Dendrobatide

The batrachotoxins were the first class of unique alkaloids to be characterized from skin extracts of frogs of the family Dendrobatidae (see ref. 23 for a review of amphibian alkaloids). Batrachotoxin was detected in only five species of dendrobatid frogs and these frogs were then classified as the monophyletic genus Phyllobates, based in part on the presence of batrachotoxins (24). However, levels of batrachotoxins differ considerably, with the Colombian Phyllobates terribilis containing nearly 1 mg of batrachotoxins per frog, while the somewhat smaller Phyllobates bicolor and Phyllobates aurotaenia, also from the rain forests of the Pacific versant in Colombia, contain 10-fold lower skin levels (8). The two... 

Two classes of dendrobatid alkaloids have potential dietary sources. The first are the pyrrolizidine oximes (32), whose carbon skeleton is identical to that of nitropolyzonamine, an alkaloid from a small millipede (33). Indeed, raising the dendrobatid frog D. auratus in Panama on leaf-litter arthropods, gathered weekly, resulted in skin levels of the... 

The proposal that all alkaloids found in skin glands of dendrobatid frogs and used in chemical defense against predators have a dietary origin leads to many questions. First, the profile of alkaloids has been found in many instances to be characteristic of a species or a population. 

Frogs of the genus Dendrobates are ant specialists. Of the more than 20 structural classes of lipophilic alkaloids found in the frogs, six occur in myrmicine ants. However, many dendrobatid alkaloids such as the batrachotoxins, histri-onicotoxins, and pumiliotoxins, have not yet been found in insects and other leaf-litter prey such as beetles and millipedes (Daly et al., 2000). The snake Lio-phis epinephelus feeds on Dendrobates and may further bioaccumulate alkaloids. 

Daly, J. W, Garaffo, H. M., Jain, P., etal. (2000). Arthropod-frog connection decahydro-quinoline and pyrrolizidine alkaloids common to microsympatric myrmicine ants and dendrobatid frogs. Journal of Chemical Ecology 16,73-85. 

Takada, W., Sakata, T., Shimano, S., Enami, Y., Mori, N., Nishida, R. and Kuva-hara, Y. 2005. Scheloribatid mites as the source of pumiliotoxins in dendrobatid frogs. Journal of Chemical Ecology, 31 2403-2415. 

A stereoselective total synthesis of dendrobatide toxin 251 D was developed by Overman et al.237) involving an epoxidation of the (S)-proline derivative (237) to furnish the oxirane (238) as major product. In their approach towards the total synthesis of the same natural product Thomas et al.238) investigated the stereoselectivity of the epoxide formation from (S)-5-acetylpyrrolidin-2-one and dimethyloxosulfonium methylide. A diastereoselectivity of d.s. 50-60% was achieved 238. ... 

First Enantioselective Synthesis of Dendrobatid Alkaloids Indolizidine 2091 and 223J 53... 

Sundarababu Baskaran of -Madras offers (Organic Lett. 5 583,2003) an alternative route to indolizidines. Exposure of the epoxide 7 to Lewis acid followed by reduction leads to 11 as a single diastereomer. The authors hypothesize that this rearrangement is proceeding via intermediates 8 -10. Tosylation of 11 followed by homologation leads to the Dendrobatid alkaloid 12. 

The Dendrobatid poison arrow frogs of Central and South America exude a potent mixture of alkaloids from their skins. It was originally thought that the frogs biosynthesized these alkaloids, but it has since been shown that they are of dietary origin. The skin exudate of the Colombian frog Minyobates bombetes causes severe locomotor difficulties, muscle spasms and convulsions upon injection in mice. The major component of the alkaloid mixture is 251F3. Jeff Aube of the University of Kansas recently described (J. Am. Chem. Soc. 2004,126,5475) the enantioselective total synthesis of 3. The key step in the synthesis was the cyclization of the keto azide 2. 

Deacetoxyalcyonin acetate synthesis 76 Dendrobatid alkaloid 25 IF synthesis 112, 168... 

ASIDE Alkaloid toxins found in dendrobatid frogs... 

There is some controversy as to whether the frogs produce the toxins themselves as secondary metabolites or whether they are simply processing their food - ants. Dendrobatid frogs raised in captivity lose their toxicity. In fact, chemical analyses of ants similar (but not identical) to those found in the natural habitat show compounds structurally related to the toxins. 

Daunomycinone, 254, 255 Debenzylation, 532 Debromination, 276, 548, 599 Decarboalkoxylation, 301 Decarboraethoxynauclechine. 185 Decarbonylation, 393 Decarboxylation-carbonylation, 392 Dehydroamination, 502 Dehydroamino acids, 6-7 Dehydrocyanation, 173 Dehydrosulfiiration, 62 Dehydroxylation, 127 Dendrobatid toxins, 43 Dendrolasin, 419 Denitration, 547 Deoxoprosophylline, 315 11-Deoxyanthracycline, 113 11-Deoxydauomycinone, 85 Dcoxyfrenolicin, 357 14-Deoxymuristerone, 127... 

Dendrobatid toxins. The first step in a synthesis of ( )-perhydrogephyrotoxin (S, a poison-frog alkaloid) involves a Diels-Alder reaction of 1 and a suitable a.ft-unsulurated aldehyde, which proceeds selectively to give the erafo-adduct 2. Another key step is the selective reduction of a bicyclic imine (3) with LiAlH4 in about 9 1 ratio from the sterically more hindered a-face.2... 

The dendrobatid alkaloid 251F 213 (Figure 12.4) was isolated from the skin exudates of a Columbian dendrobatid poison frog, Minyobates bombetes [105]. The asymmetric total synthesis of this molecule has been reported by Aube and co-workers [106], The synthesis featured a Noyori-type three-component reaction to access an advanced bicyclopentenone intermediate, and also included a tandem ROM/RCM reaction sequence and a Schmidt rearrangement as key steps. 

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