Allopumiliotoxin - Synthesis

Synthesis

Allopumiliotoxins are very biologically useful but are rare in nature. For this reason, many groups have researched syntheses for various alkaloids of this type. The main problem with allopumiliotoxin synthesis arises from the alkylidene side chain because the stereochemistry of it can be difficult to control by Wittig-type functionalizations.

Total synthesis of (+)-allopumiliotoxin 267A was achieved using a chiral dihydropyridone intermediate that was formed from the addition of ethyl lithiopropiolate to the N-acylpyridinium salt which results from the reaction of (+)-trans-2-(α-cumyl)cyclohexyl chloroformate and 4-methoxy-3-methyl-5(triisopropylsilyl)pyridine. This intermediate was then subjected to various additions and oxidations to yield the final allopumiliotoxin. The synthesis of (+)-allopumiliotoxin 323B’ has also been achieved using an intermediate from the previous synthesis.

(+)-Allopumiliotoxin 339A has been synthesized using an iodide-promoted iminium ion alkyne cyclization followed by condensation with acetylenic salt. Subsequent reactions led to the enantiopure product after 16 steps and a 7.5% yield. Other synthetic methods have been carried out for this molecule. One of which was achieved through the use of a Nozaki-Kishi Cyclization. Allopumiliotoxin 267A was synthesized using a similar cyclization.