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Total Synthesis of (−)‐Tetrodotoxin and 11‐norTTX‐6( R )‐ol
Author(s) -
Maehara Tomoaki,
Motoyama Keisuke,
Toma Tatsuya,
Yokoshima Satoshi,
Fukuyama Tohru
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201611574
Subject(s) - enantioselective synthesis , chemistry , tetrodotoxin , stereocenter , total synthesis , intramolecular force , stereochemistry , sodium methoxide , cycloaddition , combinatorial chemistry , organic chemistry , methanol , catalysis , medicine
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.