1. 1 Applications of Palladium-Catalyzed Aerobic Oxidative Kinetic Resolution of Alcohols in the Preparation of Pharmaceutical Compounds Roch Lavigne March 2 nd 2006

2. 2 Inspiration from Nature : Oxidases EC 1. Oxidoreductase 1.1. Acting on the CH-OH group donors 1.1.3. With oxygen as acceptor 1.1.3.6 Cholesterol oxidase

3. 3 On the Footsteps of Mother Nature Oxidation with a stochiometric amount of reagent Oxidation with a catalyst and a stochiometric amount of terminal oxidant Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. De Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153.

4. 4 Evolution of Oxidation Oxidation with a catalyst and O 2 as the terminal oxidant Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun. 1977, 157. Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem. 2005, 70, 3343.

5. 5 Towards Oxidases Activity Ideal cases of enantioselective oxidation with a catalyst and O 2 as the terminal oxidant

6. 6 Presentation Outline Resolution background The first reported systems Catalytic cycle Origins of the enantiodifferentiation Improvement of these systems Total synthesis of (S)-fluoxetine and (R)-tomoxetine Application to the preparation of Singulair © and an h-NK1 receptor antagonist

7. 7 Three methods : Chiral pool : most useful method when available Enantioselective synthesis : most elegant method, but sometimes expensive, requires additional steps or substrate-dependent Resolution : racemates are easier and less expensive to access but 50% of the material is lost Preparation of Enantioenriched Compounds

8. 8 About Resolution Three classes of resolution A. Classical resolution : especially useful in salt formation with carboxylic acids and amines B. Chiral chromatography : principally for analytical or preparative scale C. Kinetic resolution : particularly attractive when catalytic because of the need for only small amounts of chiral resolving agent

9. 9 Selectivity Factor Efficacy of catalytic kinetic resolution is measured by the selectivity factor (s) s = e ∆∆G ≠ /RT = k rel = k fast /k slow = ln[(1-c)(1 - ee)] ln[(1-c)(1+ ee)] where c = conversion Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5.

10. 10 Selectivity Factor The ee obtained is a function of conversion Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5. k rel 1 ∆∆G ≠ (kcal/mol) 1.50.24 20.41 50.95 101.35 502.31 1002.72 5003.66 1 1 at room temperature Enantioselective reaction of a prochiral substrate 5:1 ratio of products Therefore 67% ee

11. 11 The First Step Towards Palladium Enantioselective Aerobic Oxidation Uemura Conditions Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750.

12. 12 First reported Palladium Enantioselective Aerobic Oxidation Sigman, M. S. et al. J. Am. Chem. Soc. 2001, 123, 7475. Stoltz, B. M. et al. J. Am. Chem. Soc. 2001, 123, 7725.

13. 13 The Catalyst Structure Sigman M. S. et al. J. Am. Chem. Soc. 2001, 123, 7475.

14. 14 Pd(II) Catalytic Cycle Pd 0 cycle Pd II cycle

15. 15 Concerning the Alcohol Binding Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817. Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.

16. 16 Alcohol Binding Mecanism

17. 17 β - Hydride Elimination Looking at (-)-sparteine from a ligand point of vue Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 7971.

18. 18 Pd (II) Regeneration Mechanism A direct hydroperoxide species formation is proposed Evidences for the peroxopalladium species Uemura, S. et al. J. Org. Chem. 1999, 64, 6750. Stahl, S.S. et al. J. Am. Chem. Soc. 2001, 123, 7188.

19. 19 Pd (II) Regeneration Stahl, S.S. et al. J. Am. Chem. Soc. 2001, 123, 7188.

20. 20 Rate Determining Step ParameterResults[alcohol] first order [(-)-sparteine]saturation Hammett correlations  = -1.41  + = -1.00 KIE1.31 The β-hydride elimination would be the rate determining step. Sigman M. S. et al. J. Am. Chem. Soc. 2003, 23, 7005.

21. 21 About Sparteine Lupin alkaloid (-)-sparteine isolated from certain papilionaceous plants such as Scotch broom (-)-sparteine is commercially available (2.73 $/g) C 1 symmetric ligand Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.

22. 22 Enantioselectivity Origins Aromatic group prefers to rely in quadrant IV Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.

23. 23 Enantioselectivity Origins Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 7971.

24. 24 Another Factor Affects Enantioselectivity Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817.

25. 25 Another Factor Affects Enantioselectivity Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817.

26. 26 Limitations R 1 needs to be aromatic R 2 needs to be a methyl or a methylene Long reaction times (>24h) Need to be heated (>50 O C) Oxygen source need to be pure Relativily high equivalents of (-)-sparteine are requiered (~20 mol%) Sparteine is only easily available as a single antipode

27. 27 (+)-Sparteine Surrogate (+)-sparteine needs resolution to obtained from natural sources Only one total synthesis of (+)-sparteine reported (15 steps, 16% yield) Gram-scale quantities of diamine (+)-1 can be prepared in 3 steps with 79% overall yield. Aubé, J. et al. Org. Lett. 2002, 4, 2577. O’Brien, P. et al. J. Am. Chem. Soc. 2002, 124, 11870.

28. 28 Resolution of Non-Benzylic Alcohol R1R1R1R1 % conversion % ee Selectivity Factor (s) t BuOH DCE t Bu60.997.217 7.1 cyclopropyl59.082.69.1 5.5 1-cyclohexenyl67.995.49.0 7.0 Using t BuOH increases both reactivity and enantioselectivity Sigman, M. S. et al. J. Org. Chem. 2003, 68, 4600.

29. 29 Use of an Achiral Exogenous Base R1R1R1R1 % conversion % ee Selectivity Factor (s) Na 2 CO 3 (-)-sparteine Ph59.096.62016 t Bu42.351.29.317 cyclopropyl59.186.0109.1 1-cyclohexenyl68.192.37.69.0 Carbonate bases can be used to form the alkoxide Sigman, M. S. et al. J. Org. Chem. 2003, 68, 7535.

30. 30 Oxidation with Air and at Room Temperature R1R1R1R1 Time (h) % conversion % ee Selectivity Factor (s) Air O2O2O2O2 2462.399.82527 56.793.02023 1660.299.62828 Tremendous reactivity using CHCl 3 as solvent Stoltz, B. M. et al. Angew. Chem. Int. Ed. 2004, 43, 353.

31. 31 Other Aerobic Oxidative Kinetic Resolution Systems R1R1R1R1Solvent % conversion % ee s chlorobenzene64.794.911 60.790.611 toluene57.882.111 Photoactivated Ruthenium-Catalyzed Asymmetric Oxidation Katsuki, S. et al. Chem. Rec. 2004, 4, 96.

32. 32 R1R1R1R1 R2R2R2R2 Time (h) % conversion % ee s PhEt105199>50 Bn16579218 i- Bu i- Pr90559830 TBSOCH 2 CH 2 Me144519042 Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 1090. Vanadium-Catalyzed Asymmetric Oxidation of  –Hydroxy Esters Other Aerobic Oxidative Kinetic Resolution Systems

33. 33 Application of Oxidative Kinetic Resolution

34. 34 Formation of the Benzyl Alcohol Ali, I. S.; Sudalai A. Tett. Lett. 2002, 43, 5435.

35. 35 Oxidative Kinetic Resolution Ali, I. S.; Sudalai A. Tett. Lett. 2002, 43, 5435. Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081.

36. 36 Oxidative Kinetic Resolution for Antidepressants Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.

37. 37 Oxidative Kinetic Resolution for Singulair Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.

38. 38 Achievement of the Synthesis of Singulair Zamboni, R.J. et al. J. Org. Chem. 1996. 61, 3398.

39. 39 Oxidative Kinetic Resolution for Merck’s h-NK1 receptor antagonist Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.

40. 40 Conclusion Molecular oxygen, a readily-available and environmentallly friendly co- oxidant can be used for oxidative kinetic resolution Sparteine possesses a unique ability for the enantiodifferentiation due to its C 1 -symmetry Palladium-catalyzed oxidative kinetic resolution is a very practical system where the reagents are very inexpensive and accessible Tuning the solvent and adding carbonate bases allowed resolution of allylic and aliphatic alcohols and the usage of air as the oxygen source

41. 41 Conclusion Resolution can be useful when the racemates are obtained in few steps and good yields This system can be employed for the enantioselective preparation of a variety of pharmaceutical compounds

42. 42 Acknowledgements Prof. Louis Barriault Steve Arns Louis Morency Mélina Girardin Maxime Riou Christiane Grisé Effie Sauer Rachel Beingessner Patrick Ang Nathalie Goulet Guillaume Tessier …and you!