“Mad Honey” is well known for toxicity and analgesic effects due to a highly oxidized unique [5,7,6,5] tetracyclic diterpenoid, grayanotoxin (GTX), found in the flower of different Ericaceae family plants. These effects are associated with voltage-gated sodium channels (VGSCs) that allow the rapid influx of Na+ ions and initiate the action potential in excitable cells and therefore, are the promising target in drug discovery. Natural toxin like tetrodotoxin has been widely used to modulate VGSC’s by blocking them for pain treatment. It is believed that the same effect may be achieved with grayanotoxin through an agonistic approach by opening these sodium channels to induce neural depolarization and thereby relieve the pain. All the methods reported in the literature to access the core of grayanoids and analogs, rely on the convergent fragment coupling and involve multiple steps, and give the opposite diastereomer at a 5/7 ring junction than expected. This research is focused on the rapid and flexible synthesis of GTX and other related analogs from ent-kaurane which can be obtained from sunflower or in a few steps in &gt;decagram quantities from the commercially available stevioside. The use of ent-kaurane, a [6,6,6,5] tetracyclic carbon framework, significantly reduces the reaction steps as the majority of the carbon skeleton is in place only needing a rearrangement of two six-membered rings into five and seven-membered rings, and expected to get the desired diastereomer at 5/7 ring junction during rearrangement. To date, the scalable synthesis of (16R)-hydroxy-ent-kauran-19-oic acid skeleton has been completed in 9 steps with no use of chromatographic purification. Further reactions are in progress and will be detailed.

Progress towards the total synthesis of grayanotoxin

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