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Asymmetric Olefin Metathesis

Asymmetric Olefin Metathesis. October 4 th , 2004. 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...?. Retrosynthesis….

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Asymmetric Olefin Metathesis

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  1. Asymmetric Olefin Metathesis October 4th, 2004

  2. 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.

  3. Propaganda...?

  4. Retrosynthesis…

  5. Asymmetric Metathesis?

  6. Outline. • Development of Metathesis Catalysts and the Jump to Asymmetry • Typical Reactions of Asymmetric Metathesis. • First Asymmetric Metathesis by Grubbs and Fujimura. • Mo- (and W-) based Catalysts: Scope and Reactivity • Ru-based Catalysts: Scope and Reactivity • General Conclusions and Future Outlook

  7. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. Schrock’s Catalyst.

  8. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. Syn:Anti 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.

  9. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. The Chemistry of Schrock’s Catalyst: Decomposition. Catalyst is highly susceptible to intermolecular decomposition pathways.

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

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

  12. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. The Chemistry of Schrock’s 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.

  13. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. Syn:Anti 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.

  14. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. Syn:Anti 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 Schrock’s 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!

  16. 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

  17. 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 Let’s imagine that in a chiral environment, attack from the front face is favoured.

  18. 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 Let’s imagine that in a chiral environment, attack from the front face is favoured. The result would be a racemic product!

  19. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. What’s The Point? Last line… McConville, D. H.; Wolf, J. R.; Schrock, R.R. J. Am. Chem. Soc. 1993, 115, 4413 – 4414. ‘ Catalysts such as [these] could selectively polymerize or ring-close one enantiomer in a racemic mixture.’

  20. 1. Development of Metathesis Catalysts and the Jump to Asymmetry. What’s The Point? Last line… McConville, D. H.; Wolf, J. R.; Schrock, R.R. J. Am. Chem. Soc. 1993, 115, 4413 – 4414. ‘ 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 Schrock’s catalyst…

  21. 3. First Asymmetric Metathesis by Grubbs and Fujimura. Grubbs’ Catalysts. Grubbs’ 1st Generation Catalyst Grubbs’ 2nd Generation Catalyst

  22. 2. Typical Reactions of Asymmetric Metathesis. A. Kinetic Resolution.

  23. 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.

  24. 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.

  25. 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.

  26. 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…

  27. 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.

  28. 2. Typical Reactions of Asymmetric Metathesis. C. Desymmetrization of Trienes.

  29. 4. Mo- (and W-) based Catalysts: Scope and Reactivity. Chiral Biphen-Mo Catalysts. Grubbs-Hoveyda Catalyst

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

  31. 4. Mo- (and W-) based Catalysts: Scope and Reactivity. Chiral Biphen-Mo Catalysts. Good selectivity for 5-membered rings. Highly substrate dependent.

  32. 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.

  33. 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.

  34. 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.

  35. 2. Typical Reactions of Asymmetric Metathesis. B. AROM/CM (Asymmetric Ring-Opening Metathesis/Cross Metathesis).

  36. 2. Typical Reactions of Asymmetric Metathesis. B. AROM/CM (Asymmetric Ring-Opening Metathesis/Cross Metathesis).

  37. 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.

  38. 2. Typical Reactions of Asymmetric Metathesis. B. AROM/CM (Asymmetric Ring-Opening Metathesis/Cross Metathesis).

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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

  44. 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.

  45. 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 ee’s 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.

  46. 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.

  47. 4. Mo- (and W-) based Catalysts: Scope and Reactivity. Chiral Mo-Catalysts: Desymmetrization of Dienes viaInter-molecular CM. Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron, 2004, 60, 7345 – 7351.

  48. 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.

  49. 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.  

  50. 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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