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.
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Org. Lett., Vol. 8, No. 9, 2006