2 光学活性テトロドトキシン類縁体の化学合成研究(口頭発表の部)

概要

論文の詳細を見る
Tetrodotoxin (TTX, 1) is a well-known marine natural product acting as toxic principle of puffer fish poisoning and has been used as a specific blocker of Na-channel proteins. However, the biosynthesis, the mechanisms of bioaccumulation, the details of bound structure to Na-channel protein, etc, are remained to uncover. In order to solve such problems under molecular level, we have studied syntheses of TTX and its analogs as enantiomerically pure form. Herein we present a highly stereocontrolled synthesis of (-)-5,11-dideoxyTTX (2). The synthesis started from the Diels-Alder reaction between 9 derived from levoglucosenone (11) as a chiral starting material and isoprene (10) to construct cyclohexane ring, which was transformed to exo-allylic alcohol 7 in 5 steps. The amino functionality was introduced by the Overman rearrangement of 7 to give trichloroacetarnide 6 which has all of the carbon atoms of TTX skeleton. Hydroxylation at C-8 position of the key intermediate 6 was achieved using a neighboring group participation of the trichloroacetarnide. Inversion of the resulting hydroxy group, stereoselective epoxidation and ozonolysis of the vinyl group yielded an aldehyde 17. Stereoselective addition of magnesium acetylide to the aldehyde 17, followed by oxidative cleavage of the acetylene group with RuO_4 gave the lactone 5. Construction of guanidine function from trichloroacetamide of 5 by our new procedure resulted in failure because of the labile C-9 acetoxy group. In order to avoid such problems, we considered an urea compound 21 as a candidate of precursor for guanyl formation. The urea 21 was dehydrated to carbodiimide 22, which reacted with benzylamine to afford dibenzylguanidine 23. Finally deprotection of benzyl groups, acetyl groups and acetal furnished the 5,11-dideoxyTTX (2) along with its isomers (25, 26). This studies presents the first asymmetric synthesis of TTX analogs and provides a practical route accessible to the labeled compounds for biochemical studies. Further studies toward naturally occurring TTX (1) and other analogs are in progress in the laboratory.
天然有機化合物討論会の論文
1999-09-01

2 光学活性テトロドトキシン類縁体の化学合成研究(口頭発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク