期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 14, 期 23, 页码 5304-5309出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6ob00914j
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Daiichi-Sankyo Foundation of Life Science
- Grants-in-Aid for Scientific Research [16H04915, 26292057] Funding Source: KAKEN
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.
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