Toward A Stereoselective Synthesis of Phantasmidine and Analogs

Phantasmidine is a novel nicotinic acetylcholine receptor agonist isolated from the Ecuadoran poison frog, Epipedobates anthonyi. This molecule is a potentially important biological probe and lead compound for development of selective ligands based on its rigid structure. We are interested in an enantio- and diastereoselective route to phantasmidine and analogs in order to examine the structure-activity relationships of this useful scaffold. We have devised a synthesis beginning from trans-2-aminocyclobutanol, available in both enantiomeric series beginning from 1,3-butadiene and 2,6-dichlorohomonicotinic acid, available from 2,6-dichloropyridine. We have prepared amides of several aminoalcohols and successfully ring-closed to the corresponding pyrido-hexahydrooxazocinone. We are currently exploring a 1,4-transannular C-H insertion reaction, a potentially useful entry into phantasmidine and related pyridofurans, a potentially useful class of nicotinic ligand scaffolds.