Synthesis and target annotation of the alkaloid GB18

Abstract

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 alkaloids¹, however, has impeded their biological exploration and clinical development². 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 allowed its assignment as a potent antagonist of kappa- and mu- opioid receptors—the first new targets in 35 years—and lay the foundation to navigate and understand the biological activity of Galbulimima metabolites.