addition,11 numerous efforts have been made to improve the
stereoselectivity. Because of the poor solubility of proline in
organic solvents, researchers strived to perform the reaction in
water12 and ionic liquids13 and even utilized polymer-supported
proline14 which is hydrophilic or lipophilic. In the meantime, a
great deal of endeavors were devoted to the design of different
proline derivatives15 or to simulation of the proline structure to
construct new potential catalysts;16 unfortunately, sometimes
those new molecules failed to show satisfactory results.
Therefore, much attention has been shifted to a practical
strategy: to improve enantioselectivity or accelerate the reaction
by using additives in the reaction system.17 Additives reported
Chiral Diols: A New Class of Additives for
Direct Aldol Reaction Catalyzed by L-Proline
Yan Zhou and Zixing Shan*
Department of Chemistry, Wuhan UniVersity, Wuhan 430072,
China
ReceiVed April 16, 2006
(6) (a) For the first proline-catalyzed Mannich reaction, see: List, B. J.
Am. Chem. Soc. 2000, 122, 9336-9337. (b) List, B.; Pojarliev, P.; Biller,
W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (c) Co´rdova,
A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem.
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C. F. III. Synlett 2003, 1906-1909. (e) Notz, W.; Tanaka, F.; Watanabe,
S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III.
J. Org. Chem. 2003, 68, 9624-9634.
Nine C2 symmetric diols have been examined as additives
in the L-proline-catalyzed direct aldol reaction with signifi-
cant improvement in enantioselectivity, conversion ef-
ficiency, and yield. Loading of 1 mol % of (S)-BINOL leads
to the desired products in up to 98% ee and 90% yield. A
transition state is proposed.
(7) (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. N. Angew. Chem., Int. Ed. 2002, 41, 1790-1793. (b) List,
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In the past decades, L-proline, the simplest “enzyme”,1 has
become one of the most attractive molecules in green synthetic
chemistry. As an effective organocatalyst,2 it has been success-
fully applied in Diels-Alder reactions,3 Baylis-Hillman reac-
tions,4 Michael reactions,5 Mannich reactions,6 direct electro-
philic R-aminations,7 Robinson annulations,8 aldol reactions, and
others.9 Among them, the direct aldol reaction is particularly
interesting.10
Since the pioneering work by List and Barbas that L-proline
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10.1021/jo060802y CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/15/2006
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J. Org. Chem. 2006, 71, 9510-9512