Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Chao Wang; Mana Oki; Toru Nishikawa; Daisuke Harada; Mari Yotsu-Yamashita; Kazuo Nagasawa

doi:10.1002/anie.201604155

Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Chao Wang, Mana Oki, Toru Nishikawa, Daisuke Harada, Mari Yotsu-Yamashita, Kazuo Nagasawa

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu₄N][Ph₃SnF₂], which directly constructs the crucial C−C bond at the C11 position in SEA. The Na_VCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC₅₀value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

Original language	English
Pages (from-to)	11600-11603
Number of pages	4
Journal	Angewandte Chemie - International Edition
Volume	55
Issue number	38
DOIs	https://doi.org/10.1002/anie.201604155
Publication status	Published - 2016 Sep 12

Keywords

aldol reaction
heterocylces
natural products
saxitoxin
total synthesis

ASJC Scopus subject areas

Catalysis
Chemistry(all)

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10.1002/anie.201604155

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title = "Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels",

abstract = "11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4N][Ph3SnF2], which directly constructs the crucial C−C bond at the C11 position in SEA. The NaVCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).",

keywords = "aldol reaction, heterocylces, natural products, saxitoxin, total synthesis",

author = "Chao Wang and Mana Oki and Toru Nishikawa and Daisuke Harada and Mari Yotsu-Yamashita and Kazuo Nagasawa",

note = "Funding Information: This work was supported in part by JSPS KAKENHI Grant Number JP16H01134 in Middle Molecular Strategy, and grant from the Uehara Memorial Foundation. C.W. thanks for the Otsuka Toshimi Scholarship Foundation for supporting. Publisher Copyright: {\textcopyright} 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim",

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doi = "10.1002/anie.201604155",

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AU - Wang, Chao

AU - Oki, Mana

AU - Nishikawa, Toru

AU - Harada, Daisuke

AU - Yotsu-Yamashita, Mari

AU - Nagasawa, Kazuo

N1 - Funding Information: This work was supported in part by JSPS KAKENHI Grant Number JP16H01134 in Middle Molecular Strategy, and grant from the Uehara Memorial Foundation. C.W. thanks for the Otsuka Toshimi Scholarship Foundation for supporting. Publisher Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2016/9/12

Y1 - 2016/9/12

N2 - 11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4N][Ph3SnF2], which directly constructs the crucial C−C bond at the C11 position in SEA. The NaVCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

AB - 11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4N][Ph3SnF2], which directly constructs the crucial C−C bond at the C11 position in SEA. The NaVCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

KW - aldol reaction

KW - heterocylces

KW - natural products

KW - saxitoxin

KW - total synthesis

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Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Abstract

Keywords

ASJC Scopus subject areas

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