Chemistry and Biology

350 Pages·2014·9.32 MB·English

by  Hans-Joachim Knölker (Eds.)

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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.