Enantioselective Michael addition reactions in water using a DNA-based catalyst

Article abstract of DOI:10.1016/j.tet.2013.05.133

Enantioselective Michael addition reactions of malononitrile and cyanoesters to α,β-unsaturated 2-acylimidazoles can be achieved in water using a DNA-based catalyst consisting of double-stranded DNA and copper(II) complex. Quantitative conversions and good enantioselectivities (up to 84% ee) are obtained for a wide range of substrates. The UV-vis absorption and circular dichroism (CD) indicate that the copper(II) complex may interact with salmon testes DNA via minor groove binding.

Full text of DOI:10.1016/j.tet.2013.05.133

Tetrahedron 69 (2013) 6585e6590
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective Michael addition reactions in water using
a DNA-based catalyst
,
,
,
Yinghao Li a b, Changhao Wang a b, Guoqing Jia a, Shengmei Lu a, Can Li a
*
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
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective Michael addition reactions of malononitrile and cyanoesters to
a,b-unsaturated 2-
Received 26 March 2013
Received in revised form 24 May 2013
Accepted 30 May 2013
acylimidazoles can be achieved in water using a DNA-based catalyst consisting of double-stranded
DNA and copper(II) complex. Quantitative conversions and good enantioselectivities (up to 84% ee)
are obtained for a wide range of substrates. The UVevis absorption and circular dichroism (CD) indicate
that the copper(II) complex may interact with salmon testes DNA via minor groove binding.
Ó 2013 Published by Elsevier Ltd.
Available online 5 June 2013
Keywords:
Water
Asymmetric catalysis
Salmon testes DNA
Michael addition
Lewis acid
1. Introduction
proceed as well.7 Very recently, a human telomeric G4DNA alone
has been found to show enantioselective catalytic function and its
The development of catalytic enantioselective reactions in
aqueous media has received a great deal of attention in recent
years.1 Water is an ideal solvent because it is not only cheap, safe
and environmentally benign, but in some cases can also accelerate
the reaction rate and influence the reaction selectivity. Since the
water-enhanced DielseAlder reaction pioneered by Breslow in the
1980s,2 a series of carbonecarbon bond formation reactions and
their enantioselective fashions, e.g., aldol reactions, pericyclic re-
actions, and Mannich reactions have been developed in aqueous
media.3 In nature, many chemical transformations with high ster-
eoselectivities are catalyzed by enzymes in aqueous environments,
which inspires chemists to develop new methodologies to create
new carbonecarbon bonds and stereocentres.4 Learning from the
nature, utilizing biomolecules as sources of chiral catalysts or chiral
auxiliaries is highly promising for achieving enantioselective re-
actions in water. Amino acids and their derivatives have been
proved to be excellent organocatalysts for water-involved enan-
tioselective reactions.5 The unique structure of DNA has recently
aroused many interests in enantioselective catalysis. A DNA-based
catalyst composing of double-stranded DNA and transition metal
complex has been successfully applied to a series of enantiose-
lective reactions in water,6 and G-quadruplex DNA (G4DNA) can
copper(II) metalloenzyme can remarkably enhance the reactivity
and the enantioselectivity in DielseAlder reactions and Friedele-
Crafts reactions.8
As one of the important asymmetric reactions, enantioselective
Michael addition reaction is one of the most important
carbonecarbon bond-forming reactions in organic synthesis.9
Much effort has been devoted to the development of novel chiral
catalysts, such as organocatalysts10 and Lewis acid catalysts11 for
enantioselective Michael reactions in aqueous media. Although
DNA-based catalysis has been applied to an enantioselective Mi-
chael addition6b using nitromethane and dimethyl malonate as
nucleophiles, the requirement of useful building blocks with vari-
ous nucleophiles in the organic synthesis still needs further work.
Herein, we report that an enantioselective Michael addition re-
action in water has been achieved using a DNA-based catalyst be-
tween
a,b-unsaturated 2-acylimidazoles and nucleophiles
including malononitrile and cyanoacetates. We found that nearly
full conversions and good enantioselectivities up to 84% ee can be
obtained using DNA-based catalysts for a wide range of substrates.
2. Results and discussion
2.1. Optimization
As shown in Scheme 1, we tried to investigate whether enan-
tioselective Michael reactions of a,b-unsaturated 2-acylimidazoles
* Corresponding author. Tel.: þ86 411 84379070; fax: þ86 411 84694447; e-mail
address: canli@dicp.ac.cn (C. Li).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.05.133

6586
Y. Li et al. / Tetrahedron 69 (2013) 6585e6590
Compared with the amount of copper(II) complex at 30 mol %,
the conversion and the enantioselectivity cause no significant
changes when the copper(II) complex loading is decreased to
10 mol % (Table 1, entry 5 vs entry 6), but further deceasing the
copper(II) complex to 5 mol % leads to reduced conversion and
enantioselectivity (Table 1, entry 5 vs entry 7). In order to rule out
the influence of the source of double-stranded DNA, calf thymus
DNA (ctDNA) was tested and similar results were obtained com-
pared to those of stDNA (Table 1, entry 5 vs entry 8). In addition, we
also investigated a guanine-rich single-stranded human telomeric
DNA (htDNA, 50-G3(T2AG3)3-30), which can fold into an antiparallel
G-quadruplex in Naþ-containing solution.12 Using G-quadruplex
DNA as a chiral scaffold, nearly racemic products are obtained for
the corresponding Michael reactions either in the presence or ab-
sence of the ligand (Table 1, entries 9 and 10).
2.2. Substrate scope and limitations
The substrate scope of a,b-unsaturated 2-acylimidazoles (1aef)
Scheme 1. Schematic representation of the enantioselective Michael addition re-
actions in water catalyzed by Cu(Ln)(NO3)2 in the presence of DNA.
and nucleophiles (2aee) was investigated under optimized re-
action conditions (Table 2). Quantitative conversions are obtained
in the DNA-based asymmetric Michael reactions between 2-
acylimidazoles (1aef) and malononitrile (2a) (Table 2, entries
1e6). Compared with the Michael reaction between 1a and 2a,
there are no significant changes for the enantioselectivities of the
Michael reactions when the substrates bear with electron-donating
substituents, such as p-methylphenyl (1b) and p-methoxyphenyl
(1c) (Table 2, entries 2, 3 vs entry 1). However, the enantiose-
lectivities obviously decrease when employing the substrates with
electron-withdrawing groups, i.e., p-bromophenyl (1d) and o-bro-
mophenyl (1e) (Table 2, entries 4, 5 vs entry 1). When R1 in the 2-
acylimidazole changes from an aryl (1a, R1¼Ph) to an alkyl group
(1f, R1¼Me), decreased ee value is obtained (Table 2, entry 6). In
the case of methyl cyanoacetate (2b) as nucleophile, the
(1aef) and nucleophiles (2aee) can be achieved using DNA-based
catalysts composing of salmon testes DNA (stDNA) and achiral
copper(II) complexes. For an initial attempt, a typical Michael re-
action between (E)-1-(1-methyl-1H-imidazol-2-yl)-3-phenylprop-
2-en-1-one (1a) and malononitrile (2a) was selected to examine
the catalytic function of the DNA-based catalysts (Table 1). With
only stDNA and copper(II) salt as the catalysts, the Michael reaction
provides modest conversion (55%) and racemic product (Table 1,
entry 1). While in the presence of 1,10-phenanthroline (L1) as li-
gand, the conversion of 1a is improved to 78% and the enantiomeric
excess (ee) of 3a is at 17% (Table 1, entry 2), indicating that the
chirality of DNA can be successfully transferred to the Michael
product. When tuning the steric element of ligand to 5,6-dimethyl-
1,10-phenanthroline (L2), a little higher conversion and enantio-
selectivity were obtained compared with those of ligand L1
(Table 1, entry 3 vs entry 2). With the ligand 4,40-dimethyl-2,20-
bipyridine (L4), nearly full conversion and good enantioselectivity
at 68% ee are obtained (Table 1, entry 5), but lack of methyl groups
of L3 results in deceased conversion and ee value (Table 1, entry 4),
which is in accordance with the trend in the previous reports.6b,6d
Table 2
Substrate scope for the DNA-based enantioselective Michael addition reactionsa
Table 1
Screening of the reaction conditions for the Michael addition reactiona
Entry
1
2
Product
Conversionb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1a
1a
1a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
>99
>99
>99
>99
>99
>99
>99
>99
>99
54
68
72
64
57
31
Entry
DNA
Cu(Ln)(NO3)2
Conversionb (%)
eec (%)
Cu(NO3)2 (mM)
Ln
1
2
3
4
5
6
7
8
stDNA
0.30
0.30
0.30
0.30
0.30
0.10
0.05
0.30
0.05
0.05
None
L1
L2
L3
L4
L4
L4
L4
L4
55
78
84
0
17
31
23
68
66
55
62
2
36
4ad
4bd
4cd
4dd
5d
71e
76e
84e
67f
64f
63f
45f
72
9
>99
>99
88
>99
>99
82
10
11
12
13
95
37
<5
6d
ctDNA
htDNA
htDNA
7d
9d
10d
a
Reaction conditions:
1
(1 mmol), 2 (0.1 mmol, 100 equiv), Cu(L4)(NO3)2
None
4
(0.3 equiv), salmon testes DNA (1.4 mg/mL), 3-(N-morpholino)propanesulfonic acid
buffer (1 mL, 20 mM, pH 6.5), 4 ꢀC, 24 h. All data are averaged by two separated
experiments.
a
Reaction conditions: 1a (1 mmol), 2a (0.1 mmol, 100 equiv), salmon testes DNA
or calf thymus DNA (stDNA or ctDNA, 1.4 mg/mL), human telomeric DNA (htDNA, 50-
b
G3(T2AG3)3-30, 100
m
M), 3-(N-morpholino)propanesulfonic acid buffer (1 mL,
Determined by 1H NMR within the reproducibility of ꢁ10%.
c
20 mM, pH 6.5), 24 h, 4 ꢀC. All data are averaged by two separated experiments.
Determined by chiral HPLC within the reproducibility of ꢁ5%.
b
d
Determined by 1H NMR within the reproducibility of ꢁ10%.
Products were obtained as roughly 1:1.5 mixture of two diastereoisomers.
c
e
Determined by chiral HPLC within the reproducibility of ꢁ5%.
The same ee values were obtained for the two diastereoisomers of the products.
d
f
50 mM NaCl was added to form antiparallel G-quadruplex conformation.
The ee values were obtained for the major diastereoisomers of the products.

Y. Li et al. / Tetrahedron 69 (2013) 6585e6590
6587
40
30
enantioselectivities are all good to the Michael reaction of various
2-acylimidazoles (1aed) (Table 2, entries 7e10). In particular, the
ee value is up to 84% ee when using 1c and 2b as substrates (Table 2,
entry 9). In addition, the other substituted cyanoacetates (2cee)
were also investigated. With the ester group of nucleophiles be-
coming larger (methyl/ethyl/iso-propyl/tert-butyl), the re-
activity and the enantioselectivities of the Michael reactions
decreased obviously (Table 2, entries 7, 11e13). The above results
indicate that the electronic and steric effects cause great effect on
the enantioselective induction in the DNA-based catalysis.
In order to demonstrate the practicability of this DNA-based
enantioselective Michael addition reaction, we carried out the re-
action with the scale of 1a and 2a at 1 mmol (1a: 212 mg). The
resulting product 3a was obtained with the isolated yield 86% and
68% ee after column chromatography. Moreover, the groups that
a
b
c
d
20
e
f
10
0
-10
-20
-30
-40
a,b-unsaturated 2-acylimidazole, nitrile, and methyl cyanoacetate
240
260
280
300
320
340
in products are synthetic potential building blocks for further
transformations, which might be useful in organic synthesis and
medical design.13 The above results suggest that the DNA-based
enantioselective Michael reaction has the potential to be applied
in organic synthesis.
Wavelength / nm
Fig. 2. CD spectra of (a) 160
ratios of stDNA/Cu-L4 are (b) 10.7, (c) 5.3, (d) 2.7, (e) 1.3, (f) 120
centration of stDNA is given in base pairs. All samples are in MOPS buffer (20 mM,
m
M stDNA and its complex with Cu-L4 (bee), the molar
M Cu-L4. The con-
m
pH¼6.5).
2.3. Binding mode
there are less changes of the negative band, but larger changes of
the positive band with regard to the intensity and position. This
suggests that the interaction of copper(II) complex with DNA has
a great influence on base pairs stacking, but little influence on the
structure of chiral skeleton. For copper(II) complex, free Cu-L4 has
no intrinsic CD signal, while an obvious induced CD signal centered
at 307 nm appears upon binding to stDNA (Fig. 2). CD spectra
clearly show that the chirality can transfer from stDNA to copper(II)
center. As positive induced signals in CD spectroscopy are generally
obtained for compounds that bind in the DNA minor groove, we
propose that the binding mode between Cu-L4 and stDNA is minor
groove binding.17 Based on the results of UVevis spectra and CD
spectra, a possible catalytic model is proposed in Scheme 1.
In attempt to rationalize the catalytic model, we tried to in-
vestigate the binding mode between the copper(II) complex (Cu-
L4) and stDNA by UVevis absorption spectroscopy and circular
dichroism spectroscopy. UVevis absorption spectra (Fig. 1) show
that, upon addition of stDNA, the characteristic band of Cu-L4
centered at 307 nm has a larger degree of hypochromicity but no
distinct shift. This is in contrast to the characteristic of intercalative
binding mode, in which the hypochromicity (ꢂ35%) and red shift
(ꢂ15 nm) are usually observed.14 So we deduces that intercalation
may not be the dominant binding mode for Cu-L4 with stDNA,
which is in agreement with previous report based on the UV
melting experiment.15
3.0
2.5
2.0
3. Conclusions
Enantioselective Michael reactions of malononitrile and cya-
noacetates to a,b-unsaturated 2-acylimidazoles have been achieved
in water using DNA-based catalysts. Quantitative conversions for
a wide scope of substrates and good enantioselectivities up to 84%
ee can be obtained. Based on the spectroscopic studies, a minor
groove binding mode is proposed. This work presents another ex-
ample for the double-stranded DNA-based asymmetric catalysis
and might provide an opportunity to reveal catalytic functions
of DNA.
307 nm
1.5
1.0
0.5
0.0
a
b
c
d
4. Experimental section
e
4.1. Materials and methods
260
280
300
320
340
360
Wavelength / nm
Salmon testes DNA (stDNA) and calf thymus DNA (ctDNA) were
purchased from SigmaeAldrich. 3-(N-morpholino)propanesulfonic
acid (MOPS) and 2-(N-morpholino)ethanesulfonic acid (MES) were
purchased from Sangon (Shanghai, China). 1,10-Phenanthroline (L1,
phen), 2,20-bipyridine (L3, bpy), 4,40-dimethyl-2,20-bipyridine (L4,
dmbpy) were purchased from J&K (Beijing, China). 5,6-Dimethyl-
1,10-phenanthroline (L2, 5,6-dmp) was purchased from TCI.
Malononitrile (2a) and cyanoacetates (2bee) were purchased from
Alfa Aesar (Tianjin, China). All other chemicals and solvents were
obtained from commercial sources and used as supplied without
further purification. Water was distilled and deionized (specific
Fig. 1. UVevis absorption spectra of (a) 65
mM Cu-L4 and its complex with stDNA
(bed). The molar ratios of stDNA/Cu-L4 are (b) 0.5, (c) 1.0, (d) 3.0; (e) 195
The concentration of stDNA is given in base pairs. All samples are in MOPS buffer
mM stDNA.
(20 mM, pH¼6.5).
CD spectroscopy is sensitive to characterize the asymmetric
information of chiral materials. As shown in Fig. 2, the CD spectrum
of free stDNA has emerging two characteristic bands, a negative
band at 245 nm due to the helicity and a positive band at 276 nm
due to the base stacking, which is the characteristic of DNA in the
right-handed B-form.16 With the addition of copper(II) complex,
resistance of 18.2 M
U
at 25 ꢀC) using a Milli-Q A10 water

6588
Y. Li et al. / Tetrahedron 69 (2013) 6585e6590
purification system. Copper complexes were prepared according to
3.78e3.66 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 188.8, 160.1, 142.3,
129.9, 129.4, 128.4, 127.9, 114.6, 112.1, 111.8, 55.4, 41.0, 40.7, 36.2,
29.6; HRMS (ESþ) calcd for C17H17O2N4 [MþH]þ: 309.1352, found:
309.1345; ee’s were determined by HPLC analysis (Daicel Chiralpak-
the procedure.18
a,
b
-unsaturated 2-acylimidazoles 1aef were pre-
pared according to the literature.19
Circular dichroism (CD) spectra were recorded on a dual beam
DSM 1000 CD spectrophotometer (Olis, Bogart, GA) with a 10 mm
quartz cell. Each measurement was recorded at room temperature
(about 20 ꢀC). The average scan for each sample was subtracted by
a background CD spectrum of corresponding buffer solution.
UVevis experiments were carried out on a Shimadzu 2450 spec-
trophotometer (Shimadzu, Japan) equipped with a Peltier tem-
perature control accessory. All UVevis spectra were measured
using a sealed quartz cell with a path length of 1.0 cm. 1H NMR
spectra were recorded on 400 MHz in CDCl3 and 13C NMR spectra
were recorded on 100 MHz in CDCl3 using TMS or residual protic
solvent signals as internal standard. Data for 1H NMR are recorded
AD, n-hexane/i-PrOH 85:15, flow rate 1.0 mL/min,
tention times: 30.7 (minor) and 37.0 (major) mins (64% ee).
l
¼254 nm). Re-
4.2.4. 2-(1-(4-Bromophenyl)-3-(1-methyl-1H-imidazol-2-yl)-3-
oxopropyl)malononitrile (3d). Colorless oil. 1H NMR (400 MHz,
CDCl3):
d
7.54 (d, J¼8.1 Hz, 2H), 7.32 (d, J¼8.1 Hz, 2H), 7.17 (s, 1H),
7.08 (s, 1H), 4.46 (d, J¼4.8 Hz, 1H), 4.01e3.85 (m, 5H), 3.79e3.66 (m,
1H); 13C NMR (100 MHz, CDCl3):
d 188.3, 142.2, 135.4, 132.5, 130.0,
129.9, 128.1, 123.4, 111.8, 111.4, 41.2, 40.4, 36.3, 29.2; HRMS (ESþ)
calcd for C16H14ON4Br [MþH]þ: 357.0351, found: 357.0345; ee’s
were determined by HPLC analysis (Daicel Chiralpak-AD, n-hexane/
as follows: chemical shift
(
d
,
ppm), multiplicity (s¼singlet,
i-PrOH 85:15, flow rate 1.0 mL/min,
24.4 (minor) and 33.2 (major) mins (57% ee).
l
¼254 nm). Retention times:
d¼doublet, t¼triplet, q¼quartet, m¼multiplet or unresolved, cou-
pling constant(s) in Hz, integration). Data for 13C NMR are reported
in terms of chemical shift (
d
, parts per million). High resolution
4.2.5. 2-(1-(2-Bromophenyl)-3-(1-methyl-1H-imidazol-2-yl)-3-
mass spectra (HRMS) were obtained by the ESI ionization sources.
The enantioselectivity was determined by chiral HPLC analysis
using Daicel Chiralpak-AD or AD-H column with a UV-detector by
using isopropanol and n-hexane as eluents at 25 ꢀC.
oxopropyl)malononitrile (3e). Colorless oil. 1H NMR (400 MHz,
CDCl3):
d
7.64 (d, J¼8.0 Hz, 1H), 7.54 (d, J¼7.8 Hz, 1H), 7.36 (t,
J¼7.6 Hz, 1H), 7.22 (t, J¼7.7 Hz, 1H), 7.18 (s, 1H), 7.07 (s, 1H),
4.70e4.59 (m, 1H), 4.50 (d, J¼5.4 Hz, 1H), 4.11 (dd, J¼18.1, 7.6 Hz,
1H), 3.95 (s, 3H), 3.77 (dd, J¼18.1, 6.8 Hz, 1H); 13C NMR (100 MHz,
4.2. General procedure for the conjugate addition of
malononitrile or methyl cyanoacetate to 1
CDCl3): d 187.9, 142.3, 135.7, 133.9, 130.5, 129.9, 128.6, 128.5, 127.9,
125.0, 111.8, 111.2, 39.9, 39.8, 36.2, 27.8; HRMS (ESþ) calcd for
C16H14ON4Br [MþH]þ: 357.0351, found: 357.0348; ee’s were de-
termined by HPLC analysis (Daicel Chiralpak-AD, n-hexane/i-PrOH
A DNA-based catalyst in MOPS buffer (1000
was prepared by mixing a solution of Cu(L)(NO3)2 (100
20 mM MOPS buffer) and stDNA solution (900 L, 1.6 mg/mL in
20 mM MOPS buffer). After stirring for 1 h at 4 ꢀC,
-unsaturated
2-acylimidazole 1 (10 L of 0.1 M in CH3CN) and malononitrile 2a
m
L, 20 mM, pH 6.5)
mL, 3 mM in
85:15, flow rate 1.0 mL/min,
(minor) and 41.0 (major) mins (31% ee).
l
¼254 nm). Retention times: 19.3
m
a,b
m
4.2.6. 2-(4-(1-Methyl-1H-imidazol-2-yl)-4-oxobutan-2-yl)malono-
(6.6 mg, 0.1 mmol,100 equiv) or methyl cyanoacetate 2bee (9.9 mg,
0.1 mmol, 100 equiv) were added consecutively. The reaction
mixture was stirred for 24 h at 4 ꢀC, and then extracted with diethyl
ether (3ꢃ5 mL), dried over Na2SO4, and then removed the solvent
under reduced pressure. After a short flash chromatography, the
crude product was directly analyzed by using 1H NMR and chiral
HPLC.
nitrile (3f). Colorless oil. 1H NMR (400 MHz, CDCl3):
d 7.11 (s, 1H),
7.03 (s, 1H), 4.33 (d, J¼4.3 Hz, 1H), 3.94 (s, 3H), 3.40 (dd, J¼17.8,
4.8 Hz, 1H), 3.24 (dd, J¼17.8, 8.0 Hz, 1H), 2.84e2.62 (m, 1H), 1.30 (d,
J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 189.3, 142.1, 129.5,
127.9, 112.5, 111.6, 41.7, 36.3, 31.9, 28.20, 17.3; HRMS (ESþ) calcd for
C11H13ON4 [MþH]þ: 217.1089, found: 217.1085; ee’s were de-
termined by HPLC analysis (Daicel Chiralpak-AD-H, n-hexane/i-
PrOH 90:10, flow rate 1.0 mL/min,
(major) and 23.0 (minor) mins (36% ee).
l
¼254 nm). Retention times: 21.8
4.2.1. 2-(3-(1-Methyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)ma-
lononitrile (3a). Colorless oil. 1H NMR (400 MHz, CDCl3):
d
7.48e7.32 (m, 5H), 7.19 (s, 1H), 7.08 (s, 1H), 4.48 (d, J¼5.1 Hz, 1H),
4.2.7. Methyl 2-cyano-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-
phenylpentanoate (4a). Colorless oil. 1H NMR (400 MHz, CDCl3)
(3:2 mixture of diastereomers, with signals corresponding to the
4.06e3.86 (m, 5H), 3.87e3.69 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
188.7,142.3,136.5,129.9,129.3,129.1,128.2,127.9,112.0,111.7, 41.6,
40.6, 36.2, 29.3; [
a]
20 ꢄ1.2ꢀ (c 0.8, CHCl3, 68% ee); HRMS (ESþ) calcd
major indicated by):
4.26 (d, J¼5.7 Hz, 1H), 3.94 (s, 3H), 4.19e3.58 (m, 3H), 3.65 (s, 3H);
13C NMR (100 MHz, CDCl3):
189.5, 189.0, 165.6, 165.6, 142.6, 142.5,
d 7.45e7.19 (m, 5H), 7.12 (s, 1H), 7.03 (s, 1H),
D
for C16H15ON4 [MþH]þ: 279.1246, found: 279.1241; ee’s were de-
termined by HPLC analysis (Daicel Chiralpak-AD, n-hexane/i-PrOH
d
85:15, flow rate 1.0 mL/min,
(minor) and 33.6 (major) mins (68% ee).
l
¼254 nm). Retention times: 21.1
139.0, 138.2, 129.5, 129.4, 128.9, 128.8, 128.2, 128.1, 128.0, 127.8,
127.5, 127.4, 115.5, 115.3, 53.5, 53.3, 44.2, 43.8, 41.7, 41.0, 40.4, 36.1,
20
36.1; [
a
]
ꢄ11.6ꢀ (c 0.5, CHCl3, 71% ee); HRMS (ESþ) calcd for
D
4.2.2. 2-(3-(1-Methyl-1H-imidazol-2-yl)-3-oxo-1-p-tolylpropyl)ma-
C17H18O3N3 [MþH]þ: 312.1348, found: 312.1344; ee’s were de-
lononitrile (3b). Colorless oil. 1H NMR (400 MHz, CDCl3):
d 7.32 (d,
termined by HPLC analysis (Daicel Chiralpak-AD, n-hexane/i-PrOH
J¼7.7 Hz, 2H), 7.20 (d, J¼7.7 Hz, 2H), 7.17 (s, 1H), 7.07 (s, 1H), 4.45 (d,
85:15, flow rate 1.0 mL/min,
(minor) and 25.0 (major) mins (71% ee).
l
¼254 nm). Retention times: 22.6
J¼5.2 Hz, 1H), 4.02e3.83 (m, 5H), 3.83e3.67 (m, 1H), 2.35 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 188.7, 142.3, 139.0, 133.5, 129.9, 129.8,
128.0, 127.9, 112.1, 111.8, 41.2, 40.6, 36.2, 29.5, 21.2; HRMS (ESþ)
calcd for C17H17ON4 [MþH]þ: 293.1402, found: 293.1397; ee’s were
determined by HPLC analysis (Daicel Chiralpak-AD, n-hexane/i-
4.2.8. Methyl
2-cyano-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-p-
tolylpentanoate (4b). Colorless oil. 1H NMR (400 MHz, CDCl3) (3:2
mixture of diastereomers, with signals corresponding to the major
PrOH 85:15, flow rate 1.0 mL/min,
19.7 (minor) and 25.4 (major) mins (72% ee).
l
¼254 nm). Retention times:
indicated by):
4.22 (d, J¼5.6 Hz, 1H), 3.95 (s, 3H), 4.14e3.62 (m, 3H), 3.67 (s, 3H),
2.30 (s, 3H). 13C NMR (100 MHz, CDCl3):
189.6, 189.1, 165.8, 165.6,
d 7.29e7.21 (m, 2H), 7.17e7.08 (m, 3H), 7.03 (s, 1H),
d
4.2.3. 2-(1-(4-Methoxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)-3-
142.6, 142.5,137.9,137.8,135.9,135.1,129.7,129.5, 129.4, 128.0, 127.7,
127.5, 127.4, 115.6, 115.4, 53.5, 53.4, 44.3, 44.0, 41.7, 41.0, 40.6, 40.1,
36.2, 36.2, 21.2, 21.2; HRMS (ESþ) calcd for C18H20O3N3 [MþH]þ:
326.1505, found: 326.1497; ee’s were determined by HPLC analysis
oxopropyl)malononitrile (3c). Colorless oil. 1H NMR (400 MHz,
CDCl3):
d
7.35 (d, J¼8.6 Hz, 2H), 7.16 (s, 1H), 7.06 (s, 1H), 6.91 (d,
J¼8.6 Hz, 2H), 4.43 (d, J¼5.2 Hz,1H), 4.02e3.83 (m, 5H), 3.80 (s, 3H),

Y. Li et al. / Tetrahedron 69 (2013) 6585e6590
6589
(Daicel Chiralpak-OD, n-hexane/i-PrOH 90:10, flow rate 1.0 mL/min,
25.7 (major enantiomer, major diastereomer), 26.7 (minor enan-
tiomer, major diastereomer) mins (63% ee, major diastereomer).
l¼254 nm). Retention times: 22.7 (minor) and 24.2 (major) mins
(76% ee).
4.2.13. tert-Butyl 2-cyano-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-
phenylpentanoate (7). Colorless oil. 1H NMR (400 MHz, CDCl3) (3:2
mixture of diastereomers, with signals corresponding to the major
4.2.9. Methyl 2-cyano-3-(4-methoxyphenyl)-5-(1-methyl-1H-imida-
zol-2-yl)-5-oxopentanoate (4c). Colorless oil. 1H NMR (400 MHz,
CDCl3) (3:2 mixture of diastereomers, with signals corresponding
indicated by):
d 7.44e7.19 (m, 5H), 7.12 (s, 1H), 7.02 (s, 1H), 4.15 (d,
to the major indicated by):
1H), 6.88e6.81 (m, 2H), 4.21 (s, 1H), 3.96 (s, 3H), 4.15e3.61 (m, 3H),
3.78 (s, 3H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3):
189.7, 189.2,
d
7.33e7.25 (m, 2H), 7.15 (s, 1H), 7.04 (s,
J¼5.9 Hz, 1H), 3.94 (s, 3H), 4.12e3.58 (m, 3H), 1.29 (s, 9H). 13C NMR
(100 MHz, CDCl3):
d 189.6, 189.1, 164.0, 163.9, 142.7, 142.5, 139.0,
d
138.5, 129.5, 129.4, 128.8, 128.7, 128.4, 128.2, 128.1, 127.9, 127.5,
127.4, 116.2, 116.0, 84.3, 84.1, 77.5, 77.2, 76.9, 45.0, 44.5, 42.3, 41.6,
41.3, 40.4, 36.2, 36.1, 27.7. HRMS (ESþ) calcd for C20H24O3N3
[MþH]þ: 354.1818, found: 354.1812; ee’s were determined by
HPLC analysis (Daicel Chiralpak-AD-H, n-hexane/i-PrOH 85:15,
165.8, 165.7, 159.4, 159.3, 142.7, 142.6, 130.9, 130.2, 129.6, 129.5,
129.3, 129.0, 127.5, 127.4, 115.7, 115.5, 114.3, 114.2, 55.3, 53.5, 53.4,
44.4, 44.1, 41.9, 41.2, 40.5, 39.8, 36.2, 36.2; HRMS (ESþ) calcd for
C18H20O4N3 [MþH]þ: 342.1454, found: 342.1449; ee’s were de-
termined by HPLC analysis (Daicel Chiralpak-OD, n-hexane/i-PrOH
flow rate 1.0 mL/min,
l
¼254 nm). Retention times: 13.8 (major
90:10, flow rate 1.0 mL/min,
(minor) and 37.5 (major) mins (84% ee).
l
¼254 nm). Retention times: 35.2
enantiomer, minor diastereomer), 15.0 (minor enantiomer, minor
diastereomer), 24.0 (major enantiomer, major diastereomer), 25.8
(minor enantiomer, major diastereomer) mins (45% ee, major
diastereomer).
4.2.10. Methyl 3-(4-bromophenyl)-2-cyano-5-(1-methyl-1H-imida-
zol-2-yl)-5-oxopentanoate (4d). Colorless oil. 1H NMR (400 MHz,
CDCl3) (3:2 mixture of diastereomers, with signals corresponding
Acknowledgements
to the major indicated by):
2H), 7.15 (s, 1H), 7.05 (s, 1H), 4.23 (s, 1H), 3.96 (s, 3H), 4.15e3.59 (m,
3H), 3.69 (s, 3H). 13C NMR (100 MHz, CDCl3):
189.1, 188.7, 165.5,
d
7.44 (d, J¼3.7 Hz, 2H), 7.27 (d, J¼8.0 Hz,
We thank Dr. Y. Liu and Dr. J. Li for their helpful discussions. This
work is financially supported by National Natural Science Foun-
dation of China (grant number 31000392, 21173213).
d
165.4, 142.6, 142.4, 138.0, 137.2, 132.2, 132.1, 130.0, 129.7, 129.7,
129.6, 127.7, 127.6, 122.4, 122.2, 115.3, 115.1, 53.7, 53.6, 43.9, 43.6,
41.5, 40.8, 40.5, 39.9, 36.3, 36.2. HRMS (ESþ) calcd for C17H17O3N3Br
[MþH]þ: 390.0453, found: 390.0448; ee’s were determined by
HPLC analysis (Daicel Chiralpak-AD-H, n-hexane/i-PrOH 80:20,
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.05.133.
flow rate 1.0 mL/min,
l
¼254 nm). Retention times: 20.1 (minor
diastereomers), 23.7 (minor enantiomer, major diastereomer) and
25.9 (major enantiomer, major diastereomer) mins (67% ee, major
diastereomer).
References and notes
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d 7.42e7.21 (m, 5H), 7.13 (s, 1H), 7.03
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d
7.37 (d, J¼7.2 Hz, 2H), 7.30e7.16 (m, 3H), 7.09
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