Synlett-2013--24--323–326

CLUSTER▌323clusterProcessDevelopmentofHalaven®:SynthesisoftheC1–C13FragmentfromD-(–)-Gulono-1,4-lactoneProcessDevelopmentofHalaven®:SynthesisoftheC1–C13FragmentCharlesE.Chase,FrancisG.Fang,BryanM.Lewis,*GordonD.Wilkie,MatthewJ.Schnaderbeck,XiaojieZhuPharmaceuticalScience&Technology,EisaiProductCreationSystems,EisaiInc.,4CorporateDrive,Andover,MA01810-2441,USAFax+1(978)7944910;E-mail:[e-mail]:13.11.2012;Accepted:22.11.2012Abstract:A12-stepkilogram-scalesynthesisoftheC1–C13frag-ment,commontohalichondrinBandthetotallysyntheticanalogueHalaven®(E7389,INNeribulinmesylate),isdescribed.Thesynthe-sisfeaturesfourcrystallineintermediateswhichfacilitatesthrough-put,andenhancesqualitycontrolofallstereogeniccentersinthetitlecompound.Keywords:carbohydrates,chiralpool,drugs,glycosylation,stereoselectivesynthesisHalaven®(1;E7389,INNeribulinmesylate)isafullysyntheticanalogueofthestructurallycomplexmarinenat-uralproducthalichondrinB.1EribulinhasbeenrecentlyapprovedbytheFDAforthetreatmentofcertainpatientswithmetastaticbreastcancer.2Althoughthestructureof1issubstantiallysimplifiedrelativetothenaturalproduct(Halaven®contains19vs.32stereogeniccentersanda36vs.54carbonbackboneascomparedtohalichondrinB),thediscoveryanddevelopmentof1bytotalsynthesisstillrepresentsasignificantchallenge.Thefoundationforstartingtheseresearchanddevelopmenteffortswaspro-videdbythefirsttotalsynthesisofhalichondrinBbyKishiandco-workersatHarvardUniversity.3Theuseoftotalsynthesisallowedflexiblemodificationofembeddedstructuralelementsoftheoriginalhalichondrinmacrolide.Specifically,theC29andC30sitesofthemacrolidewerefoundtobeproductiveareasforexplorationtooptimizebiologicalactivity.Themacrocyclicketoneanalogue1,bearingasuitablysubstitutedtetrahydrofuranreplace-mentforthehalichondrin‘lefthalf’,emergedasthecan-didatecompoundforclinicalevaluation.Halaven®(1)issynthesizedinaten-stepprocessfromtheC1–C13fragment2andtheC14–C35fragment(notshown;seeaccompanyingarticle).TheC1–C13frag-ment,commontoboth1andthehalichondrins,hasprevi-ouslybeensynthesizedbyKishiandco-workersfromD-galactose,4D-(–)-mannonolactone,5andD-(–)-ribono-lactone.6TheinitialsynthesisofC1–C13thatwasusedtoproducethisfragmentforclinicalevaluationutilizedD-mannonolactone(3)5basthestartingsugar.However,availabilityandcostof3becameanobstacletoprocuringlargerquantitiesof2neededforfullclinicalevaluation.AlthoughD-mannonolactonecontainsthecorrectstereo-chemistryforfourofthestereogeniccentersin2(C8,C9,C10,andC11),oneofthesecenters,C11,isdestroyedduringthesynthesisandsubsequentlyre-established.Thus,D-gulonolactone(4),asugarepimerictoD-mannon-olactoneatonestereogeniccenter(thatcorrespondingtoScheme1SyntheticstrategyforHalaven®C1–C13fragment2OOHOHHOOOHHOCHOOOOMeO2CHHOOTBSHOCO2MeHHITBSOTBSO23:D-(–)-mannonolactone(β-OHatC11)4:D-(–)-gulonolactone(α-OHatC11)51111OOOOOMeMeOOOOHHHHOHOH2NHalaven®(1)352930114MsOH131310SYNLETT2013,24,0323–0326Advancedonlinepublication:10.01.20130936-52141437-2096DOI:10.1055/s-0032-1317919;ArtID:ST-2012-Y0971-C©GeorgThiemeVerlagStuttgart·NewYorkDownloadedby:IP-ProxyUniversityofIllinois-Urbana,UniversityofIllinois.Copyrightedmaterial.324C.E.Chaseetal.CLUSTERSynlett2013,24,323–326©GeorgThiemeVerlagStuttgart·NewYorkC11inhalichondrin.),couldserveasafunctionallyequiv-alentstartingcarbohydrate.Inotherwords,thestereo-chemistryatC11isinconsequentialintherawmaterialasbothsugarsdegeneratetothecommonaldehydeinter-mediate5(Scheme1).InordertoestablishtheroutefromD-gulonolactone,thechemistryreportedbytheKishigrouponD-mannonolactone5bwouldneedtobeextendedtotheepimericsugar,D-gulonolactone.7Thisarticledescribestherealizationofthechemicalse-quencefromD-gulonolactonetoC1–C13fragment2.Duringthecourseofthisinvestigation,severalreactivitydifferencesinthebehaviorofthetwocarbohydrateepi-merswerenotedandincorporatedintotheoverallroutedesignandpurificationstrategy.Theoverallsynthesishasbeendevelopedandexecutedonmultikilogramscaleinfixedequipment.ThesyntheticschemefortransformationofD-gulonolac-tone(4)to2isdepictedinScheme2.Theknownbiscy-clohexylidenelactone6wasreducedwithDIBAL-Htoaffordlactol7.Thepreviouslyreportedone-carbonho-mologationviaWittigmethoxymethylenationintheman-nonoserieswasconductedinrefluxingTHFanddidnotspecifyremovaloftriphenylphosphineandtriphenylphos-phineoxide.DirectapplicationoftheseconditionsinthegulonoseriesledtovaryingdegreesofepimerizationatC8.Furthermorethesubsequentosmylationstepwasfoundtobesensitivetocontaminationbyphosphines.Theseconcernswereaddressedbythefollowingproce-duralmodifications:(i)inverseadditionofsubstratetoapreformedylidat0°C,(ii)useofamaleicanhydrideworkupallowedfortheremovaloftriphenylphosphine,and(iii)precipitationoftriphenylphosphineoxidefromMTBE–heptaneaffordedcrudeproductwithacceptablestereochemicalandimpurityprofileforuseinthenextstepwithoutchromatographicpurification.Stereoselec-tiveosmylationof8,proceededaspreviouslydescribedinthemannonolactoneseriestoprovideca.3:1mixtureofcrystallineα-hydroxylactols9.DifficultieswereencounteredintheC-glycosidatio