Piperidine and pyrrolidine alkaloids

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. 

The enantioselective total syntheses of several piperidine and pyrrolidine alkaloids of tobacco were accomplished in the laboratory of J. Lebreton. ° In the final stage of the total synthesis of (S)-A/-methylanabasine, a one-pot Cbz-deprotection-hydrogenation-Eschweiler-Clarke methylation was carried out using a HCHO/MeOH/Pd(C)/H2 system at room temperature with an overall 88% yield. 

Aminohemiacetals e.g. 98) can also condense with enol ethers or enol esters to give the cross-aldol products." A number of piperidine and pyrrolidine alkaloids have been synthesized by this approach. 

A color test utilizing isatin for piperidine and pyrrolidine alkaloids containing the structural unit — NH—CH2—CH2— has been described (53). Coniine and conhydrine give a positive test but pseudoconhydrine, which lacks the above feature, does not. The Conium alkaloids have been separated by gas-liquid chromatography (54). 

Similar to the synthesis of lobelanine, other piperidine and pyrrolidine alkaloids have been prepared in a one-pot... 

O Hagan, D. 2000. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nature Product Reports, 17 435 46. 

The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made attractive targets for total synthesis, particularly since many contain a hydroxyl moiety adjacent to the amino group. This functionality is the case with the pseudodisto-mins-piperidines with antitumor activity isolated from the Okinawan tunicate Pseudodistoma kanaka. The limited availability of the natural material has prompted... 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

A new monograph on alkaloid chemistry has been published parts of it are devoted to pyrrolidine, piperidine, and pyridine alkaloids.1 A review on the synthesis of alkaloids via nitrones has appeared,2 and another on the photochemistry of alkaloids, which includes a section on alkaloids of this group.3... 

Chapter 2 Pyrrolidine, Piperidine, and Pyridine Alkaloids By A. R. Pinder... 

Two new monographs on alkaloid chemistry have appeared both contain sections on pyrrolidine, piperidine, and pyridine alkaloids.1,2... 

A wide variety of activities have been demonstrated for the alkaloids identified in myrmecine ant venoms, indicating that these small nitrogen heterocycles have been adapted to subserve multiple functions. Both the piperidines and pyrrolidines possess diverse pharmacological activities (reviewed in 1), and it seems likely that their roles in regulating both intra- and interspecific interactions are very significant. 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

Ptnder AR (1992) Azetidine, pyrrole, pyrrolidine, piperidine, and pyridine alkaloids. Nat Prod Rep 9 491-504... 

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