Necic acids Necine

Most pyrrolizidine alkaloids are esters constructed from an aminoalco-hol called a necine unit (pyrrolizidine derivative), and straight or branched chain fatty acid, called a necic acid. Necine is the derivative of pyrrolizidine, i.e., azabicyclo[3,3,0]octane, and a hydroxymethyl (-CH2OH) moiety is always attached at the C-1 position. Necines can be classified into two groups, either with or without a double bond between the C-1 and C-2 positions. The stereochemistry of the H-8 position is usually H-8a.When the C-8 position is oxidized, as in the case of otonecine, it becomes an eight-membered ring by decychzation. 

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. 

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. 

The degradation of the Senecio alkaloids continues to be effected by saponification or hydrogenolysis. The use of alkali in the hydrolysis does not alter the necine moiety but it may cause a change in the geometrical configuration about an a,j8-oarbon-carbon double bond in the necic acid. Hydrogenolysis provides important information as to the location of the esterified hydroxyl on the necine, and subsequent conversions permit a decision as to which end of a dicarboxylic necic acid (in the cyclic diesters) is attached to the allylic or primary hydroxyl of the necine. 

With a knowledge of the structures of the necines and necic acids and with the location of ester linkages ascertained, it is possible to write structural formulas to represent the pyrrolizidine alkaloids. Configurations (absolute and relative) at asymmetric carbons and double bonds are indicated when the author feels that these have been established with a reasonable degree of certainty. Structures have not been provided where the information is deemed insufficient, so that not all of the alkaloids listed in Table 1 will be given representations. The alkaloids are divided into three main categories monoesters, diesters (two different necic acids), and cyclic diesters. The amine iV -oxides are not given since their structures are obvious from the amines. 

Possible pathways of biosynthesis of the necic acids have been outlined by Adams and Gianturco (74, 134), based upon multiple condensations of acetate units. The possible derivation of the necines has been considered by Robinson to be closely analogous to the biosynthetic scheme for some of the lupin alkaloids (222-224). 

Several useful reviews and compilations of data on pyrrolizidine alkaloids have been published. These include a review of all aspects of pyrrolizidine alkaloid chemistry and biochemistry this is comprehensive, but rather idiosyncratic in its balance (sixteen pages are devoted to the synthesis of necines and necic acids whereas physical and spectroscopic properties of the alkaloids are discussed in barely two.) Nevertheless, this up-to-date work will certainly be of great interest and usefulness to workers in the field. Klasek has surveyed the investigations on pyrrolizidine alkaloids carried out at Olomouc, and Atal and Sawhney have produced a useful compilation of data on alkaloids from Indian Crotalaria species. Pyrrolizidine alkaloids from the Orchidaceae have been surveyed by Luning" and by Brandange. Pyrrolizidine alkaloids are included in a comprehensive compilation of data on alkaloids isolated from plants occurring in the U.S.S.R. ... 

The previously proposed structure (5) for swazine has been revised to (6) with reversal of the mode of attachment of the necic acid to the necine base, retronecine. The revised structure brings swazine (6) into line with the majority of cyclic diester ... 

Of all the Senecio alkaloids, the structure of monocrotaline is known with most certainty as a result of the work of Adams and his co-workers over a period of five years or more. The alkaloid monocrotaline (I) is the ester of retronecine vith monocrotalic acid. The structure of the necine portion has been proved conclusively, while the structure of the necic acid portion is considered the most likely of three possible configurations. The position of attachment of the two portions is known with certainty. The... 

These illustrations may be regarded as typical experimental procedures for the extraction, hydrolysis, and hydrogenolysis of a Senecio alkaloid. In order to assign a structure to a particular Senecio alkaloid, it is first necessary to prove the structure of the portions obtained on hydrolysis and hydrogenolysis of the alkaloid. Accordingly, the structure of the necines and necic acids will be considered before that of the parent alkaloid, which is necessarily represented by their combination. 

The necic acids are those acids which are bound in ester combination with the hydroxyl group of the necines. Due to the wide divergencies in composition, properties, and structure, they will be treated individually in the order of increasing carbon content. 

Alkaline hydrolysis of most of the Senecio alkaloids results in the formation of a necine and a necic acid. Certain of the alkaloids, however, hydrolyze to form the necine, an acid (usually), and carbon dioxide. Tri-... 

Pyrrolizidine alkaloids (PAs) belong to a class of naturally occurring compounds characterized by a bridged dipyrrole structure. They encompass more than 400 different structures, which consist of a necine base of type 25 that may also be saturated between carbons 1 and 2 and esterified with one or more necic acids which exist as 5-11 carbon membered types (Figure 5.25). Thus, there are monosters such as supi-nine 27, indicine 28 obtained from retronecine 25a, and (-)-trachelanthic acid 26. Heliosupine 29 is an example of an open-chain diester, and retrorsine 30 is, instead, a macrocyclic diester. PAs are constitutively produced by the plant and are believed... 

Figure 5.25 Pyrrolizidine alkaloids structure of necine base 25, trachelanthic acid 26, a necic acid supinine 27 and indicine 28, monoester pyrrolizidine alkaloids heliosupme 29, a diester pyrrolizidine alkaloid retrorsine 30, a macrocyclic diester pyrrolizidine alkaloid senecionine N-oxide 31, a non-toxic pyrrolizidine alkaloid.

The necic acids are linear or branched compounds constructed usually with 5,7,8, or 10 carbons. One or two necic acid(s) are combined with the necine as an ester. For example, angelic acid and tiglic acid with five carbons, and senecic acid and isatinecic acid with ten carbons, are frequent acylating units. 

Various pyrrolizidine alkaloids are produced by the combination of the necines and necic acids. For example, the combination of retronecine, a necine, and isatinecic acid, a necic acid, forms retrorsine, which was isolated from Senedo retrorsus [1]. The combination of rosmarinecine and senecic acid forms rosmarinine, which is the main alkaloid of Senedo pleis-tocephalus [2],... 

Pyrrolizidine alkaloids usually occur as complex esters of unique monobasic or dibasic acids called necic acids. Senecionine (5) is composed of both the necine base, retro-necine (1), and senecic acid (6) (Fig. 30.4). 

Pioneering tracer studies carried out in the laboratories of D. J. Robins and I. Spenser had demonstrated that the carbon skeleton of the necine base originates from ornithine or arginine via putrescine. Extension of these studies in the 1980s using precursors labeled with stable isotopes confirmed that retronecine is derived from putrescine via a symmetrical intermediate such as homospermidine [17-19]. The formation of the necic acids is less well understood. Early tracer-studies primarily carried out by D. H. G. Grout and collaborators revealed that the carbon skeletons of all aliphatic necic acids so far studied are derived from branched-chain amino acids, i. e., isoleucine, and less frequently leucine and valine [see 17]. 

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