J. zyxwvutsrqp Am. Chem. SOC. 1995,117, 7097-7104 7097 Enantio-, Diastereo-, and Regioselective Zirconium-Catalyzed Carbomagnesation of Cyclic Ethers with Higher Alkyls of Magnesium. Utility in Synthesis and Mechanistic Implications Mary T. Didiuk,'" Charles W. Johannes, James P. Morken,fband Amir H. Hoveyda* Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 021 67 Received December 2, 1994@ Abstract: Zirconocene-catalyzed carbomagnesation reactions of cyclic ethers zyxwv 4 and 7 with n-PrMgC1 and n-BuMgC1 afford homoallylic and bishomoallylic alcohols 5, 8, 9, and 11 in zyxwv -40% yield and exceptional levels of enantioselectivity and regiocontrol. Where n-BuMgC1 is used as the alkylating agent, high levels of diastereochemical control are also observed (cf. 9 vs 10 in entries 4 and 5 of Table 1). Studies reported herein underline a number of important mechanistic issues: (i) Although zirconocene-alkene complexes 3 exist as a mixture of diastereomers in solution (syn and anti), it is only one of the isomers which reacts to afford the observed products. (ii) Whereas insertion of an alkene substrate into the unsymmetric complexes 3 and 18 proceeds with low levels of regioselectivity at 22 "C, at 70 "C high levels of regiocontrol are observed (cf. intermediacy of 20 vs 24 in Scheme 4). In this context, various mechanistic experiments shed light on factors that may be responsible for the observed temperature effect. (iii) Unusual modes of preference for the regioselectivity in p-hydride abstraction of intermediate dialkylzirconocene are reported; these observations may be accounted for through consideration of the steric effects imposed by the cyclohexyl groups of the chiral ligand and the stereoelectronicrequirements of the elimination reaction. Introduction Recent work in these laboratories has demonstrated that the zirconium-catalyzed ethylmagnesation* offers a simple method for the enantioselective C-C bond formation through addition of EtMgCl to cyclic ethers in the presence of 0.4-10 mol zyxwvut % [EBTHIIZrCl, (l).3 A variety of cyclic allylic ethers can be used in this transformation, and products are obtained in 90- 98% ee and 60-75% yield^.^ Furthermore, asymmetric cata- lytic ethylmagnesation has been employed to effect the kinetic resolution of unsaturated pyrans and furan^.^ When higher alkyls of Mg are used in carbomagnesa- tion-particularly in the presence of the chiral metallocene 1-the catalytic cycle takes on added complexity. For example, unlike 2 (Scheme 1): a critical intermediate in asymmetric ethylmag- @ Abstract published in Advance ACS Abstracfs, June 15, 1995. (1) (a) Recipient of an American Chemical Society Graduate Fellowship, sponsored by Monsanto Co., 1994-1995. (b) Recipient of an American Chemical Society Graduate Fellowship, sponsored by Glaxo Inc., 1993- 1994. (2) (a) Dzhemilev, U. M.; Vostrikova, 0. S. zyxwvutsrqpo J. Organomer. Chem. 1985, 285, 43-51 and references cited therein. (b) Dzhemilev, U. M.; Sultanov, R. M.; Gaimaldinov, R. G.; Muslukhov, R. R.; Lomakina, S. I.; Tolstikov, G. A. lzv. Akad. Nauk zyxwvutsrqp SSSR, Ser. Khim. 1992, 770-788. (c) Hoveyda, A. H.; Xu, Z. J. Am. Chem. zyxwvutsrqpo SOC. 1991, 113, 5079-5080. (d) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi, M.; Rousset, C. J.; Negishi, E. J. Am. Chem. SOC. 1991, 113, 6266-6268. (e) Knight, K. S.; Waymouth, R. M. J. Am. Chem. SOC. 1991, 113, 6268-6270. (f) Hoveyda, A. H.; Xu, Z.; Morken, J. P.; Houri, A. F. J. Am. Chem. SOC. 1991,113,8950-8952. (g) Lewis, D. P.; Muller, P. M.; Whitby, R. J.; Jones, R. V. H. Tetrahedron Left. 1991, 32, 6797-6800. (h) Houri, A. F.; Didiuk, M. T.; Xu, Z-M.; Horan, N. R.; Hoveyda, A. H. J. Am. Chem. SOC. 1993,115, 6614-6624. (i) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J. Am. Chem. SOC. 1993,115,8485-8486. (3) (a) Wild, F. R. W. P.; Wasiucionek, M.; Huttner, G.; Brintzinger, H. J. Organomef. Chem. 1985, 288, 63-67. (b) Grossman, R. B.; Doyle, R. A.; Buchwald, S. L. Organomezallics 1991, zyxwvutsrqp 10, 1501-1505. (4) (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. SOC. 1993, 115, 6697-6698. (b) Houri, A. F.; Xu, Z-M.; Cogan, D.; Hoveyda, A. H. J. Am. Chem. SOC. 1995, 117, 2943-2944. (5) (a) Morken, J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. SOC. 1994,116,3123-3124. (b) Visser, M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383-4394. Scheme 1 m-1 (R)-3 anti (R)-3 S Y ~ nesation, the related zirconocenes 3, derived from n-P~-Mgcl,~ may react through either of the metal-alkene isomers (R)-3- syn or -anti to afford different product diastereomers. In addition, unlike the relatively symmetric 2, in 3 there can be two distinct modes of alkene insertion (from the more or less substituted face of the metal-alkene complex), leading to the formation of different products. Because of these and related mechanistic and structural considerations, [EBTHIIZr-catalyzed carbomagnesation with higher alkyls of Mg expands the scope of the enantioselectivebond forming process and provides useful insights into the inner workings of the asymmetric catalytic cycle. Herein, we report the results of our studies on the enantioselective addition of n-PrMgC1 and n-BuMgC1 to 25- dihydrofuran (4) and 5,6-dihydropyran (7), catalyzed by non- racemic 1. Results and Discussion Diastereo- and Enanticselective Carbomagnesations. When 4 is treated with 5 equiv of n-PrMgC1 in the presence of 10 (6) Hoveyda, A. H.; Morken, J. P. J. Org. Chem. 1993,58,4237-4244. (7) Hoveyda, A. H.; Morken, J. P.; Houri, A. F.; Xu, Z-M. J. Am. Chem. SOC. 1992, 114, 6692-6697. 0002-7863/95/1517-7097$09.00/0 0 1995 American Chemical Society