Piper amides isolation

This chapter aims to provide a relatively comprehensive, yet inevitably not exhaustive, compilation of structures of amides isolated from Piper species (Tables 1 and 2). The chemistry and biological activity of some of these compounds as well as new developments in their synthesis are reviewed.2... 

Five amides, 50(n=4,6), 55, 5 and 6(n=6), isolated from P. guineense were investigated by Candy and co-workers [10] with respect to their knockdown and lethal activity against adult houseflies, as well as the rates of recovery of M. domestica from the effects of sublethal doses of the amides. As with other insecticides, rapid and potent knockdown activity on topical application of the amides depends, apart from the intrinsic toxicities of the individual compounds, on their ability to penetrate the cuticle and relevant membranes en route to the site of action. Attempts to correlate knockdown activity in the P. guineense amide series with polarity on this basis seemed to show some inconsistencies, perhaps as a result of steric factors [10,102]. The rate of recovery from the effects of sub-lethal doses of insecticides is associated, inter alia, with processes that lead to removal of the toxicant, so that recovery from treatment with Piper amides embodying the methylenedioxyphenyl group, which retards the action of mixed function oxidases, is slower than recovery from the effects of the less stable aliphatic amides. 

Fig. 11.11 Piperidine amides isolated from Piper longum [11]...

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

A new Piperaceae amide, pipercide (27), obtained from the fruits of Piper nigrum, shows insecticidal activity against the adzuki bean weevil.25 New pungent compounds of the capsaicinoid group have been isolated from the fruits of Capsicum annuum var. annuum.26... 

The two sulfur-containing amides entadamides A (93) and B (94) have been isolated from the seeds and entadimides A and C (95) from the leaves of Entada phaseoloides Merr. (valid name Entada rheedii Spreng.) (Legu-minosae) (99-101). The known isobutylamide alkaloid pellitorine (N-isobutyl-2 ,4 -decadienamide) is found in the aerial parts of Piper ri-besoides Wall. (102). Pellitorine has also been isolated from the fruits of P. 

Sylvatine (C24H3303N mp 112° [a]D +0°) isolated from this plant was shown to be an amide of piperic acid. Mass and other spectra indicated structure 148 and confirmation was achieved by reduction, hydrolysis, and/or oxidation, the product of the latter process being 5-methylhexanoic acid (136). 

The chemistry of the pungent compounds of pepper has been under study since the isolation of piperine in 1820. Piperine was shown to be a piperidide of piperic acid, and had the trans. trans configuration. The three other possible isomers were soon postulated, and they were named isopiperine (cis.trans). isochavicine (trans. cis) and chavicine (cis.cis) even before they were synthesized. The assignment of the isomeric configuration starts from the amide end. 

Several new alkaloids have been isolated from pepper species. Tricholeine, for example, occurring in the stems of Piper trichostachyon, is the pyrrolidine amide (2) of fra s-9-(3,4-methylenedioxyphenyl)-A8-nonenoic acid, the structure being established by spectroscopic and degradative studies.4 Piper guineense seeds contain okolasine (6-methoxytrichostachine) (3),5 which is probably identical to the earlier known wisanidine. 4,5-Dihydro-wisanidine (4) is also found in the same... 

Attempts to prepare l-Z-lysergoyl-4-phenylpiperazine (1, Ri, R2 = (CH2CH2)2NC6H5) were unsuccessful. The expected amide was isolated in very low yield which was insufficient for complete identification. However, bis(4-phenyl-l-piper-azinyl)phosphinic chloride (4) was obtained in 32% yield. Compound 4 was identical with the product obtained from the reaction of 2 equiv of 1-phenylpiperazine with 1 equiv of POCl3 in the presence of Et. This was the only instance where compounds of type 4 were isolated from the reaction mixture in our synthesis of numerous lysergamides. 

Thus the kava alkaloids contain either a cinnamoyl or phenylpropionyl moiety. One would expect that a homologous series of such alkaloids may exist in the P. methysticum plant, since Achenbach and Karl (1971) isolated a series of substituted cinnamic, benzoic and phenyl propionic acids. These acids would be expected to react readily with amines to form the amide alkaloids. However, such a series of alkaloids does not appear to occur in the P. methysticum plant, although several similar alkaloids have been isolated from other Piper species, such as P. longum which yields piplactine, piperlongumine and piperlongiuninine (Chatterjee and Dutta, 1967). 

Vandopsis longicaulis Certain tumour-inhibitory plants of the Piperaceae and Rhizophoraceae families have yielded amides, e.g. A -dibydropiperine (9) occurs in Piper novae-hollandiae Miq. Macrocyclic alkaloids, e.g. azimine (10), have been fully defined. Further evidence for the nature of Lythrum bases has been obtained by synthesis of the overall skeleton. The key step in the synthesis involved formation of the 17-membered ring (11) (12). Directions for the isolation and degradation of piperine (9, with y,5-double bond) have been included in a unique laboratory text. ... 

Amide 130 was isolated from Piper amalgo and its structure was determined using MS, IR, lH NMR, and hydrolysis to give piperidine [407],... 

Plants of the Compositae, Piperaceae and Rutaceae families [2] have been used as ingredients in many medicinal preparations and as food spices and many of them are used as insecticides [6]. Several long-chain unsaturated amides have been isolated from these plants, and they can be classified into two main structural types (a) (2 , 4 )-dienamides derived from straight-chain fatty acids and isobutylamine, pyrrolidine or piperidine units (1-22) (Chart 1), and (b) amides with the piperonal unit derived mainly from piperic acid in combination with the above mentioned amines (23-34) (Chart 2). 

Pellitorine (1) has been isolated from several plants fruits of Piper sarmentosum [7], roots of Anacyclus pyrethrum [8] and seeds of Piper sylvaticum and presents insecticidal activity [10]. The Z-isomer (2), isolated from Piper guineense [11], has similar activity. Another component of the dried fruits of Piper sarmentosum, known in Thailand as Cha-plu , is sarmentine (3) which is used as an expectorant [7]. The corresponding piperidine derivative (4) is an Achillea amide [12]. 

Simple amides continue to be isolated from the Piperaceae fcunily N-trans-feruloylpiperidine, feruperine (14), and its 4,5-dihydro-derivative have been isolated for the first time from natural sources (Piper nigrum).Isopiperlonguminine (15 Z,Z R = H),... 

The prevalence of isobutylamine, pyrrolidine and piperidine as the amine component of amides from numerous species of Piper has been noted, and is clearly evident in Tables 1 and 2. In a 1973 paper, Bohlmatm [14] speculated on the biosynthetic origins of the amine moieties of some amides belonging to the same class isolated from Achillea spp. (Compositae). He drew attention to the strong probability that the isobutylamine component, where present, would be derived from valine. He proposed, further, that the piperidine portion of the amide 10(n=4), and other piperidyl amides, is biosynthesized via pipecolic acid (now known to be most commonly derived from D-lysine [13]), and that lysine (configuration unspecified) is the progenitor of the piperideine ring embodied in 14 and 18 [14]. 

In the search for potent plant insecticides, two new unsaturated amides, brachystamides A and B, have been isolated from the total aboveground parts of Piper brachystachyum. Brachystamide A is A-isobutyl-15-... 

Fig. 11.10 HPLC of red oil from Piper longum containing the mixture of the nine isolated amides (Legends see in Fig. 10.11)...

Decades of investigations in the natural products chemistry of the Piper genus yielded an important amount of monomeric and dimeric alkamides of diverse molecular architectures crnitributing to their biological activities [20-23,203,208-219]. Specifically, [4+2] dimers were isolated in P. chaba while [2 + 2] dimers were isolated in P. nigrum and P. longum, in both cases together with monomeric amides. 

Unsaturated Amides. In 1971, a group of pungent compounds (isobutylamides) obtained from members of the families Compositae and Rutaceae were described by Jacobsen (Jacobsen, 1971) to have limited use as insecticides. The compounds were characterized as unstable with a marked tendency to polymerize. Examination of extracts of the fruit of the black pepper Piper nigrum, using the aduzki bean weevil as a bioassay, resulted in the isolation of three isobutylamides (13-15) which displayed insecticidal activity (when combined equimolarly) to the pyrethrins (Miyakado et al., 1983, 1989). Based upon the observations of Miyakado and earlier reported test results for synthetic analogs of the compounds described by Jacobsen, Elliot and co-workers defined a basic amide structure to... 

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