The Rhoeadines

Rhoeadine and papaverrubine (norrhoeadine) alkaloids which were previously believed to occur only within the genus Papaver have now been found to be present in two other Papaveraceae genera, namely Bocconia and Meconopsis. In Bocconia frutescens L. rhoeadine alkaloids accompany a variety of protopine, protoberberine, and benzophenanthridine bases.  

---

Another interesting conversion of a protoberberine to a rhoeadine skeleton was developed by Murugesan et al. (100). The ketol 176 obtained easily from berberine (15) (Section IV,A,2) was oxidized with sodium periodate to the keto lactone 451, which was transformed to the rhoeadine analogs 452 and 453 by known methods (Scheme 91). Their stereochemistry at the anomeric carbon was not fully clarified. 

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. 

Snieckus et al. (158,159) demonstrated the usefulness of photocycliza-tion of the o-halogenophenethylenamide 341 in alkaloid synthesis. The bromoenamide 341 was irradiated with 2537-nm light in benzene -triethy-lamine solution to give the seven-membered product 342 in 20-21.5% yield. This (342) was then converted to the Schopf-Schweickert amine 343 on reduction (755) 343 has a structure closely related to the skeleton of the rhoeadine group of alkaloids (Scheme 121). 

The alkaloids of the rhoeadine group are benzazepines and essentially bear the same relationship to the indanobenzazepines as do the secoberberines (section 10) to the spirobenzylisoquinolines (section 13). 

The formation of ( )-/2-hydroxyreticuline by treatment of ( )-reticuline with homogenized Papaver rhoeas and hydrogen peroxide may offer an initial clue to the biosynthesis of the rhoeadine alkaloids79 (see also Section 3A). 

The structure of rhoeagenine (I) suggested that oxidation might give rise to bicuculline or adlumidine (phthalideisoquinoline alkaloids) and that by subsequent correlation the absolute configuration of the rhoeadine and the isorhoeadine series, respectively, could be determined. Reduction would then afford the corresponding diols. However, oxidation and reduction afforded products (430) which did not correspond to phthalideisoquinoline derivatives (see Section III, K). 

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. 

S,2S to the alkaloids of the rhoeadine type on the basis of the mechanism of epimerization of the C-2 atom of the alkaloids of the isorhoeadine type. 

Further support for the configuration assigned to the rhoeadine series was also provided by a comparison 426) of the rotatory properties (ORD-and CD-curves) of tetrahydrorhoeageninemethine (XVIII) with those of... 

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. 

It is of interest that all the sections of the genus Papaver (Table XXVI) contain alkaloids of the rhoeadine type (XIII) which could not be found... 

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 absolute configurations of all the rhoeadine and papaverrubine alkaloids have now been elucidated using the aromatic chirality method. For instance, ( + )-glaudine is represented by structure (191), (+ )-epiglaudine by (192), and ( + )-oreodine by (193). ... 

L. var. lecoquii (Lamotte) Fedde, some authors (38,39) found berberine (209b) as the major alkaloid, whereas in the material studied by us (40) the major alkaloids were rhoeadine (389) and isorhoeadine (389), though in some instances berberine was also detected. The plant P. commutatum also was shown to contain either alkaloids of the rhoeadine or those of the aporphine type and papaverine or all of these alkaloids simultaneously. Noticeable is the high content of isorhoeagenine glycoside (390) (41). 

R. a. are insoluble in water, chloroform, ether, poorly soluble in ethyl acetate and methylene chloride. Rhoeadine is weakly toxic [LD50 (rats i.p.) 530 mg/kg]. It effects dilatation of the pupils. Papaver rhoeas extracts are used as sedatives and expectorants, however, these uses are not attributed to the rhoeadine content. 

The benzazepinoisoindole 6, commonly referred to as Schopf Base VI, is prepared from commercially available jS-hydrastine, or by zinc in acetic acid reduction of berberinephenolbetaine. It can more conveniently be called an aporhoeadane derivative where the aporhoeadane nucleus is defined as in structure 5, the numbering system corresponding to that for the rhoeadines. 

A novel route to the rhoeadines starts with the readily available immonium salt 13 which was subjected to Schotten-Baumann conditions the aldehyde 15 was formed in 91% yield via the intermediate A-benzoylated pseudobase 14. Intramolecular aldol condensation of the aldehyde was induced by a strong base, thus generating the lactonic rhoeadine amide 16 in 56% yield. This short series of transformations represents a new benzazepine synthesis. 

The stereochemical assignments for the rhoeadine alkaloids have been confirmed by X-ray analysis of (-h) rhoeagenine methiodide which led as expected to the accepted configuration. A detailed discussion of the CD curves of rhoeadine alkaloids and their degradation products has appeared. ... 

Several new suggestions concerning the biogenesis of the rhoeadines have appeared. Using Papaver bracteatum Lindl. plants, it has been demonstrated that [N- CHa, 8- C]-( )-tetrahydropalmatine methiodide is incorporated with high efficiency into alpinigenine. A mechanism was therefore proposed which involves C-14 hydroxylation of the quaternary tetrahydroprotoberberine salt, followed by cleavage of the bond between N-7 and C-14. ... 

A third and most significant study involves tracer experiments with Papaver rhoeas L. Both 135- and 13/ -tritium labeled scoulerines were incorporated into rhoeadine, but the rhoeadine isolated from plants fed with 135-labeled scoulerine had lost 19% of the tritium present in the precursor, whereas the 13/ -Iabeled scoulerine afforded rhoeadine which had retained 74% of the original tritium. A stereospecific loss of the pro-5 hydrogen must, therefore, have occurred from the C-13 of scoulerine at some specific stage of its biotransformation into rhoeadine. It seems likely that scoulerine is converted first into stylopine which is oxidized to 42. A-Methylation and rearrangement then provide the correct skeleton from which rhoeadine can arise... 

---