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.