Bioinspired Total Synthesis Of Opioids

Opioids derived from Papaver somniferum are a series of alkaloids including naturally occurring morphine(1),codeine(2)and semi-synthetic oxycodone(8),naloxone(9),naltrexone(10)and nalbuphine(11),which possess significant narcotic and analgesic activities.Typically,opioids are characterized by their intricate pentacyclic skeletons containing five continuous chiral centers including one quaternary carbon center.There have been 37 reports of successful opioids syntheses since the Gates team published the first total synthesis of morphine in 1952,which demonstrates the extraordinary charm of organic synthesis.It’s not only of academic significance to carry out synthetic research toward opioids,but also an important direction for the development of efficient,economical and environmental-friendly opioid production methods.The content of this thesis was divided into three parts: Chapter one briefly summarized the background information of opioid research;Chapter two discussed the exploring work of constructing the opioid pentacyclic skeleton by developing the dearomatization arene coupling reaction;Chapter three discussed the bioinspired total synthesis of opioids.The successful synthesis commenced with the condensation of the primary amine and the carboxylic acid,which are derived from commercially available syringaldehyde and isovanillin,respectively.The resulting amide underwent a Bischler-Napieralski cyclization followed by an Iridium catalyzed asymmetric hydrogenation to afford the chiral tetrahydroisoquinoline-type product 240.After removing the protection group,an innovative palladium catalyzed dearomatization coupling was used as the key step to realize the biomimetic transformation of the tetrahydroisoquinoline-type compound 242 into a salutaridine-type framework 243.Finally,the pentacyclic skeleton of opioids was constructed via a dehydration cyclization and several functional-group manipulations,which led to the asymmetric total synthesis of oxycodone(8),naloxone(9),naltrexone(10),nalbuphine(11)and naturally occurring morphine(1),codeine(2).This research work accomplished the bioinspired total synthesis of a series of opioids by developing innovative synthetic methodologies with the idea of imitating opioids’ biosynthetic process,which would provide a possible solution for seeking more economical and environmental-friendly production methods of opioids.