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
2
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
3
Chauvin’s Mechanism
4
Hérrison, J-L, Chauvin, Y. Makromol. Chem. 1970, 141, 161-176
Outline
• A Brief History
• Metathesis as a Synthetic Tool
• Recent Advances in Metathesis Methodology
5
Types of Metathesis
Acyclic Diene Metathesis
(ADMET)
Polymerization
Ring-Opening Metathesis
Polymerization (ROMP)
Ene-Yne Metathesis
[Ru]
Ring-Closing Metathesis
(RCM)
Cross Metathesis
(CM)
6
Common Metathesis Catalysts
Grubbs 1st Generation
Catalyst
“Grubbs 1”
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
Grubbs 2nd Generation
Catalyst
“Grubbs 2”
Hoveyda-Grubbs
2nd Generation Catalyst
“Hoveyda 2”
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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
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Ring Closing Metathesis - Carbocycles
• Cyclopentenes
• Cyclohexenes
Hiersemann, M. Synlett. 2007, 1683
Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, 6199
9
Ring Closing Metathesis - Carbocycles
• Cycloheptenes
• Cyclooctenes
Tori, M. Bull. Chem. Soc. Jpn. 2006, 79, 1955
Prunet, J. Chem. Eur. J. 2008, 14, 7314
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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
11
Ring Closing Metathesis - Heterocycles
• Silicon
12
Evans, P.A. J. Org. Chem. 1998, 63, 6768
Evans, P.A. J. Am. Chem. Soc. 2003, 125, 14702
Ring Closing Metathesis - Heterocycles
• Phosphorus
• Sulphur
Hanson, P.R. Org. Lett. 2005, 7, 3375
Cossy, J. Tetrahedron 2006, 62, 9017
13
Ring Closing Metathesis - Heterocycles
• Sulphur
14
Cossy, J. Tetrahedron 2006, 62, 9017
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
15
Ring Closing Metathesis - Heterocycles
• Nitrogen
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
Ring Closing Metathesis - Macrocycles
• Peptidomimetics
21
Reitz, A. Org. Lett. 2001, 3, 893
Grubbs, R. J. Am. Chem. Soc. 1996, 118, 9606
Cross Metathesis (CM)
• Selectivity is the key to controlling cross metathesis reactions
– Regioselectivity of metathesis
– Stereoselectivity of alkene formation
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Regioselectivity in Cross-Metathesis
How do I control this reaction?
For 2nd gen [Ru]:
Type I
Type II
Type III
Type IV
Homodimerization
Fast
Slow
None
None
Homodimers
consumable?
Yes
Somewhat
N/A
N/A
Reactivity
High
Medium
Low
None
Example
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Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360
Regioselectivity in Cross-Metathesis
How do I control this reaction?
• What does this mean?
– Mixing identical types = statistical mixture
– Mixing different types = selective CM
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Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360
Stereoselective CM Reactions
• E-selective
– Steric bulk at allylic position
25
Crowe, W. Tet. Lett. 1996, 37, 2117
Grubbs, R. et al. J. Am. Chem. Soc. 2000, 122, 58
Stereoselective CM Reactions
• E-selective
– Electron-poor olefins
26
Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783
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
27
Stereoselective CM Reactions
• E-selective
– Electron-poor olefins
28
Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451
Stereoselective CM Reactions
• E-selective
– Electron-poor olefins
29
Bouzbouz, S. and Cossy, J. Org. Lett. 2001, 3, 1451
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
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Stereoselective CM Reactions
• Z-selective
31
Crowe, W. and Goldberg, D. J. Am. Chem. Soc. 1995, 117, 5162
Fuchs, P. J. Am. Chem. Soc. 2006, 128, 12656
Cascade and Domino Metathesis
• Multiple metathesis reactions can be linked together
• Ring-Opening-Cross Metathesis (ROCM)
• Ring Rearrangement Metathesis (RRM)
• Relay Metathesis
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Ring-Opening-Cross Metathesis (ROCM)
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Blechert, S. Angew. Chem. Int. Ed. 1996, 35, 411
Snapper, M. J. Am. Chem. Soc. 1997, 119, 1478
Ring-Opening-Cross Metathesis (ROCM)
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Kozmin, S. J. Am. Chem. Soc. 2004, 126, 9546
Ring-Rearrangement Metathesis (RRM)
• Formally a ROM + RCM cascade
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Blechert, S. Tetrahedron 1999, 55, 8179
Phillips, A. Angew. Chem. Int Ed. 2008, 47, 8499
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
36
Lee, D. Org. Lett. 2004, 6, 2035
Hoye, T. J. Am. Chem. Soc. 2004, 126, 10210
Relay-Ring Closing Metathesis (RRCM)
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Hoye, T. Angew. Chem. Int. Ed. 2010, 49, 6151
Relay-Ring Closing Metathesis (RRCM)
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Hoye, T. Angew. Chem. 2011, 123, 2189
Outline
• A Brief History
• Metathesis as a Synthetic Tool
• Recent Advances in Metathesis Methodology
39
New Conditions
• Accelerating Metathesis Reactions
Additive
Yield
None
57%
CuI
98%
Additive
Conversion
None
30%
CuI
64%
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Lipshutz, B. J. Org. Chem. 2011, 76,4697
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
41
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
42
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
43
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
44
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
45
New Catalysts
DE ≈ 4 kcal/mol
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Hoveyda, A and Schrock, R. Nature 2011, 471, 461
Grubbs, R. J. Am. Chem. Soc. 2012 (Accepted January 9, 2012)
Acknowledgements
• Barriault Group
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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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