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Asymmetric Organocatalysis

Asymmetric Organocatalysis. Sarah Maifeld September 19, 2002. Approaches to Asymmetric Catalysis. Organometallic catalysis Broad scope Ligand control Inert conditions Cost and toxicity Bioorganic catalysis Highly selective High rate of reaction Limited scope . Organocatalysis.

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Asymmetric Organocatalysis

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  1. Asymmetric Organocatalysis Sarah Maifeld September 19, 2002

  2. Approaches to Asymmetric Catalysis • Organometallic catalysis • Broad scope • Ligand control • Inert conditions • Cost and toxicity • Bioorganic catalysis • Highly selective • High rate of reaction • Limited scope

  3. Organocatalysis • Similar modes of action • Lewis acidic/Lewis basic functionality • Enzyme mimetics • Advantages • Preparative • Inexpensive • Amenable to combinatorial approaches

  4. History and Development • Early example • Applications • Kinetic resolutions • Phase transfer catalysis • Asymmetric synthesis Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7. Prelog, V.; Wilhelm, M. Helv. Chim. Acta1954, 37, 1634.

  5. Outline • Cinchona Alkaloids • Proline • Amino Acid Derivatives • Peptide-like Catalysts • Heteroazolium Species

  6. Cinchona Alkaloids • Enantiomeric b-hydroxyamine functionality • Nucleophilic catalysts Wynberg, H. Top. Stereochem.1986, 16, 87.

  7. Asymmetric b-Lactones Requires electron deficient aldehydes and aromatic ketones 68 – 98% yield 89 – 98% ee Alkyl aryl ketones react in trace amounts Staring, E. G. J.; Wynberg, H. J. Am. Chem. Soc.1982, 104, 166.Staring, E. G. J.; Wynberg, H. J. Org. Chem. 1985, 50, 1977.

  8. Aldol - Lactonization Mechanism Dijkstra, G. D. H.; Kellog, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am. Chem. Soc.1989, 111, 8069. Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc.2001, 123, 7945.

  9. Methyl Ketene Dimerization Calter, M. A. J. Org. Chem. 1996,61, 8006.

  10. Polypropionate Synthesis Guo, X.; Liao, W.; Calter, M. A. Org. Lett. 2001, 3, 1499.

  11. Asymmetric b-Lactams Taggi, A.E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J. III, Leckta, T. J. Am. Chem. Soc.2000, 122, 7831.

  12. Asymmetric Baylis-Hillman High enantioselectivities (91 – 99% ee) Modest yields (31 – 58%) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.

  13. Proline • Robinson Annulation • Intermolecular Aldol • Mannich Reaction • Michael Addition

  14. Asymmetric Robinson Annulation Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.1971, 10, 496. Hajos, Z. G.; Parrish, D. R. J. Org. Chem.1974, 39, 1615.

  15. Proposed Mechanism Enamine intermediate Secondary amine and carboxylate essential Second order in L-Proline Type I Aldolase Puchot, C.; Sevestre, H.; Agami, C. Tetrahedron Lett. 1986, 27, 1501.

  16. Synthetic Applications ent-Cholesterol Baccatin III Mickus, D. E.; Rychnovsky, S. D. J. Org. Chem.1992, 57, 2732. Danishefsky, S. et al. J. Am. Chem. Soc. 1996, 118, 2843.

  17. Direct Intermolecular Aldol Requires no preformed enolate High concentration of ketone List, B.; Pojarliev, P.; Castello, C. J. Am. Chem. Soc.2001, 3, 573. Notz, W.; List, B. J. Am. Chem. Soc.2000, 122, 7386. List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc.2000, 122, 2395.

  18. Proline-Catalyzed Mechanism Barbas III, C. F.;0 Lerner, R. A.; List, B. J. Am. Chem. Soc.2000, 2395.

  19. Mannich Reaction Good yields and high enantioselectivities with branched and unbranched aldehydes PMP group can be oxidatively removed Pojarliev, P.; Biller, W. T.; Martin, H. J.; List, B.; J. Am. Chem. Soc. 2002, 124, 827.

  20. Opposite Enantiofacial Selectivity Pojarliev, P.; Biller, W. T.; Martin, H. J.; List, B. J. Am. Chem. 2002, 124, 827.

  21. Michael Addition Shiraishi, T.; Hirama, M.; Yamaguchi, M. J. Org. Chem.1996, 61, 3520. Possible multicomponent catalyst Pham, V.; Hanessian, S.Org. Lett. 2000, 2, 2975.

  22. Amino Acid Derivatives • Diels-Alder Reaction • Strecker Reaction

  23. Diels-Alder Reaction A variety of chiral b-amino alcohols tested High yields (85 – 95 %) but moderate ee’s (< 61%) Riant, O.; Kagan, H. B. Tetrahedron Lett. 1989, 52, 7403.

  24. Diels Alder Reaction General Strategy: Formation of iminium ion to lower LUMO of dienophile Highly enantioselective Diels-Alder catalyst Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.2000, 122, 4243.

  25. Stereocontrol • Formation of E-iminium isomer • Benzyl group hinders Re-face approach of diene

  26. a,b-Unsaturated Ketones General toward diene structure Si face approach of diene Favored cis-iminium isomer Northrop, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.

  27. Strecker Reaction 76 – 86% ee for aromatic imines N-Benzhydryl group essential Hydrogen bonding and van der Waals’ interactions Grogan, M. J.; Corey, E. J. Org. Lett. 1999, 157.

  28. Peptide-based Catalysts • Hydrocyanation • Strecker Reaction • Azidation • Phosphorylation

  29. Hydrocyanation Designed as an oxynitrilase mimic Acyclic structure showed no asymmetric induction Mechanistic uncertainty Oku, J.-I. J. Chem. Soc., Chem. Commun. 1981, 229. Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181.

  30. Strecker Reaction Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910.

  31. Strecker Reaction Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.1998, 120, 4901. Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed.2000, 39, 1279.

  32. Mechanistic Insights Well-defined secondary structure Z-Imine bridges both urea protons by hydrogen bonds Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc.2002, 124, 10012.

  33. Azidation b-turn unit Methylation at the b-position of the histidine residue increased selectivity Branching at g-carbon of substrate increased selectivity (up to 92% ee) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc.2002, 124, 2134.

  34. Phosphorylation Phosphorylation of histidine is the first step in a number of signal transduction pathways Sculimibrene, B. R.; Miller, S. J. J. Am. Chem. Soc.2001, 123, 10125.

  35. Heteroazolium Catalysts • Benzoin Condensation • Stetter Reaction

  36. Thiamine Pyrophosphate • Coenzyme derived from vitamin B1 • Important role in biochemical reactions • Decarboxylation of a-keto acids • Transfer of activated aldehyde groups • Thiazolium ring is key functionality

  37. Benzoin Condensation Breslow, R. J. Am. Chem. Soc.1958, 80, 3719. Schmuck, C.; Breslow, R. Tetrahedron Lett. 1996, 8241.

  38. Asymmetric Attempts Knight, R.; Leeper, F.J. Tetrahedron Lett.1997, 38, 3611. Gerhard, A. U.; Leeper, F. J. Tetrahedron Lett.1997, 38, 3615. Dvorak, C. A.; Rawal, V. H. Tetrahedron Lett.1998, 39, 2925.

  39. Triazolium Catalysis Breuer, K.; Enders, D. Helv. Chim. Acta. 1996, 79, 1217.

  40. Stetter Reaction Lower yields for substituted aryls Moderate selectivity (41 – 71% ee) Breuer, K.; Runsink, J.; Enders, D. Helv. Chim. Acta.1996, 79, 1899.

  41. Conclusion • Classic examples of asymmetric organocatalysis • b-lactones • Asymmetric Robinson Annulation • Direct aldol and Mannich reactions are promising • Peptide catalysis offers unique opportunity for further development • Complementary approach to organometallic catalysis and bioorganic catalysis .

  42. Acknowledgements • Lee Group • Lisa Jungbauer • Terra Potocky • Rachel Weller • Susie Martins • Margaret Biddle • Marissa Rosen • Brian Lucas • Val Keller • Jodie Brice • Matthew Soellner • Shane Flickinger

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