Search

A route towards synthesis of analogues of the pumilotoxin/allopumilotoxin side-chain is described. The C15,C16 diol was introduced by asymmetric dihydroxylation using AD-mix β of C10,C17 eneyneone intermediate 14 , or of C13,C17 precursor 17 , or by using a chiron-based route from 24 . The trisubstituted alkene functionality was established using thioaryl conjugate addition to yneones 16 and 27 , followed by a copper-catalyzed stereoretentive reaction with methylmagnesium bromide. The approach enables access to C12 oxo systems and offers an approach towards new C14 analogues.

Mantelline frogs of the genus Mantella contain a variety of pumiliotoxin, allopumiliotoxin and homopumiliotoxin alkaloids in their skin. Pyrrolizidines, indolizidines and quinolizidines are also present. In contrast, captive-raised frogs (Mantella aurantiaca) have no alkaloids detectable in skin extracts. Frogs fed alkaloid-dusted fruit flies accumulate alkaloids into their skin. Thus, these mantelline frogs, like the neotropical dendrobatid frogs, appear dependent on dietary sources for their skin alkaloids and have the requisite alkaloid-sequestering system(s).

Skin extracts from the Panamanian poison-frog Dendrobates pumilio have afforded further trace alkaloids of the pumiliotoxin-A class (6-alkylidene-8-hydroxy-8-methylindolizidines) and an allopumiliotoxin subclass (7-hydroxy-PTX-As). Structures for pumiliotoxins 209F and 225F and allopumiliotoxin 225E, all with four carbon 6-alkylidene side chains, for allopumiliotoxins 309D, 325A′ and 325A″, all with ten carbon 6-alkylidene side chains, and a reassignment of the position of the keto function in the ten carbon 6-alkylidene side chain of pumiliotoxin 307F are presented. Carbon-13 magnetic resonance assignments for these and the 15-0-methyl ether artefacts of pumiliotoxin 307A and allopumiliotoxin 323B, are tabulated.

Cutaneous granular glands are a shared character of adult amphibians, including caecilians, and are thought to be the source of most biologically active compounds in amphibian skin. Data are available from one or more species in over 100 of nearly 400 genera comprising the three living orders of Amphibia. Many species contain unidentified substances judged to be noxious based on predator aversion or human taste. Additionally, there is a great diversity of known compounds, some highly toxic as well as noxious, which can be tabulated under four broad categories: biogenic amines, peptides, bufodienolides (bufogenins) and alkaloids . The last category includes alkaloids derived from biogenic amines, water-soluble alkaloids (tetrodotoxins) and lipophilic alkaloids. Most compounds are known only from skin of adult amphibians, but the toxic and noxious properties of eggs and larvae of certain salamanders and toads can be attributed to tetrodotoxins and bufodienolides, which occur also in adult tissues other than skin. Predator aversion and various antipredator behaviors and aposematic colorations clearly prove the defensive value of these diverse metabolites, whether or not they are elaborated primarily (e.g. alkaloids) nor secondarily (e.g. some peptides and biogenic amines) for this function. Lipophilic alkaloids include the samandarine alkaloids, known definitely only from an Old World genus of salamanders, and the more than 200 dendrobatid alkaloids. Nearly all the latter are unique to neotropical poison frogs of the genera Dendrobates and Phyllobates (Dendrobatidae), except for seemingly homoplastic occurrences of a few such alkaloids in small brightly colored anurans of several other families. Owing to recent discoveries and new structural information, the dendrobatid alkaloids are here partitioned among the following major and minor classes: batrachotoxins, histrionicotoxins, indolizidines, pumiliotoxin-A class and its allopumiliotoxin and homopumiliotoxin subclasses, decahydroquinolines, gephyrotoxins, 2,6-disubstituted piperidines, 2,5-disubstituted pyrrolidines, pyridyl-piperidines, indole alkaloids, azatricyclododecenes and amidine alkaloids . Except for the steroidal batrachotoxins, and the minor classes of pyrrolidine alkaloids, indole alkaloids and amidine alkaloids, all the above contain a piperidine ring. A large number of piperidine-based alkaloids occur mainly as trace compounds in Dendrobates and remain unclassified; the only water-soluble toxin so far discovered in a dendrobatid ( Colostethus ) is structurally unknown, but conceivably an alkaloid.

Magnetic resonance spectral assignments for carbon-13 and protons of pumiliotoxin A, B and 251D and of related allopumiliotoxins (7-hydroxy congeners) are presented. Pumiliotoxin A and its 7-hydroxy congener allopumiliotoxin 323B can occur as pairs of 15-hydroxy epimers in dendrobatid frogs. Allopumiliotoxin 323B' and 323B'' and allopumiliotoxin 267A (the 7-hydroxy congener of 251D ) have 7-axial hydroxy moieties. Allopumiliotoxin 339A and 339B are, respectively, the 7- axial-hydroxy and 7-equatorial-hydroxy congeners of pumiliotoxin B. Formation of ring phenyl boronides occurs only with allopumiliotoxin 339B which has the 7-equatorial hydroxy cis to the 8-axial hydroxy of the indolizidine ring.

The title reaction can be employed to assemble the allopumiliotoxin A alkaloid skeleton with either stereochemistry of the C-7 allylic hydroxyl groxyl group.