Stereoselective Construction of Tertiary Alcohol at C11 of Zetekitoxin AB

Abstract

The paralytic shellfish toxin saxitoxin (STX) is a guanidine alkaloid that potently inhibits voltage‐gated sodium channels (NaV). Among STX analogs so far reported, zetexitoxin AB (ZTX), isolated from the poison dart frog, exhibits the most potent inhibitory activity. ZTX has a macrocyclic lactam structure with a tertiary alcohol at C11. Here, we describe the construction of the characteristic structure of ZTX at C11, focusing on the C−C bond and tertiary hydroxyl group, via two approaches, i. e., Mukaiyama‐hydration reaction and 1,3‐dipolar cycloaddition. The latter approach also enabled introduction of the nitrogen group at C15. The synthesized compounds functionalized at C11 were further converted to STX‐type derivatives, and their NaV‐inhibitory activity was evaluated. STX derivatives with a C11β‐hydroxyl group exhibited more potent inhibitory activity (EC50=160±15 nM) than the C11α derivatives.