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

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

3. 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. JACS 2006, 128, 9103.

4. 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 Discovery 2005, 4, 685-697.

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

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

7. 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. 8 Why Ferrocenes? Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428. Vargas, S.; et al. Tetrahedron Let. 2005, 46, 2049. 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.

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

10. 10 Synthesis of Chiral Ferrocenes: Lithiation Marquarding, D.; et al. JACS 1970, 92, 5389-5393.

11. 11 S N 1 Retention of Stereochemistry Hayashi, T.; et al. Tetrahedron Let. 1974, 15, 4405.

12. 12 Synthesis of BPPFA Derivatives Hayashi, T.; Kawamura, N.; Ito, Y. JACS 1987 109, 7876. Hayashi, T; Kawamura, N; Ito, Y. Tetrahedron Let. 1988, 29, 5969-5972 Hayashi, T.; et al. Tetrahedron Let. 1976, 17, 1133-1134

13. 13 Modular Synthesis: Josiphos Togni, A.; et al. JACS 1994, 116, 4062-4066.

14. 14 Modular Electronic Effects Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 1995, 34, 931-933 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.

15. 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. 16 Synthesis of Unprotected β-Amino Acids: Catalyst Screening LigandYieldee (S,S)-Me-DuPHOS / Rh71%9% (S) (S)-BINAPHANE / Rh11%11% (R) (S)-f-BINAPHANE / Rh77%10% (S) (R,R)-EtFerroTANE / Rh77%88% (R) (R)-(S)-1 / Rh94%96% (S) Hsiao, Y.; et al. JACS 2004, 126, 9918-9919. 1

17. 17 Synthesis of Unprotected β-Amino Acids Hsiao, Y.; et al. JACS 2004, 126, 9918-9919.

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

19. 19 Product Inhibition Hansen, K. B.; et al. Org. Lett. 2005, 7, 4935. Addition of Boc 2 O selectively protects the free amine, preventing product inhibition and accelerating the overall reaction.

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

21. 21 Hydrogenation of Indoles LigandYieldee (R)-BINAP100%1% (S) (2S,3S)-Chiraphos100%1% (S) (R)-(S) BPPFA100%0% (-)-(2R,3R)-DIOP100%0% (R,R)-Me-DuPhos100%0% (2S,4S)-BPPM100%0% (S,S)-(R,R)-PhTRAP77%85% (R) Kuwano, R.; et al. Tetrahedron: Asymmetry. 2006, 17, 521-535.

22. 22 Hydrogenation of 2-Substituted Indoles Kuwano, R.; et al. JACS 2000, 122, 7614-7615.

23. 23 Hydrogenation of 3-Substituted Indoles 71-94% yield 95-98% ee Kuwano, R.; et al. Org. Lett. 2004, 6, 2213.. RYieldee i-Pr94%97% Ph93%96% CH 2 CH 2 OTBS94%98% CH 2­ CH 2 CO 2 (t-Bu)93%97% CH 2 CH 2 NHBoc71%95%

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

25. 25 Hydrogenation of Vinyl Bis(boronates) Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.

26. 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. JACS 2004, 126, 15338-15339.

27. 27 Hydrogenation of Vinyl Bis(boronates) Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339. entryLigand : Rh ratio % yield% eeconfiguration 10.89052R 218337R 328493S

28. 28 Hydrogenation of Vinyl Boronates Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415. 1: BCl 3, then BnN 3 ; 22 C 2: (i) ClCH 2 Li, THF, -78 C (ii) NaOH, H 2 O 2

29. 29 Hydrogenation of Vinyl Boronates Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415. R =ee (toluene)ee (DCE) cyclohex9795 n-hex8184 TBSOCH 2 CH 2 9085 PivOCH 2 CH 2 9086 PivOCH 2 CH 2 CH 2 9289 tBuO 2 CCH 2 CH 2 9459 PhCH 2 8879 >20:1 dr

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

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

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

33. 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.comwww.syngenta.com

34. 34 (S)-Metolachlor: Dual Magnum 1970: Metolachlor discovered 1978: rac-Metolachlor production started, >10,000 tons/yr produced 1982: Metolachlor stereoisomers synthesized; (S)-isomer found to be active. ACTIVE!INACTIVE! Blaser, H.; et al. Chimia 1999, 53, 275-280.

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

36. 36 (S)-Metolachlor: Enantioselective Synthesis Blaser, H.; et al. Chimia 1999, 53, 275-280. Only possible approach!

37. 37 (S)-Metolachlor: Imine Hydrogenation (4S,5S)-diop(2R,4R)-bdpp LigandTemp% convTOF avg ee diop25 C95.532 h -1 61% (S) bdpp25 C10.64 h -1 31% (S) -5 C7926 h -1 78% (S) 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. 38 (S)-Metolachlor: Imine Hydrogenation RR’% ConvTOFee PhtBu63 h -1 n/a 4-CF 3 PhCy8018 h -1 21% 4-CF 2 PhPh10044 h -1 21% Ph3,5-Xyl100 (2 hrs!)396 h -1 79% Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38. 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.

39. 39 (S)-Metolachlor: Imine Hydrogenation TBAIAcOHtime to 100% conversioninitial rate (mmol / min)% ee --10 hr0.371.2 150 mg-12 hr0.371.6 -2 mL16 hr0.156.2 150 mg2 mL0.5 hr1.578.5 Blaser, H.; et al. Chimia 1999, 53, 275-280. Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38. Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166. 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!

40. 40 (S)-Metolachlor: Imine Hydrogenation R’Time (h)Conv (%)TOF (h -1 )ee (%) 4-n-Pr 2 N-3,5-Xyl3.510028,00083 4-Me 2 N-3,5-Xyl1100100,00080 3,5-Xyl0.6100167,00076 4-(N-Pyr)-3,5-Xyl310033,00069 Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299. Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38. While other ligands have slightly higher ees, Xyliphos’ high activity makes it ideal for industrial use.

41. 41 (S)-Metolachlor: Imine Hydrogenation Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299. Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38. 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

42. 42 (S)-Metolachlor: Production Scale S/C = 2,000,000 50 C, 4 hrs 80 atm H 2 extraction, flash distillation, distillation Ir is recycled Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299. Blaser, H.; et al. Chimia 1999, 53, 275-280.

43. 43 Conclusions Ferrocenes possess unusual properties: –planar chirality –stereoretentive S N 1 substitution Ferrocenyl ligands have been used to hydrogenate a number of uncommon substrates: –N-aryl imines –indoles –unprotected enamines –vinyl boronates

44. 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