Pyrrolophenanthridones

Anhydrolycorinone [55], Hippadine [56], Oxoassoanine [46], Pratosine [57]. The syntheses of alkaloids, incorporating the pyrrolophenanthridone nucleus, in the majority of cases followed the A + CD - AG) - ACDB sequence, in which organometallic chemistry featured prominently in this transformation. 

Another useful method for effecting the ring closure of the bromo- and iodoaryl enaminones 166 (Z = Br, I) featured an intramolecular electrophilic arylation process involving benzyne intermediates (127). For example, treatment of 166 (Z = Br, I) with lithium diethylamide at room temperature afforded the pyrrolophenanthridone 169. When 169 was treated with oxygen in aqueous ethanol containing potassium hydroxide, the vinylogous imide 168 was produced... 

The short synthesis of the pyrrolophenanthridone alkaloid hippadine was accomplished by D.C. Harrowven and co-workers. " The key step of the synthetic sequence was the Ziegler modified intramolecular Ullmann biaryl coupling between two aryl bromides. One of the aryl halides was 7-bromoindole which was prepared using the Bartoli indole synthesis. The second aryl bromide was connected to 7-bromoindole via a simple A/-alkylation. 

Lycorine-type alkaloids derived from pyrrolo[3,2,l-(ie] phenanthridine/ pyrrolophenanthridone ... 

Scheme 3. Direct, short and effective synthesis of pyrrolophenanthridone alkaloids...

The cyclization of l-(6-iodo-3,4-methylenedioxy)phenylmethyl-4,5,6-trihydro-l//-indol-2-one (114) (prepared from 110) under palladium-mediated reaction conditions afforded pyrrolophenanthridone 115 in 71% yield. Hydrolysis of 115 gave the C-aromatic product anhydrolycorine-4,5-dione (116), reduction of which, followed by elimination of the hydroxyl group, produced 4,5-dehydro-anhydrolycorine (43) (126b) (Scheme 12). 

The synthesis of hippadine (44) and ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions 134) (Scheme 15). (7-Bromo-5-mesyloxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)alumi-num hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119), which was transformed to hippadine (44) in 90% yield by oxidation with DDQ. 

Padwa and co-workers reported an approach to the pyrrolophenanthridone alkaloids (e.g., hippadine) that uses an intramolecular oxazole-alkyne Diels-Alder reaction. Thus the 2-acetamidooxazole model system 217 was thermolyzed at 200°C to produce the tricyclic furan 218 in 93% yield (Fig. 3.63). 

Phenanthridinone derivatives have been reported to be found in a number of natural alkaloids and exhibit a wide range of biological activities. In the case of starting from bi-functionalized arenes with transition metal catalysts, the intramolecular cyclization of 2-bromo-iV-arylbenzamides via C-H activation is the most direct pathway, which has been applied in the synthesis of anti-hepatitis C virus agents and materials. Remarkably, Yao, Xu and their co-workers developed a one-pot procedure for the synthesis of a pyrrolophenanthridone skeleton via an intramolecular Heck reaction and oxidation of N-(2-bromobenzyl) substituted indoles. Moderate to good yields of the desired products were isolated in one step (Scheme 3.67). From the point view of academic interest, the... 

Miscellaneous Processes. A versatile synthetic route to the pyrrolophenanthridone alkaloids has been developed that involves a palladium-mediated cyclization of iV-benzoyl indolines, then 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone (DDQ)-promoted oxidation of the resulting dihydropyrrolophenanthridones. Related processes have been exploited in an elegant total synthesis of the marine alkaloid (+)-dragmacidin F and in the preparation of biologically relevant indoles. 202.203... 

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