Xu et al.
been few reports of direct aldol reactions with ketones as
acceptors, which thus remain a great challenge for organic
chemists. Recently, a proline-catalyzed direct aldol reaction of
R-keto esters with aldehydes was reported.22 In this case, only
highly active R-keto esters, which contained two electron-
withdrawing groups conjugated to a keto function, were
investigated as acceptors. More recently, the proline-catalyzed
asymmetric aldol reaction between cyclohexanone and phe-
nylglyoxylate was used for the synthesis of a key intermediate
in the preparation of (S)-oxybutynnin.23 Direct aldol reactions
between R-keto phosphonates and ketones in the presence of
proline were also performed with high enantioselectivities.24
However, with the exception of our previous work, there have
been no reports of organocatalytic direct asymmetric aldol
reaction of ketones with keto acids.25 Herein, we report our
further studies on the reaction of ketones with R-keto acids
catalyzed by organic molecules. R-Hydroxy carboxylic acids
with a tertiary stereogenic center were formed directly with high
enantioselectivities (up to 98% ee) (eq 1), and 2-hydroxy-γ-
butyrolactones were obtained with high yields from the aldol
adducts.
FIGURE 1. Organocatalysts used in this study.
enantioselective catalysts for Mukaiyama-type aldol reactions
of pyruvate and glyoxylate esters with enolates. Very recently,
a chiral amino acid-based ligand in combination with AgF2 was
reported to afford efficient and highly enantioselective catalysis
of Mukaiyama aldol reactions of enolsilanes with R-keto esters.5
Because direct aldol reactions are atom-efficient alternatives
of processes using enol or enolate derivatives as the aldol donor,
asymmetric catalytic variants have attracted considerable at-
tention. Accordingly, the highly enantioselective direct aldol
reactions of aldehydes with ketones in the presence of catalytic
amounts of bifunctional Lewis acids have been reported.6 Since
the seminal finding that L-proline could catalyze the direct aldol
reaction,7,8 many chiral organocatalysts have been discovered
for direct aldol reactions.9-21 Despite these successes, there have
(3) (a) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 1997, 119, 7893. (b) Evans, D. A.; Burgey, C. S.;
Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686. (c)
Cong-Dung Le, J.; Pagenkopf, B. L. Org. Lett. 2004, 6, 4097.
(4) (a) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984.
(b) Langner, M.; Remy, P.; Bolm, C. Chem.-Eur. J. 2005, 11, 6254.
(5) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 6532.
(6) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada, Y.
M. A.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (c)
Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (d) Trost, B. M.;
Ito, H.; Siloff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (e) Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
(7) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b)
Eder, U.; Sauer, R.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496.
(8) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am.
Chem. Soc. 2001, 123, 5260. (c) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
122, 7386.
(9) For reviews, see: (a) List, B. Tetrahedron 2002, 58, 5573. (b) List,
B. Synlett 2001, 1675. (c) Alcaide, B.; Almendros, P. Angew. Chem., Int.
Ed. 2003, 42, 858. (d) List, B. Acc. Chem. Res. 2004, 37, 548. (e) Notz,
W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. For leading
literature, see: (f) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (g) Co´rdova, A.; Notz, W.; Barbas, C. F., III J. Org.
Chem. 2002, 67, 301. (h) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620. (i) Pidathala, C.; Hoang, L.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (j) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152. (k) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343.
(10) (a) Cørdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.;
Liao, W.-W. Chem. Commun. 2005, 3586. (b) Cørdova, A.; Zou, W.;
Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383.
(c) Jiang, Z. Q.; Liang, Z. A.; Wu, X. Y.; Lu, Y. X. Chem. Commun. 2006,
2801.
Results and Discussion
Design of Organocatalysts for the Direct Aldol Reaction
of Ketones with R-Keto Acids. Molecular recognition phe-
nomena are critically important in the actions of enzymes on
substrates. A large number of enzyme-mimetic systems such
as crown ethers,26 cryptands,27 cyclodextrins,28 and capsules29
have been devised as artificial receptor sites to bind appropriate
guest molecules or ions. Since the finding by Hamilton and co-
workers that the acylaminopyridine function can form specific
hydrogen bonds with a carboxyl group (6, Scheme 1),30 organic
(15) (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.;
Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc.
Natl. Acad. Sci. U. S. A. 2004, 101, 5755. (c) Tang, Z.; Yang, Z.-H.; Cun,
L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285. (d)
Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285.
(16) Raj, M.; Vishnumaya Ginotra, S. K.; Singh, V. K. Org. Lett. 2006,
8, 4097.
(17) (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem.,
Int. Ed. 2005, 44, 3055. (b) Kano, T.; Tokuda, O.; Maruoka, K. Tetrahedron
Lett. 2006, 47, 7423. (c) Kano, T.; Tokuda, O.; Takai, J.; Maruoka, K.
Chem. Asian J. 2006, 1-2, 210.
(18) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao,
W.-J. Org. Lett. 2005, 7, 4543. (b) Samanta, S.; Liu, J.; Dodda, R.; Zhao,
C.-G. Org. Lett. 2005, 7, 5321.
(19) (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734. (b) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958.
(20) Cheng, C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.; Wu,
Y. Chem. Commun. 2006, 215.
(11) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 4542.
(12) (a) Hartikaa, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004,
15, 1831. (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983. For review, see: (c) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
(21) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III
J. Am. Chem. Soc. 2007, 129, 288. (b) Luo, S.; Xu, H.; Li, J.; Zhang, L.;
Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074. (c) Kano, T.; Yamaguchi,
Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738.
(22) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620.
(13) (a) Berkessel, A.; Koch, B.; Lex, J. AdV. Synth. Catal. 2004, 346,
1141. (b) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
(14) (a) Martin, H. J.; List, B. Synlett 2003, 1901. (b) Kofoed, J.; Nielsen,
J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445.
(23) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.; Maruoka, K. Org.
Lett. 2005, 7, 5103.
(24) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442.
(25) For preliminary results, see: Tang, Z.; Cun, L.-F.; Cui, X.; Mi, A.-
Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263.
9906 J. Org. Chem., Vol. 72, No. 26, 2007