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   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 Will Discuss:

3. Reaction Pathways Cycloisomerization Cyclocarbonylation   No net change in oxidation state   Complete “Atom Economy”   Selective geometry about alkene bearing R 1   Construction of cyclopentenones employing CO source   Pauson-Khand, Pauson-Khand type reaction

4. Reaction Pathways Reductive Cyclization Alkylative Cyclization   Incorporation of carbon containing fragment onto alkyne moiety   Selective geometry about exocyclic alkene bearing new group   Net addition of H 2 into cyclized product   Selective geometry about alkene bearing R 1

5. Cobalt (The Pauson-Khand Reaction)   Typically low yields are observed   A stoichiometric amount of Co 2 (CO) 8 is often employed   Intermolecular cyclization requires a strained olefin Original account (1973): Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc. Perkin Trans. 1 1973, 977-981.

6. PKR Applied to the Cyclocarbonylation of 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-Khand Reaction 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 Cyclocarbonylations and 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. Tetrahedron 1995, 51, 4421-4438

13. 1,7-Enynes with Propargylic Substituent Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421-4438

14. 1,7-Enynes with an Allylic Substituent Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421-4438

15. 1,6-Enynes with an Allylic Substituent

16. Synthesis of the Azatricyclo[7.3.0.0 4,9 ]dodecene System 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 Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 4912-4913. Both reactions require a stoichiometric amount of titanium

18. Catalytic Enyne Cyclization/Isocyanide Insertion 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/Isocyanide Insertion Reaction Scope

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

21. Direct Titanium Catalyzed Asymmetric Cyclocarbonylation FavoredDisfavored 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. 1999, 121, 7026-7033. Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 11688-11689.

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

24. Titanium Catalyzed Cycloisomerization   Yields 1,4-dienes selectively, unlike Pd chemistry   Enynes with a cis-olefin will not cycloisomerize Proposed catalytic cycle: 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   Aldehyde source of CO   No need for high pressure CO(g)   Rh catalyzes both a decarbonylation and cyclocarbonylation in one pot Proposed Partial Catalytic Cycle: 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 and Reductive 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 of Alkylidenecyclopentanes Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911-4920. Chemist possesses complete stereochemical control through substituent ordering

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 R1R1 R2R2 yield (%) HMe82 HBu51 + 11 reductive HPh61 HCH=CH 2 59 PhBu68 + 8 reductive BuPh38 R1R1 yield H92 Ph47 + 19 alkylative Bu58 + 16 alkylative Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099-2100.

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

38. Palladium Catalyzed Cycloisomerization of 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 Harada, K.; Tonoi, Y.; Kato, H.; Fukuyama, Y. Tetrahedron Lett. 2002, 43, 3829-3832. 7-O-methyldehydro- pinguisenol

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 D 3 Metabolite Alphacalcidiol via Pd Catalyzed Alkylative Cyclization Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 9836-9845. Alphacalcidiol

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