Phenanthridine alkaloids

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.

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. 

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). 

R. D., Synthesis of Quaternary Benzo[c]phenanthridine Alkaloids and Their Analogues, 67, 345. 

Takao and co-workers (60) have examined a number of hydro-benzo[c]phenanthridine alkaloids and their derivatives by a variety of physical methods in order to determine the conformation of the B/C rings (Fig. 18). The 13C chemical shifts (Table XVII) were particularly sensitive to the influence of substituents on the conformation of the B and C rings. Chelidonine (94) for example, with a cis ring junction, has both the B and C rings as half-chairs [see Fig. 1 in (60)]. Acetylation of the hydroxy l group to form 95 shielded C-6, C-12, and C-13 relative to 94. The interpretation of these observations was that ring C in 94 adopted a twist half-chair conformation which increased the number of gauche interactions for these carbons. 

Although phenanthridine was discovered in the late nineteenth century1, 2 neither the parent base nor its derivatives attracted attention until useful therapeutic activity was established in certain quaternary phenanthridinium compounds.3 A substantial number of substituted phenanthridines (and many phenanthridinium salts) have now been described and lists of compounds appearing in the literature from 1884 until 1955 are available.4, 6 Phenanthridines have attracted surprisingly little systematic attention, although the system is of considerable theoretical interest and, with its nine nonequivalent carbon atoms, may be expected to provide a rigorous test of molecular orbital reactivity correlations. Naturally occurring derivatives include several Amaryllidaceae and Papaveraceae alkaloids, notably, lycorine, haemanthamine, and chelidonine the chemistry of the phenanthridine alkaloids has been reviewed.6... 

Park and Cho [61] reported an extractive production system for benzo-phenanthridine alkaloids using cyclodextrins, in which production and some degree of separation occurred simultaneously. It was expected that the rapid removal of alkaloid produced from the suspension cultures was achieved by capturing alkaloid with cyclodextrins. In solid cultures of E. californica cells, alkaloid production was substantially enhanced (up to 40-fold) by the addition of /1-cyclodextrin. The enhancement of alkaloid production was also observed in suspension cultures, in which the major part of the alkaloids in the /J-cyclodex-trin treated cultures was present in the media, while the non-treated cultures contained the alkaloids in the cells. This indicated that /1-cyclodextrin not only captures the alkaloids but also helps in extracting them from cells. 

This reaction has been used to synthesize the precursors of berberine alkaloids [benzo(c)phenanthridine alkaloids]331. Thus, the photostimulated reaction of oiodoben-... 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

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