Benzo c phenanthridine

Sanguinarine is currently used in the United States in dental preparations (mouth washes, toothpastes), where there is some evidence that the products containing this alkaloid prevent dental plaque formation. 

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X-ray crystal structure, 6, 516 Benzophenanthridines synthesis from anils, 2, 416 Benzophenanthridines, tetrahydro-synthesis, 2, 469 Benzo[c]phenanthridines synthesis, 2, 414 from aryl isocyanides, 2, 411 from benzynes, 2, 432 Benzo[i]phenanthridines synthesis, 2, 414 Benzophenanthridinones... 

Synthesis of quaternary benzo[c]phenanthridine alkaloids and their analogs 97AHC(67)345. 

Recent advances on antitumor-active benzo[c]phenanthridine alkaloids 99H(50)627. 

Benzo[c]phenanthridine alkaloids are widespread in Papaveraceae, Fumariaceae, and Rutaceae. Fagaridine (118), the structure of which had to be revised, is a derivative of the unknown 5-methyl-benzo[c]phenan-thridine-8-olate (119) which is isoconjugate with the 2-methyl-chrysene anion (Scheme 43). Thus, Fagaridine is a member of class 1 of conjugated heterocyclic mesomeric betaines, which are isoconjugate with odd alternant hydrocarbon anions. 

Hydroxysanguinarinebetaine (367) is formed on Oppenauer oxidation of Chelidonine (366) as a red compound (65MI2) (Scheme 109). Deprotonation of the benzo[c]phenanthridine alkaloid Fagaronine (93T10305), which is known to inhibit various reverse transcriptases (77MI1), resulted in the... 

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. 

Scheme 35. Biosynthesis of benzo[c]phenanthridine alkaloids from protoberbines via the enamine aldehydes 193.

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin s results (118,119) and established the structure of the cyclized products 196 and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121) obtained the five-membered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 

The first successful transformation of protoberberines to benzo[c]-phenanthridines was reported by Onda et al. (122,123). Irradiation of the enamines 200 and 195, the Hofmann degradation products of the corresponding protoberberines, in benzene afforded the initial photoproducts 201, which immediately rearranged to the tetrahydrobenzo[c]phenanthridines 202 in 70% yield (Scheme 37). Dehydrogenation of 202 afforded dihydro-chelerythrine (203) and dihydrosanguinarine (204), which were further oxidized with dichlorodicyanobenzoquinone (DDQ) to yield chelerythrine (205) and sanguinarine (206), respectively. 

Another photocyclization to a benzo[c]phenanthridine was reported (127). Oppenauer oxidation of ( )-ophiocarpine (92) with potassium fm-butoxide and benzophenone in dioxane effected C-6—N bond cleavage to afford the hydroxyisoquinoline 219 via berberinephenolbetaine (121) (Scheme 39). Although photolysis of 219 gave only the oxepine 221, that of its methyl ether 220 furnished directly norchelerythrine (222) through electrocyclization followed by spontaneous elimination of methanol. 

Lead tetraacetate oxidation was applied to construct a benzo[c]-phenanthridine skeleton. The Hofmann degradation product 224 derived from the phenolic protoberberine 59a was oxidized with lead tetraacetate to afford the p-quinol acetate 225, which was cyclized to the benzo[c]-... 

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromate afforded directly oxyche-lerythrine (232) instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient... 

The above biomimetic method was successfully applied to synthesis of 2,3,8,9-tetraoxygenated fully aromatized benzo[c]phenanthridine alkaloids such as nitidine (243) (134,135), fagaronine (244) (134,135), and oxyterihanine (242) (136) (Scheme 42). The former two alkaloids attract many synthetic... 

The 2,3,7,8,10-pentaoxygenated benzo[c]phenanthridine alkaloid san-guilutine (248) was also conveniently synthesized according to the above method (Scheme 43) (138). The presence of the methoxyl group at C-5 peri to the cyclization position (C-4) was at first anticipated to retard cyclization however, the cyclization of the acetal 246 proceeded smoothly to give oxysanguilutine (247) in high yield. 

Similarly, berberine (15) was readily converted to (+)-homochelidonine (264), (+)-chelamidine (262), chelerythrine (205), and dihydrochelerythrine (203) (141). According to this method both hexahydro and fully aromatized benzo[c]phenanthridine alkaloids can be readily synthesized via a common intermediate (e.g., 260). 

The small group of 3-arylisoquinoline alkaloids are biogenetically related to benzo[c]phenanthridine alkaloids (113). Corydamine (266) was synthesized from (+ )-tetrahydrocoptisine (82) through C-6—N bond cleavage using the von Braun reaction followed by aminolysis and dehydrogenation (Scheme 46) (142). 

Fagaronine and nitidine from Zanthoxylum species represent two of the more potent antitumor benzo[c]phenanthridines of Rutaceae. Both of these alkaloids have been shown to inhibit the enzymatic activity of topoisomerase in a way similar to camptothecin (28,29). It would be interesting to learn whether further study on Z. ailanthoid.es Sieb. Zucc. discloses any benzo[c]phenanthridine alkaloid of anti-neoplastic value. 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

Fig. 10.2 Reaction catalyzed by the berberine bridge enzyme (BBE) along the biosynthetic pathway leading to protoberberine, berberine and benzo[c]phenanthridine alkaloids.

HUANG, F.-C., KUTCHAN, T.M., Distribution of morphinan and benzo[c]phenanthridine alkaloid gene transcript accumulation in Papaver somniferum, Phytochemistry, 2000,53, 555-564. 

Benzo [A] quinoline, Benzo [/] quinoline, and Benzo [c] phenanthridine Derivatives... 

Naphthof 1,2 -/] quinoline Naphtho[2,1 -/]quinoline Benzo[c]phenanthridine Benzo[i]phenanthridine Benz[o]acridine... 

The formation of a-naphthylamines 140 and 153 in reactions of 2-benzopyrylium salts with ammonia and primary amines is not always an undesirable process. The synthetic application of a-naphthylamines is connected with the chemistry of benzo[c]phenanthridine alkaloids 132 (78MI1 81H474). 

Similar types of nucleophilic substitutions have also been carried out when PIFA is activated by two equivalents of Lewis acids such as trimethylsilyl triflu-oromethanesulfonate (TMSOTf) and BF3 Et20 or heteropolyacid in standard solvents such as CH2C12 and MeCN. These reactions were applied to intramolecular reactions by the same authors leading to biaryls (49) [54-57], quinone imine derivatives (50) [58], and dihydrobenzothiophens (51) [59], which are important structures of bioactive natural products [Eqs. (7)-(9)]. Dominguez and co-workers have expanded the above biaryl coupling reaction to the syntheses of benzo[c]phenanthridine system (52) [60] and heterobiaryl compounds (53) [61] [Eqs. (10,11)]. 

These related reactions have been utilized for total syntheses of natural products such as makaluvamine D (54), makaluvamine I (55), makaluvamine M (56), makaluvamine F (57), and michellamine A (58). Furthermore, synthetic studies on ellagitannin (59),benzo[c]phenanthridines (60), and rebeccamycin (61) have also been carried out. 

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