Asymmetric Synthesis of Beta Amino Acids

AsymmetricSynthesisofβ-AminoAcids:ProgressTowardsHighlySubstitutedVariantsbyGregoryNotteLeightonGroupMeetingAugust2nd,2007GoodReviews:Juaristi,E.EnantioselectiveSynthesisofβ-AminoAcids;Wiley-VCH:NewYork,2005Seebach,D.;Abele,S.Eur.J.Org.Chem.2000,1-15.BiologicalSignificanceofβ-AminoAcids•SmallMoleculePharmaceuticals•ComponentsofNovelPeptidesandNaturalProducts•ChiralOrganicBuildingBlocks“β-Aminoacidshavefoundextensiveapplicationinthelifesciencesascomponentsofbiologicallyactivepeptidesandsmallmoleculepharmaceuticals.Syntheticderivativesofbiologicallyrelevantpeptidesincorporatingβ-aminoacidsoftendisplayinterestingpharmacologicalactivity,withincreasedpotencyandenzymaticstabilityrelativetotheirnativecounterparts,andhaveplayedimportantrolesinadvancingtheunderstandingofenzymemechanisms,proteinconformations,andpropertiesrelatedtomolecularrecognition.”-ProcessResearchersatMerckRawhayGrabowski,etal.J.Am.ChemSoc.2004,127,9918β-AminoAcidsinNaturalProductsdolastatin11taxolguineamideCSmallMoleculePharmaceuticalsNHONOCO2HH2NNHPh(+)-NSL-95301antithromboticagent(inhibitsplateletaggregation)NHCO2Memethylphenidate(Ritalin)treatmentofADDandannoyingkidsNH2CO2HcispentacinantifungalantibioticNOCO2HOHNRWJ-50042plateletfibrinogenreceptorantagonistNMe2PhCO2EttilidineopiodanalgesicSomeNecessaryNomenclatureSeebach,D.;Abele,S.Eur.J.Org.Chem.2000,1-15.H2NOHOH2NOHOH2NOHOα−aminoacidβ−aminoacidβ2−aminoacidβ3−aminoacidH2NOHOβ2,2,3−aminoacidH2NOHOβ2,3,3−aminoacidH2NOHOPhI.MethodsthatFailforHighlySubstitutedSystemsII.StoichiometricMeansIII.CatalyticAsymmetricMethodsAsymmetricSynthesisofβ-AminoAcids:ProgressTowardsHighlySubstitutedVariantsClassicalMeans:Arndt-EistertHomologationHNROOHPGHNROXPGactivationCH2N2HNROPGHN2HNROPGHN2Ag+,hv,orΔthen,Nu,WolfrearrangementHNRPGONuArndtEistertLimitations•Mostobviouslimitationisinabilitytoaccessβ2-substitutedaminoacids•UseofdiazomethanenecessaryasalternativessuchasTMS-diazomethanearegenerallyineffective•α,α-disubstitutedaminoacidsarepoorreactionpartners:Seebach,LiebigsAnn.Chem.1995,217HydrogenationofEnamines:inherentlylimitedL*=viaiminetautomer:Grabowski,etal.J.Am.ChemSoc.2004,127,9918R=Arylonlyee=93%yields=85%MichaelAdditionswithChiralNucleophilesorElectrophilesMeOOR1R2R3NHR2**ROR1R2R3NHR2MeOOR1NHR2R3R2*ROR1NHR2R3R2*Manyvariationsonthistheme,butallsufferfromthesamelimitations:AtleastoneRgroupmustbeHwhileusually2RgroupsareHApplicationtoTaxolSideChainSynthesisJuaristi,Tet.Lett.1995,36,4397PhOOtBuPhNLiPhPhOOtBuNOHPhPhPhOOMeNOHOPhONSO21)2)UtilizationofSAMPNucleophilesHNCO2tBualternatew/upcondsprovidespiperidineEnders,SynLett,1995,7,369•MethodsthatFailforHighlySubstitutedSystems•StoichiometricMeans•CatalyticAsymmetricMethodsAsymmetricSynthesisofβ-AminoAcids:ProgressTowardsHighlySubstitutedVariantsCycloadditionStrategiesNOOOPhOTMSOOMe2).005NHCl3)DBU/MeOH1diast,76%yOCO2MeNHCOPhOO1)H2Pd/C2)2NHCl3)NaIO4RuCl369%yOCO2MeNHCOPhCO2HNOOOPhONOOOOd.r.=70:305stepsCO2HNH2.HClCO2HCativiela,Tet.Asymm.1996,7,1431PhNRR'TMSOOMeLANOR'PhRNoShortageofmethodsforthistransformation,butonlywhenR=HSelectiveC-HOxidation(catalyticoxidation,butneedchiralityalreadyinstalled)DuBois,J.Am.Chem.Soc.2001,123,6935NucleophilicAdditionstoChiralSulfinimines:Abriefhistory…Allylation:Hua,D.H.J.Org.Chem.1991,56,4Mannich:Davis,F.A.J.Org.Chem.1992,57,6387OSOTolAndersenReagent(Synthesis,1981,158)RPhNLiRPhNSOTolR=Me(50%)=Bu(75%)nogoodforaliphatics!!MgBrNHSOTolPhRR=Me(98%,98:2dr)R=Bu(92%,91:9dr)5steps~50%ytofreeAARPhNSOTolOOMeLDA90%y,97:3drNHSOTolMePhOOMeTFA,MeOH85%H2NMePhOOMeEllman’sContribution:t-ButanesulfinylKetiminesR1=MeR2=iPr(85%y,99:1dr)R2=Ph(89%y,98:2dr)Ellman,J.Org.Chem.2002,67,7819SSButOHtBuNOH.25%VO(acac)2(.25%)H20293%y,91%eeSSOLiNH2,NH375%SNH2OR1=MeR2=iPr(85%y,99:1dr)R2=Ph(89%y,98:2dr)EnolateAdditionstoSulfiniminescont…Efficientaccesstoβ2,2,3,3AminoacidsOrthogonalDeprotection:StereochemicalRationale:AdditionofNucleophilestoChiralIsoxazolinesKanemasa:ONPhOHEtPhClNHOEt3NorEtMgBr+BHClNOPhOHgoodyields,excellentselectivities+widevarietyofsubstitutionpatternsaroundalkeneshownKanemasa,J.Am.Chem.Soc.1994,116,2324StereochemicalRationale:Carreira’sContributiontothisMethodologyCarriera,ACIEE,2001,40,2082ExpandsscopeofRgroupMostVersatileMethodforβ-AminoAcidSynthesisFullPaper(alsoagoodmini-review)Mapp,A.K.J.Am.Chem.Soc.2001,127,5376GeneralStrategyforIsoxazolinebasedsynthesis:SimplestScenario:Hydrideadditionandsubsequentmanipulations:Worksforawidevarietyofalkyl,arylandalkynylgroupsMovingTowardsHighlySubstitutedVariants:Asimilarscopeisdemonstratedfororganolithiumreagants,withtheaddedbonusofusing:yieldsanddr’sarecomparable…OLiSLiMeLiMapp,A.K.J.Am.Chem.Soc.2001,127,5376ConversionofIsoxazolidinestoβ-AminoAcids1)LAH,2)BOC2O3)NaIO44)NaClO2,KH2PO4,tBuOHa)b)4-stepsequenceissomewhatlengthly,butefficientandoperationallysimpleAProvocativeIntramolecularAdditionBoththealkylationandtheadditionstepsprovidewithcompleteregioselectivity!!•MethodsthatFailforHighlySubstitutedSystems•StoichiometricMeans•CatalyticAsymmetricMethodsAsymmetricSynthesisofβ-AminoAcids:ProgressTowardsHi