Indenobenzazepine alkaloids

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

A new class of indenobenzazepine alkaloids has been produced by the transformation of spirobenzylisoquinolines a reaction which probably parallels a biogenetic pathway. 8,14-Cycloberbine has been converted into the benzindanoazepine system... 

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). 

Scheme 77. Synthesis of protopine alkaloids by photooxygenation of indenobenzazepines. Reagents a, hv, 02, Methylene Blue b, LAH c, Mn02.

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,... 

The ketoaziridine 137 was also transformed into the indenobenzazepines by the ring opening of the aziridine with acid, and this conversion provided the general transformation of berberines into rheadan and indenobenzaze-pine alkaloids. 

Two new alkaloids isolated from Fumaria parviflora, lahorine and lanoraraine, have been shown to have the indenobenzazepine structures... 

S)-(+)-reticuline (20) and orientaline (25). The alkaloids of the Papaveraceae and Fumariaceae can be subdivided into several constitutional types (Fig. 3), viz., simple isoquinolines, benzylisoquinolines, pavines, isopavines, cularines, proaporphines, aporphines, promorphinanes, morphinanes, protoberberines, retroprotoberberines, secoberbines, benzophenanthridines, protopines, phthali-deisoquinolines, secophthalideisoquinolines, indenobenzazepines, spirobenzyl-isoquinolines, and rhoeadines. 

The Papaveraceae and Fumariaceae DC. are closely related families. Their relationship as well as their independence are well demonstrated by the external stmcture of the flowers, the various anatomical characteristics of their different organs, and alkaloid content. As in the Papaveraceae, the protoberberines, ben-zophenanthridines, and protopines are chemotaxonomically significant for the Fumariaceae. Characteristic for the Fumariaceae is the presence of spirobenzylis-oquinolines, indenobenzazepines, secophthalideisoquinolines, phthalideiso-quinolines, and cularines. The Fumariaceae also contain quaternary highly polar alkaloids, insoluble in nonpolar solvents (16). 

A close relationship exists between the alkaloids of the two families Papaveraceae and Fumariaceae. Their relationship, as well as their independence, is particularly well demonstrated by the external structure of the flowers and various anatomical characteristics of different organs (Novak and Preininger 1983). Characteristically, the Fumariaceae contain spirobenzylisoquinoline (7), indenobenzazepine (8), se-cophthalideisoquinoline (10) and phthalideisoquinoline (9) alkaloids, whereas rhoeadine (11), pavine (12) and isopavine (13) type alkaloids, which are characteristic of Papaveraceae, are absent. The secoberbines have been found in C. incisa (Thunb.) Pers. and in C. ochotensis Turcz. (37—39). The cularine alkaloids (40) which are characteristic of the genus Corydalis are also found in species of Dicentra which is a member of the Papaveraceae. 

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