Current issue cover. Courtesy of the research team
Concise total synthesis route for codeine (1). Courtesy of the research team
Recently, martin G. Banwell, academician of the Australian Academy of Sciences and dean of the Institute of Advanced and Applied Chemical Synthesis of the School of Pharmacy of Jinan University, has made significant progress in the field of total synthesis of morphine furan analgesics, and achieved the fast, efficient and concise synthesis of morphine with the shortest preparation process in history. The study was published in Angewandte Chemie and was selected as the cover paper for the current issue. Dr. Lorenzo White is the first author of the paper, Doctoral students Hu Nan and He Yutao are the second and third authors, and Academician Martin Banwell and Associate Researcher Lan Ping are co-corresponding authors.
Morphine furan analgesics act directly on the central nervous system, selectively reduce pain sensation in the human body, and are clinically used for acute or chronic pain. A total of nearly 1,000 tons of morphine analgesics have been produced worldwide in 2021, represented by morphine and codeine, which are widely used in clinical analgesia. At present, these analgesics mainly rely on the isolation and purification of opium poppies, and the production process is not easy to control, and it is vulnerable to climate-related disasters and geopolitical conflicts.
As the star molecule in the history of organic synthesis, the synthesis of morphine alkaloids is still challenging, and many world-renowned chemical laboratories have been committed to developing efficient and economical morphine synthesis processes. In published asymmetric total synthesis of morphine, the shortest steps are 15 steps and the longest is 31 steps, and none of the total synthesis routes have the potential for industrial application.
In this research work, the research team took the commercially available iodoisovacralin as the starting material, prepared the intermediate by Wittig enkenization reaction, and then reacted with the alcohol asymmetrically reduced and Suzuki coupled with the commercially available iodo 2-cyclohexenone to produce Mitsunobu reaction, and then constructed the morphine parent nucleus by one pot method (two Heck cyclization reactions), and then synthesized the piperidine ring structure by photocatalytic Redox reaction, and finally introduced the β-hydroxy of the allyl position to achieve morpholine alkaline. Asymmetric total synthesis of debutyline.
The process requires only 7 reaction steps, the total reaction time is only 24 hours, and the total yield is an unprecedented 12%. This is the shortest codeine total synthesis route to date, and the strategy developed by this work can greatly improve the efficiency of morphine drug synthesis, providing new opportunities for the large-scale industrial synthesis of controllable morphine drugs.
The relevant research work has been funded by the National Overseas Talents Program, the National Natural Science Foundation of China, the Foreign Young Talents Program of the Ministry of Science and Technology, and the Natural Science Foundation of Guangdong Province. (Source: China Science Daily Zhu Hanbin)
Related paper information:https://doi.org/10.1002/anie.202203186