Decagram-Scale Synthesis of GB13 and Remodeling to the Galbulimima Alkaloids

Abstract Plants in the genus Galbulimima (GB) produce a series of neuroactive alkaloids that have proven impractical to obtain and study by isolation or chemical synthesis. The role of GB extracts in traditional Papuan medicine and ritual suggests that one or more alkaloids reach the brain by ingestion; identification of potent muscarinic and opioid receptor antagonists among the GB alkaloids reinforces this idea. The remaining congeners include CNS depressants, antispasmodics, and an unidentified entheogen, but each scaffold currently requires a unique synthesis route, slowing target identification and optimization. Here, we derive a solution to 11 GB alkaloids across three classes via late-stage functionalization and scaffold remodeling of 12.97 g of GB13, which we synthesize in a single pass─a 1000-fold increase over prior best (12 mg). Exhaustive study of GB alkaloid reactivity navigates complex rearrangements, twisted olefin intermediates, and C–H functionalizations catalyzed by palladium and osmium─ultimately delivering short, efficient routes that now allow functional interrogation.