asymmetric olefin metathesis

Asymmetric Olefin Asymmetric Olefin MetathesisMetathesis

October 4th, 2004

Ring Closing Metathesis Reactions : Mechanism

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.

Propaganda...?

Diels-Alder Cycloaddition

Ring-Closing Metathesis

Retrosynthesis…

Ring-Closing Metathesis

No Stereocenters Formed

R1

R2

R1

R2

Diels-Alder Cycloaddition

R1

R3

R2

R4

R7

R8

R6

R5

+

Formation of 4 Contiguous

StereocentersR2

R7

R6R4

R1

R3

R8

R5

Asymmetric Metathesis?

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

1. Development of Metathesis Catalysts and the Jump to Asymmetry.

Schrock’s Catalyst.


Syn:Anti Alkylidenes in Mo-Catalysts.

Syn - isomer is more stable because of an agostic interaction between the C-H bond of the alkylidene and the metal center.

Angle is approx. 180o because of donation of N lone pair into

a d-orbital of Mo.


The Chemistry of Schrock’s Catalyst: Decomposition.

Catalyst is highly susceptible to intermolecular decomposition pathways.


The Chemistry of Schrock’s 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.


The Chemistry of Schrock’s 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.


The Chemistry of Schrock’s Catalyst: Polymerization.Polymerization (22 oC, PhMe) of NBDF6

Polymer with high


Polymer with high trans

content (~ 99 %).

Polymerization (22 oC, PhMe) of NBDF6





Electron withdrawing groups strengthen the pseudo-triple

bond between the imido ligand and the metal center.




Electron withdrawing groups strengthen the pseudo-triple

bond between the imido ligand and the metal center.

In turn, this hinders rotation about the alkylidene.

Consequently, the anti-isomer is estimated to be 105 times more reactive towards NBDF6 than the syn-isomer.


The Chemistry of Schrock’s Catalyst: Polymerization.

Polymerization (22 oC, PhMe) of NBDF6

Polymer with high


Polymer with high trans

content (~ 99 %).


Electron withdrawing groups (including phenols) slow rotation enough that syn-isomer is the only one available for reaction!

Electron rich groups (alkyls) speed up rotation enough to compete with polymerization, hence the anti is the reacting isomer!


Alkylidene Geometry is Essential for Asymmetric Induction.

Approach from the re

face


Approach from the si

face




face



face


face

Let’s imagine that in a chiral environment, attack from the

front face is favoured.




face


Let’s imagine that in a chiral environment, attack from the

front face is favoured.

The result would be a racemic product!


face


face


face


What’s The Point?


‘ Catalysts such as [these] could selectively polymerize or ring-close one enantiomer in a racemic mixture.’

Last line…


What’s The Point?


Grubbs and Fu demonstrate first RCM of nitrogen containing rings using Schrock’s catalyst…

‘ Catalysts such as [these] could selectively polymerize or ring-close one enantiomer in a racemic mixture.’

Last line…

Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324-5.

Historically Speaking…


Grubbs’ Catalysts.

Grubbs’ 1st Generation Catalyst

Grubbs’ 2nd

Generation Catalyst


A. Kinetic Resolution.


Grubbs’ First Attempt...

Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499.

2.0 mol %, 0 oC or 20 oC, 20 min., toluene

22 % ee 26 % ee

26 % ee 15 % ee

For di-substituted olefins, no kinetic resolution was observed due to faster ring closing versus

tri-substituted olefins.





22 % ee 26 % ee

26 % ee 15 % ee

For di-substituted olefins, no kinetic resolution was observed due to faster ring closing versus

tri-substituted olefins.

R

S


Proposed Reaction Models.

R - enantiomer favoured for 5-membered rings.

S - enantiomer favoured for 6-membered rings.

Langemann and Furstner demonstrate first macrocyclic RCM using Ru-based catalysts…

Historically Speaking…




22 % ee 26 % ee

Langemann, K.; Furstner, A. J. Org. Chem. 1996, 61, 3942.



Grubbs’ Second Attempt...

Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824-832.

Change in ligand structure led to a decrease in the efficiency of the kinetic

resolution.

First example of a desymmetrization of trienes.


C. Desymmetrization of Trienes.

4. Mo- (and W-) based Catalysts: Scope and Reactivity.

Chiral Biphen-Mo Catalysts.

Grubbs-Hoveyda Catalyst



Good selectivity for 5-membered rings. Highly substrate dependent.



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.


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.


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.


B. AROM/CM (Asymmetric Ring-Opening Metathesis/Cross Metathesis).

La, D. S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 7767-7778.


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.


Chiral Mo-Catalysts: AROM/RCM Towards Cyclopentenes.

Some good selectivities…

...but some unexplained failures as well

...only styrene used as olefin, and…


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.


Chiral Mo-Catalysts: Cyclic Amines and Medium Rings.

Some good selectivities.

Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997.

...but unsubstituted olefins still a problem.

Kiely A. F.; Jernelius J. A.; Schrock R. R.; Hoveyda A. H. J. Am. Chem. Soc. 2002, 124, 2868-9.


Chiral Mo-Catalysts: Synthesis of Tertiary Ethers and Medium Rings.


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


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.


Chiral Biphen-Mo Catalysts: Ligand Modification.

Interestingly, the previous developed catalyst still exhibits significantly better selectivity in reactions forming 5-membered rings.

High ee’s observed for forming 6-membered

rings by kinetic resolution and...

… in desymmetrization of trienes.

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.


Chiral Mo-Catalysts: RCM of Boronates.

Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron, 2004, 60, 7345 – 7351.

Example that compares asymmeric metathesis to the Noyori asymmetric reduction of -ketoesters.


Chiral Mo-Catalysts: Desymmetrization of Dienes via Inter-molecular CM.

Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron, 2004, 60, 7345 – 7351.

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.


Chiral Biphen-Mo Catalysts: Ligand Modification.


Chiral Mo-Catalysts: Cyclic Secondary Amines.

Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5, 4899-4902.

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.


Chiral Mo-Catalysts: Cyclic Secondary Amines.

Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5, 4899-4902.

Authors do not describe WHY these particular catalysts solve the problems

associated with secondary amines?

Puzzling substrate dependence??

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.


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., < 10 % conv. @ 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.

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.





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.

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.


Chiral Adamantyl-Mo 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.

In contrast to arylimido 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.



Arylimido catalysts deliver low yields, low selectivities (ee’s 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.



Arylimido catalysts deliver low yields, low selectivities (ee’s and cis/trans ratios) and significant levels of by-products.

Arylimido catalysts deliver the meso-15 as the predominant product.


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.


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.

Hultzsch, K. C.; Jernelius, J. A.; Hoveyda, A. H.; Schrock, R. R. Angew. Chem. 2002, 41, 589-593.


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.


Chiral Biphen-Mo Catalysts: First Polymer Supported Variant.

After 3 cycles catalysts showed consistent ee’s, good conversions and less than 5 % of Mo was found contaminating crude product mixtures (compared to greater

than 15 % for free catalyst.

Colour difference for free catalyst reactions (left) and polymer supported variants (right).

Dolman, S. J.; Hultzsch, K. C.; Pezet, F.; Teng, X.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2004, 126, ASAP.


Chiral Biphen-Mo Catalysts: Polystyrene Supported Variant.



Chiral Biphen-Mo Catalysts: Crossed-Linked Norbornene Derived Polymer Support.

Less 1% of Mo-quantity used remains in crude product.




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.


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

temp’s are needed.


2666.



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 -substituents.

The product-W complex is stable up to 90 oC.


2666.



Metathesis is possible, but the higher temperatures needed are to expel

ethylene and restart the catalytic cycle.

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 -substituents.

The product-W complex is stable up to 90 oC.


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 Schrock’s 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.

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.


First Ru-based Chiral Catalyst: Explaining the Stereoselectivity.



First Ru-based Chiral Catalyst.

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.


Costabile, C.; Cavallo, L. J. Am. Chem. Soc. 2004,126, 9592-9600.


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…



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.




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.




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.


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.


Recyclable Chiral Ru Catalysts: AROM/CM in Air.

Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502-12508.

Facile modification of alkylidene units reported however, modification of the N-heterocyclic carbene is much more

cumbersome.


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.


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.


New Catalysts Afford Increased Activity!

Conversion still mediocre, but ee’s 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???



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.


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.

Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288-12290.


New Catalysts With Pendant Iodines


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.

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?

asymmetric olefin metathesis

Documents

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