1、Advances in Metal Mediated Intramolecular Enyne Carbocyclizations,Patrick D. PohlhausThe 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 thecycloisomerization, cyclocarbonylation, alkylative cyclization, a
2、ndreductive cyclization of 1,6 and 1,7 enynesAdvantages/Disadvantages of each metalSubstrate scopeStereoselectivity issues, including asymmetric induction where applicableApplications of methodology to synthetic problems,Will Discuss:,Reaction Pathways,Cycloisomerization,Cyclocarbonylation,No net ch
3、ange in oxidation stateComplete “Atom Economy”Selective geometry about alkene bearing R1,Construction of cyclopentenones employing CO sourcePauson-Khand, Pauson-Khand type reaction,Reaction Pathways,Reductive Cyclization,Alkylative Cyclization,Incorporation of carbon containing fragment onto alkyne
4、moietySelective geometry about exocyclic alkene bearing new group,Net addition of H2 into cyclized productSelective geometry about alkene bearing R1,Cobalt (The Pauson-Khand Reaction),Typically low yields are observedA stoichiometric amount of Co2(CO)8 is often employedIntermolecular cyclization req
5、uires 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.,PKR Applied to the Cyclocarbonylation of Enynes,First Intramolecular account (1981):,Alkene strain requirement overcome by placing olef
6、in andalkyne in close disposition3.3.0 and 4.3.0 systems containing functionality preparedfrom simple acyclic starting material,Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436-5438.,Mechanistic and Stereochemical Considerations,Magnus, P.; Principe, L. M.; Slater, M. J. J. Org. Chem. 198
7、7, 52, 1483-1486.,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.,Catalytic Intramolecular Pauson-Khand Reaction,Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. A
8、m. Chem. Soc. 1994, 116, 3159-3160.,Zirconium Promoted Cyclocarbonylations and Reductive Cyclizations,Many groups (Z) are accommodated on the acetylene terminusReactions can typically be run at room temperatureZirconacyclopentenes are stable and isolableReactions require a stoichiometric amount of Z
9、rReactions fail with terminal acetylenesConditions 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.,Substrate Scope,Complete selectivity of olefin geometry in each reductive cyclization p
10、roduct,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.,Diastereoselectivity and Further Substrate Scope in Zr(II) Mediated Reductive Cyclizations,Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron
11、 1995, 51, 4421-4438,1,7-Enynes with Propargylic Substituent,Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421-4438,1,7-Enynes with an Allylic Substituent,Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421-4438,1,6-Enynes with an Allylic Substituent,Syn
12、thesis of the Azatricyclo7.3.0.04,9dodecene System,Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59, 5643-5649.,Titanium Promoted Cyclocarbonylation/ Isocyanide Insertion Reaction,Mechanism analogous to Zr mediated cyclocarbonylation,Also noted reactivity with isocyanides,Berk,
13、 S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 4912-4913.,Both reactions require a stoichiometric amount of titanium,Catalytic Enyne Cyclization/Isocyanide Insertion Reaction,(trialkylsilyl)cyanide- (trialkylsilyl)isocyanide equilibrium,Isocyanide insertion rendered catalytic:
14、,Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8593-8601.,Catalytic Enyne Cyclization/Isocyanide Insertion Reaction Scope,Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8593-8601.,Direct Titanium Catalyzed Asymmetric Cyclocarbonylation,Favored
15、,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.,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,
16、 118, 11688-11689.,Substrate Scope,Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 7026-7033.,Titanium Catalyzed Cycloisomerization,Yields 1,4-dienes selectively, unlike Pd chemistryEnynes with a cis-olefin will not cycloisomerize,Proposed catalytic cycle:,Sturla, S. J.; Kablaoui, N. M.;
17、Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976-1977.,Enyne Substrates,Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976-1977.,Rhodium Catalyzed Cycloisomerizations,Highly selective for 1,4-diene formationReactions carried out near room temperaturecis + trans-olefin
18、s are cycloisomerizedCycloisomerization success of a given substrateis very ligand dependant,Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490-6491.,Substrate/Ligand Combinations,Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490-6491.,Rhodium Catalyzed Asymmetric Cycloisome
19、rization of 1,6-enynes,Cao, P.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2000, 39, 4104-4106.,Substrate/Ligand Combinations,Cao, P.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2000, 39, 4104-4106.,Rhodium Catalyzed Cyclocarbonylation,Atmospheric pressure of COCatalyst commercially availableAbility to cycliz
20、e enynes bearing terminal alkynes,Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249-250,Rhodium Catalyzed CO-TransferCyclocarbonylation,Aldehyde source of CONo need for high pressure CO(g)Rh catalyzes both a decarbonylation and cyclocarbonylationin one pot,Proposed Partial Catalytic Cycle:
21、,Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806-3807.,CO-Transfer Scope,Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806-3807.,Nickel Catalyzed Alkylative and Reductive Cyclizations of Alkynyl Enones,Complete stereocontrol of
22、exocyclic olefin geometryin the construction of tri- or tetrasubstituted alkenesFreedom in olefin geometry through order of substituent introductionAlkene moiety in the enyne must be sufficiently electron poor,Montgomery, J. Acc. Chem. Res. 2000, 33, 467-473.,Stereochemical Freedom in the Synthesis
23、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,Mechanistic Considerations,Alkylative Cyclization,Reductive Cyclization,Montgomery, J.; Oblinger, E.; Savch
24、enko, A. V. J. Am. Chem. Soc. 1997, 119, 4911-4920.,Synthetic Transformations,Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099-2100.,Synthetic Problems,Strained Spirocycles,Total Synthesis of (+)-a-allokainic acid,(+)-a-allokainic acid,Montgomery, J. Acc. Chem. Res. 2000, 33, 467-4
25、73.,Palladium Catalyzed Cycloisomerization of Enynes to 1,3- and 1,4-dienes,Ability to form products not accessible from the thermal ene reactionReactions compatible with a variety of functional groupsTerminal Alkynes are acceptableSensitive to reaction conditions,Trost, B. M.; Lautens, M. J. Am. Ch
26、em. Soc. 1985, 107, 1781-1783.,Substrate Scope,Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781-1783.,Reaction Medium Dependence,Trost, B. M.; Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292-7294.,Mechanistic Possibilities (Cyclopalladation),Trost, B. M. Acc. Chem. Res. 1990, 23, 34-42.,Me
27、chanistic Possibilities (Hydropalladation),Trost, B. M. Acc. Chem. Res. 1990, 23, 34-42.,Total Synthesis of 7-O-methyldehydropinguisenol,Harada, K.; Tonoi, Y.; Kato, H.; Fukuyama, Y. Tetrahedron Lett. 2002, 43, 3829-3832.,7-O-methyldehydro- pinguisenol,Palladium Catalyzed Alkylative Cyclization of 1
28、,6- and 1,7-Enynes,Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 9836-9845.,Alkylative Cyclization Scope,Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem. Soc. 1992, 114, 1923-1924.,Efficient Synthesis of Vitamin D3 Metabolite Alphacalcidiol via Pd Catalyzed Alkylative
29、Cyclization,Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 9836-9845.,Alphacalcidiol,Summary,Various transition metal complexes effect theintramolecular carbocyclization of enynesComplex molecules can be efficiently preparedfrom simple starting materials,Reactions offer complete stereoselectivity in exocyclicolefin formation: A formidable challengeCyclizations often exhibit excellent diastereoselectivityamong ring substituentsEnyne transformations may be catalytic and/ or asymmetric,Acknowledgements,Prof. Johnson Johnson Group UNC-CH,
