Pyrrolizidines isolation

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

Xia et al. reported on the metabolism of lasiocarpine (prototype heliotridine pyrrolizidine alkaloids) by F344 rat liver microsomes, and isolated 6,7-dihydro-7-hydroxy-l -hydroxymcthyl-5//-pyrrolizinc (DHP)-derived DNA adducts, thus showing the potential use of such DHP-derived DNA adducts as biomarkers of exposure and tumorigenicity for all pyrrolizidine alkaloids <2006MI1001-02>. 

In an effort to identify possible sources of the 16 alkaloids found in the skin of the Panamanian poison frog Dendrobates auratus, ants from a total of 61 terrestrial nests were analyzed [124]. The alate queens of one species of myr-micine ants (Solenopsis (Diplorhoptrum) sp.) collected at Cerro Ancon were found to contain the decahydroquinoline (-)-ds-195A (112) which was also present as a minor alkaloid in the skin of the microsympatric population of D. auratus. Moreover, from wingless ants of two nests collected at Isla Taboga and identified as Megalomyrmex silvestrU the same workers isolated the stereo-isomeric 3,5-disubstituted pyrrolizidines rfs-251 K (117) and trans-251 K (118) in the same ratio 3 1 that was present in the skin of a microsympatric population of D. auratus (Fig. 20) [124]. 

This compound exhibits the same relationship to (3-D-fructofuranose as 1-deoxy-nojirimcin does to D-glucopyranose. In 1979, a polyhydroxyindolizidine alkaloid was isolated from the poisonous fruit of Castanospermum australe, a handsome Australian indigenous tree, and coined castanospermine (8) after its source.28 A compound subsequently isolated from the seeds of this plant was the pyrrolizidine australine (9),29 also found in Alexa leiopetala,30 along with other compounds. These discoveries increasingly supported the hypothesis that imino sugars and their structural relatives might be a fairly common family of natural products, and their widespread... 

A related oxime 304 was prepared for the total synthesis of 305, an unusual pyrrolizidine alkaloid isolated from the venom of a variety of thief ant... 

Pandey and Lakshmaiah (10) further extended their methodology to the construction of the indolizidine and pyrrolizidine bicyclic skeleta. The basic precursor 41, which was realized in three straightforward steps, underwent double desilyation and subsequent cycloaddition with ethyl acrylate to furnish the two regioisomers 42 and 43 in essentially quantitative yield and in a 17 3 ratio. The major regioisomer was isolated in a 7 3 endo/exo ratio. Further elaboration of the major products where (n=l) and (n = 2) delivered the natural products... 

LDA was used in the cyclization of tosylate 9, an intermediate in the synthesis of the pyrrolizidine alkaloid (+)-retronecine, which was prepared from (+ )-(7 )-malic acid in nine steps. The tricyclic lactone 10 was isolated in 53% yield70. 

Isolation of a lactone, structurally related to the esterifying acids of pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae. Journal of Chemical Ecology 2 263-270. 

A new synthesis of pyrrolizidine, which is based on the reaction of bis-tertiary glycols with co-chloronitriles, was reported by Meyers and Libano.28 The method involves three steps (a) condensation of 2,5-dimethyl-2,5-hexanediol (48) with 4-chlorobutyronitrile in the presence of sulfuric acid to give a derivative of A 1-pyrroline (49), (6) reduction of 49 with sodium borohydride to give the corresponding pyrrolidine (50), and (c) intramolecular cyclization of the pyrrolidine in the presence of alkali to give the pyrrolizidine derivative 51. The three-step synthesis was performed without isolation of the intermediate products. 

Biogenetic pathways leading to naturally occurring pyrrolizidine bases were proposed by Robinson, Schopf, and Lukefi (see, e.g., refs. 119-121) in their publications concerned with the biogenesis of alkaloids. The most probable precursors of the pyrrolizidine system are commonly accepted to be ornithine (176), hydroxyomithine (177), and their biogenetic equivalents. It is noteworthy that ( + )- -hydroxy-jV-methylnorvaline (178) (structurally related to ornithine) was isolated... 

A Papua New Guinea sponge, Pseudoceratina sp., contains the unusual alkaloids ceratamines A (1142) and B (1143), and a biogenesis involving histidine and tyrosine is proposed (1173). The fermentation broth from Aspergillus fischeri var. thermomutatus has yielded CJ-12662 (1144) and UK-88051 (1145) (1174). The former metabolite was confirmed by X-ray spectroscopy and partial synthesis. A marine-derived Streptomyces sp. produces the novel pyrrolizidine 5-chlorobohem-amine C (1146), which was shown not to be an isolation artifact (1175). The Chinese medicinal plant Huperzia serrata has furnished 2-chlorohyperzine E (1147) (1176). 

Five new pyrrolizidine alkaloids, each containing a novel fourteen-membered macrocyclic ring, have been isolated by Edgar et al.x Parsonsine (44) and heterophylline (45) were present in Parsonsia heterophylla A. Cunn. and P. spiralis Wall., while spiraline (46), spiranine (47), and spiracine (48) were obtained only from P. spiralis. These five alkaloids are derived from retronecine that is esterified at C-9 with (-)-trachelanthic acid i.e. indicine), and further diesterified by a series of substituted malic acid derivatives to complete the fourteen-membered ring. Indeed, partial hydrolysis of parsonsine (44) yielded indicine (49). The non-equivalence of the C-9 protons (ABq, S 4.45 and 5.20 p.p.m.) in parsonsine indicates the presence of a macrocyclic system, and... 

Russian comfrey (Symphytum x uplandicum Nyman) is widely recommended as a medicinal herb and an item of human diet. A previous investigation of this species led to the isolation of three alkaloids which were not fully characterized (cf. Vol. 7, p. 57). Culvenor and co-workers have separated eight pyrrolizidine alkaloids from the leaves of this perennial plant by counter-current distribution.21 The known alkaloids echimidine (51), symphytine (52), lycopsamine (53), and intermedine (54) were present. In addition, four new alkaloids, i.e. 7-acetyl-lycopsamine (55), 7-acetylintermedine (56), symlandine (57), and uplandicine (58), were characterized by spectroscopic methods, and by hydrolysis. The total alkaloidal extract caused chronic hepatotoxic effects in rats, and the authors... 

Two epimeric antibiotics with a pyrrolizidine ring system, clazamycins A (70) and B(71), have been isolated from a Streptomyces species.41 Clazamycin B (=antibiotic 354) is also present in S. puniceus ssp. doliceus.42 The structure of clazamycin A was established by determining the X-ray crystal structure of its hydrochloride salt.43... 

Over seven-hundred references are concerned with the isolation and chemistry of alkaloids, and approximately one-third of these are devoted to synthesis and biosynthesis. It is perhaps in these areas that the most notable research is to be found. Although it is probably invidious to attempt the exercise, a personal selection of highlights would include new results on the biosynthesis of quinoliz-idine alkaloids (p. 4), the first synthesis of an eleven-membered macrocyclic pyrrolizidine diester (p. 49), the synthesis of Poranthera alkaloids (p. 68), and, in the indole field, the synthesis of tryptoquivalines G and L (p. 152), of a chiral intermediate in the construction of heteroyohimbine alkaloids (p. 167), and of a catharanthine intermediate, using palladium catalysts (p. 186). 

Cyclopropanone equivalent. Unlike cyclopropanone, which is difficult to isolate, 1 is stable, easily obtained from 3-chloropropionic acid (Aldrich), and is a useful substitute for the ketone. Thus reaction of the silyl ether 2 with RMgBr provides adducts in which the OH group of 1 is replaced by R. The carbinol 1 is also a useful precursor to pyrroles, pyrrolines, and pyrrolizidines (equation I). 

Workers in Australia, where chronic liver disease of sheep has been related to pyrrolizidine alkaloid intake (173), have isolated microorganisms from sheep rumen capable of reductive cleavage of the side-chain ester function of heliotrine (161), supinine (163), heleurine (164), and europine (165) (165,166). In the earlier report (765), a small gram-negative coccus... 

The simple necine bases loline (18), norloline (19), and lolinine (20) have been identified previously from Lolium cuneatum Nevski.7 Further investigations on the seeds of this plant by Russian workers have established the presence of four new alkaloids. N-Formylnorloline (21),8 JV-methyl-loline (22), JV-acetylnorloline (23), and AT-formyl-loline (24)9 have been identified. In addition, a novel dimeric pyrrolizidine alkaloid, lolidine, containing chlorine, was isolated in trace amounts (7 mg from 10 kg of seeds). The structure (25) has been suggested for lolidine on the basis of spectral data.10... 

Pyrrolizidine alkaloids are included in a list of alkaloids that have been isolated from the Compositae.23 All reports this year are concerned with the tribe Sene-cioneae. Definite identification of pyrrolizidine alkaloids from two new genera,... 

Heliotridane (11) and ( )-pseudoheliotridane (12) have been isolated previously as degradation products of pyrrolizidine alkaloids. Miyano and co-workers have prepared mixtures of these compounds by reduction of the unsaturated pyrrolizidine (10) (Scheme 3).7 Catalytic hydrogenation of (10) (containing 10% of the A7,8-isomer) gave ( )-heliotridane (11) of 93% isomeric purity, while reduction of (10) with formic acid yielded ( )-pseudoheliotridane (12) with 66% isomeric purity. 

A new type of pyrrolizidine alkaloid has been isolated from the leaves of Ehretia aspera Willd. by Suri et al.n The structure (39) for ehretinine was established by spectroscopic evidence and by hydrolysis to give retronecanol and p-methoxy-benzoic acid. Confirmation of the structure (39) was obtained by synthesis of ehretinine from retronecanol and pmethoxybenzoyl chloride. This is the first reported occurrence of a retronecanol ester, although it should be pointed out that retronecanol esters can be produced by hydrogenolysis of retronecine diesters. The authors do not appear to have considered the possibility that ehretinine could have been formed by hydrogenolysis of the common type of ester (40) on treatment with the zinc and sulphuric acid that are used in their extraction procedure. 

A chemotaxonomic study of the pyrrolizidine alkaloids present in the subfamilies Heliotropioideae and Boraginoideae has been carried out, using t.l.c.19 No alkaloids were identified. Lycopsamine (41) and 9-angelylretronecine have been isolated from Messerschmidia sibirica.20 9-Angelylretronecine has only been found previously in Bhesa archboldiana (Celastraceae).21 Heliotrine A-oxide is present in Heliotropium ramosissimum.22 A full paper describing the alkaloids identified in H. curassavicum... 

Eupatorieae Tribe.—Nine Eupatorium species that are found in the U.S.A. have been screened for pyrrolizidine alkaloids by Herz et al.2i Intermedine (42) (crystalline for the first time) and echinatine were isolated from Conoclidium coelestinum (L.) DC. (syn. Eupatorium coelestinum L.). Intermedine (42) and lycopsamine (41) were present in E. compositifolium Walt. These diastereoisomeric diols were separated as their borate complexes.29 Rinderine and 7-angelyl-heliotridine (43) were isolated from E. altissimum L.28... 

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