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Advances in Metal Mediated Intramolecular Enyne Carbocyclizations

Advances in Metal Mediated Intramolecular Enyne Carbocyclizations. Patrick D. Pohlhaus The University of North Carolina at Chapel Hill March 28, 2003. Presentation Features. Will Discuss :. The ability of Co, Ti, Zr, Pd, Ni, and Rh complexes to effect the

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Advances in Metal Mediated Intramolecular Enyne Carbocyclizations

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  1. Advances in Metal Mediated Intramolecular Enyne Carbocyclizations Patrick D. Pohlhaus The University of North Carolina at Chapel Hill March 28, 2003

  2. Presentation Features Will Discuss: The ability of Co, Ti, Zr, Pd, Ni, and Rh complexes to effect the cycloisomerization, cyclocarbonylation, alkylative cyclization, and reductive cyclization of 1,6 and 1,7 enynes Advantages/Disadvantages of each metal Substrate scope Stereoselectivity issues, including asymmetric induction where applicable Applications of methodology to synthetic problems

  3. Reaction Pathways Cycloisomerization No net change in oxidation state Complete “Atom Economy” Selective geometry about alkene bearing R1 Cyclocarbonylation Construction of cyclopentenones employing CO source Pauson-Khand, Pauson-Khand type reaction

  4. Reaction Pathways Alkylative Cyclization Incorporation of carbon containing fragment onto alkyne moiety Selective geometry about exocyclic alkene bearing new group Reductive Cyclization Net addition of H2 into cyclized product Selective geometry about alkene bearing R1

  5. Cobalt (The Pauson-Khand Reaction) Original account (1973): Typically low yields are observed A stoichiometric amount of Co2(CO)8 is often employed Intermolecular cyclization requires a strained olefin Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc. Perkin Trans. 11973, 977-981.

  6. PKR Applied to the Cyclocarbonylationof Enynes First Intramolecular account (1981): Alkene strain requirement overcome by placing olefin and alkyne in close disposition [3.3.0] and [4.3.0] systems containing functionality prepared from simple acyclic starting material Schore, N. E.; Croudace, M. C. J. Org. Chem.1981, 46, 5436-5438.

  7. Mechanistic and Stereochemical Considerations Magnus, P.; Principe, L. M.; Slater, M. J. J. Org. Chem.1987, 52, 1483-1486.

  8. Application of the Intramolecular Pauson-KhandReaction to the Total Synthesis of (±)-Quadrone (±)-Quadrone Magnus, P.; Principe, L. M.; Slater, M. J. J. Org. Chem.1987, 52, 1483-1486.

  9. Catalytic Intramolecular Pauson-Khand Reaction Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc.1994, 116, 3159-3160.

  10. Zirconium Promoted Cyclocarbonylationsand Reductive Cyclizations Many groups (Z) are accommodated on the acetylene terminus Reactions can typically be run at room temperature Zirconacyclopentenes are stable and isolable Reactions require a stoichiometric amount of Zr Reactions fail with terminal acetylenes Conditions are not very compatible with ester and other polar functionalities Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A. J. Am. Chem. Soc.1985, 107, 2568-2569.

  11. Substrate Scope Complete selectivity of olefin geometry in each reductive cyclization product Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.1989, 111, 3336-3346.

  12. Diastereoselectivity and Further Substrate Scope in Zr(II) Mediated Reductive Cyclizations Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron1995, 51, 4421-4438

  13. 1,7-Enynes with PropargylicSubstituent Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron1995, 51, 4421-4438

  14. 1,7-Enynes with an Allylic Substituent Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron1995, 51, 4421-4438

  15. 1,6-Enynes with an Allylic Substituent

  16. Synthesis of the Azatricyclo[7.3.0.04,9]dodeceneSystem Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem.1994, 59, 5643-5649.

  17. Titanium Promoted Cyclocarbonylation/Isocyanide Insertion Reaction Mechanism analogous to Zr mediated cyclocarbonylation Also noted reactivity with isocyanides Both reactions require a stoichiometric amount of titanium Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.1993, 115, 4912-4913.

  18. Catalytic Enyne Cyclization/IsocyanideInsertion Reaction (trialkylsilyl)cyanide- (trialkylsilyl)isocyanide equilibrium Isocyanide insertion rendered catalytic: Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.1994, 116, 8593-8601.

  19. Catalytic Enyne Cyclization/IsocyanideInsertion Reaction Scope

  20. Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.1994, 116, 8593-8601.

  21. Direct Titanium Catalyzed AsymmetricCyclocarbonylation Favored Disfavored Ingate, S. T.; Marco-Contelles, J. Org. Prep. Proceed. Int.1998, 30, 121-143. Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.1999, 121, 7026-7033.

  22. Substrate Scope Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.1996, 118, 11688-11689. Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.1999, 121, 7026-7033.

  23. Substrate Scope Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.1999, 121, 7026-7033.

  24. Titanium Catalyzed Cycloisomerization Proposed catalytic cycle: Yields 1,4-dienes selectively, unlike Pd chemistry Enynes with a cis-olefin will not cycloisomerize Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.1999, 121, 1976-1977.

  25. Enyne Substrates Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.1999, 121, 1976-1977.

  26. Rhodium Catalyzed Cycloisomerizations Highly selective for 1,4-diene formation Reactions carried out near room temperature cis + trans-olefins are cycloisomerized Cycloisomerization success of a given substrate is very ligand dependant Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc.2000, 122, 6490-6491.

  27. Substrate/Ligand Combinations Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc.2000, 122, 6490-6491.

  28. Rhodium Catalyzed Asymmetric Cycloisomerization of 1,6-enynes Cao, P.; Zhang, X. Angew. Chem. Int. Ed. Engl.2000, 39, 4104-4106.

  29. Substrate/Ligand Combinations Cao, P.; Zhang, X. Angew. Chem. Int. Ed. Engl.2000, 39, 4104-4106.

  30. Rhodium Catalyzed Cyclocarbonylation Atmospheric pressure of CO Catalyst commercially available Ability to cyclize enynes bearing terminal alkynes Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett.1998, 249-250

  31. Rhodium Catalyzed CO-Transfer Cyclocarbonylation Proposed Partial Catalytic Cycle: Aldehyde source of CO No need for high pressure CO(g) Rh catalyzes both a decarbonylation and cyclocarbonylation in one pot Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc.2002, 124, 3806-3807.

  32. CO-Transfer Scope Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc.2002, 124, 3806-3807.

  33. Nickel Catalyzed Alkylative andReductive Cyclizations of Alkynyl Enones Complete stereocontrol of exocyclic olefin geometry in the construction of tri- or tetrasubstituted alkenes Freedom in olefin geometry through order of substituent introduction Alkene moiety in the enyne must be sufficiently electron poor Montgomery, J. Acc. Chem. Res.2000, 33, 467-473.

  34. Stereochemical Freedom in the Synthesis ofAlkylidenecyclopentanes Chemist possesses complete stereochemical control through substituent ordering Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc.1997, 119, 4911-4920.

  35. Mechanistic Considerations Alkylative Cyclization Reductive Cyclization Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc.1997, 119, 4911-4920.

  36. Synthetic Transformations Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc.1996, 118, 2099-2100.

  37. Synthetic Problems Strained Spirocycles Total Synthesis of (+)-a-allokainic acid (+)-a-allokainic acid Montgomery, J. Acc. Chem. Res.2000, 33, 467-473.

  38. Palladium Catalyzed Cycloisomerizationof Enynes to 1,3- and 1,4-dienes Ability to form products not accessible from the thermal ene reaction Reactions compatible with a variety of functional groups Terminal Alkynes are acceptable Sensitive to reaction conditions Trost, B. M.; Lautens, M. J. Am. Chem. Soc.1985, 107, 1781-1783.

  39. Substrate Scope Trost, B. M.; Lautens, M. J. Am. Chem. Soc.1985, 107, 1781-1783.

  40. Reaction Medium Dependence Trost, B. M.; Pedregal, C. J. Am. Chem. Soc.1992, 114, 7292-7294.

  41. Mechanistic Possibilities (Cyclopalladation) Trost, B. M. Acc. Chem. Res.1990, 23, 34-42.

  42. Mechanistic Possibilities (Hydropalladation) Trost, B. M. Acc. Chem. Res.1990, 23, 34-42.

  43. Total Synthesis of 7-O-methyldehydropinguisenol 7-O-methyldehydro- pinguisenol Harada, K.; Tonoi, Y.; Kato, H.; Fukuyama, Y. Tetrahedron Lett.2002, 43, 3829-3832.

  44. Palladium Catalyzed Alkylative Cyclization of 1,6- and 1,7-Enynes Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc.1992, 114, 9836-9845.

  45. Alkylative Cyclization Scope Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem. Soc.1992, 114, 1923-1924.

  46. Efficient Synthesis of Vitamin D3Metabolite Alphacalcidiol via Pd CatalyzedAlkylative Cyclization Alphacalcidiol Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc.1992, 114, 9836-9845.

  47. Summary Various transition metal complexes effect the intramolecular carbocyclization of enynes Complex molecules can be efficiently prepared from simple starting materials Reactions offer complete stereoselectivity in exocyclic olefin formation: A formidable challenge Cyclizations often exhibit excellent diastereoselectivity among ring substituents Enyne transformations may be catalytic and/ or asymmetric

  48. Acknowledgements Prof. Johnson Johnson Group UNC-CH

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