title: Total Synthesis of (-)-Tetrodotoxin and 11-norTTX-6(R)-ol.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Toma
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoshima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
mesh_terms: D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D016227:Benzoquinones; D026941:Sodium Channel Blockers; C047739:anhydrotetrodotoxin; C004532:quinone; D013779:Tetrodotoxin
keywords: alkaloids; natural products; stereocontrol; tetrodotoxin; total synthesis