Concise Total Synthesis of (−)-Codeine
Ayan Mondal, Souvik Pal, Arindam Khatua, Abhishek Mondal, Alakesh Bisai
Abstract
Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.