Asymmetric Catalysis DOI: 10.1002/anie.201310336 Highly Chemo-, Regio-, and Enantioselective Rhodium-Catalyzed Cross-Cyclotrimerization of Two Different Alkynes with Alkenes** Jun Hara, Mana Ishida, Masayuki Kobayashi, Keiichi Noguchi, and Ken Tanaka* Abstract: It has been established that a cationic rhodium(I)/ (R)-tol-binap complex catalyzes the cross-cyclotrimerization of silylacetylenes, di-tert-butyl acetylenedicarboxylates, and acrylamides with excellent chemo-, regio-, and enantioselectiv- ities. Unsymmetrical alkynoates can also be employed in place of di-tert-butyl acetylenedicarboxylate for this process, but with reduced chemoselectivity. T ransition-metal-catalyzed cross-[2+2+2] cyclotrimerization reactions of three different unsaturated compounds are efficient and atom-economical methods for the synthesis of substituted six-membered compounds. [1] However, such trans- formations have been accomplished in only a few examples because of the difficulty in achieving high chemo- and regioselectivities. For examples of the cross-cyclotrimeriza- tion of three different alkynes, [2] Ikeda and co-workers reported a nickel-catalyzed reaction [2a] and Kondoh and co- workers reported a ruthenium-catalyzed reaction. [2b] For examples of the cross-cyclotrimerization of two different alkynes with alkenes, [3–10] Ikeda and co-workers reported the nickel-catalyzed reaction [3] and Obora and co-workers reported the niobium-catalyzed reaction. [4] Saito and co- workers reported the nickel-catalyzed [3+2+2] cyclotrimeri- zation of two different alkynes and ethyl cyclopropylidene- acetate. [5] Our research group also reported the rhodium- catalyzed cross-cyclotrimerization of terminal alkynes, acety- lenedicarboxylates, and alkenyl acetates. [6] However, in these reports, at least one component is in large excess so as to obtain the three-component cyclotrimerization products in acceptable yields. In addition, regioselectivities are insuffi- cient in some cases. Recently, our research group accom- plished the rhodium-catalyzed enantioselective cross-cyclo- trimerization of electron-rich terminal alkynes, acetylenedi- carboxylates, and enamides, however the product yields were low to moderate. [7, 8] Herein, we disclose the unprecedented highly chemo-, regio-, and enantioselective catalytic cross- cyclotrimerization of two different alkynes with an alkene. Recently, our research group reported the chemo- and regioselective synthesis of substituted trienes by the rhodium- catalyzed intermolecular linear cross-trimerization of termi- nal alkynes, acetylenedicarboxylates, and acrylamides. [11, 12] For example, a CH 2 Cl 2 solution of N-methyl-N-phenylacryl- amide (3a), di-tert-butyl acetylenedicarboxylate (2a), and n- hexylacetylene (1a) or cyclohexylacetylene (1b) were sequentially added to a CH 2 Cl 2 solution of the cationic rhodium(I)/H 8 -binap catalyst at room temperature to give either the linear trimerization product 4 aaa or 4 baa in good yield (Scheme 1). [11] However, tert-butyl acetylene (1c) failed to react with 2a and 3a (Scheme 1). Surprisingly, trimethyl- silylacetylene (1d) reacted with 2a and 3a to give cyclo- trimerization product 5 daa in a good yield with an excellent ee value, along with the linear trimerization product 4 daa (Scheme 1). Thus, various axially chiral biaryl bisphosphine ligands (Figure 1) were screened (Table 1, entries 1–5), and the use of (R)-tol-binap afforded 5 daa in the highest yield with an excellent ee value (entry 4). Pleasingly, the simple addition of a CH 2 Cl 2 solution of 1d, 2a, and 3a to a CH 2 Cl 2 solution of a reduced amount of the catalyst (5 mol %) afforded 5 daa without erosion of the product yield and ee value (entry 6). The substrate scope is shown in Scheme 2. With respect to acrylamides, not only N-methyl-N-phenylacrylamide (3a) but also N,N-dimethyl (3b), N,N-dibutyl (3c), N,N-tetramethy- lene (3d), and Weinreb (3e) acrylamides could be employed. With respect to alkynoates, not only 2a, but also the Scheme 1. Rhodium-catalyzed linear trimerization versus cyclotrimeri- zation. cod = cyclo-1,5-octadiene. [*] J. Hara, M. Ishida, M. Kobayashi, Prof. Dr. K. Tanaka Department of Applied Chemistry, Graduate School of Engineering Tokyo University of Agriculture and Technology, Koganei Tokyo 184-8588 (Japan) E-mail: tanaka-k@cc.tuat.ac.jp Homepage: http://www.tuat.ac.jp/ ~ tanaka-k/ Prof. Dr. K. Noguchi Instrumentation Analysis Center, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588(Japan) Prof. Dr. K. Tanaka Japan Science and Technology Agency (JST), ACT-C, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012 (Japan) [**] This work was supported partly by a Grant-in-Aid for Scientific Research (No. 20675002) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and ACT-C from the Japan Science and Technology Agency (JST) (Japan). We are grateful to Umicore for generous support in supplying the rhodium complex, and Takasago International Corporation for the gift of H 8 -binap, segphos, and binap derivatives. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201310336. . Angewandte Communications 2956  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53, 2956 –2959