Pyrrolizidines pyrrolizidine alkaloid

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. 

Sinnlarly, f-i- -casuralme, a pentahydroxy pyrrolizidine alkaloid, is prepared by a tandem [4-i-3 /[3-i-3 cycloadchdon involving nitroalkene, chiral vinyl ether, and vinyl silane This process creates five of the six stereocenters present in this potent glycosidase inhibitor fScheme 8 35 ... 

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... 

Figure 10.31 Synthetic route to oxygenated pyrrolizidine alkaloids, and an aza-C-disaccharide as glycosidase inhibitors.

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]. 

A dietary supplement may be safe when taken in the recommended doses but may become dangerous in higher doses. However, patients may develop side effects even when ingesting recommended doses. Adverse reactions may be due to allergic reactions, dietary supplements containing toxic substances, mis-identification of plant, mislabeling of plant, natural toxic substances such as pyrrolizidine alkaloids in comfrey, unnatural toxic substances such as heavy metals, or pesticides. 

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-... 

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. 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

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. 

Nitroalkenes are shown to be effective Michael acceptor B units in three sequential reactions (A + B + C coupling) in one reaction vessel. The sequence is initiated by enolate nucleophiles (A) and is terminated by aldehydes or acrylate electrophiles (C). The utility of this protocol is for rapid assembly of complex structures from simple and readily available components. A short total synthesis of a pyrrolizidine alkaloid is presented in Scheme 10.16.114... 

Another Michael addition route for synthesis of the pyrrolizidine alkaloide trachelan-thamidin is shown in Scheme 10.18.118... 

From the hair-pencils of butterflies in Danainae and Ithomiinae (Papilion-oidea Nymphalidae), a wider variety of pyrrolizines (la-d, and 6a-d) have been identified than from Arctiidae moths. These compounds are biosynthesized from pyrrolizidine alkaloids, which are included in host plants fed by the larvae and protect them from the attacks of other herbivores [122]. In addition to novel lactones (7, 8a, and 8b) derived from an acid part of the alkaloids, many volatiles of more than 100 compounds (aromatics, terpenoids, hydrocarbons, and others) constitute scent bouquets of the male butterflies [123]. For example, the hair-pencil of Idea leuconoe (Danainae) which is distributed in South-East Asia contained 16 compounds (6b, 8a, 8b, 9, and others), and a mixture of the major volatiles applied to a butterfly dummy elicited an abdomen-curling acceptance posture in the females as a crude extract of the male hair-pencils did [ 124]. A chiral GC analysis revealed the absolute config-... 

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 aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84). 

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>. 

Heliotrine (pyrrolizidine alkaloid) (29) Senecionine (pyrrolizidine alkaloid) (30)... 

Lin G, Cui Y-Y, Liu X-Q and Wang Z-T (2002b), Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloids clivorine , Chem Res Toxicol, 15, 1421-1428. 

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. 

---