藥物合成反應(yīng)課件rearrangement

第五章重排反應(yīng)Chapter5RearrangementReaction

1,2;1,3;1,4;1,5;3,3etcNucleophilicElectrophilicRadicalRearrangement-shift親核重排親電重排自由基重排-遷移重排CC;CHeteroatom;HeteroatomCNucleophilicrearrangementsRearrangementsinvolving1,2-shiftstoelectron-deficientatoms.ElectrophilicrearrangementsRearrangementsinvolving1,2-shiftstoelectron-richatoms.FreeradicalrearrangementsSigmatropicrearrangementRearrangementBaker-VenkataramanrearrangementBenzilicacidrearrangementBrookrearrangementCiamician-DennstedtrearrangementFavorskiirearrangementHofmannrearrangementLossenrearrangementPaynerearrangementQuasi-FavorskiirearrangementRamberg-B?klundrearrangementSmilesrearrangementWittigrearrangementAnionicCationicAmadorireaction/rearrangementBeckmannrearrangementTiffeneau-DemjanovrearrangementDienone-phenolrearrangementFerrierreactionFriesrearrangementMeyer-SchusterrearrangementRuperearrangementPetasis-FerrierrearrangementPinacolrearrangementPrins-PinacolrearrangementPummererrearrangementSchmidtreactionWagner-MeerweinrearrangementRearrangementAza-ClaisenrearrangementAza-CoperearrangementAza-WittigrearrangementCarrollrearrangementClaisenrearrangementClaisen-IrelandrearrangementCoperearrangementEschenmoser-ClaisenrearrangementJohnson-ClaisenrearrangementMeisenheimerrearrangementMislow-EvansrearrangementOvermanrearrangementOxy-CoperearrangementSommelet-HauserrearrangementSigmatropic(neutral)OthersANRORC(anionicring-openingring-closing） DimrothrearrangementBiradicalordipolar

Vinylcyclopropane-cyclopentene rearrangementConcertedBaeyer-Villigeroxidation/rearrangementDipolarCornforthrearrangementNeutralWolffrearrangementCurtiusrearrangementRadicalpairStevensrearrangement5-1RearrangementfromCtoC1.Wagner-MeerweinAcid-catalyzedalkylgroupmigrationofalcoholstogivemoresubstitutedolefins.Wagner-MeerweinReview:Creary,X.Chem.Rev.1991,91,1625-1678.Migratinggroup:H<Alkyl<ArylDrivingforce:Togeneratemorestablecation鄰位促進(jìn)Wagner-MeerweinWagner-MeerweinWagner-MeerweinWagner-MeerweinTMS-inducedrearrangementGenerationofC+(a)haloalkane

(b)amine

(c)alcohol,alkene,epoxide,orcyclopropaneWagner-MeerweinWagner-Meerwein-ApplicationOgasaT.,etal:Org.ProcessRes.Dev.1998,2,344-350.DerivedfromantitumorantibioticduocarmycinB2Wagner-Meerwein-ApplicationSmith,A.B.,III,Konopelski,J.P.J.Org.Chem.1984,49,4094-4095.2.Pinacol(頻納醇重排)1860,R.FittigPinacolaryl~H~vinyl(alkenyl)>t-Bu>>cyclopropyl>2°alkyl>1°alkylnoteasytopreparecomplexvicinaldiols;forunsymmetricalsubstrates,mixturesareobtained;sidereactionssuchasβ-eliminationsareoftenobserved;theintermediatecarbocationsmayundergoequilibration;variousconformationaleffectsandneighboringgroupparticipationincyclicsystemsarecomplicatingfactors.MechanismMigratingabilityDrawbacks(limitations)Stabilityofcarbocation×

ControlledmigrationPinacol(±)-furoscrobiculinB:lactaranesesquiterpeneisolatedfrom

basidiomycetesofmushroomsKanematsu,K.,J.Chem.Soc.,PerkinTrans.11997,1707-1714.PinacolRearrangement-applicationProduct?PinacolRearrangement-applicationOvermanL.E.etal,J.Org.Chem.,62,6379(1997)Carbonyl-ene–pinacolSemipinacolRearrangementTiffeneau-Demyanov3、Benzil-BenzilicAcid

(二苯基乙二酮-二苯基乙醇酸型重排)

α-DioneDrivingforce：formationofstablecarboxylateα-hydroxyacetateBaseReview:Gill,G.B.Benzyl-benzilicacidrearrangements.inComp.Org.Synth.(eds.Trost,B.M.,Fleming,I.),3,821-838(Pergamon,Oxford,1991).Mechanism:Variation:Limitations:1.Noα-Hpresentsinthealcoholicsalt;2.Phenolicsaltcannotbeused.Why?Benzil-BenzilicAcidRearrangementBenzil-BenzilicAcidRearrangementUnsymmetricMigratinggroup?Benzil-BenzilicAcidRearrangementBenzil-BenzilicAcidRearrangementApplicationStoltz,B.M.,Wood,J.L.TetrahedronLett.1996,37,3929-3930.4.Favorski(法沃爾斯基）Rearrangement

α-haloketone(+α-proton)→branchedcarboxylicacidsMechanism:Base-selectionFavorskiRearrangementApplicationApplicationTakeshita,H.et.al.J.Org.Chem.1994,59,6490-6492.Lee,E.,Yoon,C.H.J.Chem.Soc.,Chem.Commun.1994,479-481.5、WolffRearrangementandArndt-Eistertα-diazoketoneketeneHeat,light,ormetalThermalconditionsarenotusedfrequently(sidereactions)Rh-andplexesusuallypreventtheWolffrearrangementfreshlypreparedsilver(I)oxideorsilver(I)benzoatearebestphotochemicalactivationisconvenient(lowtemperature)5、WolffRearrangementMechanismPreparationofDiazoCompoundsArndt-EistertWolffandArndt-EistertPreparationofDiazoCompoundsApplication-WolffNorbeck,D.W.,Kramer,J.B.J.Am.Chem.Soc.1988,110,7217-7218.DanheiserbenzannulationDanheiser,R.L.,Helgason,A.L.J.Am.Chem.Soc.1994,116,9471-94Application-Arndt-EistertGademann,K.,Seebach,D.etal.Angew.Chem.,Int.Ed.Engl.1999,38,1223-1226.Nicolaou,K.C.,Baran,P.S.,Angew.Chem.,Int.Ed.Engl.1999,38,1669-1675.1.Beckmann

Rearrangement

5-2

RearrangementfromCto

HeteroatomAldoximes/ketoximes→amidesTheRgroupantitotheleavinggrouponthenitrogenwillmigrate!non-catalytic!LargeamountsofstrongBr?nstedacidsLeaving-migration------Concertedprocess!MechanismBr?nsted:H+,H2SO4,HCl,H3PO4Non-Br?nsted:PCl5,SOCl2,TsCl,AlCl3

ProblemwithBr?nstedacid---IsomerizationBeckmann

Rearrangement

Migratinggroup?Foracid-sensitivesubstrateBeckmann

Rearrangement

Beckmann

Rearrangement

Beckmann

Rearrangement

ApplicationForsyntheticfibersMani,N.S.,Wu,M.Tetrahedron:Asymmetry2000,11,4687-4691.Smith,B.T.,Wendt,J.A.,Aube,J.Org.Lett.2002,4,2577-2579.

ApplicationWhite,J.D.,Hrnciar,P.,J.Org.Chem.1999,64,7871-7884.BsCl=4-bromobenzenesulfonylchloride

ApplicationWhite,J.D.,Choi,Y.Org.Lett.2000,2,2373-2376.2.Hofmann

Rearrangement1881,A.W.HoffmannAlternative:oxidativeHofmannrearrangementLTA=Pb(OAc)42.Hofmann

RearrangementMechanism2.Hofmann

RearrangementMechanism2.Hofmann

RearrangementMechanismAnalogousreactions:Curtius,Lossen,SchmidtCompleteretentionofconfiguration----concertedprocess!Whenα-hydroxy、amino、halo、orvinylpresents,aldehyde

orketonewasproduced

ApplicationApplicationApplicationSchultz,A.G.,Wang,A.J.Am.Chem.Soc.1998,120,8259-8260.hasubananalkaloidEvans,D.A.,Scheidt,K.A.,Downey,C.W.Org.Lett.2001,3,3009-3012.ApplicationDeMong,D.E.,Williams,R.M.J.Am.Chem.Soc.2003,125,8561-8565.1872,W.LossenLossenRearrangementMechanismNeeds,P.W.,etal.Carbohydr.Res.2001,333,47-58.ApplicationNonpeptidicinhibitorofhumanneutrophilelastaseOhmoto,K.,etal.Synlett2001,299-301.Acylazide→isocynate3.CurtiusRearrangementCatalyzedbybothproticandLewisacidsandthepositiontemperatureissignificantlylowered.CurtiusRearrangementMechanismHargerreactionCurtiusRearrangementPreparationofacylazidesDPPACurtiusRearrangementcytokinemodulatorApplicationMarco,J.A.etal.Tetrahedron:Asymmetry2002,13,1005-1010.Boger,D.L.,etal.J.Am.Chem.Soc.1993,115,10733-10741.ApplicationKawahara.N.etal.Tetrahedron2002,58,4917-4924.antimuscarinic

alkaloidKim,D.etal.Org.Lett.2002,4,1343-1345.4.SchmidtRearrangement1923,K.F.Schmidt.Carbonylcompoundswithhydrazoicacidoralkylazidesinthepresenceofacidcatalyststogiveamides,nitriles,andamines4.SchmidtRearrangementMechanismMigratingorder:Ar>alkylSchmidtRearrangementApplicationSchultz,A.G.,etal.J.Med.Chem.1996,39,1956-1966.Aube,J.etal.J.Am.Chem.Soc.2002,124,9974-9975.5.Baeyer-Villiger

Rearrangement(Oxidation)1899,A.BaeyerandV.VilligerOxidationwithperoxyacidsgenerallyoccursatthecarbonylgroupandnotattheC=Cdoublebond;Orderofmigration:tertiaryalkyl>secondaryalkyl>electronricharyl>aryl>primaryalkyl>methylMechanism:1953DoeringandDorfman(labelingexperiments)Baeyer-VilligerOxidatingagent:CF3CO3H>monopermaleicacid>monoperphthalicacid>3,5-dinitroperbenzoicacid>p-nitroperbenzoicacid>mCPBA~performicacid>perbenzoicacid>peraceticacid>>H2O2>t-BuOOHBaeyer-VilligerApplicationbicyclicγ-lactoneOh,J.TetrahedronLett.1997,38,3249-3250.Shing,T.K.M.,Lee,C.M.,Lo,H.Y.TetrahedronLett.2001,42,8361-8363.ApplicationMarchand,A.P.,Kumar,V.S.,Hariprakasha,H.K.J.Org.Chem.2001,66,2072-2077.Demnitz,F.W.J.etal.J.Org.Chem.1995,60,5114-51201.StevensRearrangement5-3

RearrangementfromHeteroatomtoCR1(electron-withdrawing)hastobeabletostabilizecarbanionsStevensRearrangementMechanismForallylamine,1,2-shiftversus1,4-shiftStevensRearrangementredApplicationPadwa,A.,etal.J.Org.Chem.2001,66,2414-2421.Liou,J.-P.,Cheng,C.-Y.TetrahedronLett.2000,41,915-918.ApplicationAdams,H.etal.J.Organomet.Chem.1996,524,263-266.Hanus,V.etal.J.Am.Chem.Soc.1994,116,5084-5088.McMurry:onlyintermolecularlycoupledproductswereobtained.α-chlorosulfoneprecursorfortheRamberg-B?klundrearrangementcouldnotbeprepared.2.

Sommelet-Hauser

Rearrangement[2,3]-sigmatropicrearrangementofbenzylicquaternaryammoniumsaltsinthepresenceofastrongbaseSommelet-HauserNeutralconditionSulferorPhosphineylide

canalsoundergoSommelet-Hauser

rearrangement

Sommelet-Hauser&StevensBenzylaminequaternarysaltLowtemperaturesandpolarsolvents(e.g.,NH3,DMSO,HMPA)usuallyfavortheS.-H.rearrangementHighertemperaturesandnonpolarsolvents(e.g.,hexanes,ether)facilitatetheStevensrearrangementMechanism:Sommelet-HauserSommelet-HauserApplication:Weinreb,S.M.,etal.J.Am.Chem.Soc.1982,104,536-544.AntitumorantibioticApplicationHatano,K.etal.J.Org.Chem.1994,59,148-153.Alper,P.B.,Nguyen,K.T.J.Org.Chem.2003,68,2051-2053.3.Wittig

RearrangementtheR1substituenthastobeabletostabilizethecarbanion;2)thechiralcenterinthemigratinggroupretainsitsconfiguration;3)yieldsareusuallymoderate(harshconditions/[1,4]-pathway);[2,3]-rearrangementproceedsundermilderconditionsandgiveshigheryieldsthanthe[1,2]-rearrangement;2)the[1,2]-and[2,3]-shiftsoftencompete(dependsstronglyonthestructureofthesubstrateandthereactiontemperature);Mechanism：OrderofMigration：Wittig

RearrangementThe[1,2]-Wittigrearrangementproceedsviaaradical-pairbinationmechanism(Garst,J.F.,Smith,C.D.J.Am.Chem.Soc.1973,95,6870-6871)[2,3]-WittigrearrangementN-ylideandS-ylidecanundergo2,3-WittigrearrangementWittigRearrangement[2,3]-WittigrearrangementApplicationTomooka,K.,etal.Angew.Chem.,Int.Ed.Engl.2000,39,4502-4505.Schaudt,M.,Blechert,S.J.Org.Chem.2003,68,2913-2920.StillmodificationApplicationFukuyama,Y.,etal.TetrahedronLett.1993,34,8453-8456.Nakai,T.etal.TetrahedronLett.1993,34,5923-5926.5-4.

MigrationThebondofanatomorgroupmigratestoanewposition,meanwhiletheconjugatedsystemtransferredFMO(Woodward-Hoffman)H-Migration1.Claisen

Rearrangement1912,L.ClaisenClaisenRearrangementAllallylvinylethercanundergoClaisen

rearrangementSuprafacial,concerted,nonsynchronous[3,3]-sigmatropicrearrangement.AliphaticClaisen（1）AllylvinylethertypeMoreactivedoublebondmigrates（2）VinylalcoholreactswithorthoformateAliphaticClaisenEschenmoser-ClaisenJohnson-ClaisenAromaticClaisenAromaticClaisenThioClaisenThioClaisenAminoClaisen(aza-Claisen)Lewis

acid：AminoClaisen(aza-Claisen)MechanismApplicationPaquette,L.A.etal.J.Am.Chem.Soc.2001,123,9021-9032.TebbereagentApplicationBoeckman,R.K.,Jr.etal.J.Am.Chem.Soc.2002,124,190-191.Nicolaou,K.C.,Li,J.Angew.Chem.,Int.Ed.Engl.2001,40,4264-4268.DoubleClaisenrearrangement/intramolecularDiels-AlderreactionApplicationNubbemeyer,U.J.Org.Chem.1996,61,3677-3686.diastereoselectivezwitterionicaza-ClaisenrearrangementClaisen-IrelandRearrangement1972,R.E.Ireland,EsterenolateClaisenrearrangement(1929–2012)Claisen-IrelandRearrangementMechanismApplicationPaterson,I.,Hulme,A.N.J.Org.Chem.1995,60,3288-3300.Corey,E.J.etal.J.Am.Chem.Soc.1999,121,6771-6772.ApplicationGilbert,J.C.,Selliah,R.D.J.Org.Chem.1993,58,6255-6265.EschenmoserClaisen1964,A.EschenmoserWilliams,D.R.etal.Org.Lett.2000,2,1023-1026.JohnsonClaisen1970,W.S.JohnsonBirman,V.B.,Danishefsky,S.J.J.Am.Chem.Soc.2002,124,2080-2081.2.CopeRearrangement[3,3]-

rearrangementof1,5-diene1940,A.C.CopeThetypicaltemperaturerequiredtoinduceCoperearrangementinacyclicdienesis150-260°C.2.CopeRearrangementMechanismInmostcasesthereactionsareconcertedwitharelativelylatetransitionstatewherethebondbetweenC1andC6iswell-developed.Reversible(equilibrium)

stabilityoftheethyleneCopeRearrangement92%CopeRearrangementApplicationDavies,H.M.L.,Doan,B.D.J.Org.Chem.1998,63,657-660.Hudlicky,T.,Boros,C.H.,Boros,E.E.Synthesis1992,174-178.UsuallyCoperearrangementofdivinylcyclopropanesoccursatorbelowroomtemperature1,5-Diene-3-olwillundergoOxy-Coperearrangementtogeneratealdhydeorketone(un-irreversible)Base-catalyzedOxy-Coperearrangement:lowertemperature;fasterreactionOxy-CopeRearrangementDrivingforce:carbonylcompoundformationJ.A.Berson,1964anionic-oxy-Coperearrangementslowertemperature;fasterreactionOxy-CopeRearrangementanionic-oxy-Coperearrangements：Oxy-CopeRearrangement:AnionicOxy-CopeRearrangement:Oxy-CopeRearrangementMechanismOxy-CopeRearrangementApplicationPaquette,L.A.etal.J.Am.Chem.Soc.1998,120,2543-2552.Moore,H.W.etal.J.Org.Chem.1998,63,6905-6913.1,5-diene-3-amine(ornitrogen)willundergoaza-CoperearrangementAza-CoperearrangementAza-CoperearrangementMechanismApplicationAza-CoperearrangementApplicationOverman,L.E.etal.Angew.Chem.,Int.Ed.Engl.1999,38,2934-2936.Bennett,D.J.,Hamilton,N.M.TetrahedronLett.2000,41,7961-7964.3.Fischer

IndoleSynthesisaromatichydrazoneisomerizestogenerateindole1883,E.FischerandF.Jourdan1)strongacids(e.g.,PTSA,PPA,HCl,H2SO4);2)weakacids(e.g.,pyridiniumchloride,AcOH);3)solidacids(e.g.,montmorilloniteKSFclay,Mordenite,ZelotiteY,ionexchangeresins);4)Lewisacids(PCl3,polyphosphoricacidtrimethylsilylester,ZnCl2).Catalysts:Mechanism：TheLewisacidcatalyzedreactionsoftenproceedundermilderconditions(roomtemperatureratherthanhightemperature)thanthereactionscatalyzedbyproticacidsFischer

IndoleSynthesisFischer

IndoleSynthesisFischer

IndoleSynthesisApplicationAube,J.etal.Org.Lett.2000,2,1625-1627.Roberson,C.W.,Woerpel,K.A.J.Am.Chem.Soc.2002,124,11342-11348.Fischer

IndoleSynthesisApplicationCook,J.M.etal.J.Org.Chem.1997,62,9298-9304.OtherRearrangementReactionsAmadorireaction/rearrangementTheacid-orbase-catalyzedisomerizationofN-glycosides(glycosylamines)ofaldosesto1-amino-1-deoxyketosesLewisacids(CuCl2,MgCl2,HgBr2,CdCl2,AlCl3,SnCl4,etc.)Thedark-coloredproductsformedinthisreactionareresponsibleforthenon-enzymaticbrowningobservedwithvariousfoodstuffs.OtherRearrangementReactionsAmadorireaction/rearrangementOtherRearrangementReactionsBaker-Venkataramanbase-catalyzedrearrangementofaromaticortho-acyloxyketonesOtherRearrangementReactionsBaker-Venkataraman-MechanismApplicationOtherRearrangementReactionsBrookRearrangement1950s,A.G.Brook:[1,n]-carbontooxygensilylmigrationsOtherRearrangementReactionsBrookRearrangement-MechanismE.J.CoreyApplicationOtherRearrangementReactionsCarrollrearrangement(Kimel-CoperearrangementordecarboxylativeClaisenrearrangement)OtherRearrangementReactionsCarrollrearrangementOtherRearrangementReactionsCornforthrearrangement1949J.W.CornforthOtherRearrangementReactionsCornforthrearrangementOtherRearrangementReactionsCiamician-Dennstedtrearrangement“abnormal”Reimer-Tiemannreaction.OtherRearrangementReactionsCiamician-DennstedtrearrangementOtherRearrangementReactionsDimrothrearrangementOtherRearrangementReactionsDienone-phenolrearr