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Taking Lessons from Thiamine Catalytic Umpolung Reactivity of Aldehydes

Taking Lessons from Thiamine Catalytic Umpolung Reactivity of Aldehydes. Louis-Charles Campeau University of Ottawa Dept. of Chemistry Center for Catalysis Research and Innovation. Taking Lessons From Thiamine. Taking Lessons From Thiamine. Taking Lessons From Thiamine.

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Taking Lessons from Thiamine Catalytic Umpolung Reactivity of Aldehydes

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  1. Taking Lessons from ThiamineCatalytic Umpolung Reactivity of Aldehydes Louis-Charles Campeau University of Ottawa Dept. of Chemistry Center for Catalysis Research and Innovation

  2. Taking Lessons From Thiamine

  3. Taking Lessons From Thiamine

  4. Taking Lessons From Thiamine

  5. Taking Lessons From Thiamine

  6. Overview • Umpolung Reactivity • Aldehyde Umpolung • Benzoin Reaction • Catalytic Cycle • Recent developments • Stetter Methodology • Catalytic Cycle • The Early Years: Hirsutic Acid C • Recent developments • Conclusions • Acknowledgements

  7. Umpolung Reactivity • “Umpolung” is derived from German meaning “inverse polarity” • Any process by which the normal alternating donor and acceptor reactivity pattern of a chain is interchanged, do to the presence of O or N heteroatoms. • This original meaning of the term has been extended to the reversal of any commonly accepted reactivity pattern. IUPAC Compendium of Chemical Terminology, 2nd Edition (1997).

  8. “Umpolung Chemistry” of Aldehydes • Umpolung reactivity allows chemists to look at bond disconnections in new ways D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239

  9. “Umpolung Chemistry” of Aldehydes • Umpolung reactivity allows chemists to look at bond disconnections in new ways D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239

  10. Stochiometric Methods • Cyanohydrins as aldehyde umpolung • Homologation and its reversal D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239

  11. Cyanohydrins as Aldehyde Umpolung G. Stork, T. Takahashi, I. Kawamoto, T. Suzuki, J. Am. Chem. Soc., 1978, 100, 8272

  12. Stochiometric Methods • Dithianes as aldehyde umpolung • Heteroatom exchange D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239

  13. Dithianes as Aldehyde Umpolung P. Wipf and J.T. Reeves, Chem. Comm.2002, 2066

  14. Catalytic Methods • Introduction to the benzoin reaction • Nucleophilic acylation reactions catalyzed by lyases (transketolase) in the presence of coenzyme thiamine. D. U. Nilsson, L. Meshalakina, Y. Lindqvist, G. Schneider, J. Biol. Chem., 1997, 272, 1864

  15. Nature’s Way D. Enders & T. Balensiefer, Acc. Chem. Res, 2004, 37, 534 U. Nilsson, L. Meshalakina, Y. Lindqvist, G. Schneider, J. Biol. Chem., 1997, 272, 1864

  16. Catalytic Vitamins R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719 T. Ukai, R Tanaka, T. Dokawa, J. Pharm. Soc. Jpn.,1943, 63, 296

  17. Benzoin Reaction – Early Years J.C. Sheehan, D.H. Hunneman, J. Am. Chem. Soc., 1966, 88, 3666 J.C. Sheehan, T. Hara, J. Org. Chem., 1974, 39, 1196

  18. Triazolium Catalysts • Triazolium catalysts give better yield and selectivity D. Enders, K. Breuer, J.H. Teles, Helv. Chim. Acta, 1996, 79, 1217

  19. Alternative Catalysts R.L. Knight, F.J. Leeper, Tetraheron Lett., 1997, 38, 3611 C.A. Dvorak, V.H. Rawal, Tetrahedron Lett., 1998, 39, 2925 R.L. Knight, F.J. Leeper, Perkin Trans. 1, 1998, 1891

  20. New Triazolium Catalyst D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743

  21. Catalyst Activity D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743

  22. “Cross Benzoin” Reaction X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534

  23. Inefficiency of Cross-Benzoin Methodology

  24. Inefficiency of Cross-Benzoin Methodology

  25. Silyl-Benzoin Reaction to the Rescue! X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534

  26. Catalytic Cycle of Silyl Benzoin X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534

  27. Chiral Metallophites in Silyl Benzoin X. Linghu, J.R. Potnick, J.S. Johnson, J. Am. Chem. Soc., 2004, 126, 3070

  28. TimeLine

  29. Back To The Future!!

  30. Other Electrophiles? • Can other electrophiles be used to give rise to other umpolung products

  31. Stetter Reaction H. Stetter, H. Kuhlmann, Chem. Ber., 1976, 109, 2890 H. Stetter, Angew. Chem. Int. Ed.,1976, 15, 639

  32. First Intramolecular Stetter • Trost & co-workers published the first stereocontrolled synthesis of Hirsutic Acid C • Sesquiterpene with antibiotic and antimitotic activity • 7 chiral centers B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284

  33. Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284

  34. Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284

  35. Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284

  36. Intramolecular Variant • Ciganek & co-workers reported the first study of the intramolecular variant • Enders & co-workers reported the first asymmetric intramolecular Stetter reaction E. Ciganek, Synthesis, 1995, 1311 D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta,1996, 79, 1899

  37. New Highly Enantioselective Catalyst M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc.,2002, 124, 10298

  38. Catalyst Optimization • Structural modifications were made to improve the yield of the reaction M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc.,2002, 124, 10298

  39. Scope of the Intramolecular Stetter Reaction M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc.,2002, 124, 10298

  40. Effect of the Michael Acceptor M.S. Kerr, T. Rovis, Synlett,2003, 12, 1934

  41. Quaternary Carbon Centers • Can we overcome the low reactivity when forming quaternary carbon centers?? B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284

  42. Catalytic Formation of Quaternary Carbon Centers M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876

  43. Aromatic Series : Scope M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876

  44. Aliphatic Series: Scope M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876

  45. Catalytic Cycle : Revisited J.R. de Alaniz, T. Rovis, submitted

  46. Re-investigating the Mechanism • What is the rate limiting step? • C-C Bond formation – Ketones Were Faster… • Primary Kinetic Isotope Effect Observed • Indicates C-H or X-H Bond Cleavage at the rate determining step J.R. de Alaniz, T. Rovis, submitted

  47. Catalytic Cycle : Reloaded J.R. de Alaniz, T. Rovis, submitted

  48. Deuterium NMR Studies J.R. de Alaniz, T. Rovis, submitted

  49. Diastereoselective Protonation • Accounts for presence of D-HMDS and less than 100% deuterium incorporation J.R. de Alaniz, T. Rovis, submitted

  50. Diastereoselective Protonation J.R. de Alaniz, T. Rovis, submitted

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