Pyrrolidine group alkaloids

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... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

Zard and coworkers [32] reported a simple approach to create another group of natural products, namely the lycopodium alkaloids [15]. These authors first investigated the reaction of O-benzoyl-N-allylhydroxylamide 3-60 with tributyltin hydride and ACCN in refluxing toluene, which led (after formation of the N-radical 3-61 in a 5-exo-trig/5-exo-trig cyclization) to the undesired pyrrolidine 3-62 in 48% yield. Nevertheless, a small structural modification, namely the placement of a chlorine atom at the allyl moiety as in 3-63, induced a 5-exo-/G-endo- instead of the 5-exo-/5-... 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

Nicotine Nicotine, l-methyl-2-(3-piridyl)pirrolidine (13.1.27), is an alkaloid that is isolated from the plant Nicotiana (Nicotiana tabacum, Nicotiam rustica, and others) and can be synthesized in varions ways [33-36]. In particular, it is proposed to proceed from nicotinic acid ethyl ester, which is condensed with iV-methylpyrrolidone, giving l-methyl-2-nicotinoyl pyrrolidone-2 (13.1.23). Acidic hydrolysis of this compound leads to an opening of the pyrrolidine ring giving the intermediate (13.1.24), which under the reaction conditions is decarboxylated to the /-aminoketone (13.1.25). The carbonyl group is reduced to an alcohol and the resnlting prodnct (13.1.26) undergoes dehydration to nicotine (13.1.27). 

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... 

Pyrrolidine occurs free in small quantities in tobacco and opium and is related to its mother substance pyrrole (Figure 11.2). To this group belong such alkaloids as hygrine from Erythroxylon coca and stachydrine from Stachys tuberifera (Figure 11.3). 

The alkaloids of this group are derived from a combination of a piperidine and a pyrrolidine ring, designated as tropane (Figure 14.2). The 3-hydroxy derivative of tropane is known as tropine and is the basic component of atropine. When atropine is hydrolyzed, it forms tropine and tropic acid (a-phenyl-p-hydroxy-propionic acid). Atropine is the tropic acid ester of tropine. It has been prepared synthetically. Tropic acid contains an asymmetric carbon atom. The racemic compound (atropine) as obtained naturally or as synthesized may be resolved into its optically active components, d- and /-hyoscyamine. Atropine is racemic hyoscyamine that is, it consists of equal parts of /-hyscyamine and plant cells and also in the process of extraction, so that the relative proportion of the isomers in the plants and in the preparations varies. However, atropine itself does exist in small amounts in the plants, although most of it is formed from the /-hyoscyamine in the process of extraction. 

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... 

Mescaline has been synthesized in 42% overall yield in five steps from 2,6-dimethoxyphenol.1 Analogues of mescaline with the NH2 group replaced by a pyrrolidine, a piperidine, a morpholine, and a jV-methylpiperazine group have been prepared from 3,4,5-trimethoxybenzyl chloride.2 A process for the determination of mescaline in plasma by g.l.c.-mass spectrometry has been described,3 and behavioural effects of the alkaloid have been studied.4-11... 

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