Lysine pelletierine

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). 

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... 

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. 

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). 

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. 

Lycopodine.—Lycopodine (4) is formed in Lycopodium tristachyum from lysine [via A -piperideine (2)] and acetic acid, " The labelling pattern observed with these precursors suggests that lycopodine (4) could be formed simply from two molecules of pelletierine (5) but in this case Occam s Razor does not apply since radioactive pelletierine (5) labels only one of these pelletierine units in lycopodine (4). - The hypothetical pathway proposed to take account of these results has been tested in further experiments.Piperidine-2-acetic acid (6), as its CoA ester, is one of the hypothetical intermediates but the evidence obtained most strongly points to it not being involved in lycopodine biosynthesis, [carftoxy- C]Piperidine-2-acetic acid fed in admixture with DL-[4- H]lysine [as (1)] gave lycopodine with a C ratio... 

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. ... 

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. 

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. 

C the acetic acid contained 47% of the activity of the lycopodine, and from the experiment with acetate-2- C the acetic acid contained 21% of the activity of lycopodine. These data are in harmony with the pelletierine but not with the polyketide hypothesis. When it was found (see below) that two molecules of lysine were specifically incorporated into lycopodine (65, 66) the polyketide hypothesis could be dismissed. 

Administration of both lysine-2- C and lysine-6- C led to the formation of labeled lycopodine. Degradation showed that approximately 25% of the label was located at C-5 (isolated as benzoic acid) and 25% at C-9 (isolated as formic acid). The remainder was assumed to be at C-1 (25%) and C-13 (25%) and although neither C-1 nor C-13 was isolated individually it was possible to obtain C-9 in conjunction with C-13 as 7-methyltetrahydroquinoline. This fragment contained approximately 50% of the activity of lycopodine. These results are compatible with the incorporation of two five-carbon chains derived from lysine into the lycopodine skeleton but they indicate that, unlike the incorporation of lysine into A-methylpelletierine shown in Scheme 4, the incorporation proceeds via a symmetrical intermediate. Next it was found that cadaverine-l- C was incorporated into lycopodine and gave the same distribution of activity as lysine. Thus it was likely that cadaverine was the symmetrical intermediate on the pathway from lysine to pelletierine. These findings are incorporated into Scheme 7 in which lysine-6- C is used as an example but the same distribution of activity would also apply to lysine-2- C. This scheme for the incorporation of lysine was supported by experiments with a doubly labeled lysine, 4,5- H2-6- C-lysine. 

The same precursors that were incorporated into lycopodine were also incorporated into cernuine (74, 75). Thus specific incorporation of lysine, cadaverine, A -piperideine, and pelletierine has been demonstrated through administration of labeled compounds to intact plants of L. cernuum According to the pelletierine hypothesis two molecules of pelletierine should combine as shown in Scheme 10 to yield cernuine. Provided that the incorporation follows the pattern established for lycopodine the labelled precursors under study would be expected to... 

The absolute configuration of 21 was established by two methods. First, 21 was converted to 5-phthalimido[5-2H]valerate by the use of chemical and enzymic methods and shown to have the same optical rotatory properties as those of authentic (5/ )-5-phthalimido[5- H]valerate produced from L-glutamate by an established stereochemical route. Second, 21 was converted to [l- H]cadavarine with L-lysine decarboxylase, followed by treatment with diamine oxidase to form pelletierine. Retention of all of the deuterium in the pelletierine demonstrated that the deuterium must be in the pro-(R) position, since the oxidase reaction is known to labilize hydrogen at the pro-(S) position [Eq. (51)] ... 

In this area the biosynthesis of the Lycopodium alkaloids, e.g. lycopodine (14) and cernuine (15), is of further interest. Lycopodine and cernuine were considered to be modified dimers of pelletierine (16) because two intact molecules of precursors like lysine and A -piperideine were used for the construction of a single molecule of the alkaloids. Paradoxically, however, pelletierine (16) only gives rise... 

This study with the chirally labelled cadaverines brings to light an apparent anomaly. Decarboxylation of L-[2- H]lysine by the enzyme from B. cadaveris affords [lB- H]cadaverine. When this material is converted into N-methyl-pelletierine (22) and AT-methylallosedridine in S. sarmentosum the tritium destined for C-2 is lost. On the other hand conversion of lysine into the sedamine in S. acre results in the retention of tritium originally present at C-l The simplest explanation of this is that the protonation of (28) in the micro-organism and the plants proceeds with opposite stereochemistry. 

Work on the biosynthesis of lycopodine (126) in Lycopodium tristachyum and cernuine (127) ° in L. cernuum, previously published in preliminary form and reviewed,has appeared in full lycopodine and cernuine.It was established that the two alkaloids are derived from two molecules of lysine via a symmetrical intermediate which is in all probability cadaverine. The hypothesis that the Lycopodium alkaloids were modified dimers of pelletierine (125) (Scheme 12) required reappraisal, as pelletierine gave only one each (shown with heavy bonding) of the two CgN units of (126) and (127). 

Hemscheidt and Spenser conducted feeding experiments and found that Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1). The decarboxylation of lysine (3) yields cadaverine (4), which consists of five carbons, and this, in turn, is converted into A -piperideine (5). The condensation of A -piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction. The biosynthetic process from this point to structurally complex Lycopodium alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)... 

The Piperidine Family. It was noted in section 3.2.1.2 that the piperidine ring is biosynthesized from the amino add lysine, and the example of coniine biosynthesis was given in that section. On the pathway to coniine (3.14), a highly toxic compound isolated from the hemlock tree is the ketone derivative 3.13 this happens to be the well-known alkaloid pelletierine, which is isolated from the pomegranate tree (Scheme 3.7). It has found use in the treatment of parasitic infections (called an anthelmintic agent). 

The S. a. are formed biogenetically from lysine via enzyme-bound intermediates. The side chain originates from phenylalanine. Sedamine is accompanied by structurally related piperidine alkaloids such as ( )- pelletierine and 2,6 substituted piperidines of the Lobelia alkaloid type (including sedinine, seda-crine) The acute toxicity of the S. a. is low, unambiguous pharmacological activities have not yet been confirmed. ... 

The full paper on the biosynthesis of the lycopodium alkaloids from lysine was published.29 xhe possibility that two identical pelletierine units (20). derived from lysine and acetate, would combine to form lycopodlne (21) was not corroborated by double labeling experiments with [4,5-%2 2" "P ll tierine.30 Only the portion of the molecule drawn in heavy line was derived from pelletierine. 

In the biosynthesis of pelletierine, lysine was incorporated without the involvement of a symmetrical intermediate such as cadaverine. On the other hand, it was established that in the biosynthesis of matrine, a symmetrical intermediate is incorporated, implying that cadaverine is involved. 

Pelletierine is biosynthesized through the incorporation of lysine. Among the several types of alkaloid possessing the piperidine nucleus, lobeline involves a similar biosynthetic pathway (Section 4.4) as that of pelletierine, whereas arecoline and coniine are biosynthesized through completely different pathways. The former alkaloid is derived lirom nicotinic acid (Section 10.3), and the latter alkaloid is biosynthesized via the polyketide pathway (Section 15.1). 

It was clarified by 1970 that pelletierine was biosynthesized from lysine and acetic acid, and that the C-2 position in pelletierine was labeled when C-2 labeled lysine was fed. 

That is to say, in the biosynthesis of pelletierine, lysine was transformed into an asymmetric alkaloid -piperideine without forming a symmetrical inter-... 

Coniine possesses a similar chemical structure to that of pelletierine (Section 4.2), isolated from the stem bark and root bark of Punka granatum. Thus Robinson [3] estimated coniine to be derived biosynthetically from a lysine moiety and a C4 unit as in the case of pelletierine, and as shown in the following figure. However, when [2- " C]lysine or its metabolites, [l,5- C2]cadaverine or [6- " C]-A -piperideine, were fed to hemlock,none of the alkaloids isolated from this plant were labeled. 

On the other hand, when [l- C]acetate was fed to this plant, labeled coniine was obtained. In addition, through degradation studies, it was found that the even-numbered carbons of coniine were labeled [4]. Thus, through the experiments described above, it was clarified that although the skeleton of coniine is very similar to that of peDetierine, coniine is biosynthesized through the polyketide pathway instead of fiom lysine, as in the case of pelletierine. These biosynthetic studies on coniine and related alkaloids were reviewed by Leete [5]. 

Precedent for the incorporation of a,o)-diamino acids into alkaloids of higher plants via nonsymmetrical intermediates exists in some pelletierine type alkaloids which are derived from lysine (11). Thus, it has been reported that in Sedum acre label from DL-[2- C]lysine and from DL-[6- C]lysine is introduced in a regiospecific fashion into the alkaloid sedamine (12). C-2 of (12) receives... 

Common characteristics in the biosynthesis of these alkaloids, that they are elaborated from the lysine derived A -piperideine, coupling either to an aliphatic- (from acetyl-CoA precursor, e.g., pelletierine and co-alkaloids), or an aromatic part (from cinnamoyl-CoA precursor, e.g., pipeline and other amides lobeline, lobelanine and related alkaloids). 

While for developing of simple piperidine alkaloids, e.g., pelletierine (Punica granatum), piperine (Piper nigrum et longum), and lobeline (Lobelia inflata), only one molecule of lysine is necessary, for quinolizidine alkaloids - e.g., lupinine (Lupinus luteus), sparteine of antiarrhythmic activity (Sarothamnus scoparius), and cytisine of respiratory stimulant effect (Laburnum species) - two molecules of lysines are indispensable. It was also proved that lycopodine (Lycopodium tristachyum, clubmoss) of quinolizidine structure has no polyketide origin, but it is a modified dimer of pelletierine, which, in turn, is derivable from lysine and acetate. 

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