Spirobenzylisoquinoline

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 reactions described in this section have been applied to synthesis of a variety of spirobenzylisoquinoline alkaloids (Section V,C,5). 

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). 

Biosynthesis of the spirobenzylisoquinoline alkaloid ochotensimine (282) via the quinomethide intermediate (Scheme 49) was proposed by Shamma and Jones (7J0). On the basis of this hypothesis, several biomimetic transformations of phenolic protoberberines to spirobenzylisoquinolines have been realized by the base-induced rearrangement via the quinomethide. 

Another biomimetic transformation was reported by Nalliah et al. (155). 13-Oxotetrahydroberberine (ophiocarpinone) metho salt (291), derived from berberinephenolbetaine (121), was irradiated in methanol in the presence of sodium hydride to afford the spirobenzylisoquinoline 294 in 45% yield... 

Scheme 52. Photoinduced rearrangement to the spirobenzylisoquinoline. Reagents a, LAH then Me2S04 b, hv, NaH, EtOH.

Wu et al. (156) found that photolysis of 13-substituted dihydroprotober-berine metho salts 296 in methanol similarly afforded the corresponding spirobenzylisoquinolines 297 in 23-54% yields via the quinodimethides (Scheme 53). On the other hand, 13-unsubstituted metho salts 298 furnished, on irradiation, the imino ketones 299 (Scheme 54) instead of spirobenzylisoquinolines through N-demethylation and oxidation via the quinodimethide... 

Scheme S3. Photoinduced rearrangement to spirobenzylisoquinolines. Reagents a, hv, MeOH.

Kano et al. (161,162) also investigated the Stevens rearrangement of tetrahydroprotoberberine metho salts 302 with dimsylsodium and obtained the spirobenzylisoquinolines 303 in high yield (Scheme 56). Similarly C-homoprotoberberine 304 gave the new spiro compound 305, whereas B-homoprotoberberine 306 afforded only the Hofmann degradation product 307. 

Kametani et al. (163-165) studied the Stevens rearrangement using sodium bis(2-methoxyethoxy)aluminum hydride as the base in dioxane. It became clear from studies using deuterium-labeled or optically active compounds that quasi-axially oriented hydrogens at C-8 and C-14 were independently abstracted by the base, leading to a spirobenzylisoquinoline and an 8-... 

In conclusion, although the Stevens rearrangement of a tetrahydroproto-berberine metho salt readily afforded a spirobenzylisoquinoline skeleton, there exist no reports on synthesis of functionalized spirobenzylisoquinolines or related alkaloids using this method. 

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)... 

Section V,F,3) was treated with trifluoroacetic anhydride in pyridine at room temperature followed by work-up with aqueous ammonia to rearrange to the spirobenzylisoquinoline 317 in 86% yield (Scheme 59). The product was reduced with sodium borohydride to afford ( )-raddeanine (318) which was also obtained similarly from the dihydroxyindenobenzazepin 319. 

Scheme 59. One-step conversion of indenobenzazepines to spirobenzylisoquinolines. Reagents a, (CF3C0)20, py b, aq NH3 c, NaBH4. 

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... 

Raddeanamine (360) is an unusual spirobenzylisoquinoline alkaloid having a tertiary methyl group in five-membered ring. Methylation of the corresponding ketone gave the methyl carbinol with the reverse stereochemistry, namely, the methyl carbinol 361 was obtained from the reaction of the ketone 294 with methyllithium (Scheme 64). Stereoselective synthesis of ( )-raddeanamine was accomplished by an intramolecular oxyfunctionalization via the 8-methyl-8,14-cycloberbine 364 (175). 

Transformation of phthalideisoquinolines to spirobenzylisoquinoline alkaloids is described in Section V,D,6. 

The spirobenzylisoquinoline 171b derived from berberine (15) (Section IV,A,1) was oxidized with m-chloroperbenzoic acid to the /V-oxide 389, which was treated with trifluoroacetic anhydride to afford dehydrohydrastine (370) in 56% overall yield (Scheme 71) through the Polonovski reaction (187). Holland et al. (188,189) reported the reverse reaction from dehydrophthalides to spirobenzylisoquinolines, namely, 370 was reduced with diisobutylalu-minum hydride to give a mixture of two diastereoisomeric spirobenzylisoquinolines 320 and 348 via the enol aldehyde. This reaction was applied to synthesis of various spirobenzylisoquinoline alkaloids such as (+)-sibiricine (352), ( + )-corydaine (347), (+ )-raddeanone (354), ( )-yenhusomidine (359), (+ )-ochrobirine (343), and ( )-yenhusomine (323). 

Scheme 71. Interconversion of spirobenzylisoquinolines and dehydrohydastine (370). Reagents a, MCPBA b, (CF3C0)20, CH2C12 c, DIBAL.

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 starting spirobenzylisoquinolines were originally synthesized from the corresponding phenethylamines and indanediones. Compound 329 was prepared from palmatine (64) via the 8,14-cycloberbine 442 (Scheme 88). Thus, a formal transformation of palmatine to ( )-alpinigenine (441) was accomplished (63). 

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... 

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