Synthesis of Tropono-β2,3-Amino Acid Derivatives via Benzene-to-Tropone Skeletal Editing

Abstract

Tropone-based cyclic β2,3-amino acids are rare nonproteinogenic amino acid scaffolds with limited synthetic tractability. Herein, we report a concise synthesis of tropono-β2,3-amino acid derivatives from readily available phenols and nitriles via oxidative dearomatization followed by a one-pot Michael addition/retro-6π electrocyclization/oxidation sequence. Control experiments and DFT calculations indicate a kinetically controlled ring expansion followed by rapid [1,5]-H shift leading to the thermodynamically favored anionic intermediate.