Asymmetric Synthesis DOI: 10.1002/ange.200805967 A Stable Homodinuclear Biscobalt(III)–Schiff Base Complex for Catalytic Asymmetric 1,4-Addition Reactions of b-Keto Esters to Alkynones** Zhihua Chen, Makoto Furutachi, Yuko Kato, Shigeki Matsunaga,* and Masakatsu Shibasaki* Bifunctional cooperative asymmetric catalysis is currently a popular research topic in organic synthesis. Various bifunc- tional metal and organocatalysts have been reported during the last decade. [1] As part of our ongoing research into this issue, we recently reported the utility of cooperative bimet- allic complexes of the Schiff base 1 (Scheme 1), [2–5] the catalytic properties of which differed from those of well- established monometallic salen complexes. [6] Combined com- plexes of Cu/Sm, [2] Pd/La, [3] and Ni/Ni [4] were utilized for enantioselective 1,2-addition reactions, such as nitro-Man- nich [2, 4] and nitroaldol reactions. [3] Herein, we report studies on the further expansion of the scope of bimetallic Schiff base catalysis to 1,4-addition reactions with electron-deficient alkynes. In contrast to 1,4-addition reactions to electron- deficient alkenes, [7] catalytic enantioselective a-alkenylation reactions by addition to electron-deficient alkynes are rare. [8] The utility of products with a C  C double bond that can be further functionalized makes the development of catalytic asymmetric 1,4-addition reactions to alkynes highly desirable. Jørgensen [8a] and Maruoka [8b] reported enantioselective 1,4- addition reactions of 1,3-diketones to alkynones and a- cyanoacetates to an alkynoate moiety. However, the asym- metric 1,4-addition of b-keto esters to alkynones has not been reported to date. A new homodinuclear complex Co III 2 - (OAc) 2 –1 (Scheme 1) was suitable for the 1,4-addition of b- keto esters to alkynones. Reactions performed with 2.5–0.25 mol % catalyst loading at ambient temperature afforded products with high enantioselectivity (up to 99 % ee). To find a suitable metal combination for the 1,4-addition reaction of b-keto ester 4, we selected alkynone 3a as a model substrate. The catalyst screening results are summarized in Table 1. A Ni 2 –1 complex (Scheme 1), [4] which was suitable for 1,2-addition to imines, gave moderate enantioselectivity (entry 3, 32 % ee), while rare-earth-metal complexes gave poor enantioselectivity (Table 1, entries 1 and 2). Among other metals screened (Table 1, entries 4–6), the Co III 2 - (OAc) 2 –1 complex [9] gave product 5aa in 52% ee (entry 6). By changing the ester moiety of the b-keto ester to a tert-butyl group (Table 1, entry 7, 4b) and the solvent to iPr 2 O (entry 8), the enantioselectivity improved to 97 % ee, albeit in a modest E/Z ratio. It is noteworthy that the reaction proceeded without difficulty even under solvent-free conditions at room temperature, to give product 5ab in 97% ee after 1h (entry 9). In Table 1, entries 8 and 9, high enantioselectivity was observed both for the E isomer and Z isomer. Because the absolute configurations of the E isomer and the Z isomer were the same, we investigated a one-pot sequential asym- metric 1,4-addition/isomerization process to obtain the prod- uct 5ab in both a high E/Z ratio and with high enantiose- lectivity. As shown in Table 1, entry 10, the first 1,4-addition proceeded smoothly with 2.5 mol % catalyst under solvent- free conditions within 4 h. Ph 2 MeP (30 mol %) was added to the reaction mixture for isomerization after completion of the 1,4-addition reaction, to predominantly afford the E adduct 5ab in greater than 95 % yield (calculated from the 1 H NMR spectrum) and with 96 % ee. Scheme 1. Structures of dinucleating Schiff base H 4 –1, salen ligands 2a–2c, and di- and mononuclear Schiff base complexes. [*] Z. Chen, M. Furutachi, Y. Kato, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) Fax: (+ 81) 3-5684-5206 E-mail: smatsuna@mol.f.u-tokyo.ac.jp mshibasa@mol.f.u-tokyo.ac.jp Homepage: http://www.f.u-tokyo.ac.jp/ ~ kanai/e_index.html [**] This work was supported by a Grant-in-Aid for Scientific Research (S) (to M.S.), for Scientific Research on Priority Areas (no. 20037010, Chemistry of Concerto Catalysis, to S.M.), and for Encouragements for Young Scientists (A) (to S.M.) from JSPS and MEXT. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200805967. Zuschriften 2252  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2009, 121, 2252 –2254