Enantioselective 1,4-Addition of Unmodified Ketone Catalyzed by a Bimetallic Zn-Zn-Linked-BINOL Complex Naoya Kumagai, Shigeki Matsunaga, and Masakatsu Shibasaki* Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan mshibasa@mol.f.u-tokyo.ac.jp Received October 31, 2001 ABSTRACT 1,4-Addition (Michael addition) of 2-hydroxy-2′-methoxyacetophenone (2) to various r,-unsaturated ketones was efficiently promoted by a bimetallic Zn-Zn-linked-BINOL complex 3 with good yield (up to 90%) and excellent enantiomeric excess (up to 99% ee). The resulting 2-hydroxy-1,5-diketones were successfully converted to synthetically more versatile esters and amides. The catalytic asymmetric carbon-carbon bond formation is a major focus of modern synthetic organic chemistry. 1 Moreover, the increasing demand for efficient and environ- mentally benign processes requires the development of atom economic 2 asymmetric catalysis in which enantiomerically enriched compounds are produced using unmodified sub- strates. Toward this end, we 3 and others 4,5 successfully demonstrated direct catalytic asymmetric aldol reactions that utilize unmodified ketones as donors. In contrast to these promising results 6 with aldol reactions, however, direct catalytic asymmetric 1,4-addition reactions of unmodified ketones are very rare 7 despite their importance in synthetic organic chemistry in providing 1,5-dicarbonyl chiral building blocks. 8,9 Thus, development of the direct catalytic asym- (1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer, Berlin, 1999. (b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Wiley: New York, 2000. (2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (3) Unmodified ketones as donors: (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (c) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561. (d) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569. (e) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669. Unmodified R-hydroxyketones as donors: (f) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466. (g) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539. (4) Unmodified ketones as donors: (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (b) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (e) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (f) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett. 2001, 1245. For a partially successful attempt, see: (g) Nakagawa, M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391. Unmodified R-hydroxyketones as donors: (h) The use of R-hydroxyketones with chemical catalysts has been pioneered by List et al.: Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (i) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. See, also ref 4d. (5) Review for biological and chemical methods: (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. For the use of catalytic antibodies, see: (b) Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas, C. F., III; List, B. Chem Eur. J. 2000, 6, 2772 and references therein. (6) For other promising atom economic asymmetric catalysis, see: Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. ORGANIC LETTERS 2001 Vol. 3, No. 26 4251-4254 10.1021/ol016981h CCC: $20.00 © 2001 American Chemical Society Published on Web 12/05/2001