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

Atsuo Nakazaki, Yoshiki Nakane, Yuki Ishikawa, Mari Yotsu-Yamashita, Toshio Nishikawa

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5304-5309
Number of pages6
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number23
DOIs
Publication statusPublished - 2016 Jan 1

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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