Pyrrolizidines

From the chemical point of view pyrrolizidine represents a saturated A -heterobicyclic compound (4-azabicyclo[0,3,3]octane). However, the term pyrrolizidine alkaloids (PA) is normally used for ester alkaloids consisting of a so-called necine base and one or two necic acids. Thus, PAs may be represented by  

PAs have been detected in 16 angiosperm families (Convolvulaceae included) though often only sporadically occurring. They were most studied in the Asteraceae, Fabaceae, Boraginaceae, and Orchidaceae where they are also most frequent (Robins 1995 Hartmann and Ober 2000). More than 95% of the PA-containing species belong to these four families (Hartmann 1999). Some 360 different metabolites were already known in the early 1990s (Hartmann and Witte 1995). 

Two molecules of putrescine are incorporated into the necine bases, one of them via spermidine. Homospermidine synthase (HSS) catalyzes the first 

Thongh evidence for a general occurrence of homospermidine in plants is obvious as has been proven for many species from numerous angiosperm families including Datura stramonium L. and Nicotiana tabacum L. (Ober et al. 2003), most families including the Solanaceae do not synthesize PAs. 

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If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

In a more recent paper Menschikov assigns to trachelantamidine formula (VI, p. 611), which makes it structurally identical with iso-retronecanol (p. 609). He also provides experimental evidence for the view that trachelantic acid is 2-methyl-3 4-dihydroxypentane-3-carboxylic acid, Me CH. C(OH)(COjH). CHOH. CHg, and trachelanta-mine becomes C HjaN. CHaO. OC. C(OH)Pr. CHOH. CHg, C,HjaN being the pyrrolizidine residue (1947). 

Ill spite of their importance, basicity constants rarely figure in descriptions of alkaloids. Figures for a series of alkaloids and related substances were published by Kolthoff in 1925 and have been extensively used. Recently a few more have been added by Schoorl, and Adams and Mahan have provided figures for the whole group of necines, the amino-alcohols resulting from the hydrolysis of the pyrrolizidine group of alkaloids. ... 

Pyrrolizidine and indolizidine syntheses involving 1,3-dipolar cycloadditions 99S905. 

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. 

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 ... 

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... 

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

Thus the hydroxylactam 6 affords pyrrolizidine derivative 7 in high yield in a completely stereoselective fashion36. 

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. 

Die selektivc Reduktion von Cyan-dicarbonsaure-imiden untcr Erhalt der Cyan-Grup-pen ist mit Lithiumalanat nicht durchzufiihren8. Die Methode ist zur Herstellung von Ringsystemen mit Stickstoff als Briickenkopf-Atom (z. B. Pyrrolizidin, Indolizidin) besonders geeignet13. 

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

A review article is an intensive survey of a rather narrow field for example, the titles of some recent reviews are Desulfonation Reactions Recent Developments , Pyrrolizidine and Indolizidine Syntheses Involving 1,3-Dipolar Cycloaddtion , and From Corrin Chemistry to Asymmetry Catalysis—A Personal Account. A good review article is of enormous value, because it is a thorough survey of all the work done in the field under discussion. Review articles are printed in review journals and in certain books. The most important review journals in organic chemistry (though most are not exclusively devoted to organic chemistry) are shown in Table A.3. Some of the journals listed in Table A.l, for example, the Bull Soc. Chim. Fr. and J. Organomet. Chem. also publish occasional review articles. 

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]. 

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