Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4+2] Cycloaddition/Amination Sequence

Abstract

A short synthesis of ent-hydromorphone has been achieved in twelve steps from β-bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis-dihydrodiol, Mitsunobu coupling with the ring A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.