Poisonous frogs

A novel splropentanopyrrolmdine oxime has been isolated from skin extracts of the Panamanian poison frog. This alkaloid can besynthesized via the Michael addi don of cyclop en-tanecarboxaldehyde to nitroethene fScheme 10.19. ... 

The decahydrocyclazine skeleton is also found in the alkaloid 395, currently known only by the designation 261C. This compound bears a passing resemblance to some of the myrmicarins (Section 16.6.5.2), but occurs in the skin of a totally different animal species, namely poisonous frogs of the genus Mantella <2003H(59)745>. 

In an effort to identify possible sources of the 16 alkaloids found in the skin of the Panamanian poison frog Dendrobates auratus, ants from a total of 61 terrestrial nests were analyzed [124]. The alate queens of one species of myr-micine ants (Solenopsis (Diplorhoptrum) sp.) collected at Cerro Ancon were found to contain the decahydroquinoline (-)-ds-195A (112) which was also present as a minor alkaloid in the skin of the microsympatric population of D. auratus. Moreover, from wingless ants of two nests collected at Isla Taboga and identified as Megalomyrmex silvestrU the same workers isolated the stereo-isomeric 3,5-disubstituted pyrrolizidines rfs-251 K (117) and trans-251 K (118) in the same ratio 3 1 that was present in the skin of a microsympatric population of D. auratus (Fig. 20) [124]. 

Figure 8 Venomous animals with chemotherapeutic potential, (a) Vampire bat (Desmodus rotundas (http // www.Animalpicturesarchive.com)) (b) medicinal leech [Hirudo medicinalis)-, (c) oriental fire-bellied toad (Bombina orientalis)-, (d) phantasmal poison frog [Epipedobates tricolor), (e) solitary tunicate sea peach Halocynthia aurantium), (f) glia monster (Heloderma suspectum). Photos (b)-(f) by I. Boyd (Creative Commons Attribution ShareAlike License), H. Van (Public domain), L. Ghoul (Creative Commons Attribution ShareAlike License), A. Rode (Creative Commons Attribution ShareAlike License) and Arpingstone (Public domain), respectively. See website for photo credit (a).

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

The dart-poison frog Dendrobatespumilio uses odors for homing. This species lives in the understory of lowland tropical forests in Central America. The eggs are laid on land, and the female carries the newly hatched tadpoles on her back to water-filled leaf axils of bromeliads. She feeds the tadpoles with unfertilized eggs, while the male defends the territory. Captive dart-poison frogs tested in a Y-olfactometer chose the odor from their own communal tank over odors from tanks planted with different plants. However, they did not distinguish between... 

FIGURE 10.5 Batrachotoxin from dart-poison frogs. 

Caldwell, J. P. (1996). The evolution of myrmecophagy and its correlates in poison frogs (family Dendrobatidae). 240,75-101. 

Daly, J. W. and Meyers, C. W. (1967). Toxicity of Panamanian poison frogs (Dendrohates) some biological and chemical aspects. Science 156,970-973. 

Daly, J. W., Secunda, S. I., Garaffo, H. M., et al. (1992). Variability in alkaloid profiles in neotropical poison frogs (Dendrobatidae) genetic versus environmental determinants. Toxicon 30,887-898. 

Forester, D. C. and Wisnieski, A. (1991). The significance of airborne olfactory cues to the recognition of home area by the dart-poison frog Dendrobates pumilio. Journal of Herpetology 25, 502-504. 

NOTE - An excellent reference on the frogs is the February 1983 issue of Scientific American, which contains the article "Dart-Poison Frogs", by Charles W. Myers and John W. Daly. It includes color plates of the frogs and maps showing their various habitats. 

Daly, J. W., Tokuyama, T., Fujiwara, T., Highet, R. J., Karle, I. L. A new class of indolizidine alkaloids from the poison frog, Dendrobates tricolor. X-ray analysis of 8-hydroxy-8-methyl-6-(2 -methylhexylidene)-1-azabicyclo[4.3.0]nonane, J. Am. Chem. Soc. 1980, 102, 830-836. 

Batrochotoxin. Toxin extracted from skin of Columbian arrow poison frog. Effect via irreversible increase in permeability of membranes to Naf ions... 

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. 

During the reaction silver(0) deposits on the sides of the reaction vessel. The sequence of events leading to the azomethine ylide is unclear. However, evidently single-electron transfer (SET) from the amine to silver takes place either prior or subsequent to fluoride-enabled silyl cleavage. This process is repeated with a second equivalent of silver fluoride resulting in the formation of 38 either in free form or more likely as its silver complex. The scope of the method was expanded to the synthesis of bicylic systems exemplified here by tropinone 42 (Scheme 2.11).19 Pandey has also extended the protocol to the synthesis of tricycloalkanes20 and applied it to a total synthesis of the poisonous frog alkaloid epibatidine.21... 

The neotropical dart poison frogs contain a remarkable diversity of alkaloids, and the 2,5-disubstituted decahydroquinolines represent, a major class of these amphibian alkaloids[21]. Isolation of these alkaloids from some ants strengthens a dietary hypothesis for the origin of the above alkaloids that have been detected in extracts of frog skin[22]. In addition, these alkaloids containing both cis and trans ring fusion have been identified as well as diastereomers at the C-2 and C-5 position. 

Fig. (7). Representative decahydroquinoline-type dart-poison frog alkaloids...

Ring construction approaches have also been used effectively in the diastereoselective synthesis of the fused azepine 43 from the pyrrolidinone 41 and (Z)-l,4-dichloro-2-butene 42 [01TA2205], and in the synthesis of the alkaloid 275A (44) from the Colombian poison frog Dendrobates lehmanni [01JNP421]. 

Because of the enormous biomass of mites such as oribatids, their peculiar natural products might be more abundant in unrelated animals of terrestrial ecosystems.126 So, the chemistry of skin alkaloids in poisonous frogs often reflects their recent arthropod diet such as oribatids and ants.126 Moreover, several ants might be specialized on certain oribatid mites,127 whereas certain mites often prefer food such as pigmented fungal hyphae.126 Since alkaloids in scheloribatid mites are not present in larvae but found only in adults,121 the compounds might be either biosynthesized by adult mites or sequestered by adult mites from their fungal food. 

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