Protoberberines from spirobenzylisoquinolines

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. 

The spirobenzylisoquinoline alkaloids have been reviewed (1,2,7-10,147) and compiled (148). The exact biosynthetic route to spirobenzylisoquinolines from protoberberine alkaloids has not yet been elucidated (149). 

The indenobenzazepines 314, obtainable from the corresponding protoberberines (Sections V,F,2 and V,G,2), were converted to the spirobenzyliso-quinolinediones 315 in 76% yield through hydrolytic bond cleavage and recyclization by sequential treatment with 4 N hydrochloric acid, bromine in acetic acid, and triethylamine, via the indanediones (Scheme 58) (166). A one-step stereoselective rearrangement of an indenobenzazepine to a spirobenzylisoquinoline was developed by Blasko et ah (167). O-Methylfumarofine (316)... 

Almost all types of spirobenzylisoquinoline alkaloids have been synthesized from corresponding protoberberines via 8,14-cycloberbines on the basis of the fundamental reactions described in Section IV,A,1. For example, on irradiation in methanol the phenolbetaine 325 derived from the protoberberine 324 afforded the 8,14-cycloberine 326 in excellent yield (Scheme 60). Sequential... 

Sibiricine (352) was stereoselectively synthesized from the corresponding protoberberine 330 in four steps (Scheme 63) (173). Photooxygenation of 330 in methanol in the presence of sodium methoxide and Rose Bengal produced 8-methoxyphenolbetaine 349, which was irradiated in methanol to give the spirobenzylisoquinoline 350. Reduction of 350 with sodium borohydride followed by concomitant N-methylation and deketalization... 

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... 

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

Fumaria chemically resembles Corydalis. Similarly, the genus Fumaria also contains protoberberines, protopines, and phthalideisoquinolines, and more frequently, secophthalideisoquinolines and spirobenzylisoquinolines. They also yield indenobenzazepines, which cannot be demonstrated in the genus Corydalis (Table LVI), but no aporphines and cularines, which have been isolated from the plants of the genus Corydalis. 

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