Dendrobates

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

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. 

The first example of this type of alkaloid, compound 535, known hitherto merely as 205B, has recently been isolated from the skin of the Panamanian frog Dendrobates pumilio. The absolute stereochemistry of the natural (—)-alkaloid was first established by the total synthesis of its (+)-enantiomer by a multistage route from the fused piperidine 536... 

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

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]. 

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. 

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. 

The Beckmann rearrangement was used as a key step (41% yield, under standard conditions) for the synthesis of the natural alkaloid Pumiliotoxin C 359, which was originally isolated from the skin extracts of Dendrobates pumilio (a strikingly coloured Panamanian poison arrow frog) (equation 139). ( )-Pumiliotoxin C was also synthesized by a similar ring formation process by Mehta and Praveen. ... 

The chloroform extracts are combined, dried over sodium sulfate, and concentrated under vacuum until dry. The residue will be crude, a mixture of about three different alkaloids. Yield will depend on the species of the frogs used. In one test, 5000 adult Phyllobates aurotaema yielded 157 mg of mixed alkaloids, while 750 adult Dendrobates tricolor yielded 80 nig. 

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... 

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. 

Extracts from skins of the neotropical frog Dendrobates tricolor from Ecuador have given the alkaloid 8-hydroxy-6-(2-methylhexylidene)azabicyclo[4.3.0]non-ane (4), the structure and absolute configuration of which have been determined by X-ray crystallography of the hydrochloride salt. This alkaloid is the first structurally defined member of the pumiliotoxin A class of dendrobatid alkaloids. Spectroscopic studies (m.s. and n.m.r.) have allowed the formulation of the... 

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]. 

Stereodivergent process for synthesis of the decahydroquinoline type of Dendrobates alkaloids... 

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