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.     

Total Synthesis of (−)‐N‐Methylwelwitindolinone B Isothiocyanate

The asymmetric synthesis of (−)‐N ‐methylwelwitindolinone B isothiocyanate is reported. Critical challenges overcome through these studies include the stereoselective installation of the sterically congested C13 alkyl chloride and control of the wayward reactivity of the indole unit to standard oxidants. A Pt‐catalyzed hydrosilylation helped stymie unwanted rearrangements facilitated by vinyl group participation during the chloride installation step, and a new Fe^II‐catalyzed oxidation accomplished the problematic conversion of indole into 2‐indolinone.