Synthesis of Natural Morphinans and Development of Related Alkaloids

Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. All these opioid drugs produce their biological actions through three receptor types, µ, δ, and κ, belonging to the G-protein-coupled receptor family. Currently, used opioid analgesics also share a number of severe side effects, limiting their clinical usefulness. The chemically highly versatile structure of morphine and its related natural alkaloids has continuously engaged the interest of pharmaceutical and medicinal chemistry research, aiming for the synthesis and identification of numerous semi- and synthetic opioid ligands as safer therapeutic agents or with novel therapeutic properties and with lesser unwanted side effects with the final goal to reduce complications and to improve patient compliance. This review provides the first total synthesis reported in 1952 and focuses on representative examples of various derivatives and interesting approaches for the development of structurally correlated molecules with substitutions at different rings position leading to preclinical and clinically valuable opioids.