α,β-Unsaturated 2-acyl imidazoles as a practical class of dienophiles for the DNA-based catalytic asymmetric diels-alder reaction in water

Article abstract of DOI:10.1021/ol7015274

α,β-Unsaturated 2-acyl imidazoles are a novel and practical class of dienophiles for the DNA-based catalytic asymmetric Diels-Alder reaction in water. The Diels-Alder products are obtained with very high diastereoselectivities and enantioselectivities in

Full text of DOI:10.1021/ol7015274

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3647-3650
r,â-Unsaturated 2-Acyl Imidazoles as a
Practical Class of Dienophiles for the
DNA-Based Catalytic Asymmetric
Diels−Alder Reaction in Water
Arnold J. Boersma, Ben L. Feringa,* and Gerard Roelfes*
Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute for Chemistry, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
b.l.feringa@rug.nl; j.g.roelfes@rug.nl
Received June 28, 2007
ABSTRACT
r
,
â
-Unsaturated 2-acyl imidazoles are a novel and practical class of dienophiles for the DNA-based catalytic asymmetric Diels
in water. The Diels Alder products are obtained with very high diastereoselectivities and enantioselectivities in the range of 83
catalytic reaction was performed on a 1.0 mmol scale, and the imidazole auxiliary was removed readily.
−
Alder reaction
−
−98%. The
The combination of the catalytic power of transition metal
complexes with the chiral architectures of biopolymers has
given rise to a new generation of highly enantioselective
hybrid catalysts.1 In particular, artificial metalloenzymes
formed by using the supramolecular approach, in which metal
complexes are bound to biopolymers by noncovalent interac-
tions,2 have already shown effective catalysis and high
enantioselectivity.3 In addition to proteins, polynucleotides
have proven to be versatile scaffolds for assembly of
enantioselective catalysts.4 We have introduced a novel
DNA-based asymmetric catalysis concept based on the
modular assembly of a DNA-based catalyst, using a copper
complex of a nonchiral ligand that can bind to DNA.5 As a
result, the active Cu2+ center is brought into proximity of
the DNA double helix, allowing transfer of chirality from
DNA to the product of the Cu2+-catalyzed Diels-Alder
reaction of aza-chalcone with cyclopentadiene in water,
resulting in ee values up to 99%. Here, we present R,â-
unsaturated 2-acyl imidazoles as an alternative class of
dienophiles, which greatly increases the practicality of this
DNA-based catalytic concept (Scheme 1).
An investigation of the substrate scope of our reported
asymmetric Diels-Alder reaction with aza-chalcone type
dienophiles5 revealed that the substituent at the alkene moiety
of the dienophile was amenable to variation, but the 2-acyl
pyridine moiety proved to be essential for both catalysis and
(1) (a) Letondor, C.; Ward, T. R. ChemBioChem 2006, 7, 1845-1852.
(b) Thomas, C. M.; Ward, T. R. Chem. Soc. ReV. 2005, 34, 337-346. (c)
Lu, Y. Curr. Opin. Chem. Biol. 2005, 9, 118-126. (d) Reetz, M. T. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5716-5722.
(2) Ward, T. R. Chem. Eur. J. 2005, 11, 3798-3804.
(4) (a) Roelfes, G. Mol. BioSyst. 2007, 3, 126-135. (b) Caprioara, M.;
Fiammengo, R.; Engeser, M.; Ja¨schke, A. Chem. Eur. J. 2007, 13, 2089-
2095. (c) Ropartz, L.; Meeuwenoord, N. J.; van der Marel, G. A.; van
Leeuwen, P. W. N. M.; Slawin, A. M. Z.; Kamer, P. C. J. Chem. Commun.
2007, 1556-1558. (d) Seelig, B.; Keiper, S.; Stuhlmann, F.; Ja¨schke, A.
Angew. Chem., Int. Ed. 2000, 39, 4576-4579.
(5) (a) Roelfes, G.; Boersma, A. J.; Feringa, B. L. Chem. Commun. 2006,
635-637. (b) Roelfes, G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44,
3230-3232.
(3) (a) Reetz, M. T.; Jiao, N. Angew. Chem., Int. Ed. 2006, 45, 2416-
2419. (b) Letondor, C.; Humbert, N.; Ward, T. R. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 4683-4687. (c) Mahammed, A.; Gross, Z. J. Am. Chem.
Soc. 2005, 127, 2883-2887. (d) Collot, J.; Gradinaru, J.; Humbert, N.;
Skander, M.; Zocchi, A.; Ward, T. R. J. Am. Chem. Soc. 2003, 125, 9030-
9031. (e) Ohashi, M.; Koshiyama, T.; Ueno, T.; Yanase, M.; Fujii, H.;
Watanabe, Y. Angew. Chem., Int. Ed. 2003, 42, 1005-1008. (f) Wilson,
M. E.; Whitesides, G. M. J. Am. Chem. Soc. 1978, 100, 306-307.
10.1021/ol7015274 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/09/2007

by a nucleophile. These features make R,â-unsaturated 2-acyl
imidazoles a very attractive class of substrates for DNA-
based catalytic asymmetric Diels-Alder reactions.
Scheme 1. Schematic Representation of the DNA-Based
Copper-Catalyzed Asymmetric Diels-Alder Reaction of
R,â-Unsaturated 2-Acyl Imidazoles and Cyclopentadiene
R,â-Unsaturated 2-acyl imidazoles 1a-f were prepared
via aldol condensation of 2-acetyl-1-methylimidazole and the
appropriate aldehyde, as described previously.9d Although
cyclohexyl carboxaldehyde can, in principle, also form an
enolate, dienophile 1f was the only product observed. 1-(1-
Methyl-1H-imidazol-2-yl)propenone (1h) was prepared by
addition of lithiated imidazole to acrolein, followed by
oxidation of the allylic alcohol with MnO2. This dienophile
is prone to polymerization, and therefore was prepared
freshly prior to use.
Initially a series of DNA-based catalysts from both
classes investigated to date, i.e., using ligands of the acri-
dine5b (L1-L4) and the bipyridine type5a (L5-L7), were
screened in the Diels-Alder reaction of 1a with 2 (Scheme
1, Table 1). The DNA-based catalyst was formed through
Table 1. Screening of Ligands for the Copper(II)-Catalyzed
Diels-Alder Reaction of R,â-Unsaturated 2-Acyl Imidazole 1a
and Cyclopentadiene 2 in the Presence of DNAa
enantioselectivity. Substrates lacking the pyridyl nitrogen are
less activated by Cu2+ in water.3a,6 When using the well-
known 3-alkenoyl-1,3-oxazolidinones,7 which have two
carbonyl oxygens available for coordination to Cu2+, no
catalytic effect was observed.5a Presumably, the dienophile
cannot compete effectively with H2O for binding to the
copper, suggesting that bidentate binding to Cu2+ by using
an N,O donor set is required. However, the 2-acyl pyridine
moiety of the substrate limits the synthetic potential of the
catalytic system, since the pyridyl moiety is not removed
readily or transformed after the Diels-Alder reaction.
Therefore, we sought to replace the 2-pyridyl moiety by an
alternative, removable auxiliary, which still allows for
efficient binding to Cu2+ under aqueous conditions.
Recently, R,â-unsaturated-1-acyl-3,5-dimethylpyrazoles
were reported as substrates for the catalytic Diels-Alder
reaction with use of chiral copper complexes. Although
generally good yields and enantioselectivities were reported,
only limited success was obtained in pure water.8 Evans et
al. have demonstrated that R,â-unsaturated 2-acyl imidazoles
are good substrates in a variety of Lewis acid-catalyzed
reactions,9 e.g., Friedel-Crafts reactions9a,b and 1,3-dipolar
cycloadditions.9c This substrate class was also employed in
the conjugate addition of carbonyl anions under aqueous
conditions, although not in pure water.9d Subsequently, the
imidazole group has been transformed into a good leaving
group by treatment with methyl triflate, allowing substitution
entry ligand % conversionb of 1a % eec of 3a % eec-e of 5
1
2
3
4
5
6
7
8
<5
61
83
78
93
17
25
90
n.d.f
10 (+)
48 (+)
49 (-)
37 (+)
37 (+)
72 (+)
90 (+)
99 (+)
L1
L2
L3
L4
L5
L6
L7
10 (+)
16 (-)
29 (+)
68 (+)
68 (+)
87 (+)
97 (+)
a All experiments were carried out with salmon testes DNA (1.3 mg
mL-1, 2 mM in base pairs), 0.3 mM [Cu(L)(NO3)2] (30 mol %), 1 mM 1a
in 15 mL of MOPS buffer (20 mM, pH 6.5) for 3 days at 5 °C, unless
noted otherwise. b Determined by 1H NMR. c For the endo isomer. d All
conversions >80%. e Data taken from ref 5. f n.d. ) not determined.
(6) Otto, S.; Bertoncin, F.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1996,
118, 7702-7707.
(7) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt,
P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos,
K. R. J. Am. Chem. Soc. 1999, 121, 7582-7594.
(8) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921-1924.
(9) (a) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252.
(b) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005,
127, 8942-8943. (c) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett.
2006, 8, 3351-3354. (d) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.;
Scheidt, K. A. J. Am. Chem. Soc. 2005, 127, 14675-14680.
self-assembly by mixing solutions of salmon testes DNA
(st-DNA), which is inexpensive and readily available, and
the appropriate copper complex. For screening purposes the
3648
Org. Lett., Vol. 9, No. 18, 2007

catalyst loading was 30 mol % with respect to substrate, but
this can be lowered to 5 mol % without a significant effect
on the enantioselectivity (vide infra). The reaction was
initiated by addition of 10 equiv of cyclopentadiene (2), and
continued for 3 days at 5 °C, after which the cyclopentadiene
was depleted. The catalytic reaction is ligand accelerated;10
in the absence of a ligand, i.e., using only Cu(NO3)2, no
conversion was observed (entry 1). The catalysts based on
the acridine ligands (L1-L4) gave rise to good conversion
and moderate ee values (entries 2-5). Although the enan-
tiomeric preference was always the same, significant varia-
tions in the ee were observed, compared to aza-chalcone (4).
For example, complexes based on ligands L1 and L2 gave
a lower enantiomeric excess, whereas the copper complex
based on ligand L4 gave rise to a significantly higher
enantioselectivity. In contrast, using the copper complexes
of the bipyridine class ligands (L5-L7), comparable results
are seen for aza-chalcone and 1a with respect to both the
enantiomeric excess, i.e., ee values up to 97%, and enan-
tiomeric preference, albeit with low conversion in the case
of ligands L5 and L6. Surprisingly, by using the catalyst
based on L7 90% conversion was obtained, indicating that
this catalyst is much more reactive, with 97% ee of the (+)
enantiomer. The reason for this remarkable difference in
reactivity of Cu-L7 compared to Cu-L6 is still unclear and
subject to further investigation. On the basis of these results,
it was evident that the copper complex of L7 is the catalyst
of choice, and all further experiments were performed with
this catalytic system.
substrates underwent efficient Diels-Alder reactions with
cyclopentadiene, catalyzed by Cu-L7/salmon testes DNA.
The Diels-Alder product was the sole product; no side
products were detected by NMR and HPLC analysis. In all
cases the endo diastereomer was obtained almost exclusively
and with an excellent enantiomeric excess. The best results
were obtained when the R substituent in the enone was an
aromatic group, with ee values ranging from 94% to 98%.
The electronic nature of the substituent on the aryl ring, i.e.,
electron donating or electron withdrawing, or the position
on the aryl ring did not influence the ee significantly (entry
2-6). In the case of R ) p-ClPh and o-BrPh (entry 4 and
5), the conversion was somewhat decreased, most likely
caused by the low solubility of 1c and 1d. When R was a
2-furanyl group, which is a convenient handle for further
functionalization,11 an excellent ee was obtained (entry 7).
Dienophiles 1f-h, which contain alkyl groups or are unsub-
stituted, also gave rise to high enantiomeric excess, i.e., ee
) 80-88%, although the enantioselectivity is somewhat
lower compared to when R is an aromatic group (entries 7,
8, and 10). No conversion was obtained when cyclopenta-
diene was replaced by the more water soluble diene furan.
The loading of Cu-L7 could be reduced to 5 mol %
without affecting the endo:exo selectivity and the enantio-
selectivity (entries 2, 9, and 11).12
To demonstrate that the present reaction is practical from
a synthetic point of view, we performed the DNA-based
catalytic asymmetric Diels-Alder reaction of 1a with 2 on
a 1.0 mmol (210 mg) scale, with a catalyst loading of 5 mol
%. Product 3a was obtained in 70% isolated yield (85%
conversion), and 96% ee after column chromatography. With
use of the procedure of Evans et al.,9c the imidazole of 3a
was first methylated with methyl triflate, followed by
treatment with methanol. Thus, we obtained the correspond-
ing methyl ester 6 in 41% isolated yield (80% conversion
of the Diels-Alder product; see Scheme 2).13 The optical
The substrate scope of the reaction was investigated by
using R,â-unsaturated 2-acyl imidazoles 1b-h (Table 2). All
Table 2. Substrate Scope of the Diels-Alder Reaction with
R,â-Unsaturated 2-Acyl Imidazoles Catalyzed by CuL7(NO3)2/
st-DNAa
Scheme 2. Synthesis of
3-Phenylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Methyl
Ester 6 from 3a
entry
R (substrate)
endo:exo
% eeb
1
2c
3
4d
5e
6
7
8
9c
10
11c
Ph (1a)
Ph (1a)
99:1
99:1
99:1
n.d.
96:4
97:4
94:6
>99:1
>99:1
98:2
99:1
97 (+) (2S,3S)
98 (+) (2S,3S)
p-MeOC6H4 (1b)
p-ClC6H4 (1c)
o-BrC6H4 (1d)
2-furanyl (1e)
cyclohexyl (1f)
Me (1g)
Me (1g)
H (1h)
H (1h)
98
96
94
94
88
86
88
80
83
rotation of the product was [R]20D +126.8 (c 0.401, CHCl3).
From comparison with literature values ([R]20 -130.2,
D
(10) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059-1070.
a All experiments were carried out with st-DNA (1.3 mg mL-1, 2 mM
in base pairs), 0.3 mM [Cu(L7)(NO3)2] (30 mol %), 2 mM 1 in 45 mL of
MOPS buffer (20 mM, pH 6.5) for 3 days at 5 °C, unless noted otherwise.
b For the endo isomer. c 1 mM 1, 0.05 mM Cu(L7)(NO3)2 (5 mol %), 1.3
mg mL-1 st-DNA (2 mM in base pairs). d Conversion ∼50%. e Conversion
∼70%.
(11) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1997, 38,
3013-3016.
(12) DNA concentration was kept at 1.3 mg/mL, which means that the
Cu-L7/DNA base pair ratio in this case was 1:40.
(13) The same yield and purity of 6 was observed without column
chromatography of Diels-Alder product 3a.
Org. Lett., Vol. 9, No. 18, 2007
3649

>95% ee in the 2R,3R-enantiomer)14 it can be concluded
that the Diels-Alder product is obtained from the st-DNA-
based catalytic reaction as the 2S,3S-enantiomer.
Currently, we are exploring new DNA-based catalytic
reactions using this class of substrates.
In conclusion, we have demonstrated that R,â-unsaturated
2-acyl imidazoles are an alternative and practical class of
dienophiles for the DNA-based catalytic asymmetric Diels-
Alder reaction in water. The Diels-Alder products are
obtained with excellent diastereoselectivity and enantio-
selectivity, and the imidazole auxiliary is readily displaced.
Acknowledgment. Financial support from NRSC-C is
gratefully acknowledged.
Supporting Information Available: Characterization
data, NMR spectra, and detailed experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Arai, Y.; Masuda, T.; Masaki, Y. J. Chem. Soc., Perkin Trans. 1
1999, 2165-2170.
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