Senecic acid

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

Pyrrolizidine alkaloids have a wide distribution, but are characteristic of certain genera of the Boraginaceae (e.g. Heliotropium, Cynoglossum, and Symphytum), the Compositae/Asteraceae (e.g. Senecio) and the Leguminosae/Fabaceae (e.g. Crotalaria). The pyrrolizidine bases rarely occur in the free form, but are generally found as esters with rare mono- or di-basic acids, the necic acids. Thus, senecionine (Figure 6.18) from Senecio species is a diester of retronecine with senecic acid. Inspection of the ten-carbon skeleton... 

Further experiments with threonine and isoleucine have been carried out in Senecio magnificus Both [2- " C]- and [6- " C]-isoleucine were incorporated into senecic acid (21) and degradation gave a pattern of incorporation consistent with biosynthesis from two isoleucine units (Scheme 5). [ /- " CJ-L-Threonine was equally well incorporated into senecic acid, which was shown to contain essentially no activity at C-2 and C-8, consistent with the way in which threonine condenses with pyruvic acid to give isoleucine the route from threonine to senecic acid is illustrated (Scheme 6). In these three feeding experiments the incorporation of radioactivity into the main alkaloidal component of this plant, retronecine, was very low. 

S. isatidens led independently to the same conclusion about the origin of the Cio necic acids degradation indicated a common origin for both halves of retronecic and senecic acids. 

Axillarine and axillaridine therefore contain Cjo necic acid components belonging to a new structural type. The four groups of necic aads previously known, of which senecic acid (63) may be cited, contain a common C5 structural component [indicated to the right of the dotted line in (63)], which suggests that in the biosynthesis of the necic acids this unit is coupled to various intermediates derived from common amino-acids. In the biosynthesis of axillarine and axillaridine, however, it would appear that this same C5 unit is involved, but with a different mode of coupling to the other 5-carbon unit. This adds credence to the earlier proposal that in the biosynthesis of the necic acids, the common C5 unit (derived from isoleucine ) is coupled as an intact unit. ... 

Platynecic (Probably senecic acid-f integerrinecic acid) Platyphylline 133-135 ... 

Platyphylline (156) (platyneoine and platynecio acid—may be senecic acid in the alkaloid). 

Integerrinecic Acid and Senecic Acid and Their Diastereoisomers (95,97)... 

Chart III. The structure and physical properties of senecic acid, integerrinecic acid and their diastereoisomers (755,150-1 1),... 

The (— )-senecic acid was also obtained by Mattocks and Warren (161) from the hydrolysis of isosenecionine obtained from retrosine by oxidation with sodium metaperiodate and reaction of the resulting keto compound with methylmagnesium iodide. The (-)-senecic acid was converted to (—)-integerrinecic acid lactone. The oxidation of this (— )-senecic acid with lead tetraacetate gave a keto acid (2,4-DNP, mp 183°, [aJu —11.6°) enantiomeric with that from (- -)-senecic acid (see Chart III). 

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