Table 1. Screening of Chiral Catalystsa
entry
catalyst
convn (%)
yield (%)b
ee (%)
1c
2c
3c
4
AuSMe/(R)-BINAP/AgBF4
[Ag(CH3CN)4]BF4/(R)-BINAP
[Rh((R)-BINAP)]BF4
[Pd(CH3CN)4](BF4)2/1.2(R)-BINAP
[Pd(CH3CN)4](BF4)2/1.2(R)-H8-BINAP
[Pd(CH3CN)4](BF4)2/1.2(R)-Segphos
[Pd(CH3CN)4](BF4)2/1.2(R)-Segphos
[Pd(CH3CN)4](BF4)2/1.2(R)-tol-Segphos
[Pd(CH3CN)4](BF4)2/1.2(S)-xyl-Segphos
100
8
100
100
87
100
100
100
100
50
<2
59
62
64
79
93
86
96
<5
-
64 (+)
81 (+)
89 (+)
90 (+)
88 (+)
87 (+)
94 (-)
5
6
7d
8d
9d
a Catalyst (0.0050 mmol), 1a (0.10 mmol), and (CH2Cl)2 (1.0 mL) were used. b Isolated yield. c Catalyst: 10 mol %. d Catalyst (0.010 mmol), 1a (0.20
mmol), and (CH2Cl)2 (1.0 mL) were used.
tion-metal complex with the triple bond would facilitate the
cyclization and induce enantioselective construction of axial
chirality through close interaction between the chiral catalyst
and the aryl group adjacent to the triple bond.
and 4a8 (Figure 1), showed potent pharmaceutical activities.
The method shown in Scheme 1 can provide new analogues
of this important class of compounds in enantiomerically
enriched forms.
Importantly, a number of 4-aryl-2-pyridone derivatives,
especially 4-arylquinolin-2(1H)-one derivatives such as 37
(4) Recently, a Au(I)-catalyzed cycloisomerization of (arene)chromium
complexes with 1,5-enynes directed towards axially chiral biaryls was
reported; see: Michon, C.; Liu, S.; Hiragushi, S.; Uenishi, J.; Uemura, M.
Synlett 2008, 1321.
(5) For recent reviews of cycloisomerizations of 1,n-enynes, see: (a)
Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47,
4268. (b) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348,
2271. (c) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (d) An˜orbe,
L.; Domı´nguez, G.; Pe´rez-Castells, J. Chem.-Eur. J. 2004, 10, 4938.
(6) For selected recent examples of π-electrophilic transition-metal
complex-catalyzed cycloisomerizations of 1,5-enynes leading to six-
membered heterocycles and carbocycles, see: (a) Minnihan, E. C.; Colletti,
S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem. 2007, 72, 6287. (b) Sherry,
B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 8132. (c) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2006, 128, 9705. (d) Shibata, T.; Ueno, Y.; Kanda, K. Synlett
2006, 411. (e) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128,
4592. (f) Nieto-Oberhuber, C.; MuNunez, M. P.; Nevado, C.; Herrero-
Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.-Eur. J. 2006, 12, 1677.
(g) Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. (h) Fehr, C.; Galindo,
J. Angew. Chem., Int. Ed. 2006, 45, 2901. (i) Imagawa, H.; Iyenaga, T.;
Nishizawa, M. Org. Lett. 2005, 7, 451. (j) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 6962. (k) Mamane, V.; Hannen, P.; Fu¨rstner, A.
Chem.-Eur. J. 2004, 10, 4556. (l) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 11806. (m) Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-S. J. Am.
Chem. Soc. 2003, 125, 15762, and references therein.
Figure 1. Biologically active 4-aryl-2-pyridone derivatives.
We first investigated the reaction of N-cyclohexenyl
alkynylamide 1a bearing a 2-methoxynaphthyl group at an
alkyne terminus as a model substrate (Table 1). In our
(8) Compound 4a and its derivatives have been identified by Bristol-
Myers Squibb as potent maxi-K channel openers useful for the treatment
of male erectile dysfunction; see: (a) Hewawasam, P.; Fan, W.; Ding, M.;
Flint, K.; Cook, D.; Goggings, G. D.; Myers, R. A.; Gribkoff, V. K.;
Boissard, C. G.; Dworetzky, S. I.; Starret, J. E.; Lodge, N. J. J. Med. Chem.
2003, 46, 2819. (b) Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org.
Chem. 2005, 70, 3864, and references therein.
(7) Compounds 3 are patented by Teikoku Hormone Mfg. Co., Ltd. as
oxytocin antagonists; see: Shiraiwa, M.; Ota, S.; Takefuchi, K.; Uchida,
H.; Saegusa, M.; Mitsubori, T.; Yoshizawa, M. JP 2003146972, 2003.
1806
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