AcademicPressisanimprintofElsevier 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 225WymanStreet,Waltham,MA02451,USA 32JamestownRoad,London,NW17BY,UK TheBoulevard,LangfordLane,Kidlington,Oxford,OX51GB,UK Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands Firstedition2014 Copyright©2014ElsevierInc.Allrightsreserved Nopartofthispublicationmaybereproduced,storedinaretrievalsystemortransmitted inanyformorbyanymeanselectronic,mechanical,photocopying,recordingorotherwise withoutthepriorwrittenpermissionofthepublisher. PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights DepartmentinOxford,UK:phone(þ44)(0)1865843830;fax(þ44)(0)1865853333; email:permissions@elsevier.com.Alternativelyyoucansubmityourrequestonlineby visitingtheElsevierwebsiteathttp://www.elsevier.com/locate/permissions,andselecting ObtainingpermissiontouseElseviermaterial. Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersons orpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor operationofanymethods,products,instructionsorideascontainedinthematerialherein. Becauseofrapidadvancesinthemedicalsciences,inparticular,independentverification ofdiagnosesanddrugdosagesshouldbemade ISBN:978-0-12-411565-1 ISSN:1099-4831 ForinformationonallAcademicPresspublications visitOurwebsiteatwww.store.elsevier.com PrintedandboundinUSA 141510987654321 CONTRIBUTORS VikramBhat DepartmentofChemistry,TheUniversityofChicago,Chicago,Illinois,USA ApurvaDave DepartmentofChemistry,TheUniversityofChicago,Chicago,Illinois,USA MichaelT.Davies-Coleman DepartmentofChemistry,UniversityoftheWesternCape,Bellville,SouthAfrica BernardDelpech CentredeRecherchedeGif,InstitutdeChimiedesSubstancesNaturelles,CNRS, Gif-sur-YvetteCedex,France SethB.Herzon DepartmentofChemistry,YaleUniversity,NewHaven,Connecticut,USA SandraM.King DepartmentofChemistry,YaleUniversity,NewHaven,Connecticut,USA JamesA.MacKay DepartmentofChemistryandBiochemistry,ElizabethtownCollege,Elizabethtown, Pennsylvania,USA VireshH.Rawal DepartmentofChemistry,TheUniversityofChicago,Chicago,Illinois,USA ClintonG.L.Veale DepartmentofChemistry,RhodesUniversity,Grahamstown,SouthAfrica vii PREFACE A broad range of different alkaloid classes is covered in four chapters of Volume 73 of The Alkaloids. InChapter1,ClintVealefromRhodesUniversityinGrahamstownand MikeDavies-ColemanfromtheUniversityoftheWesternCapeinBellville (bothinSouthAfrica)aredescribingtherecentfascinatingdevelopmentin the area of marine bi-, bis-, and trisindoles. Previously, bisindole alkaloids were summarized in this series by Geoffrey Cordell and Edwin Saxton in Volume 20 (published in 1981) and by Toh-Seok Kam and Yeun-Mun Choo in Volume 63 (2006), but both reviews were dealing with bisindole alkaloids from terrestrial sources. Volume 37 which was published in 1990 compiledaseriesofarticlesfocusingonbisindolealkaloidsfromCatharanthus roseus (L.). J. Sapi and G. Massiot described noniridoid bisindole alkaloids fromthemarineenvironment,microorganisms,andplantspeciesinVolume 47 (1995). Chapter 1 is covering the isolation, bioactivity, and synthesis of biindoles,bisindoles,andtrisindoleswhichhavebeenobtainedfromdiverse marine sources. VikramBhat,ApurvaDave,JamesMacKay,andVireshRawalfromthe University of Chicago (USA) summarize the chemistry of hapalindoles, fischerindoles,ambiguines,andwelwitindolinonesinChapter2.Theserel- atively young classes of alkaloids (first report of hapalindoles in 1984, fischerindoles in 1992, ambiguines in 1992, and welwitindolinones in 1994)havenotbeentreatedsofarinthisseries.Intheiroutstandingarticle, the authors are covering the occurrence, isolation, biological activity, bio- synthesis, and total synthesis of these alkaloids. In Chapter 3, Sandra King and Seth Herzon from Yale University in NewHaven(USA)provideanoverviewonrecentachievementsinthefield of the hasubanan and acutumine alkaloids. The hasubanan and the acutuminealkaloidsweretreatedfirstinthisseriesbyK.W.BentleyinVol- ume 13 (published in 1971) in several subchapters under “morphine alka- loids.” Subsequently, the hasubanan alkaloids were reviewed as an independent class of alkaloids in two chapters, by Yasuo Inubushi and Toshiro Ibuka in Volume 16 (1977) and by Matao Matsui in Volume 33 (1988). Chapter 3 summarizes the developments for both classes since theirprevioustreatmentsfocusingonoccurrence,isolationofnewalkaloids, total synthesis, biosynthesis, and pharmacology. ix x Preface The saraine alkaloids described in Chapter 4 also represent a relatively youngfamilyofalkaloids(firststructureelucidationreportedin1986).They can be considered as members of the manzamine alkaloids and have been mentioned very briefly in the last review in this serieson manzamine alka- loidswhichappearedinVolume60publishedin2003.Becauseoftheirchal- lenging structures and the tremendous development in this area, saraine alkaloidsarenowtreatedforthefirsttimeasanindependentgroup.Bernard DelpechfromGif-sur-YvetteinFrancehasprovidedanexcellentsummary oftherecentexcitingdevelopmentinthefieldofsarainealkaloidswhichis including the isolation, structure elucidation, biological properties, bioge- netic proposals, and synthetic approaches. Hans-Joachim Kno¨lker Technische Universita¨t Dresden, Dresden, Germany CHAPTER ONE Marine Bi-, Bis-, and Trisindole Alkaloids Clinton G. L. Veale*, Michael T. Davies-Coleman†,1 * DepartmentofChemistry,RhodesUniversity,Grahamstown,SouthAfrica †DepartmentofChemistry,UniversityoftheWesternCape,Bellville,SouthAfrica 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. MarineBiindoles 4 2.1 IsolationandBioactivity 4 3. MarineBisindoleEnamides 5 3.1 IsolationandBioactivity 5 3.2 Synthesis 7 4. MarineBisindoleImidazoles,Imidazolines,and1H-Imidazol-5(4H)-Ones 10 4.1 IsolationandBioactivity 10 4.2 Synthesis 16 5. MarineBisindolePiperazinesandPyrazinones 18 5.1 IsolationandBioactivity 18 5.2 Synthesis 25 6. MarineBisindolePyrimidines 38 6.1 IsolationandBiologicalActivity 38 6.2 Synthesis 38 7. MarineBisindoleDipeptides 39 7.1 IsolationandBioactivity 39 7.2 Synthesis 44 8. Marine-FusedRingBisindoles 45 8.1 CaulerpinandCaulersin 45 8.2 AplysinopsinDimers 49 9. MiscellaneousMarineBis-andTrisindoles 54 9.1 IsolationandBioactivity 54 References 60 TheAlkaloids,Volume73 #2014ElsevierInc. 1 ISSN1099-4831 Allrightsreserved. http://dx.doi.org/10.1016/B978-0-12-411565-1.00001-9 2 ClintonG.L.VealeandMichaelT.Davies-Coleman ABBREVIATIONS Boc tert-butylcarbamate CDI 1,10-carbonyldiimidazole DCC N,N0-dicyclohexylcarbodiimide DCE dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMAP dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide HBpin pinacolborane HOBt hydroxybenzotriazole IBX 2-iodoxybenzoicacid MOM methoxymethyl NaHMDS sodiumhexamethyldisilazide NBS N-bromosuccinimide NMO N-methylmorpholine-N-oxide PDC pyridiniumdichromate Py pyridine SEM 2-trimethylsilylethyoxymethyl TBAF tetra-n-butylammoniumfluoride TBS tert-butyldimethylsilyl t-BuLi tert-butyllithium Teoc 2-(trimethylsilyl)ethylcarbamate TFA trifluoroaceticacid THF tetrahydrofuran TIPS triisopropylsilyl TMS trimethylsilyl Ts tosyl 1. INTRODUCTION The oceans cover nearly three-quarters of the world’s surface and totally dominate the biosphere. Life in all its forms proliferates throughout themarineenvironment,andthesecondarymetabolismassociatedwiththe vastmajorityofmarinelifeformsprovidesacornucopiaofnovelsecondary metabolites,1 many of which serendipitously exhibit medicinally relevant bioactivity. Accessiblemetabolicnitrogen,generated viathecomplex oce- anicnitrogencyclethatcontrolsproductivityintheoceans,isofteninshort supply relative to other nutrients,2 and although, as a result, bioactive nitrogen-containing marine secondary metabolites, for example, bisindole alkaloids,aregenerallyisolatedinlowconcentrations,theycontinuetoelicit interest when encountered in targeted screening programs.3 This MarineBi-,Bis-,andTrisindoleAlkaloids 3 contemporary and undiminished interest in marine alkaloid metabolites possessing two, and occasionally three, indole rings provides the rationale for this chapter. This chapter of 130 bi-, bis-, and trisindole alkaloids (covering the chemistryliteratureuptoJune2013)followsonfromthepastcomprehen- sive review of marine bisindole alkaloids published nearly a decade ago4 and complements the extensive reviews of bisindole alkaloids that already appeared in this series.5a,b Aspects of the chemistry of marine bisindole alkaloids have occasionally appeared in more general reviews of marine alkaloids.6–9 Jiang and coworkers’ 2004 review focused entirely on marine bisindolealkaloidsinwhichthetwoindoleringsareseparatedbyahetero- cyclic moiety,4 while Mollica et al.’s recent review7 concentrated on marine-dibrominated compounds of which there are numerous bisindole examples. Our chapter of marine metabolites containing two and three indole rings has been expanded to include compounds in which the two indole rings are bonded directly to each other (biindoles) and bis- and trisindoles in which the two and three indole rings, respectively, are sep- arated by any functionality and not only by a heterocyclic ring. Selected examples of fused ring bisindole compounds, for example, the caulerpins where one or both of the indole rings are fused to larger rings, are also included. Miscellaneous bisindole alkaloids, in which the number of com- pounds reported thus far is too few to constitute a coherent structural class warranting separate treatment, are reviewed together. Marine trisindole alkaloids are less common than bisindole alkaloids, and the few reported examples of the former class of compound are not reviewed here as a sep- arate group but rather with the bisindoles with which they commonly co-occur. Threethemes,isolation,bioactivity,andsynthesis,permeatethisreview. Wherepossible, repetition with previous reviews is avoided,and if a com- prehensivetreatmentofanyofthesethemeshasbeenprovidedinaprevious review,thefocusisshiftedto provideadetailedreview ofthemorerecent work in the field. Given the paucity of bioactive alkaloids isolated directly frommarinesources,thesecompoundsareoftenattractivesynthetictargets and the syntheses of 28 marine bisindole alkaloids are comprehensively reviewed here. Although substantive details of the biosynthesis of marine bi-,bis-,andtrisindolealkaloidsremainelusive,thelogicalaminoacidpre- cursors,namely,tryptophanandtyramine,areregularlyinvokedasprecur- sors in putative biosynthetic sequences. Four of these speculative biosyntheses are presented here. 4 ClintonG.L.VealeandMichaelT.Davies-Coleman 2. MARINE BIINDOLES 2.1. Isolation and Bioactivity Indoledimersformedbyeitherdirectcarbon–carbon,carbon–nitrogen,or nitrogen–nitrogenbondingbetweentwoindolesubunitsformasmallclass of marine biindole alkaloids, containing eitheralkyl amine, halogen,ether, thioether, or sulfoxide substituents, or combinations thereof, on both indole rings. Aninvestigationofthemarineblue-greenalgaRivulariafirma,collected at Western Port, Victoria, Australia, yielded the first reported examples of biindoles from a marine source.10 A total of six biindole metabolites 1–6 were isolated from the alga with tri-, tetra-, and hexabromination patterns in addition to 3,30- 3,10- 4,10-, and 4,30-indole–indole linkages10 (Figure 1.1). While no optical rotation for the symmetrical compound 1 wasprovided,thefiveremainingcompoundswereallopticallyactive,with the chirality attributed to perpendicular dissymmetric planes induced by restrictedrotationaroundthebondlinkingtheindolerings.10Theabsolute configurationof4and5wasdeterminedasRandS,respectively.11Afurther collectionofR.firmamadeseveralyearslaterfromthesamelocationyielded a seventh biindole 7, isomeric with 1.12 The red alga Laurencia brongniartii collected off Okinawa, Japan, was found to contain several simple polybrominated and sulfur-containing 0 indoles in addition to the novel optically inactive polybrominated 3,3- biindolethioether8.13L.brongniartiicollectedoffthesoutherntipofTaiwan yieldedafurthertworelatedthioether-andsulfoxide-substitutedbiindoles9 and 10 with only compound 10 displaying optical activity14 (Figure 1.2). Biindole10wasreportedtobecytotoxicagainsttheP338andHT-29can- cer cell lines; however, no IC or MIC values were provided.14 50 H Br Br N R2 Br Br HN Br Br Br R R1 3 3(cid:2)Br R1Br Br 3N1(cid:2) Br 4N1(cid:2) Br R12 43(cid:2) Br R2 NH Br 17RR11==HBr,,RR22==BHr 2NH NH 3OMe 54RRNH1== BBOrr,,MRRe2==BHr 6R11= H,R22=Br Figure1.1 Biindoles1–7. MarineBi-,Bis-,andTrisindoleAlkaloids 5 HN Br H OH R2 N 3(cid:2) Br Br H2N Br 3 R Br NH2 1 Br N H N H OH 9180RRR111===RRS22M==e S,SROM2Me=eSOMe 11 Dendridine A Figure1.2 Biindoles8–11. Finally,aDictyodendrillasp.spongealsocollectedoffOkinawayieldeda C symmetricalbiindole,dendridineA(11)15(Figure1.2).Aputativebio- 2 0 synthesisof thiscompoundviadirect4,4 couplingof twotryptaminepre- cursorswaspostulated.15AlthoughTsudaetal.15commentedontherarity of naturally occurring 7-hydroxyindoles, this substitution pattern is com- monly encountered in many dragmacidin bisindoles.4 Dendridine Aexhibitedinhibitoryactionagainsttwogram-positivebacteriaBacillussub- tilis(IC 8.3mg/mL)andMicrococcusluteus(IC 4.2mg/mL)andthefungus 50 50 Cryptococcus neoformans (IC 8.3mg/mL) in addition to weak cytotoxicity 50 against murine leukemia L1210 cells (IC 32.5mg/mL).15 50 3. MARINE BISINDOLE ENAMIDES 3.1. Isolation and Bioactivity Two linear bisindole enamide alkaloids, chondriamide A (12) and B (13), derived from (E)-3-(indol-3-yl)acrylic acid (14) and (E)-3-(7-hydro- xyindol-3-yl)acrylicacid(15),wereisolatedfromtheredalga,Chondriasp.,col- lectedofftherockyshoresnearBuenosAires,Argentina.16Examinationof themorepolarfractionsofthealgalextractledtotheisolationandidentifi- cationof 14and15,thustentatively confirmingthebiosynthetic precursor statusofthesetwocompounds.Athirdbisindole16wasproposedbySeldes andcoworkerstobeanartifactarisingfromtheinitialethanolextractionofthe alga.Theyconsequentlyproposedthattryptophanwastheotherbiosynthetic precursorof12andthatdecarboxylationafteramidationwouldyieldthenat- urally occurring enamides.16 The extract of the Chondria sp. also yielded indole-3-carbaldehyde (17) and an interesting N-formylacrylamide 18, whichareoxidationproductsobservedinmethanolicsolutionsof12when exposed to air.16 Chondriamides A and B were also isolated together with 6 ClintonG.L.VealeandMichaelT.Davies-Coleman anovelZisomerof12chondriamideC(19),fromChondriaatropurpureacol- lectedofftheUruguayancoast.17Both14and(E)-3-(indol-3-yl)acrylamide (20)werealsoidentifiedintheC.atropurpureaextracts17(Figure1.3). ChondriamidesAandBdisplayedsimilarcytotoxicityagainstKBcancer cells(0.5and<1.0mg/mL,respectively).Compound12exhibitedantiviral activity(1.0mg/mL)againstherpessimplexvirusII,while13showedmar- ginal antifungal activity against Aspergillus oryzae and Trichophyton men- tagrophytes in zone inhibition assays.16 Both 12 and 13 were found to havemoderateantihelminthicactivityagainstNippostrongylusbrasiliensiswith EC values of 0.26 and 0.09mM, respectively.17 80 DactylamidesA(21)andB(22),structurallyrelatedto13,wereisolated from the sea hare Aplysia dactylomela collected near Northland, New Zealand18 (Figure 1.4). Interestingly, Copp and coworkers noted that the conversion of tryptophan to indoleacrylic acid occurred via a quaternary amine in a known plant biosynthetic pathway, thus suggesting that the dactylamidesmaybechondriamidebiosyntheticprecursors.18Theabsolute configurationof21wasinferredby1HNMRandfinallyconfirmedbycom- parisonoftheCDandopticalrotationdataof21withsimilardataacquired fromtwosyntheticallyderivedisomerictryptophandipeptidediastereomers of known absolute configuration.18 The absolute configuration of 22 was H N H N O O OH EtO2C NH O NH N N H H R N R H 12R=H Chondriamide A 14R=H (E)-3-(indol-3-yl)acrylic acid 16 13R=OHChondriamide B 15R=OH(E)-3-(7-hydroxyindol-3-yl)acrylic acid O O NHH O NH O NH2 O H NH NH NH NH NH 17 18 19Chondriamide C 20(E)-3-(indol-3-yl)acrylamide Figure1.3 Enamideandrelatedcompounds12–20.