Of aporphines

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. 

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. 

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). 

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). 

Woldemariam, T. Z., J. M. Betz, and P. J. Houghton. 1997. Analysis of aporphine and quinolizidine alkaloids from Caulophyllum thalictroides by densitometry and HPLC. J. Pharm. Biomed. Anal. 15 839-843. 

The c-ring expansion of aporphines via the dichlorocyclopropane ring opening238 induced by LAH has been utilized in a synthesis of homoaporphine alkaloids (equation 93). Reductive cleavage of 2-silyloxy-dibromocyclopropanes gives a,(3-unsaturated ketones directly (equation 96).239... 

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

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... 

Alternatively, reduction of the keto-imine (20) with sodium borohydride gave a mixture of two carbinols corresponding to N-demethylated (16) and (17). Irradiation of this mixture produced norushinsunine together with a little noroliveroline. Photolysis of the alcohol (21) gave rise to the oxoaporphine liriodenine (22).21 Synthetic routes to those aporphines that incorporate a hydroxyl group at C-7 that is trans to the proton at C-6a are already known.22 23 A novel synthesis of aporphines via 3-phenylphenethylamines has been developed, and is described in Scheme 1. The aporphine (23) and related species were then synthesized by a modified route.24... 

A detailed study of the carbon-13 n.m.r. spectra of aporphines has appeared,37 and an X-ray analysis of N,0-diacetyl-4-hydroxynornantenine (60) has been carried out.38 The gas-chromatographic and/or mass spectral behaviour of a series of aporphines as their trimethylsilyl or trifluoroacetyl derivatives has been... 

The alkaloids corydine, bulbocapnine, and isocorydine have an adrenolytic effect (427, 428). All of them, including glaucine, act cholinergically (429, 430) this effect is, however, smaller than that of dehydrocholic acid. For the synthesis and pharmacology of aporphine, the pharmacology of (— )-nornuciferine and of pukateine, see Kupchan, et al. (379), Weisbach et al. (431), and Smith et al. (432, 433), Burkman and Cannon (434), and Fogg (435). 

The radical or anion species generated by electroreduction of halides are able to add to unsaturated systems such as aromatic ring and carbonyl group. The intramolecular addition of a radical species formed by electroreduction of an aromatic iodide to an aromatic ring has been applied to the synthesis of aporphines as it is shown in the following scheme 32). 

Transformations of aporphines by microorganisms involving O- and N-demethylation (89, 92) and CH—CH dehydrogenation (92) have been reported. In a preliminary screening study, Wolters reported the metabolism of boldine and a related alkaloid of undisclosed structure to unidentified products by Piricularia oryzae (42). More detailed studies with a series of microorganisms have been carried out by Rosazza and co-workers (89, 92). 

Still another DA receptor model, based on the study of aporphines, takes chirality factors into consideration. This model suggested by Neumeyer (16, 96) postulates an obstruction or "obstacle" on the receptor that precludes appropriate interaction of aporphines in the 6aJ> configuration with the receptor. This model, in common with many others, also takes into account OH binding sites, conformational aspects, steric hindrance factors, and N-substitution with the observation as noted elsewhere (e.g., 97), that N-substitution with groups as large as propyl may provide supplemental binding to favor D-2 receptor interaction. As the asymmetric center of apomophine is located on the carbon ct to the N, whereas in I-III it is located on the ben-... 

Barolo, S.M., Teng, X., Cuny, G.D. and Rossi, R.A. (2006) Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via SRn1 reactions in liquid ammonia. Journal of Organic Chemistry, 71, 8493—8499. 

Many reports on tributyltin hydride-mediated intramolecular aryl-aryl coupling reactions have appeared in the literature in the 1990s [27, 121], One of the latest articles, in which many references on previous work have been included, focuses on the preparation of aporphines (Scheme 23) [122], Due to steric repulsion, an undesired 5-endo cyclization of the aryl radical on the imine nitrogen atom occurs only when more bulky substituents R are present in the benzyldihydroisoquinoline 64. With R = H, the cyclization to 65 proceeds in high yields. 

A record number of new aporphine alkaloids, sixteen, has been isolated and characterized during the year under review. Even better methods for the synthesis of aporphines in high yields have been developed,1-3 and an interesting relationship between aporphines, morphinandienones, neoproaporphines, and spirinedienones has been pointed out.1 A novel and unusual alkaloid is eupolauramine (70), which is structurally related to the aristolactams but which incorporates an additional nitrogen atom in ring A.4... 

Some of the most interesting endeavours towards the efficient synthesis of aporphines were cut short by Prof. Kupchan s untimely death. The following,... 

Another superior synthesis of aporphines is that devised by Neumeyer and Gottlieb it proceeds through the cathodic cyclization of a l-(o-iodobenzyl)iso-quinoline methiodide (Scheme 5). Electrolysis of (34) followed by reduction gave rise to 10,11-dimethoxyaporphine (35). Aporphine itself has also been prepared, by a parallel route.3... 

Acid-catalysed Grewe cyclization of the partially reduced benzylisoquinoline (38) resulted in the formation of aporphines (39)—(41).29... 

Table 216-42 includes a listing of aporphines that have recently been re-isolated. 

In a continuing study of the synthesis of aporphines via o-quinol acetates, 1,2-diacetoxyaporphines of the type (32) were obtained in good yields by treatment of solutions of the o-quinol acetates (31), in acetonitrile, with concentrated sulphuric acid in acetic anhydride.45... 

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. 

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... 

The preparation and anti-tumour activity of a series of aporphine nitrogen mustards have been reported.65... 

Photocyclization of the former type of enamides for the synthesis of aporphine alkaloids will be summarized in the following section. 

Photocyclization of 1-benzylideneisoquinolines to the Aibexao[d,e,g -quinolines is a well-studied example of the above stilbene-phenanthrene cyclization and therefore has been extended to the development of new photochemical methods for the synthesis of aporphine alkaloids (11-14). In this section, photocyclization of 2-acyl-1 -benzylideneisoquinolines to dehy-droaporphines and their subsequent conversion to aporphines and oxo-aporphines are summarized. 

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