Asymmetric Total Synthesis and Na

Herein, we present two 17(15→16)-abeo-abietane diterpenoids (1 and 2) as the first terpenoid-class NaV1.8 inhibitors, along with their first asymmetric total syntheses to enable in-depth pharmacological studies. Key steps include kinetic resolution of terminal epoxides, bioinspired polyene cyclization, and late-stage photocatalytic benzylic oxidation. Preliminary structural modifications led to 13 derivatives, among which compound 29 exhibited both a 4.3-fold improved potency compared to parent natural product 1 and preserved selectivity across other sodium-gated sodium channels.