Design of a small-molecule catalyst using intramolecular cation-π interactions for enantioselective Diels-Alder and Mukaiyama-Michael reactions: L-DOPA-derived monopeptide·Cu(II) complex

Article abstract of DOI:10.1021/ol060651l

We have designed a small-molecule artificial metalloenzyme that is prepared in situ from Cu(OTf)₂ or Cu(NTf₂)₂ (1.0 equiv) and L-DOPA-derived monopeptide (1.1 equiv). This catalyst (2-10 mol %) is highly effective for the enantioselective Diels-Alder (DA) and Mukaiyama-Michael (MM) reactions with α,β-unsaturated 1-acyl-3,5-dimethylpyrazoles. The present results demonstrate that cation-π interactions may be available for controlling the conformation of sidearms of chiral ligands, and monopeptides are readily tunable ligands that include only one chiral center.

Full text of DOI:10.1021/ol060651l

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1921-1924
Design of a Small-Molecule Catalyst
Using Intramolecular Cation−π
Interactions for Enantioselective
Diels
Reactions:
Monopeptide
Kazuaki Ishihara* and Makoto Fushimi
−
Alder and Mukaiyama
-DOPA-Derived
Cu(II) Complex
−Michael
L
‚
Graduate School of Engineering, Nagoya UniVersity,
Furo-cho, Chikusa, Nagoya 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received March 16, 2006
ABSTRACT
We have designed a small-molecule artificial metalloenzyme that is prepared in situ from Cu(OTf)2 or Cu(NTf2)2 (1.0 equiv) and
monopeptide (1.1 equiv). This catalyst (2 10 mol %) is highly effective for the enantioselective Diels Alder (DA) and Mukaiyama
reactions with -unsaturated 1-acyl-3,5-dimethylpyrazoles. The present results demonstrate that cation−π interactions may be available for
controlling the conformation of sidearms of chiral ligands, and monopeptides are readily tunable ligands that include only one chiral center.
L
-DOPA-derived
−
−
−Michael (MM)
r,â
The rational design of small-molecule asymmetric catalysts
is an important subject toward the development of economi-
cal and practical organic synthesis. We have been interested
in designing minimal artificial enzymes from natural L-amino
acids which enantioselectively catalyze synthetically useful
organic reactions.1 We report here a small-molecule chiral
catalyst, L-DOPA-derived monopeptide (1, Y ) NR2)‚Cu-
(II) complex (type I), for the enantioselective Diels-Alder
(DA) and Mukaiyama-Michael (MM) reactions with R,â-
unsaturated 1-acyl-3,5-dimethylpyrazoles (2) (Scheme 1). To
the best of our knowledge, this may be the first example of
the use of an intramolecular cation-π interaction in the
design of chiral catalysts.2
According to the pioneering studies by Engberts et al.,
the DA reaction of cyclopentadiene (CP) with 3-phenyl-1-
(2-pyridinyl)-2-propen-1-one is enantioselectively induced
by Cu(NO3)2 and L-abrine (N-methyl-L-tryptophane) or
N-methyl-L-tyrosine in water.3 In this reaction, water en-
hances the enantioselectivity up to 74% ee. Their catalysts
(type II) have not yet been shown to be a synthetically useful
with regard to enantioselectivity or the range of substrates.4
(2) For typical examples of asymmetric induction by π-π attractive
interaction between a catalyst and a dienophile, see: (a) Corey, E. J.; Loh,
T.-P. J. Am. Chem. Soc. 1991, 113, 8966-8967. (b) Ishihara, K.; Gao, Q.;
Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10412-10413.
(1) (a) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004,
126, 12212-12213. (b) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005,
127, 10504-10505.
10.1021/ol060651l CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/06/2006

Scheme 1. Design of l-DOPA Derivatives 1•Cu(II)
Table 1. [1‚Cu(II)]X (Type II)-Induced DA Reaction of CP
with 2
Complexes
T (°C),
time (h)
3,a yield eeb
entry
1 [Y, Z]
2 [R1] solvent
(%)
(%)
1c 1a [OH, Pr]
2c 1a [OH, Pr]
3f 1a [OH, Pr]
2a [H] H2O
2b [Me] H2O
2a [H] MeCNg
0, 2
3a, 88
85
72
0, 3 to 23, 8d 3b, 3e
-40, 13
-40, 13
23, 20
3a, >99 78
3a, >99 92
3b, 24h 76
4f 1b [OH, c-C5H9] 2a [H] MeCNg
5f 1b [OH, c-C5H9] 2b [Me] MeCNg
a Endo/exo ratio was >90:10. b Ee of endo-3. c 1 (17.5 mol %),
Cu(NO3)2‚2.5H2O (10 mol %), NaOH (17.5 mol %). d 0 °C, 3 h, and then
23 °C, 8 h. e 2b was hydrolyzed. f 1 (15 mol %), Cu(OTf)2 (10 mol %),
Et3N (15 mol %). g MeCN (wet) was used. h 2b was remained.
Engberts in acetonitrile (17% ee).3 The use of N-cyclopentyl
ligand 1b gave endo-(2S)-3a with 92 ee (entry 4). In contrast
to entry 2, 2b reacted to afford endo-(2S)-3b with 76% ee
without hydrolysis, but its reactivity was still very low (entry
5).
Surprisingly, [1b‚Cu(II)](OTf)2 (type I) prepared from 1b
and Cu(OTf)2 in the absence of Et3N was more active than
[1b‚Cu(II)]OTf (type II; entry 4, Table 1) in acetonitrile and
gave endo-(2S)-3a with 87% ee (entry 1, Table 2). Thus, Y
The focus of Engberts’ work3 was proof of concept with the
enantioselectivity enhanced in water and not a study to find
the most selective catalyst.
Based on Engberts’ results,3 we explored the enantiose-
lective DA reaction of CP with 25 as more synthetically val-
uable dienophiles induced by [1‚Cu(II)]NO3 (type II) in
water (Table 1). The DA reaction was heterogeneously car-
ried out under a high dilution condition ([2] ) 0.01 M) due
to the poor solubility of 2 in water. The N-alkyl substituent
of L-DOPA as well as L-abrine were highly effective for in-
creasing the enantioselectivity. The ee of endo-(2S)-3a was
increased up to 85% ee with the use of [1a‚Cu(II)]NO3 in
water (entry 1). However, the DA reaction with 1-crotonoyl-
3,5-dimethylpyrazole (2b) gave only a trace amount of endo-
(2S)-3b with 72% ee because 2b was predominantly hydro-
lyzed (entry 2). In general, [L-amino acid‚Cu(II)]X is insol-
uble in aprotic solvents and a high dilution condition is un-
desirable for scale-up, but [N-alkyl-L-amino acid‚Cu(II)]X
was soluble in acetonitrile even at -40 °C. To prevent the
hydrolysis of 2 and concentrate the reaction mixture, the DA
reaction with 2 was performed in the presence of 10 mol %
of [1‚Cu(II)]OTf in wet acetonitrile ([2] ) 0.125 M) at -40
°C. Fortunately, the DA reaction with 2a proceeded quan-
titatively to give endo-(2S)-3a with 78% ee (entry 3). This
enantioselectivity was comparable to the results achieved by
Table 2. [1‚Cu(II)](OTf)2 (Type I)-Induced DA Reaction of
CP with 2a
3a
T (°C),
time (h)
yield endo/
eea
(%)
entry
1 [Y, Z]
(%)
exo
1b
2b
3b
4c
1b [OH, c-C5H9]
-40, 7
>99
30
98:2
98:2
98:2
99:1
87
66
97
98
1c [O-i-Pr, c-C5H9]
-40, 3.5
1d [N(CH2CH2)2, c-C5H9] -40, 0.7
1d [N(CH2CH2)2, c-C5H9] -78, 7
97
99
a Ee of endo-3a. b MeCN (wet). c EtCN (dried over MS 3 A).
of 1 was further screened to attain higher enantioselectivity
under homogeneous conditions in acetonitrile (Table 2).
Isopropyl ester 1c was less effective than the corresponding
acid 1b with regard to enantioselectivity and catalytic activity
(entry 2). On the other hand, pyrrolidine monopeptide 1d
was extremely effective, and gave endo-(2S)-3a with 97%
ee (entry 3). [1d‚Cu(II)](OTf)2 was sufficiently active even
at -78 °C to give endo-(2S)-3a with 98% ee in quantitative
yield (entry 4).
The generality and scope of the DA reaction with 2
induced by [1d‚Cu(II)](OTf)2 or more active [1d‚Cu(II)]-
(NTf2)2 (2-10 mol %) were examined in acetonitrile (Table
3). The DA reaction with not only simple dienophiles 2a-c
(3) (a) Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. J. Am. Chem. Soc.
1998, 120, 4238-4239. (b) Otto, S.; Engberts, J. B. F. N. J. Am. Chem.
Soc. 1999, 121, 6798-6806.
(4) Only one successful example is shown in ref 3. The absolute
configuration of the DA adduct has not yet been determined.
(5) For reactions with 1-acryloylpyrazoles, see: (a) Kashima, C.;
Fukusaka, K.; Takahashi, K.; Yokoyama, Y. J. Org. Chem. 1999, 64, 1108-
1114. (b) Gelbert, M.; Lu¨ning, U. Supramolecular Chem. 2001, 12, 435-
444. (c) Kashima, C.; Miwa, Y.; Shibata, S.; Nakazono, H. J. Heterocycl.
Chem. 2003, 40, 681-688. (d) Kashima, C.; Shibata, S.; Yokoyama, H.;
Nishio, T. J. Heterocycl. Chem. 2003, 40, 773-782. (e) Itoh, K.; Kanemasa,
S. J. Am. Chem. Soc. 2002, 124, 13394-13395. (f) Sibi, M. P.; Itoh, K.;
Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 5366-5367.
1922
Org. Lett., Vol. 8, No. 9, 2006

Table 3. [1d‚Cu(II)]X2 (Type I)-Induced DA Reaction of
Dienes with 2
DA adducts
T (°C),
yield
(%)
endo/ eeb (%)
entry
2 [R1]
2a [H]
2a [H]
2a [H]
2a [H]
2b [Me]
2b [Me]
2c [Ph]
dienea time (h)
exo
[config]
1c
CP
PB
-40, 6
3a, >99
4, 88
98:2
97 [2S]
2
-40, 22
>99:1e 97 [-]
>99:1e 97 [-]
91 [-]
3d
MOB -40, 7
5, 85
4f
DMB
CP
CP
CP
0, 49
6, 63
5d,g
6c
-40, 24
3b, 95
97:3
95:5
93:7
91:9
97 [2S]
89 [2S]
95 [-]
98 [-]
0, 17.5 3b, 97
7d,g
8d
0, 40
-20, 7
0, 10
0, 39
23, 72
3c, 93
3d, 97
3d, >99
7, 93
8, 83
9, 96
10, 76
3e, 89
3f, 95
2d [EtO2C] CP
2d [EtO2C] CP
2d [EtO2C] PB
9c
88:12 95 [-]
>99:1e 91 [-]
93:7e 87 [-]
>99:1e 97 [-]
93 [-]
10d,g
11d,g,h 2d [EtO2C] IP
Figure 1. Transition-state assembly 11 proposed based on the
12d,g
13d,g
2d [EtO2C] MOB -20, 5
crystal structure of bis(L-tyrosinato)Cu(II) complex.6a
2d [EtO2C] DMB
0, 64
23, 6
-20, 5
14d,g,i 2e [OCOPh] CP
93:7
>99:1
90 [-]
97 [-]
15d,g
2f [Cl]
CP
denied that distortions from rigorous square planarity may
induce such a π-π interaction between 1d and 2a, it seems
that the cation-π interaction between the Cu(II) ion and 1d
should be conformationally preferable in [1d‚Cu(II)‚2a]-
(OTf)2 which is generally characterized by a square planar
geometry.
a See text. b ee of the major diastereomer. c 1d (2.2 mol %)-Cu(OTf)2
(2 mol %). d 1d (11 mol %)-Cu(OTf)2 (10 mol %). e The molar ratio of
the 4- and 3-substituted diastereomers is shown. f DMB (1.2 mL), MeCN
(1.2 mL). g Cu(NTf2)2 was used. h IP (0.6 mL), MeCN (0.6 mL). i MeCN
(2.4 mL)-THF (1.2 mL).
but also â-functionalized dienophiles 2d-f, which were
synthetically valuable, gave the DA adducts with high
enantioselectivities. More reactive 2d reacted with high
enantioselectivity not only with cyclic dienes but also acyclic
dienes such as 2-methoxybutadiene (MOB), 2-phenylbuta-
diene (PB), isoprene (IP), and 2,3-dimethylbutadiene (DMB).
The crystal structure of bis(L-tyrosinato)Cu(II) complex
has been determined by van der Helm et al. (Figure 1).6 They
observed a weak cation-π attractive interaction7 between
the Cu(II) ion and one of the phenolic rings of tyrosinates.
On the basis of this significant observation, the absolute
stereochemical outcome in the DA reaction induced by [1d‚
Cu(II)](OTf)2 can be understood through our proposed
transition state assembly, trans-s-cis-TS 11, shown in Figure
1. The cation-π interaction in [1‚Cu(II)](OTf)2 (type I)
would be stronger than that in [1‚Cu(II)]OTf (type II). In
addition, the N-cyclopentyl and pyrrolidinyl groups in 1d
would sterically assist the cation-π interaction. The 3- and
5-methyl groups of 2a would sterically control the coordina-
tion environment around the Cu(II) [cis (disfavored) or trans
(favored)] and the conformation of 2a [s-cis (favored) or
s-trans (disfavored)], respectively. In contrast, Engberts et
al. suggest that π-π attractive interaction2 between the indole
group in L-abrine and the dienophile is important for
asymmetric induction in their aqueous DA reaction catalyzed
by [L-abrine‚Cu(II)]NO3.3 Although it cannot be absolutely
Interestingly, DA adducts of 2 may be transformed into a
range of carboxylic acid derivatives by treatment with
appropriate nucleophiles: hydrolysis,8a alcoholysis,5a,c,d,8b,e
aminolysis,5e,8a,c-e reductive cleavage to aldehydes8f-h or
alcohols,5f and alkylative cleavage to ketones8i or â-ketoesters.8j
A highly asymmetric induction of [1d‚Cu(II)](OTf)2 was
also observed in the enantioselective Mukaiyama-Michael
(MM) reaction of silyl enol ethers (NuSiMe3) with 2d.
Several examples are shown in Table 4.
Table 4. [1d‚Cu(II)](OTf)2-Induced MM Reaction of NuSiMe3
with 2d
a 12 reacted at its 5-position. b The diastereomeric ratio was 86:14. c ee
of the major diastereomer.
(6) (a) van der Helm, D.; Lawson, M. B.; Enwall, E. L. Acta Crystallogr.
1972, B28, 2307-2312. (b) Muhonen, H.; Ha¨ma¨la¨inen, R. Finn. Chem.
Lett. 1983, 120-124.
(7) For cation-π interaction between Cu(II) and R-amino acids, see:
(a) Tao, W. A.; Zhang, D.; Nikolaev, E. N.; Cooks, R. G. J. Am. Chem.
Soc. 2000, 122, 10598. (b) Wu, L.; Tao, W. A.; Cooks, R. G. Anal. Bioanal.
Chem. 2002, 373, 618-627.
The present results demonstrate that cation-π interaction
is available for controlling the conformation of a sidearm of
Org. Lett., Vol. 8, No. 9, 2006
1923

chiral ligands, and monopeptides are readily tunable ligands
that include only one chiral center compared to chiral bis-
(oxazoline)s, which have been reported to be useful ligands
in various enantioselective reactions with bidentate electro-
philes.9 Further studies toward direct evidence to support the
existence of intramolecular cation-π interaction in [1d‚Cu-
(II)](OTf)2 and its application to the design of chiral catalysts
is currently under investigation in our laboratory.
(8) For hydrolysis, see: (a) Kahima, C.; Fukusaka, K.; Takahashi, K. J.
Heterocycl. Chem. 1997, 34, 1559-1565. For alcoholysis, see: (b) Kashima,
C.; Harada, H.; Kita, I.; Fukuchi, I.; Hosomi, A. Synthesis 1994, 61-65.
For aminolysis, see: (c) Ried, W.; Schleimer, B. Liebigs Ann. Chem. 1959,
626, 98-105. (d) Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A.
Heterocycles 1994, 38, 1407-1412. (e) Kashima, C.; Fukuchi, I.; Takahashi,
K.; Hosomi, A. Tetrahedron 1996, 52, 10335-10346. For reductive cleavage
to aldehydes with LiAlH4, see: (f) Ried, W.; Ko¨nigstein, F.-J. Angew. Chem.
1958, 70, 165. (g) Ried, W.; Ko¨nigstin, F.-J. Liebigs Ann. Chem. 1959,
622, 37-42. (h) Ried, W.; Deuschel, G.; Kotelko, A. Liebigs Ann. Chem.
1961, 642, 121-127. For Grignard reaction, see: (i) Kashima, C.; Kita, I.;
Takahashi, K.; Hosomi, A. J. Heterocycl. Chem. 1995, 32, 25-27. For
Reformatsky reaction, see: (j) Kashima, C.; Kita, I.; Takahashi, K.; Hosomi,
A. J. Heterocycl. Chem. 1995, 32, 723-725.
Acknowledgment. Financial support for this project was
provided by JSPS KAKENHI (15205021) and the 21st
Century COE Program of MEXT.
Supporting Information Available: Experimental pro-
cedures; full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335.
OL060651L
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Org. Lett., Vol. 8, No. 9, 2006