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Enantioselective Protonation: Fundamental Insights and New Concepts

Enantioselective Protonation: Fundamental Insights and New Concepts. A presentation by Guillaume Pelletier Literature meeting October 12 th 2011. Enantioselective Protonnation : An Extremely Simple Transformation!(?).

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Enantioselective Protonation: Fundamental Insights and New Concepts

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  1. Enantioselective Protonation: Fundamental Insights and New Concepts A presentation by Guillaume Pelletier Literature meeting October 12th 2011

  2. Enantioselective Protonnation : An Extremely Simple Transformation!(?) • Enolates are important as syntheticintermediates: regio and stereoselectivegenerationwith the desiredcounterion, increasedknowledge of their structure and reactivity • Enantioselectiveprotonnation via enoltautomerisation:requireonlycatalyticamounts of chiral reagent. • Protonnation of a chiral enolate/ligand complex

  3. What is the Important Facts to Know Before Exploring «AP» of Enolates • Enantioselective protonation processes are necessarily kinetically controlled reactions • Match the pKaof the proton donnor and the product • Be concerned about the stereochemistry of the proton acceptor : the ability to generate a stereodefined proton acceptor is critical (or not) in order to have good enantioselectivity • Detailed mechanistic explanations are rare : mixture of many mechanisms

  4. Presentation Outline • Lucette Duhamel and J.-C. Plaquevent’s Asymmetric Protonation of Benzylidene Glycinates (1978) • Charles Fehr’s Synthesis of α- and γ-Damascone (1988) • Hisashi Yamamoto’s Catalytic Asymmetric Protonation of Silyl Enol Ether with LBA (1994) • Recent Contributions (Levacher, Genet, Fu, Stoltz…) (2005+) Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587. Eames, J.; Weerasooriya, N. Tetrahedron : Asymmetry 2001, 12, 1-24. Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron : Asymmetry 2004, 15, 3653-3691. Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nature Chem. 2009, 1, 359-369.

  5. First « Synthetically Useful » Example of AP with Substituted Benzylidene Glycinates Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  6. Influence of the Chiral Acid Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  7. Influence of the Tartaric Acyl Substituents Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  8. Influence of the AminoAcidSide-Chain Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  9. Influence of the Benzylidene Electronic Properties Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  10. Influence of the Base Additive Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  11. ResultsInterpretation Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416. Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83. Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

  12. Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom • Proton donnor should be only weakly acidic (pKa~15-20) • Proton donnor should contain an electron-rich group with chelating ability • The transferred proton should be located in the proximitiy of the stereogenic center • Proton donnor should be readily accessible in both enantiomeric form and easily recoverable Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  13. Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom • Proton donnor should be only weakly acidic (pKa~15-20) • Proton donnor should contain an electron-rich group with chelating ability • The transferred proton should be located in the proximitiy of the stereogenic center • Proton donnor should be readily accessible in both enantiomeric form and easily recoverable Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  14. Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom • Proton donnor should be only weakly acidic (pKa~15-20) • Proton donnor should contain an electron-rich group with chelating ability • The transferred proton should be located in the proximitiy of the stereogenic center • Proton donnor should be readily accessible in both enantiomeric form and easily recoverable Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  15. α-Damascone Synthesis – Ligand effect

  16. α-Damascone Synthesis – Ligand effect

  17. α-Damascone Synthesis – Ligand effect

  18. α-Damascone Synthesis – Enolate Stereoselectivity Effect Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  19. α-Damascone Synthesis – Enolate Stereoselectivity Effect Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  20. α-Damascone Synthesis – Enolate Stereoselectivity Effect Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  21. γ-Damascone Synthesis – Effect of Alkoxide additives Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830. Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  22. γ-Damascone Synthesis – Effect of Alkoxide additives Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830. Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  23. γ-Damascone Synthesis – Effect of Alkoxide additives Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830. Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  24. γ-Damascone Synthesis – Effect of Alkoxide additives Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830. Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  25. γ-Damascone Synthesis – Effect of Alkoxide additives • The elucidation of the reactionmechanismisrenderedmore complexfrom the non-linearrelationshipbetweenreactionproductand H-A* enantiomericpurity. Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830. Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  26. γ-Damascone Synthesis – Effect of Alkoxide additives Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

  27. α and γ-Damascone Synthesis – Application to Thioester enolate Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.

  28. α and γ-Damascone Synthesis – Application to Thioester enolate Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552 Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem. Int. Ed. 1993, 32, 1042-1044.

  29. α and γ-Damascone Synthesis – Application to Thioester enolate Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.

  30. α and γ-Damascone Synthesis – Application to Thioester enolate Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.

  31. α and γ-Damascone Synthesis – Application to Thioester enolate Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.

  32. α-Damascone Synthesis – Catalytic Enantioselective Process • Slow and reversiblegeneration of the transientenolate

  33. α-Damascone Synthesis – Catalytic Enantioselective Process • Slow and reversiblegeneration of the transientenolate • Rapid and irreversibleprotonation of the enolate by H-A*

  34. α-Damascone Synthesis – Catalytic Enantioselective Process • Slow and reversiblegeneration of the transientenolate • Rapidand irreversibleprotonation of the enolate by H-A* • The rate of regeneration of the catalyst and enolatecanbeajustedwith the external proton source (PhSH) • Proton exchange between A*- and PhSH must berapid and complete and PhSLi must bemore nucleophilicthanLi-A* • Background reactionissuppressed by low [PhSH]

  35. α-Damascone Synthesis – Catalytic Enantioselective Process Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044. Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1044-1046.

  36. Catalytic Enantioselective Protonation – General Scheme • Withpreformedenolates, [enolate] > [H-A*] • Formally, an external, achiral proton source Z-H selectivelyprotonates A* - and not the enolate • Protonation of A*-shouldberapidwith Z-H (unlessthereis a catalyticenantioselectivetautomerisationmechanism) Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  37. What About PreformedEnolates? (Autocalatylic) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  38. What About PreformedEnolates? (Autocalatylic) • This autocatalytic process is based on subtile kinetic differences in the proton transfer reactions between H-A*, A*-, the enolate and the non-inducing proton donnor (Z-H). Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  39. Catalytic Enantioselective Protonation – General Scheme Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  40. Catalytic Enantioselective Protonation – General Scheme Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  41. Catalytic Enantioselective Protonation – General Scheme Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

  42. Catalytic Enantioselective Protonation – General Scheme

  43. Catalytic Enantioselective Protonation – Protonnation of H-A*/enolate aggregate Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.

  44. CatalyticEnantioselectiveProtonation of Cylic Lithium Enolates Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1994, 33, 107-109. Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett1995, 372-273. Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

  45. CatalyticEnantioselectiveProtonation of Cylic Lithium Enolates Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140-5149. Rebek, J., Jr.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-T. J. Am. Chem. Soc. 1987, 109, 2426-2433.

  46. CatalyticEnantioselectiveProtonation of Cylic Lithium Enolates *With a TMSCl quench at -78 °C! Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett1995, 372-273. Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

  47. CatalyticEnantioselectiveProtonation of Cylic Lithium Enolates Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett1995, 372-273. Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

  48. EnantioselectiveProtonation of ProchiralSilylEnolEthers and KeteneSilylAcetals Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180. Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

  49. EnantioselectiveProtonation of ProchiralSilylEnolEthers and KeteneSilylAcetals • Silyl enol ether is a « stable metal enolate equivalent » which can be isolated • In general, it is difficult the control the enantioselectivity with protonation of silyl enol ether with chiral Brønsted acids • Two main reason for poor induction is bonding flexibility between H and A* and chiral pool of H-A* is limited to sulfonic and carboxylic acids Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180. Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

  50. EnantioselectiveProtonation of ProchiralSilylEnolEthers Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180. Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

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