Epiquinamide: a poison that wasn't from a frog that was

Abstract

In 2003, we reported the isolation, structure elucidation, and pharmacology of epiquinamide (1), a novel alkaloid isolated from an Ecuadoran poison frog, Epipedobates tricolor. Since then, several groups, including ours, have undertaken synthetic efforts to produce this compound, which appeared initially to be a novel, beta2-selective nicotinic acetylcholine receptor agonist. Based on prior chiral GC analysis of synthetic and natural samples, the absolute structure of this alkaloid was established as (1S,9aS)-1-acetamidoquinolizidine. We have synthesized the (1R*,9aS*)-isomer (epi-epiquinamide) using an iminium ion nitroaldol reaction as the key step. We have also synthesized ent-1 semisynthetically from (-)-lupinine. Synthetic epiquinamide is inactive at nicotinic receptors, in accord with recently published reports. We have determined that the activity initially reported is due to cross-contamination from co-occurring epibatidine in the isolated material.

Figure 1

Figure 2

Pharmacologic analysis of epiquinamide and intermediates.

Figure 3

GC-MS data for natural epiquinamide.

Scheme 1

Alkylation-iminium ion aldol annulation

Scheme 2

Synthesis of epi-epiquinamide.

Scheme 3

Stereoselection in formation of nitroquinolizidine 5.

Scheme 4

Synthesis of ent-epiquinamide.