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Narcissus alkaloids
Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 © 1998 Elsevier Science B.V. All rights reserved.
323
Narcissus Alkaloids Jaume Bastida, F. Viladomat and C. Codina
1.
INTRODUCTION Since the isolation of the first Amaryllidaceae alkaloid lycorlne (1) from Narcissus
pseudonarcissus by Gerrad in 1877, around 200 species belonging to this plant family have been examined for alkaloids. Although this group of alkaloids is of minor pharmaceutical importance, it has aroused increasing interest over the last years. The several reviews in this field are a valuable source of information (1-7) and, likewise, this topic Is regularly reviewed by the journal Natural Products Reports of The Royal Society of Chemistry (8-16). Out of the different genera which make up the Amaryllidaceae family, the genus Narcissus is one of the best known from the horticultural point of view. Due to their phytochemical interest, a chapter about Narcissus alkaloids has been prepared, following the usual general lines. The literature up to August 1996 has been covered. 1.1 Geographical distribution, botanical and taxonomical aspects The Amaryllidaceae are widely distributed. They are richly represented in the tropics and have pronounced centres in South-Africa and in Andean South America. Several genera have their centre in the Mediterranean, e.g. Narcissus. The majority of Narcissus species are found in the Iberian peninsula and North Africa, which substantiates the hypotheses that landmasses of Europe and Africa were once joined taking into consideration the shared distribution of many genera and species. Narcissus can adapt to the different habitats found in this area as well as the different soils, preferring slightly acidic conditions. The genus Narcissus, belonging to the tribe Narcisseae, consists of small to medium-sized herbs with linear leaves and a solid scape bearing an inflorescence of one to several (rarely numerous) flowers. Its spathal bracts are basally fused into a tube. The flowers are actinomorphic and have six equal tepals. Inside this, a corona is
324 generally present. The colours of the tepals usually vary from white to bright yellow and the corona fronn white or light yellow to orange or orange-red. Most are spring-flowering, but a few flower in autumn. The ovary is trilocular and the fruit is a capsule with globose to angular, dry and black seeds. The taxonomy and nomenclature of the genus Narcissus is complex because of its very varied wild populations, its suitability for hybridation and also for historical reasons because many descriptions of taxons have been based on garden specimens, several of which were probably of hybrid origen. The polymorphism of this genus has meant that its taxonomical classification has been constantly changing over the years. 1.2 The Amaryllidaceae family and their alkaloids There has been considerable taxonomical controversy over which genera belong to the Amaryllidaceae family. The revisions of Dahlgren's group (17, 18) have contributed to clarify this aspect. In another direction, one of the best tools for classification of several genera and species of this family has been the type of alkaloids that are exclusively synthezised by Amaryllidaceae species. Thus, e.g. the genus Behria in spite of having been classified as Amaryllidaceae (19), does not have Amaryllidaceae type alkaloids (20) and should therefore be included in another family. Furthermore, it is unusual to find other types of alkaloids in Amaryllidaceae species, but if present, they are always accompanied by true Amaryllidaceae alkaloids. Up to now, only three alkaloids isolated from this family do not belong to this specific type but to the mesembrane {=Sceletium) type -generally found in the family Aizoaceae-, which In spite of having the same aminoacids as precursors has a quite different biosynthesis -for more information about Sceletium alkaloids see Ref. (21, 22)-. These three compounds are amisine (83), mesembrenol (84), and mesembrenone (82) isolated from Hymenocallis arenicola (23), Crinum oliganthum (24) and Narcissus pallidulus (25), respectively (Figure 1). For this reason the Amaryllidaceae alkaloids have a high chemotaxonomical value. The general characteristics of the Amaryllidaceae alkaloids could be summarized by the following points: - a fundamental ring system composed of a Ce-Ci and a N-Ca-Ce building block, derived from L-Phenilalanine
(L-Phe) and L-Tyroslne (L-Tyr),
respectively. - they are moderately weak bases (pKa 6-9) - each alkaloid contains only one nitrogen atom which is secondary, tertiary or even quaternary, and the carbon content varies from 16 to 20 atoms.
325 NMep
OMe OMe
" ^ - ^
•N'
i
Me
Ri
82 R,+ R,= = 0
83
84 R,= OH, R2 = H Fig. 1. Sceletium alkaloids isolated from Amaryllidaceae species Most of the Amaryllidaceae alkaloids may be classified Into nine principal skeletally homogeneous subgroups although there are several other alkaloids with structures derived from these main molecular frameworks. Representative alkaloids from each of these classes include: norbelladine (85), lycorine (1), homolycorine (23), crinine (86), haemanthamine (49), narciclasine (64), tazettine (59), montanine (87) and galanthamine (70). With the aim of unifying the numbering system of the different types, Ghosal's proposal will be used in this chapter (6) (Figure 2).
2.
NARCISSUS
ALKALOIDS AND THEIR
OCCURRENCE
The alkaloids isolated from Narcissus species, classified in relation to the different ring types, are provided in Table 1, and the distribution of the different alkaloids is listed in Table 2.
326
CO
CM
u> 00
^
to
X
o yiW
^\. 1 (0
ly
"r^^
2 \cD
/ « A ^
^/
(C\ *^ / I
~\ °°
\
U--""'"'CM
(» )
\ / ^ o^ o \ /
g
CO
O Q.
a:^
•D
O (Q 0
^CO CO 0
o CO .•g CO
E <
c\i d) u.
327
TABLE 1a Narcissus alkaloid structures. Lycorine type.
Alkaloid name 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
lycorine poetaminine pseudolycorine 1 -0-acetylpseudolycorine 2-0-acetylpseudolycorine 9-0-methylpseudolycorine galanthine goleptine jonquilline caranine pluviine norpluviine 9-0-demethylpluviine 1 -O-acetyl-9-O-demethylpluviine 1,9-0-diacetyl-9-0-demethylpluviine
Ri
H Ac H Ac H H H H Ac H H H H Ac Ac
Structure R, R3 OH GH2 OH GH2 OH H OH H OAc H OH Me OMe Me OMe H 0 GH2 H CH2 H Me H Me H H H H H Ac
OAc 1
OMe I
HO..
X
..OH
AcO.
X
MeO,
MeO
16 narcissidine
17 nartazine
_3i Me Me Me Me Me Me
Me H Me Me Me
328
TABLE l a (continued) Narcissus alkaloid structures. Lycorine type.
r^"^ MeO,
MeO,
MeO
MeO
18 assoanine 19 oxoassoanine
R^z=R2=H Ri + R2 = 0
20 vasconine 21 tortuosine
MeO.
MeO
22 roserine
R^ = H R^ = OMe
329
TABLE 1b Narcissus alkaloid structures. Homolycorine type.
Structure 23 24 25 26 27 28 29 30 31 32 33 34 35
Alkaloid name homolycorine 8-0-demethylhomolycorine 8-0-demethyl-8-0-acetylhomolycorine 9-O-demethylhomolycorine masonine normasonine 9-0-demethyl-2a-hydroxyhomolycorine hippeastrine lycorenine O-methyllycorenine oduline 6-0-methyloduline 2a-hydroxy-6-0-methyloduline
Ri
R2
Me Me Me H
Me H Ac Me
R3
0 0 0 0 0 0 0 0
CH2 CH2
Me
H CH2
Me Me CH2 CH2 CH2
Me Me
OH OMe OH OMe OMe
Me-CHOH-CHg-COO, OAc
MeO
36
dubiusine
A_
H H H H H
R5
H H H H H H OH OH H H H H OH
Re Me Me Me Me Me H Me Me Me Me Me Me Me
330
TABLE 1b (continued) Narcissus alkaloid structures. Homolycorine type.
MeO. OCOEt
37
8-0-demethylhomolycorine-A/-oxide
38
poetinatine
TABLE 1c Narcissus alkaloid structures. Haemanthamine type.
- R 7
Structure Alkaloid name 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
vittatine maritidine 8-O-demethylmaritldine 9-O-demethylmaritidine 0-methylmaritidine papyramine 6-epipapyramine O-methyl-6-epipapyramine 6a-hydroxy-3-0-methylepimaritidine 6p-hydroxy-3-0-methylepimaritidine haemanthamine 11-O-acetylhaemanthamine haemanthidine 6-epihaemanthidine crinamlne narcidine
Ri
OH OH OH OH OMe OMe OMe OMe H H OMe OMe OMe OMe H OMe
R, H H H H H H H H OMe OMe H H H H OMe H
R4
~^3
CH2
Me Me H Me Me Me Me Me Me
Me H Me Me Me Me Me Me Me
CH2 GH2 CH2 CH2 GH2
Me
H
1
~W^ Re H H H H H H OH OMe H OH H H H OH H H
H H H H H OH H H OH H H H OH H H H
R7
H H H H H H H H H H OH OAc OH OH OH OH
331 TABLE 1c (continued) Narcissus alkaloid structures. Haemanthamine and Crinine types.
.OMe --R4 — R.
55
cantabricine R^ = H, Rg = Me, R3 = H, R4 = OAc, R5 = H
57 6a-hydroxybuphanisine 58 6p-hydroxybuphanisine
56
narcimarkine R^ + Rg = CHg, R3 = OMe, R4 = H, R^= 0CH2CH(0H)Et
R^ = H, Rg = OH R^ = OH, Rg = H
TABLE 1d Narcissus alkaloid structures. Tazettine type. OMe
NMe
NMe
OH 59 60
tazettine criwelline
R^ = OMe, Rg = H R^ = H, Rg = OMe
61
pretazettine
63
obesine
OMe
NMe
62
3-epimacronine
332
TABLE 1e Narcissus alkaloid structures. Narciclasine and Montanine types.
OH
r i ^ ^ ^
O
OH
64
OH
narciclasine
65
r^===^
66 trisphaeridine
O
narciprinnlne
r^^^=^
67
bicolorine
OH
r ^ ^
<
^^Ij^^^L
NHMe OH
68
ismine
69
pancracine
333
TABLE I f Narcissus alkaloid structures. Galanthamine type.
MeO
70 71 72 73 74 75 76 77
Alkaloid name galanthamine epigalanthamine 0-acetylgalanthamine norgalanthamine epinorgalanthamine A/-formylnorgalanthamine narcisine narwedine
Structure R, H OH H H OH H H
R, OH H OAc OH H OH OH 0
R3
Me Me Me H H OHO Ac Me
MeO.
Structure Alkaloid name 78 lycoramine 79 norlycoramine 80 epinorlycoramine
Ri
Rg
R3
OH OH H
H H OH
Me H H
334
TABLE 1g Narcissus alkaloid structures. Miscellaneous.
OMe
OMe
81
pallidiflorine (heterodimer)
OMe OMe
k^ 1 Me
82 mesembrenone (Sceletium type)
335 TABLE 2 Occurrence of Narcissus alkaloids. Alkaloid
Wild species / cultivars
Section
References
18 assoanine
A^. assoanus Leon-Duf. A^. jacetanus Fdez. Casas N. pseudonarcissus L. cv. King Alfred
JQ PN
(26) (27) (28)
19 oxoassoanine
A^. assoanus L6on-Duf. A^. jacetanus Fdez. Casas
JQ PN
(26) (27)
67 bicolorine
A^. bicolor L. A^. obesus Salisb.
PN BC
(29) (30)
57 6a-hydroxybuphanisine
A^. cantabricus DC.
BC
(31)
58 6(3-hy(lroxybuphanisine
A^. cantabricus DC.
BC
(31)
55 cantabricine
A'; cantabricus DC.
BC
(31)
10 caranine
N. cv. Livia
53 crinamine
A^. bujei (Fdez. Casas) Fdez.Casas N. cantabricus DC. A^. cv. Salome
PN BC
(33) (31) (34)
60 criwelline
A^. tazetta L.
TZ
(35)
36 dubiusine
N. dubius Gouan A'; tortifolius Fdez. Casas
DB DB
(36) (37)
70 galanthamine
N. confusus Pugsley A^. eugeniae Fdez. Casas N. X gracilis Sabine A^. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill, cv Flower Record N. X incomparabilis Mill, cv Fortune A^. X incomparabilis Mill, cv Helios N. X incomparabilis Mill, cv John Evelyn A^. X incomparabilis Mill, cv Marion Cran A^. X incomparabilis Mill, cv Nova scotia A^. X incomparabilis Mill, cv Pluvius A^. X incomparabilis Mill, cv Suda N. jonquilla L. A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A^. kristalli N. lobularis Hort. A^. nivalis Graells A^. obesus Salisb. A^. X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A'^. poeticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne
PN PN JC
(38) (39) (40) (32) (32) (32,41) (32) (32) (32) (32) (32, 42) (32) (43) (40,44, 45) (40) (46) (32) (47) (30) (40) (48) (49, 50) (51,52) (49) (32)
(32)
JQ
PN BC BC JN TZ NC NC
336 TABLE 2 (continued) Section
Alkaloid
Wild species / cultivars
70 galanthamine (cont.)
A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Wrestler TZ N. tazetta L. A^. tazetta L. var. chinensis Roem. TZ A'^ tazetta L. cv. Geranium A^. tortifolius Fdez. Casas DB A': triandrus L. cv. Tresamble A^. cv. Inglescombe A^. cv. Texas A^. cv. Twink
(49) (53, 54) (32, 42) (32) (32) (32) (28, 32, 42, 55) (32, 42) (32) (32) (32) (32) (32, 42) (32) (35, 49 56) (57) (49) (37) (40) (32) (32) (32, 42)
72 O-acetylgalanthamine
A^. pseudonarcissus L. cv. Carlton
(58)
71 epigalanthamine
A^. tazetta L. var. chinensis Roem.
TZ
(57, 59)
73 norgalanthamine
A^. leonensis Pugsley A^. nivalis Graells A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Rockery Beauty A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A'', pseudonarcissus L. cv. Victoria A^. cv. Salome
PN BC
(60) (47) (53, 54) (32, 42) (28, 32, 42) (32, 42) (32) (32) (32) (32, 42) (32) (34)
74 epinorgalanthamine
A^. leonensis Pugsley
PN
(60)
75 A^-formylnorgalanthamine
A^' , confusus Pugsley
PN
(38)
7 galanthine
A^. cyclamineus DC. cv. Beryl N. cyclamineus DC. cv. Cairhays N. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Flower Record. A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^. X incomparabilis Mill. cv. Marion Cran A'^. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti 1A^' , X incomparabilis Mill. cv. Suda
References
(40) (40) (32) (32,42) (32) (32) (32) (32) (32) (32, 42) (32) (32)
337
TABLE 2 (continued) Alkaloid 7 galanthine (cont.)
8 goleptine 49 haemanthamine
Wild species / cultivars A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A^. panizzianus Pari. N. poeticus L. N. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A'^. pseudonarcissus L. cv. Imperator A'^, pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage N. pseudonarcissus L. cv. Music Hall A'^, pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors N. pseudonarcissus L. cv. Rockery Beauty A^. pseudonarcissus L. cv. Romaine A'^, pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler A^. tazetta L. A^. tazetta L. cv. Scarlet Gem N. cv. Insulinde A'^. cv. Livia A^. cv. Twink
Section
TZ NC NC
TZ
(32) (45) (61) (49, 50, 62) (51,52) (49) (49) (32, 42) (32) (32) (32) (28, 32,42, 62) (32) (42) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (49) (32) (32) (32, 42) (63, 64)
A^. jonquilla L. cv.Golden Sceptre A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A'^ canaliculatus Guss A^. confusus Pugsley A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Flower Record A^. X incomparabilis Mill. cv. Fortune A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^. X incomparabilis Mill. cv. Marion Cran A^. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A'^, X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Suda A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A^. lobularis Hort. A^. obesus Salisb. A^. pallidiflorus Pugsley A^. poeticus L. var. ornatus Hort. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A', pseudonarcissus L. cv. Early Glory
References
PN PN TZ PN
PN BC PN NC PN
(65) (33) (49) (38) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (32) (40, 44, 45) (32) (30) (66) (49,51) (67) (53, 54) (32, 42) (32)
338 TABLE 2 (continued) Alkaloid
Wild species / cultivars
49 haemanthamine (cont.)
A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A'^ pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Rockery Beauty N. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler TZ A'^, tazetta L. A^. tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection A^. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee N. tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem A^. tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames A'^. triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe A^. cv. Insulinde N. cv. Livia A^. cv. Texas A^. cv. Twink
50 11-O-acetylhaemanthamine
A^. bujei (Fdez. Casas) Fdez. Casas
PN
(33)
51 haemanthidine
A^. A^. A^. A^.
asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem.
PN
(65) (40) (46) (57)
A^. A^. A^. A^.
asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem.
PN
52 6-epihaemanthidine
30 hippeastrine
A'^ X incomparabilis Mill. cv. Fortune A^. jonquilla L. cv. Golden Sceptre N. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. King Alfred A^. tazetta L. A^. tazetta L. cv. Early Perfection 1N. cv. Salome
Section
TZ TZ
TZ TZ
JN
TZ
References (32) (32) (28, 32, 42, 55) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (35, 49, 56) (49) (49) (49) (49) (49) (49) (49) (49) (40) (40) (40) (32) (32) (32) (32, 68) (32,42)
(65) (40) (46) (57) (32) (40, 44) (40) (53) (55) (35) (49) (34)
339 TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
References
23 homolycorine
N. bujei (Fdez. Casas) Fdez. Casas N. confusus Pugsley N. cyclamineus DC. cv. February Gold N. eugeniae Fdez. Casas N. X incomparabilis Mill. cv. Helios A^. jonquilla L. cv. Golden Sceptre N. munozii-garmendiae Fdez. Casas N. X odorus L. var. rugulosus N. pallidiflorus Pugsley N. panizzianus Pari. N. papyraceus Ker. Gawl. N. poeticus L. N. poeticus L. var. ornatus Hort. N. poeticus L. cv. Daphne N. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. N. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Grand Maitre N. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Van Sion A^. radinganorum Fdez. Casas A'^ tazetta L. N. tazetta L. var. chinensis Roem. N. tazetta L. cv. Cragford N. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A': tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes A^. tortifolius Fdez. Casas A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas N. cv. Inglescombe
PN PN
(33) (69) (40) (39) (32) (44) (70) (40) (66) (61) (71,72) (49) (49,51,73) (32) (67) (74) (53) (32) (32) (28, 55, 62) (32, 42) (75) (76-78) (57) (49) (49) (49) (49) (49) (49) (49) (49) (37) (40) (79) (32)
PN
PN JN PN TZ TZ NC NC PN PN
PN TZ TZ
DB PN
A^. bujei (Fdez. Casas) Fdez. Casas N. pallidiflorus Pugsley A^. papyraceus Ker. Gawl. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. King Alfred A^. radinganorum Fdez. Casas A^. tazetta L. A^. tortifolius Fdez. Casas
PN PN TZ PN PN TZ DB
(33) (66) (71,72) (67) (55) (75) (77, 80) (37)
37 8-O-demethylhomolycorine-A^-oxide
A^. papyraceus Ker. Gawl.
TZ
(71,72)
25 8-0-demethyl-8-0-acetylhomolycorine
N. vasconicus Fdez. Casas
PN
(79)
26 9-O-demethylhomolycorine
A^. bicolor L. A^. confusus Pugsley
PN PN
(29) (69)
24 8-O-demethylhomolycorine
340
TABLE 2 (continued) Alkaloid 29
Wild s p e c i e s / cultivars
9-0-demethyl-2a-hydroxy- A^. dubius Gouan A^. tortifolius Fdez. Casas homolycorine
68 ismine
9 jonquilline 78 lycoramine
A^. asturiensis (Jordan) Pugsley N. bicolor L. N. obesus Salisb. A^. pallidiflorus Pugsley
Section
References
DB DB
(81) (37)
PN PN BC PN
(65) (29) (30) (66) (44)
A^. jonquilla L. cv. Golden Sceptre A^. cyclamineus DC. cv. February Gold A^. jonquilla L. A^. papyraceus Ker. Gawl. A^. pseudonarcissus L. cv. Carlton N. tazetta L. var. chinensis Roem.
JQ TZ TZ
(40) (43) (48) (53, 54) (57) (32, 42) (32, 42) (32, 42) (32) (32) (32) (32,42) (32)
79 norlycoramine
A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus
80 epinorlycoramine
A^. leonensis Pugsley A^. pseudonarcissus L. cv. Carlton
PN
(60) (54)
31 lycorenine
A^. bujei (Fdez. Casas) Fdez. Casas A^. cyclamineus DC. cv. February Gold A^. cyclamineus DC. cv. Peeping Tom A^. eugeniae Fdez. Casas A'^, X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. Suda A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A'^ munozii-garmendiae Fdez, Casas A^. poeticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Unsurpassable N. pseudonarcissus L. cv. Van Sion A^. tazetta L. var. chinensis Roem. A'^, triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe
PN
(33) (40) (40) (39, 82) (32) (32) (44) (40) (70) (62) (49) (49) (32) (49) (53, 54) (32, 42) (32) (28, 32, 42, 55, 62) (32) (32) (32, 42) (57) (40) (40) (32)
32
O-methyllycorenine
L. cv. Covent Garden L. cv. King Alfred L. cv. Magnificience L. cv. Rembrandt L. cv. Rockery Beauty L. cv. Spring Glory L. cv. Van Sion L. cv. Victoria
A^. bujei (Fdez. Casas) Fdez. Casas A^. munozii-garmendiae Fdez. Casas
PN
PN NC NC
TZ
PN PN
(33) (70)
341 TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
32 0-methyllycorenine (cont.) N. pseudonarcissus L. cv. Carlton 1 lycorine
A^. cyclamineus DC. cv. Beryl N.folli N. X gracilis Sabine A^. X incomparabilis Mill. cv. Deanna Durbin N. X incomparabilis Mill. cv. Flower Record N. X incomparabilis Mill. cv. John Evelyn N. X incomparabilis Mill. cv. Marion Cran N. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Toronto A^. jacetanus Fdez. Casas A^. jonquilla L. cv. Trevithian A^. kristalli N. leonensis Pugsley A^. X odor us L. var. rugulosus N. papyraceus Ker. Gawl. A^. posticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon N. pseudonarcissus L. A'^ pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A'^, pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A^. pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A^. tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem A^. tazetta L. cv. St. Agnes A^. tortuosus Haworth A^. triandrus L. cv. Silver Chames A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas A^. cv. Inglescombe A^. cv. Insulinde A^. cv. Irene Copeland
References (53, 54)
JC
PN PN JN TZ NC NC
PN
TZ TZ
PN
PN
(40) (46) (40) (32, 42) (32) (32) (32) (32) (32, 42) (32) (32) (27) (40) (46) (60) (40) (48,71,72) (49, 50, 83) (49,51,52) (49) (32) (49) (84) (32, 42) (32) (32) (32) (32, 42) (32, 42) (32) (32) (32) (32) (32) (32,42) (32) (35, 46, 49, 56, 7678) (57) (49) (49) (49) (49) (49) (49) (49) (49) (85) (40) (40) (79) (32) (32) (32)
342
TABLE 2 (continued) Alkaloid 1 lycorine (cont.)
Wild species / cultivars
Section
References (32) (32) (32, 42)
A^. cv. Livia N. cv. Texas A^. cv. Twink
62 3-epimacronine
A^. asturiensis (Jordan) Pugsley A^. bicolor L. A^. obesus Salisb.
PN FN BC
(65) (29) (30)
40 maritidine
N. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ
(48) (57)
41 8-O-demethylmaritidine
A^' , primigenius (Lainz) Fdez. Casas 8L Lainz
PN
(67)
42 9-0-demethylmaritidine
A'^. radinganorum Fdez. Casas
PN
(75)
43 O-methylmaritidine
A^. papyraceus Ker. Gawl. A^. tazetta L. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(71,72) (77) (57)
47 6a-hydroxy3 - 0-methy lepimaritidine
A^. tazetta L. var. chinensis Roem.
TZ
(57)
48 6p-hydroxy3 - O-methy lepimaritidine
A^. tazetta L. var. chinensis Roem.
TZ
(57)
27 masonine
A'^ bujei (Fdez. Casas) Fdez. Casas A^. jonquilla L. cv. Golden Sceptre A'^, pseudonarcissus L. A^. pseudonarcissus L. cv. Carlton A^. tazetta L.
PN
(33) (44) (74) (53, 54) (35)
PN TZ
28 normasonine
A^. pseudonarcissus L. cv. Carlton
82 mesembrenone
A^. pallidulus Graells
CM
(25)
64 narciclasine
A^. canaliculatus Guss var. tipica N. cyclamineus DC. var. tipica N. X incomparabilis Mill. cv. Carabinieri A^. X incomparabilis Mill. cv. Helios A*". X incomparabilis Mill. cv. Mercato A^. X incomparabilis Mill. cv. Orange Bruid A'^. X incomparabilis Mill. cv. Mrs. R. O. Backhouse A^. X incomparabilis Mill. cv. Scarlet Elegance A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Tunis A^. X incomparabilis Mill. cv. Walt Disney A^. jonquilla L. A^. jonquilla L. cv. Trevithian A^. X odorus L. var. rugulosus N. poeticus L. cv. Actaea A^. poeticus L. cv. Cheerfulness A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Flower Carpet A^. pseudonarcissus L. cv. Golden Harvest IA^. pseudonarcissus L. cv. King Alfred
TZ CM
(86) (86) (86) (86, 87) (86) (86) (86)
(53, 54)
JQ JN
(86) (86, 87) (86) (86) (43) (86) (86) (86) (86) (86) (86) (86) (62, 86, 87)
343
TABLE 2 (continued) Alkaloid
Wild species / cultivars
64 narciclasine (cont.)
A^. pseudonarcissus L. cv. Mount Hood A^. pseudonarcissus L. cv. President Lebrum A^. pseudonarcissus L. cv. Rembrandt N. serotinus Lofl. ex L. var. tipica N. tazetta L. var. tipica N. tazetta L. cv. Geranium A^. triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Celebrity A^. cv. Clamor A^. cv. Texas A^. cv. Totus Albus N. cv. Verger
54 narcidine
A^. pseudonarcissus L. cv. King Alfred
56 narcimarkine
A^. poeticus L.
65 narciprimine
Narcissus sp
76 narcisine
N. tazetta L.
16 narcissidine
N. cyclamineus DC. cv. Beryl A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. poeticus L. N. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Rockery Beauty A^. tazetta L. A^. tazetta L. cv. Geranium A^. tazetta L. cv. L'innocence
Section
ST TZ
References (86) (86) (86) (86) (86-88) (88) (86, 87) (86, 87) (86) (86) (86) (86) (86) (55)
NC
(50, 89) (87)
TZ
NC
TZ
(56) (40) (32, 42) (32, 42) (32) (50, 62, 83) (49) (49) (55) (32) (49) (49) (49)
17 nartazine
N. poeticus L. N. tazetta L.
NC TZ
(49) (35, 49)
77 narwedine
A^. cyclamineus DC. N. kristalli N. pseudonarcissus L. cv. Carlton N. tazetta L. N. cv. Irene Copeland A^. cv. Texas
CM
(90) (46) (53, 54) (35) (32) (32, 91)
63 obesine
A^. obesus Salisb.
BC
33 oduline
A^. X incomparabilis Mill. cv. Fortune A^. jonquilla L. cv. Golden Sceptre A^. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton
34 6-(9-methyloduline
A^. bujei (Fdez. Casas) Fdez. Casas N. pseudonarcissus L. cv. Carlton
TZ
JN FN
(30) (32) (40, 44) (40) (53, 54) (33) (53, 54)
344
TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
References
35 2a-hydroxy6-0-methyloduline
A^. cv. Salome
81 pallidiflorine
N. pallidiflorus Pugsley
PN
(66)
69 pancracine
A'', poeticus L.
NC
(92)
44 papyramine
A^. panizzianus Pari. A^. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(61) (48,71,72) (57)
45 6-epipapyramine
A^. panizzianus Pari. A^. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(61) (48,71,72) (57)
46 0-methyl6-epipapyramine
A^. papyraceus Ker. Gawl.
TZ
(71,72)
11 pluviine
A^. cyclamineus DC. cv. Cairhays A^. cyclamineus DC. cv. Peeping Tom A^. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deamia Durbin A^. X incomparabilis Mill. cv. Flower Record A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^' , X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Suda A^. poeticus L. NC A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Emst H. Krelage A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler A^. tazetta L. cv. Early Perfection TZ A^. tazetta L. var. chinensis Roem. A^. cv. Inglescombe A^. cv. Insulinde A^. cv. Livia A^. cv. Texas A^. cv. Twink
(40) (40) (32) (32, 42) (32) (32) (32) (32) (32) (32) (62) (32, 42) (32) (42, 62) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (57) (32) (32) (32) (32) (32, 42)
13 9-O-demethylpluviine
A^. pseudonarcissus L. cv. Carlton
(54, 58)
14 1-O-acetyl9-O-demethylpluviine
A^. pseudonarcissus L. cv. Carlton
(54, 58)
(34)
345
TABLE 2 (continued) Alkaloid
Wild species / cultivars
15
N. pseudonarcissus L. cv. Carlton
(58)
A'^ cv. Texas
(93)
l,9-(9-diacetyl9-O-demethylpluviine
12 norpluviine
Section
References
A^. poeticus L. var. ornatus. Hort.
NC
(51)
38 poetinatine
A^. poeticus L. var. ornatus. Hort.
NC
(52)
61 pretazettine
A^. bicolor L. A^. confusus Pugsley A^. obesus Salisb. A'^. pallidiflorus Pugsley A^. panizzianus Pari. A^. tazetta L. A^. tazetta L. var. chinensis Roem.
PN PN BC PN TZ TZ TZ
(29) (38) (30) (66) (61) (56, 76, 77) (57)
3 pseudolycorine
A^. assoanus Leon-Duf. A^. dubius Gouan A^. jacetanus Fdez. Casas A^. papyraceus Ker. Gawl. A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. cv. Salome
JQ DB PN TZ TZ TZ
(94) (81) (27) (48,71,72) (56, 76, 77) (57, 95) (34)
4
1-O-acetylpseudolycorine
A^. assoanus Leon-Duf.
JQ
(94)
5 2-0-acetylpseudolycorine
A^. assoanus Leon-Duf.
JQ
(94)
6
A^. nivalis Graells A^. poeticus L. A^. pseudonarcissus L. cv. King Alfred
BC NC
(47) (62) (28, 62)
22 roserine
A^. pallidulus Graells
CM
(96)
59 tazettine
A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A^. canaliculatus Guss A^. cantabricus DC. A'^. cyclamineus DC. cv. Peeping Tom N.folli N. X gracilis Sabine A^. jonquilla L. cv. Golden Sceptre N. jonquilla L. cv. Trevithian A^. kristalli N. X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A^. poeticus L. var. ornatus Hort. A^. pseudonarcissus L cv. Grand Maitre N. pseudonarcissus L. cv. Van Sion A^. tazetta L.
PN PN TZ BC
A^. tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A^. tazetta L. cv. Early Perfection
TZ
(65) (33) (49) (31) (40) (46) (40) (40, 44, 45) (40) (46) (40) (48) (51) (32) (32) (35, 46, 56, 77, 78, 97, 98) (57, 95) (49) (49)
2 poetaminine
9-O-methylpseudolycorine
JC
JN TZ NC
TZ
346
TABLE 2 (continued) Alkaloid
Wild species / cultlvars
59 tazettine (cont.)
N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A^. tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames
21 tortuosine
A^. tortuosus Haworth A': cv. Salome
PN
(85) (34)
66 trisphaeridine
A'^ asturiensis (Jordan) Pugsley
FN
(65)
20 vasconine
A^. bicolor L, A^. vasconicus Fdez. Casas A^. cv. Salome
PN PN
(29) (79) (34)
39 vittatine
A^. cantabricus DC. A^. pseudonarcissus L. cv. Carlton
BC
(31) (53, 54)
Section
References (49) (49) (49) (49) (49) (49) (40)
The taxonomical aspects are based on the works of J. Fernandez Casas (99-105) and other authors (106-110) for wild Narcissus species and hybrids, and those of Jefferson-Brown (111) and Boit and Piozzi (32, 40, 42, 49, 86) for Narcissus cultivars (cv.). Key to sections: BC = Bulbocodii DC; CM = Cyclaminei DC; DB = Dubii Fdez. Casas; JC = x Joncissus Fdez. Casas ( Jonquillae DC x Narcissus L.); JN = x Jonissi Fdez. Casas {Jonquillae DC x Pseudonarcissi DC); JQ = Jonquillae DC; NC = Narcissus L.; PN = Pseudonarcissii DC; ST = Serotini Pari.; and TZ = Tazettae DC
3.
BIOSYNTHETIC
PATHWAYS
The work on the biosynthesis of Amaryllidaceae alkaloids reached a peak in the period 1960-1976 with a great number of studies related with this subject. However, since then, little new work has been produced apart from the isolation of compounds predicted as biosynthetic intermediaries of a certain pathway or, more recently, a new biosynthetic proposal to obtain galanthamine (70), which differs from the initial one. Although L-Phe and L-Tyr are closely related in chemical structure, they are not interchangeable in plants. In the Amaryllidaceae alkaloids, L-Phe serves as a primary precursor of the Ce-C^ fragment, corresponding to ring A and the benzylic position (C-6), and L-Tyr is the precursor of ring C, the two-carbon side chain (C-11 and C-12) and nitrogen, C6-C2-N. The conversion of L-Phe to the Ce-Ci unit requires the loss of two carbon atoms from the side chain as well as the introduction of at least two oxygenated
347
substituents into the aromatic ring, wiiich is performed via cinnamic acids. Tiie presence of the enzyme PAL has been demonstrated in Amaryllidaceae plants (112) and the elimination of ammonia mediated by this enzyme is known to occur in an antiperiplanar manner to give frans-cinnamic acid, with loss of the B-pro-S hydrogen (113). Thus, it may be expected that L-Phe would be incorporated into Amaryllidaceae alkaloids with retention of the B-pro-R hydrogen. However, feeding experiments in Narcissus pseudonarcissus cv. King Alfred showed that tritium originally present at C-3 of L-Phe, whatever the configuration, was lost in the formation of several haemanthamine and homolycorine type alkaloids, which led to the conclusion that fragmentation of the cinnamic acids involves oxidation of C-B to ketone or acid level, the final product being protocatechuic aldehyde or its derivatives (Fig. 3). On the other hand, L-Tyr is degraded no further than tyramine before incorporation into the Amaryllidaceae alkaloids. Thus, tyramine and protocatechuic aldehyde -or derivatives of the latter- are logical components for the biosynthesis of the precursor norbelladine (85). This reaction occupies a pivotal position since it represents the entry of primary metabolites into a secundary metabolic pathway. The junction of the amine and the aldehyde results in a Schiff's base, two of which have been isolated up to now: craugsodine (114) and isocraugsodine (115). The existence of Schiff's bases in nature as well as their easy conversion into the different ring-systems of the Amaryllidaceae alkaloids allow the presumption that the initial postulate about this biosynthetic pathway was correct. Barton and Cohen (116) proposed that norbelladine (85) or related compounds could undergo oxidative coupling of phenols in Amaryllidaceae plants, once ring A had been suitably protected by methylation, resulting in the different skeletons of the Amaryllidaceae alkaloids (Fig. 4).
a.- Lycorine and IHomolycorine types. The pyrrolo[de]phenanthridine alkaloids (lycorine type) and the 2-benzopirano[3,4-g]indole alkaloids (homolycorine type) both originate from an orttio-para' phenoloxidative coupling (Fig. 5). The biological conversion of cinnamic acid via hydroxylated cinnamic acids into the Ce-Ci unit of norpluviine (12) has been used in a study of hydroxylation mechanisms In higher plants (117). When [3-3H, P-^^Q] cinnamic acid was fed to Narcissus pseudonarcissus cv. Texas a tritium retention in norpluviine (12) of 28% was observed. This is very near a predicted value of 25%, resulting from para-hydroxylation with
348
L-Phe PAL
COOH
Tyr-decarboxylase
frans-cinnamic add HO
COOH
para-coumaric acid: R= H caffeic acid: R= OH
HO^
HO"
^
^CH
protocatechuic aldehyde HO
Sciiiff's base (isomeric structures in solution) OH
HO
HO
rL3 85
Fig. 3. Biosynthetic pathway to norbelladine (85).
00
CU
CO
9o
DC Z
\
(01
i (C
CO
c
(0
£
0 C
o
i
CO
w. 0 ^C y— o 0 o C o o £ o>. SIo
349
0) •g
CO
CO
CD CO CD
•D
CO
E <
O
•Q.
o c 0
CD
c >
CD
CO
•g
x O O)
350
t
o^
.o
F z (D
IE
f (D
2
z
-o
o0)
\
^
\=o ) ^~ \ o
f
^ i
•
-o \
V--0
2
/
CO CM
CO
"Q.
o o "ctj
9o o c
0}
E o C
M—
0 0 O O
if)
Q.
^_
•D
CO
"o lO
351 hydrogen migration and retention, where half the tritium would be lost In the first hydroxylation and half the remainder in the second. In the conversion of 0-methylnorbelladine (88) into lycorine (1), the labelling position [3-3H] on the aromatic ring of L-Tyr afterwards appears at C-2 of norpluviine (12), which is formed as an intermediate, the configuration of the tritium apparently being p (93). This tritium is retained in subsequently formed lycorine (1), which means that hydroxylation at C-2 proceeds with an inversion of configuration (118) by a mechanism involving an epoxide, with ring opening followed by allylic rearrangement of the resulting alcohol (Fig. 6). Supporting evidence comes from the incorporation of [2p-^H]caranine (10) into lycorine (1) in Zephyranthes Candida (119). However, an hydroxylation of caranine (10) in Clivia miniata occuring with retention of configuration was also observed (120). Further, [2a-^H; ll-^'^Clcaranine (10) was incorporated into lycorine (1) with high retention of tritium at C-2, indicating that no 2-oxo-compound can be implicated as an intermediate. The conversion of the 0-methoxyphenol to the methylenedloxy group may occur late in the biosynthetic pathway. Tritiated norpluviine (12) is converted to tritiated lycorine (1) by Narcissus x incomparabilis cv. Deanna Durbin, which not only demonstrates the previously mentioned conversion but also indicates that the C-2 hydroxyl group of lycorine (1) is derived by allylic oxidation of either norpluviine (12) or caranine (10) (121). Regarding the conversion of [23-^H, S-OMe-^'^Clpluviine (11) into galanthine (7), in Narcissus pseudonarcissus cv. King Alfred, the retention of 79% of the tritium label confirms that hydroxylation of C-2 may occur with inversion of configuration (62). It was considered (122) that another analogous epoxide (89) could give narcissidine (16) in the way shown by loss of the pro-S hydrogen from C-11, galanthine (7) being a suitable substrate for epoxidation. Labelled [a-^'^C, p-^H]-0-methylnorbelladine (88), when fed to Narcissus x incomparabilis cv. Sempre Avanti afforded galanthine (7) (98% of tritium retention) and narcissidine (16) (46% tritium retention). Loss of hydrogen from C-11 of galanthine (7) was therefore stereospecific.
Recently,
Kihara et al. (123) have isolated a new alkaloid, incartine (89), from flowers of Lycoris incarnata, which could be considered to be the biosynthetic intermediate of this pathway (Fig. 7). The biological conversion of protocatechuic aldehyde into lycorenine (31), which proceeds via 0-methylnorbelladine (88) and norpluviine (12), first involves a reduction of
352
i
CO
c o
O O
0 SI
o c g
I
0
CO,
•g
x o
0
Q.
c
0 CO CO
CO
CD
C
I 0
o o
'iL-
o CO
0
"co
c CO
g CD
CO
Li.
0 > c o O
c g "co
D)
CO
c _cg
c
0
\—
1 " \
'££ CO c
y
o
>
i. d
o
353
the aldehyde carbonyl, and afterwards, in the generation of lycorenine (31), oxidation of this same carbon atom. The absolute stereochemistry of these processes has been elucidated In subsequent experiments (124), and the results show that hydrogen addition and removal take place on the re-face of the molecules concerned (125), the hydrogen initially introduced being the one later removed (126). It is noteworthy that norpluvilne (12), unlike pluviine (11), is converted in Narcissus pseudonarcissus cv. King Alfred primarily to alkaloids of the homolycorine type. Benzylic oxidation of position 6 would afford (90), followed by ring opening to form an amino aldehyde and then a hemiacetal formation and methylation could provide lycorenine (31) (62),
and, on subsequent
oxidation, could give homolycorine (23) as can be seen in Fig. 8.
b. Crinine, Haemanthamine, Tazettine, Narciclasine and l\/lontanine types The alkaloids derived from 5,10b-ethanophenanthridine (crinine and haemanthamine types), 2-benzopyrano[3,4c]indole (tazettine type), phenanthridine
(narciclasine
type) and 5,11b-methanomorphanthridine (montanine type) originate from a para-para' oxidative phenolic coupling (Fig. 9). Results of experiments with labelled crinine (86), and less conclusively with oxovittatine, indicate that the two naturally occurring enantiomeric series, represented in Figure 9 by crinine (86) and vittatine (39), are not interconvertible in Nerine bowdenii (127). Incorporation of 0-methylnorbelladine (88), labelled in the methoxy carbon and also in positions [3,5-^H], into the alkaloid haemanthamine (49) was without loss of tritium, half of which was sited at C-2 of (49). Consideration of the possible mechanisms involved in relation to tritium retention led to the suggestion that the tritium which is expected at C-4 of (49) might not be stereospecific (128). The conversion of Omethylnorbelladine (88) into haemanthamine (49) involves loss of the pro-R hydrogen from the C-3 of the tyramine moiety, as well as a further entry of a hydroxyl group at this site (129). The subsequent benzylic oxidation results in an epimeric mixture (51/52) which even HPLC can not separate. The epimeric forms were proposed to be interconvertible
through
(91a).
The
biosynthetic
conversion
of
the
5,10b-
ethanophenanthridine alkaloids to the 2-benzopyrano[3,4-c]indole was demonstrated by feeding tritium-labeled alkaloids to Sprekeiia formosissima. It was shown that this plant converts haemanthamine (49) to haemanthidlne/ epihaemanthamine subsequently to tazettine (59) in an essentially irreversible manner
(51/52)
and
(130). This
transformation was considered to proceed through (91a) or the related alkoxide anion.
354
It
i
f
w c o
E
-o «
]o
•g
CO
CO
CD
Q. >^ •*-' CD _C 'i_
o o _>. o E o sz o
-I—«
0 13
c > o c:
CD
c g 'co
> C o O d)
CX)
LL
X CM
O
\
X o
//
.o
y} 2 X
o^
00
00
355
D) C •Q.
O O CO
E 2 U)
«+-
c
(0
T3 0 0 O O Q. (0 •g -^
O)
356 although this intermediate (91a) and Its rotational equivalent (91b) have never been detected by spectral methods (131) (Fig. 10). It has also been proved that the alkaloid narciclasine (64) proceeds from the pathway of the biosynthesis of crinine and haemanthamine type alkaloids and not through norpluviine (12) and lycorine (1) derivatives. In fact, in view of its structural affinity to both haemanthamine (49) and lycorine (1), narciclasine (64) could be derived by either pathway. When 0-methylnorbelladine (88) labelled in the methoxy carbon and in both protons of position 3 and 5 of the tyramine aromatic ring, was administered to Narcissus plants, all four alkaloids incorporated activity. The isotopic ratio [^H:^'^C] for norpluviine (12) and lycorine (1) was, as expected, 50% that of the precursor, because of its ortho-para' coupling. On the contrary, in haemanthamine (49) the ratio was unchanged. These results prove that the methoxy group of (88) is completely retained in the alkaloids mentioned, providing a satisfactory internal standard and also, the degree of tritium retention is a reliable guide to the direction of phenol coupling. Narciclasine (64) showed an isotopic ratio (75%) higher than that of lycorine or norpluviine (12) though lower than that of haemanthamine (49). However, the fact that more than 50% of tritium is retained suggests that 0-methylnorbelladine (88) is incorporated into narciclasine (64) via para-para' phenol oxidative coupling. O-methylnorbelladine (88) and vittatine (39) are implicated as intermediates in the biosynthesis of narciclasine (64) (132-134), and the loss of the ethane bridge from the latter could occur by a retro-Prins reaction on 11-hydroxyvittatine (92). Strong support for this pathway was obtained by labelling studies. 11-Hydroxyvittatine (92) has also been proposed as an intermediate in the biosynthesis of haemanthamine (49) and montanine (87)
(a 5,11b-methanomorphanthridine
alkaloid)
following the observed
specific
incorporation of vittatine (39) into the two alkaloids in Riiodophiala bifida (127) (Fig. 11). Fuganti and Mazza, (133, 134) concluded that in the late stages of narciclasine (64) biosynthesis, the two-carbon bridge is lost from the oxocrinine skeleton, passing through intermediates bearing a pseudoaxial hydroxy-group at C-3 position and further hydrogen removal from this position does not occur. Noroxomaritidine was also implicated in the biosynthesis of narciclasine (64) and further experiments (135) showed that it is also a precursor for ismine (68). The alkaloid ismine (68) has also been shown (136) to be a transformation product of the crinine-haemanthamine series. The precursor, oxocrinine labelled with tritium in the positions 2 and 4, was administered to Sprel
0 C (D N CO
CO
o 'co
c
CD
o
CO
CD
in
357
358
39
87
92
Fig. 11. Proposed biosynthetic pathways to haemanthamine (49) and montanine (87).
359 c. Galanthamine type. The alkaloids with a dibenzofuran nucleus (galanthamine type) are obtained from a para-ortho' phenyl oxidative coupling. Although norbelladine (85) was shown not to be a precursor of galanthamine (70) in Narcissus pseudonarcissus cv. King Alfred, an incorporation of this labelled compound has been obtained in Leucojum aestivum (128). The initial studies of this pathway suggested that the phenyl oxidative coupling does not proceed from 0-methylnorbelladine (88) but that the order of methylation of the precursors should be norbelladine (85) --> A/-methylnorbelladine -->A/,0-dimethylnorbelladine (93) to finally give galanthamine (70) (137), the conversion of (94) to narwedine (77) either being not reversible or, if so, enzymically controlled (128). The precursor N,0dimethylnorbelladine (93) was first Isolated in 1988 from Pancratium maritimum (138) a species that also contains galanthamine (70) (Fig. 12a). Chlidanthine (95), by analogy with the known conversion of codeine to morphine, might be expected to arise from galanthamine (70) by 0-demethylation. This was shown to be true when both galanthamine (70) and narwedine (77), with tritium labels, were incorporated into chlidanthine (95) (139). However, the most recent studies related to the biosynthesis of galanthamine (70) seem to contradict the evidence set forth here. Experiments carried out in cell suspension cultures of Leucojum vernum have shown that the methylation of the nitrogen atom occurs after the phenolic coupling and is brought about through an acetyl intermediate (140) (Fig. 12b).
360
c 0
N CO
c
•D
o o iu •D ©
o Q. o
0
o
CO
c E CO sz c
"co x: CO
c
+-•
CM
o in xi
361 4.
SPECTROSCOPY Only ^H NMR, ^^C NMR, and mass spectrometry, the three most important
spectroscopic methods for the Amaryllidaceae alkaloids, will be treated here. A list of names of the different Narcissus alkaloids, their physical and spectroscopic properties, as well as literature is given in Table 3. With respect to the spectroscopic results, the most recent data about the mentioned alkaloids are provided, even when isolation was made from species of genera other than Narcissus.
TABLE 3 Narcissus alkaloids data
Alkaloid
melting Molecular MW point °C Formula (Ref)
[a]D° (Ref.)
Additional data (Ref.)
18 assoanine
CnHnNO^
267
175-176° (141)
UV(26),IR(26),MS(26), ^H NMR (26), *^C NMR (26)
19 oxoassoanine
CnHisNOs
281
247-250° (26)
'H
261-263° (29)
'H
67 bicolorine
Ci5H,2N02
238
UV(26),IR(26),MS(26), NMR (26), ^'C NMR (26) IR (29), MS (29), NMR (29), '^C NMR (29)
57 6a-hydroxybuphanisine
C17H19NO4
301
[ah'' +37 128-130° MeOH; c 0.25 (31) (31)
UV(142),IR(142),MS(142), 'H NMR (142), '^C NMR (143)
58 6P-hydroxybuphanisine
C,7Hi9N04
301
128-130° [OC]D'" +37 (31) MeOH; c 0.25 (31)
UV (142), IR (142), MS (142), 'H NMR (142), ^^C NMR (143)
55 cantabricine
C,8H23N04
317
75-76° (31)
M D ' " -7.14 MeOH; c 0.52 (31)
[alo''-196.6 CHCI3; c 2.0 (145)
IR(31),MS(31), ^ H N M R ( 3 1 ) , *^CNMR(31)
UV (144), IR (144), MS (144), *H NMR (144), CD (146)
10 caranine
Ci6HnN03
271
176-178° (144)
53 crinamine
CnH,9N04
301
190-192° [a]D''+180 (147) CHCI3; c 0.55 (147)
UV (148), IR (147), MS (147), ^H NMR (148), ^^C NMR (148), CD (147), X-Ray (149)
60 criwelline
C18H21NO3
331
211-212° (150)
[a]D''+278 CHCl3;c0.21 (150)
UV (150), MS (151), ^H NMR (152), '^C NMR (152), CD (153)
36 dubiusine
C23H27NO8
445
226-228° (36)
UV(36),IR(36),MS(36), 'HNMR(36),''CNMR(36)
362 TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D° (Ref.)
Additional data (Ref.)
UV(38),IR(38),MS(38), 'H N M R (38), ''C NMR (154), CD(153),X-Ray(155)
70 galanthamine
C17H21NO3
287
124-126° (38)
[aC-115 EtOH;c0.5 (154)
72 0-acetylgalanthamine
C19H23NO4
329
129° (58)
MD' -61 MeOH;cl.3 (58)
71 epigalanthamine
C17H21NO3
287
199° (156)
[ah'' -327A EtOH;c0.27 (155)
UV(156),IR(155),MS(156), 'H NMR (155), CD (153)
73 norgalanthamine
Cl6H,9N03
273
156-158° [a]D''-74 (47) CHCI3; c 0.28 (157)
UV(158),IR(47),MS(47), *H NMR (47), '^C NMR (47), CD(159),X-Ray(160, 161)
74 epinorgalanthamine
C16H19N03
273
150-152° [a]D''-62 (60) CHCI3; c 0.73 (60)
IR (60), MS (60), ^H NMR (60),^^C NMR (60)
75 JV-formylnorgalanthamine
CnH,9N04
301
190-192° (38)
UV(38),IR(38),MS(38), 'H NMR (38),'^C NMR (38)
7 galanthine
C,8H23N04
317
160-162° [a]D''-94.7 (61) CHCI3; c 0.69 (162)
UV (162), MS (61), 'H NMR (61),'^C NMR (61)
8 goleptine
C,7H2,N04
303
49 haemanthamine
CnHi9N04
301
195-198° [a]D''+38.3 CHCI3; c 0.45 (38) (163)
50 11-O-acetylhaemanthamine
C19H21NO5
343
amorph. (33)
51 haemanthidine
C,7H,9N05
317
[a]o''-14 176-179° (167) CHCI3; c 0.28 (167)
UV(168),IR(169),MS(169), 'H NMR (164), '^C NMR (65), CD (153)
52 6-epihaemanthidine
C,7H.9N05
317
176-179° (167) CHCI3; c 0.28 (167)
UV(168),IR(169),MS(169), 'H NMR (164), ^^C NMR (65), CD (153)
30 hippeastrine
CnH^NOs
315
[a]D+138 212-213° (138) CHCI3; c 0.47 (138)
' H N M R ( 3 4 ) , *'CNMR(34),
23 homolycorine
C,8H2iN04
315
141° (64)
169-171° (69)
'H
IR(64)
[aL^^-99 CHCI3; c 0.2 (64)
[a]D''-9.1 MeOH; c 0.55 (33)
[a]D''+93.5 CHCl3;cl.2 (28)
UV (58), MS (58), NMR (58), •^C NMR (58)
UV(38),IR(38),MS(38), ^H NMR (164), *^C NMR (143), CD(165),X-Ray(166)
'H
IR (33), MS (33), NMR (33), ^^C NMR (33), CD (33)
UV(168),IR(34),MS(34), CD (170) UV(69),IR(69),MS(69), ^H NMR (69), *^C NMR (170), CD (170)
363 TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D°
Additional data (Ref.)
(Ref.)
24 8-0-demethylhomolycorine
C17H19NO4
301
138-140° (170)
[a]D''+89.6 CHCl3;c0.41 (171)
UV(172),IR(172),MS(75), ^H NMR (172), ^^C NMR (172), CD(172),X-Ray(173)
37 8-O-demethylhomolycorineA^-oxide
CnHi^NOs
317
153-154° (72)
M D ' ' +19 MeOH;c0.1 (72)
UV (72), IR (72), MS (72), *H NMR (72), *^C NMR (72)
25 8-O-demethyl8-O-acetylhomolycorine
C19H21NO5
343
186-188° (79)
[aJo'' +70.4 EtOH; c 0.54 (79)
IR (79), MS (79), ' H NMR (79),^^C NMR (79)
26 9-0-demethylhomolycorine
CnHi9N04
301
270-272° (69)
29 9-O-demethyl2a-hydroxyhomolycorine
CnHigNOs
317
272-275° (37)
68 ismine
CisHisNOs
257
98° (174)
CigHnNOs
327
188-190° (44)
9 jonquilline
UV(69),IR(69),MS(69), ^H NMR (69), *^C NMR (69)
[aJo +98.8 EtOH; c 0.52 (37)
IR (37), MS (37), ^HNMR(37),*^CNMR(37)
UV(174),IR(174),MS(174), *H NMR (174), " C NMR (65), X-Ray (65)
[aC-325
UV(44),IR(44)
CHCI3; c 0.5 (44)
78 lycoramine
C17H23NO3
289
120-121° (159)
[aJo'' -67.4 CHCI3; c 0.33 (159)
IR (159), MS (159), *H NMR (159),^^C NMR (159)
79 norlycoramine
C16H21NO3
275
123-124° (175)
[a]D''-39.1 CHCI3; c 0.95 (175)
IR (175), MS (175), ^H NMR (175),
80 epinorlycoramine
C,6H2,N03
275
[a]D''+79.1 CHCl3;c0.51 (60)
IR (60), MS (60), ' H NMR (60),"C NMR (60)
31 lycorenine
C18H23NO4
317
199-203° (176)
[alo''+172.4 CHCI3; c 0.7 (176)
UV (177), MS (178), *H NMR (82), *^C NMR (82), X-Ray (179)
32
C19H25NO4
331
125° (70)
[alo'"+164.1 CHCI3; c 0.53 (70)
IR (70), MS (70), ' H NMR (70),^^C NMR (70)
C,6Hi7N04
287
250° (148)
[ah'' -62 EtOH; c 0.1 (148)
UV(148),IR(148),MS(148), ^H NMR (148),'^C NMR (148), CD (153), X-Ray (180, 181)
C18H19NO5
329
126-128° (29)
[a]D^' +225.6 CHCl3;c0.15 (175)
IR (29), MS (29), ' H NMR (175),^^C NMR (29)
0-methyllycorenine
1 lycorine
62 3-epimacronine
364 TABLE 3 (continued) Alkaloid
40 maritidine
melting Molecular MW point °C (Ref.) Formula C,7H2,N03
287
[a]D° (Ref.)
250-252° [ah'' +26.8 (163) MeOH; c 0.78 (163) 139-141° (175)
[ah'' +28 EtOH;c0.53 (67)
Additional data (Ref.)
UV(48),IR(182),MS(163), 'HNMR(163),CD(183),
X-Ray(184)
41 8-(9-demethylmaritidine
C,6H,9N03
42 9-O-demethylmaritidine
C,6H,9N03
273
238-239° (75)
43 O-methylmaritidine
C,8H23N03
301
240-242° (72)
47 6a-hydroxy3-(9-methylepimaritidine
C18H23N04
317
[a]D''-10.2 CHCI3; c 0.45 (57)
UV(57),IR(57),MS(57), ' H NMR (57), CD (57)
48 6p-hydroxy3-0-methylepimaritidine
C18H23N04
317
[a]D''-10.2 CHCI3; c 0.45 (57)
UV (57), IR (57), MS (57), ' H NMR (57), CD (57)
27 masonine
C,7HnN04
299
180° (185)
[alo'' +55.6 CHCI3; c 0.5 (53)
UV(53),IR(53),MS(53), ^H NMR (53),^^C NMR (53), CD (170)
28 normasonine
C16H15N04
285
229° (picrate) (53)
[a]D''+9.1 CHCI3; c 0.4 (53)
'HNMR(53),^^CNMR(53)
273
82 mesembrenone
C,7H2iN03
287
177-180° (picrate) (25)
64 narciclasine
CuHnNOv
307
231-233° (88)
54 narcidine
C,7H2,N04
303
IR (175), MS (175), ' H N M R (164),^^C N M R
(67)
IR (75), MS (75), ' H NMR (75) W D ' ' +16 MeOH; c 0.1 (72) j
UV(72),IR(72),MS(72), ^H NMR (72),'^C NMR (72), CD (57)
UV(53),IR(53),MS(53),
IR (25), MS (25), ^H NMR (25), ^^C NMR (186)
[aJo'' +140 EtOH;c0.1 (88) M D +16 MeOH; c 0.11 (55)
UV (87), IR (87), MS (88), 'HNMR(88),^^CNMR(88),
X-Ray(187) UV(55),IR(55),MS(55), *HNMR(55)
56 narcimarkine
C2,H27N05
373
110° (50)
IR (50), MS (50),
65 narciprimine
C14H9N05
271
315-320° (188)
UV(87),IR(87),MS(188), ' H NMR (87)
76 narcisine
Ci8H2,N04
315
158-160° (56)
[aC-18 CHCl3;c0.5 (56)
UV(56),IR(56),MS(56), 'HNMR(56),'^CNMR(56)
365 TABLE 3 (continued) Molecular Formula
melting MW point °C (Ref.)
16 narcissidine
C18H23NO5
333
17 nartazine
C20H23NO6
77 narwedine
[a]D° (Ref.)
Additional data (Ref.)
203-205° (189)
[a]D''-28.3 CHCI3; c 0.32 (189)
UV (190), IR (191), MS (192), *H NMR (193), X-Ray (191)
373
185-186° (49)
[a]D''-120 CHCI3; c 0.25 (49)
IR(49)
CnHi9N03
285
189-190° (159)
MD''+112.2 CHCl3;c0.13 (159)
UV(156),IR(159),MS(159), *H NMR (159)
63 obesine
C,6HnN04
287
[ah'' -5.6 MeOH; c 0.69 (30)
MS (30),'H NMR (30), '^C NMR (30)
33 oduline
Ci7H,9N04
301
Alkaloid
165° (53)
[alo''+149.4 MeOH; c 3.0 (53)
UV(53),IR(53),MS(53), 'HNMR(53),*^CNMR(53)
34 6-0-methyloduline
C,8H2,N04
315
164° (picrate) (53)
[a]D''+148 MeOH; c 0.13 (53)
UV (53), IR (53), MS (53), *HNMR(53),'^CNMR(53)
35 2a-hydroxy6-O-methy loduline
Ci8H2,N05
331
245-248° (34)
[a]o''+91.1 CHCI3; c 0.34 (34)
IR (34), MS (34), ^H NMR (34),^^C NMR (34)
81 pallidiflorine
C34H40N2O7
588
69 pancracine
C,6Hi7N04
287
44 papyramine
C18H23N04
317
IR (66), MS (66), 'H NMR (66),'^C NMR (66) 272° (194)
MD^+74
MeOH; c 0.6 (194)
110-112° MeOH; c 0.25 (61) (72)
45 6-epipapyramine
C18H23N04
317
110-112° MeOH; c 0.25 (61) (72)
46 O-methyl6-epipapyramine
C19H25N04
331
amorph. (72)
[a]D''-31 MeOH; c 0.1 (72)
11 pluviine
C17H21N03
287
220-222° (93)
[a]D-165 CHCI3; c 0.35 (93)
13 9-O-demethylpluviine
C16H19N03
273
148° (58)
[a]D''+61 MeOH; c 2.4 I (58)
UV (194), MS (194),*H NMR (194), ^'C NMR (194), CD (194)
UV(72),IR(61),MS(61), 'HNMR(61),^^CNMR(61)
UV(72),IR(61),MS(61), ^HNMR(61),''CNMR(61)
UV(72),IR(72),MS(72), NMR (72), ''C NMR (72)
'H
UV (93)
UV (58), MS (58), ^H NMR (58),'^C NMR (58)
366
TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D° (Ref.)
Additional data (Ref.)
UV (58), MS (58), ^HNMR(58),'^CNMR(58)
14 1-O-acetyl9-O-demethylpluviine
C.8H21NO4
315
203° (58)
[ot]D''+38 MeOH;cl.O (58)
15 1,9-0-diacetyl9-O-demethylpluviine
C20H23NO5
357
147° (58)
[a]D''+8.3 MeOH;cl.l (58)
12 norpluviine
C,6H,9N03
273
[a]D-232 239-241° (93) MeOH; c 0.06 (93)
CisHipNOs
329
221-223° (196)
[a]D^VlOO EtOH; c 0.2 (196)
UV(196),IR(196)
38 poetinatine
C20H23NO6
373
212-213° (52)
[a]D''+50 CHCl3;c0.15 (52)
IR (52), MS (52), 'H NMR (52)
61 pretazettine
C,8H2,N05
331
227-229° (175)
[aJo^'+189.9 CHCI3; c 0.64 (197)
UV(198),IR(198),MS(198), 'H NMR (198), CD (199)
3 pseudolycorine
C,6H,9N04
289
[a]D''-60 237-240° (94) MeOH; c 0.04 (72)
UV (94), IR (94), MS (94), 'H NMR (94),'^C NMR (94)
4 1-O-acetylpseudolycorine
C,8H2iN05
331
248-250° (94)
5 2-O-acetylpseudolycorine
C,8H2,N05
331
168-170° (94)
6 9-O-methylpseudolycorine
C,7H2lN04
303
22 roserine
C,8H22N03
300
59 tazettine
C,8H2lN05
331
2 poetaminine
222-226° (200)
UV (58), MS (58), (58), '^C NMR (58)
'H NMR
UV(93),IR(195)
UV(94),IR(94),MS(94), 'H NMR (94) UV(94),IR(94),MS(94), NMR (94), '^C NMR (94)
'H
[a]D''-43 EtOH; c 0.4 (200)
UV(200),IR(28),MS(200), 'H NMR (200)
MS (96),'H NMR (96), '^C NMR (96) 202-203° (167)
[(X]D''+138
CHCI3; c 0.23 (167)
UV(201),IR(202),MS(198), 'H NMR (198), *^C NMR (203), CD (153)
21 tortuosine
Ci8H,8N03
296
242-243° (85)
IR (85), MS (85), *H NMR (85),'^C NMR (85)
66 trisphaeridine
C,4H9N02
223
132-134° (174)
UV(174),IR(174),MS(174), 'H NMR (174), '^C NMR (65)
20 vasconine
CnH,6N02
266
233-235° (79)
'HNMR(34),'^CNMR(34)
IR (79), MS (79),
367
TABLE 3 (continued) melting Molecular MW point °C Formula (Ref.)
Alkaloid
39 vittatine
C,6HnN03
271
206-208° (31)
[a]D°
Additional data (Ref.)
(Ref.) [a]D''+26 MeOH; c 0.25 (31)
UV (138), IR (138), MS (138), ' H N M R (164), ''C NMR (143), CD (204)
The pairs: 6a-hydroxybuphanisine/6p-hydroxybuphanisine (57/58), haemanthidine/6-epihaemanthidme (51/52), 6ahydroxy-3-0-methylepimaritidine/6p-hydroxy-3-0-methylepimaritidine (47/48), and papyramine/6-epipapyramine (44/45), exist in solution as a mixture of C-6 epimers, and their data were obtained from these mixtures. In the case of narwedine (77), a rapid racemisation occurs in the presence of base (89). Narciprimine (65) is considered an artifact produced from narciclasine (64) during acid extraction (89), and tazettine (59) has been shown to be an artifact produced by base-catalysed rearrangement of pretazettine (61) (199, 205). Narcissamine (32, 42) is a quasi-racemic mixture consisting of equimolar amounts of norgalanthamine (73) and norlycoramine (79)
4.1 Proton Nuclear Magnetic Resonance ^H NMR spectroscopy gives important information about the different types of Amaryllidaceae alkaloids. Several early contributions about homolycorine and crinanehaemanthamlne type alkaloids were made by Hawksworth et al. (206) and Haugwitz et al. (207). In the last decade, the routine use of 2D NMR tecniques (COSY, NOESY, ROESY, etc.) has facilitated the structural assignments and the settling of their stereochemistry. A compilation of the different ^H NMR spectra, arranged according to the different skeleton types is shown in Table 4.
a." Lycorine type This group has been subject to several ^H NMR studies and lycorine (1) as well as Its main derivatives have been completely assigned. The general characteristics of the ^H NMR spectra are: i
Two singlets for the para-oriented aromatic protons in the range 5 6.5-7.2 ppm.
ii
A unique olefinic proton around 5.5 ppm.
iii
Two doublets as an AB system corresponding to the benzylic protons of C-6.
Iv
The deshielding observed in the p protons of positions 6 and 12 In relation to their a-homologues is due to the effect of the c/s-lone pair of the nitrogen atom.
368
V
Like almost all other lycorine type examples, the alkaloids isolated from Narcissus genus show a trans B/C ring junction, the coupling constant being ^4a.10b~11HZ.
In the plant, the alkaloid lycorine (1) is particularly vulnerable to the oxidation processes giving several ring-C aromatized products.
b.- Homolycorine type This group includes lactone, hemiacetal or cyclic ether (unusual) alkaloids. The general traits for this type of compounds could be summarized as follows: i
Two singlets for the para-oriented aromatic protons. In lactone alkaloids, differentiation of the H-7 and H-10 signals is readily made by virtue of the deshielding of H-7 by effect of the per/-carbonyl group,
ii
The hemiacetal alkaloids always show the substituent at C-6 in a-disposition, and the benzylic proton H-6p appears as a singlet between 5-6 ppm, depending on the substituent at C-6.
iii
The majority of compounds belong to a single enantiomeric series containing a cis B/C ring junction, which is made clear by the small size of the coupling constant J^ ^ob- '" *he Narcissus genus no exception to this rule has been observed,
iv
The large coupling constant between H-4a and H-10b (J^g^^Q^^~^OHz), is only consistent with a frans-diaxial relationship.
V
In general, the C ring presents a vinylic proton around 5.5 ppm.
vi
The singlet corresponding to the A/-methyl group is in the range 6 2.0-2.2 ppm, its non existence being very unusual,
vii If position 2 is substituted by an OH, OMe OAc group, it always displays an adisposition. viii The H-12a is more deshielded than H-12P as a consequence of the c/s-lone pair of the nitrogen atom.
An interesting study of homolycorine type alkaloids with a saturated ring C has been made by Jeff and coworkers (208). They describe empirical correlations of A/-methyl chemical shifts with stereochemical assignments of the B/C and C/D ring junction.
369 c- Crinine - Haemanthamine types The absolute configuration of these alkaloids, which allows
both series to be
differentiated, is determined through the circular dichroism spectrum. The alkaloids of the Narcissus genus usually belong to the haemanthamine type, while in genera such as Brunsvigia, Boophane etc., the crinine type alkaloids are predominant. It is also noteworthy that the alkaloids isolated from the Narcissus genus do not show additional substitutions in the aromatic ring apart from those of C-8 and C-9. On the contrary, in the genera where crinine type alkaloids predominate, the presence of compounds with a methoxy substituent at C-7 is quite common. Thus, taking into account the previous considerations, haemanthamine type alkaloids show the following characteristics: i
Two singlets for the para-oriented aromatic protons In the range 5 6.4-7.0 ppm.
ii
Using CDCI3 as the solvent, the magnitude of the coupling constants between each olefinic proton (H-1 and H-2) and H-3 gives information about the configuration of the C-3 substituent. Thus, in those alkaloids in which the twocarbon bridge (C-11 and C-12) was cis to the substituent at C-3, H-1 shows an allylic coupling with H-3 (J^ 3~1-2 Hz) and H-2 a smaller coupling with H-3 (^2,3-0" 1.5 Hz), as occurs in crinamine (53). On the contrary, in the corresponding C-3 epimeric series, e.g. haemanthamine (49), a larger coupling between H-2 and H3 (Ja.sS Hz) is shown, the coupling between H-1 and H-3 not being detectable,
iii
It is frequently possible to observe an additional coupling of H-2 with the equatorial H-4p, in a W-mechanism.
iv
The proton H-4a shows a large coupling with H-4a (J4a4a~13 Hz) due to their frans-dlaxial position, characteristic of the haemanthamine series.
V
Two doublets for an AB system corresponding to the benzylic protons of position C-6.
vi
The pairs of alkaloids with a hydroxy substituent at C-6, like papyramlne/6epipapyramine
(44/45),
haemanthidine/6-epihaemanthldine
(51/52)
etc.,
appear as a mixture of epimers not separable even by HPLC. vii Also in relation with position C-6, It is interesting to note that ismine (68), a catabolic product from the haemanthamine series, shows a restricted rotation around the biarylic bond, which makes the methylenic protons at the benzylic position magnetically non-equivalent.
370 d.- Tazettine type Although tazettine (59) is one of the most widely distributed alkaloids
in the
Amaryllidaceae family, it was found to be an extraction artifact of pretazettine (61) (209). The presence of an A/-methyl group (2.4-2.5 ppm) in tazettine type alkaloids inmediately distinguishes
them from the haemanthamine
type, from which
they
proceed
biosynthetically. Moreover the ^H NMR spectrum always shows the signal corresponding to the methylenedioxy group. We have also included the alkaloid obesine (63) in this group, although it exhibits some structural differences with the skeleton type.
e.- Galanthamine type Among the Amaryllidaceae alkaloids, only the galanthamine type shows an orthocoupling constant between both aromatic protons of ring A. The general characteristics of their ^H NMR spectra are: i Two doublets for the two OAt/7o-oriented aromatic protons with a coupling constant of J^g-SHz. ii The assignment of the substituent stereochemistry at C-3 is made In relation with the coupling constants of the olefinic protons H-4 and H-4a. When coupling constant J^^ is about 5 Hz, the substituent is pseudoaxial while if It is ~0 Hz this indicates that the substituent at C-3 is pseudoequatorlal. ill Two doublets as an AB system corresponding to the benzylic protons of C-6. iv The existence of the furan ring results in a deshielding effect in H-1. V This type of alkaloids often show an A/-methyl group but occasionally A/-formyl or A/-acetyl derivatives have been reported.
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TABLE 4a (continued) ^H NMR data of Lycorine type alkaloids. 20
21
H-1
7.31 dd
7.85 br d
8.32 d
8.13 d
H-2
6.75 t
7.27 t
7.84 t
H-3
6.99 dt
7.33 br d
7.70 d
Alkaloid
18
19
I
7.59 brs
22 2.85 ddd 3.13 dd
a
1.8-1.95 m 2.25-2.4 m
a
1.38 qd
a
2.25-2.4 m
p
3.4-3.5 m
H-4 H-6
4.09 s
10.42 s
9.55 s
9.50 s
H-7
6.64 s
7.57 s
8.09 s
7.92 s
6.95 s
H-10
7.17 s
7.81 s
7.86 s
8.34 s
H-11 (2H)
3.00 br t
3.45 brt
3.76 t
3.88 t
2.05 ddd
a P
5.42 t
5.35 t
2.70 dt 4.75-4.95 m
4.33 s
4.15 s
4.20 s
4.05 s
4.17 s
1 3.90 s
3.32 t
4.45 br t
OMe
3.93 s
4.09 s
4.19 s
OMe
3.87 s
4.03 s
4.08 s
H-12(2H)
OMe d
b
b
c
MHz
200
200
500
500
Ref.
(26)
(26)
(34)
(85)
solvent
Solvent a: DMSO-c/e, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.
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374
TABLE 4b (continued) ^H NMR data of Homolycorine type compounds: hemiacetal alkaloids. Alkaloid
31
32
33
34
35
4.35 br d 2.35 m
4.29 br d 2.35 m
4.35 d 2.31 dm
4.17 d 2.26 dd
4.15 brs
H-2p
2.65 m
2.53 dm
4.21 brs
5.50 br s
5.46 br d 2.72 br d
5.39 br s 2.69 br d
5.69 br s
2.78 br d
2.65 m 5.50 br d 2.77 dd
2.62 dm
H-3 H-4a H-6p
5.93 s
5.54 s
5.99 s
5.39 br s
5.43 s
H-7
6.93 s
6.80 s
6.85 s
6.67 s
6.73 s
H-10
6.99 s
6.93 s
6.90 s
6.77 s
6.94 s
H-10b
2.44 dd
2.44 dd
2.4-2.5 m
2.35 dd
2.85 d
H-11 (2H)
2.4-2.6 m
2.4-2.6 m
2.4-2.5 m
2.3-2.4 m
2.54 m
H-12a
3.15 ddd
3.15 ddd
3.14 ddd
3.08 dd
3.33 m
H-12|3
2.27 dd
2.23 dd
2.25 dd
2.17 dd
2.38 dt
5.97 d
5.83 d
5.91 (2d)
3.43 s
3.51 s
2.22 s
H-1a H-2a
OCH2O OMe
3.88 s
3.89 s
OMe
3.87 s
3.88 s
OMe NMe
2.87 d
3.55 s 2.08 s
2.10 s
2.11 s
2.05 s
solvent MHz
c
d
d
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4.2 Carbon^^ Nuclear Magnetic Resonance ^^C NMR spectroscopy has been extensively used for determining the carbon framework of Amaryllidaceae alkaloids, and the major contributions are due to Grain et al (203), Zetta and Gatti (210), and Frahm et al. (143). The assignments are made on the basis of chemical shifts and multiplicities of the signals (by DEPT experiment). The use of 2D NMR tecniques such as HMQG and HMBC allow the assignments to be corroborated. Table 5 shows a compilation of the different ^^G NMR spectra classified according to the different types. The ^^G NMR spectra of Narcissus alkaloids can be divided in two regions. The low-field region (>90 ppm) contains signals of the carbonyl group, the olefinic and aromatic carbons as well as that of the methylenedioxy group. The other signals, corresponding to the saturated carbon resonances are found in the high-field region, the A/-methyl being the only characteristic group, easily recognizable by a quartet signal between 40-46 ppm. The effect of the substituent (OH, OMe, OAc) on the carbon resonances is of considerable importance in localizing the position of the functional groups. The analysis of the spectra allows conclusions to be drawn about the following aspects: - The number of methine olefinic carbons. - The presence and nature of the nitrogen substituent. - The existence of a lactonic carbonyl group. - The presence of a quaternary carbon signal assignable to G-lOb in the chemical shift range of 42-50 ppm.
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Table 5d ^^C NMR data of Tazettine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OCH2O OMe NMe solvent MHz Ref.
59 130.5 128.4 72.4 26.6 69.9 65.0 127.8 103.7 146.3 146.3 109.1 125.4 50.1 101.7 61.7 100.6 55.6 41.9 d 16 (203)
60 130.1 128.9 72.1 25.4 68.2 62.6 126.2 108.5 146.6 146.2 104.2 130.9 50.0 102.6 64.5 100.9 56.7 40.6 d 75 (152)
62 131.3 126.0 72.7 29.8 63.3 168.5 118.6 103.8 147.1 152.3 111.0 142.2 46.2 80.1 53.5 102.1 56.2 42.8 d 50 (29)
63 132.4 136.5 63.6 34.4 68.5 62.2 131.0 107.3 148.4 147.3 111.0 125.0 50.3 82.7 55.7 101.9
c 62 (30)
Solvent a: DMSO-ofg, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.
Table 5e ^^C NMR data of Narciclasine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-lOa C-1 Ob OCH2O NMe solvent MHz Ref.
64 124.7 69.1 72.3 68.8 52.8 172.1 129.2 168.9 152.3 144.8 95.7 132.1 133.3 102.0
66 122.0 126.7 128.1 129.9 143.8 151.8 123.1 105.5 148.1 148.2 99.9 130.3 124.3 101.9
a 68 (88)
d 50 (65)
67 120.2 125.9 131.0 133.0 136.5 152.8 126.6 108.3 159.2 152.0 102.2 122.0 135.3 105.7 45.9 c 50 (29)
68 129.9 118.0 129.1 110.7 146.7 63.5 134.0 109.7 147.5 147.4 110.2 131.2 127.2 101.3 30.8 d 50 (65)
383
Table 5f ^^C NMR data of Galanthamine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OMe NMe NCHO OCMe OCMe solvent MHz Ref.
70 88.1 30.0 62.2 126.8 126.0 60.5 129.5 121.6 110.5 145.5 144.0 132.7 48.2 34.0 54.3 55.5 42.2
72 86.2 27.7 63.2 123.3 121.8 59.9 127.2 130.2 111.7 146.7 144.4 131.9 47.8 33.7 53.4 56.0 40.9
d
170.9 21.4 d 100 (58)
73 88.2 30.3 61.7 129.2 125.9 51.6 123.6 122.8 112.2 146.9 145.3 133.1 48.2 35.6 45.9 56.2
74 88.4 29.9 61.9 127.6 127.1 53.5 132.1 120.9 111.3 146.2 144.1 133.1 48.5 39.7 46.8 55.9
75 87.9/88.7 29.8 61.4 128.0/128.2 125.8/126.2 41.0/52.8 127.4 119.9/121.6 111.4 146.2/146.5 144.3/144.5 131.8/131.9 48.0/48.1 46.6/46.7 35.7/39.1 55.8
76 88.7 29.2 61.4 128.2 125.1 58.4 127.1 121.2 111.3 146.8 144.5 131.2 48.1 35.1 35.2 55.6
78 89.8 31.5 65.2 27.6 31.7 60.4 129.1 121.6 111.3 146.2 144.0 136.3 46.7 23.9 54.1 55.9 41.9
80 90.0 31.7 65.5 27.8 37.5 53.8 127.2 120.8 110.9 146.6 144.2 136.6 47.4 24.2 47.4 56.1
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161.2 21.4 d 50 (56)
384
4.3 Mass Spectrometry Extensive studies on the mass spectrometry of Amaryllidaceae alkaloids by electron impact were reported in the sixties and seventies (92, 151, 178, 192, 211-218). The fragmentation patterns in the EIMS of various skeletal types are fairly well documented and have considerable diagnostic value.
a.- Lycorine type The molecular ion appears as a quite intense peak, and generally suffers the loss of water, as well as C-1 and C-2 and their substituents by a retro Diels-Alder fragmentation (Fig. 13). The loss of water is not present in the spectra of acetyl derivatives. The ease of the loss of water from the molecular ion was found to be greatly dependent on the stereochemistry of the C-2 hydroxyl group. Thus, in the mass spectrum of lycorine (1) the relative intensity is low, while in 2-epilycorine it is the base peak (192).
b.- Homolycorine type In this structure type the cleavage of the labile bonds in ring C by a retro Diels-Alder reaction is dominant, generating two fragments: one, the most characteristic, represents the pyrrolidine ring (plus substituents in position 2), and the other (a less abundant fragment) encompasses the aromatic lactone or hemilactone moiety (Fig. 14). A further general and noteworthy feature is the low abundance of the molecular ion in all compounds with a double bond A^'"* (211).
c- Crinine-Haemanthamine types Several general considerations should be taken into account for these types of alkaloids: The stability of the molecular ion, which is almost always the base peak. The important role played by the aromatic ring in the stabilization of the Ions, which is retained in all fragments of high mass while the nitrogen atom is often lost. The relatively large number of nitrogen-free ions. The fragmentation mechanisms are initiated by the rupture of a bond p to the nitrogen atom which implies the opening of the C-11/C-12 bridge (215, 216).
c.1. Compounds with a saturated ring C and no bridge substituent. The configuration of the substituent on ring C plays a minor role in the fragmentation process.
385 C.2. Compounds with a double bond (A^'^) in ring C and no bridge substituent. The fragnnentation pattern involves ruptures of C-4a/C-10b and C-3/C-4 bonds. A characteristic feature is the loss of a nitrogen-containing nnoiety, C3H5N [M-55]. C.3. Compounds with a double bond (A^'^) in ring C and a hydroxyl substituent at C-11. The presence of a hydroxyl group on C-11 is responsible for dramatic changes in the fragmentation pattern (Fig. 15), and it is profoundly influenced by the stereochemistry. There are three fundamental patterns of fragmentation: Loss of CH3OH: it is more favorable when the two-carbon bridge and the substituent on C-3 are on the same side of the molecule. Loss of C2H6N: the relative significance of the loss of this neutral nitrogen moiety is governed by the ease with which the methanol is eliminated. Loss of CHO: A peak at m/z [M-29] due to the loss of an aldehyde radical is present In all compounds of this type.
d.- Tazettine type Minor changes in stereochemistry are sufficient to cause appreciable differences in the stereoisomers in these kind of structures. Thus, in the MS of tazettine (59), with a p configuration of the methoxyl group at C-3, the dominant ion occurs at m/z [M-84], following a C-ring fragmentation by a retro Diels-Alder process. In contrast, the mass spectrum of criwelline (60), which differs only in the configuration of the mentioned methoxyl group, contains a peak of low abundance at A7yz[M-84] (Fig. 16). Ions occur in both steroisomers due to the successive loss of a methyl radical and water from the molecular ion (151).
e.- Galanthamine type In this type of structures, the intense molecular ion as well as [M-1] peak, the breaking of ring C (losing a C4H6O fragment) and the elimination of elements of ring B (including the nitrogen atom) are characteristic (Fig. 17). This behavior is similar for the dihydro derivatives (213).
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BIOLOGICAL AND PHARMACOLOGICAL ACTIVITIES Plants of the genus Narcissus L. have been used throughout history to treat a va-
riety of human medical problems (219). N. poeticus L., for example, was described in the Bible as a well-established treatment for symptomatologies now defined as cancer (220). In the fourth century BO, the Greek physician Hippocrates of Cos (the "Father of Medicine") recommended a pessary prepared from narcissus oil (probably N. poeticus L.) for the management of uterine tumours (221). In the first century AD, Pliny the Elder recorded the topical use of that extract and another derived from N. pseudonarcissus L. for this purpose (N. poeticus L. is now known to contain 0.12 g of the antineoplastic agent narciclasine (64) per kg of fresh bulb) (86). Arabian, North African, Central American and Chinese medical practitioners of the middle ages continued using Narcissus oil in cancer treatment (222). For example, bulbs of N. tazetta L. var. chiinensis Roem., cultivated in China as a decorative plant, were used for treatment of tumours in folk medicine. In this case, pretazettine (61) was proved to be one of the antltumour active compounds (57). It has been known for a long time that daffodil ingestions are very dangerous, resulting in toxic symptoms. After ingestion of N. tazetta L. (43) and N. jonquilla L. (223), the first visible symptoms are nausea, vomiting and diarrhea, followed by neurological (trembling, convulsions, etc.) and cardiac sequelae, and sometimes resulting in death if eaten in quantity. N. papyraceus Ker-Gawler is believed to be toxic for herbivorous mammalians; in this case, the toxicity might be related to the alkaloid content which is five times higher in the aerial part than in the bulbs (72). Moreover, N. pseudonarcissus L. showed irritant and allergenic properties on contact with animals and men (74, 224, 225). Apart from these harmful effects of daffodils, several Narcissus extracts have shown antiviral (226-231), antimicrobial (232, 233), cytotoxic (234), antitumour (228-230, 235) and allelopathic (236) activities. Table 6 shows the different pharmacological and/or biological properties exhibited by the alkaloids from the genus Narcissus L., but only some of the activities of a reduced number of Narcissus alkaloids are known. The most extensively studied effect is that of non-specific inhibition, e.g. antitumour, antimitotic, suppression of development of splenomegaly and increase in number of nucleated blood cells. The relationship of chemical structure and biological activity of these alkaloids is largely unknown (236), and further
392
studies of several alkaloids of this plant family for therapeutic purposes remain still to be done.
TABLE 6 Biological and pharmacological activities of Narcissus alkaloids
Alkaloid
Activity
References
57 6a-hydroxybuphanisine
• Moderate cytotoxic against human tumoral Molt 4 cells
(237)
10 caranine
• • • •
Weak analgesic Convulsant and hypotensive Acetylcholinesterase inhibitor Active against the murine P-388 lymphocytic leukaemia (as acetylcaranine)
(89) (89) (89) (238)
53 crinamine
• • • • • •
Powerful transient hypotensive in dogs Respiratory depressant Moderate antimalarial Antimicrobial Strong cytotoxic Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines • Weak cytotoxic against HepG2 hepatoma
(89) (89) (148) (239) (148) (240)
36 dubiusine
• Cytotoxic against non-tumoral LMTK cells • Moderately active against Molt 4 lymphoma
(240) (240)
70 galanthamine
• • • • •
(89,241,242) (243) (244) (245) (246, 247)
• • • •
•
Powerful analgesic Anticonvulsive Hypotensive Inductor ofhypothermia in rat Cholinesterase inhibitor with peripheral and central pharmacological effects Centrally-acting competitive acethylcholinesterase inhibitor under investigation as therapeutic agent in treating Alzheimer's disease Reverses cognitive deficits induced by nBM (nucleus basalts magnocellularis) lesions in mice Anticurare and antimorphine as well as memory-influencing Combines both physostigmine and neostigmine properties: * like physostigmine, reverses opioid-induced respiratory depression, but not the concomitant analgesia * like neostigmine, antagonises muscle paralysis induced by cZ-tubocurarine, also antagonises the ganglionic blockade and increases the contraction response As hydrobromide has several central and peripheral effects: * has central effects such as antagonism of the respiratory depressant effect of morphine-like compounds * is capable of penetrating the blood-brain barrier and it is used in the treatment of the central effects of scopolamine (hyoscine) intoxication. It has certain advantages over physotigmine for this purpose. * is able to reverse the central anticholinergic syndrome
(240)
(89, 248-254) (230,249,251) (255) (256) (255, 257) (244)
(257- 259) (247, 260)
256,
(256, 258)
257,
393 TABLE 6 (continued) Alkaloid
Activity
70 galanthamine (cont.)
• • • •
* is used for its anticholinesterase activity in the treatment of disturbances in the peripheral sympathetic synaptic transmission. * reverses the neuromuscular blocking effect of curare-type muscle relaxants and has been used safely in anaesthesia and in the treatment of various neurologic disorders (pareses, paralysis of different origins, myasthenia gravis, progressive muscular dystrophy, etc.). Energix®, a preparation composed of galanthamine, increases endurance during exercise and delays the onset of fatigue Used in a pharmaceutical composition for treatment of alcoholism Cytotoxic against non-tumoral LMTK cells Produces poisoning of digestive, respiratory, neuromuscular and central nervous systems
References (259) (242, 246, 250, 255-258,261-263)
(264-266) (267) (240) (43)
71 epigalanthamine
• More hypotensive and less toxic than galanthamine • Anticholinesterase activity lower than galanthamine
(268) (268, 269)
73 norgalanthamine
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines
(240)
75 7V-formylnorgalanthamine
• Moderate cytotoxic against Molt 4 lymphoma and HepG2 hepatoma • Cytotoxic against non-tumoral LMTK cells
(240) (240)
• Hypotensive • Weak cytotoxic against Molt 4 lymphoid cells
(89) (240)
• • • • • • •
Hypertensive Cytotoxic against a variety of cultured cells (in vitro) Cytotoxic against fibroblastic LMTK cells Moderately active against Molt 4 lymphoid cells Moderately active against Rauscher leukaemia Inhibitor of HeLa cell growth Inhibitor of protein synthesis, blocking the peptide bond formation step on the peptidyl transferase centre of the 60S ribosomal subunit • Slightly reduces DNA synthesis, whereas RNA synthesis is practically unaffected
(270) (271) (240) (240) (234) (272) (272, 273)
51 haemanthidine
• Active against A-431, KB, Lul, Mel2 and ZR-75-1 cell lines • Significantly active against LNCaP and HT cell lines
(167) (167)
30 hippeastrine
• • • • •
(274) (7) (167) (240) (240)
23 homolycorine
• Inductor of delayed hypersensitivity in animals • Cytotoxic against fibroblastic LMTK cells
(74) (240)
24 8-O-demethylhomolycorine
• Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against Molt 4 lymphoid cells
(240) (240)
7 galanthine
49 haemanthamine
Antiviral. Active against Herpes simplex type 1 (HS-1) Weak insect antifeedant Significantly active against the LNCaP and HT cell lines Cytotoxic against non-cancerous LMTK cells Weak cytotoxic against Molt 4 lymphoid cells
(272)
394 TABLE 6 (continued) A kaloid
Activity
References
29 9-O-demethyl2a-hydroxyhomolycorine
• Cytotoxic against fibroblastic LMTK cells • Moderately active against Molt 4 lymphoid cells
(240) (240)
68 ismine
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines
(240)
78 lycoramine
• Central anticholinesterase activity stronger than galanthamine • Like neostigmine, antagonises muscle paralysis induced by dtubocurarine, also antagonises the ganglionic blockade, and increases the contraction response • Produces acute poisoning of digestive, respiratory, cardiovascular. neuromuscular and central nervous systems
(244) (244)
31 lycorenine
• Weak hypotensive • Cytotoxic against murine LMTK and human HepG2 cell lines
(270) (240)
32 O-methyllycorenine
• Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against HepG2 hepatoma
(240) (240)
• Respiratory stimulant • Relaxant of isolated epinephrine-precontracted pulmonary artery • Increases contractility and rate of isolated perfused heart. These effects are mediated by stimulation of p-adrenergic receptors • Specific inhibitor of ascorbic acid (AA) biosynthesis. Seems to act as a non-competitive inhibitor on galactano-gamma-lactone oxidase • Most of the effects of lycorine on physiological processes have been ascribed to its ability to inhibit ascorbic acid biosynthesis in
(89, 275) (275) (275)
1 lycorine
(43, 244)
(275-279) (144)
VIVO.
• The ability to inhibit the ascorbic acid biosynthesis has made this substance a valuable tool for studying the AA-dependent reactions • Inhibitor of cyanide-resistant respiration. AA is needed for the in vivo synthesis of hydroxyproline-containing proteins, specifically utilised for the development of KCN-resistant respiration. • Inhibitor of peroxidase enhancement, which seems related with the synthesis of hydroxyproline-containing proteins • Inhibitor of cell division in rat fibroblasts. Ascorbic acid is required for cell division • Inhibitor of protein blocking peptide bond formation • Inhibitor of DNA synthesis. • Moderate antitumoural • Cytotoxic against a variety of cultured cell lines • Inhibitor of HeLa cells growth • Decreases the growth of several viruses through its inhibitory action on viral protein synthesis • Active against several RNA and DNA viruses. Inhibits the growth of Herpes simplex type I, poliomyelitis, coxsackie, Semliki Forest and measles viruses • Active against RNA-containing flaviviruses and bunyaviruses • Does not inhibit the activity of reverse transcriptase • Weak protozoicide • Plant growth inhibitor by inhibition of protein synthesis • Inhibitor of growth and cell division in plants, inhibiting the cell cycle during interphase. Ascorbic acid is required for cell division
(279-282) (144, 281)
277,
279,
(144,281) (240, 282) (272, 273, 283) (272, 283) (89, 274, 275) (148,271,240) (272) (284-287) (89, 274, 275, 286288) (289) (228) (89) (89) (144, 275, 277, 279, 282)
395 TABLE 6 (continued) Activity
References
• Inhibitor of germination of seeds and growth of roots. Lycorine-1O-P-D-glucose has the reverse effect, and may also produce mitogenic activity in animal cells • Ungeremine, a natural metabolite of lycorine, is responsible, at least in part, for the growth-inhibitory and cytotoxic effects of lycorine • Certain bacteries transform lycorine into pancrassidine, which is less cytotoxic than ungeremine. • The changes observed in response to stress suggest its role in protective and repair mechanisms of producer plants • Inhibits the feeding of the desert locust Schistocerca gregaria
(283, 290)
(294)
62 3-epimacronine
• Weak cytotoxic against human Molt 4 and murine LMTK cell Imes
(240)
27 masonine
• Inductor of delayed hypersensitivity in animals
(74)
82 mesembrenone
• Cytotoxic against Molt 4 lymphoid cells • Weak cytotoxic agamst fibroblastic LMTK cells
(240) (240)
64 narciclasine
• Antimitotic • Strong tumour inhibitor. One of the most important antineoplastic components of Amaryllidaceae species • Active against larynx and cervix carcinomas • Inhibitor of HeLa cells growth • Inhibitor of growth of Ehrlich tumour cells • Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. • Resistance to narciclasine in a mutant strain of Saccharomyces cerevisiae is due to an alteration on the peptidyl transferase centre • Reduces DNA synthesis, whereas RNA synthesis is practically unaffected • Inhibitor of ascorbic acid biosynthesis in vivo • Strong antibiotic. Active against Corynebacterium fascians • Active against RNA-containingflavivirusesand bunyaviruses • Inhibitor of cell division in tobacco tissue culture • Inhibitor of Avena coleoptile sections and rice seedling test • Inhibitor of seed germination and root growth at low concentrations. The O-glucoside of narciclasine has the reverse effect • Narciclasine-4-O-P-D-glucopyranoside shows cytotoxic and antitumour activity very similar to narciclasine • The peculiar activity of narciclasine seems to arise from the ftmctional groups and conformationalfreedomof its C-ring
(88, 89, 295) (89, 222,296, 297)
• Increases the amplitude andfrequencyof respiratory movements • Increases the amplitude and decreases the frequency of cardiac contractions • Decreases the soporific effects of ethanol and barbiturics • Increases the analgesic effect of morphine • Protective against thiopental poisoning • Enhances the effects of caffeine, corazole, arecoline, and nicotine • Probably acts primarily on m-cholinoreactive structures of the brain
(304) (304)
Alkaloid 1 lycorine (cont.)
11 narwedine
(291) (292) (293)
(298) (272) (221,299,300) (89, 273, 299-301) (299) (272) (88, 144) (88) (289) (297) (297) (302) (303) (88)
(304) (304) (304) (90) (90)
44 papyramine
(240) • Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against human tumoral cell lines Molt 4 and HepG2 (240)
61 pretazettine
• Active against murine Rauscher viral leukaemia
(89, 205, 230, 234, 288)
396 TABLE 6 (continued) Alkaloid 61 pretazettine (cont.)
3 pseudolycorine
j Activity
References
• Active against spontaneous AKR T cells in mice • Active against intraperitoneally and subcutaneously implanted LLC (Lewis lung carcinomas) • Effective against Ehrlich ascites tumour, a non viral transplantable tumour • Cytotoxic against fibroblastic LMTK and Molt 4 lymphoid cell lines • Inhibitor ofHeLa cell growth • Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. • Slightly reduces DNA synthesis; has no effect on RNA synthesis • Active against Herpes simplex type 1 (HS-1) • Active against neurotropic RNA viruses • Potent inhibitor of viral reverse transcriptase of RNA tumour viruses, binding to the polymerase enzyme • Demonstrates synergistic effect in combination with standard cytotoxic drugs • In combination with ryllistine inhibits nucleic acid synthesis • Can be administrated over a long period of time without apparent toxicity
(199, 305-308) (307)
• Effective against murine Rauscher leukaemia in mice, suppressing the splenomegaly and the increase of nucleated blood cells, and decreasing the virus level in plasma without apparent toxicity • Inhibitor of protein synthesis in tumour cells at the step of peptide bond formation. It has a different binding site than lycorine on the peptidyl transferase centre of the 60S ribosomal subunit • Reduces DNA synthesis. RNA synthesis is practically unaffected • Cytotoxic against human Molt 4 and murine LMTK cells • Moderately active against HepG2 hepatoma • Moderately active against Ehrlich ascites tumour cells • Inhibitor ofHeLa cell growth • Antiviral. Active against Herpes simplex type 1 (HS-1) • Active against neurotropic RNA viruses • Does not inhibit the activity of reverse transcriptase
(230, 312)
(307-309) (240) (272) (205, 272, 307310) (272, 308) (274) (289,310) (167, 229, 230, 273, 288) (230, 307, 308) (311) (306) 235,
(272,273,310) (272) (240) (240) (231) (272) (274) (289,310,312) (228, 230)
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines • Weak cytotoxic against HepG2 hepatoma
(240)
59 tazettine
• • • •
(89, 270)) (167) (240) (205)
39 vittatine
• Weak analgesic in mice • Tachycardic in dogs
5 2-O-acetylpseudolycorine
Weak hypotensive Active against the Co 12 cell line Weak cytotoxic against fibroblastic LMTK cell lines The stereochemical rearrangement from pretazettine to tazettine inactivates the biological activity of pretazettine
310,
(240)
(89) (89)
397
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323
Narcissus Alkaloids Jaume Bastida, F. Viladomat and C. Codina
1.
INTRODUCTION Since the isolation of the first Amaryllidaceae alkaloid lycorlne (1) from Narcissus
pseudonarcissus by Gerrad in 1877, around 200 species belonging to this plant family have been examined for alkaloids. Although this group of alkaloids is of minor pharmaceutical importance, it has aroused increasing interest over the last years. The several reviews in this field are a valuable source of information (1-7) and, likewise, this topic Is regularly reviewed by the journal Natural Products Reports of The Royal Society of Chemistry (8-16). Out of the different genera which make up the Amaryllidaceae family, the genus Narcissus is one of the best known from the horticultural point of view. Due to their phytochemical interest, a chapter about Narcissus alkaloids has been prepared, following the usual general lines. The literature up to August 1996 has been covered. 1.1 Geographical distribution, botanical and taxonomical aspects The Amaryllidaceae are widely distributed. They are richly represented in the tropics and have pronounced centres in South-Africa and in Andean South America. Several genera have their centre in the Mediterranean, e.g. Narcissus. The majority of Narcissus species are found in the Iberian peninsula and North Africa, which substantiates the hypotheses that landmasses of Europe and Africa were once joined taking into consideration the shared distribution of many genera and species. Narcissus can adapt to the different habitats found in this area as well as the different soils, preferring slightly acidic conditions. The genus Narcissus, belonging to the tribe Narcisseae, consists of small to medium-sized herbs with linear leaves and a solid scape bearing an inflorescence of one to several (rarely numerous) flowers. Its spathal bracts are basally fused into a tube. The flowers are actinomorphic and have six equal tepals. Inside this, a corona is
324 generally present. The colours of the tepals usually vary from white to bright yellow and the corona fronn white or light yellow to orange or orange-red. Most are spring-flowering, but a few flower in autumn. The ovary is trilocular and the fruit is a capsule with globose to angular, dry and black seeds. The taxonomy and nomenclature of the genus Narcissus is complex because of its very varied wild populations, its suitability for hybridation and also for historical reasons because many descriptions of taxons have been based on garden specimens, several of which were probably of hybrid origen. The polymorphism of this genus has meant that its taxonomical classification has been constantly changing over the years. 1.2 The Amaryllidaceae family and their alkaloids There has been considerable taxonomical controversy over which genera belong to the Amaryllidaceae family. The revisions of Dahlgren's group (17, 18) have contributed to clarify this aspect. In another direction, one of the best tools for classification of several genera and species of this family has been the type of alkaloids that are exclusively synthezised by Amaryllidaceae species. Thus, e.g. the genus Behria in spite of having been classified as Amaryllidaceae (19), does not have Amaryllidaceae type alkaloids (20) and should therefore be included in another family. Furthermore, it is unusual to find other types of alkaloids in Amaryllidaceae species, but if present, they are always accompanied by true Amaryllidaceae alkaloids. Up to now, only three alkaloids isolated from this family do not belong to this specific type but to the mesembrane {=Sceletium) type -generally found in the family Aizoaceae-, which In spite of having the same aminoacids as precursors has a quite different biosynthesis -for more information about Sceletium alkaloids see Ref. (21, 22)-. These three compounds are amisine (83), mesembrenol (84), and mesembrenone (82) isolated from Hymenocallis arenicola (23), Crinum oliganthum (24) and Narcissus pallidulus (25), respectively (Figure 1). For this reason the Amaryllidaceae alkaloids have a high chemotaxonomical value. The general characteristics of the Amaryllidaceae alkaloids could be summarized by the following points: - a fundamental ring system composed of a Ce-Ci and a N-Ca-Ce building block, derived from L-Phenilalanine
(L-Phe) and L-Tyroslne (L-Tyr),
respectively. - they are moderately weak bases (pKa 6-9) - each alkaloid contains only one nitrogen atom which is secondary, tertiary or even quaternary, and the carbon content varies from 16 to 20 atoms.
325 NMep
OMe OMe
" ^ - ^
•N'
i
Me
Ri
82 R,+ R,= = 0
83
84 R,= OH, R2 = H Fig. 1. Sceletium alkaloids isolated from Amaryllidaceae species Most of the Amaryllidaceae alkaloids may be classified Into nine principal skeletally homogeneous subgroups although there are several other alkaloids with structures derived from these main molecular frameworks. Representative alkaloids from each of these classes include: norbelladine (85), lycorine (1), homolycorine (23), crinine (86), haemanthamine (49), narciclasine (64), tazettine (59), montanine (87) and galanthamine (70). With the aim of unifying the numbering system of the different types, Ghosal's proposal will be used in this chapter (6) (Figure 2).
2.
NARCISSUS
ALKALOIDS AND THEIR
OCCURRENCE
The alkaloids isolated from Narcissus species, classified in relation to the different ring types, are provided in Table 1, and the distribution of the different alkaloids is listed in Table 2.
326
CO
CM
u> 00
^
to
X
o yiW
^\. 1 (0
ly
"r^^
2 \cD
/ « A ^
^/
(C\ *^ / I
~\ °°
\
U--""'"'CM
(» )
\ / ^ o^ o \ /
g
CO
O Q.
a:^
•D
O (Q 0
^CO CO 0
o CO .•g CO
E <
c\i d) u.
327
TABLE 1a Narcissus alkaloid structures. Lycorine type.
Alkaloid name 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
lycorine poetaminine pseudolycorine 1 -0-acetylpseudolycorine 2-0-acetylpseudolycorine 9-0-methylpseudolycorine galanthine goleptine jonquilline caranine pluviine norpluviine 9-0-demethylpluviine 1 -O-acetyl-9-O-demethylpluviine 1,9-0-diacetyl-9-0-demethylpluviine
Ri
H Ac H Ac H H H H Ac H H H H Ac Ac
Structure R, R3 OH GH2 OH GH2 OH H OH H OAc H OH Me OMe Me OMe H 0 GH2 H CH2 H Me H Me H H H H H Ac
OAc 1
OMe I
HO..
X
..OH
AcO.
X
MeO,
MeO
16 narcissidine
17 nartazine
_3i Me Me Me Me Me Me
Me H Me Me Me
328
TABLE l a (continued) Narcissus alkaloid structures. Lycorine type.
r^"^ MeO,
MeO,
MeO
MeO
18 assoanine 19 oxoassoanine
R^z=R2=H Ri + R2 = 0
20 vasconine 21 tortuosine
MeO.
MeO
22 roserine
R^ = H R^ = OMe
329
TABLE 1b Narcissus alkaloid structures. Homolycorine type.
Structure 23 24 25 26 27 28 29 30 31 32 33 34 35
Alkaloid name homolycorine 8-0-demethylhomolycorine 8-0-demethyl-8-0-acetylhomolycorine 9-O-demethylhomolycorine masonine normasonine 9-0-demethyl-2a-hydroxyhomolycorine hippeastrine lycorenine O-methyllycorenine oduline 6-0-methyloduline 2a-hydroxy-6-0-methyloduline
Ri
R2
Me Me Me H
Me H Ac Me
R3
0 0 0 0 0 0 0 0
CH2 CH2
Me
H CH2
Me Me CH2 CH2 CH2
Me Me
OH OMe OH OMe OMe
Me-CHOH-CHg-COO, OAc
MeO
36
dubiusine
A_
H H H H H
R5
H H H H H H OH OH H H H H OH
Re Me Me Me Me Me H Me Me Me Me Me Me Me
330
TABLE 1b (continued) Narcissus alkaloid structures. Homolycorine type.
MeO. OCOEt
37
8-0-demethylhomolycorine-A/-oxide
38
poetinatine
TABLE 1c Narcissus alkaloid structures. Haemanthamine type.
- R 7
Structure Alkaloid name 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
vittatine maritidine 8-O-demethylmaritldine 9-O-demethylmaritidine 0-methylmaritidine papyramine 6-epipapyramine O-methyl-6-epipapyramine 6a-hydroxy-3-0-methylepimaritidine 6p-hydroxy-3-0-methylepimaritidine haemanthamine 11-O-acetylhaemanthamine haemanthidine 6-epihaemanthidine crinamlne narcidine
Ri
OH OH OH OH OMe OMe OMe OMe H H OMe OMe OMe OMe H OMe
R, H H H H H H H H OMe OMe H H H H OMe H
R4
~^3
CH2
Me Me H Me Me Me Me Me Me
Me H Me Me Me Me Me Me Me
CH2 GH2 CH2 CH2 GH2
Me
H
1
~W^ Re H H H H H H OH OMe H OH H H H OH H H
H H H H H OH H H OH H H H OH H H H
R7
H H H H H H H H H H OH OAc OH OH OH OH
331 TABLE 1c (continued) Narcissus alkaloid structures. Haemanthamine and Crinine types.
.OMe --R4 — R.
55
cantabricine R^ = H, Rg = Me, R3 = H, R4 = OAc, R5 = H
57 6a-hydroxybuphanisine 58 6p-hydroxybuphanisine
56
narcimarkine R^ + Rg = CHg, R3 = OMe, R4 = H, R^= 0CH2CH(0H)Et
R^ = H, Rg = OH R^ = OH, Rg = H
TABLE 1d Narcissus alkaloid structures. Tazettine type. OMe
NMe
NMe
OH 59 60
tazettine criwelline
R^ = OMe, Rg = H R^ = H, Rg = OMe
61
pretazettine
63
obesine
OMe
NMe
62
3-epimacronine
332
TABLE 1e Narcissus alkaloid structures. Narciclasine and Montanine types.
OH
r i ^ ^ ^
O
OH
64
OH
narciclasine
65
r^===^
66 trisphaeridine
O
narciprinnlne
r^^^=^
67
bicolorine
OH
r ^ ^
<
^^Ij^^^L
NHMe OH
68
ismine
69
pancracine
333
TABLE I f Narcissus alkaloid structures. Galanthamine type.
MeO
70 71 72 73 74 75 76 77
Alkaloid name galanthamine epigalanthamine 0-acetylgalanthamine norgalanthamine epinorgalanthamine A/-formylnorgalanthamine narcisine narwedine
Structure R, H OH H H OH H H
R, OH H OAc OH H OH OH 0
R3
Me Me Me H H OHO Ac Me
MeO.
Structure Alkaloid name 78 lycoramine 79 norlycoramine 80 epinorlycoramine
Ri
Rg
R3
OH OH H
H H OH
Me H H
334
TABLE 1g Narcissus alkaloid structures. Miscellaneous.
OMe
OMe
81
pallidiflorine (heterodimer)
OMe OMe
k^ 1 Me
82 mesembrenone (Sceletium type)
335 TABLE 2 Occurrence of Narcissus alkaloids. Alkaloid
Wild species / cultivars
Section
References
18 assoanine
A^. assoanus Leon-Duf. A^. jacetanus Fdez. Casas N. pseudonarcissus L. cv. King Alfred
JQ PN
(26) (27) (28)
19 oxoassoanine
A^. assoanus L6on-Duf. A^. jacetanus Fdez. Casas
JQ PN
(26) (27)
67 bicolorine
A^. bicolor L. A^. obesus Salisb.
PN BC
(29) (30)
57 6a-hydroxybuphanisine
A^. cantabricus DC.
BC
(31)
58 6(3-hy(lroxybuphanisine
A^. cantabricus DC.
BC
(31)
55 cantabricine
A'; cantabricus DC.
BC
(31)
10 caranine
N. cv. Livia
53 crinamine
A^. bujei (Fdez. Casas) Fdez.Casas N. cantabricus DC. A^. cv. Salome
PN BC
(33) (31) (34)
60 criwelline
A^. tazetta L.
TZ
(35)
36 dubiusine
N. dubius Gouan A'; tortifolius Fdez. Casas
DB DB
(36) (37)
70 galanthamine
N. confusus Pugsley A^. eugeniae Fdez. Casas N. X gracilis Sabine A^. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill, cv Flower Record N. X incomparabilis Mill, cv Fortune A^. X incomparabilis Mill, cv Helios N. X incomparabilis Mill, cv John Evelyn A^. X incomparabilis Mill, cv Marion Cran A^. X incomparabilis Mill, cv Nova scotia A^. X incomparabilis Mill, cv Pluvius A^. X incomparabilis Mill, cv Suda N. jonquilla L. A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A^. kristalli N. lobularis Hort. A^. nivalis Graells A^. obesus Salisb. A^. X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A'^. poeticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne
PN PN JC
(38) (39) (40) (32) (32) (32,41) (32) (32) (32) (32) (32, 42) (32) (43) (40,44, 45) (40) (46) (32) (47) (30) (40) (48) (49, 50) (51,52) (49) (32)
(32)
JQ
PN BC BC JN TZ NC NC
336 TABLE 2 (continued) Section
Alkaloid
Wild species / cultivars
70 galanthamine (cont.)
A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Wrestler TZ N. tazetta L. A^. tazetta L. var. chinensis Roem. TZ A'^ tazetta L. cv. Geranium A^. tortifolius Fdez. Casas DB A': triandrus L. cv. Tresamble A^. cv. Inglescombe A^. cv. Texas A^. cv. Twink
(49) (53, 54) (32, 42) (32) (32) (32) (28, 32, 42, 55) (32, 42) (32) (32) (32) (32) (32, 42) (32) (35, 49 56) (57) (49) (37) (40) (32) (32) (32, 42)
72 O-acetylgalanthamine
A^. pseudonarcissus L. cv. Carlton
(58)
71 epigalanthamine
A^. tazetta L. var. chinensis Roem.
TZ
(57, 59)
73 norgalanthamine
A^. leonensis Pugsley A^. nivalis Graells A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Rockery Beauty A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A'', pseudonarcissus L. cv. Victoria A^. cv. Salome
PN BC
(60) (47) (53, 54) (32, 42) (28, 32, 42) (32, 42) (32) (32) (32) (32, 42) (32) (34)
74 epinorgalanthamine
A^. leonensis Pugsley
PN
(60)
75 A^-formylnorgalanthamine
A^' , confusus Pugsley
PN
(38)
7 galanthine
A^. cyclamineus DC. cv. Beryl N. cyclamineus DC. cv. Cairhays N. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Flower Record. A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^. X incomparabilis Mill. cv. Marion Cran A'^. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti 1A^' , X incomparabilis Mill. cv. Suda
References
(40) (40) (32) (32,42) (32) (32) (32) (32) (32) (32, 42) (32) (32)
337
TABLE 2 (continued) Alkaloid 7 galanthine (cont.)
8 goleptine 49 haemanthamine
Wild species / cultivars A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A^. panizzianus Pari. N. poeticus L. N. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A'^. pseudonarcissus L. cv. Imperator A'^, pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage N. pseudonarcissus L. cv. Music Hall A'^, pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors N. pseudonarcissus L. cv. Rockery Beauty A^. pseudonarcissus L. cv. Romaine A'^, pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler A^. tazetta L. A^. tazetta L. cv. Scarlet Gem N. cv. Insulinde A'^. cv. Livia A^. cv. Twink
Section
TZ NC NC
TZ
(32) (45) (61) (49, 50, 62) (51,52) (49) (49) (32, 42) (32) (32) (32) (28, 32,42, 62) (32) (42) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (49) (32) (32) (32, 42) (63, 64)
A^. jonquilla L. cv.Golden Sceptre A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A'^ canaliculatus Guss A^. confusus Pugsley A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Flower Record A^. X incomparabilis Mill. cv. Fortune A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^. X incomparabilis Mill. cv. Marion Cran A^. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A'^, X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Suda A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A^. lobularis Hort. A^. obesus Salisb. A^. pallidiflorus Pugsley A^. poeticus L. var. ornatus Hort. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A', pseudonarcissus L. cv. Early Glory
References
PN PN TZ PN
PN BC PN NC PN
(65) (33) (49) (38) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (32) (40, 44, 45) (32) (30) (66) (49,51) (67) (53, 54) (32, 42) (32)
338 TABLE 2 (continued) Alkaloid
Wild species / cultivars
49 haemanthamine (cont.)
A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A'^ pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Rockery Beauty N. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler TZ A'^, tazetta L. A^. tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection A^. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee N. tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem A^. tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames A'^. triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe A^. cv. Insulinde N. cv. Livia A^. cv. Texas A^. cv. Twink
50 11-O-acetylhaemanthamine
A^. bujei (Fdez. Casas) Fdez. Casas
PN
(33)
51 haemanthidine
A^. A^. A^. A^.
asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem.
PN
(65) (40) (46) (57)
A^. A^. A^. A^.
asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem.
PN
52 6-epihaemanthidine
30 hippeastrine
A'^ X incomparabilis Mill. cv. Fortune A^. jonquilla L. cv. Golden Sceptre N. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. King Alfred A^. tazetta L. A^. tazetta L. cv. Early Perfection 1N. cv. Salome
Section
TZ TZ
TZ TZ
JN
TZ
References (32) (32) (28, 32, 42, 55) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (35, 49, 56) (49) (49) (49) (49) (49) (49) (49) (49) (40) (40) (40) (32) (32) (32) (32, 68) (32,42)
(65) (40) (46) (57) (32) (40, 44) (40) (53) (55) (35) (49) (34)
339 TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
References
23 homolycorine
N. bujei (Fdez. Casas) Fdez. Casas N. confusus Pugsley N. cyclamineus DC. cv. February Gold N. eugeniae Fdez. Casas N. X incomparabilis Mill. cv. Helios A^. jonquilla L. cv. Golden Sceptre N. munozii-garmendiae Fdez. Casas N. X odorus L. var. rugulosus N. pallidiflorus Pugsley N. panizzianus Pari. N. papyraceus Ker. Gawl. N. poeticus L. N. poeticus L. var. ornatus Hort. N. poeticus L. cv. Daphne N. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. N. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Grand Maitre N. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Van Sion A^. radinganorum Fdez. Casas A'^ tazetta L. N. tazetta L. var. chinensis Roem. N. tazetta L. cv. Cragford N. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A': tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes A^. tortifolius Fdez. Casas A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas N. cv. Inglescombe
PN PN
(33) (69) (40) (39) (32) (44) (70) (40) (66) (61) (71,72) (49) (49,51,73) (32) (67) (74) (53) (32) (32) (28, 55, 62) (32, 42) (75) (76-78) (57) (49) (49) (49) (49) (49) (49) (49) (49) (37) (40) (79) (32)
PN
PN JN PN TZ TZ NC NC PN PN
PN TZ TZ
DB PN
A^. bujei (Fdez. Casas) Fdez. Casas N. pallidiflorus Pugsley A^. papyraceus Ker. Gawl. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. King Alfred A^. radinganorum Fdez. Casas A^. tazetta L. A^. tortifolius Fdez. Casas
PN PN TZ PN PN TZ DB
(33) (66) (71,72) (67) (55) (75) (77, 80) (37)
37 8-O-demethylhomolycorine-A^-oxide
A^. papyraceus Ker. Gawl.
TZ
(71,72)
25 8-0-demethyl-8-0-acetylhomolycorine
N. vasconicus Fdez. Casas
PN
(79)
26 9-O-demethylhomolycorine
A^. bicolor L. A^. confusus Pugsley
PN PN
(29) (69)
24 8-O-demethylhomolycorine
340
TABLE 2 (continued) Alkaloid 29
Wild s p e c i e s / cultivars
9-0-demethyl-2a-hydroxy- A^. dubius Gouan A^. tortifolius Fdez. Casas homolycorine
68 ismine
9 jonquilline 78 lycoramine
A^. asturiensis (Jordan) Pugsley N. bicolor L. N. obesus Salisb. A^. pallidiflorus Pugsley
Section
References
DB DB
(81) (37)
PN PN BC PN
(65) (29) (30) (66) (44)
A^. jonquilla L. cv. Golden Sceptre A^. cyclamineus DC. cv. February Gold A^. jonquilla L. A^. papyraceus Ker. Gawl. A^. pseudonarcissus L. cv. Carlton N. tazetta L. var. chinensis Roem.
JQ TZ TZ
(40) (43) (48) (53, 54) (57) (32, 42) (32, 42) (32, 42) (32) (32) (32) (32,42) (32)
79 norlycoramine
A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus
80 epinorlycoramine
A^. leonensis Pugsley A^. pseudonarcissus L. cv. Carlton
PN
(60) (54)
31 lycorenine
A^. bujei (Fdez. Casas) Fdez. Casas A^. cyclamineus DC. cv. February Gold A^. cyclamineus DC. cv. Peeping Tom A^. eugeniae Fdez. Casas A'^, X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. Suda A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A'^ munozii-garmendiae Fdez, Casas A^. poeticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Unsurpassable N. pseudonarcissus L. cv. Van Sion A^. tazetta L. var. chinensis Roem. A'^, triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe
PN
(33) (40) (40) (39, 82) (32) (32) (44) (40) (70) (62) (49) (49) (32) (49) (53, 54) (32, 42) (32) (28, 32, 42, 55, 62) (32) (32) (32, 42) (57) (40) (40) (32)
32
O-methyllycorenine
L. cv. Covent Garden L. cv. King Alfred L. cv. Magnificience L. cv. Rembrandt L. cv. Rockery Beauty L. cv. Spring Glory L. cv. Van Sion L. cv. Victoria
A^. bujei (Fdez. Casas) Fdez. Casas A^. munozii-garmendiae Fdez. Casas
PN
PN NC NC
TZ
PN PN
(33) (70)
341 TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
32 0-methyllycorenine (cont.) N. pseudonarcissus L. cv. Carlton 1 lycorine
A^. cyclamineus DC. cv. Beryl N.folli N. X gracilis Sabine A^. X incomparabilis Mill. cv. Deanna Durbin N. X incomparabilis Mill. cv. Flower Record N. X incomparabilis Mill. cv. John Evelyn N. X incomparabilis Mill. cv. Marion Cran N. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Toronto A^. jacetanus Fdez. Casas A^. jonquilla L. cv. Trevithian A^. kristalli N. leonensis Pugsley A^. X odor us L. var. rugulosus N. papyraceus Ker. Gawl. A^. posticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon N. pseudonarcissus L. A'^ pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A'^, pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A^. pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A^. tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem A^. tazetta L. cv. St. Agnes A^. tortuosus Haworth A^. triandrus L. cv. Silver Chames A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas A^. cv. Inglescombe A^. cv. Insulinde A^. cv. Irene Copeland
References (53, 54)
JC
PN PN JN TZ NC NC
PN
TZ TZ
PN
PN
(40) (46) (40) (32, 42) (32) (32) (32) (32) (32, 42) (32) (32) (27) (40) (46) (60) (40) (48,71,72) (49, 50, 83) (49,51,52) (49) (32) (49) (84) (32, 42) (32) (32) (32) (32, 42) (32, 42) (32) (32) (32) (32) (32) (32,42) (32) (35, 46, 49, 56, 7678) (57) (49) (49) (49) (49) (49) (49) (49) (49) (85) (40) (40) (79) (32) (32) (32)
342
TABLE 2 (continued) Alkaloid 1 lycorine (cont.)
Wild species / cultivars
Section
References (32) (32) (32, 42)
A^. cv. Livia N. cv. Texas A^. cv. Twink
62 3-epimacronine
A^. asturiensis (Jordan) Pugsley A^. bicolor L. A^. obesus Salisb.
PN FN BC
(65) (29) (30)
40 maritidine
N. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ
(48) (57)
41 8-O-demethylmaritidine
A^' , primigenius (Lainz) Fdez. Casas 8L Lainz
PN
(67)
42 9-0-demethylmaritidine
A'^. radinganorum Fdez. Casas
PN
(75)
43 O-methylmaritidine
A^. papyraceus Ker. Gawl. A^. tazetta L. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(71,72) (77) (57)
47 6a-hydroxy3 - 0-methy lepimaritidine
A^. tazetta L. var. chinensis Roem.
TZ
(57)
48 6p-hydroxy3 - O-methy lepimaritidine
A^. tazetta L. var. chinensis Roem.
TZ
(57)
27 masonine
A'^ bujei (Fdez. Casas) Fdez. Casas A^. jonquilla L. cv. Golden Sceptre A'^, pseudonarcissus L. A^. pseudonarcissus L. cv. Carlton A^. tazetta L.
PN
(33) (44) (74) (53, 54) (35)
PN TZ
28 normasonine
A^. pseudonarcissus L. cv. Carlton
82 mesembrenone
A^. pallidulus Graells
CM
(25)
64 narciclasine
A^. canaliculatus Guss var. tipica N. cyclamineus DC. var. tipica N. X incomparabilis Mill. cv. Carabinieri A^. X incomparabilis Mill. cv. Helios A*". X incomparabilis Mill. cv. Mercato A^. X incomparabilis Mill. cv. Orange Bruid A'^. X incomparabilis Mill. cv. Mrs. R. O. Backhouse A^. X incomparabilis Mill. cv. Scarlet Elegance A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Tunis A^. X incomparabilis Mill. cv. Walt Disney A^. jonquilla L. A^. jonquilla L. cv. Trevithian A^. X odorus L. var. rugulosus N. poeticus L. cv. Actaea A^. poeticus L. cv. Cheerfulness A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Flower Carpet A^. pseudonarcissus L. cv. Golden Harvest IA^. pseudonarcissus L. cv. King Alfred
TZ CM
(86) (86) (86) (86, 87) (86) (86) (86)
(53, 54)
JQ JN
(86) (86, 87) (86) (86) (43) (86) (86) (86) (86) (86) (86) (86) (62, 86, 87)
343
TABLE 2 (continued) Alkaloid
Wild species / cultivars
64 narciclasine (cont.)
A^. pseudonarcissus L. cv. Mount Hood A^. pseudonarcissus L. cv. President Lebrum A^. pseudonarcissus L. cv. Rembrandt N. serotinus Lofl. ex L. var. tipica N. tazetta L. var. tipica N. tazetta L. cv. Geranium A^. triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Celebrity A^. cv. Clamor A^. cv. Texas A^. cv. Totus Albus N. cv. Verger
54 narcidine
A^. pseudonarcissus L. cv. King Alfred
56 narcimarkine
A^. poeticus L.
65 narciprimine
Narcissus sp
76 narcisine
N. tazetta L.
16 narcissidine
N. cyclamineus DC. cv. Beryl A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. poeticus L. N. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Rockery Beauty A^. tazetta L. A^. tazetta L. cv. Geranium A^. tazetta L. cv. L'innocence
Section
ST TZ
References (86) (86) (86) (86) (86-88) (88) (86, 87) (86, 87) (86) (86) (86) (86) (86) (55)
NC
(50, 89) (87)
TZ
NC
TZ
(56) (40) (32, 42) (32, 42) (32) (50, 62, 83) (49) (49) (55) (32) (49) (49) (49)
17 nartazine
N. poeticus L. N. tazetta L.
NC TZ
(49) (35, 49)
77 narwedine
A^. cyclamineus DC. N. kristalli N. pseudonarcissus L. cv. Carlton N. tazetta L. N. cv. Irene Copeland A^. cv. Texas
CM
(90) (46) (53, 54) (35) (32) (32, 91)
63 obesine
A^. obesus Salisb.
BC
33 oduline
A^. X incomparabilis Mill. cv. Fortune A^. jonquilla L. cv. Golden Sceptre A^. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton
34 6-(9-methyloduline
A^. bujei (Fdez. Casas) Fdez. Casas N. pseudonarcissus L. cv. Carlton
TZ
JN FN
(30) (32) (40, 44) (40) (53, 54) (33) (53, 54)
344
TABLE 2 (continued) Alkaloid
Wild species / cultivars
Section
References
35 2a-hydroxy6-0-methyloduline
A^. cv. Salome
81 pallidiflorine
N. pallidiflorus Pugsley
PN
(66)
69 pancracine
A'', poeticus L.
NC
(92)
44 papyramine
A^. panizzianus Pari. A^. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(61) (48,71,72) (57)
45 6-epipapyramine
A^. panizzianus Pari. A^. papyraceus Ker. Gawl. A^. tazetta L. var. chinensis Roem.
TZ TZ TZ
(61) (48,71,72) (57)
46 0-methyl6-epipapyramine
A^. papyraceus Ker. Gawl.
TZ
(71,72)
11 pluviine
A^. cyclamineus DC. cv. Cairhays A^. cyclamineus DC. cv. Peeping Tom A^. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deamia Durbin A^. X incomparabilis Mill. cv. Flower Record A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^' , X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Suda A^. poeticus L. NC A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnet A^. pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Emst H. Krelage A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler A^. tazetta L. cv. Early Perfection TZ A^. tazetta L. var. chinensis Roem. A^. cv. Inglescombe A^. cv. Insulinde A^. cv. Livia A^. cv. Texas A^. cv. Twink
(40) (40) (32) (32, 42) (32) (32) (32) (32) (32) (32) (62) (32, 42) (32) (42, 62) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (57) (32) (32) (32) (32) (32, 42)
13 9-O-demethylpluviine
A^. pseudonarcissus L. cv. Carlton
(54, 58)
14 1-O-acetyl9-O-demethylpluviine
A^. pseudonarcissus L. cv. Carlton
(54, 58)
(34)
345
TABLE 2 (continued) Alkaloid
Wild species / cultivars
15
N. pseudonarcissus L. cv. Carlton
(58)
A'^ cv. Texas
(93)
l,9-(9-diacetyl9-O-demethylpluviine
12 norpluviine
Section
References
A^. poeticus L. var. ornatus. Hort.
NC
(51)
38 poetinatine
A^. poeticus L. var. ornatus. Hort.
NC
(52)
61 pretazettine
A^. bicolor L. A^. confusus Pugsley A^. obesus Salisb. A'^. pallidiflorus Pugsley A^. panizzianus Pari. A^. tazetta L. A^. tazetta L. var. chinensis Roem.
PN PN BC PN TZ TZ TZ
(29) (38) (30) (66) (61) (56, 76, 77) (57)
3 pseudolycorine
A^. assoanus Leon-Duf. A^. dubius Gouan A^. jacetanus Fdez. Casas A^. papyraceus Ker. Gawl. A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. cv. Salome
JQ DB PN TZ TZ TZ
(94) (81) (27) (48,71,72) (56, 76, 77) (57, 95) (34)
4
1-O-acetylpseudolycorine
A^. assoanus Leon-Duf.
JQ
(94)
5 2-0-acetylpseudolycorine
A^. assoanus Leon-Duf.
JQ
(94)
6
A^. nivalis Graells A^. poeticus L. A^. pseudonarcissus L. cv. King Alfred
BC NC
(47) (62) (28, 62)
22 roserine
A^. pallidulus Graells
CM
(96)
59 tazettine
A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A^. canaliculatus Guss A^. cantabricus DC. A'^. cyclamineus DC. cv. Peeping Tom N.folli N. X gracilis Sabine A^. jonquilla L. cv. Golden Sceptre N. jonquilla L. cv. Trevithian A^. kristalli N. X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A^. poeticus L. var. ornatus Hort. A^. pseudonarcissus L cv. Grand Maitre N. pseudonarcissus L. cv. Van Sion A^. tazetta L.
PN PN TZ BC
A^. tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A^. tazetta L. cv. Early Perfection
TZ
(65) (33) (49) (31) (40) (46) (40) (40, 44, 45) (40) (46) (40) (48) (51) (32) (32) (35, 46, 56, 77, 78, 97, 98) (57, 95) (49) (49)
2 poetaminine
9-O-methylpseudolycorine
JC
JN TZ NC
TZ
346
TABLE 2 (continued) Alkaloid
Wild species / cultlvars
59 tazettine (cont.)
N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A^. tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames
21 tortuosine
A^. tortuosus Haworth A': cv. Salome
PN
(85) (34)
66 trisphaeridine
A'^ asturiensis (Jordan) Pugsley
FN
(65)
20 vasconine
A^. bicolor L, A^. vasconicus Fdez. Casas A^. cv. Salome
PN PN
(29) (79) (34)
39 vittatine
A^. cantabricus DC. A^. pseudonarcissus L. cv. Carlton
BC
(31) (53, 54)
Section
References (49) (49) (49) (49) (49) (49) (40)
The taxonomical aspects are based on the works of J. Fernandez Casas (99-105) and other authors (106-110) for wild Narcissus species and hybrids, and those of Jefferson-Brown (111) and Boit and Piozzi (32, 40, 42, 49, 86) for Narcissus cultivars (cv.). Key to sections: BC = Bulbocodii DC; CM = Cyclaminei DC; DB = Dubii Fdez. Casas; JC = x Joncissus Fdez. Casas ( Jonquillae DC x Narcissus L.); JN = x Jonissi Fdez. Casas {Jonquillae DC x Pseudonarcissi DC); JQ = Jonquillae DC; NC = Narcissus L.; PN = Pseudonarcissii DC; ST = Serotini Pari.; and TZ = Tazettae DC
3.
BIOSYNTHETIC
PATHWAYS
The work on the biosynthesis of Amaryllidaceae alkaloids reached a peak in the period 1960-1976 with a great number of studies related with this subject. However, since then, little new work has been produced apart from the isolation of compounds predicted as biosynthetic intermediaries of a certain pathway or, more recently, a new biosynthetic proposal to obtain galanthamine (70), which differs from the initial one. Although L-Phe and L-Tyr are closely related in chemical structure, they are not interchangeable in plants. In the Amaryllidaceae alkaloids, L-Phe serves as a primary precursor of the Ce-C^ fragment, corresponding to ring A and the benzylic position (C-6), and L-Tyr is the precursor of ring C, the two-carbon side chain (C-11 and C-12) and nitrogen, C6-C2-N. The conversion of L-Phe to the Ce-Ci unit requires the loss of two carbon atoms from the side chain as well as the introduction of at least two oxygenated
347
substituents into the aromatic ring, wiiich is performed via cinnamic acids. Tiie presence of the enzyme PAL has been demonstrated in Amaryllidaceae plants (112) and the elimination of ammonia mediated by this enzyme is known to occur in an antiperiplanar manner to give frans-cinnamic acid, with loss of the B-pro-S hydrogen (113). Thus, it may be expected that L-Phe would be incorporated into Amaryllidaceae alkaloids with retention of the B-pro-R hydrogen. However, feeding experiments in Narcissus pseudonarcissus cv. King Alfred showed that tritium originally present at C-3 of L-Phe, whatever the configuration, was lost in the formation of several haemanthamine and homolycorine type alkaloids, which led to the conclusion that fragmentation of the cinnamic acids involves oxidation of C-B to ketone or acid level, the final product being protocatechuic aldehyde or its derivatives (Fig. 3). On the other hand, L-Tyr is degraded no further than tyramine before incorporation into the Amaryllidaceae alkaloids. Thus, tyramine and protocatechuic aldehyde -or derivatives of the latter- are logical components for the biosynthesis of the precursor norbelladine (85). This reaction occupies a pivotal position since it represents the entry of primary metabolites into a secundary metabolic pathway. The junction of the amine and the aldehyde results in a Schiff's base, two of which have been isolated up to now: craugsodine (114) and isocraugsodine (115). The existence of Schiff's bases in nature as well as their easy conversion into the different ring-systems of the Amaryllidaceae alkaloids allow the presumption that the initial postulate about this biosynthetic pathway was correct. Barton and Cohen (116) proposed that norbelladine (85) or related compounds could undergo oxidative coupling of phenols in Amaryllidaceae plants, once ring A had been suitably protected by methylation, resulting in the different skeletons of the Amaryllidaceae alkaloids (Fig. 4).
a.- Lycorine and IHomolycorine types. The pyrrolo[de]phenanthridine alkaloids (lycorine type) and the 2-benzopirano[3,4-g]indole alkaloids (homolycorine type) both originate from an orttio-para' phenoloxidative coupling (Fig. 5). The biological conversion of cinnamic acid via hydroxylated cinnamic acids into the Ce-Ci unit of norpluviine (12) has been used in a study of hydroxylation mechanisms In higher plants (117). When [3-3H, P-^^Q] cinnamic acid was fed to Narcissus pseudonarcissus cv. Texas a tritium retention in norpluviine (12) of 28% was observed. This is very near a predicted value of 25%, resulting from para-hydroxylation with
348
L-Phe PAL
COOH
Tyr-decarboxylase
frans-cinnamic add HO
COOH
para-coumaric acid: R= H caffeic acid: R= OH
HO^
HO"
^
^CH
protocatechuic aldehyde HO
Sciiiff's base (isomeric structures in solution) OH
HO
HO
rL3 85
Fig. 3. Biosynthetic pathway to norbelladine (85).
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351 hydrogen migration and retention, where half the tritium would be lost In the first hydroxylation and half the remainder in the second. In the conversion of 0-methylnorbelladine (88) into lycorine (1), the labelling position [3-3H] on the aromatic ring of L-Tyr afterwards appears at C-2 of norpluviine (12), which is formed as an intermediate, the configuration of the tritium apparently being p (93). This tritium is retained in subsequently formed lycorine (1), which means that hydroxylation at C-2 proceeds with an inversion of configuration (118) by a mechanism involving an epoxide, with ring opening followed by allylic rearrangement of the resulting alcohol (Fig. 6). Supporting evidence comes from the incorporation of [2p-^H]caranine (10) into lycorine (1) in Zephyranthes Candida (119). However, an hydroxylation of caranine (10) in Clivia miniata occuring with retention of configuration was also observed (120). Further, [2a-^H; ll-^'^Clcaranine (10) was incorporated into lycorine (1) with high retention of tritium at C-2, indicating that no 2-oxo-compound can be implicated as an intermediate. The conversion of the 0-methoxyphenol to the methylenedloxy group may occur late in the biosynthetic pathway. Tritiated norpluviine (12) is converted to tritiated lycorine (1) by Narcissus x incomparabilis cv. Deanna Durbin, which not only demonstrates the previously mentioned conversion but also indicates that the C-2 hydroxyl group of lycorine (1) is derived by allylic oxidation of either norpluviine (12) or caranine (10) (121). Regarding the conversion of [23-^H, S-OMe-^'^Clpluviine (11) into galanthine (7), in Narcissus pseudonarcissus cv. King Alfred, the retention of 79% of the tritium label confirms that hydroxylation of C-2 may occur with inversion of configuration (62). It was considered (122) that another analogous epoxide (89) could give narcissidine (16) in the way shown by loss of the pro-S hydrogen from C-11, galanthine (7) being a suitable substrate for epoxidation. Labelled [a-^'^C, p-^H]-0-methylnorbelladine (88), when fed to Narcissus x incomparabilis cv. Sempre Avanti afforded galanthine (7) (98% of tritium retention) and narcissidine (16) (46% tritium retention). Loss of hydrogen from C-11 of galanthine (7) was therefore stereospecific.
Recently,
Kihara et al. (123) have isolated a new alkaloid, incartine (89), from flowers of Lycoris incarnata, which could be considered to be the biosynthetic intermediate of this pathway (Fig. 7). The biological conversion of protocatechuic aldehyde into lycorenine (31), which proceeds via 0-methylnorbelladine (88) and norpluviine (12), first involves a reduction of
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the aldehyde carbonyl, and afterwards, in the generation of lycorenine (31), oxidation of this same carbon atom. The absolute stereochemistry of these processes has been elucidated In subsequent experiments (124), and the results show that hydrogen addition and removal take place on the re-face of the molecules concerned (125), the hydrogen initially introduced being the one later removed (126). It is noteworthy that norpluvilne (12), unlike pluviine (11), is converted in Narcissus pseudonarcissus cv. King Alfred primarily to alkaloids of the homolycorine type. Benzylic oxidation of position 6 would afford (90), followed by ring opening to form an amino aldehyde and then a hemiacetal formation and methylation could provide lycorenine (31) (62),
and, on subsequent
oxidation, could give homolycorine (23) as can be seen in Fig. 8.
b. Crinine, Haemanthamine, Tazettine, Narciclasine and l\/lontanine types The alkaloids derived from 5,10b-ethanophenanthridine (crinine and haemanthamine types), 2-benzopyrano[3,4c]indole (tazettine type), phenanthridine
(narciclasine
type) and 5,11b-methanomorphanthridine (montanine type) originate from a para-para' oxidative phenolic coupling (Fig. 9). Results of experiments with labelled crinine (86), and less conclusively with oxovittatine, indicate that the two naturally occurring enantiomeric series, represented in Figure 9 by crinine (86) and vittatine (39), are not interconvertible in Nerine bowdenii (127). Incorporation of 0-methylnorbelladine (88), labelled in the methoxy carbon and also in positions [3,5-^H], into the alkaloid haemanthamine (49) was without loss of tritium, half of which was sited at C-2 of (49). Consideration of the possible mechanisms involved in relation to tritium retention led to the suggestion that the tritium which is expected at C-4 of (49) might not be stereospecific (128). The conversion of Omethylnorbelladine (88) into haemanthamine (49) involves loss of the pro-R hydrogen from the C-3 of the tyramine moiety, as well as a further entry of a hydroxyl group at this site (129). The subsequent benzylic oxidation results in an epimeric mixture (51/52) which even HPLC can not separate. The epimeric forms were proposed to be interconvertible
through
(91a).
The
biosynthetic
conversion
of
the
5,10b-
ethanophenanthridine alkaloids to the 2-benzopyrano[3,4-c]indole was demonstrated by feeding tritium-labeled alkaloids to Sprekeiia formosissima. It was shown that this plant converts haemanthamine (49) to haemanthidlne/ epihaemanthamine subsequently to tazettine (59) in an essentially irreversible manner
(51/52)
and
(130). This
transformation was considered to proceed through (91a) or the related alkoxide anion.
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356 although this intermediate (91a) and Its rotational equivalent (91b) have never been detected by spectral methods (131) (Fig. 10). It has also been proved that the alkaloid narciclasine (64) proceeds from the pathway of the biosynthesis of crinine and haemanthamine type alkaloids and not through norpluviine (12) and lycorine (1) derivatives. In fact, in view of its structural affinity to both haemanthamine (49) and lycorine (1), narciclasine (64) could be derived by either pathway. When 0-methylnorbelladine (88) labelled in the methoxy carbon and in both protons of position 3 and 5 of the tyramine aromatic ring, was administered to Narcissus plants, all four alkaloids incorporated activity. The isotopic ratio [^H:^'^C] for norpluviine (12) and lycorine (1) was, as expected, 50% that of the precursor, because of its ortho-para' coupling. On the contrary, in haemanthamine (49) the ratio was unchanged. These results prove that the methoxy group of (88) is completely retained in the alkaloids mentioned, providing a satisfactory internal standard and also, the degree of tritium retention is a reliable guide to the direction of phenol coupling. Narciclasine (64) showed an isotopic ratio (75%) higher than that of lycorine or norpluviine (12) though lower than that of haemanthamine (49). However, the fact that more than 50% of tritium is retained suggests that 0-methylnorbelladine (88) is incorporated into narciclasine (64) via para-para' phenol oxidative coupling. O-methylnorbelladine (88) and vittatine (39) are implicated as intermediates in the biosynthesis of narciclasine (64) (132-134), and the loss of the ethane bridge from the latter could occur by a retro-Prins reaction on 11-hydroxyvittatine (92). Strong support for this pathway was obtained by labelling studies. 11-Hydroxyvittatine (92) has also been proposed as an intermediate in the biosynthesis of haemanthamine (49) and montanine (87)
(a 5,11b-methanomorphanthridine
alkaloid)
following the observed
specific
incorporation of vittatine (39) into the two alkaloids in Riiodophiala bifida (127) (Fig. 11). Fuganti and Mazza, (133, 134) concluded that in the late stages of narciclasine (64) biosynthesis, the two-carbon bridge is lost from the oxocrinine skeleton, passing through intermediates bearing a pseudoaxial hydroxy-group at C-3 position and further hydrogen removal from this position does not occur. Noroxomaritidine was also implicated in the biosynthesis of narciclasine (64) and further experiments (135) showed that it is also a precursor for ismine (68). The alkaloid ismine (68) has also been shown (136) to be a transformation product of the crinine-haemanthamine series. The precursor, oxocrinine labelled with tritium in the positions 2 and 4, was administered to Sprel
0 C (D N CO
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Fig. 11. Proposed biosynthetic pathways to haemanthamine (49) and montanine (87).
359 c. Galanthamine type. The alkaloids with a dibenzofuran nucleus (galanthamine type) are obtained from a para-ortho' phenyl oxidative coupling. Although norbelladine (85) was shown not to be a precursor of galanthamine (70) in Narcissus pseudonarcissus cv. King Alfred, an incorporation of this labelled compound has been obtained in Leucojum aestivum (128). The initial studies of this pathway suggested that the phenyl oxidative coupling does not proceed from 0-methylnorbelladine (88) but that the order of methylation of the precursors should be norbelladine (85) --> A/-methylnorbelladine -->A/,0-dimethylnorbelladine (93) to finally give galanthamine (70) (137), the conversion of (94) to narwedine (77) either being not reversible or, if so, enzymically controlled (128). The precursor N,0dimethylnorbelladine (93) was first Isolated in 1988 from Pancratium maritimum (138) a species that also contains galanthamine (70) (Fig. 12a). Chlidanthine (95), by analogy with the known conversion of codeine to morphine, might be expected to arise from galanthamine (70) by 0-demethylation. This was shown to be true when both galanthamine (70) and narwedine (77), with tritium labels, were incorporated into chlidanthine (95) (139). However, the most recent studies related to the biosynthesis of galanthamine (70) seem to contradict the evidence set forth here. Experiments carried out in cell suspension cultures of Leucojum vernum have shown that the methylation of the nitrogen atom occurs after the phenolic coupling and is brought about through an acetyl intermediate (140) (Fig. 12b).
360
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361 4.
SPECTROSCOPY Only ^H NMR, ^^C NMR, and mass spectrometry, the three most important
spectroscopic methods for the Amaryllidaceae alkaloids, will be treated here. A list of names of the different Narcissus alkaloids, their physical and spectroscopic properties, as well as literature is given in Table 3. With respect to the spectroscopic results, the most recent data about the mentioned alkaloids are provided, even when isolation was made from species of genera other than Narcissus.
TABLE 3 Narcissus alkaloids data
Alkaloid
melting Molecular MW point °C Formula (Ref)
[a]D° (Ref.)
Additional data (Ref.)
18 assoanine
CnHnNO^
267
175-176° (141)
UV(26),IR(26),MS(26), ^H NMR (26), *^C NMR (26)
19 oxoassoanine
CnHisNOs
281
247-250° (26)
'H
261-263° (29)
'H
67 bicolorine
Ci5H,2N02
238
UV(26),IR(26),MS(26), NMR (26), ^'C NMR (26) IR (29), MS (29), NMR (29), '^C NMR (29)
57 6a-hydroxybuphanisine
C17H19NO4
301
[ah'' +37 128-130° MeOH; c 0.25 (31) (31)
UV(142),IR(142),MS(142), 'H NMR (142), '^C NMR (143)
58 6P-hydroxybuphanisine
C,7Hi9N04
301
128-130° [OC]D'" +37 (31) MeOH; c 0.25 (31)
UV (142), IR (142), MS (142), 'H NMR (142), ^^C NMR (143)
55 cantabricine
C,8H23N04
317
75-76° (31)
M D ' " -7.14 MeOH; c 0.52 (31)
[alo''-196.6 CHCI3; c 2.0 (145)
IR(31),MS(31), ^ H N M R ( 3 1 ) , *^CNMR(31)
UV (144), IR (144), MS (144), *H NMR (144), CD (146)
10 caranine
Ci6HnN03
271
176-178° (144)
53 crinamine
CnH,9N04
301
190-192° [a]D''+180 (147) CHCI3; c 0.55 (147)
UV (148), IR (147), MS (147), ^H NMR (148), ^^C NMR (148), CD (147), X-Ray (149)
60 criwelline
C18H21NO3
331
211-212° (150)
[a]D''+278 CHCl3;c0.21 (150)
UV (150), MS (151), ^H NMR (152), '^C NMR (152), CD (153)
36 dubiusine
C23H27NO8
445
226-228° (36)
UV(36),IR(36),MS(36), 'HNMR(36),''CNMR(36)
362 TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D° (Ref.)
Additional data (Ref.)
UV(38),IR(38),MS(38), 'H N M R (38), ''C NMR (154), CD(153),X-Ray(155)
70 galanthamine
C17H21NO3
287
124-126° (38)
[aC-115 EtOH;c0.5 (154)
72 0-acetylgalanthamine
C19H23NO4
329
129° (58)
MD' -61 MeOH;cl.3 (58)
71 epigalanthamine
C17H21NO3
287
199° (156)
[ah'' -327A EtOH;c0.27 (155)
UV(156),IR(155),MS(156), 'H NMR (155), CD (153)
73 norgalanthamine
Cl6H,9N03
273
156-158° [a]D''-74 (47) CHCI3; c 0.28 (157)
UV(158),IR(47),MS(47), *H NMR (47), '^C NMR (47), CD(159),X-Ray(160, 161)
74 epinorgalanthamine
C16H19N03
273
150-152° [a]D''-62 (60) CHCI3; c 0.73 (60)
IR (60), MS (60), ^H NMR (60),^^C NMR (60)
75 JV-formylnorgalanthamine
CnH,9N04
301
190-192° (38)
UV(38),IR(38),MS(38), 'H NMR (38),'^C NMR (38)
7 galanthine
C,8H23N04
317
160-162° [a]D''-94.7 (61) CHCI3; c 0.69 (162)
UV (162), MS (61), 'H NMR (61),'^C NMR (61)
8 goleptine
C,7H2,N04
303
49 haemanthamine
CnHi9N04
301
195-198° [a]D''+38.3 CHCI3; c 0.45 (38) (163)
50 11-O-acetylhaemanthamine
C19H21NO5
343
amorph. (33)
51 haemanthidine
C,7H,9N05
317
[a]o''-14 176-179° (167) CHCI3; c 0.28 (167)
UV(168),IR(169),MS(169), 'H NMR (164), '^C NMR (65), CD (153)
52 6-epihaemanthidine
C,7H.9N05
317
176-179° (167) CHCI3; c 0.28 (167)
UV(168),IR(169),MS(169), 'H NMR (164), ^^C NMR (65), CD (153)
30 hippeastrine
CnH^NOs
315
[a]D+138 212-213° (138) CHCI3; c 0.47 (138)
' H N M R ( 3 4 ) , *'CNMR(34),
23 homolycorine
C,8H2iN04
315
141° (64)
169-171° (69)
'H
IR(64)
[aL^^-99 CHCI3; c 0.2 (64)
[a]D''-9.1 MeOH; c 0.55 (33)
[a]D''+93.5 CHCl3;cl.2 (28)
UV (58), MS (58), NMR (58), •^C NMR (58)
UV(38),IR(38),MS(38), ^H NMR (164), *^C NMR (143), CD(165),X-Ray(166)
'H
IR (33), MS (33), NMR (33), ^^C NMR (33), CD (33)
UV(168),IR(34),MS(34), CD (170) UV(69),IR(69),MS(69), ^H NMR (69), *^C NMR (170), CD (170)
363 TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D°
Additional data (Ref.)
(Ref.)
24 8-0-demethylhomolycorine
C17H19NO4
301
138-140° (170)
[a]D''+89.6 CHCl3;c0.41 (171)
UV(172),IR(172),MS(75), ^H NMR (172), ^^C NMR (172), CD(172),X-Ray(173)
37 8-O-demethylhomolycorineA^-oxide
CnHi^NOs
317
153-154° (72)
M D ' ' +19 MeOH;c0.1 (72)
UV (72), IR (72), MS (72), *H NMR (72), *^C NMR (72)
25 8-O-demethyl8-O-acetylhomolycorine
C19H21NO5
343
186-188° (79)
[aJo'' +70.4 EtOH; c 0.54 (79)
IR (79), MS (79), ' H NMR (79),^^C NMR (79)
26 9-0-demethylhomolycorine
CnHi9N04
301
270-272° (69)
29 9-O-demethyl2a-hydroxyhomolycorine
CnHigNOs
317
272-275° (37)
68 ismine
CisHisNOs
257
98° (174)
CigHnNOs
327
188-190° (44)
9 jonquilline
UV(69),IR(69),MS(69), ^H NMR (69), *^C NMR (69)
[aJo +98.8 EtOH; c 0.52 (37)
IR (37), MS (37), ^HNMR(37),*^CNMR(37)
UV(174),IR(174),MS(174), *H NMR (174), " C NMR (65), X-Ray (65)
[aC-325
UV(44),IR(44)
CHCI3; c 0.5 (44)
78 lycoramine
C17H23NO3
289
120-121° (159)
[aJo'' -67.4 CHCI3; c 0.33 (159)
IR (159), MS (159), *H NMR (159),^^C NMR (159)
79 norlycoramine
C16H21NO3
275
123-124° (175)
[a]D''-39.1 CHCI3; c 0.95 (175)
IR (175), MS (175), ^H NMR (175),
80 epinorlycoramine
C,6H2,N03
275
[a]D''+79.1 CHCl3;c0.51 (60)
IR (60), MS (60), ' H NMR (60),"C NMR (60)
31 lycorenine
C18H23NO4
317
199-203° (176)
[alo''+172.4 CHCI3; c 0.7 (176)
UV (177), MS (178), *H NMR (82), *^C NMR (82), X-Ray (179)
32
C19H25NO4
331
125° (70)
[alo'"+164.1 CHCI3; c 0.53 (70)
IR (70), MS (70), ' H NMR (70),^^C NMR (70)
C,6Hi7N04
287
250° (148)
[ah'' -62 EtOH; c 0.1 (148)
UV(148),IR(148),MS(148), ^H NMR (148),'^C NMR (148), CD (153), X-Ray (180, 181)
C18H19NO5
329
126-128° (29)
[a]D^' +225.6 CHCl3;c0.15 (175)
IR (29), MS (29), ' H NMR (175),^^C NMR (29)
0-methyllycorenine
1 lycorine
62 3-epimacronine
364 TABLE 3 (continued) Alkaloid
40 maritidine
melting Molecular MW point °C (Ref.) Formula C,7H2,N03
287
[a]D° (Ref.)
250-252° [ah'' +26.8 (163) MeOH; c 0.78 (163) 139-141° (175)
[ah'' +28 EtOH;c0.53 (67)
Additional data (Ref.)
UV(48),IR(182),MS(163), 'HNMR(163),CD(183),
X-Ray(184)
41 8-(9-demethylmaritidine
C,6H,9N03
42 9-O-demethylmaritidine
C,6H,9N03
273
238-239° (75)
43 O-methylmaritidine
C,8H23N03
301
240-242° (72)
47 6a-hydroxy3-(9-methylepimaritidine
C18H23N04
317
[a]D''-10.2 CHCI3; c 0.45 (57)
UV(57),IR(57),MS(57), ' H NMR (57), CD (57)
48 6p-hydroxy3-0-methylepimaritidine
C18H23N04
317
[a]D''-10.2 CHCI3; c 0.45 (57)
UV (57), IR (57), MS (57), ' H NMR (57), CD (57)
27 masonine
C,7HnN04
299
180° (185)
[alo'' +55.6 CHCI3; c 0.5 (53)
UV(53),IR(53),MS(53), ^H NMR (53),^^C NMR (53), CD (170)
28 normasonine
C16H15N04
285
229° (picrate) (53)
[a]D''+9.1 CHCI3; c 0.4 (53)
'HNMR(53),^^CNMR(53)
273
82 mesembrenone
C,7H2iN03
287
177-180° (picrate) (25)
64 narciclasine
CuHnNOv
307
231-233° (88)
54 narcidine
C,7H2,N04
303
IR (175), MS (175), ' H N M R (164),^^C N M R
(67)
IR (75), MS (75), ' H NMR (75) W D ' ' +16 MeOH; c 0.1 (72) j
UV(72),IR(72),MS(72), ^H NMR (72),'^C NMR (72), CD (57)
UV(53),IR(53),MS(53),
IR (25), MS (25), ^H NMR (25), ^^C NMR (186)
[aJo'' +140 EtOH;c0.1 (88) M D +16 MeOH; c 0.11 (55)
UV (87), IR (87), MS (88), 'HNMR(88),^^CNMR(88),
X-Ray(187) UV(55),IR(55),MS(55), *HNMR(55)
56 narcimarkine
C2,H27N05
373
110° (50)
IR (50), MS (50),
65 narciprimine
C14H9N05
271
315-320° (188)
UV(87),IR(87),MS(188), ' H NMR (87)
76 narcisine
Ci8H2,N04
315
158-160° (56)
[aC-18 CHCl3;c0.5 (56)
UV(56),IR(56),MS(56), 'HNMR(56),'^CNMR(56)
365 TABLE 3 (continued) Molecular Formula
melting MW point °C (Ref.)
16 narcissidine
C18H23NO5
333
17 nartazine
C20H23NO6
77 narwedine
[a]D° (Ref.)
Additional data (Ref.)
203-205° (189)
[a]D''-28.3 CHCI3; c 0.32 (189)
UV (190), IR (191), MS (192), *H NMR (193), X-Ray (191)
373
185-186° (49)
[a]D''-120 CHCI3; c 0.25 (49)
IR(49)
CnHi9N03
285
189-190° (159)
MD''+112.2 CHCl3;c0.13 (159)
UV(156),IR(159),MS(159), *H NMR (159)
63 obesine
C,6HnN04
287
[ah'' -5.6 MeOH; c 0.69 (30)
MS (30),'H NMR (30), '^C NMR (30)
33 oduline
Ci7H,9N04
301
Alkaloid
165° (53)
[alo''+149.4 MeOH; c 3.0 (53)
UV(53),IR(53),MS(53), 'HNMR(53),*^CNMR(53)
34 6-0-methyloduline
C,8H2,N04
315
164° (picrate) (53)
[a]D''+148 MeOH; c 0.13 (53)
UV (53), IR (53), MS (53), *HNMR(53),'^CNMR(53)
35 2a-hydroxy6-O-methy loduline
Ci8H2,N05
331
245-248° (34)
[a]o''+91.1 CHCI3; c 0.34 (34)
IR (34), MS (34), ^H NMR (34),^^C NMR (34)
81 pallidiflorine
C34H40N2O7
588
69 pancracine
C,6Hi7N04
287
44 papyramine
C18H23N04
317
IR (66), MS (66), 'H NMR (66),'^C NMR (66) 272° (194)
MD^+74
MeOH; c 0.6 (194)
110-112° MeOH; c 0.25 (61) (72)
45 6-epipapyramine
C18H23N04
317
110-112° MeOH; c 0.25 (61) (72)
46 O-methyl6-epipapyramine
C19H25N04
331
amorph. (72)
[a]D''-31 MeOH; c 0.1 (72)
11 pluviine
C17H21N03
287
220-222° (93)
[a]D-165 CHCI3; c 0.35 (93)
13 9-O-demethylpluviine
C16H19N03
273
148° (58)
[a]D''+61 MeOH; c 2.4 I (58)
UV (194), MS (194),*H NMR (194), ^'C NMR (194), CD (194)
UV(72),IR(61),MS(61), 'HNMR(61),^^CNMR(61)
UV(72),IR(61),MS(61), ^HNMR(61),''CNMR(61)
UV(72),IR(72),MS(72), NMR (72), ''C NMR (72)
'H
UV (93)
UV (58), MS (58), ^H NMR (58),'^C NMR (58)
366
TABLE 3 (continued) Alkaloid
melting Molecular MW point °C (Ref.) Formula
[a]D° (Ref.)
Additional data (Ref.)
UV (58), MS (58), ^HNMR(58),'^CNMR(58)
14 1-O-acetyl9-O-demethylpluviine
C.8H21NO4
315
203° (58)
[ot]D''+38 MeOH;cl.O (58)
15 1,9-0-diacetyl9-O-demethylpluviine
C20H23NO5
357
147° (58)
[a]D''+8.3 MeOH;cl.l (58)
12 norpluviine
C,6H,9N03
273
[a]D-232 239-241° (93) MeOH; c 0.06 (93)
CisHipNOs
329
221-223° (196)
[a]D^VlOO EtOH; c 0.2 (196)
UV(196),IR(196)
38 poetinatine
C20H23NO6
373
212-213° (52)
[a]D''+50 CHCl3;c0.15 (52)
IR (52), MS (52), 'H NMR (52)
61 pretazettine
C,8H2,N05
331
227-229° (175)
[aJo^'+189.9 CHCI3; c 0.64 (197)
UV(198),IR(198),MS(198), 'H NMR (198), CD (199)
3 pseudolycorine
C,6H,9N04
289
[a]D''-60 237-240° (94) MeOH; c 0.04 (72)
UV (94), IR (94), MS (94), 'H NMR (94),'^C NMR (94)
4 1-O-acetylpseudolycorine
C,8H2iN05
331
248-250° (94)
5 2-O-acetylpseudolycorine
C,8H2,N05
331
168-170° (94)
6 9-O-methylpseudolycorine
C,7H2lN04
303
22 roserine
C,8H22N03
300
59 tazettine
C,8H2lN05
331
2 poetaminine
222-226° (200)
UV (58), MS (58), (58), '^C NMR (58)
'H NMR
UV(93),IR(195)
UV(94),IR(94),MS(94), 'H NMR (94) UV(94),IR(94),MS(94), NMR (94), '^C NMR (94)
'H
[a]D''-43 EtOH; c 0.4 (200)
UV(200),IR(28),MS(200), 'H NMR (200)
MS (96),'H NMR (96), '^C NMR (96) 202-203° (167)
[(X]D''+138
CHCI3; c 0.23 (167)
UV(201),IR(202),MS(198), 'H NMR (198), *^C NMR (203), CD (153)
21 tortuosine
Ci8H,8N03
296
242-243° (85)
IR (85), MS (85), *H NMR (85),'^C NMR (85)
66 trisphaeridine
C,4H9N02
223
132-134° (174)
UV(174),IR(174),MS(174), 'H NMR (174), '^C NMR (65)
20 vasconine
CnH,6N02
266
233-235° (79)
'HNMR(34),'^CNMR(34)
IR (79), MS (79),
367
TABLE 3 (continued) melting Molecular MW point °C Formula (Ref.)
Alkaloid
39 vittatine
C,6HnN03
271
206-208° (31)
[a]D°
Additional data (Ref.)
(Ref.) [a]D''+26 MeOH; c 0.25 (31)
UV (138), IR (138), MS (138), ' H N M R (164), ''C NMR (143), CD (204)
The pairs: 6a-hydroxybuphanisine/6p-hydroxybuphanisine (57/58), haemanthidine/6-epihaemanthidme (51/52), 6ahydroxy-3-0-methylepimaritidine/6p-hydroxy-3-0-methylepimaritidine (47/48), and papyramine/6-epipapyramine (44/45), exist in solution as a mixture of C-6 epimers, and their data were obtained from these mixtures. In the case of narwedine (77), a rapid racemisation occurs in the presence of base (89). Narciprimine (65) is considered an artifact produced from narciclasine (64) during acid extraction (89), and tazettine (59) has been shown to be an artifact produced by base-catalysed rearrangement of pretazettine (61) (199, 205). Narcissamine (32, 42) is a quasi-racemic mixture consisting of equimolar amounts of norgalanthamine (73) and norlycoramine (79)
4.1 Proton Nuclear Magnetic Resonance ^H NMR spectroscopy gives important information about the different types of Amaryllidaceae alkaloids. Several early contributions about homolycorine and crinanehaemanthamlne type alkaloids were made by Hawksworth et al. (206) and Haugwitz et al. (207). In the last decade, the routine use of 2D NMR tecniques (COSY, NOESY, ROESY, etc.) has facilitated the structural assignments and the settling of their stereochemistry. A compilation of the different ^H NMR spectra, arranged according to the different skeleton types is shown in Table 4.
a." Lycorine type This group has been subject to several ^H NMR studies and lycorine (1) as well as Its main derivatives have been completely assigned. The general characteristics of the ^H NMR spectra are: i
Two singlets for the para-oriented aromatic protons in the range 5 6.5-7.2 ppm.
ii
A unique olefinic proton around 5.5 ppm.
iii
Two doublets as an AB system corresponding to the benzylic protons of C-6.
Iv
The deshielding observed in the p protons of positions 6 and 12 In relation to their a-homologues is due to the effect of the c/s-lone pair of the nitrogen atom.
368
V
Like almost all other lycorine type examples, the alkaloids isolated from Narcissus genus show a trans B/C ring junction, the coupling constant being ^4a.10b~11HZ.
In the plant, the alkaloid lycorine (1) is particularly vulnerable to the oxidation processes giving several ring-C aromatized products.
b.- Homolycorine type This group includes lactone, hemiacetal or cyclic ether (unusual) alkaloids. The general traits for this type of compounds could be summarized as follows: i
Two singlets for the para-oriented aromatic protons. In lactone alkaloids, differentiation of the H-7 and H-10 signals is readily made by virtue of the deshielding of H-7 by effect of the per/-carbonyl group,
ii
The hemiacetal alkaloids always show the substituent at C-6 in a-disposition, and the benzylic proton H-6p appears as a singlet between 5-6 ppm, depending on the substituent at C-6.
iii
The majority of compounds belong to a single enantiomeric series containing a cis B/C ring junction, which is made clear by the small size of the coupling constant J^ ^ob- '" *he Narcissus genus no exception to this rule has been observed,
iv
The large coupling constant between H-4a and H-10b (J^g^^Q^^~^OHz), is only consistent with a frans-diaxial relationship.
V
In general, the C ring presents a vinylic proton around 5.5 ppm.
vi
The singlet corresponding to the A/-methyl group is in the range 6 2.0-2.2 ppm, its non existence being very unusual,
vii If position 2 is substituted by an OH, OMe OAc group, it always displays an adisposition. viii The H-12a is more deshielded than H-12P as a consequence of the c/s-lone pair of the nitrogen atom.
An interesting study of homolycorine type alkaloids with a saturated ring C has been made by Jeff and coworkers (208). They describe empirical correlations of A/-methyl chemical shifts with stereochemical assignments of the B/C and C/D ring junction.
369 c- Crinine - Haemanthamine types The absolute configuration of these alkaloids, which allows
both series to be
differentiated, is determined through the circular dichroism spectrum. The alkaloids of the Narcissus genus usually belong to the haemanthamine type, while in genera such as Brunsvigia, Boophane etc., the crinine type alkaloids are predominant. It is also noteworthy that the alkaloids isolated from the Narcissus genus do not show additional substitutions in the aromatic ring apart from those of C-8 and C-9. On the contrary, in the genera where crinine type alkaloids predominate, the presence of compounds with a methoxy substituent at C-7 is quite common. Thus, taking into account the previous considerations, haemanthamine type alkaloids show the following characteristics: i
Two singlets for the para-oriented aromatic protons In the range 5 6.4-7.0 ppm.
ii
Using CDCI3 as the solvent, the magnitude of the coupling constants between each olefinic proton (H-1 and H-2) and H-3 gives information about the configuration of the C-3 substituent. Thus, in those alkaloids in which the twocarbon bridge (C-11 and C-12) was cis to the substituent at C-3, H-1 shows an allylic coupling with H-3 (J^ 3~1-2 Hz) and H-2 a smaller coupling with H-3 (^2,3-0" 1.5 Hz), as occurs in crinamine (53). On the contrary, in the corresponding C-3 epimeric series, e.g. haemanthamine (49), a larger coupling between H-2 and H3 (Ja.sS Hz) is shown, the coupling between H-1 and H-3 not being detectable,
iii
It is frequently possible to observe an additional coupling of H-2 with the equatorial H-4p, in a W-mechanism.
iv
The proton H-4a shows a large coupling with H-4a (J4a4a~13 Hz) due to their frans-dlaxial position, characteristic of the haemanthamine series.
V
Two doublets for an AB system corresponding to the benzylic protons of position C-6.
vi
The pairs of alkaloids with a hydroxy substituent at C-6, like papyramlne/6epipapyramine
(44/45),
haemanthidine/6-epihaemanthldine
(51/52)
etc.,
appear as a mixture of epimers not separable even by HPLC. vii Also in relation with position C-6, It is interesting to note that ismine (68), a catabolic product from the haemanthamine series, shows a restricted rotation around the biarylic bond, which makes the methylenic protons at the benzylic position magnetically non-equivalent.
370 d.- Tazettine type Although tazettine (59) is one of the most widely distributed alkaloids
in the
Amaryllidaceae family, it was found to be an extraction artifact of pretazettine (61) (209). The presence of an A/-methyl group (2.4-2.5 ppm) in tazettine type alkaloids inmediately distinguishes
them from the haemanthamine
type, from which
they
proceed
biosynthetically. Moreover the ^H NMR spectrum always shows the signal corresponding to the methylenedioxy group. We have also included the alkaloid obesine (63) in this group, although it exhibits some structural differences with the skeleton type.
e.- Galanthamine type Among the Amaryllidaceae alkaloids, only the galanthamine type shows an orthocoupling constant between both aromatic protons of ring A. The general characteristics of their ^H NMR spectra are: i Two doublets for the two OAt/7o-oriented aromatic protons with a coupling constant of J^g-SHz. ii The assignment of the substituent stereochemistry at C-3 is made In relation with the coupling constants of the olefinic protons H-4 and H-4a. When coupling constant J^^ is about 5 Hz, the substituent is pseudoaxial while if It is ~0 Hz this indicates that the substituent at C-3 is pseudoequatorlal. ill Two doublets as an AB system corresponding to the benzylic protons of C-6. iv The existence of the furan ring results in a deshielding effect in H-1. V This type of alkaloids often show an A/-methyl group but occasionally A/-formyl or A/-acetyl derivatives have been reported.
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TABLE 4a (continued) ^H NMR data of Lycorine type alkaloids. 20
21
H-1
7.31 dd
7.85 br d
8.32 d
8.13 d
H-2
6.75 t
7.27 t
7.84 t
H-3
6.99 dt
7.33 br d
7.70 d
Alkaloid
18
19
I
7.59 brs
22 2.85 ddd 3.13 dd
a
1.8-1.95 m 2.25-2.4 m
a
1.38 qd
a
2.25-2.4 m
p
3.4-3.5 m
H-4 H-6
4.09 s
10.42 s
9.55 s
9.50 s
H-7
6.64 s
7.57 s
8.09 s
7.92 s
6.95 s
H-10
7.17 s
7.81 s
7.86 s
8.34 s
H-11 (2H)
3.00 br t
3.45 brt
3.76 t
3.88 t
2.05 ddd
a P
5.42 t
5.35 t
2.70 dt 4.75-4.95 m
4.33 s
4.15 s
4.20 s
4.05 s
4.17 s
1 3.90 s
3.32 t
4.45 br t
OMe
3.93 s
4.09 s
4.19 s
OMe
3.87 s
4.03 s
4.08 s
H-12(2H)
OMe d
b
b
c
MHz
200
200
500
500
Ref.
(26)
(26)
(34)
(85)
solvent
Solvent a: DMSO-c/e, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.
1 ^ 1
250 (96)
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TABLE 4b (continued) ^H NMR data of Homolycorine type compounds: hemiacetal alkaloids. Alkaloid
31
32
33
34
35
4.35 br d 2.35 m
4.29 br d 2.35 m
4.35 d 2.31 dm
4.17 d 2.26 dd
4.15 brs
H-2p
2.65 m
2.53 dm
4.21 brs
5.50 br s
5.46 br d 2.72 br d
5.39 br s 2.69 br d
5.69 br s
2.78 br d
2.65 m 5.50 br d 2.77 dd
2.62 dm
H-3 H-4a H-6p
5.93 s
5.54 s
5.99 s
5.39 br s
5.43 s
H-7
6.93 s
6.80 s
6.85 s
6.67 s
6.73 s
H-10
6.99 s
6.93 s
6.90 s
6.77 s
6.94 s
H-10b
2.44 dd
2.44 dd
2.4-2.5 m
2.35 dd
2.85 d
H-11 (2H)
2.4-2.6 m
2.4-2.6 m
2.4-2.5 m
2.3-2.4 m
2.54 m
H-12a
3.15 ddd
3.15 ddd
3.14 ddd
3.08 dd
3.33 m
H-12|3
2.27 dd
2.23 dd
2.25 dd
2.17 dd
2.38 dt
5.97 d
5.83 d
5.91 (2d)
3.43 s
3.51 s
2.22 s
H-1a H-2a
OCH2O OMe
3.88 s
3.89 s
OMe
3.87 s
3.88 s
OMe NMe
2.87 d
3.55 s 2.08 s
2.10 s
2.11 s
2.05 s
solvent MHz
c
d
d
d
d
250
200
400
400
500
Ref.
(82)
(70)
(53)
(53)
(34)
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4.2 Carbon^^ Nuclear Magnetic Resonance ^^C NMR spectroscopy has been extensively used for determining the carbon framework of Amaryllidaceae alkaloids, and the major contributions are due to Grain et al (203), Zetta and Gatti (210), and Frahm et al. (143). The assignments are made on the basis of chemical shifts and multiplicities of the signals (by DEPT experiment). The use of 2D NMR tecniques such as HMQG and HMBC allow the assignments to be corroborated. Table 5 shows a compilation of the different ^^G NMR spectra classified according to the different types. The ^^G NMR spectra of Narcissus alkaloids can be divided in two regions. The low-field region (>90 ppm) contains signals of the carbonyl group, the olefinic and aromatic carbons as well as that of the methylenedioxy group. The other signals, corresponding to the saturated carbon resonances are found in the high-field region, the A/-methyl being the only characteristic group, easily recognizable by a quartet signal between 40-46 ppm. The effect of the substituent (OH, OMe, OAc) on the carbon resonances is of considerable importance in localizing the position of the functional groups. The analysis of the spectra allows conclusions to be drawn about the following aspects: - The number of methine olefinic carbons. - The presence and nature of the nitrogen substituent. - The existence of a lactonic carbonyl group. - The presence of a quaternary carbon signal assignable to G-lOb in the chemical shift range of 42-50 ppm.
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Table 5d ^^C NMR data of Tazettine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OCH2O OMe NMe solvent MHz Ref.
59 130.5 128.4 72.4 26.6 69.9 65.0 127.8 103.7 146.3 146.3 109.1 125.4 50.1 101.7 61.7 100.6 55.6 41.9 d 16 (203)
60 130.1 128.9 72.1 25.4 68.2 62.6 126.2 108.5 146.6 146.2 104.2 130.9 50.0 102.6 64.5 100.9 56.7 40.6 d 75 (152)
62 131.3 126.0 72.7 29.8 63.3 168.5 118.6 103.8 147.1 152.3 111.0 142.2 46.2 80.1 53.5 102.1 56.2 42.8 d 50 (29)
63 132.4 136.5 63.6 34.4 68.5 62.2 131.0 107.3 148.4 147.3 111.0 125.0 50.3 82.7 55.7 101.9
c 62 (30)
Solvent a: DMSO-ofg, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.
Table 5e ^^C NMR data of Narciclasine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-lOa C-1 Ob OCH2O NMe solvent MHz Ref.
64 124.7 69.1 72.3 68.8 52.8 172.1 129.2 168.9 152.3 144.8 95.7 132.1 133.3 102.0
66 122.0 126.7 128.1 129.9 143.8 151.8 123.1 105.5 148.1 148.2 99.9 130.3 124.3 101.9
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68 129.9 118.0 129.1 110.7 146.7 63.5 134.0 109.7 147.5 147.4 110.2 131.2 127.2 101.3 30.8 d 50 (65)
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Table 5f ^^C NMR data of Galanthamine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OMe NMe NCHO OCMe OCMe solvent MHz Ref.
70 88.1 30.0 62.2 126.8 126.0 60.5 129.5 121.6 110.5 145.5 144.0 132.7 48.2 34.0 54.3 55.5 42.2
72 86.2 27.7 63.2 123.3 121.8 59.9 127.2 130.2 111.7 146.7 144.4 131.9 47.8 33.7 53.4 56.0 40.9
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73 88.2 30.3 61.7 129.2 125.9 51.6 123.6 122.8 112.2 146.9 145.3 133.1 48.2 35.6 45.9 56.2
74 88.4 29.9 61.9 127.6 127.1 53.5 132.1 120.9 111.3 146.2 144.1 133.1 48.5 39.7 46.8 55.9
75 87.9/88.7 29.8 61.4 128.0/128.2 125.8/126.2 41.0/52.8 127.4 119.9/121.6 111.4 146.2/146.5 144.3/144.5 131.8/131.9 48.0/48.1 46.6/46.7 35.7/39.1 55.8
76 88.7 29.2 61.4 128.2 125.1 58.4 127.1 121.2 111.3 146.8 144.5 131.2 48.1 35.1 35.2 55.6
78 89.8 31.5 65.2 27.6 31.7 60.4 129.1 121.6 111.3 146.2 144.0 136.3 46.7 23.9 54.1 55.9 41.9
80 90.0 31.7 65.5 27.8 37.5 53.8 127.2 120.8 110.9 146.6 144.2 136.6 47.4 24.2 47.4 56.1
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161.2 21.4 d 50 (56)
384
4.3 Mass Spectrometry Extensive studies on the mass spectrometry of Amaryllidaceae alkaloids by electron impact were reported in the sixties and seventies (92, 151, 178, 192, 211-218). The fragmentation patterns in the EIMS of various skeletal types are fairly well documented and have considerable diagnostic value.
a.- Lycorine type The molecular ion appears as a quite intense peak, and generally suffers the loss of water, as well as C-1 and C-2 and their substituents by a retro Diels-Alder fragmentation (Fig. 13). The loss of water is not present in the spectra of acetyl derivatives. The ease of the loss of water from the molecular ion was found to be greatly dependent on the stereochemistry of the C-2 hydroxyl group. Thus, in the mass spectrum of lycorine (1) the relative intensity is low, while in 2-epilycorine it is the base peak (192).
b.- Homolycorine type In this structure type the cleavage of the labile bonds in ring C by a retro Diels-Alder reaction is dominant, generating two fragments: one, the most characteristic, represents the pyrrolidine ring (plus substituents in position 2), and the other (a less abundant fragment) encompasses the aromatic lactone or hemilactone moiety (Fig. 14). A further general and noteworthy feature is the low abundance of the molecular ion in all compounds with a double bond A^'"* (211).
c- Crinine-Haemanthamine types Several general considerations should be taken into account for these types of alkaloids: The stability of the molecular ion, which is almost always the base peak. The important role played by the aromatic ring in the stabilization of the Ions, which is retained in all fragments of high mass while the nitrogen atom is often lost. The relatively large number of nitrogen-free ions. The fragmentation mechanisms are initiated by the rupture of a bond p to the nitrogen atom which implies the opening of the C-11/C-12 bridge (215, 216).
c.1. Compounds with a saturated ring C and no bridge substituent. The configuration of the substituent on ring C plays a minor role in the fragmentation process.
385 C.2. Compounds with a double bond (A^'^) in ring C and no bridge substituent. The fragnnentation pattern involves ruptures of C-4a/C-10b and C-3/C-4 bonds. A characteristic feature is the loss of a nitrogen-containing nnoiety, C3H5N [M-55]. C.3. Compounds with a double bond (A^'^) in ring C and a hydroxyl substituent at C-11. The presence of a hydroxyl group on C-11 is responsible for dramatic changes in the fragmentation pattern (Fig. 15), and it is profoundly influenced by the stereochemistry. There are three fundamental patterns of fragmentation: Loss of CH3OH: it is more favorable when the two-carbon bridge and the substituent on C-3 are on the same side of the molecule. Loss of C2H6N: the relative significance of the loss of this neutral nitrogen moiety is governed by the ease with which the methanol is eliminated. Loss of CHO: A peak at m/z [M-29] due to the loss of an aldehyde radical is present In all compounds of this type.
d.- Tazettine type Minor changes in stereochemistry are sufficient to cause appreciable differences in the stereoisomers in these kind of structures. Thus, in the MS of tazettine (59), with a p configuration of the methoxyl group at C-3, the dominant ion occurs at m/z [M-84], following a C-ring fragmentation by a retro Diels-Alder process. In contrast, the mass spectrum of criwelline (60), which differs only in the configuration of the mentioned methoxyl group, contains a peak of low abundance at A7yz[M-84] (Fig. 16). Ions occur in both steroisomers due to the successive loss of a methyl radical and water from the molecular ion (151).
e.- Galanthamine type In this type of structures, the intense molecular ion as well as [M-1] peak, the breaking of ring C (losing a C4H6O fragment) and the elimination of elements of ring B (including the nitrogen atom) are characteristic (Fig. 17). This behavior is similar for the dihydro derivatives (213).
386
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BIOLOGICAL AND PHARMACOLOGICAL ACTIVITIES Plants of the genus Narcissus L. have been used throughout history to treat a va-
riety of human medical problems (219). N. poeticus L., for example, was described in the Bible as a well-established treatment for symptomatologies now defined as cancer (220). In the fourth century BO, the Greek physician Hippocrates of Cos (the "Father of Medicine") recommended a pessary prepared from narcissus oil (probably N. poeticus L.) for the management of uterine tumours (221). In the first century AD, Pliny the Elder recorded the topical use of that extract and another derived from N. pseudonarcissus L. for this purpose (N. poeticus L. is now known to contain 0.12 g of the antineoplastic agent narciclasine (64) per kg of fresh bulb) (86). Arabian, North African, Central American and Chinese medical practitioners of the middle ages continued using Narcissus oil in cancer treatment (222). For example, bulbs of N. tazetta L. var. chiinensis Roem., cultivated in China as a decorative plant, were used for treatment of tumours in folk medicine. In this case, pretazettine (61) was proved to be one of the antltumour active compounds (57). It has been known for a long time that daffodil ingestions are very dangerous, resulting in toxic symptoms. After ingestion of N. tazetta L. (43) and N. jonquilla L. (223), the first visible symptoms are nausea, vomiting and diarrhea, followed by neurological (trembling, convulsions, etc.) and cardiac sequelae, and sometimes resulting in death if eaten in quantity. N. papyraceus Ker-Gawler is believed to be toxic for herbivorous mammalians; in this case, the toxicity might be related to the alkaloid content which is five times higher in the aerial part than in the bulbs (72). Moreover, N. pseudonarcissus L. showed irritant and allergenic properties on contact with animals and men (74, 224, 225). Apart from these harmful effects of daffodils, several Narcissus extracts have shown antiviral (226-231), antimicrobial (232, 233), cytotoxic (234), antitumour (228-230, 235) and allelopathic (236) activities. Table 6 shows the different pharmacological and/or biological properties exhibited by the alkaloids from the genus Narcissus L., but only some of the activities of a reduced number of Narcissus alkaloids are known. The most extensively studied effect is that of non-specific inhibition, e.g. antitumour, antimitotic, suppression of development of splenomegaly and increase in number of nucleated blood cells. The relationship of chemical structure and biological activity of these alkaloids is largely unknown (236), and further
392
studies of several alkaloids of this plant family for therapeutic purposes remain still to be done.
TABLE 6 Biological and pharmacological activities of Narcissus alkaloids
Alkaloid
Activity
References
57 6a-hydroxybuphanisine
• Moderate cytotoxic against human tumoral Molt 4 cells
(237)
10 caranine
• • • •
Weak analgesic Convulsant and hypotensive Acetylcholinesterase inhibitor Active against the murine P-388 lymphocytic leukaemia (as acetylcaranine)
(89) (89) (89) (238)
53 crinamine
• • • • • •
Powerful transient hypotensive in dogs Respiratory depressant Moderate antimalarial Antimicrobial Strong cytotoxic Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines • Weak cytotoxic against HepG2 hepatoma
(89) (89) (148) (239) (148) (240)
36 dubiusine
• Cytotoxic against non-tumoral LMTK cells • Moderately active against Molt 4 lymphoma
(240) (240)
70 galanthamine
• • • • •
(89,241,242) (243) (244) (245) (246, 247)
• • • •
•
Powerful analgesic Anticonvulsive Hypotensive Inductor ofhypothermia in rat Cholinesterase inhibitor with peripheral and central pharmacological effects Centrally-acting competitive acethylcholinesterase inhibitor under investigation as therapeutic agent in treating Alzheimer's disease Reverses cognitive deficits induced by nBM (nucleus basalts magnocellularis) lesions in mice Anticurare and antimorphine as well as memory-influencing Combines both physostigmine and neostigmine properties: * like physostigmine, reverses opioid-induced respiratory depression, but not the concomitant analgesia * like neostigmine, antagonises muscle paralysis induced by cZ-tubocurarine, also antagonises the ganglionic blockade and increases the contraction response As hydrobromide has several central and peripheral effects: * has central effects such as antagonism of the respiratory depressant effect of morphine-like compounds * is capable of penetrating the blood-brain barrier and it is used in the treatment of the central effects of scopolamine (hyoscine) intoxication. It has certain advantages over physotigmine for this purpose. * is able to reverse the central anticholinergic syndrome
(240)
(89, 248-254) (230,249,251) (255) (256) (255, 257) (244)
(257- 259) (247, 260)
256,
(256, 258)
257,
393 TABLE 6 (continued) Alkaloid
Activity
70 galanthamine (cont.)
• • • •
* is used for its anticholinesterase activity in the treatment of disturbances in the peripheral sympathetic synaptic transmission. * reverses the neuromuscular blocking effect of curare-type muscle relaxants and has been used safely in anaesthesia and in the treatment of various neurologic disorders (pareses, paralysis of different origins, myasthenia gravis, progressive muscular dystrophy, etc.). Energix®, a preparation composed of galanthamine, increases endurance during exercise and delays the onset of fatigue Used in a pharmaceutical composition for treatment of alcoholism Cytotoxic against non-tumoral LMTK cells Produces poisoning of digestive, respiratory, neuromuscular and central nervous systems
References (259) (242, 246, 250, 255-258,261-263)
(264-266) (267) (240) (43)
71 epigalanthamine
• More hypotensive and less toxic than galanthamine • Anticholinesterase activity lower than galanthamine
(268) (268, 269)
73 norgalanthamine
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines
(240)
75 7V-formylnorgalanthamine
• Moderate cytotoxic against Molt 4 lymphoma and HepG2 hepatoma • Cytotoxic against non-tumoral LMTK cells
(240) (240)
• Hypotensive • Weak cytotoxic against Molt 4 lymphoid cells
(89) (240)
• • • • • • •
Hypertensive Cytotoxic against a variety of cultured cells (in vitro) Cytotoxic against fibroblastic LMTK cells Moderately active against Molt 4 lymphoid cells Moderately active against Rauscher leukaemia Inhibitor of HeLa cell growth Inhibitor of protein synthesis, blocking the peptide bond formation step on the peptidyl transferase centre of the 60S ribosomal subunit • Slightly reduces DNA synthesis, whereas RNA synthesis is practically unaffected
(270) (271) (240) (240) (234) (272) (272, 273)
51 haemanthidine
• Active against A-431, KB, Lul, Mel2 and ZR-75-1 cell lines • Significantly active against LNCaP and HT cell lines
(167) (167)
30 hippeastrine
• • • • •
(274) (7) (167) (240) (240)
23 homolycorine
• Inductor of delayed hypersensitivity in animals • Cytotoxic against fibroblastic LMTK cells
(74) (240)
24 8-O-demethylhomolycorine
• Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against Molt 4 lymphoid cells
(240) (240)
7 galanthine
49 haemanthamine
Antiviral. Active against Herpes simplex type 1 (HS-1) Weak insect antifeedant Significantly active against the LNCaP and HT cell lines Cytotoxic against non-cancerous LMTK cells Weak cytotoxic against Molt 4 lymphoid cells
(272)
394 TABLE 6 (continued) A kaloid
Activity
References
29 9-O-demethyl2a-hydroxyhomolycorine
• Cytotoxic against fibroblastic LMTK cells • Moderately active against Molt 4 lymphoid cells
(240) (240)
68 ismine
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines
(240)
78 lycoramine
• Central anticholinesterase activity stronger than galanthamine • Like neostigmine, antagonises muscle paralysis induced by dtubocurarine, also antagonises the ganglionic blockade, and increases the contraction response • Produces acute poisoning of digestive, respiratory, cardiovascular. neuromuscular and central nervous systems
(244) (244)
31 lycorenine
• Weak hypotensive • Cytotoxic against murine LMTK and human HepG2 cell lines
(270) (240)
32 O-methyllycorenine
• Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against HepG2 hepatoma
(240) (240)
• Respiratory stimulant • Relaxant of isolated epinephrine-precontracted pulmonary artery • Increases contractility and rate of isolated perfused heart. These effects are mediated by stimulation of p-adrenergic receptors • Specific inhibitor of ascorbic acid (AA) biosynthesis. Seems to act as a non-competitive inhibitor on galactano-gamma-lactone oxidase • Most of the effects of lycorine on physiological processes have been ascribed to its ability to inhibit ascorbic acid biosynthesis in
(89, 275) (275) (275)
1 lycorine
(43, 244)
(275-279) (144)
VIVO.
• The ability to inhibit the ascorbic acid biosynthesis has made this substance a valuable tool for studying the AA-dependent reactions • Inhibitor of cyanide-resistant respiration. AA is needed for the in vivo synthesis of hydroxyproline-containing proteins, specifically utilised for the development of KCN-resistant respiration. • Inhibitor of peroxidase enhancement, which seems related with the synthesis of hydroxyproline-containing proteins • Inhibitor of cell division in rat fibroblasts. Ascorbic acid is required for cell division • Inhibitor of protein blocking peptide bond formation • Inhibitor of DNA synthesis. • Moderate antitumoural • Cytotoxic against a variety of cultured cell lines • Inhibitor of HeLa cells growth • Decreases the growth of several viruses through its inhibitory action on viral protein synthesis • Active against several RNA and DNA viruses. Inhibits the growth of Herpes simplex type I, poliomyelitis, coxsackie, Semliki Forest and measles viruses • Active against RNA-containing flaviviruses and bunyaviruses • Does not inhibit the activity of reverse transcriptase • Weak protozoicide • Plant growth inhibitor by inhibition of protein synthesis • Inhibitor of growth and cell division in plants, inhibiting the cell cycle during interphase. Ascorbic acid is required for cell division
(279-282) (144, 281)
277,
279,
(144,281) (240, 282) (272, 273, 283) (272, 283) (89, 274, 275) (148,271,240) (272) (284-287) (89, 274, 275, 286288) (289) (228) (89) (89) (144, 275, 277, 279, 282)
395 TABLE 6 (continued) Activity
References
• Inhibitor of germination of seeds and growth of roots. Lycorine-1O-P-D-glucose has the reverse effect, and may also produce mitogenic activity in animal cells • Ungeremine, a natural metabolite of lycorine, is responsible, at least in part, for the growth-inhibitory and cytotoxic effects of lycorine • Certain bacteries transform lycorine into pancrassidine, which is less cytotoxic than ungeremine. • The changes observed in response to stress suggest its role in protective and repair mechanisms of producer plants • Inhibits the feeding of the desert locust Schistocerca gregaria
(283, 290)
(294)
62 3-epimacronine
• Weak cytotoxic against human Molt 4 and murine LMTK cell Imes
(240)
27 masonine
• Inductor of delayed hypersensitivity in animals
(74)
82 mesembrenone
• Cytotoxic against Molt 4 lymphoid cells • Weak cytotoxic agamst fibroblastic LMTK cells
(240) (240)
64 narciclasine
• Antimitotic • Strong tumour inhibitor. One of the most important antineoplastic components of Amaryllidaceae species • Active against larynx and cervix carcinomas • Inhibitor of HeLa cells growth • Inhibitor of growth of Ehrlich tumour cells • Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. • Resistance to narciclasine in a mutant strain of Saccharomyces cerevisiae is due to an alteration on the peptidyl transferase centre • Reduces DNA synthesis, whereas RNA synthesis is practically unaffected • Inhibitor of ascorbic acid biosynthesis in vivo • Strong antibiotic. Active against Corynebacterium fascians • Active against RNA-containingflavivirusesand bunyaviruses • Inhibitor of cell division in tobacco tissue culture • Inhibitor of Avena coleoptile sections and rice seedling test • Inhibitor of seed germination and root growth at low concentrations. The O-glucoside of narciclasine has the reverse effect • Narciclasine-4-O-P-D-glucopyranoside shows cytotoxic and antitumour activity very similar to narciclasine • The peculiar activity of narciclasine seems to arise from the ftmctional groups and conformationalfreedomof its C-ring
(88, 89, 295) (89, 222,296, 297)
• Increases the amplitude andfrequencyof respiratory movements • Increases the amplitude and decreases the frequency of cardiac contractions • Decreases the soporific effects of ethanol and barbiturics • Increases the analgesic effect of morphine • Protective against thiopental poisoning • Enhances the effects of caffeine, corazole, arecoline, and nicotine • Probably acts primarily on m-cholinoreactive structures of the brain
(304) (304)
Alkaloid 1 lycorine (cont.)
11 narwedine
(291) (292) (293)
(298) (272) (221,299,300) (89, 273, 299-301) (299) (272) (88, 144) (88) (289) (297) (297) (302) (303) (88)
(304) (304) (304) (90) (90)
44 papyramine
(240) • Cytotoxic against fibroblastic LMTK cells • Weak cytotoxic against human tumoral cell lines Molt 4 and HepG2 (240)
61 pretazettine
• Active against murine Rauscher viral leukaemia
(89, 205, 230, 234, 288)
396 TABLE 6 (continued) Alkaloid 61 pretazettine (cont.)
3 pseudolycorine
j Activity
References
• Active against spontaneous AKR T cells in mice • Active against intraperitoneally and subcutaneously implanted LLC (Lewis lung carcinomas) • Effective against Ehrlich ascites tumour, a non viral transplantable tumour • Cytotoxic against fibroblastic LMTK and Molt 4 lymphoid cell lines • Inhibitor ofHeLa cell growth • Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. • Slightly reduces DNA synthesis; has no effect on RNA synthesis • Active against Herpes simplex type 1 (HS-1) • Active against neurotropic RNA viruses • Potent inhibitor of viral reverse transcriptase of RNA tumour viruses, binding to the polymerase enzyme • Demonstrates synergistic effect in combination with standard cytotoxic drugs • In combination with ryllistine inhibits nucleic acid synthesis • Can be administrated over a long period of time without apparent toxicity
(199, 305-308) (307)
• Effective against murine Rauscher leukaemia in mice, suppressing the splenomegaly and the increase of nucleated blood cells, and decreasing the virus level in plasma without apparent toxicity • Inhibitor of protein synthesis in tumour cells at the step of peptide bond formation. It has a different binding site than lycorine on the peptidyl transferase centre of the 60S ribosomal subunit • Reduces DNA synthesis. RNA synthesis is practically unaffected • Cytotoxic against human Molt 4 and murine LMTK cells • Moderately active against HepG2 hepatoma • Moderately active against Ehrlich ascites tumour cells • Inhibitor ofHeLa cell growth • Antiviral. Active against Herpes simplex type 1 (HS-1) • Active against neurotropic RNA viruses • Does not inhibit the activity of reverse transcriptase
(230, 312)
(307-309) (240) (272) (205, 272, 307310) (272, 308) (274) (289,310) (167, 229, 230, 273, 288) (230, 307, 308) (311) (306) 235,
(272,273,310) (272) (240) (240) (231) (272) (274) (289,310,312) (228, 230)
• Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines • Weak cytotoxic against HepG2 hepatoma
(240)
59 tazettine
• • • •
(89, 270)) (167) (240) (205)
39 vittatine
• Weak analgesic in mice • Tachycardic in dogs
5 2-O-acetylpseudolycorine
Weak hypotensive Active against the Co 12 cell line Weak cytotoxic against fibroblastic LMTK cell lines The stereochemical rearrangement from pretazettine to tazettine inactivates the biological activity of pretazettine
310,
(240)
(89) (89)
397
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