A Seven-Step Total Synthesis of (–)-Thebaine

Abstract

The morphinan alkaloid (–)-thebaine (1) is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, we report a seven-step total synthesis of this natural product from simple, commercially available starting materials. The pivotal substrate 13, which was obtained through successive Suzuki-Miyaura cross-coupling and Mitsunobu substitution reactions, was engaged in a double-Heck cyclization sequence. The tetracyclic product of these processes was subjected to a photochemical hydroamination reaction that generated compound 15, which embodies the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine (1).