Poison-dart frog alkaloids synthesis

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

A synthesis of pumiliotoxin C, one of the arrow poison alkaloids isolated from the skin of Dendrobatespumilio, the strawberry poison dart frog, is shown in the following. Study it, and answer the questions posed ... 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

The active principle of dart frog poisons is alkaloids. The study of the den-drobatid poisons led to the discovery of over 200 new alkaloids, including batrachotoxins Pig. 10.5), pumiliotoxins, histrionicotoxins, gephyrotoxins, and decahydroquinolines (Daly et al., 1994). The most common compounds have the basic structure of piperidine and include histrionotoxin. In Phyllobates, the synthesis of other alkaloids is suppressed in favor of batrachotoxins. These are... 

---