Dendrobates histrionicus

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... 

Gephyrotoxins are unique in Nature to amphibians and, indeed, occur only in certain populations of the extremely variable Colombian poison frog, Dendrobates histrionicus (1). Gephyrotoxin might be derived by cyclization of a c/.r-decahydroquinoline having a trans orientation of the... 

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 is a defensive toxin that protects Dendrobates histrionicus from potential predators. These small poison dart frogs inhabit the moist humid floor of tropical rainforests, and are commonly found in western Ecuador and Colombia. Histrionicotoxin acts by interfering with nerve transmission in mammals, resulting in prolonged muscle contraction. 

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. 

Malassene and co-workers recently examined the application of the Thorpe-Ziegler cyclization for synthesis of perhydrohistrionicotoxin, a skin extract of the Colombian poison arrow frog, Dendrobates histrionicus. Under standard conditions, dinitrile 37 was directly converted into spiropiperidine 38 through the Thorpe-Ziegler cyclization, completing construction of the carbon framework of perhydrohistrionicotoxin. 

Alkynes are less common in nature than alkenes, although more than 1000 different alkynes have been isolated from natural sources. One such example is histrionicotoxin, which is one of the many toxins secreted by the South American frog, Dendrobates histrionicus, as a defense against predators. For many centuries. South American tribes have extracted the mixture of toxins from the frog s skin and placed it on the tips of arrows to produce poison arrows. 

---