Ruthenium Catalyzed Olefin Metathesis

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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 MetathesisApplications in Natural Product SynthesisTravis SchwantjeSupervisor: Dr. Louis BarriaultJanuary 12, 2012Outline
  • A Brief History
  • Metathesis as a Synthetic Tool
  • Recent Advances in Metathesis Methodology
  • 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
  • Chauvin’s MechanismHérrison, J-L, Chauvin, Y. Makromol. Chem. 1970, 141, 161-176Outline
  • A Brief History
  • Metathesis as a Synthetic Tool
  • Recent Advances in Metathesis Methodology
  • [Ru]Types of MetathesisAcyclic Diene Metathesis(ADMET) PolymerizationRing-Opening MetathesisPolymerization (ROMP)Ring-Closing Metathesis(RCM)Cross Metathesis(CM)Ene-Yne MetathesisCommon Metathesis CatalystsGrubbs 2nd GenerationCatalyst“Grubbs 2”Grubbs 1stGenerationCatalyst“Grubbs 1”Hoveyda-Grubbs2nd Generation Catalyst“Hoveyda 2”Grubbs, R. J. Am. Chem. Soc. 1996, 118, 100Grubbs, R. J. Am. Chem. Soc. 1999, 1, 953Hoveyda, A. J. Am. Chem. Soc. 2000, 122, 8168Blechert, S. Tet. Lett. 2000, 41, 9973Ring Closing Metathesis
  • First reported in 1980 by Villemin and Tsuji
  • Most common application of metathesis
  • Dozens of reviews
  • Villemin, D. Tet. Lett. 1980, 21, 1715Tsuji, J. Tet. Lett. 1980, 21, 2955R. Grubbs (Ed.) Handbook of Metathesis: Volume 2. 2003, Wiley-VCHFogg, D. NATO. Scie. Peace.. Secu. 2010,11, 129Ring Closing Metathesis - Carbocycles
  • Cyclopentenes
  • Cyclohexenes
  • Hiersemann, M. Synlett. 2007,1683Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, 6199Ring Closing Metathesis - Carbocycles
  • Cycloheptenes
  • Cyclooctenes
  • Tori, M. Bull. Chem. Soc. Jpn. 2006, 79, 1955Prunet, J. Chem. Eur. J. 2008, 14, 7314Ring Closing Metathesis - Carbocycles
  • Cyclononenes
  • Cyclodecenes
  • Clark, J. S. Org. Biomol. Chem. 2008, 6, 4012Barrett, A.G.M. J. Am. Chem. Soc. 2006, 128, 14042Ring Closing Metathesis - Heterocycles
  • Silicon
  • Evans, P.A. J. Org. Chem. 1998, 63, 6768Evans, P.A. J. Am. Chem. Soc. 2003, 125, 14702Ring Closing Metathesis - Heterocycles
  • Phosphorus
  • Sulphur
  • Hanson, P.R. Org. Lett. 2005, 7, 3375Cossy, J. Tetrahedron 2006, 62,9017Ring Closing Metathesis - Heterocycles
  • Sulphur
  • Cossy, J. Tetrahedron 2006, 62, 9017Ring Closing Metathesis - Heterocycles
  • Oxygen
  • Fu, G. and Grubbs, R.; J. Am. Chem. Soc. 1992, 114, 5426Rutjes, F. Synlett. 1998, 192Grubbs, R. J. Org. Chem. 1998, 63, 864Ring 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, 7324Grubbs, R. J. Am. Chem. Soc. 1995, 117, 5855Van Maarseveen, J. Org. Lett. 2002, 4, 2673Ring Closing Metathesis - Macrocycles
  • Peptidomimetics
  • Reitz, A. Org. Lett. 2001, 3, 893Grubbs, R. J. Am. Chem. Soc. 1996, 118, 9606Cross Metathesis (CM)
  • Selectivity is the key to controlling cross metathesis reactions
  • Regioselectivityof metathesis
  • Stereoselectivity of alkene formation
  • Regioselectivity in Cross-MetathesisHow do I control this reaction?Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360Regioselectivity 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, 11360Stereoselective CM Reactions
  • E-selective
  • Steric bulk at allylic position
  • Crowe, W. Tet. Lett. 1996, 37, 2117Grubbs, R. et al. J. Am. Chem. Soc. 2000, 122, 58Stereoselective CM Reactions
  • E-selective
  • Electron-poor olefins
  • Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783Stereoselective CM Reactions
  • E-selective
  • Electron-poor olefins
  • Grubbs, R. Angew. Chem. Int. Ed. 2001, 40, 1277Grubbs, R. Synlett. 2001, 1034Grela, K. and Bieniek, M. Tet. Lett. 2001, 42, 6425Stereoselective CM Reactions
  • E-selective
  • Electron-poor olefins
  • Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451Stereoselective CM Reactions
  • E-selective
  • Electron-poor olefins
  • Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451Stereoselective CM Reactions
  • E-selective
  • Other useful functional groups
  • Miyaura, N. Synlett. 2002, 128Grubbs, R. Angew. Chem. Int. Ed. 2002, 41, 3172Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783Lautens, M. Angew. Chem. Int. Ed. 2000, 39, 4079Stereoselective CM Reactions
  • Z-selective
  • Crowe, W. and Goldberg, D. J. Am. Chem. Soc. 1995, 117, 5162Fuchs, P. J. Am. Chem. Soc. 2006, 128, 12656Cascade and Domino Metathesis
  • Multiple metathesis reactions can be linked together
  • Ring-Opening-Cross Metathesis (ROCM)
  • Ring Rearrangement Metathesis (RRM)
  • Relay Metathesis
  • Ring-Opening-Cross Metathesis (ROCM)Blechert, S. Angew. Chem. Int. Ed. 1996, 35, 411Snapper, M. J. Am. Chem. Soc. 1997, 119, 1478Ring-Opening-Cross Metathesis (ROCM)Kozmin, S. J. Am. Chem. Soc. 2004, 126, 9546Ring-Rearrangement Metathesis (RRM)
  • Formally a ROM + RCM cascade
  • Blechert, S. Tetrahedron 1999, 55, 8179Phillips, A. Angew. Chem. Int Ed. 2008, 47, 8499Relay 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, 2035Hoye, T. J. Am. Chem. Soc. 2004, 126, 10210Relay-Ring Closing Metathesis (RRCM)Hoye, T. Angew. Chem. Int. Ed. 2010, 49, 6151Relay-Ring Closing Metathesis (RRCM)Hoye, T. Angew. Chem. 2011, 123, 2189Outline
  • A Brief History
  • Metathesis as a Synthetic Tool
  • Recent Advances in Metathesis Methodology
  • New Conditions
  • Accelerating Metathesis Reactions
  • Lipshutz, B. J. Org. Chem. 2011, 76,4697New Conditions
  • Metathesis Reactions in Water?
  • Special catalysts required historically
  • Another discovery by the Lipshutz group:
  • Grubbs, R. J. Org. Chem. 1998,63, 9904Lipshutz, B. J. Org. Chem. 2011,76,4379New 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, 9904Lipshutz, B. J. Org. Chem. 2011,76,4379Lipshutz, B. J. Org. Chem. 2011,76,4697New 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, 4954Collins, S. Organometallics 2007, 26, 2945Blechert, S. Angew. Chem. Int. Ed. 2011, 50, 3299New 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, 461Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525Grubbs, R. J. Am. Chem. Soc. 2011 ASAPNew CatalystsHoveyda, A and Schrock, R. Nature 2011, 471, 461Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525Grubbs, R. J. Am. Chem. Soc. 2011 ASAPNew CatalystsDE ≈ 4 kcal/molHoveyda, A and Schrock, R. Nature 2011, 471, 461Grubbs, R. J. Am. Chem. Soc. 2012(Accepted January 9, 2012)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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