Dendrobates histrionicus alkaloids

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

Decahydroquinolines are another important class of alkaloids isolated from the skin of tropical frogs. Frogs of the family Dendrobates pumilio produce highly toxic alkaloids, the pumiliotoxins [58]. Pumiliotoxin C, one of the prominent members of this class of compounds, has a ds-annulated decahydroquinoline structure, whereas toxins of the related family of Dendrobates histrionicus have fraras-annulated decahydroquinoline structures [49]. These decahydroquinoline systems can be synthesized from the galactosylamine auxiliary 2 in a 12-step pathway(see Scheme 33) [59]. 

An unusual acetylenic alkaloid, gephyrotoxin, has been isolated from skin extracts of the Colombian frog Dendrobates histrionicus, and it has been shown tobe[lS,3a5,5a5,65(Z),9ai ,10/ ]-dodecahydro-6-(pent-2-en-4-ynyl)pyrrolo[l,2-a]quinoline-l-ethanol (5) by X-ray crystal structure analysis of gephyrotoxin... 

The histrionicotoxins probably represent the first examples of the occurrence of the acetylene and allene moieties in the animal kingdom. They presented the opportunity to establish the bond lengths and angles for these unsaturated moieties in the crystalline state. Subsequently, other alkaloids occurring in smaller quantities in the skins of Dendrobates histrionicus were shown, by means of mass spectra and NMR spectra, to be dihydro-, tetrahydro-, octahydro-, neodihydro-, allodihydro-, and allotetrahydro-histrionicotoxins, among others (36). The congeners differ only in the... 

Histrionicotoxins were first discovered in the extremely variable dendrobatid species Dendrobates histrionicus of western Colombia and northwestern Ecuador (54). Histrionicotoxin (238A), allodihydrohistrionico-toxin (285C), and isodihydrohistrionicotoxin (285A) represent major alkaloids in nearly all populations of this species (1,71). In one population from northwestern Ecuador, octahydrohistrionicotoxin (291A) is a major alkaloid (71), whereas in one population from the lower Rio San Juan... 

In dendrobatid frogs, pyrrolidines have been detected only in certain populations of Dendrobates histrionicus and Dendrobates pumilio (/). Pyrrolidine trans-iSH is the only pyrrolidine to occur as a major alkaloid, and it appears only in the most northern populations of Dendrobates histrionicus. In nondendrobatid frogs, 2,5-disubstituted pyrrolidines have not been detected. 

Piperidines, like pyrrolidines, appear to have a very limited distribution in dendrobatid frogs. Piperidine 241D occurs as a major alkaloid in one population of Dendrobates speciosus and as a trace alkaloid in a population of Dendrobates pumilio (1). 2,6-Disubstituted piperidines 225B and 2391 have been detected as trace alkaloids in Dendrobates histrionicus (two populations) and Epipedobates trivittatus (one population), respectively (1). In nondendrobatid frogs, 2,6-disubstituted piperidines have not been detected. 

At present there are not sufficient data to formulate structures for 283B and 2 C, which were major alkaloids in one population of Dendrobates histrionicus, and in a sympatric sister species, Dendrobates occultator (60). 

Histrionicotoxin, one of the spiropiperidine alkaloids from the skin of the Colombian frog Dendrobates histrionicus, containing two c/s-but-3-en-l-yne groups, is the first acetylenic alkaloid and also the first acetylene of animal origin. (The acid 12, present in the secretion of the soldier beetle, ChauHognatus lecontei. ... 

The 2,6-dialkyl piperidines 212 and 213 have been detected in Dendrobates histrionicus and Dendrobates trivittatus, respectively [488]. Alkaloid 241D (211) was isolated from Dendrobates speciosusand its structure determined by HRMS, CIMS, and one- and two-dimensional Iff NMR [489]. The structure of 211 was confirmed in a two-step synthesis via condensation of 3-penten-2-one, decanal, and ammonia, followed by sodium borohydride reduction [490]. 

The first total synthesis of racemic histrionicotoxin (58), the parent structure in a family of related spirocyclic alkaloids isolated from the skins of Dendrobates histrionicus, utilized the Eschenmoser reaction to generate the anchor of what would become the enyne group extending from the a-position of the piperidine nucleus. The spirothiolactam intemiediate (77) was condensed with ethyl 2-bromoace-toacetate in the presence of sodium bicarbonate to produce (78) in good yield (Scheme 18). Prior to further reaction on the vinylogous carbamate, the pendent allylic acetate was elalx>rated to the enyne (79). Subsequent deacylation and enyne protection yielded spirobicycle (80), which gave a 1 1 mixture of isomers upon reduction. The desired diastereomer (81) was isolated and subsequently converted to racemic histrionicotoxin (58). 

Details of the X-ray crystallographic determination of the structure of dihydro-isohistrionicotoxin (17), a unique spiropiperidine alkaloid from the Colombian frog Dendrobates histrionicus, have appeared. 

T. Fukuyama, L. V. Dunkerton, M. Aratani, and Y. Kishi, ibid., 40, 2011 (1975). Histrionicotoxins are toxic alkaloids from the venom of the frog Dendrobates histrionicus they inhibit the cholinergic receptor. 

Histrionicotoxin (HTXs) are a family of spirocyclic piperidine alkaloids that were isolated in 1971 from the Colombian frog Dendrobates histrionicus. HTX and its analogs have generated considerable pharmacological interest as... 

B is an alkaloid isolated from skin extracts of high and low elevation populations of poisonous frog Dendrobates histrionicus These alkaloids show a wide spectrum of biological activity including most importantly antibiotic and hemolytic property. But the biological properties of most members of this family remain anonymous as they are isolated from the natural source in very small... 

Histrionicotoxins. Another poison frog, Dendrobates histrionicus occurred sympatric with the poison-dart frog Phyllobates aurotaenia in Western Colombia. Preliminary studies based primarily on mass spectrometry of compounds isolated by thin-layer chromatography, indicated the presence of another class of relatively simple alkaloids in extracts from a few specimens of this species. Three major alkaloids were later isolated from skin extracts of a population of Dendrobates histrionicus from southwestern Colombia and the structures of two of these were reported in 1971 (81). The compounds were unique spiropiperidine alkaloids with remarkable acetylenic and allenic centers of unsaturation in the side chain substituents. The parent compound was named histrionicotoxin after the specific name of the frog Dendrobates histrionicus from which it was first isolated. A number of histrionicotoxins were subsequently isolated and structurally defined 86, 253). Like pumiliotoxin C, the histrionicotoxins exhibit relatively low toxicity to mammals. 

Gephyrotoxins. One of the major alkaloids from Dendrobates histrionicus proved to be not a histrionicotoxin but instead a tricyclic alkaloid... 

Some of these compounds have been isolated in sufficient quantities for partial characterization by nuclear magnetic resonance spectroscopy. These include three trace compounds designated I, II and III which were isolated from extracts of some 3200 skins of Dendrobates histrionicus (86). All three compounds were bicyclic and based on the mass spectra and proton resonance spectra were proposed to be members of the pumiliotoxin-C class (cw-decahydroquinolines) of alkaloids. 

DihydroHTX was previously referred to as syn-dihydroHTX (253). It was first prepared by partial reduction of histrionicotoxin, but has now been isolated as a trace alkaloid from Dendrobates histrionicus, Guayacana, Narino, Colombia (255). The spectrum (100 MHz) of iso-dihydrohistrionicotoxin is depicted in Fig. 11. The spectrum (100 MHz) of allodihydroHTX is depicted in (86). Assignments of the protons to side chains of octahydroHTX are arbitrary with respect to R and R and may be reversed. 

Histrionicotoxin has similar effects in neuromuscular preparations from Rana pipiens and from the frog Dendrobates histrionicus, which produces the alkaloid 10). Muscle contractions are potentiated and muscle action potentials prolonged in both species, but blockade of neuromuscular transmission requires higher concentrations in the Dendrobates than in the Rana. Thus, whatever the site of action of histrionicotoxin it is retained in the frog that produces the alkaloid. It should be pointed out that histrionicotoxin has very low toxicity and that the toxin designation is indeed a misnomer. Thus, the dendrobatid frog probably has no reason to completely protect itself from the action of this class of alkaloids. 

Daly, J. W., I. Karle, C. W. Myers, T. Tokuyama, J. A. Waters, and B. Witkop Histrionicotoxins Roentgen-ray analysis of the novel allenic and acetylenic spiro-alkaloids isolated from a Colombian frog, Dendrobates histrionicus. Proc. Nat. Acad. Sci. (USA) 68, 1870—1875 (1971). 

Tokuyama, T., K. Uenoyama, G. Brown, J. W. Daly, and B. Witkop Allenic and acetylenic spiropiperidine alkaloids from the neotropical frog, Dendrobates histrionicus, Helv. Chim. Acta 57, 2597—2604 (1974). 

Pumiliotoxins and/or allopumiliotoxins are major alkaloids in most species of the dendrobatid genus Dendrobates (1). The exceptions are a few populations of D. pumilio, one population of D. auratus, all the populations of D. histrionicus except those north of or in the Rio San Juan drainage, and D. occultator and D. truncatus. In the dendrobatid genus Epipedobates, pumiliotoxins and/or allopumiliotoxins are major alkaloids in 4 of the 11 species examined, namely, E. erythromus, E. espinosai, E. silverstonei. 

---