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Ruthenium Catalyzed Olefin Metathesis

Ruthenium Catalyzed Olefin Metathesis. Applications in Natural Product Synthesis. Travis Schwantje Supervisor: Dr. Louis Barriault January 12, 2012. Outline. A Brief History Metathesis as a Synthetic Tool Recent Advances in Metathesis Methodology.

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Ruthenium Catalyzed Olefin Metathesis

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

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

  3. An Abridged Timeline of Olefin Metathesis • 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

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

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

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

  7. Common Metathesis Catalysts Grubbs 2nd Generation Catalyst “Grubbs 2” Grubbs 1stGeneration Catalyst “Grubbs 1” Hoveyda-Grubbs 2nd 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. Ring Closing Metathesis • First reported in 1980 by Villemin and Tsuji • Most common application of metathesis • Dozens of reviews 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. Ring Closing Metathesis - Carbocycles • Cyclopentenes • Cyclohexenes Hiersemann, M. Synlett. 2007,1683 Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, 6199

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

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

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

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

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

  15. Ring Closing Metathesis - Heterocycles • Oxygen 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

  16. Ring Closing Metathesis - Heterocycles • Nitrogen Yields over 7 steps: n = 0: 15% n = 1: 42% n = 2: 33% n = 3: 34% n = 4: 37% 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

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

  18. Cross Metathesis (CM) • Selectivity is the key to controlling cross metathesis reactions • Regioselectivityof metathesis • Stereoselectivity of alkene formation

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

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

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

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

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

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

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

  26. Stereoselective CM Reactions • E-selective • Other useful functional groups 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

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

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

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

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

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

  32. Relay Metathesis (RM) • 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 Lee, D. Org. Lett. 2004, 6, 2035 Hoye, T. J. Am. Chem. Soc. 2004, 126, 10210

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

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

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

  36. New Conditions • Accelerating Metathesis Reactions Lipshutz, B. J. Org. Chem. 2011, 76,4697

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

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

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

  40. New Catalysts • 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 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

  41. New Catalysts 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

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

  43. Acknowledgements • 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

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