Oxidation of aporphines

The photo-oxidation of aporphines to dehydroaporphines has been described.48 A stereospecific and quantitative oxidation of (+)-glaucine (45) to dehydroglaucine (46) was achieved with Fusarium solani. Using this same micro-organism, (—)-glaucine was not metabolized, while ( )-glaucine was oxidized to the extent of 50%.49... 

Thermolysis of aporphine A -oxides (184), easily obtained by peracid oxidation of aporphines, gives variable yields of yV-phenanthrylethyl hydroxylamines (185). These may be transformed by reduction and N-alkylation into the corre-... 

The oxidation of aporphines containing phenolic hydroxy-groups has been studied. The mode of oxidation of apomorphine has been shown to be dependent... 

The oxidation of aporphines with air, iodine, or mercuric acetate has been shown to be dependent on the presence and position of hydroxy-groups, and isothebaine has been shown to give the salt (67). ... 

The reagent that had originally been used commonly for the oxidation of aporphines to oxoaporphines was chromium trioxide in pyridine (14-16). A recent study by Cava and co-workers of the oxidation of aporphines and dehydroaporphines has led to the development of superior methods of oxidation which may be summarized as follows (27a). 

It has been pointed out that oxoaporphines are probably formed in nature by the oxidation of aporphines. Substantial support for this hypothesis comes from the fact that in several instances the corresponding aporphine or noraporphine base is found in the same plant... 

Aristolochic acids and aristolactams possess skeleta (66) and (67), respectively, and are often found in the same plant. The aristolochic acids are among the small group of natural products incorporating a nitro-function. Compounds belonging to these two classes are non-basic, but can nevertheless be classified as alkaloids since they are derived from in vivo oxidation of aporphines. The last review on this dual topic appeared in 1961. ... 

For a description of methods of oxidation of aporphines and noraporphines to oxoaporphines, see Sec. 10.3.1. Total syntheses of oxoaporphines usually involve the elaboration of a C-2 or a C-6 appropriately functionalized aromatic benzylisoquinoline, which is then cyclized by a Pschorr or photochemical sequence. 

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. 

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... 

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. 

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... 

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). 

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... 

On the other hand, the oxidation of the tetrahydrobenzylisoquinoline (23) by thallium(m) acetate resulted in cyclization as well as in acetoxylation, so that the aporphine (30) was obtained in 35% yield.1... 

The oxidation of the nor-reticuline derivatives (40a) and (40b), using a variety of tetraethylammonium diacyloxyiodates as oxidizing agents, supplied good yields of the norisoboldines (41a) and (41b).46a This marks the first recorded use of diacyliodates for the synthesis of aporphines. 

Oxidation of noraporphines and aporphines with Fremy s salt gives oxoaporphines and oxoaporphinium salts, respectively.75 Aerial oxidation of dehydro-aporphines in the presence of alkali provides the corresponding oxoaporphines, 4,5-dioxoaporphines, and A-methylaristolactams.76 An analysis of the 13C n.m.r. 

Corunnine, Nandazurine, ( )-Caaverine, ( )-Isoboldine, ( )-Thalicmi-dine, and ( )-Domesticine. Relative to the aporphine synthesis by enamide photocyclization, Kupchan and O Brien (141) have developed the oxidative photochemical synthesis of aporphine alkaloids. 

MonophenoUe oxidative coupling. Kupchan et al have reported use of the VOF3-TFA/TFAA system for synthesis of aporphines by monophenolic intramolecular oxidative coupling. 

Hoffmann degradation is a classic way to transform aporphines into phe-nanthrene alkaloids. This transformation involves the thermolysis of the quaternary ammonium hydroxide formed by sequential treatment of an aporphine with an alkylating agent and silver oxide. This degradation was extensively used in initial degradative studies of the structure of aporphines. The alkylations are usually done with methyl iodide (20,30,45,60,85,86,88) or dimethyl sulfate... 

The first synthesis of an aporphine using phenolic oxidative coupling was reported in 1962 when oxidation of W-methyllaudanosoline meth-... 

Exciting new developments have occurred related to the synthesis of aporphines. It has been conclusively shown that VOF3-TFA oxidation of N-formylnorlaudanosine (15) provides in high yield the neospirinedienone (17) via the morphinandienone intermediate (16) which undergoes loss of the original C-6 methyl substituent (Scheme 1)/... 

The drugs were dissolved in degassed ultra pure water with approximately 0.5 mg/ml ascorbic acid to prevent oxidation of the compounds and stocked in a concentration of 300 nmol/ml for subcutaneous administration and 10 pmol/2 ml for oral administration and diluted, if necessary, with degassed ultra pure water before administration. To dissolve R-(-)-ll-hydroxy-aporphine a drop of glacial acetic acid was added. Drugs used were R-(-)-apomorphine.HCl (11), R-(-)-ll-hydroxyaporphine (79), R-(-)-N- -... 

In the early 1970s, our attention was directed to the Wessely acetoxy-lation (13). LTA oxidation of phenolic tetrahydroisoquinolines was exploited in our laboratory to give the corresponding p-quinol acetates, which were proved to be the reactive intermediates for the aporphine synthesis (14-15)-, that is, when an electron-rich benzene ring was present in a given p-quinol acetate, C-C bond formation occurred intramolecu-larly on its acid treatment. 

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