1. Enolate Heterocoupling: A Different Kind of Direct Functionalization A Phil S. Baran Methodology 27 October 2009 A Phil S. Baran Methodology 27 October 2009

2. 2 1,4-Dicarbonyl Moeities Needless to say this group is omnipresent

3. 3 How Would YOU Make This?

4. 4 Added Complexity? Tetrahedron, 1999, 55, 13983 Bioorg. Med. Chem., 2002, 10, 2569 J. Am. Chem. Soc., 2006, 128, 2552Synlett., 2002, 1069 Org. Lett., 2001, 3, 2591 J. Am. Chem. Soc., 1998, 120, 2658

5. 5 A More Direct Approach Historical Perspective on Enolate Coupling Origins of the Work in the Baran Group Intramolecular Enolate Heterocoupling Intermolecular Enolate Heterocoupling

6. 6 Origins of Enolate Coupling Ivanoff, D.; Spassoff, A. Bull. Soc. Chim. Fr., 1935, 2, 76 Renaud, P.; Fox, M. A. J. Org. Chem., 1988, 53, 3745

7. 7 A Forgotten Reaction Re-Discovered Kauffmann, T.; Beissner, G.; Berg, H.; Köppelmann, E.; Legler, J.; Schönfelder, M. Angew. Chem. Int. Ed. Engl., 1968, 7, 540 Rathke, M. W.; Lindert, A. J. Am. Chem. Soc., 1971, 93, 4605 Yields are starting to be synthetically useful Limited to homocoupling

8. 8 How About Some Heterocoupling? Saegusa, T. et al. J. Am. Chem. Soc. 1975, 97, 2912 and J. Am. Chem. Soc. 1977, 99, 1487

9. 9 How About Some Heterocoupling? Tokuda, M.; Shigei, T.; Itoh, M. Chem. Lett., 1975, 621 Reaction once again forgotten for 30 years Still room for improvement Yields moderate and excess reagents required For more comprehensive summary see: Baran, P. S. et al. J. Am. Chem. Soc., 2007, 129, 12857 Baran, P. S. et al. J. Am. Chem. Soc., 2008, 130, 11546 9

10. 10 Phil Baran Date of Birth: 10 Aug 1977 1991 - 1995 Simultaneous high school graduation from Mt. Dora High School and A.A. degree with honors from Lake Sumter Community College, Florida 1995 - 1997 B.S. with Honors in Chemistry, New York University Advisor: Professor D.I. Schuster 1997 - 2001 Ph.D. graduate student in Chemistry, The Scripps Research Institute Advisor: Professor K.C. Nicolaou 2001 - 2003 Postdoctoral Associate, Harvard University Advisor: Professor E.J. Corey - 83 Papers and 4 Patents (30-40 undergrad thru post-doc) - Awards: Sackler Prize, 2009 NationalFresenius Award,ACS, 2007 Novartis Lecturer, 2007 – 2008 Hirata Gold Medal, 2007 Pfizer Award for Creativity in Organic Synthesis, 2006 Beckman Foundation Fellow, 2006 – 2008 Alfred P. Sloan Foundation Fellow, 2006 – 2008 BMS Unrestricted “Freedom to Discover” Grant, 2006 – 2010 NSFCAREERAward, 2006 – 2010 Eli Lilly Young Investigator Award, 2005 – 2006 AstraZeneca Excellence in Chemistry Award, 2005 DuPont Young Professor Award,2005 Roche Excellence in Chemistry Award, 2005 Amgen Young Investigator Award, 2005 Searle Scholar Award, 2005 GlaxoSmithKline Chemistry Scholar Award, 2005 – 2006 Nobel Laureate Signature Award in Chemistry, ACS, 2003 National Institutes of Health Post-Doctoral Fellowship Award, Harvard, 2001 – 2003 Hoffmann-La Roche Award for Excellence in Organic Chemistry, 2000 Lesly Starr Shelton Award for Excellence in Chemistry Graduate Studies, Scripps, 2000 National Science Foundation Pre-Doctoral Research Fellowship Award, Scripps, 1998 – 2001 William and Sharon Bauce Family Foundation Fellowship Award, Scripps, 1997 Dean’ s Undergraduate Research Fund Award in Chemistry, NYU,1996 – 1997 George Granger Brown Award for Excellence in Chemistry, NYU, 1996 – 1997 NYU College of Art and Sciences Scholarship, 1995 – 1997 Herman and Margaret Sokol Chemistry Fellowship, NYU, 1995 – 1997

11. 11 Let’s Start with Indoles Baran, P. S.; Richter J. M. J. Am. Chem. Soc. 2004, 126, 7450 Disconnection places a positive charge on a negative site Clearly not an enolate but...... NB!! Direct Approach!! Vaillancourt, V.; Albizati, K. F. J. Am. Chem. Soc. 1993, 115, 3499

12. 12 Direct Enolate Coupling with Indoles Baran, P. S.; Richter J. M. J. Am. Chem. Soc. 2004, 126, 7450 “Isolated as colorless cubes” “Can perform the reaction on 100 mmol scale without diminished yields”

13. 13 Selected Scope of the Reaction Baran, P. S.; Richter J. M. J. Am. Chem. Soc. 2004, 126, 7450 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857 13

14. 14 Application to Natural Products Baran, P. S.; Richter J. M. J. Am. Chem. Soc. 2004, 126, 7450 Baran, P. S.; Richter J. M. J. Am. Chem. Soc. 2005, 127, 15394 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857

15. 15 A Different Heterocycle.... Sort of Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615

16. 16 Coupling of Pyrroles Towards (S)-Ketorolac Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Frazier, R. H.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408 How does the reaction work?

17. 17 Mechanism of Indole and Pyrrole Coupling Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857 ρ = -0.61

18. 18 Mechanism of Indole and Pyrrole Coupling Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857

19. 19 Mechanism of Indole and Pyrrole Coupling Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857 Other observations: Dimerization of the indole is not observed, unless the ketone is not present or cannot be oxidized N-protections kills the reaction Ferrocenium does not promote inter- molecular reaction, and Cu does not promote intramolecular Jahn, U.; Harmann, P. Chem. Commun. 1998, 209 Jahn, U.; Harmann, P. J. Chem. Soc. Perkin Trans. 1 2001, 2277

20. 20 Mechanism of Indole and Pyrrole Coupling Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Baran, P. S., et al. J. Am. Chem. Soc. 2007, 129, 12857

21. 21 Mechanism of Indole and Pyrrole Coupling Baran, P. S.; Richter J. M.; Lin, D. W. Angew. Chem. 2005, 117, 615 Proposed radical but not ‘free’ radical They do not really propose anything

22. 22 Lessons Learned Can get ‘heterocoupling’ if both reagents are not equivalent Ketones, amides, esters tolerated Mechanism is radicalar and tunable Need ~1.5 equiv oxidant relative to more reactive partner

23. 23 Towards Heteroenolate Coupling Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int. Ed. 2005, 44, 3892 Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem. Int. Ed. 2005, 44, 606 Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678

24. 24 Intramolecular Heteroenolate Coupling Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int. Ed. 2005, 44, 3892 Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem. Int. Ed. 2005, 44, 606 Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678 Now they had a model system

25. 25 Intramolecular Heteroenolate Coupling Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int. Ed. 2005, 44, 3892 Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem. Int. Ed. 2005, 44, 606 Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678

26. 26 Intramolecular Heteroenolate Coupling Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int. Ed. 2005, 44, 3892 Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem. Int. Ed. 2005, 44, 606 Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678 This product is the precursor to the others

27. 27 Intramolecular Heteroenolate Coupling Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int. Ed. 2005, 44, 3892 Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem. Int. Ed. 2005, 44, 606 Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678 Proposed models

28. 28Recap

29. 29Optimization Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

30. 30 Selected Scope with Iron Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

31. 31 Selected Scope with Iron Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

32. 32 Selected Scope with Copper Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

33. 33Applications Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

34. 34 Mechanistic Studies - Evidence for Radicals Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 SET Test Yang, D.; et al. Tetrahedron: Asymmetry 2003, 12, 2927 Suggests that single electron transfer is likely

35. 35 Mechanistic Studies - Evidence for Radicals Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 Homodimerization Test Radical Transfer Test

36. 36 Mechanistic Studies - Evidence for Radicals Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 ρ = -0.63

37. 37 Mechanistic Studies - Evidence for Radicals Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 ρ = -0.25

38. 38 Transition-State Models - Evan’s Oxazolidinone Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 Suggests that model for each system is different Proposed models based on metal loadings

39. 39 Transition-State Models - Effects of M Loading Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546 Adjusted Yield based on Oxidant Stoichiometry

40. 40 Transition-State Models - Iron Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

41. 41 Transition-State Models - Copper Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083 DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546

42. 42Conclusions Versatile, scalable, cheap, powerful method Simplifies access to 1,4-dicarbonyl compounds even if yields are moderate Tolerant of complex functionality Will undoubtedly be used in industry Some limitations / work to do (WIP?) Quartenary centres difficult to access dr’s are quite low Rely on ‘dated’ auxilliary chemistry Can have only 1 enolizable center per partner Versatile, scalable, cheap, powerful method Simplifies access to 1,4-dicarbonyl compounds even if yields are moderate Tolerant of complex functionality Will undoubtedly be used in industry Some limitations / work to do (WIP?) Quartenary centres difficult to access dr’s are quite low Rely on ‘dated’ auxilliary chemistry Can have only 1 enolizable center per partner

43. 43 HAPPY HALLOWEEN!!!!