Development of Novel Bioactive Alkaloids Based on Specific Reactions of the 4,5-Epoxymorphinan Framework

Abstract Morphinan alkaloids, such as morphine, codeine, heroin, and thebaine, are referred to as opioids and are pharmacologically important compounds. They are widely known to exhibit diverse pharmacological effects by acting on μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). Naltrexone, a commercially available 4,5-epoxymorphinan alkaloid, is a drug primarily used to manage alcohol and opioid dependence. From a pharmacological perspective, naltrexone is classified as an MOR antagonist. On the other hand, from an organic chemistry perspective, naltrexone contains a wealth of functional groups and possesses four consecutive asymmetric centers within a single molecule, giving rise to its unique chemical reactivity. While this reactivity may not be universally applicable, gaining a clear understanding of it is crucial for researchers working on the organic chemistry of morphinan alkaloids. In this account, we provide a comprehensive overview of our research findings over the past decade, with a particular focus on the specific reactions of the 4,5-epoxymorphinan framework. We hope this account will be useful for both organic synthetic and medicinal chemists. 1 Introduction 2 Influence of the E-Ring in the 4,5-Epoxymorphinane Framework 2.1 Reaction of the C6 Ketone with a Stabilized Sulfur Ylide 2.2 Reaction of the C14 Hydroxy Group with Thionyl Chloride 2.3 Reaction of the C14 Hydroxy Group with Acetic Anhydride 2.4 Reaction of 14-Aminonaltrexone with Acetic Anhydride 2.5 Baeyer–Villiger-Type Oxidation of the 4,5-Epoxymorphinan 2.6 Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan 2.7 Unique Rearrangement of Morphinan Into Arylmorphan 3 Synthesis of Bioactive Compounds Based on 4,5-Epoxymorphinan 3.1 Synthesis of (–)-Galanthamine 3.2 Synthesis of (–)-Homogalanthamine 4 Summary