Aporphines

The latter may in turn undergo dienone-phenol rearrangement to aporphines of the 12 

A study of two Xylopla species has led to the characterization of five new aporphines. Norisodomesticine (3), xyloguyelline (4), and danguyelline (5) were 

0-Trimethylsparsiflorine (8) has been isolated from Thalictrum foliolosum and Laurelia philippiana has furnished 4-hydroxyanonaine 

In connection with a continuing investigation of the alkaloidal content of rmosan Stephania sasakii, (-)-roeme] have been isolated and characterized. 

Studies of a variety of Annonaceae species have furnished some most unusual aporphines. The two 7-dlmethylated aporphines melosmine (15) and melosmidine 

A detailed study of the alkaloidal content of the Formosan Stephania sasakii (Menispermaceae) has led to four new aporphines stesakine (4), dehydrostesakine (5), dehydrocrebanine (6),11 and dehydrophanostenine (7).4 Additionally, dehydro-stephanine (8) has been isolated from S. kwangsiensis.12 

A total of five other new aporphines have also been found and characterized, including isocorytuberine (9), dehydrocorydine (10), and corydine JV-oxide (11), all from Glaucium fimbrilligerum,13 laetine (12), from Litsea laeta,H and anaxagoreine (13), from Anaxagorea dolichocarpa and A. prinoides.15 

The reaction of reticuline A-oxide (14) with cuprous chloride in methanol, followed by treatment with sodium hydrosulphite, furnished corytuberine (15) in 

In a modification of a known sequence, base-catalysed condensation of hydrastininium iodide (18) with 6-methoxy-2-nitrotoluene (19) provided (20) and (21). Catalytic hydrogenation of (20), followed by Pschorr cyclization, afforded stephanine (22).44 

Oxidation of the tetrahydroisoquinoline (23) by thallium(m) trifluoroacetate in methanol leads to ocoteine (24) in 46% yield. When the same oxidizing reagent, in trifluoroacetic acid, was used in connection with the acetyl amide (25), 7V-acetyl3-methoxynornantenine (26) and the corresponding dehydroaporphine 

A careful investigation of the alkaloidal content of the Brazilian plant Ocotea minarum (Lauraceae) has led to five new aporphines, namely ocotominarine (3), ocominarine (4), norleucoxylonine (5), iso-oconovine (6), and 4-hydroxy-dicentrine (7).4 

Other new aporphines are (+)-hernagine (8), found in Hernandia nym-phaefolia (Hernandiaceae),10 (+)-bulbocapnine JV-metho-salt (9), obtained from Corydalis cava (Fumariaceae),11 and glaufidine (10), which is present in Glaucium fimbrilligerum (Papaveraceae).12 

Slavik and L. Slavikova, Collect. Czech. Chem. Commun., 1979, 44, 2261. 

Known aporphines that have recently been re-isolated, and their sources, are  

The readily available reagent diphenyl selenoxide has been used as a mild and selective oxidant in the synthesis of aporphines (and homoaporphines). When the benzylisoquinoline (13) was treated with one equivalent of the reagent at room temperature in methanol, and the product was O- methylated with diazomethane, the aporphine (14) was obtained in 80% yield. The alternative use of chloranil, which is a commonly used oxidant for catechols, yielded less than 10% of (14).20 

Interest in the aporphine alkaloids has principally centred on the range and number of oxidised bases that have been discovered. A considerable number of 7-hydroxy and 7-methoxy aporphines have been isolated and both 7a and 73 forms have been encountered. These probably represent intermediates in the formation of dehydroaporphines, into which they are easily converted in the laboratory, by dehydration. Alkaloids of this type isolated include oliveroline (104, R =Me, R =H) and its A/-oxide ushinsunine which is the 7a-hydroxy isomer of oliveroline pachypodanthine (104, R =, R =Me), iv-methylpach-ypodanthine (104, R =R =Me) and its -oxide oliverine (105, Ri=R2=Me) and oliveridine (105, R =Me, R =H) and their iv-oxi-des the related secondary bases noroliverine (105, R =H, R =Me) and noroliveridine (105, R =R =H) polysuavine (106) guatterine (107, R=H) and its y-oxide polyalthine (107, R= 

Derived from these bases, no doubt, by dehydration, several dehydroaporphines have been identified as natural products. These incluyde dehydroisolaureline, dehydrostephanine and de- 

Three dehydroaporphines of unusual c-methylated structures are belmine (117, R =H, R =0H, R =Me) (D. Cortes et al., Compt Rend, 1984, 299, 311) and melosmine (122, R=H) and melosmid-ine (122, R=Me), the last two being methylated in the same position as the unusual cularine alkaloid gouregine (V. Zabel et at., J.nat.Prod., 1982, 94). Two other c-methylated 

Itokawa and M. Fujita, ibid., 1974, 3609 Kunimo-to, Y. Murakami and Akaso, Yakugaku Zasshi, 1980, 100, 337  

Zhu et at., Heterocycles, 1982, T7 345. The structure (125, Ri=R2=oMe) for pontevedrine has been confirmed by synthesis of the alkaloid by photo-catalysed cyclisation and oxidation of the lactam (128) in alkaline solution, followed by y-methy-lation (Castedo et al.. Tetrahedron Letters, 1978, 2179) and norcepharadione-B has been synthesised by a Diels-Alder addition of benzyne to the masked diene 1,6,7-trimethoxy-l-methyl-tetrahydroisoquinol ine-3,4-dione (Castedo et al.. Tetrahedron Letters, 1982, 23, 451). 

New aporphine alkaloids are cabudine (11), from Thalictrum isopyroides, which is also the first aporphinoid to incorporate a hydroxymethyl substituent and liridinine (12), obtained from Liriodendron tulipifera L. tulipifera has also yielded N-acetylnornuciferine (13), as well as 7V-acetylasimilobine (14). Interestingly 

Known aporphines reisolated from natural sources are  

Kiryakov, I. A. Israilov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1974,411 Chem. Natural Compounds, 1975,10, 418. 

Ocotea macrophylla Pteridophyllum racemosum Alphonsea ventricosa Ocotea macrophylla Liriodendron tulipifera Liriodendron tulipifera Alphonsea ventricosa Ocotea glaziovii  

marschalliana Cissampelos pareira Glaucium ftavum Cissampelos pareira Corydalis cava  

Aporphine synthesis is classified in this section into four subsections A, B, C, and D according to the location of the guiacol-type oxygenation pattern. 

Reagents a. Pb(0Ac)4, AcOHjb. ACjO, c.H2SO4 c. 4NHCI,MeOH ci. LiAIH4, THF e. CH2N2, MeOH 

Aporphines having various oxygenation patterns in ring D were also synthesized by a similar methodology (29). Starting from ( )-l-(4-benzyloxy-3-methoxybenzyl)- and ( )-1 -(3-benzy loxy-4-methoxyben-zyl)-l,2,3,4-tetrahydro-6-methoxy-2-methylisoquinolin-7-ols (30 and 31), 

Reagents a. PbfOAclu, AcOH t). CF3COOH, CH2CI2 c, 5oPd-C, H2, MeOH, H il. CH2N2, MeOH 

9-phenoxyaporphine (46) was obtained in 49% yield from ( )-l,2,3,4-tetrahydro-6-methoxy-l-(4-methoxy-3-phenoxybenzyl)-2-methylisoquin-olin-7-ol (45). Reductive dephenoxylation of 46 with sodium in liquid ammonia (34) gave ( )-1-hydroxy-2,10-dimethoxyaporphine (47), methylation of which afforded ( )-l,2,IO-trimethoxyaporphine (48), 

The simplest biosynthetic sequence is found in bulbocapnine 6.129). Oxidative coupling occurs here between the sites ortho to the 

The importance of 0-methylation pattern in deciding the course of coupling is well illustrated by results of a study on the biosynthesis of thebaine 6.151) and isothebaine 6.135) which are both natural constituents oiPapaver orientale. Whereas reticuline 6.127) is modified to give thebaine 6.151) (Section 6.3.4) orientaline 6.132) differing from reticuline in the location of one methyl group, has a quite different fate in isothebaine 6.135). In other cases a precursor, with the wrong methylation pattern, fails to yield alkaloid. 

A key role for dienones, e.g. [6.133) and [6.137), in aporphine alkaloid biosynthesis is apparent. Their importance is emphasized by their natural occurrence. One such is crotonosine [6.141) formed 

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Tuduranine, CjgHjgOgN. This member of the aporphine group (p. 306) is the most recent addition to Sinomenium alkaloids and was isolated by Goto from the mother liquors of sinomenine. It is crystalline, has m.p. 125° (with softening at 105°), and yields a sparingly soluble hydrochloride, m.p. 286° (dec.), [a] f — 148° (dilute MeOH), is freely soluble in alkali, and gives feeble ferric chloride and diazo-colour reactions and a fuchsin-red colour with formaldehyde and sulphuric acid. It behaves as a secondary base and yields a diacetyl derivative, m.p. 170°, [a] / — 321-71° (MeOH), which does not form a methiodide, but can be hydrolysed to A -acetyl-tuduranine, m.p. 277°, — 395-24°, and this can be methylated to... 

Later Goto and Shishido prepared di-3-ethoxy-5 6-dimethoxy-A -ethylnoraporphine ethiodide, m.p. 186-7°, and this, by the Hofmann degradation process, gave the ethiodide of the de-At-ethyl base, m.p. 194°, from which the dimethoxyethoxyvinylphenanthrene, m.p. 108°, was obtained, identical with that from natural Z-tuduranine. The latter is therefore 3-hydroxy-5 6-dimethoxy-A -H0)aporphine. A later paper (1941) also relating to tuduranine is not yet accessible. 

Eximidine, Ci,Hj40N(0Me)3. (Item 36 list, p. 172.) A phenolic base, m.p. 133°, yielding a methiodide, m.p. 218° (dec.). It is isomeric with corydine and possibly belongs to the aporphine group (Manske). ... 

It is convenient at this point to deal with the remaining alkaloids of the aporphine group, viz., domesticine, roemerine and the alkaloids of the Anonaceae, Lauraceae and Monimiaceae. 

Alkaloids of the Anonace. This botanical family belongs to the natural order Anonales, which is nearly related to the Laurales, in which are included the families Lauraeeas and Monimiaeeas. It is not surprising, therefore, that the characteristic alkaloids found in these families are of one type, namely derivatives of aporphine. 

Berberine is probably the most widely distributed alkaloid. It and the allied alkaloids palmatine, jatrorrhizine, columbamine and coptisine occur somewhat frequently in the Rhcnadales (list, p. 169) as the tetrahydro-derivatives, but, in the botanical families referred to in the distribution list below, the tetrahydro-derivatives are exceptional and the unreduced alkaloids usual. The associated alkaloids include two members of the aporphine group, domesticine and t odomesticine (p. 315), one member of the cryptopine group, y-homochelidonine (p. 294) and two members of the double woquinoline type, viz., berbamine and oxyacanthine (p. 346). 

If the union occurs in such a position that loss of hydrogen with re-formation of a true aromatic nucleus is feasible, an aporphine base will result. 

Centrine and aporphine have been synthesized by cyclizations analogous to that of Eq. (23). 

The addition products were used for the total synthesis of racemic aporphine, protoberine, quettamin, and phthalide alkaloids26,24. 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

Langlois, A., Mulholland, D. A., Crouch, N. R. and Grace, O. M. 2004. Aporphine alkaloid from Papaver aculeatum (sect. Horrida Papaveraceae) of southern Africa. Biochem. Syst. Ecol. 32 1087-1090... 

Although several oxidative C—C bond cleavages have been observed, the only method useful for transformation is C-8—C-8a bond cleavage. Treatment of berberine (15) with m-chloroperbenzoic acid in dichloromethane in the presence of sodium bicarbonate at - 78°C gave polyberbine (66) and N-formylnoroxyhydrastinine (69, R1 + R2 = CH2) in 20 and 15% yield, respectively (Scheme 16) (54). Similar treatment of palmatine (64) and coptisine (65) led to polycarpine (67) and the enamide 68, respectively, in 40-50% yield (55). The yield of polyberbine was improved to 76% when.the oxidation was carried out in tetrahydrofuran in the presence of sodium hydride however, the yields of 67 and 68 could not be improved under the, same reaction conditions (56). The products were used for synthesis of tetrahydroprotoberberine (Section V,I,5) and aporphine alkaloids (Section V,J,3). 

Oxidative conversion of palmatine, berberine, and coptisine to polycarpine, polyberbine, and its analog was described in Section II,B. These products were further transformed to aporphine alkaloids having a phenolic hydroxyl group at C-2 in the bottom ring (55). Hydrolysis with concomitant air oxidation of polyberbine (66) furnished 3,4-dihydrorugosinone, which was further air-oxidized in ethanolic sodium hydroxide to give rise to rugosinone (501) (Scheme 105). Successive reduction of the enamide 68 with lithium aluminum hydride and sodium borohydride afforded a mixture of ( )-norledecorine and (+ )-ledecorine (502). N-Methylation of the former with formaldehyde and sodium borohydride led to the latter. 

Scheme 105. Synthesis of the aporphine alkaloids rugosinone (501) and ledecorine (502). Reagents a, MeOH b, NaOH, EtOH c, LAH d, NaBH e, HCHO then NaBH4.

The pseudobenzylisoquinoline alkaloids are fairly widespread in nature, being found among members of Berberidaceae, Annonaceae, Fumariaceae, and Ranunculaceae. The biogenesis of the pseudobenzylisoquinoline alkaloids assumes their formation from protoberberinium salts by C-8—C-8a bond scission in a Baeyer-Villiger-type oxidative rearrangement to produce the enamides of type 73 and 74. These amides may be further biotransformed either to rugosinone (76) type alkaloids by hydrolytic N-deformylation followed by oxidation or to ledecorine (75) by enzymatic reduction. These transformations were corroborated by in vitro studies (80-82). It is suggested that enamide seco alkaloids may be precursors of aporphine alkaloids (80), on one hand, and of cularine alkaloids (77), on the other. 

The following secodimeric alkaloids have been isolated from natural sources (+)-hernandaline (197), from Hernandia ovigera L. (158), (—)-natalinine (198) (759), and (+)-coyhaiquine (199) (160), the two latter from Berberis empetrifolia Lam. with the yields 0.00005 and 0.00008%, respectively. Appropriate aporphine-benzylisoquinoline or proaporphine-benzylisoqui-noline dimers are probably precursors of these seco alkaloids, although... 

The synthesis of morphinandienone (22) and aporphine (23) derivatives has been achieved photochemically through irradiation of diazo compound (21) 40) ... 

The potential properties of A. suaveolens Bl. has a source of topoisomerase II inhibitor is open for exploration. The plant probably elaborates aporphine alkaloids because aporphines are known to occur in the genus Artabotrys (2,3), Liriodenine and athero-spermidine from Artabotrys undnatus and artabotrine from Artabotrys zeylanicus abrogated the survival of cancer cells cultured in vitro (4). 

In Malaysia, a paste of leaves is applied to sore legs, and a decoction of the leaves is drunk as a protective remedy given after childbirth. To date, the pharmacological potential of F. fulgens (Hk. f. et Th.) Merr. is unexplored. It would be interesting to learn whether further study on this medicinal plant disclose any aporphines of chemotherapeutic interest. 

The plant is used by Malays to assuage body pains, and a decoction of roots is drunk as a protective remedy after childbirth. The pharmacological properties of this plant are unknown, but it is very probable that it elaborates aporphines and flavonoids as characterized in Oxymitra velutina (5). 

Cassytha filiformis L., mentioned earlier, contains aporphine alkaloids such as actin odaphnine, cassythine, and dicentrine, which effectively bind to DNA and behave as typical intercalating agents and interfere with the catalytic activity of topoisomerases (3,10,11). 

The family Hernandiaceae consists of four genera Hernandia, Illigera, Gyrocarpus, and Sparattanthelium, and about 60 species of trees, shrubs, and woody climbers widespread in tropical regions. An example of Hernandiaceae is Hernandia ovigera L., which is grown as a tropical street tree. Hernandiaceae are member of the order Laurales and are known to abound with aporphines and lignans. 

In the Philippines, the sap expressed from the stem is drunk to alleviate headache. Using antiplatelet aggregation as a guide to fractionation, Chen et al. isolated a series of aporphines including actinodaphnine, N-methylactinodaphnine, launobine, dicentrine, O-methylbulbocapnine, hernovine, bulbocapnine, and oxoaporphines dicentrinone and liriodenine were isolated from the stems of I. luzonensis (13). 

N-methyl-actinodaphnine possesses 5-hydroxytryptamine receptor blocking activity and a selective antagonist of cq-adrenoceptors, selective for the a1B. than for the a1A-adrenoceptor subtype (14). What are the activities of N-methyl-actinodaphnine and other aporphines of Illigera and Hernandia species against topoisomerase ... 

Wu YC, Chen CH, Yang TH, et al. Cytotoxic aporphines from Artabotrys uncinatus and the structure and stereochemistry of artacinatine. Phytochemistry 1989 28 2191-2195. 

Later, squamolone was isolated from Hexalobus crispiflorus A.Rich, along with aporphine alkaloids, and the methoxyurea 31 (70) H. crispiflorus was collected in Nigeria. The genus Hexalobus consists of five species growing in southern and tropical Africa and Madagascar. The possibility of 31 being an extraction artifact of an unknown precursor has been considered. 

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