Phantasmidine, a Nicotinic Receptor Agonist from Ecuadoran Poison Frogs

IIn 1992, the lab of the late John Daly at NIH reported the isolation of epibatidine (1) from the skin of an Ecuadorian poison frog.  In addition to being a toxin, epibatidine has potent analgesic activity. Subsequent studies showed that this activity resulted from interaction with acetylcholine nicotinic receptors (nAChRs) with binding to some of the receptors at sub nanomolar levels.  The binding to several different types of nAChRs may be responsible for its non-selective activity.

In 2010, the Daly group reported the isolation and tentative structure determination of the epibatidine congener phantasmidine (2) from a total sample of only 20 micrograms. Preliminary biological studies with the limited material available indicated that phantasmidine (2) differs from epibatidine (1) by being selective for β4-containing nicotinic receptors, suggesting that phantasmidine might fill a niche for characterization of these receptors. However, the limited natural material available precluded detailed pharmacological analysis and definitive structure determination.

In their recent paper in Organic Letters entitled the Synthesis of Phantasmidine, the Snider lab at Brandeis reported a short and efficient synthesis of phantasmidine that confirmed the tentative structure and makes ample material readily available for further biological evaluation, which is currently in progress.  To prepare the tetracyclic framework, they invented a new tandem intramolecular aldol reaction-nucleophilic aromatic substitution reaction to form both five membered rings in a single reaction.   Treatment of keto amide 3 with sodium hydroxide gave aldol adduct 4 which cyclized to lactam 5.  Reduction of the lactam completed a practical synthesis of phantasmidine (2).

Protected by Akismet
Blog with WordPress

Welcome Guest | Login (Brandeis Members Only)