Deciphering DNA-based asymmetric catalysis through intramolecular Friedel-Crafts alkylations

Article abstract of DOI:10.1039/c2cc35625b

We describe asymmetric intramolecular Friedel-Crafts alkylations with a DNA-based hybrid catalyst and propose a plausible binding model. This study shows promise for studying relationships between the helical chirality of DNA and enantioselectivity of the chemical reaction.

Full text of DOI:10.1039/c2cc35625b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 10398–10400
www.rsc.org/chemcomm
COMMUNICATION
Deciphering DNA-based asymmetric catalysis through intramolecular
Friedel–Crafts alkylationsw
Soyoung Park,a Keiichi Ikehata,a Ryo Watabe,a Yuta Hidaka,a Arivazhagan Rajendrana and
Hiroshi Sugiyama*abc
Received 17th May 2012, Accepted 3rd September 2012
DOI: 10.1039/c2cc35625b
We describe asymmetric intramolecular Friedel–Crafts alkylations
with a DNA-based hybrid catalyst and propose a plausible binding
model. This study shows promise for studying relationships between
the helical chirality of DNA and enantioselectivity of the chemical
reaction.
intramolecular Friedel–Crafts alkylations with a DNA-based
hybrid catalyst and propose a plausible stereochemical model
to explain the obtained enantioselective outcome.6,7
We first investigated the reaction of 1 with DNA-based
catalysts consisting of st-DNA-bound copper(II) complexes
with the 4,40-dimethyl-2,20-bipyridine (dmbpy) ligand, which
gave the best result for intermolecular reactions performed in
water at 5 1C for two days. It was found that the combination
of st-DNA and Cu(dmbpy) provided cyclized product 2 in
18% yield with 35% enantiomeric excess (ee) (Fig. 1).2g The
absence of st-DNA resulted in the corresponding product as
racemates (see ESIw).
The absolute configuration of the product was determined
by HPLC analysis by comparison with the previous report.7b
In the present reaction system, it was found that the (S)-
enantiomer is obtained as the major enantiomer. To improve
the reaction, the various ligands were examined (see ESIw,
Fig. S1 and Table S1). The catalysts based on the phenanthroline
ligands improved enantioselectivity to 58% ee. The best ee
value was obtained with a phenanthroline derivative, namely
5,6-dimethyl-1,10-phenanthroline (5,6-dmp), up to 71% ee (for
the (S)-enantiomer). All further experiments were performed
using the copper complex of 5,6-dmp selected as the optimized
catalytic system.
The application of DNA-based hybrid catalysts for enantio-
selective synthesis emerged only a few years ago. In 2005,
Feringa and Roelfes introduced the concept of a novel catalyst
on the basis of supramolecular assembly using a copper
complex of a nonchiral ligand that can bind to DNA.1 Since
then, DNA-based hybrid catalysts have been successfully
applied to various asymmetric carbon–carbon or carbon–
heteroatom bond-forming reactions such as the Diels–Alder
reaction, Michael addition and Friedel–Crafts reactions.2 The
use of DNA in these Lewis-acid catalyzed reactions led to high
enantioselectivity, whereas the corresponding products were
obtained as racemates in the absence of DNA. Therefore, it is
clear that the enantioselectivity of the reactions originated
from DNA; however, the stereoinduction mechanism has been
much less studied to date.3,4 This aroused our curiosity as to
how DNA induces enantioselectivity in the reactions. To
investigate the stereoinduction mechanism of DNA-based
asymmetric synthesis, we thought that an intramolecular
reaction system might be more suitable because it significantly
reduces the conformational freedom compared with an inter-
molecular reaction. Of the reported intermolecular reactions,
we selected the Friedel–Crafts reaction as a model reaction for
the intramolecular reaction.5 The previously reported intra-
molecular cyclization reaction of 1 by bis(oxazolinyl)pyridine-
scandium(III) triflate complexes can be considered as a good
candidate for our investigation.7b Herein, we report asymmetric
To construct a molecular model of the DNA-mediated
enantioselective reaction, the effect of the DNA sequence on
this catalysis was investigated using synthetic oligonucleotides;
the results are summarized in Table 1. Oligonucleotides with
sequences d(TCAGGGCCCTGA)2, reported to afford high
enantioselectivity for an intermolecular Friedel–Crafts reaction,
a Department of Chemistry, Graduate School of Science,
Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku,
Kyoto 606-8502, Japan
b Institute for Integrated Cell-Material Sciences (iCeMS),
Kyoto University, Yoshida-ushinomiyacho, Sakyo-ku,
Kyoto 606-8501, Japan
c CREST, Japan Science and Technology Corporation (JST),
Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan.
E-mail: hs@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-3670;
Tel: +81-75-753-4002
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc35625b
Fig. 1 DNA-based intramolecular Friedel–Craft alkylation.
c
10398 Chem. Commun., 2012, 48, 10398–10400
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 1 Dependence of the ee on the DNA sequence in the case of
Cu-(5,6-dmp)
Table 2 Substrate scope
Entry DNA sequence
eea (%)
1
2
3
4
5
6
st-DNA
71
60
50
60
74
77
d(CGCGCGCGCGCG)2
d(TCAGGGCCCTGA)2
d(AAAAAATTTTTT)2
d(TATATATATATA)2
d(TGTGTGCACACA)2
Yielda (%)
st-DNA
eea (%)
st-DNA
eeb (%)
DNA-1
Entry
R1
R2
R3
1
2
3
Ph
py
lm
lm
lm
lm
lm
lm
H
H
H
H
H
H
Me
Bn
H
H
H
F
Br
MeO
H
No conv.
nd
38
71
70
77
78
7
nd
nd
77
70
80
82
nd
nd
7
8
9
10
11
12
13b
14c
15c
d(GTGTGTGTGTGT) + d(ACACACACACAC) 74
2
54
64
41
51
45
91
12
d(GTGTGTGTGTGT)
d(ACACACACACAC)
3
4c
5d
6e
7
d(TGCA)2
d(TGTGCACA)2
d(TGTGTGTGTGTGCACACACACACA)2
d(CMeGCGCMeGCGCMeGCG)2
h-telo d(AGGGTTAGGGTTAGGGTTAGGG)
0
50
77
40
19
8
H
4
c-myc d(AGGGAGGGCGCTGGGAGGAGGG) 26
a
Experiments were carried out with 0.045 mM of substrates, 1.4 mg mLꢀ1
st-DNA, 30 mol% Cu-ligand, at 5 1C, in 20 mM MOPS buffer (pH 6.5), for
1 day, unless otherwise mentioned. b DNA-1: d(TGTGTGCACACA)2,
1.1 mM of substrates, 1.4 mg mLꢀ1 st-DNA, 30 mol% Cu-ligand, at 5 1C,
in 20 mM MOPS buffer (pH 6.5), for 1 day. c Reaction time: 12 h.
d Reaction time: 18 h. e Reaction time: 8 h. nd: no experiment was
performed and no datum is available.
a
All experiments were carried out with 1.1 mM of substrates, 1.4 mg mLꢀ1
DNA, 30 mol% Cu-ligand, at 5 1C, in 20 mM MOPS buffer (pH 6.5),
for 1 day, unless otherwise noted. Experiments were carried out with
50 mM NaCl, MeG = 8-methylguanine. Experiments were carried
out with 100 mM KCl.
b
c
Although the N-methyl indole afforded the corresponding
product with high ee in the intermolecular system, the tethered
N-alkylated indole substrates gave products with very low
enantioselectivities in this intramolecular system (Table 2,
entries 7 and 8).2g Unfortunately, we observed that the corres-
ponding reaction to form the five-membered ring was
unsuccessful.7b
resulted in lower ee values (50%) than st-DNA in the present
reaction system.2g GC-rich duplexes gave rise to a slight decrease
in enantioselectivity (60%), whereas the presence of TA-rich
duplexes was beneficial to this reaction. These results indicate that
the sequence selectivity of the catalytic reaction differs from that of
the intermolecular system. In the present reaction system, oligo-
nucleotides with sequences d(TGTGTGCACACA)2 induced the
highest ee (up to 77% ee; Table 1, entry 6). As shown in entry 7,
while duplex DNA consisting of d(GTGTGTGTGTGT) and
d(CACACACACACA) gave the product with 74% ee, each
single-stranded DNA sequence resulted in an almost racemic
product (Table 1, entries 8 and 9). When the length of the
oligonucleotides was reduced from a dodecamer to an octamer,
the ee value dropped, and the product was obtained as racemates
using a tetramer (Table 1, entries 10 and 11). Increasing the DNA
length above that of the dodecamer did not lead to further
improvement in the enantioselectivity (Table 1, entry 12). In
regard to chirality of the DNA double helix, Z-DNA with a left-
handed double helical structure was used as a chiral scaffold.
Z-DNA gave rise to a decrease in enantioselectivity for the
present system, contrary to our expectation that left-handed
Z-DNA could primarily induce the opposite enantiomer com-
pared with right-handed B-DNA (Table 1, entry 13). In addition
to the duplex, two G-quadruplex-forming sequences (h-telo and
c-myc) were investigated and gave the desired product, albeit
with low enantioselectivity (Table 1, entries 14 and 15).8
Based on these data we constructed a tentative binding model,
which will allow us to decipher the DNA-based asymmetric
catalysis. The oligonucleotides with sequences d(TGTGTGCA-
CACA)2, which afforded the best enantioselectivity for the present
reaction to date, were selected as receptors for the copper(II)
complexes. In regard to the binding mode to DNA, the melting
temperature of d(TGTGTGCACACA)2 slightly increased in the
presence of Cu(5,6-dmp), suggesting that the DNA duplex is
stabilized by binding to Cu(5,6-dmp).10 Furthermore, viscosity
studies of st-DNA solution with Cu(5,6-dmp) gave the results to
support the intercalative binding. Because it is also known that
planar heterocyclic aromatic rings such as phenanthroline or
acridine insert between the base pairs of the DNA double helix
through intercalative binding,11 we postulate that Cu(5,6-dmp)
complexes insert into the base-pair layers in the DNA
minor groove by intercalation. Subsequently, the binding
model was constructed based on (S)-enantiomer complex with
Cu(5,6-dmp) (Fig. 2). These models are tentative and we are
currently undertaking computational studies to explain the
stereoinduction mechanism.
The scope of this intramolecular system was investigated
under optimized reaction conditions (Table 2). The inability to
form a chelate with copper led to inability to perform the
present catalysis (Table 2, entry 1).9 In place of 2-acyl imidazole,
use of the 2-acyl pyridyl group decreased enantioselectivity of the
product (Table 2, entry 2). Tethered indole derivatives containing
electron-withdrawing or electron-donating substituents catalyzed
by st-DNA/Cu(5,6-dmp) gave the corresponding product in
moderate yield with good enantioselectivity (Table 2, entries
3–6). The obtained ee values indicate that the substituents on
indole do not have a significant influence on enantioselectivity.
In this study, we describe asymmetric intramolecular Friedel–
Crafts alkylations with a DNA-based hybrid catalyst and propose
a plausible binding model on the basis of the inference from the
data. Although further investigation is needed to understand the
binding mode of the copper complex to DNA, our model shows
promise for studying relationships between the helical chirality of
DNA and enantioselectivity of the chemical reaction. Further
studies are under way to explore more details of the present
catalysis, including mechanistic studies as well as the improve-
ment of enantioselectivity.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10398–10400 10399

View Article Online
(g) A. J. Boersma, B. L. Feringa and G. Roelfes, Angew. Chem.,
Int. Ed., 2009, 48, 3346–3348; (h) A. J. Boersma, D. Coquiere,
D. Geerdink, F. Rosati, B. L. Feringa and G. Roelfes, Nat. Chem.,
2010, 2, 991–995.
3 (a) A. J. Boersma, J. E. Klijn, B. L. Feringa and G. Roelfes, J. Am.
Chem. Soc., 2008, 130, 11783–11790; (b) F. Rosati, A. J. Boersma,
J. E. Klijn, A. Meetsma, B. L. Feringa and G. Roelfes, Chem.–Eur.
J., 2009, 15, 9596–9605.
4 For reviews, see: (a) S. Park and H. Sugiyama, Angew. Chem., Int.
Ed., 2010, 49, 3870–3878; (b) E. W. Dijk, A. J. Boersma,
B. L. Feringa and G. Roelfes, Org. Biomol. Chem., 2010, 8,
3868–3873; (c) F. Rosati G. Roelfes, ChemCatChem, 2010, 2,
916–927; (d) A. J. Boersma, R. P. Megens, B. L. Feringa and
G. Roelfes, Chem. Soc. Rev., 2010, 39, 2083–2092;
(e) S. K. Silverman, Angew. Chem., Int. Ed., 2010, 49, 7180–7201.
5 DNA-templated synthesis based on DNA complexation is also
essentially intramolecular. For reviews, see: (a) L. E. Orgel, Acc.
Chem. Res., 1995, 28, 109–118; (b) D. Summerer and A. Marx,
Angew. Chem., Int. Ed., 2002, 41, 89–90; (c) X. Li and D. R. Liu,
Angew. Chem., Int. Ed., 2004, 43, 4848–4870.
6 For nonasymmetric examples of intramolecular Friedel–Crafts
alkylations, see: M. Bandini, A. Melloni, S. Tommasi and
A. Umani-Ronchi, Synlett, 2005, 1199–1222.
7 For the asymmetric intramolecular Friedel–Crafts alkylations, see:
(a) M. G. Banwell, D. A. Beck and J. Smith, Org. Biomol. Chem.,
2004, 2, 157–159; (b) D. A. Evans, K. R. Fandrick, H.-J. Song,
K. A. Scheidt and R. Xu, J. Am. Chem. Soc., 2007, 129,
10029–10041.
Fig. 2 Tentative binding model of DNA and (S)-enantiomer complex
with Cu(5,6-dmp) based on the intercalation.
8 S. Roe, D. J. Ritson, T. Garner, M. Searle and J. E. Moses, Chem.
Commun., 2010, 46, 4309–4311.
9 S. Otto, F. Bertoncin and J. B. F. N. Engberts, J. Am. Chem. Soc.,
1996, 118, 7702–7707.
10 Feringa and Roelfes proposed a mixture of binding modes,
including intercalation. In the case of Cu(dmbpy), they suggest
that intercalation may not be the dominant binding mode because
the melting temperature of st-DNA decreased slightly in the
presence of Cu(dmbpy).
We express our sincere thanks for the CREST grant from
the Japan Science and Technology Corporation (JST), grants
from the WPI program (iCeMS, Kyoto University), and for
the global COE program from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
A. R. expresses sincere thanks to the Japan Society for the
Promotion of Science (JSPS) for the Postdoctoral fellowship.
11 (a) A. Sawaryn, B. Leps and H. Bradaczek, J. Comput. Chem., 1983,
4, 333–336; (b) A. Wolfe, G. H. Shimer Jr. and T. Meehan,
Biochemistry, 1987, 26, 6392–6393; (c) L. D. Williams, M. Egli,
Q. Gao and A. Rich, Structure & Function, Volume I: Nucleic Acids,
1992, pp. 107–125; (d) K. E. Erkkila, D. T. Odom and J. K. Barton,
Chem. Rev., 1999, 99, 2777–2795; (e) N. W. Luedtke, J. S. Hwang,
E. Nava, D. Gut, M. Kol and Y. Tor, Nucleic Acids Res., 2003, 31,
5732–5740; (f) A. D. Richards and A. Rodger, Chem. Soc. Rev.,
2007, 36, 471–483; (g) B. M. Zeglis, V. C. Pierre and J. K. Barton,
Notes and references
1 G. Roelfes and B. L. Feringa, Angew. Chem., Int. Ed., 2005, 44,
3230–3232.
2 (a) G. Roelfes, A. J. Boersma and B. L. Feringa, Chem. Commun.,
2006, 635–637; (b) A. J. Boersma, B. L. Feringa and G. Roelfes,
Org. Lett., 2007, 9, 3647–3650; (c) D. Coquiere, B. L. Feringa and
G. Roelfes, Angew. Chem., Int. Ed., 2007, 46, 9308–9311;
(d) N. Shibata, H. Yasui, S. Nakamura and T. Toru, Synlett,
2007, 1153–1157; (e) N. Sancho Oltra and G. Roelfes, Chem.
Commun., 2008, 6039–6041; (f) E. W. Dijk, B. L. Feringa and
G. Roelfes, Tetrahedron: Asymmetry, 2008, 19, 2374–2377;
¨
Chem. Commun., 2007, 4565–4579; (h) O. Persil and N. V. Hud,
Trends Biotechnol., 2007, 25, 433–436; (i) Y. J. Jang, G.-Y. Yeo,
B. Park and S. K. Kim, Biophys. Chem., 2011, 158, 38–45;
(j) H.-K. Liu and P. J. Sadler, Acc. Chem. Res., 2011, 44, 349–359.
c
10400 Chem. Commun., 2012, 48, 10398–10400
This journal is The Royal Society of Chemistry 2012