COMMUNICATIONS
[4] For discussions of the transition state geometry of the aldol reaction,
see a) H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
1920 ± ; b) S. E. Denmark, B. R. Henke, J. Am. Chem. Soc. 1991, 113,
2177 ± 2194, and references therein; c) C. Gennari, S. Vieth, A.
Comotti, A. Vulpetti, J. M. Goodman, I. Paterson, Tetrahedron 1992,
48, 4439 ± 4458.
approximately 1000-fold higher than that reported for any
other catalytic antibody.[3f, 10] The catalytic efficiency of
1
the antibody for this substrate, 3.3 Â 105 s 1 m , compares
favorably with the efficiency of natural muscle aldolase,
1
4.9 Â 104 s 1 m , in the retro-aldolization of its substrate
fructose-1,6-bisphosphate.[11]
[5] a) P. G. Schultz, R. A. Lerner, Science 1995, 269, 1835 ± 1842; b) N. R.
Thomas, Nat. Prod. Rep. 1996, 13, 479 ± 511.
In conclusion, we have demonstrated that combining
transition state analogy and reactive immunization design
into a single hapten can result in increases both in the output
of catalysts from the immune system as well as their efficiency.
This strategy resulted in the characterization of the most
proficient antibody catalysts prepared to date. Antibodies
93F3 and 84G3 catalyze a wide array of aldol reactions with ee
values exceeding 95% in most of the cases studied. A new
stereogenic center is formed when acetone is the aldol donor
substrate by attack on the re-face of the aldehyde, which
provides the antipodal complement of ab38C2 in aldol
reactions. Both aldol enantiomers may be accessed through
aldol and retro-aldol reactions. These catalysts should provide
access to a wide variety of enantiomerically enriched synthons
with application to natural product syntheses.
[6] B. List, C. F. Barbas III, R. A. Lerner, Proc. Natl. Acad. Sci. USA
1998, 95, 15351 ± 15355.
[7] I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K.
McClure, R. D. Norcross, Tetrahedron 1990, 46, 4663 ± 4684.
[8] We have identified two catalysts with enantioselectivities similar to
ab38C2.
[9] A. R. Radzicka, R. A. Wolfenden, Science 1995, 267, 90 ± 93.
[10] N. R. Thomas, Appl. Biochem. Biotechnol. 1994, 47, 345 ± 372.
[11] Data for muscle aldolase was reported at 48C: A. J. Morris, D. R.
Tolan, Biochemistry 1994, 33, 12291 ± 12297.
Received: April 29, 1999
Revised version: August 4, 1999 [Z13339IE]
German version: Angew. Chem. 1999, 111, 3957 ± 3960
Enantioselective [1,2] Wittig Rearrangement
Using an External Chiral Ligand**
Keywords: aldol reactions ´ asymmetric synthesis ´ catalytic
antibodies ´ enantiomeric resolution ´ retro reactions
Katsuhiko Tomooka,* Kyoko Yamamoto, and
Takeshi Nakai*
[1] For reviews of the aldol reaction, see a) S. Masamune, W. Choy, J. S.
Peterson, L. R. Sita, Angew. Chem. 1985, 97, 1 ± 31; Angew. Chem. Int.
Ed. Engl. 1985, 24, 1 ± 30; b) C. H. Heathcock, Aldrichim. Acta 1990,
23, 99 ± 111; c) D. A. Evans, Science 1988, 240, 420 ± 426; d) C. J.
Cowden, I. Paterson, Org. React. 1997, 51, 1; e) A. S. Franklin, I.
Paterson, Contemp. Org. Synth. 1994, 1, 317.
[2] a) S. G. Nelson, Tetrahedron: Asymmetry 1998, 9, 357 ± 389; b) A.
Yanagisawa, Y. Matsumoto, H. Nakashima, K. Asakawa, H. Yama-
moto, J. Am. Chem. Soc. 1997, 119, 9319 ± 9320; c) E. M. Carreira, W.
Lee, R. A. Singer, J. Am. Chem. Soc. 1995, 117, 3649 ± 3650; d) D. A.
Evans, D. W. C. MacMillan, K. R. Campos, J. Am. Chem. Soc. 1997,
119, 10859 ± 10860; e) D. J. Ager, M. B. East, Asymmetric Synthetic
Methodology, CRC Press, Boca Raton, 1996; f) C. H. Wong, G. M.
Whitesides, Enzymes in Synthetic Organic Chemistry, Pergamon,
Oxford, 1994; g) C. H. Wong, R. L. Halcomb, Y. Ichikawa, T.
Kajimoto, Angew. Chem. 1995, 107, 453 ± 474; Angew. Chem. Int.
Ed. Engl. 1995, 34, 412 ± 432; h) W. D. Fessner, Curr. Opin. Chem.
Biol. 1998, 2, 85 ± 89.
[3] a) J. Wagner, R. A. Lerner, C. F. Barbas III, Science 1995, 270, 1797 ±
1880; b) R. Björnestedt, G. Zhong, R. A. Lerner, C. F. Barbas III, J.
Am. Chem. Soc. 1996, 118, 11720 ± 11724; c) G. Zhong, T. Hoffmann,
R. A. Lerner, S. Danishefsky, C. F. Barbas III, J. Am. Chem. Soc. 1997,
119, 8131 ± 8132; d) C. F. Barbas III, A. Heine, G. Zhong, T.
Hoffmann, S. Gramatikova, R. Björnestedt, B. List, J. Anderson,
E. A. Stura, E. A. Wilson, R. A. Lerner, Science 1997, 278, 2085 ±
2092; e) T. Hoffmann, G. Zhong, B. List, D. Shabat, J. Anderson, S.
Gramatikova, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 1998,
120, 2768 ± 2779; f) G. Zhong, D. Shabat, B. List, J. Anderson, S. C.
Sinha, R. A. Lerner, C. F. Barbas III, Angew. Chem. 1998, 110, 2609 ±
2612; Angew. Chem. Int. Ed. 1998, 37, 2481 ± 2484; g) S. C. Sinha, J.
Sun, G. Miller, C. F. Barbas III, R. A. Lerner, Org. Lett. 1999, in press;
h) B. List, D. Shabat, G. Zhong, J. M. Turner, A. Li, T. Bui, J.
Anderson, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 1999, 121,
7283 ± 7291; i) For an alternative aldolase antibody strategy see J. L.
Reymond, Angew. Chem. 1995, 107, 2471 ± 2473; Angew. Chem. Int.
Ed. Engl. 1995, 34, 2285 ± 2287; J. L. Reymond, Y. Chen, J. Org. Chem.
1995, 60, 6970 ± 6979.
Since its discovery by Wittig and Löhmann in 1942,[1] the
reaction of a-lithiated ethers, now known as the [1,2] Wittig
rearrangement, has attracted much interest from both mech-
anistic and synthetic points of view.[2] This type of carbanion
rearrangement is recognized to proceed by means of the
radical dissociation ± recombination mechanism [Eq. (1)].[2, 3]
Despite its long history, however, no enantioselective
versions of the Wittig rearrangement have been developed
yet. Clearly, the radical character provides a great challenge.
We now disclose the first enantioselective Wittig rearrange-
ment which relies upon an asymmetric lithiation protocol[4] in
which (S,S)-bis(dihydrooxazol) 3 serves as an external chiral
ligand[5, 6] [Eq. (2)]. The most striking feature is that the
[*] Prof. Dr. K. Tomooka, K. Yamamoto, Prof. Dr. T. Nakai
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
Meguro-ku, Tokyo 152-8552 (Japan)
Fax: (81)3-5734-3931
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports and Culture, Japan
and by the Research for the Future Program, administered by the
Japan Society of the Promotion of Science.
Angew. Chem. Int. Ed. 1999, 38, No. 24
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