Pyrrolizidines functionalized

Surzur and Stella have utilized the radical bicyclization of ethylenic N-chloroamines to produce pyrrolizidines functionalized at C-2.14 Reaction of allylamine with l-bromopent-4-ene, followed by chlorination, gave the N-chloroamine (11). Treatment of 11 with aqueous acetic acid and titanium(III)... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

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. 

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). 

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

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-... 

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. 

B. Cyclization op Halides and Halogenoamines, and Intramolecular Cyclodehydration This method is of rather wide importance its scope extends to include the synthesis of various alkyl pyrrolizidines and, as shown recently, some functional pyrrolizidine derivatives. It can be outlined by several routes (see Scheme I). 

Intramolecular alkylation of the amino group has been applied more recently to the synthesis of functionally substituted pyrrolizidine derivatives. For example, Seiwerth and Djokic20 reported the synthesis of 3-substitutedpyrrolizidines. y-Tetrahydrofurylbutyric acid, via... 

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 Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

Many pyrrolizidine alkaloids are known to produce pronounced hepatic toxicity and there are many recorded cases of livestock poisoning. Potentially toxic structures have 1,2-unsaturation in the pyrrolizidine ring and an ester function on the side-chain. Although themselves non-toxic, these alkaloids are transformed by mammalian liver... 

Workers in Australia, where chronic liver disease of sheep has been related to pyrrolizidine alkaloid intake (173), have isolated microorganisms from sheep rumen capable of reductive cleavage of the side-chain ester function of heliotrine (161), supinine (163), heleurine (164), and europine (165) (165,166). In the earlier report (765), a small gram-negative coccus... 

Alkaloids are generally bitter, which suggests that these compounds could be utilized as either animal deterrents or in intra- or interspecific competition of plant species. In some cases repellent alkaloids (e.g., pyrrolizidine alkaloids) are sequestered by herbivores and converted to compounds that function as sex pheromones while still possessing deterrent activities. The insect derivation of sex pheromones from known repellent alkaloids that accompany the ingested nutrients... 

Some alkaloids interfere with the assembly of microtubules (taxol, colchicine, maytansine), inhibit key enzymes such as adenylate cyclase (papaverine, theophylline, theobromine), activate neuromuscular systems involving ACH (physostigmine, coniine, nicotine), inhibit digestive processes (emetine, lobeline, morphine), modulate liver and kidney function (pyrrolizidine alkaloids, amanitine), and destabilize the blood and circulatory system (vinblastine, colchicine). 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78... 

The effects of pyrrolizidine alkaloids on the mixed-function oxidase enzyme system in rat liver have been studied.79,80 Dehydroheliotridine and heliotrine (at higher dose rates) have similar effects on pregnant rats and their embryos.81 The development of pulmonary hypertension and obstructive lesions in rats after administration of monocrotaline (48) has been studied.82 Butylated hydroxyanisole protects young mice against the acute toxicity of monocrotaline.83 Reduced levels of pyrrole metabolites were observed. 

Pyrrolizidine alkaloids with no oxygen function in 7 (128) are cleaved at bonds a and b, losing an ethylene derivative, (128)- -[129]- [130]. 

Although the biologieal activities of many alkaloids have not yet been studied and their ecological functions remain to be elucidated or proved, we can nevertheless safely say that alkaloids are neither waste nor functionless molecules, but rather they are important fitness factors, probably mostly antiherbivore compounds. Since Nature obviously favored multitasking, additional activities, such as allelopathic or antimicrobial activities, are plausible. For quinolizidine and pyrrolizidine alkaloids, these multiple functions are already well documented (Tables 1-X). 

Extension of diis methodology to nitrogenous compounds (Scheme 53) has been implemented via azide cycloadditions to dienes as a facile means of synthesis of functionalized pyrrolizidines. Recently a [2 -I- 3] methodology was developed (Scheme 54) that promises to have wide tqrplicability in the synthesis of cyclopentanoids, bridged systems and dihydrofurans. ... 

In the presence of a suitable functionalization, the pyrrolidine nitrogen can suffer intramolecular acylation or alkylation to afford the pyrrolizidine or indolizidine skeleton common to several natural and unnatural biologically active compounds (Scheme 51) <1997JA125, 2000JOC2875, 1999JA3046>. 

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