I-M. Alkene MetathesisI. Basic Principles19901991199219931994199519961997199819992000200120020102030405060708090100110Grubbs IIpublishedGrubbs IIpublishedDr. P. WipfPage 1 of 382/25/2008The CatalystsThe CatalystsSchrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O'Reagan, M.J. Am. Chem. Soc. 1990, 112, 3875NMoOOMeF3CCF3MeF3CCF3C(Me)2Phi-Pr i-PrHSchrock ICy3PRuPCy3PhClClCl2(PCy3)2Ru=CHPhGrubbs ISchwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.Angew. Chem. Int. Ed. Engl. 1995, 34, 2039H(H2IMes)(PCy3)Cl2Ru=CHPhGrubbs IIRuPCy3PhClClNNScholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.Org. Lett. 1999, 1, 953RuPhClClNMesMesNNNBrBr(H2IMes)(3-Br-py)2Cl2Ru=CHPhGrubbs IIILove, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H.Angew. Chem. Int. Ed. 2002, 41, 4035RuClClNMesMesNOGreen GrubbsKingsbury, J. S.; Harrity, J. P. A.; Hoveyda, A. H.J. Am. Chem. Soc. 1999, 121, 791Dr. P. WipfPage 2 of 382/25/2008Hoveyda, A. H.; Zhugralin, A. R., "The remarkable metal-catalysed olefin metathesis reaction." Nature2007, 450, 243-251.Dr. P. WipfPage 3 of 382/25/2008 The Nobel Prize in Chemistry 2005Yves ChauvinInstitut Français du Pétrole, Rueil-Malmaison, France,Robert H. GrubbsCalifornia Institute of Technology (Caltech),Pasadena, CA, USA andRichard R. SchrockMassachusetts Institute of Technology(MIT), Cambridge, MA, USA"for the development of the metathesismethod in organic synthesis".Ring-Closing Metathesis (RCM) and Ring-Opening Metathesis (ROMP)• Introduction• RCM• Cross-Metathesis• ROMPhttp://nobelprize.org/chemistry/laureates/2005/animation.htmlDr. P. WipfPage 4 of 382/25/2008[M]R1R2R2[M]R1R2R2[M]R2R1R2[M]R1OR1[M]OR1R2[M]OR1R2Dr. P. WipfPage 5 of 382/25/2008RCM-C2H4ROM+C2H4ROMPMnADMET-nC2H4R1R2CM-C2H4R2R1R1R1R2R2Important types of metathesis reactions:RCM = ring-closing metathesisROM = ring-openingmetathesisROMP = ring-openingmetathesis polymerizationADMET = acyclic dienemetathesis polymerizationCM = cross-metathesisDr. P. WipfPage 6 of 382/25/2008Stille, J. R.; Grubbs, R. H., "Synthesis of (+-)-d9,12-capnellene using titanium reagents." J. Am.Chem. Soc. 1986, 108, 855-856.Nicolaou, K. C.; Bulger, P. G.; Sarlah, D., "Metathesis reactions in total synthesis." Angew.Chem., Int. Ed. 2005, 44, 4490-4527.History of RCMCO2tBuCp2TiClAlMe2CO2tBuCp2Ti10 steps!9,12-CapnellenetBuOCO2tBuCp2TiCp2Ti=CH2 + Me2AlClDr. P. WipfPage 7 of 382/25/2008From the point of view of organic synthesis, the firstnoteworthy, but largely ignored, example of a ring closingdiene metathesis reaction appeared in 1980:History of RCMOO20 mol% WClO4 + 24 mol% Cp2TiCl221OO12%Tsuji, J.THL 1980, 21, 2955 Dr. P. WipfPage 8 of 382/25/2008Important Technical ApplicationsPhillips triolefin process++Shell higher olefin process+10-202-79-13[Mo][cat]SHOPRRRDr. P. WipfPage 9 of 382/25/2008Important Technical ApplicationsNorsorex processn[W]ROMPnHüls-Vestenamer process[cat]nnROMPDr. P. WipfPage 10 of 382/25/2008Molybdenum-Based Olefin MetathesisMoO2Cl2(THF)2+ArNH(TMS)2lutidineTMSClDMEMo(NAr)2Cl2(DME)RCH2MgCl2Mo(NAr)2(CH2R)2TfOHDMEMo(NAr)(CH2R)(OTf)2(DME)LiOR'2Mo(NAr)(CHR)(OR')2C(Me)2PhR':C(Me)(CF3)2Schrock, JACS 1990, 112, 3875R:Dr. P. WipfPage 11 of 382/25/2008Molybdenum-Based Ring-Closing Olefin MetathesisOPhMoNOOF3CF3CCF3F3CPhA (5 mol%)OPh93%Dr. P. WipfPage 12 of 382/25/2008Molybdenum-Based Ring-Closing Olefin MetathesisXu, Z.; Johannes, C. W.; Salman, S. S.; Hoveyda, A. H. J.Am. Chem. Soc. 1996, 118, 10926.Dr. P. WipfPage 13 of 382/25/2008Ruthenium-Based Olefin MetathesisThe synthesis of ruthenium vinylcarbene complexes allowedthe development of well-defined, late transition metal, lowoxidation state complexes that catalyze olefin metathesis.Ruthenium carbene complexes are significantly easier tomake and handle than the Schrock molybdenum complex.In addition to the metathesis of strained cyclic and exocyclicolefins, the remarkable functional group tolerance (alcohols,aldehydes, carboxylic acids) and stability toward air, water,and acid has made this class of compounds particularlyattractive for practical applications (Grubbs, R. H.; Miller, S. J.;Fu, G. C. Acc. Chem. Res. 1995, 28, 446).Dr. P. WipfPage 14 of 382/25/2008Ruthenium-Based Olefin Metathesis: MechanismDias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.1997, 119, 3887.(PCy3)2Cl2Ru=CH2 +K1(PCy3)2Cl2Ru=CH2K2-PCy3+PCy3(PCy3)Cl2Ru=CH2k3(PCy3)Cl2Ru+PCy3-H2C=CH2+ (PCy3)2Cl2Ru=CH2k4I1I2(PCy3)2Cl2Ru-H2C=CH2Dr. P. WipfPage 15 of 382/25/2008Ruthenium-Based Olefin Metathesis: MechanismMechanistically, the major pathway (>95%) was found to involve phosphinedissociation from the metal center, such that a minor associative pathway in whichboth phosphines remain bound can be considered to operate only at higherphosphine concentrations. The formation of the 14-electron metallacyclobutaneintermediate is the rate-determining step. The rate and catalyst activity are directlyproportional to (a) K1, the equilibrium constant for olefin binding, (b) K2, theequilibrium constant for phosphine dissociation, (c) k3, the rate constant formetallacyclobutane formation from the monophosphine olefin complex I2.RuCy3PPCy3ClR1HClK1K2RRRuCy3PPCy3ClR1HClRI1- PCy3+ PCy3RuCy3PClHR1ClRI2k3k4RuCy3PClHR1ClR- H2C=CHR1+ PCy3PRODUCT- H2C=CHR1PRODUCTSRuCy3PClHR1ClRPCy3Dr. P. WipfPage 16 of 382/25/2008Ruthenium-Based Olefin Metathesis: ApplicationsNNHNNHOHNNCO2EtOPhHCO2MeNNOHCH2OBDPSOONNHCH2OBDPSOOONNOPhHCO2MeONNOPhHCO2MeOManzamine AB, 1equiv. rt, 5 days30%Pandit, THL 1994, 35, 3191Martin, THL 1994, 35,691A, benzene50°C, 63%(Z only)MoNOOF3CF3CCF3F3CPhARuPCy3PCy3ClClPhPhBDr. P. WipfPage 17 of 382/25/2008NONOHNOOONSNMeOHNCO2HBILN 2061Large-scale preparation of pharmaceutical candidates: Hepatitis Cprotease inhibitor BILN 2061 developed by Boehringer-IngelheimNOHNOHNOOOCO2MeSOOBrORuClClPtoluene, 80 °C>400 kg scaleNOHNOHNOOOCO2MeSOOBr83%, >99% cisDr. P. WipfPage 18 of 382/25/2008Cross-MetathesisChallenges for successful cross-metathesis include:control of olefin geometrysuppression of homodimer formationextending functional group compatibilityOOCO2MeMoNArRF6ORF6OHCMe2Ph5 mol%OOCO2MeCNCN92% yieldexclusively ZADr. P. WipfPage 19 of 382/25/2008Cross-MetathesisChatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H., "Synthesis offunctionalized olefins by cross and ring-closing metathesis." J. Am. Chem. Soc.2000, 122, 3783.Dr. P. WipfPage 20 of 382/25/200810 mol% Grubbs II,CH2Cl2, reflux, 6 hRClR ClLiu, B.; Das, S. K.; Roy, R. Org. Lett. 2002,
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