Nakazaki Atsuo, Nakane Yoshiki, Ishikawa Yuki, Yotsu-Yamashita Mari, Nishikawa Toshio
Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.
Org Biomol Chem. 2016 Jun 21;14(23):5304-9. doi: 10.1039/c6ob00914j. Epub 2016 May 24.
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.
本文描述了克拉贝辛B羧酸两种对映体的合成。一种顺式烯炔起始原料在胜木不对称环氧化条件下进行环氧化反应，得到ee值为95%的环氧化物，该环氧化物通过溴鎓离子引发的串联环化反应作为关键步骤转化为克拉贝辛B羧酸。还从串联反应产物合成了对映体纯的克拉贝辛A和C羧酸。使用这些合成化合物针对电压门控钠通道（VGSC）抑制的构效关系（SAR）研究表明，克拉贝辛B羧酸的天然对映体活性最高，与河豚毒素相当，未烷基化的环状胍结构是必不可少的，而羧酸盐部分并不重要。通过比较天然克拉贝辛A衍生的甲酯与本研究中合成的立体化学定义的克拉贝辛A羧酸衍生的甲酯，确定了克拉贝辛A的绝对立体化学。
