An Oxidative Dearomatization Approach to Tetrodotoxin via a Masked ortho-Benzoquinone

Progress toward a stereoselective synthesis of tetrodotoxin (TTX) is presented. Oxidative dearomatization of a tetrasubstituted guaiacol arene yielded a masked ortho-benzoquinone that intercepted an acyl nitroso species generated in situ by the copper-catalyzed aerobic oxidation of an acyl hydroxylamine. The subsequent alkene dihydroxylation and reduction of a bis-neopentylic ketone proceeded with perfect diastereoselectivity to reveal advanced intermediates toward the synthesis of TTX.

Automated summary

Progress towards achieving a stereoselective synthesis of tetrodotoxin (TTX) is demonstrated in this research. By conducting oxidative dearomatization of a tetrasubstituted guaiacol arene and subsequent alkene dihydroxylation and reduction of a bis-neopentylic ketone, advanced intermediates towards the synthesis of TTX were successfully obtained with perfect diastereoselectivity.