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“The Use of Ferrocenyl Ligands in Asymmetric Catalytic Hydrogenation”

“The Use of Ferrocenyl Ligands in Asymmetric Catalytic Hydrogenation”. Beth Moscato-Goodpaster April 12, 2007. Utility of Ferrocenyl Ligands. Weiss, M; et al. Angew. Chem. Int. Ed. 2006 , 45 , 5694. Genov, M.; et al. Tetrahedron: Asymmetry 2006 , 17, 2593. Utility of Ferrocenyl Ligands.

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“The Use of Ferrocenyl Ligands in Asymmetric Catalytic Hydrogenation”

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  1. “The Use of Ferrocenyl Ligands in Asymmetric Catalytic Hydrogenation” Beth Moscato-Goodpaster April 12, 2007

  2. Utility of Ferrocenyl Ligands Weiss, M; et al.Angew. Chem. Int. Ed.2006, 45, 5694. Genov, M.; et al. Tetrahedron: Asymmetry2006, 17, 2593

  3. Utility of Ferrocenyl Ligands Lopez, F.; et al. JACS 2004, 126, 12784-12785. Cho, Y.-h.;et al. JACS 2006,128, 6837. Harutyunyan, S. R.; et al.JACS2006, 128, 9103.

  4. Asymmetric Hydrogenation “…hydrogenation is arguably the most important catalytic method in synthetic organic chemistry….” “Of the <20 full-scale chemo-catalyzed [asymmetric] reactions known to be running [in industry] currently, more than half are used for reducing various functionalities….” Blaser, H.; et al. Adv. Synth. Catal.2003, 345, 103-151. Federsel, H. Nat. Rev. Drug Discovery2005, 4, 685-697.

  5. General Scope of Hydrogenation Olefins Ketones and Imines Blaser, H.; et al. Adv. Synth. Catal.2003, 345, 103-151.

  6. Outline • Features of Ferrocenyl Ligands • why ferrocenes? • reactivity and synthesis • modularity • Applications of Ferrocenyl Ligands to Specific Substrates in Asymmetric Hydrogenation • Conclusions

  7. Why Ferrocenes? Xiao, D.; Zhang, X. Angew. Chem. Int. Ed.2001, 40, 3425-3428. Xiao, D; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679-1681.

  8. Why Ferrocenes? • low rotation barrier of ferrocenyl backbone offers flexibility, facilitating binding of sterically demanding imines. • electron donating ability and large P-M-P bite angle increases electron back-donating ability from Ir to an imine substrate. Xiao, D.; Zhang, X. Angew. Chem. Int. Ed.2001, 40, 3425-3428. Vargas, S.; et al. Tetrahedron Let.2005, 46, 2049.

  9. Why Ferrocenes? (R,R)-f-binaphane has unprecedented enantioselectivity! Xiao, D.; Zhang, X. Angew. Chem. Int. Ed.2001, 40, 3425-3428. Vargas, S.; et al. Tetrahedron Let.2005, 46, 2049.

  10. Synthesis of Chiral Ferrocenes: Lithiation Marquarding, D.; et al. JACS1970, 92, 5389-5393.

  11. SN1 Retention of Stereochemistry Hayashi, T.; et al. Tetrahedron Let.1974, 15, 4405.

  12. Synthesis of BPPFA Derivatives Hayashi, T.; Kawamura, N.; Ito, Y. JACS1987109, 7876. Hayashi, T; Kawamura, N; Ito, Y. Tetrahedron Let.1988, 29, 5969-5972 Hayashi, T.; et al. Tetrahedron Let.1976, 17, 1133-1134

  13. Modular Synthesis: Josiphos Togni, A.; et al. JACS1994, 116, 4062-4066.

  14. Modular Electronic Effects Best results are obtained with: σ-donating, electron-rich pyrazole nitrogen and strongly π-accepting phosphorous. The resulting “electronic asymmetry” at the metal center enhances enantioselectivity. Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed.1995, 34, 931-933

  15. Outline • Features of Ferrocenyl Ligands • Applications of Ferrocenyl Ligands to Specific Substrates in Asymmetric Hydrogenation • hydrogenation of unprotected enamines • hydrogenation of 2- and 3-substituted indoles • hydrogenation of vinyl boronates • hydrogenation of (S)-Metolachlor • Conclusions

  16. Synthesis of Unprotected β-Amino Acids: Catalyst Screening 1 Hsiao, Y.; et al.JACS2004, 126, 9918-9919.

  17. Synthesis of Unprotected β-Amino Acids Hsiao, Y.; et al.JACS2004, 126, 9918-9919.

  18. Product Inhibition Results are consistent with either a first-order dependence on [substrate] OR product inhibition. Results are consistent with product inhibition! Hansen, K. B.; et al. Org. Lett. 2005,7, 4935.

  19. Product Inhibition Addition of Boc2O selectively protects the free amine, preventing product inhibition and accelerating the overall reaction. Hansen, K. B.; et al. Org. Lett. 2005,7, 4935.

  20. Synthesis of β-Amino Acid Pharmacophore Kubryk, M.; Hansen, K. Tetrahedron: Asymmetry 2006, 17, 205-209.

  21. Hydrogenation of Indoles Kuwano, R.; et al. Tetrahedron: Asymmetry.2006, 17, 521-535.

  22. Hydrogenation of 2-Substituted Indoles Kuwano, R.; et al. JACS2000, 122,7614-7615.

  23. Hydrogenation of 3-Substituted Indoles 71-94% yield 95-98% ee Kuwano, R.; et al. Org. Lett. 2004, 6, 2213..

  24. Hydrogenation of N-Boc Protected Indoles Kuwano, R.; Kashiwabara, M.Org. Lett.2006, 8, 2653-2655.

  25. Hydrogenation of Vinyl Bis(boronates) Morgan, J. B.; Morken, J. P. JACS2004, 126, 15338-15339.

  26. Hydrogenation of Vinyl Bis(boronates) Single Pot Diboronation / Hydrogenation / Oxidation of Phenylacetylene Single Pot Hydrogenation / Homologation / Oxidation of Vinyl Bis(boronate) Morgan, J. B.; Morken, J. P. JACS2004, 126, 15338-15339.

  27. Hydrogenation of Vinyl Bis(boronates) Morgan, J. B.; Morken, J. P. JACS2004, 126, 15338-15339.

  28. Hydrogenation of Vinyl Boronates 1: BCl3, then BnN3; 22 C 2: (i) ClCH2Li, THF, -78 C (ii) NaOH, H2O2 Moran, W. J.; Morken, J. P. Org. Lett.2006, 8, 2413-2415.

  29. Hydrogenation of Vinyl Boronates Moran, W. J.; Morken, J. P. Org. Lett.2006, 8, 2413-2415.

  30. Hydrogenation of Vinyl Boronates 70% conv 84% conv <10% conv 32% conv Boronate is activating: sterics alone are not responsible for high reactivity. Moran, W. J.; Morken, J. P. Org. Lett.2006, 8, 2413-2415.

  31. Hydrogenation of Vinyl Boronates 70% conv 84% conv <10% conv 32% conv Reactivity not due solely to the π-acceptor properties of boronate: methyl methacrylate exhibits much less reactivity. Moran, W. J.; Morken, J. P. Org. Lett.2006, 8, 2413-2415.

  32. Hydrogenation of Vinyl Boronates 70% conv 84% conv <10% conv 32% conv Enhanced reactivity not due to inductive donation from boron to carbon: inductively withdrawing phenyl ring provides similar levels of reactivity, but no enantioselectivity. Moran, W. J.; Morken, J. P. Org. Lett.2006, 8, 2413-2415.

  33. (S)-Metolachlor: Dual Magnum • Important grass herbicide used in corn and other crops. • Over 10,000 tons / year produced by Syngenta AG (trademark: Dual Magnum) • Hydrogenation is largest enantioselective catalytic process used in industry; one of fastest homogeneous systems known. Arrayas, R.; Andreo, J.; Carretaro, J. Angew. Chem. Int. Ed.2006, 45, 7674-7715. Blaser, H.; et al. Top. Catal.2002, 19, 3-16. Dorta, R.; et al. Chem. Eur. J.2004, 10, 4546-4555. Syngenta website: www.syngenta.com

  34. (S)-Metolachlor: Dual Magnum ACTIVE! INACTIVE! 1970: Metolachlor discovered 1978:rac-Metolachlor production started, >10,000 tons/yr produced 1982: Metolachlor stereoisomers synthesized; (S)-isomer found to be active. Blaser, H.; et al. Chimia1999, 53, 275-280.

  35. Enantioselectivity Catalyst productivity Catalyst activity Catalyst stability Availability and quality of starting material ee > 80% S/C > 50,000 TOF > 10,000 h-1 (S)-Metolachlor: Requirements for Industrially Feasible Process Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166.

  36. (S)-Metolachlor: Enantioselective Synthesis Only possible approach! Blaser, H.; et al. Chimia1999, 53, 275-280.

  37. (S)-Metolachlor: Imine Hydrogenation (2R,4R)-bdpp (4S,5S)-diop • Conclusions from Initial Screening: • Addition of halogen anions increases rate, esp. with both Cl- and I- in sol’n. • Catalyst deactivation major problem: rates dependant on ligand structure, solvent and temperature. Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166.

  38. (S)-Metolachlor: Imine Hydrogenation • Conclusions so far: • Only ferrocenyl diphosphine ligands gave medium to good ees and catalyst stability. • Matched chirality necessary. • Aryl groups at two phosphines necessary for good performance. Blaser, H.; et al. J Organomet Chem2001, 621, 34-38.

  39. (S)-Metolachlor: Imine Hydrogenation In the presence of AcOH and I-, the rate of reaction is accelerated by a factor of 5, and the time for 100% conversion is twenty times shorter than without additives! Blaser, H.; et al. Chimia1999, 53, 275-280. Blaser, H.; et al. J Organomet Chem2001, 621, 34-38. Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166.

  40. (S)-Metolachlor: Imine Hydrogenation While other ligands have slightly higher ees, Xyliphos’ high activity makes it ideal for industrial use. Blaser, H.; Spindler, F. Chimia 1997,51, 297-299. Blaser, H.; et al. J. Organomet Chem2001,621, 34-38.

  41. (S)-Metolachlor: Imine Hydrogenation Original Requirements: • ee > 80% • S/C > 50,000 • TOF > 10,000 h-1 • Final Results: • ee = 79% • S/C > 1,000,000 • TOF > 1,800,000 h-1 Blaser, H.; Spindler, F. Chimia 1997,51, 297-299. Blaser, H.; et al. J. Organomet Chem2001,621, 34-38.

  42. (S)-Metolachlor: Production Scale 80 atm H2 S/C = 2,000,000 50 C, 4 hrs extraction, flash distillation, distillation Ir is recycled Blaser, H.; Spindler, F. Chimia 1997,51, 297-299. Blaser, H.; et al. Chimia1999, 53, 275-280.

  43. Conclusions • Ferrocenes possess unusual properties: • planar chirality • stereoretentive SN1 substitution • Ferrocenyl ligands have been used to hydrogenate a number of uncommon substrates: • N-aryl imines • indoles • unprotected enamines • vinyl boronates

  44. Acknowledgements • Clark Landis and Landis Group Members • Practice Talk Attendees: • Brian Hashiguchi • Avery Watkins • Katherine Traynor • Hairong Guan • Ram Neupane • Family • Dow Chemical, for funding

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