Synthesis of Protoberberine Alkaloids by C–H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors

5’-Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis, and its activation has garnered attention for treating chronic metabolic diseases. Inhibitors of AMPK are underdeveloped but bear implications in treating cancers, controlling autophagy, and elderly wasting. Protoberberine alkaloids are typically regarded as AMPK activators. Herein, we report a modular synthesis strategy to access a collection of oxyberberine alkaloids, including the first synthesis of stepharotudine. In vitro assays reveal how subtle structural modifi-cations can negate AMPK activation while conferring unprecedented inhibitory properties within the same class of com-pounds, which was previously unknown. Key steps in the synthesis include an oxidative Rh(III)-catalyzed C–H function-alization using electron-rich alkenes, NaH-mediated reductive N–O bond cleavage, and the first example of an anionic aza-6π-electrocyclization. Additionally, we provide mechanistic support for nucleophilic hydride transfer reactivity with NaH in DMF.