Total Synthesis Highlights

The next stage of the synthesis was ring oxygenation, to convert 8 into 13. The key to this
transformation was the observation that the amide oxygen of 8 participated in the solvolysis of the
allylic bromide, setting, after hydrolysis, the new secondary stereocenter of 9. Hydroxyl-directed
epoxidation gave 10, which was rearranged with Ti(O-i-Pr) 4 to 11. After some experimentation, it
was found that the derived dione 12 could be reduced to the desired cis diol 13 with LiBr and
LiAlH(O-t-Bu) 3 followed by NaBH 4 /CeCl 3 .
Silylation followed by selenium dioxide oxidation converted 13 into 14. Epoxidation of the
derived TES ether proceeded by addition of oxygen to the more open face of the alkene, leading to
15. Ozonolysis followed by diastereoselective one-carbon homologation provided 17. This set the
stage for intramolecular epoxide opening by the carboxylate, to give 2, in which all of the
stereogenic centers of tetrodotoxin have been established.
Justin Du Bois of Stanford University has put forward (J. Am. Chem. Soc. 2003, 125, 11510. ) a
quite different total synthesis of tetrodotoxin, including an elegant late-stage introduction of the
nitrogen