The Huang lab has a longstanding interest in understanding the mechanisms that underlie the therapeutic effects of AMPK modulators such as metformin and berberine (1, Figure ), and have uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation that is accompanied by modulation of the anti-microbial peptide (AMP)controlled gut microbiota. 2c Given how metabolic intermediates of berberine are similarly bioactive or may be the active forms following oral administration, we hypothesized that the rarer biosynthetic precursors of berberine, such as prepseudopalmatine (2), 8oxypseudopalmatine (3), and stepharotudine (4) could also exert AMPK modulation activity. Unlike berberine, protoberberine alkaloids resembling 2-4 make up minor components of the Magnoliaceae, Ranunculaceae, Berberidaceae, and Menispermaceae families of plants and are not accessible to the biomedical community. We have thus devised a convergent strategy to prepare natural and unnatural protoberberine analogs de novo highlighting methodologies developed in the Kou lab. The strength of this synthesis strategy compared to others 7 lies in its modularity in enabling derivatization of all four rings within the protoberberine scaffold. Compounds 2-4 and their derivatives were envisioned to arise from tetracyclic intermediate 5. We imagined disconnecting ring B of the tetracycle through a novel 6π-aza-electrocyclic transform, thus simplifying the structure to dihydroisoquinolone 6, which can be assembled directly from silyl enol ether 7 and hydroxamic ester 8 by oxidative C-H functionalization. This strategy led to the preparation of thirteen protoberberine-type alkaloids to survey the structureactivity relationship (SAR) with respect to AMPK modulation. We found that the absence of the cationic charge imposed by the quaternized nitrogen (i.e., berberine) stymies AMPK activation ability, and the neutral protoberberines synthesized in this study represent novel examples of AMPK inhibitors.