Published on Web 08/08/2006
Remarkably Stable Chiral Zirconium Complexes for
Asymmetric Mannich-Type Reactions
Kowichiro Saruhashi and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
The HFRE DiVision, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received April 21, 2006; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Abstract: Isolable, air-stable, storable, and highly selective chiral zirconium catalysts for asymmetric
Mannich-type reactions have been developed. The reactions of imines with silicon enolates proceeded
smoothly using 1-10 mol % of the powdered zirconium catalyst to afford the corresponding adducts in
high yields with high stereoselectivities. The catalyst could be recovered and reused without significant
loss of activity. On the other hand, zirconium single crystals for X-ray analysis were obtained, and the
crystals also showed high performance in the asymmetric Mannich-type reactions. Although NMR analyses
of these zirconium catalysts showed different structures in dichloromethane, the formation of the same
key intermediate from the different catalysts was indicated.
Development of chiral Lewis acids is among the most
important tasks in current organic chemistry.1 While several
efficient asymmetric reactions using chiral Lewis acids have
been developed, a drawback is that most Lewis acids are
unstable in the presence of water and are even sensitive to
moisture.2 Therefore, many Lewis acid catalysts are prepared
in situ in an appropriate dry solvent just before use, and they
cannot be stored for extended periods. Contrary to this, we report
here remarkably stable chiral zirconium complexes, which are
isolable, air-stable, and highly active for asymmetric Mannich-
type reactions.
Catalytic asymmetric Mannich-type reactions of imines
derived from aldehydes and amines with enolate compounds
provide very effective ways to construct optically active â-amino
ketones or esters, which are useful chiral building blocks for
the synthesis of â-amino acids, â-lactams, â-amino alcohols,
[1,3]oxazinan-2-one, and so forth.3 Previously, we have reported
chiral zirconium-catalyzed enantioselective Mannich-type reac-
tions of imines with silicon enolates.4 Because chiral zirconium
catalysts have been widely used in several enantioselective
reactions,5 we have focused on the structure of the zirconium
catalysts.
The zirconium catalyst for the asymmetric Mannich-type
reactions was prepared in situ from a zirconium alkoxide, a 1,1′-
bi-2-naphthol (BINOL) derivative, and an imidazole derivative
in dichloromethane just before use.4 In our attempts to obtain
single crystals of the zirconium catalyst for X-ray analysis, we
discovered that the species prepared from zirconium alkoxides,
(R)-6,6′-dibromo BINOL, and N-methylimidazole (NMI) were
soluble in dichloromethane, toluene, or benzene. However,
addition of hexane to the dichloromethane solution of the
catalyst formed white powder (Figure 1). The powder was not
suitable for X-ray analysis, unfortunately, but was found to be
a remarkably stable but highly active catalyst.
The activity of the powdered catalyst was tested in the
Mannich-type reaction of the imine (1) prepared from benzal-
dehyde and 2-aminophenol with the ketene silyl acetal (2)
derived from methyl isobutyrate. It was found that the reaction
proceeded smoothly in the presence of 10 mol % of the isolated
catalyst to afford the desired Mannich adduct in 86% yield with
85% ee. It should be noted that the yield and the enatioselectivity
were comparable to those obtained using in situ prepared
catalysts.4 In addition, the isolated catalyst was found to be
remarkably stable to air and moisture. Indeed, it could be stored
for at least 6 months in air at room temperature without loss of
activity (Table 1), while a significant decrease of yields and
selectivities was observed when the in situ prepared catalyst
was used after 1 day of storage in air at room temperature.
(1) (a) SelectiVities in Lewis Acid Promoted Reaction; Schinzer, D., Ed.; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 1989. (b) Lewis acid
in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VHC: Weinheim,
Germany, 2000.
(2) For water-compatible Lewis acids, (a) Kobayashi, S.; Nagayama, S.;
Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287. (b) Kobayashi, S.; Ogino,
T.; Shimizu, H.; Ishikawa, S.; Hamada, T.; Manabe, K. Org. Lett. 2005, 7,
4729 and references therein.
(3) (a) Kobayashi, S.; Ueno, M. In ComprehensiVe Asymmetric Catalysis,
Supplement I; Jacobsen, E. N., Pfalz, A., Yamamoto, H., Eds.; Springer:
Berlin, 2003; Chapter 29.5. (b) Kobayashi, S. Ishitani, H. Chem. ReV. 1999,
99, 1069. (c) Cordova, A. Acc. Chem. Res. 2004, 37, 102
(4) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180. (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997,
119, 7153. For related work, see (c) Xue, S.; Yu, S.; Deng, Y.; Wulff, W.
D. Angew. Chem., Int. Ed. 2001, 40, 2271. (d) Wenzel, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 12964. (e) Josephsohn, N. S.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734.
(5) For example, (a) Ihori, Y.; Yamashita, Y.; Ishitani, H., Kobayashi, S. J.
Am. Chem. Soc. 2005, 127, 15528. (b) Yamashita, Y.; Kobayashi, S. J.
Am. Chem. Soc. 2004, 126, 11279. (c) Kobayashi, J.; Nakamura, M.; Mori,
Y.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 9192. (d)
Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85. (e) Huo, S.; Shi,
J.-C.; Negishi, E.-I. Angew. Chem., Int. Ed. 2002, 41, 2141. (f) Gastner,
T.; Ishitani, H.; Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2001,
40, 1896. (g) Negishi, E.-I. Pure Appl. Chem. 2001, 73, 239. (h) Kobayashi,
S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. J. Am. Chem.
Soc. 2002, 124, 13678. (i) Ishitani, H.; Yamashita, Y.; Shimizu, H.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 5403.
9
11232
J. AM. CHEM. SOC. 2006, 128, 11232-11235
10.1021/ja062776r CCC: $33.50 © 2006 American Chemical Society