Diapositive 1

1
Asymmetric Olefin Metathesis
October 4th, 2004
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First proposed by Chauvin Herrison, J. L.
Chauvin, Y. Makromol. Chem. 1970, 141, 161. and
later expanded upon by Katz Katz, T. J.
McGinnis, J. L. J. Am. Chem. Soc. 1975, 97, 1592.
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Propaganda...?
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Retrosynthesis
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Asymmetric Metathesis?
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Outline.

1. Development of Metathesis Catalysts and the Jump
   to Asymmetry
2. Typical Reactions of Asymmetric Metathesis.
3. First Asymmetric Metathesis by Grubbs and
   Fujimura.
4. Mo- (and W-) based Catalysts Scope and
   Reactivity
5. Ru-based Catalysts Scope and Reactivity
6. General Conclusions and Future Outlook

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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Schrocks Catalyst.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. SynAnti Alkylidenes in
Mo-Catalysts.
Angle is approx. 180o because of donation of N
lone pair into a d-orbital of Mo.
Syn - isomer is more stable because of an agostic
interaction between the C-H bond of the
alkylidene and the metal center.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. The Chemistry of Schrocks
Catalyst Decomposition.
Catalyst is highly susceptible to intermolecular
decomposition pathways.
10
1. Development of Metathesis Catalysts and the
Jump to Asymmetry. The Chemistry of Schrocks
Catalyst Decomposition.
Bulky imido ligands function to limit
intermolecular decomposition of the catalyst
1. Alkoxide can vary greatly but must be large
and bulky enough to limit intermolecular
decomposition.
2. Electron withdrawing alkoxides also influence
the alkylidene geometry.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. The Chemistry of Schrocks
Catalyst Polymerization.
Polymerization (22 oC, PhMe) of NBDF6
Polymer with high cis content ( 95 ).
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. The Chemistry of Schrocks
Catalyst Polymerization.
Polymerization (22 oC, PhMe) of NBDF6
Polymer with high cis content ( 95 ).
Polymerization (22 oC, PhMe) of NBDF6
Polymer with high trans content ( 99 ).
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. SynAnti Alkylidenes in
Mo-Catalysts.
Electron withdrawing groups strengthen the
pseudo-triple bond between the imido ligand and
the metal center.
Syn - isomer is more stable because of an agostic
interaction between the C-H bond of the
alkylidene and the metal center.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. SynAnti Alkylidenes in
Mo-Catalysts.
In turn, this hinders rotation about the
alkylidene.
Electron withdrawing groups strengthen the
pseudo-triple bond between the imido ligand and
the metal center.
Consequently, the anti-isomer is estimated to be
105 times more reactive towards NBDF6 than the
syn-isomer.
Syn - isomer is more stable because of an agostic
interaction between the C-H bond of the
alkylidene and the metal center.
15
1. Development of Metathesis Catalysts and the
Jump to Asymmetry. The Chemistry of Schrocks
Catalyst Polymerization.
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Polymerization (22 oC, PhMe) of NBDF6
Polymer with high cis content ( 95 ).
Electron withdrawing groups (including phenols)
slow rotation enough that syn-isomer is the only
one available for reaction!
Polymer with high trans content ( 99 ).
Electron rich groups (alkyls) speed up rotation
enough to compete with polymerization, hence the
anti is the reacting isomer!
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Alkylidene Geometry is
Essential for Asymmetric Induction.
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Approach from the si face
Approach from the re face
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Alkylidene Geometry is
Essential for Asymmetric Induction.
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Approach from the si face
Approach from the re face
Approach from the re face
Lets imagine that in a chiral environment,
attack from the front face is favoured.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Alkylidene Geometry is
Essential for Asymmetric Induction.
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Approach from the si face
Approach from the re face
Approach from the re face
Approach from the si face
Lets imagine that in a chiral environment,
attack from the front face is favoured.
The result would be a racemic product!
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Whats The Point?
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Last line
Catalysts such as these could selectively
polymerize or ring-close one enantiomer in a
racemic mixture.
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1. Development of Metathesis Catalysts and the
Jump to Asymmetry. Whats The Point?
McConville, D. H. Wolf, J. R. Schrock, R.R. J.
Am. Chem. Soc. 1993, 115, 4413 4414.
Last line
Catalysts such as these could selectively
polymerize or ring-close one enantiomer in a
racemic mixture.
Historically Speaking
Fu, G. C. Grubbs, R. H. J. Am. Chem. Soc. 1992,
114, 7324-5.
Grubbs and Fu demonstrate first RCM of nitrogen
containing rings using Schrocks catalyst
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Grubbs Catalysts.
Grubbs 1st Generation Catalyst
Grubbs 2nd Generation Catalyst
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2. Typical Reactions of Asymmetric Metathesis. A.
Kinetic Resolution.
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Grubbs First Attempt...
22 ee
26 ee
2.0 mol , 0 oC or 20 oC, 20 min., toluene
26 ee
15 ee
For di-substituted olefins, no kinetic resolution
was observed due to faster ring closing versus
tri-substituted olefins.
Fujimura, O. Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 2499.
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Grubbs First Attempt...
R
22 ee
26 ee
2.0 mol , 0 oC or 20 oC, 20 min., toluene
S
26 ee
15 ee
For di-substituted olefins, no kinetic resolution
was observed due to faster ring closing versus
tri-substituted olefins.
Fujimura, O. Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 2499.
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Proposed Reaction Models.
R - enantiomer favoured for 5-membered rings.
S - enantiomer favoured for 6-membered rings.
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Grubbs First Attempt...
Fujimura, O. Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 2499.
22 ee
26 ee
2.0 mol , 0 oC or 20 oC, 20 min., toluene
Historically Speaking
Langemann, K. Furstner, A. J. Org. Chem. 1996,
61, 3942.
Langemann and Furstner demonstrate first
macrocyclic RCM using Ru-based catalysts
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3. First Asymmetric Metathesis by Grubbs and
Fujimura. Grubbs Second Attempt...
Change in ligand structure led to a decrease in
the efficiency of the kinetic resolution.
First example of a desymmetrization of trienes.
Fujimura, O. Grubbs, R. H. J. Org. Chem. 1998,
63, 824-832.
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2. Typical Reactions of Asymmetric Metathesis.
C. Desymmetrization of Trienes.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts.
Grubbs-Hoveyda Catalyst
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts.
Good selectivity for 5-membered rings. Highly
substrate dependent.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts.
Good selectivity for 5-membered rings. Highly
substrate dependent.
6-Membered rings are still a problem.
Alexander, J. B. La, D. S. Cefalo, D. R.
Hoveyda, A. H. Schrock, R. R. J. Am. Chem. Soc.
1998, 120, 4041-4042.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Desymmetrization of Trienes.
Some good selectivities but
substituted olefins still necessary.
La, D. S. Alexander, J. B. Cefalo, D. R. Graf,
D. D. Hoveyda, A. H. Schrock, R. R. J. Am.
Chem. Soc. 1998, 120, 9720-9721.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts Tandem
AROM/RCM.
Some good selectivities.
Weatherhead, G. S. Ford, J. G. Alexanian, E.
J. Schrock, R. R. Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 1828-1829.
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2. Typical Reactions of Asymmetric Metathesis.
B. AROM/CM (Asymmetric Ring-Opening
Metathesis/Cross Metathesis).
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2. Typical Reactions of Asymmetric Metathesis.
B. AROM/CM (Asymmetric Ring-Opening
Metathesis/Cross Metathesis).
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts AROM/RCM Towards
Cyclopentenes.
Some good selectivities
La, D. S. Sattely, E. S. Ford, J. G. Schrock,
R. R. Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 7767-7778.
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2. Typical Reactions of Asymmetric Metathesis.
B. AROM/CM (Asymmetric Ring-Opening
Metathesis/Cross Metathesis).
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts AROM/RCM Towards
Cyclopentenes.
Some good selectivities
...only styrene used as olefin, and
...but some unexplained failures as well
La, D. S. Sattely, E. S. Ford, J. G. Schrock,
R. R. Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 7767-7778.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Mo-Catalysts in AROM/RCM Olefins
Other Than Styrene.
Weatherhead, G. S. Ford, J. G. Alexanian, E.
J. Schrock, R. R. Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 1828-1829.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts Cyclic Amines
and Medium Rings.
Some good selectivities.
...but unsubstituted olefins still a problem.
Dolman, S. J. Sattely, E. S. Hoveyda, A. H.
Schrock, R. R. J. Am. Chem. Soc. 2002, 124,
6991-6997.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts Synthesis of
Tertiary Ethers and Medium Rings.
Kiely A. F. Jernelius J. A. Schrock R. R.
Hoveyda A. H. J. Am. Chem. Soc. 2002, 124,
2868-9.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Desymmetrization of Trienes and an Application to
Natural Product Synthesis
Burke, S. D. Mueller, N. Beaudry, C. M. Org.
Lett. 1999, 1, 1827-1829.
55 59 ee
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts Imido
Ligand Modification.
Weatherhead, G. S. Houser, J. H. Ford, J. G.
Jamieson, J. Y. Schrock, R. R. Hoveyda, A. H.
Tetrahedron Lett. 2000, 41, 9553-9559.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts Ligand
Modification.
Zhu, S. S. Cefalo, D. R. La, D. S. Jamieson,
J. Y. Davis, W. M. Hoveyda, A. H. Schrock, R.
R. J. Am. Chem. Soc. 1999, 121, 8251-8259.
High ees observed for forming 6-membered rings
by kinetic resolution and...
in desymmetrization of trienes.
Interestingly, the previous developed catalyst
still exhibits significantly better selectivity
in reactions forming 5-membered rings.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts RCM of Boronates.
Example that compares asymmeric metathesis to the
Noyori asymmetric reduction of b-ketoesters.
Jernelius, J. A. Schrock, R. R. Hoveyda, A. H.
Tetrahedron, 2004, 60, 7345 7351.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts Desymmetrization
of Dienes via Inter-molecular CM.
Jernelius, J. A. Schrock, R. R. Hoveyda, A. H.
Tetrahedron, 2004, 60, 7345 7351.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts Ligand
Modification.
Cefalo, D. R. Kiely, A. F. Wuchrer, M.
Jamieson, J. Y. Schrock, R. R. Hoveyda, A. H.
J. Am. Chem. Soc. 2001, 123, 3139-3140.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts Cyclic Secondary
Amines.
Important compounds for medicinal chemistry.
Sterically more accessible nitrogen can
deactivate catalysts through binding.
NH bonds cleave Mo-O bonds of chiral ligands
through protonation.
Dolman, S. J. Schrock, R. R. Hoveyda, A. H.
Org. Lett. 2003, 5, 4899-4902.  
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Mo-Catalysts Cyclic Secondary
Amines.
Authors do not describe WHY these particular
catalysts solve the problems associated with
secondary amines?
Puzzling substrate dependence??
Dolman, S. J. Schrock, R. R. Hoveyda, A. H.
Org. Lett. 2003, 5, 4899-4902.  
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts The THF
Effect?
THF only binds to syn-alkylidenes at reaction
temperatures and Et2O is ineffective as an
additive.
Less Lewis-acidic catalysts do not exhibit the
THF effect, meaning it is unique to these
catalysts.
Teng, X. Cefalo, D. R. Schrock, R. R. Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 10779-10784.
For crystal structures of THF adducts see
Schrock, R. R. Jamieson, J. Y. Dolman, S. J.
Miller, S. A. Bonitatebus, P. J., Jr. Hoveyda,
A. H. Organometallics 2002, 21, 409-417.
52
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts The THF
Effect?
THF only binds to syn-alkylidenes at reaction
temperatures and Et2O is ineffective as an
additive.
Less Lewis-acidic catalysts do not exhibit the
THF effect, meaning it is unique to these
catalysts.
Adding 2,5-Dimethyl-THF in place of THF slows the
reaction AND lowers the ee of the product! (10
eq., lt 10 conv. _at_ 24 h, 27 ee.)
Hoveyda et al. theorize that bulky
2,5-dimethyl-THF may inhibit substrate bonding
but they cannot prove it and cannot explain the
drop in selectivity.
Teng, X. Cefalo, D. R. Schrock, R. R. Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 10779-10784.
For crystal structures of THF adducts see
Schrock, R. R. Jamieson, J. Y. Dolman, S. J.
Miller, S. A. Bonitatebus, P. J., Jr. Hoveyda,
A. H. Organometallics 2002, 21, 409-417.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts The THF
Effect?
BE WARNED! Adding THF does not always lead to an
increase in enantioselectivity. The THF effect
is NOT general and should be screened on a case
by case basis.
Teng, X. Cefalo, D. R. Schrock, R. R. Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 10779-10784.
For crystal structures of THF adducts see
Schrock, R. R. Jamieson, J. Y. Dolman, S. J.
Miller, S. A. Bonitatebus, P. J., Jr. Hoveyda,
A. H. Organometallics 2002, 21, 409-417.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Adamantyl-Mo Catalysts.
In contrast to arylimido catalysts..
Catalyst is solvent free and THF does not bind to
the catalyst above -60 oC. No anti-alkylidene
signals are observed in the presence of electron
donating ligands (eg. THF) that are normally
observed (albeit minimumly) for arylimido
complexes. Hoveyda and co-workers claim that the
smaller adamantyl unit is farther away from the
alkylidene and this causes the Lewis acidity of
the metal to decrease. Identical functional
group tolerance as previous catalysts.
Tsang, W. C. P. Jernelius, J. A. Cortez, G. A.
Weatherhead, G. S. Schrock, R. R. Hoveyda, A.
H. J. Am. Chem. Soc. 2003, 125, 2591-2596.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Adamantyl-Mo Catalysts.
Arylimido catalysts deliver low yields, low
selectivities (ees and cis/trans ratios) and
significant levels of by-products.
Tsang, W. C. P. Jernelius, J. A. Cortez, G. A.
Weatherhead, G. S. Schrock, R. R. Hoveyda, A.
H. J. Am. Chem. Soc. 2003, 125, 2591-2596.
56
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Adamantyl-Mo Catalysts.
Arylimido catalysts deliver low yields, low
selectivities (ees and cis/trans ratios) and
significant levels of by-products.
Arylimido catalysts deliver the meso-15 as the
predominant product.
Tsang, W. C. P. Jernelius, J. A. Cortez, G. A.
Weatherhead, G. S. Schrock, R. R. Hoveyda, A.
H. J. Am. Chem. Soc. 2003, 125, 2591-2596.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts User
Friendly Synthesis.
The Mo precursor is stable to air and moisture
and is commercially available from Strem
Chemicals. The Postassium salt can be generated
in-situ and added to the Mo species. The
resulting THF solution is stable for weeks.
Aeilts, S. L. Cefalo, D. R. Bonitatebus, P. J.,
Jr. Houser, J. H. Hoveyda, A. H. Schrock, R.
R. Angew. Chem. 2001, 40, 1452-1456.
58
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts User
Friendly Synthesis.
Original catalyst still gives higher
selctivities in some cases.
For more information of the alteration of chiral
backbone see (a) Tsang, W. C. P. Schrock, R.
R. Hoveyda, A. H. Organometallics 2001, 20,
5658-5669. (b) Hultzsch, K. C. Bonitatebus, P.
J., Jr. Jernelius, J. Schrock, R. R. Hoveyda,
A. H. Organometallics 2001, 20, 4705-4712.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts First
Polymer Supported Variant.
Hultzsch, K. C. Jernelius, J. A. Hoveyda, A.
H. Schrock, R. R. Angew. Chem. 2002, 41,
589-593.
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4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts First
Polymer Supported Variant.
Colour difference for free catalyst reactions
(left) and polymer supported variants (right).
After 3 cycles catalysts showed consistent ees,
good conversions and less than 5 of Mo was
found contaminating crude product mixtures
(compared to greater than 15 for free catalyst.
Hultzsch, K. C. Jernelius, J. A. Hoveyda, A.
H. Schrock, R. R. Angew. Chem. 2002, 41,
589-593.
61
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Polystyrene Supported Variant.
Dolman, S. J. Hultzsch, K. C. Pezet, F. Teng,
X. Hoveyda, A. H. Schrock, R. R. J. Am. Chem.
Soc. 2004, 126, ASAP.
62
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Polystyrene Supported Variant.
Dolman, S. J. Hultzsch, K. C. Pezet, F. Teng,
X. Hoveyda, A. H. Schrock, R. R. J. Am. Chem.
Soc. 2004, 126, ASAP.
63
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Crossed-Linked Norbornene Derived Polymer Support.
Dolman, S. J. Hultzsch, K. C. Pezet, F. Teng,
X. Hoveyda, A. H. Schrock, R. R. J. Am. Chem.
Soc. 2004, 126, ASAP.
64
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Chiral Biphen-Mo Catalysts
Polystyrene Supported Variant.
Less 1 of Mo-quantity used remains in crude
product.
Dolman, S. J. Hultzsch, K. C. Pezet, F. Teng,
X. Hoveyda, A. H. Schrock, R. R. J. Am. Chem.
Soc. 2004, 126, ASAP.
65
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Is W-Catalyzed (Asymmetric)
Metathesis Possible?
THF does not bind strongly but complex normally
isolated as a THF adduct. THF freely
disassoiates at rt in solution. Syn-alkylidene
still favoured.
Good selectivity reported, especially with
6-membered rings!
In general higher reaction temps are needed.
Tsang, W. C. P. Hultzsch, K. C. Alexander, J.
B. Bonitatebus, P. J., Jr. Schrock, R. R.
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
2652-2666.
66
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Is W-Catalyzed (Asymmetric)
Metathesis Possible?
1H NMR captured the generation (in the presence
of ethylene) of various metallocyclobutanes
intermediates. These tungstacyclobutanes are
the resting states of the catalyst.
Initial metallocycle the least stable due to the
combined steric repulsion of the a-substituents.
The product-W complex is stable up to 90 oC.
Tsang, W. C. P. Hultzsch, K. C. Alexander, J.
B. Bonitatebus, P. J., Jr. Schrock, R. R.
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
2652-2666.
67
4. Mo- (and W-) based Catalysts Scope and
Reactivity. Is W-Catalyzed (Asymmetric)
Metathesis Possible?
1H NMR captured the generation (in the presence
of ethylene) of various metallocyclobutanes
intermediates. These tungstacyclobutanes are
the resting states of the catalyst.
Metathesis is possible, but the higher
temperatures needed are to expel ethylene and
restart the catalytic cycle.
Initial metallocycle the least stable due to the
combined steric repulsion of the a-substituents.
The product-W complex is stable up to 90 oC.
Tsang, W. C. P. Hultzsch, K. C. Alexander, J.
B. Bonitatebus, P. J., Jr. Schrock, R. R.
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
2652-2666.
68
4. Mo- (and W-) based Catalysts Scope and
Reactivity. General Comments on Mo-Catalysts.

1. Can be quite effective for a number of
   transformations but it seems best to screen a
   number of catalysts.
2. Reactions normally carried out in C6H6 at 21 oC
   or around 50 oC in some rare cases.
3. Several pre-catalysts are available from Strem.
4. Substrate scope and functional group tolerance
   are similar to those of Schrocks achiral
   catalyst.
5. Typically require rigorous exclusion of air and
   moisture (H2O and O2).
6. Generally good for 5-membered ring formation
   although some catalysts have been developed for
   six membered rings. Some new catalysts show
   potential for activity that bridges both
   substrate classes.
7. Ligands influence stereoselectivity as well and
   alkylidene geometry.
8. The THF effect is variable and should be screened
   for as well.

69
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst.
Generally poor enantioselectivities.
NaI additive increases enantioselectivity ?
Seiders, T. J. Ward, D. W. Grubbs, R H. Org.
Lett. 2001, 3, 3225-3228.
70
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst
Explaining the Stereoselectivity.
Seiders, T. J. Ward, D. W. Grubbs, R H. Org.
Lett. 2001, 3, 3225-3228.
71
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst.
Seiders, T. J. Ward, D. W. Grubbs, R H. Org.
Lett. 2001, 3, 3225-3228.
Historically Speaking
Sanford, M. S. Love, J. A. Grubbs, R. H. J. Am.
Chem. Soc. 2001, 123, 6543-6554.
Grubbs and co-workers elucidate the mechanism of
Ru-catalysed olefin metathesis.
72
5. Ru-based Catalysts Scope and
Reactivity. Ru-Catalysts Origin of
Stereoselectivity in Kinetic Resolutions.
B is approx. 20 kcal/mol higher in energy than A.
C could not be modeled and always coverged to
either A or B.
The authors then replaced the Cl ions by I in
order to mimic the experimental results reported
by Grubbs. The substrate selected was
Costabile, C. Cavallo, L. J. Am. Chem. Soc.
2004,126, 9592-9600.  
73
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst
Origin of Stereoselectivity in Kinetic
Resolutions.
2A-6E-si is preferred (lower in energy) by 6
kcal/mol
NOTE There is no relationship between olefin
enantioface and configuartion of the products
because no prochiral center has been included in
the substrate.
Costabile, C. Cavallo, L. J. Am. Chem. Soc.
2004,126, 9592-9600.  
74
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst
Origin of Stereoselectivity in Kinetic
Resolutions.
Try placing the Me group in an equatorial
position- does this change the preference for the
si-face? No! 2A-7E-si-Seq is preferred (lower in
energy) by 10 kcal/mol
This makes sense since this catalyst has shown
experimentally to favour the S enantiomer in
kinetic resolutions.
Costabile, C. Cavallo, L. J. Am. Chem. Soc.
2004,126, 9592-9600.  
75
5. Ru-based Catalysts Scope and
Reactivity. First Ru-based Chiral Catalyst
Origin of Stereoselectivity in Kinetic
Resolutions.
Try placing the Me group in an equatorial
position- does this change the preference for the
si-face? No! 2A-7E-si-Seq is preferred (lower in
energy) by 10 kcal/mol
This makes sense since this catalyst has shown
experimentally to favour the S enantiomer in
kinetic resolutions.
All other transition states modelled that either
a) had the Me in an axial position or b) would
lead to the S product were on average 25 kcal/mol
higher in energy.
Heavier halogens decrease the size of the
reaction pocket leading to a more selective
metathesis.
Costabile, C. Cavallo, L. J. Am. Chem. Soc.
2004,126, 9592-9600.  
76
5. Ru-based Catalysts Scope and
Reactivity. Recyclable Chiral Ru Catalysts
AROM/CM in Air.
Van Veldhuizen, J. J. Garber, S. B. Kingsbury,
J. S. Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 4954-4955.
77
5. Ru-based Catalysts Scope and
Reactivity. Recyclable Chiral Ru Catalysts
AROM/CM in Air.
Facile modification of alkylidene units reported
however, modification of the N-heterocyclic
carbene is much more cumbersome.
Van Veldhuizen, J. J. Gillingham, D. G. Garber,
S. B. Kataoka, O. Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 12502-12508.  
78
5. Ru-based Catalysts Scope and
Reactivity. Recyclable Chiral Ru Catalysts
Steric Modification.
Facile modification of alkylidene units reported
however, modification of the N-heterocyclic
carbene is much more cumbersome.
Large difference in reactivity observed between
3d and 3.
Van Veldhuizen, J. J. Gillingham, D. G. Garber,
S. B. Kataoka, O. Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 12502-12508.  
79
5. Ru-based Catalysts Scope and
Reactivity. Recyclable Chiral Ru Catalysts
Steric Modification.
Suffers from the difficulty associated with
functionalized NOBIN derivatives (lengthy
synthesis).
Van Veldhuizen, J. J. Gillingham, D. G. Garber,
S. B. Kataoka, O. Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 12502-12508.  For more examples
of the use of these bidentate carbene ligands
see Larsen, A. O. Leu, W. Oberhuber, C. N.
Campbell, J. E. Hoveyda, A. H. J. Am. Chem. Soc.
2004, ASAP.
80
5. Ru-based Catalysts Scope and Reactivity. New
Catalysts Afford Increased Activity!
Conversion still mediocre, but ees range from
modest to very good in some cases
The bigger question is What is the source of the
increased activity between 3 and 3d???
Van Veldhuizen, J. J. Gillingham, D. G. Garber,
S. B. Kataoka, O. Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 12502-12508.  
81
5. Ru-based Catalysts Scope and Reactivity. New
Catalysts Afford Increased Activity!
The extra phenyl group pushes the iso-propyl
group towards the carbene center. Hoveyda and
co-workers have proposed that this is responsible
for the increased rates of initiation of the
catalyst and hence the greater reactivity.
82
5. Ru-based Catalysts Scope and Reactivity. New
Catalysts Afford Increased Activity!
Van Veldhuizen, J. J. Gillingham, D. G. Garber,
S. B. Kataoka, O. Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 12502-12508.  
83
5. Ru-based Catalysts Scope and
Reactivity. Other Application of Bi-Dentate
Heterocyclic Ligands
Larsen, A. O. Leu, W. Oberhuber, C. N.
Campbell, J. E. Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 11130-11131.
84
5. Ru-based Catalysts Scope and Reactivity. New
Catalysts With Pendant Iodines
Gillingham, D. G. Kataoka, O. Garber, S. B.
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
12288-12290.
85
5. Ru-based Catalysts Scope and Reactivity. New
Catalysts With Pendant Iodines
These examples are representative. Hoveyda and
co-workers increase reaction rates by performing
reactions in the absence of solvent.
Application in the preparation of pyrans.
86
6. General Conclusions and Future Outlook. What
Does the Future Hold?
1. Despite the obvious practical drawbacks to Mo
versus Ru- at this point in time Mo-catalysts
have been further developed. Ru-catalysis will
definitely be a target for the future 2. Need
to see more applications of ARCM in (total)
synthesis 3. Need better catalysts- in terms of
activity and selectivity and with respect
substrate dependence and breadth of reactions
4. Must find better way of optimizing the
ligand structure- particularly for Ru
catalysts 5. Are there new applications and
reactions for these catalysts?