The Pyrrolizidine Alkaloids

The structures of more than 200 known pyrrolizidine alkaloids are presented in Table 3, classified according to the necine they contain, with the fully saturated and less hydroxylated necines appearing first. For the macrocyclic diester alkaloids, further subdivision according to ring size is made. Attention should be drawn to several key points. 

In their study of neutral, terpenoid metabolites from the Compositae, Bohlmann and his co-workers have discovered a series of dihydro-pyrrolizinone derivatives in Senecio species (Table 3 U). These are all macrocyclic diesters containing 12-membered rings, although it is interesting that macrocyclic diesters with both a and p stereochemistry at C-7 of the necine have been isolated. A related series of open chain esters, the senampelines (Table 3 T), have also been discovered. This work does indicate the need to carry out careful examination of both basic and neutral fractions from plant extracts when searching for pyrrolizidine derivatives. The extent of these new derivatives should also be ascertained by reinvestigating species of other families known to contain pyrrolizidine alkaloids. 

The most common ring size in pyrrolizidine alkaloids is 11 or 12 membered. However, a few examples of 13-membered macrocyclic diesters are known for platynecine (Table 3 M) and retronecine (Table 3 O iv), and the recent discovery of the first 14-membered derivatives of retronecine (Table 3 Ov) is worthy of note. 

Tissue cultures of Crotalaria juncea have been reported by Khanna and Manot 156) to produce the pyrrolizidine alkaloid junceine (Table3 Oii). 

Reagents i. MeS02a, C5H5N ii, H2-Pd(C) iii, POOs, C5H5N iv, UAIH4, AIQa- 

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The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

Another Michael addition route for synthesis of the pyrrolizidine alkaloide trachelan-thamidin is shown in Scheme 10.18.118... 

The aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84). 

The ketal hydrochloride 322 has been used for X-ray crystallographic analysis to establish the stmcture and stereochemistry of the pyrrolizidine alkaloid l,7a-diepialexine <1990P111>, and the fused isoxazolidine 323 is an intermediate in a model synthetic approach to alkaloids such as laccarin, 324 <2002SL1344>. 

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

Extensive metabolic work continues with the pyrrolizidine alkaloids many of which are known toxic principles of plants responsible for conditions such as irreversible hemorrhagic liver necrosis, megalocytosis, and cancer. Considerable interest remains in the metabolism of pyrrolizidine alkaloids and their A-oxides to metabolic pyrroles thought to participate in molecular events associated with the above-mentioned toxicities. The chemistry and pharmacological properties of the pyrrolizidine alkaloids is authoritatively discussed by Wrobel in Volume 26 of this treatise. 

This methodology has been applied to the diastereoselective synthesis of the pyrrolizidine alkaloid 196 from 194 via 195 (Scheme 15.62) [123], Furthermore, the diastereoselectivity of these reactions for different dipolarophiles has been investigated in detail [124] and could be extended to a ring closure to seven-membered nitrogen heterocycles [125,126]. 

Griffin, D.S., and SegaU, H.J., 1987, Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans-4-OH-2-hexenal,... 

We have extended our work on a new synthesis of the antiprotozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy-carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and g-erythrose, using reactions of high stereoselectivity. 

The availabihty of enantioenriched 2-tribntylstannylpyrrolidines ° can be used to advantage in these reactions. Conversion to a snbstrate snitable for cyclization allows, after transmetalation, the determination of the stereoselectivity on intramolecnlar carbolithia-tion. Treatment of the enantioenriched stannane shown in Scheme 23 with bntyllithinm resnlted in the formation of the pyrrolizidine alkaloid psendoheliotridane. The prodnct was formed as a single diastereomer and with no loss of optical pnrity, occnrring with overall retention of confignration at the carbanion center. Related cychzation reactions... 

Lactam systems have been synthesized by rehance on configurational matching, as exemplified in the synthesis of the pyrrolizidine alkaloid (-)-heliotridane (Scheme 15.9)... 

White, I. N. H., Mattocks, A. R. and Butler, W. H. 1973. The conversion of the pyrrolizidine alkaloid retrorsine to pyrrolic derivatives in vivo and in vitro and its acute toxicity to various animal species. Chemistry-Biology Interaction, 6 207-218. 

Hartmann, T. and Witte, L. 1995. Chemistry, biology and chemoecology of the pyrrolizidine alkaloids. In Alkaloids Chemical and Biological Perspectives. Vol. 9 (Pelletier, S. W., ed.), pp. 155-233. Oxford Pergamon Press. 

LDA was used in the cyclization of tosylate 9, an intermediate in the synthesis of the pyrrolizidine alkaloid (+)-retronecine, which was prepared from (+ )-(7 )-malic acid in nine steps. The tricyclic lactone 10 was isolated in 53% yield70. 

Bull, L. B., Culvenor, . C. J. and Dick, A. T. (1968). The Pyrrolizidine Alkaloids. Amsterdam North-Holland Biomedical Press. 

Eisner, T. and Eisner, M. (1991). Unpalatability of the pyrrolizidine alkaloid-containing moth Utetheisa ornatrix, and its larva, to wolf spiders. Psyche 98 111-118. 

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

Monocarboxylic [as in heliotrine (5) and trachelanthamine (6)] and dicarboxylic acids [in senecionine (7) and thesine (8)] are found among the carboxylic acid moieties. All the pyrrolizidine alkaloids afford pyrrolizidine alcohols under conventional conditions of ester hydrolysis. Formerly, these alcohols were used as starting materials for all the studies dealing with pyrrolizidine chemistry synthetic approaches have now been developed. Some pyrrolizidine alcohols, and other derivatives like 1-methylenepyrrolizidine, occur in plants in the free state, forming the special group of the so-called non-ester pyrrolizidine alkaloids. 

Pyrrolizidine derivatives with at least one substituent, and particularly the pyrrolizidine alkaloid components, have one or more asymmetric carbon atoms. The stereochemistry of pyrrolizidine was clarified for the most part in the course of investigation of the naturally occurring pyrrolizidine alcohols. Here, the problems of relative and absolute configuration and of stereoisomeric transformations will be considered. 

Lactonization Cydization of the thioester 1 cannot be effected with mercuric trifluoroacetate or coppcr(I) trifluroacctatc. The usual reagents used for this reaction (6, 582. 7, 444) are ineffective, but cydization is effected with CuOTf complexed With benzene. Two isomeric lactones (2 and 3) are obtained in 62% yield. One of IhcNC is the acetate, of the pyrrolizidine alkaloid crobarbatine. Unfortunately dcucctylation of these products is accompanied by further hydrolysis to the pyrrolizidine unit (retronecine). 

Intramolecular cyclization of ally lie stannanes.1 The pyrrolizidine alkaloid isoretronecanol (3) can be synthesized efficiently by cyclization of the mesylate of the hydroxylactam 1 to give 2 stereoselectively. Oxidative cleavage followed by reduction of the keto group gives 3. 

Imidate-derived dipoles have played a prominent role in the synthesis of the pyrrolizidine alkaloid retronecine (121).119 The imidate salt derived from lactam (118) was found to undergo a smooth desilylation reaction to produce azomethine ylide (119). Trapping of this dipole with methyl acrylate affords... 

The pyrrolizidine alkaloids, found in the genus Senecio and a number of other plant genera, are plant toxins of environmental interest that have been implicated in a number... 

From the family Euphorbiaceae, Phyllanthus niruri L. yielded the new alkaloid nirurine (105) in addition to the former reported occurrence of 4-methoxynorsecurinine and norsecurinine in the same plant (115,116). The structure of (105) was elucidated by analysis of spectral data and X-ray crystallography (117). The pyrrolizidine alkaloid phalaenopsine La (106)... 

Edgar J. A., Culvenor C. C. J. and Pliske T. E. (1976b) Isolation of a lactone, structurally related to the esterifying acids of the pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae. J. Chem. Ecol. 2, 263-270. 

The toxicity of plants that contain pyrrolizidine alkaloids has been discussed in an earlier volume of this series (163), and the relationship between the toxic nature of the plants and the metabolism of their alkaloids by the victim has been reviewed (164). Since the toxicity of the pyrrolizidine alkaloids in mammals seems to be due to their metabolites rather than to the alkaloids themselves (164), considerable effort has been expended in the identification of the metabolites produced both in vivo and in vitro by mammalian systems. The material summarized in Table V (165-172) is supplementary to that discussed in reference 164. 

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