Pyrrolizidines alkyl

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. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Reductive coupling of the corresponding nitrones with alkyl acrylate is the key step in the short synthetic route of the selective and irreversible GABA inhibitor of amino transferase (S)-vigabatine (534) and of polyhydroxy pyrrolizidine alkaloid (+ )-hyacinthacine A2 (535). 

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

Selective ring closure of cyclic secondary alkyl radicals onto the central carbon atom of allenes have been investigated in the course of pyrrolizidine alkaloid syntheses [69]. Thus, reduction of the phenylselenyl-substituted N-(l,2-buten-4-yl)pyrroli-done 42 with Bu3SnH via a radical chain mechanism provides 51% of target compound 44 as a 78 22 mixture of diastereomers (Scheme 11.14). The stereoselectivity... 

A) Pyrrolizidine syntheses involving cyclization of alkyl-substituted A-halogenopyrrolidines,... 

The first synthetic method which afforded the pyrrolizidine system was proposed by Menshikov. The approach was based on the reaction of A-halogenoamines studied by Hofmann,6 i.e. cyclization of 2-alkyl-JV-bromopyrroIidines in the presence of concentrated sulfuric acid. 

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... 

Pyrrolizidine ethers can be obtained by alkylation. Culvenor and Smith104 used this reaction in partial synthesis of the recently discovered alkaloids l-methoxymethyl-l,2-dehydro-8a-pyrrolizidine (158a) and 7hydroxy-1 -methoxymethyl-1,2-dehydro-8 a-pyrrolizi-dine (158b). The compounds were obtained by alkylating supinidine (157a) or retronecine (157b) with methyl iodide in the presence of... 

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... 

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. 

DNA can also be a target for alkaloids planar and lipophilic alkaloids, such as berberine and sanguinarine (Figure 1.6) are intercalating compounds that assemble between the stacks of paired nucleotides in the DNA double helix [2,3,18,23]. DNA intercalation can disturb replication, DNA repair, and DNA topoisomerases. Frameshift mutations are one of the adverse consequences of intercalating compounds. Some alkaloids, such as pyrrolizidine alkaloids, aristolochic acids, cycasin, and furoquinoline alkaloids, are known to form covalent adducts with DNA bases. Mutations and tumor formation can be the result of such interactions. DNA alkylation occurs in some alkaloids only after activation by liver enzymes, such as cytochrome p450 oxidases (pyrrolizidine alkaloids, aristolochic acids) [17,18,24]. 

Fig. 10. Structures of 3,5-disubstituted pyrrolizidines from dendrobatid and ranid frogs andbufonid toads (31,73,81, and J. W. Daly, H. M. Garraffo, andT. F. Spande, unpublished). Absolute configurations are unknown. It is assumed, based on analogy to other amphibian alkaloids, that n-alkyl side chains are present. The configurational nomenclature for these pyrrolizidines follows the system devised by Sonnet el at. (122) for 3,5-disubstituted indolizi-dines where the H-S and H-8 configurations are related to that at H-3 and are either cis (Z) or trans (E).

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

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>. 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

Mattocks has reviewed the metabolic activation of pyrrolizidine alkaloids. Schoen-taP has amplified her hypothesis that the acute effects of pyrrolizidine alkaloid toxidty are due to the alkylation of coenzymes. A summary of the physiological activity and biosynthesis of the pyrrolizidine alkaloids has appeared. ... 

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],... 

Russian workers have continued their studies on the production of alkyl-pyrrolizidines from furan derivatives by catalytic dehydration. The original catalyst used was thorium oxide on alumina, but improved yields were obtained with zirconium oxide on alumina [Eq. (5)]. In the formation of... 

Hydrogenation of nitropimelates under drastic conditions has been widely used for the construction of simple alkyl-substituted pyrrolizidines. Colonge and PouchoP have developed a milder route to 3,5-dioxopyrrolizidines starting from 4-nitropimelate esters [Eq. (10)]. Raney nickel reduction of the nitroester gave a pyrrolidone that afforded the 3,5-dioxo compound (18) on distillation. 

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