Taking Lessons from Thiamine Catalytic Umpolung Reactivity of Aldehydes

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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

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Taking Lessons From Thiamine
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Taking Lessons From Thiamine
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Taking Lessons From Thiamine
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Taking Lessons From Thiamine
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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

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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).
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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
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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
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Stochiometric Methods

• Cyanohydrins as aldehyde umpolung
• Homologation and its reversal

D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
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Cyanohydrins as Aldehyde Umpolung
G. Stork, T. Takahashi, I. Kawamoto, T. Suzuki,
J. Am. Chem. Soc., 1978, 100, 8272
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Stochiometric Methods

• Dithianes as aldehyde umpolung
• Heteroatom exchange

D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
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Dithianes as Aldehyde Umpolung
P. Wipf and J.T. Reeves, Chem. Comm. 2002, 2066
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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
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Natures 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
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Catalytic Vitamins
R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719 T.
Ukai, R Tanaka, T. Dokawa, J. Pharm. Soc. Jpn.,
1943, 63, 296
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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
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Triazolium Catalysts

• Triazolium catalysts give better yield and
  selectivity

D. Enders, K. Breuer, J.H. Teles, Helv. Chim.
Acta, 1996, 79, 1217
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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
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New Triazolium Catalyst
D. Enders, U. Kallfass, Angew. Chem. Int. Ed.,
2002, 41, 1743
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Catalyst Activity
D. Enders, U. Kallfass, Angew. Chem. Int. Ed.,
2002, 41, 1743
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Cross Benzoin Reaction
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed.,
2003, 42, 2534
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Inefficiency of Cross-Benzoin Methodology
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Inefficiency of Cross-Benzoin Methodology
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Silyl-Benzoin Reaction to the Rescue!
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed.,
2003, 42, 2534
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Catalytic Cycle of Silyl Benzoin
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed.,
2003, 42, 2534
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Chiral Metallophites in Silyl Benzoin
X. Linghu, J.R. Potnick, J.S. Johnson, J. Am.
Chem. Soc., 2004, 126, 3070
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TimeLine
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Back To The Future!!
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Other Electrophiles?

• Can other electrophiles be used to give rise to
  other umpolung products

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Stetter Reaction
H. Stetter, H. Kuhlmann, Chem. Ber., 1976, 109,
2890 H. Stetter, Angew. Chem. Int. Ed., 1976, 15,
639
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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
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Hirsutic Acid C
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S.
McElvain, J. Am. Chem. Soc., 1979, 101, 1284
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Hirsutic Acid C
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S.
McElvain, J. Am. Chem. Soc., 1979, 101, 1284
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Hirsutic Acid C
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S.
McElvain, J. Am. Chem. Soc., 1979, 101, 1284
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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
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New Highly Enantioselective Catalyst
M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem.
Soc., 2002, 124, 10298
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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
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Scope of the Intramolecular Stetter Reaction
M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem.
Soc., 2002, 124, 10298
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Effect of the Michael Acceptor
M.S. Kerr, T. Rovis, Synlett, 2003, 12, 1934
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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
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Catalytic Formation of Quaternary Carbon Centers
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004,
126, 8876
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Aromatic Series Scope
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004,
126, 8876
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Aliphatic Series Scope
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004,
126, 8876
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Catalytic Cycle Revisited
J.R. de Alaniz, T. Rovis, submitted
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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
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Catalytic Cycle Reloaded
J.R. de Alaniz, T. Rovis, submitted
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Deuterium NMR Studies
J.R. de Alaniz, T. Rovis, submitted
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Diastereoselective Protonation

• Accounts for presence of D-HMDS and less than
  100 deuterium incorporation

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

• Potential for generating two contiguous chiral
  centers with one catalytic reaction !!!

J.R. de Alaniz, T. Rovis, submitted
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Setting Contiguous Stereocenters
J.R. de Alaniz, T. Rovis, submitted
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Contiguous Stereocenters via Asymmetric Stetter
Reaction
J.R. de Alaniz, T. Rovis, submitted
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Conclusion
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Acknowledgements

• Prof. Keith Fagnou
• Prof. Tom Rovis ... And you!!
• Fagnou Research Group
• Mathieu Parisien
• Marc Lafrance
• Mélissa Leblanc
• Valérie Charbonneau
• Irina Dessinova
• Julien Dugal-Tessier
• Praew Thansandote
• Nicole Blaquiere