The Alkaloids: Chemistry and Biology 66

268 Pages·2008·3 MB·English

by  Geoffrey A. Cordell (Eds.)

THE ALKALOIDS
Chemistry and Biology
66
VOLUME
Edited by
Geoffrey A. Cordell
Evanston, Illinois
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CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
Brad J. Andersh (191), Department of Chemistry and Biochemistry, Bradley
University, Peoria, IL 61625-0208, USA
AtharAta(191),DepartmentofChemistryandBiochemistry,BradleyUniversity,
Peoria, IL 61625-0208, USA
Jaume Bastida (113), Departament de Productes Naturals, Biologia Vegetal i
Edafologia, Facultat de Farma`cia, Universitat de Barcelona, 08028 Barcelona,
Spain
Mary J. Garson (215), School of Molecular and Microbial Sciences, The
University of Queensland, Brisbane, Qld 4072, Australia
Toh-Seok Kam (1), Department of Chemistry, University of Malaya, 50603
Kuala Lumpur, Malaysia
Kuan-Hon Lim (1), Department of Chemistry, University of Malaya, 50603
Kuala Lumpur, Malaysia
Maribel G. Nonato (215), Research Center for the Natural Sciences, College
of Science, Graduate School, University of Santo Tomas, Espan˜a, Manila 1015,
Philippines
EdisonJ.Osorio(113),GrupodeInvestigacio´nenSustanciasBioactivas,Facultadde
Qu´ımica-Farmace´utica, Universidad de Antioquia, A. A. 1226, Medell´ın, Colombia
Sara M. Robledo (113), Programa de Estudio y Control de Enfermedades
Tropicales,FacultaddeMedicina,UniversidaddeAntioquia,Medell´ın,Colombia
Hiromitsu Takayama (215), Graduate School of Pharmaceutical Sciences, Chiba
University, Chiba 263-8522, Japan
vii
PREFACE
Thefourchaptersinthisvolumereflectsomeveryinterestingaspectsofthediversity
of global alkaloid research in its various chemical and biological applications with
contributions from several different countries.
KamandLimreviewthestructuraldiversityandbiologicalactivitiesrepresented
bythemonomericandbis-monoterpenoidindolealkaloidsisolatedinrecentstudies
of the alkaloids of Kopsia. An important aspect of this work is the continuing
evolution of the structural diversity of the indole alkaloids, which represent some
significant challenges in developing biogenetic pathways for their formation.
Osorio, Robledo, and Bastida summarize another important aspect of the
biological applications of alkaloids, their antiprotozoal activity. This activity was
founded in the 17th century discovery of the antimalarial activity of Cinchona, and
extends today to a diverse array of alkaloid structures and protozoa.
ThegenusBuxusisanimportantsourceofaselecttypeofsteroidalalkaloids.As
Ata and Andersh have summarized, in the recent past, this group has expanded
rapidly to yield a series of interesting structures and biological activities.
Pandanus species are an important economic product in several countries
of Southeast Asia, yet they have received limited chemical and biological study.
A collaboration between groups in the Republic of the Philippines (Nonato), Japan
(Takayama), and Australia (Garson) describes their studies on the alkaloids of the
genus Pandanus and those of other research groups.
Geoffrey A. Cordell
Evanston, Illinois
ix
1
CHAPTER
Alkaloids of Kopsia
(cid:2)
Toh-Seok Kam and Kuan-Hon Lim
Contents I. Introduction 1
II. MonoterpeneAlkaloids 2
III. SimpleIndoleAlkaloids 6
IV. Corynanthe,Akuammiline, Vincorine,Aspidodasycarpine, and
Pleiocarpamine Alkaloids 8
V. Condylocarpine, Stemmadenine, and Akuammicine Alkaloids 12
VI. Eburnane Alkaloids 16
VII. Aspidospermine–Aspidofractinine and Related Alkaloids 20
A. Aspidospermine Alkaloids 20
B. Aspidofractinine Alkaloids 30
C. Kopsine, Fruticosine,and Related Alkaloids 39
D. Syntheses ofAspidofractinine and KopsaneAlkaloids 44
E. Kopsidasinine Alkaloids 52
F. Pauciflorines and Related Alkaloids 52
G. Lapidilectines andLundurines 59
H. Kopsifolines 66
I. Mersinine Alkaloids 69
VIII. Miscellaneous NovelAlkaloids 76
IX. BisindoleAlkaloids 84
X. Electroorganic Transformations of KopsiaAlkaloids 88
XI. AlkaloidDistribution inthe GenusKopsia 91
References 105
I. INTRODUCTION
PlantsofthegenusKopsia(Apocynaceae)aredistributedfromsouthernChinaand
BurmatonorthernAustraliaandVanuatu.Thegenusis,however,mostdiversein
Peninsular Malaysia and Sarawak (Malaysian Borneo) (1). All species are shrubs
DepartmentofChemistry,UniversityofMalaya,50603KualaLumpur,Malaysia
(cid:2)
Correspondingauthor.
E-mailaddress:[email protected](T.S.Kam).
TheAlkaloids,Volume66 r2008ElsevierInc.
ISSN:1099-4831, DOI10.1016/S1099-4831(08)00201-0 Allrightsreserved
1
2 Toh-SeokKamandKuan-HonLim
or small trees, and due to their attractive appearance (the most distinguishing
featurebeingtheshowywhiteflowerswithred,pink,oryellow‘‘eyes’’),anumber
have become widely cultivated as garden or ornamental plants. The genus was
firstpublishedin1823byBlumeinhonoroftheDutchbotanistJ.Kops,withone
speciesK.arborea(2).Laterbotanicalstudiesincludeapreliminarypartialrevision
byMarkgraf(3)andachemotaxonomicstudybySe´venetetal.(4).Themostrecent
andcomprehensiverevisionofthegenus,however,isthatofMiddletoninwhich
24speciesarerecognizedandfournewspeciesaredescribed(1,5).Inthisreview,
we shall follow the classification according to Middleton (1), with the species
attributed in the original reports cited in parenthesis.
The first Kopsia alkaloid isolated was kopsine (1) (6). The structure was,
however, only solved in the 1960s after considerable classical degradation studies
coupled with the introduction of high-resolution mass spectrometry (7–17).
Additional confirmation was later provided by chemical correlation of kopsine
with minovincine (18), as well as by X-ray crystallographic analysis of the methyl
iodide salt of ((cid:2))-kopsanone (19,20). Other notable examples of early Kopsia
alkaloids include fruticosine (2) and fruticosamine (3) fromK. fruticosa (14,21–25),
and kopsingine (4) fromK. singapurensis (26). These alkaloids have also been
discussedinpreviousvolumesofthis,aswellasother,series(27–31).Inmorerecent
times,plantsofthisgenushaveproventobefertilesourcesofmanyalkaloidswith
unusual and fascinating molecular structures, as well as interesting biological
activities,andareviewchapterdevotedexclusivelytotheKopsiaalkaloidsappears
timely.Thepresentreviewshallthereforefocusonthechemistryandpharmacology
ofthesemorerecentKopsiaalkaloids.Theorganizationofthechapterwillbebased
onthealkaloidstructuretype,inorderofincreasingcomplexity,andapproximately
along the lines of a progressing biosynthetic pathway. Under each section, aspects
ofstructureelucidation,chemistry,synthesis,andbiologicalactivityofthealkaloids
concerned will be addressed. Finally, the occurrence of alkaloids in Kopsia species
which have been chemically investigated will be summarized.
N N N
H H H
O
OH
O
N N N
H
MeO2C MeO2C OMeR R
OH R2 R1 OH
1kopsine 2 R1 = OH, R2 = H 4 R = CO2Me kopsingine
3 R1 = H, R2 = OH
II. MONOTERPENE ALKALOIDS
Themonoterpenealkaloidsconstitutearelativelysmallgroupofcompoundsand
occur in several species, including K. pauciflora, K. profunda (K. macrophylla), and
K. dasyrachis, from which several new monoterpene alkaloids (5–13) related to
skytanthine have been recently isolated.
AlkaloidsofKopsia 3
TheNorthBorneospeciesK.paucifloraprovidedsixsuchmonoterpenealkaloids,
namely, kinabalurines A–F (5–10), which are hydroxyskytanthine derivatives
(32,33). The first alkaloid isolated was kinabalurine A (5), which was obtained as
colorlessplates.Themassspectrumshowedamolecularionatm/z183(C H NO)
11 21
accompanied by fragments due to loss of H, Me, and OH, and other fragments at
m/z 84, 58, and 44, characteristic of skytanthine-type alkaloids. The IR spectrum
indicatedthepresenceofahydroxylgroup(3357cm(cid:2)1),andthiswassupportedby
thepresenceofanOHresonanceca.d3.27inthe1HNMRspectrum.The13CNMR
spectrumaccountedforall11carbonatomsandthepresenceofanoxymethinewas
confirmed by the resonance at d 80.0. Other significant peaks in the 1H NMR
spectrum included a pair of three-H doublets at d 0.97 and 1.06, corresponding to
two CH CH– groups, and an N-methyl singlet at d 2.25. The spectral data thus
3
suggested that kinabalurine A is a hydroxyskytanthine derivative, and COSYand
HETCOR experiments confirmed that hydroxy substitution was at C(7) and
allowed the full assignments of the NMR spectral data. In addition, the observed
J value of 10Hz required a trans ring junction. The NMR data, however, were
1–9
insufficient to establish the stereochemistry completely and unequivocally and for
this purpose X-ray diffraction analysis was undertaken, which established the
structure of kinabalurine A. Kinabalurine Awas the second 7-hydroxyskytanthine
reported, the first being incarvilline (14) isolated from the Chinese plantIncarvillea
sinensis. The structure of incarvilline was also established by X-ray analysis (34).
Kinabalurine A differs from incarvilline in having a trans ring junction, a 7b-OH
substituent, and a 4a-methyl group. Kinabalurine B (6) is the 7-oxo derivative of
kinabalurineAasshownbythespectraldata,aswellasbyitsreadyformationvia
oxidation of kinabalurine A. Similarly, kinabalurine C (7) was readily shown to be
the N-demethyl derivative of kinabalurine B from the spectral data (loss of the
N-methyl signal in the 1H and 13C NMR, and the presence of a secondary amine
absorption in the IR at 3400cm(cid:2)1). The trans ring junction in kinabalurine C was
clearlyshowninthe600MHz1HNMRspectrum,whichshowedtheH(9)signalas
a quartet of doublets (J ¼J ¼J ¼12Hz, J ¼4Hz).
5b–9a 1b–9a 8b–9a 1a–9a
OH O OH O
7
H Me H Me H Me H Me
Me Me Me Me
9
5 H H H H
3 N 1 N N N
Me R Me Me
5 6 R = Me; 7 R = H 8 9
OH OH
H Me H Me H Me H Me
Me Me Me Me
H OH H R
+
N N N N
Me Me O− Me Me
10 11 14 15 R = OH; 16 R = H
4 Toh-SeokKamandKuan-HonLim
The spectral data for kinabalurine D (8) showed it to be yet another
7-hydroxyskytanthinediastereomer,butprovedinadequatefordefinitiveassign-
ment of stereochemistry. To this end, kinabalurine D was converted to the
quaternary ammonium salt, which provided suitable crystals for X-ray
analysis. Kinabalurine D differs from kinabalurines A–C in having a 4b-methyl
group and a trans ring junction in which the stereochemistry of H(5) and H(9)
are now reversed. Kinabalurine E (9) is the 7-oxo derivative of kinabalurine D,
as shown by the spectral data and by chemical correlation (PCC oxidation)
with 8.
Kinabalurine F (10) was obtained in minute amounts, and its structure
elucidation relied mainly on analysis of the 600MHz NMR data and by
comparison with 5, 8, and incarvilline (14). The orientation of the 7-hydroxy
group of kinabalurine F was deduced to be b based on comparison of the
observed C(7) shift (d 81) with those of 5 (d 80) and 8 (d 81), which also have a
7b-OH. The C(7) shift in incarvilline, which has a 7a-OH, was shifted upfield to
aboutd73.TheobservedNOEinteractionsfromH(7a)tothe8-methylandfrom
H(6a) to H(5) fixed their respective stereochemistry. Likewise, the observed
H(1b)/H(8b) NOE interaction allowed the assignmentof H(1a),which appeared
asatripletwithJ¼10.5Hz,requiringH(9)andH(1a)tobetrans-diaxial,whichis
possible only if H(9) is b. The observed H (3) signals as a triplet with J¼11Hz
2
andadoubletofdoublets(J¼11,2Hz)areonlyconsistent withH(4b),resulting
inH(4b)andH(3a)beingtrans-diaxialtoeachother.The4-methylofkinabalurine
F therefore has an a-orientation.
KinabalurineG(11)wasisolatedfromtheleafextractofK.dasyrachis,another
Kopsia from Malaysian Borneo (35). It was the most polar alkaloid from the leaf
extract. The mass spectrum showed fragments typical of skytanthine-type
alkaloids, while the IR spectrum indicated the presence of a hydroxyl group.
The 1H NMR spectrum indicated the presence of two CH CH groups and an
3
N-methyl group, which was rather deshielded at d 3.17. This observation,
coupledwiththepolarnatureofthiscompound,andtheobservationofastrong
M-16fragmentinthemassspectrum,suggestedthatcompound11isanN-oxide.
This was readily confirmed by FeSO reduction of 11, which yielded the parent
4
monoterpene alkaloid 15. The N-methyl signal was shifted upfield to d 2.30,
while the resonances of the two a-carbons, C(1) and C(3), were also shifted
upfield from d 67.3 and 67.2 to d 62.5 and 57.7, respectively. The presence of a
low-field, quaternary carbon signal at d 79.1 indicated that the hydroxyl
C
function was attached to a quaternary carbon, i.e., C(5) or C(9), based on a
skytanthine-type carbon skeleton.
Detailed analysis of the 1H and 13C NMR spectral data (COSY, HMQC,
HMBC,NOE)andcomparisonwithd-skytanthine(16)(36)enabledplacementof
the OH function on C(9) and allowed full assignment of the NMR spectral
data, as well as elucidation of the stereochemistry. The parent monoterpene,
9-hydroxy-d-skytanthine (15), is unknown, and was not detected in this study,
although a 9-hydroxyskytanthine of unknown stereochemistry, as well as a
b-skytanthineN-oxide,havebeenpreviouslyreportedfromTecomastans(37)and
AlkaloidsofKopsia 5
Skytanthusacutus(38),respectively.Thekinabalurines,togetherwithincarvilline,
provide a useful array of stereoisomers in this series with various ring junction,
7-hydroxy, and 4- and 8-methyl group stereochemistry.
K. profunda (K. macrophylla) (1) provided two more new monoterpene
alkaloids, kopsilactone (12) and kopsone (13), in addition to the known
alkaloids 5,22-dioxokopsane, dregamine, akuammiline, tabernaemontanine,
deacetylakuammiline, norpleiomutine, and kopsoffine (39). The IR spectrum
of kopsilactone (12) indicated the presence of a g-lactone unit (1770cm(cid:2)1),
which was supported by the observation of a quaternary carbon resonance at
d 176. The observed J value of 11Hz required a trans-diaxial arrangement
3–4
between H(3a) and H(4b), while the estimated J value of ca. 4Hz suggested a
4–5
cis relationship between H(4) and H(5). An equatorial H(5) required a cis ring
junction between the piperidine and the five-membered ring, which, in turn,
fixed the stereochemistry of the lactone–piperidine ring junction.
The second monoterpene alkaloid, kopsone (13), gave a molecular ion,
which analyzed for C H NO. The IR (1720cm(cid:2)1) and 13C NMR (d 218) data
11 19
indicated the presence of a ketone function. Other groups indicated by the
NMR spectra were two CHMe, an N-methyl, three methylenes (one deshielded
at d 56), and four methines (one deshielded at d 72). These, as well as a
C C
postulated common origin of 12 and 13 from the hypothetical 9-hydroxysky-
tanthine precursor 17 (Scheme 1), led to the proposed structure for kopsone.
The relative stereochemistry was deduced from analysis of the 1H NMR
spectrum.
The leaves of K. dasyrachis also gave kopsirachine (18), which is
constituted from union of the flavonoid, catechin, and two units of skytanthine.
The gross structure was deduced from spectroscopic and chemical
H Me H Me H Me
Me Me Me
[O] b a
OH O H OH
+ CoA
N N a N
Me Me CH CCoA Me O
2
17 O
b CoA
H H Me
Me O Me
O
Me
N H N O
Me Me
13 12
Scheme1
6 Toh-SeokKamandKuan-HonLim
evidence, but the stereochemistry of the skytanthine units in 18 remains to be
firmly established (36).
Me
OH
N OH
Me
Me
HO O
Me
N
OH
OH
Me Me
18 kopsirachine
III. SIMPLE INDOLE ALKALOIDS
The simple b-carboline alkaloid harmane (19), although widely distributed in
several plant families, is rarely encountered in the Apocynaceae. It has been
recentlyobtainedforthefirsttimefromKopsiafromK.griffithiiandwasfoundto
display moderate leishmanicidal activity against Leishmania donovani (40,41).
N N N N N N
H Me H H H H
19 20 21
Anewb-carboline,(+)-harmicine(2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]
indole), which has been previously synthesized in racemic form (42–46) was
also isolated for the first time as an optically active natural product from
K. griffithii, and was assigned the structure 20 (40). Recent enantioselective
syntheses of both (S)-((cid:2))- and (R)-(+)-harmicine resulted in the correct assign-
mentoftheabsoluteconfigurationofnaturallyoccurring(+)-harmicineas(R),as
shown in 21 (47–49).
The synthesis of (S)-harmicine (Scheme 2) was based on the use of the
(S)-1-allyl-1,2,3,4-tetrahydro-b-carboline (23) as the starting compound, which
was in turn obtained by a diastereoselective C(1)-allylation of the appropriate
b-carboline precursor 22, incorporating a glutamic acid-derived chiral auxiliary.
Subsequent hydroboration, followed in succession by removal of the trichloro-
ethoxycarbonyl group, and cyclization through a Mitsunobu reaction, led
eventually to (S)-harmicine (20) (47,48).
Thesynthesisof(R)-harmicine(21),ontheotherhand,wasbasedonanasym-
metric transfer hydrogenation of the appropriate iminium salt 24, in the presence
ofthechiralRu(II)catalyst(S,S)-25,asthekeystep(Scheme3).Thestructureofthe
product was also confirmed by an X-ray crystallographic analysis (49).