to effect 6π-electrocyclic ring closure following NaHmediated N-O bond cleavage. When cyclization precursor 11d was subjected to NaH in deuterated DMF, deprotected isoquinolone 34 was observed as the sole product with 27% deuterium-labeling at the internal site of the alkene (Scheme 3a). Prolonged heating led to a mixture of monodeuterated isoquinolone 34-d1 and dideuterated 8oxypseudopalmatine 3-d2 in a 2.2:1 ratio in favor of the acyclic intermediate. Incorporation of deuterium into the alkene is rationalized to occur by 6π-azaelectrocyclization, deuteration by DMF-d1, and basemediated 6π-electrocyclic ring-opening or elimination. Extended exposure to NaH and heat would promote cyclization to dideuterated 3-d2. These observations are consistent with the DFT calculations that suggest azaelectrocyclization to be endergonic. Under KOt-Bu catalysis conditions, electrocyclic ring-closure to 8oxypseudopalmatine 3-d1 is irreversible due to KOt-Bu's lower basicity (Scheme 3b). In contrast to dideuteration of the tetracycle, only monodeuterated 3-d1 is generated from protonation by t-BuOH or the isoquinolone that are more acidic than DMF. Past mechanistic studies on reactions involving KOt-Bu in DMF generally invoke singleelectron transfer pathways; 30 however, the current deprotection/6π-aza-electrocyclization sequence is better consistent with a polar 2-electron pathway, proceeding under air, inert atmosphere, and in the presence of TEMPO (see SI). The base-mediated anionic 6π-aza-electrocyclization reported herein is distinct from and complementary to the acid-mediated 6π-aza-electrocyclization for benzoquino-Scheme 4. C-H functionalization/Suzuki/anionic aza-6πelectrocyclization sequence en-route to aminoprotoberberine with C-ring derivatization. line synthesis 31 and C-H alkenylation/6π-electrocyclization cascade for dihydropyridine synthesis. 32 2.4. Modification of the Protoberberine C-Ring: Restoration of AMPK Activation Activity. Contrary to previous reports of protoberberine synthesis, the present modular and convergent strategy stands out as the sole method capable of modifying all four rings of the tetracyclic scaffold, thereby facilitating the preparation of diverse analogs. Schemes 1a and 1b show rings A and D being modified by starting with various readily accessible silyl enol ethers 7 and hydroxamic esters 8 as coupling partners. While this study focused on introducing a vinyl group by Suzuki cross-coupling, incorporating substituted alkenes would generate novel B-ring analogs. Distorted Bring analogs 4-iso and 20-iso were formed as minor side products and isolated for bioassays; however, they can be deliberately synthesized by Markovnikov hydration of the vinyl group, followed by cyclization. The oxidative C-H functionalization of N-methoxybenzamides with silyl enol ethers was necessary to access natural protoberberines without substitution on the alkene of the C-ring. This strategy is also amenable in employing related C-H functionalization reactions with the broader class of internal alkynes to generate C-ring analogs. 34 This is exemplified in the synthesis of aminoprotoberberine 40 (Scheme 4). The annulative coupling between ynamide 35 and Npivaloylbenzamide 36 yields aminoisoquinolone 37 in 57% yield. Despite the additional sulfonamide group, Suzuki cross-coupling to append on the vinyl substituent proceeds in 69% yield. Since the N-O bond is cleaved in the C-H functionalization step, aza-6π-electrocyclization can be initiated by treating isoquinolone 38 with catalytic KOt-Bu, presumably forming anionic intermediate 39 en-route to the target tetracycle (40) in 37% yield (51% brsm). Western blot analysis revealed that C-ring modification with a sulfonamide group restored AMPK activation (see SI).