Dart-poison frog alkaloids

Scheme 18.29 Allenic alkaloids isolated from the skin of Dendrobates poison-dart frogs .

The toxic alkaloids of poison dart frogs appear to depend on diet (Daly etal, 1994,2000 Caldwell, 1996). Details are described in Section 10.2.2. 

Daly, J. W, Garraffo, H. M., Spande, T. F., Jaramillo, C., and Stanley, R. A. (1994). Dietaiy source for skin alkaloids of poison dart frogs Dendrobatidae) Journal ofChemicalEcology 20,943-955. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

Epibatidine (5, Figure 11.5), a natural alkaloid isolated by Daly et al.55 from the Ecuadorian poison dart frog, Epipedobates tricolor, has recently proved that the proposed pharmacophores are not complete. Epibatidine is the most potent central nicotinic receptor ligand reported to... 

Synonyms Fhyllobates toxin Pitohui toxin Ifrita toxin poison dart frog toxin Chemical/Pharmaceutical/Other Class Steroidal alkaloid neurotoxin Chemical Formulas o Batrachotoxin C31H42N2O6 o Homobatrachotoxin C32H44N2O6 o Batrachotoxinin-A C24H35NO5... 

Several synthetic approaches toward the poison-dart frog alkaloids, including pumiliotoxin C (56), ge-phyrotoxin (57) and histrionicotoxin (58), have utilized the Eschenmoser reaction in a variety of distinct applications. These structurally related alkaloids are isolated from skin extracts of various Central and South American frogs in the Dendrohates genus and possess neurotoxic properties. Since their initial isolation and characterization, these toxins have attracted considerable attention for both their synthetic challenge and their interesting biological properties. ... 

The poison dart frogs of Central and South America store toxic substances such as the acetylenic alkaloid histrionicotoxin within their bodies to deter attacks by other animals. Histrionicotoxin disrupts neuromuscular transmission in animals through its interaction with receptors for the neurotransmitter acetylcholine. 

Rather than waiting to be attacked before launching a defense, poison dart frogs advertise themselves with bright colors. Potential predators recognize the threat these frogs present and avoid them. Frogs do not biosynthesize their alkaloids directly, but obtain them or their precursors from ants that they feed upon. The ants probably get their alkaloids from plants. 

Three calycanthine-type alkaloids, (—)-calycanthine (149) (the optical antipode of (+ )-calycanthine (150)), (—)-isocalycanthine (151), and we,so-chimonanthine (152) were isolated from Psychotria forsteriana, from New Caledonia, and complete and NMR assignments were reported (101). This represents the second isolation of the levorotatory isomer of calycanthine (the first was from Pausinystalia macroceras, Rubiaceae, (102)) as well as the first isolation of we,so-chimonanthine. (—)-Calycanthine and (+ )-chimonanthine (153) were also found to occur in the skin of the Colombian poison dart frog, Phyllobates terribilis (103). 

A synthesis of pumiliotoxin C, one of the arrow poison alkaloids isolated from the skin of Dendrobatespumilio, the strawberry poison dart frog, is shown in the following. Study it, and answer the questions posed ... 

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. 

Recently, two indole alkaloids, calycanthine and chimonanthine, and a piperidinyldipyridine alkaloid, noranabasamine (Fig. 26) were isolated as minor compounds in extracts from the Colombian poison-dart frog... 

Fig. 26. Structures of A chimonanthine, B calycanthine, and C noranabasamine Minor alkaloids isolated from skin extracts of the poison-dart frog Phyllobates terribilis (254). Structures are not intended to depict absolute configurations...

Daly, J. W., G. B. Brown, M. Mensah-Dwumah, and C. W. Myers Classification of skin alkaloids from neotropical poison-dart frogs (Dendrobatidae). Toxicon 16,163— 188 (1978). 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

The active principle of dart frog poisons is alkaloids. The study of the den-drobatid poisons led to the discovery of over 200 new alkaloids, including batrachotoxins Pig. 10.5), pumiliotoxins, histrionicotoxins, gephyrotoxins, and decahydroquinolines (Daly et al., 1994). The most common compounds have the basic structure of piperidine and include histrionotoxin. In Phyllobates, the synthesis of other alkaloids is suppressed in favor of batrachotoxins. These are... 

Batrachotoxin A (III), just one of many steroidal alkaloids, is one of the most lethal substances known (LD50 = 2/xg/kg subcutaneously in mice). It is found in the skin secretions of the brightly colored tropical frog Phyllobates aurotaenia and is used by Colombian Indians to prepare poison darts. 

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