Utilizing C-H functionalization and anionic aza-6πelectrocyclization strategies developed in our lab, we have orchestrated a concise and convergent strategy that generates diverse protoberberine natural and unnatural products with derivatization at all the A, B, C and D rings. De-rivatives with electron-donating groups on the D-ring tend to be unstable to purification. In the process, we have uncovered nucleophilic hydride reactivity elicited by NaH in DMF and in the absence of external additives such as NaI. The natural product stepharotudine (4) was synthesized for the first time. Traditionally, protoberberine derivatives have been developed and studied under the presumption that they act as AMPK activators, as evidenced by several studies and patents 37 focused on their potential use in treating diabetes. However, our findings challenge this paradigm by demonstrating that many protoberberines are AMPK inhibitors, a previously unappreciated property. This insight opens new avenues for the biomedical relevance of these compounds, particularly in areas where AMPK inhibition could be therapeutically beneficial. Furthermore, we found that incorporating a sulfonamide group into the C-ring restores AMPK activation, providing a novel insight for future explorations of berberine-derived AMPK modulators. There is currently substantial interest in advancing AMPK activators for obesity, diabetes, and liver illnesses, and we envision that the advancement of AMPK inhibitors will have novel therapeutic applications in cancer treatment, controlling autophagy, and elderly wasting.