Issue 9, 2022

Concise total synthesis of opioids

Abstract

Morphine and its related alkaloids are among the most representative natural medicines that have benefited human beings for over two centuries. Industrial manufacturing of these therapeutically valuable and structurally fascinating molecules relies on farming of opium poppies, causing severe soil erosion and regulation issues. Despite the advances in the development of numerous biosynthesis and chemical synthesis methods, a truly efficient approach to opioids which is competitive in terms of cost with the current manufacturing protocol remains highly desirable. Here we present a concise total synthesis of opioids exemplified by (−)-codeine, (−)-oxycodone, (−)-naloxone, and (−)-naltrexone with by far the highest overall yields (16–34%) from readily available starting materials. Remarkably, central to the success of the present synthesis is the development of a Pd-catalyzed dearomatization arene coupling reaction using an inexpensive, air stable, and robust phosphonium ligand. This bio-inspired step constructs the tetracyclic morphinan core in a manner with excellent regioselectivity, efficiency, and scalability.

Graphical abstract: Concise total synthesis of opioids

Supplementary files

Article information

Article type
Research Article
Submitted
07 fev 2022
Accepted
12 mar 2022
First published
14 mar 2022

Org. Chem. Front., 2022,9, 2322-2327

Concise total synthesis of opioids

H. He, F. Xue, Z. Hu, P. Li, Q. Xiao, M. Zhang, F. Xue, D. Zhang, H. Song, X. Liu, Z. Zheng, S. Li, W. Zhong and Y. Qin, Org. Chem. Front., 2022, 9, 2322 DOI: 10.1039/D2QO00202G

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