Amphibians alkaloids

In the overall cycloaddition-rearrangement process [64], the C-3 - C-8a relative stereochemistry of the indolizidinone obtained by rearrangement of the isoxazolidine derives from the cycloaddition step and is not affected during the rearrangement. This allowed the control of two out of three chiral centers in a synthetic protocol for a synthesis of the amphibian alkaloid ( + )-Gephyro-toxin 223AB (Scheme 46) [65c]. 

The isoxazoline 355 (Table 27, entry 9) served as precursor for the total synthesis of the amphibian alkaloid ( + )-Pumiliotoxin C 358 (Scheme 50) [89]. 

FIGURE 1 Structures of lipophilic amphibian alkaloids. Alkaloids indicated by asterisks represent structural classes that have not been detected in nature except in amphibians and, in the case of batrachotoxins, in one species of bird (9). 

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... 

Another class of these amphibian alkaloids, the pumiliotoxins, contain an alkylidene side chain on C-6 of the indolizidine ring (Table 2). Due to their myotonic and cardiotonic activity, and challenging structure, they also have been the object of synthetic interest. A review points out the state of the art at the beginning of the decade <1996CRV505>. 

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. 

A number of reviews in the last decade (i-5) have focused on synthesis of amphibian alkaloids. The present chapter will not treat synthesis but will document only the structural diversity, spectral and chemical properties, biological activity, and distribution in Nature of the nearly 300 known amphibian alkaloids. 

Most amphibian alkaloids are not as complex in structure as the steroidal batrachotoxins and samandarines. Of the 300 known amphibian alkaloids, most have been characterized from the skin extracts of frogs of the family Dendrobatidae and, hence, have been referred to as dendrobatid alkaloids. The major bicyclic classes of dendrobatid alkaloids are the histrionicotox-ins, decahydroquinolines, and pumiliotoxin-A class. Because of the presence of a piperidine ring in most dendrobatid alkaloids, they also have been referred to as piperidine-based alkaloids. 

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