The Alkaloids, Volume 74

430 Pages·2015·23 MB·English

by  Hans-Joachim Knölker

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CONTRIBUTORS
JacksonRobertoGuedesdaSilvaAlmeida
UniversidadeFederaldoValedoS~aoFrancisco,Petrolina,Pernambuco,Brazil
MercedesAmat
LaboratoryofOrganicChemistry,FacultyofPharmacy,andInstituteofBiomedicine
(IBUB),UniversityofBarcelona,Barcelona,Spain
WilliamAtkatlian
LaboratoiredePharmacognosieUMRCNRS8638,UniversitéParisDescartes,Paris,France
RobertoBallette
LaboratoryofOrganicChemistry,FacultyofPharmacy,andInstituteofBiomedicine
(IBUB),UniversityofBarcelona,Barcelona,Spain
JoanBosch
LaboratoryofOrganicChemistry,FacultyofPharmacy,andInstituteofBiomedicine
(IBUB),UniversityofBarcelona,Barcelona,Spain
EgorChirkin
LaboratoiredePharmacognosieUMRCNRS8638,UniversitéParisDescartes,Paris,France
EmídioVasconcelosLeit~aoda-Cunha
UniversidadeFederaldaParaíba,Jo~aoPessoa,Paraíba,Brazil;UniversidadeEstadualda
Paraíba,CampinaGrande,Paraíba,Brazil
StephenG.Davies
DepartmentofChemistry,ChemistryResearchLaboratory,UniversityofOxford,Mansfield
Road,Oxford,OX13TA,UK
JoséMariaBarbosaFilho
UniversidadeFederaldaParaíba,Jo~aoPessoa,Paraíba,Brazil
AthanassiosGiannis
Institutfu€rOrganischeChemie,Universit€atLeipzig,Leipzig,Germany
PhilippHeretsch
DepartmentofChemistry,BioscienceResearchCollaborative,RiceUniversity,Houston,
TX,USA
AnaSilviaSuassunaCarneiroLu(cid:2)cio
UniversidadeFederaldaParaíba,Jo~aoPessoa,Paraíba,Brazil
MariaPérez
LaboratoryofOrganicChemistry,FacultyofPharmacy,andInstituteofBiomedicine
(IBUB),UniversityofBarcelona,Barcelona,Spain
François-HuguesPorée
LaboratoiredePharmacognosieUMRCNRS8638,UniversitéParisDescartes,Paris,France
j
vii
viii Contributors
StefanoProto
LaboratoryofOrganicChemistry,FacultyofPharmacy,andInstituteofBiomedicine
(IBUB),UniversityofBarcelona,Barcelona,Spain
JoseanFechineTavares
UniversidadeFederaldaParaíba,Jo~aoPessoa,Paraíba,Brazil
JamesE.Thomson
DepartmentofChemistry,ChemistryResearchLaboratory,UniversityofOxford,Mansfield
Road,Oxford,OX13TA,UK
PREFACE
Volume 74 of the series The AlkaloidsdChemistry and Biology is covering
diverse aspects of five classes of alkaloids.
Inthefirstchapter,François-HuguesPoréeandcoworkersfromtheLab-
oratory of Pharmacognosy of the University Paris Descartes summarize
recent achievements in the field of Securinega alkaloids. The last coverage
of Securinega alkaloids in this series was the treatise by Victor Snieckus in
Chapter 11 of Volume 14, published in 1973. The authors of the present
articledemonstratetheenormousdevelopmentwhichhastakenplacesince
then. Isolations, synthetic efforts, biosynthetic proposals, and pharmacolog-
ical activities are discussed.
StephenDaviesandJamesThomsonfromtheDepartmentofChemistry
at the University of Oxford describe in Chapter 2 the isolation, structural
elucidation, and synthesis of homalium alkaloids. This relatively small class
of alkaloids currently comprises only four members. Although homalium
alkaloidshavebeenknownformorethan45years,sofartheywerenotcov-
ered in our series.
In Chapter 3, Mercedes Amat and coworkers from the Laboratory of
Organic Chemistry at the University of Barcelona describe the alkaloids
of the madangamine group. The madangamines were treated previously
in this series as a subgroup of the manzamine alkaloids in Chapter 4 of
Volume 60 published in 2003. As the term manzamine alkaloids is usually
restricted to b-carboline-containing alkaloids and because of the tremen-
dousdevelopmentinthefieldofmadangaminealkaloids,theyarenowtrea-
tedforthefirsttimeinthisseriesasanindependentgroup.Besidesisolation,
biogenesis, and biological activities, the major focus of this article is on the
diversesyntheticapproachestothemadangamines.Despitealltheeffortsby
prominent synthetic groups, no total synthesis of a madangamine alkaloid
had been known until the author’s group reported the first total synthesis
of (+)-madangamine D in early 2014.
Philipp Heretsch and Athanassios Giannis summarize the scientific pro-
gress in the area of veratrum and solanum alkaloids. Previously, solanum
and veratrum alkaloids have been covered in this series by V. Prelog and
O.JegerinChapter21ofVolume3(publishedin1953)andintheChapters
16 and17 of Volume 7 (1960), Klaus Schreiber in Chapter 1 andS. Morris
Kupchan and Arnold W. By in Chapter 2 of Volume 10 (1968), and
j
ix
x Preface
J.TomkoandZ.VotickýinChapter1ofVolume14(1973).Mostrecently,
thecevanesubgroupoftheveratrumalkaloidshasbeencoveredbyJohnV.
GreenhillandPaulGrayshaninChapter4ofVolume41(1992).Chapter4of
the present volume compiles newly isolated alkaloids of the solanum and
veratrum groups, their chemistry including recent total syntheses, and their
biologicalproperties.
InChapter5,EmídioVasconcelosLeit~aoDaCunhaandcoworkershave
summarized in an enormous effort the occurrence and the biological activ-
itiesoftheAnnonaceaealkaloids.Thisarticlerepresentsavaluableandvery
useful lexical compendium for everybody who is working in this field of
alkaloids.
Hans-Joachim Kno€lker
Technische Universit€at Dresden, Dresden, Germany
CHAPTERONE
The Securinega Alkaloids
Egor Chirkin, William Atkatlian, and François-Hugues Porée1
LaboratoiredePharmacognosieUMRCNRS8638,UniversitéParisDescartes,Paris,France
1Correspondingauthor:E-mail:[email protected]
Contents
1. Introduction 5
2. Occurrence 7
3. Securinine-typeAlkaloids 8
3.1 Securinine(1)/Virosecurinine(2),Allosecurinine(3)(Phyllochrysine)/ 8
Viroallosecurinine(4)
3.1.1 NMRSpectrumAnalysisofSecurinine 18
3.1.2 ConformationalStudyonSecurinegaAlkaloids 22
3.1.3 X-RayCrystalStructureofSecurinine/VirosecurinineFreeBase 24
3.2 14,15-Dihydrosecurinine(5) 24
3.3 Phyllanthidine(6),Ent-Phyllanthidine(7) 25
3.4 Secu’amamineD(8) 27
3.5 Margaritarine(9) 28
3.6 Secu’amamineB(10) 29
3.7 Secu’amamineC(11) 29
3.8 15a-Methoxy-14,15-Dihydrophyllochrysine(12) 30
3.9 15-a-Hydroxy-14,15-dihydroallosecurinine/SecurinolC(13) 30
3.10 4a-Hydroxy-15a-Methoxy-14,15-Dihydroallosecurinine(14) 31
3.11 4a,15a-Dimethoxy-14,15-Dihydrosecurinine(15) 32
3.12 4a-Hydroxyallosecurinine(16) 33
3.13 Phyllanthine(17) 33
3.14 4-Epiphyllanthine(18) 34
3.15 Securitinine(19) 35
3.16 Flueggedine(20) 35
4. NeosecurinaneAlkaloids 37
4.1 SecurinolA(21)andVirosineA(SecurinolB)(22) 37
4.2 VirosineB(23) 38
4.3 Secu’amamineE(24) 39
4.4 Secu’amamineFandG(25and26) 40
5. Norsecurinine-typeAlkaloids 40
5.1 Norsecurinine(27) 40
5.2 14,15-Dihydronorsecurinine(Virosine)(28) 41
5.3 14,15-Epoxynorsecurinine(29) 41
5.4 Simplexine(30) 42
5.5 4-Methoxynorsecurinine(31) 43
5.6 Flueggeainol(32)andFluggeainolEther(33) 43
TheAlkaloids,Volume74
ISSN1099-4831 ©2015ElsevierInc. j
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2 EgorChirkinetal.
5.7 15b-Hydroxy-14,15-Dihydronorsecurinine(34) 44
5.8 15b-Methoxy-14,15-Dihydronorsecurinine(35) 44
5.9 15a-Methoxy-14,15-Dihydronorsecurinine(36) 45
5.10 Secu’amamineA(37) 45
5.11 VirosainesA(38)andB(39) 46
6. NeonorsecurinaneAlkaloids 47
6.1 Bubbialine(40) 48
6.2 Bubbialidine(41) 49
6.3 Isobubbialine(42) 49
6.4 Epibubbialine(43) 50
6.5 Niruroidine(44) 50
6.6 Nirurine(45) 51
7. Norsecurinine-DerivedOligomericAlkaloids 52
7.1 FlueggineA(46) 52
7.2 FlueggineB(47) 53
7.3 FlueggenineA(48) 54
7.4 FlueggenineB(49) 55
7.5 FlueggenineC(50) 56
7.6 FlueggenineD(51) 56
7.7 FluevirosineA(52) 57
7.8 FluevirosineB(53) 58
7.9 FluevirosineC(54) 59
7.10 FluevirosineD(55) 59
7.11 FluevirosinineA(56) 60
8. Synthesis 61
8.1 SynthesisofSecurinine(1)anditsStereoisomers(2e4) 61
8.1.1 HoriiSynthesis 62
8.1.2 HondaSynthesisofCompound82 62
8.1.3 LirasSynthesis 64
8.1.4 HondaSynthesis 64
8.1.5 KerrSynthesis 67
8.1.6 BusquéanddeMarchSynthesis 68
8.1.7 ThadaniSynthesis 70
8.1.8 Alib(cid:1)esanddeMarchSynthesis 71
8.1.9 WoodSynthesis 72
8.1.10 Bay(cid:3)onandFigueredoSynthesis 74
8.2 SynthesisofNorsecurinine(27) 75
8.2.1 HeathcockSynthesis 76
8.2.2 JacobiSynthesis 78
8.2.3 MagnusSynthesis 78
8.2.4 WeinrebSynthesis 81
8.2.5 Bay(cid:3)onandFigueredoSynthesis 82
8.2.6 YangandLiSynthesis 83
8.3 Synthesisof14,15-Dihydronorsecurinine(28) 83
8.4 SynthesisofNirurine(45) 84
TheSecurinegaAlkaloids 3
8.5 SynthesisofPhyllanthine(17) 85
8.6 SynthesisofEnt-Phyllanthidine(7) 86
8.7 SynthesisofSecu’amamineA(37) 88
8.8 Synthesisof3-Deshydroxy-secu’amamineA(222) 89
8.9 SynthesisofFlueggineA(46) 92
8.10 SynthesisofVirosaineB(39) 93
8.11 SynthesisofBubbialidine(41)andVirosaineA(38) 94
8.12 SynthesisofAllonorsecurinine(254) 96
9. Biosynthesis 97
9.1 GeneralPathway 97
9.2 BiosynthesisofNirurine(45) 100
9.3 BiosynthesisofSecu’amamineA(37) 101
9.4 BiosynthesisofVirosainesA(38)andB(39) 102
9.5 BiosynthesisofNorsecurinine-BasedOligomers 104
9.6 BiosynthesisofFlueggedine(20) 106
10. BiologicalActivitiesdPharmacologicalActivities 107
10.1 CentralNervousSystemProperties 108
10.2 OncologicProperties 110
10.3 AntimicrobialProperties 113
11. SummaryandConclusions 114
Acknowledgments 115
References 116
Abstract
Securinegaalkaloidsrepresentafamilyofplantsecondarymetabolitesknownfor50years.
Securinine (1), the most abundant and studied alkaloid of this series was isolated by
Russian researchers in 1956. In the following years, French and Japanese scientists re-
ported other Securinega compounds and extensive work was done to elucidate their
intriguingstructures.Thehomogeneityofthisfamilyreliesmainlyonitstetracyclicchem-
icalbackbone,whichfeaturesabutenolidemoiety(cycleD)andanazabicyclo[3.2.1]oc-
taneringsystem(ringsBandC).Interestingly,afteraperiodoflatencyof20years,the
Securinega topic reemerged as a prolific source of new natural structures and to date
morethan50compoundshavebeenidentifiedandcharacterized.Theoligomericsub-
groupgatheringdimeric,trimeric,andtetramericunitsisofparticularinterest.Theunprec-
edentedstructureoftheSecurinegaalkaloidswasthesubjectofextensivesyntheticefforts
culminatinginseveralefficientandeleganttotalsyntheses.Thebotanicaldistributionof
thesealkaloidsseemslimitedtotheSecurinega,Flueggea,Margaritaria,andBreyniagenera
(Phyllanthaceae).However,onlyalimitednumberofplantspecieshavebeenconsidered
for their alkaloidcontents,andadditionalphytochemicalaswellasgeneticstudies are
needed.Concerningthebiosynthesis,experimentscarriedoutwithradiolabelledamino-
acidsallowedtoidentifylysineandtyrosineastheprecursorsofthepiperidineringAand
theCDringsofsecurinine(1),respectively.Besides,plausiblebiosyntheticpathwayswere
proposedforvirosaineA(38)andB(39),flueggineA(46),andalsothedifferentoligomers
flueggenineA–D(48–51),fluevirosinineA(56),andflueggedine(20).Thecaseofnirurine
(45) and secu’amamine (37) remains elusiveand additional studies seem necessary to
4 EgorChirkinetal.
understandtheirmodeofproduction.ThescopeofbiologicalofactivitiesoftheSecuri-
negaalkaloidswasmainlycenteredon theCNSactivityofsecurinine(1),althoughthe
exact mechanism of action remained in part unknown. Nevertheless, for its stimulant
andantispasmodiceffects securininenitratewasmarketedasa druginthe USSR until
theearly1990s.Moreover,securinine(1)andseveralotherSecurinegaalkaloidsrecently
demonstratedpromisinganticancerproperties.Inparticularsecurinine(1)demonstrated
markedlybenefitsinthetreatmentofacutemyeloidleukemia.
Abbreviations
(imid) C]S Thiocarbonyldiimidazole
2
Ac O Aceticanhydride
2
AcOH Aceticacid
AIBN 2,2’-Azobisisobutyronitrile
CCDC Cambridgecrystallographicdatacenter
CD Circulardichroism
COSY Correlationspectroscopy
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC N,N-dicyclohexylcarbodiimide
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DFT Densityfunctionaltheory
DIAB Disiamylborane
DIAD Diisopropylazodicarboxylate
DIBAL-H Diisobutylaluminumhydride
DIEA N,N-diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMDO Dimethyldioxirane
DMF Dimethylformamide
DMP Dess-Martinperiodinane
DMSO Dimethylsulfoxide
ee Enantiomericexcess
EtOH Ethanol
Et O Diethylether
2
Glc Glucose
HMBC Heteronuclearmultiplebondcorrelation
HMDS Hexamethyldisilazide
HMPA Hexamethylphosphoramide
HRESIMS High-resolutionelectrosprayionisationmassspectrometry
HSQC Heteronuclearsinglequantumcoherence
iPrOH iso-Propanol
IBX 2-Iodoxybenzoicacid
KHMDS Potassiumhexamethyldisilazane
LDA Lithiumdiisopropylamide
LiBHEt Lithiumtriethylborohydride
3
LiHMDS Lithiumhexamethyldisilazane
m-CPBA meta-Chloroperoxybenzoicacid
MeCN Acetonitrile
MeI Methyliodide
MeOH Methanol
MOM Methyloxymethyl
TheSecurinegaAlkaloids 5
Ms Methylsulfonyl
MS Massspectrometry
n-Bu NI Tetra-n-butylammoniumiodide
4
n-BuLi n-Butyllithium
AcONa Sodiumacetate
NBS N-bromosuccinimide
Ni(COD) Bis(1,5-cyclooctadiene)nickel
2
NMO N-methylmorpholine-N-oxide
NMR Nuclearmagneticresonance
NOESY NuclearOverhausereffectspectroscopy
p-ABSA p-Acetamidobenzenesulfonylazide
p-TsOH p-Toluenesulfonicacid
p-TsCl p-Toluenesulfonicchloride
PhIO Iodosylbenzene
PhNTf N-phenylbis(trifluoromethanesulfonimide)
2
PhSeBr Phenylselenylbromide
PPh Triphenylphosphine
3
PPTS Pyridiniump-toluenesulfonate
pyr Pyridine
rt Roomtemperature
ROESY RotatingframenuclearOverhausereffectspectroscopy
SAR Structureactivityrelationship
s-BuLi sec-Butyllithium
TBAF Tetra-n-butylammoniumfluoride
TBDPSCl tert-Butyl(chloro)diphenylsilane
TBSCl tert-Butyl(chloro)dimethylsilane
TBSOTf tert-Butyldimethylsilyltrifluoromethanesulfonate
TFA Trifluoroaceticacid
THF Tetrahydrofurane
TIPSOTf Triisopropylsilyltrifluoromethanesulfonate
TMEDA Tetramethylethylenediamine
TMS Trimethylsilyl
1. INTRODUCTION
Securinega alkaloids represent a family of plant secondary metabolites
known for 50 years. The first representative, securinine (1), was isolated in
1956 by Murav’eva and Ban’kovskii1 and to date more than 50 compounds
have been identified and characterized. The homogeneity of this family relies
mainlyonitstetracyclicchemicalstructure,whichfeaturesabutenolidemoiety
(cycleD)andanazabicyclo[3.2.1]octanesystem(ringsBandC).Convention-
ally,twogroupshavebeendistinguishedaccordingtothenatureofthecycleA
(Scheme 1): the securinine-type group, which comprises a six-membered piperi-
dineandthenorsecurinine-typegroupderivedfrompyrrolidine.Thisterminology
is commonly accepted. Therefore, the securinane skeleton refers to the