Methyl-pelletierine

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

Punica granatum L. Shi Liu Pi (Pomegranate) (pericarp, root bark) Pelletierine, isopelletierine, methylisopelletierine, methyl-pelletierine, pseudopelletierine, gallotannic acid, sitosterol, ursolic acid, maslinic acid, elegic and gallic acid.33-450 This herb is toxic. Purges intestinal parasites. 

Punica granatum L. China Pelletierine, isopelletierine, methyl-pelletierine, methylisopelletierine, pseudopelletierine, tannic acid, granatin.33 This herb is toxic. Treat intestinal parasties, antibacterial. 

Methyl-corypalline Methyl eugenol Methyl isobutyl ketone Methyl isocupressate Methyl-l-propenyl disulfide Methyl-laurate Methyl-n-amyl ketone Methyl n-nonyl ketone Methyl nigakinone Methyl palmitate Methyl-pelletierine Methyl salicylate Methyl-swertianin Methylacetic acid Methylanthranilate Methylchavicol Methylcytisine... 

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. 

The bark of the pomegranate tree (Punica granatum L.) was first investigated by C. Tanret who isolated from it four alkaloids which he named pelletierine (204), isopelletierine, methylpelletierine, and pseudo-pelletierine (205, 206). Methylpelletierine and pelletierine were observed to be optically active while isopelletierine and pseudopelletierine were inactive. Later, Piccinini (207) found a fifth alkaloid, isomethylpelletierine in the mother liquors obtained from the preparation of pseudopelletierine. Eventually, however, Hess (208) while reinvestigating the bark obtained pseudopelletierine, Piccinini s isomethylpelletierine and a third, optically inactive base, but found no trace of Tanret s optically active methylpelletierine. He could not find any optically active alkaloids and, considering his third base identical with Tanret s isopelletierine (185) renamed the latter base pelletierine. Further, Hess and Eichel (209) considered Tanret s methylpelletierine and Piccinini s isomethylpelletierine as identical but different from methylated pelletierine and named it methyliso-pelletierine (185). 

Scheme 8. Four possible paths for the introduction of the acetate-derived Cj unit of N-methyl-pelletierine 23 and hygrine 16...

Biogenetically, pelletierine is derived from lysine via piperidine and a C3 unit (acetate), and pseudopelletierine is formed by oxidative cyclization of A -methyl-pelletierine (Fig. 5.2.4). 

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°. 

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 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 — ... 

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). 

An improved synthesis of myrtine (23) from ( )-pelletierine (21) has been reported (Scheme 3) (c/. Vol. 9, p. 71). Stereospecific addition of methyl-magnesium iodide to the cyclic enaminone (22) gave ( )-myrtine, which was converted into natural (+)-myrtine by resolution with (-)-tartaric acid.31... 

Hanaoka et al, (39, 71) condensed pelletierine (126) with 6-bromoisovanillin and obtained in quantitative yield the /raw-quinolizidone (149). The methyl ether (150) was selectively reduced with Henbest catalyst, and the axial (151) and equatorial (153) alcohols were separated in 9 1 ratio. The Ullmann condensation of the acetyl derivative (152) with methyl 4-hydroxy hydro-... 

In the third approach (39, 40, 72) the quinolizidone ester was alternatively prepared. The Ullmann reaction of 6-bromoveratraldehyde with methyl 4-hydroxycinnamate afforded biphenyl ether aldehyde (164) in 55% yield. The alkaline condensation of 164 with pelletierine gave a mixture of stereo-isomeric quinolizidone acids (158 and 159). Esterification with dimethyl sulfate yielded a mixture of trans- and cis-fused quinolizidine esters (160 and 161) in a 13 1 ratio after separation on silica gel. 

The compound proposed as having the structure of lagerine (55) was synthesized by Hanaoka et al. (45) in a similar way from o-vanillin (167a), pelletierine, and methyl 4-benzyloxy-3-bromohydrocinnamate. In the condensation of pelletierine with 167a in aqueous sodium hydroxide two compounds were formed, a trans-fused quinolizidone (164) and a cw-hemiacetal (165) in the ratio of 1 3. 

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). 

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. ... 

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). 

Pelletlerine Tannate. Punicine tannate. A mixture of the tan nates of the several alkaloids from pomegranate, pelletierine, methyl- and pseudopelletierine. It contains an amount of the alkaloids equivalent to not less than 20% as the hydrochloride. 

As expected for a methyl ketone, hypobromite oxidation of A-benzoylisopelletierine gives bromoform (9). Attempts to prepare the compound C10H20NO2CI described by Hess have been unsuccessful (7,8). The procedure described by Hess (19) for the isolation of pelletierine from pomegranate root has been repeated (JJ) and a urethane different from synthetic 3-(2-piperidyl)propanal urethane but identical with synthetic (2-piperidyl)-2-propanone urethane was isolated. 

In view of the fact that pelletierine and isopelletierine are identical it has been proposed that the name isopelletierine be dropped and that the name pelletierine be used to represent (2-piperidyl)-2-propanone and iV-methylpelletierine to represent the corresponding iV -methyl compound (12). Tanret s pelletierine is thus Z-pelletierine Tanret s isopelletierine, Hess s racemic isopelletierine, and Hess s pelletierine are cZZ-pelletierine. A detailed review of the chemistry of pelletierine has appeared (13). 

Tropane alkaloids comprise a large group of bases occurring predominantly in the family of the Solanaceae. Structurally they are esters of carboxylic acids with tropine (3-hydroxy-8-aza-8-methyl-[3.2.1]-bicyclooctane) and are biosynthetically derived from amino acid and acetate precursors. Despite the relative structural simplicity of the alkaloids, their biosynthesis is not well understood from a mechanistic point of view. In this article the available information pertaining to this question is summarized and discussed in context with the information that is available from the analogous pelletierine class of alkaloids. A new proposal for the mechanism of assembly of the acetate derived C, fragment of these alkaloids is introduced. 

In an attempt to rationalize the underlying chemistry depicted in Scheme 13, one is bound to arrive at the same conclusion that was reached when the successful incorporation of (22) into tropane (1) was being considered. Apparently activation of the C-3 methyl group of pelletierine, destined to become C-8 of lycopodine (27), as a methylene placed between two carbonyl groups is required for successful formation of the C-15/C-8 bond. 

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