Substrate-Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis

Article abstract of DOI:10.1002/anie.201910399

An artificial system of substrate-induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen-bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich-like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen-bonding interaction sites. Inspired by the guest-induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β-ketoacid by a cooperative hydrogen-bonding network enabled by sulfamate-induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.

Full text of DOI:10.1002/anie.201910399

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Accepted Article
Title: Substrate Induced Dimerization Assembly of Chiral Macrocycle
Catalysts toward Cooperative Asymmetric Catalysis
Authors: Hao Guo, Lie-Wei Zhang, Hao Zhou, Wei Meng, Yu-Fei Ao,
De-Xian Wang, and Qi-Qiang Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910399
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10.1002/anie.201910399
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Substrate Induced Dimerization Assembly of Chiral Macrocycle
Catalysts toward Cooperative Asymmetric Catalysis
Hao Guo,[a,b] Lie-Wei Zhang,[a,b] Hao Zhou,[a,b] Wei Meng,[a] Yu-Fei Ao,[a] De-Xian Wang,[a,b] and Qi-
Qiang Wang*[a,b]
Abstract: We reported herein a rare artificial system on substrate-
induced dimerization assembly of chiral macrocycle catalysts,
enabling a highly cooperative hydrogen-bonding activation network
for efficient and enantioselective transformation. These macrocycles
contain two thiourea and two chiral diamine moieties and were found
to dimerize with sulfate to form a sandwich-like assembly. Upon
dimerization, the macrocycles adopt an extended conformation and
reciprocally complement the hydrogen-bonding interaction sites.
Inspired by the guest-induced dynamic assembly, these macrocycles
were applied on catalyzing decarboxylative Mannich reaction of
chiral boroxinate catalysts has also been shown by Wulff et al.
on catalyzing asymmetric cycloaddition reactions.[10] Herein we
reported the first example of substrate-induced noncovalent
dimerization assembly of chiral macrocycle catalysts, which
enables a highly cooperative hydrogen-bonding network for
efficient and enantioselective transformation.
Recently we initiated a project on construction of macrocycle
catalysts by taking prominent catalytic groups as direct building
components to form macrocyclic scaffolds. In this way, the
definitive catalytic functionalities can be integrated and eternally
embedded within a confined macrocyclic cavity. We chose
thiourea, specially diarylthiourea units, as the building
components due to their superior binding and activation
cyclic aldimines containing
a sulfamate heading group. As
anticipated, the imine substrate can be activated toward nucleophilic
attack of β-ketoacid through a highly cooperative hydrogen-bonding
network enabled by sulfamate-induced dimerization assembly of the
macrocycle catalysts. By this strategy, highly efficient (>95% yield in
most cases) and enantioselective (up to 97.5:2.5 er) transformation
of a variety of substrates using only 5 mol% macrocycle was
achieved, providing a potent means for organocatalytic asymmetric
transformation of the titled reactions.
abilities.[11-15]
A series of chiral diamine scaffolds were
incorporated as linkers to, on one hand, introduce a chiral
environment, and on other hand, furnish bifunctional thiourea-
Lewis base sites for dual activation of both electrophile and
nucleophile.[16] Following this design, the multifunctionalized
tetraamino-bisthiourea chiral macrocycles M1-M4 were
constructed (Scheme 1). In M3 and M4, the hetero-combination
of different diamine linkers as well as the diastereomeric forms
was intended to provide a delicate control on both macrocyclic
conformation and chiral microenvironment.
The synthesis of the chiral macrocycles was straightforward
and gram-scale preparation can be easily realized (see
Supporting Information). Enantiomerically pure dimethylated 1,2-
cyclohexanediamine or 1,2-diphenylethylenediamine was firstly
reacted with two equiv. 3-nitro-5-trifluoromethylbenzyl bromide,
followed by nitro reduction, affording bis-amine fragments which
can be further converted to bis-isothiocyanates in high yields.
Macrocyclization between bis-amine and bis-isothiocyanate
fragments went smoothly and gave the final chiral macrocycles
in 39%-72% yields.
Taking the inspiration of enzyme catalysis, many cavity-
containing macrocycle and cage compounds have been applied
as supramolecular catalysts to facilitate otherwise disfavored
transformation.[1-4] One important feature of enzyme catalysis is
induced-fit of substrate and active sites to obtain most favorable
interactions for maximum transition state stabilization.[5-6] This
induced-fit can sometimes operate through cooperation of
individual proteins by reciprocal complementation of their active
sites.[5] For example, dynamin,
a prototypical member of
GTPases, has been recently shown to undergo G domain
dimerization that leads to assembly-stimulated catalytic
activity.[7] For synthetic catalytic systems, however, the
substrate-induced catalyst assembly and regulatory mechanism
are underdeveloped. Among the only few examples, Otto et al.
nicely showed transient, substrate-induced macrocyclic catalyst
formation in a disulfide-based dynamic combinatorial library.[8]
Prins and Chen et al. demonstrated that a phosphate ester
substrate can induce the formation of vesicular assemblies
which act as cooperative catalysts for hydrolysis of the same
substrate.[9] A substrate induced covalent assembly formation of
[a]
Mr. H. Guo, Ms. L.-W. Zhang, Mr. H. Zhou, Dr. W. Meng, Dr. Y.-F.
Ao, Prof. Dr. D.-X. Wang, Prof. Dr. Q.-Q. Wang
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190, China
E-mail: qiqiangw@iccas.ac.cn
[b]
Mr. H. Guo, Ms. L.-W. Zhang, Mr. H. Zhou, Prof. Dr. D.-X. Wang,
Prof. Dr. Q.-Q. Wang
University of Chinese Academy of Sciences
Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Structure of the tetraamino-bisthiourea chiral macrocycles.
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During binding studies of these macrocycles prior to catalysis,
reaction of cyclic aldimines 1 with β-ketoacids provides an
alternative means to the direct Mannich reaction[17] for accessing
valuable β-amino ketones, but efficient organocatalytic
asymmetric transformation is lacking.[18] We speculated that the
imine substrate could be activated toward nucleophilic attack
through induced dimerization assembly of the chiral macrocycle
catalysts (Figure 2). The generating negative charge on the
sulfamate heading group (analogue to sulfate) could be
stabilized through a cooperative H-bonding network enabled by
the as-formed dimeric assembly. According to the modelling, the
exposing cleft on the assembly surface is suitable for incoming
ketoacid substrate that is activated through deprotonation by the
tertiary amine site (Figure S33).
a
complex crystal, [(M1)2•SO42−][TBA+]2, was reproducibly
obtained from a solution of M1 and tetra(n-butyl)ammonium
sulfate in acetonitrile. Crystal structure showed two macrocycles
and one sulfate anion form a sandwich-like complex (Figure 1).
Sulfate is embedded in between the two macrocycles, forming
four pairs of bifurcated hydrogen bonds with the four thiourea
groups from both macrocycles (N-H∙∙∙O distances: 2.87-2.93 Å).
The two macrocycles are packed crosswise so that the four
thioureas are allowed to spatially surround the sulfate. In this
packing way, the CF3-attached benzene rings can enjoy π-π
stacking with neighboring ones and also avoid steric hindrance
between the bulky CF3 groups. Upon dimerization, the
macrocycle adopts an extended conformation and forms an
exposing cleft. This is in contrast to a self-folded conformation in
the monomeric chloride complex [M1•(Cl−)2][TBA+]2 where two
aryl-thiourea moieties are packed onto each other (Figure S1).
Figure 2. Proposed mode for substrate-induced dimerization assembly of
chiral macrocycle catalysts toward cooperative asymmetric catalysis.
The reaction between 1a and 2a was initially performed in 1,4-
dioxane with a 2 mol% loading of the chiral macrocycles (Table
S2). The reaction went very quickly and achieved complete
conversion in 20 min. While M1-M3 gave a low enantiomeric
ratio (er), M4 enabled a considerable enantioselectivity (74:26
er). This suggests subtle structural change on the macrocycle
could have a large influence on asymmetric induction. Solvent
screening showed THF was the best (Table S2). Increasing the
macrocycle loading to 5 mol% led to a further improved
enantioselectivity (85:15 er) and complete conversion in 5 min,
suggesting a very high efficiency (Table 1, entry 4). Decreasing
reaction temperature to 0 oC resulted in a better selectivity
(Table 1, entry 7). Finally, the reaction concentration was also
screened. Under optimal conditions (5 mol% M4, THF, c 0.05 M,
Figure 1. Crystal structure of [(M1)2•SO42−][TBA+]2. TBA+ counterions are
omitted for clarity. H-bonding distances: N1-H∙∙∙O4, 2.917; N2-H∙∙∙O4, 2.929;
N5-H∙∙∙O2, 2.917; N6-H∙∙∙O2, 2.899; N1A-H∙∙∙O3, 2.898; N2A-H∙∙∙O3, 2.901;
N5A-H∙∙∙O1, 2.867; N6A-H∙∙∙O1, 2.902 Å.
The sulfate-induced macrocycle dimerization was also
observed in solution. As shown by 1H NMR titrations, upon
addition of sulfate to the solution of M1, a new set of signals,
including significantly downfield shifted NH signal (Δδ = 3.0 ppm),
gradually emerged and became dominant at about 0.5 eq. of
sulfate (Figure S2). At this point, the original macrocycle signals
almost completely disappeared. This was consistent with 2:1
macrocycle-sulfate assembly formation. The slow-exchange
dynamic and the dominant assembly signals suggested a strong
dimerization tendency. With excess of sulfate, a second set of
signals started to appear, which can be assigned to 1:1
macrocycle-sulfate complex. The strong dimerization tendency
was also suggested by high-resolution ESI-MS, where
predominant peaks corresponding to [(M1)2•SO42−] and related
species were observed (Figure S6). For M2-M4, similar
dimerization assembly was also observed (Figures S2-S9).
Upon sulfate-induced dimerization, the macrocycles adopt an
extroversive conformation and reciprocally complement the
interaction sites. As inspired by the induced-fit regulation of
enzymes, we wondered if this dynamic assembly system can be
applied on cooperative catalysis. Decarboxylative Mannich
o
-10 C), 99% yield and a high enantioselectivity (94:6 er) was
achieved (Table 1, entry 12). As anticipated, in the presence of
only 2.5 mol% (TBA+)2SO42−, the enantioselectivity was totally
lost, implying that sulfate can replace the imine substrate by
occupation within the assembly (Table 1, entry 14).
To gain more insight on the catalytic mechanism, a series of
experiments were performed. 2:1 binding species between the
macrocycle and imine substrate can be detected by ESI-MS with
a signal of [2M4 + 1a]− observed (Figure S12). The in situ ESI-
MS analysis of the reaction mixture was also carried out (Figure
3a and Figure S20). Multiple signals corresponding to the
addition intermediate A− and its macrocycle-associated species
were observed, indicating that the reaction operates by the
Mannich addition of the β-ketoacid to the imine prior to
subsequent decarboxylation.[19] Especially, in the very high m/z
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Table 1. Reaction optimization for macrocycle-catalyzed decarboxylative
Mannich reaction of cyclic aldimine 1a with β-ketoacid 2a.[a]
Cat.
(mol%)
Conc.
[M][d]
Yield
[%][e]
Entry
T [oC]
Time
er[f]
1
M4 (2%)
M4 (0.5%)
M4 (1%)
M4 (5%)
M4 (10%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M4 (5%)
M1 (5%)
M2 (5%)
M3 (5%)
25
25
25
25
25
25
0
0.2
20 min
60 min
40 min
5 min
5 min
10 min
90 min
8 h
99
99
98
99
99
98
99
99
99
98
99
99
98
99
99
99
99
81.5:18.5
81:19
2
0.2
3
0.2
81.5:18.5
85:15
4
0.2
5
0.2
85.5:14.5
85.5:14.5
89.5:10.5
85.5:14.5
92:8
6[b]
7[b]
8[b]
9[b]
10[b]
11[b]
12[b]
13[b]
14[b,c]
15[b]
16[b]
17[b]
0.2
0.2
-20
0
0.2
0.1
100 min
100 min
2 h
0
0.05
0.033
0.05
0.05
0.05
0.05
0.05
0.05
93:7
0
91.5:8.5
94:6
-10
-20
-10
-10
-10
-10
3 h
9 h
94:6
3 h
51:49
3.5 h
24 h
51:49
62.5:37.5
63:37
8 h
[a] Reaction conditions: 1a (0.2 mmol) and 2a (1.5 equiv). [b] 1.2 equiv 2a
used. [c] In the presence of 2.5 mol% (TBA+)2SO42−. [d] Concentration of 1a.
[e] Isolated yields after column chromatography. [f] Determined by HPLC
analysis on a chiral stationary phase.
region, the signal of the dimeric species [2M4 + A−] can also be
detected, implying that two macrocycles can work together to
cooperatively bind and activate the substrates. During DFT
optimization of macrocycle-complexed reaction species,
a
structure of the addition species captured within the dimeric
assembly can be identified, showing the anticipated cooperative
H-bonding network (Figure 3e).
Figure 3. (a) HR ESI-MS of reaction mixture of 1a and 2a catalyzed by M4. (b)
Conversion of 1a over time and (c) the dependence of the initial reaction rate
on concentration of M4. (d) Dependence of ee of the product 3a on ee of M4.
(e) DFT modelling (B3LYP/3-21G) of the addition intermediate fitting within the
dimeric assembly. Nonessential hydrogen atoms are omitted for clarity.
Reaction kinetics analysis was performed and a second order
dependence of the initial reaction rate on the concentration of
M4 was found, in line with the dimeric assembly catalysis mode
(Figures 3b and 3c, and Figures S26-S32). Moreover, the
relationship between the enantioselectivity of the reaction and
the enantiomeric purity of M4 was examined, and a slight
positive non-linear effect was observed (Figure 3d). The small
non-linear effect could reflect that the hetero-dimerization (M4,
ent-M4) may not dominate as the homo-dimerization (M4, M4),
or that their activity cannot be largely differentiated. Binding
studies between rac-M4 and sulfate showed the hetero-
dimerization did co-exist with homo-dimerization (Figure S22).
Interestingly, sulfate-induced dimerization between two different
kinds of macrocycles (e.g. M1, M4) was also observed (Figures
S23-S25). With this in mind, the catalyzed reactions using the
two mixed macrocycle catalysts were also tested (Scheme 2A).
While M1 gave a very low but slightly positive ee (+2%), the 1:1
mixture of M4+M1 gave 55% ee; however, an even higher ee
(58%) was obtained for M4+ent-M1 (1:1). This opposite direction
of the ee difference wouldn’t be expected if the two kinds of
macrocycle catalysts had operated independently, thus
suggested a cooperative interaction of the two macrocycles.
Scheme 2. Comparison and control reactions. Conditions: 1 (0.2 mmol), 2a
(1.2 equiv), and macrocycle catalyst (5 mol%) in 4 mL of THF at -10 oC.
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As the dimeric motif has a deep binding and activation pocket,
imine substrates with different steric hinderance (1a-1c) were
subjected (Scheme 2B). While the uncatalyzed reactions of the
three substrates showed very similar reactivity, the catalyzed
reaction of substrate 1c with bulky t-butyl group adjacent to the
sulfamate group was much slower and gave decreased ee
compared to that of 1a and 1b. This suggests increased steric
hinderance may interfere with the sulfamate heading group
inserting within the assembly. For the 5-membered cyclic imine
substrate 1d, the reaction was also interfered (Scheme 2C),
which could be due to that the sulfonamide heading group
(analogue to sulfonate) cannot induce dimeric assembly
formation (Figure S11).
Finally, substrate scope of the reaction was explored (Scheme
3). Regardless of the electron-donating and electron-
withdrawing substituents on both the cyclic aldimines (6-
position) and phenyl β-ketoacids, high yield (>95% in most
cases) and enantioselectivity (up to 97.5:2.5 er) was achieved.
As noticed, the substitution changed to 7 and 8-position of the
cyclic aldimine slowed down the reaction (e.g. 3e vs 3f vs 3g, 3o
vs 3p) and even disrupted the enantioselectivity (3p). This
reflects the steric effect when the sulfamate heading group
inserting within the assembly.
like assembly. Through dimerization, an extended macrocyclic
conformation and
a
reciprocal complementation of the
interaction sites was achieved. Taking these advantages, this
dynamic assembly system was applied on catalyzing
decarboxylative Mannich reaction of cyclic aldimine substrates
containing a sulfamate heading group. The sulfamate-induced
dimerization of the chiral macrocycles provided
a highly
cooperative hydrogen-bonding network for activating the imine
substrate itself toward the nucleophilic attack of β-ketoacid. This
system enabled highly efficient and enantioselective
transformation of a variety of substrates, providing a potent
means for organocatalytic asymmetric transformation of the
titled reactions. This substrate-induced chiral catalyst assembly,
resembling induced-fit regulation of an enzyme, complements
the conventional asymmetric catalytic principles and would
enrich the exploitation of efficient artificial catalysis systems
toward challenging transformations.
Acknowledgements
Financial supports from National Natural Science Foundation of
China (21871276, 21502200, 21521002) and Chinese Academy
of
Sciences
(QYZDJ-SSW-SLH023)
are
gratefully
acknowledged.
Keywords: supramolecular catalysis • chiral macrocycles • self-
assembly • anion binding • cooperative asymmetric catalysis
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Scheme 3. Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (1.2 equiv),
and M4 (5 mol%) in 4 mL of THF at -10 oC.
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Entry for the Table of Contents
COMMUNICATION
It takes two to tango: a rare
example on substrate-induced
dimerization assembly of chiral
macrocycle catalysts, which
enables a highly cooperative
hydrogen-bonding activation
network for efficient and
Hao Guo, Lie-Wei Zhang, Hao
Zhou, Wei Meng, Yu-Fei Ao, De-
Xian Wang, and Qi-Qiang Wang*
Page No. – Page No.
Substrate Induced Dimerization
Assembly of Chiral Macrocycle
Catalysts toward Cooperative
Asymmetric Catalysis
enantioselective transformation,
was realized.
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