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

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:

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

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

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 ,

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,

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

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,

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

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,

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,

Diastereoselectivity and Further Substrate Scope in Zr(II) Mediated Reductive Cyclizations Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51,

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

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

1,6-Enynes with an Allylic Substituent

Synthesis of the Azatricyclo[ ,9 ]dodecene System Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59,

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, Both reactions require a stoichiometric amount of titanium

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,

Catalytic Enyne Cyclization/Isocyanide Insertion Reaction Scope

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

Direct Titanium Catalyzed Asymmetric Cyclocarbonylation FavoredDisfavored Ingate, S. T.; Marco-Contelles, J. Org. Prep. Proceed. Int. 1998, 30, Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,

Substrate Scope Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,

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

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,

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

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,

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

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

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

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,

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,

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

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,

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

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

Synthetic Transformations R1R1 R2R2 yield (%) HMe82 HBu reductive HPh61 HCH=CH 2 59 PhBu reductive BuPh38 R1R1 yield H92 Ph alkylative Bu alkylative Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118,

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

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,

Substrate Scope Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107,

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

Mechanistic Possibilities (Cyclopalladation) Trost, B. M. Acc. Chem. Res. 1990, 23,

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

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

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

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

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, Alphacalcidiol

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

Acknowledgements Prof. Johnson Johnson Group UNC-CH