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

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. Zwölf Stufen führen von β‐Bromethylbenzol zu ent‐Hydromorphon. Als Schlüsselschritte dieser kurzen Synthese sind eine oxidative Desaromatisierung, die anschließende [4+2]‐Cycloaddition zur Bildung des Morphinan‐B‐Rings und eine intramolekulare Aminierung an C9 hervorzuheben. Boc=tert‐Butoxycarbonyl, TBS=tert‐Butyldimethylsilyl.