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首页 氨基酸保护基的最新力作

氨基酸保护基的最新力作.pdf

氨基酸保护基的最新力作

mashizhong
2010-09-22 0人阅读 举报 0 0 暂无简介

简介:本文档为《氨基酸保护基的最新力作pdf》,可适用于高等教育领域

SubscriberaccessprovidedbySHANDONGUNIVChemicalReviewsispublishedbytheAmericanChemicalSocietySixteenthStreetNW,Washington,DCReviewAminoAcidProtectingGroupsAlbertIsidroLlobet,MercedesA#lvarez,andFernandoAlbericioChemRev,ArticleASAP•DOI:crs•PublicationDate(Web):AprilDownloadedfromhttp:pubsacsorgonApril,MoreAboutThisArticleAdditionalresourcesandfeaturesassociatedwiththisarticleareavailablewithintheHTMLversion:•SupportingInformation•Accesstohighresolutionfigures•Linkstoarticlesandcontentrelatedtothisarticle•CopyrightpermissiontoreproducefiguresandortextfromthisarticleAminoAcidProtectingGroupsAlbertIsidroLlobet,†MercedesA´lvarez,*,†,‡,§andFernandoAlbericio*,†,‡,|InstituteforResearchinBiomedicine,BarcelonaSciencePark,BaldiriReixac,Barcelona,SpainCIBERBBN,NetworkingCentreonBioengineering,BiomaterialsandNanomedicine,BarcelonaSciencePark,BaldiriReixac,Barcelona,SpainLaboratoryofOrganicChemistry,FacultyofPharmacy,UniversityofBarcelona,Barcelona,SpainandDepartmentofOrganicChemistry,UniversityofBarcelona,Martı´iFranque´s,Barcelona,SpainReceivedApril,ContentsIntroductionBRAminoCGeneralCIntroductionoftheProtectingGroupsCRemovalCProtectingGroupsRemovedbyAcid(Table)CProtectingGroupsRemovedbyBase(Table)EOtherProtectingGroups(Table)FLysine(Lys),Ornithine(Orn),DiaminopropionicAcid(Dap),andDiaminobutyricAcid(Dab)IGeneralIIntroductionoftheProtectingGroupsLRemovalMProtectingGroupsRemovedbyAcid(Table)MProtectingGroupsRemovedbyBase(Table)MOtherProtectingGroups(Table)MRCarboxylicAcidMGeneralMIntroductionoftheProtectingGroupsNRemovalNProtectingGroupsRemovedbyAcid(Table)NProtectingGroupsRemovedbyBase(Table)OOtherProtectingGroups(Table)PAspartic(Asp)andGlutamic(Glu)AcidsSGeneralSIntroductionoftheProtectingGroupsSRemovalSProtectingGroupsRemovedbyAcid(Table)SProtectingGroupsRemovedbyBase(Table)TOtherProtectingGroups(Table)TAmideBackboneVGeneralVIntroductionoftheProtectingGroupsVRemovalVProtectingGroupsRemovedbyAcid(Table)VOtherProtectingGroups(Table)WAsparagine(Asn)andGlutamine(Gln)XGeneralXIntroductionoftheProtectingGroupsYRemovalYProtectingGroupsRemovedbyAcid(Table)YArginine(Arg)ZGeneralZIntroductionoftheProtectingGroupsZRemovalZProtectingGroupsRemovedbyAcid(Table)ZProtectingGroupsRemovedbyBase(Table)AAOtherProtectingGroups(Table)AACysteine(Cys)AAGeneralAAIntroductionoftheProtectingGroupsAARemovalACProtectingGroupsRemovedbyAcid(Table)ADProtectingGroupsRemovedbyBase(Table)ADOtherProtectingGroups(Table)ADMethionine(Met)AHGeneralAHIntroductionoftheProtectingGroupsAHRemoval:SulfoxideReductionAHHistidine(His)AIGeneralAIIntroductionoftheProtectingGroupsAIRemovalAIProtectingGroupsRemovedbyAcid(Table)AIProtectingGroupRemovedbyBase(Table)AKOtherProtectingGroups(Table)AKSerine(Ser),Threonine(Thr),andHydroxyproline(Hyp)ALGeneralALIntroductionoftheProtectingGroupsAMRemovalAMProtectingGroupsRemovedbyAcid(Table)AMOtherProtectingGroups(Table)AMTyrosine(Tyr)AMGeneralAM*TowhomcorrespondenceshouldbeaddressedFax:Email:mercedesalvarezirbbarcelonaorgalbericioirbbarcelonaorg†InstituteforResearchinBiomedicine‡CIBERBBN§LaboratoryofOrganicChemistry,FacultyofPharmacy,UniversityofBarcelona|DepartmentofOrganicChemistry,UniversityofBarcelonaChemRevXXXX,xxx,–AcrsCCC:$XXXXAmericanChemicalSocietyIntroductionoftheProtectingGroupsAORemovalAOProtectingGroupsRemovedbyAcid(Table)AOOtherProtectingGroups(Table)AOTryptophan(Trp)AQGeneralAQIntroductionoftheProtectingGroupsAQRemovalAQProtectingGroupsRemovedbyAcid(Table)AQProtectingGroupsRemovedbyBaseAQOtherProtectingGroups(Table)AQAbbreviationsAQAcknowledgmentsARReferencesARIntroductionSyntheticorganicchemistryisbasedontheconcourseofreagentsandcatalyststoachievethecleanformationofnewbonds,andappropriateprotectinggroupsarerequiredtopreventtheformationofundesiredbondsandsidereactions,Thus,apromisingsyntheticstrategycanbejeopardizedifthecorrespondingprotectinggroupsarenotproperlychosenEmilFischerwaspossiblythefirsttorecognizetheneedtotemporallymaskafunctionalgrouptoallowregioselectivebondformationinthesynthesisofcarbohydratesHowever,thefirst“modern”protectinggroupwasthebenzylozycarbonyl(Z)developedbyBergmannandZervasZfitswiththemaincharacteristicsassociatedwithaprotectinggroup:(i)itiseasilyintroducedintothefunctionalgroup(ii)itisstabletoabroadrangeofreactionconditionsand(iii)itissafelyremovedattheendofthesyntheticprocessorwhenthefunctionalgrouprequiresmanipulationAnothercornerstoneinthisfieldwaswhenBaranyetal,describedtheconceptoforthogonality,inthesensethatthetwoormoreprotectinggroupsbelongtoindependentclassesandareremovedbydistinctmechanismsThegroupscanberemoved,therefore,inanyorderandinthepresenceoftherestProfessorFernandoAlbericiowasborninBarcelona,Spain,inHereceivedhisPhDinChemistryattheUniversityofBarcelona,inFollowingpostdoctoralworkatTuftsUniversity(Boston),attheUniversite´d’AixMarseille(France),andattheUniversityofMinnesota(),hereturnedtoBarcelonaasAssociateProfessorDuringtheperiod,hewasDirectorofPeptideResearchwithMilligenBiosearchinBostonHerejoinedtheUniversityofBarcelona,wherehewaspromotedtoprofessorinNowadays,heisholdingvariousappointments:GeneralDirectoroftheBarcelonaSciencePark,ProfessorattheUniversityofBarcelona,andGroupLeaderattheInstituteforResearchinBiomedicineProfessorAlbericio’smajorresearchinterestscoverpracticallyallaspectsofpeptidesynthesisandcombinatorialchemistrymethodologies,aswellassynthesisofpeptidesandsmallmoleculeswiththerapeuticactivitiesHehaspublishedoverpapers,severalreviewarticles,andpatents,andheiscoauthorofbooksHeiseditorofseveralscientificjournalsandactsintheeditorialboardofseveralothersInaddition,professorAlbericioisdeeplyinvolvedinthedevelopmentofthethirdmissionoftheUniversity,thetransferenceofknowledgeandtechnologytosocietyHehasfoundedseveralbiotechcompaniesandisactingintheboardofdirectorsofseveralfoundationsandcompaniesFurthermore,heisconsultantforseveralcompaniesinthechemicalandpharmaceuticalareasAlbertIsidroLlobetwasborninElPratdeLlobregat(Spain)inHestudiedChemistryattheUniversityofBarcelona(Spain)andobtainedhisPhDinattheBarcelonaSciencePark(UniversityofBarcelona)underthesupervisionofProfessorsFernandoAlbericioandMercedesA´lvarezHisPhDworkinvolvedthedevelopmentofnewprotectinggroupsforthesynthesisofcomplexpeptidesInOctober,hemovedtoDrDavidRSpring’sgroupattheUniversityofCambridge(UK)whereheiscurrentlyapostdoctoralfellowworkinginDiversityOrientedSynthesisofsmallmoleculesasantibioticsHisresearchinterestsincludethedevelopmentofnewmethodologiesforsolidandsolutionphasepeptidesynthesisandtheresearchfornewbioactivecompoundsMercedesA´lvarezreceivedherPhDinChemistryfromtheUniversityofBarcelonaunderthesupervisionofProfRicardoGranadosShehasapermanentpositionintheUniversityofBarcelonaasAssociateProfessorintheFacultyofPharmacyIn,shespentasabbaticalyearinTheManchesterUniversityworkingwithProfJohnAJouleAfterthatperiod,shestartedalongcollaborationbetweenManchesterandBarcelonaUniversitiesfordevelopingnewproceduresforthesynthesisofmarinenaturalproductswithpolyheterocyclicstructureandbiologicalactivitiesIn,shewasinvitedtojointwiththegroupledbyProfFernandoAlbericioandtomoveherresearchgrouptotheScienceParcofBarcelonaCurrently,sheholdsadoubleappointmentasProfessorattheUniversityofBarcelonaandResearcherattheBarcelonaBiomedicalResearchInstituteintheBarcelonaScienceParkHermajorresearchinterestscoversynthesisofnaturalproducts,heterocyclicchemistry,combinatorialchemistry,andsolidphasemethodology,aswellassynthesisofsmallmoleculeswiththerapeuticactivitiesBChemicalReviews,XXXX,Volxxx,NoxxIsidroLlobetetalOrthogonalprotectionschemesareusuallymilderbecauseselectivedeprotectionisgovernedbyalternativecleavagemechanismsratherthanbyreactionratesSincethepioneernigworkofBergmannandZervas,thedevelopmentofnewprotectinggroupshasbeendeeplytiedtopeptidechemistryProtectionistotallymandatoryfortheconstructionofthesepolyfunctionalmolecules,whichcontainuptoeightdistinctfunctionalgroupsinadditiontoindoleandimidazolerings,whichshouldalsobeprotectedOnlythecarbonylfunctionisabsentfromthenaturalaminoacids,becauseevenphosphateprotectinggroupshavebeendevelopedforthesynthesisofphosphopeptidesThus,theprotectinggroupsfirstdevelopedforpeptidesynthesishavebeenrapidilyadaptedfortheprotectionofbuildingblocksusedforthecontructionofnonpeptidemolecules,Herein,weprovideaconcisebutdeepanalysisoftheprotectionofaminoacidsThereviewisdividedintosectionsdependingontheaminoacidfuncionalitiesprotectedForeachcase,methodsfortheintroductionoftheprotectinggroupsaswellasfortheirremovalarediscussedIneachsection,protectinggroupsareclassifiedbasedonthefollowingcriteria:(i)themostusedinaBocBnstrategy(ii)themostusedinaFmoctBustrategy(iii)decreasedorderoflabilityand(iv)themostrecentlydescribed,forwhich,inmostcases,theirpotentialhasnotyetbeenexploredInallcases,familiesofprotectinggroupsareclassifiedtogetherThecompatibilityofeachprotectinggroupwithregardtotheothersisindicatedinthecolumn“stabilitytotheremovalof”,whichshowswhichofthefollowingRaminoprotectinggroups(Boc,Fmoc,Z,Trt,Alloc,andpNZ)canberemovedwithoutaffectingaparticularprotectorSpecialattentionhasbeengiventonewprotectinggroupsdescribedinThosedescribedintheliteratureearlierandthosethatnothavefoundabroadusehavebeenomittedfromthisreviewrAminoGeneralProtectionoftheRaminofunctionalityofaminoacidsisoneofthemostimportantissuesinpeptidechemistryandismandatorytopreventpolymerizationoftheaminoacidonceitisactivatedBecausemostpeptidesyntheses,bothinsolutionandonsolidphase,arecarriedoutintheCtoNdirection,Raminoprotectinggroups(temporaryprotectinggroups)areremovedseveraltimesduringthesynthesis,andtherefore,removalmustbedoneinmildconditionsthatdonotaffecttheremainingprotectinggroups(permanent,usuallyremovedinthelaststepofthesyntheticprocess,andsemipermanent,usuallyattheCterminus,removedinthepresenceofallotherprotectinggroups,whenthepeptideistobecoupledatitsCterminus)oreventhepeptidicchainTheRaminoprotectinggroupshouldconfersolubilityinthemostcommonsolventsandpreventorminimizeepimerizationduringthecoupling,anditsremovalshouldbefast,efficient,andfreeofsidereactionsandshouldrendereasilyeliminatedbyproductsOtherdesiredcharacteristicsofRaminoprotectedaminoacidsarethattheyarecrystallinesolids,therebyfacilitatingmanipulation,andstableenoughThemostcommonRaminoprotectinggroupsforsolidphasepeptidesynthesis(SPPS)arethefluorenylmethoxycarbonyl(Fmoc)andthetertbutyloxycarbonyl(Boc)groups,usedintheFmoctertbutyl(tBu)andBocbenzyl(Bn)strategies,respectivelyForsolutionsynthesis,otherRaminoprotectinggroupsusedaretheZ,theNps(nitrophenylsulfenyl),andtheBpoc(biphenyl)isopropoxycarbonylincombinationwithtButypesidechainprotection,ortheBocgroupincombinationwithBntypesidechainprotectionIntroductionoftheProtectingGroupsBecausethereareseveraltypesofRaminoprotectinggroups,thereisawiderangeofprotectionmethodologiesMostofthesearebasedonthereactionofthefreeaminoacids(sidechainprotectedifnecessaryseeωaminoprotectionpartforselectiveLysandOrnsidechainprotection),withahaloformateordicarbonate,oftheprotectinggroupunderSchottenBaumannconditions(useofbiphasicsystem:organicsolventaqueousbasicconditions)orwiththecorrespondinghalideinorganicsolventsNevertheless,insomecases,thepresenceofthefreeRcarboxylicacidcaninterfereinthereactionandlead,forinstance,totheformationofdipeptides(Figure)Themethodologiesusedtoovercomethisproblemcanbedividedintotwotypes:thosethatinvolveacarboxylicacidprotectinggroupthatisremoveduponaminoprotectionandthosethatinvolvelessreactiveelectrophilesonthereagentusedtointroducetheprotectinggroupAnexampleoftheformeristheuseoftrimethylsilylestersofaminoacidspreparedinsitu,,whileanillustrationofthelatteristheuseofNhydroxysuccinimido(HOSu)derivativeorthecorrespondingazide,asinthecaseoftheintroductionofFmocwhereFmocOSuorFmocNareusedinsteadofFmocClHowever,theuseofFmocOSucanleadtotheformationoftinyamountsofFmoc�AlaOHorevenofFmoc�AlaAAOH(Figure),whichcanjeopardizethepreparationofFmocaminoacidsfortheproductionofpeptidebasedactivepharmaceuticalingredients(API),RemovalProtectingGroupsRemovedbyAcid(Table)tertButyloxycarbonyl(Boc),Bocaminoacidsaregenerallycrystallinesolids,andtheirparticularsuitabilityforSPPShasbeenclearlydemonstrated,TheBocgrouphasbeenusedforthesolidphasesynthesis(SPS)ofanumberofrelevantpeptidesusingthesocalledBocBnstrategyThemostcommonremovalconditionsforBocareTFAinDCM,butotheracids,suchasMtrimethylsilylchlorideFigureMechanismfortheformationofprotecteddipeptidesduringtheprotectionofaminoacidswithhaloformatesAdaptedwithpermissionfromrefCopyrightWileyBlackwellAminoAcidProtectingGroupsChemicalReviews,XXXX,Volxxx,NoxxC(TMSCl)phenolinDCM,MHClindioxane,andMMeSOHindioxane,havebeensuccessfullyusedforsolutionandsolidphasesyntheticstrategiesTheBocgroupisstabletobasesandnucleophilesaswellastocatalytichydrogenationTrityl(Trt),ItisremovedwithTFAinDCMorMHOBtin,,trifluoroethanol(TFE)insolutionItcanberemovedinevenmilderconditionssuchasTFA,HOinDCM,ortrichloroaceticacid(TCA)inDCM,whicharecompatiblewiththeTFAlabile(hydroxymethylphenoxy)propionicacid(AB)linkerorevenwiththemoreacidlabileRinikerhandle,aswellaswiththesynthesisofoligonucleotidepeptideconjugatesCouplingyieldsofTrtaminoacidsarelowerthanthoseofcarbamateprotectedaminoacidsAnimportantapplicationoftheTrtgroupisfortheprotectionofthesecondCterminalaminoacidinordertopreventdiketopiperazines(DKPs)formationinasimilarwayasfortheBocstrategy,ThisprocedureinvolvesthecouplingofthethirdaminoacidwithinsituneutralizationaftertheremovaloftheTrtgroupIncorporationofTrtaminoacidsismoredifficultthanthatofcarbamateprotectedaminoacids,whichimpliestheuseofmorepowerfulactivatingconditionsHowever,thebulkinessoftheTrtgroupprotectstheRprotonfromthebaseabstractionand,therefore,makesTrtAAOHmoredifficulttoracemizer,rDimethyl,dimethoxybenzyloxycarbonyl(Ddz)AlthoughDdzismoreacidstablethantheBpocandtheTrtgroups,itsremovalwithTFAinDCMmakesitcompatiblewithtButypesidechainprotectionItcanalsoberemovedbyphotolysisatwavelengthsabovenm,whichmakesitpotentiallyveryusefulforSPSlibraryscreeningproceduresIthasbeenusedtopreventDKPformationinthebackboneamidelinker(BAL)strategyinasimilarwayastheTrtgroupHowever,anadvantageofDdzoverTrtaminoacidsisthattheirincorporationiseasier,whichisacrucialfactorwhenthecorrespondingaminoacidsaretobeincorporatedonhinderedamines(Biphenyl)isopropoxycarbonyl(Bpoc)Itisahighlyacidsensitivecarbamatetypeprotectinggroup,whichisremovedwithofTFAexceptwhenusedinpoly(ethyleneglycol)basedresins,inwhichmoreTFAisrequiredbecausesomeoftheacidisusedtoprotonatetheoxymethylmoietiesThisisacommoncharacteristicofseveralacidlabileprotectinggroupsMostBpocaminoacidsareoilsandareunstablebecausethefreeRcarboxylicacidisacidicenoughtoremovetheBpocgroupThus,theseaminoacidsareusuallystoredeitherasDCHAsaltsoraspentafluorophenylestersIntheearlystagesofSPPS,beforetheintroductionoftheFmocgroup,BpocaminoacidshavebeenusedincombinationwithtButypesidchainprotectionCurrently,Bpocaminoacidsareusedmostlyforpeptidederivativescontainingphosphategroupssuchasphosphopeptidesorpeptideoligonucleotideconjugates,Nitrophenylsulfenyl(Nps)ItisremovedmostconvenientlywithdilutedsolutionsofHClinAcOHItisresistanttobasesbutcanberemovedbynucleophilessuchasmercaptopyridineincombinationwithAcOHinMeOH,DMF,orDCMRemovalusingaNiRaneycolumnandorganicsolvents,suchasDMF,hasalsobeendescribedFigureMechanismfortheformationofFmoc�AlaOHandFmoc�AlaAAOHduringtheprotectionofaminoacidsAdaptedwithpermissionfromrefCopyrightWileyBlackwellDChemicalReviews,XXXX,Volxxx,NoxxIsidroLlobetetalNpshasbeenappliedinbothsolutionandSPSItshighacidlabilityrequiressimilarprecautionstotheBpocgroupinthepresenceofthefreeRcarboxylicacidBenzyloxycarbonyl(Z)Seesectionon“otherprotectinggroups”ProtectingGroupsRemovedbyBase(Table)Fluorenylmethoxycarbonyl(Fmoc),Itisremovedbybases(mainlysecondaryamines,becausetheyarebetteratcapturingthedibenzofulvenegeneratedduringtheremoval)andisstabletoacidsItisnotcompletelystabletothecatalytichydrogenolysistreatmentrequiredto

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氨基酸保护基的最新力作

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