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Development of a Chiral Lewis Base Catalyzed Allylation Reaction

Development of a Chiral Lewis Base Catalyzed Allylation Reaction. Jason Poulin Barriault Lab March 20 th 2008. Presentation Outline. Generalities Allylation/crotylation reactions Lewis base catalysis (initial trials) Nonlinear effects in asymmetric synthesis Improved catalyst system

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Development of a Chiral Lewis Base Catalyzed Allylation Reaction

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  1. Development of a Chiral Lewis Base Catalyzed Allylation Reaction Jason Poulin Barriault Lab March 20th 2008

  2. Presentation Outline • Generalities • Allylation/crotylation reactions • Lewis base catalysis (initial trials) • Nonlinear effects in asymmetric synthesis • Improved catalyst system • Conclusion

  3. Definitions • Lewis Acid: Employs a lone pair from another molecule to complete the stable group of one of its atoms (electron acceptor). • Lewis Base: Contains a lone pair which can be used to complete the stable group of another atom (electron donor).

  4. Lewis Acid Electrophilic Activation X

  5. Lewis Acid Electrophilic Activation X

  6. Lewis Acid Electrophilic Activation X Increased Electrophilicity Increase in dipole

  7. Lewis Acid Electrophilic Activation X

  8. Lewis Base Nucleophilic Activation:The Baylis-Hillman Reaction

  9. Lewis Base Nucleophilic Activation:The Baylis-Hillman Reaction

  10. Lewis Base Nucleophilic Activation:The Baylis-Hillman Reaction

  11. Lewis Base Nucleophilic Activation:The Baylis-Hillman Reaction

  12. Lewis Base Nucleophilic Activation:The Baylis-Hillman Reaction

  13. Lewis Base Electrophilic Activation:Acylation Reactions

  14. Lewis Base Electrophilic Activation:Acylation Reactions

  15. Lewis Base Electrophilic Activation:Acylation Reactions

  16. Lewis Base Electrophilic Activation:Acylation Reactions

  17. X-Ray Studies Lewis Acid Crystalline Solid Lewis Base Gutmann, Coord. Chem. Rev.1975, 15, 207

  18. X-Ray Studies Gutmann, Coord. Chem. Rev.1975, 15, 207

  19. Effects on Lewis Base + 7 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  20. Effects on Lewis Base + 7 pm + 7 pm - 8 pm - 2 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  21. Effects on Lewis Base + 7 pm + 7 pm - 8 pm - 2 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  22. Effects on Lewis Base + 7 pm + 7 pm - 8 pm - 2 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  23. Effects on Lewis Base + 7 pm + 7 pm - 8 pm - 2 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  24. Effects on Lewis Base + 7 pm + 7 pm - 8 pm - 2 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  25. Increased Reactivity Increased Electrophilicity Gutmann, Coord. Chem. Rev.1975, 15, 207

  26. Effects on Lewis Acid Gutmann, Coord. Chem. Rev.1975, 15, 207

  27. Effects on Lewis Acid + 2-5 pm Gutmann, Coord. Chem. Rev.1975, 15, 207

  28. Increased Reactivity Increased Electrophilicity Increased Nucleophilicity Gutmann, Coord. Chem. Rev.1975, 15, 207

  29. Charge Distribution of Silicon Species Sakurai et al., Chem. Lett. 1991, 387.

  30. Application in Synthesis:Allylation Reactions Allyl

  31. Allylation/ Crotylation Reactions Syn-Crotyl

  32. Allylation/ Crotylation Reactions 1,3-sigmatropic shift

  33. Allylation/ Crotylation Reactions Anti-Crotyl

  34. Type I Reagents • E/Z ratio determines Syn/Anti ratio • Zimmerman-Traxler transition state • B, Al and some Sn reagents

  35. Chair-like Transition State

  36. Chair-like Transition State

  37. Chair-like Transition State

  38. Chair-like Transition State

  39. Chair-like Transition State

  40. Chair-like Transition State

  41. Type II Reagents • Syn selective (independent of E/Z ratio) • Open-chain transition state • Usually require lewis acid activation • Si, Ti and some Sn reagents

  42. Open-Chain Transition State

  43. Lewis Base Promoted Allylation Kobayashi et al., J. Org. Chem.1994, 59, 6620.

  44. Lewis Base Promoted Allylation Kobayashi et al., J. Org. Chem.1994, 59, 6620.

  45. 29Si NMR Studies Upfield shift suggests that solvent is binding to silicon Kobayashi et al., J. Org. Chem.1994, 59, 6620. Kennedy and McFarlane, Multinuclear NMR, Plenum, New York, 1987, Chap.11, p. 305.

  46. Diastereoselectivity E/Z 97/3 <1/>99 Syn/Anti 97/3 <1/>99 • Diastereoselectivity is governed by E/Z ratio • Suggests a chair-like transition state Kobayashi et al., J. Org. Chem.1994, 59, 6620.

  47. Proposed Transition State Kobayashi et al., J. Org. Chem.1994, 59, 6620.

  48. Stoichiometric Screening Enantiomerically enriched Denmark et al., J. Org. Chem.1994, 59, 6161.

  49. Stoichiometric Screening Enantiomerically enriched Denmark et al., J. Org. Chem.1994, 59, 6161.

  50. Phosphoramide Optimization Denmark et al., J. Org. Chem.1994, 59, 6161.

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