DNA-based catalytic enantioselective Michael reactions in water

Article abstract of DOI:10.1002/anie.200703459

High, but not dry: A highly enantioselective Michael reaction in water has been developed by using a simple DNA-based catalyst. Enantioselectivities of up to 99% ee could be obtained by using nitromethane and dimethyl malonate as the nucleophiles and αf,β-unsaturated 2-acylimidazoles as the Michael acceptors. The reactions can be performed on a preparative scale and the catalyst can be recycled. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200703459

Communications
DOI: 10.1002/anie.200703459
Asymmetric Catalysis
DNA-Based Catalytic Enantioselective Michael Reactions in Water**
David Coqui›re, Ben L. Feringa, and Gerard Roelfes*
The increasing appreciation of the special properties of water
as a reaction medium, combined with the potential advan-
tages of replacing organic solvents by water, have fueled the
development of catalytic methodologies for use in water or
further by applying it to the catalytic asymmetric Michael
reaction in water.[11,12] a,b-Unsaturated 2-acylimidazoles (1a–
f), which can bind to CuII ions in a bidentate fashion under
aqueous conditions, were selected as the enone substrates. An
additional attractive feature of these compounds is that
following the catalyzed reaction, the N-methylimidazole
auxiliary is readily displaced, thus giving rapid access to
interesting chiral building blocks. This novel class of substrate
has been applied recently with considerable success in a
variety of reactions, such as carbonyl anion additions, Friedel–
Crafts alkylations, nitrone cycloadditions, and also the DNA-
based catalytic asymmetric Diels–Alder reaction.[10c,13] Nitro-
methane and dimethyl malonate, both of which readily
enolize, were employed as nucleophiles.
aqueous media.[1] Despite significant progress in the area of
[2]
À
catalytic asymmetric C C bond-forming reactions in water,
many challenges remain. For example, a particularly impor-
tant transformation is the catalytic enantioselective Michael
addition reaction, in which an enone substrate undergoes
conjugate addition with a carbon nucleophile. The reaction
can be catalyzed by Lewis acids.[3] To our knowledge, only two
examples of transition-metal-catalyzed enantioselective
Michael reactions in water have been reported to date.
Maximum ee values of 83[4] and 86% ee[5] have been obtained
by using AgI- or PdII-based catalysts, respectively.[6,7] Here we
report a highly enantioselective Michael reaction in water
that is mediated by a DNA-based catalyst.
The DNA-based catalyst was self-assembled from salmon
testes DNA (st-DNA) and the appropriate copper complex.
The reaction of 1a (Scheme 1) with 100 equivalents of
An emerging approach in aqueous-phase catalysis is the
use of hybrid catalysts, which combine the catalytic power of
transition-metal complexes with the chiral architecture of
biopolymers.[8] Enantioselective catalysis has been achieved
for a number of reactions through the use of protein-based
hybrid catalysts.[9] The double helix of DNA represents a very
attractive scaffold for hybrid catalysis, and we have demon-
strated that its chirality can be transferred to a catalytic
reaction, that is, the CuII-catalyzed asymmetric Diels–Alder
reaction.[10] This was achieved by binding a copper complex,
based on an achiral ligand, to DNA in a noncovalent fashion.
To date, two families of ligands have been investigated.
Initially, a metal-binding domain was linked through a short
spacer to a DNA intercalator.[10a] In an improved and much
simpler design, the DNA-binding moiety was integrated into
the metal-binding domain. Enantioselectivities of up to
99% ee were obtained in the Diels–Alder reaction of
azachalcone with cyclopentadiene by using ligands of this
class.[10b] Furthermore, it was demonstrated that the catalytic
reactions could be performed on a synthetically relevant
scale.[10c]
Encouraged by these results, we decided to explore the
scope and versatility of the DNA-based catalysis concept
Scheme 1. Schematic representation of the asymmetric Michael addi-
tion reaction catalyzedby complexes formedbetween copper(II) ions
andachiral ligands (L1–L3) in the presence of DNA.
[*] Dr. D. Coqui›re, Prof. Dr. B. L. Feringa, Dr. G. Roelfes
Department of Organic andMolecular Inorganic Chemistry
Stratingh Institute for Chemistry
dimethyl malonate was used to screen for the most efficient
catalytic system (Table 1). An excess of the nucleophile was
necessary to achieve good conversion (see below). Reactions
were performed at 58C and pH 6.5, the optimum conditions
with regard to both conversion and enantioselectivity.[14] The
reaction mixture was heterogeneous, as a result of the low
solubility of 1a in water. Nevertheless, in all cases the reaction
proceeded cleanly, with only formation of the Michael
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: j.g.roelfes@rug.nl
[**] We thank A. J. Boersma for useful discussions and for providing the
substrates, andthe NRSC-Catalysis for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
9308
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Chemie
Table 1: Results of Michael addition reactions catalyzed by DNA/[Cu(L1–L3)(NO3)2].[a]
[Cu(Ln)(NO3)2] Substrate CH2(CO2Me)2
equiv[b] conv [%][c] ee [%][d] conv [%][c] ee [%][d]
tion did result in a slightly lower
ee value.[14] Conversely, the amount
of 1a could be increased up to
20 equivalents with respect to the
CuII concentration (5 mol% cata-
lyst loading) and still obtain full
conversion with 90% ee (entries 9–
12). Further increasing the amount
of 1a led to a decrease in the
conversion, but without a decrease
in the enantioselectivity (entry 13).
Nitromethane is also a good
CH3NO2
[mm]
L
R
1
2
3
4
0.3
0.3
0.3
0.3
0.3
0.3
0.15
0.05
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
–
Ph (1a)
3.3
3.3
3.3
3.3
3.3
3.3
6.6
19.8
6.6
6.6
13.3
20
26
4
90
<2
0
–
–
97
n.d.[l]
–
–
L1
L2
L3
56 (À)
80 (À)
91 (À)
–
92 (À)
92 (À)
92 (À)
87 (À)
quant.
54
85 (À)
5[e]
6
36
–
92[f]
quant.
66
65[g]
85 (À)
7
8
9
61
–
85 (À)
–
quant.
quant.
84 (À)
10[h]
11
12
13
14
15
16
17[j]
quant. (86)[i] 85 (À)
96 (90)[i]
84 (À)
nucleophile in this reaction,
although it proved to be somewhat
less reactive than dimethyl malo-
nate; 1000 equivalents of nitrome-
thane were required to achieve full
conversion. The origin of this
reduced reactivity is unclear. The
pKa values of nitromethane and
dimethyl malonate are 10.3[15] and
13,[16] respectively, which suggests
that the reactivity is not directly
related to the acidity of the nucle-
ophiles. The corresponding Michael
adduct was obtained with very good
enantioselectivity when nitrome-
thane was used as the nucleophile
(85% ee, entry 4). Higher [Cu(L3)-
(NO3)2] loadings were generally
quant.
quant.
40
91 (À)
90 (À)
89 (À)
86
58
69
–
89
72
70
–
83 (À)
83 (À)
33
–
p-MeOPh (1b)
p-ClPh (1c)
o-BrPh (1d)
3.3
3.3
3.3
6.6
6.6
13.3
3.3
3.3
94
75
quant.
87 (80)[i]
79 (72)[i]
34
82
85
94
–
–
–
90
99 (À)
99 (À)
99 (À)
98 (À)
86
18[j,k] 0.3
19
20
21
–
–
0.3
0.3
0.3
2-furanyl (1e)
Me (1 f)
96
92
quant.
95
87
62
58
[a] Typical experiments were carriedout with salmon testes DNA (1.3 mgmL À1) in MOPS buffer (20 mm
pH 6.5) for 3 days at 58C using 100 equiv of dimethyl malonate or 1000 equiv of nitromethane, with
respect to enone. [b] Equivalents of substrate 1a–f with respect to CuII ions. [c] Conversion values were
determined by 1H NMR spectroscopy and are the average of duplicate experiments (standard deviation:
Æ3%). [d] The ee values were determined by analytical chiral HPLC. [e] Reaction performed without
DNA. [f] 40 equiv of dimethyl malonate. [g] 200 equiv of nitromethane. [h] Reaction performed on a 80-
mg scale [i] Yieldof isolatedproduct after column chromatography. [j] Reaction performedon a 1-mmol
scale. [k] Using recycledcatalyst solution from entry 17. [l] Not determined.
required
with
nitromethane
addition product 2a (entries 2–4). In the absence of a ligand,
that is, with only [Cu(H2O)3(NO3)2] and DNA, low conver-
sion and no enantioselectivity was observed (entry 1). The
reactivity decreased even further when 1,10-phenanthroline
(L1) was used as the ligand, but a moderate ee value was
obtained (entry 2). In contrast, a significantly increased
activity and enantioselectivity was found by using 2,2’-
bipyridyl (L2) as the ligand (entry 3). However, the best
results were obtained with 4,4’-dimethyl-2,2’-bipyridine (L3),
which resulted in full conversion and an enantioselectivity of
91% ee (entry 4). In all cases the (À) enantiomer was
obtained in excess. Remarkably, the reaction proved to be
not only accelerated by the presence of a ligand, but it was
also accelerated by DNA; in the absence of DNA, only 54%
conversion was observed over the same reaction time
(entry 5). On the basis of these results [Cu(L3)(NO3)2] was
selected as the catalyst of choice and further experiments
were performed using this catalytic system.
Decreasing the amount of dimethyl malonate to 40 equiv-
alents with respect to 1a resulted in a slight drop in the
conversion (entry 6). The concentration of [Cu(L3)(NO3)2]
could be lowered to 0.15 mm (15 mol%), using the same
DNA concentration, without affecting the conversion
(entry 7). However, reduced conversion was observed at
0.05 mm [Cu(L3)(NO3)2] (entry 8). In both cases the ee value
remained the same, thus indicating that decreasing the
[Cu(L3)(NO3)2]/DNA base pair ratio does not affect the
enantioselectivity. However, lowering the DNA concentra-
because of its lower reactivity. Decreasing the catalyst
concentration resulted in a significant decrease in the
conversion (entry 7) and, similarly, using larger amounts of
1a also led to a rapid decrease in the conversion (entries 11
and 12).
The scope of the reaction was investigated using a,b-
unsaturated 2-acylimidazole substrates 1a–f, which contain
different R groups.[13a,c] Good to excellent conversion was
observed in all cases, with the corresponding Michael addition
product being the sole product detected.[17] Very good
enantioselectivities, ranging from 82–94% for nitromethane
and from 86–99% in the case of dimethyl malonate as the
nucleophile (entries 14–20), were obtained when R = aryl. In
both cases the Michael acceptor containing an ortho-bromo-
phenyl substituent gave rise to the highest enantioselectivities
(entry 16). A significant decrease in the enantioselectivity was
obtained when R = Me (entry 21). Replacement of the N-
methylimidazole moiety in the substrate with a noncoordi-
nating group (namely, phenyl) resulted in a complete loss of
activity, thereby underlining the importance of the bidentate
coordination of the substrate to the CuII ion.[14]
The reaction of 1d with dimethyl malonate was performed
on a preparative scale, namely, 1 mmol 1d (291 mg). The
corresponding Michael adduct 2d was obtained in 80% yield
(87% conversion) and 99% ee after column chromatography
(entry 17). This catalyst solution was then reused for another
reaction on a 1 mmol scale without significant decrease in the
ee value or yield; from this experiment 2d was obtained in
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Communications
72% yield and 99% ee (entry 18). These results demonstrate
the potential of the DNA-based catalyis concept for applica-
tions in synthesis.
Experimental Section
Representative procedure for the [Cu(L3)(NO3)2]/DNA-catalyzed
Michael addition reaction: A catalyst solution of the copper(II)
complex (0.3 mm) and salmon testes DNA (1.3 mgmLÀ1) in 2 0 mm 3-
(N-morpholine)propanesulfonic acid (MOPS) buffer at pH 6.5 was
prepared by adding a solution of salmon testes DNA (10 mL,
2mgmL À1 in 30 mm MOPS buffer, pH 6.5; prepared 24 h in advance)
to a solution of [Cu(L3)(NO3)2] in water (5 mL, 0.9 mm). A fresh
stock solution of Michael acceptor (30 mL) in CH3CN was then added.
After addition of dimethyl malonate (174 mL) or nitromethane
(1 mL) at 08C, the reaction mixture was kept for 3 days at 58C with
continuous inversion. The product was isolated by extraction with
Et2O (2” 10 mL). After drying the reaction mixture (Na 2SO4) and
removal of the solvent, the crude product was analyzed by NMR
spectroscopy and HPLC.
To gain insight into the stereochemical course of the
catalytic reaction the Michael adducts 2a and 3a were
isolated from an 80-mg-scale reaction (entry 10) in 86 and
90% yields and 85 and 84% ee, respectively. The imidazole
groups of 2a and 3a (Scheme 2) were methylated using
methyl triflate[13b] and then treated with methanol to give the
corresponding optically active carboxylic esters 4a and 5a
(Scheme 2). Measurement of the optical rotation of 4a
Received: July 31, 2007
Published online: October 30, 2007
Keywords: asymmetric catalysis · copper · DNA ·
.
Michael addition
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Scheme 2. a) Synthesis of 4a and 5a andb) schematic representation
of the stereochemistry of the attack of the nucleophile in the DNA-
based catalytic asymmetric Michael addition.
([a]D25 = À10.8 degcm3 gÀ1 dmÀ1) allowed us to conclude that
the R enantiomer had been formed,[18] whereas the optical
rotation of 5a ([a]D25 = À14.5 degcm3 gÀ1 dmÀ1) indicates that
the S enantiomer was formed in this case.[19] Consequently,
the DNA-based catalyst system appears to direct the nucle-
ophile towards attack on the Si face of the Michael acceptor
(Scheme 2). This approach coincides with the face from which
cyclopentadiene reacts in the related DNA-based catalytic
enantioselective Diels–Alder reaction, which suggests that
the DNA shields the Re face of the coordinated a,b-unsatu-
rated 2-acylimidazole substrate.[10c] Current efforts are aimed
at elucidating the structure of the DNA-bound activated
complex.
In conclusion, we have developed a highly enantioselec-
tive Michael reaction in water by using a simple DNA-based
catalyst. Enantioselectivities of up to 99% ee could be
obtained by using nitromethane and dimethyl malonate as
the nucleophiles and a,b-unsaturated 2-acylimidazoles as the
Michael acceptors. To our knowledge these represent the
highest enantioselectivities obtained in the catalytic Michael
addition in water to date. The reactions can be performed on a
preparative scale and the catalyst can be recycled. These
results are a clear demonstration of the versatility of the
DNA-based catalysis concept.
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9310
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[14] See the Supporting Information.
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detected (< 8%).
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