Phenanthroindolizidine alkaloid

Phenanthroindolizidine Alkaloids.—The phenanthroindolizidine alkaloids, e.g. tylophorine (14) and tylophorinine (15), are assembled in Tylophora asthmatica from fragments derived from ornithine, phenylalanine, and tyrosine (cf. Vol. 8, p. 6 Vol. 9, p. 5). The last amino-acid is the source of ring B plus C-9 and C-10. It has now been shown that dopa is a better precursor than tyrosine for this fragment. Label from [2-14C]dopa was specifically incorporated into C-10 of (14) and (15).16 

Mizusaki, T. Kisaki, and E. Tamaki, Agric. and Biol. Chem. (Japan), 1965, 29, 714. 

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The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

Phenanthroindolizidine Alkaloids.—These alkaloids, which may be exemplified by tylophorine (17), have been shown to have their genesis in tyrosine,34 phenylalanine,35 and probably ornithine,35,36 as shown in Scheme 4 the phenylalanine is... 

The phenanthroindolizidine alkaloid antofine has been synthesized by a new method, based on the direct metallation of the amide of a phenanthrenecarboxylic acid.10 Tylophorine11 and septicine12 have been synthesized by a modification of an earlier biosynthetic route to the phenanthroindolizidines. 

The joint occurrence of tylophorine and tylocrebrine with the seco-phenanthroindolizidine alkaloid septicine (XXI) in Ficus septica (4) lends support to the biogenetic scheme outlined above. It is also of interest that septicine is transformed to a mixture of tylophorine and tylocrebrine on UV-irradiation. It is quite possible that the amorphous base (mp 125°-130°), of Chopra et al. 10) is in fact septicine. 

Tylophorine (1) and its analogs, the phenanthroindolizidine alkaloids also referred to as tylophora alkaloids, have been isolated primarily from plants of the family Asclepiadaceae [13-16], Fig. (1), including members of the genus Tylophora, Vincetoxicum, Pergularia, Cynanchum, but also from Hypoestes verticillaris (Acanthaceae) [17], Cryptocarya phyllostemmon (Lauraceae) [18], Ficus hispida and F. septica (Moraceae) [2, 19]. TTie isolations of these alkaloids are summarized in Table 1. The most significant phenanthroindolizidine alkaloids are tylophorine (1), tylocrebrine (2), antofine (3), and tylophorinine (4), Fig. (2). 

Fig. (2). Chemical stnacturcs of tylophorine, lylocrebrine, antogine, tylophorinine (phenanthroindolizidine alkaloids) and cryptopieurine (phenctnlhroquinolizidine alkaloid)...

Pure dried tylophorine is a yellow powder, and crystallization from common solvents is difficult. Spectral data, including MS, H-NMR, C-IMMR and chiroptical (ORD and CD), of phenanthroindolizidine alkaloids have been well established [18, 42, 44-45]. The three-dimensional crystal structure of tylophorine (1) was first determined by Wang et al [46]. The structure of tylophorine B, as the benzene solvate, has conjoined phenanthrene and indolizidine moieties. The aromatic rings lie almost in the same plane with dihedral angles of 1.7° (A/B), 2.8° (B/C), 2.2° (A/C), and 7.3° (B/D). The E ring adopts an envelope conformation and makes a dihedral angle of 6.7(3)° with the D ring [46]. 

In 1996, Ciufoiini and Roschanger reported a total synthesis of phenanthroindolizidine alkaloids (tylophorine and antofine) from the sterically congested 2-substituted 4,5-diarylpyridine 61, which was prepared by a modified Knoevenagel-Stobbe synthesis [61]. Scheme (6) outlines the steps in their approach. Central to the success of this effort was the ability of a-dicarbonyl enone 58 to combine in a formal [4+2]-cycloaddition with the sterically demanding vinyl ether 56, The resultant pyran 59 was treated with DIBAL and protected with benzyl chloride giving 60, which was then treated with hydroxylamine hydrochloride to give diarylpyridine 61, After a two-step conversion of 61 to 63, a cyano... 

Gupta et al. [72] performed an extensive structure-activity comparison regarding cross-resistance in two emetine-resistant CHO cell variants. This study showed that phenanthroindolizidine alkaloids, phenanthroquinolizidine alkaloids, and emetine-related benzoquinolizidines may have the same site of action. The conformation of emetine was suggested to have a close spatial relationship to the other three compound classes, and thus, they could bind to the same hypothetical binding site, Fig. (7). 

The tylophorine (phenanthroindolizidine alkaloid) nucleus was first synthesized by Govindachari et al. in 1958 [48] followed by the synthesis of cryptopleurine (6-membered E ring, phenanthroquinolizidine alkaloid) by Bradsher and Berger [49] as well as Marchini and Belleau [50]. Many naturally occurring tylophorine alkaloids (e.g., tylophorine, tylophrinine and tylocrebine) have been synthesized, and the earlier routes before 1985 were well summarized in a comprehensive review by M. Suffness [5]. In this paper, only the more recently reported synthetic methods will be described. 

The structural relationship between benzoisoquinolines and phenanthroindolizidine alkaloids, examples of which exhibit anti-leukemia activity, has prompted some interest in the former heterocycle. The... 

Secophenanthroindolizidine alkaloids and their secophenanthroquinolizidine analogs were last surveyed in Volume 28 of this series (i). A comprehensive review on the occurrence, structural elucidation, biosynthesis, synthesis, and biological activity of the phenanthroindolizidine alkaloids, including their seco variants, was published in 1987 (57P). The topic was also included in several more general reviews on indolizidine alkaloid chemistry 14,19,563). 

The aerial parts of Cynanchum vincetoxicum (L.) Pers. (Asclepiadaceae) contain three phenanthroindolizidine alkaloids, which have been shown to be tylophorine (34), 7-demethoxytylophorine (Alkaloid A, 35), and 7-demethoxy-demethyltylophorine (Alkaloid C, 36). The trimethoxy-base (35) has also been isolated, together with two unidentified alkaloids, from the dried roots of the same plant,and from Vincetoxicum officinale Moench., in which it occurs along with tylophorine. The early work on this trimethoxy-base indicated that it was either (35) or the 3,6,7-trimethoxy isomer, but this latter possibility has now been excluded. The n.m.r. spectrum did not allow a distinction to be made between (35) and the 3,6,7-trimethoxy analogue, hence the alkaloid was oxidised by mercuric acetate, and the immonium salt so obtained was... 

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