total synthesis of the daphniphyllum alkaloid daphenylline

1、TotalsynthesisoftheDaphniphyllumalkaloiddaphenyllineZhaoyongLu?YongLi?JunDengAngLiTheDaphniphyllumalkaloidsarealargeclassofnaturalproductsisolatedfromagenusofevergreenplantswidelyusedinChineseherbalmedicine.Theydisplayar

2、emarkablerangeofbiologicalactivitiesincludinganticancerantioxidantvaselaxationpropertiesaswellaselevationofnervegrowthfact.DaphenyllineisastructurallyuniquememberamongthepredominatelyaliphaticDaphniphyllumalkaloidscontai

3、nsatetrasubstitutedarenemoietymountedonastericallycompacthexacyclicscaffold.Hereinwedescribethefirsttotalsynthesisofdaphenylline.Agoldcatalysed6exodigcyclizationreactionasubsequentintramolecularMichaeladditionreactionins

4、piredbyDixon’sseminalwkwereexploitedtoconstructthebridged665tricyclicmotifofthenaturalproductatanearlystagethearomaticmoietywasfgedthroughaphotoinducedolefinisomerization6pelectrocyclizationcadefollowedbyanoxidativearoma

5、tizationprocess.Plantnaturalproductshaveplayedanimptantroleinchemistrybiologymedicalsciencefcenturies1chemicalsynthesiscontinuestoserveasapowerfultooltounderstthefunctionsofthesecompounds2–5.Daphniphyllumisagenusofdioeci

6、ousevergreenplantsnativetoAsiatheleavesrootsofwhichareusedwidelyinChineseherbalmedicine6.About250Daphniphyllumalkaloidshavebeenisolatedfromthisgenustodate7.Fromastructuralperspectivethesenaturallyoccurringmoleculesusuall

7、ypossessabridgedfusedhexapentacyclicscaffoldthatcontainscontinuousstereogeniccentresbasedontheirconnectivitymodestheycanbefurtherclassifiedintomethan20subfamilies.ShowninFig.1arethemoleculararchitecturesthatrepresentseve

8、ralmajsubfamiliesofDaphniphyllumalkaloids.Intriguedbythesefinatingstructuresaseriesofbiosynthetichypothesesweresuggested7ledbyHeathcock’selegantproposalfthebiosynthesisofmethylhomosecodaphniphyllate(1Fig.1)fromasqualened

9、erivative89.Althoughsomeisotopiclabellingexperimentswerecarriedout7identifyingthebiosyntheticwkthatconnectsallthesubfamiliesofDaphniphyllumalkaloidsatthebiochemicallevelremainsafablechallenge.Thesestructurallydiversecomp

10、lexnaturalproductsdisplayaremarkablerangeofbiologicalactivities7suchasanticancer10antioxidation11elevationofnervegrowthfact12vaselaxation13.HoweverthesystematicbiologicalprofilingoftheDaphniphyllumalkaloidstheirderivativ

11、esishamperedbythescarcesupplyofthesecompoundsfromnaturalsources.ThefablechallengeposedbytheirintricatestructuresresultedinintensiveefftstoachievethetotalsynthesisofDaphniphyllumalkaloids7814–33whichwouldalsoprovideagreat

12、opptunitytoacceleratebiologicalbiosyntheticstudiesofthem.Heathcockcowkersaccomplishedalmarksynthesisofmethylhomosecodaphniphyllate(1)guidedbytheirbiosynthetichypothesis814whichfmedthebasisftheirsuccessfulsynthesesofmethy

13、lhomodaphniphyllate16daphnilactoneA17bukittinggine18(2–4Fig.1)aswellassecodaphniphylline19codaphniphyllin20(sidechainanaloguesof12respectively).RecentlyCarreiracowkersdisclosedthetotalsynthesisofdaphmanidinE(5Fig.1)froma

14、nonmethylhomodaphniphyllatetypesubfamily21whichrepresentsthefirstbreakthroughinDaphniphyllumalkaloidsynthesisinnearlytwodecades.Todatehowevertheremainingmembersofthislargenaturalproductfamilyincludingthosefromthecalyciph

15、yllineA(6)daphnicyclidin(7)subfamilies7whichfeaturea6n5brigedtricyclicmoiety(Fig.1totalnumberuptoabout50)havenotbeensynthesizedsuccessfully.NotablyDixoncowkersdevelopedanelegantsynthesisofthetricyclicceofcalyciphyllineAt

16、ypeDaphniphyllumalkaloids(Fig.2)26whichsetsanimptantbasisfthecollectivesynthesisoftheabovementionedsubfamilymembers.ThehighlydiastereoiveintramolecularMichaeladditionreactionusedftheirconstructionofthe56bicyclicsystem262

17、7isparticularlyinspiringtothiswk(videinfra).AstructurallyuniquecalyciphyllineAfamilymemberisolatedbyHaocowkersfromthefruitsofD.longeracemosumin2009namelydaphenylline(Fig.18)34attractedouraswellasothers’attention3031.Daph

18、enyllineistheonlyDaphniphyllumalkaloidtoincpateanarenemotifincontrasttotheothermembersofthisaliphaticnaturalproductfamily.Hereinwereptthefirsttotalsynthesisofdaphenylline(8).ResultsdiscussionThestructuralfeaturesofthebri

19、dged6n5tricyclic(n67)motif(Fig.1bottomright)ofdaphenylline(8)itscongeners(fexample67)aswellasDixon’sseminalwk26describedabove(Fig.2)inspiredustoenvisionacommonintermediatesuchas9(Fig.3)potentiallyusefulfthedivergentsynth

20、esisofanumberofstructurallyrelatedDaphniphyllumalkaloids.Inthecaseofdaphenyllinethemostsignificantsyntheticchallenge(theassemblyofthestericallyencumberedtetrasubstitutedarenesetinastericallydemingenvironment)couldbeachie

21、vedbya6pelectrocyclizationaromatizationsequencesimilartothatusedduringourtotalsynthesisoftubingensinA35.WiththisstrategyinmindweundertookaretrosyntheticanalysisasshowninFig.3.Hexacyclicketolactam10wasconsideredtobeadirec

22、tprecursofdaphenylline(8)thesevenmemberedringofwhichcouldbedisassembledtoaffdapentacycliciodide11asthesubstratefa7exotrigradicalcyclization.Basedonthe6pelectrocyclizationStateKeyLabatyofBioganicNaturalProductsChemistrySh

23、anghaiInstituteofganicChemistryChineseAcademyofSciences345LinglingRoadShanghai200032China?Theseauthscontributedequallytothiswk.email:CLESPUBLISHEDONLINE:30JUNE2013|DOI:10.1038NCHEM.1694NATURECHEMISTRY|ADVANCEONLINEPUBLIC

24、ATION|naturechemistry1?2013MacmillanPublishersLimited.Allrightsreserved.intetrahydrofuran(THF)at2788CaffdedtheundesiredC6epimerasthemajproduct(?3:1diastereomericratio(d.r.)).IncontrastDixoncowkersobservedthedesiredstereo

25、chemistryatC6whensynthesizingthe56bicyclicsystemthroughanintramolecularMichaeladditionunderKHMDSconditions(Fig.2)26.Thestructureof9wasconfirmedbyXraycrystallographicanalysisofitsdesilylatedderivative(Fig.4Tm144–1478Cethy

26、lacetate(EtOAc)nhexane1:1).Alltheabovetransfmationswereperfmedreadilyonamultigramscalewithconsistentefficiency.Withthetricyclicintermediate9inhwefocusedourattentionontheconstructionofthechallengingtetrasubstitutedarenemo

27、tifasshowninFig.5a.cisTriene12wasconsideredasuitableprecurstoexplethefeasibilityofthe6pelectrocyclizationaromatizationstrategy.Howeverwellrecognizedapproachessuchaspartialhydrogenation41ofthecrespondingynedieneprovedtobe

28、unsatisfactybecauseofthepopositionalivityattemptstoprepareseeminglysimplecisbonatestannanereagentswerealsofruitless.Toourdelighthoweverphotoisomerizationofthetranstrieneaffdedthedesiredcisisomer.Indeedtreatmentofketone9w

29、ithKHMDSNphenylbis(trifluomethanesulfonie)(PhNTf2)furnishedthecrespondingtriflatewhichfurtherunderwentSuzukicouplingwithtransbonate22torendertriene23withgoodoverallefficiency.Irradiationof23witha125WHglampffiveminutespro

30、vided12readily42.Surprisinglythiscistrienewasfoundtobereluctanttoenterthe6pelectrocyclizationpathwayunderthermalconditions43elevatingthereactiontemperaturemerelyledtoskeletaldecomposition.InspiredbyTrauner’sseminalwk4445

31、weexamined6pelectrocyclizationpromotedbyaLewisacidtotakeadvantageofthecarbonylfunctionalityconjugatedtothetrienesystemof12.UnftunatelyavarietyofLewisacidssuchasdiethylaluminiumchlidebontrifluidediethyletherateSnCl4copper

32、(I)trifluomethanesulfonate35failedtoeffectthedesiredcyclizationdesilylationfollowedbydecompositiongraduallyoccurredundertheseconditions.Thefailureoftheseefftsmaybeattributabletothefablesterichindrancegeneratedinthedisrot

33、atycyclizationprocess.Theconrotatypathwayisexpectedtodeveloplessstericcongestionencouraginglyweoccasionallydetectedatraceamountofcyclizationproductunderphotoirradiationconditionsintheprocessoftrieneisomerization.Underopt

34、imizedconditions(500WHglamp15minutes)transtriene23convertedcleanlyintopentacycliccompound24(asasinglediastereomerin71%yield)throughaphotoinducedisomerizationelectrocyclizationcadewiththeintermediacyofcis188DaphenyllineNH

35、MeHMeCO2MeOTBSHO2CNHMeHMeOadicalcyclizationNMeOONMeOO6πelectrocyclizationaromatizationNMeOONHOPdcatalysedcouplingMichaeladditionAefmationMeAucatalysedalkynecyclizationOOHMeHNSOOO2NCO2MeICO2MeOTBSCO2MeOTBS101112193161714O

36、MeNoNs15131Figure3|Retrosyntheticanalysisofdaphenylline.Thekeystrategiesinclude(1)aradicalcyclizationftheassemblyofthesevenmemberedring(2)asequenceof6pelectrocyclizationaromatizationftheconstructionofthetetrasubstituteda

37、rene(3)anintramolecularMichaeladditiontofmthepyrrolidineringwiththedesiredstereochemistry(4)agold(I)catalysed6exodigcyclizationtopreparethebridged66bicyclicbuildingblock(13).InspiredbyDixon’swk26intermediate9isdevisedont

38、hebasisofthecommonstructuralmotifofdaphenyllinerelatedDaphniphyllumalkaloids.The6pelectrocyclizationaromatizationstrategywhichwasappliedtoourprevioussynthesisoftubingensinAplaysadeterminingroleintheentiredaphenyllineplan

39、.oNs2nitrobenzenesulfonyl.OMeOMeOH17PPh3DIAD0oCNoNsi.TBDPSOTf26lutidine?78oCii.Au(PPh3)ClAgOTfMeOHNOMeoNsi.K2CO3pthiocresolii.14HOBtEDCHClEt3NNOOMeCO2MeOTBSK2CO3100oC161520219TEPof9a(desilylated9)6NOMeOCO2MeOTBSOSiR2RMeN

40、oNs18OSiR2RNoNs19OMeNoNs15R2RSiOTfbase86%70%(twosteps29%of15recovered)72%(twosteps)86%Figure4|Constructionofthebridgedtricycle9.Agold(I)catalysedalkynecyclizationwasexploitedtoconstructthebridged66bicycle20.Silylenolethe

41、r18thesubstratefthisreactionwaspreparedfromenone15(inset)26lutidineasabasewasfoundtosuppressthefmationoftheundesiredregioisomericsilylenolether19.AnintramolecularMichaeladditionassembled9inadiastereoivemanner.DIADdiisopr

42、opylazodicarboxylateTBDPSOTftertbutyldiphenylsilyltrifluomethanesulfonate.NATURECHEMISTRYDOI:10.1038NCHEM.1694ARTICLESNATURECHEMISTRY|ADVANCEONLINEPUBLICATION|naturechemistry3?2013MacmillanPublishersLimited.Allrightsrese