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

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

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

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

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

[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

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

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 , Wiley-VCH Fogg, D. NATO. Scie. Peace.. Secu. 2010, 11, 129

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

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

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,

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

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

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

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,

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,

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

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

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

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

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

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

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

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,

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

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

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,

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

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

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,

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,

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

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

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

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

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

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

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

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

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

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

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)

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

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 ASAP

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 ASAP

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

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