to both the indoles and the Michael acceptors. In contrast, a
catalytic enantioselective 1,2-nucleophilic addition that is
broadly applicable to both indoles and carbonyl compounds
is lacking, although such a reaction represents another direct
and versatile means to synthesize enantiomerically enriched
chiral indole derivatives. Although high enantioselectivity
has been achieved with chiral metal and organic catalysts,
catalysts for enantioselective Friedel-Crafts reactions of
indoles with carbonyl compounds with broad scope.
To verify this assumption, we investigated the cinchona
alkaloid-catalyzed reaction of indole (2A) with an alkynyl
R-ketoester 3a. As summarized in Table 1, 6′-OH cinchona
respectively, these catalysts are only effective toward ethyl
6
Table 1. Asymmetric Friedel-Crafts Reaction of Indole 2A to
R-Ketoester 3a
3,3,3-trifluoropyruvate. To fully realize the potential of this
important strategy for generating chiral indole derivatives,
7
more generally effective chiral catalysts must be developed.
We wish to report here a highly enantioselective Friedel-
Crafts reaction that is applicable to a wide range of both
indoles and carbonyl compounds with bifunctional cinchona
alkaloids.
entry
catalyst
temp/°C time/h conversion/%a ee/%b
In their recent report of the cinchonine- or cinchonidine-
catalyzed addition of indoles to ethyl 3,3,3-trifluoropyruvate,
T o¨ r o¨ k, Prakash, and co-workers demonstrated that blocking
either the quinuclidine or the 9-OH led to dramatically
1
2
3
4
5
6
7
8
quinidine
cinchonine
QD-1a
QD-1b
QD-1c
QD-1d
Q-1d
23
23
23
23
23
23
23
23
20
20
20
20
20
20
20
20
68
<10
82
54
<10
74
-72
7
83
88
85
89
-87
11
6b
reduced enantioselectivity by the natural cinchona alkaloids.
Thus, cinchonine was postulated to function as a base-acid
bifunctional catalyst to simultaneously activate both the
indoles and ethyl 3,3,3-trifluoropyruvate via the quinuclidine
and the 9-OH moiety, respectively, to achieve synthetically
useful enantioselectivity. Recent studies by us and others
establish that cooperative hydrogen-bonding catalysis with
78
<5
1e
a
Determined by 1H NMR analysis. b Enantiomeric excess was deter-
mined by HPLC.
6′-OH and 9-thiourea cinchona alkaloids (1, Figure 1) as
alkaloids 1 were found to afford better activity and enantio-
selectivity than that by quinidine or cinchonine, and the
highest enantioselectivity was obtained with QD-1d. Impor-
tantly, a complete reaction could be accomplished with QD-
1
d to produce the corresponding Friedel-Crafts adduct in
9
6% yield and 88% ee (entry 1, Table 2). In stark contrast,
the same reaction in the presence of 9-thiourea cinchona
alkaloid 1e, a highly efficient catalyst for the enantioselective
7
c
Friedel-Crafts addition of indoles to imines, proceeded in
less than 5% conversion and afforded the Friedel-Crafts
adduct in only 11% ee (entry 8, Table 1).
Figure 1. 6′-OH cinchona alkaloid derivatives.
Further studies revealed that catalyst 1d tolerates structural
alterations of either the indoles or the alkynyl R-ketoesters
base-acid bifunctional catalysts provides a useful platform
for the development of a wide range of highly enantio-
selective C-C bond forming reactions.7c,8,9 The high ef-
ficiency of bifunctional cinchona alkaloid catalysts 1 in the
promotion of mechanistically unrelated C-C bond forma-
tions led us to envision that they might function as efficient
(entries 1-3, Table 2). Moreover, the scope of the reaction
could be readily extended to aryl R-ketoesters (entries 4-17,
Table 2). With aryl R-ketoesters bearing a strong electron-
(8) For asymmetric C-C bond forming reactions with 6′-OH cinchona
alkaloids as acid-base bifunctional catalysts, see: (a) Li, H.; Wang, Y.;
Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105. (c) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005,
7, 167. (d) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127,
8948. (e) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (f)
Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947.
(g) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (h)
Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006,
45, 4301. For asymmetric C-C bond forming reactions with 9-thiourea
cinchona alkaloids as acid-base bifunctional catalysts, see: (i) Li, B.; Jiang,
L.; Liu, M.; Chen, Y.; Ding, L.; Wu, Y. Synlett 2005, 4, 603. (j) Vakulya,
B.; Varga, S.; Cs a´ mpai, A.; So o´ s, T. Org. Lett. 2005, 7, 1967. (k) Mccooey,
S. H.; Connon S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (l) Ye, J.;
Dixon, D. J.; Hynes, P. Chem. Commun. 2005, 35, 4481. (m) Tillman, A.
L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (n) Song, J.; Wang,
Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(
5) For catalytic asymmetric Michael additions of indoles catalyzed by
an organic catalyst, see: (a) Austin, J. F.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 1172. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Austin, J.
F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl.
Acad. Sci U.S.A. 2004, 101, 5482. (d) Zhuang, W.; Hazell, R. G.; Jørgensen,
K. A. Org. Biomol. Chem. 2005, 3, 2566. (e) Herrera, R. P.; Sgarzani, V.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576.
(6) For catalytic asymmetric addition of indoles to ethyl 3,3,3-trifluoro-
pyruvate, see: (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2001, 66, 1009. (b) T o¨ r o¨ k, B.; Abid, M.; London, G.;
Esquibel, J.; T o¨ r o¨ k, M. S.; Mhadgut, C.; Yan, P.; Prakash, G. K. S. Angew.
Chem., Int. Ed. 2005, 44, 3086.
(
7) For catalytic asymmetric Friedel-Crafts additions of indoles to
imines, see: (a) Johannsen, M. Chem. Commun. 1999, 2233. (b) Jia, Y.;
Xie, J.; Duan, H.; Wang, L.; Zhou, Q. Org. Lett. 2006, 8, 1621. (c) Wang,
Y.-Q.; Song, J.; Ran, H.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128,
(9) For a review of asymmetric catalysis by chiral hydrogen-bond donors,
see: Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
8
156.
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Org. Lett., Vol. 8, No. 18, 2006