The Qi Synthesis of Tetrodotoxin

Tetrodotoxin (3), the toxic principle from puffer fish, has intrigued organic synthesis chemists for more than thirty years. Recent applications in pain treatment and heroin detoxification have made a practical synthesis a high priority. Xiangbing Qi of Tsinghua University established a straightfoward route, based on the construction of the key α-quaternary amine by the opening of the epoxide 1 with azide to give 2 (Nature Commun. 2024, 15, 679. DOI: 10.1038/s41467-024-45037-0).

The starting point for the synthesis was Diels-Alder cycloaddition between the camphanic acid ester of furfuryl alcohol 4 with maleic anhydride 5 to give the crystalline adduct 6, carried out on a 100-gram scale. Selective quinine-catalyzed opening of the anhydride with methanol followed by osmylation and protection led to 7. Decarboxylative coupling with TEMPO gave 8. Removal of the camphanic acid followed by iodide formation provided 9, that was reduced, protected and further reduced to give the diol 10.

Optimization of the selective Mitsunobu coupling of 10 led to methoxyacetic acid 11. Osmylation followed by protection gave the bis-acetonide 12. Face-selective addition of deprotonated dichloromethane formed the epoxide, and also cleaved the ester. Reprotection of the secondary alcohol completed the assembly of 1.

Like acetylide, azide is a small, concentrated nucleophile. Opening of the epoxide would initially have given the alkoxide 13, that collapsed to the aldehyde 2.

The addition of acetylide to the aldehyde of 2 was highly diastereoselective, but in the wrong sense. This was remedied by oxidation followed by reduction, to give 14. Selective oxidation of the primary alcohol to the aldehyde followed by acetal formation, oxidative cleavage of the alkyne and esterification then led to 15, having in place the complete carbon skeleton and all the stereogenic centers of tetrodotoxin (3).

It is interesting to follow the evolution of approaches to tetrodotoxin (3) (inter alia, 2005, May 2; 2018, May 7; 2023, December 7; 2023, June 5) since the first synthesis by Yoshito Kishi, then at Nagoya University, in 1972 (J. Am. Chem. Soc. 1972, 94, 9219. DOI: 10.1021/ja00781a039).