1. Center for Catalysis Research and Innovation
The Chiral Urea and Thiourea Scaffold: From Novel Catalyst to Privileged Motif
David R. Stuart
University of Ottawa
Center for Catalysis Research and Innovation
Nov. 23, 2006

2. What Are Hydrogen Bonds?
“An X-H---A interaction is called a “hydrogen bond”, if 1. it constitutes a local bond, and 2. X-H acts as a proton donor to A.”
T. Steiner, Angew. Chem. Int. Ed. 2002, 41, 48 – 76.

3. How Strong Are Hydrogen Bonds?
G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997

4. Hydrogen Bonding In Bio-Catalysis
Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543.

5. Hydrogen Bonding in Small Molecule Catalysis: Phase-Transfer Catalysis
T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126,

6. Hydrogen Bonding in Small Molecule Catalysis: Single H-Bond Donation
Y. Huang, A.K. Unni, A.N. Thandani, V.H. Rawal, Nature 2003, 424, 146

7. Hydrogen Bonding in Small Molecule Catalysis: Double H-Bond Donation
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

8. Outline
Discovery of Jacobsen’s novel catalyst for the Asymmetric Strecker Reaction
Analysis of the Strecker Reaction and Substrate-Catalyst interactions
Optimization of Jacobsen’s Catalyst to a general catalyst for an array of Carbon-Carbon bond forming reaction.

9. The Strecker Reaction Discovered

10. The Strecker Reaction Discovered

11. The Modern Strecker Reaction

12. The Modern Asymmetric Strecker Reaction

13. The Modern Asymmetric Strecker Reaction

14. The Modern Asymmetric Strecker Reaction: Corey’s Contribution
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1,

15. The Modern Asymmetric Strecker Reaction: Corey’s Contribution
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1,

16. Jacobsen’s Approach to the Asymmetric Strecker Reaction
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120,

17. Jacobsen’s Approach to the Asymmetric Strecker Reaction
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120,

18. Catalyst Screening By Parallel Library Synthesis
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120,

19. Catalyst Screening By Parallel Library Synthesis
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120,

20. Optimization by Parellel Library Synthesis
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39,

21. A Novel Organo-Catalyst Realized
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39,

22. Application to the Hydrocyanation of Ketoimines
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2,

23. Synthesis of Enantiomerically Enriched Amino-acids: D-tert-leucine
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2,

24. Synthesis of Enantiomerically Enriched Amino-acids: D-tert-leucine
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2,

25. Optimized Synthesis of Urea Catalyst
J.T. Su, P. Vachal, E.N. Jacobsen, Adv. Syn. Catal. 2001, 343,

26. A Closer Look at the Catalyst
How does the catalyst activate the substrate and what
are the major factors for enantioselective induction?

27. Kinetic Analysis
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

28. Kinetic Analysis: HCN The reaction displays 1st-order
dependance on HCN
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

29. Kinetic Analysis: Catalyst
The reaction displays 1st-order
dependance on the catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

30. Kinetic Analysis: Imine
The reaction displays saturation
kinetics on the imine
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

31. A Mechanistic Proposal
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987

32. A Mechanistic Proposal
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987

33. A Mechanistic Proposal
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987

34. Experimental Distances Obtained From a ROESY Experiment

35. Experimental Distances Obtained From a ROESY Experiment
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

36. Another Look at the Catalyst
Catalyst 1 adopts a well-defined secondary structure in solution.
The transformation obeys Michaelis-Menten kinetics and this implies the reversible formation of an imine-catalyst complex.
What role do the four acidic hydrogens play in substrate activation?

37. Pin-pointing the site of Catalyst Binding: Effect of Amide
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

38. Pin-pointing the site of Catalyst Binding: Effect of Phenol
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

39. Pin-pointing the site of Catalyst Binding: Effect of Urea
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

40. Isotope (15N) shift experiments as further proof
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

41. An Interesting Observation Regarding Imine Stereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

42. Which Isomer Interacts with the Catalyst?
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

43. 1H NMR Spectroscopic Proof of Imine Stereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

44. What Is the 3-D Structure of the Catalyst-Imine Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

45. What Is the 3-D Structure of the Catalyst-Imine Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

46. Making Sense of Old Results with New Information
large substituent of imine
N-substituent of the
imine
H (aldimine) or Me (ketoimine) of the imine
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

47. Making Sense of Old Results with New Information
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

48. Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

49. Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

50. Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

51. Extention of the Methodology: Asymmetric Mannich Reaction

52. Extention of the Methodology: Asymmetric Mannich Reaction
A.G. Wenzel, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124,

53. What Effect do the Amide and Urea Moieties Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

54. What Effect do the Amide and Urea Moieties Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

55. What Effect do the Amide and Urea Moieties Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

56. What Effect does the Amino Acid Moiety Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

57. What Effect does the Amino Acid Moiety Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

58. What Effect does the Amino Acid Moiety Have on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

59. What Effect Does the Diamine Moiety Have on Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

60. What Effect Does the Diamine Moiety Have on Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

61. What Effect Does the Diamine Moiety Have on Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

62. What Effect Does the Diamine Moiety Have on Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

63. A New Catalyst for the Asymmetric Mannich Reaction
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett ,

64. Application of the Chiral Thiourea Scaffold to Date

65. Conclusion
A novel Organo-Catalyst was discovered for the asymmetric Strecker reaction.
Analysis of the reaction and catalyst structure led to the optimization of the catalyst.
The catalyst is amenable to derivatization and the general thiourea/amino-acid scaffold was found to be applicable in numerous enantioselective reactions.

66. Acknowledgments Prof. Keith Fagnou Marc Lafrance L.C. Campeau
J.P. Leclerc
Megan ApSimon
Kayode Akinnusi
Nicole Blaquiere
Derek Schipper
David Lapointe
Elisia Villemure
Sophie Rousseaux
Daniel Shore
Catherine Crawford
Benoit Liegault