Total Synthesis of Aporphine Alkaloids via Benzyne Chemistry: Progress Towards a Late-Stage Enantioselective Hydrogenation and Neuroprotective Activity Evaluations

A dehydroaporphine intermediate obtained via benzyne chemistry was used to accomplish the enantioselective total synthesis of (S)-nuciferine, the first total synthesis of (& PLUSMN;)-urabaine, and our second-generation total synthesis of lysicamine. (S)-Nuciferine was obtained by an unprecedented late-stage asymmetric hydrogenation employing a chiral iridium(I) catalyst. The first total synthesis of (& PLUSMN;)-urabaine and the second-generation total synthesis of lysicamine, which exhibited low cytotoxicity and neuroprotective activity, were completed by oxidation reactions in 7 and 6 steps, respectively. The enantioselective total synthesis of (S)-nuciferine, the first total synthesis of (& PLUSMN;)-urabaine, and our second-generation total synthesis of lysicamine were accomplished employing a dehydroaporphine intermediate obtained via benzyne chemistry, an unprecedented late-stage asymmetric hydrogenation, and oxidation reactions. Lysicamine and (& PLUSMN;)-urabaine presented low cytotoxicity and promising neuroprotective activity.image

Automated summary

A dehydroaporphine intermediate obtained via benzyne chemistry was used to accomplish the enantioselective total synthesis of (S)-nuciferine, the first total synthesis of (& PLUSMN;)-urabaine, and our second-generation total synthesis of lysicamine. Low cytotoxicity and promising neuroprotective activity were observed for lysicamine and (& PLUSMN;)-urabaine.