b-Phenylethylamines and the isoquinoline alkaloids

22 Pages·1999·0.84 MB·English

b-Phenylethylamines and the isoquinoline alkaloids
Kenneth W. Bentley
Marrview, Tillybirloch, Midmar, Aberdeenshire, UK AB51 7PS
Received 10th December 1998
OMe
Covering: July 1997 to June 1998
MeO
Previous review: 1998, 15, 341
O OH
HO
1 b-Phenylethylamines
N
2 Isoquinolines
H
3 Naphthylisoquinolines
O
4 Benzylisoquinolines
H
5 Bis-benzylisoquinolines
N
6 Pavines and isopavines
HO
7 Berberines and tetrahydoberberines
O OH
8 Secoberberines
MeO
9 Protopines
1 OMe
10 Phthalide-isoquinolines
11 Spirobenzylisoquinolines H
12 Indanobenzazepines MeO N MeO
Ac
13 Rhoeadines
O N
14 Emetine and related alkaloids MeO MeO
15 Benzophenanthridines Me Me
16 Aporphinoid alkaloids 2 3
16.1 Propaporphines
16.2 Aporphines
16.3 Phenanthrenes Me O
16.4 Oxoaporphines
Me
16.5 Dioxoaporphines N
H
16.6 Aristolochic acids and aristolactams OH F H
16.7 Azafluoranthenes 4
17 Alkaloids of the morphine group
18 Phenethylisoquinolines 2 Isoquinolines
19 Colchicine and related alkaloids O-Methylcorypalline has been isolated from Berberis densi-
20 Erythrinaalkaloids flora4 and from Phoebe minutiflora14 and stephaoxocanidine
20.1 Erythrinan alkaloids has been isolated from Stephania cepharantha.15 A review of
20.2 Homoerythrinan alkaloids the alkaloids of cacti of Gymnocalycium species has been
20.3 Cephalotaxine and related alkaloids published.16An X-ray crystallographic study of corydaldine has
21 Other isoquinolines been reported.17 The iminium salt 5 has been cyclised to the
A comprehensive review of the chemistry of the alkaloids (1R)-tetrahydroisoquinoline 6.18
within the scope of this review, other than those of the morphine
group, has been pubished.1
MeO MeO
1 b-Phenylethylamines +N NMe
MeO C Me MeO
N-trans-Feruloyltyramine has been isolated from Tinospora CF3 CF3
cordifolia.2 The novel bimolecular alkaloid cherinonaine, S S
isolated from Annona cherimola, has been assigned the O O
structure 1on the basis of its NMR spectra and of its fission to 5 Me 6 Me
trans-ferulic acid and 4-hydroxy-3-methoxyamphetamine.3The
new alkaloid densine 2, isolated from Berberis densiflora,4 is
structurally a b-phenylethylamine, but, since it is doubtless
3 Naphthylisoquinolines
derived from dehydrosalsolidine 3, it is more properly classified
with the isoquinoline alkaloids. Naphthylisoquinoline alkaloids have been isolated from the
The treatment of pseudoephedrine with (R)-a-fluoropropio- following plant species, the thirteen marked with asterisks being
namide has afforded the amide 4, a-C-alkylation of which new alkaloids:
proceeds with a high degree of stereoselectivity and hydrolysis Ancistrocladus cochinchinensis19
of the products gives the corresponding chiral acids.5 The ancistrocladinine, 6-O-methylhamateine* 7, 6-O-methyl-
physico-chemical properties of soap solutions generated by hamatinine* 8b, hamatinine 8a, 7-epi-ancistrobrevine D*
ephedrine and pseudoephedrine myristates, which form bimo- 9a, 6-O-demethyl-7-epi-ancistrobrevine D* 9b and 6-O-
lecular fibres in water,6 and the crystal structure of N- demethyl-8-O-methyl-7-epi-ancistrobrevine D* 9c
cyanomethylpseudoephedrine7have been studied. Ancistrocladus guineaensis20
The pharmacological properties and physiological effects of ancistrotectorine, ancistroguineine A* 10 and ancis-
ephedrine,8–11 of (+)- and (±)-norephedrine12and of pseudoe- troguineine B* 11
phedrine13have been studied. Ancistrocladus korupensis21,22
Nat. Prod. Rep., 1999, 16, 367–388 367
OMe OMe OMe OMe Me OMe
HN
Me Me Me OH
MeO Me RO Me OH OMe Me
OH OMe
N N
OMe Me OMe Me Me OMe OH
Me
7 8a R = H
8b R = Me HO Me HO Me
NH
R1O Me NH
Me
OMe Me
OMe Me
NH 12 13
OR2 Me Me OMe
MeO
HN
MeO
9a R1 = Me, R2 = H Me OH
9b R1 = R2 = H
9c R1 = H, R2 = Me Me
OH OMe
OMe OH
OMe OH OMe OH Me
HO Me
NH
Me Me
HO Me HO Me OMe Me
14
NH NH
Me OMe
OMe Me OMe Me
N
10 11
Me OH
Me
korupensamine E* 12, michellamine D* 13, michellamine OH OMe
E* 14, michellamine F* 15, yaoudamine A* 16 and
yaoudamine B* 17
Ancistrocladus robertsoniorum23 OMe OH
ancistrobrevine B, ancistrocladine, ancistrorobertsonine* Me
18and hamatine. HO Me
The structures of the new alkaloids have been determined by
NH
spectroscopic studies, by the correlation of 9a, 9band 9cwith
7-epi-ancistrobrevine D and by the degradation of ancis-
OMe Me
troguineine A to the amino acids 19and 20.20 15
The absolute configuration of dioncophylline A 21has been
OH
confirmed by an anomalous X-ray dispersion crystal analysis of OH
the 5-bromo-N,O-dibenzyl derivative24 and the configurations H O OH
Me
of several of the alkaloids at the biaryl axis has been determined
HO Me O Me
by studies of long range nuclear Overhauser effects.25 The
Fourier transform Raman spectra of the alkaloids from
N N
Ancistrocladus heyneanushave been examined.26
The enzyme involved in the bimolecular coupling of OMe Me OMe Me
korupensamines A and B to give michellamines A and C has HO HO
been identified and partially purified. It has been shown to be a
MeO Me MeO Me
single polypeptide and it effects the first dimerisation of the
16 17
korupensamines to be achieved without protection of the
hydroxy and secondary amino groups.27 Following previous
practice, with protection of the hydroxy and amino groups, OMe OH
dioncophylline C 22 has been oxidised to the bimolecular
josimine C 23, which is an analogue of the michellamines but
has not been encountered as a natural product.28
Me
Dioncophylline C 22has been found to effect a complete cure
HO Me
of Plasmodium berghei malaria, even of strains resistant to
conventional antimalarials, at a dosage of 50 mg kg21over four H
NMe Me HO2C NH2
days, without toxic effects. Dioncopeltine A is also effective HO2C
against the same organism.29 N,N-Dimethyldioncophylline A OMe Me H NH2 Me
iodide has been found to have enhanced antiplasmodial activity 18 19 20
over the free secondary base.30 A review of the biological
368 Nat. Prod. Rep., 1999, 16, 367–388
Me MeO
Me
Cl–
NH +NMe2 HO OMe
MeO
OH Me OH N
MeO MeO OH
Me
MeO OMe
21 25 26
Me OH
MeO
HN
N
MeO
Me
OMe
OH OMe Me MeO
OH OMe
OMe
27
Me OMe OH
Me
Me ethanol buffered with sodium acetate to give an 80% yield of an
Me
aporphine that gave glaucine on O-methylation (see section
NH 16.2).41
NH
Pictet–Spengler cyclisation of the enol methyl ether of
OH Me OH Me 3,4-dimethoxyphenylacetaldehyde 29awith the (2)-8-phenyl-
22 23
menthyl carbamate 28a affords a marked enantiomeric excess
of the (1R)-tetrahydroisoquinoline 30a, reduction of which with
activities of the naphthylisoquinoline alkaloids has been lithium aluminium hydride affords (R)-(+)-laudanosine 30b,
published.31 A series of analogues of the michellamines, in which is the enantiomer of the natural alkaloid. Improved
which the tetrahydroisoquinoline system has been replaced by a stereoselectivity was achieved using 29bin place of 29a. Since
variety of simple aromatic systems, have been found to exhibit the (+)-8-phenylmenthol is not readily available, the corre-
no activity against human immunodeficiency virus.32 sponding carbamates of (2)-trans-2-(a-cumenyl)cyclohexanol
28band its (+)-enantiomer have been converted into 2A-bromo-
(1R)-laudanosine 30cand its (1S)-isomer.42
4 Benzylisoquinolines
1-Benzylisoquinoline alkaloids have been isolated from the MeO Me R
Me
following plant species, the two marked with asterisks being N Ph MeO OMe
new alkaloids: MeO H CO2
Annona cherimola33
R MeO
orientaline 28a R = Me 29a R = H
Aristolochia triangularis34 28b R = H 29b R = Br
oblongine
MeO
Berberis densiflora4
densiberine* 24 NR1
MeO R2
H
MeO OMe
Cl–
+NMe
MeO OMe
OMe 3300ab RR11 == OM2eC, - (R–2) -=8 -HPhenylmenthyl, R2 = H
30c R1 = Me, R2 = Br
OMe
24
In the previous review it was reported that the benzylisoqui-
Cocculus laurifolius35 noline 32a is not identical with the alkaloid fumarizine, to
coclaurine which this structure had previously been assigned. This alkaloid
Croton celtidifolius36 is also not identical with the isomeric base 32b, obtained by the
laudanidine and reticuline asymmetric reduction of the iminium salt 31.43 In a similar
Phoebe minutiflora14 manner the alkaloid dehassiline, to which the structure 33has
armepavine, N-methylarmepavine, coclaurine, N-methyl- been assigned,44 has been shown to be different from the
isococlaurine, juziphine, norjuziphine, laudanidine and product of reduction of the iminium salt 34.45(R)-(+)-Norroe-
reticuline fractine 35 has been synthesised and shown to be a selective
Papaver triniifolium37 ligand at the dopamine D receptor, where it displaces
2
militanthaline* 25and papavarine raclopride.46
The novel 2-benzylisoquinoline alkaloid numularine 26 has The 3,4-dihydroisoquinoline 36, prepared by Bischler–
been isolated from Berberis numularia.38 Napieralsky ring closure, on treatment with base and methyl
The 1H, 13C and 15N NMR spectra of (2)-armepavine have 2-methoxymethoxy-5-methoxybenzoate affords the ketone 37,
been studied39and an X-ray crystallographic study of the same which reacts with ethyl bromoacetate to give the ester 38a,
alkaloid has been reported.39The anion of papaverinol has been easily converted into 38b. Treatment of this with triethylamine
methylated to give the alkaloid setigerine 27.40Laudanosoline effects cyclisation to lamellarin D 39a, which can be demethy-
hydrobromide has been oxidised by ferric chloride in aqueous lated to lamellarin H 39b.47 In an alternative approach to this
Nat. Prod. Rep., 1999, 16, 367–388 369
O replication of poliomyelitis virus56 have been studied, and a
O
method of estimation of atracurium has been described.57
NMe
+NMe O
O
R3
O 5 Bis-benzylisoquinolines
MeO R2 Bis-benzylisoquinoline alkaloids have been isolated from the
MeO O R1 following plant species, the four marked with asterisks being
31 32a R1R2 = OCH2O, R3 = H new alkaloids:
32b R1 = H, R2R3 = OCH2O Anisocyla jollyana58
cycleanine, cycleanine-2-N-oxide, dehydroapateline, fas-
MeO MeO
trine* 42, homoaromoline, isochondodendrine, jollya-
NMe +NMe nine* 43, limacusine, limacusine-2A-N-oxide and O-me-
HO HO thylcosculine
H
OH OH
OH
OH MeO
MeO MeO
33 34 MeO
NMe
MeO
HO NMe O H
MeO
O H
NH
MeO
H
H O
OMe
OMe H O MeN
35 OMe
MeN
OMe
system the dihydroisoquinolinium salt 40has been cyclised by OMe OH
42 43
base to 41a, which was selectively cleaved by aluminium
chloride to lamellarin K 41b.48
Berberis densiflora4
Ph Ph oxyacanthine
Stephania tetrandra59
O O fenfangjine H* 44aand fenfangjine I* 44b.
Fastrine and jollyanine are the first head-to-tail linked bis-
N N
MeO MeO benzylisoquinoline alkaloids bearing an oxygen substituent at
position 5 to be discovered. The structures of the new alkaloids
MeO MeO O OMe
were determined by spectroscopic methods. Fenfangjines H and
O I are secobis-benzylisoquinoline alkaloids clearly formed by
O O
oxidative cleavage of fenfangjine D 45, previously isolated
Ph Ph MeO
36 37 OMe MeO
RO HO MeN +NMe
HO
O H OH–
N CO2Et N O
MeO RO
MeO O OMe O
O R
RO
O
RO
MeO
HO
MeO RO 44a R = CH2OH
38a R = CH2Ph 39a R = Me 44b R = CHO
38b R = H 39b R = H
OMe MeO
MeO
O
MeO MeN +NMe
N+ HO
MeO O N O H O OH–
OPri MeO
O
OR O
MeO
OPri MeO 45
OMe
MeO
OPri RO MeO OR from the same plant.60 These two alkaloids were shown to be
inhibitors of the angiotensin-I converting enzyme.59
40 41a R = Pri
Cycleanine has been oxidised by m-chloroperbenzoic acid to
41b R = H
a mixture of the 2aand 2bN-oxides 46aand 46b.61
The pharmacological properties and physiological effects of
The pharmacological properties and physiological effects of bebeerine,62of berbamine,63,64of O-benzoyl, O-ethyl, O-butyl
atracurium,49–52of higenamine53and of papaverine54,55and the and O-4-ethoxybutyl-berbamines65 of tetrandrine66–72 and of
effects of O-methylarmepavine and of reticuline on the tubocurarine73 and the antitrypanosmal activities of curine, of
370 Nat. Prod. Rep., 1999, 16, 367–388
MeO excess, and these were cleaved by hydrogenolysis to 49a and
R2 49b. Alkylation of these with bromoacetaldehyde diethyl acetal
+N
MeO R1 afforded 50aand 50b, which were cyclised by acid through the
O H intermediate 4-ethoxytetrahydroisoquinolines 51a and 51b to
the isopavine secondary bases, which were N-methylated to
(2)-O-methylthalisopavine 52a and (2)-amurensinine 52b.75
Acid-catalysed cyslisation of the dihydroisoquinoline 53 has
afforded the racemic isopavine, which was resolved to give
H O
OMe (2)-thalimonine 54, confirming the assignments of the posi-
MeN
tions of the substituents in this alkaloid.76
OMe
46a R1 = Me, R2 = O–
46b R1 = O–, R2 = Me 7 Berberines and tetrahydroberberines
Alkaloids of the berberine group have been isolated from the
cycleanine, of isotetrandrine, of limacine and of phaeanthine74 following plant species, the three marked with asterisks being
have been studied. new alkaloids:
Annona cherimola33
kikenamine
6 Pavines and isopavines Aristolochia constricta77
the unnamed base 55*
Condensation of phenylglycinol with veratric aldehyde and
with piperonal affords the imines 47aand 47b, and these have
MeO
been found to react with 3,4-dimethoxybenzylmagnesium
N
R1O Ph MeO
OH H
NH OH
R2O
R1O OH
55
N
R2O OH OMe
Ph OMe Aristolochia gigantea78
47a R1 = R2 = Me 48a R1 = R2 = Me the unnamed glucoside 56* and the cis-N-oxide 57*
47b R1R2 = CH2 48b R1R2 = Me
EtO OEt MeO
R1O R1O
N
R2O NH2 R2O NH HO H
OH
OH
O
OMe OMe
OH O OH
OMe OMe OH
49a R1 = R2 = Me 50a R1 = R2 = Me HO
49b R1R2 = CH2 50b R1R2 = CH2 56
MeO
OEt
O–
R1O +N
HO
H
NH
R2O OH
OMe
OH
O
R1O
OMe
OMe NMe OH O OHOH
OMe R2O HO
57
51a R1 = R2 = Me 52a R1 = R2 = Me
51b R1R2 = CH2 52b R1R2 = Me
O Berberis densiflora4
O berberine
Berberis stenophylla79
NMe berberine
MeO
O Corydalis dasypterma80
O OMe coptisine, tetrahydrocoptisine, corysamine and tetrahy-
drocorysamine
NMe
OMe Papaver pseudo-orientale81
OMe MeO OMe mecambridine and orientalidine.
53 54
A method for the estimation of berberine in body fluids has
been described.82
chloride with a high degree of steroespecificity to give the The 8-oxopseudoberberine 58 has been cleaved by sodium
1,2-diarylethylamines 48aand 48bwith the (S,S) forms in 95% hydride to the olefin 59, which has been converted into the
Nat. Prod. Rep., 1999, 16, 367–388 371
O O MeO MeO
H
O N O O N O MeO N BCrO2 MeO N O
H Ph H
OMe OMe OMe OMe
OMe OMe OMe OMe
58 59 60 61
MeO
MeO
Me H Me H MeO H Me
N
MeO
H O N Ph MeO H NOH NMe Ph MeO N O O NMe Ph
H
Me Me
OMe
OMe
62 63 64 65 66
MeO MeO
MeO
MeO H
N O N O
N MeO MeO
N O MeO O O O O
MeO O
H O
– O
MeO
– O
OMe
67 68 69 70
MeO
Me O Br– R1 MeO
N O
MeO O O +N (CH2)n O +N Me
O MeO
OMe R2 OMe
O
OMe OMe
71 72a R1 = H, R2 = Cl 73
72b R1 = H, R2 = NO2
72c R1 = H, R2 = CO2Et
72d R1 = H, R2 = Me
72e R1 = Me, R2 = H
72f R1 = NO2, R2 = H
72g R1 = NO2, R2 = Cl
72h R1 = R2 = Cl
72i R1=R2=H
benzophenanthridine alkaloid oxonitidine83 (see section 15). 8 Secoberberines
The chiral carbamate 60, prepared from (1S)-norlaudanosine,
The new secoberberine alkaloid fumaflorine 74 has been
has been cyclised by tert-butyllithium to 8-oxoxylopinine 61,
isolated from Fumaria densiflora.101
which, on reduction with Redal, afforded (S)-(2)-xylopinine
62.42 In a model approach to the chiral synthesis of tetra- MeO
hydroberberines the anion of the chiral o-toluamide 63has been
condensed with 3,4-dimethoxy-3,4-dihydroisoquinoline (dehy- N
MeO CO2H
droheliamine) to give a mixture of the amide 64 and the (S)-
lactam 65, the latter being the sole product under certain O O
conditions. In a similar way the enantiomeric toluamide 66
O
yielded the (R)-lactam 67.84Dehydroheliamine also reacts with 74
the anion of 3-methoxyphthalide 68giving, via69, the 13-spiro-
8-oxoberberine 70. The similar reaction with dehydrosalsoli-
dine 3 affords 71, with the opposite configuration at position
13a.85 Quaternary tetrahydroberberinium salts of structures
9 Protopines
72a–i, in which n = 2 and 3, have been prepared and examined
as cardiac antiarrhythmic agents.86A patent claiming the use of Alkaloids related to protopine have been isolated from the
coralyne 73 and its analogues as topoisomerase inhibitors has following plant species, the four marked with asterisks being
been published.87 new alkaloids:
The pharmacological properties and physiological effects of Aristolochia constricta77
berberine,88–95 of 8-oxoberberine,96 of tetrahydroberberine,97 constrictosine* 75a, O-methylconstrictosine* 75b, O,O-
of berberrubine,92 of palmatine,92 of 7-chlorobenzyltetrahy- dimethylconstrictosine* 75c, 5,6-dihydroconstrictosine*
dropalmatinium salts,98 of 13-hydroxytetrahydropalmatine,92 76aand O,O-dimethyl-5,6-dihydroconstrictosine* 76b
of 13-alkyltetrahydropalmatines up to the hexyl compound92 Berberis densiflora4
and of stepholidine99,100have been studied. allocryptopine
372 Nat. Prod. Rep., 1999, 16, 367–388
HO RO
R1O R1O
N N MeO NMe MeO N CO2Et
O O CH2 CO2H
O O
OR2 OR2
75a R1 = R2 = H 76a R1 = R2 = H O O
75b R1 = Me, R2 = H 76b R1 = R2 = Me 80 81a R = CO2Et
75c R1 = R2 = Me 81b R = Me
RO
Glaucium fimbrilligerum102
RO
protopine N
MeO O
Papaver fugax103 N CO2Et
MeO
protopine. O O
The substitution pattern of the new alkaloids from Aris- O
tolochia constricta is unprecedented in this group and their
O
origin from tyrosine is possibly in doubt since the original
O
tyrosine hydroxy group is missing from the left hand half of the
O O
system. These alkaloids all cause a significant dose-dependent 82a R = CO2Et 83a R = CO2Et
reduction in contractions of isolated guinea pig ileum induced 82b R = Me 83b R = Me
by electricity, acetylcholine and histamine.77The physiological
effects of allocrypropine have been studied.104 84awas converted through 84binto the lithium derivative 84c,
which was condensed with the aminoindanone 85 to give the
10 Phthalide-isoquinolines amino alcohol 87 in 91% yield, together with the related
diastereoisomer (7%). Acid hydrolysis of this afforded only the
a-Narcotine and narceine have been isolated from Papaver elimination product 88a and its geometrical isomer, but basic
triniifolium.37 The alkaloid fumaflorine 74, isolated from hydrolysis afforded mainly the indanobenzazepine 89, together
Fumaria densiflora, could also be regarded as a member of this with 25% of the olefin 88b. Reduction of the lactam 89 with
group. bis(methylthio)boron hydride yielded the alcohol 90a, which
An X-ray crystallographic study of racemic narlumicine was converted only with difficulty into 90b. The alcohol 90a
hydrobromide has confirmed the relative stereochemistry as was oxidised by Fremy’s salt to 91a, which was cleaved by
that shown in 79105 and a synthesis of the alkaloid has been trifluoroacetic acid to the norribasine analogue 91b, isolated as
effected by the reaction of the aldehyde 77with the lithium salt an equilibrium mixture with the imine 92. Natural norribasine
of the appropriate phthalide 78.106 93ddoes not equilibrate with the corresponding imine.
Li+
–
O NMe2 O 13 Rhoeadines
O Two new alkaloids of the rhoeadine group, triniifoline 94aand
O CHO O O O-ethyltriniifoline 94b have been isolated from Papaver
77 78 triniifolium.37
O NMe2
OH 14 Emetine and related alkaloids
O
H The following new alkaloids have been isolated from Alangium
lamarckii:115,116 6A-O-b-d-glucopyranosylalangiside 95, 3A-O-
O
b-d-glucopyranosylalangiside 96, 6A-a-d-glucopyranosylalan-
O giside 97a, 6A-O-a-d-glucopyranosyl-3-O-demethyl-2-O-me-
O O thylalangiside 97b, 6A-O-a-d-xylopyranosylalangiside 98 and
79
the diastereoisomeric methoxy compounds 99a and 99b. The
structures of these alkaloids were determined on the basis of
A method for the estimation of narcotine in body fluids has
their NMR spectra. The methoxy compounds 99a and 99b,
been described.107The pharmacological properties and physio-
which have been found to be produced from alangiside on long
logical effects of narcotine108,109 and of bicuculline110 have
storage of the alkaloid in methanol, are clearly products of
been studied.
oxidation of the alkaloid, being simple derivatives of the
dialdehyde 100, which has been reasonably postulated as an
11 Spirobenzylisoquinolines intermediate in the biotransformation of alangiside into the
azaberberine alkaloid alangimaridine 101. Both 99aand 99bare
The chemistry of the alkaloids of this group isolated from
converted into alangimaridine under conditions identical with
Fumariaspecies has been reviewed.111In an attempt to repeat
those normally used in the extraction of alkaloids from plant
a previously reported synthesis112of ochotensine 80, cyclode-
material.116
hydration of the acids 81a and 81b with polyphosphoric acid
has been found to give only the acid anhydrides 82aand 82b,
rather than the ketones 83aand 83b.113
15 Benzophenanthridines
Benzophenanthridine alkaloids have been isolated from the
12 Indanobenzazepines
following plant species:
The first synthesis of the 6,7-indano-3,4-benzazepine system Papaver nudicaule117
encountered in the alkaloids ribasine 93a, himalayine 93band chelidonine
ribasidine 93c has been reported.114 2-Cyanobenzyl bromide Zanthoxylum roifolium118
Nat. Prod. Rep., 1999, 16, 367–388 373
MeO
R CN O R Ph HO N O
H
N
H
O
H OH
O O H
8844ab RR == BTerBun 85 R = 86 86 H O H O O OH
84c R = Li O HO
OH OH
HO
O H R O R2 OH
95
N N
H H MeO
O CN O R1
HO N O
HO
H
87 R = 86 88a R1 = CONH2, R2 = 86 H
88b R1 = CN, R2 = 86 O
OH
H H
O H R O H R O
N N O OH OH
O O O HO H
O
HO HO O
OH
HO
96 OH
89 R = 86 90a R = 86 R1O
90b R = H
N O
O H R O R2O
H
N N
O O
O H
HO O
H H
O OH
91a R = 86 92 O O
OH
91b R = H
R2 HO OH HHO O OH
O H R3 97a R1 = Me, R2 = H OH
97b R1 = H, R2 = Me
N
O MeO
O
R1 O N O
HO
H
O
93a R1 = R2 = H, R3 = Me
93b R1 = H, R2 = OH, R3 = Me H O
93c R1 = OH, R2 = H, R3 = Me
93d R1 = R2 = R3 = H H H
O
O O
OH
O HO OH H O OH
HO
NMe 98 OH
O H
H MeO
O
N O
RO HO
H OMe H R1
MeO
94a R = H R2
94b R = Et
O
OH
dihydronitidine, 6-oxonitidine and zanthoxyline 102. H O H
Zanthoxyline, which is a new alkaloid, has an unusual O
OH
substitution pattern, being the first alkaloid of the group not to HO
OH
bear an oxygen substituent at position 8. The conformation of 99a R1 = H, R2 = OMe
methyl (+)-corydalate 103has been studied by NMR spectros- 99b R1 = OMe, R2 = H
copy and the trans-stereochemistry has been confirmed.119
MeO
Photo-oxidation of sanguinarine has been shown to give
6-oxosanguinarine 104.120 N O MeO
HO
Sanguilutine, on treatment with potassium cyanide, gives H
N O
6-cyanodihydrosanguilutine 105a and treatment with sodium CHO HO
carbonate yields 6-hydroxydihydrosanguilutine 105b, which in H
non-polar solvents spontaneously loses water to give the CHO
bimolecular amine ether 106, the structure of which has been N
confirmed by X-ray crystallography. The related dimeric amine 100 101
107is formed directly from sanguilutine and ammonia.121
374 Nat. Prod. Rep., 1999, 16, 367–388
CO2Me 16 Aporphinoid alkaloids
Me O 16.1 Proaporphines
O
OMe
O Proaporphine alkaloids have been isolated from the following
HO O H plant species:
NMe
Annona cherimola33
N O
stepharine
O
102 103
Papaver fugax103
pronuciferine
O
Papaver triniifolium37
mecambrine and N-methylcrotonosine.
O
NMe
O
O O 16.2 Aporphines
104
Aporphine alkaloids have been isolated from the following
plant species, the five marked with asterisks being new
alkaloids:
OMe Annona cherimola33
OMe anolobine, anonaine, N-formylanonaine, asimilobine, N-
methylasimilobine, isocorydine, laurotetanine, N-methyl-
OMe
laurotetanine, norisocorydine* 110, norushinsunine, ush-
NMe insunine and xylopine
MeO
OMe R
105a R = CN MeO
105b R = OH
NH
OMe MeO
OMe H
HO
OMe
NMe MeO
MeO 110
OMe O OMe
OMe
MeN Aristolochia triangularis34
MeO magnoflorine and N,N-dimethyllindecarpine
Berberis densiflora4
OMe glaucine, isocorydine and thalicmidine
MeO
106 Cassytha filiformis123
actinodaphnine, cassamedine, cassameridine, cassythi-
OMe
OMe cine, cathafiline* 111, cathaformine* 112and isoboldine
OMe
O OMe
NMe
MeO O N CO2Me O
OMe NH OMe
H O N CO2Me
OMe
MeN H
MeO MeO
OMe OH MeO
MeO 111 112
107
Cocculus laurifolius35
A synthesis of 6-oxonitidine 109has been achieved from the isoboldine and norisoboldine
8-oxopseudoberberine 58 by cleavage with sodium hydride to Corydalis dasyptera80
the olefin 59, followed by N-methylation and oxidation with corytuberine
thallium(iii) nitrate in methanol to the acetal 108, which was Croton celtidifolius36
cyclised by acid to 109.83 isoboldine
Glaucium fimbrilligerum102
bulbocapnine, isocorydine, lindecarpine and thalipor-
MeO O O
phine
MeO
MeO MeO Illigera luzonensis124
O O
actinodaphine, N-methylactinodaphnine, bulbocapnine, O-
NMe NMe methylbulbocapnine, dicentrine, hernovine and launobine
MeO MeO
Magnolia obovata125
O O
anonaine, isolaureline N-oxide* 113and roemerine
108 109
Papaver fugax103
roemerine
The pharmacological properties and physiological effects of Papaver pseudo-orientale81
chelerythrine have been studied.122 bracteoline and isothebaine
Nat. Prod. Rep., 1999, 16, 367–388 375
O RO MeO
Me
O +N O– RO NR MeO N CO2
H H Ph
RO MeO
OMe OR OMe
113 118a R = H 119
118b R = Me
Phoebe formosana126 to (S)-N-2-trans-(a-cumenyl)cyclohexyloxycarbonylnorglau-
N-formylanonaine, N-formyldehydroanonaine and laur- cine 119, which on reduction with lithium aluminium hydride
odionine* 114 afforded (S)-glaucine 118b.42
The pharmacological properties and physiological effects of
HO
actinodaphnine,124 of N-methylactinodaphnine,124 of apomor-
phine,134–147of boldine,56of isoboldine,56of bulbocapnine,124
N
MeO O of O-methylbulbocapnine,124 of cassythicine,56 of dicen-
trine,124 of guatterine,56 of glaucine,148 of hernovine,124 of
launobine,124of laurolitsine,148of N-methyllaurotetanine56and
O
of pachystaudine56have been studied.
MeO
OH
114 16.3 Phenanthrenes
N-Methylsecoglaucine (glaucine methine) has been isolated
Phoebe minutiflora14 from Phoebe minutiflora14and the new alkaloid fenfangjine F
corytuberine, isoboldine, laurolitsine and norisocorydine 120has been isolated from Stephania tetrandra.59Fenfangjine
110
Telitoxicum glaziovii127 OH
imenine. O
A review of alkaloids isolated from Thalictrum species has
been published.128 O NMe2
Oxidation of N-trifluoroacetylwilsonine 115a and of N-
trifluoroacetylnordomesticine 115b with lead tetraacetate has
afforded the 4 a-acetoxy compounds 116and 117, respectively,
120
OAc
MeO MeO
F is the first phenanthrene alkaloid of the aporphinoid group to
be discovered bearing a hydroxy group in the side-chain. The
N COCF3 N COCF3
HO HO stereochemistry of the alcoholic group has not been deter-
H H
mined.
Laurolitsine 121ahas been N-alkylated to the tertiary bases
121b, 121c and 121d and solvolysis of these with aqueous
R1O MeO
ammonium acetate has given the phenanthrenes 122a, 122band
OR2 OMe
122c. Mannich condensation of these amino phenols with
115a R1 = R2 = Me 116
formaldehyde yielded the homologues 123b, 123cand 123dof
115b R1,R2 = CH2 the alkaloid litebamine 123a.149
OAc
MeO
16.4 Oxoaporphines
HO N COCF3 Oxoaporphine alkaloids have been isolated from the following
H plant species:
Annona cherimola33
liriodenine, lysicamine, oxoanolobine, oxoglaucine and
O oxoxylopine
O Cassytha filiformis123
117
lysicamine
Guatteria lehmanii150
with no trace of the 4 b-isomers.129 A kinetic study of the lysicamine
oxidation of boldine by singlet oxygen has been published.130 Illigera luzonensis124
Methods for the estimation of apomorphine, apocodeine and dicentrinone and liriodenine
their glucuronides,131,132and of boldine133have been described. Magnolia obovata125
The acid-catalysed rearrangement of thebaine in mercaptans has lanuginosine and liriodenine
yielded sulfur-containing derivatives of apomorphine and Telitoxicum glaziovii127
apocodeine (see section 17). O-methylmoschatoline, splendidine and teliglazine 124
In syntheses of alkaloids of the group, racemic laudanosoline Zizyphus jujuba151
has been oxidised with alcoholic ferric chloride buffered with lysicamine.
sodium acetate to O,O-didemethyllaurolitsine 118a, which has The quaternary betaine teliglazine is a new alkaloid.
been methylated to (±)-glaucine 118b.41The (S)-2A-bromolau- Dicentrinone and liriodenine have been found to inhibit
danosine derivative 60has been cyclised by tributyltin hydride significantly platelet aggregation.124
376 Nat. Prod. Rep., 1999, 16, 367–388