Necic acid

Most of the necic acids are Cio-acids. Because they can apparently be divided into two isoprene units, they were originally believed to be derived from mevalonate, even though the oxidation patterns and mode of coupling of the Cs units were quite different from those of terpenoid compounds. Indeed, acetate and mevalonate were found not to be specific precursors for the Cio-necic acid portions of pyrrolizidine alkaloids (J4,123). All of the acids investigated so far have been shown to be formed from common branched-chain amino acids. 

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The necic acids have received little attention from investigators, but when more is known about them they may prove to be less variable in character than appears to be the case at present. Those acids which have merely been characterised are described briefly under the appropriate alkaloids, but the few that have been more fully examined are described together later. 

The Necic Acids. There appears to be much more variety among the necic acids than among the necines, possibly because so little is known about them. Most of them are described briefly under their appropriate alkaloids, but there are at least four which need more detailed description. 

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... 

Pyrrolizidine Alkaloids.—The necic acid component of senecionine (8) derives from two molecules of isoleucine, radioactivity from precursor amino-acid being equally incorporated into both halves of the necic acid fragment, as shown in Scheme 2 (c/. Vol. 9, p. 4). It has now been shown that biotransformation of isoleucine into the necic acid involves loss of half of a tritium label from C-4 in each of the two amino-acid fragments.6 Removal of a proton is, therefore, stereospecific, and oxidation at C-4 does not proceed beyond the two-electron level i.e., a higher intermediate oxidation level, corresponding to a ketone, is excluded. Further results indicate that for each molecule of isoleucine it is the 4-pro-S proton [see (14)] which is lost. 

The known alkaloids senecionine, senkirkine, and retrorsine have been isolated from Senecio vernalis Wald, et Kit. by Roder et al.26 A new alkaloid, named senecivernine (59), was also present. The mass spectrum of (59) showed a molecular ion at m/z 335, and fragment ions at m/z 291, 248, and 220, characteristic for a macrocyclic diester of retronecine, arising from cleavage of the allylic ester.17 Basic hydrolysis of senecivernine gave a new necic acid which had spectroscopic data in accord with the proposed structure. Retronecine was not isolated. The necic acid from senecivernine is a Ci0 acid of an unusual structural type (cf. Vol. 8, p. 55). 

Arctiid moths are also capable of synthesizing their own PAs from a necine base of plant origin and a necic acid synthesized from isoleucine in their own metabolism. Callimorphine, a PA not produced by plants, is synthesized by many arctiid moths and is sequestered as a defensive compound after re-esterification of retronecine of plant origin. Creatonotine, another insect PA, is produced by adults of C. transiens by esterifying ingested retroncine with a distinctive necic acid. These moths are unique in adding de novo-synthesized PAs to plant-derived alkaloids as part of their defensive arsenal. 

Axillarine (40) was isolated from C. axillaris Ait. by Crout.20 The crystal structure of the ethanol solvate of axillarine hydrobromide has been determined by X-ray diffraction methods.21 The absolute configurations of the four chiral centres in the necic acid portion have been established. The overall shape of axillarine is somewhat similar to fulvine (41),22 which also has an 11-membered macrocyclic... 

An apparently similar, antiperiplanar elimination with loss of the isoleucine 4-pro-S proton, to generate a double-bond of opposite geometry in alkaloidal necic acid fragments, has been observed13 (cf. Vol. 11, p. 2). 

The biosynthesis of the necic acid moiefy has, in contrast received relafively little attention. Label from C-isoleucine is effectively... 

The mode of attachment of the necic acid in crotastriatine (from Crotalaria striata) to the nedne (retronedne) has been investigated. Hydrogenolysis of crotastriatine gave a product, presumably the zwitterion (41) the i.r. spectrum of which indicated the presence of an intact a/S-unsaturated ester function, confirming the mode of attachment as in (40). Crotastriatine (40) is the acetate of nilgirine (42) which has also been found in Crotalaria striata (= C. mucronata). Acetylation of nilgirine (42) with acetic anhydride-perchloric acid gave crotastriatine (40). 

Pyrrolizidine Group.—Evidence from two sources indicates that the Cio necic acids are derived by the coupling of two units derived from isoleucine. Earlier work had indicated that the left-hand C5 unit of seneciphyllic acid (22) is derived from isoleucine and its biological precursors threonine and aspartic acid. Mevalonic acid was not incorporated but the S-methyl group of methionine served as a fairly specific precursor for C-8. 

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. 

The absolute configuration of monocrotalic acid (44), the necic acid component of monocrotaline (45), has been elucidated aside from the acid derived from retusamine, whose structure has been defined by X-ray crystallography, this is the first necic acid component of a pyrrolizidine diester alkaloid containing an eleven-membered ring to have its stereochemistry unambiguously established. 

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. ... 

The absolute configuration at C-2 of some other necic acids has also been established by examination of their o.r.d. spectra." In contrast to clivonecic... 

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