Pyrrolizidines, amino-, reactions

The hydroxy groups of pyrrolizidine amino-alcohols are readily replaced by chlorine atoms upon treatment with thionyl chloride (see, e.g., refs. 101 and 103). In this reaction, the allylic hydroxyl group is more reactive and can be selectively replaced by chlorine.79 In some particular cases, methoxyl groups can also be substituted for halogen e.g., l/3-methoxymethyl-8a-pyrrolizidine, when treated with hydro-bromic acid, gives rise to the corresponding bromo derivative.104... 

Pyrrolizidine amino-alcohols are readily dehydrated for example, hydroxyheliotridane and retronecanol, when treated with sulfuric acid, afford heliotridene (see e.g., refs. 105 to 107). A more complicated dehydration reaction is the transformation of the alkaloid rosmarinine into the alkaloid senecionine.83 Dehydration of 1-hydroxy-l-carbethoxypyrrolizidine53 in the presence of phosphorus oxychloride in pyridine results mainly in the formation of the A1,8-unsaturated ester (see Section II, E). The authors61,62 claimed that the dehydration product of l-carbethoxy-2-hydroxy-3-oxopyrrolizidine contained a A1,2-double bond (159). Later, however, the UV, IR, and NMR spectra67 revealed that the double bond had migrated the... 

Note It is reported that the use of chlorobenzene as solvent is essential when the reagent is to be used to detect aromatic amines [1]. In the case of steroids, penicillins, diuretics and alkaloids the reaction should be accelerated and intensified by spraying afterwards with dimethylsulfoxide (DMSO) or dimethylformamide (DMF), indeed this step makes it possible to detect some substances when this would not otherwise be possible [5,9-11] this latter treatment can, like heating, cause color changes [5,9]. Penicillins and diuretics only exhibit weak reactions if not treated afterwards with DMF [10, 11]. Steroids alone also yield colored derivatives with DMSO [9]. Tlreatment afterwards with diluted sulfuric acid (c = 2 mol/L) also leads to an improvement in detection sensitivity in the case of a range of alkaloids. In the case of pyrrolizidine alkaloids it is possible to use o-chloranil as an alternative detection reagent however, in this case it is recommended that the plate be treated afterwards with a solution of 2 g 4-(dimethyl-amino)-benzaldehyde and 2 ml boron trifluoride etherate in 100 ml anhydrous ethanol because otherwise the colors initially produced with o-chloranil rapidly fade [12]. 

Ornithine is a metabolically quite active amino acid, and the important precursor of pyrrolidine nucleus, which is found in pyrrolizidine alkaloids. Ornithine itself is a non-protein amino acid formed mainly from L-glumate in plants, and synthesized from the urea cycle in animals as a result of the reaction catalyzed by enzymes in arginine. 

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). ... 

The synthesis of pyrrolizidine developed by LukeS and Sorm31 and by Micheel and Flitsch32 starts with furylacrylic acid (56) which is converted by the Markwald reaction into y-ketopimelic acid (57). The carbonyl group in 57 is replaced by an amino group via the oxime or by the Leuckart-Wallach reaction this substitution results immediately in the formation of the lactam 58, which can be converted by heat into 3,5-dioxopyrrolizidine (59). The latter compound yields pyrrolizidine... 

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. 

Mechanistically, it was suggested [92] that this cyclization does not involve the free a-amino radical formed by cleavage of the C—Si bond of the trimethylsilylmethyl-amine radical cation. Instead, it was pointed out that cleavage of the C—Si a-bond from the delocalized trimethylsilylmethylamine radical cation, produced by a vertical overlap of the C—Si bond and empty p-orbital of nitrogen, is assisted by the 71-orbitals of the olefin. This strategy was applied to the stereoselective synthesis of pyrrolizidine and indolizidine ring systems [93]. The synthetic utility of this reaction is also demonstrated by the synthesis of ( )-iso-retronecanol [94]. 

Benzophenones have been described as useful sensitisers for PET catalysed conjugate addition reactions of a-amino alkyl radicals to enones (Bertrand et al. 2000). We tried to modify this reaction and synthesised the pyrrolidinylethyl-substituted quinolone 35 from the known bromide (Bauer et al. 2005). Upon electron transfer from the pyrrolidine to a given acceptor, a radical cyclisation occurs (Scheme 15), which after electron and proton transfer generates a pyrrolizidine. We found 4,4/-dimethoxybenzophenone to be a suitable catalyst for this reaction. Remarkably, the reaction proceeded with excellent simple diastereos-electivity and a single diastereoisomeric product rac-36 was obtained. With 10 mol% of the catalyst, a chemical yield of 71% was achieved. 

Pyrrolizidines and indolizidines may be prepared by reaction between the electrogenerated anion of methyl dichloroacetate and acylated a-aminoaldehydes, obtained from amino acids. High diastereoselectivity (> 99%) was observed in the reaction of some cyclic a-aminoaldehydes [137]. 

Hydroamination/bicyclization of aminodialkenes, aminodialkynes, and amino-alkenynes opens a straightforward route to pyrrolizidines and indolizidines in a tandem C-N and C-C bond forming process. An important prerequisite for the success of this reaction sequence is a sufficient lifetime of the rare-earth metal alkyl intermediate formed in the initial insertion process of the alkene/alkyne in the Ln-amide bond in order to permit the carbocyclization step (Scheme 9) [99,174],... 

A similar strategy generated two of the simplest members in the pyrrolizidine family of alkaloids, isoretronecanol (120) and trachelanthamidine (121). The enamino ester (117) was prepared via the Es-chenmoser reaction by the condensation of thiolactam (116) and ethyl bromoacetate (Scheme 23). A second alkylation with bromoacetate on the resulting vinylogous carbamate (117) yielded the amino diester... 

MBH derivatives 782, prepared from the reaction of MBH acetate with pyrrole-2-carbaldehyde or the reaction of MBH bromide with MBH acetate in the presence of K2CO3, were procured to examine the intramolecular [3 + 2] cycloaddition. The condensation of 782 with sarcosine (783) in refluxing toluene under Dean-Stark conditions produced cw-adducts 784 in moderate yields (Scheme 4.228). " Further broadening of the scope of amino acids to proline and thiazolidine revealed that all of the reactions proceeded very well -the corresponding pyrrolizidine and thiopyrrolizidine heterocycles were obtained in similar yields. To improve the yield, the same reactions were also carried out under microwave irradiation, affording adducts 784 and 787 in higher yields (78-87%). 

A further extension of the Pd-catalyzed intramolecular 1,4-oxidation was the use of amide, whose amino functionality had the ability of making a twofold nucleophilic attack. The use of nitrogen as nucleophile led to pyrrolizidine and indolizidine derivatives. This strategy was applied for the synthesis of another alkaloid, ( )-heliotridanef (Scheme 36). Pd-catalyzed reaction of dieneamide, obtained from the known ester 167, in THF employing CUCI2/O2 as the oxidant afforded the azabicyclic product 168 in 85% yield. The mechanism of this tandem cyclization involved a TT-allylpalladium... 

Amino complexes of rare-earth elements can undergo intramolecular alkene insertion rather than alkene activation followed by nucleophilic attack (Scheme 6.59). Treatment of the amino diene 6.170 with a scandium complex 6.174 resulted in insertion of one double bond to give a d5-pyrrolidine 6.171. Raising the reaction temperature then caused insertion of the second alkene to give the pyrrolizidine 6.172. The thiophene group had been chosen to activate the first alkene it also serves as a surrogate alkyl group, and the synthesis was completed by desulfurization-reduction. The product is the alkaloid, xenovenine 6.173 (see Schemes 6.65 and 6.74 for related syntheses, and Scheme 9.46 for a different approach.)... 

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