A versatile method of synthesis of the quaternary benzo [c] phenanthridine alkaloid (1), having a tertiary benzo [c] phenanthridine skeleton, from the norbase (3) is described. Treatment of the norbase (3) with sodium borohydride in formic or in acetic acid gave the N-methyl-(5) or the N-ethyl-(7) dihydrobase, respectively, in good yield. The N-methyldihydrobase (5) could also be prepared by treatment of the norbase (3) with sodium borohydride and dimethyl sulfate in hexamethylphosphoric triamide. The dihydrobases (5 and 7) were readily convertible to the corresponding quaternary benzo [c] phenanthridine alkaloids by oxidation with Jones reagent or with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) in good yields. In addition, we found that the air-oxidation of the carbanions derived from the ψ-cyanides (11) of the quaternary bases (1) gave the corresponding oxybases (10) in excellent yields.
Chemical constituents in the alkaloidal fraction of the bark of Formosan X. nitidum (ROXB.) D.C. (F. nitida ROXB.) (Japanese name : Teriha-Zansho), Rutaceae, which was collected in the area of Ping-Tung Hsien, were examined. Twelve alkaloids [nitidine (1), oxynitidine (2), 6-methoxy-5, 7-dihydrochelerythrine (4), oxychelerythrine (6), des-N-methyl-chelerythrine (7), chelerythrine (14), arnottianamide (24), liriodenine (25), bocconoline (26), decarine (27), integriamide (28), and isoarnottianamide (13)] and three lignans [l-asarinin (20), l-sesamin (21), and l-syringaresinol (29)], a coumarin, aesculetin dimethyl ether (22), together with β-sitosterol (23) were isolated. Other than the above seventeen known compounds a new phenolic benzo [c] phenanthridone alkaloid designated as oxyterihanine (30a) was also isolated as a minor component. While the past three groups reported that nitidine (1) was a sole quaternary benzo-[c] phenanthridine alkaloid in the same plants collected in the areas of Hong-Kong and of China mainland (Gauanx and Gauantung), in our case, chelerythrine (14) was isolated as a major component. Nitidine (1) was isolated from the plant collected at March as a second component, but chelecythrine (14) was essentially a sole benzo [c] phenanthridine alkaloid in the case of the plant collected at July and at September. The seasonal variation of the contents of the quaternary benzo [c] phenanthridine alkaloids is discussed.
In order to establish a versatile method for the preparation of antiumor benzo [c] phenanthridine alkaloids, the reaction steps from the 2-aryl-1-formamido-1, 2, 3, 4-tetrahydronaphthalenes (2) to the fully aromatized benzo [c] phenanthridine derivatives (5) via the 4b, 10b, 11, 12-tetrahydrobenzo [c] phenanthridines (4) in the Robinson preparative sequence were examined in detail. Bischler-Napieralski reaction of the formamide (2) having an alkoxy group at the para position to the cyclizing point of the 2-phenyl ring substituent gave a mixture of the trans-and cistetrahydrobenzo [c] phenanthridines (4) with or without formation of the 2-aryl-3, 4-dihydronaphthalene derivative (6). There is a limitation in that the presence of the alkoxy group at the para position is required for success in cyclizing the formamide derivative (2). Otherwise, the 2-aryl-3, 4-dihydronaphthalene derivative (6) is the sole product. For the dehydrogenation of the resulting trans-and cis-tetrahydrobenzo [c] phenanthridines (trans-and cis-4) into the fully aromatized product (5), catalytic dehydrogenation with 30% palladium-charcoal in p-cymene and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) oxidation in the presence of or in the absence of 5% sodium hydroxide aqueous solution were investigated. The catalytic dehydrogenation provided either the desired fully aromatized product (5) or the dihydrobenzo [c] phenanthridine (8). The species of the product depends upon the species of the starting material (4). The DDQ-oxidation gave a variety of results. The mode of product formation seems to be regulated by various factors, including the reaction conditions, the species of substituents of the starting material (4), and the stereochemistry of the starting material (4). The mechanisms of formation of various products are discussed.
Several nonphenolic benzo [c] phenanthridine alkaloids including naturally occurring nitidine (1a) and avicine (1e) were synthesized in excellent yields through an efficient synthetic method developed by us. Antitumor activities of twelve alkaloids including four naturally occurring O5-alkaloids [chelilutine (1g), chelirubine (1h), sanguilutine (1k), and sanguirubine (11)] against Sarcoma 180 were tested. The structure-activity relationship of these alkaloids is discussed.
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