Pyrrolizidine derivatives

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. 

Thus the hydroxylactam 6 affords pyrrolizidine derivative 7 in high yield in a completely stereoselective fashion36. 

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... 

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

The reductive cleavage of the N-O bond in 159 can also be achieved with [Mo(CO)6] in aqueous MeCN, yielding the pyrrolizidine derivative 160 (Equation 26) <2003HCA3066>. 

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. ... 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

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). 

Another route to pyrrolizidine derivatives starting from furan derivatives was devised by Ponomarev et af.18,19 The method is based... 

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. 

A number of syntheses of pyrrolizidine derivatives are based on cyclization of amino acids such as /3-(pyrrolidin-2-yl)propionic acid, 4-aminopimelic acid, and their homologues to give 3-oxo- and 3,5-dioxo-pyrrolizidines. Reduction of these cyclic amides leads to pyrrolizidines. 

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. 

Pyrrolizidine derivatives with at least one substituent, and particularly the pyrrolizidine alkaloid components, have one or more asymmetric carbon atoms. The stereochemistry of pyrrolizidine was clarified for the most part in the course of investigation of the naturally occurring pyrrolizidine alcohols. Here, the problems of relative and absolute configuration and of stereoisomeric transformations will be considered. 

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. 

Naturally, 3- and 5-oxopyrrolizidines fall outside the group they show the properties typical of lactams. This section is concerned with a brief discussion of the following types of reactions of pyrrolizidine derivatives ... 

Dioxopyrrolizidine was widely used by Micheel et al33,118 as starting compound in the syntheses of some pyrrolizidine derivatives. Its reaction with phosphorus pentasulfide gave rise to pyrrolizidine-3,5-dithione, and it was converted via a Reformatsky reaction into ethyl 3-oxo-5-hydroxypyrrolizidine-5-acetate (165) and ethyl 3-oxo-pyrrolizylidene-5-acetate (166). Condensation with organomagnesium... 

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... 

Some semi-synthetic quaternary pyrrolizidine derivatives have marked biological activities. Ganglion- and neuromuscular-blocking activities were... 

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. 

The uses of pyrrolizidine derivatives are many and varied. Pyrrolizidine (1) and simple alkylpyrrolizidines are used as catalysts for the preparation of polymers and resins, particularly polyurethans. They have been utilized also as lubricating oil additives and as hardeners for epoxyresins. A wide... 

Simanek et al. and Gupta et al. have each recorded the UV spectra of about 20 pyrrolizidine derivatives. In the latter study, the UV spectra of platynedne (43) and retronecine (127) were examined. Platynecine showed three absorption bands in hexane (206.0,225.6, and 266.9 nm) and only one in methanol (207.0 nm). Retronecine also showed three bands in hexane (206.0,... 

Several groups of workers have pointed out that in many pyrrolizidine derivatives, H-7j8 [as shown in (109)] is subject to an unusually large shielding influence because of its position in the fold of the two rings. This shielding applies to pyrrolizidine itself and also to 3-oxopyrrolizidine derivatives. The H-NMR spectra of the fairly rigid, symmetrical 3,5-dioxopyrrolizidine... 

Rearrangement of the iminium ion 61 derived from the ( )-amino alcohol 60 produces diastereomeric pyrrolizidine derivatives 62 and 63 in 84% and 6% yield, respectively. The rearrangement of the corresponding (Z)-amino alcohol is less selective1148. 

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