Lecture: Transition Metal Catalyzed Complexity Generating Reactions 2 MetathesisOutline Overview of olefin metathesis Olefin metathesis 1. Ring closing metathesis 2. Ring opening metathesis 3. Cross metathesis Enyne metathesis Diyne metathesisReference ACIEE., 2000, 39, 3012 ACIEE., 1997, 36, 2036 JCS. PT1, 1998, 371 Tetrahedron. 1998, 54, 4413 Acc. Chem. Res. 1995, 28, 446更多资源xiti123.taobao.com Organo-transition Metal ChemistryChemistry involves intermediates containing transition metal- carbon bondsOlefin MetathesisOlefin Metathesis: metal-catalyzed exchange of olefins. Metal-carbene ComplexOlefin metathesis catalysts tend to be between Schrock and Fischer carbenesRepresentative CatalystsDevelopment of well-defined metal-carbene complexes as pre-catalystsDevelopments in CatalystSigma-donating N-heterocyclic carbene ligands increase general reactivity and thermal stability Arduengo A. et al Acc. Chem. Res. 1999, 32, 913Attaching Privileged chiral ligand Possible bench top use Hoveyda. A. H. et al Angew. Chem. Int. Ed. 2001, 40, 1452Still useful for some substrates Air and moisture sensitive (glove box)J. Org. Chem. 1998, 63, 8626Mechanistic Model of the Metathesis ReactionConsists of a sequence of reversible formal 2+2 cycloaddition/ cycloreversion processes.Grubbs. R. H. et al J. Am. Chem. Soc. 1975, 97, 3265Categories of Metathesis EventsRCM (Ring-closing metathesis)A B CROM (Ring-opening metathesis) C B ACM (Cross metathesis)A B DROMP (Ring-opening metathesis polymerization)C B EEngineering the Direction of the Equilibrium for Ring Closing MetathesisEthylene gas generally decreases RCM rate Lower concentration can prevent polymerization and cross metathesis Higher temperature usually promotes RCM process (S gain)Detailed Mechanistic Model of RCMDissociative pathway dominates Grubbs. R. H. et al J. Am. Chem. Soc. 1997, 119, 3887Factors Affecting RCMSubstitution effects on metal carbene and olefin exchange (sterics and electronics)Grubbs. R. H. et al. Organometallics 1998, 17, 2484RCM is one of the most useful strategies for ring closure but it cannot be used to make three or four membered rings due to ring strain and the reversibility of the processMaier. M. E. et al. Angew. Chem. Int. Ed. 2000, 39, 2073Substitution Effects on RCM: A Comparison of CatalystsChemtracts (Org. Chem) 2000, 88RCM: An Invaluable Tool for Generation of Cyclic Structures in TOSRemarkable functional group toleranceDanishesky. S. J. et al J. Am. Chem. Soc. 1997, 119, 10073Martin. S. F. et al J. Am. Chem. Soc. 1999, 121, 866 Furstner. A. et al J. Org. Chem. 1996, 61, 8746 Hoveyda. A. H et al J. Am. Chem. Soc. 1995, 117, 2943Clark. J. et al Angew. Chem. Int. Ed. 2000, 39, 372Double RCM 1Diastereoselective two-directional RCMAbout “Two-directional chain synthesis in TOS”Schreiber. S. L. et al Acc. Chem. Res. 1994, 27, 9Double RCM 2Wallace. D. J. et al Tet. Lett. 2000, 41, 2027 Harrity. J. P. et al Tet. Lett. 1999, 40, 3247Differentiation of diastereotopic olefinsROM/Double RCM 1 A powerful topology-altering reaction.Schreiber. S. L. et al, Org. Lett. 2000, 2, 709Shair M. D. et al, unpublishedROM/Double RCM or RCMSchreiber. S. L. et al unpublishedOne stereocenter dictates mode of cyclization ROM/RCM 2Unstrained cyclic olefin (cyclopentane, cyclohexane). Ethylene gas prevents polymerization. Subtle differences in substrates frequently alter the equilibrium.Blechert. S. et al Chem. Comm. 2000, 1501ROM/Double RCM 3Burke. S. D. et al J. Org. Chem. 1998 63 8826Difference in reactivity of two catalystsRCM: Macrocycle SynthesisFurstner. A. et al, Synthesis 1997 792En Masse Generation of Macrocycles Using Conformational AnalysisSchreiber. S. L. et al J. Am. Chem. Soc. 1999, 121, 10648.Expanded six-membered ring leads to higher effective molarity between two reactive termini Minimization of Syn-pentane interaction and A1,3 strainEn Masse Generation of Macrocycles Using Conformational AnalysisSchreiber S. L. et al unpublishedPreference for E-olefin formation due to the conformational bias.Cross Metathesis 1In general, lack of control of homo- and hetero-dimerization Employment of an excess of the disubstituted olefin counterpart (preformed homo-dimer) relative to terminal olefin leads to selective formation of hetero-dimer. Grubbs. R. H. et al. J. Am. Chem. Soc. 2000, 122, 58Cross Metathesis 2Grubbs. R. H. et al. J. Am. Chem. Soc. 2000, 122, 3783Smith III. A. B. et al J. Am. Chem. Soc. 2000, 122, 4984Also Furstner. A. et al Org. Lett. 2001, 3, 449CM/Macro-RCM 1Target product is much lower in energy than other possible products Remarkable robustness of metal carbene species Exploitation of reversible nature of cross-metathesis processCM-RCM 2 Convergence of Intermediates to ProductsSmith III. A. B. et al J. Am. Chem. Soc. 2000, 122, 4984Enyne MetathesisMechanism: Yne-ene type or Ene-yne typeEnyne-RCM giv