Total Synthesis of (−)-Oxycodone via Anodic Aryl–Aryl Coupling

Abstract

A fully regio- and diastereoselective electrochemical 4a–2′-coupling of a 3′,4′,5′-trioxygenated laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (−)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

Organic Electrosynthesis: Applications in Complex Molecule Synthesis

“…Early studies by the Waldvogel laboratory have demonstrated that phenols can be electro‐oxidatively coupled to produce biphenols as well as polycyclic scaffolds . A related strategy was recently employed by the Opatz and Waldvogel groups in the syntheses of (−)‐thebaine and (−)‐oxycodone . Here, regio‐ and diastereoselective intramolecular anodic coupling of laudanosine derivatives afforded the corresponding morphinandienone motifs, which were further elaborated to the desired target structures (Schemes and ).…”

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

“…In 2019, Opatz and co-workers reported one of the most efficient and elegant total syntheses of (-)-oxycodone, using as key steps an electrochemical cyclization and an endoperoxidation photocatalyzed by TPP in an almost gram-scale (Scheme 38) [88].…”

‐Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis

“…Later, this general route was combined with anodic C−C aryl coupling to provide a biomimetic access to the natural product (−)‐thebaine ( 137 ) and the semisynthetic opioid (−)‐oxycodone (see Scheme ) . As starting materials for these syntheses, bromides 126 and 125 were prepared from methyl gallate 123 .…”