Phenanthroindolizidines

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. 

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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]. 

Cynanchum vincetoxicum (L.) Pers. contains traces of an alkaloid vincetene, which shows an interesting relationship to the phenanthroindolizidines found in Tylophora and other genera of the Asclepiadaceae. Spectroscopic study has shown vincetene to be the benzopyrroloisoquinoline derivative (2), and this structure has been confirmed by synthesis of the racemic dihydro-desoxy-deriva-tive (3).2... 

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. 

The major alkaloid was antofine. Bases of the phenanthroindolizidine type appeared to be present but were not identified (70). 

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... 

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... 

Phenanthroindolizidine and phenanthroquinolizidine alkaloids involve a phenanthrene (Phe ] Phe Phe (angular)) fused with an indolizidine or quinolizidine, respectively. The phenanthroindolizidines tylophorine (phenanthrene G5N G4N ) and tylocrebrine (phenanthrene G5N C4N ) and the phenanthroquinolizidine crypto-pleurine (phenanthrene G5N C5N ) are toxic, cytotoxic protein synthesis inhibitors. The phenanthroindolizidines tylophorine and pergularinine are thymidylate synthase inhibitors. 

Tylocrebrine, C24H27O4N (mp 218°-220°), is a tertiary base having four methoxyl groups, no N-methyl group, and no easily reducible unsaturation. Its UV-spectrum with absorption maxima at 263, 342, and 360 mp. (loge 4.81, 3.25, 3.09) is practically superposable on that of 3,4,6,7-tetramethoxy-9-methylphenanthrene. The IR-spectrum confirms the absence of OH, NH, or carbonyl functions. Since the alkaloid is isomeric and occurs jointly with tylophorine, it may be assumed to have the same phenanthroindolizidine system on the basis of the UV-spectrum two structures (XIX or XX) may be proposed. A choice between the two structures was made by synthesis as described in the next section. 

The presence of a phenanthroindolizidine ring system can be assumed on the basis of the UV- and mass-spectra. Oxidation of the alkaloid with alkaline hydrogen peroxide yielded m-hemipinic acid as the only isolable product. On the basis of its IR-spectrum and biogenetic considerations, the methoxyl groups can be assigned to the 2,3,6- or 3,6,7-positions on the phenanthroindolizidine system leading to the alternate structures XVa and XVI. It is of interest that racemic forms of both the possible structures have already been synthesized (12, 18). 

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. 

A convenient synthesis of the unsubstituted seco-phenanthroindolizidine ring system and of the alkaloid septicine (1) has been based on the probable biosynthetic... 

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]. 

The structure of (+)-ficuseptine-A (15), Fig, (5), a new phenanthroindolizidine N-oxide isolated from leaf extracts of Ficus septica, was elucidated by means of comprehensive spectroscopic methods [3]. The relative stereochemistry was deduced from NOE correlations, while the (13aS) absolute configuration was inferred from a positive optical rotation at the sodium D line and a positive Cotton effect at 265 nm, a well-established correlation in this alkaloid series. Seven known alkaloids were also isolated in this investigation, including (+)-... 

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... 

Kim et al. used an enantioselective catalytic phase transfer alkylation, together with a ring-closing metathesis for pyrrolidine ring constmction, to first synthesize the phenanthroindolizidine (-)-antofine [(-)-3] [63, 63]. Two similar approaches were developed, but only the later approach is illustrated in Scheme (8). As the key intermediate of this synthetic pathway, 77 is in enantiomerically pure form and was achieved by using a... 

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). 

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