Aporphines, synthesis

Recently, Castedo et al. (137) studied enamide photocyclization for aporphine synthesis and modified Cava s procedure (135 -137) after consideration of the reaction course and structural requirement for the exclusive formation of aporphine. Castedo s group concluded that an enamide should have a forced m-stilbene geometry, in order to avoid an undesired mode of cyclization leading to protoberberine-type compounds and also to avoid a facile conversion to oxoaporphines after cyclization. 

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. 

PSCHORR APORPHINE SYNTHESIS 6-Methoxy-7-hydroxy-3,4-dihydroisoquino-linium melhiodide. 

Pschorr aporphine synthesis, Kupchan el al.2 have reported an improved synthesis of aporphines by using (1) for condensation with o-nitrotoluenes (2) in the presence of potassium t-butoxide in DMA to give l-(2-nitrobenzyl)-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinolines (3) in yields of 88-95%. These are hydrogenated to the... 

Since the mid-1950s, phenol oxidative coupling (7) has been actively applied to the synthesis of many types of alkaloids, with considerable progress being achieved especially in the field of isoquinoline alkaloids (8-H). As to aporphine synthesis, employment of new reagents such as vanadium oxyfluoride (12) greatly improved yields as compared to classical methods such as oxidation with potassium ferricyanide and ferric chloride. 

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. 

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. 

Aporphine synthesis via a p-quinol acetate was first achieved in our laboratory (14,15). LTA oxidation in AcOH of ( )-codamine (11) gave a p-quinol acetate (12) (Scheme 2), the structure of which was characterized by spectroscopic means. Treatment of acetate 12 with acetic anhydride in the presence of concentrated sulfuric acid gave ( )-( -acetylthaliporphine... 

The above-mentioned procedure for aporphine synthesis starting from... 

The use of lead tetra-acetate in aporphine synthesis " has been extended by the conversion of ( )-thaliporphine (30) into the 4-acetoxythaliporphine (31), which could be converted into cataline (32) in high yield (see Scheme). ... 

Scheme 10. Novel photochemical aporphine synthesis via neoproaporphine (40) (416a).

Reissert compounds are useful in the preparation of the benzylisoquino-lines required for aporphine synthesis, and the field has been reviewed. Reissert intermediates have also been used in the preparation of 7-hydroxylated aporphines by the oxazolinone method. 

Aporphine Synthesis - The chemistry of the proaporphine alkaloids (typified by pronuciferine) has been reviewed, including their known conversions, both in vivo and in vitro, to aporphines. 

A new non-oxidative photochemical aporphine synthesis has been discovered, in which the key step involves loss of hydrogen halide on photolysis of an appropriately substituted o-halostilbene- In this way, the natural aporphine dehydroglaucine was synthesized as shown below. ... 

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... 

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). 

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

Recently, a photosensitized synthesis of phenanthrene heterocycles from 1- and 9-(aminoalkyl)phenanthrenes has been achieved109. Irradiation of l-(2-aminoethyl)phen-anthrene and m-DCNB in 9 1 acetonitrile water solution for 2 hours gives 70% of the aporphine 114 and 15% of the dehydroaporphine 115 with 87% conversion of starting material (equation 50). 

Reductive cyclization of the 2-halogenophenyl group onto an adjacent phenyl substituent is a useful reaction for the preparation of condensed ring nitrogen heterocycles. Examples of the process include the formation of aromatic and conjugated 7t-systems [168, 169]. It has been applied to the synthesis of an aporphine... 

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). 

The photocyclization of stilbenes to phenanthrenes has been used in the synthesis of the aporphine ring system347,348 conversion of the... 

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... 

H. Guinaudeau, M. Leboeuf, and A. Cave, J. Nat. Prod. 42, 133 (1979). Dimeric aporphine-benzylisoquinoline and aporphine-pavine alkaloids. Tabulates physical properties, sources, and references to synthesis of 28 alkaloids. 

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... 

Reduction of the keto-iminium salt (15) with sodium borohydride furnished a mixture of alcohols (16) and (17) upon photolysis in acid solution, this mixture afforded oliveroline (18) and ushinsunine (19). The preparation of oliveroline represents the first synthesis of an aporphine that bears an alcohol function attached to C-7 that is cis to the proton attached to C-6a.21... 

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... 

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