Pyrrolizidines 3- substituted

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

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. 

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... 

SAM, samandarines BTX, batrachotoxins HTX, histrionicotoxins PTX, pumiliotoxins aPTX, allopumiliotoxins hPTX, homopumiliotoxins DHQ, 2,5-disubstituted decahydroquinolines 3,5-P, 3,5-d [substituted pyrrolizidines 3,5-1 and 5,8-1, disubstituted indolizidines 1,4-Q, 1,4-disubstituted quinolizidines Epi, epibatidine Pseudophry, pseudophrynamines. With the exception of 3,5-P and 3,5-1, these alkaloids are not known to occur in arthropods (see text). Histrionicotoxins may occur in Minyobates and Mantella, but the evidence is not conclusive. 

Both pyrrolizidines and indolizidines may be similarly formed by cyclization at the less-substituted, internal position of trialkyl-substituted al-kene radical cations (Scheme 29) [139,143]. Related processes featuring exo-digonal radical cyclizations have also been described (Scheme 30) [139,141 — 143]. 

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 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-... 

Plumet et al. described domino metathesis of propargyl (2-endo-7-oxanorborn-5-enyl) ethers 62a-62c with allyl acetate in the presence of Grubbs ruthenium catalyst Ic (Scheme 22). The reaction proceeds stereoselectively to produce substituted m-fused bicyclic ethers 63a-63c. In a similar manner, indolizidinone derivative 64 is obtained from compound 62d instead of pyrrolizidine derivative 63d. ... 

In an interesting fragmentation reaction, the hexahydroazocine (23) is formed by solvolysis of (22) in the presence of NaBHt in 94% yield (75TL2613). A related compound (24) can be prepared from 4-cycloheptenone oxime tosylate via the unsaturated lactam (25) (79JOC287). Whereas (25) adds bromine to the double bond, (24) undergoes a transannular reaction to give a 1-substituted pyrrolizidine (26). The latter type of reaction also occurs... 

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

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 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... 

A few published pyrrolizidine syntheses cannot be classified under any of the above headings. An interesting synthesis of 3-substituted pyrrolizidines was described by Murakoshi.71 A-Acyl derivatives of ethyl (a-pyrrolidine)- -propionate can be converted by distillation over soda-lime into 3-substituted 2,3-dehydropyrrolizidines (121), which afford 3-substituted pyrrolizidines (122) on catalytic hydrogenation. 

It is well known that iraras-bicyclo[3,3,0]octane is a rigid and strained system, whereas the cis-isomer is almost strain-free. Pyrrolizidine differs in that one of the carbon atoms is substituted by a trivalent nitrogen atom which does not rigidly fix the bicyclic system. For this reason, pyrrolizidine, although it probably occurs in the preferred cia-conformation,74 has no stereoisomers. The two rings of the pyrrolizidine system form a dihedral angle with the axis along the C(8)—N bond. 

B) Reactions of hydroxy-, oxo-, car boxy-, and other substituted pyrrolizidines. 

B. Reactions of Hydroxy,- Oxo-, Carboxy-, and Other Substituted Pyrrolizidines... 

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... 

A variety of alkaloid skeletons can be prepared from 5-exo cyclizations of aminium cation radicals derived from PTOC carbamates, and some are listed in Table VI (90T2329). Perhydroindoles (entry 1), 1-, 2-, and 3-substituted pyrrolizidines (entry 2-4), tropanes (entry 5), and other pyrrolidine containing ring systems were obtained in 50-96% yields. Direct com-... 

Five new pyrrolizidine alkaloids, each containing a novel fourteen-membered macrocyclic ring, have been isolated by Edgar et al.x Parsonsine (44) and heterophylline (45) were present in Parsonsia heterophylla A. Cunn. and P. spiralis Wall., while spiraline (46), spiranine (47), and spiracine (48) were obtained only from P. spiralis. These five alkaloids are derived from retronecine that is esterified at C-9 with (-)-trachelanthic acid i.e. indicine), and further diesterified by a series of substituted malic acid derivatives to complete the fourteen-membered ring. Indeed, partial hydrolysis of parsonsine (44) yielded indicine (49). The non-equivalence of the C-9 protons (ABq, S 4.45 and 5.20 p.p.m.) in parsonsine indicates the presence of a macrocyclic system, and... 

Cyclopropanone equivalent. Unlike cyclopropanone, which is difficult to isolate, 1 is stable, easily obtained from 3-chloropropionic acid (Aldrich), and is a useful substitute for the ketone. Thus reaction of the silyl ether 2 with RMgBr provides adducts in which the OH group of 1 is replaced by R. The carbinol 1 is also a useful precursor to pyrroles, pyrrolines, and pyrrolizidines (equation I). 

So as to expand the methodology by incorporating a cyclic amino acid, compound 53 was treated with sodium prolinate in hot DMSO to afford the crude substitution adduct 58 (Scheme 9). Subsequent cyclodehydration using acetic anhydride provided the pyrido[3,4-b]pyrrolizidin- 1-one S949 in high overall yield for the two steps. Following the protocol... 

---