Pelletierine

The pomegranate alkaloids, pelletierine (46) and pseudopelletierine (48) as well as minor accompanying bases, have a long history as salts of tannic acid as an anthelmintic mixture for intestinal pinworms (see Antiparasitic AGENTS, ANTHELMINTICS). The alkaloids themselves (as the taimates) are obtained from pomegranate tree (Punkagranatum L.) root bark and are among the few bases named after an individual (P. J. Pelletier) rather than a plant. 

Hess and Eichel have shown that d-coniine with formaldehyde and formic acid yields an active A -methyl-d-coniine, and that methylZso-pelletierine hydrazone (see p. 57) yields ZV-methyl-dZ-coniine when heated with sodium ethoxide at 150-70°. 

Constitution. Pelletierine behaves as a secondary amine and the oxygen atom of the alkaloid is present in the form of an aldehyde group, since the base yields an oxime, convertible by the action of phosphorus pentachloride into a nitrile, b.p. 104-6°/13 mm., which is hydrolysed by caustic potash in alcohol to an acid, the ethyl ester of which is Loffler and Kaim s ethyl -2-piperidylpropionate. Pelletierine is not directly oxidisable to this acid. It also yields a liquid hydrazone, b.p. 130°/20 ram., which with sodium in alcohol at 136-70° reduces to dZ-eoniine. These reactions are explained by the following formulas, in which pelletierine is represented as -2-piperidylpropionaldehyde. 

In view of these reactions methylfsopelletierine must be N-inethylpiperidine with one of the following side-chains in position 2 (a) —CHa. CHa. CHO (b) —CO. CH. CH3 (c) CH. CO. CH3. If the side-chain were (a) methylfsopelletierine should be formed by A -methylation of pelletierine, which is not the case. Decision between b) and (c) proved difficult. If the side-chain were (c) the alkaloid should be a-N-methylpiperidyl-2-propan- -one (I). This substance was synthesised by Hess and Eichel and appeared not to be identical with nriethylfsopelletierine, and Hess was, therefore, led to the conclusion that the side-chain must be (b), which would make methylisopelletierine structurally identical with methylconhydrinone. The difficulty was... 

Piccinini, therefore, adopted formula (XIV) for 0-pelletierine, which is based on Willstatter s tropinone formula (p. 77) by cliange from a heptamethylene to an octamethylene ring. ... 

The following synthesis of p ewdopelletierine is of special interest, since it involves only materials and conditions which could occur in plants and is therefore a possible bio-synthesis. Menzies and Robinson showed that when calcium acetonedicarboxylate, glutardialdehyde and methyl-amine are mixed in aqueous solution under specified conditions and the mixture is kept for twenty-four hours, a produet (XX) is formed, which can be decarboxylated to -pelletierine (XXI) and the latter isolated as the picrate, whieh after recrystallisation yields the pure base (m.p. 48-5°), the identity of which can be established by eonversion to the characteristic dipiperonylidene derivative. The course of the synthesis is represented as follows — ... 

The same authors have made a number of analogues of -pelletierine in whieh sulphur, selenium, or a seeond atom of nitrogen, is introdueed into... 

Sehdpf and Lehmann have effeeted syntheses on this prineiple under varying conditions. Thus, using buffered solutions of glutardialdehyde, raethylamine hydrochloride and acetonedicarboxylic acid, they have obtained yields of 60-72 per cent, of A-pelletierine working at pH 3-7, with smaller, but still important, yields at pH 9-0-13 0. 

Pelletierine and associated bases, pharmacological action, 62, 108 isoPelletierine, 55, 57, 58 pserwfoPelletierine, 55, 58 constitution, 59 synthesis, 61 Pellitorine, 2... 

Schopf and Lehmann synthesised by similar methods, which are referred to later, tropinone, -pelletierine and lobelanine These syntheses illustrate the dependence of yield on the pH of the reaction mixture, as the following table for yields of lobelanine hydrochloride shows. -—... 

The study above does not account for the extra six carbons acquired in the conversion of piperideine (8, 10 carbons) to phlegmarine (9, 16 carbons). It was initially proposed that the carbons were incorporated via pelletierine (12), which was incorporated twice into lycopodine resulting in two symmetrical halves of the alkaloid (Scheme 6.2). However, when 14C-labeled pelletierine (12, label at C2) was fed to the plant, degradation studies of lycopodine revealed that only one half consisted of the 14C label from pelletierine (the half containing C9-C16) [10]. The other half does not result from pelletierine 12 but must be something similar in structure since it does contain the piperideine unit (8) resulting from lysine. It was of interest then to determine the exact source of the three-carbon propionate unit in pelletierine (12). 

Further studies by Spenser demonstrated that l,2-13C-labeled acetate (13) was incorporated into lycopodine but gave a distribution of the labels that did not account for the pelletierine-route that was hypothesized (Scheme 6.2) [11]. An intact 3-carbon unit was desired for testing, but labeled acetoacetate (l,2,3,4-13C-acetoacetate (14), which could undergo decarboxylation to provide an intact 3-carbon unit) was found to give the same incorporation pattern as acetate (and therefore must have been cleaved to acetate prior to uptake). In addition, feeding studies using deuterated, 13C-labeled acetate provided a loss or washout of deuterium at the C16 methyl group. This could only occur if an intermediate had formed that would provide for facile enolization. Both the equal distribution of the 13C labels and loss of the deuteriums led the researchers to propose that the intermediate was symmetric, such as acetone dicarboxylic acid (15). 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

The 13C labels allow for use of 13C NMR in which the peaks containing the 13C label enrichment show satellites corresponding to a 1JCc coupling ( 30 Hz). The distribution pattern of 13C labels found was more complicated than one single pathway and pointed toward both pelletierine and cocaine-derived alkaloid pathways, both which incorporate two acetate units Hemscheidt T, Spenser ID (1993) J Am Chem Soc 115 3020... 

L-lysine Piperidine alkaloids Piperidine Anaferine Lohelanine Lohehne A-methyl pelletierine Pelletierine Piperidine Piperine Pseudopelletierine Sedamine... 

L-lysine derived alkaloids Punicaceae Punica granatum Pelletierine Pseudopelletierine Methylpelletierine Anaferine... 

Alkaloids with the piperidine nucleus, such as pelletierine (Punica grana-tum), lobelanine Lobelia inflata) and piperine Piper nigrum), have a typical biosynthesis pathway. It starts with L-lysine and continues via cadaverine (biogenic amine), A -piperideine and A -piperidinium cations and lobelanine, to be synthesized as lobeline. Piperine is synthesized from A -piperideine via piperidine (Figure 49). For the transformation from A -piperideine to A -piperideine cation, the residue from acetyl-CoA is needed, together with SAM activity in the transformation to lobelanine. Piperine is synthesized from piperidine through the formation of amide. 

Figure 49. Diagram of the pelletierine, lobelanine and piperine synthesis pathway.

In the case of protein amino acid-derived alkaloids, the second obligatory intermedia is synthesized from the obligatory intermedia by chemical reactions. In the pelletierine synthesis pathway started with L-lysine, the second obligatory intermedia is A -piperidinium cation. It is formed by a Maimich reaction from A -piperidine (obligatory intermedia) and COSCoA. The second obligatory intermedia, by hydrolysis decarboxylation, produces pelletierine. 

Myrtine and 4-epimyrtine were obtained from Vaccinum myrtillus 110). The structure of myrtine (60) and the absolute configuration at C-4 (R) and C-10 (R) were established on the basis of IR and H-NMR spectra. Synthesis was accomplished from (/ )-(-)-pelletierine (61) and acetaldehyde (Scheme 1) 111). Racemic myrtine (60) and 4-epimyrtine (64) were also obtained by the method of Scheme 1. 

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