Assembly of a Key Dienic Intermediate for Tetrodotoxin via a Machetti–DeSarlo Reaction

A route
to a racemic diene intermediate for the synthesis of tetrodotoxin
is described. Key steps of the sequence leading to such a compound
include the oxidative amidation of a phenol, a Cu­(II)-catalyzed cyclocondensation
of a nitroketone with an olefin (Machetti–DeSarlo reaction),
and a nucleophilic fragmentation of the resulting isoxazoline. Several
unusual reactions encountered in the course of this study are thoroughly
discussed.