1,2-Dehydropyrrolizidine alkaloids

C-7 position will result in ions with the same m/z ratio, one of which wUl be protonated under the ESI conditions. The difference in molecular ion data between peak 4 and peaks 6 and 7 is consistent with an additional hydroxylation relative to sarracine-N-oxide and it is tentatively suggested that this extra hydroxylation is a result of hydration of the 1,2 olefinic center of triangularine-N-oxide to yield 2-hydroxysarracine-N-oxide. In support of this, the abundant presence of an ion at m/z 138 in the ESI-MS/MS spectra of peak 4, and its redox resin reduction product, can be rationalized as the 1,2-hydrated analog of the m/z 120 ion characteristically observed in the ESI-MS spectra of 1,2-dehydropyrrolizidine alkaloids [33]. In contrast to the proposed structure for peak 4, the MS/MS data for the minor, but isobaric, peak 2 clearly indicated the structural difference between the two (Figure 13.16) and suggested the extra hydroxylation of the C-9 esterifying add rather than in the necine base as with peak 4. 

In mammals, including humans, 1,2-dehydropyrrolizidine alkaloids incorporated internally are hydrolyzed to form retronecine. A pyrrole derivative, dehydroretronecine, is derived from retronecine by introducing a second double bond through oxidative didehydrogenation. It is this dehy-droretoronecine that manifests the liver toxicity [6,7]. 

Edgar, J.A. Danaine (Lep.) and 1,2 Dehydropyrrolizidine Alkaloid - Containing Plants - with Reference to Observations Made in the New Hebrides. Phil. Trans. R. Soc. London 272 B, 467-476 (1973). 

Brown, K.S., Jr. Chemical Ecology of Dehydropyrrolizidine Alkaloids in Adult Ithomiinae (Lepidoptera Nymphalidae). Rev. Bras. Biol. 44, 435-460 (1985). 

While 1,2-dehydropyrrolizidine alkaloids are metabolized by liver P-450 isozymes into hazardous dihydropyrrolizines (e.g.. Ill) with a pyrrolic A ring, saturated pyrrolizidine alkaloids produce nontoxic, metabolites [79, 111]. The saturated alkaloids platyphylline and rosmarinine (Fig. 13.6), for example, are converted by liver microsomes into pyrrolic metabolites with an aromatic B-ring [79]. These are devoid of biological alkylating properties and are nontoxic. 

The structural features responsible for the genotoxicity are a double bond in the necine base between C-1 and C-2, presence of hydroxy groups at C-1 and C-9, and esterification of at least one of these hydroxy groups with a branched carbon chain (Frei et al., 1992). In most vertebrates and insect herbivores, the alkaloid A -oxides are reduced in the gut to their free bases. The reduced alkaloids are then taken up and bioactivated by cytochrome P450-dependent monooxygenases of the liver to highly reactive dehydropyrrolizidine alkaloids that react with nucleophilic groups of proteins and DNA (Roder, 1995). 

By using the same method, an attempt toward the synthesis of 3-epiaustraline (371) was unsuccessful (70) (Scheme 9.70). Thermolysis of the azido-diene 367 afforded the dehydropyrrolizidine 368 and the triazoline 369 in equal amounts. All attempts to hydrolyze the vinyl sulfide unit of 368 to the ketone 370 were futile, although a more conventional route to these alkaloids proved to be successful. 

Sheep rumen contents are known to detoxify pyrrolizidine alkaloids. A new, obligate anaerobe, Peptococcus heliotrinreductans, has been identified from the rumen.74 It is a Gram-positive coccus, and reduces 1,2-dehydropyrrolizidines, using hydrogen gas or formate as hydrogen donors. 

Extensive examinations of the circular dichroism curves of pyrrolizidine alkaloids have been carried out by Culvenor et a/. and Hrbek et The free bases tested were divided into four groups, all possessing 8a-hydrogen atoms. Saturated 1-substituted pyrrolizidines [e.g., 1-methylpyrrolizidine (7) and isoretronecanol (22)] showed negative Cotton effects while with 1,7-disubstituted pyrrolizidines [e.g., platynecine (43)], the Cotton effects were positive. Dehydropyrrolizidines with 1-substituents [e.g., supinidine (96)] displayed positive Cotton effects, and those with 1,7-disubstitution patterns [e.g., retronecine (127) and heliotridine (109)] exhibited large positive... 

Full details of the work3 of Culvenor and his collaborators on the dihydro-pyrrolizine analogues of the pyrrolizidine alkaloids have now been published.12,13 In particular, the ready oxidation of 1,2-dehydropyrrolizidine derivatives containing C(7)—OH or C(l)—CH2OH groups with manganese dioxide is rationalized and explained mechanistically. 

In pyrrolizidine alkaloids of type la and Ib (1,2-dehydropyrrolizidine diesters) the C-O bonds A and A" occur in a normal range of 1.45 A the following C-O bonds B and B are considerably shortened, whereas the keto functions C and C show a moderate shortening. The C-C bonds D and D show - similar to A and A -normal values of about 1.54 A. 

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