Alkaloids, aporphine

Aporphine Alkaloids.—The biosynthesis of the proaporphine and aporphine alkaloids of Croton sparsiflorus has been investigated and found to be unexceptional. Thus [2- C]tyrosine was found to be a precursor for crotsparine (74), crotsparinine (75), and sparsiflorine (76). Moreover, labelled ( )-coclaurine (77), but not ( )-isococlaurine (78), was found to give radioactive alkaloids. Coclaurine was also shown to be present in C. sparsiflorus by means of a trapping experiment using [2- C]tyrosine and inactive coclaurine radioactive coclaurine was isolated at the end of the experiment. 

These results provide strong evidence that coclaurine is a normal intermediate in the biosynthesis of the alkaloids in this plant, and they are in accord with theory and the substantial body of results obtained for alkaloids of this type in all cases the benzylisoquinoline precursor on which cyclization occurs has hydroxy-groups ortho or para to the sites involved in ring closure. Further detail is that crotsparine (74), crotsparinine (75), and sparsiflorine (76) are converted in vivo into their respective N-methyl derivatives.  

The possible interrelationships of (74), (75), and (76) have not been investigated, but it is to be noted that (74) and (76) are of opposite configuration to (75) at C-1, suggesting that (74) and (76) biosynthesis diverges from that of (75) by way of the appropriate enantiomer of coclaurine (77). 

In practice a particular aporphine alkaloid may be derived a priori from a number of diphenolic benzylisoquinoline precursors either by direct coupling or through the genesis of a dienone intermediate as seen above. Thus in the study of the superficially simple alkaloid boldine (79), a number of benzylisoquinoline precursors had to be tested. Experiments were carried out with labelled samples of ( )-norprotosinomenine (83), ( )-nororientaline (84), ( )-4 -o-methyl- 

The methylation pattern of boldine (79) might have been taken to indicate a biosynthetic pathway similar to that of the aporphine alkaloids of Dicentra but the above results clearly refute this idea. The change in the methylation pattern from reticuline (82) to boldine (79) is not apparently due to methyl migration for ( )-[6-0 CH3,l- H]reticuline [as (82)] was incorporated with loss of 64% of the labelsimilar results have been obtained in the related case of crotonosine biosynthesis.  

Aporphine Alkaloids.—Isothebaine (65) derives from orientaline (62) along a pathway which involves thedienone(63)and the dienol(64). The biosynthesis of the aporphine alkaloids of Dicentra eximia is quite different but dienone intermediates are also implicated. By comparison the biosynthesis of bulbocapnine (66) is simple, for the alkaloid arises directly from reticuline (67), in Corydalis cava, by ortho-ortho phenol oxidative coupling. 

Further experiments have been directed towards proving that reticuline is a natural constituent of C. cava. Thus it could be diluted out with inactive material 

Mizusaki, T. Kisaki, and E. Tamaki, Agric. and Biol. Chem. (Japan), 1965. 29, 

Ratych, and J. Salnikow, Hoppe-Seyleds Z. physiol. Chem., 1967, 

Blaschke, G. Waldheim, M. von Schantz, and P. Peura, Arch. Pharm., 1974, 307, 

RELATIVE RETENTION TIMES OF APORPHINE DERIVATIVES VS. 2-CHLOROAPORPHINE1 

A highly specific and sensitive method for the determination of berberine in urine was de- 

RETENTION TIMES OF SILYLATED DERIVATIVES OF APORPHINE AND TETRAHYDROPROTOBERBERINE ALKALOIDS2 

CHROMATOGRAPHIC SEPARATION OF SILYLATED APORPHINES AND TETRAHYDR0PR0T0BERBERINES2 Glass column 6 ft by 4 mm, 3 % OV-1 on Gas Chrom Q 100-120 mesh at 260°C 

Because N-n-propylnorapomorphine is reported to be several times more potent than apomor- 

The conversion of reticuline (41) into protoberberine alkaloids (coreximine and scoulerine), a morphinandienone alkaloid (pallidine), and an aporphine alkaloid (isoboldine) by rat-liver enzyme has been reported.  

The configuration of (76) at C-1 is (5), indicating its derivation from (5)-reticuline. This was confirmed in a feeding experiment with the enantiomers of nor-reticuline (80). 

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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 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). 

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). 

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. 

Goren, A. C., Zhou, B.-N. and Kingston, D. G. I. 2003. Cytotoxic and DNA damaging activity of some aporphine alkaloids from Stephania dinklagei. Planta Medica, 69 867-868. 

Apomorphine 169, 170 Aporphine alkaloids 151, 152 Apparicine 16, 147 Arborine 105, 106 Arctigenin 39 Aren tin 41, 47 Arecaidine 86... 

A novel and efficient synthesis of aporphinic alkaloids has been developed by Kupchan and O Brien (55) via oxidative photocyclization of l-(a-hydroxy-2-iodobenzyl)-6-hydroxy-7-methoxyisoquinolines such as 120, 121, or 122, all prepared by the Reissert method shown in Scheme 17. N-Methylation of oxo-aporphines 124 and 125 yielded corunnine (127) and nandazurine (128), respectively. Reduction of 124 with Zn-AcOH resulted in thalicmidine (130), and similar reduction of 125 gave domesticine (131) in racemic form. Caaverine (129) has also been prepared by this route (55). 

Misik, V., L. Bezakova, L. Malekova, and D. Kostalova. 1995. Lipoxygenase inhibition and antioxidant properties of protoberberine and aporphine alkaloids isolated from Mahonia aquifolium. Planta Med. 61 372-373. 

Aporphine alkaloids have been identified in Eupomatia laurina, which also gave a positive test in this study. 

The novel aporphine alkaloids romucosine F (1140) from Annona purpurea... 

A minor constituent of P. somniferum is the aporphine alkaloid isoboldine (Figure 6.58). Other species of poppy, e.g. Papaver orientale and P. pseudoorientale, are known to synthesize aporphine alkaloids as principal constituents rather than morphinan structures. (Aj-Isoboldinc is readily appreciated to be the product of oxidative coupling of (5)-reticuline, coupling ortho to the phenol group in the tetrahydroisoquinoline, and para to the phenol of the benzyl substituent... 

The H NMR spectrum of glaucine [12] (18) shows features typical of aporphine alkaloid spectra, with low frequency absorption of the... 

A survey of the H NMR spectra of the benzylisoquinoline-aporphine alkaloids [60]—[65] enables assignment of some of the methoxyl proton resonances. The lowest frequency methoxyl proton signals at ca. 8 3-58 are characteristic of a 7 -methoxyl function, and the 10-methoxyl protons are found to absorb to higher frequency of 8 3-90. (52) This latter shift is also shown in the spectrum of fetedine [66] the aromatic proton signals of which are completely resolved at 220 MHz. (53) In the... 

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