- 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.
- Maehara, Tomoaki,Motoyama, Keisuke,Toma, Tatsuya,Yokoshima, Satoshi,Fukuyama, Tohru
-
supporting information
p. 1549 - 1552
(2017/02/05)
-
- An efficient total synthesis of optically active tetrodotoxin
-
The toxic principle of puffer-fish poison, (-)-tetrodotoxin (1), has been recognized as a formidable synthetic target since its structure elucidation in 1964. An efficient total synthesis of 1 via the intermediate 2, which was used previously for the synthesis of 11-deoxytetrodotoxin, is described.
- Nishikawa, Toshio,Urabe, Daisuke,Isobe, Minoru
-
p. 4782 - 4785
(2007/10/03)
-
- First asymmetric total synthesis of tetrodotoxin
-
Tetrodotoxin, a toxic principle of puffer fish poisoning, is one of the most famous marine natural products because of the complex structure having many functional groups and its potent biological activity leading to death. Since the structure elucidation in 1964, this toxin has been recognized as a formidable target molecule for total synthesis. We have recently achieved the first asymmetric total synthesis from 2-acetoxy-tri-O-acetyl-D-glucal as a chiral starting material. The highly hydroxylated cyclohexane ring was constructed by Claisen rearrangement and regioselective hydroxylations of an acetone moiety and an intramolecular directed aldol condensation of the precursor having methyl ketone with dihydroxyacetone, which was synthesized through Sonogashira coupling. Installation of nitrogen functionality was unsuccessful through an attempted Overman rearrangement. We, therefore, employed a new intramolecular conjugate addition strategy between the carbamate and unsaturated ester groups. The α-hydroxyl lactone moiety was synthesized through an intramolecular epoxide opening by the Z-enolate of aldehyde, which was followed by oxidation - reduction of the resulting cyclic vinyl ether. The lactone was then converted to a protected ortho ester, and then gunanidinylation was followed by cleavage of the 1,2-glycol to give the fully protected tetrodotoxin. Selection of the protective groups has finally led us to accomplish the total synthesis of tetrodotoxin in an enantiomerically pure form. All the stereogenic centers were controlled with high selectivity, and the hydroxyl groups were differently protected to discriminate for the future analogue synthesis of a bioorganic program. The synthetic tetrodotoxin was purifed by ion exchange chromatography and characterized to be identifical with the natural compound.
- Ohyabu, Norio,Nishikawa, Toshio,Isobe, Minoru
-
p. 8798 - 8805
(2007/10/03)
-
- ISOLATION OF 11-OXOTETRODOTOXIN FROM THE PUFFER AROTHRON NIGROPUNCTATUS
-
A novel tetrodotoxin analog was isolated from the puffer Arothron nigropunctatus and identified as 11-oxotetrodotoxin hydrate on the basis of NMR and chemical transformation studies.
- Khora, Samanta S.,Yasumoto, Takeshi
-
p. 4393 - 4394
(2007/10/02)
-
