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

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.

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

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

Hydrogen Bonding in Small Molecule Catalysis: Phase-Transfer Catalysis T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 6844 - 6845

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

Hydrogen Bonding in Small Molecule Catalysis: Double H-Bond Donation A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

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.

The Strecker Reaction Discovered

The Strecker Reaction Discovered

The Modern Strecker Reaction

The Modern Asymmetric Strecker Reaction

The Modern Asymmetric Strecker Reaction

The Modern Asymmetric Strecker Reaction: Corey’s Contribution E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157 - 160

The Modern Asymmetric Strecker Reaction: Corey’s Contribution E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157 - 160

Jacobsen’s Approach to the Asymmetric Strecker Reaction M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902

Jacobsen’s Approach to the Asymmetric Strecker Reaction M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902

Catalyst Screening By Parallel Library Synthesis M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902

Catalyst Screening By Parallel Library Synthesis M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902

Optimization by Parellel Library Synthesis M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 - 1281

A Novel Organo-Catalyst Realized M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 - 1281

Application to the Hydrocyanation of Ketoimines P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870

Synthesis of Enantiomerically Enriched Amino-acids: D-tert-leucine P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870

Synthesis of Enantiomerically Enriched Amino-acids: D-tert-leucine P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870

Optimized Synthesis of Urea Catalyst J.T. Su, P. Vachal, E.N. Jacobsen, Adv. Syn. Catal. 2001, 343, 197 - 200

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

Kinetic Analysis P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Kinetic Analysis: HCN The reaction displays 1st-order dependance on HCN P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Kinetic Analysis: Catalyst The reaction displays 1st-order dependance on the catalyst P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Kinetic Analysis: Imine The reaction displays saturation kinetics on the imine P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

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

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

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

Experimental Distances Obtained From a ROESY Experiment

Experimental Distances Obtained From a ROESY Experiment P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

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?

Pin-pointing the site of Catalyst Binding: Effect of Amide P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Pin-pointing the site of Catalyst Binding: Effect of Phenol P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Pin-pointing the site of Catalyst Binding: Effect of Urea P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Isotope (15N) shift experiments as further proof P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

An Interesting Observation Regarding Imine Stereochemistry P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Which Isomer Interacts with the Catalyst? P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

1H NMR Spectroscopic Proof of Imine Stereochemistry P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

What Is the 3-D Structure of the Catalyst-Imine Complex P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

What Is the 3-D Structure of the Catalyst-Imine Complex P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

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, 10012 - 10014

Making Sense of Old Results with New Information P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Re-optimization of the Catalyst P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Re-optimization of the Catalyst P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Re-optimization of the Catalyst P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Extention of the Methodology: Asymmetric Mannich Reaction

Extention of the Methodology: Asymmetric Mannich Reaction A.G. Wenzel, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964 - 12965

What Effect do the Amide and Urea Moieties Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect do the Amide and Urea Moieties Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect do the Amide and Urea Moieties Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect does the Amino Acid Moiety Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect does the Amino Acid Moiety Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect does the Amino Acid Moiety Have on Stereoinduction? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect Does the Diamine Moiety Have on Stereochemistry? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect Does the Diamine Moiety Have on Stereochemistry? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect Does the Diamine Moiety Have on Stereochemistry? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

What Effect Does the Diamine Moiety Have on Stereochemistry? A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

A New Catalyst for the Asymmetric Mannich Reaction A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922

Application of the Chiral Thiourea Scaffold to Date

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.

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