1. Applications in Natural Product Synthesis Ruthenium Catalyzed Olefin Metathesis Travis Schwantje Supervisor: Dr. Louis Barriault January 12, 2012

2. A Brief History Metathesis as a Synthetic Tool Recent Advances in Metathesis Methodology Outline 2

3. 1955 – Initial discovery by Ziegler 1971 – Mechanism postulated by Chauvin 1990 – Schrock describes the first well-defined Mo catalyst 1993 – Ru catalyst system proposed by Grubbs 2005 – Grubbs, Schrock and Chauvin share Nobel Prize An Abridged Timeline of Olefin Metathesis 3

4. Chauvin’s Mechanism Hérrison, J-L, Chauvin, Y. Makromol. Chem. 1970, 141, 161-176 4

5. A Brief History Metathesis as a Synthetic Tool Recent Advances in Metathesis Methodology Outline 5

6. [Ru] 6 Ring-Opening Metathesis Polymerization (ROMP) Acyclic Diene Metathesis (ADMET) Polymerization Ring-Closing Metathesis (RCM) Cross Metathesis (CM) Ene-Yne Metathesis Types of Metathesis

7. Common Metathesis Catalysts 7 Grubbs 1 st Generation Catalyst “Grubbs 1” Grubbs 2 nd Generation Catalyst “Grubbs 2” Hoveyda-Grubbs 2 nd Generation Catalyst “Hoveyda 2” Grubbs, R. J. Am. Chem. Soc. 1996, 118, 100 Grubbs, R. J. Am. Chem. Soc. 1999, 1, 953 Hoveyda, A. J. Am. Chem. Soc. 2000, 122, 8168 Blechert, S. Tet. Lett. 2000, 41, 9973

8. First reported in 1980 by Villemin and Tsuji Most common application of metathesis Dozens of reviews Ring Closing Metathesis 8 Villemin, D. Tet. Lett. 1980, 21, 1715 Tsuji, J. Tet. Lett. 1980, 21, 2955 R. Grubbs (Ed.) Handbook of Metathesis: Volume 2. 2003, Wiley-VCH Fogg, D. NATO. Scie. Peace.. Secu. 2010, 11, 129

9. Cyclopentenes Cyclohexenes Ring Closing Metathesis - Carbocycles 9 Hiersemann, M. Synlett. 2007, 1683 Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, 6199

10. Cycloheptenes Cyclooctenes Ring Closing Metathesis - Carbocycles 10 Tori, M. Bull. Chem. Soc. Jpn. 2006, 79, 1955 Prunet, J. Chem. Eur. J. 2008, 14, 7314

11. Cyclononenes Cyclodecenes Ring Closing Metathesis - Carbocycles Clark, J. S. Org. Biomol. Chem. 2008, 6, 4012 Barrett, A.G.M. J. Am. Chem. Soc. 2006, 128, 14042 11

12. Silicon Ring Closing Metathesis - Heterocycles Evans, P.A. J. Org. Chem. 1998, 63, 6768 Evans, P.A. J. Am. Chem. Soc. 2003, 125, 14702 12

13. Phosphorus Sulphur Ring Closing Metathesis - Heterocycles Hanson, P.R. Org. Lett. 2005, 7, 3375 Cossy, J. Tetrahedron 2006, 62, 9017 13

14. Sulphur Ring Closing Metathesis - Heterocycles 14 Cossy, J. Tetrahedron 2006, 62, 9017

15. Oxygen Ring Closing Metathesis - Heterocycles Fu, G. and Grubbs, R.; J. Am. Chem. Soc. 1992, 114, 5426 Rutjes, F. Synlett. 1998, 192 Grubbs, R. J. Org. Chem. 1998, 63, 864 15

16. Brevetoxin B –Neurotoxin isolated from Gymnodinium breve Davis –3 RCM steps –Longest linear sequence, 63 steps –108 steps total, 0.28% yield Ring Closing Metathesis - Heterocycles Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9246 16

17. Nitrogen Ring Closing Metathesis - Heterocycles Fu, G. and Grubbs, R. J. Am. Chem. Soc. 1992, 114, 7324 Grubbs, R. J. Am. Chem. Soc. 1995, 117, 5855 Van Maarseveen, J. Org. Lett. 2002, 4, 2673 Yields over 7 steps: n = 0: 15% n = 1: 42% n = 2: 33% n = 3: 34% n = 4: 37% 17

18. Nitrogen Ring Closing Metathesis - Heterocycles 18 Lebreton, J. J. Org. Chem. 2001, 66, 6305

19. Macrolides Ring Closing Metathesis - Macrocycles 19 Unreactive! Fürstner, A. J. Am. Chem. Soc. 1997, 119, 9130

20. Macrolides Ring Closing Metathesis - Macrocycles Fürstner, A. J. Am. Chem. Soc. 1997, 119, 9130 20

21. Peptidomimetics Ring Closing Metathesis - Macrocycles Reitz, A. Org. Lett. 2001, 3, 893 Grubbs, R. J. Am. Chem. Soc. 1996, 118, 9606 21

22. Selectivity is the key to controlling cross metathesis reactions –Regioselectivity of metathesis –Stereoselectivity of alkene formation Cross Metathesis (CM) 22

23. Regioselectivity in Cross-Metathesis How do I control this reaction? Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360 23

24. What does this mean? –Mixing identical types = statistical mixture –Mixing different types = selective CM Regioselectivity in Cross-Metathesis How do I control this reaction? Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360 24

25. E-selective –Steric bulk at allylic position Stereoselective CM Reactions Crowe, W. Tet. Lett. 1996, 37, 2117 Grubbs, R. et al. J. Am. Chem. Soc. 2000, 122, 58 25

26. E-selective –Electron-poor olefins Stereoselective CM Reactions Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783 26

27. E-selective –Electron-poor olefins Stereoselective CM Reactions Grubbs, R. Angew. Chem. Int. Ed. 2001, 40, 1277 Grubbs, R. Synlett. 2001, 1034 Grela, K. and Bieniek, M. Tet. Lett. 2001, 42, 6425 27

28. E-selective –Electron-poor olefins Stereoselective CM Reactions 28 Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451

29. E-selective –Electron-poor olefins Stereoselective CM Reactions 29 Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451

30. E-selective –Other useful functional groups Stereoselective CM Reactions Miyaura, N. Synlett. 2002, 128 Grubbs, R. Angew. Chem. Int. Ed. 2002, 41, 3172 Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783 Lautens, M. Angew. Chem. Int. Ed. 2000, 39, 4079 30

31. Z-selective Stereoselective CM Reactions Crowe, W. and Goldberg, D. J. Am. Chem. Soc. 1995, 117, 5162 Fuchs, P. J. Am. Chem. Soc. 2006, 128, 12656 31

32. Multiple metathesis reactions can be linked together Ring-Opening-Cross Metathesis (ROCM) Ring Rearrangement Metathesis (RRM) Relay Metathesis Cascade and Domino Metathesis 32

33. Ring-Opening-Cross Metathesis (ROCM) Blechert, S. Angew. Chem. Int. Ed. 1996, 35, 411 Snapper, M. J. Am. Chem. Soc. 1997, 119, 1478 33

34. Ring-Opening-Cross Metathesis (ROCM) Kozmin, S. J. Am. Chem. Soc. 2004, 126, 9546 34

35. Formally a ROM + RCM cascade Ring-Rearrangement Metathesis (RRM) Blechert, S. Tetrahedron 1999, 55, 8179 Phillips, A. Angew. Chem. Int Ed. 2008, 47, 8499 35

36. Recent discovery by multiple groups: –Hoye group (U. Minnesota) –Piscopio group (Array Biopharma) –Lee Group (U. Wisconsin-Madison) “Tricks” catalyst into binding to unreactive olefins Allows for high degree of control of catalyst reactivity Entropically favoured Relay Metathesis (RM) 36 Lee, D. Org. Lett. 2004, 6, 2035 Hoye, T. J. Am. Chem. Soc. 2004, 126, 10210

37. Relay-Ring Closing Metathesis (RRCM) 37 Hoye, T. Angew. Chem. Int. Ed. 2010, 49, 6151

38. Relay-Ring Closing Metathesis (RRCM) 38 Hoye, T. Angew. Chem. 2011, 123, 2189

39. A Brief History Metathesis as a Synthetic Tool Recent Advances in Metathesis Methodology Outline 39

40. Accelerating Metathesis Reactions New Conditions 40 AdditiveYield None57% CuI98% Lipshutz, B. J. Org. Chem. 2011, 76,4697 AdditiveConversion None30% CuI64%

41. Metathesis Reactions in Water? –Special catalysts required historically Another discovery by the Lipshutz group: New Conditions 41 Grubbs, R. J. Org. Chem. 1998,63, 9904 Lipshutz, B. J. Org. Chem. 2011, 76,4379

42. Metathesis Reactions in Water? –Special catalysts required historically Another discovery by the Lipshutz group: New Conditions 42 Grubbs, R. J. Org. Chem. 1998,63, 9904 Lipshutz, B. J. Org. Chem. 2011, 76,4379 Lipshutz, B. J. Org. Chem. 2011, 76,4697 “TPGS-750M” 2% wt. solution – 100mL for $74.10 (Aldrich)

43. Chiral Metathesis Catalysts –Several forms of chiral catalysts exist –Chiral NHC’s are popular among Ru catalysts New Catalysts 43 Hoveyda, A. J. Am. Chem. Soc. 2002, 124, 4954 Collins, S. Organometallics 2007, 26, 2945 Blechert, S. Angew. Chem. Int. Ed. 2011, 50, 3299

44. First Z-selective Metathesis Catalyst –Effective in CM of alkenes, enol ethers, ROCM Grubbs Z-selective Ru Catalyst –Highly reactive (<1 mol% loadings) –Adamantyl group critical for Z selectivity New Catalysts 44 Hoveyda, A and Schrock, R. Nature 2011, 471, 461 Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525 Grubbs, R. J. Am. Chem. Soc. 2011 ASAP

45. New Catalysts 45 Hoveyda, A and Schrock, R. Nature 2011, 471, 461 Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525 Grubbs, R. J. Am. Chem. Soc. 2011 ASAP

46. New Catalysts 46 Hoveyda, A and Schrock, R. Nature 2011, 471, 461 Grubbs, R. J. Am. Chem. Soc. 2012 (Accepted January 9, 2012)  E ≈ 4 kcal/mol

47. Barriault Group –Daniel Newbury –Boubacar Sow –Gabriel Bellavance –Phillipe McGee –Francis Barabé –Mathieu Morin –Joel Marcotte –David Lapointe –Guillaume Revol –Patrick Levesque –Jason Poulin –Stephanie Lanoix –Geneviève Bétournay –Louis Barriault Acknowledgements 47