SOMO catalysis and
Photoredox Organocatalysis:
Work of David W.C. MacMillan
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Dominic Fiset
05/10/11
About Me
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RIP 1972-1995
About Me
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Outline
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 Introduction
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David W.C. MacMillan
First Developments in Organocatalysis
Aminocatalysis: Activation modes
 Singly-Occupied Molecular Orbital catalysis
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Previously Reported Radical Alkylation
Mechanistic Considerations
Scope and Limitations
 Photoredox Organocatalysis
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Merging SOMO Catalysis with Photoredox Chemistry
Mechanistic Considerations
Synthetic Utility
Pr. David W.C. MacMillan
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Biography
- Born in Bellshill, Scotland, in 1968
- 1987-91: Undergrad with Dr. Ernie Colvin at the University of Glasgow
- 1991- 96: PhD. with Professor Larry E. Overman
- 1996-98: Postdoctoral research fellow with Professor David E. Evans
- 1998-2000: Independent Research at University of California, Berkeley
-2000-2006: Professor of Chemistry at the California Institute of Technology
-2006-...: Professor of Chemistry at Princeton University
-2o10-…: Editor-in-Chief of Chemical Science published by RSC
Research Interests
- Organocatalysis
- Mechanist investigation
- SOMO catalysis
- Merging photoredox catalysis and organocatalysis
- Total synthesis of complex natural products
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h http://www.princeton.edu/chemistry/macmillan/index.xml
Birth of Organocatalysis
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Hajos-Parrisch-Eder-Sauer-Wiechert reaction (1970s)
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(a) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Çelebi-Ö lçü m, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042
(b) Hajos, A. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1612
(c) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
Advent of Mordern Organocatalysis:
Asymmetric Aminocatalysis
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Enamine catalysis: Aldol reaction
Iminium catalysis: Diels-Alder reaction
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(a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395.
(b) List, B. Synlett 2001, 1675
2. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243
Asymmetric aminocatalysis: Activation Modes
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(a) Grondal, C.; Jeanty, M.; Enders, D. Nat .Chem. 2010, 2, 167.
(b) MacMillan, D. W. C. Nature 2008, 455, 304
The Holy Grail Reaction
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Pioneering work by List and Córdeva
Catalytic asymmetric intermolecular α-alkylation of aldehydes
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(a) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 126, 450
(b) Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed. 2006, 45, 1952
Melchiorre, P. Angew. Chem. Int. Ed. 2009, 48, 1360
The Holy Grail Reaction: A New Activation Mode
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Asymmetric intermolecular α-alkylation of aldehyde
Is there a solution ?
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MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at
http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf
A New Activation Mode:
Singly-Occupied Molecular Orbital Catalysis
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Aminocatalysis: A new activation mode 1
SOMO catalysis: A new synthetic paradigm
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
Enamine oxidation: Racemic SOMO catalysis
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Stereoselective addition of radicals to chiral enamines: work of Shubert
Cation radicals of enamines: work of Murakami and coworkers
Construction of quaternary center: work of Cossy
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Renaud, P.; Schubert, S. Synlett 1990, 624
Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett. 1992, 21, 2099
(a) Cossy, J.; Bouzide, A. J. Chem. Soc., Chem. Commun. 1993, 1218 (b) Cossy, J.; Bouzide, A.; Leblanc, C. Synlett 1993, 202
SOMO catalysis: Work of D.W.C. MacMillan
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
Intermolecular Allylation of Aldehydes
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
Potential for a Broad Scope
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
SOMO Catalysis: Evidence for Radical Pathway
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(a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
(b) Le Tadic-Biadatti, M.-H.; Newcomb, M. Journal of the Chemical Society, Perkin Transactions 2 1996, 1467
Organo-SOMO Catalysis
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1.
(a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
(b) Le Tadic-Biadatti, M.-H.; Newcomb, M. Journal of the Chemical Society, Perkin Transactions 2 1996, 1467
Chemoselective Oxidation
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(a) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem. Int. Ed. 2010, 49, 6106
(b) Beel, R.; Kobialka, S.; Schmidt, M. L.; Engeser, M. Chem. Commun. 2011, 47, 3293
(c) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001
Origin of the Enantioselectivity
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Steric Control Approach
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
Catalytic Turnovers
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Water Plays a Key Role
- Concentration of catalyst is maintained by H2O (below 2.00 eq, the catalyst is
deactivated)
- Effect on the phase-transfer process that controls the homogenous concentration
of the oxidant (CAN)
- Bench-grade DME contains sufficient water to achieve optimal results
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(a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
(b) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem. Int. Ed. 2010, 49, 6106
SOMO catalysis: Work of M. P. Sibi
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(a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124
(b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012
Work of M. P. Sibi: Revisited by MacMillan
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(a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124
(b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012
Work of M. P. Sibi: Revisited by MacMillan
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Conditions Recently Re-Optimized by MacMillan: ‘’Synergistic catalysis’’
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(a) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012
(b) Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C. Chemical Science 2011, ASAP, DOI: 10.1039/C1SC00556A
a-Enolation of Aldehydes
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Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004
a-Vinylation of Aldehydes: Mechanism
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Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008 130, 39
a-Vinylation of Aldehydes: Scope
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Synthetic Application
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Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008 130, 39
Carbo-oxidation of Styrenes
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Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
Carbo-oxidation of Styrenes
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Rapid Acess to Heterocyclic Rings
Homobenzylation of aldehyde
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Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
Organo-SOMO Cascade Cycloadditions
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Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Organo-SOMO Cascade Cycloadditions
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Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Organo-SOMO Cascade Cycloadditions
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Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Intramolecular a-Allylation
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Catalyst –controlled stereoselective piperidine formation
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Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chemical Science 2011, 2, 1470
Intramolecular a-Arylation of Aldehydes
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(a) Nicolaou, K. C.; Reingruber, R. d.; Sarlah, D.; Brä se, S. J. Am. Chem. Soc. 2009, 131, 6640
(b) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11640
(c) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001
a-Chlorination and Terminal Epoxide Formation
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Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
a-Chlorination and Terminal Epoxide Formation
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Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
a-Chlorination and Terminal Epoxide Formation
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Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
a-Allylation of Ketones
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(a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458
(b) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.; MacMillan, D. W. C. Proceedings of the National Academy of Sciences 2010, 107, 20648
Polyene Cyclization
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(a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at
http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf
(b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Polyene Cyclization: Mechanism
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(a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at
http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf
(b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Polyene Cyclization: Scope
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Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Merging SOMO and Photoredox catalysis
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Reversing the role of the aminocatalyst
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Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Light Photoredox Catalysis
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Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102
Light Photoredox Catalysis
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Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85
Merging SOMO and Photoredox catalysis
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Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
Merging SOMO and Photoredox catalysis
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Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
Photoredox organocatalysis: Mechanism
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Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
Photoredox Organocatalysis: Control Experiments
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- Rigorous exclusion of light:
 No alkylation product
- Removal of Ru(bpy)32+:
<10% of alkylation product over an extended timeframe (24h)
- Ru(bpy)32+ can be replaced by high-energy UV irradiation source
Reaction efficiency over 80%
- Fluorescent quenching experiments with Ru(bpy)32+*
Ru(bpy)32+* excited state behaves as an oxidant in the photoredox cycle
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Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
Enantioselective a-Trifluoromethylation
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Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875
Enantioselective a-Trifluoromethylation
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Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875
Enantioselective a-Benzylation
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Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600
Enantioselective a-Benzylation: Mechanism
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Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600
Conclusion
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MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at
http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf