Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, December 7, 2020
Douglass F. Taber
University of Delaware

The Yokoshima Synthesis of Tetrodotoxin

In 1981, an individual who had been drinking ate an Oregon rough-skinned newt - and died from poisoning by tetrodotoxin (4). Satoshi Yokoshima of Nagoya University devised a direct route to the highly substituted central cyclohexane of 4, based on the diastereoselective Diels-Alder cycloaddition of 1 with 2 to give 3 (Angew. Chem. Int. Ed. 2020, 59, 6253. DOI: 10.1002/anie.201916611).

The enone 1 was readily prepared from the inexpensive ribose (5). Protection followed by iodination and reduction led to the aldehyde 6. Addition of the Grignard reagent 7 followed by ring-closing metathesis and oxidation with PCC gave the enone 8. Iodination of the enone followed by Sonogashira coupling with TMS acetylene completed the assembly of 1.

The addition of 1 to 2 proceeded smoothly. Reduction followed by protection, unravelling of the enone and resilylation of the alkyne delivered the crystalline 9. Coupling of the derived enol triflate with 10 gave 11, that was converted to the diol with singlet oxygen, then epoxidized. Oxidation to the dione followed by reduction led to 12, that was carried on to the aldehyde 13 and then to the amine 14.

The amine 14 was combined with the reagent 15 to give 16, setting the stage for the end game of the synthesis. Removal of the acetonide followed by oxidative cleavage led to a dialdehyde, that cyclized to the corresponding lactol. Oxidation then gave the lactone 17. On exposure to acid, the lactone was hydrolyzed to the free acid, that then opened the epoxide, completing the assembly of 18. Deprotection delivered tetrodotoxin (4).

D. F. Taber, Org. Chem. Highlights 2020, December 7.