Phenanthroindolizidine alkaloids isolation

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). 

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... 

The final steps shown in Scheme 4 include oxidative phenol coupling (65, 64,75) and other reactions analogous to those which occur during tqroiphine biosynthesis (74, 76). In addition to the final products (13 and 6) indicated in Scheme 4, any of the other phenanthroindolizidine alkaloids so far isolated could be produced by simple modifications of the scheme similar to those that take place in the biogenesis of aporphines. It is interesting that in spite of the apparent synunetry in substitution pattern of rings A and B of tylophorine (13), they are formed by separate pathways from phenylalanine and tyrosine, respectively. 

Cryptopleurine (24) and julandine (25) are phenanthroquinoUzidine alkaloids. Together with phenanthroindolizidine alkaloids, they are constituted by over 70 compounds. These alkaloids are commonly isolated from plants of Asclepiadaceae and Moraceae famihes [109,110]. They have exhibited similar biological activities, which include antiviral, antifungal, cytotoxic, and vesicant [111]. 

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 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 (+)-... 

Septicine (866), the prototypical alkaloid in this group, is a seco variant of the more populous phenanthroindolizidine class of alkaloids, of which tylophorine (867) and antofme (868) are commonly encountered examples. All fte known analogs of septicine are metabolites of the unrelated genera Cryptocarya (Lauraceae), Ficus (Moraceae), and Tylophora (Asclepiadaceae). In addition to Ihe previously described alkaloids 8a-hydroxysepticine (869) and hispidine (870) (7), seven new members of the family have been isolated (Table II and Fig. 16). 

In addition to benzylisoquinolines, the family Lauraceae furnishes phenanthro-quinolizidine alkaloids such as the previously mentioned cryptopleurine (31) [77], a highly cytotoxic and vesicant substance first isolated from Cryptocarya pleurosperma [78]. These alkaloids are closely related structurally to the phenanthroindolizidines, a group of bases found in the families Asclepidaceae and Moraceae that are likewise vesicant. An example is tylocrebrine (56), which is elaborated by a Queensland plant from each family, Tylophora crebriflora [79] and Ficus septica [80], respectively. In the latter it occurs along with the seco analogue septicine (57), its presumed biosynthetic precursor. Apart from phenanthroindolizidines, certain Ficus spp. produce some simple pyrrolidine bases such as ficine (58) that are noteworthy because of their flavonoid substituents [81],... 

Isolation, total synthesis, and biological activity of phenanthroindolizidine and phenanthroquinolizidine alkaloids 01S2365. 

Phenanthroindolizidine and phenanthroquinolizidine alkaloids have similar pentacyclic structures however, the latter compounds contain a 6-membered piperidine E ring rather than the 5-membered pyrrolidine E ring found in the former compounds. Cryptopleurine (5), Fig. (2), is a representative and important phenanthroquinolizidine alkaloid. It is isolated primarily from Cryptocarya pleurosperma [20], but also from Cryptocarya laevigata [21], Boehmeria cylindrica [22, 23], Boehmeria platyphylla [24], Boehmeria caudate [21], and Cissus rheifolia [25], and is known as a highly toxic skin irritant and vesicant. 

Four alkaloids have been isolated from Tylophora crehriflora (Family Asclepiadaceae) by systematic fraetionation, namely Tylophorine Tylocrebrine, Tylophorinine, and Phenanthroindolizidine. 

In this section structures are shown for the 16 phenanthroindolizidine and two phenanthroquinolizidine alkaloids that have so far been described, together with the stereochemistry where known. References to their isolation... 

Li ZG, Jin Z, Huang RQ (2001) Isolation, total synthesis and biological activity of phenanthroindolizidine and phenanthroquinolizidine alkaloids. Synthesis-Stuttgart... 

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