-3) was obtained for protonated macrocycles.
Macrocycles (Sic)-6g-l which contain an electron-donating
group on the pyridine subunit displayed almost the same
chiroptical properties including CPL reversal upon interaction
with an acid. In the case of products (Sic)-6a and (Sic)-6f devoid
of an electron-donating group on the pyridine ring, however,
their CPL activities were quenched by an acid. No CPL reversal
was observed (Supporting Information). The CPL switch was
The acquired enantiopure macrocycles
6 exhibited
excellent ECD and CPL properties and most excitingly an
unusual chiroptical switching effect (Figure 3). Recorded in
acetonitrile, ECD spectra of (Sic)-6h showed two negative
Cotton effects at 268 and 316 nm and two positive ones at 284
and 300 nm. Being the enantiomer of (Sic)-6h, (Ric)-6h’ gave the
expected mirror-imaged ECD spectra. Compounds (Sic)-6h and
n
also reversible. Deprotonation of [(Sic)-6-H]+ with Bu4NOH
resulted in the recovery of ECD and CPL of (Sic)-6. No
appreciable decay of the intensity of the signals were observed
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Research Program for financial support. S. Tong also thanks the
Thousand Young Talents Program for support.
after three cycles of chiroptical switching triggered by
protonation and deprotonation (Supporting Information). To the
best of our knowledge, chiral molecules exhibited both the sign
inversion and the blueshift of CPL upon interaction with
stimulus are unprecedented25,26. Though the mechanism of this
unusual CPL switching effect displayed by inherently chiral
tetraazacalix[4]aroamtics awaits an in-depth study,27 the
complete sign inversion of CPL was not resulted from the
inversion of absolute configuration of the macrocycles because
of the stability of 1,3-alternate conformation of 6 (vide supra).
Inversion of macrocyclic conformation would lead to
racemization. It was most probably attributable to the reversal
of the order of polarity of constitutional aromatic rings of
macrocyclic skeleton. In other words, after protonation,
pyridine subunit become the most electron-deficient moiety
instead of triazine ring, reversing the handedness of
macrocyclic molecule. The blueshift of CPL was likely owing
to switching of fluorophore from pyridine to pyrimidine after
protonation of pyridine moiety.
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In conclusion, we have developed a Pd-catalyzed highly
enantioselective synthesis of ABCD-type inherently chiral
tetraazacalix[4]aromatics. The fascinating chirality expression
from catalyst to inherently chiral macrocycles stemmed most
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diastereomeric intermediate in which the chiral ligand dictated
the handedness of organometallic macrocycle prior to reductive
elimination. The outcomes opened a new avenue to access
various enantiopure inherently chiral molecules with ease in an
asymmetric catalytic fashion. The acquired enantiopure
inherently chiral tetraazacalix[4]aromatics were excellent
chiroptical molecules, displaying a unique pH-triggered
chiroptical switching effect. We believe that the inherently
chiral macrocycles would expand extraordinarily the chiral
chemical space leading to the great opportunity both in the
development of stereochemistry and in the discovery of chiral
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AUTHOR INFORMATION
Corresponding Author
* E-mails: tongshuo@mail.tsinghua.edu.cn;
wangmx@mail.tsinghua.edu.cn
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
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ACKNOWLEDGMENT
(20) Wang, M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Synthesis, structure
We are grateful to B.-J. Li (Tsinghua University) for useful
discussion on the reaction mechanism. We thank the National
Natural Science Foundation of China (21920102001, 21732004,
21901137, 21821001) and Tsinghua University Initiative Scientific
and
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complexation
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(27) We carried out TDDFT ECD calculation to model the inversion
of ECD (cf. the Supporting Information for details).
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