Rhoeadines synthesis

The protoberberine alkaloids (5-75) play important roles as precursors in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, inde-nobenzazepine, secoberbine, and benzo[c]phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. 

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). 

Indenobenzazepines have been used as key intermediates for synthesis of rhoeadine, protopine, phthalideisoquinoline, and spirobenzylisoquinoline alkaloids. Several new alkaloids possessing an indenobenzazepine skeleton have been isolated, and they are presumably biosynthesized from proto-berberine alkaloids. 

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... 

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,... 

Scheme 91. Synthesis of rhoeadine analogs via indenobenzazepines. Reagents a, NaI04 b, NaBH4 c, HC1 d, DIBAL e, HC(OMe)3. ...

Secophthalideisoquinoline enol lactones of type 128 were used by Klotzer et al. (95,103-105) for the synthesis of benzazepine system 129 which was further transformed to alkaloids of rhoeadine type. 

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. 

Rhodium compounds, 19 644-648 synthesis of, 19 646 uses for, 19 646-648 Rhodium oxide, 10 42 Rhodium plating, 9 822 19 648 Rhodium-platinum alloys, 19 602 Rhodochrosite, 15 540 Rhodochrosite ore, 15 589 Rhodococcus, as a host system for gene expression, 12 478 Rhodonite, 15 540 color, 7 331 Rhodopsin, 9 512 Rhoeadine, 2 90 Rhoedales... 

Methods of synthesis of rhoeadines have been reviewed.120... 

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). 

Scheme 55. Total synthesis of the alkaloid rhoeadine (154a) (731).

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. ... 

Battersby and his group have recently reported the details of an extensive study of biogenetic interrelations among tetrahydroprotoberberines, benzophenanthridines, rhoeadines, and phthalideisoquinolines. A key step in this study of the stereospecificity of enzyme reactions was the use of horse liver alcohol dehydrogenase to prepare the complementary R- and 5-benzyl alcohols shown. These tritiated materials were needed for the synthesis of chirally labeled scoulerine. 

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 rhoeadines are a group of alkaloids isolated from plants of the genus Papaver (Papaveraceae), and are characterized by a benzazepine structure and a c/s-fused six-membered acetal ring. In the synthesis of rhoeadine outlined below, the requisite 3-benzazepine skeleton has been constructed from a benzylic spiroisoquinoline intermediate (B) by a skeletal rearrangement. ... 

The final stages of the synthesis, viz., conversion of rhoeagenine diol (C) to rhoeadine had already been accomplished during work on constitution of rhoeadine by F. Santavy, J. L. Kaul, L. Hruben, L. Dolejs, V. Hanus, K. Blaha and A. D. Cross, Coll. Czech. Chem. Commun., 30, 3479 (1965). 

The synthesis of alpinine illustrates a different approach to rhoeadine alkaloids, and is based on the photosensitized oxidation of the enaminoketone (A) and rearrangement of the resuiting dioxetan to a spiro keto lactone (B). The rest of the synthesis closely follows the pathway laid down earlier at Hoffman-La Roche for the synthesis of rhoeadine. ... 

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