Studies toward the Total Synthesis of Grandisine A: Synthesis of 9-epi-Grandisine A

A concise synthesis of 9-epi-grandisine A is described, which makes use of a Lewis acid-promoted hetero-Diels-Alder reaction to construct the tricyclic skeleton.Attempts to obtain grandisine A through a late-stage controlled epimerization are also discussed.Recently, several novel indolizidine alkaloids, grandisine A (1), B 1 and C-F, 2 were isolated by Carroll and co-workers from the leaves of the Australian rainforest tree, Elaecarpus grandis.In addition to their interesting structures, these compounds possess modest binding affinity (~1-75 μM) for the human -opioid receptor.Opioid receptors (μ, , ) are G-protein coupled receptors, long known to be involved in the modulation of pain.Interestingly, activation of both the μ and -receptors by an agonist (i.e.morphine) causes a number of undesired side effects, including nausea, itching and reduced blood pressure.However, it has been shown in animal models that selective activation of the -receptor by agonists results in pain modulation without these adverse side effects. 3Thus, higher affinity small molecule agents, perhaps based on the grandisine lead, which may selectively bind to the -receptor, could represent valuable avenues for exploration in the ongoing search for improved therapeutic agents for the management of pain.