ja0617800

TotalSynthesesoftheTelomeraseInhibitorsDictyodendrinB,

C,andE

AloisFu¨rstner,*MathiasM.Domostoj,andBodoScheiper

ContributionfromtheMax-Planck-Institutfu¨rKohlenforschung,

D-45470Mu¨lheim/Ruhr,Germany

ReceivedMarch15,2006;E-mail:fuerstner@mpi-muelheim.mpg.de

Abstract:Conciseandflexibletotalsynthesesofthepyrrolo[2,3-c]carbazolealkaloidsdictyodendrinB(2),

C(3),andE(5)aredescribed.Thesepolycyclictelomeraseinhibitorsofmarineoriginderivefromthecommonintermediate18whichwaspreparedonamultigramscalebyasequencecomprisingaTosMICcycloadditionwithformationofthepyrroleA-ring,atitanium-inducedreductiveoxoamidecouplingreactiontogenerateanadjacentindolenucleus,andaphotochemical6π-electrocyclization/aromatizationtandemtoforgethepyrrolocarbazolecore.Conversionof18intodictyodendrinCrequiredselectivemanipulationsofthelateralprotectinggroupsandoxidationwithperoxoimidicacidtoformthevinylogousbenzoquinonecoreofthetarget.Zinc-inducedreductivecleavageofthetrichloroethylsulfateesterthencompletedthefirsttotalsynthesisof3.Itsrelatives2and5alsooriginatefromcompound18byaselectivebrominationofthepyrroleentityfollowedbyelaborationoftheresultingbromide27viametal-halogenexchangeorcross-couplingchemistry,respectively.Particularlynoteworthyinthiscontextisthegenerationoftheverylabilep-quinomethidemotifofdictyodendrinEbyapalladium-catalyzedbenzylcross-couplingreactionfollowedbyvinylogousoxidationoftheresultingproduct41withDDQ.TheSuzukistepcouldonlybeachievedwiththeaidoftheboratecomplex40formedinsitufromp-methoxybenzylmagnesiumchlorideand9-MeO-9-BBN,whereasalternativemethodsemployingbenzylicboronates,-trifluoroborates,or-stannanesmetwithfailure.

Introduction

Eukaryoticchromosomesareterminatedbynonencoding,single-strandedtelomericends,whichplayessentialrolesinchromosomeprotection,positioning,andcelldivision.Mostnotably,theyareprogressivelyshortenedbyca.50-200nucleotidesineachsuccessiveroundofreplication;onceacriticallengthisreached,asignalingpathwayistriggeredleadingtoapoptoticcelldeathtopreventfurtheraging.Thetelomereshenceconstituteadecisivemitoticclockthatisultimatelyresponsibleforthefinitelifespanofsomaticcells.1Morethan85%ofmalignanttumorsarereprogrammedtocircumventthisprotectivemechanismbyupregulationofhumantelomerase.Thisribonucleoproteinwithreverse-transcriptasepropertiesiscapableofaddingTTAGGGrepeatstothe3′-endsoftelomerswhichtherebykeepacertainlength,escapefromapoptosis,andhencegaincellularimmortalityasthecharac-teristictraitofcancer.2,3Therefore,itcomesasnosurprisethatinhibitionoftelomeraseactivitymightbeconsideredascancer’s“Achillesheel”andconsiderableeffortsarepresentlydirectedtoexploitthiscancer-specificvulnerabilityinthequestformoreselectivechemotherapeuticagentsand/orthedevelopmentofadjuvantclinicalregimens.4,5

(1)(a)Telomeres;Blackburn,E.H.,Greider,C.W.,Eds.;ColdSpringHarbor

Lab:Plainview,NY,1995.(b)Cech,T.R.Angew.Chem.,Int.Ed.2000,39,34.

(2)(a)Greider,C.W.;Blackburn,E.H.Cell1985,43,405.(b)Morin,G.B.

Cell1989,59,521.

(3)Foraveryrecentfirststructuralinvestigationontelomerase,see:Jacobs,

S.A.;Podell,E.R.;Cech,T.R.Nat.Struct.Mol.Biol.2006,13,218.

10.1021/ja0617800CCC:$33.50©2006AmericanChemicalSociety

Smallmoleculetelomeraseinhibitors,however,arestillrare.6,7Thereby,itisparticularlystrikingthattelomeraseinhibitorsofmarineoriginarelargelyunknowneventhoughtheseahasyieldedahugenumberofnovelbioactivemetabolitesincludingsomeofthemostpromisingleadsforthedevelopmentofanticancerdrugsduringthepastdecades.8Inviewofthisconspicuouslackofinhibitors,arecentpublicationfromFusetanietal.deservesparticularattention,disclosinganew

(4)Reviews:(a)Neidle,S.;Parkinson,G.Nat.ReV.DrugDiscoVery2002,1,

383.(b)Neidle,S.;Thurston,D.E.Nat.ReV.Cancer2005,5,285.(c)Kelland,L.R.Eur.J.Cancer2005,41,971.(d)Beltz,L.A.;Manfredi,K.P.Med.Chem.ReV.-Online2005,2,325.

(5)Seethefollowingforleadingreferencesandliteraturecitedtherein:(a)

Kim,N.W.;Piatyszek,M.A.;Prowse,K.R.;Harley,C.B.;West,M.D.;Ho,P.L.C.;Coviello,G.M.;Wright,W.E.;Weinrich,S.L.;Shay,J.W.Science1994,266,2011.(b)Herbert,B.-S.;Pitts,A.E.;Baker,S.I.;Hamilton,S.E.;Wright,W.E.;Shay,J.W.;Corey,D.R.Proc.Natl.Acad.Sci.U.S.A.1999,96,14276.(c)Keppler,B.R.;Jarstfer,M.B.Biochemistry2004,43,334.(d)Hahn,W.C.;Stewart,S.A.;Brooks,M.W.;York,S.G.;Eaton,E.;Kurachi,A.;Beijersbergen,R.J.;Knoll,J.H.M.;Meyerson,M.;Weinberg,R.A.Nat.Med.1999,5,1164.

(6)Forleadingreferencesonsynthetictelomeraseinhibitors,seethefollowing

referencesandliteraturecitedtherein:(a)Moore,M.J.B.;Schultes,C.M.;Cuesta,J.;Cuenca,F.;Gunaratnam,M.;Tanious,F.A.;Wilson,W.D.;Neidle,S.J.Med.Chem.2006,49,582.(b)Pascolo,E.;Wenz,C.;Lingner,J.;Hauel,N.;Priepke,H.;Kauffmann,I.;Garin-Chesa,P.;Rettig,W.J.;Damm,K.;Schnapp,A.J.Biol.Chem.2002,277,15566.

(7)Forselectedstudiesofnaturalproductswithtelomeraseinhibitoryproperties,

see:(a)Shin-ya,K.;Wierzba,K.;Matsuo,K.;Ohtani,T.;Yamada,Y.;Furihata,K.;Hayakawa,Y.;Seto,H.J.Am.Chem.Soc.2001,123,1262.(b)Lambert,T.H.;Danishefsky,S.J.J.Am.Chem.Soc.2006,128,426.(c)Kim,M.-Y.;Vankayalapati,H.;Shin-ya,K.;Wierzba,K.;Hurley,L.H.J.Am.Chem.Soc.2002,124,2098.(d)Warabi,K.;Hamada,T.;Nakao,Y.;Matsunaga,S.;Hirota,H.;vanSoest,R.W.M.;Fusetani,N.J.Am.Chem.Soc.2005,127,13262.

(8)DrugsfromtheSea;Fusetani,N.,Ed.;Karger:Basel,2000.

J.AM.CHEM.SOC.2006,128,8087-8094

9

8087

ARTICLESfamilyofalkaloidsisolatedfromthespongeDictyodendrillaVerongiformiscollectedofftheSouthJapanesecoast.9Thedictyodendrins1-5wereclaimedtobethefirstmarinenaturalproductswithtelomeraseinhibitoryproperties(100%inhibitionat50µg/mLconcentration),althoughnofurtherdetailsorbiochemicalprofilinghasbeenreported.Theyarecloselyrelatedtothealdosereductaseinhibitors6and7previouslyisolatedfromaDictyodendrillasp.10Collectively,thesetyramine-derivedalkaloidsfeatureacharacteristicanduniquepyrrolo[2,3-c]-carbazolemoietythatisdecoratedwithelectron-richareneringsandcarriesatleastonesulfategroupintheperiphery.Assuch,thedictyodendrinsaredistantlyrelatedtoaseriesofothermarinepyrrolealkaloidssuchasthelamellarins,lukianol,ningalin,storniamide,polycitone,purpurone,orhalitulin,manyofwhicharealsopotentanticanceragents.11-13Overall,thescarcityofthedictyodendrins,theasofyetincompleteunderstandingoftheirphysiologicalproperties,thepromiseofefficienttelomeraseinhibition,andtheircompactanddemandingstructuralchar-acteristicsrenderthesemarinenaturalproductsformidabletargetsforasynthesis-driveninvestigationatthechemistry/biologyinterface.Astheinitialstepofthisendeavor,wenow

(9)Warabi,K.;Matsunaga,S.;vanSoest,R.W.M.;Fusetani,N.J.Org.Chem(10)2003Sato,,A.;68,Morishita,2765.

.

T.;Shiraki,T.;Yoshioka,S.;Horikoshi,H.;Kuwano,

(11)H.;(a)Handy,Bailly,Hanzawa,S.T.;C.H.;Curr.Hata,T.J.Org.Chem.1993,58,7632.

Zhang,Med.Y.Org.Chem.:Prep.Anti-CancerProced.IntAgents.2005,200417,411.,4,363.(b)

8088J.AM.CHEM.SOC.

9

VOL.128,NO.24,2006

Fu¨rstneretal.presentthefirsttotalsynthesisofthreeprototypemembersof

thisfamily,whichisconciseandefficient,mapsthepertinentchemicalbehaviorofthesecompounds,andisalsoflexiblebydesigntoallowforsubstantialvariationsatalaterstage.14,15

ResultsandDiscussion

RetrosyntheticConsiderationsandPreparationofaCom-monSynthesisPlatform.Theindividualdictyodendrins1-5differonlywithregardtotheiroxidationpatternandthesubstituentsattachedtotheC.2positionofthepyrroleA-ring.Therefore,itseemedpossibletoaccesstheentirefamilybysuitablemanipulationsofacommonsyntheticintermediateoftype9(Scheme1).Anysuchattempt,however,mustconsiderthelabilityoftheconspicuoussulfatedecoratingcompounds1-5.Mostlikely,itisadvantageoustointroducethisgroupataverylatestageofthesynthesis,thusmakingasuitableandorthogonalprotectionofthephenolicpositionatC.10necessary;thepresenceoftheintactsulfategroup,however,wasreportedtobeessentialfortelomeraseinhibitoryactivity.9

Moreover,itisknownthattheindividualdictyodendrinsundergorapidfragmentationinaqueousacidicmediabywhichtheylosetheirC.2substituentsaswellasthesulfategroupsandconvergetocompound8asthecommon“degradation”product.9Thisinformationsuggeststhatthevinylogousquinonein8representsathermodynamicsinkthatbenefitsfromadditionalstabilizationbythelonepairsoftheflankingN-atoms.Inrecognitionofthischemicalbias,weenvisagedthegenerationofthischaracteristicstructuralmotifintheprojectedsynthesisofdictyodendrinC(3)directlyfromcompound9,providedthatanoxidantcanbefoundthatselectivelyattackstheC.14OHgroupandtheelectronicallycoupledC-HbondattheremoteC.2position.AlthoughsuchatransformationshouldultimatelyopenaccesstodictyodendrinC(3)asthemoststablecompoundofthisseries,itshighercongenerswouldalsoderivefromthesameprecursor9viasuitableacylationoralkylation/oxidationofthepyrroleA-ring.

Thepreparationofasuitablyfunctionalizedsurrogateofthecommonsynthesisplatform9commencedwithreadilyavailable

(12)Forsee,selectedstudiesdirectedtothesynthesisofsuchpyrrolealkaloids,

Am.e.g.:Albericio,Chem.(a)SocHamasaki,.2005,127A.;,10767.Zimpleman,(b)Pla,J.M.;D.;Marchal,Hwang,I.;Boger,D.L.J.P.;S.Kagan,F.;R.K.;Alvarez,Ruchirawat,M.J.Org.S.J.ChemOrg..2005,70,8231.A.;(c)Olsen,Ploypradith,C.A.;M.;T.;Zhang,Y.;Bregman,H.J.Org.ChemChem..20052004,,7069,,5119.2362.(d)(e)Handy,Iwao,2003Takeuchi,Chem,44,4443.T.;(f)Fujikawa,Bullington,N.;Fukuda,J.L.;Wolff,T.;Ishibashi,R.R.;Jackson,F.TetrahedronP.Lett.Lukens,.20022003J.R.;,67Henry,,9439.C.(g)A.;Gupton,J.T.;Clough,S.C.;Miller,F.J.R.Org.B.;A.;R.;Jin,,59,207.(h)Boger,D.Kanters,L.;Boyce,R.P.C.F.;W.;Sikorski,Labroli,J.M.A.A.;TetrahedronSehon,C.(j)Boyce,Q.J.C.Am.W.;Chem.Hedrick,SocM..1999P.;,Jin,121Q.,54.(i)Boger,D.L.;Soenen,D.CommunBanwell,H..1997M.G.;Flynn,B.L.;Hamel,J.E.;Org.Hockless,Chem.D.2000C.,65R.,Chem.2479.Steglich,N.C.J.Org.,207.Chem(k).2000Liu,,J.-H.;65,3587.Yang,(l)Q.-C.;Peschko,Mak,T.C.W.;Wong,(13)TetrahedronW.Chem.(a)Lett.2000-Eur.,41J.,20009477.,6,1147.(m)Peschko,C.;C.;Winklhofer,Steglich,C.;W.(b)FuFu¨¨rstner,rstner,A.;A.;Weintritt,Krause,H.;H.;Hupperts,A.J.Org.Chem.1995,60,6637.

(14)FuPreliminary¨rstner,A.Angew.Chem.,Thiel,Int.EdO..2003R.Tetrahedron,42,3582.2002,58,6373.(c)(15)J.ForAm.FustudiesChem.communication:Fu¨rstner,A.;Domostoj,M.M.;Scheiper,B.

onSocother.2005bioactive,127,11620.

2777.¨rstner,Chem(b)A.;FuRadkowski,K.;Peters,pyrroleH.alkaloidsAngew.Chem.,fromourInt.group,Ed.2005see:,44(a)

,20012004¨,rstner,5,1575.A.;(c)Reinecke,Fu¨rstner,K.;A.;Prinz,Grabowski,H.;Waldmann,E.J.ChemBioChemH.ChemBio-T.;Org.Nagai,,2,706.K.(d)ChemBioChemFu¨rstner,A.;2001Grabowski,,2,60.(e)J.;Lehmann,Fu¨C.W.;Kataoka,W.Mynott,J.ChemOrg..R.Chem1999,64,8281.(f)Fu¨rstner,A.;Grabowski,rstner,A.;J.;Krause,Lehmann,H.C.J.J.Am..1999Chem.,64Soc,8275..1998(g),120Fu¨rstner,,8305.

A.;Szillat,H.;Gabor,B.;SynthesesoftheTelomeraseInhibitorsDictyodendrinsScheme1.EnvisagedGenerationoftheIndividualDictyodendrinsfromaCommonPrecursor9andTheirKnownDegradation,ConvergingtoCompound8aa

Numberingschemeusedthroughoutthispaper.

acetophenone10,16whichwasconvertedintoisopropylether11priortobase-inducedcondensationwithp-methoxybenzal-dehyde(Scheme2).Theresultingchalcone12cleanlyreactedwithtoluenesulfonylmethylisocyanide(TosMIC)inthepresenceofNaHatlowtemperature17togiveapyrrolewhichwasN-alkylatedinsituwithp-MeOC6H4(CH2)2Br.Reductionofthenitrogroupintheresultingproduct13withFe/HClfurnishedaniline14inexcellentyieldonamultigramscale,whichwascondensedwithacidchloride1518understandardconditionstogiveamide16withoutincident.

Previousinvestigationsfromthislaboratoryhadshownthatketoamides,ontreatmentwith“low-valent”titanium,converttoindolederivativeseveninthepresenceofotherreduciblesites.19,20Thisreactionisbestperformedwithtitaniumon

(16)(17)Butenandt,vanLeusen,A.;A.Hallmann,M.;Siderius,G.;Beckmann,H.;Hoogenboom,R.Chem.B.BerE.;.1957,90,1120.(18)TetrahedronPreparedacid;fordetails,inthreeLett.1972,13,5337.

vanLeusen,D.

consultsimplestepstheSupportingfromcommercialInformation.

p-hydroxyphenylpyruvic

ARTICLESgraphitepreparedfromTiCl3andKC8(2equiv)21asthereagent,althoughothersourcesoflow-valenttitaniumalsoprovidegoodtoexcellentresultsinmanycases.22Suchintramolecularreductivecouplingreactionsaredistinguishedbyanexceptionaldrivingforceandaremarkablechemoselectivityprofile,23whichallowsforapplicationseventofairlyelaboratecases.19-24

Thisnotionwasconfirmedbytheapplicationofthisprotocoltoketoamide16whichaffordedthedesiredindole17inupto93%isolatedyieldonexposuretotitanium-graphiteinrefluxingDME.Thereby,itwasnecessarytobuffertheslightlyLewis-acidicreactionmediumwithpyridinetopreventpartialcleavageofthelabileenolethermoietyofthesubstrate.Duringthesynthesiscampaigndescribedherein,thistransformationwascarriedoutrepeatedlyondifferentscalesandhasprovidedmultigramamountsofindole17,thusattestingtotherobustnessandreliabilityofthismethodologyforreductiveheterocyclesynthesis.

Indole17thusformedissetupforsubsequentclosureofthedictyodendrincorebya6π-electrocyclization.ThispivotaltransformationproceededsmoothlyuponirradiationwithUVlight(HanoviaHglamp,250W)inMeCN;additionofPd/Candnitrobenzenetothereactionmediumcausesconcomitantaromatizationoftheproductinitiallyformed,25thusgivingrisetothedesiredpyrrolocarbazole18in81%yieldinasingleoperation.26Since18representsafullyfunctionalintermediateforthepreparationofallindividualmembersofthedictyoden-drinfamily,averyshort,convenient,andscaleablegambitofourtotalsynthesisprojecthasbeensecuredemployingonlyinexpensivestartingmaterials(sevensteps,ca.40%overallyield).Moreover,thechosenrouteshouldallowforsubstantialvariationsasdesirableforasynthesis-drivenexplorationofpertinentstructure/activityrelationshipsofthisseriesofalkaloidsatalaterstage.

TotalSynthesisofDictyodendrinC.Inafirstattempt,compound18wasreactedwithBBr3inCH2Cl2at-78°Cinthepresenceofexcesscyclohexeneasanacidscavenger(Scheme3).Althoughtheperipheralmethyl-andisopropyletherscouldnotbedistinguishedundertheseconditionsandwerecleavedoffconcomitantly,wewerepleasedtoobservethattheresultingpolyphenolunderwentspontaneousairoxida-tionduringtheacidic/basicworkup,thusfurnishingcompound8inanunoptimized49%isolatedyield.Asdescribedabove,thiscompoundrepresentsthecommondegradationproductofallnaturallyoccurringdictyodendrins.9Itsspontaneousforma-tionalsosupportsthenotionthatthevinylogousp-quinonemotifembeddedintoitscoreconstitutesaformidablethermodynamicsink,thusauguringwellforthefinalstagesoftheprojectedtotalsynthesisofdictyodendrinC.

(19)(a)Fu¨rstner,A.;Hupperts,A.;Ptock,A.;Janssen,(20)59,(a)5215.(b)Fu¨rstner,A.;Jumbam,D.N.TetrahedronE.J.Org.1992Chem,48.,19945991.,

(21)2442.Fu¨rstner,(b)McMurry,A.;Bogdanovic,J.E.B.Angew.Chem.,Int.Ed.Engl.1996,35,

(22)Fu(a)¨rstner,A.Angew.Chem.,Chem.Int.Ed.ReVEngl.1989.1993,89,,1513.32Fu¨Fu¨rstner,A.;Hupperts,A.J.Am.Chem.Soc.,1995164.,117,4468.(b)

(23)Fu(a)¨rstner,rstner,A.;A.;Seidel,Hupperts,G.SynthesisA.;Seidel,1995G.Org.Synth.1999,76,142.(c)211.Fu¨(b)rstner,Fu¨A.;Jumbam,D.N.J.Chem.,63.Soc.,Chem.Commun.1993,

(24)Angew.(a)Chem.,rstner,Int.A.;Ed.Ptock,Engl.A.;1995Weintritt,,34,678.H.;Goddard,R.;Kru¨ger,C.Ernst,Fu¨rstner,A.;Krause,A.;Ernst,H.;A.Tetrahedron1995,51,773.(b)Fu¨rstner,A.;

(25)A.;Jumbam,D.N.;Seidel,Ptock,G.A.Chem.TetrahedronBer.19941996,,52,7329.(c)Fu¨rstner,(26)Rawal,ReviewsV.H.;Jones,R.J.;Cava,M.P.Tetrahedron127Lett,1125.

.1985,26,2423.ReSocV..19942002on,,71102carbazole,,443.

4303.synthesis:(b)Kawasaki,(a)KnoT.;¨lker,Sakamoto,H.-J.;Reddy,M.J.IndianK.R.Chem.

Chem.J.AM.CHEM.SOC.

9

VOL.128,NO.24,20068089

ARTICLESScheme2.PreparationoftheCommonSynthesisIntermediateaFu¨rstneretal.[a]2-Bromopropane,K2CO3,DMF,100°C,99%;[b]p-MeOC6H4CHO,NaOMe,MeOH,70°C,74%;[c](i)TosMIC,NaH,THF,-30°C;(ii)

p-MeOC6H4(CH2)2Br,reflux,83%;[d]Fepowder,aq.HCl,EtOH,96%;[e]acidchloride15,CH2Cl2,Et3N,DMAPcatalyst,89%;[f]TiCl3/2KC8,DME,pyridine,reflux,71-93%;[g]hν,MeCN,Pd/Ccatalyst,C6H5NO2,81%.Scheme3.PreparationofDesulfatedDictyodendrinCaa

a

[a]BBr3,cyclohexene,CH2Cl2,-78°Cfroomtemperature,49%.

Infact,aslightmodificationofthedeprotectionregimepavedthewaytothisparticulartarget(Scheme4).Specifically,theselectivecleavageoftheisopropyletherof18wasachievedin75%yieldsimplyuponswitchingfromBBr3toBCl3asthereagent.Theresultingphenol19wasreactedwithtrichloroethylchlorosulfuricacidester27toaffordarylsulfate20whichturnedouttobehydrolyticallylabileandhadtobeprocessedwithoutunduedelay.Gratifyingly,however,itwithstoodexhaustivedeprotectionoftheremainingmethylgroupswiththeaidofBCl3andtetra-n-butylammoniumiodideinCH2Cl2.28Ratherthanrelyingonairoxidation,29theresultingphenolwasreactedwithH2O2inMeCNtogivequinone21inasuperblycleantransformation;itisbelievedthatperoxyimidicacidistheactualoxidantundertheseconditions.30,31

(27)(a)Liu,Y.;Lien,I.F.;Ruttgaizer,S.;Dove,P.;Taylor,S.D.Org.Lett.

2004,6,209.(b)Forarecentapplication,see:Yamaguchi,T.;Fukuda,T.;Ishibashi,F.;Iwao,M.TetrahedronLett.2006,47,3755.

(28)Brooks,P.R.;Wirtz,M.C.;Vetelino,M.G.;Rescek,D.M.;Woodworth,

G.F.;Morgan,B.P.;Coe,J.W.J.Org.Chem.1999,64,9719.

(29)Asobservedinthecaseof8,theairoxidationoccursduringtheacidic/

basicworkup.Becausethesulfategroupof3,however,islabileundertheseconditions,theH2O2/MeCNprotocolhadtobeimplemented.Thismethodhastheadditionaladvantagethatnoextractiveworkupisnecessary,thusmakingtheisolationoftheverypolarfinalproductmuchmoreefficientandconvenient.8090J.AM.CHEM.SOC.

9

Compound21wasthentreatedwithexcesszincdustandammoniumformateinMeOHtoeffectreductivecleavageofthetrichloroethylestermoiety.27Eventhoughpartialreductionofthequinonewithformationof22wasobserved,removaloftheexcesszincdustfollowedbystirringofthecrudemixtureunderanoxygenatmosphereresultedintheformationofasingleproductwhichwasisolatedin76%yieldovertwosteps.TheanalyticalandspectroscopicdataofthiscompoundwereinexcellentagreementwiththoseofdictyodendrinC(3)reportedintheliterature,9thusfinishingthefirsttotalsynthesisofthisstructurallyuniquemarinealkaloidintheformofitsammoniumsalt.

DictyodendrinB.Theconversionoftherelaycompound18intodictyodendrinB(2)seemedstraightforward,requiringacylationofthepyrrolicC.2position32andsuitableprotectinggroupmanagementonly.Exploratorystudiesusingtheper-methylatedcompound2333asamodel,however,showedthatthisseeminglyconventionaltransformationisfarmoredelicatethananticipated(Scheme5).

Althoughsubstrate23wascompletelyconsumedonreactionwithp-methoxybenzoylchlorideinthepresenceofSnCl4,noneoftheexpectedketonewasobtained.Rather,thenewproduct24formedin64%yieldhadthesamemassasthesubstrateandgaveverysimilarNMRspectraaswell,thussuggestingthatanisomerizationratherthantheattemptedFriedel-Craftsacylationhadoccurredunderthechosenconditions.Sincenoincorporationoftheacidpartwasobserved,itcameasno

(30)Foradiscussion,seethefollowingforleadingreferencesandliterature

citedtherein:(a)Shu,L.;Shi,Y.J.Org.Chem.2000,65,8807.(b)Payne,G.B.;Deming,P.H.;Williams,P.H.J.Org.Chem.1961,26,659.(31)Forrelatedoxidationsofpyrroles,see:(a)Shrout,D.P.;Lightner,D.A.

Synthesis1990,1062.(b)Auerbach,J.;Franck,R.W.J.Chem.Soc.D1969,991.

(32)Forarelatedmaneuverinthetotalsynthesisofacomplexpyrrolealkaloid,

see:(a)Fu¨rstner,A.;Weintritt,H.J.Am.Chem.Soc.1998,120,2817.(b)Fu¨rstner,A.;Weintritt,H.J.Am.Chem.Soc.1997,119,2944.

(33)Thepreparationofcompound23essentiallyfollowstheroutedescribed

for18;detailswillbereportedinaforthcomingpaperdescribingvariousanaloguesofthenaturallyoccurringdictyodendrins.

VOL.128,NO.24,2006

SynthesesoftheTelomeraseInhibitorsDictyodendrinsScheme4.TotalSynthesisofDictyodendrinCaa

[a]BCl3,CH2Cl2,0°C,75%;[b]Cl3CCH2OSO2Cl,DABCO,THF,71%;[c](i)BCl3,(n-Bu)4NI,CH2Cl2,0°C;(ii)aq.H2O2(30%w/w),MeCN,57%;[d]Zn,HCOONH4,MeOH;[e]O2(1atm),MeOH,76%(combinedyield).

surprisethatthesameproductwasformedinsimilaryieldontreatmentwithSnCl4,TiCl4,orBF3‚Et2Oonly.Extensivespectroscopicstudiesfinallyrevealedthatthep-methoxyphenylringattachedtotheC.3positionin23hadmigratedtothevicinalcarbonatomC.2.ThisrearrangementpresumablyinvolvescomplexationoftheLewisacidatthemostelectron-richC.3carbonatomwithformationofaresonance-stabilizediminiumcation25thatispronetointramolecularelectrophilicattackontothearenemoietygivingrisetothebridgingWhelandcomplex26.34Subsequentcollapseofthisreactiveintermediatereadilyexplainsthisunusual3f2arylshift.

Thisunexpectedbehaviorenforcedaredesignofoursynthesisstrategy(Scheme6).Tothisend,compound18wastreatedwithNBSinTHFat0°C,whichresultedinselectivebrominationatC.2withformationofproduct27.Althoughthiscompoundcanbestoredforsometimeinthefreezerinsolidform,itissubjecttoarapid“brominedance”whenkeptinCDCl3solutionatambienttemperature.35ThisvectorialprocessshiftsthebrominesubstituentfromtheA-ringin27totheelectron-rich

(34)CarboniumIons;(35)1970;Olah,G.A.,vonR.Schleyer,P.,Eds.;Wiley:NewYork,

AlthoughVol.(hetero)arenebase-induced2.

“halogendance”processesarewell-knownin

65common;,2005andchemistry(cf.:Duan,X.-F.;Zhang,Z.-B.Heterocycles2005,Heterocycl.foraliteraturepertinentcitedtherein),uncatalyzedprocessesarelesswasChem.1981,18example,,1261.Evensee:thoughPress,strictlyJ.B.;neutralizedEudy,N.CDClH.J.3withused,thesolventitisassumedthatmightthatcatalyzetracesoftheacidobservedaregeneratedhalideshift,uponcf.reactionref36.

ARTICLESScheme5aa

[a]p-MeOC6H4COCl,SnCl4,1,2-dichloroethane,reflux,64%.

Scheme6aa

[a]NBS,THF,0°C,69%;[b]CHCl3,roomtemperature,cf.text;[c](i)MeLi,THF,-78°C;(ii)n-BuLi,-78°C;(iii)p-MeOC6H4CHO,-78°Cfroomtemperature,97%.

C.8positionlocatedintheD-ring,thusfurnishingtheisomericproduct28;thishalidewalkcanbenicelyfollowedbyNMR.36Gratifyingly,however,thearyllithiumspeciesformedon

(36)MScontaininganalysisduringoneshowsbrominethattracesandoneofadibrominatedchlorineatomcompoundareformedandasacompound

thethesesolventthishalideminormightwalk.productsgiveAlthoughhassomenotmechanisticincorporationbeeninvestigatedhints,ofanytheachloridebyproductsfurther.

exactconstitutionderivedfromofJ.AM.CHEM.SOC.

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VOL.128,NO.24,20068091

ARTICLESScheme7aa

[a]TPAP(10%),NMO,MS4Å,CH2Cl2at0.1Mconcentration:22%

(30)+57%(31);at0.01Mconcentration:66%(30)+16%(31).

N-deprotonationof27withMeLifollowedbymetal-halogenexchangewithn-BuLi37couldbequenchedwithp-MeOC6H4-CHOtoaffordalcohol29inremarkablyhighyield.38

Theseeminglytrivialoxidationofthiscompoundtothecorrespondingketoneagainposedsignificantproblems.Al-thoughtheuseofclassicaloxidantseitherresultedinnoconversion(MnO2,SO3/pyridine)orledtorapiddegradationonly(PDC,PCC,Dess-Martinperiodinane,TEMPOcatalyst/NaOCl,Swern),theuseofcatalyticamountsoftetra-n-propylammoniumperruthenate(TPAP,10mol%)39incombi-nationwithN-methylmorpholine-N-oxide(NMO)inCH2Cl2(0.1M)affordedaproductmixture,ofwhichthedesiredketone30wastheminorconstituentonly(22%)(Scheme7).Massspectrometryindicatedthedimericnatureofthemajorproduct31(57%)formedundertheseconditions;however,ittookconsiderableeffortstounambiguouslyelucidateitsconstitution.ExtensiveNMRinvestigationswerenecessarytoshowthatthetwosubunitsin31arejoinedbyaC-Nbondbetweenthe“indolic”nitrogenN.12ofonemoleculeandtheelectron-richC.8positionofthesecondentity.40Inrecognitionofthisfact,werepeatedtheoxidationundermorediluteconditions,hopingthatthedimerizationcouldbedisfavored.Infact,thereactionrespondedwelltothechosenconcentration,withc)0.01Mbeingthebestcompromiseamongproductdistribution,overallyield,andreactiontime.Undertheseconditions,ketone30wasobtainedin66%isolatedyield.

Theremainingprotectinggroupmanipulationsproceededuneventfully,followingthesuccessfulsequencepursuedinthedictyodendrinCseries.Thus,cleavageoftheisopropyletherin30withBCl3,attachmentoftheprotectedsulfateestertotheresultingphenol32,followedbyexhaustivedemethylationof

(37)TheexchangesequentialuseofMeLiandn-BuLiforaandtandemhasprecedenceintheliterature;deprotonation/metalforanearly-examplehalogen

(38)SocIn.aninstructivediscussion,see:Kelly,T.R.;Kim,M.H.J.Am.Chem.withstriking1994,p-MeOCcontrast,116,7072.

COClhowever,ortheattemptscorrespondingtoquenchWeinrebtheorganolithiumamidewerespecies

6H4by(39)largeLey,S.unsuccessful.

andV.;Norman,J.;Griffith,W.P.;Marsden,S.P.Synthesis1994,

(40)639.

AKraus,relatedprocessisreportedin:Bringmann,G.;Tasler,S.;123,2703.J.;Messer,K.;Wohlfarth,M.;Lobin,W.J.Am.Chem.Endress,Soc.2001H.;

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Fu¨rstneretal.Scheme8.CompletionoftheTotalSynthesisofDictyodendrinBaa

[a]BCl3,CH2Cl2,-20°C,85%;[b]Cl3CCH2OSO2Cl,DABCO,CH2Cl2,92%;[c]BCl3,TBAI,CH2Cl2,0°Cfroomtemperature;[d]Zn,HCOONH4,MeOH,58%(overbothsteps).

33,andreductivecleavageoftheremainingtrichloroethylmoietyin34withZn/HCO2NH4cleanlyledtodictyodendrinB(2)(Scheme8).Allanalyticalandspectroscopicdataofthesyntheticsamplesperfectlymatchedthoseofthenaturalproductreportedintheliterature.9

DictyodendrinE.DictyodendrinE(5)isarguablythemostchallengingtargetofthisfamilyofmarinealkaloids.ThisisevidentfromthefactthatthisparticularcompoundcouldnotbeisolatedfromthespongeinpureformbutwasobtainedbyFusetanietal.asaninseparablemixturewithamethanoladduct.9ThisinformationlikelyindicatesthehighreactivityofitsvinylogousquinomethidecorestructureextendingfromthebenzylidenesubstituentatC.2tothecarbonylgroupatC.14.Ourinitialapproachto5envisagedthevinylogouseliminationofMeOHfromproduct35,whichinturnderivesfromalcohol29bytheestablishedprotectinggroupregimen(Scheme9).Thisstrategy,however,hadtobeabandonedbecauseoftheexceptionallabilityof35,whichdecomposedonattemptedpurificationbyflashchromatography.

Forarouteto5tobeviable,itwasthereforeessentialtopassthroughmorerobustintermediates.Thesuccessoftheoxidationreactionleadingtothevinylogousp-quinonemoietyofdictyodendrinCinspiredsuchanalternativestrategy,envisagingformationofthevinylogousquinomethideof5byasimilarprocess.Therequiredsubstrate41carryingap-methoxybenzylsubstituentatC.2mightderivefrombromide27thathadalreadyservedasthekeyintermediateenroutetodictyodendrinB(seeabove).

Unfortunately,however,ourinitialattemptstogetaccessto41bypalladium-catalyzedcross-couplingofbromide27with

SynthesesoftheTelomeraseInhibitorsDictyodendrinsScheme9aa

[a](i)BCl3,CH2Cl2,-20°C,82%;(ii)Cl3CCH2OSO2Cl,DABCO,CH2Cl2.

Scheme10.DifferentaBorateComplex40viap-MethoxybenzylDonorsandPreparationofthe9-MeO-9-BBNVariantoftheSuzukiCoupling

suitablebenzyldonors(Scheme10)metwithfailure.Theuseofthestannane36,thetrifluoroborate37,41ortheboronate3842previouslyrecommendedforbenzylationreactionswasnotencouraging.Debrominationofthesubstratewithformationofcompound18wastheonlytransformationthatoccurredunderavarietyofexperimentalconditions(Scheme11).Inviewofthissetback,wewereparticularlypleasedtoseethatthe9-MeO-9-BBNvariantoftheSuzukireactionpreviouslydevelopedbyourgroupgavemuchmorefavorableresults.43-45Inthismethod,thecrucialboratecomplexservingastheactualnucleophileinthepalladium-catalyzedcross-couplingstepisgeneratedinsitufrom9-MeO-9-BBNandapolarorganometallicreagent,inthepresentcasethereadilyavailablep-methoxybenzylmagnesiumchloride(Scheme10).IncombinationwithPd(OAc)2andBuchwald’sstericallyencumberedS-PHOSligand,46,47thereactiveintermediate40thusformedallowedforthealmostquantitativebenzylationoftheelectron-richandratherlabilebromide27.

Forexploratorypurposes,theresultingproduct41wasgloballydeprotectedwithBBr3togivepolyphenol42which

(41)(42)Molander,G.A.;Ito,T.Org.Lett.2001,(43)Flaherty,(a)Leitner,Fu¨rstner,A.;A.;Trunkfield,Seidel,G.A.;TetrahedronBarton,W.1995Org.3,393.

,51Lett,.2005,7,4975.1996quist,,2107.A.SynlettJ.A.;(d)Matos,The2001K.;method,290.Rane,was(c)FuA.;also¨rstner,11165.(b)Fu¨rstner,A.;

Ramos,independentlyA.;Nikolakis,J.TetrahedronreportedK.LiebigsAnn.Lettby:.1995Soder-,36,(44)2401.

This(45)halides;methodhadpreviouslyallowedforveryefficientallylationsofaryl

ForOrganomet.generalcf.:reviewsFu¨rstner,Chem.1999onA.;theSeidel,G.Synlett1998,161.

,576Suzuki,reaction,see,e.g.:(a)Suzuki,A.J.

(46)Re(a)VChem.Barder,.1995,95Soc.T.,2005E.;2457.

147.(b)Miyaura,N.;Suzuki,A.Chem.,Walker,127,4685.S.D.;(b)Martinelli,Walker,S.J.D.;R.;Barder,Buchwald,T.E.;S.Martinelli,L.J.Am.

(47)J.InR.;Buchwald,S.L.Angew.Chem.,Int.Ed.2004,43,1871.

forthisaffordSuzukiparticularrichthecross-couplingreactionscase,accordingtheuseproduct.toof(dppf)PdCl2previouslyrecommended

Thistheis“9-MeO-9-BBN”tentativelyascribedprotocoltothefailedelectron-todonatingnaturecessfuloxidativeandofstericallysubstrate27,whichrenderstheuseofthemoreelectron-insertiondemandingofthePd(0)S-PHOStemplate.

ligandimperativeforsuc-ARTICLESScheme11aa

[a]Compound38,Pd(PPh3)4catalyst,CsF,THF,reflux;orcompound37,(dppf)PdCl2,Cs2CO3,THF/H2O(10:1),reflux;orcompound37,(dppf)PdCl2,Et3N,iPrOH;orcompound36,Pd(PPh3)4catalyst,copperthiophene-2-carboxylate(1.5equiv),DMF;orcompound36,Pd(PPh3)4catalyst,CuCl(5equiv),LiCl(6equiv),DMSO;or(PPh3)2PdCl2catalyst,THF;[b]borate40(4equiv),Pd(OAc)2(10mol%),S-PHOS(20mol%),DMF/THF,90%.

Scheme12.PreparationofDesulfatedDictyodendrinEaa

[a]BBr3,CH2Cl2,-78°Cfroomtemperature;[b]DDQ,THF,83%(overbothsteps).

wasprocessedfurtherbyDDQoxidationinTHFatambienttemperature(Scheme12).Inlinewithourexpectations,thevinylogousquinomethide43wasformedin83%isolatedyieldovertwosteps,whichrepresentsdesulfateddictyodendrinE.Thecompoundwasstableenoughtobeisolatedinanalyticallypureformandcouldbeunambiguouslycharacterized.ItsNMRdataareinexcellentaccordancewiththoseofdictyodendrinEitself,exceptfortheprotonsH.7,H.8,andH.9whichareshiftedtoalowerfieldinthenaturalproductbecauseoftheirvicinitytothesulfategroupresidingattheadjacentO.10position.Theproofofthisconceptspurredoureffortstocompletethetotalsynthesisofthesulfatednaturalproduct5aswell(Scheme13).Followingtheestablishedprotocolstartingwiththeselectiveremovaloftheisopropylgroupin41andsubsequentintroduc-tionofthetrichloroethylsulfatemoiety,27compound45wasobtained;thisproductwashighlysusceptibletohydrolysisandhadtobeprocessedwithoutdelay.ThecleavageofitsmethyletherswithBCl3/(n-Bu)4NI,28however,proceededwellaffordingtheevenmoresensitivecompound46whichwasimmediately

J.AM.CHEM.SOC.

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ARTICLESSchemea13.CompletionoftheTotalSynthesisofDictyodendrinEa

[a]BCl3,CH2Cl2,-20°Cfroomtemperature;[b]Cl3CCH2OSO2Cl,DABCO,THF,83%(overbothsteps);[c]BCl3,TBAI,CH2Cl2,0°C,85%;[d](i)Zn,HCOONH4,MeOH;(ii)DDQ,THF,75%(overbothsteps);[e]MeOH,cf.text;[f](i)DDQ,THF;(ii)Zn,HCOONH4,MeOH.

subjectedtoreductivecleavageofthetrichloroethylgroupfollowedbyDDQoxidation.Gratifyingly,thisreactionsequenceallowedfortheisolationofdictyodendrinE(5)inpureforminrespectable75%yieldovertwosteps.

Forsolubilityreasons,however,thepurificationoftheproducthadtobeperformedwithMeOH.AnydelayduringthismanipulationoranytraceofacidinthemixtureatthatpointcausespartialadditionofMeOHwithformationoftheinseparableadduct47,thusconfirmingFusetani’soriginalfindingthattheextendedquinomethidemoietyof5actsasanexcellentMichaelacceptorforexternalnucleophiles.9,48Inthiscontext,itisalsoworthmentioningthattheorderofthefinalstepsleadingfrom46to5iscriticalforsuccess:thus,DDQoxidationof46priortoreductivecleavageofthetrichloroethylsulfateesterresultsinanoverallfragmentationwithlossofthebenzylideneunitatC.2,therebygivingrisemainlytodictyo-dendrinC3(Scheme13).Thisfindingreinforcestheprevious

(48)Control1weekatexperimentsambienttemperatureshowedtheinMeOHtheabsenceadditionoftoexternalbecompletecatalysts.afterca.

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Fu¨rstneretal.observationthatallnaturallyoccurringdictyodendrinsultimately

convertto3oritsdesulfatedanalogue8asthethermodynami-callymostfavorablecompoundsofthisseries9andmayforecastsomewhatlimitedstructuralflexibilitywithregardtothesubstitutionpatternatC.2infutureSARstudies.

Conclusions

Challengedbytheintriguingstructuresofthetelomeraseinhibitorsbelongingtothedictyodendrinfamily,aconciseapproachtothesescarcealkaloidsofmarineoriginwasdeveloped.Thechosenroutetakesadvantageoftheproclivityofketoamidestoundergoreductivecouplingontreatmentwithlow-valenttitanium20aswellasofanefficientphotochemical6π-electrocyclization,whichisrenderedirreversiblewhenperformedintandemwiththearomatizationofthecyclohexa-dienederivativeinitiallyformed.Thedenselyfunctionalizedpyrrolo[2,3-c]carbazole18thusobtainedinmultigramquantitieswithexcellentoverallyieldservedasacommonintermediateforthefirsttotalsynthesesofthequinoiddictyodendrinC,itsverylabilequinomethideanaloguedictyodendrinE,andtheacylatedcongenerdictyodendrinB.Theindividualendgamesuncoversomeoftheuniquechemicalcharacteristicsofthesenaturalproducts,mostnotablytheirtendencytoformextendedquinoidchromophoresunderoxidativeconditionsaswellasthelabilityofsubstituentsatC.2.Themigratoryaptitudeofthebromideatthisposition,thepreferenceofa1,2-arylshiftoverconventionalFriedel-Craftschemistry,andthesomewhatsurprisingtendencyofsuchcompoundstoengageindimeriza-tionatseeminglyremotesites(C.8)areequallyremarkablefeatures.Finally,thesuccessofthepalladium-catalyzedben-zylationbymeansofthe9-MeO-9-BBNvariantoftheSuzukicouplingisnoteworthy,whichmightbeusefulinotherdelicateapplicationsaswell.49Havingcompletedthisfirstroundofchemicalexplorationsofthisinterestingclassofbioactivealkaloids,wearenowinthephaseofredirectingthetotalsynthesesoutlinedabovetowardthepreparationof“naturalproductlike”analoguesaswellastoastudyoftheirbiochemicalandbiologicalproperties.Theresultsoftheseinvestigationswillbereportedshortly.

Acknowledgment.GenerousfinancialsupportbytheMax-

Planck-SocietyandtheMerckResearchCouncilisgratefullyacknowledged.M.M.D.andB.S.thanktheAlexander-von-HumboldtFoundationandtheFondsderChemischenIndustrie,respectively,forfellowships.WealsothankProf.N.FusetaniandProf.S.Matsunaga,Tokyo,forkindlyprovidingsamplesofthedictyodendrinsandcopiesoftheoriginalspectraforcomparisonaswellasDr.R.MynottandC.Wirtzfortheirinvaluablehelpwiththestructureassignmentofseveralintermediates.

SupportingInformationAvailable:Fullexperimentaldetails

includinganalyticalandspectroscopicdataofallnewproducts.ThismaterialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.

JA0617800

(49)ThisBBNnotionissupportedbyseveralrecentapplicationsofachievevariantChem.,J.Int.underofEd.standardtheSuzukireactionwhichweredifficultortheimpossible9-MeO-9-to2005,44conditions;,3462.cf.:(a)Fu¨rstner,A.;Turet,L.Angew.Am.Am.Org.Chem.Chem.SocSoc.2004.2004,126,126(b)Lepage,O.;Kattnig,E.;Fu¨rstner,A.,,15970.(c)Yuan,Y.;Men,H.;Lee,C.J.DeV.Chem.2004,81998,113,-63121.

,7885.14720.(e)Mickel,(d)Marshall,S.J.etal.,J.A.;Org.Johns,ProcessB.A.Res.J.