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Organocatalysis: Chiral Amines in Asymmetric Synthesis

Organocatalysis: Chiral Amines in Asymmetric Synthesis. Natalie Nguyen March 4, 2003. Chiral Organocatalysts in Asymmetric Synthesis. Acylation of Alcohols and Amines Kinetic Resolution. Baylis-Hillman Reaction. R = OMe (Quinine) R = H (Cinchonidine). R = OMe (Quinidine)

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Organocatalysis: Chiral Amines in Asymmetric Synthesis

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  1. Organocatalysis:Chiral Amines in Asymmetric Synthesis Natalie Nguyen March 4, 2003

  2. Chiral Organocatalysts in Asymmetric Synthesis Acylation of Alcohols and Amines Kinetic Resolution Baylis-Hillman Reaction R = OMe (Quinine) R = H (Cinchonidine) R = OMe (Quinidine) R = H (Cinchonine) -Lactone and -Lactam formation Friedel-Crafts Alkylation Indole Alkylation Diels-Alder Cycloadditon Aldol Reaction Mannich Reaction Michael Additions France, S.; Guerin, D.J.; Miller, S.J.; Lectka, T. Chem. Rev. 2003, 2985

  3. Chiral Amines in Asymmetric Synthesis Proline Catalyzed: • Aldol Reaction • Mannich Reaction Imidazolidinone Catalyzed: • Diels – Alder Cycloaddition Total Synthesis of (+)-Hapalindole Q

  4. Proline: Enzyme Mimic • Inexpensive • Available in both enantiomeric forms • “Chemzyme”: Mode of action very similar to enzymes (S)-proline (R)-proline Bifunctional Acid and Base Hydrogen-bond donor and acceptor Iminium Enamine

  5. Proline in Asymmetric Synthesis • The proline catalyzed Robinson annulation was one of the earliest examples of an enantioselective reaction Yamada, 1969 Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 4237

  6. Proline in Asymmetric Synthesis Hajos and Parrish, 1974 Synthesis of Taxol (Danishefsky, 1996) Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615 Danishefsky, S. et al. J. Am. Chem. Soc. 1996, 118, 2843

  7. Intramolecular Aldol Reaction:Solvents and Catalyst • Intramolecular aldol cyclization works best in aprotic polar solvents • Protic solvents lower the enantioselectivity drastically Catalyst Screening • Pyrrolidine ring, secondary nitrogen and carboxylic acid are important to catalysis Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615 Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1976,9, 412

  8. Intramolecular Aldol Reaction:Mechanism Brown, K.L.; Damm, L.; Dunitz, J.D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta. 1978, 61, 3108

  9. Attack occurs on the face opposite the carboxylic acid Transition state is controlled and stablized by N-H-----O hydrogen bonding Intramolecular Aldol Reaction:Proposed Transition State Houk, 2001-2003 Agami, 1984-1986 • Transition state is controlled and stablized by O-H-----O hydrogen bonding Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984,40, 1031 Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

  10. Attack occurs on the face opposite the carboxylic acid Transition state is controlled and stablized by N-H-----O hydrogen bonding Transition state is controlled and stablized by O-H-----O hydrogen bonding Favorable electrostatic interactions +NCH-----O - (2.4 Å) Intramolecular Aldol Reaction:Proposed Transition State Houk, 2001-2003 Agami, 1984-1986 Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984,40, 1031 Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

  11. Reaction is second order in proline A negative non-linear effect was observed Two prolines are involved Reaction is first order in proline A linear effect was observed One proline involved Intramolecular Aldol Reaction:Proposed Transition State Houk, 2001-2003 List, 2003 Agami, 1984-1986 Agami, C.; Puchot, C.; Sevestre, H. Tetrahedron Lett.1986,27, 1501 Hoang, L.; Bahmanyar, S.; Houk, K.N.; List, B. J. Am. Chem. Soc. 2003, 125, 16

  12. Intramolecular Aldol Reaction:Proposed Transition State si-face attack re-face attack • The hydrogen bonding allows the iminium double bond to be almost planer • Favorable electrostatic interactions +NCH-----O - (2.4 Å) • The hydrogen bonding forces the iminium double bond out of planarity • Small electrostatic interaction +NCH-----O - (3.4 Å) • Transition state is 3.4 kcal/mol higher in energy Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

  13. Intermolecular Aldol Reaction Evans’ Oxazolidinone Chiral auxillary First Proline Catalyzed Direct Aldol Reaction (List, 2000) List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395

  14. Intermolecular Aldol Reaction:Mechanism • Previously proposed Zimmerman-Traxler transition state is unlikely because N-H bonding does not occur List, B. Tetrahedron, 2002, 58, 5573 Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 11273

  15. Intermolecular Aldol Reaction:Amino Acid Catalysts List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

  16. Intermolecular Aldol Reaction:Amino Acid Catalysts List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

  17. Intermolecular Aldol Reaction: Substrate Scope • Reaction works best with large excess of ketone • Reaction is general to: • aromatic aldehydes • -substituted aldehydes • -Unsubstituted aldehydes: • Aldol condensation product was the major product 1 2 List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

  18. Intermolecular Aldol Reaction: Anti-Aldol Products • Thiaproline (2): • Not as general as proline 1 2 Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260 List, B.; Pojarliev, P.; Castello, C. Org. Lett.2001, 3, 573

  19. Cross Aldol Reaction Transition State Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798

  20. Mannich Reaction • The rate of the Mannich reaction must be faster than the rate of aldol reaction First Proline Catalyzed Direct Mannich Reaction (List, 2000) List, B. J. Am. Chem. Soc. 2000, 122, 9336 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  21. Mannich Reaction: Transition State (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  22. Mannich Reaction: Transition State (E)-imine (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  23. Mannich Reaction: Transition State Nonbonding interactions (E)-imine (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  24. Mannich Reaction:Amino Acid Catalysts List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  25. Mannich Reaction:Amino Acid Catalysts List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  26. Mannich Reaction:Variation in Aldehydes Transition State List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  27. Mannich Reaction:Variation in Ketones Transition State List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

  28. Aldol and Mannich Reaction Direct Aldol • Deprotonation or silylation is not required Direct Mannich • Imine electrophile can be generated in situ Proline proved to the optimal catalyst • Nontoxic • Inexpensive • Both enantiomers available • Can be used in wet solvents and open to air • Can be removed from reaction mixture by aqueous workup (S)-proline

  29. Organocatalyzed Diels-Alder Cycloaddition Asymmetric Diels-Alder Reaction by Chiral Bases (Kagan, 1989) Transition State Riant, O.; Kagan, H.B.; Tetrahedron, 1989, 30, 7403

  30. Diels-Alder Cycloaddition Exo vs Endo exo endo Enantioselectivity in Diels Alder Reaction

  31. Diels-Alder Cycloaddition : Lewis Acids and Iminiums Lewis Acids and Iminiums • lowers the energy of the LUMO Energy

  32. Organocatalytic Diels-Alder Cycloaddition MacMillan’s Catalyst Design: • Lowers the energy of LUMO of the dienophile • Kinetically labile ligand for catalytic turnover • Chiral molecule would induce stereoselectivity Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  33. Diels-Alder Cycloaddition:Catalyst Screening Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  34. Diels-Alder Cycloaddition:Catalyst Screening Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  35. Diels-Alder Cycloaddition:Variation in Dienophiles Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  36. Diels-Alder Cycloaddition:Variation in Dienes Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  37. Diels-Alder Cycloaddition:Transition State • Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls • Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  38. Diels-Alder Cycloaddition:Transition State • Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls • Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  39. Diels-Alder Cycloaddition:Transition State • Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls • Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  40. Diels-Alder Cycloaddition:Catalyst Screening Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  41. Diels-Alder Cycloaddition:Variation in Dienophiles Transition State Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  42. Diels-Alder Cycloaddition:Variation in Dienes Transition State Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

  43. Diels-Alder Cycloadditon: Conclusions Organocatalyzed Diels-Alder Cycloadditions • Highly enantioselective • Applicable to a variety of substrates Chiral Amines • Nontoxic • Can be used in wet solvents and open to air • Can be removed from reaction mixture by aqueous workup

  44. The Total Synthesis of (+)-Hapalindole Q by an Organomediated Diels-AlderReaction Aaron C. Kinsman and Michael Kerr J. Am. Chem. Soc. 2003, 125, 14120 • Isolated from the terrestrial blue-green algae Hapalosiphon fontinalis • Cyanobacterium indigenous to the Marshall Islands • Isolated in 1984 by Moore and co-workers • Exhibits antimycotic activity through its ability to directly inhibit RNA polymerase • Has been synthesized by 5 groups • Hapalindoles • R1 = NC, NCS • R2 = H, Cl, OH

  45. (+)-Hapalindole Q: Retrosynthesis

  46. (+)- Hapalindole Q: Synthesis

  47. (+)- Hapalindole Q: Synthesis

  48. (+)- Hapalindole Q: Synthesis

  49. (+)- Hapalindole Q:Synthesis

  50. (+)- Hapalindole Q: Synthesis

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