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Asymmetric Baylis-Hillman Reaction

Asymmetric Baylis-Hillman Reaction. Matt Bowman Blackwell Group April 24, 2003. Outline. General remarks History Utility Mechanism Improvements Asymmetric variants. General Reaction. Strengths: Complete Atom Economy Adducts are “Loaded with Functionality” Weaknesses:

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Asymmetric Baylis-Hillman Reaction

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  1. Asymmetric Baylis-Hillman Reaction Matt Bowman Blackwell Group April 24, 2003

  2. Outline • General remarks • History • Utility • Mechanism • Improvements • Asymmetric variants

  3. General Reaction • Strengths: • Complete Atom Economy • Adducts are “Loaded with Functionality” • Weaknesses: • Long Reaction Times • Side Reactions

  4. Early Years • 1968- Morita used Cy3P as a catalyst • “Carbinol Addition” Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.

  5. Early Years • 1968- Morita used Cy3P as a catalyst • “Carbinol Addition” Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.

  6. Early Years • 1968- Morita used Cy3P as a catalyst • “Carbinol Addition” 2 hours at reflux Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.

  7. Middle Ages • 1972- A.B. Baylis and M.E.D. Hillman • Celanese Corporation 1 week room temperature Baylis, A.B.; Hillman, M.E.D. German Patent 2155113, 1972; Chem. Abstr. 1972, 77, 34174q.

  8. Renaissance • 1983-1988 • Reaction scope was explored. • Main Players: Drewes and Basavaiah • 1988- Termed “Baylis-Hillman reaction” Drewes, S.E.; Roos, G.H.P. Tetrahedron1988,44, 4653-4670.

  9. Today • 1988-Present day attention • New catalysts • Broadened scope • Asymmetric variants Basavaiah, D.; Rao, A.J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811-891.

  10. Utility • Inexpensive starting materials • Lots of functionality • Complete atom economy • Amenable to industrial scale reactions

  11. Utility: Sampatrilat • Pfizer • Inhibitor • zinc metalloprotease • neutral endopeptidadase • angiotensin converting enzyme Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article

  12. Utility: Sampatrilat Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article

  13. Utility: Sampatrilat Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article

  14. Utility: Natural Products

  15. Proposed Mechanism

  16. Mechanistic Studies • rate=k[Acrylonitrile][MeCHO][DABCO] • kH/kD=1.03  0.1 • Strong solvent dependence • Polar Protic Solvents Hill, J.S.; Isaacs, N.S. J. Phys. Org. Chem. 1990,40, 5611-5614.

  17. Baylis-Hillman Advances • Focus on increasing reaction rate

  18. Baylis-Hillman Advances • Focus on increasing reaction rate • Increased pKa of Lewis base Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700.

  19. Baylis-Hillman Advances • Focus on increasing reaction rate • Increased pKa of Lewis base • Lewis acid Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700. Aggarwal, V.K.; Mereu, A.; Tarver, G.J.; McCague, R. J. Org. Chem. 1998, 63, 7183-7189.

  20. Baylis-Hillman Advances • Focus on increasing reaction rate • Increased pKa of Lewis base • Lewis acid Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700. Aggarwal, V.K.; Mereu, A.; Tarver, G.J.; McCague, R. J. Org. Chem. 1998, 63, 7183-7189. Kataoka, T.; Iwama, T.; Tsujiyama, S-I.; Iwamura, T.; Watanabe, S-I. Tetrahedron1998, 54, 11813-11824.

  21. Asymmetric Variants • Traditional Baylis-Hillman: 3 component • Electrophile • Activated alkene • Lewis-Base catalyst • 4th component • Lewis-Acid catalyst • Kinetic resolution

  22. Electrophile:

  23. Electrophile: Chiral Glyoxylates Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12, 1741-1745.

  24. Electrophile: Chiral Glyoxylates 21 hours 0°C Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12, 1741-1745.

  25. Electrophile: Chiral N-Sulfinimines Shi, M.; Xu, Y-M. Tetrahedron: Asymmetry 2002, 13, 1195-1200.

  26. Electrophile: Chiral N-Sulfinimines 5 days 20°C Shi, M.; Xu, Y-M. Tetrahedron: Asymmetry 2002, 13, 1195-1200.

  27. Activated Alkene:

  28. Activated Alkene: Oppolzer’s Sultam Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.

  29. Activated Alkene: Oppolzer’s Sultam 12 hours 0°C Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.

  30. Activated Alkene: Oppolzer’s Sultam Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.

  31. Activated Alkene: Oppolzer’s Sultam Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.

  32. Activated Alkene: Acryloylhydrazide 4 days 25°C Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.

  33. Activated Alkene: Acryloylhydrazide 4 days 25°C Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.

  34. Activated Alkene: Acryloylhydrazide 4 days 25°C Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.

  35. Activated Alkene: 4-Menthyloxy-butenolide 4 hours -60°C Jauch, J. J. Org. Chem. 2001, 66, 609-611.

  36. Activated Alkene: 4-Menthyloxy-butenolide Jauch, J. J. Org. Chem. 2001, 66, 609-611.

  37. Activated Alkene: 4-Menthyloxy-butenolide Jauch, J. J. Org. Chem. 2001, 66, 609-611.

  38. Lewis-Base Catalyst: chiralDABCO? Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  39. Lewis-Base Catalyst: cinchona alkaloids Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  40. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  41. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  42. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  43. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  44. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  45. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  46. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.

  47. Lewis-Base Catalyst: cinchona alkaloid derivatives Iwabuchi, Y.; Furukawa, M. Esumi, T.; Hatakeyama, S. Chem. Comm.2001, 2030-2031.

  48. Lewis-Base Catalyst: cinchona alkaloid derivatives Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.

  49. Lewis-Base Catalyst: cinchona alkaloid derivatives 24 hours -30°C Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.

  50. Lewis-Base Catalyst: cinchona alkaloid derivatives Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.

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