Progress toward the total synthesis of falcatin A

Abstract

GIRK channels (G protein mediated inwardly-rectifying potassium ion channels) have been shown to regulate the elec. activity of several cell types including neurons, cardiac atrial myocytes, and b-pancreatic cells. As such, the malfunction of GIRK channels has also been implicated in disorders such as neuropathic pain, drug addiction, and cardiac arrhythmias. Falcatin A is a myrsinane diterpenoid that possesses inhibitory activity against GIRK channels with an IC50 value of 2.5 ± 0.2 uM. We hypothesize that the 5/7/6 carbocyclic framework of the natural product could be constructed in a single step through a combination of hydrogen bonding, hydrogen atom transfer, and photoredox catalysis to bring together two complex fragments in a convergent coupling strategy, allowing for the rapid and efficient synthesis of falcatin A and analogs. The synthesis and studies of falcatin A and its analogs could potentially provide some insight into the modulation of GIRK channels. Herein, we describe our synthetic progress toward the total synthesis of falcatin A.