Naturally pyrrolizidines

Figure 12.5 Utetheisa ornatrix. A Male (above) stroking its everted coremata against female during courtship. B Larva feeding on seed pod of its natural, pyrrolizidine alkaloid-containing food plants (Crotalaria spectabilis). C Scanning electronmicrograph of abdominal tip of male, showing coremata in everted (left) and retracted condition. [Bar = 1 mm A and C from Eisner, 1980].

Culvenor and co-workers have completed a major study of the H-NMR spectra of natural pyrrolizidine bases in the free and esterified states. A detailed analysis was made of the spectra of retronecine (127) and its C-7 epimer, heliotridine (109). From consideration of the coupling constants in these two bases, it was concluded that retronecine and its derivatives have an exo-buckled conformation, whereas heliotridine and its derivatives are usually a mixture of rapidly interconverting exo- and endo-buckled con-formers of approximately equal populations. This same situation was shown to exist by Pachler et al. in their study of heliotridene (133). Furthermore, it was demonstrated that the proportion of endo-buckled form increased to about 75% on acidification. 

Robinson s original suggestion that the natural pyrrolizidine bases are derived in vivo from two molecules of ornithine (149) has been supported by studies using C-labeled compounds. Ornithine has been shown to be a specific precursor for the pyrrolizidine nucleus present in a variety of alkaloids. The feeding experiments carried out to date are listed in Table I. Three groups of workers have obtained labeled alkaloids after feeding C-labeled ornithines.Hydrolysis of the alkaloid to yield the free base, retronecine (127), has established that almost all the radioactivity is in the base portion. It is likely that ornithine is incorporated into retronecine after decarboxylation to putrescine (150) [Eq. (40)] since labeled putrescine is also specifically incorporated into retronecine (Table I). 

Pyrrolizines and hydrogenated derivatives (pyrrolizidines) are covered here, however, the chemistry of natural pyrrolizidines (see Section 8.01.11) is beyond the scope of this Chapter. 

An efficient one-pot synthesis of cyclobutanones from chiral enol ethers, which uses Zn/Cu in diethyl ether to achieve the dechlorination, affords the cyclobutanones in >90 % yield and 100 % stereoselectivity. The [2-1-2] cycloaddition of dichloroketene with chiral enol ethers is the key step in the synthesis of natural pyrrolizidines. ... 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

A dietary supplement may be safe when taken in the recommended doses but may become dangerous in higher doses. However, patients may develop side effects even when ingesting recommended doses. Adverse reactions may be due to allergic reactions, dietary supplements containing toxic substances, mis-identification of plant, mislabeling of plant, natural toxic substances such as pyrrolizidine alkaloids in comfrey, unnatural toxic substances such as heavy metals, or pesticides. 

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. 

Pyrrolizines, partially reduced pyrrolizines, benzopyrrolizines, and pyrrolizinones are covered in this chapter however, the chemistry of naturally occurring pyrrolizidines and analogous compounds is beyond the scope of this chapter. 

Edgar, J.A. and Smith, L.W. (2000). Transfer of pyrrolizidine alkaloids into eggs Food safety implications, in Tu, A.T. and Gaffield W., Eds., Natural and selected synthetic toxins biological implications, American Chemical Society, Washington, pp. 118-128. 

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... 

There exists evidence that some insects store dietary alkaloids derived from natural sources. Figure 98 presents insect species that are known to accumulate pyrrolizidine alkaloids during different developmental stages. The larvae and adults of these insects can metabolize pyrrolizidine alkaloids in current physiological activities. These alkaloids are not toxic for these organisms. Moreover, there is observed trace accumulation of a portion of these compounds in the liver. There is no definitive purpose for these traces. Generally, the opinion presented in 1888 by Stahl in Germany that the accumulation of alkaloids is for defensive purposes has been most often cited in the research literature. 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

Pandey and Lakshmaiah (10) further extended their methodology to the construction of the indolizidine and pyrrolizidine bicyclic skeleta. The basic precursor 41, which was realized in three straightforward steps, underwent double desilyation and subsequent cycloaddition with ethyl acrylate to furnish the two regioisomers 42 and 43 in essentially quantitative yield and in a 17 3 ratio. The major regioisomer was isolated in a 7 3 endo/exo ratio. Further elaboration of the major products where (n=l) and (n = 2) delivered the natural products... 

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). 

The influence of solvent on the nature and efficiencies of imide photoreactions has been demonstrated <1999JOC4411>. While irradiation of an acetonitrile solution of silylpropyl imide 140 results in quantitative conversion to the [2+2] photodimer (Equation 41), similar treatment of the imide in H2O-CH3CN mixtures produces only the functionalized pyrrolizidine. 

More recently, Naidu and West have utilized a ring expansion reaction of spiro azetidinium ylide 167 in the synthesis of pyrrolizidine alkaloids. Spiro azetidinium ylide 167 is generated through a Cu(acac)2-catalyzed intramolecular reaction of a copper carbene complex with a pendant amino moiety. Subsequent [l,2]-shift gives fused bicyclic products 168 and 169 as a diastereomeric mixture. Each diastereomer was further converted to naturally occurring pyrrolizidines ( )-turneforcidine and ( )-platynecine, respectively (Scheme 18). ... 

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