Aporphines oxidation

Domesticine, C19H19O4N was obtained by Kitasato (38) from Nandina domestica Thunb. (Berberidaceae) along with isodomesticine. The fonner melts at 115-117° and has [a] +60.5°. Isodomesticine was obtained in the amorphous condition, but its 0-methyl ether (m.p. 139°, [ ]d +101 to +102° in chloroform) was identical with domesticine 0-methyl ether. Both alkaloids are tertiary, and contain one methoxyl, one phenolic hydroxyl, and a methylenedioxy group. The absorption spectra indicate that these alkaloids are aporphines. Oxidation of domesticine with permanganate was stated to yield 4,5-methylenedioxybenzene-l,2,3-tri-carboxylic acid (38), but this cannot be so in view of the work of Kitasato and Shishido (39) who synthesized epidicentrine and resolved it and showed that the d-base (m.p. 138-139°, [a] +102° in chloroform) was identical with domesticine 0-methyl ether. There remained the determination of the position of the hydroxyl, and this was achieved by a s3mthesis of domesticine 0-ethyl ether (m.p. 132°) (40). Both syntheses followed the well-known routes leading to aporphines. In the first case 6,7-dimethoxy-... 

In the first authenticated dimerization of an aporphine, oxidation of (+)> bulbocapnine methyl ether (30) with iodine provided the dimer 36. Reduction of 36 with zinc in dilute sulfuric acid led to racemic 30, whereas reduction with lithium aluminum hydride supplied a pair of diastereomeric dimers 37. ... 

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. 

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. 

Oxidative coupling of aryl tetrahydroisoquinolines. This reagent is superior to thallium(III) trifluoroacetate or vanadium oxyfluoride for nonphenolic oxidative coupling of substrates such as 2 to provide aporphines and homoaporphines (3). 

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). 

Initially Robinson and Sugasawa (8) proposed that laudanosoline (5), prepared from laudanosine (4) by O-demethylation with aluminium chloride in refluxing xylene, could be oxidized to an aporphine or morphine prototype. To demonstrate that no rearrangement had occurred, 4 was regenerated from 5 by O-methylation. Oxidation of 5 was accomplished with chloranil in buffered alcohol solution, and 6 was isolated in 60% yield as the chloride (Scheme 1). Di-benzopyrrocoline 6 was also obtained in 30-50% yield when aqueous solutions... 

Lead tetraacetate in acetic acid oxidizes phenolic 1-benzylisoquinolines to p-quinol acetates which usually rearrange to aporphines in trifluoroacetic acid (25). However, Blasko et al. (24) recently reported that lead tetraacetate oxidized ( )-A -norlaudanosine (34) to dibenzopyrrocoline 35 in 16% yield. 

Oxidative coupling of (5)-(-)-laudanosoline (5) with horseradish peroxidase in the presence of hydrogen peroxide, studied by Brossi et al. (27), afforded dibenzopyrrocoline (—)-6 in 81% yield, and conversion to (5)-(—)-0-meth-ylcryptaustoline (14) by methylation provided additional proof for the absolute configuration of this and related alkaloids. Enzyme specificity in the C— coupling reaction was demonstrated with similar oxidation of (/ )-(—)-laudanosoline methiodide, which afforded an aporphine converted by O-meth-ylation to (R)-(-)-glaucine. 

Oxidative phenolic coupling.1 A new hiomimetic approach to morphine alkaloids involves oxidative intramolecular coupling of the reticuline derivative 1 to a salutaridine derivative 2 with VOCl3 in ether.1 If the reaction is conducted in CH2C12 2 is obtained in markedly lower yield and the undesired aporphine 3 is formed as a major product. The dienone 2 has been converted into 2-hydroxycodeine (4). 

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... 

M. Shamma and H. Guinaudeau, Tetrahedron 40, 479S (1984). Biosynthesis of aporphinoid alkaloids. In addition to monomeric alkaloids, discusses proaporphine- and aporphine-benzyliso-quinoline dimers, dimeric oxidized aporphines, and types derived by catabolism of benzyliso-quinoline-derived dimers. 

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... 

A full paper has appeared describing the oxidation of 6-hydroxylated tetrahy-drobenzylisoquinolines of type (38) with lead tetra-acetate, to furnish the corresponding ortho-quinol acetates (39), which can readily undergo cyclization to the corresponding aporphines in acid solution. Predicentrine (40), isodomesticine (41), boldine (42), and 2,10-dihydroxy-1,9-dimethoxyaporphine (43) were prepared by such a route, which is, therefore, a practical pathway for the synthesis of 2-hydroxylated aporphines.27... 

The conversion of reticuline N- oxide into the aporphine corydine under the influence of cuprous chloride has been described in full.28... 

A new biogenetic route to the aporphines has been proposed which does not involve phenolic oxidative coupling, and which proceeds through the intermediacy of protoberberinium salts.6 The alkaloid polycarpine (44) must be derived biogenetically from palmatine (45), and indeed oxidation of (45) in vitro with m-chloroperoxybenzoic acid, followed by hydrolysis, leads to polycarpine (44). Since it is known that photocyclization of simple benzylisoquinoline... 

Glaunine (67) and glaunidine (68) are two new oxoaporphines from Glaucium fimbrilligerum (Papaveraceae).47 Arosine, found in G. flavum Cr. var. vestitum, must be identical with glaunidine, while arosinine, from the same source, possesses structure (69).48 Oxidation of the aporphine corydine with iodine and... 

Three other new 7-hydroxylated aporphines have also been isolated from the tuberous roots of S. venosa they are all identified to be the /V-oxides of identical configuration, namely, (-)-sukhodianine /3-N-oxide (46), (-)-ushinsunine /3-,/V-oxide (47), and (-)-stephadiolamine f3-N-oxide (48). The cis relationship between H-6a and H-7 is indicated from the NMR spectrum, and a partial NMR NOE study clarified the configuration of the N-oxide function (30). 

It is interesting to note that the occurrence of C-7 oxygenated aporphine alkaloids with the C-6a R configuration is limited to the families Annonaceae, Lauraceae, Magnoliaceae, and Menispermaceae. Aporphine alkaloids oxygenated at both C-4 and C-7 have been found in the Annonaceae, but (-)-stephadiolamine /3-A-oxide (48) is the first known alkaloid hydroxyl-ated at both C-4 and C-7 and having a cis relationship between H-6a and H-7. (-)-O-Acetylsukhodianine is the first known example of a naturally occurring 7-acetoxylated aporphine (30). 

The oxidation of non-basic and monophenolic tetrahydrobenzylisoquinolines with VOF3-TFA is a superior method for aporphine preparation. N-Trifluoroacetylnorcodamine (32), under these conditions, gives a 70% yield of N-trifluoroacetylnorthaliporphine, while the codamine-borane complex (33) provides thaliporphine (28) in 80% yield. The reaction has also been extended to the preparation of homoaporphines.2... 

Full experimental details have appeared on the synthesis of bracteoline, isoboldine, N-methyl-laurotetanine, and related aporphines, through oxidation with... 

An improved method for the preparation of apomorphine has been claimed, the details of which were not available to the Reporter.35 A promising new approach to the aporphines is through the oxidative coupling of two aromatic rings to furnish a biaryl system, using thallium trifluoroacetate.36... 

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