Pyrrolizidines structures

The Senecio alkaloids discussed above are esters of mono-, di-, and trihydroxy-1-methylpyrrolizidines, and a few of these necine bases or their derivatives have been found free in the plant. The pyrrolizidine structure has more recently been found in a number of other alkaloids. 

Peduncularine was obtained from Aristotelia peduncularis (Labill.) Hook f. by Bick et al who postulated an indole-pyrrolizidine structure (44) for this alkaloid. On the basis of more extensive spectroscopic studies (including C n.m.r. spectroscopic data) and degradative work, a revised structure (45) has been proposed by Ros et al which shows that peduncularine belongs to the class of monoterpene indole alkaloids, and has no connection with pyrrolizidine alkaloids. 

Retronecine (A), which is a simple pyrrolizidine alkaloid, commonly occurs in nature. The formation of the pyrrolizidine structure is presented in Figure 2.35. Retronecine and its P, the senecionine, necine, heliotrine, indicine-A-oxide, malaxine, monocrotaline and absulin, are typical repre-sentatives of this group of alkaloids. Pyrrolizidine alkaloids... 

In a more recent paper Menschikov assigns to trachelantamidine formula (VI, p. 611), which makes it structurally identical with iso-retronecanol (p. 609). He also provides experimental evidence for the view that trachelantic acid is 2-methyl-3 4-dihydroxypentane-3-carboxylic acid, Me CH. C(OH)(COjH). CHOH. CHg, and trachelanta-mine becomes C HjaN. CHaO. OC. C(OH)Pr. CHOH. CHg, C,HjaN being the pyrrolizidine residue (1947). 

The combination of positive and negative charges within the same molecule causes a more complicated situation, which obviously has not been well-defined to date. A quite large number of pyrrolizidine alkaloids are related to Otonecine (8) (Scheme 3). Spectroscopic investigations show that these alkaloids exist in the nonionized form in CDCI3, and in the zwitterionic form in D2O (00JNP857, 71TL3421). The dipolar structure is the result of an intramolecular interaction between a nucleophilic and an electrophilic center. 

Nitroalkenes are shown to be effective Michael acceptor B units in three sequential reactions (A + B + C coupling) in one reaction vessel. The sequence is initiated by enolate nucleophiles (A) and is terminated by aldehydes or acrylate electrophiles (C). The utility of this protocol is for rapid assembly of complex structures from simple and readily available components. A short total synthesis of a pyrrolizidine alkaloid is presented in Scheme 10.16.114... 

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). 

Monocrotaline (170) has been the subject of extensive metabolic study with mammalian and microbiological systems. Pyrrolizidine alkaloids such as monocrotaline require metabolic activation to the corresponding pyrrole derivatives or dehydro alkaloids before they are capable of forming covalent bonds with critical macromolecules within the cell. The X-ray structure of dehydromonocrotaline has recently been determined (226), and the ability of dihydroretronicine derived from monocrotaline to react with deoxyguanosine has been demonstrated in vitro (225). 

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. 

This compound exhibits the same relationship to (3-D-fructofuranose as 1-deoxy-nojirimcin does to D-glucopyranose. In 1979, a polyhydroxyindolizidine alkaloid was isolated from the poisonous fruit of Castanospermum australe, a handsome Australian indigenous tree, and coined castanospermine (8) after its source.28 A compound subsequently isolated from the seeds of this plant was the pyrrolizidine australine (9),29 also found in Alexa leiopetala,30 along with other compounds. These discoveries increasingly supported the hypothesis that imino sugars and their structural relatives might be a fairly common family of natural products, and their widespread... 

Some natural products, or their degradation products, represent a hazard for mammals not because of general toxicity but for subtle, adverse properties, such as carcinogenicity and tumor promotion. They are best known fi om marine dinoflagellates (okadaic acid and structural analogues), filamentous fungi (trichothecenes and ochratoxins), and plants (pyrrolizidine alkaloids). 

Some Senecio alkaloids have opened pyrrolizidine ring systems which show transannular interactions and are closely related in structure to the compounds discussed above. The alkaloid senkirkine is a cyclic ester of (37) (74JA6165) and its X-ray structure shows a rather short transannular contact of 2.23 A. 

Isolation of a lactone, structurally related to the esterifying acids of pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae. Journal of Chemical Ecology 2 263-270. 

Figure 6.7 The structure of the pyrrolizidine alkaloid monocrotaline and the microsomal enzyme-mediated metabolic activation of the pyrrolizidine alkaloid nucleus.

Pyrrolizidine (1) and its derivatives have attracted the attention of chemists during the last two or three decades because this bicyclic system occurs in a number of alkaloids from various families of Compositae, Boraginaceae, Leguminosae, etc. Structural analysis of these substances, study of their reactions, and attempted syntheses have afforded considerable information concerning the chemistry of this class of compounds. Although the field has been covered by a... 

The absolute configuration was also established unequivocally for C-8 of naturally occurring pyrrolizidine bases.88 It was demonstrated in the course of the structural analysis of isoheliotridene (146), obtained by degradation of the alkaloid monocrotaline, that ozonolysis of this compound affords 2-acetylpyrrolidine-l-acetic acid (147).66 The (— )-methyl ester of this acid was condensed with methylmagnesium iodide to give (— )-l-(2-hydroxy-2-methylpropyl)-2-(l-hydroxy-l-methylethyl)pyrrolidine (148). The same glycol (148) was obtained... 

The chemical behavior and reactions of pyrrolizidine derivatives were investigated for the most part during structural analysis of naturally occurring pyrrolizidine alkaloids and in the course of the syntheses of their degradation fragments there are several publications concerned specially with this subject. Pyrrolizidine derivatives are typical tertiary amines, and consequently their chemical behavior is a combination of the properties of tertiary amines and of those of the substituent functions. However, some peculiarities of the class can be explained only in terms of the configuration of the bicyclic system. 

The properties and reactions of amino-alcohols, obtained largely by hydrolysis of naturally occurring alkaloids, were investigated primarily for the purposes of structural analysis and the preparation of physiologically active derivatives. Many authors have described acylation of pyrrolizidine alcohols with benzoyl chloride and acetic anhydride (see, e.g., refs. 83 and 101). Trachelanthamidine benzoate and p-aminobenzoate were prepared especially for testing of their physiological activity.102 The p-aminobenzoate was obtained by treatment of trachelanthamidine with p-nitrobenzoyl chloride and subsequent reduction of the nitro group with iron in 20% acetic acid. The compound exhibited an anesthetic activity close to that of cocaine. 

Biogenetic pathways leading to naturally occurring pyrrolizidine bases were proposed by Robinson, Schopf, and Lukefi (see, e.g., refs. 119-121) in their publications concerned with the biogenesis of alkaloids. The most probable precursors of the pyrrolizidine system are commonly accepted to be ornithine (176), hydroxyomithine (177), and their biogenetic equivalents. It is noteworthy that ( + )- -hydroxy-jV-methylnorvaline (178) (structurally related to ornithine) was isolated... 

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