Stereoselective Construction of Tertiary Alcohol at C11 of Zetekitoxin AB

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.