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

Abstract

AbstractThe morphinan alkaloid (–)-thebaine is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, a seven-step total synthesis of this natural product is reported from simple, commercially available starting materials. The pivotal aryl allyl ether substrate, which is 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 a N-Boc piperidine derivative embodying the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine.