Pyrrolizidine Group

Ill spite of their importance, basicity constants rarely figure in descriptions of alkaloids. Figures for a series of alkaloids and related substances were published by Kolthoff in 1925 and have been extensively used. Recently a few more have been added by Schoorl, and Adams and Mahan have provided figures for the whole group of necines, the amino-alcohols resulting from the hydrolysis of the pyrrolizidine group of alkaloids. ... 

Pyrrolizidine Group.—Evidence from two sources indicates that the Cio necic acids are derived by the coupling of two units derived from isoleucine. Earlier work had indicated that the left-hand C5 unit of seneciphyllic acid (22) is derived from isoleucine and its biological precursors threonine and aspartic acid. Mevalonic acid was not incorporated but the S-methyl group of methionine served as a fairly specific precursor for C-8. 

Pinidine and Coniine Nicotiana Alkaloids yV-Methylpelletierine Lycopodium Alkaloids Lyduraceae Alkaloids Pyrrolizidine Group Tropane and Pyrrolidine Alkaloids Quinoline and Acridme Alkaloids Benzodiazepine Alkaloids Tylophora Alkaloids Cactus Alkaloids Ephedrine... 

Enantioenriched (-)-rosmarinecine, which belongs to the group of pyrrolizidine alkaloids [413], has been synthesized by Goti, Brandi and coworkers applying an intramolecular 1,3-dipolar cycloaddition as the key step [414]. The required nitrone was obtained in situ from L-malic acid. Moreover, 1,3-dienes as precursors for a cy-... 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

The pyrrolizidines and indolizidines are a group of alkaloids that are characterized by the presence of the basic azabicyclo[3.3.0]octane and azabicyclo[4.3.0]nonane frameworks, respectively. These alkaloids exhibit remarkably diverse types of biological activity and have been reported to act as antitumor, hypotensive, anti-inflammatory, carcinogenic, or hepatoxic agents. Various pyrrolizidines and indolizidines have been prepared by 1,3-dipolar cycloaddition.115 Synthesis of these is described in the section 8.2 discussing cycloaddition. 

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

Schmitz et al. <2001JP090> developed two group increment schemes for converting HF/6-31G(d) and B3LYP/6-31G(d) calculated energies of aliphatic amines to estimations of heats of formation. Application to the pyrrolizidine yielded calculated values of —1.09 (HF) and —1.02 (B3LYP) instead of — 0.93 kcal mob1 (experimental). 

Similar strategies have been used for the synthesis (286) of the tetrahydro-pyrrolizidine 323 from 2,3 5,6-di-O-isopropylidene-D-g/yccroD-ta/o-hep-tono-1,4-lactone (322). These polyhydroxylated pyrrolidines and pyrrolizi-dines are potential specific inhibitors of glycosidases. The stereochemistry of the hydroxyl groups have a profound effect on the selectivity of the inhibition (286-288). 

A wide application of Newcomb s method provides a variety of N-heterocyc-lic systems, such as perhydroindoles, pyrrolizidines and aza-brigded bicycles [59, W, 146], The mild reaction conditions are compatible with several funtional groups of the substrate and several trapping agents to functionalize the cyclized product. 2-Substituted pyrrolizidines 132 are accessible by tandem cyclization of iV-allyl-substituted PTOC carbamate 131. In this case the allyl group on the nitrogen serves as an internal trap for the intermediate carbon radical. The Af-methylcyclohept-4-enaminium radical cation, produced from the corres-... 

A chiral pyrrolizidine (53) catalyses asymmetric Baylis-Hillman reactions. Important structural features include an accessible nitrogen lone pair and a strategically placed hydroxy group the latter may also interact with alkali metal cations, which catalyse the reaction. 

The pyrrolizidine nucleus is characteristic of this group of alkaloids. The a is either L-ornithine or L-arginine, and the /3 is a biogenic amine, the putrescine. Oxidative deamination by enzyme NAD+ converts two molecules of putrescine... 

Pearson et al. (68) reported a versatile approach to pyrrolizidine and indolizidine alkaloids such as 355, 247, and 362 using intramolecular cycloadditions of azides with electron-rich dienes (Scheme 9.68). Azido dienes 353, 357, and 360 that possess a electron-donating group on the diene were prepared from the respective compounds 352, 356, and 359. On heating at 100 °C, the azido diene 353 underwent smooth intramolecular 1,3-dipolar cycloaddition in a stereoselective... 

An intramolecular version offers useful synthetic methods for heterocycles. The total syntheses of a- and 7-lycoranes (373 and 374) have been carried out by applying the intramolecular aminochlorination of the carbamate of 5-(2-aminoethyl)-l,3-cyclohexadiene (372) as a key reaction[312,313]. Interestingly, the 4,6- and 5,7-diene amides 375 and 377 undergo the intramolecular animation twice via tr-allylpalladium to form alkaloid skeletons of pyrrolizidine (376) and indolizidine (378), showing that amide group is reactive[314]. 

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