Highly Efficient Cyclic Dinucleotide Based Artificial Metalloribozymes for Enantioselective Friedel–Crafts Reactions in Water

Article abstract of DOI:10.1002/anie.201912962

The diverse secondary structures of nucleic acids are emerging as attractive chiral scaffolds to construct artificial metalloenzymes (ArMs) for enantioselective catalysis. DNA-based ArMs containing duplex and G-quadruplex scaffolds have been widely investigated, yet RNA-based ArMs are scarce. Here we report that a cyclic dinucleotide of c-di-AMP and Cu²⁺ ions assemble into an artificial metalloribozyme (c-di-AMP?Cu²⁺) that enables catalysis of enantioselective Friedel–Crafts reactions in aqueous media with high reactivity and excellent enantioselectivity of up to 97 % ee. The assembly of c-di-AMP?Cu²⁺ gives rise to a 20-fold rate acceleration compared to Cu²⁺ ions. Based on various biophysical techniques and density function theory (DFT) calculations, a fine coordination structure of c-di-AMP?Cu²⁺ metalloribozyme is suggested in which two c-di-AMP form a dimer scaffold and the Cu²⁺ ion is located in the center of an adenine-adenine plane through binding to two N7 nitrogen atoms and one phosphate oxygen atom.

Full text of DOI:10.1002/anie.201912962

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Highly Efficient Cyclic Dinucleotide Based Artificial
Metalloribozymes for Enantioselective Friedel-Crafts Reactions in
Water
Authors: Changhao Wang, Min Hao, Qianqian Qi, Jingshuang Dang,
Xingchen Dong, Shuting Lv, Ling Xiong, Huanhuan Gao,
Guoqing Jia, Yashao Chen, Jörg S. Hartig, and Can Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912962
Angew. Chem. 10.1002/ange.201912962
Link to VoR: http://dx.doi.org/10.1002/anie.201912962
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Angewandte Chemie International Edition
10.1002/anie.201912962
COMMUNICATION
Highly Efficient Cyclic Dinucleotide Based Artificial
Metalloribozymes for Enantioselective Friedel-Crafts Reactions in
Water
+
+
Changhao Wang ,* Min Hao , Qianqian Qi, Jingshuang Dang, Xingchen Dong, Shuting Lv, Ling Xiong,
Huanhuan Gao, Guoqing Jia, Yashao Chen,* Jörg S. Hartig, and Can Li
Abstract: The diverse secondary structures of nucleic acids are
emerging as attractive chiral scaffolds to construct artificial
metalloenzymes (ArMs) for enantioselective catalysis. DNA-based
ArMs using duplex and G-quadruplex scaffolds have been widely
investigated, yet RNA-based ArMs are scarce. Here we report that a
2+
cyclic dinucleotide of c-di-AMP and Cu ions assemble into an
2+
artificial metalloribozyme (c-di-AMP·Cu ) that enables catalysis of
enantioselective Friedel-Crafts reactions in aqueous media with high
reactivities and excellent enantioselectivities up to 97% ee. The
2+
assembly of c-di-AMP·Cu gives rise to a 20-fold rate acceleration
2+
compared to Cu ions. Based on various biophysical techniques
and density function theory (DFT) calculations, a fine coordination
2+
structure of c-di-AMP·Cu metalloribozyme is suggested where two
2+
c-di-AMP form a dimer scaffold and the Cu ion locates in the center
of an adenine-adenine plane via binding to two N7 and one
phosphate-oxygen.
With ever-increasing interest for developing new-to-nature
biocatalysts, much attention has been attracted to rationally
designed artificial metalloenzymes (ArMs) that are merging the
features of enzymatic catalysis and homogeneous catalysis.[1]
ArMs are originating from incorporating metallo-cofactors into
biomolecular scaffolds, which are used to expand the reaction
reservoir and explore the novel functions of biomolecules.[2]
Beside the extensive studies of proteins as chiral scaffolds for
ArMs, nucleic acids have recently raised much interest to
construct ArMs because of their diverse tertiary structures,
chemical stability and easy synthetic access. In 2005, Roelfes
and Feringa pioneered the DNA-based asymmetric catalysis
using duplex DNA as scaffold to embed achiral copper(II)
complexes to achieve an enantioselective Diels-Alder reaction.[3]
This concept of DNA-based ArMs has been successively applied
to many enantioselective transformations[4] and in some cases
the presence of DNA could accelerate the reaction rates.[4g, 5]
Scheme 1. Schematic representation of enantioselective Friedel-Crafts
reactions of α,β-unsaturated 2-acyl imidazoles (1) and indoles (2) by a cyclic
2+
dinucleotide based artificial metalloribozyme of c-di-AMP∙Cu
.
Owing to the tunable structures, G-quadruplex DNA-based ArMs
have been developed and the enantioselective catalytic
performances are largely dependent on the G-quadruplex
structures.[6] In addition, an assembly of G-triplex DNA and Cu
2+
ions was built to modestly promote a Diels-Alder reaction.[7]
Since RNA is comparably less stable than DNA, few examples
of RNA-based enantioselective catalysis were described.
Jäschke and coworkers reported the selection of a ribozyme that
achieves a Diels-Alder reaction with over 90% ee.[8] Smietana
and Arseniyadis constructed double-stranded RNA hybrid
catalysts for Friedel-Crafts (F-C) reactions with modest
[9]
enantioselectivities. The Hennecke group discussed the results
that DNA is superior to RNA as scaffold in nucleic acid based
enantioselective catalysis.[10] Although nucleic acid based ArMs
[*]
Dr. C. Wang,[+] M. Hao,[+] Q. Qi, Dr. J. Dang, X. Dong, S. Lv, L. Xiong,
H. Gao, Prof. Y. S. Chen
successfully transfer the chirality from nucleic acids to the aimed
products and achieve some challenging synthetic reactions, yet
there are still many concerns to be solved e.g. lack of RNA-
based ArMs, unclear fine structures and few explorations on
reaction mechanisms. In particular, the current nucleic acid
based ArMs contain several tens to several hundreds of
oligonucleotides to form the second coordination sphere on a
macroscale, thus the insight of the precise chiral
microenvironment for targeting the metal cofactors is insufficient.
Herein, we report an artificial metalloribozyme resulting from
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of
Education, School of Chemistry and Chemical Engineering, Shaanxi
Normal University, Xi’an 710119 (China)
E-mail: changhaowang@snnu.edu.cn
yschen@snnu.edu.cn
Dr. G. Jia, Prof. C. Li
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, Dalian 116023 (China)
Prof. J. S. Hartig
Department of Chemistry, Konstanz Research School Chemical
Biology (KoRS-CB), University of Konstanz, Konstanz 78457
(Germany)
[+
]
These authors contributed equally to this work.
incorporation of Cu2+ ions into the scaffold of
a cyclic
dinucleotide of c-di-AMP that could effectively catalyze the
enantioselective F-C reactions in aqueous media (Scheme 1).
Supporting information for this article is given via a link at the end of the
document.
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Angewandte Chemie International Edition
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COMMUNICATION
Cyclic dinucleotides (CDNs) are natural cyclic RNA molecules
containing two ribonucleotide units and a 12-membered ring
structure. So far, four canonical 3’-5’ linked CDNs of c-di-GMP,
c-di-AMP, c-AMP-GMP, c-AMP-UMP and one non-canonical
CDN of 2’,3’-c-GAMP have been discovered in nature[11] and
identified as important second messengers in transduction of
biological signals and regulation of many cellular processes.[12]
These naturally occurring CDNs are easily produced by their
specific cyclases and the canonical CDNs are readily
synthesized in large scale using a one-pot chemical strategy.[13]
Moreover, CDNs are able to form three-dimensional structures.
C-di-GMP could fold into diverse structures in the presence of
alkaline metal ions or aromatic planar intercalators.[14] Xi and
Plavec reported that the monomeric CDNs are stable in U-type
structures and prone to form dimer and tetramer.[15] The Hartig
group proved that some of the formerly unknown CDNs form
higher order structures.[13b] In addition, a heme analogue was
embedded into a c-di-GMP octameric scaffold that mimicked the
G-quadruplex DNA peroxidase.[16] Hence, the multiple structures
of CDNs raise our interest to employ them as chiral scaffolds to
construct RNA-based hybrid catalysts.
selected as a probe reaction. We initially tested c-di-GMP that
could form G-quadruplex structure in the presence K+ ions
(Figure S1). However, the sole c-di-GMP showed low activity
and nearly racemic products of 3a were obtained using either c-
di-GMP or c-di-GMP·Cu2+ (Table 1, entries 1-2). Since different
CDNs displayed distinct profiles in circular dichroism (CD)
spectra (Figure S2), we examined c-AMP-GMP and c-di-AMP
hybrid catalysts. In K -containing media, c-AMP-GMP·Cu2+
provided 3a with 93% conversion and 10% ee (Table 1, entry 3).
Surprisingly, c-di-AMP·Cu2+ in the presence of K ions achieved
the F-C reaction with a quantitative conversion and a good
enantioselectivity of 72% ee (Table 1, entry 4), suggesting that
c-di-AMP and Cu2+ ions are effectively interacting in order to
+
+
function as
a
potent hybrid catalyst. Furthermore, we
2+
investigated the reaction conditions for c-di-AMP·Cu catalyzed
F-C reaction by varying additives, cofactors, temperatures and
buffers. Different alkaline metal ions and alkaline earth metal
ions as additives caused negative effects to the
enantioselectivities and the highest 85% ee was obtained with
no additives (Table 1, entries 4-7, Tables S1 and S2). This
+
+
phenomenon is different from Na or K promoted G-quadruplex
DNA-based enantioselective catalysis.[
6b, 6c, 17]
For the cofactors
in the c-di-AMP hybrid catalysts, Cu2 ion served as the best
cofactor to assist c-di-AMP to achieve the enantioselectivity
regardless of the used counter anions (Table S3). However, the
introduction of achiral ligands to c-di-AMP·Cu2+ resulted in
decreased ee values (Table 1, entries 8-10). With increasing the
+
Table 1: Enantioselective Friedel-Crafts reaction catalyzed by CDN-based
[
a]
hybrid catalysts.
2
+
ratio of c-di-AMP/Cu , the enantioselectivity was gradually
increasing up to 90% ee using c-di-AMP·Cu2+ (5:1) yet further
increasing the c-di-AMP/Cu2+ ratio caused no significant
changes (Table 1, entry 11, Table S4). When increasing the
reaction temperature, a reduced ee was obtained (Table 1, entry
Entry
CDN
Cofactor[b]
none
Additive
Conversion
%]
ee
[%]
[
1
2
3
4
5
6
7
8
9
c-di-GMP
c-di-GMP
c-AMP-GMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
c-di-AMP
KCl
KCl
KCl
KCl
NaCl
20
4
1
2). For the buffers of either 4-morpholinepropanesulfonic acid
(MOPS) or 4-morpholineethanesulfonic acid (MES), MES (pH
.5) was selected as the optimal buffer for the following studies
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
2
2
96
2
5
93
10
72
71
55
85
45
55
59
90
60
87
(
Table 1, entry 13, Table S5).
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
MgCl
none
none
none
none
none
none
none
2
4000
3330
Cu(bpy)(NO
Cu(dmbpy)(NO
3 2
Cu(phen)(NO )
3 2
)
3
000
000
3 2
)
1860
1
1
1
1
0
2
1[c]
2[d]
3[e]
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
1000
0
[
a] Reaction conditions: 1a (1 mM), 2a (5 mM), CDN (100 μM), cofactor (50
170
0
.5
o
μM), additive (100 mM), MOPS buffer (1 mL, 20 mM, pH 6.5), 4 C, 24 h.
The conversion and ee were determined from the crude product by HPLC
analysis on a chiral stationary phase. All data were averaged by at least
2+
Cu
2+
2+
c-di-AMP
c-di-AMP·Cu
2:1)
c-di-AMP·Cu
(5:1)
(
duplicated experiments with the reproducibility of ±5%. [b] OTf
=
trifluoromethanesulfonate, bpy = 2,2’-bipyridine, dmbpy = 4,4’-dimethyl-
Figure 1. The rate acceleration effect (kapp,cat/kapp,uncat) for c-di-AMP, Cu2+, and
c-di-AMP·Cu2+. The apparent second-order rate constant (kapp) was estimated
from the initial rate of the F-C reaction with 1a (0.8 mM) and 2a (5 mM) in MES
2
,2’-bipyridyl, phen
=
1,10-phenathroline. [c] c-di-AMP (250 μM) and
o
Cu(OTf)
2
(50 μM). [d] Reaction at 37 C. [e] MES buffer (20 mM, pH 5.5).
o
buffer (1 mL, 20 mM, pH 5.5) at 4 C without catalyst (kapp,uncat) and with
To investigate the enantioselective catalytic functions of CDNs,
an enantioselective F-C reaction of (E)-1-(1-methyl-1H-imidazol-
catalysts of c-di-AMP (100 μM), Cu2+ (50 μM), c-di-AMP·Cu (2:1, 100 μM c-
2+
di-AMP and 50 μM Cu2+), and c-di-AMP·Cu2+ (5:1, 250 μM c-di-AMP and 50
μM Cu2+), respectively.
2
-yl)but-2-en-1-one (1a) and 5-methoxy-1H-indole (2a) was
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Angewandte Chemie International Edition
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COMMUNICATION
2
+
Compared to 1a bearing R1 = methyl reacted with 2a, the
substrates 1b and 1c with larger R groups (ethyl, iso-propyl)
In order to evaluate the catalytic roles of c-di-AMP and Cu in
2
+
1
c-di-AMP·Cu , we determined the apparent second-order rate
constant (kapp) for the F-C reaction as previously described.[5d]
Compared to the uncatalyzed reaction (kapp,uncat), c-di-AMP
slightly inhibited the reaction with kapp,c-di-AMP/kapp,uncat = 0.5 ± 0.1,
while Cu2+ ions remarkably accelerated the reaction with
app,Cu2+/kapp,uncat = (1.7 ± 0.1) × 10 (Figure 1 and Table S6).
provided decreased ee values (3a vs. 3b-c). Once changing c-
di-AMP·Cu2+ (2:1) to c-di-AMP·Cu2+ (5:1), the corresponding
enantioselectivities of 3a-c slightly increased. For tuning the R2
group in α,β-unsaturated 2-acyl imidazoles of methyl, ethyl and
iso-propyl, no significant differences for the enantioselectivities
2
k
2+
2+
Once the c-di-AMP and Cu were assembled with the molar
ratio of 5:1, the c-di-AMP·Cu2+ (5:1) gave rise to a rate
enhancement of 3330-fold compared to the uncatalyzed reaction
and 20-fold compared to Cu2+ ions (Figure 1 and Table S6).
Compared to c-di-AMP·Cu2+ (5:1), c-di-AMP·Cu2+ (2:1) caused a
bit lower rate acceleration effect (Figure 1). These results
suggest that c-di-AMP and Cu2+ are assembling into a CDN-
based artificial metalloribozyme where Cu2+ ions are the main
catalytic species and the c-di-AMP provides a chiral second
coordination sphere. This phenomenon is similar to the
descriptions of duplex DNA and G-quadruplex DNA
metalloenzymes.[
were obtained (3a,3d-e) using either c-di-AMP·Cu (2:1) and c-
di-AMP·Cu2+ (5:1). Surprisingly, once the R group of 1f was
2
substituted by
a tert-butyl moiety, the corresponding F-C
reactions showed modest conversions but excellent
enantioselectivities of 3f at 95% ee and 97% ee by c-di-
AMP·Cu2+ (2:1) and c-di-AMP·Cu2+ (5:1), respectively. When the
R2 groups in the substrates were substituted by aromatic
moieties, both reactivities and enantioselectivities were
obviously suppressed (3g-i). Furthermore, different indoles (2a-
d) were examined to react with 1a and varied
enantioselectivities were obtained (3j-l). To examine the
3, 6b]
2+
synthetic potential of c-di-AMP·Cu , we conducted the
With c-di-AMP·Cu2+ metalloribozyme in hand, we tested
different α,β-unsaturated 2-acyl imidazoles (1a-i) and indoles
benchmark reaction on a large scale (1a, 75 mg) using c-di-
AMP·Cu2+ (2:1) of 2 mol%. After gel column chromatography, we
obtained 3a at 80% isolated yield and 85% ee, indicating that c-
di-AMP·Cu2 is potentially applied for practical synthesis.
(
2a-d) for the enantioselective F-C reactions (Scheme 2).
+
a
b
c-di-AMP
c-di-dAMP
87%
87%
c-AMP-CMP
c-AMP-UMP
c-AMP-GMP
c-di-GMP
50%
38%
11%
4%
3'-pApA 2%
3',5'-cyclic AMP <1%
AMP <1%
Adenine <1%
c-di-AMP
0
20
40
60
80
100
ee (3a, %)
c
c-di-AMP/Cu2+
H4’,H5’
H5’
d c-di-AMP/Cu2+
H1’
H8 H2
Pα
2
3
5
1
3
0:1
20:1
0:1
30:1
0:1
50:1
00:1
00:1
100:1
300:1
500:1
1000:1
c-di-AMP
5
00:1
000:1
c-di-AMP
1
1
0
9
8
7
6
5
4
15
10
5
0
-5
-10
-15
Chemical shift (ppm)
Chemical shift (ppm)
Figure 2. a) Chemical structure of c-di-AMP. b) Control experiments for the
2+
Cu -catalyzed F-C reaction with different c-di-AMP analogues. Reaction
conditions: 1a (1 mM), 2a (5 mM), c-di-AMP analogue (100 μM), Cu(OTf)
2
(50
o
μM), MES buffer (1 mL, 20 mM, pH 5.5),
4
C, 24 h. All the control
1
31
experiments were at conversions beyond 98%. c) H NMR and d) P NMR
spectroscopic titrations of c-di-AMP (9.4 mM) by varying the concentration of
2 2
CuCl (9.4-470 μM) in D O.
For c-di-AMP (Figure 2a), the possible coordination sites for
Cu2+ ions are N1, N3, N6, N7, O2’ and phosphate oxygen atoms
as described previously for copper/nucleic acid complexes.[ In
Scheme 2. Substrate scope of the c-di-AMP∙Cu2+ catalyzed F-C reactions.
Reaction conditions: 1 (1 mM), 2 (5 mM), c-di-AMP (100 μM), Cu(OTf)
μM), MES buffer (1 mL, 20 mM, pH 5.5), 4 C, 24 h. The conversion (conv.) of
2
(50
18]
o
a was calculated by HPLC and the conversions of 3b-l were estimated by 1
NMR from the crude products. The ee values were determined from the crude
products on chiral HPLC. The data in parentheses represented the
corresponding F-C reactions using c-di-AMP·Cu (5:1) with 250 μM c-di-AMP
H
2+
2+
3
an attempt to probe the location of Cu ion in c-di-AMP·Cu ,
we conducted a series of control experiments for the benchmark
F-C reaction with different c-di-AMP analogues (Figure 2b).
Cyclic dideoxyribonucleotide (c-di-dAMP) instead of c-di-AMP
a
2+
2+
and 50 μM Cu ions. All data were averaged by two independent experiments
with the reproducibility of conversions at ±5% and ee values at ±3%.
2
+
resulted the similar enantioselectivity in Cu -catalyzed F-C
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Angewandte Chemie International Edition
10.1002/anie.201912962
COMMUNICATION
reaction, indicating that O2’ in c-di-AMP is not a primary binding
site of Cu2+ ions. Compared to c-di-AMP, the CDNs containing
one AMP moiety (c-AMP-CMP, c-AMP-UMP and c-AMP-GMP)
based metalloribozymes yielded the decreased ee values and c-
di-GMP provided a very low ee, showing that Cu2+ ions could be
specifically targeted by adenine in CDNs. Moreover, the non-
cyclic form of c-di-AMP (3’-pApA), 3’,5’-cyclic AMP, AMP and
adenine gave nearly racemic products in Cu -catalyzed F-C
reaction. The above results suggest that the 12-membered
cyclic scaffold and two adenines are indispensable for CDN-
based metalloribozymes to exert high enantioselective catalysis.
To investigate the interaction between c-di-AMP and Cu2+ ions,
a
b
2
+
c-di-AMP
Cu2+
O
Cu
O
1a
several biophysical techniques were employed. With increasing
the amount of Cu2+ ions, UV-Vis and CD spectra of the c-di-AMP
exhibited slight concentration-dependent behaviors (Figure S13),
indicating that c-di-AMP and Cu2+ ions are indeed interacting.
The binding affinity between c-di-AMP and Cu2+ ions was
quantitatively analyzed with an apparent dissociation constant
No chiral
induction
c-di-AMP·Cu2+ (momomer)
The intermediate of
c-di-AMP·Cu (momomer) and 1a
2+
dimerization
d
(K ) of 646 ± 32 μM by UV titration experiments (Figure S16).
Nuclear magnetic resonance (NMR) technique was also used
although Cu2+ ions are paramagnetic species. Compared to H
NMR of c-di-AMP, the titration of Cu2+ ions broadened and
shifted downfield the signals of H8 and H2, yet other protons
remained almost unchanged (Figure 2c). These results suggest
that the magnetic environment around H8 and H2 of c-di-AMP is
disturbed upon the addition of Cu2+ ions, leading us to assume
1
N7
O
Cu
N7
N7 N7
Cu Cu
N7 N7
O
O
N7
N7
Cu
O
side view
top view
that N1, N3 and N7 are likely the binding sites of Cu2 ions.
+
c-di-AMP·Cu2+ (dimer)
Moreover, the addition of Cu2+ ions to c-di-AMP caused the
broadening and a small shift downfield for the Pα signal (Figure
1a
2
d), indicating that phosphates in c-di-AMP are likely another
Re face favored
2
+
binding site of Cu
ions. Taken together the c-di-AMP
analogues experiments and biophysical characterizations, we
conclude that Cu2+ ions are most likely interacting with N7, N3,
N1 and phosphate in c-di-AMP to assemble a CDN-based
metalloribozyme.
Si face blocked
To clarify the structure of c-di-AMP·Cu2+ and explore the
plausible reaction mechanism, density function theory (DFT)
calculations were conducted. In experimental study, the absolute
configuration of 3a was confirmed in R type in c-di-AMP·Cu2
catalyzed F-C reaction (Figure 3a and Figure S17) that
The intermediate of c-di-AMP·Cu2+ (dimer) and 1a
+
Figure 3. a) c-di-AMP·Cu2+ catalyzed F-C reaction of 1a and 2a to yield 3a in
[
19]
corresponds to the literature reported. In DFT calculations, c-
di-AMP is stable in U-type scaffold with an intramolecular π-π
stacking between two adenines (Figure 3b), which is consistent
with the recent literature.[15] Once the Cu2+ ions are added, two
possible c-di-AMP·Cu2+ monomers were obtained (Figure S18).
The stable one shows that the Cu2+ ion binds to two oxygens
from two phosphates, but this c-di-AMP·Cu2+ monomer
interacting with 1a provides an intermediate with no further chiral
induction (Figure 3b). Another c-di-AMP·Cu2+ monomer is less
stable and yields the product 3a in S configuration that conflicts
with the experimental result (Figure S18). Intriguingly, the stable
c-di-AMP·Cu2+ monomer tends to reconstruct a more stable
dimer with intermolecular π-π stacking of adenines (Figure 3b),
which undergoes an exothermic process with a binding energy
of -85.4 kcal/mol. In this c-di-AMP·Cu2+ dimer, two Cu ions are
locating equivalently in the center of two adenine-adenine
planes and each Cu ion is trapped by two N7 atoms from
different c-di-AMP and one nearby phosphate-oxygen (Figure
R configuration. b) DFT calculations of the optimized conformations of c-di-
AMP, c-di-AMP·Cu2+ and the intermediates of c-di-AMP·Cu and 1a.
2+
forms an intermediate that allows 2a to preferentially attack from
the Re face rather than Si face (Figure 3b), leading to the
product 3a in R configuration which is in accordance with the
experimental result. Taken together of the above experimental
data and the DFT calculations, a plausible fine structure of c-di-
AMP·Cu2 metalloribozyme is depicted in dimeric form where the
Cu2+ ion is located in the center of an A-A plane via binding to
two N7 and one phosphate-oxygen.
In conclusion, we found that c-di-AMP and Cu2+ ions enable to
assemble into a CDN-based artificial metalloribozyme that
shows quantitative conversions and up to 97% ee in the
enantioselective F-C reactions. The resulted c-di-AMP·Cu2+
provides a significant rate acceleration effect in comparison of
+
2+
2
+
Cu ions. The enantioselective catalytic performance of c-di-
AMP·Cu is largely dependent on the 12-membered cyclic
b). Importantly, the addition of 1a to the c-di-AMP·Cu2+ dimer
2+
3
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Angewandte Chemie International Edition
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COMMUNICATION
scaffold and the two adenines moieties. Based on biophysical
characterizations and DFT calculations, the structure of c-di-
Roelfes, Chem. Sci. 2013, 4, 2013-2017; g) A. Rioz-Martinez, J.
Oelerich, N. Segaud, G. Roelfes, Angew. Chem. Int. Ed. 2016, 55,
14136-14140; Angew. Chem. 2016, 128, 14342-14346.
AMP·Cu is proposed as a dimeric complex where the Cu2+ ion
2+
[
[
5]
6]
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Conflict of interest
The authors declare no conflict of interest.
Keywords: nucleic acid based catalysts • cyclic dinucleotide • c-
di-AMP • artificial metalloribozyme • enantioselective catalysis
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10.1002/anie.201912962
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C. Wang ,* M. Hao , Q. Qi, J. Dang, X.
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Cu2+
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Self-assembly
Highly Efficient Cyclic Dinucleotide
Based Artificial Metalloribozymes for
Enantioselective Friedel-Crafts
Reactions in Water
c-di-AMP
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c-di-AMP·Cu2+ metalloribozyme
up to full conversions
up to 97% ee
A cyclic dinucleotide based artificial metalloribozyme assembled by c-di-AMP and Cu2+ ions enables the catalysis of
enantioselective Friedel-Crafts reactions with high reactivities and excellent enantioselectivities up to 97% ee.
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