Pyrrolizidines experiments

Pyrrolizidine Alkaloids.—Retronecine (23), the most common base portion found in the pyrrolizidine alkaloids, has been shown to derive from two molecules of ornithine (1) via putrescine (3) by the use of 14C-labelled precursors19 (cf. Vol. 10, p. 13). Unequivocal evidence on the manner of incorporation of putrescine comes from experiments in Senecio isatideus with 13C-labelled samples of putrescine.20... 

Special steric or electronic influences may thwart the expected reaction pathway, as in the regio- and stereo-selective conversion of (86) to the pyrrolizidine (87 Scheme 42). This surprising formation of a five- instead of a six-membered ring is interpreted in terms of an aza-Cope equilibrium between the expected iminium salt (88) and its isomer (89 The latter finally cyclizes regioselectively in an exo-type mode to give (87). Further support for this assumption was obtained from quenching experiments with related compounds. ... 

Robinson s original suggestion that the natural pyrrolizidine bases are derived in vivo from two molecules of ornithine (149) has been supported by studies using C-labeled compounds. Ornithine has been shown to be a specific precursor for the pyrrolizidine nucleus present in a variety of alkaloids. The feeding experiments carried out to date are listed in Table I. Three groups of workers have obtained labeled alkaloids after feeding C-labeled ornithines.Hydrolysis of the alkaloid to yield the free base, retronecine (127), has established that almost all the radioactivity is in the base portion. It is likely that ornithine is incorporated into retronecine after decarboxylation to putrescine (150) [Eq. (40)] since labeled putrescine is also specifically incorporated into retronecine (Table I). 

There are only two known, naturally occurring trihydric saturated pyrrolizidine bases. The relative stereochemistry of rosmarinecine (123) was determined by Warren and co-workers.78 For the other base, croalbinecine (124), the chirality at C-l, C-7, and C-8 was defined by Sawhney et al.19 by correlation with turneforcidine (113) as shown in Eq. (33). The location of the third hydroxy group at C-2, indicated by NMR spectroscopy, was confirmed by decoupling experiments. It was further suggested by these workers79 that the configuration at C-2 is /i-hydroxy, on the basis of the... 

Pyrrolizidine Alkaloids.—The Cjo necic acids of the senecic acid type, which appear as diesters in alkaloids like senecionine (47), have been shown to be formed from two units of L-isoleucine as illustrated in Scheme 8. Further experiments have shown... 

In further experiments the synthetic pyrrole derivative (61) was shown also to produce the characteristic toxic effects of the poisonous pyrrolizidine alkaloids this is the first time that this toxicity has been demonstrated in compounds containing a simple pyrrole ring. ... 

Other significant experiments have corroborated the metabolic pyrrole hypothesis. When cells other than those capable of microsomal oxidation (i.e., cells other than liver) were incubated with pyrrolizidine alkaloids toxicity was not observed. However when these cells were exposed to synthetically prepared necine pyrroles, severe mitotic inhibition was observed. The chemical stability of the pyrrolic alkaloids is much less than that of the corresponding necine pyrroles and the former have not been detected Ija vivo. However when synthetic monocrotaline pyrrole was injected into the mesenteric vein of rats it produced the lesions typical of pyrrolizidine alkaloid poisoning portal vascular degeneration, hepatic necrosis, and inhibition of hepatocyte mitosis (63,64). Injected into the jugular veins of rats and dogs... 

Intramolecular 1,3-dipolar cycloadditions of azides have also been investigated as a route to the pyrrolizidine ring system. For example, ethyl 8-azidoocta-2,4-dienoate (56) was converted in high yield into the labile vinylaziildine 57 when it was heated under reflux in toluene. In other experiments it was demonstrated that activation of one of the double bonds of the diene was essential in order to achieve efficient intramolecular cycloaddition. The vinylaziridine 57 was then converted into the pyrrolizidine 58 by flash pyrolysis followed by catalytic hydrogenation of the product (Scheme 6.26). 

What experiment do you suggest to discover whether pyrrolizidine alkaloids are reduced from the N-oxide form of the plants to the free base in the gut of an insect and later re-oxidized ... 

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