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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 ThiamineCatalytic Umpolung Reactivity of Aldehydes Louis-Charles Campeau University of Ottawa Dept. of Chemistry Center for Catalysis Research and Innovation
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
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).
“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
“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
Stochiometric Methods • Cyanohydrins as aldehyde umpolung • Homologation and its reversal D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239
Cyanohydrins as Aldehyde Umpolung G. Stork, T. Takahashi, I. Kawamoto, T. Suzuki, J. Am. Chem. Soc., 1978, 100, 8272
Stochiometric Methods • Dithianes as aldehyde umpolung • Heteroatom exchange D. Seebach, Angew. Chem. Int. Ed.,1979, 18, 239
Dithianes as Aldehyde Umpolung P. Wipf and J.T. Reeves, Chem. Comm.2002, 2066
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
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
Catalytic Vitamins R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719 T. Ukai, R Tanaka, T. Dokawa, J. Pharm. Soc. Jpn.,1943, 63, 296
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
Triazolium Catalysts • Triazolium catalysts give better yield and selectivity D. Enders, K. Breuer, J.H. Teles, Helv. Chim. Acta, 1996, 79, 1217
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
New Triazolium Catalyst D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743
Catalyst Activity D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743
“Cross Benzoin” Reaction X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
Silyl-Benzoin Reaction to the Rescue! X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
Catalytic Cycle of Silyl Benzoin X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
Chiral Metallophites in Silyl Benzoin X. Linghu, J.R. Potnick, J.S. Johnson, J. Am. Chem. Soc., 2004, 126, 3070
Other Electrophiles? • Can other electrophiles be used to give rise to other umpolung products
Stetter Reaction H. Stetter, H. Kuhlmann, Chem. Ber., 1976, 109, 2890 H. Stetter, Angew. Chem. Int. Ed.,1976, 15, 639
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
Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284
Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284
Hirsutic Acid C B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc.,1979, 101, 1284
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
New Highly Enantioselective Catalyst M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc.,2002, 124, 10298
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
Scope of the Intramolecular Stetter Reaction M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc.,2002, 124, 10298
Effect of the Michael Acceptor M.S. Kerr, T. Rovis, Synlett,2003, 12, 1934
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
Catalytic Formation of Quaternary Carbon Centers M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876
Aromatic Series : Scope M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876
Aliphatic Series: Scope M.S. Kerr, T. Rovis, J. Am. Chem. Soc.,2004, 126, 8876
Catalytic Cycle : Revisited J.R. de Alaniz, T. Rovis, submitted
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
Catalytic Cycle : Reloaded J.R. de Alaniz, T. Rovis, submitted
Deuterium NMR Studies J.R. de Alaniz, T. Rovis, submitted
Diastereoselective Protonation • Accounts for presence of D-HMDS and less than 100% deuterium incorporation J.R. de Alaniz, T. Rovis, submitted
Diastereoselective Protonation J.R. de Alaniz, T. Rovis, submitted