Synthesis of chiral bisphosphines with tunable bite angles and their applications in asymmetric hydrogenation of beta-ketoesters.

Although many effective chiral bisphosphines have been developed, there is no general solution in dealing with the many challenging transition metal-catalyzed asymmetric transformations since enantioselectivities are often substrate-dependent. Subtle changes in geometric, steric, and/or electronic properties of chiral ligands can lead to dramatic variations of reactivity and enantioselectivity. Conformationally rigid and yet tunable chiral ligands offer a great advantage in optimizing the enantioselectivity of a reaction by maximizing the possibility of a low energy enantiotopic approach of substrates in the stereochemistry defining step. Recently, we have developed two conformationally rigid chiral bisphosphines1 (BICP and PennPhos) which have been shown to be effective for several asymmetric reactions. We envision that a strategy to restrict sp2-sp2 rotation in chiral biaryl ligands such as BINAP,2 BIPHEMP,3 and MeO-BIPHEP3 (Figure 1) will be useful in generating new chiral ligands with tunable bite angles. A closely related idea has been applied to generate chiral biaryl compounds with a range of dihedral angles.4 Extensive studies by several research groups have demonstrated that changing bite angles of chelating bisphosphines have a dramatic effect on the reactivity and selectivity of reactions.5 The correlation of bite angles of chiral chelating phosphines with the enantioselectivity of a reaction may provide significant insights for future ligand design and therefore is of fundamental importance. Chiral atropisomeric biaryl diphosphines such as BINAP, BIPHEMP, and MeO-BIPHEP are very effective ligands for many asymmetric reactions.2,3 The sp2-sp2 rotation in these chiral biaryl ligands causes only a small energy change within a wide range of bite angles with transition metals. While these ligands have been proven effective, sometimes they are not efficient for certain substrates due to the lack of ligand rigidity. To overcome this drawback, we proposed to introduce a bridge with variable length to link the diaryl groups so that the new ligands are rigid with tunable bite angles.4 Ideally, a change in the bite angle of the metal-ligand complex will allow highly enantioselective transformation with certain substrates. We chose MeO-BIPHEP as the starting compound to make these type of chiral bisphosphines, which are called TunaPhos ligands (Scheme 1). Enantiomerically pure MeO-BIPHEP was made according to a reported procedure3 and demethylated to provide HO-BIPHEP (7) in high yield. Reaction of 7 with alkyl dihalides in the presence of excess anhydrous K2CO3 in DMF formed C1-C6TunaPhos ligands (1-6) (Scheme 1). The dihedral angles of TunaPhos, MeO-BIPHEP, and BINAP based on a CAChe MM2 calculation are listed in Table 1. The bite angle (P-metal-P) of CnTunaPhos with transition metals should increase with an increase in the dihedral angle. Furthermore, the TunaPhos ligands should be less flexible compared with BINAP and (1) For PennPhos, see (a) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. Engl. 1998, 37, 1100-1103. (b) Jiang, Q.; Xiao, D,; Zhang, Z.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. Engl. 1999, 38, 516. (c) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem. 1999, 64, 1774. For BICP, see: (d) Zhu, G.; Cao, P.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 1799. (e) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J. Org. Chem. 1998, 63, 8100. (f) Zhu, G.; Zhang, X. J. Org. Chem. 1998, 63, 9590. (g) Cao, P.; Zhang, X. J. Org. Chem. 1999, 64, 2127. (h) Cao, P.; Zhang, X. J. Am. Chem. Soc. 1999, 121, 7708. (2) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b) Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (3) (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.; Hansen, H.-J. Helv. Chim. Acta 1988, 71, 897. (b) Schmid, R.; Foricher, J.; Cereghetti, M.; Schonhoizer, P. Helv. Chim. Acta 1991, 74, 370. (c) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricehr, J.; Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68, 131. (4) (a) Lustenberger, P.; Martinborough, E.; Denti, T. M.; Diederich, F. J. Chem. Soc., Perkin. Trans. II 1998, 747. (b) Harada, T.; Takeuchi, M.; Hatsuda, M.; Ueda, S.; Oku, A. Tetrahedron: Asymmetry 1996, 7, 2479. (c) Lipshutz, B. H.; Shin, Y.-J. Tetrahedron Lett. 1998, 7017. (5) (a) Davies, I. W.; Deeth, R. J.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 1999, 40, 1233. (b) Kamer, P. C. J.; Reek, J. N. H.; van Leeuwen, P. W. N. M. CHEMTECH 1998, 28(9), 27. 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(k) Yamamoto, K.; Momose, S.; Fanahashi, M.; Ebata, S.; Ohmura, H.; Kamatsu, H.; Miyazawa, M. Chem. Lett. 1994, 189. (l) Casey, C. P.; Whiteker, G. T. Israel J. Chem. 1990, 30, 299. (m) Casey, C. P.; Whiteker, G. T.; Melville, V.; Petrovich, L. M.; Gavney, J. A.; Powell, D. R. J. Am. Chem. Soc. 1992, 114, 5535. Figure 1. Chiral atropisomeric bisphosphines. 6223 J. Org. Chem. 2000, 65, 6223-6226