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1RESEARCHPLANApplicant’sInformationName:FangWeiIDNumber:421182198809134739TypeofApplication：□Master□Doctor√JointPhDMacau(CooperativeUniversity)DepartmentAppliedofSUSTC:___DepartmentofChemistry___________________Supervisor’sName:___LiChuangchuang___________________________________DepartmentAppliedofcooperativeuniversity:_InstitueofChineseMedicalSciencesSupervisor’sName:____ZhaoJing____________________________________1.ResearchProposal(2000characterslimited)TotalsynthesisofsaikosaponinaanddBackgroundSaikosaponinaanddbelongtothegroupofsaikosaponinsClassifiedinoleananetypetriterpenoidsaoponins.SaikosaponinsmainlyexistintherootsofBupleurumplantsandmorethan120saikosaponinshavebeenisolateduptonow,Thesesaikosaponinsshowawiderangeofpharmacologicalactivities,suchasanti-inflammatory,anti-cancer,anti-virus,hepatoprotectiveandantidepressant.Amongthesesaikosaponins,saikosaponinaanddhavethemostintenseactivity.Whenanalyzingthedefinitestructures,thesaikosaponinsareassembledbythesugarchainandaglyconeandtheyareconnectedthroughthecarbonandoxygencovalentbond.Therearethreekindsofaglyconetypesinsaikosaponinsandtheyareoleananetype,Ursanetypeandlupinetype.Themostcommonareoleananetype.TherearealwaysoneortwodoublebondsattheCringandC-3andC-23intheAring,C-16intheDringaregenerallyhydroxylsubstitutedtoformchiralcenters.AtypeofthemostimportantsaikosaponinsisrepresentbysaikosaponinaanddinwhichthereisanepoxyetherlocatedatC-13andC-28.Thesugarchaininthethesecompoundsaregenerallyshort,whicharealwayscomposedoftwotofivesugarunitsandtheshapesarelinearorbranching.Inaddition,thecompositionofthesugarresiduesarerelativelysimple,themainlycontainedsugarsareD-Glucose(D-Glc),D-Galactose(D-Gal),D-Xylose(D-Xyl),Fucose(D-Fuc),L-Rhamnose(L-Rha),L-Arabinose(L-Ara),D-Glucuronicacid(D-GlcA)andD-galacturonicacid(D-GalA).Thediversityofsugarchainstructurebringsmanydifficultiesforthestudyofsaikosaponinmolecules.2Therearesomerulesinthestereochemistryofsaikosaponins.TheconfigurationsofA/B,B/CandC/Dringsaretrans,whileD/Eringisintheformofcis.ThehydroxylgroupsatC-3,C-23andC-28arealwaysβ-orientation.ThehydroxylgroupattachedatC-16couldbebothβorαoriented.Thetwoorientationsareheterogeneoustoeachotherandoftencoexistintheplants.Becauseβorientationismorestable,theαorientationiseasytobeconvertedtoβorientationandtheβorientationneedstobeheatedtoconverttoαorientation.Althoughsaikosaponinaanddhadbeenisolatedsince1960s,noreportonthechemicalsynthesisofthemisreportedsofarduetothecomplexityandinstabilityofthemolecularstructures.Buttherearealotofreportsaboutthetotalsynthesisofotheroleananetypetriterpenoidsaoponins.ResearchstatusThetotalsynthesisofsaikosapoinsneedstodrawonthetotalsynthesisofotheroleananetypetriterpenoidsaponins.Forthesynthesisofaglycone,themethodoftotalsynthesisofoleananetypetriterpeneshasbeenreportedabouttwodirections,ofwhichoneiscalleddenovosynthesisandtheotheroneisusingthecommercializedursolicacidandoleanolicacidmaterialassubstratestopreparethembystructuremodification.Therearealsotwostrategiesfortheconnectionofaglyconeandsugarchains.Oneisalinearstepwisesynthesisstrategy,whichwillfirstlyconnectthemonosaccharideandaglyconewhentheprotectiongroupsareoperated,thengraduallyconnecttheremainingsugarunits,finallyremovetheprotectivegroupsandgetthesaponins.Theotheroneisaconvergentsynthesisstrategy.Atfirst,thesugarchainsaremadeandthenConnectedtoaglycone.Finally,theprotectiongroupsweretakenofftoobtainthefinalproduct.Aftermanyyearsofresearch,themethodofdenovosynthesisiscyclizingtwosmallmoleculeswhichhaveadecahydronaphthaleneastheskeleton.Throughstructuralmodificationoftheskeleton,differenttypesoftriterpenoidsaponinscouldbeobtained.TheexampleforusingoleanolicacidtoprepareLobatosideE:3TotalSynthesisofLobatosideE,APotentAntitumorCyclicTriterpeneSaponin:J.Am.Chem.Soc.2008,130,5872Theexampleofdenovosynthesis:Synthesisoftheoleananeskeleton:TetrahedronLett.1962,10,429ContentsandmethodThisprojectaimstocompoundsaikosaponinaanddandtoseekforasimpleandefficientmethodforthesynthesisofepoxyethertypesaikosaponins.Atfirst,IwillImplementInversesyntheticanalysisofsaikosaponinaandd.Accordingtothereversesynthesisstrategy,thetargetcompoundscantheoreticallybeconsistsoftwoparts:oligosaccharideresiduepartandaglyconepart.TheoligosaccharidesresidueCanbeobtainedbythereactionofGlucoseandtheexposedhydroxylgroupatC-3ofactiveprecursorfucose.Themaintaskisthesynthesisofthepartofaglycone.SoIwilldesigntwosyntheticpathsfirstly.Oneisusingoleanolicacidasthestartingpointandtheotheroneisusingdecahydronaphthaleneasthestartingpoint.Pathone:usingoleanolicacidassubstratesThemaintaskofthismethodistheintroductionofhydroxylgroupsandtheconstructionofepoxyetherbond.ThepositionthatrequirestheintroductionofhydroxylgroupsisC-16andC-23,Therearealotofothercompetitivepositionsinthesetwolocations,thenitisneedtouseamethodfordirectedoxidation.TheepoxyetherbondislocatedatC-13andC-28andthesetwocarbonsthenformedarigidstructureandthisstepisexpectedtoencounteralotofproblems.Referencetopreviousstudies,thestepsIintendtoadoptareasfollows.4a:B.meg