Stereochemistry of 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. 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

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... 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

The synthesis of pyrrolizidine alkaloid (-)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cA relationship at the three contiguous centers C(l), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot. 

The ketal hydrochloride 322 has been used for X-ray crystallographic analysis to establish the stmcture and stereochemistry of the pyrrolizidine alkaloid l,7a-diepialexine <1990P111>, and the fused isoxazolidine 323 is an intermediate in a model synthetic approach to alkaloids such as laccarin, 324 <2002SL1344>. 

Similar strategies have been used for the synthesis (286) of the tetrahydro-pyrrolizidine 323 from 2,3 5,6-di-O-isopropylidene-D-g/yccroD-ta/o-hep-tono-1,4-lactone (322). These polyhydroxylated pyrrolidines and pyrrolizi-dines are potential specific inhibitors of glycosidases. The stereochemistry of the hydroxyl groups have a profound effect on the selectivity of the inhibition (286-288). 

The stereochemistry of the other pyrrolizidine alcohols and related compounds was determined on the basis of comparison of their configurations with those of the above basic compounds.2,45,81 For example, platynecine can be converted into (— )-isoretronecanol (134) under conditions which cannot affect the configuration at C-l, and 134 can then be transformed into (— )-heliotridane (135). On the basis of these data, the compounds can be named, respectively, as 1 -endo-hydroxymethylpyrrolizidine and 1 -ewdo-methylpyrrolizidine, and their diastereoisomers (- )-trachelanthamidine (136) and (— )-pseudoheliotridane (137) as I -exo-hydroxymethylpyrrolizidine and 1 -eso-methylpyrrolizidine. 

The stereochemistry of indolizidine and pyrrolizidine metho salts was studied by Meyer and Sapianchiay.289 They found that methylation of indolizidine gave a 50 50 mixture of isomers from which only the cis-metho salt could be obtained pure. Cyclization of either 250 or 251 gave only the cis isomer, which can be accounted for on the basis of less... 

The venomous constituent of the cryptic thief ant, Solenopsis xenovenenum, has been identified as the 3-heptyl-5-methylpyrrolizidine (50) from its mass spectrum and the fact that a related pyrrolidine (51) has been isolated from another species of ant.47 This is the first reported occurrence of a 3,5-dialkyl-pyrrolizidine, and its structure was confirmed by synthesis. Reductive amination of the known triketone (52) with sodium cyanoborohydride and ammonium acetate gave a mixture of four isomers of 3-heptyl-5-methylpyrrolizidine, which were separated by preparative g.l.c. The stereochemistry of the ring-junction of each isomer was established from its i.r. and n.m.r. spectra. 

ROBINS, D.J., Stereochemistry of enzymic processes in the biosynthesis of pyrrolizidine alkaloids. Experientia, 1991,47, 1118-1122. 

Bromine and iodine were both effective for the cyclization of l-aza-4-cyclooctene to the corresponding pyrrolizidine 3 which is obtained in good yield without conflicting amine oxidation. The cyclization of l-aza-5-cyclonene and of cyclophenylalkanamines was similarly performed (Table 6) 3-121 23>, The total stereoselectivity is dependent on either the strain connected with the polycyclic system or the tram addition to the double bond. The stereochemistry of the products was confirmed by X-ray analysis. 

When oxygenated diene (175 X = OR) was utilized, a single isomer of pyrrolizidine (177) was formed on thermolysis.(The stereochemistry of the carboxylate was rationalized by the endo effect.) Thus a highly selective procedure for the exhaustive synthesis of pyrrolizidine alkadoids was developed (see Sections 8.1.8 and 8.1.9). ... 

A transannular route to 1-substituted pyrrolizidines has recently been reported by Wilson and Sawicki. The lactam (79) was prepared by Beckmann rearrangement of the oxime p-toluenesulfonate of cyclohept-4-enone. Reduction with lithium aluminum hydride gave the amine (80), which on treatment with bromine yielded the 1-bromopyrrolizidine (81) in one stereospecific step (95%). The stereochemistry of the product corresponds to a disfavored exo-mode of cyclization by attack of the nitrogen on the bromonium ion. Further modification of this route to produce naturally occurring alkaloids would appear feasible, but has not yet been reported. 

There are four known, naturally occurring fully saturated pyrrolizidine diols. The relative stereochemistry of platynecine (43) is known from chemical interconversions of the bases, and the absolute configuration was defined by degradation of heliotridane (7) to S-(-i-)-3-methylheptane. ... 

There are only two known, naturally occurring trihydric saturated pyrrolizidine bases. The relative stereochemistry of rosmarinecine (123) was determined by Warren and co-workers. For the other base, croalbinecine... 

A number of closely related naturally occurring pyrrolizidine cyclic ethers have been identified.74 Four of these, loline (=festucine75) (119), norloline (120), lolinine (121), and decorticasine (122), have had their structures and relative configurations established by chemical methods. In addition, the relative stereochemistry of loline has been defined by an X-ray crystal structure determination of its dihydrochloride.76 The absolute configurations for all these alkaloid bases have now been established by the X-ray technique of anomalous dispersion using the same dihydrochloride of loline (119).7 7... 

There are only two known, naturally occurring trihydric saturated pyrrolizidine bases. The relative stereochemistry of rosmarinecine (123) was determined by Warren and co-workers.78 For the other base, croalbinecine (124), the chirality at C-l, C-7, and C-8 was defined by Sawhney et al.19 by correlation with turneforcidine (113) as shown in Eq. (33). The location of the third hydroxy group at C-2, indicated by NMR spectroscopy, was confirmed by decoupling experiments. It was further suggested by these workers79 that the configuration at C-2 is /i-hydroxy, on the basis of the... 

A full paper by Wilson andSawicki on their transannular route to 1-substituted pyrrolizidines has been published. Transannular electrophilic attack on the amine (7) produced a range of endo-1 -substituted pyrrolizidines in 63-91% yield (Scheme 3). The stereochemistry of (8 R = Br) was confirmed by X-ray crystallography. 

In last year s Report, reference was made to the discovery of three examples of a new type of pyrrolizidine alkaloid containing the dihydropyrrolizinone ring system. Two closely related acyl-pyrroles have now been detected in aerial parts of Kleinia kleinioides (Sch. Bip.) M. R. F. Taylor by Bohlmann and Knoll. Spectral data on the first pyrrole showed it to be an isomer of senaetnine (29), with different stereochemistry at C-7, C-12, or C-13. Lack of material prevented clarification of the stereochemistry of isosenaetnine (29). The second new compound differed from isosenaetnine in replacement of one methyl group by methylene, and it is therefore formulated as dehydroisosenaetnine (30). The stereochemistry is again uncertain. 

Most pyrrolizidine alkaloids are esters constructed from an aminoalco-hol called a necine unit (pyrrolizidine derivative), and straight or branched chain fatty acid, called a necic acid. Necine is the derivative of pyrrolizidine, i.e., azabicyclo[3,3,0]octane, and a hydroxymethyl (-CH2OH) moiety is always attached at the C-1 position. Necines can be classified into two groups, either with or without a double bond between the C-1 and C-2 positions. The stereochemistry of the H-8 position is usually H-8a.When the C-8 position is oxidized, as in the case of otonecine, it becomes an eight-membered ring by decychzation. 

Cahill R, Crout DHG, Gregorio MVM, Mitchell MB, Miiller US (1983) Pyrrolizidine alkaloid biosynthesis stereochemistry of the formation of isoleucine in senecio species and of its conversion into necic acid. J Chem Soc, Perkin Trans 1173-180... 

The importance of the 15,16 double bond of esterified pyrrolizidines was also borne out in a study using the spruce budworm larvae (Choristoneura fumiferana) as a model test system (see Table 2.1). Anti-feeding behavior was recorded for a variety of alkaloids and plant extracts containing alkaloids (1). Of the 14 pyrrolizidine alkaloids examined, only two, senkirkine and lasio-carpine, were highly deterrent (> 75%). When the stereochemistry of the 15,16 double bond of these compounds was modified, as in the case of neosenkirkine, or the double bond was epoxidized, as in otosenine, the deterrent activity of the alkaloid was decreased dramatically. This is in sharp contrast to the increase of toxicity associated with epoxide formation in the case of jacobine... 

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