The Synthesis of Pyrrolizidine Derivatives

The cyclization of 2-alkyl-N-bromopyrrolidines to give alkylpyrrolizidines (2) was the first synthetic method used to generate the pyrrolizidine nucleus.1 This procedure is now mainly of historical interest and has limited practical importance. 

This group of methods is useful for the preparation of simple alkylpyrrolizidines. Several routes are available to pyrrolizidine (1) from common starting materials. Dedek and Trska6 converted y-butyrolactone into pyrrolizidine in five steps with an overall yield of 12% [Eq. (1)]. 

A frequently used intermediate in pyrrolizidine syntheses is the hydroxy-alkylpyrrolidine (3). This has been prepared in an improved yield of 40% from pyrrole by Kray and Reinecke,7 by Grignard reaction of pyrryl magnesium chloride with trimethylene oxide, followed by catalytic reduction [Eq. (2)]. Some 20% of the product was the isomeric compound (4). Cyclization of the mixture gave the two azabicyclic derivatives (1) and (5). A similar 

Another synthesis of a quaternary salt (8) was developed by Meyer and Sapianchiay for the purpose of studying the steric course of formation of the pyrrolizidine system.9 Photolysis of the N-chloroamine (9) in a Hofmann-Loeffler-Freytag reaction [Eq. (4)], gave an intermediate that yielded the pyrrolizidine salt (8) in an intramolecular N-alkylation. The product was the cis-isomer, reflecting the greater degree of strain in the trans-fusion of two five-membered rings. 

Russian workers have continued their studies on the production of alkyl-pyrrolizidines from furan derivatives by catalytic dehydration.1 The original catalyst used was thorium oxide on alumina, but improved yields were obtained with zirconium oxide on alumina10 [Eq. (5)]. In the formation of 3-methylpyrrolizidines (10, R = Me), different isomer ratios were observed  

3-methylpyrrolizidines (10, R = Me), different isomer ratios were observed  

Surzur and Stella have utilized the radical bicyclization of ethylenic N-chloroamines to produce pyrrolizidines fimctionalized at C-2. Reaction of allylamine with l-bromopent-4-ene, followed by chlorination, gave the N-chloroamine (11). Treatment of 11 with aqueous acetic add and titanium(III) 

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The synthesis of pyrrolizidine derivatives by condensation of di-(4-oxo-ra-butyl)amine is considered in Section V in conjunction with the biogenesis of naturally occurring pyrrolizidines. 

An example of such structures is an a-haloamide skeleton bearing a double bond. In this context, Mori et al. [78] reported the synthesis of pyrrolizidine derivatives 103,104 and 105 from A-iodoacetyl-2-vinylpyrrolidine (102) (Scheme 6.27). 

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. 

Dipolarophiles D14. The 1,3-dipolar cycloaddition of nitrones to dimethyl maleate and dimethyl fumarate is widely used in the synthesis of polyhydroxy alkaloid derivatives of dihydroindolizidinone (81), pyrrolizidine (119), (—)-codonopsinine, and (+ )-hyacinthacines Ai and A2 (312). In cases of unstable nitrones, syntheses of cycloadducts are performed in situ (81). 

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... 

A new synthesis of pyrrolizidine, which is based on the reaction of bis-tertiary glycols with co-chloronitriles, was reported by Meyers and Libano.28 The method involves three steps (a) condensation of 2,5-dimethyl-2,5-hexanediol (48) with 4-chlorobutyronitrile in the presence of sulfuric acid to give a derivative of A 1-pyrroline (49), (6) reduction of 49 with sodium borohydride to give the corresponding pyrrolidine (50), and (c) intramolecular cyclization of the pyrrolidine in the presence of alkali to give the pyrrolizidine derivative 51. The three-step synthesis was performed without isolation of the intermediate products. 

Rapid advances in the synthesis of naturally occurring pyrrolizidine bases can be expected, and the most promising method for this purpose is the Dieckmann cyclization of pyrrolidine derivatives. 

Micheel and Flitsch116,118 used 3,5-dioxopyrrolizidine (59) and 3-(ethoxycarbonylmethylene)pyrrolizid-5-one (166) as starting compounds in the synthesis of various pyrrolizidine derivatives. The series... 

Imidate-derived dipoles have played a prominent role in the synthesis of the pyrrolizidine alkaloid retronecine (121).119 The imidate salt derived from lactam (118) was found to undergo a smooth desilylation reaction to produce azomethine ylide (119). Trapping of this dipole with methyl acrylate affords... 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

Synthesis from erythrose An efficient approach for the synthesis of (-l-)-trihy-droxyheliotridane (180) via a chiral erythrose derivative has been reported (Scheme 16). Wittig reaction of 2,3-(9-isopropylidene-L-erythrose (172) with Ph3P=CHCH=CHC02Et produced a 1 5 mixture of the ( , )-173 and (Z,A)-174 isomeric dienes, respectively. The diene 173 could be quantitatively obtained by isomerization of 174 with E. The diene 174 was converted to the azide 177, which upon boiling in benzene gave the vinyl aziridine 176. Pyrolysis of 176 furnished the pyrrolizidine 178. On the other hand, the diene 173 was... 

Robertson has shown that treatment of iV-(3-bromo-3-butenyl)pyrrolidine derivatives with tributyltin hydride and AIBN leads to pyrrolizidine derivatives [142]. This reaction was used for the synthesis of dihydroxyheliotridane (Eq. 42,2). 

This reagent was used to reduce 112 to the hydroxymethyl derivative (113) in 91%, without racemization of the stereogenic center at C5, taken from Smith s synthesis of pyrrolizidine alkaloids.Hojo showed that silica gel is an effective catalyst for several other reactions. 1 ... 

Abstract This review is devoted to the stereoselectivity of intermolecular (intramolecular cycloadditions are not included) 1,3-dipolar cycloadditions of sugar-derived nitrones. Stereoselective cycloaddition (transformation of isoxazolidine followed by reduction of the N O bond to produce both an amino and a hydroxy function) allows the synthesis of tailor-made products of possible biological interest such as pol>4iydroxylated pyrrolidines, pyrrolizidines, indolizidines, fi-aminocarbonyl compounds, and disaccharides. Attention is focused on the preparation of isoxazolidinyl nucleosides and to the catalysis of the cycloaddition by Lewis acids. This review has concentrated on the new developments achieved from 1999 to February 2007. 

An account of a lecture by Jager incorporates some new work in this area, including the synthesis of the cycloadduct 178 by cycloaddition of a glucose-derived nitrone with ethyl acrylate (sugar numbers indicated), and its subsequent conversion to the pyrrolizidine 179. ... 

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