STUDIESONTHERING-OPENING/CROSSMETATHESISOF8- OXABICYCLO[3.2.1]OCTENEDERIVATIVESANDITSAPPLICATION TOWARDSTHESYNTHESISOFLATRUNCULINB By MARIAE.ESTRELLA-JIMENEZ ADISSERTATIONPRESENTEDTOTHEGRADUATESCHOOL OFTHEUNIVERSITYOFFLORIDAINPARTIALFULFILLMENT OFTHEREQUIREMENTSFORTHEDEGREEOF DOCTOROFPHILOSOPHY UNIVERSITYOFFLORIDA 2005 Copyright2005 by MariaE.Estrella-Jimenez Dedicatedtomyfamily,themostimportantthinginmylife,andtoallofthosewhohave taughtmeinsomeway ACKNOWLEDGMENTS Ineedtothankmybigandwonderfulfamily;theyaremylife'sengine. Especially, Ithankmyparents,SheilaJimenezandFelixA.Estrella,mybrotherFelixA.EstrellaJr., andmysisterJohannaEstrellafortheirunconditionalloveandsupport. Inaddition,a specialthankyougoestoWilfredoOrtiz,whohasalwaysbeentheretogivemehislove, help,supportandpositiveinput. Withouthim,everythingwouldhavebeen overwhelming. Iwouldliketothankmyfriendsforkeepingmysociallifeinhealthy status. Professionally,Iwouldliketothankmyundergraduateadvisor,Dr.JohnA. Soderquist. Iamverygratefulforthetrusthegavemeasastudentandforgivingmethe opportunitytostartorganicchemistryinhisresearchgroup. Ialsothankhimforhishelp innumerousopportunitiesandfellowships. Ithankmyadvisor,Dr.DennisL.Wright,forgivingmetheopportunityofbeing partofhisresearchgroupandforrespectingmydecisionofstayingattheUniversityof Florida,afterhemovedtoDartmouthCollegeforanewfacultyposition. Ialsothank himforhisadvicesandexcitingchemistrydiscussions. IofferspecialthankstoProfessorMerleA.Battiste. Hewasakeypersoninmy finalyearatUniversityofFlorida. Icouldnotbemoregratefulofhissupport,positive input,confidenceandfriendship. Ireallyappreciatedtheconcernandinteresthetookin me. Healwayshadthetimetolisten,regardlessofthematter. IV Iwouldliketothanktheothermembersofmycommittee,ProfessorWilliamR. Dolbier,ProfessorKenSloanandProfessorDavidH.Powell,fortakingtheirtimetobe partofmyprofessionaldevelopment. Dr.IonGhiviriganeedstobegivenspecialthanks forallhishelpwiththeNMRandforhisfriendship. Hewasagreatcollaboratorand friend. Nomatterhowbusyhewas,hewouldalwaystakesometimetohelpme. In addition,themassspectroscopyteamneedstobethankedfortheirsuggestionsandwork ingettingthemolecularweightofmycompounds. Iamverygratefulformyformerand presentcolleaguesforofferingmetheirknowledgeandfriendship,especiallyLynn Usher,ChrisWhiteheadandRaviOrogunty. LynnUshertrainedmeduringmyfirstyear asagraduatestudentandofferedmetremendoushelpthroughtheyearswithheradvice, friendshipand,Ineedtoadd,theEnglishlessons. IwillalwaysrememberChris Whitehead;hementoredmeonmanyoccasionswithlabtechniques. IappreciateRavi Oroguntyforsharinghiswisdomwithmemanytimes. Inaddition,Iwouldliketothank ChrisBakerforhisfriendshipduringthispastyear. Furthermore,Iwouldliketoexpressmythankstomycolleaguesandfriends, TheodoreMartinotandJedHasting. IthankTheodoreMartinotforallthehelpand adviceheofferedmethispastyear. JedHastingistrulyappreciatedforhiswonderful friendship,helpandpatienceinlisteningtomeduringstressfultimes. DavePirman,the undergraduatethatworkedwithmeduringmylastyear,alsodeservesspecialmentioning forallthehelpheprovidedinthelab. Last,butnotleast,forallthenon-research-related work,IamverygratefulforsecretariesLoriClarkandGwenMcCannfromthe DepartmentofChemistry. Theyareefficient,friendlyandwonderfulsecretaries. Finally,IwouldliketothanktheUniversityofFloridaforgivingmethe opportunityofcomingheretopursuemygraduatestudiesandforthefellowship provided. VI 1 TABLEOFCONTENTS page ACKNOWLEDGMENTS iv ABSTRACT « CHAPTER 1 INTRODUCTION 1 Ring-Openingof8-Oxabicyclo[3.2.1]OcteneDerivativesanditsApplicationin Synthesis 3 CleavageoftheUnsaturatedDoubleBond,C6-C7,oftheOxabicyclo[3.2.1] System 4 CleavageoftheCarbonylandthea-Carbon,C3-C4,oftheOxabicyclo[3.2.1] System 8 CleavageoftheCarbon-OxygenBridgeheadBond,C1-C2,ofthe Oxabicyclo[3.2.1]System 9 OlefinMetathesis 13 TypesofOlefinMetathesisReactions 16 Ring-openingmetathesispolymerization 16 Acyclicdienemetathesis 17 Crossmetathesis 18 Ring-closingmetathesis 19 Ring-openingcrossmetathesis 23 TandemMetathesis 26 CatalyticAsymmetricOlefinMetathesis 29 TheLatrunculins 36 TotalSynthesesofLatrunculinB 37 Smith'stotalsynthesis 37 Fiirstner'stotalsynthesis 39 TotalSynthesesofLatrunculinA 40 Smith'stotalsynthesis 40 White'stotalsynthesis 41 Kashman'sApproachtotheLatrunculinSynthon 44 Kashman'sSynthesisofLatrunculinMandC 45 VI 2 RESULTS/DISCUSSION 47 IntermolecularRing-OpeningCrossMetathesis(ROCM) 47 KineticStudies 49 BridgeheadSubstituted8-Oxabicyclo[3.2.1]OcteneDerivatives 59 IntramolecularRing-OpeningCrossMetathesis(ROCM) 65 ApproachesTowardsLatrunculinBfromRing-OpeningMetathesisof8- Oxabicyclo[3.2.1]OcteneDerivatives 71 3 CONCLUSIONSANDFUTUREWORK 80 4 EXPERIMENTALPROCEDURES 82 APPENDIX A SELECTEDSPECTRA 118 B LISTOFTABLESFORKINETICSTUDIES 151 C LISTOFGRAPHSFORKINETICSTUDIES 157 LISTOFREFERENCES 188 BIOGRAPHICALSKETCH 194 vni AbstractofDissertationPresentedtotheGraduateSchool oftheUniversityofFloridainPartialFulfillmentofthe RequirementsfortheDegreeofDoctorofPhilosophy STUDIESONTHERING-OPENING/CROSSMETATHESISOF8- OXABICYCLO[3.2.1]OCTENEDERIVATIVESANDITSAPPLICATION TOWARDSTHESYNTHESISOFLATRUNCULINB By MariaE.Estrella-Jimenez May2005 Chair: DennisL.Wright Cochair: MerleA.Battiste MajorDepartment: Chemistry Thepyranmoietyisacommonstructuralfeaturefoundinmanynaturalproducts, andoftenseenasanintegralpartofcarbohydratesandmacrolidesofmarineorigin. This workdisclosestheuseofring-openingcrossmetathesis(ROCM)of8- oxabicyclo[3.2.1]octenederivativesforthepreparationofsubstitutedpyrans,using Grubbs'ruthenium-basedmetathesiscatalyst. Theoxabicyclicsystemsweresynthesized usingFohlishconditions,whichinvolvethe[4+3]cycloadditionbetweenfuranandan oxallylcation. AnunusualinfluenceinthereactivityandselectivityoftheROCM reactionswasdiscovereduponsubstituentvariationattheC3positionoftheoxabicyclo. Theseresultsledtofurtherinvestigationsthatinvolvedthesynthesisofaseriesof8- oxabicyclo[3.2.l]octenederivativeswithdifferentsubstituentsatC3. Kinetic experimentswereconductedwiththesubstrates,usingNMRtomonitorthereactions. Theseexperimentsprovidedrelativeratesofring-openingmetathesispolymerizationfor IX theseriesofoxabicyclicderivativeswhencomparedwith4,10-dioxa-tricyclo[5.2.1.0 2'6]dec-8-ene-3,5-dione(adductoffuranandmaleicanhydride). Therelativeratetrend observedamongthesubstratesshowedthattheirreactivityisaffectedbythecombination ofelectronicandstericeffects. Theknowledgeobtainedcanbeusedtoaccelerate sluggishROCMreactionsinthesynthesisofpyransfromthesetypesofsubstrates. Substitutionatthebridgeheadpositionoftheoxabicycledecreasesthereactivityofthe systemandbringsintofocustheproblemofregioisomers. However,thecareful considerationofthesubstituentattheC3positiongavegoodyieldsofthepyrans,and excellentregioselectivitywasobtainedhavinganendo-a\coho\asasubstituentatthat position. Inaddition,theintramolecularROCMofoxabicyclicsystemhavingatethered alkeneattheC2positionwasstudiedandledtolinear-fusedpyrans. Furthermore,preliminaryworkwasdonetowardsthesynthesisoflatrunculinB usingtheROCMapproach.