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1 SOMO catalysis and Photoredox Organocatalysis: Work of David W.C. MacMillan Dominic Fiset 05/10/11.

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Presentation on theme: "1 SOMO catalysis and Photoredox Organocatalysis: Work of David W.C. MacMillan Dominic Fiset 05/10/11."— Presentation transcript:

1 1 SOMO catalysis and Photoredox Organocatalysis: Work of David W.C. MacMillan Dominic Fiset 05/10/11

2 About Me 2 RIP

3 About Me 3

4 Outline 4 Introduction  David W.C. MacMillan  First Developments in Organocatalysis  Aminocatalysis: Activation modes Singly-Occupied Molecular Orbital catalysis  Previously Reported Radical Alkylation  Mechanistic Considerations  Scope and Limitations Photoredox Organocatalysis  Merging SOMO Catalysis with Photoredox Chemistry  Mechanistic Considerations  Synthetic Utility

5 Pr. David W.C. MacMillan 5 - Born in Bellshill, Scotland, in : Undergrad with Dr. Ernie Colvin at the University of Glasgow : PhD. with Professor Larry E. Overman : Postdoctoral research fellow with Professor David E. Evans : Independent Research at University of California, Berkeley : Professor of Chemistry at the California Institute of Technology : Professor of Chemistry at Princeton University -2o10-…: Editor-in-Chief of Chemical Science published by RSC Biography Research Interests - Organocatalysis - Mechanist investigation - SOMO catalysis - Merging photoredox catalysis and organocatalysis - Total synthesis of complex natural products 1.h

6 Birth of Organocatalysis 6 Hajos-Parrisch-Eder-Sauer-Wiechert reaction (1970s) 1.(a) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; C ̧ elebi-O ̈ lc ̧ u ̈ 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.

7 Advent of Mordern Organocatalysis: Asymmetric Aminocatalysis 7 Enamine catalysis: Aldol reaction 1.(a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, (b) List, B. Synlett 2001, Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243 Iminium catalysis: Diels-Alder reaction

8 Asymmetric aminocatalysis: Activation Modes 8 1.(a) Grondal, C.; Jeanty, M.; Enders, D. Nat.Chem. 2010, 2, 167. (b) MacMillan, D. W. C. Nature 2008, 455, 304

9 The Holy Grail Reaction 9 1.(a) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 126, 450 (b) Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed. 2006, 45, Melchiorre, P. Angew. Chem. Int. Ed. 2009, 48, 1360 Catalytic asymmetric intermolecular α-alkylation of aldehydes Pioneering work by List and Córdeva

10 The Holy Grail Reaction: A New Activation Mode 10 1.MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at Asymmetric intermolecular α-alkylation of aldehyde Is there a solution ?

11 A New Activation Mode: S ingly- O ccupied M olecular O rbital Catalysis 11 1.Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582 Aminocatalysis: A new activation mode 1 SOMO catalysis: A new synthetic paradigm

12 Enamine oxidation: Racemic SOMO catalysis 12 Cation radicals of enamines: work of Murakami and coworkers Construction of quaternary center: work of Cossy 1.Renaud, P.; Schubert, S. Synlett 1990, Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett. 1992, 21, (a) Cossy, J.; Bouzide, A. J. Chem. Soc., Chem. Commun. 1993, 1218 (b) Cossy, J.; Bouzide, A.; Leblanc, C. Synlett 1993, 202 Stereoselective addition of radicals to chiral enamines: work of Shubert

13 SOMO catalysis: Work of D.W.C. MacMillan 13 1.Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582

14 14 1.Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582 Intermolecular Allylation of Aldehydes

15 15 Potential for a Broad Scope 1.Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582

16 16 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 , 1467 SOMO Catalysis: Evidence for Radical Pathway

17 17 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 , 1467 Organo-SOMO Catalysis

18 18 1.(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 Chemoselective Oxidation

19 19 Origin of the Enantioselectivity Steric Control Approach 1.Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582

20 20 1.(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 Catalytic Turnovers Water Plays a Key Role - Concentration of catalyst is maintained by H 2 O (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

21 21 1.(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, SOMO catalysis: Work of M. P. Sibi

22 22 1.(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, Work of M. P. Sibi: Revisited by MacMillan

23 23 1.(a) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, (b) Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C. Chemical Science 2011, ASAP, DOI: /C1SC00556A Work of M. P. Sibi: Revisited by MacMillan Conditions Recently Re-Optimized by MacMillan: ‘’Synergistic catalysis’’

24 24 1.Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004  -Enolation of Aldehydes

25 25 1.Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc , 39  -Vinylation of Aldehydes: Mechanism

26 Synthetic Application 26  -Vinylation of Aldehydes: Scope 1.Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc , 39

27 27 1.Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, Carbo-oxidation of Styrenes

28 28 1.Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, Carbo-oxidation of Styrenes Homobenzylation of aldehyde Rapid Acess to Heterocyclic Rings

29 29 1.Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, Organo-SOMO Cascade Cycloadditions

30 30 1.Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, Organo-SOMO Cascade Cycloadditions

31 31 1.Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, Organo-SOMO Cascade Cycloadditions

32 32 1.Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chemical Science 2011, 2, 1470 Intramolecular  -Allylation Catalyst –controlled stereoselective piperidine formation

33 33 1.(a) Nicolaou, K. C.; Reingruber, R. d.; Sarlah, D.; Bra ̈ 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, (c) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001 Intramolecular  -Arylation of Aldehydes

34 34 1.Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121  -Chlorination and Terminal Epoxide Formation

35 35 1.Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121  -Chlorination and Terminal Epoxide Formation

36 36 1.Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121  -Chlorination and Terminal Epoxide Formation

37 37 1.(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,  -Allylation of Ketones

38 38 1.(a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at (b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027 Polyene Cyclization

39 39 1.(a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at (b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027 Polyene Cyclization: Mechanism

40 40 1.Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027 Polyene Cyclization: Scope

41 41 1.Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027 Merging SOMO and Photoredox catalysis Reversing the role of the aminocatalyst

42 42 1Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102 Light Photoredox Catalysis

43 43 1 Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85 Light Photoredox Catalysis

44 44 Merging SOMO and Photoredox catalysis 1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77

45 45 Merging SOMO and Photoredox catalysis 1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77

46 46 Photoredox organocatalysis: Mechanism 1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77

47 47 Photoredox Organocatalysis: Control Experiments 1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77 - Rigorous exclusion of light:  No alkylation product - Removal of Ru(bpy) 3 2+:  <10% of alkylation product over an extended timeframe (24h) - Ru(bpy) 3 2+ can be replaced by high-energy UV irradiation source  Reaction efficiency over 80% - Fluorescent quenching experiments with Ru(bpy) 3 2+ *  Ru(bpy) 3 2+ * excited state behaves as an oxidant in the photoredox cycle

48 48 1Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, Enantioselective  -Trifluoromethylation

49 49 Enantioselective  -Trifluoromethylation 1Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875

50 50 Enantioselective  -Benzylation 1 Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600

51 51 1 Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, Enantioselective  -Benzylation: Mechanism

52 52 Conclusion 1.MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at


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