Macrocyclic pyrrolizidine alkaloids

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). 

Adenostyles and Doronicum, is of chemotaxonomical interest. Pimenov et ai24 have studied the variation in alkaloid content of subspecies of A. rhombifolia (Willd.) Pim. All plants contained varying amounts of platyphylline (42), sene-ciphylline (43), and sarracine. Platyphylline and seneciphylline were also extracted from the roots of A. alliariae.25 The genus Adenostyles has been classified by some taxonomists in the tribe Eupatorieae, but its content of macrocyclic pyrrolizidine alkaloids is in accord with its current position in the Senecioneae. 

Fig. 13.8 General structures of some pyrrolizidine alkaloids. A Pyrrolizidine alkaloid esters, B 1,2-dehydro pyrrolizidine alkaloid esters, C the N-oxide of 1,2-dehydro pyrrolizidine alkaloid esters, and D an otonecine-based alkaloid. Ri and R2 can be H or esters of carboxylic acids that may or may not be cyclized forming a macrocyclic diester.

This procedure was developed by Yamaguchi and coworkers [36]. Yamada and coworkers [37] applied it to the synthesis of the macrocyclic pyrrolizidine alkaloids ( — )-integemmine and (—)-monocrotaline. For instance, in the synthesis of (—)-integerrimine 58) [37a], treatment of seco acid 56 with 1.1 equiv of... 

Morphinan and related compounds, synthesis of 88YGK626. Macrocyclic pyrrolizidine alkaloids, total synthesis of 88YGK693. Pyrrolizidine alkaloids, syntheses of 87YGK873 89CSR375,89YZ345, 89YZ685 90H(30)1231, 90MI58. 

The outstanding highlights of this year s work are undoubtedly the long-awaited first successful syntheses of macrocyclic pyrrolizidine alkaloids. Devlin and Robins have prepared (+)-dicrotaline... 

Previous investigations of Tussilago farfara L. (coltsfoot) have yielded two macrocyclic pyrrolizidine alkaloids, senecionine and... 

Segall, H.J., Wilson, D.W., Dallas, J.L. and Haddon, W.F. (1985) /ra/w-4-Hydroxy-2-hexenal a reactive metabolite from macrocyclic pyrrolizidine alkaloid senedonine. Science 229, 472-475. 

Edgar, J. A., N. J. Eggers, A. J. Jones, and G. B. Russell Unusual Macrocyclic Pyrrolizidine Alkaloids from Parsonsia heterophylla A. Cunn and Parsonsia spiralis Wall. (Apocynaceae). Tetrahedron Lett. 1980, 2657. 

Tashkhodzhaev, B., M. V. Telezhenetskaya, and S. Yu. Yunusov Crystal and Molecular Structure of the Macrocyclic Pyrrolizidine Alkaloid Incanine. Khim. Prir. Soedin. 1979, 363 [Chem. Abstr. 92, 111199 (1980)]. 

Devlin, J. A., and D. J. Robins Synthesis and Stereochemistry of Dicrotaline, a Macrocyclic Pyrrolizidine Alkaloid. J. Chem. Soc., Chem. Commun. 1981, in the press. 

Huang, J., and J. Meinwald Synthesis of Crobarbatine Acetate. A Macrocyclic Pyrrolizidine Alkaloid Ester. J. Am. Chem. Soc. 103, 861 (1981). 

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... 

A different type of macrocyclic diester has been prepared by Drewes and Pitchford.17 They coupled the dipotassium salt of retronecic acid with 2,6-bis(bromomethyl)pyridine to give a 9.7% yield of pyridine-retronecate (38). The authors claim that this product contains many of the characteristics responsible for the toxicity of pyrrolizidine alkaloids. However, the results of their biological tests with (38) on mice were inconclusive. 

Careful analysis of M S and the MS/MS data for the major components of S. ovatus identified sarradne-related alkaloids. For example, the molecular ion data for peak 7 (Figure 13.14) (MH m/z354) potentially corresponded to the N-oxides of several 1,2-saturated, macrocyclic or open chain diester pyrrolizidine alkaloids previously... 

The crystal structures of pyrrolizidine alkaloids that have been determined may be divided into structural groups on the basis of the necine they contain. Alkaloids with retronecine (127) as base are fulvine and axillarine, which both have an 11-membered macrocyclic diester ring, and jacobine and swazine, which contain 12-membered diester rings. Heliotrine is a C-9 monoester of heliotridine (109). Retusamine, clivorine, and senkirkine, all include otonecine (125) as the base portion. The alkaloids... 

Macrolide-producing organisms are classified as shown in Table 11. Actino-mycetes produce the largest number of macrolides (more than 800). Myxobacte-ria produce about 100 macrolides, and the other bacteria produce about only 40 macrolides. A rather large number of macrolides have been isolated from fungi (about 200). Lichens produce only three compounds. About 70 macrolides have been isolated from algae. Though plants produce about 700 macrocyclic lactone compounds, most of them are tannins or alkaloids such as pyrrolizidines. So they... 

Some alkaloids have macropolylide skeletons in their structures in particular, many pyrrolizidine alkaloids have structures with each pyrrolizidine skeleton fused to a macrocyclic dilactone or trilactone [169]. Crotalarine (Fig. 25,141) is a 10-membered ring macrodiolide isolated from Crotalaria burhia [170]. Seneci-phylline (142) is a 12-membered ring macrodiolide isolated from Senecio spp. 

We have recently explored the application of glass capillary gc to trimethylsilyl (tms) ether derivatives of pyrrolizidine alkaloids. The high resolution capabilities of capillary columns offered promise in separating the complex and closely related alkaloid mixtures often encountered in plant extracts. The gc trace shown in Figure 5 illustrates the application of a capillary system to a mixture of tms-ethers of the 12 pure macrocyclic di-ester alkaloids shown in Figures 2 and 3. 

There is no uniform classification for the A. In the literature divisions according to origin (examples Aconitum, Amaryllidaceae, Aspidosperma, cactus, Catharanthus, Cephalotaxus, Cinchona, coca, Corydalis, curare, Dendrobates, ergot, Erythrina, Iboga, Lycopodium, Maytenus, opium, Rauvol-fia, Senecio, Strychnos, tobacco, Vinca alkaloids, salamander, Solanum, Veratrum steroid alkaloids) in addition to divisions according to chemical structure (examples aporphine, benzylisoquinoline, bis-benzylisoquinoline, berberine, carboline, diterpene, inudazole, indole, indolizidine, isoquinoline, lupinane, macrocyclic, morphine, peptide, / -phenyl-ethylamine, piperidine, purine, pyridine, pyrrolidine, pyrrolizidine, quinoline, quinolizidine, quinucli-dine, spermine, spermidine, steroid, terpene, tro-pane, tropolone alkaloids) are used. 

GC of pyrrolizidine alkaloids was extensively investigated by Chalmers et al. (1965) using packed columns. They described the analysis of 58 underivatized monocarboxylic acid esters and macrocyclic diester alkaloids and derivatives. 

Dimenna GP, Krick TP, Segall HJ (1980) Rapid high-performance liquid chromatography isolation of monoesters, diesters and macrocyclic diester pyrrolizidine alkaloids from Senecio jacobaea an Amsinckia intermedia. J Chromatogr 192 474-478 Edgar JA, Culvenor CCJ (1974) Pyrrolizidine ester alkaloid in danaid butterflies. Nature 248 614-616... 

Pyrrolizidine alkaloids (PAs) belong to a class of naturally occurring compounds characterized by a bridged dipyrrole structure. They encompass more than 400 different structures, which consist of a necine base of type 25 that may also be saturated between carbons 1 and 2 and esterified with one or more necic acids which exist as 5-11 carbon membered types (Figure 5.25). Thus, there are monosters such as supi-nine 27, indicine 28 obtained from retronecine 25a, and (-)-trachelanthic acid 26. Heliosupine 29 is an example of an open-chain diester, and retrorsine 30 is, instead, a macrocyclic diester. PAs are constitutively produced by the plant and are believed... 

Figure 5.25 Pyrrolizidine alkaloids structure of necine base 25, trachelanthic acid 26, a necic acid supinine 27 and indicine 28, monoester pyrrolizidine alkaloids heliosupme 29, a diester pyrrolizidine alkaloid retrorsine 30, a macrocyclic diester pyrrolizidine alkaloid senecionine N-oxide 31, a non-toxic pyrrolizidine alkaloid.

Pyrrolizidine alkaloids (PAs) contain two fused five-membered rings in which a nitrogen atom is coirunon to both rings. The precursor is ornithine. A hydrogen atom nsnally occurs opposite the nitrogen atom in the a position, with a hydroxymethyl substitute at the adjacent C-1 position. Most pyrrolizidines have diester groups at C-1 and C-7—these may be non-cyclic, for example echimidine, or macrocyclic, for example senedonine. Toxicity (see below) appears to be mainly linked to the macrocyclic diester type (Denham 1996). The alkaloids also occur as water-soluble nitrogen oxides. 

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