Reactions of pyrrolizidines

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 ... 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

With nonracemic chiral diazoacetates the insertion process occurs with evident match/mismatch characteristics. This has been demonstrated in reactions of optically pure 2-methylcyclohexyl diazoacetates (Eq. 9) [85] and in carbon-hydrogen insertion reactions of steroidal diazoacetates (Eq. 10) [86], as well as with the synthesis of pyrrolizidines 36 and 37 [84]. The mechanistic preference for formation of a /J-lactone in Eq. 10 over insertion into the 4-position is not clear,but there are other examples of /J-lactone formation [87]. In these and related examples, selectivities in match/mismatch examples are high, and future investigations are anticipated to show even greater applicability. 

Note It is reported that the use of chlorobenzene as solvent is essential when the reagent is to be used to detect aromatic amines [1]. In the case of steroids, penicillins, diuretics and alkaloids the reaction should be accelerated and intensified by spraying afterwards with dimethylsulfoxide (DMSO) or dimethylformamide (DMF), indeed this step makes it possible to detect some substances when this would not otherwise be possible [5,9-11] this latter treatment can, like heating, cause color changes [5,9]. Penicillins and diuretics only exhibit weak reactions if not treated afterwards with DMF [10, 11]. Steroids alone also yield colored derivatives with DMSO [9]. Tlreatment afterwards with diluted sulfuric acid (c = 2 mol/L) also leads to an improvement in detection sensitivity in the case of a range of alkaloids. In the case of pyrrolizidine alkaloids it is possible to use o-chloranil as an alternative detection reagent however, in this case it is recommended that the plate be treated afterwards with a solution of 2 g 4-(dimethyl-amino)-benzaldehyde and 2 ml boron trifluoride etherate in 100 ml anhydrous ethanol because otherwise the colors initially produced with o-chloranil rapidly fade [12]. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

As discussed previously, radical ring-opening reactions of three-membered systems via cyclopropylmethyl and oxiranylmethyl radicals represent a fruitful method in organic synthesis [111]. De Kimpe and coworkers have now shown that azirid-ines can also be used, featuring a radical one-step synthesis of pyrrolizidines 3-280... 

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... 

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 Michael reaction of nitromethane with methyl vinyl ketone and l-decene-3-one followed by reductive cyclization gives two isomeric pyrrolizidines, depending on reduction conditions (Eq. 10.74).117... 

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. 

An interesting approach to the pyrrolizidine skeleton was devised wherein pyrrole-2-carboxaldehyde (70) underwent A-allylation under basic conditions and subsequent olefmation with ethyl p-tolylsulfinylmethanephosphonate to produce the pyrrolyl alkene 71 <00TL1983>. Intramolecular Heck reaction of the iodo species then produced the 1 -p-tolylsulfinyl-1,3-diene 72. 

Highly selective 1,3-dipolar cycloaddition reactions of nitrone (154) with acrylates have been used in the total syntheses of pyrrolizidine alkaloids, 7-deoxy-casuarine (572) and hyacinthacine A2 (573) (Scheme 2.263) (772). 

Cycloaddition reaction of nitrone (—)-(394) with dimethyl maleate D14 has been used for the synthesis of two new polyhydroxyl pyrrolizidines (687) and (688) (Schemes 2.293, 2.294). These compounds are analogs of alkaloids ros-marinecine and crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)- a-epi-crotanecine) (—)-(688) is a potent and selective inhibitor of a-mannosidases (310). The reaction of (—)-(394) with dimethyl maleate gave a 9.6 6 1 mixture of cycloadducts (—)-(680), (+ )-(680), and (—)-(681), which arise from anti-exo,... 

We have extended our work on a new synthesis of the antiprotozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy-carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and g-erythrose, using reactions of high stereoselectivity. 

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