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Enantioselective Formation of Quaternary Carbon Centers

Enantioselective Formation of Quaternary Carbon Centers. Cory C. Bausch November 18, 2004. Outline. Introduction Types of Reactions Alkylations Diels-Alder Cyclopropanation Pd Catalyzed Reactions Chiral Transfer Reactions Summary. Introduction.

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Enantioselective Formation of Quaternary Carbon Centers

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  1. Enantioselective Formation of Quaternary Carbon Centers Cory C. Bausch November 18, 2004

  2. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  3. Introduction • Chiral quaternary center: Carbon with four different non-hydrogen substituents • Quaternary Center in this context: Carbon with four non-equivalent carbon substituents

  4. Synthetic Targets

  5. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  6. a,a-Alkylated Ketones a) Based on optical rotation of pure enantiomer Shun-ichi Hashimoto and Kenji Koga Tetrahedron Lett. 1978, 6, 573

  7. Tandem Michael Addition/Aldol Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K.Tetrahedron Lett. 1980, 21, 4005

  8. Scope of Addition/Alkylation Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K.Tetrahedron Lett. 1980, 21, 4005 Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron1981, 37, 3951

  9. Alkylation of b-Keto Esters • Achieve both enantiomers with the same chiral species • Binding properties of ligand affect orientation of enamine Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718

  10. Orientation of Addition • THF is poor coordinating ligand • HMPA is strong coordinating ligand Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. Tetrahedron Lett. 1984, 25, 5677

  11. Scope of Alkylation Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718

  12. Chiral Phase Transfer Catalysis Hermann, K. and Wynberg, H. J. Org. Chem. 1979, 44, 2238

  13. PTC, cont. • Reaction gives up to 95% yield, 92% ee Dolling, U.H.; Davis, P.; Grabowski, E.J. J. Am. Chem. Soc. 1984, 106, 446

  14. PTC, cont. • Convenient, efficient Robinson annulation. • Product can be obtained in 78% ee and 99% yield. Dolling, U.H., et al. Angew. Chem. Int. Ed. Engl. 1986, 25, 476

  15. Nucleophilic Chiral Pd Enolates • Works for b-keto esters as well • Reaction scope gives 69-92% yield and 89-93% ee Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240

  16. Salen-Al Catalyzed Michael Additions Taylor, M.S. and Jacobsen, E.N. J. Am. Chem. Soc. 2003, 125, 11204

  17. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  18. Enantioselective Diels Alder Cycloadditions • Reaction scope gives 40-91% yield and 82-96% ee Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamota, H. J. Org. Chem. 1989, 54, 1481

  19. Cr(III)-Salen Catalyzed Enantioselective Diels-Alder Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

  20. Cr(III)-Salen Catalyzed, cont. Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

  21. Cr(III)-Salen Catalyzed, cont. Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

  22. Advances of Cr(III)-Salen Catalyzed Diels-Alder • Preserves second stereocenter • Possesses more functionality • General reaction scope • Mild and convenient conditions Huang, Y.; Iwama, T.; Rawal, V.H. Org. Lett. 2002, 4, 1163

  23. Rare-Earth Metal Catalyzed Quinone Diels-Alder • New effective chiral lewis acid in quinone Diels-Alder reactions • Sm, Gd are optimal metals from lanthanide metal screen Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162

  24. Quinone Diels-Alder Reaction Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162

  25. Application of Enantioselective Diels-Alder • Key step in the synthesis of Aspidosperma alkaloids • Generates two key stereocenters in one step • Synthesis gives >95% ee in 12 overall steps • Can be completed on >1 g scale Kozmin, S.A.; Iwama, T.; Huang, Y.; Rawal, V.H. J. Am. Chem Soc. 2002, 124, 4628

  26. Further Applications • Diels-Alder sets stereocenter in high ee • Efficient synthesis of 6-membered ring backbone Corey, E.J.; Guzman-Perez, A.; Teck-Peng, L. J. Am. Chem. Soc. 1994, 116, 3611

  27. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  28. Enantioselective Cyclopropanation • Asymmetric Modified Simmons-Smith Reaction • Reported in 1985 by Yamamoto, et al. and Mash, et al. Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256

  29. Cyclopropanation, cont. Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256

  30. Cyclopropanation in Total Synthesis • Cyclopropanation in 84% yield, 89% ee • 15% overall yield in 14 Steps Mash, E.A.; Math, S.K.; Flann, C.J. Tetrahedron Lett. 1988, 29, 2147

  31. Cyclopropanation of Allylic Alcohols • General substrate scope • No stoichiometric chiral source necessary • Order of addition of reagents is important Denmark, S.E. and O’Connor, S.P. J. Org. Chem. 1997, 62, 584

  32. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  33. Pd-Catalyzed Heck Reactions • Thoroughly explored pathway to quaternary carbons • Reaction is enantioselective and catalytic Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738

  34. Heck Reactions • Cis-decalin derivatives among first systems studied Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738

  35. Heck Reactions • Improvements using vinyl triflates • No silver salt needed • Higher enantiomeric excess obtained Sato, Y.; Watanabe, S.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589

  36. Heck Reactions • Synthesis of hydrindans Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593

  37. Heck-Type Reactions • Palladium catalyzed polyene cyclizations of trienyl triflates Carpenter, N.E.; Kucera, D.J.; Overman, L.E. J. Org. Chem. 1989, 54, 5846

  38. Application of Polyene Cyclization • Enantioselective total synthesis • Heck reaction unsuccessful, polyene cyclization works well Maddaford, S.P.; Anderson, N.G.; Cristofoli, W.A.; Keay, B.A. J. Am. Chem. Soc. 1996, 118, 10766

  39. Heck Reaction, cont. • Form enantioenriched spirocycles • Achieve either enantiomer with same catalyst Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477

  40. Enantioenriched Spirocycles • Silver salt works better than amine base • Scope is fairly general Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477

  41. Enantioenriched Natural Products • Heck cyclization can obtain either enantiomer Matsuura, T.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6500

  42. Synthesis of Vicinal Stereogenic Quaternary Carbon Centers Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702

  43. Vicinal Quaternary Centers, cont. • Both products formed with complete stereocontrol • Variation in protecting group allows access to both stereogenic products Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702

  44. Further Expansion of Heck Coupling Lebsack, A.D.; Link, J.T.; Overman, L.E.; Stearns, B.A. J. Am. Chem. Soc. 2002, 124, 9008

  45. Pd-Catalyzed Allylation • Chiral ferrocenylphosphine ligands among first used • Works for wide array of b-diketones Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113

  46. Pd-Catalyzed Allylation Trost, B.M.; Radinov, R.; Grenzer, E.M. J. Am. Chem. Soc. 1997, 119, 7879 Trost, B.M.; Schroeder, G.M. J. Am. Chem. Soc. 1999, 121, 6759

  47. Enantioselective Tsuji Allylation Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP

  48. Tsuji Allylation, cont. • Catalytic cycle of racemic allylation Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP Tsuji, J. and Minami, I. Acc. Chem. Res. 1987, 20, 140

  49. Outline • Introduction • Types of Reactions • Alkylations • Diels-Alder • Cyclopropanation • Pd Catalyzed Reactions • Chiral Transfer Reactions • Summary

  50. Chiral Transfer Reactions • Chirality transfer based on thermodynamic stability Hiroi, K.; Nakamura, H.; Anzai, T. J. Am. Chem. Soc. 1987, 109, 1249

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