Pelletierine alkaloids

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. 

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... 

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). 

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. 

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. 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62), Wrobel and Gol biewski condensed pelletierine (126) with isovanillin (128) and obtained a transfused quinolizidine derivative (130, jS H-5) (64) in 75% yield. A model condensation of pelletierine (126) with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52) condensed A -pjperideine (132) with /J-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinna-mic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful. 

The synthesis of 54 was similarly performed from 2-bromoveratraldehyde (166), methyl 4-hydroxycinnamate, and pelletierine. The product was shown to be identical to the natural alkaloid and the structural assignment was confirmed (42). 

Most of the work on the biosynthesis of Lythraceae alkaloids has been done by Spenser et al. (10, 84-87). First, the validity of the pelletierine hypothesis (c) of Ferris et al. (62) has been tested. The pelletierine (126) nucleus is generated from L-lysine (181) via cadaverine (182), and presumably A -piperideine (132) and its side chain originate from the acetate. Incorporation of radioactivity from 14C-labeled samples of these precursors to decodine (6) and decinine (2) in Decodon verticilatus has been investigated (85, 87). 

In light of the present evidence the biogenesis of metacyclophane Ly-thraceae alkaloids required revision, since the only published proposal (9) was based on pelletierine. A new biogenetic scheme was proposed which invoked intermediacy of A piperideine and two C6-C4 units [derived from /i-kctoester (193)]. An intermediate disubstituted piperidine (194) would give rise to two types of metacyclophane alkaloids as a result of reduction and phenol coupling as well as Michael addition in the case of the quinoli-zidine bases (10). 

Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone (11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8) with an aromatic aldehyde followed by intramolecular Michael-type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10). 

The piperidine alkaloid pelletierine was mentioned in the chapter but full details of its biosynthesis were not given. There follows an outline of the intermediates and reagents used. Fill in the details. Pyridoxal chemistry is discussed in Chapter 50. 

Coniine (12), implicated by Plato in the death of Socrates, is the major toxic constituent of Comum mamlatum L. (poison hemlock) and, as pointed out earlier, was apparently the first alkaloid to be synthesized. For years it was thought that coniine was derived from lysine (24), as were many of its obvious relatives containing reduced piperidine nuclei and a side chain, eg, pelletierine (46). However, it is now known (99) that coniine is derived from a polyketooctanoic acid [7028-40-2] (138), C8H10O5, or some other similar straight chain analogue. 

Now the enol of acetyl CoA adds to the iminium salt to complete the skeleton of the piperidine alkaloids. Hydrolysis and decarboxylation by the usual cyclic mechanism (p. 678) gives pelletierine. 

The piperidine alkaloid pelletierine, mentioned in problem 9, is made in nature from the amino acid lysine by pyridoxal chemistry. Fill in the details from this outline ... 

Lycopodium Alkaloids.—It has been suggested that lycopodine (16), cernuine (17), and related alkaloids are modified dimers of pelletierine (15) (Scheme 3). Lysine and acetate serve as specific precursors of lycopodine. Further, [2- " C]lysine has been specifically incorporated into cernuine (17) in Lycopodium cernuum The data suggest that this alkaloid, like lycopodine, is biosynthesised... 

Only routes (a) and (b) are consistent with these results. It is interesting to note that if pelletierine is implicated in the biosynthesis of these alkaloids [route (a)] it should be derived from a symmetrical intermediate as is apparently true for pelletierine in the biosynthesis of lycopodine alkaloids (see above). On the other hand, A -piperideine [route (b)] is derived in an unsymmetrical way from lysine in the biosynthesis of anabasine and iV-methylpelletierine (see above). Route (a) would, therefore, seem more likely. ... 

Two interesting syntheses of the unstable piperidine alkaloid, nigrifactine (8), have been developed. In one report, " the highly unsaturated ketone (14), prepared by conventional means, was converted into (8) via an unusual reaction which may involve a phosphine-imine intermediate in the other route, elaboration of the side chain (16) - (15) was achieved by a condensation which takes advantage of the acidic methyl protons in (16). 1,4-Dihydro-1-methy 1-4-oxonico-tinonitrile and pelletierine specifically labelled with have been prepared. ... 

Many 2-substituted piperidine alkaloids are produced by Sedum. In one study, for example, TLC and GC/MS were used, to survey alkaloids in sixteen Sedum species. The alkaloids reported were sedridine (167), /V-methylsedridine (168), pelletierine (169), N-methylpelletierine (170), 4-hydroxysedamine (172), norsedamine (177), allosedamine (178), 3-hydroxyallosedamine (175), as well as the 2,6-disubstituted piperidines sedacrine (231), sedinine (236), and sedinone (232) [426]. 

It will be interesting to see if the hydrogen at C(2) of lysine is retained in the biosynthesis of the other alkaloids of this family, such as anabasine (86) and pelletierine (89), where the nitrogen atom is not methylated. It is significant that the pipecolic acid (88) produced along with the sedamine in this experiment, was devoid of tritium. Therefore, the pathway a could be in operation for this natural product and it may be the normal route for some of the alkaloids also. 

In experiments with intact plants, the activity from [l-14C]acetate was found to be incorporated specifically into the predicted position for each alkaloid. In parallel experiments with [2-14C]acetate, iV-methylpelletierine was degraded and shown to have, as expected, 50% of the activity located in the C-methyl group. The sequence of intermediates in the late stages of the pathway were investigated with the following results (i) iV-methylpelletierine (90) is incorporated into pseudopelletierine (91), and (ii) pelletierine (89) is a precursor of anaferine (92). 

The alkaloid (93) which is produced by Haloxylon salicornicum shows a structural resemblance to pelletierine (89). A feeding experiment58 with [6-14C]-lysine in intact plants has supported the related biosynthesis in Scheme 18. Activity was incorporated at C(6) of the alkaloid as shown. Surprisingly, no activity was incorporated from [2-14C]acetate but this negative result could be due to the failure of acetate to reach the site of synthesis. 

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