Pyrrolidine-piperidine alkaloids

The utility of strained disubstituted cycloheptenes in alkaloid syntheses is highlighted by Blechert s total syntheses of the bis-pyrrolidine alkaloid (+)-dihydrocuscohydrine (390) [161],thebis-piperidine alkaloid (-)-anaferin (in the form of its dihydrochloride 393) [162], and indolizine 167B (397) [163] (Scheme 77). 

Besides piperidine alkaloids, a total of 19 pyrrolidines have been found in the secretions of thief ants and fire ants of the genera Solenopsis and Monomorium. Among these, compounds 80-84 are simple pyrrolidines with two saturated linear all-carbon side chains only in Solenopsis latinode is there a secondary amine (82) and its methylated analog (85). One or two terminal unsaturations are present in compounds 86-91, which all possess a (hex-l-en)-6-yl chain and a 5-, 7-, or 9-carbon saturated chain. Compounds 93, 94, 96, 97, and 98 are the A-l-pyrrolines corresponding to pyrrolidines 80, 82, 90 (93 and 96 corresponding to 80, 94 to 82, and 97 and 98 to 90). 

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 total syntheses of these pepper alkaloids are not those of pyrrolidines but rather syntheses of their acid parts. Thus dihydrowisanidine (137) has been prepared by a series of reactions, the key step of which is the formation of the carbon-carbon double bond by a Wittig-Homer reaction (217, 218). Schemes 41 and 42 summarize two syntheses of okolasine from sesamolmethyl ether (279) of course, routes to okolasine also yield the corresponding piperidine alkaloid wisanine. Molybdenum-catalyzed elimination of allylic acetate (149) yielded (E,E)-diene ester 150 en route to trichonine (220) worthy of note is the use of an aluminum amide in the preparation of amide 143 from ester 150 (Scheme 43). 

The bioactive secondary metabolites reported from Broussonetia kazinoki can be classified into major two groups, alkaloids and flavonoids (Table 1), Fig. (1). The Kusano group at Osaka University of Pharmaceutical Sciences in Japan reported over 20 pyrrolidine alkaloids, broussonetines A-H, K-M, O-T, V-X, and Mi, and broussonetinines A and B, four pyrrolidinyl piperidine alkaloids, broussonetines I, J, Ji, and J2, two pyrroline alkaloids, broussonetines U and U, and one pyrrolizidine alkaloid, broussonetine N, from hot water extracts of B. kazinoki [16-24]. As shown in Table 1, some of these alkaloids exhibited strong... 

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... 

Alkaloids are basic plant natural products that typically have a nitrogen atom as part of a heterocyclic ring system and indeed are classified on this basis. Thus major classes of alkaloids are based on indole, isoquinoline, pyrrolidine, piperidine, pyrrolizidine, quinoline, tropane, quinolizidine or other heterocyclic ring systems. Other alkaloids are basic monoterpenoid, sesquiterpenoid, diterpenoid, steroid, purine, pyrimidine or peptide entities. Some of these compounds are exceptionally toxic [1,6, 7-12]. 

Numerous UCNMR investigations on alkaloids have been reported in the literature [598, 599]. In Table 5.13 the 13C chemical shifts and structures of representative alkaloids of different types are collected Pyrrolidine, piperidine and pyridine [600-602], tropane [600, 603-605], izidine [606-612], indole [600, 603, 613-633], isoquinoline [599, 630, 634-647], quinolinic [648-656], imidazole [657], yuzurimine alkaloids [658], alkaloids with exocyclic nitrogen [659, 660], diterpenoid [661-663], steroid [664-666] and peptide alkaloids [667-671], The complete signal assignment for the alkaloids given in Table 5.13 was achieved using the correlations between 13C NMR spectral parameters and structural properties and the 13C chemical shift values of model compounds described in Chapters 3 and 4 of this monograph. 

Alkaloids are often classified according to the nature of the nitrogen-containing structure, e.g. pyrrolidine, piperidine, quinoline, isoquinoline, indole, etc, though the structural complexity of... 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

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... 

Conveniently N-protected 2,2/-bis(trimethylsilylmethyl)pyrrolidine, -piperidine and -azepane were prepared and reacted with phenylvinylsulfone in the presence of silver fluoride (2 equiv.). The X-azabicyclo[m.2.1]alkane framework in each case is obtained in good to excellent yields. Being very efficient, this technique provides a new strategy to synthesize tropinone, an important member of the tropane class of alkaloids.451... 

Just as terpenes could be viewed as being formed from isoprene units, alkaloids can be viewed as being derived from amino acids. Four amino acids give rise to important classes of alkaloids. As shown in Table 28.1, the pyrrolidine alkaloids are derived from the amino acid ornithine (not one of the 20 standard amino acids), the piperidine alkaloids from lysine, the isoquinoline alkaloids from tyrosine, and the indole alkaloids from tryptophan. 

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... 

There are many pyrrolidine alkaloids derived from ornithine and another large family of piperidine alkaloids derived from lysine by similar pathways involving... 

Glycosidase-inhibiting alkaloids from plants are classified into five structural classes polyhydroxylated pyrrolidines, piperidines, indolizidines, pyrrolizidines, and nortropanes. Furthermore, they also occur as the glycosides. This review describes recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of the sugar-mimicking alkaloids from plants. 

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

The piperidine alkaloids were mentioned in the chapter (p. 1418) where the pathway was described as similar to that of the pyrrolidine alkaloids . We can follow the same reactions starting from lysine instead of ornithine. The first stage produces the cyclic iminium salt fi om lysine by decarboxylation with pyridoxal. 

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