J. Am. Chem. Soc. 2000, 122, 2395-2396
2395
the course of these studies, we found that one of our aldolase
catalytic antibodies (Aldolase Antibody 38C2, Aldrich) is an
efficient catalyst for enantiogroup-differentiating aldol cyclode-
hydrations of 2,6-heptanediones to give cyclohexenones, including
the Wieland-Miescher ketone.8,9 These intramolecular reactions
are also catalyzed by proline (Hajos-Eder-Sauer-Wiechert
reaction)10 and it has been postulated that they proceed via an
enamine mechanism.11 However, the proline-catalyzed direct
intermolecular asymmetric aldol reaction has not been described.
Further, there are no asymmetric small-molecule aldol catalysts
that use an enamine mechanism.7 Based on our own results and
Shibasaki’s work on lanthanum-based small-molecule aldol
catalysts,4,6 we realized the great potential of catalysts for the
direct asymmetric aldol reaction.
Proline-Catalyzed Direct Asymmetric Aldol
Reactions
Benjamin List,* Richard A. Lerner, and Carlos F. Barbas III
The Skaggs Institute for Chemical Biology
and the Department of Molecular Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed December 7, 1999
Most enzymatic transformations have a synthetic counterpart.
Often though, the mechanisms by which natural and synthetic
catalysts operate differ markedly. The catalytic asymmetric aldol
reaction as a fundamental C-C bond forming reaction in
chemistry and biology is an interesting case in this respect.
Chemically, this reaction is dominated by approaches that utilize
preformed enolate equivalents in combination with a chiral
catalyst.1 Typically, a metal is involved in the reaction mechanism.1d
Most enzymes, however, use a fundamentally different strategy
and catalyze the direct aldolization of two unmodified carbonyl
compounds. Class I aldolases utilize an enamine based mecha-
nism,2 while Class II aldolases mediate this process by using a
zinc cofactor.3 The development of aldolase antibodies that use
an enamine mechanism and accept hydrophobic organic substrates
has demonstrated the potential inherent in amine-catalyzed
asymmetric aldol reactions.4 Recently, the first small-molecule
asymmetric class II aldolase mimics have been described in the
form of zinc, lanthanum, and barium complexes.5,6 However,
amine-based asymmetric class I aldolase mimics have not been
described in the literature.7 Here we report our finding that the
amino acid proline is an effective asymmetric catalyst for the
direct aldol reaction between unmodified acetone and a variety
of aldehydes.
We initially studied the reaction of acetone with 4-nitroben-
zaldehyde. Reacting proline (30 mol %) in DMSO/acetone (4:1)
with 4-nitrobenzaldehyde at room temperature for 4 h furnished
aldol product (R)-1 in 68% yield and 76% ee (eq 1). This result
is quite remarkable since it is known that proline can undergo a
variety of reactions with aldehydes. For example, aliphatic
aldehydes react with proline to give either the oxazolidinone and/
or various other compounds, including products of self-aldoliza-
tion.12 Aromatic aldehydes (including 4-nitrobenzaldehyde) can
condense with proline to form azomethine ylides that undergo
further 1,3-dipolar cycloaddition reaction.13 The high concentration
of acetone we use in the reaction mixture suppresses these side
reactions. The only significant side product is the R,â-unsaturated
ketone, formed by aldol (or Mannich-type) condensation. After
screening several solvents,14 we found anhydrous DMSO at room
temperature to be the most suitable condition regarding reaction
times and enantioselectivity. We also compared a variety of
different commercially available amino acid derivatives under
standard conditions with 30-40 mol % of catalyst (Table 1).
Interestingly, primary amino acids and acyclic secondary amino
acids failed to give significant amounts of the desired product
(entries 1 and 2). While 2-azetidinecarboxylic acid showed some
catalysis (entry 3), both pipecolic acid (entry 5) and 2-pyrrolidine
carboxamide (entry 6) were uneffective. Clearly both the pyrro-
lidine ring and the carboxylate are essential for efficient catalysis
to occur. On the other hand, none of the commercially available
proline derivatives (entries 7-9) showed significantly improved
enantioselectivity compared to proline itself. Synthesis of other
Recently we developed broad scope aldolase antibodies that
show very high enantioselectivities, have enzymatic rate accelera-
tions, and use the enamine mechanism of class I aldolases.4 During
(1) Reviews: (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-
389. (b) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137.
(c) Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417. (d) A notable
exception is Denmark’s chiral Lewis base-catalyzed Mukayama-type aldol
reaction: Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. J. Org. Chem. 1998,
63, 918-919.
(2) (a) March, J. J.; Lebherz, H. G. TIBS 1992, 17, 110. (b) Rutter, W. J.
Fed. Proc. Am. Soc. Exp. Biol. 1964, 23, 1248. (c) Lai, C. Y.; Nakai, N.;
Chang, D. Science 1974, 183, 1204. (d) Morris, A. J.; Tolan, D. R.;
Biochemistry 1994, 33, 12291.
(3) Fessner, W.-D.; Schneider, A.; Held, H.; Sinerius, G.; Walter, C.; Hixon,
M.; Schloss, J. D. Angew. Chem., Int. Ed. Engl. 1996, 35, 2219-2221.
Phosphoenolpyruvate aldolases use a preformed enolate, phosphoenolpyruvate,
to accomplish aldol addition reactions. For studies of this and other aldolase
enzymes in organic synthesis see: Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong,
C.-H. Chem. ReV. 1996, 96, 443-473.
(4) (a) Wagner, J.; Lerner, R. A.; Barbas, C. F., III Science 1995, 270,
1797. (b) Barbas, C. F., III; Heine, A.; Zhong, G.; Hoffmann, T.; Gramatikova,
S.; Bjo¨rnestedt, R.; List, B.; Anderson, J.; Stura, E. A.; Wilson, E. A.; Lerner,
R. A. Science 1997, 278, 2085-2092. (c) Hoffmann, T.; Zhong, G.; List, B.;
Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F., III J.
Am. Chem. Soc. 1998, 120, 2768-2779. (d) List, B.; Shabat, D.; Barbas, C.
F., III; Lerner, R. A. Chem. Eur. J. 1998, 881-885. (e) Zhong, G.; Shabat,
D.; List, B.; Anderson, J.; Sinha, S. C.; Lerner. R. A.; Barbas, C. F., III Angew.
Chem., Int. Ed. 1998, 37, 2481-2484. (f) Zhong, G.; Lerner. R. A.; Barbas,
C. F., III Angew. Chem., Int. Ed. 1999, 38, 3738-3741. (g) Sinha, S. C.;
Sun, J.; Miller, G.; Barbas, C. F., III; Lerner, R. A. Org. Lett. 1999, 1, 1623-
1626. (h) Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas, C. F., III; List, B.
Manuscript submitted for publication.
(7) For aldol and retro aldol reactions that are catalyzed by achiral primary
amines, see: (a) Pollack, R. M.; Ritterstein, S. J. Am. Chem. Soc. 1972, 94,
5064-5069. (b) Koshechkina, L. P.; Mel’nichenko, I. V. Ukr. Khim. Zh. 1974,
40, 172-174.
(8) Zhong, G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas, C.
F., III J. Am. Chem. Soc. 1997, 119, 8131.
(9) List, B.; Lerner, R. A.; Barbas, C. F., III Org. Lett. 1999, 1, 59-62.
(10) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b)
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10,
496. (c) Agami, C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 2,
358-360.
(11) (a) Agami, C.; Puchot, C.; Sevestre, H. Tetrahedron Lett. 1986, 27,
1501-1504. (b) Agami, C. Bull. Soc. Chim. Fr. 1988, 3, 499-507.
(12) (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem.
Soc. 1983, 105, 5390-5398. (b) Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti,
M.; Bombieri, G.; Benetollo, F. J. Heterocycl. Chem. 1989, 26, 837-841.
(13) (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069. (b) Orsini, F.; Pelizzoni,
F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988, 44, 519-541.
(14) Solvent (ee): CH3CN (56%), acetone (67%), THF (60%), DMF (76%),
DMF/H2O [10:1] (35%), DMSO (76%).
(5) (a) Nakagawa, M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391-
394. (b) Yamada, Y.; Watanabe, K.-I.; Yasuda, H. Utsunomiya Daigaku
Kyoikugakubu Kiyo, Dai-2-bu 1989, 39, 25-31.
(6) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yamada, Y. M. A.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 5561. (c) Yoshikawa, N.; Yamada, Y. M. A.;
Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178.
10.1021/ja994280y CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/26/2000