Total Synthesis of (−)‐Tetrodotoxin and 11‐norTTX‐6(R)‐ol

The enantioselective total synthesis of (−)‐tetrodotoxin [(−)‐TTX] and 4,9‐anhydrotetrodotoxin, which are selective blockers of voltage‐gated sodium channels, was accomplished from the commercially available p‐benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]‐sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3‐dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11‐norTTX‐6(R)‐ol and 4,9‐anhydro‐11‐norTTX‐6(R)‐ol through late‐stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11‐norTTX‐6(R)‐ol without competing dehydration to their 4,9‐anhydro forms. Pick your poison: Total synthesis of the voltage‐gated sodium channel inhibitor (−)‐tetrodotoxin (TTX) was achieved from p‐benzoquinone in 31 steps. The synthesis, which is also applicable to TTX congeners like 11‐norTTX‐6(R)‐ol, features efficient stereoselective oxygenation at C‐6, C‐7, and C‐8 by taking advantage of the tricyclic skeleton, diastereoselective [3,3]‐sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3‐dipolar cycloaddition of a nitrile oxide.