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The Amaryllidaceae Alkaloids
THE AMARYLLIDACEAE ALKALOIDS OSAMU HOSHINO Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo 162, Japan
.............................. I. Introduction and Botanical Sources 11. Lycorine-Type Alkaloids ..........................................
...................................
324 342
................................. ral Elucidation ............
............................................................
365
A. Isolation and Structural Elucidation B. Synthetic Studies ......................... C. Biological Activity V. Galanthamine-Type A ....................... A. Isolation and Struc
......................
387
.....................
393
ral Elucidation
B. Synthetic Studies
X. Miscellaneous ............................
............... 410
A. Pallidiforine B. Obesine ................
F. Joubertiamine-Type Alkaloids References .................... THE ALKALOIDS. VOL. 51 00YY-YSYR/Y8 $25.00
................ 323
Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.
324
OSAMU HOSHINO
I. Introduction and Botanical Sources The Amaryllidaceae alkaloids have been isolated from the plants of almost all of the genera of the family Amaryllidaceae and are members of the large group of isoquinoline alkaloids. Although their structures appear to be very different, they are known to be formed biogenetically by intramolecular oxidative coupling of norbelladines. At present, almost 200 Amaryllidaceae alkaloids have been isolated from plants, and many of their structures have been determined. Structures of the alkaloids are classified mainly into seven types, for which the representative alkaloids are lycorine (1)(lH-pyrrolo[3,2,1-d,e]phenanthridinetype), crinine (135) (5,lOb-ethanophenanthridinetype), narciclasine (lycoricidine) (204) (isocarbostyril type), galanthamine (261) (6H-benzofuro[3a,3,2-e,f]-2-benzazepine type), tazettine (298)(2-benzopyrano[3,4-c]indoletype), lycorenine (316)(2-benzopyrano-[3,4-g]indoletype), and montanine (338)($1 l-methanomorphanthridine type). Besides these seven structure types, there are mesembrine (387)and cherylline (440)(4-aryltetrahydroisoquinolinetype). The former structure belongs to the Sceletiurn alkaloids (Aizoaceae), but not the Amaryllidaceae (Fig. 1). Among these alkaloids, narciclasine (1ycoricidine)-type alkaloids are highly oxygenated compounds, the significant antitumor activity of which attracts the attention of biologists and pharmacologists. Recent developments in analytical techniques, as well as isolation procedures, have resulted in the rapid characterization of many structures. In the sections on the alkaloids that have been isolated for the first time from the Amaryllidaceae plants, not only the novel, but also the known, structures have been included. This chapter is a review of the Amaryllidaceae alkaloids that have appeared in the literature (1-7) since a previously published review in this series (8). Noteworthy results in the phytochemical studies, the N-oxides of several Amaryllidaceae alkaloids have been found for the first time in Amaryllidaceae plants, accompanied by the corresponding free bases (52): ungiminorine N-oxide (10)(from Puncrutium muritimurn), and 0-methyllycorenine N-oxide (329)and homolycorine N-oxide (330)(from Lupiedru muritinezii). The stereochemistry of their nitrogen atoms was deduced based on 2 D NOESY experiments. Furthermore, it has been established that these Noxide derivatives are genuine natural products, and not artifacts, by the demonstration that the free bases are not converted into N-oxides when subjected to the same extraction procedure. It is noteworthy that the N oxides have been isolated accompanied by the corresponding free bases.
4.
Lycorine (1)
Crinine (135) OMe
w
M
e
O
a
o N,
325
THE AMARYLLIDACEAE ALKALOIDS
Narciclasine (204)
n
H
Me
Galanthamine (261)
Tazettine (298)
&H Lycorenine (316)
OH
,OMe
<
HO&. '0
'NH
Montanine (338)
a
G O M e
0
Me
Mesembrine (387)
MHO e o a N M e
Cherylline (440)
FIG.1
Following the first examples of the isolation of naturally occurring N oxides from Amaryllidaceae family, extensive investigation of extracts of the bulbs of Lycoris sanguineu has revealed, for the first time, the presence of galanthamine N-oxide (281),sanguinine N-oxide (283),and lycoramine N-oxide (284), together with the corresponding free bases (62). The structures of the N-oxides were characterized by spectroscopic evidence ('H and I3C NMR). Also, hippeastrine N-oxide (332)has been isolated newly from the flowers of Lycoris rudiuta, accompanied by galanthamine N-oxide (281),lycoramine N-oxide (284),0-methyllycorenine N-oxide (329),and homolycorine N-oxide (330) and their corresponding free bases (60).
326
OSAMU HOSHINO
Furthermore,examination of the extracts of the flowers of Lycoris incarnata (58) has shown the presence of ungiminorine N-oxide (10) and galanthamine N-oxide (281),together with the corresponding free bases. The interesting N-oxide oxoassoianine N-oxide (49) has been found in the bulbs of Narcissus bicolor (64). The structures of these metabolites are shown in Fig. 2.
3-O- Acetyl-
Ungiminorine N-oxide (10)
narcissidine N-oxide (22)
Oxoassoanine N-oxide (49)
Me0
Lycoramine N-oxide (284)
Galanthamine N-oxide (281) R=Me Sanguinine N-oxide (283) R=H
Me0
Me0
OMe
O-Methyllycorenine N-oxide (329)
'OH
0
Homolycorine N-oxide (330) R=Me 8-0-Demethylhomo1ycorine N-oxide (331) R=H FIG.2
0
Hippeastrine N-oxide (332)
4.
THE AMARYLLIDACEAE ALKALOIDS
327
Numerous alkaloids have been isolated from Narcissus species as a result of the continuing exploration for novel alkaloids with pharmacological activity in the Amaryllidaceae family. Among them, the alkaloids isolated for the first time are included: norpluviine (25),l-O-acetyl-lO-0demethylpluviine (26), 1,10-0-diacetyl-10-0-demethylpluviine(27), and 0-acetylgalanthamine (262)(from N. pseudonarcissus) (83),oxoassoanine (46) (from N. assoanus) (63),vasconine (55) and 8-0-acetylhomolycorine (320)(from N. vasconicus) (93),roserine (57)and mesemberenone (371) (from N. pallidufus) (78), haemanthamine (155), 8-0-demethylmaritidine (174),homolycorine (318), and 8-0-demethylhomolycorine (319) (from N. primigenius) (82), cantabricine (176) (from N. canraricus) (65), 9-0demethylmaritidine (175)(from N. radinganorum) (86),O-methylmaritidine (179)and 0-methylpapyramine (182)(from N. papyraceus) (81),narcisine (268) (from N. tazetta) (89),0-methyllycorenine (317) (from N . munozii-garnendiae) (73), 9-0-demethylhomolycorine (321) (from N. confusus) (66),5a-hydroxy-9-0-demethylhomolycorine (322)(from N. forriflolius) (91), dubiusine (324)(from N. dubius) (69),and 5,6-dihydrobicolorine (432)and bicolorine (433)(from N . bicolor) (64), accompanied by other known Amaryllidaceae alkaloids. A complete structural analysis of 0-methyllycorenine (317)has now established that the methoxy substituent at C-6 is a rather than the previously reported fl (found in Lapiedra rnartinezii) (52). A reexamination of the polar alkaloid components of the bulbs of Hyrnenocalfis caymanensis (47) has disclosed a glucoalkaloid l-fl-~-glycosyl-2-flD-glycosylpseudolycorine (15). Also, a new glucosyloxy derivative 206 of narciclasine is found in the polar alkaloid components of P. marititimum (96), and both the parent alkaloid and this new derivative were shown to possess strong mitotoxic activity Further examination of the polar alkaloids from a methanolic extract of L. martinezii has revealed the new quaternary alkaloids, N-methylassoaninium chloride (53) and N-chloromethylnarcissidinium chloride (23), together with the lycorine-type alkaloids ungiminorine (8), narcissidine (20),and hippadine (44)(51).However, the latter quaternary alkaloid (23)is thought to have been produced by the isolation procedure (51). A similar observation regarding extraction has been reported; galanthamine (261)forms a quaternary salt N-chloromethylgalanthanium chloride (266),when extracted with methylene chloride or crystallized from the same solvent. The structure and absolute configuration of the quaternary alkaloid were determined by X-ray crystallography (109).This study emphasizes the care that needs to be taken when choosing a solvent to extract plant materials. As a method for the determination of the alkaloids, a microchemical identification procedure (4,210), which provides for the differentiation of
328
OSAMU HOSHINO
MeO& Me0
10-0-Norpulviine (24) R=R~=H 1-0-Acetyl- 100-norpluviine (25) R=Ac, R ' = H 1,lO-0-Diacetyl-100-norpluviine (26) R=R'=AC
Me0
Vasconine (50)
8-0-Demethylmaritidine (174) R = H, R' = Me 9-0-DemethyL maritidine (175) R =Me, R' = H
Me0
Me0
Roserine (52)
R
0-Me thylmaritidine (178) R=H O-Methylpapyramine (182) R = OMe
& n
Cantabricine (176)
R20
R'O OMe
O-Methyllycorenine (317) O-Acetylgalanthamine (262) R=Ac,R'=Me N-Formylgalanthamine (264) R = H,R' = CHO Narcisine 268) R = H, = Ac
5.6-Dih ydrobicolorine (432)
0
Bicolorine (433)
FIG.3
'R I 0io
8-0-Demethylhomolycorine (319) R=R'=H,R2=Me 8-O- Acetylhomolycorine (320) R = H , R' = Ac, R2 =Me S~t-Hydroxy9-0-demethylhomolycorine (322) R = OH, R' =Me, R2 = H 9-0-Demethylhomolycorine (321) R = H , R' =Me. R2 = H Dubiusine (324) R = Ac, R' =Me, R2 = COCH2CH(OH)Me
4.
329
THE AMARYLLIDACEAE ALKALOIDS
OH (0 flZ-D-Gb~osyl
OH 0 4-0-pD-Gl~~0~ylnarciclasine (204)
1-0-p-D-GlUcOSylpseudolycorine (15) OMe
N-Chloromethylnarcissidinium chloride (23)
N-Methylassoaninium chloride (53)
N-Chloromethylgalanthaminiurn chloride (266)
FIG.4
the Amaryllidaceae alkaloids, has been applied to, among others, 3-0acetylcrinine (136), 6c~-ethoxycrinine,6a-ethoxybuphanisine, bulbisine, flexinine (142),augustisine, 3-0-acetylpowelline (163),trisphaeridine (426), and cherylline (440).This procedure ( 4 ) involves microcrystalline techniques and color reactions. Also, a zone refining partition coefficient technique has been developed to separate the alkaloids present in a crude extract of Crinum moorei (32). The crystal structures of haemanthamine (155) (from N. confusus) and eugenine (325)(from N. eugeniae) have been determined by X-ray crystallography. The structure of the former as 155 was confirmed to be the anti position C (11)-OH with respect to the aromatic ring and the half-chair conformation of ring C (111).Also, the structure of the latter alkaloid, 325, was shown to be far from planar, only the benzene ring being so configured (70). Interestingly, although the occurrence of the Schiff 's base craugsodine (28)in Crinum augustum has been reported (23),a new Schiff 's base named isocraugsodine (29)was isolated from the fruits of C. asiaticum (20) (Fig. 5 ) . Its structure was assigned by chemical transformation and comprehensive spectroscopic evidence. Also, the temperature-gradient distribution of the
330
OSAMU HOSHINO
Meo<3 Ho69 HO
Me0
H/
Craugsodine (28)
H O & 9
Me0
-
Isocraugsdne (29)
-
A /
H
E-Isomeric form
H/
Me0
Quinont methide
Me0
H
Z-Isomeric form
FIG.5
three isomeric forms (E-isomer quinone methide 2-isomer) of the Schiff's base was determined by high-resolution 'H NMR analysis. Thus, this compound is considered as a direct precursor to the Amaryllidaceae alkaloids. Isolation and botanical sources of the Amaryllidaceae alkaloids that have been reported in the literature since 1987 are summarized in Table I. Extensive exploration of the pharmacological utility of the Amaryllidaceae alkaloids has been carried out. For example, studies (112) on the effects of Amaryllidaceae alkaloids and their derivatives (prepared by biosynthesis and chemical transformation) upon Herpes simplex virus (type l), the relationship between their structure and antiviral activity, and the mechanism of this activity have been performed, suggesting that the alkaloids that may eventually prove to be antiviral agents had a hexahydroindole ring with two functional hydroxyl groups. Furthermore, the antiviral activity of the alkaloids was found to be due to the inhibition of multiplication, and not to the direct inactivation of extracellular viruses, and the mechanism of the antiviral effect was partially explained as a blocking of viral DNA polymerase activity. Also, the extract of the bulbs of Haemanthus albiflos was found to inhibit viral DNA synthesis (113). It is reported that the total alkaloidal extract of this plant possesses antiviral activity (113). Reviews that include these biological data have appeared (114,215).
4.
331
THE AMARVLLIDACEAE ALKALOIDS
TABLE I THEISOLATION OF AMARYLLIDACEAE ALKALOIDS Species Boophane frava
Brunsvigia josephinae
Clivia nobilis Crinum amabile
Crinum americanum
Alkaloids (sources) 0-Ace1 ylhamayne (bulbs) Augustine (bulbs) Buflavine (bulbs) Buphanisine (bulbs) Crinamine (bulbs) Crinine (bulbs) 8-0-Demethylbuflavine (bulbs) 5,6-Dihydrobicolorine (bulbs) Epi-buphanine (bulbs) Epi-vittatine (bulbs) Hamayne (bulbs) Lycorine (bulbs) Montabuphine (bulbs) Undulatine (bulbs) 11-0-Acetylambelline (bulbs) 3-0-Acetylhamayne (bulbs) Ambelline (bulbs) Brunsbelline (bulbs) Buphariidine (bulbs) Buphariisine (bulbs) Crinamine (bulbs) Crinine (bulbs) Hamayne (bulbs) Hippadine (bulbs) Josephinine (bulbs) Sternbergine (bulbs) Undulatine (bulbs) Clivatine (whole plants) Lycoririe (whole plants) Nobilisine (whole plants) Amabiline (bulbs) Augustine (bulbs) Crinamine (bulbs) Buphanisine (bulbs) Lycorine (bulbs) 0-Acetylcrinine (rhizomes) Augustine (bulbs) Buphanisine (leaves) Crinamine (leaves) Crinan type (rhizomes) Crinine (Crinidine) (leaves) Crinine (bulbs) Dihydrocrinidine (rhizomes) Flexinine (bulbs) Haemanthamine (leaves)
Reference 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 11 II 9 10
10 II 10
11 11 11 II 12 12 12 12 13 13 13 13 13 14 15 16
16 17 16 14 15 14 16
(continues)
TABLE I (continued) Soecies
Crinum asiaticum
Alkaloids (sources)
Reference
Hamayne (rhizomes) Hippadine (bulbs) Lycorine (bulbs) Lycorine (leaves) Oxocrinine (bulbs) Pratorimine (bulbs) Pratorinine (bulbs) Pratosine (bulbs) Tazettine (leaves) Trisphaeridine (bulbs) Ungeremine (bulbs) Criasbetaine
1,2-O-P-o-Diglucosyllycorine (fruits)
Isocraugsodine (fruits) 2-Oxolycorine N-oxide (fruits) 1-O-Palmitoyl-2-0-(1‘-O-palmitoyl-2’-Oo1eoyl)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-O-(l’-O-palmitoyl-2‘-0oleoy1)glycerophosphorylpseudolycorine (fruits) l-O-Palmitoyl-2-0-(1 ’-O-palmitoyl-2’-0stearoy1)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-0-( l’-O-palmitoyl-2’-0stearoy1)glycerophosphorylpseudolycorine (fruits) Ungeremine Crinum asiaticum var. sinicum Crinine (bulbs) Crinsin (bulbs) Lycorine (bulbs) Powelline (bulbs) Crinum augustum Augustamine (whole plant) Craugsodine Hippadine (bulbs) 6a-Hydroxybuphanisine (whole plant) 6a-Hydroxycrinine (whole plant) Pratorimine (bulbs) Pratorinine (bulbs) Telastaside (phathenocarpic fruits) Crinum bulbispermurn Powelline (whole plant) Pratorinine (whole plant) Crinum firmifoliurn var. Crinamine (whole plants) hygrophilum Criwelline (whole plants) Hamayne (whole plants) 6-Hydroxycrinamine(whole plants) 3-Hydroxy-8,9-methylenedioxyphenanthridine (whole plants) Ismine (whole plants) Lycorine (whole plants) Trisphaeridine (whole plants) 332
15 14 14 16 14 14 14 14 16 14 16 18 19 20 19 19 19 19 19 18 21 21 21 21 22 23 24 22 22 24 24 25 22 22 26 26 26 26 26 26 26 26
TABLE I (continued) Species Crinum giganteum
Crinum jagus
Crinum kirkii
Crinum latifolium
Crinum moorei Crinaum zeylanicum
Galanthus elwesii
Haemanthus albiflos
Alkaloids (sources) Crinine (crinidine) Gal anthamine Hippeastrine Lycorine Tazettine Crinamine (whole plants) Hainayne (whole plants) 6-Hydroxycrinamine (whole plants) Lycorine (whole plants) 3-0-Acetylhamayne (bulbs) Crinine (bulbs) 8-0-Demethylvasconine (bulbs) Hamayne (bulbs) Kirkine (bulbs) Crinafolidine Crinafoline 4,5-Dehydroanhydrolycorine(flower stem fluid) Epi-lycorine (flower stem fluid) Epr-pancrassidine (flower stem fluid) Hippadine (flower stem fluid) Latifine (bulbs) Lycorine (flower stem fluid) Pancrassidine (flower stem fluid) Crinamidine Crinine Powelline Crinine (crinidine) (bulbs) Flexinine (bulbs) 6-Hydroxypowelline (bulbs) Zeylarnine (air-dried rhizomes) N-Demethylgalanthamine (whole plants) 9-0-Demethylgalwesie (whole plants) 9-0-Demethylhomolycorine(whole plants) Galanthamine (whole plants) Galanthine (whole plants) Galasine (whole plants) 16-Hydroxy-9-0-demethylgalwesine(whole plants) 11-Hydroxyvittatine (whole plants) 16-Hydroxygalwesine (whole plants) Galwesine (whole plants) Leucotamine (whole plants) Lycorine (whole plants) 5-Methoxy-9-0-demethylhomolycorine (whole plants) Narwedine (whole plants) Sanguinine (whole plants) Albiflomanthine (bulbs) 333
Reference 27 27 27 27 27 28 28 28 28 29 29 29 29 29 30 30 31 31 31 31 197 31 31 32 32 32 33 33 33 34 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36
(continues)
TABLE I (continued) Species
Haemanthus kalbreyeri
Haemanthus multiflorus
Hippeastrum equestre
Hippeastrum hybrids
Hippeastrum puniceum Hippeastrum solandriflorum
Hymenocallis caribaea Hymenocallis caymanensis Hymenocallis expansa
Alkaloids (sources)
Reference
Albomaculine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine' (bulbs) Lycoramine (bulbs) 7-Deoxypancratistatin (rhizomes) 7-Deoxynarciclasine (rhizomes) Haemanthamine (rhizomes) Haemanthidine (rhizomes) Hippadine (rhizomes) Kalbretorine (rhizomes) Lycorine (rhizomes) Narciclasine (rhizomes) Pancratistatin (rhizomes) Pancratiside (2-~-P-~-Gh1cosylpancratistatin) (rhizomes) 2-0-Acetylchlidanthine (bulbs) Galanthamine (bulbs) Galanthamine Haemultine (bulbs) Hippadine (bulbs) Lycorine Lycorine (bulbs) Sanguinine Hippeastrine (bulbs) Lycorine (bulbs) Phamine (bulbs) Phamine (bulbs) Tazettine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) 11-Hydroxyvittatine (bulbs) Lycorine (bulbs) Montanine (bulbs) Pancracine (bulbs) Tazettine (bulbs) Vittatine (bulbs) 0-Acetylnarcissidine (bulbs) 11-Hydroxyvittatine (bulbs) Vittatine (bulbs) Hamayne (aerial parts and bulbs) Ismine (aerial parts and bulbs) Lycorine (aerial parts and bulbs) Vittatine (aerial parts and bulbs) Ungeremine (aerial parts and bulbs) 7-Deoxy-frans-dihydronarciclasine(bulbs) 4-Hydroxyanhydrolycorine (leaves) Glucoalkaloid (bulbs) Haemanthidine (bulbs/leaves) 334
36 .36 36 36 36 37 37 37 37 37 37 37 37 37 -37 38 38 39 38 38 39 38 40 40 40 40 41 40 42 42 42 42 42 42 42 42 43 43 43 44 44 44 44 44 45 46 47 48
TABLE I (conrinued) Species
Hyrnenocallis latifolia Hyrnenocallis littoralis
Hyrnenocallis rotata
Lapiedra martinezii
Alkaloids (sources)
Reference
Hippeastrine (bulbs/leaves) Tazettine (bulbs/leaves) 7-Deoxy-trans-dihydronarciclasine (bulbs) 5,6-Dihydrobicolorine (bulbs) 8-0-Demethylmaritidine (bulbs) 7-Deoxynarciclasine (bulbs) 7-Deoxy-trans-dihydronarciclasine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Littoraline (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Marconine (bulbs) 0-Methyllycorenine (bulbs) Narciclasine (bulbs) Pancratistatin (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitlatine (bulbs) Alkaloid 13 (bulbs) N-Demethylgalanthamine (bulbs) N-Demethyllycoramine (bulbs) 8-0-Demethylmaritidine (bulbs) 3-Epi-marconine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Ismine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitratine (bulbs) N-Chloromethylnarcissidinium chloride Hippadine Homolycorine (aerial parts) Hornolycorine N-oxide (aerial parts) Ismine (bulbs/leaves) N-hlethylassoaninium chloride N-hlethylcrinasiadine (N-methyl-8,9-
48 48 45 49 49 45 45 49 49 49 49 49 49 49 49 49 45 45 49 49 49 50 50 50 50 50 50 50 50 50 50 50 50 50 51 51 52 52 53 51 53
methylenedioxyphenanthridin-6-one) (bulbs/leaves)
8,9-Methylenedioxyphenanthridine(bulbs/
53
N-hlethyl-8,9-methylenedioxyp henanthridinium chloride (bulbs/leaves)
53
leaves)
0-Methyllycorenine N-oxide (aerial parts) Narcissidine 335
52 51
(continues)
TABLE I (continued) Species
Leucojum aestivum sub. pulchellum Leucojum autummale Lycoris ichinensis
Lycoris guangxiensis
Lycoris incarnata
Lycoris radiata
Alkaloids (sources) Ungiminorine Ungiminorine N-oxide (aerial parts) Elwesine Galanthamine Lycorine Sanguinine 3-0-acetylnarcissidine 3-0-acetylnarcissidine N-oxide Crinine (bulbs) Epi-lycoramine (bulbs) Galanthamine (bulbs) Haemanthidine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Narciclasine (bulbs) Pulviine (bulbs) N-Allylnorgalanthamine (bulbs) Crinine (bulbs) Galanthamine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Narwedine (bulbs) Norgalanthamine (bulbs) Pseudolycorine (bulbs) 0-Demethyllycoramine (flowers) Galanthamine (flowers) Galanthamine N-oxide (flowers) Galanthine (flowers) lncartine (flowers) Lycoramine (flowers) Lycorine (flowers) Narcissidine (flowers) Sanguinine (flowers) Unigiminorine (flowers) Unigiminorine N-oxide (flowers) 0-Demethylhomolycorine (flowers) 0-Demethyllycoramine (flowers) Galanthamine (flowtrs) Galanthamine N-oxide (flowers) Hippeastrine (flowers) Hippeastrine N-oxide (flowers) Homolycorine (flowers) Homolycorine N-oxide (flowers) Lycoramine (flowers) Lycoramine N-oxide (flowers)
336
Reference 51 52 54 54 54 54 55 55 56 56 56 56 56 56 56 56 56 56 56 57 57 57 57 57 57 57 57 58 58 58 58,59 58,59 58 58 58 58 58 58 60 60 60 60 60 60 60 60 60 60
TABLE I (confinued) Species
Lycoris sanguinea
Narcissus assoanus Narcissus bicolor
Narcissus cantaricus
Narcissus confusus
Narcissus dubius Narcissus eugeniae Narcissus jacetanus
Narcissus leonensis
Alkaloids (sources) Lycorine (flowers) 0-Methyllycorenine (flowers) 0-Methyllycorenine N-oxide (flowers) Tazettine (flowers) Vittatine (flowers) Galanthamine (bulbs) Galanthamine N-oxide (bulbs) Galanthine (bulbs) Lycoramine (bulbs) Lycoramine N-oxide (bulbs) Lycorine (bulbs) Norbutsanguinine (bulbs) Norsanguinine (bulbs) Pseudolycorine (bulbs) Sanguinine (bulbs) Sanguinine N-oxide (bulbs) Assoanine (fresh plants) Oxoassoanine (fresh plants) Bicolorine (bulbs) 5,6-IXhydrobicolorine (bulbs) 3-Epi-macronine (bulbs) Oxoassoanine N-oxide (bulbs) Pretazettine (bulbs) Cantabricine (whole plant) Crinamine (whole plant) 6a-/b&Hydroxybuphanisine (whole plant) Tazettine (whole plant) Vittatine (whole plant) 1-0-Acetylpseudolycorine 2-O- Acetylpseudolycorine 9-0-Demethylhomolycorine (fresh plants) 9-0-Demethylhomolycorine (aerial parts/ bulbs) N-Formylgalanthamine (fresh plants) Galanthamine (fresh plants) Haemanthamine (fresh plants) Homolycorine (aerial partshulbs) Pretazettine (fresh plants) Pseudolycorine Duhiusine (aerial parts) 5a-Hydroxy-10-0-demethylhomolycorine (aerial part) Eugenine (whole plant) Assoanine (whole plant) Lycorine (whole plant) Oxoassoanine (whole plant) Pseudolycorine (whole plant) Epi-norgalanthamine (whole plant) Epi-norlycoramine (whole plant) 337
Reference 60 60 60 60 60 61,62 61 62 61 61 62 62 62 62 61,62 61 63 63 64 64 64 64 64 65 65 65 65 65 66 66 67 68 67 67 67 68 67 66 69 69 70 71 71 71 71 72 72
(continues)
TABLE I (continued) Species Narcissus rnunoziigarmendiae Narcissus nivalis
Narciassusobesus
Narcissus pallidiflorus
Narcissus pallidulus Narcissus panizzianus
Narcissus papyraceus
Narcissus primigenius
Narcissus pseudonarcissus
Alkaloids (sources) Lycorine (whole plant) Homolycorine (whole plant) Lycorenine (whole plant) 0-Methyllycorenine (whole plant) N-Demethylgalanthamine (fresh aerial parts and bulbs) Galanthamine (fresh aerial parts and bulbs) 9-0-Methylpseudolycorine (fresh aerial parts and bulbs) Bicolorine (whole plants) 5.6-Dihydrobicolorine (whole plants) Epi-macronine (whole plants) Galanthamine (whole plants) Haemanthamine (whole plants) Obesine (whole plants) Pretazettine (whole plants) 8-0-Demethylhomolycorine (whole plants) 5,6-Dihydrobicolorine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) Pallidiflorine (whole plants) Pretazettine (whole plants) Mesembrenone (aerial parts) Mesembrenone (whole plants) Roserine (whole plants) 6-Epi-papyramine (whole plants) Galanthine (whole plants) Galanthine (aerial parts and bulbs) Homolycorine (aerial parts and bulbs) Homolycorine (whole plants) Papyramine (whole plants) Pretazettine (whole plants) Pretazettine (aerial parts and bulbs) 0-Demethylhomolycorine (aerial parts) 0-Demethylhomolycorine N-oxide (aerial parts) Homolycorine (aerial parts) Lycorine (aerial parts) 0-Methylmaritidine (aerial parts) 0-Methylpapyramine (aerial parts) Papyramine" (aerial parts) Pseudolycorine (aerial parts) 9-0-Demethylhomolycorine (whole plants) 0-Demethylmaritidine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) 0-Acetylgalanthamine (bulbs) 1-0-Acetyl-10-0-demethylpluviine (bulbs) 1-0-Acetyl-10-0-demethylpluviine(bulbs) 338
Reference 72 73 73 73 74 74 74 75 75 75 75 75 75 75 76 76 76 76 76 76 77 78 78 79 79 80 80 79 79 80 80 81 81
81 81 81 81 81 81
82 82 82 82 83 83 84
TABLE I (continued) Species
Alkaloids (sources) N-Demethylgalanthamine (bulbs) N-Demethylmasconine (bulbs) 10-0-Demethylpluviine (bulbs)
Narcissus radinganorum Narcissus var. “Fortune” Narcissus tazetta
Narcissus tortifolius
Narcissus tortuosus Narcissus vasconicus
Reference
1,10-Diacetyl-10-0-demethylpluviine (bulbs) Epi-norlycoramine (bulbs) Galanthamine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Masconine (bulbs) 8-0-Methylhomolycorine (bulbs) 0-Methyloduline (bulbs) Narcidine (bulbs) Narcissidine (bulbs) Nanvedine (bulbs) 10-horpluviine Oduline (bulbs) Vittatine (bulbs) 9-0-Demethylmaritidine (fresh plants) 8-0-Demethylhomolycorine (fresh plants) Homolycorine (fresh plants) Fortucine (leaves) 10-0-Demethylhomolycorine (whole plants) Galanthamine (bulbs) Haemanthine (bulbs) Honiolycorine Lycorine Lycorine (bulbs) Narcishe (bulbs) Pretazettine (bulbs) Pseudolycorine (bulbs) Tazettine Tazettine (bulbs) 8-ODemethylhomolycorine (whole plants) 9-0. Demethyl-2a-h ydroxyhomolycorine (whole plants) Dubiusine (whole plants) Galanthamine (whole plants) Honiolycorine (whole plants) Lycorine (whole plants) Tortuosine (whole plants) 8-0-Acetylhomolycorine (whole plants) Homolycorine (whole plants) Lycorine (whole plants) Vasconine (whole plants) 339
84 84 84 83 84 85 84 85 85 85 84 84 84 84 85 84 85 85 84 83 84 84 86 86 86 87 88 89 89 90 90 89 89 89 89 90 89 Y1
91 91 91 91
92 92 93 93 93 93
(continues)
TABLE I (continued) ~~
Species Pancratium biflorum Pancratium maritimum
Alkaloids (sources) Telastaside (parthenocarpic fruits) Crinine (bulbs) 9-0-Demethylhomolycorine(bulbs) 6-0-Methylhaemanthidine (bulbs)
3P,lla-Dihydroxy-l,2-dehydrocrinane(bulbs) (bulbs)
0,N-Dimethylnorbelladine (bulbs)
Sceletium subvelutinum
Sternbergia clusiani
Galanthamine (bulbs) 4-~-P-~-G~ucopyranosyharciclasine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) Habranthine (bulbs) Hippadine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) 11-Hydroxygalanthamine(habranthine) (bulbs) 8-Hydroxy-9-methoxycrinine(bulbs) 11-Hydroxyvittatine(bulbs) Lycorenine (bulbs) Lycorine (bulbs) 6-0-Methylhaemanthidine (bulbs) Pancracine (bulbs) Pseudolycorine (bulbs) Sickernbergine (bulbs) Tazettine (bulbs) Trisphaeridine (aerial parts) Trisphaeridine (bulbs) Ungeremine (bulbs) Ungiminorine (bulbs) Ungiminorine N-oxide (bulbs) Vittatine (bulbs) Zefbetaine (bulbs) Dehydrojouvertiamine (whole plants) Dihydrojoubertiamine (whole plants) N,N-Dimethyltyramine (whole plants) Ouvertiamine (whole plants) 0-Methyldehydrojoubertiamine(whole plants) 0-Methyldihydrojoubertiamine(whole plants) 0-Methyljoubertiamine (whole plants) Crinine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) 11-Hydroxyvittatine(bulbs) Lycorine (bulbs) Pretazettine (bulbs)
Reference 25 94 95-97 97 98
97 96,97 96 96,97 96,97 97 96 97 96 97 98 96,97 96 94-97 97 96 96 96 96 99 %
96,100 97 52,97 97 96,100 101 101 101 101 101 101 101 102 102 102 102 102 102 102
TABLE I (continued) Species Sternbergia lutea
Sternbergia sicula
Ungernia minor Zephyranthes Java
Alkaloids (sources) Deniethylmaritidine (whole plants) Epi-maritinamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) Hippadine (bulbs) 11-Hydroxyvittatine (whole plants) Lycorine (bulbs) Maritinamine (whole plants) Tazettine (whole plants) Vittatine (whole plants) Ungiminorine (bulbs) Buphanisineb (whole plants) Deniethylmaritidine (whole plants) 11-Epi-haemanthamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) 11-Hydroxyvittatine (whole plants) Siculine (whole plants) Siculinine (whole plants) Tazettine (whole plants) Ungiminorine (deacetyllutessine) (whole plants) Vittatine (whole plants) 1,3-O-Diacetyldihydroungerenine 2-0-Glycerophosphoryllycorine (flowers) 2-041‘-0-Palmitoyl-2’-0-oleoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-oleoyl) glycerophosphorylpseudolycorine(flowers) 2-041 ’-0-Palmitoyl-2’-0-stearoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-stearyl/oleoyl) glycerophosphorylpseudolycorine(flowers) 2-0-(1 ’-0-Palmitoyl-2’-0-stearyl) glycerophosphory llycorinium methocationsc (flowers) Criasbetaine (fresh mature seeds) Crinamine (fresh mature seeds) Haemanthamine (fresh mature seeds) Haemanthidine (fresh mature seeds) Kalhreclassine (fresh mature seeds) Lycorine (fresh mature seeds) l-0-B-D-Glucopyranosyllycorine(fresh mature seeds) Maritidine (fresh mature seeds) Melhylpseudolycorine (fresh mature seeds) Narciclasine (fresh mature seeds) Pratorinine (fresh mature seeds) Prerazettine (fresh mature seeds) 341
Reference 103 103 103 103 104 103 104 103 103 103 104 103 103 103 103 103 103 103 104 103 103 103 105 106 106 106 106 106 106
107 107 107 107 107 107 107 107 107 107 107 107
(continues)
342
OSAMU HOSHINO
TABLE I (continued) Alkaloids (sources)
Species
Pseudolycorine (fresh mature seeds) 1-0-P-D-Glucopyranosylpseudolycorine (fresh mature seeds) Ungeremine (fresh mature seeds) Zefbetaine (fresh mature seeds) Zeflabetaine (fresh mature seeds) a
Reference 107 107
107 107 I07
As a mixture of 6a- and 6p-epimers. Enantiomer of (-)-byhankhe. As a mixture of a-and fl-N-methyl epimers.
II. Lycorine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION
The structures of the representative alkaloids isolated since 1987 are listed in Fig. 6. Investigation of the components of the flowers of Amaryllidaceae plants has not been carried out extensively, compared with that of the bulbs and the whole plants, because of the limitation for the collection of these plants. The flower stem fluid of Crinum lutifolium (31) has been examined, from which numerous Amaryllidaceae alkaloids have been isolated. Among them, two lycorine-type alkaloids, 2-epi-lycorine (4) and 2-epi-pancrassidine (7), are included, structures of which were determined by spectroscopy. In addition, a study of the metabolism of lycorine (1) and 2-epi-lycorine (4) has been performed using the flower stem fluid in a phosphate buffer, revealing that lycorine (1) produces, in succession, 2-oxolycorine (5) and 2-0x0-pyrrolophenanthridiniumbetaine (ungeremine) (a), and that 2-epilycorine (4) forms 2-epi-pancrassidine (7), 4,5-dehydroanhydrolycorine (43), and hippadine (44) (31) (Scheme 1). As a result of these in vitro studies, a reexamination of the flower stem fluid has shown that trace amounts of 2-epi-pancrassidine (15) are indeed present. Further investigations of the flowers of Amaryllidaceae species has revealed several new alkaloidal phospholipids, 2-0-glycerophosphoryllycorine (30), phosphatidyllycorine (31-34), phosphatidyllycorinium methocations (39, and phosphatidylpseudolycorine (36-39), respectively, in an extract of the flowers of Zephyranthesflava (107) (Fig. 7). The structures of the alkaloids were established by comprehensive spectroscopic analyses
Lycorine (1)
Lycorine N-oxide (3)
R=H
1-0-Acetyllycorine (2) R=Ac
OMe HO.&ORU
Pancrassidhe (6) R = P-OH 2-Epi-pancrassidine (7)
2-Oxolycorine (5)
& <& Q '0
0 0
2-Epi-lycorine (4)
0
Ungiminorine (8) R=H 3-0-Acetylungiminorine (9) R=Ac
Ungiminorine N-oxide (10)
Siculinine (11)
9-0-Methylpseudolycorine (17)
Incartine (19)
R = a-OH
HO
R=H
Stembergine (16)
Me0
Pseudo1 corine (12) R = RY = H 1-0-Acetylpseudolycorine (13) R = AC. R' = H 2-O- AcetvlMe0
Galanthine (18) R=Me
OMe HO.&.ofl
I!
CHzCl
3-O- Acetylnarcissidine N-oxide (22)
N-Chloromethylnarcissidinium chlorode (23) RIO&
Rlo&9 Me0
RO
MeO&
/
H
HO
Formcine (Kirkine) (27)
hugsodine (28) R =H, R' = M e Isocraugsodine (29) R = Me, R' =H FIG.6
10-0-Norpulviine (24) R=R'=H l-O-Acetyl-100-norpluviine (25) R-AC. R ' = H lJ0-O-Diacetyl- 100-norpluviine (26) R = R ' =AC
344
OSAMU HOSHINO
OH
0
-Q& 0
Lycorine (1)
2-Oxolycorine (5).
2-Epl-lycorine (4)
{)& 0
Ungerenine (48)
2-Epi-pancrassidine (7) SCHEME 1
and chemical transformation. For example, the location of the acylglycerophosphoryl substituent at the allylic position of the pseudolycorine moiety was determined by the demonstration that diacetylphosphorylpseudolycorine when treated with sodium methoxide (NaOMe) in tetrahydrofuran (THF) containing palladium(0) catalyst (116), produced 1,lO-di-Oacetylpseudolycorine. As for the presence of both the free and conjugated alkaloids in the plants, their biochemical role has been examined using the fruits of Crinum usiuticum during stress (incisional injury and attack by an insect) (19). Wounding of C. usiuticum fruits caused almost complete hydrolysis of the alkaloidal conjugates and also produced oxidized metabolites of lycorine: Its analogs, e.g., 1-0-palmitoyl-2-0-(1'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine (33), gave lycorine (1) and the N-oxide 3. Prior treatment of the fruits with anesthetic agents, e.g., ether or lidocaine, not only protected the alkaloidal conjugates from enzymatic hydrolysis, but also prevented their oxidation. These observations reveal that even "fresh" plant extracts can be modified by enzymatic activity. Further exploration on components of the Amaryllidaceae flowers revealed a new lycorine-type alkaloid, incartine (19), from the flowers of Lycoris incurnatu (58),together with lycorine (l),ungiminorine (8), ungiminorine N-oxide (lo), galanthine (18), and galanthamine-type alkaloids (58,59).Their structures were established by spectroscopic methods. Moreover, this epoxide 19 is regarded as a significant intermediate in the biosynthesis of narcissidine (20) from galanthine (18) (59) (Scheme 2).
2-O-Glycerophosphoryllycorine (30) H.R2 ~poCH2CH(OH)CH2OH
R'
2-0-(l'-O-Palmitoyl-2'-0-stearoy1)glycerophosphoryllycorine(31) R' = H,Rz = O#OCH$HCH2O-palrnitoyl 0-stearoyl 2-04 l'-O-Palmitoyl-2'-0-oleoyl)glycerophosphayllycorine (32) R' = H,Rz= O#OCH2
2-0-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphorylpseudolycorine(36) R' = H, R2 = &POCH2
2-041'-0-Palmitoyl-2'-0-oleoyl)glycemphosphorylpseudolycorine(37) R' = H, R2 = QPoCH2CHCH2O-palmitoyl b-oleoy1 1-0-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-steamyl)glycerophosphorylpseudolycorine(38) R' = palmitoyl, R~= O~POCH~
l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine(33) l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)R'= palmitoyl. R2 = 02~~2CHCH20-pa1mitoY1 glycerophosphorylpseudolycorine(39) b-stearoyl R' = palmitoyl, R2 = QPoCH2 l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)glycerophosphoryllycorine(34) R'= palmitoyl. R2 = O~KKFI~CHCH20-palmitoyl 6-oleoy 1
Me
2-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphoryllycoriniummethocations (35) (a mixture of a-and P-N-methyl isomers) R=
02POCH2j'HsHa~~palmitoyl FIG.7
-
Me0
-
Me0
Me0
Me0
Me0
Galanthine (18)
Me0
hicartine (19) SCHEME 2
Narcissidine (20)
346
OSAMU HOSHINO
The extract of Sternbergiu siculu gave a new lycorine-type alkaloid, siculinine (11)(104, accompanied by lycorine (l),ungiminorine (8), and hippadine (44),structural elucidation of which was performed by spectroscopic evidence. In this study, deacetyllutessine (41), which was reported previously (117), was found to be identical to ungiminorine (8). Therefore, it is likely that lutessine (40) corresponds to acetylungimimorine (9), although final confirmation of the structure of lutessine remains to be achieved (Fig. 8). A new lycorine-type alkaloid named fortucine has been found in the leaves of Narcissus variety “Fortune” and its structure reported as 27 (87). From the bulbs of Crinum kirkii, two new alkaloids, kirkine (27) and 8-0demethylvasconine (56), have been isolated and their structures established by physical and spectroscopic methods (29). In this study, the structure of kirkine was determined to be the same structure as that proposed for fortucine (87). Therefore, confirmation by direct comparison of each alkaloid remains to be conducted. C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-0x0-pyrrolophenanthridinium alkaloids, zefbetaine (59)and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephrunthesfluvuby gradient solvent extraction, chromatography, and derivatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9.
& OMe
Q
.OMe
0
0
Siculinine (11)
Lutessine (40) R=Ac Deacetyllutessine (41)
R=H
FIG.8
347
4. THE AMARYLLIDACEAE ALKALOIDS
Me0 "eO&
4Hydroxyanhydrolycorine (42)
R
4,s-Dehydroanhydrolycorine (43) RzHz Hippadine (44) R=O
Assoanine (45) R=H2 Oxoassoanine (46) R=O
.-& Me0
0
c1Anhydrolycorinium chloride (47)
0 0Oxoassoanine N-oxide (49)
Ungeremine (48)
Me0
0 Ratorinine 50) R'=H.R =Me
1
Ratorimine (51) R' =Me, Rz = H Ratosine (52) R' =R2 =Me
N-Methylassoaninium chloride (53)
0
0'
Tormesine (54) R' = R2 = OMe Vasconine (55) R' = H. RZ= OMe 8-O-Demeth ylvasconine (56) R' = H, R~ = OH
MeO&
Me0
Roserine (57)
OMe
Criasbetaine (58) ~1~ ~2 = M~ Zefbetaine (59) R'=Me. R 2 = H
FIG.9
Zeflabetaine (60)
Kalbretorine (61) R=H O-Methylkalbntorine (62) R=Me
348
OSAMU HOSHINO
B. SYNTHETIC STUDIES The synthesis of lycorine-type alkaloids has received the attention of chemists as a target for exploration of new synthetic methods, because the stereoselective construction of the contiguous asymmetric centers reported until now is not always efficient. Since the previously published review (8),two investigations of the total synthesis of (2)-lycorine (1) (128), and the first total syntheses of optically active (+)-lycorine (1)and (+)-1deoxylcorine (84) (119), the unnatural enantiomer of lycorine (l), were reported. Both of the synthetic strategies involve the construction of highly functionalized hexahydroindoline derivatives, followed by cyclization to form ring B. A key step in the one case (128)involves an intramolecular Diels-Alder reaction to form a Slactone 64and its conversion to functionalized hexahydroindoline derivatives (Scheme 3). Specifically, intramolecular DielsAlder reaction (in a sealed tube) of (3E)-hexa-3,5-dienyl-(E)-(3,4-methy1enedioxy)cinnamate(63)in o-dichlorobenzene at 235°C afforded in 86% yield the Slactone 64, along with its stereoisomer. Oxidation of 64 with silver carbonate-Celite in boiling benzene produced a regioisomer 65 of Slactone 64 in 98% yield. Iodolactonization of 65 in the usual manner, and protection as a tetrahydropyranyl ether, afforded tetrahydropyranyloxyiodo-y-lactone, dehydroiodation of which provided tetrahydropyranyloxyy-dehydrolactone 66,Deprotection of 66,followed by Jones oxidation, led to dehydro-y-lactonecarboxylic acid 67. The acid 67 was converted into hexahydroindoline 68, possessing stereochemistry similar to that of the ring juncture in the rings B-C-D of lyconine through Curtius rearrangement of the acid. Epoxidation of the acetate afforded a 5,6-cr-epoxy acetate 69, the Payne rearrangement of which, under mild basic conditions, produced, on acetylation, the 4J-&epoxy acetate 70 in a moderate yield. Phenylselenylation of 70,followed by acetylation, afforded, in 98% yield (two steps), 5~,6a-diacetoxy-4a-phenylselenylhexahydroindolin-2-one (71),possessing the necessary functional groups and a masked double bond. Finally, 71 was converted into (2)-lycorine (1) (86% yield) in two steps (228). On the other hand, 71 gave, in 57% yield, 0-diacetyllycorin-5-one (74),which was previously (220) transformed to (2)-lycorine (l), by way of 5P,6a-Odiacetyl-4a-phenylselenyllycorin-5-one (73). In the other synthetic route (129),Birch reduction-alkylation and transformation of functionalized hexahydroindoline derivatives constitute key reactions (Schemes 4 and 5). Birch reduction of N-(2-methoxybenzoyl)(2s)-methoxymethylpyrrolidine,followed by alkylation with 2-acetoxyethyl bromide, produced a key compound 76, azidation of which, followed by hydrolysis with acid, gave the azide 77in 69% yield (two steps). Iodolactoni-
4.
349
THE AMARYLLIDACEAE ALKALOIDS
66
67
68
69
70
(f)-Lycorine (1) R=H (&)- 1,2-O-Diacetyllycorine (75) R=Ac Reagents and Condirionr : a) o-dichlorobenzene (a sealed tube), 235OC, 86% and 5% (stereoisomer);
b) LiAl&, THF, rt ,97% ;c) Ag&Og-Celite,benzene, reflux, 98% ;d) aq. KzCO3, rt, then 12, aq. KI, rt, 92% ; e) dihydropyran, p-TsOH, CH&, rt, 87% ; f ) 1,8-diazabicyclo[5.4.0]undec-7-ene, benzene, reflux, 98% ; g) p-TsOH, CH2Clz-MeOH (1: l), rt, 92% ;h) Jones oxidation,OOC, 63% ; i) (PhO),P(O)N3, r-BuOH, reflux, 79% ;j) CF$QH, CHzClz, rt, 98% ; k) NaOMe, MeOH. rt, 98% ; I) r-BuMQSiCl, imidazole, DMF,rt, 98% ;m) m-C1@-L&O3H, CHzC12,rt, 85% ;n) Bu4N?-, THF, rt, 38% ;0 ) AczO, pyridine, rt ; p) 5964. KzC03,THF, rt, 61%, 5% (regioisomer); q) (PhSe)z, NaB&, EtOH, reflux. 99%; r) 35% formalin, saturated aq.NazC03,THF, rt ;s) NaI04, THF, MeOH. rt. 57% ;t) NaA1(OCHzCHzOMehHz, toluene, reflux, then CH~=N%QI-, THF, rt, 44% ; u) Ref.
120. SCHEME 3
350
OSAMU HOSHINO
zation of 77 afforded iodo-y-lactone 78 in 82% yield, reductive cyclization of which, followed by treatment with (6-iodo-3,4-methylenedioxy)benzoyl chloride, produced the N-aroylenamido-y-lactone 79. The enamido-ylactone 79 was treated with benzyl alcohol and then butyllithium to produce, spontaneously, the benzyl p-epoxy enamido-carboxylate 80 in 93% yield. Radical-mediated cyclization of 80 with tributyltin hydride (Bu3SnH) in boiling benzene containing azobis(isobutyronitri1e)(AIBN) produced in 53% yield a key intermediate, the 2,3-p-epoxy-a-lycoran-7-one ester 81, having the lycorine ring system. Benzyl 2,3-p-epoxy-a-lycoran-7-one-3a~carboxylate (81) was converted into the thiazoline-2-thion-3-yl carboxylate 82. Oxirane ring opening, followed by elimination of a carboxyl group under chemically mediated radical reaction conditions gave successfully (+)-2-epi-l-deoxylycorin-7-one (83). Finally, 83 produced (+)-l-deoxylycorine (84)by the Mitsunobu reaction and successive reduction with lithium aluminum hydride (LiA1H4) in 56 (from benzoate) or 37% (from acetate) yield (two steps) (Scheme 4). On the other hand, phenylselenylation and dephenylselenylation of 81 provided the allylic alcohol 85, allylic rearrangement of which, with a mixture of acetic anhydride, acetic acid, and concentrated sulfuric acid, afforded a rearranged allylic acetate 86 in 28% yield (three steps). Epoxidation of 86 with dimethyldioxirane gave the corresponding epoxide 87. Catalytic hydrogenolysis of 87 followed by protolysis through a Pyrex filter in benzene containing acridine and t-butyl thioalcohol proceeded effectively to give 1O-acetyllycorin-7-one (88) in 45% yield (two steps). Acetylation of 88 gave 1,2-O-diacetyllycorine (89), the spectral data of which were identical to those reported for the racemate (221).Finally, (+)-lycorine (1)was obtained in 70% yield by reduction of 88 (Scheme 5). The syntheses of (+)-a-lycorane (92) and (+)-trianthine (97) using the retro-Cope elimination step (222), and of (+)-y-lycorane (100) using the palladium-mediated reaction (223), have been reported. When optically active 2-(cyclohex-2-enyl)ethylhydroxylamine (90) [derived from methyl 3-(3,4-methylenedioxy)phenylcyclohex-2-enylacetate] was heated at 140°C, the N-hydroxyhexahydroindoline 91 was obtained in 83% yield. Reductive cyclization of 91 then gave (+)-a-lycorane (92) (Scheme 6). This reaction has been applied to the optically active 5,6-O-isopropylidene-2-(cyclohex-2-enyl)ethylhydroxylamine (95) for the synthesis of (+)-trianthine (97). l-Acetoxy-l-[(3,4-methylenedioxy)phenyl]-5,6-Oisopropylidenecyclohex-2-ene (93) reacted with vinylmagnesium bromide in the presence of copper(1) bromide to give a vinyl compound, which was converted into cyclohexeneacetaldehyde 94. A starting ma-
4.
76
77
79
82
351
THE AMARKLLIDACEAE ALKALOIDS
78
81
(+)-1-Deoxylycorine (84)
83
Reugenrs and Conditions: a) (PhO)2PON3, DEAD, THF, O°C tort, 73%;b) 6M HCl, MeOH, rf, 95%;c) Iz, THF, H20, rt, 82%;d) PPh3,THF, reflux, W% ; e) 6-I-3,4-(CH20&HzCOCI, Et3n, CH2C12, 0 ° C to rt, 98% ;f) PhCH20H, THF, then normal BuLi, -78 to 25"C,93% ; g) Bu3SnH, AIBN, benzene, reflux, 5 3 8 ;h) 10%Pd-C, H2, EtOH, rt, 84% ; i) DCC, Nhydroxy-4-methylthiazolin-2-thione, 4pyrrolidinopyridine,CH2C12,86% ;j) DEAD, PPh3, PhC02H (73%)or AcOH (50%), THF ;k) LiAlH.,, THF, reflux, 76% (from benzoate), 73% (tiom acetate). SCHEME 4
terial95 was obtained by reductive hydroxyamination of 94. The cyclization reaction of 95 proceeded smoothly in degassed benzene at 80°C to afford Nhydroxyhexahydroindoline 96 in 96%yield, reduction of which with Raney nickel, followed by the modified F'ictet-Spengler reaction with Eschenmoser's salt (CH2=N+Me21-),gave (+)-trianthine (97) in 50% yield (two steps) by deprotection (Scheme 7).
352
&
OSAMU HOSHINO
a,b
( 0
0
0
0
89 Reagenrs and Condiriom : a) (PhSe)2,NaBh, EtOH, rt, 93%; b) NaI04, THF, H20, rt, 87% ; c) Ac20, AcOH, H2SO4, 50°C, 35% ;d) dimethyldioxirane,acetone, OOC, 46% ; e) 10%Pd-C, H2,
EtOH, R, 90% ;f) hu, Pyrex filter, acridine, f-BuSH, benzene, rt, 50% ; g) LiAlH4, THF, reflux, 70% ;h) Ac20, 4-dimethylaminopyridine,CHzC12, rt, quantitative ; i) Ref. 121. SCHEME 5
91
(+)-a-Lycorane (92)
Reagents and Conditions :a) degassed mesitylene, 140°C, 83% ;b) Raney Ni, wet Et20, then
CH2=NtMe21-,THF, 40 OC, 74-80%. SCHEME 6
4.
93
353
THE AMARYLLIDACEAE ALKALOIDS
95
94
%
(+)-Trimthine (97)
Reagents and Conditions : a) CHz=CHMgBr, CuBr, Me#, 95% ; b) 9-BBN, H202, then Swern
oxidation ;c) NHzOH, then NaBCNH3, aq. MeOH, pH 3.0,82% ; d) degassed benzene, reflux, 93% ;e) Raney Ni, then CHz=N+MeI-, 'IFIF. 89% ;f) AcCI, MeOH, 56%.
SCHEME7
Intramolecular cyclization of optically active N-[(6-bromo-3,4-methylenedioxy)phenylmethyl]cyclohex-2-enylacetamide (98) (prepared from 1S,4R-dibenzoyloxycyclohex-2-ene)under palladium-mediated reaction conditions afforded 4-methoxycarbonyl-l,2-dehydro-y-lycoran-5-one (99) in 58% yield, carboxylation of which, followed by stepwise reduction, afforded (+)-y-lycorane (100) (Scheme 8). The synthesis of (+)-y-lycorane (loo), or (5)-a-lycorane (92) and ( 2 ) y-lycorane (loo), has been achieved through arylation using the modified Suzuki reaction (124) (Scheme 9) or the cross Grignard coupling reaction (125) (Scheme 10). In the former case (124),methyl dibromo-bicyclo[3.1.0]2-(hexy1)ethylcarbamate (101) (prepared from 3-acetoxycyclopentene) underwent cation-n-cyclization with silver acetate in 2,2,2-trifluoroethanoI (CF3CH20H)containing potassium carbonate to afford a starting material 7-bromo-N-methoxycarbonyl-A6~7-tetrahydroindoline (102) in 87% yield. The cross coupling reaction of 102 with (3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions produced 7-(3,4-methylenedioxy)phenyl-Af'~7-tetrahydroindoline (103) in 87% yield.
354
OSAMU HOSHINO
98
99
Reagents and Condirions : a) Pd(OAc)z, dppb, NaH,
(+)-y-Lycorane (100)
DMF,50°C then i-Pr2EtN,100"C,58% ;
b) NaCl, DMSO-H20, 160°C; c) Pd-C, H2, MeOH ; d) LiAIH,, THF, reflux, 23% (3 steps). SCHEME 8
Reduction of 103, followed by cyclization, produced (+)-y-lycoran-7-one (104), which was reduced in the usual manner to lead to (2)-y-lycorane (100)(Scheme 9). In the latter case (125), palladium-catalyzed intramolecular 1,4-chloroamidation of N-benzyloxycarbonyl-2-(cyclohexa-2,4-dienyl)ethylamine (105) (derived from methyl cyclohexa-2,4-dienylacetate)proceeded regioand stereoselectively to produce N-benzyloxycarbonyl-5-chloro-A6~7tetrahydroindoline (106) in 95% yield. The cross Grignard coupling reaction of 106 with (3,4-methylenedioxy)phenylmagnesiumbromide in the presence of lithium copper( 11) chloride (Li2CuC14)in THF afforded 7-
101
I;~Hco~M~
102
103
(f)-y-Lycorane (100)
104
Reagenrs and Conditions : a) AgOAc, CF~CH2OH,K2CO3,18OC, 87% ;b) 3,4-(CH2O,)W3B(OH),, Pd(PPh&, aq. Na2C03, benzene, EtOH. 8OoC, 87%; c) 10%Pd-C, H2, 18°C. 95% ; d) NC13,
8OoC, 79% ;e) LMW,
THF,65°C. 84%. SCHEME 9
4.
THE AMARYLLIDACEAE ALKALOIDS
355
[(3,4-methylenedioxy)phenyl]-A~6-tetrahydroindoline(107) in 77% yield, which was converted into (2)-a-lycorane (92) or (+)-y-lycorane (loo), respectively, through 108 or 109 by changing the order of the procedure for reduction and cyclization (Scheme 10). Synthesis of (?)-a-lycorane (92) using radical-mediated cyclization of N-bromoaryl-3-hydroxy-3,4,S,6-tetrahydro-lH-indol-2-one has been carried out (226). 1-[(6-Bromo-3,4-methylenedioxy)phen ylmethyl]-3cyclohexylamino-A3~3a~~7~7a~-dihydroindolin-2-one (111) (derived from 3-cyclohexylaminodihydroindolin-~2-one (110) was transformed to 1-[(6bromo-3,4-methylenedioxy)phenylmethyl]-3-hydroxy-A7 (7a)-tetrahydroindolin-Zone (112)by hydrolysis and reduction. Radical-mediated cyclization of 112 with Bu3SnH in boiling benzene containing AIBN gave ( 2 ) hydroxy-a-lycoran-5-one (113)in 79% yield. Dehydroxylation of 113 under radical reaction conditions gave (+)-a-lycoran-5-one, which was reduced with LiAlH4 in boiling THF to afford (+)-a-lycorane (92)(Scheme 11). Cobalt-mediated [2+2+2] cycloaddition of an alkyne to the double bond of an enamide has been found to give spontaneously the lycorane ring system (227). Thus, a formal total synthesis of (+)-y-lycorane (100) has been achieved by this methodology. Also, (+)-y-lycorane (100)has been synthesized starting with pyrrole (228) or homophthalimide (229).
(*)-yLycorane (100)
109
(*)-a-Lycorane (92)
Reugenrs and Conditions : a) Pd(0Ach (5 mo1%), benzoquinone, LEI. acetone-AcOH( 4 1 ) . 95%; b) 3,4-(CHz01)C&MgBr, Li2cUCl4. THF, 77% ;c) P Q . H2. EtOH, rt, 95% ;d) POCI3 (neat), 7OOC, 72% ;e) L A W , THF,7OOC. 92%;9 POC13 (neat), 75OC. 71% ; g) POz,Hz (6.5 kg/cm2), EtOH, rt, 95%;h) LiAM4, THF, 65'C. 85%. SCHEME10
356
OSAMU HOSHINO
113
(It)-a-Lycorane(92)
Reagents and Conditions : a)
6-Br-3,4-(CH2O2)C,+I2CH2Br, NaH,DMF, rt, 74%;b) (C02H)2, THF-HzO, reflux, 70%; f) N a B h , MeOH, rt, 46% ; d) BqSnH, AIBN, benzene, reflux ;e) PhOCSCl, DMAP, pyridine, rt, 85% ; f) LiAW, THF, reflux, 51% (3 steps). SCHEME 11
The C-aromatic pyrrolophenanthridine-type alkaloids are members of the Amaryllidaceae alkaloid group. They have attracted the attention of chemists and pharmacologists because of their significant pharmacological properties (130). Hence, numerous studies directed toward the synthesis of these alkaloids have been conducted. During the past decade, several reports involving mainly two methodologies have appeared; one is based on the construction of ring B, whereas the other concerns the construction of ring C. The cyclization of 1-(6-iodo-3,4-methylenedioxy)phenylmethyl-4,5,6trihydro-1H-indol-2-one (114) (prepared from 110) under palladiummediated reaction conditions afforded pyrrolophenanthridone 115 in 71% yield. Hydrolysis of 115 gave the C-aromatic product anhydrolycorine-4,5dione (116),reduction of which, followed by elimination of the hydroxyl group, produced 4,5-dehydro-anhydrolycorine(43)(126b) (Scheme 12). The reaction of an o-methoxyaryloxazoline with an arylmagnesium halide has been known to cause replacement of a methoxy group with an aryl
4.
357
THE AMARYLLIDACEAE ALKALOIDS
a
110
114
115
0'
0
.
116
3,4-Dehydroanhydrolycorine(43)
Reagents and Conditions :a) 6-I-3.4-(CHz~)C&CHzCl, NaH. DMF, rt, 76%; b) Pd(OAc)z, Bu4N+ CI'*H@, KOAc, DMF,loOOC, 71% ;C) (C02H)2, THF-H20, reflux. 80% ;d) DDQ. benzene, reflux. 21%;e) LiAU& THF,reflux,42%;9 MeS@Cl, Et3N, CH2C12,rt, 9%. SCHEME 12
group, leading to a biaryl. This methodology has been developed for the synthesis of pyrrolophenanthridone-type alkaloids (131) (Scheme 13). The reaction of 2-[(6-methoxy-3,4-methylenedioxy)phenyl]oxazoline123 with the magnesium derivative of N-benzyl-7-bromoindoline (117)in tetrabromodifluoroethane gave the corresponding 7-arylindoline 118 in 68% yield. Hydrolysis and successive cyclization of 118 produced anhydrolycorin-7one (119), which was previously (232) transformed to hippadine (44) by oxidation with 2,3-dichloro-4,5-dicyanobenzoquinone(DDQ). Similarly, the intermediate 7-arylindoline 120 (prepared from 2-aryloxazoline 124) gave kalbretorine (61)through 4,5dihydrokalbretorine (121).The intermediate 7-arylindoline 122, which was synthesized in 73% yield by the reaction of 2-[(2,4,5-trimethoxy)phenyl]oxazoline125 with the magnesium derivative of 117, led to oxoassoanine (46) in a manner similar to that noted previously. Reduction of 46 produced pratosine (52) in 55% yield. Coupling of N-[(2-iodo-4,5;-dimethoxy)benzylidene]cyclohexylamine (126)with 7-[(N-t-butoxycarbonyl (Boc)]indolinyl)copper in ether at -45 to 20°C gave, on treatment with '1 M hydrochloric acid (HCl), N-Boc-7-[(6-
358
OSAMU HOSHINO
Me
(2 steps)
122
0
Oxoassoanine (46)
73% O
0
Ratosine (52)
Reagents and Codifions : a) Mg, BrF2CCF2Br, nflux, then 123.68% ;b) lO%aq. H2S04, EtOH, heat ; c) Pd-C,H2, MeOH, z t ;d) DDQ ;e) Mg, BrFzCCFzBr, nflux, then 124.78% ;f ) Mg. BrF2CCF2Br, reflux, then 125.73%;g) Ref. 132. SCHEME 13
formyl-3,4-dimethoxy)phenyl]indoline(127) in 65% yield. N-Deprotection and concomitant cyclization of the 7-(6-formylaryl)indoline(127) with anhydrous hydrogen chloride in chloroform gave vasconine (50) in quantita-
4. THE AMARYLLIDACEAE
359
ALKALOIDS
tive yield, reduction of which with sodium borohydride (NaBH4) afforded assoanine (45) in 93% yield. On the other hand, oxidation of 50 with alkaline aqueous potassium perrnanganate gave oxoassoanine (46) (133) (Scheme 14). The synthesis of hippadine (4and ) ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions (134) (Scheme 15). (7-Bromo-5-mesy1oxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119),which was transformed to hippadine (44)in 90% yield by oxidation with DDQ. Hippadine (a), ungeremine (48)) and anhydrolycorin-7-one (119) were also synthesized by the radical-mediated cyclization approach. Namely, cyclization of 7-bromo-1-[(3,4~~methylenedioxy)benzoyl]-5-nitroindoline (129) in dimethyl sulfoxide (DMSO) in the presence of benzyltriethylammonium chloride (BTAC) at 155°C gave 2-nitroanhydrolycorin-7-one (130), and a regioisomer, in 60% yield (product ratio of 1:1). Catalytic hydro(131) in good yield. genation of 130 led to 2-amino-anhydrolycorin-7-one
n
a
' 6 OMe O M e
126
Me0
b
OHC
127
MeO& Me0
MeO&
Me0
C1Vasconine (SO)
/ Id Me0
0
Assoanine (45)
Oxoassoanine(46)
Reagenrs and Condirions :a) N-Boc-indoline,s-BuLi, TEMEDA, EtzO. -45OC, CuI. P(OEt)3,rt, then 1M HCI. 65%;b) gaseous HCI, CHC13, quantitative ;c) NaBH.+ EtOH, rt, 93%; d) KMn04, 3M NaOH. CH2C12.2OoC, 84%. SCHEME 14
360
Br
OSAMU HOSHINO
- <" a
0
-("
C
0 128
I
a
L
0
Ungeremine (48)
< 0 0 " & 0 A ? & Anhydrolycorin-7-one (119)
Hippadine (44)
Reugents and Conditions : a) ~ ~ e 3 , 4 - ( ~ ~ o ~ ) C k H , B ( O Pd(PPh3)4. H ) z , NazC03. DME,reflux.
(4049%) ;b) NaAl(OCHZCH~0Me)~Hz. toluene, reflux. 54%;c) DDQ,dioxanc, reflux, 90%. SCHEME 15
Transformation of 131 to hippadine (a), ungeremine (a), and anhydrolycorin-7-one (119) was accomplished in the usual manner (135)(Scheme 16). The intramolecular Diels-Alder reaction of 5-(3-butynyl)-3H-pyran[2,3c]isoquinoline-3,6-dione (132) in boiling benzene afforded a pyrrolophe(136). Hipnanthridone, which yielded 2-methoxy-anhydrolycorin-7-one padine (44) was synthesized by means of l-aza-l'-oxa[3.3]sigmatropic rearrangement of N-(2-methoxycarbonylvinyloxy)-8,9-methylenedioxyphenanthridin-6-one (133)(137) or by palladium-mediated intramolecular cyclization of 7-bromo-N-[(6-bromo-3,4-methylenedioxy)benzoyl]indoline (134)(138) (Fig. 10). C. BIOLOGICAL ACTIVITY Lycorine (1) and pseudolycorine (12) were evaluated to determine their in vitro inhibitory properties against the RNA-containing flaviviruses ( Japa-
nese encephalitis, yellow fever, and dengue type 4 viruses); bunyaviruses (Punta Toro, sandfly fever-Sicilian, and Rift Valley fever); the alphavirus (family Togaviridae); Venezuelan equine encephalomyelitis viruses; the lentivirus; HIV-1; and the DNA-containing vaccinia virus. Antiviral activity was observed against the flaviviruses tested, and to a slightly lesser degree against the bunyaviruses. Also, 1 and l2 showed inhibitory activity against Punta Tor0 and Rift Valley fever viruses, but with low selectivity (139).
4. THE
361
AMARYLLIDACEAE ALKALOIDS
'& (&
('0
0
Anhydrolycorin-7-one (119)
d
'0
0
Hippadine (44)
0
131
(& 0 o Ungeremine (48)
Reugenrs and Conditions : a) BudN'Cl-, K2CO3, M%SO. 155"C, 60% (1 : 1); b) Pd-C, H2, CF3CO2H. 25'C. 93% ; c) aq H3PO4, Cu20, CICH2CH2C1, 7OoC, 50% ; d) DDQ,benzene, 100°C, 76% ;e) ONOS03H. aq. H2SO4, NaBFs, OOC, 76%; f) CF3CO2H. reflux. 40% ;g) NaH, Cd-ISCH2Br,DMF, 7OoC,51% ;h) LiAM4, THF. reflux, 95% ;i) Pd-C. H2, EtOH, 7OoC, then H202, AcOH, Mn02 (HzO),, 25OC, 80% (2 steps).
SCHEME16
132
133 FIG.10
134
362
OSAMU HOSHINO
The pharmacological effects of lycorine (1) have been studied using the guinea pig; it caused concentration-dependent relaxation of the isolated epinephrine-precontacted pulmonary artery. In this study, its effects on heart were suggested to be mediated by the stimulation of P-adrenergic receptors (102).
111. Crinine-Type Alkaloids
A. Isolation and Structural Elucidation Since 1987, the isolation and characterization of several new crinine-type alkaloids have been reported. The structures of the representative alkaloids isolated are depicted in Figs. 11 and 12. It is noteworthy that oxocrinine (138), an intermediate in the biosynthesis of crinine (135)and related compounds in Amaryllidaceae alkaloids, was isolated for the first time from the bulbs of Crinum umericanum (14). Its structure was elucidated by spectroscopic evidence, including 'H-coupled I3CNMR experiments, and finally confirmed by comparison with a sample prepared from crinine (135) by oxidation. The extract of the bulbs of Pancratium maritimum grown in Turkey has been found to contain two new chine-type alkaloids, 3& 1la-dihydroxy-1,Zdehydrocrinane (141)and 8-hydroxy-9-methoxycrinine (172)(98), together with the lycorine-type alkaloids (95). A more hydroxylated crinine-type alkaloid, crinisin (171), was found in the bulbs of C.asiaticurn var. sinicum, accompanied by lycorine (l), crinine (135), and powelline (163) (21). 11-Hydroxyvittatine (152), which hitherto had only been found in plants belonging to the genus Sternbergia (102), has been isolated from the bulbs of Hippeastrum hybrids (42). The structure determination was performed by a comprehensive NMR study of the alkaloids involving 2D techniques such as HOHAHA, ROESY, and HMBC for 'H and '3C assignments, which enabled structural elucidation to be facilitated. Vittatine (147)and 11-hydroxyvittatine (152) were found in the extract of the dried bulbs of Hippeastrum puniceum (43). Hamayne (153), 3-0-acetylhamayne (154), crinamine (156), ambelline (161),and a new alkaloid named josephine (144),together with the lycorinetype alkaloid sternbergine (16), were isolated from the bulbs of Brunsvigia josephinae (11). The mass spectrum of 144 showed the molecular peak at m/z 331, and prominent fragments at m/z 289, 242, and 202 that are characteristic of a 1,Zdisubstituted crinane alkaloid (140).Its spectroscopic ('H and 13CNMR) evidence established the structure as 144. A new alka-
4.
W i n e (Crinidine) (135) R=R~=H 0-Acetylcrinine (136) R = AC, R' = H 6a-Hydroxycrinine (137) R = H. R' = a-OH
363
THE AMARYLLIDACEAE ALKALOIDS
Oxocrinine (138)
Buphanisine (139) R=H 6a-Hydroxybuphanisine (140) R =a-OH
3p.1 la-Dihydroxy-1.2dehydrocrinane (141)
R
O&R .
H 0 . A
Flexinine (142) R=OH Augustine (143) R = OMe
Josephinine (1.44) R = P-OAC Amabiline (145) R = a-OH
OH
Epi-vittatine (149) R=H Epi-buphanisine(150) R=Me $
Alkaloid 13 (151)
, l 'OH
0
Vittatine (147)
Elwesine (146) @ih ydrocrinine)
0 OH
Albiflomanthine (159)
[(+)-Crinine]
R=H (+)-Buphanisine (148) R=Me
..
ll-Hy&oylvitattine (152) R=a-OH,R'=H Hamayne (153) R = a-OH, R' =H 3-0-Acetylhamayne (154) R = a-OAc, R'= H Haemanthamine (155) R = p-OMe. R' = H
Crinamine (156) R = a-OMt. ' R'=H Haemanthidine (157) R = POMe, 6-Hydro~yR' = OH
tT=%iMe*
crinamine (158)
FIG.11
loid, albiflomanthine (159), was found in the bulbs of Haemanthus afbijlos (36). The molecular formula was measured by high-resolution mass spectrometry as CI7Hl9NO5,and the structure was determined as 159 on the basis of spectroscopic (UV and 'H, and 13CNMR) analyses. Interestingly, it possesses the unusual feature: of an oxygen substituent at C-4.
364
OSAMU HOSHINO
R
HO
.OMe
Q 0
0 OMe
OM9
Buphandrine (160) R=H Ambelline (161) R=OH 1I-O-A~etylambelline (162) R = OAC
Powelline (163) R = OH, R' = H 3-O- Acetylpowelline (164)
Crinafoline (166)
powelline (165) R=R'=OH
Bumsbelliie (168)
Me0
Crinafolidine (167)
OH
Crinamidine (169) R=H Undulalinc (170) R=Me
H
Me0 HO
OM9
8-HY&OXY-9methoxycrinine (172)
Crinisin (171)
Siculine (173)
H Me0
Me0
HO 8-0-&methylmaritidine (174) R =H, R' = ~e 9-O-Demeth ylmaritidine (175) R=MC,R~=H
Cantabricine(176)
R
Narcidine (177) R
m O M e
Ms.O&,
MeO
HO
R
Papyramine (180) R = WOH 6-Epi-papyramine(181) R = &OH 6kO-M~thylpapyramine (182) R = POMe FIG.12
Maritinamine(183) R = p-OH Epi-maritinamine (184) R = a-OH
Maritidine (178) R=H O-Methylmaritidine R = M e (179)
4.
THE AMARYLLIDACEAE ALKALOIDS
365
New crinine-type alkaloids, as well as several known Amaryllidaceae alkaloids, were isolated from two Sternbergiu species of Turkish origin. They are maritinamine (183) and epi-maritinamine (184) (from S. lutea), and (+)-buphanisine (148) and siculine (173) (from S. sicuh) (203).The structure determination of the new alkaloids was performed on the basis of an extensive analysis of 'H NMR spectral data for the known crininetype alkaloids. The spectral data for (+)-buphanisine (148) were in good agreement with those for (-)-buphanisine (139), except for its positive specific rotation. Indeed, the CD curve of (+)-buphanisine was the opposite of that described for (-)-buphanisine in the literature (142).Therefore, (+)-buphanisine was established to be a new alkaloid, enantiomeric with the known (-)-buphanisine. Furthermore, all of the Sternbergiu alkaloids, new as well as known, possess the identical absolute configuration, with the ethano bridge below the mean plane of the molecule.
B. SYNTHETIC STUDIES Since the previously published review (8),some interesting methods for the synthesis of crinine-type alkaloids have appeared. The 2-aza-ally1 anion cyclization method gave (2)-crinine (135) and ( 2 ) epi-crinine (188) ( 1 4 2 ~ Treatment ). of tributylstannylmethylimine 186 [prepared from 6-[(3,4-methylenedioxy)phenyl]-6-methylenehex-4-enal(185) and tributylsannylmethylamine] with butyllithium in THF at -78°C led to formation of the 2-aza-ally1 anion, whose concomitant intramolecular cycloaddition led to 3-0-methoxymethylnormesembrene(187) in 80%yield. The Pictet-Spengler reaction of 187 with formalin using 6 M HC1 in methanol (MeOH) afforded (+)-6-epi-crinine (188). The 6-hydroxy group was epimerized by treatment of the corresponding mesate with cesium acetate to furnish on hydrolysis (+)-crinine (135) (Scheme 17). This methodology was expanded to the synthesis of (-)-amabiline (145)(242c). Namely, 2-aza-allylstannane 189 (derived from 2S,3S-Oisopropylidene-y-butyrolactone) was exposed to butyllithium in THF at -78°C to provide 3a-(3,4-methylenedioxy)phenylhexahydroindoline(190) along with a diastereomer in 74% yield (a 5 : 1 mixture of two diastereomers). The Pictet-Spengler cyclization of 190, followed by acid treatment, afforded (- )-amabiline (145), confirming the absolute stereochemistry of the natural product (Scheme 17). The synthesis of (+)-oxomaritidine (192) and a formal synthesis of (+)-marhidine (178) were achieved by intramolecular oxidative coupling of phenol derivatives using a hypervalent iodine reagent as a key step (2 43). 2-[(4-H ydrox y )phen yl] -hi-[(3,4-dimethoxy)phenyl]4-trifluoroacetylethylamine was treated with phenyliodonium bis(trifluor0acetate) in
366
OSAMU HOSHINO
MOMOc A SArn B u + M O M O e *
f
MOMO
185
186
Ar = 3,4-(CH2O2)%H3 ; MOM = MeOCH2
187
(f)-Epi-crinine (188)
(f)-Crinine (135)
Me
189
190
(-)-Amabiline (145)
Reagents and Conditions : a) Bu3SnCH2NH2, MS4A (50wt%), EbO, rt, 100%; b) BuLi (2.1 equiv.), THF, -78OC. 80%;c) 37% formalin (32 equiv.), MeOH, then 6M HCl. 5OoC, 75% ;d) (MeSO2)20,
Et20, THF, OOC, then CsOAc, rt ; e) KzC03,MeOH. 72% (2 steps) ;F) BuLi (1.9 equiv), THF, -78°C 74% (5 : 1mixture of two diastereomers); g) Me2N+=CH21-,MeCN, reflux ; h) HCl, MeOH, 92% (2 steps). SCHEME 17
CF3-CH20H at -40°C to produce a spirocyclohexadienone 191 in 61% yield, which was converted into (5)-oxomaritidine (192). Application of this methodology to methyl (R)-N-trifluoroacetyl-N-[(3,4-dimethoxy)phenyll-4-hydroxyphenylalanategave the optically active spirocyclodienone 193 in 64% yield, which was previously (144) transformed to (+)-maritidine (178). Hence, this result constitutes a formal synthesis of (+)-maritidine (Scheme 18). Condensation of 2-chloro-A'-pyrrolidinium chloride (prepared in situ from N-benzylpyrrolidin-2-one194 and phosgene) with t-butyl 3-oxo-4pentenoate, followed by acid treatment under ultrasound irradiation condi-
4.
367
THE AMARYLLIDACEAE ALKALOIDS
%e
OH
0
OMe
CF&O
/ OMe
b
I
H
~
Me0
CF3CO'
191
(f)-Oxomaritidine (192)
OH
OMe
..
CFsCO
CF3CO'
(+)-Maritidhe (178)
193
Reagents and Codifions : a) PhI(OCmCF3)2, CF3CH2OH, -40 'C, 191 (61%), 193 (64%) ; b) K2C03, MeOH-H20 ; c) Ref. 144. SCHEME 18
tions, afforded N-benzyl-A'-mesembren-6-one (195) in 29% yield (three steps). Reduction of 195 with sodium in liquid ammonia gave the known hexahydroindolin-6-one 196, which was earlier (14.5) transformed to (?)dihydromaritidine (197) (146) (Scheme 19). OMe
194
195
1%
Bn = GH5CH2
(f)-Dihydromaritidine (197)
Reagents and Conditions : a) COC12; b:l CH2=CHCOCH2C02r-Bu,Et,N, CH2C12,reflux ;
c) CF3C02H, (3 equiv.), ultrasound, 29%(3 steps) ;d) Na, liq. NH3,76% ;e) Ref. 145. SCHEME 19
368
OSAMU HOSHINO
Starting with 6-allylcyclohexanones 198 and 199, the synthesis of (?)dihydromaritidine (197), (+)-6-epi-dihydromaritidine (202), and ( 2 ) elwesine (146) and (+)-6-epi-elwesine (203) through 200 and 201, respectively, has appeared (147). Also, a formal synthesis of (+)-elwesine (146) by a protocol similar to that noted for (2)-mesembrine (377) has been carried out (Z48)(Fig. 13). C. BIOLOGICAL ACTIVITY
The ethanol extract of the bulbs of Crinum amabile on preliminary biological evaluation was shown to possess cytotoxic and antimalarial properties (13).Although all the isolated alkaloids showed antimalarial activity against two strains of Plasmodium faleiparum, a new crinine-type alkaloid, amabiline (145), was the most effective (lO,OOOX), and augustine (143) the least active (140X). All were significantly more active than the commercial antimalarial drug chloroquine (1.3X).
RO&f2
I
0 RO
RO
R=Me 198 R+R=CH2 199
Bn = C&sCH2
R=Me 200 R+R=CH2 201
RO
RO
(f)-Epi-dihydromaritidine (202) R=Me (*)-Epielwesine (203) R+R=CH2
(f)-Dihydromaritidine (197) R=Me (*)-Elwesine (146) R+R=CH2 FIG.13
4.
THE AMARYLLIDACEAE ALKALOIDS
369
IV. Narciclasine (Lycoricidine)-TypeAlkaloids
A. Isolation and Structural Elucidation 7-Deoxynarciclasine (204),and narciclasine (205),7-deoxypancratistatin (210),and pancratistatin (211)were found in the resting bulbs of Haemanthus kalbreyeii (37). Also, narciclasine (205),7-deoxypancratistatin (210), and pancratistatin (211)have been isolated from the bulbs of Hymenocallis littoralis (45).The glucosidal alkaloids, pancratiside (212)(37),kalbreclasine (206) (108),and 4-O-~-~-glucopyranosylnarciclasine (207) (96), were obtained from resting bulbs of Haemanthus kalbreyeii, the fresh mature seeds of Zephyranthesflava, and the bulbs of Pancratium maritimum, respectively. Elucidation of the structures was performed by spectroscopic and chemical methods. 7-Deoxy-trans-dihydronarciclasine(208)has been isolated from the bulbs of Hymenocallis caribrzea, H. latifolia, and H. littoralis (45). Also, trans-dihydronarciclasine (209) was found in the fresh ground bulbs of Zephyranthes candida (directed by results of a bioassay employing the P388 lymphocylic leukemia) by acetylation (106) (Fig. 14). Plant alkaloids are frequently considered to be protective agents for their hosts; their toxicity and antifeeding properties present a directing environment to predators. An interesting investigation regarding them has been reported (25). One specialized herbivore, Polytela gloriosa Fab (Noctuidae), a smoky-grey moth, utilizes Amaryllidaceae plants, which are avoided by other insects. A remarkable association of alkaloid metabolism by P. gloriosa adapted to a number of Amaryllidaceae species, e.g., Amaryllis, Crinum, and Pancratium, has been noted. The larvae of this insect were found to store large amounts [ca. 0.5-1% (fresh weight)] of the common pyrrolo- and ethano-phenanthridine alkaloids, such as lycorine (l), crinine (135) (and their equivalents), and haemanthamine (155), from the flowers and leaves of Crinum latifolium L. A new isocarbostyri1-Nacetylaminoglucoside conjugate named telastaside (213)was isolated from the insect (P. gloriosa). The structure of the alkaloid was characterized by spectroscopic evidence and chemical transformation. It was treated with hesperidinase in sodium acetate-AcOH buffer (pH 5.1) at 30°C to afford 7-deoxypancratistatin (210)and N-acetylglucosamine, respectively. On the other hand, it was heated with 4 M HCl in 30% aqueous ethanol at 100°C to produce 4-hydroxyphenanthridone (431)and D-glucosamine hydrochloride. A strikingly common association of the alkaloid in the secondary metabolism of the host and the feeder species, during stress, has been discerned. The alkaloid was not present in any part of healthy (uninfested) C. latifolium, nor was it detected in the moth when collected from the natural habitat (earthen cocoon in the rhizosphere of C. latifolium).
370
OSAMU HOSHINO
OH
R
OH
OH
0
7-DeOXYnarciclasine (204) (Lycoricidine)
Narciclasine (205) R = CX-OH Kalbreclasine (206) R = bD-Glucosyl
4-O-P-D-Gl~cosylnarciclasinc (207) R = ~D-Glucosyl
OR
OH
)&Io: NH
R
O
7-hOxytrans-dihydronarciclasine (208) R=H Trans-dihydronatciclasine (209) R-OH
NH
'0
A1
0
7-Deoxypancratistatin(210) R=R~=H Pancratistatin (211) R = H, R*= OH Pancratiside (212) R = P-D-Glucosyl, R' = OH
Telastaside (213)
FIG.14
B. SYNTHETIC STUDIES Regarding the synthesis of the narciclasine (1ycoricidine)-type alkaloids, an important strategic element is how to construct the functionalized ring C in these alkaloids. Therefore, extensive efforts to explore a new method for preparing a key intermediate have been made. Among these extensive studies, the first total synthesis of (+)-pancratistatin (211) has been reported (149) (Scheme 20). Tricyclic 1,2dihydroxy-Slactone 214 was converted into vicinal acetoxy-bromo-6lactone 215 in 88% yield along with the regioisomers. Osmium tetroxide oxidation of 215, followed by introduction of a double bond and selective protection of the hydroxyl groups, gave the corresponding allylic alcohol
4.
214
216
L
OH
371
THE AMAKYLLIDACEAE ALKALOIDS
Br
Bn = C&I5CHz
215
217
219
218
(i)-Pancratistatin(211)
Reagents and Condirions :a) 2-acetoxyisobutyryl bromide, MeCN, rt, 88% ;b) Os04(cat.), NMO, CH2CI2, THF, rt, 88% ;c) (Bu3Snh0, MS3A, toluene, reflux ;d) 4 M e m C H 2 B r . B u ~ ~ I - , 80°C, 84%;e) AgzO, C5H5CH2Br, DMF,rt, 95% ;r) DDQ,4. a&h,rt, 75 % ;g) Zn,~ Z C ~ Z . HzO, AcOH, reflux, 81% ;h) NaH, C13CCN,THF, 0°C to rt, 74%;i) pyrolysis at 100-105°C (0.05-O.lmmHg), 56% ;j) OsOd (cat.), NMO, THF,rt, 75% ;k) KzCO3, dry MeOH-CHzC12 (5 ; 21, reflux, 82% ; I) Pd(OH)2-C, Hz,EtOAc, 90%. SCHEME 20
216 by skillfully stereocontrolled reactions. Following these reactions, the Claisen rearrangement of imino ether 217 (prepared by the reaction of 216 with trichloroacetonitrile in the presence of NaH at 100-105°C under reduced pressure) proceeded effectively to afford the amide 218 in 56% yield, 1,2-cis-dihydroxylationof which, followed by hydrolysis with base, produced 2,7-O-dibenzylpancratistatin(219)by way of an amino acid. Finally, (+)-pancratistatin (211)was synthesized in 90% yield by debenzylation using catalytic hydrogenation.
372
OSAMU HOSHINO
Following this report, a total synthesis of optically active (+)-lycoricidine
(204) (150) and (+ )-Zepi-lycoricidine (224) (1506) starting from D-glucose
was described in the literature (Scheme 21). In this case, the modified Heck reaction of amide 220 bearing fully protected functional groups, which was prepared from SS,6S-bis(methoxymethoxy)-4-(4R)-azidocyclohex-2-enone, is a key step. The protected amide 220 underwent intramolecular cyclization with palladium acetate in the presence of thallium(1) acetate and 1,2-bis(diphenylphosphono)ethane
0
-
OMPM
a-c,b
OMOM A3
0
NMPM
0
-
OMPM
0
220
0
221
OAC OH
MPM = 4-MeOC&CH2 MOM = MeOCH2
OH
(100%) 222
221
0
0
(+)-Lycoricidine(204)
223
(+)-2-epi-Lycoricidine(224)
Reogenrs and Conditions :a) NaB%, &C13*7H20, MeOH, OOC, 86% ;b) 4-MeOCaCH2C1, NaH, DMF, rt ;c) LiAW, Et20, OOC. then 6-Br-3,4-(CH2O&J-I3CQH,(EtO)2P(O)CN,Et3N, DMF,O°C, 89%;d) Pd(OAc)? (20 mol%),TlOAc (2 mol%),DIPHOS (40mol %). DMF,140°C, 68% ;e) DDQ. CH2U2-H20(18 : 1). 0°C ;r) P h W H , PPh3, DEAC. THF, rt. 78% ;g) NaOMe, MeOH-THF (5 : 1). rt, 99% ;h) 1N HU, THF-fi20 (1 : 1). 50°C, then AczO, pyrkline, rt, 5 1% ; i) CF3CO2H-CHCl3(1 : 1). It.
SCHEME21
4.
373
THE AMARYLLIDACEAE ALKALOIDS
(DIPHOS) in dimethylformamide (DMF) at 140°C to give protected 2-epilycoricidine 221 in 68% yield. Selective deprotection of 221 followed by inversion of a hydroxy group at the 2-position using the Mitsunobu reaction afforded 0-triacetyllycoricidine (222). Hydrolysis of 222 with base led to (+)-lycoricidine (204). On the other hand, 221 was transformed to 2-epilycoricidine (224) through the triacetate 223 by stepwise deprotection. As interesting synthetic approaches toward lycoricidine, starting with optically active tribenzyloxy-5-hexenal or L-arabinose, protected versions 226 (252) or 228 (252) of (+)-lycoricidine have been synthesized through 225 or 227 (Fig. 15). Recently, oxidation of a halobenzene using a microbiological procedure was found to give optically active 3-halo-1,2-cis-dihydroxycyclohexa-3,5diene in good yield. This compound has received the attention of chemists for constructing ring C in the narciclasine-type alkaloids (253). An example is as follows. After protection as a silyl ether, amidation of benzyl N-(5,6-O-isopropylidene-4-hydroxycyclohex-2-enyl)carbamate229 (prepared from 3-bromo-lS, 2S-(3-isopropylidenecyclohexa-3,5-diene) with (6-bromo-3,4-methylenedioxy)benzoylchloride gave the protected N benzyloxycarbonyl-N-(cyclohex-~2-enyl)benzamide230. A modified Heck reaction of 230 in anisole produced the protected lycoricidine 231 in 27% yield (two steps) by N-detosylation. Acid treatment of 231 provided (+)-lycoricidine (204) in 85% yield (Scheme 22).
OBn
p n O-OBn
Bn = C&CH2
225
226
OMe
OM9
0 221
Ts = 4-MeCASO2 FIG.15
0
228
374
OSAMU HOSHINO
OSiMed-Pr
S)SiMe2CPr
- < “d G
0
-
NH
-0
0
0 231
(+)-Lycoricidine (204)
Reagenrs and Conditions :a) i-PrMe2SiC1. imidazole ;b) BuLi, THF, -78OC. then 6-Br-3,4-(a2%)-
C!&COCl; c) Pd(OAc)z, TIOAc, DIPHOS, anisole, 27%; d) Pd-C, cyclohexene, EtOH, 99%;e) C F 3 Q H . OOC. 85%. SCHEME 22
A sequence of reactions similar to those noted previously has been constituting a formal synapplied to 1,2-cis-dihydroxycyclohexa-3,5-diene, thesis of (+-)-lycoricidine (204)(154). Since the isolation and discovery of the significant biological activity of 7-deoxypancratistatin (210) and pancratistatin (211), which have more oxygenated functional substituents than lycoricidine (204),synthetic studies have been performed extensively. The total synthesis of optically active (+)7-deoxypancratistatin (210)and (+)-pancratistatin (211)has been reported independently by four research groups. The first group led by Hudlicky reported a synthesis of (+)-7-deoxypancratistatin (210)and (+)-pancratistatin (211)starting with a key intermediate, the optically active aziridine derivative 232 (derived from 3-bromo1S,2S-O-isopropylidenecyclohexa-3,5-diene) (155). A full paper regarding these efforts has been published (256) (Schemes 23 and 24). Reaction of the N-( p-tosy1)aziridine 232 with lithium bis[(3,4-methylenedioxy)phenyl]cyanocuprate in the presence of borontrifluoride etherate (BF3 - Et20) at -78 to -30°C gave rise to stereoselective opening of the aziridine ring to afford methyl N-[SP,6P-dihydroxy-2-(3,4-methylenedioxy)phenylcyclohex-3-enyl]carbamate (233)in 34% yield by deprotection with
4.
232
233
234
OAc
NHCQMe
0
235
375
THE AMARYLLIDACEAE ALKALOIDS
236
I
~
NH
0
0
(+)-7-DeOXypancatistatin (210)
Reagents and Conditions : a) dilithium dipiperonylcyanocuprate, BFyEt20, THF,-78 to -30°C, 32%; b) s-BuLi, THF, rt, then (MeOC0)20,76%;c) Na, anthracene, DME, -78OC, 69% ;d) AcOH-THF-H20 (2l:l). 65OC, 94% ; e) r-BuOOH, VO(acac)z, benzene, 7OoC, 85% ; f ) P h 0 2 N a (cat.), H20,100°C, 82%; g) AczO, DMAP, pyridine, 84% ; h) TfZO, DMAP, CH2C12,5°C. 69% ;i) NaOMe, MeOH, THF, rt. 72%. SCHEME 23
acid. Sharpless epoxidation furnished, stereoselectively, methyl N-[3,4pepoxy-5/3,6P-dihydroxy)-2-( 3,4-methylenedioxy)phenylcyclohexyl]carbamate (234)in 45% yield. Ring opening of the epoxide 234 with a catalytic amount of sodium benzoate in boiling water afforded on acetylation methyl N-[3,4,5,6-tetra-acetoxy-2-(3,4-rnethylenedioxy)phenylcyclohexyl]urethane (235).Intramolecular cyclization of 235 with trifluoromethanesulfonic anhydride (Tf20)took place successfully to yield 0-tetra-acetyl-7-deoxypancratistatin (236),which was treated with NaOMe in MeOH-THF to provide (+)-7-deoxypancratistatin (210)in 72% yield. The overall yield was 3% (11 steps from bromobenzene). The synthesis of (k )-pancratistatin (211) has been achieved by application of a sequence of the reactions noted previously to a [3-0-tbutyldimethylsilyl (TBS)-4,5-methylenedioxy]phenyl derivative. Namely, coupling of N-( p-tosy1)aziridine 232 with the cuprate derivative of [3O-TBS-2-(N,N-dimethyIcarboxamido)-4,5-methylenedioxy]benzene,in a manner similar to that noted for 210, produced N-(6-arylcyclohex4-enyl)-N-(p-tosy1)amide as a mixture of atropisomers, reductive N -
376
OSAMU HOSHINO
232
a-Auopisomer (238)
239
Ts = p - M e W S 0 2 TBS = r-BuMezSi BOC= C02Bu-t Bn = C&CH2
HO
0
(+)-Pancratistatin(211) Reagents and Condirionr : a) Liz [2-(MezNCo)-4,5-(CHz@)-3-(r-BuMczsio) C&]2
(CNCu), BF3* THF, reflux, 68% (a mixture of uEt20, THF. -78OC, 75% ; b) s-BuLi, THF, OOC, then (BOC)~O, and p-atropisomers) ;c) Na, anthracene, DME,-78"C, 62% (p-atropisomer), 20% (a-ampisomer) ; d) TBAF, THF,OOC, 93% ;e) SMEAH, morpholine, THF, -45"C, 72% ;f ) C&&HzBr, KzCO3, DMF, rt, 83% ; g) NaC102, KH2P04, 2-methyl-2-butene,r-BuOH, HzO, rt, then CH2N2, EtzO, 98% ; h) AcOH-THF-HzO (2 : 1 : l), 6O"C, 73% ;i) r-BuOOH, VO(a~ac)~, benzene, 6O"C, 53% ; j) H20, PhW2Na (cat), 100aC. 6 days, 51% ;k) H20, PhC@Na (cat), l W C , 48 h ;I) Pd(OH)2, H2, EtOAc. rt, quantitative. SCHEME 24
detosylation of which, followed by N-protection with a Boc group, afforded the N-Boc product 237 (0-atropisomer) and the 0-desilylated N-Boc product 238 (a-atropisomer) in 62 and 20% yield, respectively. 0Desilylation of the former 237 with tributylammonium fluoride (TBAF) in THF at 0°C caused equilibration between the 0-desilylated a- and 0-
4. THE AMAKYLLIDACEAE ALKALOIDS
377
atropisomers to give the 0-desilylated N-Boc product 238 (a-atropisomer) in 93% yield, which was identical with the product obtained by reduction of a mixture of atropisomers. Reduction of the N,N-dimethylcarboxamido group with SMEAH in THF containing morpholine (1 eq)(257) at -45°C followed by 0-benzylation furnished the corresponding 0-benzylated aldehyde, which was converted into 6-[(3-benzyloxy-2 -methoxycarbonyl- 4,5 methy1enedioxy)phenyll- N - Boc- (4,5-epoxy-2,3 -dihydroxy) - cyclohexanecarboxamide (239) by successive oxidation, methylation, deprotection, and Sharpless epoxidation. The reaction of 239 in boiling water containing a catalytic amount of sodium benzoate for 6 days gave spontaneously (+)pancratistatin (211) in 3% yield. Interestingly, when the reaction under similar reaction conditions was quenched after 48 h, 0-benzylpancratistatin (240) was obtained, which was transformed to (2)-panctatistatin (210) in quantitative yield by 0-debenzglation. Therefore, the prolonged reaction under the reaction conditions supported oxirane ring opening, N-deprotection, and cyclization leading to 0-benzylpancratistatin (240). The overall yield was 2% (14 steps from bromobenzene). A second group has synthesized (+)-7-deoxypancratistatin (210) starting from D-glucose (258) by a method involving an intramolecular radicalmediated cyclization of an oxinie as a key step (Scheme 25). 0-TBS-0benzyloxime 241 (derived from D-glucose) was reduced with NaBH4 to afford the corresponding alcohol, reduction of which, followed by treatment with thiocarbonyldiimidazole, afforded a radical precursor 1imidazolylthiocarboxylicester 242. Radical-mediated reaction of O-TBS0-benzyloxime 1-imidazolylthiocarboxylicester 242 with Bu3SnH in boiling toluene containing AIBN gave rise to an intramolecular addition of a carbon radical to the C = N bond in the oxime to provide a cyclized product 243 in 70% yield. Trifluoroacetylation of 243, followed by subsequent 0desilylation and oxidation with tetrapropylammonium perruthenate (TPAP)(259) and N-methylmorpholine N-oxide (NMO), gave the N-benzyloxyamino-N-trifluoroacetyl-Slactone 244. Cleavage of the N-0 bond in 244 was effected with samarium(I1) iodide (SmI,) to afford a trifluoroacetamide, cyclization of which under acidic conditions, followed by hydrolysis with base, provided (+)-7-deoxypancratistatin (209). Furthermore, this methodology was developed to afford the synthesis of ent-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (260). Photolysis of 4-(4R)-hydroxy-6-[(2-methoxycarbonyl-4,5-methylenedioxy)phenyl]-2S,3S-0-isopropylidenehex-5-ynal0benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce 1-(N-benzyloxyamino)J-phenylthiocyclohex-5-ene 246. Cleavage of the N-0 bond and reductive elimination of the phenylthio group in 246 with SmIz in THF
378
OSAMU HOSHINO
OMOM
241
MOM = MeOCHz
243
242
TBS = r-BuMe#i Bn = C,HsCH2
v
244
-
(+)-7-Deoxypancratistatin (210)
Reagenrs and Conditions : a) N a B h , MeOH ; b) thiocarbonyldiimidazle, DMAP, ClCH2CH2Cl. 80% (2 steps) ;c) Bu3SnH, AIBN, toluene, 90°C, 70%;d) (CF3CO)20, pyridine, DMAP ; e) Bu4N'F-. THF ; f') TPAP. NMO ;g) Sm12 ;h) Dowex , ' H MeOH, 65OC, 88% ; i) K2CO3, dry MeOH. 70% (3 steps). SCHEME 25
proceeded effectively to give 3,4-0-isopropylidene-ent-lycoricidine (247), deprotection of which with trifluoroacetic acid afforded ent-lycoricidine (248) in 77% yield (Scheme 26). Trost's group has also achieved the synthesis of (+)-pancratistatin (211) starting with the optically active cyclohexenetetraol derivative 249 (161) (Scheme 27). Optically active 6-[(2-bromo-3-methoxy-4,5-methylenedioxy) phenyl]-2,3-0-bis(triethylsilyl)(TES)-cyclohexane (250)(derived from 249) was transformed to isocyanate 251 (by reduction and treatment with phosgene), which was treated with t-butyllithium in ether at -78°C to undergo spontaneous intramolecular addition leading to 3,4-0isopropylidene-7-0-methyl-1-isopancratistatin (252)in 65% yield by way of 251. Conversion of the cis-vicinal dihydroxy groups into trans-vicinal dihydroxy groups was performed through a cyclic sulfonate. Namely, a cyclic sulfonate of the cis-vicinal dihydroxy compound (derived from 252
OH
245
246
H (0-
,,
-
T
NH
0
0
0
247
ent-Lycoricidine (248)
Reagents and Conditions : a) hv, PhSH, 27OC, 91%; b) Srn12, THF,76% ; c) CF3C02H,77%. SCHEME 26
0 Me Me0
0
252
h, i Me0
0
HO
'
253
0
(+)-Panmatistatin (211)
Reagents and Conditions:a) Me3P,
THF,HzO ;b) COC12, Et3N. M 2 c I 2 ;C) t-BuLi, Et20, -78OC, 62-65%(3 steps) ; d) Bu4N+F-,THF,-78 to O°C ;e) SOCl2, Et3N ; f) RuC13*H20,NaIO4, rt, 72% (2 steps) ; g) PhCQCs, DMF.then workup with THF-H20, HzSO4 CCl,, MeCN,H20, (cat), 85%;h) K2C03, MeOH, rt ; i)LiI, IMF, 8OoC, 85% (2 steps). SCHEME 21
380
OSAMU HOSHINO
by 0-desilylation with TBAF, treatment with sulfuryl chloride, and oxidation) was treated with cesium benzoate in DMF followed by O-deisopropylidenation to give 1-0-benzoyl-7-0-methylpancratistatin (253). Removal of the benzoyl and methoxy groups of 253 gave (+)-pawratistatin (211). The overall yield was 11%in 15 steps (from 249). The synthesis of (+)-7-deoxy-trans-dihydronarciclasine (208) and (+)7-deoxypancratistatin (210) employing the key intermediate 221 previously reported in the synthesis of (+)-lycoricidine (204) (250) has been published by a fourth group (162) (Schemes 28 and 29). Catalytic hydrogenation of the protected 7-deoxylycoricidine 221, followed by conversion of the 200-(p-meth0xy)phenylmethyl (MPM) group into a 2a-acetoxy substituent, produced the protected (+)-7-deoxy-frans-dihydronarciclasine 254. Stepwise deprotection of 254 afforded (+)-7-deoxy-trans-dihydronarciclasine (208) (Scheme 28). A1(2)-N-MPM-7-deoxypancratistatin (256), which was prepared by elimination and 0-demethoxymethylation of 254, was also transformed to (+)-7-deoxypancratistatin (210) from the epoxide 257 by way of the tetraacetate 236 (Scheme 29). Protected derivatives 259 and 260 of (+)-7-
OAc
254
221
255
MPM = 4-MeOcd-bCH2 MOM = MeOCH2
- (O@Z ff
A
?H O
H
0
0 (+)-7-DcOXy-
WUnS-dihydronarciclasine (208) Reugenrs and Conditionr : a) H2,5%Pd-C,EtOH-EtOAc (14 : 11, rt, 87% ; b) (CF3S02)20,pyridine, CHzClz, OOC ;c) KOAc, 18-crown-6, benzene. n,81%(2 steps) ;d) 1N HCI-THF (1 : 1). 5OoC,then
AczO, pyridine, rt ;e) CF3C02H-CHC13(1 : 1). rt, 64%(3 steps) ; f ) NaOMe, MeOH, OOC. 83%. SCHEME 28
4. THE
236
AMARYLLIDACEAE ALKALOIDS
381
(+)-7-Deoxy-
pancratistatin (210)
Reagents and Conditions : a) NaOMe, MeOH, O°C ; b) (CF3SQ)z0, qyridine, CH2ClZ,O°C ;c) KOAc, 18-crown-6, benzene, rt, 74% (3 steps) ; d) 1N HCl-THF (1 : I), 5OoC, 92% ;e) m-ClCJ-I4CO& C1CHzCH2C1-phosphatebuffer (IM, pH 8)(1 :l), 5OoC,46% ;f) NaOAc, DMF-H20 (4 : 1). 60°C. then AczO, ZnC12, rt, 51% ; g) 5% Pd-C. H2, 1N HCI (cat.), EtOH, rt, 83%. SCHEME29
0-methyl-4a-epi-narciclasine and 7-0-methyl-iso-narciclasine have been synthesized starting with 258 (derived from ~-glucose)(l63). C. BIOLOGICAL ACTIVITY Narciclasine (205) and its glucoside 207 showed similar toxic activity (against Artemia salina), with LDS0values of 0.29 and 0.88 pglml for 205 and 207, respectively. When assayed on a potato disk infested by Agrobacferium
258
(+)-3,4-O-Isopropylidene-7-0methyl-4a-epi-aarciclasine(259) FIG.16
3,4-O-Isopropylidene-7-0methyl-iso-narciclasine(260)
382
OSAMU HOSHINO
tumefucienns, 205 showed a strong antitumor initiation (60% inhibition), and the latter alkaloid, 207,also exhibited similar activity (53% inhibition) in the same assay (96). Antiviral (RNA) activity of narciclasine-type alkaloids and the related compounds have been examined extensively (139). Among these experiments, evaluation of pancratistatin (211)and 7-deoxypancratistatin (210) in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors) has given interesting results. In two experiments (low LDsoviral challenge, variant I), prophylactic administration of 211 at 4 mg and 6 mg/kg/day (2% EtOHhaline, sc, once daily for 7 days, day - 1to +5) increased the survival of Japanese encephalitis-virus-infected mice to 100 and 90%,respectively. In the same model, prophylactic administration of 210 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to + 5 ) increased the survival of Japanese encephalitisvirus-infected mice to 80%.In a second variant (high LDsoviral challenge), administration of 211 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 210 and 211 demonstrated activity in mice infected with Japanese encephalitis virus, but only at near-toxic concentrations. This represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in the Japanese encephalitis-virus-infected mouse model. Telastaside (213)showed dose-dependent biphasic immunomodulatory responses (25). Its effects suggested inhibition or augmentation of enzyme (proteinase) and membrane integrity, as revealed from the viability or inhibition of growth of both normal and tumor cells (164).
V. Galanthamine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION
Extraction of the flowers of Lycoris incarnata (58) led to the isolation of galanthamine (261),sanguinine (272),lycoramine (276),O-demethyllycoramine (277),and galanthamine N-oxide (281),along with l-palmitoyl2-linoleoylphosphatidylethanolamineand 1-palmitoyl-2-linoleoylphospatidylmethanol sodium salt. In addition, the extract of the bulbs and aerial parts of Narcissus leonensis grown in Northern Spain, and closely related to N. nobilis and N. primigeninus, has been found to contain two new alkaloids, epi-norgalanthamine (267) and epi-norlycoramine (280) (72). (-)-N-Demethyllycoramine (278)has been also isolated for the first time from the bulbs of Hymenocallis rotuta (50).
4.
383
THE AMAKYLLIDACEAE ALKALOIDS
Sanguinine (272), reported previously as a constituent of Leucojum aestivum sub. was obtained from Leiucojum aestivum sub. pulchelum (54).The structures of the representative alkaloids isolated are shown in Fig. 17. R
Me0
Galanthamine (261) R =H,R' =Me 0-A~etylgalanthamine (262) R = Ac, R' = Me N-Allylgalanthamine (263) R = H,R' = ~ i i y i Norgalanthaminc (264) R=R~=H N-Fmylgalanthamine (265) R =H, R' = CHO
N. CH&I
N-Chloromethylgalanthaminium chloride (266)
Epi-norgalanthamine(267)
R=H
Narcisine (268) R=Ac
R
Nanvedine (269)
Leucotamine (270) R=H 0-Methylleucotamine (271) R=Me
HO
Sanguinine (272) R = H. R'= Me 2-O-A~~tylchlidanthine (273) R =Ac,R'=Me Nmanguininc (274) R =R~=H Norbutsanguinine. (275) R = COCH2CH(OH)Me, R'=H
R Lycoraniine (276) R = R' = M e O-Demtthyllycoramine (277) R =Me,R'=H Norlycoramine (278) R =H,R'=Me
0 Galanthamine N-oxide (281) R =R,R'=Me 0-Acetylgalanthamine N-oxide (282) R =Ac,R'=Me Sanguinine N-oxide (283) R =R'=H
FIG. 17
Epi-lycoramine (279) R=Me Epi-norlycoramine (280) R=H
Lycoramine N-oxide (284)
384
OSAMU HOSHINO
B. SYNTHETIC STUDIES Galanthamine (261) has been characterized as an acetylcholinesterase inhibitor, and its epimer epi-galanthamine and its oxidized analog narwedine (269) have been evaluated as potential agents for the treatment of Alzheimer’s disease. However, supply of the alkaloids has been limited, although they are found in several Amaryllidaceae species. Therefore, supply by synthesis is a necessary requirement. The synthesis of 261 was initiated using phenolic oxidative coupling as a biomimetic method, and extensive synthetic studies have been performed. Since 1987,some reports on the synthesis of 261 and related compounds using phenolic oxidation and radical-mediated cyclization have appeared. Phenolic oxidation of the diphenolic amide 285 using potassium ferric (111) cyanide afforded (+)-N-formyldibromonarwedine (286), which was reduced successively with lithium tri-s-butylborohydride (L-Selectride) and with LiA1H4 to afford (?)-261.Resolution of (2)-261 using d-camphoric acid provided (-)- and ( +)-galanthamines (261) through the camphanate derivatives 287 and 288 (265) (Scheme 30). Phenolic oxidation of the phenolic palladium complex 290 (prepared by N-methylation and metallation of 289) using thallium(111) trifluoroacetate gave (t)-narwedine (269) in 51% yield by way of the cyclized intermediates 291 and 292 (166) (Scheme 31). The synthesis of ( t)-lycoramine (276) and ( t)-epi-lycoramine (279) using radical-mediated reactions as key steps has been reported (167) (Scheme 32). Dehydration of ethyl 2-[1-(6-bromo-2-methoxy)phenoxy-4, 4-ethylenedioxy-l-hydroxycyclohexyl]acetate(293) [prepared from ethyl (6-bromo-2-methoxy)phenoxyacetateand 4,4-ethylenedioxycyclohexanone] with phosphoryl chloride in pyridine at 90°C produced a radical precursor cyclohexene derivative 294, along with a regioisomer. Radical reaction of 294 with Bu3SnH in boiling o-xylene containing AIBN provided the cyclic spirobenzofuran derivative 295 in 91% yield, which was transformed to Bseco-oxolycoramine 2% in four steps (cleavage of benzofuran ring with Sm12,deprotection, introduction of a double bond, and amidation, followed by concomitant cyclization). The modified Pictet-Spengler reaction of 296 with paraformaldehyde in CF3C02H in dichloroethane led to (2)-0x0dihydronarwedine (297), whose reduction with LiA1H4 in boiling THF yielded ( t)-lycoramine (276) and (2)-epi-lycoramine (279) in 85% yield (a product ratio of 5 :1). A practical and total spontaneous resolution process for the asymmetric transformation of (?)-narwedine (269) into either of its enantiomers, depending on which enantiomer is used as the seeds, and a highly stereospecific conversion of (-)-narwedine (269) into (-)-galanthamine (261) by reduc-
4.
THE AMARYLLIDACEAE ALKALOIDS
a
&OH
Me0$H !O OH
b c
MeO.@&
IMe
286
(+)-Galanthaminyl (-)-camphanate (287)
e
(*)-Galanthamine (261)
MeO@*oH Me
(+)-Galanthamine (261)
+ (-)-Galanthaminyl (-)-camphanate (288)
. . o B o H
CHO
Rr
285
385
~
(-)-Galanthamine(261) Reagents and Conditions : a) K3Fe(CN)6.NaHC03, CHC13,H20, 60°C, 37% ;b) Zn, EtOH,
reflux, 98%;c) L-Selectride@, THF, -78OC, then LiAM4, THF, reflux, 70% ;d) (1s)(-)-camphanicchloride, Et3N, THF-CHC13, (4 : 15), then chromatography, 287 (45%), 288 (43%); e) LiAlH4, THF, 0 ° C then dry HCl, MeOH, (+)-261*HC1(96%),(-)-261*HC1 (92%). SCHEME 30
tion have been reported (168). (+)-Narwedine was dissolved in a solvent mixture of 95% ethanol-triethylamine (9: 1) at 80°C. (-)-Narwedine seeds (2.5%) were added to the supersaturated solution at 68°C. The suspension was kept at 40°C to afford a highly enriched (-)-narwedine in 80% yield from (+)-narwedine. A similar process was successfully employed to prepare (+)-narwedine in 85%yield from (2)-narwedine by seeding the supersaturated racemic solution with (+)-namedine. The concept was expanded to achieve a total spontaneous resolution of (2)-narwedine using either enantiomer of galanthamine as the “catalyst.” (?)-Narwedine was dissolved into a solvent mixture similar to that noted previously at 80°C in the
386
OSAMU HOSHINO
290
289
Reagenrs and Condirions :a) fonnalin. NaCNBH3, MeOH, 90%(from isovanillin) ;b) LiFdC14, Et Ni-R2, -78OC, 95%(1 : 1 mixture of diastereomers) ;c) n ( o 2 c a 3 ) 3 , THF-CH2C!12 (2 : 1). -lO°C;then Ph3P, -10' to 25OC, 51%. SCHEME 31
presence of a catalytic (1%)amount of natural (-)-galanthamine. The resulting suspension gave enantiomerically pure (+)-namedine in 75% yield from ( ?)-namedine. Similarly, optically pure (-)-namedine was obtained from (2)-narwedine, using a catalytic (1%)amount of (+)-galanthamine, in 76% yield. Moreover, (-)-namedine obtained from the above process was reduced stereoselectively by L-Selectride at -78°C to produce (-)galanthamine in 99% yield (99% ee). The process is considered to be attributable to the unique conglomerate nature of narwedine. C. BIOLOGICAL ACTIVITY Galanthamine (261) has been prominent in the popular and general scientific press because of its purported usefulness in healing Alzheimer's disease, presumably due to its acetylcholinesterase and muscarinic activity.
4.
293
2%
387
THE AMARYLLIDACEAE ALKALOIDS
294
297
295
(f)-Lycoramine(276) R=OH,RI=H (i)-Epi-lycoramine (279) R = H, R1 =OH
Reagents and Conditions :a) FOCI3.pyridme, 9OOC ;b) Bu3SnH, AIBN, o-xylene, xeflux. 91%; C) SmIz, HMPA, MeOH, THF, rt, 81% ;d) 3NHCI. 81% ; e) (PhSeOhO, toluene, 76%; f) 40% aq. MeNH2. THF, n, 97% ;g) paraformaldehyde,CF3C02H. CICHzCHzCl. n,81% ; h) THF, nflux, 85% (276 :279 = 5 : 1).
w,
SCHEME 32
VI. Tazettine-Type Alkaloids A. ISOLATIONAND STRUCTURAL ELUCIDATION Tazettine (298) has been isolated from Crinum americanum (leaves) (16), C. giganteum (27),Hippeastrum eyuestre (bulbs) (40),Hippeastrum hybrids (bulbs) (42),Hymenocallis expansa (bulbs and leaves) (48), Lycoris radiata (bulbs) (60),Narcissus tazetta (901, N. cantaricus (whole plants) (65),Pancratium maritinum (bulbs) (%), and Sternbergia sicula (whole plants) (103). Pretazettine (300)has been found in N. pallidiflorus (whole plants) (76), N. panizzianus (whole plants) (79)(aerial and bulbs) (80),S. culsiani (bulbs) (102), and Zephyranthes flava (fresh mature seeds) (108). Tazettine (298), pretazettine (300), littoraline (301), and marconine (302) have been isolated
388
OSAMU HOSHINO
from Hymenocullis littorutu (bulbs), in which littoraline (301) is a new tazettine-type alkaloid (49). A new tazettine-type alkaloid, zeylamine (304),was isolated in 0.18%yield from the air-dried rhizomes of C. zeylunicum (34). Continuing exploration of the extracts of the Amaryllidaceae plants has established the presence of tazettine (298), pretazettine (300), and 3-epi-marconine (303) in Hymenocullis rotutu (50);of tazettine (298) and pretazettine (300)in N. tuzettu (bulbs) (89) and S. luteu (whole plants) (203); and of criwelline (299) in C. firmifolium var. hygrophilum (whole plants) (26).The alkaloids isolated are shown in Fig. 18.
B. SYNTHETIC STUDIES The syntheses of (2)-pretazettine (300) and (%)-haemanthidine (157) (169) (Scheme 33) and (2)-tazettine (298) and 6a-epi-pretazettine (314) (270) (Scheme 34) have been reported. In the one case (269),a key intermediate, the ally1 N-methylcarbamate 305, was transformed to N-methyl-3pivaloyloxy-3a-[(3,4-methylenedioxy)phenyl]-3a,6,7,7a-tetrahydro-6-oxo-
r!
Tazettine (298) R = PQMe Criwelline (299) R = aQMe
Pretazettine (300)
$2-
R
Q 0
0 Maxonine (302) R = a-OMe 3-Epi-macronine (303) R = P-OMe
0 Zeylamine (304)
FIG.18
Littoraline (301)
4.
t-Bucoo.
t.Buc00
-<
0
t-BuCOO
0
0
Q
389
THE AMARYLLIDACEAE ALKALOIDS
ac
0 0
305
0
306
307 R = M e
308 R=CHO t-&COO
Q 0
Me
h
OH
309
OH (f)-Haemanthidine (157)
OH
(f)-Preulzettine (300)
Reagemand Conditons :a) conc. HzS04. EtOAc, rt, then PhN+mBr3-, rt ;b) DBU, benzene, rcflux,
77%(2 steps) ;c) 2cthylhexanoic acid, (Ph$).,Pd. Ph3P, CHzC12,rt, 90% (1.5 : 1) ;d) DIBALH, THF, -78OC (3 :2 :5 :3) ;e) (MeSO&O, EbN, THF. OOC. then MeOH, 0°C to rt, 59% (35 : 24) ;r) 9, Pt black, aq. dioxane, rt, then AcOCHO, pyridine. rt, 57% ; g) POCl,, 8VC, then THF-Hp (1 : I), rt, 7 1% (2 steps) ;h) LiOH. &OH, rt, 78%; i) MeI, MeOH, rt. 66%. SCHEME 33
indoline (306) by oxidation followed by an intramolecular Michael addition. Conversion of the 6 0 x 0 group in 306 to a 6fl-methoxy group produced the methoxy compound 307, oxidative N-demethylation of which, followed by treatment with acetic4ormic anhydride, furnished the N-formyl product 308. The Bischler-Napieralski reaction and continuous hydrolysis of 308 provided (?)-haemanthidine (157). Treatment of 157 with methyl iodide in MeOH led to rearrangement of the skeleton to lead to (5)-pretazettine (300) in 66% yield (Scheme 33). In the other synthesis (270),the modified Heck reaction served as a key step for the construction of the spiro compound 311. Namely, the reaction of N-methoxycarbonyl-2-[(2-iodo-4,5-methylenedioxy)phenyllmethoxy]-2(cyclohexeny1)ethylamine 310 with palladium(0) in boiling THF in the presence of silver carbonate caused an intramolecular cyclization to give the spiro compound 311 in 90% yield. Michael reaction of 311 with 1 N HC1 in boiling THF, followed by introduction of a double bond through a
390
OSAMU HOSHINO
bH
(&)-6a-Epipretazettine(314)
k TBS = t-BuMQSi
OTBS
315
(f)-Tazettine (298)
Reagem and Condirions :a) ClCOzMe ;b) Pd(0Ac)z (lOmol%),Ph3P (4Omol%), AgzC03 (2 eqUiV.), THF, =flux, 90% re ~tatc63-70%) ;C) 1N HCI, THF, reflux, 94% ;d) CF3SQTMS. E t g , CHzC12,OOC, then Pd(0Ac)z. MeCN, rt, 67% (2 steps) ;e) NaBH4, CeC13.7Hz0. MeOH, ;f) KH. MI, THF, rt, 75% ;g) C Q , 3,5-dirncthylpyrazole, CH2C12,-78OC. 95% (p :a = 36 : 1) ._~. 400 to -45'C, 63% ;h) LiA& THF-EtzO, rt, 98% ;i) De.ss-Maxtin oxidation,73% ;j) Swern oxidation,298 (61%). 315 (90%) ;k) TBSCl, 76% ;I) B u 4 M , 93%. SCHEME34
silyl enol ether, afforded the spirocyclohexenone 312 in 63% yield (three steps). After the transformation of an 0x0 group to a methoxy group and subsequent oxidation, LiAlH4 reduction of the resulting spiro Slactone led to the dihydroxy compound 313. Interestingly, Swern oxidation of 313 afforded (2)-tazettine (298) in 61% yield, whereas Dess-Martin oxidation of 313 produced (2)-6a-epi-pretazettine (314) in 73% yield (Scheme 34).
4.
THE AMARYLLIDACEAE ALKALOIDS
391
On the other hand, 0-silylation and Swern oxidation of 313 provided Nmethyl-3a-[(2-O-TBS-4,5-methylenedioxy)phenyl]-3-oxo-3a,6,7,7a-tetrahydroindoline (315)in 68%yield, 0-desilylation of which with TBAF gave rise to a spontaneous intramolecular hemiacetalization to afford ( 5 ) tazettine (298)in 93% yield. Intramolecular 2-aza-ally1anion cycloaddition was employed for the syn) (-)thesis of the crinine-type alkaloids (t)-crinine (135) ( 1 4 2 ~ and amabiline (145)( 2 4 2 ~and ) has been reported to provide potential precursors of 6a-epi-pretazettine (314)and 6a-epi-precriwelline (methoxy epimer of 314) (142b). C. BIOLOGICAL ACTIVITY
The extracts of the bulbs and leaves of Hymenocaflis expansa have been re-examined for cytotoxic activity. Both plant parts showed significant activity against different human and murine tumor cell lines. Tazettine (298) showed activity, to varying extents, against the cell lines tested (48). Pretazettine (300)has also been reported to exhibit marginal activity (TIs0 < 4.5)(239).
W.Lycorenine-Type Alkaloids A.
ISOLATION A N D
STRUCTURAL ELUCIDATION
Six new lycorenine-type alkaloids, 5a-methoxy-9-0-demethylhomolycorine (323), galwesine (333),9-0-demethylgalwesine (334),16-hydroxygalwesine (335),16-hydroxy-9-O-demethylgalwesine (336),and galasine (337), have been isolated from whole plants of Galanthus efwesii accompanied by 12 known Amaryllidaceae alkaloids, including lycorine and galanthamine. Of these alkaloids, only lycorine and galanthamine were found previously in this plant. Identification and structural elucidation of these alkaloids were achieved using spectroscopic ('H and 13C NMR, CD, UV) techniques coupled with X-ray crystallographic analyses (for 334,335,and 337) and chemical transformation (35).Interestingly, although the known alkaloid, 9-0-demethylhomolycorine (321),was isolated as five different crystalline samples from five different subfractions of this plant, two of them were nitrogen inversion conformers and the other samples were compounds including different solvent molecules in the crystals (35,171). This is the first time that it has been demonstrated by X-ray crystallographic analyses that, depending on the crystallization conditions, both nitrogen inverted
392
OSAMU HOSHINO
isomers of the same natural alkaloid could be crystallized. In solution, the interchange between the axial and equatorial forms are too fast to be observed. The representative lycorenine-type alkaloids isolated since 1987 are shown in Fig. 19.
'R
RO
Lycmnine (316) R=H 0-Meth yllycmnine (317) R=Me
n
1
0
0
0
Nobilisine (326)
Me0
0
0
Clivatine (327) R = COCHZCH(0H)Me
Hippeastrine (328)
-
0
Homolycorine N-oxide (330) R=Me 8-O-Demeth ylhomo1ycorine N-oxide (331) R=H
0
Galwesine (333) R = H, R' Me 9-0-Demethylgalwesine (334) R R' = H
-
RO
OMe
'OMe
R'O
0
Me0
0-Methyllycmnine N-oxide (329)
Me0
'OH
Hippeastrine N-oxide (332)
S~-Hydroxy9-O-demeth ylhomolycorine (322) R =OH, R' = Me, R* = H Su-Methoxy9-Odemethylhomolycorine (323) R = OMe, R' = Me, R~=H Dubiusine (324) R = OAc, R' = Me, R2 COCHzCH(0H)M~
Me0
'OR
0
0
8-0-Acetylhomolycorine (320) R = Ac,R' =Me 9-0-Demethylhomolycorine (321) R = Me, R' = H
a0"
Q
OEt
Q
Homo1 corine (318) R = R7 =Me 8-O-Demeth y lhomolycorine (319) R = H, R' = Me
1 1-Hydroxygalwesine (335) R = OH, R' = Me 16-Hydroxy9-0-&methylgalwesine (336) R = OH, R' = H
FIG.19
Me0 Meo
0
Galasine (337)
4.
THE AMARYLLIDACEAE ALKALOIDS
393
VIII. Montanine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION The montanine-type alkaloids possess a unique structure, called the 5, 11-methanomorphanthridine skeleton 343, and are a minor group in the Amaryllidaceae alkaloid family, of which only seven representatives had been isolated until recently. Montanine (338) and pancracine (339) were isolated from the bulbs of Hippeastrum hybrids (42). The eighth montaninetype alkaloid montabuphine (340), with a P-5,11-methanomorphanthridine skeleton was found for the first time in the bulbs of Boophaneflava (9) growing in the winter rainfall area in South Africa. The structure was determined by physical and spectroscopic [COSY and ROESY (172)]experiments in the 'H NMR, and HMQC (173) and HMBC (174) correlations in the 13C NMR spectra. The molecular ellipticity of the alkaloid (342) showed a CD curve that was qualitatively the reverse of the known 5,11methanomorphanthridine alkaloids with an a-configuration for the methano-bridge (141,175). Therefore, the 5,11-methano bridge was established to have a /3-configuration (42). As they do not show remarkable biological activity, their synthesis had not been performed, excluding synthetic studies for structure elucidation. The structures of the montaninetype alkaloids isolated are listed in Fig. 20. B. SYNTHETIC STUDIES Although synthetic approaches toward the montanine-type alkaloids had been made by intramolecular cyclization of 3-(3,4-methylenedioxy)phenylhexahydroindoline derivatives (I76), these attempts were thus far unsuccessful. The 5,11-methanomorphanthridinering systems 341-343 (Fig. 21)
'0
Montabuphine (340)
Montanine (338) R = p-OMe, R' = a-OH Pancracine (339) R = &OH, R' = P-OH FIG.20
394
OSAMU HOSHINO
342
341
&g
NH
343
Ts = 4-MeC!&SO2
344
FIG.21
were found to be effectivelyformed by intramolecular reductive cyclization of 11-hydroxymethyl-N-(p-tosy1)morphanthridines 344 using SMEAH (177,178) in boiling toluene. Afterwards, a total synthesis of this type of alkaloid was achieved independently by two research groups; a key step in one of the syntheses involves stereoselective hydroboration-oxidation and cyclization with SMEAH (178,179) as a result of development of a method for the synthesis of $11-methanomorphanthridine343. In the other, a tandem aza-Cope rearrangement-Mannich cyclization and the PictetSpengler reaction (180) are key synthetic steps. A third research group has reported the enantioselective total syntheses of this type of alkaloid by means of an intramolecular allenylsilane ene reaction coupled with the intramolecular Heck reaction (181). The synthetic route used by the first research group is depicted in Schemes 35-37 (178,179). Namely, 2-[(3,4-methylenedioxy)benzoyl]cyclohex-4-ene carboxylic acid (345) (prepared from 1,2-cis-cyclohex-4-ene dicarboxylic anhydride and the Grignard reagent of 6-bromo-3,4-methylenedioxybenzene) was transformed to 3,4-diacetoxy-6-[1-(3,4-methylenedioxy)phenylvinyll-N-(p-tosy1)cyclohexylamine (346) in six steps. (Curtius rearrangement, hydrolysis, N-tosylation, Os04 oxidation, acetylation, and Wittig reaction). Hydroboration-oxidation of 346 in the usual manner proceeded stereoselectively to produce a hydroxymethyl product, acetylation of which gave 2~,3~-diacetoxy-llcr-acetoxymethyl-N-(ptosy1)morphanthridine (347) in good yield. Hydrolysis and successive 0benzylidenation of 347 afforded 2,3-0-benzylidene-llcr-acetoxymethyl-N(p-tosyl)morphanthridine, treatment of which with SMEAH in boiling o-xylene led to smoothly intramolecular cyclization to give 2,3-O-benzyli-
4.
THE AMARYLLIDACEAE ALKALOIDS
345
346
/OAc
OAC
Ts
-
347
348
Bn = Ca5CHZ Ts = p-MeC&I4S0z
Y 0
395
OH
(f)-Coccinine (351) Reagents and Conditions :a) ClC@Et, Et3N. acetone, then aq. NaN3,5OC ;b) t -BuOH, reflux, 94% (3 steps) ;c) CF~COZH,CHzClz,xt ;d) p-TsC1, Et3N, CHzClz, rt, 71% (2 steps) ; e) Os04 (cat.), NMO, dioxane-HZO (4 :1 ) ;f ) AczO, pyridine. DMAP, rt ;,g) Ph3PMeBr, KOt-Bu, THF,rt, 71% ; h) BH3, THF,then 30% Hz@. aq. NaOH, O°C, quantitative ;i) AczO, MeSO$I, (CHZO),,CICHzCHzCl,rt, 81% ;j) NaOMe, MeOH, rt, quantitative ;k) PhCH(OMeh,p-TsOH* HzO, CHC13,rt, 83% ;I) SMEAH, o-xylene, reflux, 91% ;m) DIBAL-H, toluene, rt. 347 (75%). a regioisomer (22%) ;n) Jones oxidation, 59% ;0 ) DDQ, NazHP04, dioxane, reflux, 26%; p) CH(OMe)3,p-TsOH*H20,MeOH, rt, 99% ;q ) MeSSiI, C H C l 3 , rt, 87%. SCHEME35
dene-5,ll-methanomorphanthridine348 in 91% yield. Selective cleavage of 348 with diisobutyl aluminum hydride (DIBALH) in toluene at room temperature produced 3-benzyloxy-2-hydroxy-5,ll-methanomorphanthridine (349)
396
OSAMU HOSHINO
along with a regioisomer. Jones oxidation of 349, followed by oxidation with DDQ, afforded 3-benzyloxyd1(11a)-5,11-methanomorphanthridin-2one (350). Finally, 350 gave (&)-coccinine (351)in 68% yield (three steps) through dimethyl ketalization, stereoselective removal of a methoxyl group, and 0-debenzylation (Scheme 35) (178,179). The same intermediate 349 was also converted into (+)-montanine (338), (+)-parmacine (339), and (+)-brunsvigine (356).Dehydroxylation of 349 by way of a mesate gave 3-benzyloxy-A1~-5,11-methanomorphanthridine (352), along with the regioisomer, in 70% yield. Chlorophenylselenylation-dephenylselenylation of 352 gave 3-benzyloxy-2-chloro-A1~11a)-5,11-
0 [ & NH OBn a,b
~
p&
C
0
MH
349
OBn
___)
352
Bn = GHsCHz
r
r
OH
(*)-Montanine (338) 353
354
t
(*)-Pancracine (339) H
H
'OAc (f)-0-Diacetylbrunsvigine (355)
0
NH
'OH
(f)-Brunsvigine (356)
Reagents am Conditions : a) leS02C1, Et3N, CH2C12,5OC, 100% ; b) KOt-Bu, Me$O, rt, 70% ;c)
PhSeC1, MeOH, ultrasound, 15-20°C, then NaIO4,82% ; d) Me3Si1, CHC13, rt, 87% ;e) BFpEt20, MeOH, 5OC, 94% ;9 H2SO4, THF- H 2 0 (1: l), reflux. 78% ; g) Me3SiC1, NaI, MeCN, rt, 55% ;h) Os04 (cat.), NMO, dioxane-Hz0, rt ;i) Ac20, DMAP, pyridine, 86% ;j) NaOMe, MeOH, n, 90%. SCHEME 36
4.
THE AMARYLLIDACEAE ALKALOIDS
397
methanomorphanthridine (353), which was treated with iodotrimethylsilane to lead spontaneously to 2,3-P-epoxy-A1("")-5,11-methanomorphanthridine 354. Treatment of 354 with BF3 Et20 in MeOH, or aqueous sulfuric acid, brought about oxirane ring opening to produce (?)-montanine (338) or (+)-pancracine (339). On the other hand, 354 was transformed into (?)brunsvigine (356) through (2)-0-diacetylbrunsvigine (355) (prepared by exchange of the oxirane ring to a double bond, Os04 oxidation, and acetylation) (Scheme 36) (179). Radical-mediated reaction of a radical precursor tetrahydroisoquinoline derivative has been found to produce the $11-methanomorphanthridine ring system (182).Thus, a formal total synthesis of this type of alkaloid was performed by means of the present methodology. Namely, the reaction of 1,2,3,4-tetrahydro-N(4-oxocyclohex-2-enyl)-4-phenylthioisoquinoline (357) with Bu3SnH in boiling o-xylene containing AIBN led to 5,llmethanomorphanthridin-2-one (358) in 80%yield, which was transformed to A2~3-5,11-methan~m~rphanthridine 359 by way of a mesate. In continuation, 359 provided the 2,3-O-benzylidene derivative 349 in two steps (Os04 oxidation and 0-bemylidenation), which was previously (179)converted into this type of alkaloid (Scheme 37).
-
-
H
(f)-Montanine (338) (f)-Pancracine (339) (f)-Coccinine (351)
0
349
Reagenrs and Conditions : a) BqSnH, AIBN, o-xylene, reflux, 80%;b) N a B a , MeOH, 5OC, quantitative (a mixture of a-and P-alcohols) ; c) MeSO2C1, EgN, CHC13, 5OC, 95% (1 : 1mixture of a-and pmesates) ; d) KOr-Bu, DMSO, rt, 82% (1 : 1 mixtutre of regioisomers from p-mesate) ; e) OsO4 (cat.), MNO, dioxane-HzO (4 : l), n ; f) PhCH(OMe)?, p-TsOH, CHC13, rt, 75% (2 steps) ; g) Ref. 179. SCHEME 37
398
OSAMU HOSHINO
The synthetic route in the second report (180) is as follows. Reaction of the N-benzyloxazoline derivative 361 {prepared from cis-2-benzylamino-l[(3,4-methylenedioxy)phenylethynyl]-l-cyclopentanol (360) by reduction and treatment with formalin} with BF3 Et20 in CH2C12at -20 to 23°C consisted of a tandem aza-Cope rearrangement-Mannich reaction to furnish 3-[(3,4-methylenedioxy)phenyl]-N-benzylhexahydroindol~n-4one (362).Interestingly, N-debenzylation of 362, followed by the PictetSpengler reaction using formalin and camphorsulfonic acid, afforded the 5,ll-methanomorphanthridin-1-onering system 363. The present finding may be attributable to the stereochemistry of 3-arylhexahydroindoline ring system. Compound 363 was converted into the A'(''a)-5,11-methanomorphanthridin-2-one 364 in four steps (reduction of an 0x0 group with LSelectride, dehydration of a hydroxyl group with thionyl chloride, hydroxylation with Se02, and Swern oxidation). Finally, 3P-hydroxylation of 364 through the silyl enol ether gave 3P-hydro~y-A~("~)-5,1 l-methanomorphanthridin-2-one, which was reduced with NaBH4 in acetic acid at -35°C to produce (2)-pancracine (339)in 53% yield (three steps) (180) (Scheme 38). e
360
363
Ar = 3,4-(CH2O&H3 Bn = C6H5CH2
361
364
362
(f)-Pancracine(339)
Reagents and Conditions : a) LiAIH4, EtzO, -20% then reflux, 94% ; b) 37% formalin, Na2S04, camphorsulfonic acid, CH~CIZ,2 3 T , 81% ;c) BF3*OEt2, CH2ClZ,-20 to 2 3 T , 97% ;d) Pd-C, H2, HCI, MeOH, 96% ;e) 37% formalin,Et3N, MeOH, 23'C, then HC1, MeOH, 23"C, 67% ; r) [email protected], -78'C. 99% ;g) SOC12, CHC13, -30 to 23'C, then S e a , dioxanc, 85"C, 62% ; h) Swern oxidation, 91% ; i) MeS03SiMe3, EgN, EtzO, -60to O°C, then Os04(cat), NMO, r-BuOH, HzO. pyridine, -5 to 23°C 82% ;j) NaBh, AcOH, MeCN (1 : l), -35'C. 65%.
SCHEME38
4.
THE AMARYLLIDACEAE ALKALOIDS
399
Starting with optically active cis-2-[N-cyanomethyl-N-(lS-phenethyl]-l[(3,4-methylenedioxy)phenylethynyl]cyclopentanol (365), 3-[(3,4-methylenedioxy)phenyl]-N-[(1S-phenethyl[hexahydroindolin-4-one (366) was synthesized in a manner similar to that noted previously. Thus, the synthesis of (-)-pancracine (339) was achieved in 25% overall yield through 366 by a sequence of reactions similar to those noted for (+)-339 (Z80b) (Scheme 39). Also, the same intermediate 364 employed for the synthesis of (+)339 was transformed to (2)-desmethyl-a-isocrinamine (368) by way of the 3a-acetoxy derivative 367. Intramolecular imino ene reaction of an allenylsilane has recently been found to generate cyclohexyl systems with adjacent cis-amino and -alkynyl moieties. This enantioselective ene cyclization was developed for the enantioselective total syntheses of (-))-montanine (338), (-)-coccinine (351), (-)pancracine (339), and (-)-brunsvigine (356) (a formal total synthesis) by the same research group (181) (Schemes 40 and 41). A precursor allenylsilanealdehyde 370 for the enantioselective ene cyclization was synthesized from scalemic epoxy alcohol 369 in nine steps. The allenylsilane-aldehyde 370 thus obtained reacted with N-triphenylphosphinyl-(2-bromo-4,5-methy1enedioxy)phenylmethylimine in boiling mesitylene to lead to a cyclized product 371 in 63% yield after protodesilylation. Hydrogenation of 371
364
367
WDesmethyla-isocrinamine (368)
Reugents and Condirionr :a) AgN03. aq. EtOH, 23OC, sonicaaon, 95% ;b) Red-A1 (100%) or LiAlH,, (89%). Et20. 23OC ;c) 37%formalin. Na2S04.camphorsulfonic acid, CH2C12, 23OC, 75% ; d) BFp 0Et2. CH2C12. 5OC. 95% ;e) Pd-C, H2 (50 psi), HCl, MeOH, 96% ; 9 in a manner similar ~ O , nflux. 86% ;h) to that noted for (i)-pancracine, 25% overall yield ;g) M ~ ( O A C ) ~ - Wbenzene, DBU, acetone, 23'C, then NaBh. CeCI3*7H20.n. 75% (2 steps) ;i) K2CO3, MeOH, 23OC, 69%. SCHEME 39
400
OSAMU HOSHINO
369
370
371
Bn = G H Q I z ; TBS = t-BuMe$i ;Ts = p-MeC&I.,S&
374
375
376
(-)-Panmacine(339)
0
I-m( 0
Reagents and Conditions : a) nine steps ;b) 2-Br-4,5-(CHzOz)CN=PPh3, mesitylene, 50°C to nflux ;c) TBAF, THF, 0°C 63% (2 steps) ;d) Lindlar catalyst, Hz. quinoline. MeOH, 93% ;e) Pd(PPh3),. Mc$TTI-I$'ha',Et3N, MeCN, 1U)oC.74% ;f) p-TsCl, pyridine, DMAP, l W C , 92% ;g) dimethyldioxirane, acetone,-u)oC, 89% (2 : 1 mixture of two diastemmers) ;h) FeC13, CH& -78OC. then DIBALH, OOC, 88% ; i) 10% Pd-C, Hz,MeOH. 97% ; j) Na, naphthalene, DME,-78OC, 63% ; k) 12, PPb3, imidazole, MeCN, EtzO, O O C , 82% ;I) "PAP, NMO,CH2C!lz, MS 4A,%% ;m) LDA, Mc$iCl, THF, -78'C ;n) Pd(OAc)z, MeCN, 67% ; 0 ) TBAF, THF,OOC to R,98% ;p) NaBH(OAc)3, -35°C. SCHEME 40
over Lindlar catalyst in MeOH containing quinoline, followed by an intramolecular Heck reaction, provided an N-(p-tosy1)-1l-methylenemorphanthridine ring system 373 by N-tosylation. Hydroxylation of 373 was per-
4.
0
THE AMARYLLIDACEAE ALKALOIDS
401
BS
376
377
Bn =C&CH2 TBS = r-BuMe$i Ts =p-MeC&i4S4
374
(-)-Montanine (338)
378
(-)-Brunsvigine (356)
Reagents and Conditions : a) TsOH, CH(OMe)3,MeOH, 0 "Cto n, 91%;b) DIBALH, toluene, rt, 81 % ;c) TBAF,T€IF, 0 ' C to rt, 99%;d) DIBALH, toluene, rt. 41 5% ; e) H2,Pd-C,MeOH; f ) TBAF, THF, 97% (2 steps) ; g) Ref. 179. SCHEME41
formed using the corresponding epoxy derivative of 373 to produce protected 1l-hydroxymethylmorphanthridine374 in 78%yield (three steps). The structure of 374 was confirmed by its conversion into 3P-acetoxy2~-benzyloxy-5,11-methanomorphanthridine, a racemic form of which was previously (I79)transformed to the montanine-type alkaloids. Transformation of 374 to the $11-methanomorphanthridine ring system 375 was successfully achieved in 96% yield by treatment of 3-O-TBS-2-hydroxy-11hydroxymethylmorphanthridine (derived from 374 by O-debenzylation and N-detosylation) with a mixture of imidazole, triphenylphosphine, and iodine in MeCN-ether at 0°C. Thus, (--)-pancracine (339) was synthesized from 375 by way of 376 in five steps (oxidation, formation of 376 through a silyl enol ether, deprotection, and reduction) (Scheme 40). Furthermore, synthesis of ( -)-montanine (338) and (-)-coccinine (351) was carried out in 41 and 91% yield, respectively, from the same intermediate 376 by way of the dimethyl ketal377. Also, the key intermedip-tosyl) ate 374 was converted into 2~,3/3-dihydroxy-ll-hydroxymethyl-N-( morphanthridine 378, a racemic form of which was previously (179)trans-
402
OSAMU HOSHINO
formed to (2)-brunsvigine (356). Thus, the present result constitutes an enantioselective formal total synthesis of (-)-brunsvigine (356) (181) (Scheme 41).
IX. Mesembrine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION Few isolations of mesembrine-type alkaloids have been reported. Two examples are the isolation of amisine (379)(from Hymenocallis arenicolu) (183) and of mesembrenol(380) (from Crinum oliganthum) (184) from the Amaryllidaceae family. A third example is the isolation of mesembrenone (Ml), belonging to the mesembrine group, from the aerial parts of Narcissus palladulus (77) growing in Iberia. The structure was elucidated by spectroscopic and chemical methods (Fig. 22). Although both the Amaryllidaceae and Sceletium-type alkaIoids have common biogenetic precursors, further investigations have revealed that the biosyntheses of these two classes of alkaloids are fundamentally different (185). Therefore, the presence of mesembrenone in Narcissus plants is of chemotaxonomic interest because mesembrines seem to be restricted to Aizoaceae-Mesembrylanthemoidaceae (Dicotyledons) (186). The present finding reveals the presence in the Amaryllidaceae of such unexpected alkaloids as those found in some Scefetium species.
B. SYNTHETIC STUDIES The synthesis of mesembrine-type alkaloids belonging to the Sceletium alkaloid family has been carried out extensively in order to seek a
OoMe 6""' OMe
Amisine (379)
Q
q?
HO
0
Mesembrenol(380)
Mesembrenone (381)
FIG.22
4.
THE AMARYLLIDACEAE ALKALOIDS
403
new method for the construction of quaternary carbon centers. As shown in Scheme 42 (187), a formal synthesis of natural (-)-mesembrine (387), in which a key step involves the enantiospecific ring expansion of 2-cyclopropylidene-2-[(3,4-dimethoxy-6-trimethylsilyl)phenyl]ethanol (382) to ( -)-(S)-2-hydroxymethyl-2-[(3,4-dimethoxy)phenyl)cyclobutanone (383), has been reported. Namely, 382 was exposed under asymmetric epoxidation conditions to give 383 in 65% yield. Allylation of 383 through a phenylsulfonyl derivative gave ZS-(but-3-enyl)-2-[(3,4-dimethoxy)phenyl]cyclobutane (384), which was converted into (-)-2S-(but-3-enyl)-2-[(3,4dimethoxy)phenyl]-y-butyrolactone (385) through ozonolysis of the silyl enol ether. Finally, Wacker oxidation of 385 provided (-)-2S-(3-oxobutyl)2-[(3,4-dimethoxy)phenyl]-y-butyrolactone (386), transformation of which to (-)-mesembrine (387) was previously (188) achieved. The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (R)-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed (189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl 1R[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-eny1acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-0x0-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps; ketalization of an 0x0 group, reduction of lactam, and deketalization)(189). (-)-Mesembrine (387) has been synthesized using thermolysis of an aziridine ester (190). A diastereomeric mixture of 2-[(3,4-dimethoxy)phenyl]-4-(4R)-benzyloxymethyl-y-butyrolactone(392) [obtained from ( S ) - 0 benzylglycidol] was transformed to the lS-benzyloxy-3-[(3,4-dimethoxy) phenyllbut-3-enyl N-benzylaziridine carboxylate 393, thermolysis of which in degassed toluene (in a sealed tube) at 250°C gave, in 85% yield, the pyrrolidine Slactone derivative 394 bearing a quaternary carbon center. Conversion of 394 into 6-benzyloxy-3a-[(3,4-dimethoxy)phenyl]A6*7-tetrahydro-N-methylindolin-5-one (395) was performed in four steps (N-debenzylation, N-methylation and spontaneous reduction of the S lactone, Swern oxidation, and aldol reaction) through intramolecular aldol condensation of a keto-aldehyde. After reduction and subsequent acetylation of 395, Birch reduction gave (-)-mesembrine (387) (Scheme 44) (190). A formal synthesis of (+:)-mesembrine (387) has been performed by means of an intramolecular conjugate addition (146).Namely, condensation
OMe
OMe
382
383
384
60Me - 0
OMe
DL0
0
386 (-)-Mesembrine (387) Reagents and Conditions : a) L-(+)-DIPT,Z-BuOOH,Ti(Oi-R)4, MS 4A. CHzClz, -40°C. 65% ( 9 5 % ~;)b) (PhQZ,Bu~P, THF, nflpx. 91% ;c) ethylene glyco1,p-TsOH, benzene. reflux, 88% ; d) m-ClC&CQH, NaHC03, CHzClz,H20, rt ;e) BuLi, ally1 bromide, THF, rt, 91% ;f) p-TsOH, acetone, HzO, reflux, then N a b , MeOH. rt, quantitative ; g) f-BuMqSiOTf, Et3N ;h) Na Wg). NazfIP04, MeOH, R ;i) ByN+F-, THF, rt ;1) Swern oxidation, -78°C.82% ; k) Et3SiOSOZMe, 2,6-lutidine, CH2CI2. rt ;I) 03, CH2Cl2, -78OC;m) NaBh ;n) 10% H a . rt ;0 ) &,PdClz. CuCl, DMF,HzO (Wacker oxidation), rt, quantitative; p) Ref. 187. 385
SCHEME 42
390
389: X = H or CI
388 Ar = 3,4-(MeO)&& M
e
g
o
e
_____)
O
H Me
f-i
M
e
0
H Me
391 (+)-Mesembrine (387) Reagents and Conditions : a) %I3CCOCl(3equiv.), Zn-Cu, THF, 0°C ;b) Zn, AcOH, 0°C;c) AcOH,H20, 60°C;d) K2C03, MeOH ; e) CH2N2. Et2O ;f') M e w 2 (excess), THF, reflux, 83% ;g) pyridinium p-toluenesulfonate, EtC(0Me)zMe ;h) LiAW, THF ;i) H30+,then NH3, HzO, 79% (3 steps). SCHEME 43
4.
392
405
THE AMARYLLIDACEAE ALKALOIDS
393
Bn = C&IsCHz
Jq-Q
0
f-i P
394
j-I
BnO
0
395
H
(-)-Mesembrine (387)
Reagents and Conditions : a) LiAW, THF, 0°C ;b) o-N02Q&9eCN, B u g . THF, rt ;i)Br-
CHzCHzBrCOCl, Et3N, CHzCl,, -lO°C, then CfjH5cI%H,m2, rt ; d) 30%Hz@. CHzClz,0°C to rt ;e) 250°C degassed xylene (sealed tube), 85% ;f) 20%Pd(OH)z-C, Hz, MeOH, rt ; g) formalin, MeOH, 0°C then N a b 4 ,0°C to rt ; h) Swern oxidation, -71°C to rt ;i) 0.5N NaOH, EtOH, rt, 75% (2 steps) ;j) N a b , CeCly7Hz0, MeOH, O°C ;k) AczO, Et3N, DMAP, CH~CIZ, 0°C to rt. 76% (2 steps) ;I) Li. liq. N H 3 , -33"C, (27%overall yield). SCHEME 44
of 3-[(3,4-dimethoxy)phenyl]N-methyl-2-methylthiopyrrolidinium iodide (generated by the reaction of pyrrolidine-2-thione 3% with methyl iodide in MeOH) with t-butyl3-oxo-4-pentenoateunder basic conditions produced pyrrolidine derivative 397 and t-butyl A7(7a)-tetrahydroindolin-5-one-7carboxylate (398) in 56 and 17% yield, respectively. Each of 397 and 398, when exposed to CF3C02H under ultrasonication, afforded the same A7mesembrenone (399), which was already (245) transformed to ( 2 ) mesembrine (387) (Scheme 45) (246). There is a report on the synthesis of (2)-mesembrine (387) by a reaction involving aryl rearrangement and Robinson annulation through an enamine (191) (Scheme 46). Reaction of 3-bromo-N-methoxycarbonyl2-methoxypyrrolidine (400) with 1,2-dimethoxybenzene under acidic conditions gave 3-bromo-N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]pyrrolidine (401), treatment of which, with silver ion in MeOH, caused
406
OSAMU HOSHINO C
OMe
396
397
398
399
OMe
(k)-Mesembrine (387) Reagents and Conditions : a) MeI, CHzClz ; b) CH2=CHCOCHzC@r-Bu, Et3N, CH2C12, rt, 397 (56%), 398 (17%) ; e) CF3C02H (neat), ultrasound, 71% ;d) C F s Q H (3 equiv.), CHC13, ultrasound, 82% ;e) Ref. 145. SCHEME 45
rearrangement of an aryl group to afford N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]-2,3-dehydropyrrolidine(402) in 66%yield. LiAlH4 reduction of 402 gave an enamine, Robinson annulation of which, with methyl vinyl ketone, produced (2)-mesembrine (387). OMe
400
401
402
OMe
(f)-Mesembrine (387)
Reagents and Conditions : a) 1,2-dimethoxybenzene,Htor Lewis acid, 83% ;b) AgN03, MeOH, then H+or reflux, 66%;c) LiALH,, THF, 67% ;d) methyl vinyl ketone, 93%. SCHEME 46
4.
6
8
+
COzEt
$cozEt
'
OMe-
407
THE AMARYLLIDACEAE ALKALOIDS
- b.f
OM0
OUe OMe
403
404
g
OMe
o& H Me
OMe
405
(*)-Mesembrine (387)
Reagenrs and Conditions : a) CHCl3,1,10-phenanthroline,55OC,57% ; b) ethylene glycol,p-TsOH, toluene, rtflux, 88% ; c) LiAH4, EtzO, n, 84%; d) p-TsC1. pyridine. rt, 79% ;e) Bu4N+CN-, HMPA, 8OoC,77% ; f) aq. HCI, THF,rt,94%;g) Ref. 191. SCHEME47
Formation of the quaternary carbon center was also carried out by the reaction of ethyl 4-oxo-cyclohex-~2-ene carboxylate with 3,4-dimethoxyphenyllead triacetate (403) in chloroform containing 1,lO-phenanthroline at 55°C to give ethyl 4-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-ene carboxylate (404) in 57% yield. Thus, 4-[(3,4-dimethoxy)phenyl]-4-oxo-cyclohex2-ene carbonitrile (409,which was previously (192) transformed into ( 2 ) mesembrine (387),was obtained in 61% yield from 404 (193) (Scheme 47). The synthesis of (-)- and (+)-mesembrines (387)from 406 by way of 407 using a sequence of reactions involving double Sharpless asymmetric addition and radical-initiated reaction has appeared (194) (Fig. 23). The synthesis of ( -) and (2)-mesembranol (413) has been described in two reports; construction of the quaternary carbon center in the former involved Claisen rearrangement (195) (Scheme 48), whereas that in the latter case was performed by radical-mediated cyclization (148) (Scheme 49). The former synthesis (195) proceeds as follows. (2S,3S,4R))-2-Benzyloxy3,4-O-bis(MOM)-cyclohex-2-enone(408) (derived from D-glucose) reacted OMe
OMe
406
407
Me
0
FIG.23
408
OSAMU HOSHINO
- OMe
OMe
"'"*J$
a, b
MOMO'
f
c-e
MOMO'
HO
Ho& OMOM
MOM0
MOM = MeOCHz BZ = QH&O
408
OMOM
409
410
MeHNf18
OMe
OMe
OMe
OMe
i, I
09 h
OMOM
411
OMOM
b
HO'
(-)-Mesembranol(413)
412
Reagents and Condirions : a) (3,4-MeO)zC&&i, EtzO, -78OC, then NaOMe, McOH, 56%;
b) Pd(OH)Z, H2, EtOAc, 100%;c) l,l'-thiocatgonyldiimidazole,acetone, &lux, 95% ; d) P(OMe)3, EtOAc, reflux, 74% ; e) 30% aq. H Q H , 3OoC, then KzCO3, MeOH. a-OH (39%), POH (18%) ; f) MeCH(OEt)3, E t w H , MS 3A, 135OC. 56% ; g) DIBALH, toluene, -78OC, 82% ;h) 30% aq. MeNH2-MeOH, NaBCNH,, MeOH, rt, 65% ;1) H ~ ( O A C ) ~ , THF,rt, then NaBH4, aq. NaOH, THF, rt, quantitative ;j) aq. Ha-MeOH (1 : 2), rt, 68%.
SCHEME 48
with (3,4-dimethoxy)phenyllithium in ether at -78°C followed by catalytic hydrogenation to afford (lR,2S,3S,4R)-1,2-dihydroxy-3,4-0-bis(MOM)cyclohexanone (409). Conversion of the cis-1,2-dihydroxy groups in 409 into a double bond, followed by selective cleavage of a protecting group, gave a mixture of (4R)-3-hydroxy-4-0-MOM-cyclohexanones (410).The Claisen rearrangement of 410 with triethyl orthoacetate at 136°Cproduced aceethyl 4-(1R,4R)-0-MOM-1-[(3,4-dimethoxy)phenyl]cyclohex-2-enyl tate (411) in 56% yield. Reduction of 411 with DIBALH, followed by reductive amination, furnished (lR,4R)-4-0-MOM-l-[(3,4-dimethoxy) phenyl]-l-[2-(N-methylamino)ethyl]cyclohex-2-enol(412). Acetoxymercuration of 412 with mercury(I1) acetate and treatment with NaBH4 provided 0-MOM-mesembranol, deprotection of which with acid produced (-)-mesembranol (413)in 68% yield (195) (Scheme 48).
4.
'NHMe
414
409
THE AMARYLLIDACEAE ALKALOIDS
-
415
BnO
'ie 0
416
Bn = C&15CH2
(f)-mesembranol(413)
417
Reagents ond Conditions : a) NBS, MeCN-H20 (4 : l), 83% and 10%(regioisomer) ;b) K2CO3, MCOH, rt ;c) 40% aq. MeNH2, MeOH, 100°C, 78% ; d) Cl2CHC0Cl, Et3N, CH2Cl2. rt, 79 9%;
e) p-TsOH, benzene, reflux, 80%and 15% (regioisomer);f) BgSnH, AIBN. toluene, reflux, 51%; g) BH3, THF,reflux ;h) 5% Pd-C, H2 (4 kg/cm2), 68% ;i) Raney Ni (W-2). EtOH, reflux, 81% (3.7 : 1 mixture of a-and p-isomers) ;j) AlH3, THF, rf, 413 (71%), 418 (19%).
SCHEME 49
The second synthetic procedure (148) is shown in Scheme 49. Namely, 4-benzyloxy-l-[(3,4-dimethoxy)phenyl]-2-methylaminocyclohexanol (415) {prepared from 4-benzyloxy-l-~(3,4-dimethoxy)phenyl]cyclohexene(414) by epoxidation and subsequent oxirane ring opening with methylamine} was converted into the N-(methy1)dichloroacetamide 416 in two steps (dichloroacetylation and dehydroxylation with acid). Radical cyclization of 416 with Bu3SnH in boiling toluene containing AIBN produced, in 51% yield, 6-benzyloxymesembran-2-~one (417), reduction of which with borane, followed by catalytic hydrogenation, gave (*)-mesembranol (413) in 68% yield. However, reduction of 417 with Raney nickel gave rise to partial epimerization of a hydroxyl group to yield a mixture of a-and P-hydroxy
410
OSAMU HOSHINO
isomers, which was reduced by combined LIA1H4and aluminum( 111) chloride in THF to afford (t)-mesembranol (413) and (2)-epi-mesembranol (418) in 71 and 17% yield, respectively.
X. Miscellaneous A. PALLIDIFORINE A new heterodimer alkaloid named pallidiforine (419) was isolated as a yellow crystalline compound from whole plants of Narcissus pallidiflorus (76) belonging to the Pseudonarcissus DC section. Its high-resolution mass spectrum indicated the molecular formula CxH40N207 (M', dz.588.2775), suggesting a dimeric structure. The I3C NMR spectrum appeared to be almost exactly superimposable on those of lycoramine (276) (57) and tazettine (298) (296). However, the presence of one carbonyl carbon at 210.5 ppm and the disappearance of the C-11 of the tazettine moiety and that of the N-methyl protons of tazettine or lycoramine were observed. As a result of further examination of the NMR spectrum using 'H-'H (COSY) and lH-13C 2D experiments, its structure 419 was elucidated to be a heterodimer formed by lycoramine and tazettine units linked together. The formation of the alkaloid 419 can be explained by the attack of the nitrogen of N-demethyllycoramine (278) on C-6' of tazettine (298) with opening of the B ring and formation of the keto group (Fig. 24).
Pallidiflorine (419)
Obesine (420) FIG.24
Augustamine (421)
4. THE AMARYLLIDACEAE
ALKALOIDS
411
B. OBESINE Phytochemical studies on Narcissus obesus have resulted in the isolation of a new alkaloid named obesine (420) (see Fig. 24), accompanied by several known Amaryllidaceae alkaloids (74). The stereochemistry and structural determination of the alkaloid 420 have been carried out by spectroscopic analyses and by application of 2D NMR techniques. Although the H-6P proton (6 4.38) is masked by the H-3 proton (6 4.30-4.40), the H-6a proton (6 4.02) was assigned at higher field on the basis of the nuclear Overhauser effect (NOE) with H-12 endo (63.10) observed in the 2D NMR experiment. On the other hand, the a disposition of H-3 was confirmed by the NOE between H-3 (6 4.30-4.40) and H-12 ex0 (6 3.01). In the 13C-NMRspectrum of 420 a characteristic signal due to the C-11 carbon was observed at 82.7 (singlet) ppm. Also, a comparison of the 'H and 13C NMR spectra of obesine (420) with those of the related alkaloid 3-epi-marconine (303) (50) was performed. C. AUCUSTAMINE
Augustamine (421) (see Fig. 24) has been found in Crinum augustum and characterized (8), and its pharmacological properties have received attention (22). However, its absolute stereochemistry remained uncertain. The synthesis of the alkaloid 421 has been achieved using intramolecular 2-aza-ally1 anion cycloaddition ( 1 4 2 ~ (Scheme ) 50). Namely, the reaction of the (2-aza-ally1)stannane 189 in a way similar to that reported for the synthesis of (-)-amabiline (145) (see Scheme 17) and subsequent N-methylation with methyl iodide produced 3a-[(3,4-methylenedioxy) phenyl]-4,5-O-isopropylidene-N-methylhexahydroindoline(422) in 82% yield as a 5 : 1 mixture of two diastereomers. Removal of the isopropylidene group with methanolic HC1, followed by treatment with trimethyl orthoformate, afforded the corresponding orthoformate 423, which, without purification, was exposed to methanesulfonic acid in CH2ClZat room temperature to provide (-)-augustamhe (421) in 78% yield (three steps). Thus, this finding established the absolute stereochemistry of the natural alkaloid. D. PHENANTHRIDINE-TYPE ALKALOIDS Ismine (424) and three new phenanthridine derivatives, N-methylcrinasidine (425), 8,9-methylenedioxyphenanthridine (426) and N-methyl-8,9methylenedioxyphenanthridiniumchloride (427), were found in the leaves and bulbs of Lapiedra martinezii (53).The co-occurrence of ismine (424) in the plant gives an indication of the biosynthetic relationship between the four alkaloids (53).The three alkaloids isolated are not artifacts since
412
OSAMU HOSHINO
Ar = 3,4-(CH20z)C,H3
d
____t
r (-)-Augustamine (421)
Reagents and Conditions: a) BuLi (1.9 equiv), THF,-78OC, then Me1 (1.9 equiv), 82% (5 : 1 mixture of two diastereomers) ; b) conc. HCI, MeOH ; c) PPA, CH(OMe)3 ; d) M e S w , CH2C12.78%(3 steps). SCHEME 50
ismine (424) was not metabolized under the extraction conditions employed in this work. Buflavine (428) and 8-demethylbuflavine (429) were isolated for the first time from the bulbs of Boophane$ova. Their structures have been established by spectroscopic ('H and I3CNMR) methods and are representative of the unusual natural Amaryllidaceae alkaloids with an eight-membered Nheterocyclic ring, which had been previously reported only from Galonthus nivalis (197). A new alkaloid phamine (430),which is a phenanthridone alkaloid belonging to the narciclasine group, has been isolated from the bulbs of Hippeastrum equestre along with known Amarylldaceae alkaloids (47). Its structure was determined by spectroscopic (MS, UV, 'H and I3C NMR) analyses. Also, phamine indicated interesting antimitotic activity. The alkaloids isolated since 1987 are shown in Fig. 25. With respect to the synthesis of phenanthrine type alkaloids, 5,6dihydrobicolorine (432) (198),crinasiadine (199),and N-methylcrinasiadine (425) (199) were synthesized using combination of the Suzuki cross coupling reaction and the Bischler-Napieralksi reaction.
4. THE
413
AMARYLLIDACEAE ALKALOIDS
0 OH
Ismine (424)
N-Methylcrinasiadine (425)
Trisphaeridine (426)
427
RO Buflavine (428) R=Me 8-0-Demethylbuflavine (429)
Phamine (430)
431
R=H
("0. 5,dDihydrobicolorine (432)
Bicolorine (433) FIG.25
E.
4-ARYLTETRAHYDROISOQUINOLINE-TYPE ALKALOIDS
Since the previously published review (8), novel 4-aryltetrahydroisoquinoline type alkaloids have not been found in the Amaryllidaceae plants. Only latifine (437) has been isolated from the bulbs of Crinum lafifolium (200). The structure was confirmed by spectroscopic evidence, X-ray crystallographic analysis, and synthesis (198). Regarding synthetic studies, the syntheses of (?)-latifine (437) (200), of (?)-cherylline (440) and (+)-latifine (437) (201), and of (?)-O,Odimethylcherylline (445) and (2:)-0,O-dimethyllatifine (446)(202) have been performed using the Pomeranz-Fritsch-type cyclization (Scheme 51), the Bischler-Napieralski-type reaction (Scheme 52), and intramolecular nucleophilic addition of aryllithium (generated by butyllithium) to a carbony1 group (Scheme 53).
414
OSAMU HOSHINO
OH
OH
a
Me0
Me0
b,c
___)
Meo
H -
Me
Br
BI
43s
(f)-Latifhe (437)
436
Reagenfs and Conditions : a) conc. HCl, EOH, reflux. 63.8%;b) HCQEt, EtOH, K Z W ,MS 3A, reflux ;c) Lim,MeOCH2CHz0Me,reflux, 35.4%. SCHEME 51
F.
JOUBERTIAMINE-TYPE ALKALOIDS
In order to prove the biosynthesis of the Sceletium alkaloids, an extensive study has been carried out using Sceletium subvelutinum L. Bolus that were grown from seed, and the six alkaloids (447-452) (Fig. 26) produced by S. subvelutinum (101) isolated. These six alkaloids were separated chromato-
8-
Me0
d-f
8-c
Me0
Me0
ChH
0 439
438
Me0
8-C
___)
M
e
O
a
HO
(i)-Cherylline (440)
H
C02H
d-f
M e 0 d M e
0
441
442
(*)-Latifine (437)
Reagents and Conditions : a) (COCI)z, benzene, rt ;b) aq. NaN3, acetone, then benzene, reflux ;c)
FOCI3, 90-95"C, then SnCI4,CH&!lz, IT,67%(3 steps) ; d) NaH, benzene, reflux, then MeI, reflux; e) Me& MeSO3H, 5OoC, 50% ; f) LiAIH,, THF, reflux. SCHEME 52
4.
443
THE AMARYLLIDACEAE ALKALOIDS
444 OMe
415
(st)-0,O-Dimethylcherylline (445)
M e 0 a N M e
(k)-0,O-Dimethyllatifine (446) Reagents and Conditions : a) BuLi, THF, -78"C, 77% ; b) HCl, EtOH ;c) NaBH4, 70% (2 steps). SCHEME 53
graphically in order of increasing polarity: 0-methyldehydrojoubertiamine (452), 0-methyljoubertiamine (450), 0-methyldihydrojoubertiamine(448), dehydrojoubertiamine (451), joubertiamine (449), and dihydrojoubertiamine (447). The structures of the alkaloids were characterized by 'H
Dihydrojoubertiamine (447) R=H O-Methyldihydrojoubertiamine (448) R=Me
Joubertiamine (449) R=H O-Methyljoubertiamine (450) R -: Me FIG. 26
Dehydrojoubertiamine (451) R=H O-Methyldehydrojoubertiamine (452) R=Me
416
OSAMU HOSHINO
NMR and mass spectrometric evidence. Based on the results, the incorporation of radioactivity into the alkaloids was examined, and a key, late biosynthetic intermediate, or a compound that is closely related to that intermediate, was deduced to be the N-methylamine 454 formed from 4hydroxydihydrocinnamic acid by way of the corresponding aldehyde 453 (Scheme 54). As for the synthesis of the joubertiamine-type alkaloids, (-+)-Omethyljoubertiamine (450) has been produced using a transition-metalmediated reaction (203), in which a key step involves the introduction of aryl and 2-dimethylaminoethyl groups by a sequence of two nucleophilic additions to a cationic ($-cyclohexadienyl) iron (1+) intermediate. Namely, treatment of 1,4-dimethoxycyclohexa-1,3-dienecomplex 455 with triphenylmethylium hexafluorophosphate, followed by addition of (4methoxy)phenyllithiumto the resulting cationic complex at -78"C, afforded the (4-methoxy)phenyl adduct 456. The adduct 456 was treated with CF3C02H and then ammonium hexafluorophosphate (NH4PF6)to produce the salt, cyanomethylation of which with the lithium enolate of triethylsilyl cyanoacetate and subsequent treatment with TBAF afforded the cyanomethyl complex. Catalytic hydrogenation of the cyanomethyl complex with hydrogen and Raney nickel in the presence of dimethylamine afforded the 2-dimethylaminoethyl complex 457 in 60% yield, demetalation of which, using anhydrous trimethylamine N-oxide, followed by hydrolysiswith oxalic
9 $= OH
+ NHMe
0
CHO
453
, ,,
454
SCHEME 54
4.
455
417
THE AMARYLLIDACEAE ALKALOIDS
456
457
(k)-O-Methyljoubertiamine (450) Reagents and Conditions : a) Ph+?PFi, then 4-Me0w4Li, 85% ;b) CF3C$H, W P F 6 , 94%; c) Li’[CN~C02(CH2hSiMe,]-, then f-Bu4NF, 84%;d) Raney Ni, H2, MQNH, 609%; e) Et3N0, then (C02H)2,92%. SCHEME 55
acid, furnished (2)-O-methyljoubertiamine (450) in 92%yield. The overall yield was 40% (seven steps from 455) (Scheme 55) (203). In another report (193), (+)-O-methyljoubertiamine (450) has been prepared from the intermediate 404 (see Scheme 47) employed for the synthesis of (2)-mesembrine (387).
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418
OSAMU HOSHINO
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4.
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420
OSAMU HOSHINO
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4.
THE AMARYLLIDACEAE ALKALOIDS
42 1
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422
OSAMU HOSHINO
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4.
THE AMARYLLIDACEAE ALKALOIDS
423
164. U.Chattopadhyay, S. Das, S. Guha, and S.Ghosal, Cancer Lett. 37,293 (1987); Chem. Abstr. 108,48954 (1988). 165. (a) J. Szewczyk, A. H. Lewin, and F. I. Carroll, J. Heterocycl. Chem. 25, 1809 (1988); (b) J. Szewczyk, J. W. Wilson, A. H. Lewin, and F. I. Carroll, J. Heterocycl. Chem. 32, 195 (1995). 166. R.A. Holton, M. P. Sibi, and W. S. Murphy, J. Am. Chem. SOC. 110,314 (1988). 167. M. Ishizaki, K. Ozaki, A. Kanematsu, T. Isoda, and 0. Hoshino, J. Org. Chem. 58, 3877 (1988). 168. W.-C. Shieh and J. A. Carlson, J. Org. Chem. 59, 5463 (1994). 169. S. F. Martin, S. K. Davidsen, and J. A. Puckette, J. Org. Chem. 52, 1962 (1987). 170. L. Abelman, L. E. Overman, and V. D. Tran, J. Am. Chen. SOC. 112,6959 (1990). 171. A. Latvala, M. A. dnllr, T. GBzler, A. Linden, B. KivGak, and M. Hesse, Tetrahedron: Asymmetry 6, 361 (1995). 172. A. Bax and D. G. Davis, J. Magn. Res. 63,207 (1985). 173. A.Bax and S. Subramanian, J. Magn. Res. 67,565 (1986). 174. A. Bax and M. F. Summers, J. Am. Chem. SOC. 108,2093 (1986). 175. A. A. Ali, M. K. Mesbah, and A. W. Frahm, Planta Med. 50, 188 (1984). 176. I. H. Sbnchez, M. I. Larraza, I. Rojas, F. K. Brena, H. J. Flores, and K. Jankowski, Heterocycles 23,3033 (1985). 177. 0.Hoshino, M. Ishizaki, K. Saitoh, and K. Yumoto, J. Chem. Soc., Chem. Commun., 420 (1990). 178. 0. Hoshino and M. Ishizaki, Chem. Lett., 1817 (1990). 179. (a) M.Ishizaki, 0.Hoshino, and Y. Iitzka, Tetrahedron Lea 32, 7082 (1991); (b) M. Ishizaki, 0. Hoshino, and Y. Iitaka, J. Org. Chem. 56, 5005 (1991). 180. (a) L. E.Overman and J. Shim, J. Org. Chem. 56,5005 (1991); (b) L. E. Overman and J. Shim, J. Org. Chem. 58,4662 (1993). 181. J. Jin and S. M. Weinreb, J. Am. Chem. SOC.119, 5773 (1997). 182. M.Ishizaki, K. Kurihara, E. Tanasawa, and 0. Hoshino, J. Org. Chem. 58,3877 (1993). 183. W. DBpke, E. Swerin, and Z. Trimino, 2. Chem. 20, 298 (1980); Chem. Abstr. 94, 309726 (1981). 184. W. DBpke, E. Swerin, Z. Trimino, and C. Julierrez, Z. Chem. 21, 298 (1981); Chem. Abstr. %, 3554 (1982). 185. P.W. Jeffs, J. M. Karle, and N. H. Martin, Phytochemistry 17, 719 (1978). 186. R.Hegnauer, Phytochemistry 27,2423 (1988). 187. (a) H. Nemoto, T. Tanabe, and K. Fukumoto, Tetrahedron Lett. 35,6499 (1994); (b) H. Nemoto, T. Tanabe, and K. Fukumoto, J. Org. Chem. 60,6785 (1995). 188. S. Takano, Y. Imamura, and K. Ogasawara, Tetrahedron Lett. 22,4479 (1981). 189. H. Kosugi, Y.Miura, H. Hanna, and H. Uda, Tetrahedron:Asymmetry 4, 1409 (1993). 190. S. Takano, K. Samizu, and K. Ogasawara, Chem. Lett., 1239 (1990). 191. Y. Matsuura, J. Terauchi, T. Yamamoto, T. Konno, and T. Shono, Terahedron 49, 8503 (1993). 192. I. H. Sanchez and F. R. Tallabs, Chem. Lett., 891 (1981). 193. C. J. Parkinson and J. T. Pinhey, J. Chem. SOC., Perkin Trans 1, 1053 (1991). 194. T. Yoshimatsu and K. Ogasawara, Heterocycles 42, 135 (1996). 195. N.Chida, S. Sugihara, and S. Ogawa, J. Chem. SOC., Chem. Commun., 901 (1994). 196. S. Kobayashi, K. Kihara, T. Shingu, and K. Shingu, Chem. Pharm. Bull. 28, 2924 (1980). 197. L. Bubewa-Iwanowa, Chem. Ber. 95,1348 (1962). 198. C.J. Cowden, M. G. Banwell, and 1. C. S.Ho, J. Nut. Prod. 57, 1746 (1994). 199. M.G. Banwell and C. J. Cowden, Aust. J. Chem. 47,2235 (1994).
424
OSAMU HOSHINO
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.............................. I. Introduction and Botanical Sources 11. Lycorine-Type Alkaloids ..........................................
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324 342
................................. ral Elucidation ............
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A. Isolation and Structural Elucidation B. Synthetic Studies ......................... C. Biological Activity V. Galanthamine-Type A ....................... A. Isolation and Struc
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387
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393
ral Elucidation
B. Synthetic Studies
X. Miscellaneous ............................
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A. Pallidiforine B. Obesine ................
F. Joubertiamine-Type Alkaloids References .................... THE ALKALOIDS. VOL. 51 00YY-YSYR/Y8 $25.00
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Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.
324
OSAMU HOSHINO
I. Introduction and Botanical Sources The Amaryllidaceae alkaloids have been isolated from the plants of almost all of the genera of the family Amaryllidaceae and are members of the large group of isoquinoline alkaloids. Although their structures appear to be very different, they are known to be formed biogenetically by intramolecular oxidative coupling of norbelladines. At present, almost 200 Amaryllidaceae alkaloids have been isolated from plants, and many of their structures have been determined. Structures of the alkaloids are classified mainly into seven types, for which the representative alkaloids are lycorine (1)(lH-pyrrolo[3,2,1-d,e]phenanthridinetype), crinine (135) (5,lOb-ethanophenanthridinetype), narciclasine (lycoricidine) (204) (isocarbostyril type), galanthamine (261) (6H-benzofuro[3a,3,2-e,f]-2-benzazepine type), tazettine (298)(2-benzopyrano[3,4-c]indoletype), lycorenine (316)(2-benzopyrano-[3,4-g]indoletype), and montanine (338)($1 l-methanomorphanthridine type). Besides these seven structure types, there are mesembrine (387)and cherylline (440)(4-aryltetrahydroisoquinolinetype). The former structure belongs to the Sceletiurn alkaloids (Aizoaceae), but not the Amaryllidaceae (Fig. 1). Among these alkaloids, narciclasine (1ycoricidine)-type alkaloids are highly oxygenated compounds, the significant antitumor activity of which attracts the attention of biologists and pharmacologists. Recent developments in analytical techniques, as well as isolation procedures, have resulted in the rapid characterization of many structures. In the sections on the alkaloids that have been isolated for the first time from the Amaryllidaceae plants, not only the novel, but also the known, structures have been included. This chapter is a review of the Amaryllidaceae alkaloids that have appeared in the literature (1-7) since a previously published review in this series (8). Noteworthy results in the phytochemical studies, the N-oxides of several Amaryllidaceae alkaloids have been found for the first time in Amaryllidaceae plants, accompanied by the corresponding free bases (52): ungiminorine N-oxide (10)(from Puncrutium muritimurn), and 0-methyllycorenine N-oxide (329)and homolycorine N-oxide (330)(from Lupiedru muritinezii). The stereochemistry of their nitrogen atoms was deduced based on 2 D NOESY experiments. Furthermore, it has been established that these Noxide derivatives are genuine natural products, and not artifacts, by the demonstration that the free bases are not converted into N-oxides when subjected to the same extraction procedure. It is noteworthy that the N oxides have been isolated accompanied by the corresponding free bases.
4.
Lycorine (1)
Crinine (135) OMe
w
M
e
O
a
o N,
325
THE AMARYLLIDACEAE ALKALOIDS
Narciclasine (204)
n
H
Me
Galanthamine (261)
Tazettine (298)
&H Lycorenine (316)
OH
,OMe
<
HO&. '0
'NH
Montanine (338)
a
G O M e
0
Me
Mesembrine (387)
MHO e o a N M e
Cherylline (440)
FIG.1
Following the first examples of the isolation of naturally occurring N oxides from Amaryllidaceae family, extensive investigation of extracts of the bulbs of Lycoris sanguineu has revealed, for the first time, the presence of galanthamine N-oxide (281),sanguinine N-oxide (283),and lycoramine N-oxide (284), together with the corresponding free bases (62). The structures of the N-oxides were characterized by spectroscopic evidence ('H and I3C NMR). Also, hippeastrine N-oxide (332)has been isolated newly from the flowers of Lycoris rudiuta, accompanied by galanthamine N-oxide (281),lycoramine N-oxide (284),0-methyllycorenine N-oxide (329),and homolycorine N-oxide (330) and their corresponding free bases (60).
326
OSAMU HOSHINO
Furthermore,examination of the extracts of the flowers of Lycoris incarnata (58) has shown the presence of ungiminorine N-oxide (10) and galanthamine N-oxide (281),together with the corresponding free bases. The interesting N-oxide oxoassoianine N-oxide (49) has been found in the bulbs of Narcissus bicolor (64). The structures of these metabolites are shown in Fig. 2.
3-O- Acetyl-
Ungiminorine N-oxide (10)
narcissidine N-oxide (22)
Oxoassoanine N-oxide (49)
Me0
Lycoramine N-oxide (284)
Galanthamine N-oxide (281) R=Me Sanguinine N-oxide (283) R=H
Me0
Me0
OMe
O-Methyllycorenine N-oxide (329)
'OH
0
Homolycorine N-oxide (330) R=Me 8-0-Demethylhomo1ycorine N-oxide (331) R=H FIG.2
0
Hippeastrine N-oxide (332)
4.
THE AMARYLLIDACEAE ALKALOIDS
327
Numerous alkaloids have been isolated from Narcissus species as a result of the continuing exploration for novel alkaloids with pharmacological activity in the Amaryllidaceae family. Among them, the alkaloids isolated for the first time are included: norpluviine (25),l-O-acetyl-lO-0demethylpluviine (26), 1,10-0-diacetyl-10-0-demethylpluviine(27), and 0-acetylgalanthamine (262)(from N. pseudonarcissus) (83),oxoassoanine (46) (from N. assoanus) (63),vasconine (55) and 8-0-acetylhomolycorine (320)(from N. vasconicus) (93),roserine (57)and mesemberenone (371) (from N. pallidufus) (78), haemanthamine (155), 8-0-demethylmaritidine (174),homolycorine (318), and 8-0-demethylhomolycorine (319) (from N. primigenius) (82), cantabricine (176) (from N. canraricus) (65), 9-0demethylmaritidine (175)(from N. radinganorum) (86),O-methylmaritidine (179)and 0-methylpapyramine (182)(from N. papyraceus) (81),narcisine (268) (from N. tazetta) (89),0-methyllycorenine (317) (from N . munozii-garnendiae) (73), 9-0-demethylhomolycorine (321) (from N. confusus) (66),5a-hydroxy-9-0-demethylhomolycorine (322)(from N. forriflolius) (91), dubiusine (324)(from N. dubius) (69),and 5,6-dihydrobicolorine (432)and bicolorine (433)(from N . bicolor) (64), accompanied by other known Amaryllidaceae alkaloids. A complete structural analysis of 0-methyllycorenine (317)has now established that the methoxy substituent at C-6 is a rather than the previously reported fl (found in Lapiedra rnartinezii) (52). A reexamination of the polar alkaloid components of the bulbs of Hyrnenocalfis caymanensis (47) has disclosed a glucoalkaloid l-fl-~-glycosyl-2-flD-glycosylpseudolycorine (15). Also, a new glucosyloxy derivative 206 of narciclasine is found in the polar alkaloid components of P. marititimum (96), and both the parent alkaloid and this new derivative were shown to possess strong mitotoxic activity Further examination of the polar alkaloids from a methanolic extract of L. martinezii has revealed the new quaternary alkaloids, N-methylassoaninium chloride (53) and N-chloromethylnarcissidinium chloride (23), together with the lycorine-type alkaloids ungiminorine (8), narcissidine (20),and hippadine (44)(51).However, the latter quaternary alkaloid (23)is thought to have been produced by the isolation procedure (51). A similar observation regarding extraction has been reported; galanthamine (261)forms a quaternary salt N-chloromethylgalanthanium chloride (266),when extracted with methylene chloride or crystallized from the same solvent. The structure and absolute configuration of the quaternary alkaloid were determined by X-ray crystallography (109).This study emphasizes the care that needs to be taken when choosing a solvent to extract plant materials. As a method for the determination of the alkaloids, a microchemical identification procedure (4,210), which provides for the differentiation of
328
OSAMU HOSHINO
MeO& Me0
10-0-Norpulviine (24) R=R~=H 1-0-Acetyl- 100-norpluviine (25) R=Ac, R ' = H 1,lO-0-Diacetyl-100-norpluviine (26) R=R'=AC
Me0
Vasconine (50)
8-0-Demethylmaritidine (174) R = H, R' = Me 9-0-DemethyL maritidine (175) R =Me, R' = H
Me0
Me0
Roserine (52)
R
0-Me thylmaritidine (178) R=H O-Methylpapyramine (182) R = OMe
& n
Cantabricine (176)
R20
R'O OMe
O-Methyllycorenine (317) O-Acetylgalanthamine (262) R=Ac,R'=Me N-Formylgalanthamine (264) R = H,R' = CHO Narcisine 268) R = H, = Ac
5.6-Dih ydrobicolorine (432)
0
Bicolorine (433)
FIG.3
'R I 0io
8-0-Demethylhomolycorine (319) R=R'=H,R2=Me 8-O- Acetylhomolycorine (320) R = H , R' = Ac, R2 =Me S~t-Hydroxy9-0-demethylhomolycorine (322) R = OH, R' =Me, R2 = H 9-0-Demethylhomolycorine (321) R = H , R' =Me. R2 = H Dubiusine (324) R = Ac, R' =Me, R2 = COCH2CH(OH)Me
4.
329
THE AMARYLLIDACEAE ALKALOIDS
OH (0 flZ-D-Gb~osyl
OH 0 4-0-pD-Gl~~0~ylnarciclasine (204)
1-0-p-D-GlUcOSylpseudolycorine (15) OMe
N-Chloromethylnarcissidinium chloride (23)
N-Methylassoaninium chloride (53)
N-Chloromethylgalanthaminiurn chloride (266)
FIG.4
the Amaryllidaceae alkaloids, has been applied to, among others, 3-0acetylcrinine (136), 6c~-ethoxycrinine,6a-ethoxybuphanisine, bulbisine, flexinine (142),augustisine, 3-0-acetylpowelline (163),trisphaeridine (426), and cherylline (440).This procedure ( 4 ) involves microcrystalline techniques and color reactions. Also, a zone refining partition coefficient technique has been developed to separate the alkaloids present in a crude extract of Crinum moorei (32). The crystal structures of haemanthamine (155) (from N. confusus) and eugenine (325)(from N. eugeniae) have been determined by X-ray crystallography. The structure of the former as 155 was confirmed to be the anti position C (11)-OH with respect to the aromatic ring and the half-chair conformation of ring C (111).Also, the structure of the latter alkaloid, 325, was shown to be far from planar, only the benzene ring being so configured (70). Interestingly, although the occurrence of the Schiff 's base craugsodine (28)in Crinum augustum has been reported (23),a new Schiff 's base named isocraugsodine (29)was isolated from the fruits of C. asiaticum (20) (Fig. 5 ) . Its structure was assigned by chemical transformation and comprehensive spectroscopic evidence. Also, the temperature-gradient distribution of the
330
OSAMU HOSHINO
Meo<3 Ho69 HO
Me0
H/
Craugsodine (28)
H O & 9
Me0
-
Isocraugsdne (29)
-
A /
H
E-Isomeric form
H/
Me0
Quinont methide
Me0
H
Z-Isomeric form
FIG.5
three isomeric forms (E-isomer quinone methide 2-isomer) of the Schiff's base was determined by high-resolution 'H NMR analysis. Thus, this compound is considered as a direct precursor to the Amaryllidaceae alkaloids. Isolation and botanical sources of the Amaryllidaceae alkaloids that have been reported in the literature since 1987 are summarized in Table I. Extensive exploration of the pharmacological utility of the Amaryllidaceae alkaloids has been carried out. For example, studies (112) on the effects of Amaryllidaceae alkaloids and their derivatives (prepared by biosynthesis and chemical transformation) upon Herpes simplex virus (type l), the relationship between their structure and antiviral activity, and the mechanism of this activity have been performed, suggesting that the alkaloids that may eventually prove to be antiviral agents had a hexahydroindole ring with two functional hydroxyl groups. Furthermore, the antiviral activity of the alkaloids was found to be due to the inhibition of multiplication, and not to the direct inactivation of extracellular viruses, and the mechanism of the antiviral effect was partially explained as a blocking of viral DNA polymerase activity. Also, the extract of the bulbs of Haemanthus albiflos was found to inhibit viral DNA synthesis (113). It is reported that the total alkaloidal extract of this plant possesses antiviral activity (113). Reviews that include these biological data have appeared (114,215).
4.
331
THE AMARVLLIDACEAE ALKALOIDS
TABLE I THEISOLATION OF AMARYLLIDACEAE ALKALOIDS Species Boophane frava
Brunsvigia josephinae
Clivia nobilis Crinum amabile
Crinum americanum
Alkaloids (sources) 0-Ace1 ylhamayne (bulbs) Augustine (bulbs) Buflavine (bulbs) Buphanisine (bulbs) Crinamine (bulbs) Crinine (bulbs) 8-0-Demethylbuflavine (bulbs) 5,6-Dihydrobicolorine (bulbs) Epi-buphanine (bulbs) Epi-vittatine (bulbs) Hamayne (bulbs) Lycorine (bulbs) Montabuphine (bulbs) Undulatine (bulbs) 11-0-Acetylambelline (bulbs) 3-0-Acetylhamayne (bulbs) Ambelline (bulbs) Brunsbelline (bulbs) Buphariidine (bulbs) Buphariisine (bulbs) Crinamine (bulbs) Crinine (bulbs) Hamayne (bulbs) Hippadine (bulbs) Josephinine (bulbs) Sternbergine (bulbs) Undulatine (bulbs) Clivatine (whole plants) Lycoririe (whole plants) Nobilisine (whole plants) Amabiline (bulbs) Augustine (bulbs) Crinamine (bulbs) Buphanisine (bulbs) Lycorine (bulbs) 0-Acetylcrinine (rhizomes) Augustine (bulbs) Buphanisine (leaves) Crinamine (leaves) Crinan type (rhizomes) Crinine (Crinidine) (leaves) Crinine (bulbs) Dihydrocrinidine (rhizomes) Flexinine (bulbs) Haemanthamine (leaves)
Reference 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 11 II 9 10
10 II 10
11 11 11 II 12 12 12 12 13 13 13 13 13 14 15 16
16 17 16 14 15 14 16
(continues)
TABLE I (continued) Soecies
Crinum asiaticum
Alkaloids (sources)
Reference
Hamayne (rhizomes) Hippadine (bulbs) Lycorine (bulbs) Lycorine (leaves) Oxocrinine (bulbs) Pratorimine (bulbs) Pratorinine (bulbs) Pratosine (bulbs) Tazettine (leaves) Trisphaeridine (bulbs) Ungeremine (bulbs) Criasbetaine
1,2-O-P-o-Diglucosyllycorine (fruits)
Isocraugsodine (fruits) 2-Oxolycorine N-oxide (fruits) 1-O-Palmitoyl-2-0-(1‘-O-palmitoyl-2’-Oo1eoyl)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-O-(l’-O-palmitoyl-2‘-0oleoy1)glycerophosphorylpseudolycorine (fruits) l-O-Palmitoyl-2-0-(1 ’-O-palmitoyl-2’-0stearoy1)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-0-( l’-O-palmitoyl-2’-0stearoy1)glycerophosphorylpseudolycorine (fruits) Ungeremine Crinum asiaticum var. sinicum Crinine (bulbs) Crinsin (bulbs) Lycorine (bulbs) Powelline (bulbs) Crinum augustum Augustamine (whole plant) Craugsodine Hippadine (bulbs) 6a-Hydroxybuphanisine (whole plant) 6a-Hydroxycrinine (whole plant) Pratorimine (bulbs) Pratorinine (bulbs) Telastaside (phathenocarpic fruits) Crinum bulbispermurn Powelline (whole plant) Pratorinine (whole plant) Crinum firmifoliurn var. Crinamine (whole plants) hygrophilum Criwelline (whole plants) Hamayne (whole plants) 6-Hydroxycrinamine(whole plants) 3-Hydroxy-8,9-methylenedioxyphenanthridine (whole plants) Ismine (whole plants) Lycorine (whole plants) Trisphaeridine (whole plants) 332
15 14 14 16 14 14 14 14 16 14 16 18 19 20 19 19 19 19 19 18 21 21 21 21 22 23 24 22 22 24 24 25 22 22 26 26 26 26 26 26 26 26
TABLE I (continued) Species Crinum giganteum
Crinum jagus
Crinum kirkii
Crinum latifolium
Crinum moorei Crinaum zeylanicum
Galanthus elwesii
Haemanthus albiflos
Alkaloids (sources) Crinine (crinidine) Gal anthamine Hippeastrine Lycorine Tazettine Crinamine (whole plants) Hainayne (whole plants) 6-Hydroxycrinamine (whole plants) Lycorine (whole plants) 3-0-Acetylhamayne (bulbs) Crinine (bulbs) 8-0-Demethylvasconine (bulbs) Hamayne (bulbs) Kirkine (bulbs) Crinafolidine Crinafoline 4,5-Dehydroanhydrolycorine(flower stem fluid) Epi-lycorine (flower stem fluid) Epr-pancrassidine (flower stem fluid) Hippadine (flower stem fluid) Latifine (bulbs) Lycorine (flower stem fluid) Pancrassidine (flower stem fluid) Crinamidine Crinine Powelline Crinine (crinidine) (bulbs) Flexinine (bulbs) 6-Hydroxypowelline (bulbs) Zeylarnine (air-dried rhizomes) N-Demethylgalanthamine (whole plants) 9-0-Demethylgalwesie (whole plants) 9-0-Demethylhomolycorine(whole plants) Galanthamine (whole plants) Galanthine (whole plants) Galasine (whole plants) 16-Hydroxy-9-0-demethylgalwesine(whole plants) 11-Hydroxyvittatine (whole plants) 16-Hydroxygalwesine (whole plants) Galwesine (whole plants) Leucotamine (whole plants) Lycorine (whole plants) 5-Methoxy-9-0-demethylhomolycorine (whole plants) Narwedine (whole plants) Sanguinine (whole plants) Albiflomanthine (bulbs) 333
Reference 27 27 27 27 27 28 28 28 28 29 29 29 29 29 30 30 31 31 31 31 197 31 31 32 32 32 33 33 33 34 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36
(continues)
TABLE I (continued) Species
Haemanthus kalbreyeri
Haemanthus multiflorus
Hippeastrum equestre
Hippeastrum hybrids
Hippeastrum puniceum Hippeastrum solandriflorum
Hymenocallis caribaea Hymenocallis caymanensis Hymenocallis expansa
Alkaloids (sources)
Reference
Albomaculine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine' (bulbs) Lycoramine (bulbs) 7-Deoxypancratistatin (rhizomes) 7-Deoxynarciclasine (rhizomes) Haemanthamine (rhizomes) Haemanthidine (rhizomes) Hippadine (rhizomes) Kalbretorine (rhizomes) Lycorine (rhizomes) Narciclasine (rhizomes) Pancratistatin (rhizomes) Pancratiside (2-~-P-~-Gh1cosylpancratistatin) (rhizomes) 2-0-Acetylchlidanthine (bulbs) Galanthamine (bulbs) Galanthamine Haemultine (bulbs) Hippadine (bulbs) Lycorine Lycorine (bulbs) Sanguinine Hippeastrine (bulbs) Lycorine (bulbs) Phamine (bulbs) Phamine (bulbs) Tazettine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) 11-Hydroxyvittatine (bulbs) Lycorine (bulbs) Montanine (bulbs) Pancracine (bulbs) Tazettine (bulbs) Vittatine (bulbs) 0-Acetylnarcissidine (bulbs) 11-Hydroxyvittatine (bulbs) Vittatine (bulbs) Hamayne (aerial parts and bulbs) Ismine (aerial parts and bulbs) Lycorine (aerial parts and bulbs) Vittatine (aerial parts and bulbs) Ungeremine (aerial parts and bulbs) 7-Deoxy-frans-dihydronarciclasine(bulbs) 4-Hydroxyanhydrolycorine (leaves) Glucoalkaloid (bulbs) Haemanthidine (bulbs/leaves) 334
36 .36 36 36 36 37 37 37 37 37 37 37 37 37 -37 38 38 39 38 38 39 38 40 40 40 40 41 40 42 42 42 42 42 42 42 42 43 43 43 44 44 44 44 44 45 46 47 48
TABLE I (conrinued) Species
Hyrnenocallis latifolia Hyrnenocallis littoralis
Hyrnenocallis rotata
Lapiedra martinezii
Alkaloids (sources)
Reference
Hippeastrine (bulbs/leaves) Tazettine (bulbs/leaves) 7-Deoxy-trans-dihydronarciclasine (bulbs) 5,6-Dihydrobicolorine (bulbs) 8-0-Demethylmaritidine (bulbs) 7-Deoxynarciclasine (bulbs) 7-Deoxy-trans-dihydronarciclasine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Littoraline (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Marconine (bulbs) 0-Methyllycorenine (bulbs) Narciclasine (bulbs) Pancratistatin (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitlatine (bulbs) Alkaloid 13 (bulbs) N-Demethylgalanthamine (bulbs) N-Demethyllycoramine (bulbs) 8-0-Demethylmaritidine (bulbs) 3-Epi-marconine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Ismine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitratine (bulbs) N-Chloromethylnarcissidinium chloride Hippadine Homolycorine (aerial parts) Hornolycorine N-oxide (aerial parts) Ismine (bulbs/leaves) N-hlethylassoaninium chloride N-hlethylcrinasiadine (N-methyl-8,9-
48 48 45 49 49 45 45 49 49 49 49 49 49 49 49 49 45 45 49 49 49 50 50 50 50 50 50 50 50 50 50 50 50 50 51 51 52 52 53 51 53
methylenedioxyphenanthridin-6-one) (bulbs/leaves)
8,9-Methylenedioxyphenanthridine(bulbs/
53
N-hlethyl-8,9-methylenedioxyp henanthridinium chloride (bulbs/leaves)
53
leaves)
0-Methyllycorenine N-oxide (aerial parts) Narcissidine 335
52 51
(continues)
TABLE I (continued) Species
Leucojum aestivum sub. pulchellum Leucojum autummale Lycoris ichinensis
Lycoris guangxiensis
Lycoris incarnata
Lycoris radiata
Alkaloids (sources) Ungiminorine Ungiminorine N-oxide (aerial parts) Elwesine Galanthamine Lycorine Sanguinine 3-0-acetylnarcissidine 3-0-acetylnarcissidine N-oxide Crinine (bulbs) Epi-lycoramine (bulbs) Galanthamine (bulbs) Haemanthidine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Narciclasine (bulbs) Pulviine (bulbs) N-Allylnorgalanthamine (bulbs) Crinine (bulbs) Galanthamine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Narwedine (bulbs) Norgalanthamine (bulbs) Pseudolycorine (bulbs) 0-Demethyllycoramine (flowers) Galanthamine (flowers) Galanthamine N-oxide (flowers) Galanthine (flowers) lncartine (flowers) Lycoramine (flowers) Lycorine (flowers) Narcissidine (flowers) Sanguinine (flowers) Unigiminorine (flowers) Unigiminorine N-oxide (flowers) 0-Demethylhomolycorine (flowers) 0-Demethyllycoramine (flowers) Galanthamine (flowtrs) Galanthamine N-oxide (flowers) Hippeastrine (flowers) Hippeastrine N-oxide (flowers) Homolycorine (flowers) Homolycorine N-oxide (flowers) Lycoramine (flowers) Lycoramine N-oxide (flowers)
336
Reference 51 52 54 54 54 54 55 55 56 56 56 56 56 56 56 56 56 56 56 57 57 57 57 57 57 57 57 58 58 58 58,59 58,59 58 58 58 58 58 58 60 60 60 60 60 60 60 60 60 60
TABLE I (confinued) Species
Lycoris sanguinea
Narcissus assoanus Narcissus bicolor
Narcissus cantaricus
Narcissus confusus
Narcissus dubius Narcissus eugeniae Narcissus jacetanus
Narcissus leonensis
Alkaloids (sources) Lycorine (flowers) 0-Methyllycorenine (flowers) 0-Methyllycorenine N-oxide (flowers) Tazettine (flowers) Vittatine (flowers) Galanthamine (bulbs) Galanthamine N-oxide (bulbs) Galanthine (bulbs) Lycoramine (bulbs) Lycoramine N-oxide (bulbs) Lycorine (bulbs) Norbutsanguinine (bulbs) Norsanguinine (bulbs) Pseudolycorine (bulbs) Sanguinine (bulbs) Sanguinine N-oxide (bulbs) Assoanine (fresh plants) Oxoassoanine (fresh plants) Bicolorine (bulbs) 5,6-IXhydrobicolorine (bulbs) 3-Epi-macronine (bulbs) Oxoassoanine N-oxide (bulbs) Pretazettine (bulbs) Cantabricine (whole plant) Crinamine (whole plant) 6a-/b&Hydroxybuphanisine (whole plant) Tazettine (whole plant) Vittatine (whole plant) 1-0-Acetylpseudolycorine 2-O- Acetylpseudolycorine 9-0-Demethylhomolycorine (fresh plants) 9-0-Demethylhomolycorine (aerial parts/ bulbs) N-Formylgalanthamine (fresh plants) Galanthamine (fresh plants) Haemanthamine (fresh plants) Homolycorine (aerial partshulbs) Pretazettine (fresh plants) Pseudolycorine Duhiusine (aerial parts) 5a-Hydroxy-10-0-demethylhomolycorine (aerial part) Eugenine (whole plant) Assoanine (whole plant) Lycorine (whole plant) Oxoassoanine (whole plant) Pseudolycorine (whole plant) Epi-norgalanthamine (whole plant) Epi-norlycoramine (whole plant) 337
Reference 60 60 60 60 60 61,62 61 62 61 61 62 62 62 62 61,62 61 63 63 64 64 64 64 64 65 65 65 65 65 66 66 67 68 67 67 67 68 67 66 69 69 70 71 71 71 71 72 72
(continues)
TABLE I (continued) Species Narcissus rnunoziigarmendiae Narcissus nivalis
Narciassusobesus
Narcissus pallidiflorus
Narcissus pallidulus Narcissus panizzianus
Narcissus papyraceus
Narcissus primigenius
Narcissus pseudonarcissus
Alkaloids (sources) Lycorine (whole plant) Homolycorine (whole plant) Lycorenine (whole plant) 0-Methyllycorenine (whole plant) N-Demethylgalanthamine (fresh aerial parts and bulbs) Galanthamine (fresh aerial parts and bulbs) 9-0-Methylpseudolycorine (fresh aerial parts and bulbs) Bicolorine (whole plants) 5.6-Dihydrobicolorine (whole plants) Epi-macronine (whole plants) Galanthamine (whole plants) Haemanthamine (whole plants) Obesine (whole plants) Pretazettine (whole plants) 8-0-Demethylhomolycorine (whole plants) 5,6-Dihydrobicolorine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) Pallidiflorine (whole plants) Pretazettine (whole plants) Mesembrenone (aerial parts) Mesembrenone (whole plants) Roserine (whole plants) 6-Epi-papyramine (whole plants) Galanthine (whole plants) Galanthine (aerial parts and bulbs) Homolycorine (aerial parts and bulbs) Homolycorine (whole plants) Papyramine (whole plants) Pretazettine (whole plants) Pretazettine (aerial parts and bulbs) 0-Demethylhomolycorine (aerial parts) 0-Demethylhomolycorine N-oxide (aerial parts) Homolycorine (aerial parts) Lycorine (aerial parts) 0-Methylmaritidine (aerial parts) 0-Methylpapyramine (aerial parts) Papyramine" (aerial parts) Pseudolycorine (aerial parts) 9-0-Demethylhomolycorine (whole plants) 0-Demethylmaritidine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) 0-Acetylgalanthamine (bulbs) 1-0-Acetyl-10-0-demethylpluviine (bulbs) 1-0-Acetyl-10-0-demethylpluviine(bulbs) 338
Reference 72 73 73 73 74 74 74 75 75 75 75 75 75 75 76 76 76 76 76 76 77 78 78 79 79 80 80 79 79 80 80 81 81
81 81 81 81 81 81
82 82 82 82 83 83 84
TABLE I (continued) Species
Alkaloids (sources) N-Demethylgalanthamine (bulbs) N-Demethylmasconine (bulbs) 10-0-Demethylpluviine (bulbs)
Narcissus radinganorum Narcissus var. “Fortune” Narcissus tazetta
Narcissus tortifolius
Narcissus tortuosus Narcissus vasconicus
Reference
1,10-Diacetyl-10-0-demethylpluviine (bulbs) Epi-norlycoramine (bulbs) Galanthamine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Masconine (bulbs) 8-0-Methylhomolycorine (bulbs) 0-Methyloduline (bulbs) Narcidine (bulbs) Narcissidine (bulbs) Nanvedine (bulbs) 10-horpluviine Oduline (bulbs) Vittatine (bulbs) 9-0-Demethylmaritidine (fresh plants) 8-0-Demethylhomolycorine (fresh plants) Homolycorine (fresh plants) Fortucine (leaves) 10-0-Demethylhomolycorine (whole plants) Galanthamine (bulbs) Haemanthine (bulbs) Honiolycorine Lycorine Lycorine (bulbs) Narcishe (bulbs) Pretazettine (bulbs) Pseudolycorine (bulbs) Tazettine Tazettine (bulbs) 8-ODemethylhomolycorine (whole plants) 9-0. Demethyl-2a-h ydroxyhomolycorine (whole plants) Dubiusine (whole plants) Galanthamine (whole plants) Honiolycorine (whole plants) Lycorine (whole plants) Tortuosine (whole plants) 8-0-Acetylhomolycorine (whole plants) Homolycorine (whole plants) Lycorine (whole plants) Vasconine (whole plants) 339
84 84 84 83 84 85 84 85 85 85 84 84 84 84 85 84 85 85 84 83 84 84 86 86 86 87 88 89 89 90 90 89 89 89 89 90 89 Y1
91 91 91 91
92 92 93 93 93 93
(continues)
TABLE I (continued) ~~
Species Pancratium biflorum Pancratium maritimum
Alkaloids (sources) Telastaside (parthenocarpic fruits) Crinine (bulbs) 9-0-Demethylhomolycorine(bulbs) 6-0-Methylhaemanthidine (bulbs)
3P,lla-Dihydroxy-l,2-dehydrocrinane(bulbs) (bulbs)
0,N-Dimethylnorbelladine (bulbs)
Sceletium subvelutinum
Sternbergia clusiani
Galanthamine (bulbs) 4-~-P-~-G~ucopyranosyharciclasine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) Habranthine (bulbs) Hippadine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) 11-Hydroxygalanthamine(habranthine) (bulbs) 8-Hydroxy-9-methoxycrinine(bulbs) 11-Hydroxyvittatine(bulbs) Lycorenine (bulbs) Lycorine (bulbs) 6-0-Methylhaemanthidine (bulbs) Pancracine (bulbs) Pseudolycorine (bulbs) Sickernbergine (bulbs) Tazettine (bulbs) Trisphaeridine (aerial parts) Trisphaeridine (bulbs) Ungeremine (bulbs) Ungiminorine (bulbs) Ungiminorine N-oxide (bulbs) Vittatine (bulbs) Zefbetaine (bulbs) Dehydrojouvertiamine (whole plants) Dihydrojoubertiamine (whole plants) N,N-Dimethyltyramine (whole plants) Ouvertiamine (whole plants) 0-Methyldehydrojoubertiamine(whole plants) 0-Methyldihydrojoubertiamine(whole plants) 0-Methyljoubertiamine (whole plants) Crinine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) 11-Hydroxyvittatine(bulbs) Lycorine (bulbs) Pretazettine (bulbs)
Reference 25 94 95-97 97 98
97 96,97 96 96,97 96,97 97 96 97 96 97 98 96,97 96 94-97 97 96 96 96 96 99 %
96,100 97 52,97 97 96,100 101 101 101 101 101 101 101 102 102 102 102 102 102 102
TABLE I (continued) Species Sternbergia lutea
Sternbergia sicula
Ungernia minor Zephyranthes Java
Alkaloids (sources) Deniethylmaritidine (whole plants) Epi-maritinamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) Hippadine (bulbs) 11-Hydroxyvittatine (whole plants) Lycorine (bulbs) Maritinamine (whole plants) Tazettine (whole plants) Vittatine (whole plants) Ungiminorine (bulbs) Buphanisineb (whole plants) Deniethylmaritidine (whole plants) 11-Epi-haemanthamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) 11-Hydroxyvittatine (whole plants) Siculine (whole plants) Siculinine (whole plants) Tazettine (whole plants) Ungiminorine (deacetyllutessine) (whole plants) Vittatine (whole plants) 1,3-O-Diacetyldihydroungerenine 2-0-Glycerophosphoryllycorine (flowers) 2-041‘-0-Palmitoyl-2’-0-oleoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-oleoyl) glycerophosphorylpseudolycorine(flowers) 2-041 ’-0-Palmitoyl-2’-0-stearoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-stearyl/oleoyl) glycerophosphorylpseudolycorine(flowers) 2-0-(1 ’-0-Palmitoyl-2’-0-stearyl) glycerophosphory llycorinium methocationsc (flowers) Criasbetaine (fresh mature seeds) Crinamine (fresh mature seeds) Haemanthamine (fresh mature seeds) Haemanthidine (fresh mature seeds) Kalhreclassine (fresh mature seeds) Lycorine (fresh mature seeds) l-0-B-D-Glucopyranosyllycorine(fresh mature seeds) Maritidine (fresh mature seeds) Melhylpseudolycorine (fresh mature seeds) Narciclasine (fresh mature seeds) Pratorinine (fresh mature seeds) Prerazettine (fresh mature seeds) 341
Reference 103 103 103 103 104 103 104 103 103 103 104 103 103 103 103 103 103 103 104 103 103 103 105 106 106 106 106 106 106
107 107 107 107 107 107 107 107 107 107 107 107
(continues)
342
OSAMU HOSHINO
TABLE I (continued) Alkaloids (sources)
Species
Pseudolycorine (fresh mature seeds) 1-0-P-D-Glucopyranosylpseudolycorine (fresh mature seeds) Ungeremine (fresh mature seeds) Zefbetaine (fresh mature seeds) Zeflabetaine (fresh mature seeds) a
Reference 107 107
107 107 I07
As a mixture of 6a- and 6p-epimers. Enantiomer of (-)-byhankhe. As a mixture of a-and fl-N-methyl epimers.
II. Lycorine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION
The structures of the representative alkaloids isolated since 1987 are listed in Fig. 6. Investigation of the components of the flowers of Amaryllidaceae plants has not been carried out extensively, compared with that of the bulbs and the whole plants, because of the limitation for the collection of these plants. The flower stem fluid of Crinum lutifolium (31) has been examined, from which numerous Amaryllidaceae alkaloids have been isolated. Among them, two lycorine-type alkaloids, 2-epi-lycorine (4) and 2-epi-pancrassidine (7), are included, structures of which were determined by spectroscopy. In addition, a study of the metabolism of lycorine (1) and 2-epi-lycorine (4) has been performed using the flower stem fluid in a phosphate buffer, revealing that lycorine (1) produces, in succession, 2-oxolycorine (5) and 2-0x0-pyrrolophenanthridiniumbetaine (ungeremine) (a), and that 2-epilycorine (4) forms 2-epi-pancrassidine (7), 4,5-dehydroanhydrolycorine (43), and hippadine (44) (31) (Scheme 1). As a result of these in vitro studies, a reexamination of the flower stem fluid has shown that trace amounts of 2-epi-pancrassidine (15) are indeed present. Further investigations of the flowers of Amaryllidaceae species has revealed several new alkaloidal phospholipids, 2-0-glycerophosphoryllycorine (30), phosphatidyllycorine (31-34), phosphatidyllycorinium methocations (39, and phosphatidylpseudolycorine (36-39), respectively, in an extract of the flowers of Zephyranthesflava (107) (Fig. 7). The structures of the alkaloids were established by comprehensive spectroscopic analyses
Lycorine (1)
Lycorine N-oxide (3)
R=H
1-0-Acetyllycorine (2) R=Ac
OMe HO.&ORU
Pancrassidhe (6) R = P-OH 2-Epi-pancrassidine (7)
2-Oxolycorine (5)
& <& Q '0
0 0
2-Epi-lycorine (4)
0
Ungiminorine (8) R=H 3-0-Acetylungiminorine (9) R=Ac
Ungiminorine N-oxide (10)
Siculinine (11)
9-0-Methylpseudolycorine (17)
Incartine (19)
R = a-OH
HO
R=H
Stembergine (16)
Me0
Pseudo1 corine (12) R = RY = H 1-0-Acetylpseudolycorine (13) R = AC. R' = H 2-O- AcetvlMe0
Galanthine (18) R=Me
OMe HO.&.ofl
I!
CHzCl
3-O- Acetylnarcissidine N-oxide (22)
N-Chloromethylnarcissidinium chlorode (23) RIO&
Rlo&9 Me0
RO
MeO&
/
H
HO
Formcine (Kirkine) (27)
hugsodine (28) R =H, R' = M e Isocraugsodine (29) R = Me, R' =H FIG.6
10-0-Norpulviine (24) R=R'=H l-O-Acetyl-100-norpluviine (25) R-AC. R ' = H lJ0-O-Diacetyl- 100-norpluviine (26) R = R ' =AC
344
OSAMU HOSHINO
OH
0
-Q& 0
Lycorine (1)
2-Oxolycorine (5).
2-Epl-lycorine (4)
{)& 0
Ungerenine (48)
2-Epi-pancrassidine (7) SCHEME 1
and chemical transformation. For example, the location of the acylglycerophosphoryl substituent at the allylic position of the pseudolycorine moiety was determined by the demonstration that diacetylphosphorylpseudolycorine when treated with sodium methoxide (NaOMe) in tetrahydrofuran (THF) containing palladium(0) catalyst (116), produced 1,lO-di-Oacetylpseudolycorine. As for the presence of both the free and conjugated alkaloids in the plants, their biochemical role has been examined using the fruits of Crinum usiuticum during stress (incisional injury and attack by an insect) (19). Wounding of C. usiuticum fruits caused almost complete hydrolysis of the alkaloidal conjugates and also produced oxidized metabolites of lycorine: Its analogs, e.g., 1-0-palmitoyl-2-0-(1'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine (33), gave lycorine (1) and the N-oxide 3. Prior treatment of the fruits with anesthetic agents, e.g., ether or lidocaine, not only protected the alkaloidal conjugates from enzymatic hydrolysis, but also prevented their oxidation. These observations reveal that even "fresh" plant extracts can be modified by enzymatic activity. Further exploration on components of the Amaryllidaceae flowers revealed a new lycorine-type alkaloid, incartine (19), from the flowers of Lycoris incurnatu (58),together with lycorine (l),ungiminorine (8), ungiminorine N-oxide (lo), galanthine (18), and galanthamine-type alkaloids (58,59).Their structures were established by spectroscopic methods. Moreover, this epoxide 19 is regarded as a significant intermediate in the biosynthesis of narcissidine (20) from galanthine (18) (59) (Scheme 2).
2-O-Glycerophosphoryllycorine (30) H.R2 ~poCH2CH(OH)CH2OH
R'
2-0-(l'-O-Palmitoyl-2'-0-stearoy1)glycerophosphoryllycorine(31) R' = H,Rz = O#OCH$HCH2O-palrnitoyl 0-stearoyl 2-04 l'-O-Palmitoyl-2'-0-oleoyl)glycerophosphayllycorine (32) R' = H,Rz= O#OCH2
2-0-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphorylpseudolycorine(36) R' = H, R2 = &POCH2
2-041'-0-Palmitoyl-2'-0-oleoyl)glycemphosphorylpseudolycorine(37) R' = H, R2 = QPoCH2CHCH2O-palmitoyl b-oleoy1 1-0-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-steamyl)glycerophosphorylpseudolycorine(38) R' = palmitoyl, R~= O~POCH~
l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine(33) l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)R'= palmitoyl. R2 = 02~~2CHCH20-pa1mitoY1 glycerophosphorylpseudolycorine(39) b-stearoyl R' = palmitoyl, R2 = QPoCH2 l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)glycerophosphoryllycorine(34) R'= palmitoyl. R2 = O~KKFI~CHCH20-palmitoyl 6-oleoy 1
Me
2-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphoryllycoriniummethocations (35) (a mixture of a-and P-N-methyl isomers) R=
02POCH2j'HsHa~~palmitoyl FIG.7
-
Me0
-
Me0
Me0
Me0
Me0
Galanthine (18)
Me0
hicartine (19) SCHEME 2
Narcissidine (20)
346
OSAMU HOSHINO
The extract of Sternbergiu siculu gave a new lycorine-type alkaloid, siculinine (11)(104, accompanied by lycorine (l),ungiminorine (8), and hippadine (44),structural elucidation of which was performed by spectroscopic evidence. In this study, deacetyllutessine (41), which was reported previously (117), was found to be identical to ungiminorine (8). Therefore, it is likely that lutessine (40) corresponds to acetylungimimorine (9), although final confirmation of the structure of lutessine remains to be achieved (Fig. 8). A new lycorine-type alkaloid named fortucine has been found in the leaves of Narcissus variety “Fortune” and its structure reported as 27 (87). From the bulbs of Crinum kirkii, two new alkaloids, kirkine (27) and 8-0demethylvasconine (56), have been isolated and their structures established by physical and spectroscopic methods (29). In this study, the structure of kirkine was determined to be the same structure as that proposed for fortucine (87). Therefore, confirmation by direct comparison of each alkaloid remains to be conducted. C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-0x0-pyrrolophenanthridinium alkaloids, zefbetaine (59)and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephrunthesfluvuby gradient solvent extraction, chromatography, and derivatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9.
& OMe
Q
.OMe
0
0
Siculinine (11)
Lutessine (40) R=Ac Deacetyllutessine (41)
R=H
FIG.8
347
4. THE AMARYLLIDACEAE ALKALOIDS
Me0 "eO&
4Hydroxyanhydrolycorine (42)
R
4,s-Dehydroanhydrolycorine (43) RzHz Hippadine (44) R=O
Assoanine (45) R=H2 Oxoassoanine (46) R=O
.-& Me0
0
c1Anhydrolycorinium chloride (47)
0 0Oxoassoanine N-oxide (49)
Ungeremine (48)
Me0
0 Ratorinine 50) R'=H.R =Me
1
Ratorimine (51) R' =Me, Rz = H Ratosine (52) R' =R2 =Me
N-Methylassoaninium chloride (53)
0
0'
Tormesine (54) R' = R2 = OMe Vasconine (55) R' = H. RZ= OMe 8-O-Demeth ylvasconine (56) R' = H, R~ = OH
MeO&
Me0
Roserine (57)
OMe
Criasbetaine (58) ~1~ ~2 = M~ Zefbetaine (59) R'=Me. R 2 = H
FIG.9
Zeflabetaine (60)
Kalbretorine (61) R=H O-Methylkalbntorine (62) R=Me
348
OSAMU HOSHINO
B. SYNTHETIC STUDIES The synthesis of lycorine-type alkaloids has received the attention of chemists as a target for exploration of new synthetic methods, because the stereoselective construction of the contiguous asymmetric centers reported until now is not always efficient. Since the previously published review (8),two investigations of the total synthesis of (2)-lycorine (1) (128), and the first total syntheses of optically active (+)-lycorine (1)and (+)-1deoxylcorine (84) (119), the unnatural enantiomer of lycorine (l), were reported. Both of the synthetic strategies involve the construction of highly functionalized hexahydroindoline derivatives, followed by cyclization to form ring B. A key step in the one case (128)involves an intramolecular Diels-Alder reaction to form a Slactone 64and its conversion to functionalized hexahydroindoline derivatives (Scheme 3). Specifically, intramolecular DielsAlder reaction (in a sealed tube) of (3E)-hexa-3,5-dienyl-(E)-(3,4-methy1enedioxy)cinnamate(63)in o-dichlorobenzene at 235°C afforded in 86% yield the Slactone 64, along with its stereoisomer. Oxidation of 64 with silver carbonate-Celite in boiling benzene produced a regioisomer 65 of Slactone 64 in 98% yield. Iodolactonization of 65 in the usual manner, and protection as a tetrahydropyranyl ether, afforded tetrahydropyranyloxyiodo-y-lactone, dehydroiodation of which provided tetrahydropyranyloxyy-dehydrolactone 66,Deprotection of 66,followed by Jones oxidation, led to dehydro-y-lactonecarboxylic acid 67. The acid 67 was converted into hexahydroindoline 68, possessing stereochemistry similar to that of the ring juncture in the rings B-C-D of lyconine through Curtius rearrangement of the acid. Epoxidation of the acetate afforded a 5,6-cr-epoxy acetate 69, the Payne rearrangement of which, under mild basic conditions, produced, on acetylation, the 4J-&epoxy acetate 70 in a moderate yield. Phenylselenylation of 70,followed by acetylation, afforded, in 98% yield (two steps), 5~,6a-diacetoxy-4a-phenylselenylhexahydroindolin-2-one (71),possessing the necessary functional groups and a masked double bond. Finally, 71 was converted into (2)-lycorine (1) (86% yield) in two steps (228). On the other hand, 71 gave, in 57% yield, 0-diacetyllycorin-5-one (74),which was previously (220) transformed to (2)-lycorine (l), by way of 5P,6a-Odiacetyl-4a-phenylselenyllycorin-5-one (73). In the other synthetic route (129),Birch reduction-alkylation and transformation of functionalized hexahydroindoline derivatives constitute key reactions (Schemes 4 and 5). Birch reduction of N-(2-methoxybenzoyl)(2s)-methoxymethylpyrrolidine,followed by alkylation with 2-acetoxyethyl bromide, produced a key compound 76, azidation of which, followed by hydrolysis with acid, gave the azide 77in 69% yield (two steps). Iodolactoni-
4.
349
THE AMARYLLIDACEAE ALKALOIDS
66
67
68
69
70
(f)-Lycorine (1) R=H (&)- 1,2-O-Diacetyllycorine (75) R=Ac Reagents and Condirionr : a) o-dichlorobenzene (a sealed tube), 235OC, 86% and 5% (stereoisomer);
b) LiAl&, THF, rt ,97% ;c) Ag&Og-Celite,benzene, reflux, 98% ;d) aq. KzCO3, rt, then 12, aq. KI, rt, 92% ; e) dihydropyran, p-TsOH, CH&, rt, 87% ; f ) 1,8-diazabicyclo[5.4.0]undec-7-ene, benzene, reflux, 98% ; g) p-TsOH, CH2Clz-MeOH (1: l), rt, 92% ;h) Jones oxidation,OOC, 63% ; i) (PhO),P(O)N3, r-BuOH, reflux, 79% ;j) CF$QH, CHzClz, rt, 98% ; k) NaOMe, MeOH. rt, 98% ; I) r-BuMQSiCl, imidazole, DMF,rt, 98% ;m) m-C1@-L&O3H, CHzC12,rt, 85% ;n) Bu4N?-, THF, rt, 38% ;0 ) AczO, pyridine, rt ; p) 5964. KzC03,THF, rt, 61%, 5% (regioisomer); q) (PhSe)z, NaB&, EtOH, reflux. 99%; r) 35% formalin, saturated aq.NazC03,THF, rt ;s) NaI04, THF, MeOH. rt. 57% ;t) NaA1(OCHzCHzOMehHz, toluene, reflux, then CH~=N%QI-, THF, rt, 44% ; u) Ref.
120. SCHEME 3
350
OSAMU HOSHINO
zation of 77 afforded iodo-y-lactone 78 in 82% yield, reductive cyclization of which, followed by treatment with (6-iodo-3,4-methylenedioxy)benzoyl chloride, produced the N-aroylenamido-y-lactone 79. The enamido-ylactone 79 was treated with benzyl alcohol and then butyllithium to produce, spontaneously, the benzyl p-epoxy enamido-carboxylate 80 in 93% yield. Radical-mediated cyclization of 80 with tributyltin hydride (Bu3SnH) in boiling benzene containing azobis(isobutyronitri1e)(AIBN) produced in 53% yield a key intermediate, the 2,3-p-epoxy-a-lycoran-7-one ester 81, having the lycorine ring system. Benzyl 2,3-p-epoxy-a-lycoran-7-one-3a~carboxylate (81) was converted into the thiazoline-2-thion-3-yl carboxylate 82. Oxirane ring opening, followed by elimination of a carboxyl group under chemically mediated radical reaction conditions gave successfully (+)-2-epi-l-deoxylycorin-7-one (83). Finally, 83 produced (+)-l-deoxylycorine (84)by the Mitsunobu reaction and successive reduction with lithium aluminum hydride (LiA1H4) in 56 (from benzoate) or 37% (from acetate) yield (two steps) (Scheme 4). On the other hand, phenylselenylation and dephenylselenylation of 81 provided the allylic alcohol 85, allylic rearrangement of which, with a mixture of acetic anhydride, acetic acid, and concentrated sulfuric acid, afforded a rearranged allylic acetate 86 in 28% yield (three steps). Epoxidation of 86 with dimethyldioxirane gave the corresponding epoxide 87. Catalytic hydrogenolysis of 87 followed by protolysis through a Pyrex filter in benzene containing acridine and t-butyl thioalcohol proceeded effectively to give 1O-acetyllycorin-7-one (88) in 45% yield (two steps). Acetylation of 88 gave 1,2-O-diacetyllycorine (89), the spectral data of which were identical to those reported for the racemate (221).Finally, (+)-lycorine (1)was obtained in 70% yield by reduction of 88 (Scheme 5). The syntheses of (+)-a-lycorane (92) and (+)-trianthine (97) using the retro-Cope elimination step (222), and of (+)-y-lycorane (100) using the palladium-mediated reaction (223), have been reported. When optically active 2-(cyclohex-2-enyl)ethylhydroxylamine (90) [derived from methyl 3-(3,4-methylenedioxy)phenylcyclohex-2-enylacetate] was heated at 140°C, the N-hydroxyhexahydroindoline 91 was obtained in 83% yield. Reductive cyclization of 91 then gave (+)-a-lycorane (92) (Scheme 6). This reaction has been applied to the optically active 5,6-O-isopropylidene-2-(cyclohex-2-enyl)ethylhydroxylamine (95) for the synthesis of (+)-trianthine (97). l-Acetoxy-l-[(3,4-methylenedioxy)phenyl]-5,6-Oisopropylidenecyclohex-2-ene (93) reacted with vinylmagnesium bromide in the presence of copper(1) bromide to give a vinyl compound, which was converted into cyclohexeneacetaldehyde 94. A starting ma-
4.
76
77
79
82
351
THE AMARKLLIDACEAE ALKALOIDS
78
81
(+)-1-Deoxylycorine (84)
83
Reugenrs and Conditions: a) (PhO)2PON3, DEAD, THF, O°C tort, 73%;b) 6M HCl, MeOH, rf, 95%;c) Iz, THF, H20, rt, 82%;d) PPh3,THF, reflux, W% ; e) 6-I-3,4-(CH20&HzCOCI, Et3n, CH2C12, 0 ° C to rt, 98% ;f) PhCH20H, THF, then normal BuLi, -78 to 25"C,93% ; g) Bu3SnH, AIBN, benzene, reflux, 5 3 8 ;h) 10%Pd-C, H2, EtOH, rt, 84% ; i) DCC, Nhydroxy-4-methylthiazolin-2-thione, 4pyrrolidinopyridine,CH2C12,86% ;j) DEAD, PPh3, PhC02H (73%)or AcOH (50%), THF ;k) LiAlH.,, THF, reflux, 76% (from benzoate), 73% (tiom acetate). SCHEME 4
terial95 was obtained by reductive hydroxyamination of 94. The cyclization reaction of 95 proceeded smoothly in degassed benzene at 80°C to afford Nhydroxyhexahydroindoline 96 in 96%yield, reduction of which with Raney nickel, followed by the modified F'ictet-Spengler reaction with Eschenmoser's salt (CH2=N+Me21-),gave (+)-trianthine (97) in 50% yield (two steps) by deprotection (Scheme 7).
352
&
OSAMU HOSHINO
a,b
( 0
0
0
0
89 Reagenrs and Condiriom : a) (PhSe)2,NaBh, EtOH, rt, 93%; b) NaI04, THF, H20, rt, 87% ; c) Ac20, AcOH, H2SO4, 50°C, 35% ;d) dimethyldioxirane,acetone, OOC, 46% ; e) 10%Pd-C, H2,
EtOH, R, 90% ;f) hu, Pyrex filter, acridine, f-BuSH, benzene, rt, 50% ; g) LiAlH4, THF, reflux, 70% ;h) Ac20, 4-dimethylaminopyridine,CHzC12, rt, quantitative ; i) Ref. 121. SCHEME 5
91
(+)-a-Lycorane (92)
Reagents and Conditions :a) degassed mesitylene, 140°C, 83% ;b) Raney Ni, wet Et20, then
CH2=NtMe21-,THF, 40 OC, 74-80%. SCHEME 6
4.
93
353
THE AMARYLLIDACEAE ALKALOIDS
95
94
%
(+)-Trimthine (97)
Reagents and Conditions : a) CHz=CHMgBr, CuBr, Me#, 95% ; b) 9-BBN, H202, then Swern
oxidation ;c) NHzOH, then NaBCNH3, aq. MeOH, pH 3.0,82% ; d) degassed benzene, reflux, 93% ;e) Raney Ni, then CHz=N+MeI-, 'IFIF. 89% ;f) AcCI, MeOH, 56%.
SCHEME7
Intramolecular cyclization of optically active N-[(6-bromo-3,4-methylenedioxy)phenylmethyl]cyclohex-2-enylacetamide (98) (prepared from 1S,4R-dibenzoyloxycyclohex-2-ene)under palladium-mediated reaction conditions afforded 4-methoxycarbonyl-l,2-dehydro-y-lycoran-5-one (99) in 58% yield, carboxylation of which, followed by stepwise reduction, afforded (+)-y-lycorane (100) (Scheme 8). The synthesis of (+)-y-lycorane (loo), or (5)-a-lycorane (92) and ( 2 ) y-lycorane (loo), has been achieved through arylation using the modified Suzuki reaction (124) (Scheme 9) or the cross Grignard coupling reaction (125) (Scheme 10). In the former case (124),methyl dibromo-bicyclo[3.1.0]2-(hexy1)ethylcarbamate (101) (prepared from 3-acetoxycyclopentene) underwent cation-n-cyclization with silver acetate in 2,2,2-trifluoroethanoI (CF3CH20H)containing potassium carbonate to afford a starting material 7-bromo-N-methoxycarbonyl-A6~7-tetrahydroindoline (102) in 87% yield. The cross coupling reaction of 102 with (3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions produced 7-(3,4-methylenedioxy)phenyl-Af'~7-tetrahydroindoline (103) in 87% yield.
354
OSAMU HOSHINO
98
99
Reagents and Condirions : a) Pd(OAc)z, dppb, NaH,
(+)-y-Lycorane (100)
DMF,50°C then i-Pr2EtN,100"C,58% ;
b) NaCl, DMSO-H20, 160°C; c) Pd-C, H2, MeOH ; d) LiAIH,, THF, reflux, 23% (3 steps). SCHEME 8
Reduction of 103, followed by cyclization, produced (+)-y-lycoran-7-one (104), which was reduced in the usual manner to lead to (2)-y-lycorane (100)(Scheme 9). In the latter case (125), palladium-catalyzed intramolecular 1,4-chloroamidation of N-benzyloxycarbonyl-2-(cyclohexa-2,4-dienyl)ethylamine (105) (derived from methyl cyclohexa-2,4-dienylacetate)proceeded regioand stereoselectively to produce N-benzyloxycarbonyl-5-chloro-A6~7tetrahydroindoline (106) in 95% yield. The cross Grignard coupling reaction of 106 with (3,4-methylenedioxy)phenylmagnesiumbromide in the presence of lithium copper( 11) chloride (Li2CuC14)in THF afforded 7-
101
I;~Hco~M~
102
103
(f)-y-Lycorane (100)
104
Reagenrs and Conditions : a) AgOAc, CF~CH2OH,K2CO3,18OC, 87% ;b) 3,4-(CH2O,)W3B(OH),, Pd(PPh&, aq. Na2C03, benzene, EtOH. 8OoC, 87%; c) 10%Pd-C, H2, 18°C. 95% ; d) NC13,
8OoC, 79% ;e) LMW,
THF,65°C. 84%. SCHEME 9
4.
THE AMARYLLIDACEAE ALKALOIDS
355
[(3,4-methylenedioxy)phenyl]-A~6-tetrahydroindoline(107) in 77% yield, which was converted into (2)-a-lycorane (92) or (+)-y-lycorane (loo), respectively, through 108 or 109 by changing the order of the procedure for reduction and cyclization (Scheme 10). Synthesis of (?)-a-lycorane (92) using radical-mediated cyclization of N-bromoaryl-3-hydroxy-3,4,S,6-tetrahydro-lH-indol-2-one has been carried out (226). 1-[(6-Bromo-3,4-methylenedioxy)phen ylmethyl]-3cyclohexylamino-A3~3a~~7~7a~-dihydroindolin-2-one (111) (derived from 3-cyclohexylaminodihydroindolin-~2-one (110) was transformed to 1-[(6bromo-3,4-methylenedioxy)phenylmethyl]-3-hydroxy-A7 (7a)-tetrahydroindolin-Zone (112)by hydrolysis and reduction. Radical-mediated cyclization of 112 with Bu3SnH in boiling benzene containing AIBN gave ( 2 ) hydroxy-a-lycoran-5-one (113)in 79% yield. Dehydroxylation of 113 under radical reaction conditions gave (+)-a-lycoran-5-one, which was reduced with LiAlH4 in boiling THF to afford (+)-a-lycorane (92)(Scheme 11). Cobalt-mediated [2+2+2] cycloaddition of an alkyne to the double bond of an enamide has been found to give spontaneously the lycorane ring system (227). Thus, a formal total synthesis of (+)-y-lycorane (100) has been achieved by this methodology. Also, (+)-y-lycorane (100)has been synthesized starting with pyrrole (228) or homophthalimide (229).
(*)-yLycorane (100)
109
(*)-a-Lycorane (92)
Reugenrs and Conditions : a) Pd(0Ach (5 mo1%), benzoquinone, LEI. acetone-AcOH( 4 1 ) . 95%; b) 3,4-(CHz01)C&MgBr, Li2cUCl4. THF, 77% ;c) P Q . H2. EtOH, rt, 95% ;d) POCI3 (neat), 7OOC, 72% ;e) L A W , THF,7OOC. 92%;9 POC13 (neat), 75OC. 71% ; g) POz,Hz (6.5 kg/cm2), EtOH, rt, 95%;h) LiAM4, THF, 65'C. 85%. SCHEME10
356
OSAMU HOSHINO
113
(It)-a-Lycorane(92)
Reagents and Conditions : a)
6-Br-3,4-(CH2O2)C,+I2CH2Br, NaH,DMF, rt, 74%;b) (C02H)2, THF-HzO, reflux, 70%; f) N a B h , MeOH, rt, 46% ; d) BqSnH, AIBN, benzene, reflux ;e) PhOCSCl, DMAP, pyridine, rt, 85% ; f) LiAW, THF, reflux, 51% (3 steps). SCHEME 11
The C-aromatic pyrrolophenanthridine-type alkaloids are members of the Amaryllidaceae alkaloid group. They have attracted the attention of chemists and pharmacologists because of their significant pharmacological properties (130). Hence, numerous studies directed toward the synthesis of these alkaloids have been conducted. During the past decade, several reports involving mainly two methodologies have appeared; one is based on the construction of ring B, whereas the other concerns the construction of ring C. The cyclization of 1-(6-iodo-3,4-methylenedioxy)phenylmethyl-4,5,6trihydro-1H-indol-2-one (114) (prepared from 110) under palladiummediated reaction conditions afforded pyrrolophenanthridone 115 in 71% yield. Hydrolysis of 115 gave the C-aromatic product anhydrolycorine-4,5dione (116),reduction of which, followed by elimination of the hydroxyl group, produced 4,5-dehydro-anhydrolycorine(43)(126b) (Scheme 12). The reaction of an o-methoxyaryloxazoline with an arylmagnesium halide has been known to cause replacement of a methoxy group with an aryl
4.
357
THE AMARYLLIDACEAE ALKALOIDS
a
110
114
115
0'
0
.
116
3,4-Dehydroanhydrolycorine(43)
Reagents and Conditions :a) 6-I-3.4-(CHz~)C&CHzCl, NaH. DMF, rt, 76%; b) Pd(OAc)z, Bu4N+ CI'*H@, KOAc, DMF,loOOC, 71% ;C) (C02H)2, THF-H20, reflux. 80% ;d) DDQ. benzene, reflux. 21%;e) LiAU& THF,reflux,42%;9 MeS@Cl, Et3N, CH2C12,rt, 9%. SCHEME 12
group, leading to a biaryl. This methodology has been developed for the synthesis of pyrrolophenanthridone-type alkaloids (131) (Scheme 13). The reaction of 2-[(6-methoxy-3,4-methylenedioxy)phenyl]oxazoline123 with the magnesium derivative of N-benzyl-7-bromoindoline (117)in tetrabromodifluoroethane gave the corresponding 7-arylindoline 118 in 68% yield. Hydrolysis and successive cyclization of 118 produced anhydrolycorin-7one (119), which was previously (232) transformed to hippadine (44) by oxidation with 2,3-dichloro-4,5-dicyanobenzoquinone(DDQ). Similarly, the intermediate 7-arylindoline 120 (prepared from 2-aryloxazoline 124) gave kalbretorine (61)through 4,5dihydrokalbretorine (121).The intermediate 7-arylindoline 122, which was synthesized in 73% yield by the reaction of 2-[(2,4,5-trimethoxy)phenyl]oxazoline125 with the magnesium derivative of 117, led to oxoassoanine (46) in a manner similar to that noted previously. Reduction of 46 produced pratosine (52) in 55% yield. Coupling of N-[(2-iodo-4,5;-dimethoxy)benzylidene]cyclohexylamine (126)with 7-[(N-t-butoxycarbonyl (Boc)]indolinyl)copper in ether at -45 to 20°C gave, on treatment with '1 M hydrochloric acid (HCl), N-Boc-7-[(6-
358
OSAMU HOSHINO
Me
(2 steps)
122
0
Oxoassoanine (46)
73% O
0
Ratosine (52)
Reagents and Codifions : a) Mg, BrF2CCF2Br, nflux, then 123.68% ;b) lO%aq. H2S04, EtOH, heat ; c) Pd-C,H2, MeOH, z t ;d) DDQ ;e) Mg, BrFzCCFzBr, nflux, then 124.78% ;f ) Mg. BrF2CCF2Br, reflux, then 125.73%;g) Ref. 132. SCHEME 13
formyl-3,4-dimethoxy)phenyl]indoline(127) in 65% yield. N-Deprotection and concomitant cyclization of the 7-(6-formylaryl)indoline(127) with anhydrous hydrogen chloride in chloroform gave vasconine (50) in quantita-
4. THE AMARYLLIDACEAE
359
ALKALOIDS
tive yield, reduction of which with sodium borohydride (NaBH4) afforded assoanine (45) in 93% yield. On the other hand, oxidation of 50 with alkaline aqueous potassium perrnanganate gave oxoassoanine (46) (133) (Scheme 14). The synthesis of hippadine (4and ) ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions (134) (Scheme 15). (7-Bromo-5-mesy1oxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119),which was transformed to hippadine (44)in 90% yield by oxidation with DDQ. Hippadine (a), ungeremine (48)) and anhydrolycorin-7-one (119) were also synthesized by the radical-mediated cyclization approach. Namely, cyclization of 7-bromo-1-[(3,4~~methylenedioxy)benzoyl]-5-nitroindoline (129) in dimethyl sulfoxide (DMSO) in the presence of benzyltriethylammonium chloride (BTAC) at 155°C gave 2-nitroanhydrolycorin-7-one (130), and a regioisomer, in 60% yield (product ratio of 1:1). Catalytic hydro(131) in good yield. genation of 130 led to 2-amino-anhydrolycorin-7-one
n
a
' 6 OMe O M e
126
Me0
b
OHC
127
MeO& Me0
MeO&
Me0
C1Vasconine (SO)
/ Id Me0
0
Assoanine (45)
Oxoassoanine(46)
Reagenrs and Condirions :a) N-Boc-indoline,s-BuLi, TEMEDA, EtzO. -45OC, CuI. P(OEt)3,rt, then 1M HCI. 65%;b) gaseous HCI, CHC13, quantitative ;c) NaBH.+ EtOH, rt, 93%; d) KMn04, 3M NaOH. CH2C12.2OoC, 84%. SCHEME 14
360
Br
OSAMU HOSHINO
- <" a
0
-("
C
0 128
I
a
L
0
Ungeremine (48)
< 0 0 " & 0 A ? & Anhydrolycorin-7-one (119)
Hippadine (44)
Reugents and Conditions : a) ~ ~ e 3 , 4 - ( ~ ~ o ~ ) C k H , B ( O Pd(PPh3)4. H ) z , NazC03. DME,reflux.
(4049%) ;b) NaAl(OCHZCH~0Me)~Hz. toluene, reflux. 54%;c) DDQ,dioxanc, reflux, 90%. SCHEME 15
Transformation of 131 to hippadine (a), ungeremine (a), and anhydrolycorin-7-one (119) was accomplished in the usual manner (135)(Scheme 16). The intramolecular Diels-Alder reaction of 5-(3-butynyl)-3H-pyran[2,3c]isoquinoline-3,6-dione (132) in boiling benzene afforded a pyrrolophe(136). Hipnanthridone, which yielded 2-methoxy-anhydrolycorin-7-one padine (44) was synthesized by means of l-aza-l'-oxa[3.3]sigmatropic rearrangement of N-(2-methoxycarbonylvinyloxy)-8,9-methylenedioxyphenanthridin-6-one (133)(137) or by palladium-mediated intramolecular cyclization of 7-bromo-N-[(6-bromo-3,4-methylenedioxy)benzoyl]indoline (134)(138) (Fig. 10). C. BIOLOGICAL ACTIVITY Lycorine (1) and pseudolycorine (12) were evaluated to determine their in vitro inhibitory properties against the RNA-containing flaviviruses ( Japa-
nese encephalitis, yellow fever, and dengue type 4 viruses); bunyaviruses (Punta Toro, sandfly fever-Sicilian, and Rift Valley fever); the alphavirus (family Togaviridae); Venezuelan equine encephalomyelitis viruses; the lentivirus; HIV-1; and the DNA-containing vaccinia virus. Antiviral activity was observed against the flaviviruses tested, and to a slightly lesser degree against the bunyaviruses. Also, 1 and l2 showed inhibitory activity against Punta Tor0 and Rift Valley fever viruses, but with low selectivity (139).
4. THE
361
AMARYLLIDACEAE ALKALOIDS
'& (&
('0
0
Anhydrolycorin-7-one (119)
d
'0
0
Hippadine (44)
0
131
(& 0 o Ungeremine (48)
Reugenrs and Conditions : a) BudN'Cl-, K2CO3, M%SO. 155"C, 60% (1 : 1); b) Pd-C, H2, CF3CO2H. 25'C. 93% ; c) aq H3PO4, Cu20, CICH2CH2C1, 7OoC, 50% ; d) DDQ,benzene, 100°C, 76% ;e) ONOS03H. aq. H2SO4, NaBFs, OOC, 76%; f) CF3CO2H. reflux. 40% ;g) NaH, Cd-ISCH2Br,DMF, 7OoC,51% ;h) LiAM4, THF. reflux, 95% ;i) Pd-C. H2, EtOH, 7OoC, then H202, AcOH, Mn02 (HzO),, 25OC, 80% (2 steps).
SCHEME16
132
133 FIG.10
134
362
OSAMU HOSHINO
The pharmacological effects of lycorine (1) have been studied using the guinea pig; it caused concentration-dependent relaxation of the isolated epinephrine-precontacted pulmonary artery. In this study, its effects on heart were suggested to be mediated by the stimulation of P-adrenergic receptors (102).
111. Crinine-Type Alkaloids
A. Isolation and Structural Elucidation Since 1987, the isolation and characterization of several new crinine-type alkaloids have been reported. The structures of the representative alkaloids isolated are depicted in Figs. 11 and 12. It is noteworthy that oxocrinine (138), an intermediate in the biosynthesis of crinine (135)and related compounds in Amaryllidaceae alkaloids, was isolated for the first time from the bulbs of Crinum umericanum (14). Its structure was elucidated by spectroscopic evidence, including 'H-coupled I3CNMR experiments, and finally confirmed by comparison with a sample prepared from crinine (135) by oxidation. The extract of the bulbs of Pancratium maritimum grown in Turkey has been found to contain two new chine-type alkaloids, 3& 1la-dihydroxy-1,Zdehydrocrinane (141)and 8-hydroxy-9-methoxycrinine (172)(98), together with the lycorine-type alkaloids (95). A more hydroxylated crinine-type alkaloid, crinisin (171), was found in the bulbs of C.asiaticurn var. sinicum, accompanied by lycorine (l), crinine (135), and powelline (163) (21). 11-Hydroxyvittatine (152), which hitherto had only been found in plants belonging to the genus Sternbergia (102), has been isolated from the bulbs of Hippeastrum hybrids (42). The structure determination was performed by a comprehensive NMR study of the alkaloids involving 2D techniques such as HOHAHA, ROESY, and HMBC for 'H and '3C assignments, which enabled structural elucidation to be facilitated. Vittatine (147)and 11-hydroxyvittatine (152) were found in the extract of the dried bulbs of Hippeastrum puniceum (43). Hamayne (153), 3-0-acetylhamayne (154), crinamine (156), ambelline (161),and a new alkaloid named josephine (144),together with the lycorinetype alkaloid sternbergine (16), were isolated from the bulbs of Brunsvigia josephinae (11). The mass spectrum of 144 showed the molecular peak at m/z 331, and prominent fragments at m/z 289, 242, and 202 that are characteristic of a 1,Zdisubstituted crinane alkaloid (140).Its spectroscopic ('H and 13CNMR) evidence established the structure as 144. A new alka-
4.
W i n e (Crinidine) (135) R=R~=H 0-Acetylcrinine (136) R = AC, R' = H 6a-Hydroxycrinine (137) R = H. R' = a-OH
363
THE AMARYLLIDACEAE ALKALOIDS
Oxocrinine (138)
Buphanisine (139) R=H 6a-Hydroxybuphanisine (140) R =a-OH
3p.1 la-Dihydroxy-1.2dehydrocrinane (141)
R
O&R .
H 0 . A
Flexinine (142) R=OH Augustine (143) R = OMe
Josephinine (1.44) R = P-OAC Amabiline (145) R = a-OH
OH
Epi-vittatine (149) R=H Epi-buphanisine(150) R=Me $
Alkaloid 13 (151)
, l 'OH
0
Vittatine (147)
Elwesine (146) @ih ydrocrinine)
0 OH
Albiflomanthine (159)
[(+)-Crinine]
R=H (+)-Buphanisine (148) R=Me
..
ll-Hy&oylvitattine (152) R=a-OH,R'=H Hamayne (153) R = a-OH, R' =H 3-0-Acetylhamayne (154) R = a-OAc, R'= H Haemanthamine (155) R = p-OMe. R' = H
Crinamine (156) R = a-OMt. ' R'=H Haemanthidine (157) R = POMe, 6-Hydro~yR' = OH
tT=%iMe*
crinamine (158)
FIG.11
loid, albiflomanthine (159), was found in the bulbs of Haemanthus afbijlos (36). The molecular formula was measured by high-resolution mass spectrometry as CI7Hl9NO5,and the structure was determined as 159 on the basis of spectroscopic (UV and 'H, and 13CNMR) analyses. Interestingly, it possesses the unusual feature: of an oxygen substituent at C-4.
364
OSAMU HOSHINO
R
HO
.OMe
Q 0
0 OMe
OM9
Buphandrine (160) R=H Ambelline (161) R=OH 1I-O-A~etylambelline (162) R = OAC
Powelline (163) R = OH, R' = H 3-O- Acetylpowelline (164)
Crinafoline (166)
powelline (165) R=R'=OH
Bumsbelliie (168)
Me0
Crinafolidine (167)
OH
Crinamidine (169) R=H Undulalinc (170) R=Me
H
Me0 HO
OM9
8-HY&OXY-9methoxycrinine (172)
Crinisin (171)
Siculine (173)
H Me0
Me0
HO 8-0-&methylmaritidine (174) R =H, R' = ~e 9-O-Demeth ylmaritidine (175) R=MC,R~=H
Cantabricine(176)
R
Narcidine (177) R
m O M e
Ms.O&,
MeO
HO
R
Papyramine (180) R = WOH 6-Epi-papyramine(181) R = &OH 6kO-M~thylpapyramine (182) R = POMe FIG.12
Maritinamine(183) R = p-OH Epi-maritinamine (184) R = a-OH
Maritidine (178) R=H O-Methylmaritidine R = M e (179)
4.
THE AMARYLLIDACEAE ALKALOIDS
365
New crinine-type alkaloids, as well as several known Amaryllidaceae alkaloids, were isolated from two Sternbergiu species of Turkish origin. They are maritinamine (183) and epi-maritinamine (184) (from S. lutea), and (+)-buphanisine (148) and siculine (173) (from S. sicuh) (203).The structure determination of the new alkaloids was performed on the basis of an extensive analysis of 'H NMR spectral data for the known crininetype alkaloids. The spectral data for (+)-buphanisine (148) were in good agreement with those for (-)-buphanisine (139), except for its positive specific rotation. Indeed, the CD curve of (+)-buphanisine was the opposite of that described for (-)-buphanisine in the literature (142).Therefore, (+)-buphanisine was established to be a new alkaloid, enantiomeric with the known (-)-buphanisine. Furthermore, all of the Sternbergiu alkaloids, new as well as known, possess the identical absolute configuration, with the ethano bridge below the mean plane of the molecule.
B. SYNTHETIC STUDIES Since the previously published review (8),some interesting methods for the synthesis of crinine-type alkaloids have appeared. The 2-aza-ally1 anion cyclization method gave (2)-crinine (135) and ( 2 ) epi-crinine (188) ( 1 4 2 ~ Treatment ). of tributylstannylmethylimine 186 [prepared from 6-[(3,4-methylenedioxy)phenyl]-6-methylenehex-4-enal(185) and tributylsannylmethylamine] with butyllithium in THF at -78°C led to formation of the 2-aza-ally1 anion, whose concomitant intramolecular cycloaddition led to 3-0-methoxymethylnormesembrene(187) in 80%yield. The Pictet-Spengler reaction of 187 with formalin using 6 M HC1 in methanol (MeOH) afforded (+)-6-epi-crinine (188). The 6-hydroxy group was epimerized by treatment of the corresponding mesate with cesium acetate to furnish on hydrolysis (+)-crinine (135) (Scheme 17). This methodology was expanded to the synthesis of (-)-amabiline (145)(242c). Namely, 2-aza-allylstannane 189 (derived from 2S,3S-Oisopropylidene-y-butyrolactone) was exposed to butyllithium in THF at -78°C to provide 3a-(3,4-methylenedioxy)phenylhexahydroindoline(190) along with a diastereomer in 74% yield (a 5 : 1 mixture of two diastereomers). The Pictet-Spengler cyclization of 190, followed by acid treatment, afforded (- )-amabiline (145), confirming the absolute stereochemistry of the natural product (Scheme 17). The synthesis of (+)-oxomaritidine (192) and a formal synthesis of (+)-marhidine (178) were achieved by intramolecular oxidative coupling of phenol derivatives using a hypervalent iodine reagent as a key step (2 43). 2-[(4-H ydrox y )phen yl] -hi-[(3,4-dimethoxy)phenyl]4-trifluoroacetylethylamine was treated with phenyliodonium bis(trifluor0acetate) in
366
OSAMU HOSHINO
MOMOc A SArn B u + M O M O e *
f
MOMO
185
186
Ar = 3,4-(CH2O2)%H3 ; MOM = MeOCH2
187
(f)-Epi-crinine (188)
(f)-Crinine (135)
Me
189
190
(-)-Amabiline (145)
Reagents and Conditions : a) Bu3SnCH2NH2, MS4A (50wt%), EbO, rt, 100%; b) BuLi (2.1 equiv.), THF, -78OC. 80%;c) 37% formalin (32 equiv.), MeOH, then 6M HCl. 5OoC, 75% ;d) (MeSO2)20,
Et20, THF, OOC, then CsOAc, rt ; e) KzC03,MeOH. 72% (2 steps) ;F) BuLi (1.9 equiv), THF, -78°C 74% (5 : 1mixture of two diastereomers); g) Me2N+=CH21-,MeCN, reflux ; h) HCl, MeOH, 92% (2 steps). SCHEME 17
CF3-CH20H at -40°C to produce a spirocyclohexadienone 191 in 61% yield, which was converted into (5)-oxomaritidine (192). Application of this methodology to methyl (R)-N-trifluoroacetyl-N-[(3,4-dimethoxy)phenyll-4-hydroxyphenylalanategave the optically active spirocyclodienone 193 in 64% yield, which was previously (144) transformed to (+)-maritidine (178). Hence, this result constitutes a formal synthesis of (+)-maritidine (Scheme 18). Condensation of 2-chloro-A'-pyrrolidinium chloride (prepared in situ from N-benzylpyrrolidin-2-one194 and phosgene) with t-butyl 3-oxo-4pentenoate, followed by acid treatment under ultrasound irradiation condi-
4.
367
THE AMARYLLIDACEAE ALKALOIDS
%e
OH
0
OMe
CF&O
/ OMe
b
I
H
~
Me0
CF3CO'
191
(f)-Oxomaritidine (192)
OH
OMe
..
CFsCO
CF3CO'
(+)-Maritidhe (178)
193
Reagents and Codifions : a) PhI(OCmCF3)2, CF3CH2OH, -40 'C, 191 (61%), 193 (64%) ; b) K2C03, MeOH-H20 ; c) Ref. 144. SCHEME 18
tions, afforded N-benzyl-A'-mesembren-6-one (195) in 29% yield (three steps). Reduction of 195 with sodium in liquid ammonia gave the known hexahydroindolin-6-one 196, which was earlier (14.5) transformed to (?)dihydromaritidine (197) (146) (Scheme 19). OMe
194
195
1%
Bn = GH5CH2
(f)-Dihydromaritidine (197)
Reagents and Conditions : a) COC12; b:l CH2=CHCOCH2C02r-Bu,Et,N, CH2C12,reflux ;
c) CF3C02H, (3 equiv.), ultrasound, 29%(3 steps) ;d) Na, liq. NH3,76% ;e) Ref. 145. SCHEME 19
368
OSAMU HOSHINO
Starting with 6-allylcyclohexanones 198 and 199, the synthesis of (?)dihydromaritidine (197), (+)-6-epi-dihydromaritidine (202), and ( 2 ) elwesine (146) and (+)-6-epi-elwesine (203) through 200 and 201, respectively, has appeared (147). Also, a formal synthesis of (+)-elwesine (146) by a protocol similar to that noted for (2)-mesembrine (377) has been carried out (Z48)(Fig. 13). C. BIOLOGICAL ACTIVITY
The ethanol extract of the bulbs of Crinum amabile on preliminary biological evaluation was shown to possess cytotoxic and antimalarial properties (13).Although all the isolated alkaloids showed antimalarial activity against two strains of Plasmodium faleiparum, a new crinine-type alkaloid, amabiline (145), was the most effective (lO,OOOX), and augustine (143) the least active (140X). All were significantly more active than the commercial antimalarial drug chloroquine (1.3X).
RO&f2
I
0 RO
RO
R=Me 198 R+R=CH2 199
Bn = C&sCH2
R=Me 200 R+R=CH2 201
RO
RO
(f)-Epi-dihydromaritidine (202) R=Me (*)-Epielwesine (203) R+R=CH2
(f)-Dihydromaritidine (197) R=Me (*)-Elwesine (146) R+R=CH2 FIG.13
4.
THE AMARYLLIDACEAE ALKALOIDS
369
IV. Narciclasine (Lycoricidine)-TypeAlkaloids
A. Isolation and Structural Elucidation 7-Deoxynarciclasine (204),and narciclasine (205),7-deoxypancratistatin (210),and pancratistatin (211)were found in the resting bulbs of Haemanthus kalbreyeii (37). Also, narciclasine (205),7-deoxypancratistatin (210), and pancratistatin (211)have been isolated from the bulbs of Hymenocallis littoralis (45).The glucosidal alkaloids, pancratiside (212)(37),kalbreclasine (206) (108),and 4-O-~-~-glucopyranosylnarciclasine (207) (96), were obtained from resting bulbs of Haemanthus kalbreyeii, the fresh mature seeds of Zephyranthesflava, and the bulbs of Pancratium maritimum, respectively. Elucidation of the structures was performed by spectroscopic and chemical methods. 7-Deoxy-trans-dihydronarciclasine(208)has been isolated from the bulbs of Hymenocallis caribrzea, H. latifolia, and H. littoralis (45). Also, trans-dihydronarciclasine (209) was found in the fresh ground bulbs of Zephyranthes candida (directed by results of a bioassay employing the P388 lymphocylic leukemia) by acetylation (106) (Fig. 14). Plant alkaloids are frequently considered to be protective agents for their hosts; their toxicity and antifeeding properties present a directing environment to predators. An interesting investigation regarding them has been reported (25). One specialized herbivore, Polytela gloriosa Fab (Noctuidae), a smoky-grey moth, utilizes Amaryllidaceae plants, which are avoided by other insects. A remarkable association of alkaloid metabolism by P. gloriosa adapted to a number of Amaryllidaceae species, e.g., Amaryllis, Crinum, and Pancratium, has been noted. The larvae of this insect were found to store large amounts [ca. 0.5-1% (fresh weight)] of the common pyrrolo- and ethano-phenanthridine alkaloids, such as lycorine (l), crinine (135) (and their equivalents), and haemanthamine (155), from the flowers and leaves of Crinum latifolium L. A new isocarbostyri1-Nacetylaminoglucoside conjugate named telastaside (213)was isolated from the insect (P. gloriosa). The structure of the alkaloid was characterized by spectroscopic evidence and chemical transformation. It was treated with hesperidinase in sodium acetate-AcOH buffer (pH 5.1) at 30°C to afford 7-deoxypancratistatin (210)and N-acetylglucosamine, respectively. On the other hand, it was heated with 4 M HCl in 30% aqueous ethanol at 100°C to produce 4-hydroxyphenanthridone (431)and D-glucosamine hydrochloride. A strikingly common association of the alkaloid in the secondary metabolism of the host and the feeder species, during stress, has been discerned. The alkaloid was not present in any part of healthy (uninfested) C. latifolium, nor was it detected in the moth when collected from the natural habitat (earthen cocoon in the rhizosphere of C. latifolium).
370
OSAMU HOSHINO
OH
R
OH
OH
0
7-DeOXYnarciclasine (204) (Lycoricidine)
Narciclasine (205) R = CX-OH Kalbreclasine (206) R = bD-Glucosyl
4-O-P-D-Gl~cosylnarciclasinc (207) R = ~D-Glucosyl
OR
OH
)&Io: NH
R
O
7-hOxytrans-dihydronarciclasine (208) R=H Trans-dihydronatciclasine (209) R-OH
NH
'0
A1
0
7-Deoxypancratistatin(210) R=R~=H Pancratistatin (211) R = H, R*= OH Pancratiside (212) R = P-D-Glucosyl, R' = OH
Telastaside (213)
FIG.14
B. SYNTHETIC STUDIES Regarding the synthesis of the narciclasine (1ycoricidine)-type alkaloids, an important strategic element is how to construct the functionalized ring C in these alkaloids. Therefore, extensive efforts to explore a new method for preparing a key intermediate have been made. Among these extensive studies, the first total synthesis of (+)-pancratistatin (211) has been reported (149) (Scheme 20). Tricyclic 1,2dihydroxy-Slactone 214 was converted into vicinal acetoxy-bromo-6lactone 215 in 88% yield along with the regioisomers. Osmium tetroxide oxidation of 215, followed by introduction of a double bond and selective protection of the hydroxyl groups, gave the corresponding allylic alcohol
4.
214
216
L
OH
371
THE AMAKYLLIDACEAE ALKALOIDS
Br
Bn = C&I5CHz
215
217
219
218
(i)-Pancratistatin(211)
Reagents and Condirions :a) 2-acetoxyisobutyryl bromide, MeCN, rt, 88% ;b) Os04(cat.), NMO, CH2CI2, THF, rt, 88% ;c) (Bu3Snh0, MS3A, toluene, reflux ;d) 4 M e m C H 2 B r . B u ~ ~ I - , 80°C, 84%;e) AgzO, C5H5CH2Br, DMF,rt, 95% ;r) DDQ,4. a&h,rt, 75 % ;g) Zn,~ Z C ~ Z . HzO, AcOH, reflux, 81% ;h) NaH, C13CCN,THF, 0°C to rt, 74%;i) pyrolysis at 100-105°C (0.05-O.lmmHg), 56% ;j) OsOd (cat.), NMO, THF,rt, 75% ;k) KzCO3, dry MeOH-CHzC12 (5 ; 21, reflux, 82% ; I) Pd(OH)2-C, Hz,EtOAc, 90%. SCHEME 20
216 by skillfully stereocontrolled reactions. Following these reactions, the Claisen rearrangement of imino ether 217 (prepared by the reaction of 216 with trichloroacetonitrile in the presence of NaH at 100-105°C under reduced pressure) proceeded effectively to afford the amide 218 in 56% yield, 1,2-cis-dihydroxylationof which, followed by hydrolysis with base, produced 2,7-O-dibenzylpancratistatin(219)by way of an amino acid. Finally, (+)-pancratistatin (211)was synthesized in 90% yield by debenzylation using catalytic hydrogenation.
372
OSAMU HOSHINO
Following this report, a total synthesis of optically active (+)-lycoricidine
(204) (150) and (+ )-Zepi-lycoricidine (224) (1506) starting from D-glucose
was described in the literature (Scheme 21). In this case, the modified Heck reaction of amide 220 bearing fully protected functional groups, which was prepared from SS,6S-bis(methoxymethoxy)-4-(4R)-azidocyclohex-2-enone, is a key step. The protected amide 220 underwent intramolecular cyclization with palladium acetate in the presence of thallium(1) acetate and 1,2-bis(diphenylphosphono)ethane
0
-
OMPM
a-c,b
OMOM A3
0
NMPM
0
-
OMPM
0
220
0
221
OAC OH
MPM = 4-MeOC&CH2 MOM = MeOCH2
OH
(100%) 222
221
0
0
(+)-Lycoricidine(204)
223
(+)-2-epi-Lycoricidine(224)
Reogenrs and Conditions :a) NaB%, &C13*7H20, MeOH, OOC, 86% ;b) 4-MeOCaCH2C1, NaH, DMF, rt ;c) LiAW, Et20, OOC. then 6-Br-3,4-(CH2O&J-I3CQH,(EtO)2P(O)CN,Et3N, DMF,O°C, 89%;d) Pd(OAc)? (20 mol%),TlOAc (2 mol%),DIPHOS (40mol %). DMF,140°C, 68% ;e) DDQ. CH2U2-H20(18 : 1). 0°C ;r) P h W H , PPh3, DEAC. THF, rt. 78% ;g) NaOMe, MeOH-THF (5 : 1). rt, 99% ;h) 1N HU, THF-fi20 (1 : 1). 50°C, then AczO, pyrkline, rt, 5 1% ; i) CF3CO2H-CHCl3(1 : 1). It.
SCHEME21
4.
373
THE AMARYLLIDACEAE ALKALOIDS
(DIPHOS) in dimethylformamide (DMF) at 140°C to give protected 2-epilycoricidine 221 in 68% yield. Selective deprotection of 221 followed by inversion of a hydroxy group at the 2-position using the Mitsunobu reaction afforded 0-triacetyllycoricidine (222). Hydrolysis of 222 with base led to (+)-lycoricidine (204). On the other hand, 221 was transformed to 2-epilycoricidine (224) through the triacetate 223 by stepwise deprotection. As interesting synthetic approaches toward lycoricidine, starting with optically active tribenzyloxy-5-hexenal or L-arabinose, protected versions 226 (252) or 228 (252) of (+)-lycoricidine have been synthesized through 225 or 227 (Fig. 15). Recently, oxidation of a halobenzene using a microbiological procedure was found to give optically active 3-halo-1,2-cis-dihydroxycyclohexa-3,5diene in good yield. This compound has received the attention of chemists for constructing ring C in the narciclasine-type alkaloids (253). An example is as follows. After protection as a silyl ether, amidation of benzyl N-(5,6-O-isopropylidene-4-hydroxycyclohex-2-enyl)carbamate229 (prepared from 3-bromo-lS, 2S-(3-isopropylidenecyclohexa-3,5-diene) with (6-bromo-3,4-methylenedioxy)benzoylchloride gave the protected N benzyloxycarbonyl-N-(cyclohex-~2-enyl)benzamide230. A modified Heck reaction of 230 in anisole produced the protected lycoricidine 231 in 27% yield (two steps) by N-detosylation. Acid treatment of 231 provided (+)-lycoricidine (204) in 85% yield (Scheme 22).
OBn
p n O-OBn
Bn = C&CH2
225
226
OMe
OM9
0 221
Ts = 4-MeCASO2 FIG.15
0
228
374
OSAMU HOSHINO
OSiMed-Pr
S)SiMe2CPr
- < “d G
0
-
NH
-0
0
0 231
(+)-Lycoricidine (204)
Reagenrs and Conditions :a) i-PrMe2SiC1. imidazole ;b) BuLi, THF, -78OC. then 6-Br-3,4-(a2%)-
C!&COCl; c) Pd(OAc)z, TIOAc, DIPHOS, anisole, 27%; d) Pd-C, cyclohexene, EtOH, 99%;e) C F 3 Q H . OOC. 85%. SCHEME 22
A sequence of reactions similar to those noted previously has been constituting a formal synapplied to 1,2-cis-dihydroxycyclohexa-3,5-diene, thesis of (+-)-lycoricidine (204)(154). Since the isolation and discovery of the significant biological activity of 7-deoxypancratistatin (210) and pancratistatin (211), which have more oxygenated functional substituents than lycoricidine (204),synthetic studies have been performed extensively. The total synthesis of optically active (+)7-deoxypancratistatin (210)and (+)-pancratistatin (211)has been reported independently by four research groups. The first group led by Hudlicky reported a synthesis of (+)-7-deoxypancratistatin (210)and (+)-pancratistatin (211)starting with a key intermediate, the optically active aziridine derivative 232 (derived from 3-bromo1S,2S-O-isopropylidenecyclohexa-3,5-diene) (155). A full paper regarding these efforts has been published (256) (Schemes 23 and 24). Reaction of the N-( p-tosy1)aziridine 232 with lithium bis[(3,4-methylenedioxy)phenyl]cyanocuprate in the presence of borontrifluoride etherate (BF3 - Et20) at -78 to -30°C gave rise to stereoselective opening of the aziridine ring to afford methyl N-[SP,6P-dihydroxy-2-(3,4-methylenedioxy)phenylcyclohex-3-enyl]carbamate (233)in 34% yield by deprotection with
4.
232
233
234
OAc
NHCQMe
0
235
375
THE AMARYLLIDACEAE ALKALOIDS
236
I
~
NH
0
0
(+)-7-DeOXypancatistatin (210)
Reagents and Conditions : a) dilithium dipiperonylcyanocuprate, BFyEt20, THF,-78 to -30°C, 32%; b) s-BuLi, THF, rt, then (MeOC0)20,76%;c) Na, anthracene, DME, -78OC, 69% ;d) AcOH-THF-H20 (2l:l). 65OC, 94% ; e) r-BuOOH, VO(acac)z, benzene, 7OoC, 85% ; f ) P h 0 2 N a (cat.), H20,100°C, 82%; g) AczO, DMAP, pyridine, 84% ; h) TfZO, DMAP, CH2C12,5°C. 69% ;i) NaOMe, MeOH, THF, rt. 72%. SCHEME 23
acid. Sharpless epoxidation furnished, stereoselectively, methyl N-[3,4pepoxy-5/3,6P-dihydroxy)-2-( 3,4-methylenedioxy)phenylcyclohexyl]carbamate (234)in 45% yield. Ring opening of the epoxide 234 with a catalytic amount of sodium benzoate in boiling water afforded on acetylation methyl N-[3,4,5,6-tetra-acetoxy-2-(3,4-rnethylenedioxy)phenylcyclohexyl]urethane (235).Intramolecular cyclization of 235 with trifluoromethanesulfonic anhydride (Tf20)took place successfully to yield 0-tetra-acetyl-7-deoxypancratistatin (236),which was treated with NaOMe in MeOH-THF to provide (+)-7-deoxypancratistatin (210)in 72% yield. The overall yield was 3% (11 steps from bromobenzene). The synthesis of (k )-pancratistatin (211) has been achieved by application of a sequence of the reactions noted previously to a [3-0-tbutyldimethylsilyl (TBS)-4,5-methylenedioxy]phenyl derivative. Namely, coupling of N-( p-tosy1)aziridine 232 with the cuprate derivative of [3O-TBS-2-(N,N-dimethyIcarboxamido)-4,5-methylenedioxy]benzene,in a manner similar to that noted for 210, produced N-(6-arylcyclohex4-enyl)-N-(p-tosy1)amide as a mixture of atropisomers, reductive N -
376
OSAMU HOSHINO
232
a-Auopisomer (238)
239
Ts = p - M e W S 0 2 TBS = r-BuMezSi BOC= C02Bu-t Bn = C&CH2
HO
0
(+)-Pancratistatin(211) Reagents and Condirionr : a) Liz [2-(MezNCo)-4,5-(CHz@)-3-(r-BuMczsio) C&]2
(CNCu), BF3* THF, reflux, 68% (a mixture of uEt20, THF. -78OC, 75% ; b) s-BuLi, THF, OOC, then (BOC)~O, and p-atropisomers) ;c) Na, anthracene, DME,-78"C, 62% (p-atropisomer), 20% (a-ampisomer) ; d) TBAF, THF,OOC, 93% ;e) SMEAH, morpholine, THF, -45"C, 72% ;f ) C&&HzBr, KzCO3, DMF, rt, 83% ; g) NaC102, KH2P04, 2-methyl-2-butene,r-BuOH, HzO, rt, then CH2N2, EtzO, 98% ; h) AcOH-THF-HzO (2 : 1 : l), 6O"C, 73% ;i) r-BuOOH, VO(a~ac)~, benzene, 6O"C, 53% ; j) H20, PhW2Na (cat), 100aC. 6 days, 51% ;k) H20, PhC@Na (cat), l W C , 48 h ;I) Pd(OH)2, H2, EtOAc. rt, quantitative. SCHEME 24
detosylation of which, followed by N-protection with a Boc group, afforded the N-Boc product 237 (0-atropisomer) and the 0-desilylated N-Boc product 238 (a-atropisomer) in 62 and 20% yield, respectively. 0Desilylation of the former 237 with tributylammonium fluoride (TBAF) in THF at 0°C caused equilibration between the 0-desilylated a- and 0-
4. THE AMAKYLLIDACEAE ALKALOIDS
377
atropisomers to give the 0-desilylated N-Boc product 238 (a-atropisomer) in 93% yield, which was identical with the product obtained by reduction of a mixture of atropisomers. Reduction of the N,N-dimethylcarboxamido group with SMEAH in THF containing morpholine (1 eq)(257) at -45°C followed by 0-benzylation furnished the corresponding 0-benzylated aldehyde, which was converted into 6-[(3-benzyloxy-2 -methoxycarbonyl- 4,5 methy1enedioxy)phenyll- N - Boc- (4,5-epoxy-2,3 -dihydroxy) - cyclohexanecarboxamide (239) by successive oxidation, methylation, deprotection, and Sharpless epoxidation. The reaction of 239 in boiling water containing a catalytic amount of sodium benzoate for 6 days gave spontaneously (+)pancratistatin (211) in 3% yield. Interestingly, when the reaction under similar reaction conditions was quenched after 48 h, 0-benzylpancratistatin (240) was obtained, which was transformed to (2)-panctatistatin (210) in quantitative yield by 0-debenzglation. Therefore, the prolonged reaction under the reaction conditions supported oxirane ring opening, N-deprotection, and cyclization leading to 0-benzylpancratistatin (240). The overall yield was 2% (14 steps from bromobenzene). A second group has synthesized (+)-7-deoxypancratistatin (210) starting from D-glucose (258) by a method involving an intramolecular radicalmediated cyclization of an oxinie as a key step (Scheme 25). 0-TBS-0benzyloxime 241 (derived from D-glucose) was reduced with NaBH4 to afford the corresponding alcohol, reduction of which, followed by treatment with thiocarbonyldiimidazole, afforded a radical precursor 1imidazolylthiocarboxylicester 242. Radical-mediated reaction of O-TBS0-benzyloxime 1-imidazolylthiocarboxylicester 242 with Bu3SnH in boiling toluene containing AIBN gave rise to an intramolecular addition of a carbon radical to the C = N bond in the oxime to provide a cyclized product 243 in 70% yield. Trifluoroacetylation of 243, followed by subsequent 0desilylation and oxidation with tetrapropylammonium perruthenate (TPAP)(259) and N-methylmorpholine N-oxide (NMO), gave the N-benzyloxyamino-N-trifluoroacetyl-Slactone 244. Cleavage of the N-0 bond in 244 was effected with samarium(I1) iodide (SmI,) to afford a trifluoroacetamide, cyclization of which under acidic conditions, followed by hydrolysis with base, provided (+)-7-deoxypancratistatin (209). Furthermore, this methodology was developed to afford the synthesis of ent-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (260). Photolysis of 4-(4R)-hydroxy-6-[(2-methoxycarbonyl-4,5-methylenedioxy)phenyl]-2S,3S-0-isopropylidenehex-5-ynal0benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce 1-(N-benzyloxyamino)J-phenylthiocyclohex-5-ene 246. Cleavage of the N-0 bond and reductive elimination of the phenylthio group in 246 with SmIz in THF
378
OSAMU HOSHINO
OMOM
241
MOM = MeOCHz
243
242
TBS = r-BuMe#i Bn = C,HsCH2
v
244
-
(+)-7-Deoxypancratistatin (210)
Reagenrs and Conditions : a) N a B h , MeOH ; b) thiocarbonyldiimidazle, DMAP, ClCH2CH2Cl. 80% (2 steps) ;c) Bu3SnH, AIBN, toluene, 90°C, 70%;d) (CF3CO)20, pyridine, DMAP ; e) Bu4N'F-. THF ; f') TPAP. NMO ;g) Sm12 ;h) Dowex , ' H MeOH, 65OC, 88% ; i) K2CO3, dry MeOH. 70% (3 steps). SCHEME 25
proceeded effectively to give 3,4-0-isopropylidene-ent-lycoricidine (247), deprotection of which with trifluoroacetic acid afforded ent-lycoricidine (248) in 77% yield (Scheme 26). Trost's group has also achieved the synthesis of (+)-pancratistatin (211) starting with the optically active cyclohexenetetraol derivative 249 (161) (Scheme 27). Optically active 6-[(2-bromo-3-methoxy-4,5-methylenedioxy) phenyl]-2,3-0-bis(triethylsilyl)(TES)-cyclohexane (250)(derived from 249) was transformed to isocyanate 251 (by reduction and treatment with phosgene), which was treated with t-butyllithium in ether at -78°C to undergo spontaneous intramolecular addition leading to 3,4-0isopropylidene-7-0-methyl-1-isopancratistatin (252)in 65% yield by way of 251. Conversion of the cis-vicinal dihydroxy groups into trans-vicinal dihydroxy groups was performed through a cyclic sulfonate. Namely, a cyclic sulfonate of the cis-vicinal dihydroxy compound (derived from 252
OH
245
246
H (0-
,,
-
T
NH
0
0
0
247
ent-Lycoricidine (248)
Reagents and Conditions : a) hv, PhSH, 27OC, 91%; b) Srn12, THF,76% ; c) CF3C02H,77%. SCHEME 26
0 Me Me0
0
252
h, i Me0
0
HO
'
253
0
(+)-Panmatistatin (211)
Reagents and Conditions:a) Me3P,
THF,HzO ;b) COC12, Et3N. M 2 c I 2 ;C) t-BuLi, Et20, -78OC, 62-65%(3 steps) ; d) Bu4N+F-,THF,-78 to O°C ;e) SOCl2, Et3N ; f) RuC13*H20,NaIO4, rt, 72% (2 steps) ; g) PhCQCs, DMF.then workup with THF-H20, HzSO4 CCl,, MeCN,H20, (cat), 85%;h) K2C03, MeOH, rt ; i)LiI, IMF, 8OoC, 85% (2 steps). SCHEME 21
380
OSAMU HOSHINO
by 0-desilylation with TBAF, treatment with sulfuryl chloride, and oxidation) was treated with cesium benzoate in DMF followed by O-deisopropylidenation to give 1-0-benzoyl-7-0-methylpancratistatin (253). Removal of the benzoyl and methoxy groups of 253 gave (+)-pawratistatin (211). The overall yield was 11%in 15 steps (from 249). The synthesis of (+)-7-deoxy-trans-dihydronarciclasine (208) and (+)7-deoxypancratistatin (210) employing the key intermediate 221 previously reported in the synthesis of (+)-lycoricidine (204) (250) has been published by a fourth group (162) (Schemes 28 and 29). Catalytic hydrogenation of the protected 7-deoxylycoricidine 221, followed by conversion of the 200-(p-meth0xy)phenylmethyl (MPM) group into a 2a-acetoxy substituent, produced the protected (+)-7-deoxy-frans-dihydronarciclasine 254. Stepwise deprotection of 254 afforded (+)-7-deoxy-trans-dihydronarciclasine (208) (Scheme 28). A1(2)-N-MPM-7-deoxypancratistatin (256), which was prepared by elimination and 0-demethoxymethylation of 254, was also transformed to (+)-7-deoxypancratistatin (210) from the epoxide 257 by way of the tetraacetate 236 (Scheme 29). Protected derivatives 259 and 260 of (+)-7-
OAc
254
221
255
MPM = 4-MeOcd-bCH2 MOM = MeOCH2
- (O@Z ff
A
?H O
H
0
0 (+)-7-DcOXy-
WUnS-dihydronarciclasine (208) Reugenrs and Conditionr : a) H2,5%Pd-C,EtOH-EtOAc (14 : 11, rt, 87% ; b) (CF3S02)20,pyridine, CHzClz, OOC ;c) KOAc, 18-crown-6, benzene. n,81%(2 steps) ;d) 1N HCI-THF (1 : 1). 5OoC,then
AczO, pyridine, rt ;e) CF3C02H-CHC13(1 : 1). rt, 64%(3 steps) ; f ) NaOMe, MeOH, OOC. 83%. SCHEME 28
4. THE
236
AMARYLLIDACEAE ALKALOIDS
381
(+)-7-Deoxy-
pancratistatin (210)
Reagents and Conditions : a) NaOMe, MeOH, O°C ; b) (CF3SQ)z0, qyridine, CH2ClZ,O°C ;c) KOAc, 18-crown-6, benzene, rt, 74% (3 steps) ; d) 1N HCl-THF (1 : I), 5OoC, 92% ;e) m-ClCJ-I4CO& C1CHzCH2C1-phosphatebuffer (IM, pH 8)(1 :l), 5OoC,46% ;f) NaOAc, DMF-H20 (4 : 1). 60°C. then AczO, ZnC12, rt, 51% ; g) 5% Pd-C. H2, 1N HCI (cat.), EtOH, rt, 83%. SCHEME29
0-methyl-4a-epi-narciclasine and 7-0-methyl-iso-narciclasine have been synthesized starting with 258 (derived from ~-glucose)(l63). C. BIOLOGICAL ACTIVITY Narciclasine (205) and its glucoside 207 showed similar toxic activity (against Artemia salina), with LDS0values of 0.29 and 0.88 pglml for 205 and 207, respectively. When assayed on a potato disk infested by Agrobacferium
258
(+)-3,4-O-Isopropylidene-7-0methyl-4a-epi-aarciclasine(259) FIG.16
3,4-O-Isopropylidene-7-0methyl-iso-narciclasine(260)
382
OSAMU HOSHINO
tumefucienns, 205 showed a strong antitumor initiation (60% inhibition), and the latter alkaloid, 207,also exhibited similar activity (53% inhibition) in the same assay (96). Antiviral (RNA) activity of narciclasine-type alkaloids and the related compounds have been examined extensively (139). Among these experiments, evaluation of pancratistatin (211)and 7-deoxypancratistatin (210) in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors) has given interesting results. In two experiments (low LDsoviral challenge, variant I), prophylactic administration of 211 at 4 mg and 6 mg/kg/day (2% EtOHhaline, sc, once daily for 7 days, day - 1to +5) increased the survival of Japanese encephalitis-virus-infected mice to 100 and 90%,respectively. In the same model, prophylactic administration of 210 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to + 5 ) increased the survival of Japanese encephalitisvirus-infected mice to 80%.In a second variant (high LDsoviral challenge), administration of 211 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 210 and 211 demonstrated activity in mice infected with Japanese encephalitis virus, but only at near-toxic concentrations. This represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in the Japanese encephalitis-virus-infected mouse model. Telastaside (213)showed dose-dependent biphasic immunomodulatory responses (25). Its effects suggested inhibition or augmentation of enzyme (proteinase) and membrane integrity, as revealed from the viability or inhibition of growth of both normal and tumor cells (164).
V. Galanthamine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION
Extraction of the flowers of Lycoris incarnata (58) led to the isolation of galanthamine (261),sanguinine (272),lycoramine (276),O-demethyllycoramine (277),and galanthamine N-oxide (281),along with l-palmitoyl2-linoleoylphosphatidylethanolamineand 1-palmitoyl-2-linoleoylphospatidylmethanol sodium salt. In addition, the extract of the bulbs and aerial parts of Narcissus leonensis grown in Northern Spain, and closely related to N. nobilis and N. primigeninus, has been found to contain two new alkaloids, epi-norgalanthamine (267) and epi-norlycoramine (280) (72). (-)-N-Demethyllycoramine (278)has been also isolated for the first time from the bulbs of Hymenocallis rotuta (50).
4.
383
THE AMAKYLLIDACEAE ALKALOIDS
Sanguinine (272), reported previously as a constituent of Leucojum aestivum sub. was obtained from Leiucojum aestivum sub. pulchelum (54).The structures of the representative alkaloids isolated are shown in Fig. 17. R
Me0
Galanthamine (261) R =H,R' =Me 0-A~etylgalanthamine (262) R = Ac, R' = Me N-Allylgalanthamine (263) R = H,R' = ~ i i y i Norgalanthaminc (264) R=R~=H N-Fmylgalanthamine (265) R =H, R' = CHO
N. CH&I
N-Chloromethylgalanthaminium chloride (266)
Epi-norgalanthamine(267)
R=H
Narcisine (268) R=Ac
R
Nanvedine (269)
Leucotamine (270) R=H 0-Methylleucotamine (271) R=Me
HO
Sanguinine (272) R = H. R'= Me 2-O-A~~tylchlidanthine (273) R =Ac,R'=Me Nmanguininc (274) R =R~=H Norbutsanguinine. (275) R = COCH2CH(OH)Me, R'=H
R Lycoraniine (276) R = R' = M e O-Demtthyllycoramine (277) R =Me,R'=H Norlycoramine (278) R =H,R'=Me
0 Galanthamine N-oxide (281) R =R,R'=Me 0-Acetylgalanthamine N-oxide (282) R =Ac,R'=Me Sanguinine N-oxide (283) R =R'=H
FIG. 17
Epi-lycoramine (279) R=Me Epi-norlycoramine (280) R=H
Lycoramine N-oxide (284)
384
OSAMU HOSHINO
B. SYNTHETIC STUDIES Galanthamine (261) has been characterized as an acetylcholinesterase inhibitor, and its epimer epi-galanthamine and its oxidized analog narwedine (269) have been evaluated as potential agents for the treatment of Alzheimer’s disease. However, supply of the alkaloids has been limited, although they are found in several Amaryllidaceae species. Therefore, supply by synthesis is a necessary requirement. The synthesis of 261 was initiated using phenolic oxidative coupling as a biomimetic method, and extensive synthetic studies have been performed. Since 1987,some reports on the synthesis of 261 and related compounds using phenolic oxidation and radical-mediated cyclization have appeared. Phenolic oxidation of the diphenolic amide 285 using potassium ferric (111) cyanide afforded (+)-N-formyldibromonarwedine (286), which was reduced successively with lithium tri-s-butylborohydride (L-Selectride) and with LiA1H4 to afford (?)-261.Resolution of (2)-261 using d-camphoric acid provided (-)- and ( +)-galanthamines (261) through the camphanate derivatives 287 and 288 (265) (Scheme 30). Phenolic oxidation of the phenolic palladium complex 290 (prepared by N-methylation and metallation of 289) using thallium(111) trifluoroacetate gave (t)-narwedine (269) in 51% yield by way of the cyclized intermediates 291 and 292 (166) (Scheme 31). The synthesis of ( t)-lycoramine (276) and ( t)-epi-lycoramine (279) using radical-mediated reactions as key steps has been reported (167) (Scheme 32). Dehydration of ethyl 2-[1-(6-bromo-2-methoxy)phenoxy-4, 4-ethylenedioxy-l-hydroxycyclohexyl]acetate(293) [prepared from ethyl (6-bromo-2-methoxy)phenoxyacetateand 4,4-ethylenedioxycyclohexanone] with phosphoryl chloride in pyridine at 90°C produced a radical precursor cyclohexene derivative 294, along with a regioisomer. Radical reaction of 294 with Bu3SnH in boiling o-xylene containing AIBN provided the cyclic spirobenzofuran derivative 295 in 91% yield, which was transformed to Bseco-oxolycoramine 2% in four steps (cleavage of benzofuran ring with Sm12,deprotection, introduction of a double bond, and amidation, followed by concomitant cyclization). The modified Pictet-Spengler reaction of 296 with paraformaldehyde in CF3C02H in dichloroethane led to (2)-0x0dihydronarwedine (297), whose reduction with LiA1H4 in boiling THF yielded ( t)-lycoramine (276) and (2)-epi-lycoramine (279) in 85% yield (a product ratio of 5 :1). A practical and total spontaneous resolution process for the asymmetric transformation of (?)-narwedine (269) into either of its enantiomers, depending on which enantiomer is used as the seeds, and a highly stereospecific conversion of (-)-narwedine (269) into (-)-galanthamine (261) by reduc-
4.
THE AMARYLLIDACEAE ALKALOIDS
a
&OH
Me0$H !O OH
b c
MeO.@&
IMe
286
(+)-Galanthaminyl (-)-camphanate (287)
e
(*)-Galanthamine (261)
MeO@*oH Me
(+)-Galanthamine (261)
+ (-)-Galanthaminyl (-)-camphanate (288)
. . o B o H
CHO
Rr
285
385
~
(-)-Galanthamine(261) Reagents and Conditions : a) K3Fe(CN)6.NaHC03, CHC13,H20, 60°C, 37% ;b) Zn, EtOH,
reflux, 98%;c) L-Selectride@, THF, -78OC, then LiAM4, THF, reflux, 70% ;d) (1s)(-)-camphanicchloride, Et3N, THF-CHC13, (4 : 15), then chromatography, 287 (45%), 288 (43%); e) LiAlH4, THF, 0 ° C then dry HCl, MeOH, (+)-261*HC1(96%),(-)-261*HC1 (92%). SCHEME 30
tion have been reported (168). (+)-Narwedine was dissolved in a solvent mixture of 95% ethanol-triethylamine (9: 1) at 80°C. (-)-Narwedine seeds (2.5%) were added to the supersaturated solution at 68°C. The suspension was kept at 40°C to afford a highly enriched (-)-narwedine in 80% yield from (+)-narwedine. A similar process was successfully employed to prepare (+)-narwedine in 85%yield from (2)-narwedine by seeding the supersaturated racemic solution with (+)-namedine. The concept was expanded to achieve a total spontaneous resolution of (2)-narwedine using either enantiomer of galanthamine as the “catalyst.” (?)-Narwedine was dissolved into a solvent mixture similar to that noted previously at 80°C in the
386
OSAMU HOSHINO
290
289
Reagenrs and Condirions :a) fonnalin. NaCNBH3, MeOH, 90%(from isovanillin) ;b) LiFdC14, Et Ni-R2, -78OC, 95%(1 : 1 mixture of diastereomers) ;c) n ( o 2 c a 3 ) 3 , THF-CH2C!12 (2 : 1). -lO°C;then Ph3P, -10' to 25OC, 51%. SCHEME 31
presence of a catalytic (1%)amount of natural (-)-galanthamine. The resulting suspension gave enantiomerically pure (+)-namedine in 75% yield from ( ?)-namedine. Similarly, optically pure (-)-namedine was obtained from (2)-narwedine, using a catalytic (1%)amount of (+)-galanthamine, in 76% yield. Moreover, (-)-namedine obtained from the above process was reduced stereoselectively by L-Selectride at -78°C to produce (-)galanthamine in 99% yield (99% ee). The process is considered to be attributable to the unique conglomerate nature of narwedine. C. BIOLOGICAL ACTIVITY Galanthamine (261) has been prominent in the popular and general scientific press because of its purported usefulness in healing Alzheimer's disease, presumably due to its acetylcholinesterase and muscarinic activity.
4.
293
2%
387
THE AMARYLLIDACEAE ALKALOIDS
294
297
295
(f)-Lycoramine(276) R=OH,RI=H (i)-Epi-lycoramine (279) R = H, R1 =OH
Reagents and Conditions :a) FOCI3.pyridme, 9OOC ;b) Bu3SnH, AIBN, o-xylene, xeflux. 91%; C) SmIz, HMPA, MeOH, THF, rt, 81% ;d) 3NHCI. 81% ; e) (PhSeOhO, toluene, 76%; f) 40% aq. MeNH2. THF, n, 97% ;g) paraformaldehyde,CF3C02H. CICHzCHzCl. n,81% ; h) THF, nflux, 85% (276 :279 = 5 : 1).
w,
SCHEME 32
VI. Tazettine-Type Alkaloids A. ISOLATIONAND STRUCTURAL ELUCIDATION Tazettine (298) has been isolated from Crinum americanum (leaves) (16), C. giganteum (27),Hippeastrum eyuestre (bulbs) (40),Hippeastrum hybrids (bulbs) (42),Hymenocallis expansa (bulbs and leaves) (48), Lycoris radiata (bulbs) (60),Narcissus tazetta (901, N. cantaricus (whole plants) (65),Pancratium maritinum (bulbs) (%), and Sternbergia sicula (whole plants) (103). Pretazettine (300)has been found in N. pallidiflorus (whole plants) (76), N. panizzianus (whole plants) (79)(aerial and bulbs) (80),S. culsiani (bulbs) (102), and Zephyranthes flava (fresh mature seeds) (108). Tazettine (298), pretazettine (300), littoraline (301), and marconine (302) have been isolated
388
OSAMU HOSHINO
from Hymenocullis littorutu (bulbs), in which littoraline (301) is a new tazettine-type alkaloid (49). A new tazettine-type alkaloid, zeylamine (304),was isolated in 0.18%yield from the air-dried rhizomes of C. zeylunicum (34). Continuing exploration of the extracts of the Amaryllidaceae plants has established the presence of tazettine (298), pretazettine (300), and 3-epi-marconine (303) in Hymenocullis rotutu (50);of tazettine (298) and pretazettine (300)in N. tuzettu (bulbs) (89) and S. luteu (whole plants) (203); and of criwelline (299) in C. firmifolium var. hygrophilum (whole plants) (26).The alkaloids isolated are shown in Fig. 18.
B. SYNTHETIC STUDIES The syntheses of (2)-pretazettine (300) and (%)-haemanthidine (157) (169) (Scheme 33) and (2)-tazettine (298) and 6a-epi-pretazettine (314) (270) (Scheme 34) have been reported. In the one case (269),a key intermediate, the ally1 N-methylcarbamate 305, was transformed to N-methyl-3pivaloyloxy-3a-[(3,4-methylenedioxy)phenyl]-3a,6,7,7a-tetrahydro-6-oxo-
r!
Tazettine (298) R = PQMe Criwelline (299) R = aQMe
Pretazettine (300)
$2-
R
Q 0
0 Maxonine (302) R = a-OMe 3-Epi-macronine (303) R = P-OMe
0 Zeylamine (304)
FIG.18
Littoraline (301)
4.
t-Bucoo.
t.Buc00
-<
0
t-BuCOO
0
0
Q
389
THE AMARYLLIDACEAE ALKALOIDS
ac
0 0
305
0
306
307 R = M e
308 R=CHO t-&COO
Q 0
Me
h
OH
309
OH (f)-Haemanthidine (157)
OH
(f)-Preulzettine (300)
Reagemand Conditons :a) conc. HzS04. EtOAc, rt, then PhN+mBr3-, rt ;b) DBU, benzene, rcflux,
77%(2 steps) ;c) 2cthylhexanoic acid, (Ph$).,Pd. Ph3P, CHzC12,rt, 90% (1.5 : 1) ;d) DIBALH, THF, -78OC (3 :2 :5 :3) ;e) (MeSO&O, EbN, THF. OOC. then MeOH, 0°C to rt, 59% (35 : 24) ;r) 9, Pt black, aq. dioxane, rt, then AcOCHO, pyridine. rt, 57% ; g) POCl,, 8VC, then THF-Hp (1 : I), rt, 7 1% (2 steps) ;h) LiOH. &OH, rt, 78%; i) MeI, MeOH, rt. 66%. SCHEME 33
indoline (306) by oxidation followed by an intramolecular Michael addition. Conversion of the 6 0 x 0 group in 306 to a 6fl-methoxy group produced the methoxy compound 307, oxidative N-demethylation of which, followed by treatment with acetic4ormic anhydride, furnished the N-formyl product 308. The Bischler-Napieralski reaction and continuous hydrolysis of 308 provided (?)-haemanthidine (157). Treatment of 157 with methyl iodide in MeOH led to rearrangement of the skeleton to lead to (5)-pretazettine (300) in 66% yield (Scheme 33). In the other synthesis (270),the modified Heck reaction served as a key step for the construction of the spiro compound 311. Namely, the reaction of N-methoxycarbonyl-2-[(2-iodo-4,5-methylenedioxy)phenyllmethoxy]-2(cyclohexeny1)ethylamine 310 with palladium(0) in boiling THF in the presence of silver carbonate caused an intramolecular cyclization to give the spiro compound 311 in 90% yield. Michael reaction of 311 with 1 N HC1 in boiling THF, followed by introduction of a double bond through a
390
OSAMU HOSHINO
bH
(&)-6a-Epipretazettine(314)
k TBS = t-BuMQSi
OTBS
315
(f)-Tazettine (298)
Reagem and Condirions :a) ClCOzMe ;b) Pd(0Ac)z (lOmol%),Ph3P (4Omol%), AgzC03 (2 eqUiV.), THF, =flux, 90% re ~tatc63-70%) ;C) 1N HCI, THF, reflux, 94% ;d) CF3SQTMS. E t g , CHzC12,OOC, then Pd(0Ac)z. MeCN, rt, 67% (2 steps) ;e) NaBH4, CeC13.7Hz0. MeOH, ;f) KH. MI, THF, rt, 75% ;g) C Q , 3,5-dirncthylpyrazole, CH2C12,-78OC. 95% (p :a = 36 : 1) ._~. 400 to -45'C, 63% ;h) LiA& THF-EtzO, rt, 98% ;i) De.ss-Maxtin oxidation,73% ;j) Swern oxidation,298 (61%). 315 (90%) ;k) TBSCl, 76% ;I) B u 4 M , 93%. SCHEME34
silyl enol ether, afforded the spirocyclohexenone 312 in 63% yield (three steps). After the transformation of an 0x0 group to a methoxy group and subsequent oxidation, LiAlH4 reduction of the resulting spiro Slactone led to the dihydroxy compound 313. Interestingly, Swern oxidation of 313 afforded (2)-tazettine (298) in 61% yield, whereas Dess-Martin oxidation of 313 produced (2)-6a-epi-pretazettine (314) in 73% yield (Scheme 34).
4.
THE AMARYLLIDACEAE ALKALOIDS
391
On the other hand, 0-silylation and Swern oxidation of 313 provided Nmethyl-3a-[(2-O-TBS-4,5-methylenedioxy)phenyl]-3-oxo-3a,6,7,7a-tetrahydroindoline (315)in 68%yield, 0-desilylation of which with TBAF gave rise to a spontaneous intramolecular hemiacetalization to afford ( 5 ) tazettine (298)in 93% yield. Intramolecular 2-aza-ally1anion cycloaddition was employed for the syn) (-)thesis of the crinine-type alkaloids (t)-crinine (135) ( 1 4 2 ~ and amabiline (145)( 2 4 2 ~and ) has been reported to provide potential precursors of 6a-epi-pretazettine (314)and 6a-epi-precriwelline (methoxy epimer of 314) (142b). C. BIOLOGICAL ACTIVITY
The extracts of the bulbs and leaves of Hymenocaflis expansa have been re-examined for cytotoxic activity. Both plant parts showed significant activity against different human and murine tumor cell lines. Tazettine (298) showed activity, to varying extents, against the cell lines tested (48). Pretazettine (300)has also been reported to exhibit marginal activity (TIs0 < 4.5)(239).
W.Lycorenine-Type Alkaloids A.
ISOLATION A N D
STRUCTURAL ELUCIDATION
Six new lycorenine-type alkaloids, 5a-methoxy-9-0-demethylhomolycorine (323), galwesine (333),9-0-demethylgalwesine (334),16-hydroxygalwesine (335),16-hydroxy-9-O-demethylgalwesine (336),and galasine (337), have been isolated from whole plants of Galanthus efwesii accompanied by 12 known Amaryllidaceae alkaloids, including lycorine and galanthamine. Of these alkaloids, only lycorine and galanthamine were found previously in this plant. Identification and structural elucidation of these alkaloids were achieved using spectroscopic ('H and 13C NMR, CD, UV) techniques coupled with X-ray crystallographic analyses (for 334,335,and 337) and chemical transformation (35).Interestingly, although the known alkaloid, 9-0-demethylhomolycorine (321),was isolated as five different crystalline samples from five different subfractions of this plant, two of them were nitrogen inversion conformers and the other samples were compounds including different solvent molecules in the crystals (35,171). This is the first time that it has been demonstrated by X-ray crystallographic analyses that, depending on the crystallization conditions, both nitrogen inverted
392
OSAMU HOSHINO
isomers of the same natural alkaloid could be crystallized. In solution, the interchange between the axial and equatorial forms are too fast to be observed. The representative lycorenine-type alkaloids isolated since 1987 are shown in Fig. 19.
'R
RO
Lycmnine (316) R=H 0-Meth yllycmnine (317) R=Me
n
1
0
0
0
Nobilisine (326)
Me0
0
0
Clivatine (327) R = COCHZCH(0H)Me
Hippeastrine (328)
-
0
Homolycorine N-oxide (330) R=Me 8-O-Demeth ylhomo1ycorine N-oxide (331) R=H
0
Galwesine (333) R = H, R' Me 9-0-Demethylgalwesine (334) R R' = H
-
RO
OMe
'OMe
R'O
0
Me0
0-Methyllycmnine N-oxide (329)
Me0
'OH
Hippeastrine N-oxide (332)
S~-Hydroxy9-O-demeth ylhomolycorine (322) R =OH, R' = Me, R* = H Su-Methoxy9-Odemethylhomolycorine (323) R = OMe, R' = Me, R~=H Dubiusine (324) R = OAc, R' = Me, R2 COCHzCH(0H)M~
Me0
'OR
0
0
8-0-Acetylhomolycorine (320) R = Ac,R' =Me 9-0-Demethylhomolycorine (321) R = Me, R' = H
a0"
Q
OEt
Q
Homo1 corine (318) R = R7 =Me 8-O-Demeth y lhomolycorine (319) R = H, R' = Me
1 1-Hydroxygalwesine (335) R = OH, R' = Me 16-Hydroxy9-0-&methylgalwesine (336) R = OH, R' = H
FIG.19
Me0 Meo
0
Galasine (337)
4.
THE AMARYLLIDACEAE ALKALOIDS
393
VIII. Montanine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION The montanine-type alkaloids possess a unique structure, called the 5, 11-methanomorphanthridine skeleton 343, and are a minor group in the Amaryllidaceae alkaloid family, of which only seven representatives had been isolated until recently. Montanine (338) and pancracine (339) were isolated from the bulbs of Hippeastrum hybrids (42). The eighth montaninetype alkaloid montabuphine (340), with a P-5,11-methanomorphanthridine skeleton was found for the first time in the bulbs of Boophaneflava (9) growing in the winter rainfall area in South Africa. The structure was determined by physical and spectroscopic [COSY and ROESY (172)]experiments in the 'H NMR, and HMQC (173) and HMBC (174) correlations in the 13C NMR spectra. The molecular ellipticity of the alkaloid (342) showed a CD curve that was qualitatively the reverse of the known 5,11methanomorphanthridine alkaloids with an a-configuration for the methano-bridge (141,175). Therefore, the 5,11-methano bridge was established to have a /3-configuration (42). As they do not show remarkable biological activity, their synthesis had not been performed, excluding synthetic studies for structure elucidation. The structures of the montaninetype alkaloids isolated are listed in Fig. 20. B. SYNTHETIC STUDIES Although synthetic approaches toward the montanine-type alkaloids had been made by intramolecular cyclization of 3-(3,4-methylenedioxy)phenylhexahydroindoline derivatives (I76), these attempts were thus far unsuccessful. The 5,11-methanomorphanthridinering systems 341-343 (Fig. 21)
'0
Montabuphine (340)
Montanine (338) R = p-OMe, R' = a-OH Pancracine (339) R = &OH, R' = P-OH FIG.20
394
OSAMU HOSHINO
342
341
&g
NH
343
Ts = 4-MeC!&SO2
344
FIG.21
were found to be effectivelyformed by intramolecular reductive cyclization of 11-hydroxymethyl-N-(p-tosy1)morphanthridines 344 using SMEAH (177,178) in boiling toluene. Afterwards, a total synthesis of this type of alkaloid was achieved independently by two research groups; a key step in one of the syntheses involves stereoselective hydroboration-oxidation and cyclization with SMEAH (178,179) as a result of development of a method for the synthesis of $11-methanomorphanthridine343. In the other, a tandem aza-Cope rearrangement-Mannich cyclization and the PictetSpengler reaction (180) are key synthetic steps. A third research group has reported the enantioselective total syntheses of this type of alkaloid by means of an intramolecular allenylsilane ene reaction coupled with the intramolecular Heck reaction (181). The synthetic route used by the first research group is depicted in Schemes 35-37 (178,179). Namely, 2-[(3,4-methylenedioxy)benzoyl]cyclohex-4-ene carboxylic acid (345) (prepared from 1,2-cis-cyclohex-4-ene dicarboxylic anhydride and the Grignard reagent of 6-bromo-3,4-methylenedioxybenzene) was transformed to 3,4-diacetoxy-6-[1-(3,4-methylenedioxy)phenylvinyll-N-(p-tosy1)cyclohexylamine (346) in six steps. (Curtius rearrangement, hydrolysis, N-tosylation, Os04 oxidation, acetylation, and Wittig reaction). Hydroboration-oxidation of 346 in the usual manner proceeded stereoselectively to produce a hydroxymethyl product, acetylation of which gave 2~,3~-diacetoxy-llcr-acetoxymethyl-N-(ptosy1)morphanthridine (347) in good yield. Hydrolysis and successive 0benzylidenation of 347 afforded 2,3-0-benzylidene-llcr-acetoxymethyl-N(p-tosyl)morphanthridine, treatment of which with SMEAH in boiling o-xylene led to smoothly intramolecular cyclization to give 2,3-O-benzyli-
4.
THE AMARYLLIDACEAE ALKALOIDS
345
346
/OAc
OAC
Ts
-
347
348
Bn = Ca5CHZ Ts = p-MeC&I4S0z
Y 0
395
OH
(f)-Coccinine (351) Reagents and Conditions :a) ClC@Et, Et3N. acetone, then aq. NaN3,5OC ;b) t -BuOH, reflux, 94% (3 steps) ;c) CF~COZH,CHzClz,xt ;d) p-TsC1, Et3N, CHzClz, rt, 71% (2 steps) ; e) Os04 (cat.), NMO, dioxane-HZO (4 :1 ) ;f ) AczO, pyridine. DMAP, rt ;,g) Ph3PMeBr, KOt-Bu, THF,rt, 71% ; h) BH3, THF,then 30% Hz@. aq. NaOH, O°C, quantitative ;i) AczO, MeSO$I, (CHZO),,CICHzCHzCl,rt, 81% ;j) NaOMe, MeOH, rt, quantitative ;k) PhCH(OMeh,p-TsOH* HzO, CHC13,rt, 83% ;I) SMEAH, o-xylene, reflux, 91% ;m) DIBAL-H, toluene, rt. 347 (75%). a regioisomer (22%) ;n) Jones oxidation, 59% ;0 ) DDQ, NazHP04, dioxane, reflux, 26%; p) CH(OMe)3,p-TsOH*H20,MeOH, rt, 99% ;q ) MeSSiI, C H C l 3 , rt, 87%. SCHEME35
dene-5,ll-methanomorphanthridine348 in 91% yield. Selective cleavage of 348 with diisobutyl aluminum hydride (DIBALH) in toluene at room temperature produced 3-benzyloxy-2-hydroxy-5,ll-methanomorphanthridine (349)
396
OSAMU HOSHINO
along with a regioisomer. Jones oxidation of 349, followed by oxidation with DDQ, afforded 3-benzyloxyd1(11a)-5,11-methanomorphanthridin-2one (350). Finally, 350 gave (&)-coccinine (351)in 68% yield (three steps) through dimethyl ketalization, stereoselective removal of a methoxyl group, and 0-debenzylation (Scheme 35) (178,179). The same intermediate 349 was also converted into (+)-montanine (338), (+)-parmacine (339), and (+)-brunsvigine (356).Dehydroxylation of 349 by way of a mesate gave 3-benzyloxy-A1~-5,11-methanomorphanthridine (352), along with the regioisomer, in 70% yield. Chlorophenylselenylation-dephenylselenylation of 352 gave 3-benzyloxy-2-chloro-A1~11a)-5,11-
0 [ & NH OBn a,b
~
p&
C
0
MH
349
OBn
___)
352
Bn = GHsCHz
r
r
OH
(*)-Montanine (338) 353
354
t
(*)-Pancracine (339) H
H
'OAc (f)-0-Diacetylbrunsvigine (355)
0
NH
'OH
(f)-Brunsvigine (356)
Reagents am Conditions : a) leS02C1, Et3N, CH2C12,5OC, 100% ; b) KOt-Bu, Me$O, rt, 70% ;c)
PhSeC1, MeOH, ultrasound, 15-20°C, then NaIO4,82% ; d) Me3Si1, CHC13, rt, 87% ;e) BFpEt20, MeOH, 5OC, 94% ;9 H2SO4, THF- H 2 0 (1: l), reflux. 78% ; g) Me3SiC1, NaI, MeCN, rt, 55% ;h) Os04 (cat.), NMO, dioxane-Hz0, rt ;i) Ac20, DMAP, pyridine, 86% ;j) NaOMe, MeOH, n, 90%. SCHEME 36
4.
THE AMARYLLIDACEAE ALKALOIDS
397
methanomorphanthridine (353), which was treated with iodotrimethylsilane to lead spontaneously to 2,3-P-epoxy-A1("")-5,11-methanomorphanthridine 354. Treatment of 354 with BF3 Et20 in MeOH, or aqueous sulfuric acid, brought about oxirane ring opening to produce (?)-montanine (338) or (+)-pancracine (339). On the other hand, 354 was transformed into (?)brunsvigine (356) through (2)-0-diacetylbrunsvigine (355) (prepared by exchange of the oxirane ring to a double bond, Os04 oxidation, and acetylation) (Scheme 36) (179). Radical-mediated reaction of a radical precursor tetrahydroisoquinoline derivative has been found to produce the $11-methanomorphanthridine ring system (182).Thus, a formal total synthesis of this type of alkaloid was performed by means of the present methodology. Namely, the reaction of 1,2,3,4-tetrahydro-N(4-oxocyclohex-2-enyl)-4-phenylthioisoquinoline (357) with Bu3SnH in boiling o-xylene containing AIBN led to 5,llmethanomorphanthridin-2-one (358) in 80%yield, which was transformed to A2~3-5,11-methan~m~rphanthridine 359 by way of a mesate. In continuation, 359 provided the 2,3-O-benzylidene derivative 349 in two steps (Os04 oxidation and 0-bemylidenation), which was previously (179)converted into this type of alkaloid (Scheme 37).
-
-
H
(f)-Montanine (338) (f)-Pancracine (339) (f)-Coccinine (351)
0
349
Reagenrs and Conditions : a) BqSnH, AIBN, o-xylene, reflux, 80%;b) N a B a , MeOH, 5OC, quantitative (a mixture of a-and P-alcohols) ; c) MeSO2C1, EgN, CHC13, 5OC, 95% (1 : 1mixture of a-and pmesates) ; d) KOr-Bu, DMSO, rt, 82% (1 : 1 mixtutre of regioisomers from p-mesate) ; e) OsO4 (cat.), MNO, dioxane-HzO (4 : l), n ; f) PhCH(OMe)?, p-TsOH, CHC13, rt, 75% (2 steps) ; g) Ref. 179. SCHEME 37
398
OSAMU HOSHINO
The synthetic route in the second report (180) is as follows. Reaction of the N-benzyloxazoline derivative 361 {prepared from cis-2-benzylamino-l[(3,4-methylenedioxy)phenylethynyl]-l-cyclopentanol (360) by reduction and treatment with formalin} with BF3 Et20 in CH2C12at -20 to 23°C consisted of a tandem aza-Cope rearrangement-Mannich reaction to furnish 3-[(3,4-methylenedioxy)phenyl]-N-benzylhexahydroindol~n-4one (362).Interestingly, N-debenzylation of 362, followed by the PictetSpengler reaction using formalin and camphorsulfonic acid, afforded the 5,ll-methanomorphanthridin-1-onering system 363. The present finding may be attributable to the stereochemistry of 3-arylhexahydroindoline ring system. Compound 363 was converted into the A'(''a)-5,11-methanomorphanthridin-2-one 364 in four steps (reduction of an 0x0 group with LSelectride, dehydration of a hydroxyl group with thionyl chloride, hydroxylation with Se02, and Swern oxidation). Finally, 3P-hydroxylation of 364 through the silyl enol ether gave 3P-hydro~y-A~("~)-5,1 l-methanomorphanthridin-2-one, which was reduced with NaBH4 in acetic acid at -35°C to produce (2)-pancracine (339)in 53% yield (three steps) (180) (Scheme 38). e
360
363
Ar = 3,4-(CH2O&H3 Bn = C6H5CH2
361
364
362
(f)-Pancracine(339)
Reagents and Conditions : a) LiAIH4, EtzO, -20% then reflux, 94% ; b) 37% formalin, Na2S04, camphorsulfonic acid, CH~CIZ,2 3 T , 81% ;c) BF3*OEt2, CH2ClZ,-20 to 2 3 T , 97% ;d) Pd-C, H2, HCI, MeOH, 96% ;e) 37% formalin,Et3N, MeOH, 23'C, then HC1, MeOH, 23"C, 67% ; r) [email protected], -78'C. 99% ;g) SOC12, CHC13, -30 to 23'C, then S e a , dioxanc, 85"C, 62% ; h) Swern oxidation, 91% ; i) MeS03SiMe3, EgN, EtzO, -60to O°C, then Os04(cat), NMO, r-BuOH, HzO. pyridine, -5 to 23°C 82% ;j) NaBh, AcOH, MeCN (1 : l), -35'C. 65%.
SCHEME38
4.
THE AMARYLLIDACEAE ALKALOIDS
399
Starting with optically active cis-2-[N-cyanomethyl-N-(lS-phenethyl]-l[(3,4-methylenedioxy)phenylethynyl]cyclopentanol (365), 3-[(3,4-methylenedioxy)phenyl]-N-[(1S-phenethyl[hexahydroindolin-4-one (366) was synthesized in a manner similar to that noted previously. Thus, the synthesis of (-)-pancracine (339) was achieved in 25% overall yield through 366 by a sequence of reactions similar to those noted for (+)-339 (Z80b) (Scheme 39). Also, the same intermediate 364 employed for the synthesis of (+)339 was transformed to (2)-desmethyl-a-isocrinamine (368) by way of the 3a-acetoxy derivative 367. Intramolecular imino ene reaction of an allenylsilane has recently been found to generate cyclohexyl systems with adjacent cis-amino and -alkynyl moieties. This enantioselective ene cyclization was developed for the enantioselective total syntheses of (-))-montanine (338), (-)-coccinine (351), (-)pancracine (339), and (-)-brunsvigine (356) (a formal total synthesis) by the same research group (181) (Schemes 40 and 41). A precursor allenylsilanealdehyde 370 for the enantioselective ene cyclization was synthesized from scalemic epoxy alcohol 369 in nine steps. The allenylsilane-aldehyde 370 thus obtained reacted with N-triphenylphosphinyl-(2-bromo-4,5-methy1enedioxy)phenylmethylimine in boiling mesitylene to lead to a cyclized product 371 in 63% yield after protodesilylation. Hydrogenation of 371
364
367
WDesmethyla-isocrinamine (368)
Reugents and Condirionr :a) AgN03. aq. EtOH, 23OC, sonicaaon, 95% ;b) Red-A1 (100%) or LiAlH,, (89%). Et20. 23OC ;c) 37%formalin. Na2S04.camphorsulfonic acid, CH2C12, 23OC, 75% ; d) BFp 0Et2. CH2C12. 5OC. 95% ;e) Pd-C, H2 (50 psi), HCl, MeOH, 96% ; 9 in a manner similar ~ O , nflux. 86% ;h) to that noted for (i)-pancracine, 25% overall yield ;g) M ~ ( O A C ) ~ - Wbenzene, DBU, acetone, 23'C, then NaBh. CeCI3*7H20.n. 75% (2 steps) ;i) K2CO3, MeOH, 23OC, 69%. SCHEME 39
400
OSAMU HOSHINO
369
370
371
Bn = G H Q I z ; TBS = t-BuMe$i ;Ts = p-MeC&I.,S&
374
375
376
(-)-Panmacine(339)
0
I-m( 0
Reagents and Conditions : a) nine steps ;b) 2-Br-4,5-(CHzOz)CN=PPh3, mesitylene, 50°C to nflux ;c) TBAF, THF, 0°C 63% (2 steps) ;d) Lindlar catalyst, Hz. quinoline. MeOH, 93% ;e) Pd(PPh3),. Mc$TTI-I$'ha',Et3N, MeCN, 1U)oC.74% ;f) p-TsCl, pyridine, DMAP, l W C , 92% ;g) dimethyldioxirane, acetone,-u)oC, 89% (2 : 1 mixture of two diastemmers) ;h) FeC13, CH& -78OC. then DIBALH, OOC, 88% ; i) 10% Pd-C, Hz,MeOH. 97% ; j) Na, naphthalene, DME,-78OC, 63% ; k) 12, PPb3, imidazole, MeCN, EtzO, O O C , 82% ;I) "PAP, NMO,CH2C!lz, MS 4A,%% ;m) LDA, Mc$iCl, THF, -78'C ;n) Pd(OAc)z, MeCN, 67% ; 0 ) TBAF, THF,OOC to R,98% ;p) NaBH(OAc)3, -35°C. SCHEME 40
over Lindlar catalyst in MeOH containing quinoline, followed by an intramolecular Heck reaction, provided an N-(p-tosy1)-1l-methylenemorphanthridine ring system 373 by N-tosylation. Hydroxylation of 373 was per-
4.
0
THE AMARYLLIDACEAE ALKALOIDS
401
BS
376
377
Bn =C&CH2 TBS = r-BuMe$i Ts =p-MeC&i4S4
374
(-)-Montanine (338)
378
(-)-Brunsvigine (356)
Reagents and Conditions : a) TsOH, CH(OMe)3,MeOH, 0 "Cto n, 91%;b) DIBALH, toluene, rt, 81 % ;c) TBAF,T€IF, 0 ' C to rt, 99%;d) DIBALH, toluene, rt. 41 5% ; e) H2,Pd-C,MeOH; f ) TBAF, THF, 97% (2 steps) ; g) Ref. 179. SCHEME41
formed using the corresponding epoxy derivative of 373 to produce protected 1l-hydroxymethylmorphanthridine374 in 78%yield (three steps). The structure of 374 was confirmed by its conversion into 3P-acetoxy2~-benzyloxy-5,11-methanomorphanthridine, a racemic form of which was previously (I79)transformed to the montanine-type alkaloids. Transformation of 374 to the $11-methanomorphanthridine ring system 375 was successfully achieved in 96% yield by treatment of 3-O-TBS-2-hydroxy-11hydroxymethylmorphanthridine (derived from 374 by O-debenzylation and N-detosylation) with a mixture of imidazole, triphenylphosphine, and iodine in MeCN-ether at 0°C. Thus, (--)-pancracine (339) was synthesized from 375 by way of 376 in five steps (oxidation, formation of 376 through a silyl enol ether, deprotection, and reduction) (Scheme 40). Furthermore, synthesis of ( -)-montanine (338) and (-)-coccinine (351) was carried out in 41 and 91% yield, respectively, from the same intermediate 376 by way of the dimethyl ketal377. Also, the key intermedip-tosyl) ate 374 was converted into 2~,3/3-dihydroxy-ll-hydroxymethyl-N-( morphanthridine 378, a racemic form of which was previously (179)trans-
402
OSAMU HOSHINO
formed to (2)-brunsvigine (356). Thus, the present result constitutes an enantioselective formal total synthesis of (-)-brunsvigine (356) (181) (Scheme 41).
IX. Mesembrine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION Few isolations of mesembrine-type alkaloids have been reported. Two examples are the isolation of amisine (379)(from Hymenocallis arenicolu) (183) and of mesembrenol(380) (from Crinum oliganthum) (184) from the Amaryllidaceae family. A third example is the isolation of mesembrenone (Ml), belonging to the mesembrine group, from the aerial parts of Narcissus palladulus (77) growing in Iberia. The structure was elucidated by spectroscopic and chemical methods (Fig. 22). Although both the Amaryllidaceae and Sceletium-type alkaIoids have common biogenetic precursors, further investigations have revealed that the biosyntheses of these two classes of alkaloids are fundamentally different (185). Therefore, the presence of mesembrenone in Narcissus plants is of chemotaxonomic interest because mesembrines seem to be restricted to Aizoaceae-Mesembrylanthemoidaceae (Dicotyledons) (186). The present finding reveals the presence in the Amaryllidaceae of such unexpected alkaloids as those found in some Scefetium species.
B. SYNTHETIC STUDIES The synthesis of mesembrine-type alkaloids belonging to the Sceletium alkaloid family has been carried out extensively in order to seek a
OoMe 6""' OMe
Amisine (379)
Q
q?
HO
0
Mesembrenol(380)
Mesembrenone (381)
FIG.22
4.
THE AMARYLLIDACEAE ALKALOIDS
403
new method for the construction of quaternary carbon centers. As shown in Scheme 42 (187), a formal synthesis of natural (-)-mesembrine (387), in which a key step involves the enantiospecific ring expansion of 2-cyclopropylidene-2-[(3,4-dimethoxy-6-trimethylsilyl)phenyl]ethanol (382) to ( -)-(S)-2-hydroxymethyl-2-[(3,4-dimethoxy)phenyl)cyclobutanone (383), has been reported. Namely, 382 was exposed under asymmetric epoxidation conditions to give 383 in 65% yield. Allylation of 383 through a phenylsulfonyl derivative gave ZS-(but-3-enyl)-2-[(3,4-dimethoxy)phenyl]cyclobutane (384), which was converted into (-)-2S-(but-3-enyl)-2-[(3,4dimethoxy)phenyl]-y-butyrolactone (385) through ozonolysis of the silyl enol ether. Finally, Wacker oxidation of 385 provided (-)-2S-(3-oxobutyl)2-[(3,4-dimethoxy)phenyl]-y-butyrolactone (386), transformation of which to (-)-mesembrine (387) was previously (188) achieved. The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (R)-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed (189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl 1R[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-eny1acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-0x0-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps; ketalization of an 0x0 group, reduction of lactam, and deketalization)(189). (-)-Mesembrine (387) has been synthesized using thermolysis of an aziridine ester (190). A diastereomeric mixture of 2-[(3,4-dimethoxy)phenyl]-4-(4R)-benzyloxymethyl-y-butyrolactone(392) [obtained from ( S ) - 0 benzylglycidol] was transformed to the lS-benzyloxy-3-[(3,4-dimethoxy) phenyllbut-3-enyl N-benzylaziridine carboxylate 393, thermolysis of which in degassed toluene (in a sealed tube) at 250°C gave, in 85% yield, the pyrrolidine Slactone derivative 394 bearing a quaternary carbon center. Conversion of 394 into 6-benzyloxy-3a-[(3,4-dimethoxy)phenyl]A6*7-tetrahydro-N-methylindolin-5-one (395) was performed in four steps (N-debenzylation, N-methylation and spontaneous reduction of the S lactone, Swern oxidation, and aldol reaction) through intramolecular aldol condensation of a keto-aldehyde. After reduction and subsequent acetylation of 395, Birch reduction gave (-)-mesembrine (387) (Scheme 44) (190). A formal synthesis of (+:)-mesembrine (387) has been performed by means of an intramolecular conjugate addition (146).Namely, condensation
OMe
OMe
382
383
384
60Me - 0
OMe
DL0
0
386 (-)-Mesembrine (387) Reagents and Conditions : a) L-(+)-DIPT,Z-BuOOH,Ti(Oi-R)4, MS 4A. CHzClz, -40°C. 65% ( 9 5 % ~;)b) (PhQZ,Bu~P, THF, nflpx. 91% ;c) ethylene glyco1,p-TsOH, benzene. reflux, 88% ; d) m-ClC&CQH, NaHC03, CHzClz,H20, rt ;e) BuLi, ally1 bromide, THF, rt, 91% ;f) p-TsOH, acetone, HzO, reflux, then N a b , MeOH. rt, quantitative ; g) f-BuMqSiOTf, Et3N ;h) Na Wg). NazfIP04, MeOH, R ;i) ByN+F-, THF, rt ;1) Swern oxidation, -78°C.82% ; k) Et3SiOSOZMe, 2,6-lutidine, CH2CI2. rt ;I) 03, CH2Cl2, -78OC;m) NaBh ;n) 10% H a . rt ;0 ) &,PdClz. CuCl, DMF,HzO (Wacker oxidation), rt, quantitative; p) Ref. 187. 385
SCHEME 42
390
389: X = H or CI
388 Ar = 3,4-(MeO)&& M
e
g
o
e
_____)
O
H Me
f-i
M
e
0
H Me
391 (+)-Mesembrine (387) Reagents and Conditions : a) %I3CCOCl(3equiv.), Zn-Cu, THF, 0°C ;b) Zn, AcOH, 0°C;c) AcOH,H20, 60°C;d) K2C03, MeOH ; e) CH2N2. Et2O ;f') M e w 2 (excess), THF, reflux, 83% ;g) pyridinium p-toluenesulfonate, EtC(0Me)zMe ;h) LiAW, THF ;i) H30+,then NH3, HzO, 79% (3 steps). SCHEME 43
4.
392
405
THE AMARYLLIDACEAE ALKALOIDS
393
Bn = C&IsCHz
Jq-Q
0
f-i P
394
j-I
BnO
0
395
H
(-)-Mesembrine (387)
Reagents and Conditions : a) LiAW, THF, 0°C ;b) o-N02Q&9eCN, B u g . THF, rt ;i)Br-
CHzCHzBrCOCl, Et3N, CHzCl,, -lO°C, then CfjH5cI%H,m2, rt ; d) 30%Hz@. CHzClz,0°C to rt ;e) 250°C degassed xylene (sealed tube), 85% ;f) 20%Pd(OH)z-C, Hz, MeOH, rt ; g) formalin, MeOH, 0°C then N a b 4 ,0°C to rt ; h) Swern oxidation, -71°C to rt ;i) 0.5N NaOH, EtOH, rt, 75% (2 steps) ;j) N a b , CeCly7Hz0, MeOH, O°C ;k) AczO, Et3N, DMAP, CH~CIZ, 0°C to rt. 76% (2 steps) ;I) Li. liq. N H 3 , -33"C, (27%overall yield). SCHEME 44
of 3-[(3,4-dimethoxy)phenyl]N-methyl-2-methylthiopyrrolidinium iodide (generated by the reaction of pyrrolidine-2-thione 3% with methyl iodide in MeOH) with t-butyl3-oxo-4-pentenoateunder basic conditions produced pyrrolidine derivative 397 and t-butyl A7(7a)-tetrahydroindolin-5-one-7carboxylate (398) in 56 and 17% yield, respectively. Each of 397 and 398, when exposed to CF3C02H under ultrasonication, afforded the same A7mesembrenone (399), which was already (245) transformed to ( 2 ) mesembrine (387) (Scheme 45) (246). There is a report on the synthesis of (2)-mesembrine (387) by a reaction involving aryl rearrangement and Robinson annulation through an enamine (191) (Scheme 46). Reaction of 3-bromo-N-methoxycarbonyl2-methoxypyrrolidine (400) with 1,2-dimethoxybenzene under acidic conditions gave 3-bromo-N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]pyrrolidine (401), treatment of which, with silver ion in MeOH, caused
406
OSAMU HOSHINO C
OMe
396
397
398
399
OMe
(k)-Mesembrine (387) Reagents and Conditions : a) MeI, CHzClz ; b) CH2=CHCOCHzC@r-Bu, Et3N, CH2C12, rt, 397 (56%), 398 (17%) ; e) CF3C02H (neat), ultrasound, 71% ;d) C F s Q H (3 equiv.), CHC13, ultrasound, 82% ;e) Ref. 145. SCHEME 45
rearrangement of an aryl group to afford N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]-2,3-dehydropyrrolidine(402) in 66%yield. LiAlH4 reduction of 402 gave an enamine, Robinson annulation of which, with methyl vinyl ketone, produced (2)-mesembrine (387). OMe
400
401
402
OMe
(f)-Mesembrine (387)
Reagents and Conditions : a) 1,2-dimethoxybenzene,Htor Lewis acid, 83% ;b) AgN03, MeOH, then H+or reflux, 66%;c) LiALH,, THF, 67% ;d) methyl vinyl ketone, 93%. SCHEME 46
4.
6
8
+
COzEt
$cozEt
'
OMe-
407
THE AMARYLLIDACEAE ALKALOIDS
- b.f
OM0
OUe OMe
403
404
g
OMe
o& H Me
OMe
405
(*)-Mesembrine (387)
Reagenrs and Conditions : a) CHCl3,1,10-phenanthroline,55OC,57% ; b) ethylene glycol,p-TsOH, toluene, rtflux, 88% ; c) LiAH4, EtzO, n, 84%; d) p-TsC1. pyridine. rt, 79% ;e) Bu4N+CN-, HMPA, 8OoC,77% ; f) aq. HCI, THF,rt,94%;g) Ref. 191. SCHEME47
Formation of the quaternary carbon center was also carried out by the reaction of ethyl 4-oxo-cyclohex-~2-ene carboxylate with 3,4-dimethoxyphenyllead triacetate (403) in chloroform containing 1,lO-phenanthroline at 55°C to give ethyl 4-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-ene carboxylate (404) in 57% yield. Thus, 4-[(3,4-dimethoxy)phenyl]-4-oxo-cyclohex2-ene carbonitrile (409,which was previously (192) transformed into ( 2 ) mesembrine (387),was obtained in 61% yield from 404 (193) (Scheme 47). The synthesis of (-)- and (+)-mesembrines (387)from 406 by way of 407 using a sequence of reactions involving double Sharpless asymmetric addition and radical-initiated reaction has appeared (194) (Fig. 23). The synthesis of ( -) and (2)-mesembranol (413) has been described in two reports; construction of the quaternary carbon center in the former involved Claisen rearrangement (195) (Scheme 48), whereas that in the latter case was performed by radical-mediated cyclization (148) (Scheme 49). The former synthesis (195) proceeds as follows. (2S,3S,4R))-2-Benzyloxy3,4-O-bis(MOM)-cyclohex-2-enone(408) (derived from D-glucose) reacted OMe
OMe
406
407
Me
0
FIG.23
408
OSAMU HOSHINO
- OMe
OMe
"'"*J$
a, b
MOMO'
f
c-e
MOMO'
HO
Ho& OMOM
MOM0
MOM = MeOCHz BZ = QH&O
408
OMOM
409
410
MeHNf18
OMe
OMe
OMe
OMe
i, I
09 h
OMOM
411
OMOM
b
HO'
(-)-Mesembranol(413)
412
Reagents and Condirions : a) (3,4-MeO)zC&&i, EtzO, -78OC, then NaOMe, McOH, 56%;
b) Pd(OH)Z, H2, EtOAc, 100%;c) l,l'-thiocatgonyldiimidazole,acetone, &lux, 95% ; d) P(OMe)3, EtOAc, reflux, 74% ; e) 30% aq. H Q H , 3OoC, then KzCO3, MeOH. a-OH (39%), POH (18%) ; f) MeCH(OEt)3, E t w H , MS 3A, 135OC. 56% ; g) DIBALH, toluene, -78OC, 82% ;h) 30% aq. MeNH2-MeOH, NaBCNH,, MeOH, rt, 65% ;1) H ~ ( O A C ) ~ , THF,rt, then NaBH4, aq. NaOH, THF, rt, quantitative ;j) aq. Ha-MeOH (1 : 2), rt, 68%.
SCHEME 48
with (3,4-dimethoxy)phenyllithium in ether at -78°C followed by catalytic hydrogenation to afford (lR,2S,3S,4R)-1,2-dihydroxy-3,4-0-bis(MOM)cyclohexanone (409). Conversion of the cis-1,2-dihydroxy groups in 409 into a double bond, followed by selective cleavage of a protecting group, gave a mixture of (4R)-3-hydroxy-4-0-MOM-cyclohexanones (410).The Claisen rearrangement of 410 with triethyl orthoacetate at 136°Cproduced aceethyl 4-(1R,4R)-0-MOM-1-[(3,4-dimethoxy)phenyl]cyclohex-2-enyl tate (411) in 56% yield. Reduction of 411 with DIBALH, followed by reductive amination, furnished (lR,4R)-4-0-MOM-l-[(3,4-dimethoxy) phenyl]-l-[2-(N-methylamino)ethyl]cyclohex-2-enol(412). Acetoxymercuration of 412 with mercury(I1) acetate and treatment with NaBH4 provided 0-MOM-mesembranol, deprotection of which with acid produced (-)-mesembranol (413)in 68% yield (195) (Scheme 48).
4.
'NHMe
414
409
THE AMARYLLIDACEAE ALKALOIDS
-
415
BnO
'ie 0
416
Bn = C&15CH2
(f)-mesembranol(413)
417
Reagents ond Conditions : a) NBS, MeCN-H20 (4 : l), 83% and 10%(regioisomer) ;b) K2CO3, MCOH, rt ;c) 40% aq. MeNH2, MeOH, 100°C, 78% ; d) Cl2CHC0Cl, Et3N, CH2Cl2. rt, 79 9%;
e) p-TsOH, benzene, reflux, 80%and 15% (regioisomer);f) BgSnH, AIBN. toluene, reflux, 51%; g) BH3, THF,reflux ;h) 5% Pd-C, H2 (4 kg/cm2), 68% ;i) Raney Ni (W-2). EtOH, reflux, 81% (3.7 : 1 mixture of a-and p-isomers) ;j) AlH3, THF, rf, 413 (71%), 418 (19%).
SCHEME 49
The second synthetic procedure (148) is shown in Scheme 49. Namely, 4-benzyloxy-l-[(3,4-dimethoxy)phenyl]-2-methylaminocyclohexanol (415) {prepared from 4-benzyloxy-l-~(3,4-dimethoxy)phenyl]cyclohexene(414) by epoxidation and subsequent oxirane ring opening with methylamine} was converted into the N-(methy1)dichloroacetamide 416 in two steps (dichloroacetylation and dehydroxylation with acid). Radical cyclization of 416 with Bu3SnH in boiling toluene containing AIBN produced, in 51% yield, 6-benzyloxymesembran-2-~one (417), reduction of which with borane, followed by catalytic hydrogenation, gave (*)-mesembranol (413) in 68% yield. However, reduction of 417 with Raney nickel gave rise to partial epimerization of a hydroxyl group to yield a mixture of a-and P-hydroxy
410
OSAMU HOSHINO
isomers, which was reduced by combined LIA1H4and aluminum( 111) chloride in THF to afford (t)-mesembranol (413) and (2)-epi-mesembranol (418) in 71 and 17% yield, respectively.
X. Miscellaneous A. PALLIDIFORINE A new heterodimer alkaloid named pallidiforine (419) was isolated as a yellow crystalline compound from whole plants of Narcissus pallidiflorus (76) belonging to the Pseudonarcissus DC section. Its high-resolution mass spectrum indicated the molecular formula CxH40N207 (M', dz.588.2775), suggesting a dimeric structure. The I3C NMR spectrum appeared to be almost exactly superimposable on those of lycoramine (276) (57) and tazettine (298) (296). However, the presence of one carbonyl carbon at 210.5 ppm and the disappearance of the C-11 of the tazettine moiety and that of the N-methyl protons of tazettine or lycoramine were observed. As a result of further examination of the NMR spectrum using 'H-'H (COSY) and lH-13C 2D experiments, its structure 419 was elucidated to be a heterodimer formed by lycoramine and tazettine units linked together. The formation of the alkaloid 419 can be explained by the attack of the nitrogen of N-demethyllycoramine (278) on C-6' of tazettine (298) with opening of the B ring and formation of the keto group (Fig. 24).
Pallidiflorine (419)
Obesine (420) FIG.24
Augustamine (421)
4. THE AMARYLLIDACEAE
ALKALOIDS
411
B. OBESINE Phytochemical studies on Narcissus obesus have resulted in the isolation of a new alkaloid named obesine (420) (see Fig. 24), accompanied by several known Amaryllidaceae alkaloids (74). The stereochemistry and structural determination of the alkaloid 420 have been carried out by spectroscopic analyses and by application of 2D NMR techniques. Although the H-6P proton (6 4.38) is masked by the H-3 proton (6 4.30-4.40), the H-6a proton (6 4.02) was assigned at higher field on the basis of the nuclear Overhauser effect (NOE) with H-12 endo (63.10) observed in the 2D NMR experiment. On the other hand, the a disposition of H-3 was confirmed by the NOE between H-3 (6 4.30-4.40) and H-12 ex0 (6 3.01). In the 13C-NMRspectrum of 420 a characteristic signal due to the C-11 carbon was observed at 82.7 (singlet) ppm. Also, a comparison of the 'H and 13C NMR spectra of obesine (420) with those of the related alkaloid 3-epi-marconine (303) (50) was performed. C. AUCUSTAMINE
Augustamine (421) (see Fig. 24) has been found in Crinum augustum and characterized (8), and its pharmacological properties have received attention (22). However, its absolute stereochemistry remained uncertain. The synthesis of the alkaloid 421 has been achieved using intramolecular 2-aza-ally1 anion cycloaddition ( 1 4 2 ~ (Scheme ) 50). Namely, the reaction of the (2-aza-ally1)stannane 189 in a way similar to that reported for the synthesis of (-)-amabiline (145) (see Scheme 17) and subsequent N-methylation with methyl iodide produced 3a-[(3,4-methylenedioxy) phenyl]-4,5-O-isopropylidene-N-methylhexahydroindoline(422) in 82% yield as a 5 : 1 mixture of two diastereomers. Removal of the isopropylidene group with methanolic HC1, followed by treatment with trimethyl orthoformate, afforded the corresponding orthoformate 423, which, without purification, was exposed to methanesulfonic acid in CH2ClZat room temperature to provide (-)-augustamhe (421) in 78% yield (three steps). Thus, this finding established the absolute stereochemistry of the natural alkaloid. D. PHENANTHRIDINE-TYPE ALKALOIDS Ismine (424) and three new phenanthridine derivatives, N-methylcrinasidine (425), 8,9-methylenedioxyphenanthridine (426) and N-methyl-8,9methylenedioxyphenanthridiniumchloride (427), were found in the leaves and bulbs of Lapiedra martinezii (53).The co-occurrence of ismine (424) in the plant gives an indication of the biosynthetic relationship between the four alkaloids (53).The three alkaloids isolated are not artifacts since
412
OSAMU HOSHINO
Ar = 3,4-(CH20z)C,H3
d
____t
r (-)-Augustamine (421)
Reagents and Conditions: a) BuLi (1.9 equiv), THF,-78OC, then Me1 (1.9 equiv), 82% (5 : 1 mixture of two diastereomers) ; b) conc. HCI, MeOH ; c) PPA, CH(OMe)3 ; d) M e S w , CH2C12.78%(3 steps). SCHEME 50
ismine (424) was not metabolized under the extraction conditions employed in this work. Buflavine (428) and 8-demethylbuflavine (429) were isolated for the first time from the bulbs of Boophane$ova. Their structures have been established by spectroscopic ('H and I3CNMR) methods and are representative of the unusual natural Amaryllidaceae alkaloids with an eight-membered Nheterocyclic ring, which had been previously reported only from Galonthus nivalis (197). A new alkaloid phamine (430),which is a phenanthridone alkaloid belonging to the narciclasine group, has been isolated from the bulbs of Hippeastrum equestre along with known Amarylldaceae alkaloids (47). Its structure was determined by spectroscopic (MS, UV, 'H and I3C NMR) analyses. Also, phamine indicated interesting antimitotic activity. The alkaloids isolated since 1987 are shown in Fig. 25. With respect to the synthesis of phenanthrine type alkaloids, 5,6dihydrobicolorine (432) (198),crinasiadine (199),and N-methylcrinasiadine (425) (199) were synthesized using combination of the Suzuki cross coupling reaction and the Bischler-Napieralksi reaction.
4. THE
413
AMARYLLIDACEAE ALKALOIDS
0 OH
Ismine (424)
N-Methylcrinasiadine (425)
Trisphaeridine (426)
427
RO Buflavine (428) R=Me 8-0-Demethylbuflavine (429)
Phamine (430)
431
R=H
("0. 5,dDihydrobicolorine (432)
Bicolorine (433) FIG.25
E.
4-ARYLTETRAHYDROISOQUINOLINE-TYPE ALKALOIDS
Since the previously published review (8), novel 4-aryltetrahydroisoquinoline type alkaloids have not been found in the Amaryllidaceae plants. Only latifine (437) has been isolated from the bulbs of Crinum lafifolium (200). The structure was confirmed by spectroscopic evidence, X-ray crystallographic analysis, and synthesis (198). Regarding synthetic studies, the syntheses of (?)-latifine (437) (200), of (?)-cherylline (440) and (+)-latifine (437) (201), and of (?)-O,Odimethylcherylline (445) and (2:)-0,O-dimethyllatifine (446)(202) have been performed using the Pomeranz-Fritsch-type cyclization (Scheme 51), the Bischler-Napieralski-type reaction (Scheme 52), and intramolecular nucleophilic addition of aryllithium (generated by butyllithium) to a carbony1 group (Scheme 53).
414
OSAMU HOSHINO
OH
OH
a
Me0
Me0
b,c
___)
Meo
H -
Me
Br
BI
43s
(f)-Latifhe (437)
436
Reagenfs and Conditions : a) conc. HCl, EOH, reflux. 63.8%;b) HCQEt, EtOH, K Z W ,MS 3A, reflux ;c) Lim,MeOCH2CHz0Me,reflux, 35.4%. SCHEME 51
F.
JOUBERTIAMINE-TYPE ALKALOIDS
In order to prove the biosynthesis of the Sceletium alkaloids, an extensive study has been carried out using Sceletium subvelutinum L. Bolus that were grown from seed, and the six alkaloids (447-452) (Fig. 26) produced by S. subvelutinum (101) isolated. These six alkaloids were separated chromato-
8-
Me0
d-f
8-c
Me0
Me0
ChH
0 439
438
Me0
8-C
___)
M
e
O
a
HO
(i)-Cherylline (440)
H
C02H
d-f
M e 0 d M e
0
441
442
(*)-Latifine (437)
Reagents and Conditions : a) (COCI)z, benzene, rt ;b) aq. NaN3, acetone, then benzene, reflux ;c)
FOCI3, 90-95"C, then SnCI4,CH&!lz, IT,67%(3 steps) ; d) NaH, benzene, reflux, then MeI, reflux; e) Me& MeSO3H, 5OoC, 50% ; f) LiAIH,, THF, reflux. SCHEME 52
4.
443
THE AMARYLLIDACEAE ALKALOIDS
444 OMe
415
(st)-0,O-Dimethylcherylline (445)
M e 0 a N M e
(k)-0,O-Dimethyllatifine (446) Reagents and Conditions : a) BuLi, THF, -78"C, 77% ; b) HCl, EtOH ;c) NaBH4, 70% (2 steps). SCHEME 53
graphically in order of increasing polarity: 0-methyldehydrojoubertiamine (452), 0-methyljoubertiamine (450), 0-methyldihydrojoubertiamine(448), dehydrojoubertiamine (451), joubertiamine (449), and dihydrojoubertiamine (447). The structures of the alkaloids were characterized by 'H
Dihydrojoubertiamine (447) R=H O-Methyldihydrojoubertiamine (448) R=Me
Joubertiamine (449) R=H O-Methyljoubertiamine (450) R -: Me FIG. 26
Dehydrojoubertiamine (451) R=H O-Methyldehydrojoubertiamine (452) R=Me
416
OSAMU HOSHINO
NMR and mass spectrometric evidence. Based on the results, the incorporation of radioactivity into the alkaloids was examined, and a key, late biosynthetic intermediate, or a compound that is closely related to that intermediate, was deduced to be the N-methylamine 454 formed from 4hydroxydihydrocinnamic acid by way of the corresponding aldehyde 453 (Scheme 54). As for the synthesis of the joubertiamine-type alkaloids, (-+)-Omethyljoubertiamine (450) has been produced using a transition-metalmediated reaction (203), in which a key step involves the introduction of aryl and 2-dimethylaminoethyl groups by a sequence of two nucleophilic additions to a cationic ($-cyclohexadienyl) iron (1+) intermediate. Namely, treatment of 1,4-dimethoxycyclohexa-1,3-dienecomplex 455 with triphenylmethylium hexafluorophosphate, followed by addition of (4methoxy)phenyllithiumto the resulting cationic complex at -78"C, afforded the (4-methoxy)phenyl adduct 456. The adduct 456 was treated with CF3C02H and then ammonium hexafluorophosphate (NH4PF6)to produce the salt, cyanomethylation of which with the lithium enolate of triethylsilyl cyanoacetate and subsequent treatment with TBAF afforded the cyanomethyl complex. Catalytic hydrogenation of the cyanomethyl complex with hydrogen and Raney nickel in the presence of dimethylamine afforded the 2-dimethylaminoethyl complex 457 in 60% yield, demetalation of which, using anhydrous trimethylamine N-oxide, followed by hydrolysiswith oxalic
9 $= OH
+ NHMe
0
CHO
453
, ,,
454
SCHEME 54
4.
455
417
THE AMARYLLIDACEAE ALKALOIDS
456
457
(k)-O-Methyljoubertiamine (450) Reagents and Conditions : a) Ph+?PFi, then 4-Me0w4Li, 85% ;b) CF3C$H, W P F 6 , 94%; c) Li’[CN~C02(CH2hSiMe,]-, then f-Bu4NF, 84%;d) Raney Ni, H2, MQNH, 609%; e) Et3N0, then (C02H)2,92%. SCHEME 55
acid, furnished (2)-O-methyljoubertiamine (450) in 92%yield. The overall yield was 40% (seven steps from 455) (Scheme 55) (203). In another report (193), (+)-O-methyljoubertiamine (450) has been prepared from the intermediate 404 (see Scheme 47) employed for the synthesis of (2)-mesembrine (387).
References
I
1. M. F.Grundon, Nut. Prod. Rep. 6, 7!) (1989). 2. J. R. Lewis, Nat. Prod. Rep. 7 , 549 (1990). 3. J. R.Lewis, Nat. Prod. Rep. 9, 183 (1992). 4. J. R.Lewis, Nut. Prod. Rep. 10, 291 (1993). 5. J. R.Lewis, Nat. Prod. Rep. 11, 329 (1994). 6. J. R.Lewis, Nat. Prod. Rep. l2, 339 (1995). 7. (a) J. R. Lewis, Nut. Prod. Rep. 13, 171 (1996); (b) J. R. Lewis, Nut. Prod. Rep. 14, 303 (1997). 8. S. F.Martin, in “The Alkaloids”, (A. Brossi, ed.), Academic Press, 1987,Vol. 30,p. 251, and references cited therein. 9. F. Viladomat, C. Codina, J. Bastida, ‘W. E. Campbell, and S. Mathee, Phytochernistry 40,307 (1995).
418
OSAMU HOSHINO
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