Asymmetric Total Synthesis of 11-Deoxytetrodotoxin, a Naturally Occurring Congener

• Published in: Journal of the American Chemical Society Vol. 124; no. 26; pp. 7847 - 7852
• Main Authors: Nishikawa, Toshio, Asai, Masanori, Isobe, Minoru
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.07.2002; Amer Chemical Soc
• Subjects: Animal poisons toxicology. Antivenoms; Animals; Biological and medical sciences; Chemistry; Chemistry, Multidisciplinary; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Medical sciences; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Tetraodontiformes; Tetrodotoxin - chemical synthesis; Toxicology; TETRODOTOXIN BINDING-PROTEIN; PUFFER FISH; NA+ CHANNEL; (-)-TETRODOTOXIN; CHEMISTRY; FUGU-PARDALIS; SODIUM-CHANNEL; DERIVATIVES; STEREOCONTROLLED SYNTHESIS; STEREOSELECTIVE SYNTHESIS; Toxin; Asymmetric synthesis; Nitrogen heterocycle; Animal origin; Polycyclic compound; Oxygen heterocycle; Total synthesis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0265153

Tetrodotoxin, a toxic principle of puffer fish poisoning, is a specific blocker of sodium channel. Despite many synthetic efforts since the structure elucidation in 1964, the only total synthesis of the racemic tetrodotoxin has been reported by Kishi and co-workers. In the course of our studies directed toward the total synthesis to analyze biologically interesting issues associated with tetrodotoxin, we accomplished a highly stereocontrolled synthesis of (−)-5,11-dideoxytetrodotoxin in 1999. Based on the synthesis, we describe herein the first total synthesis of 11-deoxytetrodotoxin, a naturally occurring analogue. The synthesis started from an allylic alcohol, the same intermediate for the synthesis of 5,11-dideoxytetrodotoxin. Epoxidation of the allylic alcohol was followed by isomerization with Ti(i-PrO)4 to give an α-hydroxy allylic alcohol, in which the configurations of the two hydroxyl groups were inverted by oxidation and then a 2-step reduction. Further epoxidation of the allylic alcohol and ozonolysis of the remaining vinyl group gave an aldehyde, which reacted with magnesium acetylide to give a propargyl alcohol in a stereoselective manner. Oxidative cleavage of the acetylenic moiety with RuO4 afforded a fully functionalized lactone for 11-deoxytetrodotoxin. Crucial guanidinylation was achieved from trichloroacetamide according to our own method to give acetyldibenzylguanidine. Finally, deprotection of benzyl groups, acetates, and acetal furnished 11-deoxytetrodotoxin.