Piperine synthesis

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

Otera and coworkers developed an alternative procedure to the Julia method for generating dienes or alkynes in the same reaction by the double elimination of /J-acetoxy or /1-alkoxy sulphones with potassium /-butoxide (equation 58)98,99. The reaction pathway leading to the diene or an alkyne depends on the substrate structure and the reaction conditions. If an allylic hydrogen is present in the substrate then diene is formed, otherwise, the alkyne is the product of the reaction. This modified Julia methodology has een applied to the synthesis of vitamin A (equation 59)100, alkaloids piperine (equation and trichonine (equation 61)102. 

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. 

Piperonyl acrolein is obtained from piperonal and acetaldehyde. This is the initial step in the synthesis of piperine, one of the first alkaloids synthesised. (B., 27, 2958.)... 

Piperine is the major constituent of pepper oleoresin (Borges and Pino, 1993). The isolation of piperanine, a new pungent component of black pepper oleoresin, is described and its structure is shown by synthesis to be trans-5-(3,4-methylenedioxyphenyl)-2-pentenoic acid piperidide. The pungency of black pepper (P. nigrum L.) was attributed to the presence of piperine, the structure of which was later proven to be trans,trans-5-(3,4-methylenedi-oxyphenyl)-2, 4-pentadi-enoic acid piperidide. Further investigations into the pungency of this spice revealed that unidentified materials other than piperine also contributed to its pungency. 

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. ... 

An acyl transferase which catalyzed the synthesis of piperine in the presence of piperine and piperoyl-coenzyme A was isolated from shoots of Piper nigrum and characterized [396], The prior synthesis of piperoyl-coenzyme A assisted in this study [397]. 

Schulze and Oediger have used such a reaction in the synthesis of piperine (26), the sharp principle of black pepper. Condensation of piperonal with N-crotonylpiperidine in DMSO in the presence of benzyl-triethylammonium hydroxide provides piperine in 80% yield (equation 91). ... 

The same type of coupling, catalyzed by palladium(O), can be carried out using alkenylboronates (generated by hydroboration of acetylenes) and -P-bromoacrylamides [49]. This Suzuki methodology has been used for the synthesis of pellitorine (1), trichonine (13), piperlonguminine (23), piperine (25), dehydropipernonaline (29) and 1-piperettylpyrrolidine (34) [34] (Scheme 6). 

Piperine (25) [56] and trichonine (13) [57] have been prepared by reaction of the corresponding a-sulfonyl organolithium compound with N-(4-oxobutanoyl)piperidine and pyrrolidine, respectively, followed by acetylation of the resulting (3-hydroxy sulfone and final base-promoted double elimination (Scheme 13). Using 4-oxobutanoic ethyl ester, this methodology has been applied to the synthesis of dodecatetraeneamide (19) [23],... 

Sigmatropic rearrangements of ynamines followed by dehydrosulfenylation have been applied to the synthesis [61] of piperine (25) and trichostachine (24) (Scheme 17). 

Boiss.), and (23) and (24) (from A. grandifolia Friv,). A one-step synthesis of piperine involves base-catalysed condensation of piperonal with N-crotonylpiperidine.The 2-trans, 4-cis isomer (25) of all-trans wisaninehas been found in the root bark of Piper... 

Chim. Belg. 84, 435 (1975). Synthesis of isomers R. Grewe el aL. Ber. 103, 3752 (1970) of piperine and isochavidne S. Tsuboi el at. Tetrahedron Letters 1979, 1043. Stereoselective synthesis of pipeline R. A. Olsen, G. O. Spessard, J. Agr. Food Chem. 29, 942 (1981). More toxic to houseflies than pyrethrum Harvill et al Contrtb. Boyce Thompson Inst 13, 87 (1943). 

Ethnopharmacological research on natural products can contribute to the discovery of new active compounds with novel structures which may serve as leads to the development of new antiepileptic drugs. An example is the isolation of the active alkaloid piperine from Piper nigrum L. which is one of the component herbs of an ancient Chinese medicine used for the treatment of epilepsy. Its structural modifications resulted in the synthesis of seven derivatives including antiepilepserine which was found to be more potent than the parent compound with fewer side effects and it has been used as an antiepileptic drug [10-12]. 

A terse paper by Kaga et al. reports the synthesis of dienamides in moderate yield by palladium-catalyzed coupling of P-bromoacrylamides with alkenyl boronates. (Scheme 13) [138]. Employing alkenyl boronates derived from appropriate alkynes, the strategy was applied to the synthesis of piperlongumine, 36(n=0), piperine, 42, trichonine, 9(n=14), pellitorine, 5, and the trienyl amide, 48. An alkyl boronate, prepared from l-(3, 4 -methylenedioxyphenyl)-l,5-hexadiene, was similarly used for the synthesis of the non-conjugated dienamide, pipernonaline, 46(n=4) (Scheme 13) [138]. 

A new synthesis of piperine (15) and isochavicine (16) has been reported. It is shown in outline in Scheme 3, the key step being the thermal condensation of a propargylic alcohol with an acetal to yield an allene (steps ii and iii). The mixture was separated by preparative t.l.c."... 

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