Rhoeadine alkaloids

Analogous results were obtained from the reaction of another cycloberbine (183), as depicted in Scheme 33 (102-104). These reactions were applied to synthesis of indenobenzazepine (Section V,F,5) and rhoeadine alkaloids (Section V,G,2). 

Rearrangement of spirobenzylisoquinolines, having a hydroxyl group on ring C trans to the nitrogen, to indenobenzazepines was first reported by Irie et al. (209,210) in their synthesis of rhoeadine alkaloids (Section V,G,1). This... 

Rhoeadine alkaloids have been reviewed (1,2,7-10,217) and compiled (218). Only a few transformations have been developed despite the interesting structural features of these alkaloids. 

The first synthesis of a rhoeadine alkaloid was achieved by Irie et al. (209,210) through skeletal rearrangement of a spirobenzylisoquinoline to an indenobenzazepine. The trans-alcohols 434 and 329 were treated with methanesulfonyl chloride and rearranged to the indenobenzazepine 435,... 

Ronsch (129,130) described the synthesis of ene lactam 152, formally belonging to cordrastine series, from the rhoeadine alkaloid, alpinigenine (150), by Hofmann degradation of its derivative 151 (Scheme 26). Treatment of the nitrile 151 with methyl iodide and then with potassium hydroxide gave ene lactam 152, for which the Z configuration could be deduced on the grounds of UV (365 nm) and H-NMR (57.09 and 7.39, J = 8 Hz) spectral data. 

The structural features that characterize the rhoeadine alkaloids are a seven-membered ring B and the presence of a cyclic acetal or hemiacetal function (2,5) (Fig. 21). In the 13C spectrum of rhoeadine (110) (67) (Table XX) both C-4 and C-5 appear at lower field than the corresponding carbon atoms in most of those alkaloids that have a six-membered ring B. The acetal carbon C-14 is readily differentiated by its low field position relative to other resonances in the aliphatic region of the spectrum. The chemical shifts of the aromatic carbon atoms are similar to those of other classes of alkaloids that carry methylenedioxy substituents on rings A and D. 

I. Phthalideisoquinoline and Rhoeadine Alkaloids.—Spectrophotometric,55,57 precipitation,63 and thin-layer chromatographic (with isobaric solvent systems)61 methods have been reported for the determination of narcotine. 

The IR spectra of oxyrhoeagenine (VIII) showed that the compound contains a six-membered lactone ring in contrast to phthalideisoquinoline alkaloids. A substantial difference in pA values for these two lactone types was also noticed (430). It followed that the suggested tetrahydro-isoquinoline constitution of the rhoeadine alkaloids had to be revised (430). 

The known papaverrubines (Table XX) are A-demethylated compounds of the rhoeadine or isorhoeadine type. Similar to the rhoeadine alkaloids, the papaverrubines occur exclusively in the genus Papaver. The constitution of these compounds was elucidated (388) by correlation of the mass spectra with those of the corresponding rhoeadine-isorhoeadine compounds (126, 430). By methylation of the secondary nitrogen the individual papaverrubines are converted (287, 387, 434) into the rhoeadine or isorhoeadine alkaloids. 

Scheme 19. Probable pathway of the biosynthesis of the rhoeadine alkaloids.

Another possibility might be that the rhoeadine alkaloids arise from protopine alkaloids (see Scheme 20) which are always found present in the plants of the genus Papaver. 

Alkaloid MR-1, MR-3, allocryptopine, coptisine, corysamine, magnoflorine, papaverrubine D and E. protopine, rhoeadine Alkaloids MR-1 and MR-3, allocryptopine, coptisine, corysamine, magnoflorine, papaverrubine D, protopine Alkaloids MR-1 (C Hi O), MR-2, MR-3, and MR-4, allocryptopine. amurensinine methohydroxide, coptisine, magnoflorine, papaverrubine D and E, protopine, rhoeadine ( )... 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

The plant P. dubium differs in that rhoeadine alkaloids or proaporphine and aporphine alkaloids or both types together are present therein. Papaver litwinovii Fedde resembles this type, containing aporphine alkaloids. The major alkaloids found therein are aporheine (115) and its methohydroxide (116). In P. dubium... 

Studies of the section Orthorhoeades have shown the occurrence of at least two chemotypes in this section. One chemotype contains rhoeadine alkaloids and the other, proaporphine and aporphine alkaloids. This is consistent with the theory postulated by Mothes about chemical races (43). The question also arises how firmly some hereditary features are fixed to the plant, consequently, how easily the change in the geographical or climatic conditions may affect the spectrum of the alkaloids. 

Benzyl(tetrahydro)isoquinoline alkaloids. B. a. occur especially in various Annonaceae, Lauraceae, Rhamnaceae, Ranunculaceae, Papaveraceae, and Fa-baceae. They are soluble in ethanol, chloroform, ether and poorly soluble in water. Laudanidine is toxic, it acts as a convulsive and respiratory stimulant, laudan-osine is a tetanic toxin, orientaline is the biosynthetic precursor of isothebaine. Pwtosinomenine occurs especially in Erythrina lithosperma (Fabaceae). Papaverine [ 1 -(3,4-dimethoxybenzyl)-6,7-dimethoxyiso-quinoline] acts as a parasympathicolyticum relaxing smooth musculature, it promotes cerebral perfusion (vasodilatation). It is an antiasthmatic and oral anti-spasmodic agent used in the treatment of gastrointestinal spasms LD50 (mouse i. v.) 25 mg/kg. Reticuline is an important precursor of protoberberines, morphi-nans, aporphines, spirobenzylisoquinolines, and rhoeadine alkaloids. 

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