The Chiral Urea and Thiourea Scaffold: From Novel Catalyst to Privileged Motif

1
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, 6844 - 6845
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.. 2003, 1919 - 1922
8
Outline

• Discovery of Jacobsens novel catalyst for the
  Asymmetric Strecker Reaction
• Analysis of the Strecker Reaction and
  Substrate-Catalyst interactions
• Optimization of Jacobsens 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 Coreys
Contribution
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157
- 160
15
The Modern Asymmetric Strecker Reaction Coreys
Contribution
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157
- 160
16
Jacobsens Approach to the Asymmetric Strecker
Reaction
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901 - 4902
17
Jacobsens Approach to the Asymmetric Strecker
Reaction
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901 - 4902
18
Catalyst Screening By Parallel Library Synthesis
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901 - 4902
19
Catalyst Screening By Parallel Library Synthesis
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901 - 4902
20
Optimization by Parellel Library Synthesis
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew.
Chem. Int. Ed. 2000, 39, 1279 - 1281
21
A Novel Organo-Catalyst Realized
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew.
Chem. Int. Ed. 2000, 39, 1279 - 1281
22
Application to the Hydrocyanation of Ketoimines
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867
- 870
23
Synthesis of Enantiomerically Enriched
Amino-acids D-tert-leucine
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867
- 870
24
Synthesis of Enantiomerically Enriched
Amino-acids D-tert-leucine
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867
- 870
25
Optimized Synthesis of Urea Catalyst
J.T. Su, P. Vachal, E.N. Jacobsen, Adv. Syn.
Catal. 2001, 343, 197 - 200
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, 10012 - 10014
28
Kinetic Analysis HCN
The reaction displays 1st-order dependance on HCN
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
29
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
30
Kinetic Analysis Imine
The reaction displays saturation kinetics on the
imine
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
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, 10012 - 10014
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, 10012 - 10014
38
Pin-pointing the site of Catalyst Binding Effect
of Phenol
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
39
Pin-pointing the site of Catalyst Binding Effect
of Urea
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
40
Isotope (15N) shift experiments as further proof
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
41
An Interesting Observation Regarding Imine
Stereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
42
Which Isomer Interacts with the Catalyst?
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
43
1H NMR Spectroscopic Proof of Imine
Stereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
44
What Is the 3-D Structure of the Catalyst-Imine
Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
45
What Is the 3-D Structure of the Catalyst-Imine
Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
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, 10012 - 10014
47
Making Sense of Old Results with New Information
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
48
Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
49
Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
50
Re-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 10012 - 10014
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, 12964 - 12965
53
What Effect do the Amide and Urea Moieties Have
on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
54
What Effect do the Amide and Urea Moieties Have
on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
55
What Effect do the Amide and Urea Moieties Have
on Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
56
What Effect does the Amino Acid Moiety Have on
Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
57
What Effect does the Amino Acid Moiety Have on
Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
58
What Effect does the Amino Acid Moiety Have on
Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
59
What Effect Does the Diamine Moiety Have on
Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
60
What Effect Does the Diamine Moiety Have on
Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
61
What Effect Does the Diamine Moiety Have on
Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
62
What Effect Does the Diamine Moiety Have on
Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
63
A New Catalyst for the Asymmetric Mannich Reaction
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen,
Synlett.. 2003, 1919 - 1922
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