Synthesis and target annotation of the alkaloid GB18.

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans 1-4 . Limited, variable supply of GB alkaloids 5 , however, has impeded their biological exploration and clinical development 6 . Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally dynamic pyridine. Reliable, gram-scale access to GB18 enabled its assignment as a potent antagonist of κ- and μ-opioid receptors-the first new targets in 35 years-and lays the foundation to navigate and understand the biological activity of Galbulimima metabolites.