Expeditious Access to Morphinans by Chemical Synthesis

• Published in: Angewandte Chemie International Edition Vol. 61; no. 27; pp. e202203186 - n/a
• Main Authors: White, Lorenzo V., Hu, Nan, He, Yu‐Tao, Banwell, Martin G., Lan, Ping
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 04.07.2022; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkaloids; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Climate change; Codeine; Medicine; Opiates; Palladium Catalysis; Photo-Redox Chemistry; Physical Sciences; Piperidine; Reaction time; Science & Technology; Supply chains; Total Synthesis; Work capacity; Total Synthesis; Alkaloids; ALKENES; Opiates; Palladium Catalysis; Photo-Redox Chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202203186

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven‐step, asymmetric chemical synthesis of (−)‐codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo‐redox hydroamination protocol provides a novel, atom‐economical means for assembling the piperidine D‐ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N‐demethyl codeine. Our work highlights the capacity for contemporary, stand‐alone chemical synthesis regimes to diversify access to essential opiate medicines. A benchmark chemical synthesis of codeine creates an opportunity to diversify essential opiate‐medicine supply chains. The brevity of this approach derives from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot, while a subsequent photo‐redox hydroamination protocol is deployed to provide a novel, atom‐economical means for assembling the morphinan piperidine D‐ring.