Pyrrolizidines stereochemistry

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. 

Some male arctiid moths produce their courtship pheromone from dietary pyrrolizidine alkaloids acquired during feeding by the larvae [ 126]. Conversion of monocrotaline to hydroxydanaidal by males is accomplished by aromatiza-tion, ester hydrolysis and oxidation of an alcohol to the aldehyde [7]. In the case of Utetheisa ornatirx the stereo-configuration at C7 of the dietary alkaloid is the same as the pheromone released (R). In contrast, another arctiid, Creatono-tos transiens, can convert a dietary precursor alkaloid with the (S) configuration at C7 (heliotrine) to (l )-hydroxydanaidal. The biosynthesis occurs by first oxidation-reduction at C7 to convert the stereochemistry and then proceeds through aromatization, hydrolysis, and oxidation [7]. 

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>. 

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

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). 

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 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. 

DCP-hased Chiral Auxiliaries in Total Synthesis. DCP-based chiral auxiliaries have proven amenable to asymmetric total synthesis, including Denmark s syntheses of of the pyrrolizidine alkaloid (-)-rosmarinecine and the pentahydroxy pyrrolizidine alkaloid (+ )-casuarine. Denmark s synthesis of (+)-casuarine involves [4 + 2] cycloaddition of dienophile 15 with nitrobenzoate followed by [3 + 2] cycloaddition of the resulting nitronate 17 with a vinyl silane 18 (eq 10). During formation of the [4 + 2] cycloadduct, the relative configuration between C4 and C5 is a direct consequence of the vinyl ether geometry, while the stereochemistry at C6 is determined by the ability of the chiral auxiliary to differentiate the diastereotopic n faces (Re of Si) of the vinyl ether (termed internal diastereoselection). Thus, this tandem sequence... 

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... 

This conclusion has been confirmed by a total synthesis of macronecine (7), which involves successive reductions of the racemic pyrrolizidine ester (8) by zinc and acetic acid, followed by lithium aluminium hydride. Resolution was achieved via the a-bromo-D-camphor-n-sulphonate salts. The conclusion concerning the relative stereochemistry in macronecine was substantiated by the preparation of the other three racemates having the same gross structure as macronecine, and a detailed comparison of their n.m.r. spectra. In consequence of this work, the complete structure of macrophylline is as given in (9). ... 

The absolute configuration of monocrotalic acid (44), the necic acid component of monocrotaline (45), has been elucidated aside from the acid derived from retusamine, whose structure has been defined by X-ray crystallography, this is the first necic acid component of a pyrrolizidine diester alkaloid containing an eleven-membered ring to have its stereochemistry unambiguously established. 

Clivorine, the alkaloid of Ligularia clivorum Maxim., was earlier shown to be a pyrrolizidine alkaloid whose basic constituent is otonecine (64). The acid component is a hydroxydicarboxylic acid which readily lactonises, on attempted isolation, to clivonecic acid (65). The structure of this acid has now been firmly established on the basis of chemical and spectroscopic evidence, and its stereochemistry has also been discussed. The present proposal" is that clivonecic acid has the S-configuration at C-2 since the o.r.d. spectrum of tetrahydroclivonecic acid exhibits a positive Cotton effect, in agreement with the modified octant rule. ... 

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