An overview of grayanane diterpenoids and their biological activities from the Ericaceae family in the last seven years

Convergent Total Synthesis of (+)-Principinol D, a Rearranged Kaurane Diterpenoid

“…The following procedure was modified from the reported protocol. 2,3 2,2-dimethylcyclopentanedione (10.4 g, 254 mmol) was dissolved in toluene (170 mL, 0.5 M). Et 2 NPh (4.0 mL, 41.2 mmol, 0.5 equiv) and (R)-(+)-2-Butyl-CBS-oxazaborolidine solution (1 M in toluene; 8.25 mL, 8.25 mmol, 0.1 equiv) were added.…”

“…The grayanane diterpenoids -well known as the active components in "mad honey" due to inhibition of voltage-gated sodium ion channels 1 -have recently been identified as structurally novel allosteric inhibitors of carbonic anhydrases 2 and phosphatases. 3 Due to the ubiquity of various subtypes of these molecular targets, potential therapeutic development could span numerous different disease areas from neurological dysfunction to cancer. 4,5 Grayananes are among a broader class of rearranged kauranes that also includes gibberellanes and 6,7-seco-kauranes ( Figure 1A).…”

“…This topological simplification to mark external rings for preservation differs significantly from prior work in the grayanane class, but is a powerful strategy in diterpenoid synthesis. 14 We planned to utilize two robust C-C bond-forming reactions to merge the fragments, as this would maximize success for creating derivatives for SAR investigations: fragment union via a 1,2addition reaction between a cyclopentyl fragment (4) and a bicyclo [3.2.1]octane fragment (3), and subsequent reductive cyclization using SmI 2 . Dissection of the bicyclic fragment by an exendo bond using a Ni-catalyzed α-vinylation reaction would reveal a 6membered ring that could be obtained by vicinal difunctionalization of cyclohexenone.…”

“…This synthetic route is expected to lead to laboratory access to a variety of derivatives, including ones which selectively act on phosphatases, carbonic anhydrases, or voltage-gated sodium ion channels; all are known targets of the grayananes. 2,3 ASSOCIATED CONTENT Materials: All reaction solvents were purified using a Seca solvent purification system by Glass Contour, with the exception of 1,4-dioxane, ethanol, and dimethylsulfoxide, which were used as received without further purification. Methanol was distilled over magnesium.…”

Total Synthesis of (−)‐Glaucocalyxin A

“…[2][3][4][5] Among these diterpenoids, about half contain 14(b)oxygenation patterns (Figure 1). [6,7] As shown, the 14-oxygenated bicyclo[3.2.1]octane ring system contains four to five continuous stereocenters. Some of these natural products, such as glaucocalyxin A (1), [8] oridonin (3), [9] and grayanotoxin I (4), [7] exhibit a variety of promising therapeutic properties and have been used as leads in drug development.…”