Of pyrrolizidines

The combination of positive and negative charges within the same molecule causes a more complicated situation, which obviously has not been well-defined to date. A quite large number of pyrrolizidine alkaloids are related to Otonecine (8) (Scheme 3). Spectroscopic investigations show that these alkaloids exist in the nonionized form in CDCI3, and in the zwitterionic form in D2O (00JNP857, 71TL3421). The dipolar structure is the result of an intramolecular interaction between a nucleophilic and an electrophilic center. 

Hudlicky and coworkers also reported a related 2-pyrroline formation from viny-laziridines [81], which are extremely useful for the synthesis of pyrrolizidine alkaloids such as the protected (+)-trihydroxyheliotridane 210 (Scheme 2.51). Since the pyrolysis of either diastereomer of 208 furnished the cyclized product 209 as a... 

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. 

Hartmann T, Ober D (2000) Biosynthesis and Metabolism of Pyrrolizidine Alkaloids in Plants and Specialized Insect Herbivores. 209. 207-243 Haseley SR, Kamerling JP, Vliegenthart JFG (2002) Unravelling Carbohydrate Interactions with Biosensors Using Surface Plasmon Resonance (SPR) Detection. 218 93-114... 

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]. 

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. 

As in the case of aminodialkenes (see above), hydroamination/bicyclizations of aminoalkenynes allow the regiospecific synthesis of pyrrolizidine skeletons (Eq. 4.87) [138, 303]. 

Enantioenriched (-)-rosmarinecine, which belongs to the group of pyrrolizidine alkaloids [413], has been synthesized by Goti, Brandi and coworkers applying an intramolecular 1,3-dipolar cycloaddition as the key step [414]. The required nitrone was obtained in situ from L-malic acid. Moreover, 1,3-dienes as precursors for a cy-... 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

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... 

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. 

An interesting strategy for the synthesis of pyrrolizidines and indolizidines has been developed by Brandi and co-workers. Cycloaddition between nitrones or nitrile oxides with methylenecyclopropanes generates strained tricyclic spiro compounds, which are prone toward further transformations, such as rearrangement, ring opening, and new ring closure (Scheme 10.17).116... 

Macel G L, Klinkhamer P, Vrieling K and van der Meijden E (2002), Diversity of pyrrolizidine alkaloids in Senecio species does not affect the specialist herbivore Tyria jacobaeae , Oecologia, 133, 541-550. 

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). 

Extensive metabolic work continues with the pyrrolizidine alkaloids many of which are known toxic principles of plants responsible for conditions such as irreversible hemorrhagic liver necrosis, megalocytosis, and cancer. Considerable interest remains in the metabolism of pyrrolizidine alkaloids and their A-oxides to metabolic pyrroles thought to participate in molecular events associated with the above-mentioned toxicities. The chemistry and pharmacological properties of the pyrrolizidine alkaloids is authoritatively discussed by Wrobel in Volume 26 of this treatise. 

Selective ring closure of cyclic secondary alkyl radicals onto the central carbon atom of allenes have been investigated in the course of pyrrolizidine alkaloid syntheses [69]. Thus, reduction of the phenylselenyl-substituted N-(l,2-buten-4-yl)pyrroli-done 42 with Bu3SnH via a radical chain mechanism provides 51% of target compound 44 as a 78 22 mixture of diastereomers (Scheme 11.14). The stereoselectivity... 

Scheme 11.14 The synthesis of building block 44 in the total synthesis of (+)-heliotridine, a necine base present in a large diversity of pyrrolizidine alkaloids [69], a)78 22 mixture of diastereomers.

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

An exchange quantity, S(,(tert/sec, sec, sec), not previously calculated, is found to be ca —59 kJmol-1 from this example. By comparison with other exchange quantities in Table 2 this value seems inaccurate26. However, we note that the cis/trans enthalpy difference of pyrrolizidine (ca 14 kJ mol-1 from Reference 25) is significantly less than the ca 26 kJmol-1 we deduce for bicyclooctane. This should not surprise us because trivalent nitrogen has been known to accommodate strain by partial or total planarization27. 

Figure 2.12 Metabolic activation by the liver of pyrrolizidine alkaloid to the toxic pyrrole (liver bound and highly toxic) and the glutathione conjugate (excretion metabolite).

Edgar, J.A. and Smith, L.W. (2000). Transfer of pyrrolizidine alkaloids into eggs Food safety implications, in Tu, A.T. and Gaffield W., Eds., Natural and selected synthetic toxins biological implications, American Chemical Society, Washington, pp. 118-128. 

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