for both aldol and retro-aldol reactions with rate accelerations
approaching those of natural aldolase enzymes.8 Furthermore,
and in contrast to its natural counterparts, this antibody is a
broad scope aldol catalyst that has been shown to work with
over 200 different substrate combinations.9 We have used
antibody 38C2 in the enantioselective synthesis of naturally
occurring pheromone derivatives,10 deoxy-sugars,11 and in
a total synthesis of epothilone A.12 Furthermore, we dem-
onstrated its use in a preparative scale synthesis of the
Wieland-Miescher ketone (2) from achiral triketone 1
(Scheme 1).13 Traditionally, this reaction is catalyzed by
former case (1 f 2) the enantiodifferentiation follows
enamine formation, while in the latter case (3 f 4)
enantiodifferentiation occurs upon enamine formation.
In the L-proline-catalyzed reaction, typically low yields
and enantioselectivities are observed.
We found that antibody 38C2 catalyzes the cyclodehy-
dration of 3 (R ) H) quite efficiently with kcat ) 0.082 min-1,
KM ) 2 mM, and kcat/kuncat ) 1.2 × 107.9a The question was
whether antibody 38C2 was capable of catalyzing this
transformation with enantiogroup selectivity when provided
with substrates 3 where R * H.
For the synthesis of the starting 1,5-diketones 3a-c, we
followed a route that has been developed by Sakurai and
co-workers.16 Thus, Lewis acid mediated conjugate addition
of allyltrimethylsilane to R,â-unsaturated ketones 5a-c gave
olefins 6a-c.17 Wacker oxidation of δ,ꢀ-unsaturated ketones
6a-c then furnished diketones 3a-c.18 Interestingly, we
found that the Wacker oxidation did not require an oxygen
atmosphere. Simple stirring under air furnished the products
in equivalent yield.19 Racemic reference compounds 4a-c
can be prepared by base treatment (KOH/MeOH) of ketones
3a-c (Scheme 3).20
Scheme 1
Scheme 3
L-proline.14 However, here the product is obtained with an
ee of 71%. A related transformation that has been catalyzed
by L-proline is the enantioselective cyclodehydration of
4-substituted-2,6-heptanediones (3) to the 5-substituted-3-
methyl-2-cyclohexen-1-ones (4) (Scheme 2).15 Stereochemi-
Scheme 2
cally, both reactions are enantiogroup-differentiating and
probably occur via an enamine mechanism. However, in the
(8) (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,
I. A.; Lerner, R. A. Science 1997, 278, 2085-2092.
The results of the antibody-catalyzed cyclization of dike-
tones 3 are shown in Scheme 4.
(9) (a) 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. (b) Zhong, G.; Shabat, D.; List, B.; Anderson, J.; Sinha,
S. C.; Lerner. R. A.; Barbas, C. F., III. Angew. Chem., Int. Ed. Engl. 1998,
37, 2481-2484. (c) List, B.; Barbas, C. F., III; Lerner, R. A. Proc. Natl.
Acad. Sci. U.S.A. 1998, 15351-15355.
(14) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496-497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615-1621.
(15) Agami, C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 2,
358-360.
(16) Hosomi, A.; Kobayashi, H.; Sakurai, H. Tetrahedron Lett 1980, 21,
955-958.
(10) List, B.; Shabat, D.; Barbas, C. F., III; Lerner, R. A. Chem. Eur. J.
1998, 4, 881-885.
(17) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673-1675.
The yield of olefin 6c was diminished from concurrent cyclobutane
formation. A similar observation has been made by Hosomi et al. (ref 16).
(18) Tsuji, J.; Shimizu, I.; Yamamoto, K. Tetrahedron Lett. 1976, 2975-
2976.
(11) Shabat, D.; List, B.; Lerner, R. A.; Barbas, C. F., III. Tetrahedron
Lett. 1999, 40, 1437-1440.
(12) Sinha, S. C.; Barbas, C. F., III; Lerner, R. A. Proc. Natl. Acad. Sci.
U.S.A. 1998, 14603-14608.
(13) Zhong, G.; Hoffmann, T., Lerner, R. A., Danishefsky, S.; Barbas,
C. F., III. J. Am. Chem. Soc. 1997, 119, 8131-8132.
(19) Doron Shabat, The Scripps Research Institute, personal communica-
tion.
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Org. Lett., Vol. 1, No. 1, 1999