Asymmetric Formation of Quaternary Carbon Centers Catalyzed by Novel Chiral 2,5-Dialkyl-7-phenyl-7-phosphabicyclo- [2.2.1]heptanes

Many important biologically active compounds contain quaternary carbon centers. Efficient asymmetric syntheses of these compounds represent a significant challenge in organic chemistry.1 Some catalytic synthetic methods directed toward this problem include prolinecatalyzed aldol reactions,2 Michael additions,3 alkylations with phase-transfer catalysts,4 palladium-catalyzed allylations,5 Heck reactions,6 Diels-Alder reactions,7 and cyclopropanations.8 Recently, we prepared a new class of chiral monophosphines, 2,5-dialkyl-7-phenyl-7-phosphabicyclo[2.2.1]heptanes (1, 2, Figure 1). High enantioselectivities (>90% ee) have been obtained for Pd-catalyzed allylic alkylations9 and phosphine-catalyzed [3 + 2] cycloadditions10 using these species. The success of asymmetric phosphine-catalyzed [3 + 2] annulation between 2,3butadienoates and electron-deficient olefins has prompted us to look at other phosphine-catalyzed reactions.11 One such reaction, discovered by Trost, is the phosphinecatalyzed C-C bond formation at the γ-position of 2-butynoates with malonate-type nucleophiles (Scheme 1).12 The potential for asymmetric synthesis of quaternary carbon centers based on this transformation seemed to us to be an attractive synthetic strategy. In this phosphine-catalyzed C-C bond-forming reaction, generation of electrophilic character at the γ-carbon of 2-butynoates creates a regiochemical complement to the Michael addition. The mechanistic rationale proposed by Trost is illustrated in Scheme 2. The first intermediate 7 comes from Michael addition of PPh3 to ethyl 2-butynoate. Proton transfer within 7 generates 8. Deprotonation of a pronucleophile by 8 produces a vinylphosphonium species 9 and the anionic nucleophile. Nucleophilic addition of this species to 9 leads to 10. Facile proton transfer then affords 11 with subsequent elimination of PPh3 to give the final γ-addition products. Since some aspects of this γ-addition process are similar to the phosphine-catalyzed [3 + 2] cycloaddition discovered by Lu,13 which we previously developed as an asymmetric reaction, we investigated the asymmetric version of this reaction using chiral phosphabicyclo[2.2.1]heptanes 1 and 2 as catalysts (Table 1). Under conditions similar to those cited by Trost, moderate enantioselectivities (42-68% ee, Table 1, entries 1-4) have been obtained between ethyl 2-butynoate and several pronucleophiles with 1 as the catalyst; however, these reactions do not proceed at room temperature. Because the nucleophilic addition of a phosphine to ethyl 2,3-butadienoate readily gives the intermediate 8 (Scheme 2), Lu et al.14 have demonstrated that the C-C bond formation can be effected under mild conditions using ethyl 2,3-butadienoate instead of 2-butynoate. Using this alternative electrophile, we have studied the γ-addition reaction under various conditions by changing catalysts, additives, and substrates. Table 2 lists the results of this asymmetric reaction with several chiral phosphines (1-6). The new phosphines 1 and 2 (Table 2, entries 1-2) are more selective and active catalysts than the previously reported chiral phosphines 4-6 (Table 2, entries 4-6). Compared to the conformationally rigid dimethyl phosphabicyclo[2.2.1]heptane 1 (Table 2, entry 1, 74% ee), the corresponding five-membered ring phosphacycle 415 gives much lower enantioselectivity (1) For a recent review, see: Fuji, K. Chem. Rev. 1993, 93, 2037. (2) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (b) Agami, C.; Levisalles, J.; Puchot, C. J. Chem. Soc., Chem. Commun. 1985, 441. (3) (a) Hermann, K.; Wynberg, H. J. Org. Chem. 1979, 44, 2238. (b) Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625. (c) Brunner, H.; Hammer, B. Angew. Chem., Int. Ed. Engl. 1984, 23, 312. (d) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295. (4) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. Org. Chem. 1987, 52, 4745. (c) Conn, R. S. E.; Lovell, A. V.; Karady, S.; Weinstock, L. M. J. Org. Chem. 1986, 51, 4710. (5) (a) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113. (b) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586. (c) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879. (6) (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738. (b) Kagechika, K.; Shibasaki, M. J. Org. Chem. 1991, 56, 4093. (c) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989, 54, 5836. (d) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571. (7) Maruoka, K.; Yamamoto, H. in Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 9, p 413. (8) Doyle, M. P. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 3, p 63. (9) Chen, Z.; Jiang, Q.; Zhu, G.; Xiao, D.; Cao, P.; Guo, C.; Zhang, X. J. Org. Chem. 1997, 62, 4521. (10) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (11) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Rafel, S.; Leahy, J. J. Org. Chem. 1997, 62, 1521. (c) Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996, 61, 4516. (d) Vedejs, E.; Dangulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430. (e) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (f) Hanamoto, T.; Baba, Y.; Inanaga, J. J. Org. Chem. 1993, 58, 299. (g) Roth, F.; Hygax, P.; Frater, G. Tetrahedron Lett. 1992, 33, 1045. (12) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (13) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (14) Zhang, C.; Lu, X. Synlett 1995, 645. Figure 1. Chiral phosphines. 5631 J. Org. Chem. 1998, 63, 5631-5635