Synthesis and Application of a New Bisphosphite Ligand Collection for Asymmetric Hydroformylation of Allyl Cyanide Christopher J. Cobley,* Kelli Gardner, † Jerzy Klosin,* ,‡ Ce ´line Praquin, Catherine Hill, Gregory T. Whiteker,* ,† and Antonio Zanotti-Gerosa § Dowpharma, Chirotech Technology Limited, a subsidiary of The Dow Chemical Company, 321 Cambridge Science Park, Cambridge CB4 0WG, UK Jeffrey L. Petersen Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506 Khalil A. Abboud Department of Chemistry, University of Florida, Gainesville, Florida 32611 whitekgt2@dow.com Received February 5, 2004 A series of mono- and bidentate phosphites was prepared with (S)-5,5′,6,6′-tetramethyl-3,3′-di-tert- butyl-1,1′-biphenyl-2,2′-dioxy [(S)-BIPHEN] as a chiral auxiliary and screened in the asymmetric hydroformylation of allyl cyanide. These hydroformylation results were compared with those of two existing chiral ligands, Chiraphite and BINAPHOS, whose utility in asymmetric hydrofor- mylation has been previously demonstrated. Bisphosphite 11 with a 2,2′-biphenol bridge was found to be the best overall ligand for asymmetric hydroformylation of allyl cyanide with up to 80% ee and regioselectivities (branch-to-linear ratio, b/l) of 20 with turnover frequency of 625 [h -1 ] at 35 °C. BINAPHOS gave enantioselectivities up to 77% ee when the reaction was conducted in either acetone or neat but with poor regioselectivity (b/l 2.8) and activities 7 times lower than that of 11. The product of allyl cyanide hydroformylation using (R,R)-11 was subsequently transformed into (R)-2-methyl-4-aminobutanol, a useful chiral building block. Single-crystal X-ray structures of (S,S)- 11 and its rhodium complex 19 were determined. Introduction Asymmetric chemocatalysis is one of the most powerful synthetic methodologies for producing high value added chiral compounds. Its success and potential are due to the achievable combination of high selectivity, high activity, and reduced environmental impact. 1 This has been best demonstrated in the field of asymmetric hydrogenation, which can be regarded as the most highly developed asymmetric chemocatalytic technology to date. 2 Conversely, while hydroformylation is the largest volume homogeneous transition-metal-catalyzed reaction used today, its asymmetric version is relatively underdevel- oped. Asymmetric hydroformylation enantioselectively introduces a highly versatile aldehyde functional group that is amenable to a number of synthetic transforma- tions. 3 It is therefore surprising that the development of such a route for the production of highly functionalized chiral building blocks has not been utilized industrially. To date, most efforts in this field have concentrated on a relatively narrow substrate range, notably the asymmetric hydroformylation of vinylarenes to access enantiomerically enriched 2-aryl propionic acids (the profen class of nonsteroidal antiinflammatory drugs). 4 An important breakthrough in this area was made during the early 1990s with the introduction by Union Carbide of a rhodium-catalyzed system involving chiral bisphos- phites, such as (R,R)-Chiraphite (1). Enantioselectivities of up to 90%, along with high branched regioselectivity, were obtained for several prochiral vinylarenes. 5 Van Leeuwen et al. reported detailed studies of the effects of † Chemical Sciences, The Dow Chemical Company, South Charles- ton, WV. ‡ Chemical Sciences, The Dow Chemical Company, Midland, MI. § Current address: Johnson Matthey Catalysts, 28 Cambridge Science Park, Cambridge CB4 0FP, U.K. (1) Blaser, H. U.; Spindler, F.; Studer, M. App. Catal. A 2001, 221, 119. (2) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; Wiley-Interscience: New York: 1994; Chapter 2, p 16. (b) Brown, J. M.; Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer, Berlin: 1999; Vol. 1, Chapters 5 and 6, pp 101 and 199. (c) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York: 2000; Chapter 1, p 1. (3) Stille, J. K. In Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford: 1991; Vol. 4, p 913. (4) Claver, C., van Leeuwen, P. W. N. M. In Rhodium Catalysed Hydroformylation; Claver, C., van Leeuwen, P. W. N. M., Eds.; Kluwer Academic Publishers: Dordrecht: 2000; Chapter 5, p 107 and refer- ences therein. (5) (a) Babin J. E.; Whiteker G. T. Patent WO 93/03830, 1992. (b) Whiteker, G. T.; Briggs, J. R.; Babin, J. E.; Barner, B. A. In Catalysis of Organic Reactions; Morrell, D. G., Ed.; Marcel Dekker: New York, 2003; p 359. 10.1021/jo040128p CCC: $27.50 © 2004 American Chemical Society J. Org. Chem. 2004, 69, 4031-4040 4031 Published on Web 05/19/2004