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Issue 23, 2016
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Asymmetric synthesis of crambescin A–C carboxylic acids and their inhibitory activity on voltage-gated sodium channels

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Abstract

Synthesis of both enantiomers of crambescin B carboxylic acid is described. A cis-enyne starting material was epoxidized under the conditions of Katsuki asymmetric epoxidation to give 95% ee of the epoxide, which was transformed to crambescin B carboxylic acid via bromocation-triggered cascade cyclization as the key step. Enantiomerically pure crambescin A and C carboxylic acids were also synthesized from the product of the cascade reaction. Structure–activity relationship (SAR) studies against voltage-gated sodium channel (VGSC) inhibition using those synthetic compounds revealed that the natural enantiomer of crambescin B carboxylic acid was most active and comparable to tetrodotoxin, and the unalkylated cyclic guanidinium structure is indispensible, while the carboxylate moiety is not important. The absolute stereochemistry of crambescin A was determined by a comparison of the methyl ester derived from natural crambescin A with that derived from the stereochemically defined crambescin A carboxylic acid synthesized in this study.

Graphical abstract: Asymmetric synthesis of crambescin A–C carboxylic acids and their inhibitory activity on voltage-gated sodium channels

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Supplementary files

Article information


Submitted
28 Apr 2016
Accepted
16 May 2016
First published
16 May 2016

Org. Biomol. Chem., 2016,14, 5304-5309
Article type
Paper

Asymmetric synthesis of crambescin A–C carboxylic acids and their inhibitory activity on voltage-gated sodium channels

A. Nakazaki, Y. Nakane, Y. Ishikawa, M. Yotsu-Yamashita and T. Nishikawa, Org. Biomol. Chem., 2016, 14, 5304
DOI: 10.1039/C6OB00914J

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