Enantioselective Friedel-Crafts reactions in water catalyzed by a human telomeric G-quadruplex DNA metalloenzyme

Article abstract of DOI:10.1039/c2cc31320k

A human telomeric G-quadruplex (G4DNA) metalloenzyme, assembled with G4DNA and Cu²⁺ ions, can catalyze the enantioselective Friedel-Crafts (F-C) reaction in water with good enantioselectivity (up to 75% ee). Furthermore, we found that the absolute configuration and the enantioselectivity of the product largely depend on the conformation and the sequence of G4DNA. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31320k

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Enantioselective Friedel–Crafts reactions in water catalyzed by a human
telomeric G-quadruplex DNA metalloenzymew
Changhao Wang,ab Yinghao Li,ab Guoqing Jia,a Yan Liu,a Shengmei Lua and Can Li*a
Received 22nd February 2012, Accepted 2nd May 2012
DOI: 10.1039/c2cc31320k
A human telomeric G-quadruplex (G4DNA) metalloenzyme,
assembled with G4DNA and Cu2+ ions, can catalyze the enantio-
selective Friedel–Crafts (F–C) reaction in water with good enantio-
selectivity (up to 75% ee). Furthermore, we found that the absolute
configuration and the enantioselectivity of the product largely
depend on the conformation and the sequence of G4DNA.
The Friedel–Crafts (F–C) reaction and its enantioselective
variants are powerful carbon–carbon bond formation reac-
tions in organic synthesis, and their application to alkylation
of indole nucleus is an ongoing interest in the synthesis of
natural products and potential medicinal intermediates.1,2 In
previous reports on the enantioselective F–C reactions, they
were normally conducted under strictly anhydrous conditions,
since only a few examples can tolerate even a small amount of
water.3 Boersma et al. reported the first catalytic enantio-
Scheme 1 Schematic representation of the enantioselective F–C reactions
in water catalyzed by the G4DNA metalloenzyme (ODN-1–Cu2+).
selective F–C alkylation in water using a DNA-based catalyst,
which is composed of the double-stranded DNA and
copper(II) complex with a special ligand.4
that the absolute configuration and the enantioselectivity of the
scaffold for designing artificial metalloenzymes.5 Recently, a
product largely depend on the DNA sequence, and the loop
DNA, commonly existing in duplex structure, is an attractive
sequence in the G4DNA metalloenzyme plays a crucial role in
catalysts.4,6 Amongst the possible conformations of DNA,
the chiral expression.
series of chemical reactions have been achieved by DNA-based
A model enantioselective F–C reaction using 2-acylimidazole
G-quadruplex DNA (G4DNA) is found to form at the end of
(1a) and 5-methoxy indole (2a) as the substrates in 3-(N-
human telomeres, which is composed of a repeating string of
morpholino)propanesulfonic acid (MOPS) buffer was chosen
TTAGGG units. The conformation of G4DNA is intrinsically
to probe the catalytic properties of G4DNA.4 In the presence
tunable when factors such as strand orientation, loop type and
of Na+ ions, we found that human telomeric DNA (ODN-1,
50-G3(TTAG3)3-30) in antiparallel structure9 could catalyze the
F–C reaction and the corresponding product 3a was obtained in
an enantiomeric excess (ee) of 13% (Table 1, entry 2). Although
the conversion and the enantioselectivity are not very high, it
clearly shows that ODN-1 can work as a direct chiral catalyst.
Ribozyme usually binds divalent metal ions to stabilize the
structure but in some cases can promote the catalysis,10 thus
the same strategy could be applied to DNA. When a G4DNA
metalloenzyme (ODN-1–Cu2+) was assembled with G4DNA
and Cu2+ ions, it is very interesting that ODN-1–Cu2+ shows
remarkably higher catalytic performance than ODN-1
(Table 1, entry 2) or Cu2+ ions (Table 1, entry 3), and generates
the corresponding product 3a in 75% ee and nearly quantita-
tive conversion in 24 hours (Table 1, entry 4). In addition,
nickel(II), zinc(II) and cobalt(II) nitrates were also introduced
to form the DNA metalloenzymes for the enantioselective F–C
arrangement, and glycosyl torsion angles are considered.7 The
variable topology of the G4DNA provides an opportunity to
study the relationship between DNA structures and catalytic
reaction performances. Until now, G4DNA has been used as a
structural template to assist the catalytic functions,8 and
employed as a chiral scaffold to transfer the chirality.6f In this
work, we report that the enantioselective F–C alkylations in
water can be achieved using a human telomeric G4DNA
metalloenzyme simply assembled by G4DNA and Cu2+ ions
without additional ligands (Scheme 1). Furthermore, we found
a State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, Dalian 116023, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049,
China. E-mail: canli@dicp.ac.cn
w Electronic supplementary information (ESI) available: Experimental
details, supplementary figures and tables, 1H-NMR spectra and HPLC
traces. See DOI: 10.1039/c2cc31320k
c
6232 Chem. Commun., 2012, 48, 6232–6234
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Table 1 Enantioselective F–C reaction catalyzed by ODN-1 and its
metalloenzymesa
dichroism (CD) spectra (Fig. 1b), the conformation of
ODN-1–Cu2+ is in a labile state of antiparallel G-quadruplex
structure without Na+ ions, and the F–C reaction gives the
product 3a with 49% ee (Fig. 1a). As the concentration
of Na+ ions is increased, the antiparallel conformation of
ODN-1–Cu2+ becomes stable and compact, resulting in the
increased enantioselectivity for the F–C reaction (Fig. 1a and b).
When the concentration of Na+ ions attains 50 mM,
ODN-1–Cu2+ provides 3a in good enantioselectivity of
up to 75% ee. The compact antiparallel conformation of
ODN-1–Cu2+ is still maintained at higher concentration
of Na+ ions according to the CD spectra, but results in
decreased enantioselectivity (Fig. 1a and b).
In the presence of K+ ions, the conformations of the
G4DNA are usually in hybrid types.11 Without K+ ions, as
mentioned above, ODN-1–Cu2+ is in a labile state and gives
the F–C product in 49% ee (Fig. 1c and d). After a small
amount of K+ ions (2 mM) was added, the conformation of
ODN-1–Cu2+ becomes compact (Fig. 1d), but the enantio-
selectivity is decreased to 9% ee (Fig. 1c). A little higher
concentration of K+ ions (5 mM) allows the ODN-1–Cu2+
to adopt the compact conformation, yet provides the reversed
configuration of the product in 13% ee (Fig. 1c and d). As the
concentration of K+ ions is increased to 10–100 mM, the
enantioselectivities of the F–C reaction do not change signifi-
cantly (Table S1, ESIw), whereas the conformation of ODN-
1–Cu2+ is converted to a hybrid type (Fig. 1d). In much higher
concentration of K+ ions (>200 mM), both the activity and
the enantioselectivity decrease for the F–C reaction (Fig. 1c,
Table S1 in ESIw).
Entry
Catalyst
Conversionb (%)
eec (%)
1
2
3
4
5
6
7
No
ODN-1
9
18
62
99
20
25
30
0
13
0
75
11
8
Cu2+
ODN-1–Cu2+
ODN-1–Ni2+
ODN-1–Zn2+
ODN-1–Co2+
3
a
Reaction conditions: 1a (1 mmol, 1 eq.), 2a (5 eq.), ODN-1 (0.1 eq.),
metal(II) nitrate (0.05 eq.), NaCl (50 mM), MOPS buffer (20 mM,
pH 6.5), 4 1C, 24 h. All data are averaged by two experiments.
b
Determined by chiral-phase HPLC for the crude product (Scheme S1,
c
ESI). Reproducible within ꢀ5%. Determined by chiral-phase HPLC.
Reproducible within ꢀ5%.
reaction. Compared with the F–C reaction catalyzed by
ODN-1–Cu2+ (Table 1, entry 4), lower conversions and
enantioselectivities were obtained by using ODN-1–Ni2+
ODN-1–Zn2+ and ODN-1–Co2+ (Table 1, entries 5–7).
,
The conformation of G4DNA is tunable,7 so it is possible to
find out the effect of the ODN-1 conformation on enantio-
selective induction in the F–C reaction. In the presence of Na+
ions, ODN-1 can fold intramolecularly into an antiparallel
G-quadruplex conformation.9 According to the circular
Under molecular crowding conditions with PEG200, the
conformation of ODN-1–Cu2+ can be switched from anti-
parallel type to parallel one by increasing the amount of
PEG200 (Fig. 1f).12 However, both the activity and the
enantioselectivity of the enantioselective F–C reaction are
decreasing (Fig. 1e, Table S2 in ESIw).
To investigate the sequence variations of the G4DNA
metalloenzyme in the enantioselective F–C reaction, 21-mer
oligodeoxynucleotides with different loop sequences were tested.
In the presence of Na+ ions, ODN-1–Cu2+ (loop sequence
TTA) and ODN-2–Cu2+ (loop sequence TTT) generate the
product 3a with 75% ee and 6% ee, respectively (Table 2,
entries 1 and 2). However, ODN-3–Cu2+ (loop sequence
ATA), ODN-4–Cu2+ (loop sequence TAT), ODN-5–Cu2+
Table 2 Loop sequence variations of the G4DNA metalloenzymea
Entry Catalyst
ODN sequence
Conversionb (%) eec (%)
1
2
3
4
5
6
ODN-1–Cu2+ 50-G3(TTAG3)3-30 99
ODN-2–Cu2+ 50-G3(TTTG3)3-30 92
ODN-3–Cu2+ 50-G3(ATAG3)3-30 95
ODN-4–Cu2+ 50-G3(TATG3)3-30 95
ODN-5–Cu2+ 50-G3(AAAG3)3-30 85
ODN-6–Cu2+ 50-G3(AATG3)3-30 95
75
6
ꢁ7
ꢁ6
ꢁ17
ꢁ16
a
Reaction conditions: 1a (1 mmol, 1 eq.), 2a (5 eq.), ODN (0.1 eq.),
Cu(NO3)2 (0.05 eq.), NaCl (50 mM), MOPS buffer (20 mM, pH 6.5),
Fig. 1 The ee values of product 3a for the F–C reaction catalyzed by
ODN-1–Cu2+ with tuning the concentration of (a) Na+ ions, (c) K+
ions, and (e) PEG200. The corresponding CD spectra of
ODN-1–Cu2+ by varying the concentration of (b) Na+ ions,
(d) K+ ions, and (f) PEG200.
b
4 1C, 24 h. All data are averaged by two experiments. Determined by
chiral-phase HPLC for the crude product (Scheme S1, ESI). Repro-
c
ducible within ꢀ5%. Determined by chiral-phase HPLC. Repro-
ducible within ꢀ5%.
c
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Table 3 Substrate scope for the enantioselective F–C reactionsa
avenue to construct a controllable DNA metalloenzyme for
chemical and enzymatic synthesis using the accessible DNA.
We thank Prof. Z. Feng, Prof. Q. Yang and Dr J. Li for
their helpful discussions. This work was supported by the
NSFC (20773123, 20621063, 31000392).
Entry
1
2
3
Conversionb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
99
99
93
99
91
61
72
37
75
67
66
8
44
21
7
Notes and references
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a
Reaction conditions: 1 (1 mmol, 1 eq.), 2 (5 eq.), ODN-1 (0.1 eq.),
Cu(NO3)2 (0.05 eq.), NaCl (50 mM), MOPS buffer (20 mM, pH 6.5),
4 1C, 24 h. Determined by 1H-NMR for the crude product averaged
b
c
by two experiments. Reproducible within ꢀ10%. Determined by
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(loop sequence AAA) and ODN-6–Cu2+ (loop sequence
AAT) provide the product 3a in the reversed configuration
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entries 3–6). Minor mutations in the loop sequence of G4DNA
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ODN-1–Cu2+, non-structured 21-mer oligodeoxynucleotides
containing d(TTA) combining with Cu2+ ions show the
racemic products, indicating that the G-quadruplex structure
is essential for the enantioselective F–C reaction (Table S3,
ESIw).
Various substituted 2-acylimidazoles (1a–e) and substituted
indoles (2a–e) were tested for the enantioselective F–C reac-
tions catalyzed by ODN-1–Cu2+. We were pleased to find that
the ODN-1–Cu2+ could provide nearly full conversions for the
F–C reactions with 2-acylimidazole (1a) and a variety of
substituted indoles (2a–e). Compared to the F–C reaction
between 1a and indole (2b) that generates 67% ee (Table 3,
entry 2), the reactions with 1a and 5-methoxy indole (2a) and
5-chloro indole (2c) provide the corresponding product 3a in
75% ee and 3c in 66% ee (Table 3, entries 1 and 3), which
indicates that the electronic effect of the substitute substantially
influences the F–C reaction. In addition, substituted indoles
such as 1-methyl indole (2d) and 2-methyl indole (2e) reacted
with 1a to generate the corresponding products in 8% ee and
44% ee, respectively (Table 3, entries 4 and 5). Moreover,
2-acylimidazoles with aromatic moieties (1b–e) reacted with
2a yield the corresponding F–C products in low enantio-
selectivities (Table 3, entries 6–9). Compared to the F–C reaction
between 1b and 2a (Table 3, entry 6), the 2-acylimidazoles with
another substituent (p-Br, p-Cl and p-MeO) in the aromatic
moiety of R1 reacted with 2a yield the corresponding F–C
products with decreased activities and enantioselectivities.
In summary, we found that human telomeric G4DNA can
serve as a direct chiral catalyst for the enantioselective F–C
reaction. When a G4DNA metalloenzyme is derived from
Cu2+ ions and G4DNA, the activity and the enantioselectivity
of the F–C reaction are considerably enhanced. Furthermore,
we found that the absolute configuration and the enantio-
selectivity of the product are sensitive to the DNA sequence,
and the loop sequence in the G4DNA metalloenzyme plays an
important role in the chiral expression. This work opens a new
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6234 Chem. Commun., 2012, 48, 6232–6234
This journal is The Royal Society of Chemistry 2012