Total Synthesis of Aspidosperma Family Indole Alkaloids through the iORC Domino Process THÈSE NO 6607 (2015) PRÉSENTÉE LE 3 JUILLET 2015 À LA FACULTÉ DES SCIENCES DE BASE LABORATOIRE DE SYNTHÈSE ET PRODUITS NATURELS PROGRAMME DOCTORAL EN CHIMIE ET GÉNIE CHIMIQUE ÉCOLE POLYTECHNIQUE FÉDÉRALE DE LAUSANNE POUR L'OBTENTION DU GRADE DE DOCTEUR ÈS SCIENCES PAR Olivier WAGNIÈRES acceptée sur proposition du jury: Prof. N. Cramer, président du jury Prof. J. Zhu, directeur de thèse Dr T. Gaich, rapporteuse Prof. H.-U. Reissig, rapporteur Prof. J. Waser, rapporteur Suisse 2015 Ilfauttoujoursconnaîtreleslimitesdupossible. Paspours’arrêter,maispourtenterl’impossible danslesmeilleursconditions —RomanGary Acknowledgements Ifeeltheneedtowritethissection inacomprehensivemorethansuccinct way,asit isthe bestopportunityformetoexpressmygratitude,inwriting,toallthepeoplewhosupported meandhelpedmeduringmygraduatecareer. First of all, I would like to thank my PhD supervisor Jieping for accepting me to his groupandhavingtheconfidenceinmetobeagoodchemist.Itwasafascinatingexperience towork onthesechallenging projectswithhissupportandsupervision. Iamalsoinspired andimpressedbyJieping,byhisenthusiasmforchemistry,hisspirittochallengesomeofthe hardestproblems,hissharingofgreatideas,andhishard-workingattitude.IwishIwouldbe anexcellentchemistashiminthefuture. Iappreciatehispatiencewithme,hisadvicesand hisconstantsupportforme. Next, I want to express my gratitude to Professor Reissig, Professor Gaich, Professor Cramer andProfessor Waserfortakingtime toreview myPhDwork andfor servingonmy graduatecommittee. I would also like to thank Qian for her valuable guidance of my work, her kindness to help me under any circumstances and her rigor in the attention to detail. Her positive attitudeandprofessionaldedicationsetupamodelforustofollow. IcertainlycouldnotaccomplishmyPhDworkwithouttheassistanceofmywonderful colleagues. FirstgoestoJB,withwhomIstartedmyacademicstudiestenyearsagoinEPFL. Heisagenerousfriendandgreatcompanionwithadarkhumorbutshiningpersonality. We havegonethoughsomanygreatmomentstogether,fromourBachelor,whileplayingvideo games,toourPhDdefence,withallthegreatlunchesandcoffeebreaksandthemutualsup- portduringthetough dayswhere nothingwas working. Iwill always keepwith me partof hiswisdom,ashisfamousquote"Situpensesquelaviolencenerésoutrien,c’estquetun’as pasfrappéassezfort".Iamalsogratefulforhispatienceandhelpinproofreadingmypapers andcorrectingmyEnglish. AndnowIamluckyenoughtohavehimasmybestmanonmy mostimportantday. I have to thank Thomas, who has been an amazing colleague to me. I enjoyed dis- cussing with himabout chemistry as well aslife, his silly jokes andoptimistic vision could v Acknowledgements lightupmydays. IwanttoexpressmyappreciationtoSolène,fromtheneighbouringlab,forhersupport thoughmyentirePhDwork. IhaveknownhersinceourmasterstudiesinEPFLandalways admire her positive outlook and her ability to smile despite the situation. She is always a greatfriendtomeandIthinkfondlyoftimehavinglunchwithher,discussingandgossiping, orhavingadrinkintheGreatEscape. I am always thankful to my former colleague but forever mate Nick, for his unique humorandhiswisdom.Wenotonlygoouttogetherforthemusicfestivalandbrunches,but alsohaveinsightfuldiscussionsaboutchemistryandsupporteachotherthoughthedarkest times. HealsocontributessignificantlytomyPhDthesisasproofreaderandlaterontomy weddingasmybestman. ThefollowingpersonIwouldexpressmyappreciationisClaire,whobroughtfreshair tothelabeventhoughsheonlystayedwithusforninemonths. Sheissofriendlyandcheerful, andcouldalwayslightupourdaysbyherparticular“GoodMorning”greetingsalongwithher smile.Besides,sheisamongstfewpeoplewhotrulyunderstandmysillyjokesandalwaysgive meagreatlaughterinsteadofapitylook. Ibelieveshorttimesaregone,butmorefuntimes willcome. Next,IwouldliketothankDylanandAntonin,whoaretalentedchemistsandverycool guys. Ihadasmuchfuninthelabwiththemasinthebarsdrinkinganddancing. Theyhave beensosupportivetomeandsharetheirinsightsaboutchemistryandlifewithme. IamalsogratefultoViktoria,asmartandinterestinggirlwithwhoIalwayslovetotalk. Shehasherspecialphilosophyoflifeandshetaughtmenottoletthestresstakethebestof me. Wesharedgreatlaughinthelabduringthepastfouryears,andhopefullyinthefuture too. IwouldliketodedicateaspecialthankstoZhengrenandShuo,thetwoexcellentpost- docswhohadfundamentalinfluenceonme. Zhengrenwhoiscurrentlydoinganotherpost- docin theUnitedStatesinspiredme with hisefficiency, professional, enthusiastic, andhis dedicationtochemistrywork. Heismyprimaryresourcetosolvescientificconfusionsand washelpingmethoughmyPhDtime.Besides,ZhengrenwasmyChineseteacherwhoalways kindlycorrectsmyChinese.Shuowhoworkednexttomemotivatedmewithhersupport,her kindnessandsweetness.ShehadalwaysbeenthereformewhenIhadquestionsandtriedto helpmeout. Certainly,Iowemythankstoallmyremarkableco-workers.Itisagreatpleasureforme toworkwithCyril,TuandNico,whoIvaluedallthelovelydiscussionsandenjoyedsharing vi Acknowledgements great afternooncoffee time; Weiwu and Yang, who I appreciate their help andnice discus- sions;Xu,whoisalwaysbeenfriendlytome;andBo,whosharedhisgoodideaswithus. TherearemorecolleaguesinmyPhDtimeIwouldliketothankto,whoarenotonly greathelpersformyPhDworkbutalsolovelyfriendsinmylife: Ioulia,forherconstantsup- port,herinsightfuladvice,andthegreatesttricksofallasthe“emergencychocolate”;Giulia, forhersmileandherencouragementtomywork;Stephan,forhis“keepcalm,workhardand partyharder”spiritwhichinspiredmetoenjoylife;Hugo,forhisclassichumorthatalways brought me smiles; Yann, for his generous sharingof his own experience; Martina, for her kindnessandfriendliness; andAla, for theunique spiritshe passedon uswhich brought a brandnewperspective in our lives. Andlastly, a special thankstoall the young promising chemistsinourlabwhoIhadthepleasuretoworkwith: Marion,Mathias,Samuel,Raphael, Sjaak,David,BalázsandJohan. Particularly, I would like to express my gratitude to Monique, our secretary, for her kindnessandpatience,aswellasalltheadministrationworkshedidforus. Inthepastfouryears,Iwashonouredtomeetandworkwithsomebrilliantscientists whoinspiredandmotivatedmeallthetime. Sandrine,myMentor,whowasarolemodelas aresearcherandteacher;Davide,whoIadmirehisfashionstyleaswellashistimemanage- ment skills and multitasking capability; Francoise, who I cherish her laughter andher free spirit;Slavo,whoIadorehisworkingattitude;Francois,whoIlikehislivingstyle;andPascal, whoalwayssurprisesmewith hiswide knowledge. Therearealsosomanyotherawesome scientistsfromtheLCSAandLCSO,withwhomIhavethelucktosharegreatmomentsduring BarbecuesandAperosandgottoknowthem. MyPhDworkcouldcertainlynothavegonewellwithouttheassistanceofthetechni- calteamsofISIC.IwouldthanktheNMRservice(Anto,PascalandMartial),fortheireffort tomaintainthemachines;theMassService(Laure,DanielandFrancisco),fortheirfast,effi- cientandaccurateanalysisofoursamples;Luc,forhishardworkindevelopingallthefantas- ticinformaticstoolstohelpus;theMagasin(Giovanni,Annelise,Gladys,andBenjamin),for their efficiency in providing us requested new chemicals and equipments; the Mechanical workshop, for designing personalized sparepartsfor our machines; and finally Patrick, for hispatienceinsolvingourvarioushardwareproblems. Besidesmywork,familyandfriendsarethebestpartofmylife.Icouldnotsuccessfully finishmyPhDworkwithouttheircontinuoussupport. Iwouldexpressmygreatestappreci- ation to my beloved family: my parents, Philippe and Dominique, who taught me to be a gentleman and always support my decisions; my dear brother Raphaël, who is the coolest and best brother everyone wishes to have. Also, I would like to thank my life-long friends who grew up with me and mean so much to me, especially Simon, Marc, Laurence, Laura, vii Acknowledgements ValentineandAmaniel,foralwayscheeringmeupandgivingmeahandwhenIneededthe most.Icherishtheloveandfriendshipyouconstantlygivetome. The best outcome in the past four years is not only finish my PhD, but more impor- tantlyfindmylifelongsoulmateHuiwen. Shehasbeenatrueandgreatsupportersincewe aretogetherandalwayshasfaithinme. Shecheeredmeupinthedepressingtime,worked alongwithmeinthelabuntil3am,andsharedliferesponsibilitieswithmeintoughperiod andhappydays.Iamtheluckiestmantohaveheronmysideandwillloveherfromnowand forever. Lausanne,June8,2015 O.W. viii Abstract This thesis describes a unified strategy for the synthesis of monoterpene indole alkaloids of the Aspidosperma family. These syntheses feature two key steps: (1) a palladium- catalyzed decarboxylative vinylation that provides quick access to cyclopentene interme- diates containing all of the carbons present in the natural products and (2) an integrated oxidation/reduction/cyclization (iORC) sequence for skeletal reorganisation that converts the cyclopentenes to the corresponding pentacyclic structures of the naturalproducts. By incorporation of a geometric constraint to the iORC substrates, both the chemoselectivity (C7 versus N1 cyclization) and the stereoselectivity (trans- versus cis-fused ring system) of the cyclization process can be controlled. Using this method, we achieved the total syn- thesis of racemic aspidospermidine and dehydroaspidospermidine in seven steps; both of which featurea cis-fusedringsystem. We thenaccomplished a ten-steps synthesis of kop- sihainanine A featuringa trans-fusedring system. The work towards the total synthesis of aspidoalbidineandkopsinitarineEusingthesametwokeystepswasattempted,butwasnot completed in thetime provided. ThisPhD will also cover oursynthetic effortstowardsthe alkaloidminfiensine,featuringadominoreduction/cyclizationsequenceperformedpriorto thedevelopmentoftheiORCprocess. Keywords: natural product, indole alkaloids, domino reaction, iORC, total synthesis, min- fiensine, aspidospermidine, dehydroaspidospermidine, vincadifformine, aspidoalbidine, kopsihainanineA,kopsinitarineE. ix