ORGANIC
LETTERS
2002
Vol. 4, No. 18
3051-3054
Highly Enantioselective Reformatsky
Reaction of Ketones:
Chelation-Assisted Enantioface
Discrimination
Akio Ojida,† Toru Yamano,* Naohiro Taya, and Akihiro Tasaka
Medicinal Chemistry Research Laboratories, Takeda Chemical Industries, Ltd.,
Osaka 532-8686, Japan
Received June 6, 2002
ABSTRACT
Highly enantioselective Reformatsky reaction of ketones was accomplished using cinchona alkaloids as chiral ligands. Chelation with the
sp2-nitrogen adjacent to the reactive carbonyl center contributed the enantioface discrimination for the high enantioselectivities.
The asymmetric Reformatsky reaction is a versatile and
straightforward approach to obtaining chiral alcohols (â-
hydroxy esters), a motif found in biologically active com-
pounds and synthetic intermediates.1 Although a variety of
asymmetric Reformatsky reactions have been developed,2,3
there have been no reports so far of efficient methods for
achieving high enantioselectivity in useful chemical yield.
Furthermore, in most cases, aromatic aldehydes have been
employed as substrates, and there are few examples of
asymmetric Reformatsky reactions with ketones. Representa-
tive work was reported by Soai et al.,3 in which chiral tertiary
alcohols were obtained from aryl ketones in moderate
enantioselectivity using N,N-dialkylnorephedrines as chiral
ligands. This moderate selectivity might be attributed to poor
enantioface discrimination of the ketone due to the bulkiness
of both carbonyl substituents. It was thought that this
difficulty could be overcome by the introduction of a
substituent that participates in the formation of a geo-
metrically defined complex between zinc and the ketone as
a reactive intermediate. Herein, we describe highly enantio-
selective Reformatsky reactions of ketones appended to a
nitrogen-containing aromatic ring using cinchona alkaloids
as chiral ligands.
† Present address: Department of Chemistry and Biochemistry, Graduate
School of Engineering, Kyushu University, 6-10-1, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan.
(1) For reviews, see: (a) Organozinc Reagent; Knohel, P., Philip, J.,
Eds.; Oxford University Press: New York, 1999. (b) Fu¨rstner, A. Synthesis
1989, 571.
(2) (a) Andre´s, J. M.; Pedrosa, R.; Pe´rez-Encabo, A. Tetrahedron 2000,
56, 1217. (b) Ukaji, Y.; Yoshida, Y.; Inomata, K. Tetrahedron: Asymmetry
2000, 11, 733. (c) Andre´s, J. M.; Mart´ın, Y.; Pedrosa, R.; Pe´rez-Encabo,
A. Tetrahedron 1997, 53, 3787. (d) Mi, A.; Wang, Z.; Zhang, J.; Jiang, Y.
Synth. Commun. 1997, 27, 1469. (e) Mi, A.; Wang, Z.; Chen, Z.; Jiang, Y.;
Chan, A. S. C.; Yang T. K. Tetrahedron: Asymmetry 1995, 6, 2641. (f)
Mastantuono, A.; Pini, D.; Rolfini, C.; Salvadori, P. Chirality 1995, 7, 499.
(g) Braun, M.; Vonderhagen, A.; Waldmu¨ller, D. Liebigs Ann. 1995, 1447.
(h) Guette´, M.; Guette´, C. J.-P. Tetrahedron 1973, 29, 3659. (i) Zhang, Y.;
Wu, W. Tetrahedron: Asymmetry 1997, 8, 3575.
In the course of our research into the synthesis of an
optically active pharmaceutical compound, we were faced
with the problem of developing an efficient and practical
construction of a chiral tertiary alcohol. After setting our
attention on the Reformatsky reaction, we screened several
chiral ligands. We focused on chiral 1,2-amino alcohol
derivatives, since a variety of these have been reported to
be effective in the enantioselective organozinc addition to
carbonyl compounds, including the Reformatsky reaction.2,4
Cinchona alkaloids are among the most prominent and
(3) Soai, K.; Oshio, A.; Saito, T. J. Chem. Soc., Chem. Commun. 1993,
811.
10.1021/ol0263189 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002