Bioinspired Scalable Total Synthesis of Opioids

As one of the largest and most representative families of natural medicines harvested from plants, the mass production of opioids legitimately occupies large, worldwide farmland cultivation of opium poppies, causing severe regulation limitations and supply uncertainty. Due to their complex structures, the chemical synthesis of opioids has been criticized as infeasible for large-scale production in view of lengthy synthetic steps and overall low efficiency. Here, we report a practical and scalable total synthesis of oxycodone, codeine, and related opioids by imitating the biosynthetic dearomatization arene coupling reaction, which allowed efficient preparation of a key thebaine-like core on a decagram scale. For the synthesis of oxycodone and codeine, less than eight continuous operations and one column chromatography purification were required throughout the process, resulting in overall 11% and 13% yields, respectively. Our current synthetic approach has demonstrated potential application in the industrial manufacturing opioids. [GRAPHICS] .