Organic Chemistry

Synthesis and target annotation of GB18

Authors

Abstract

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans. Only a single target, the muscarinic acetylcholine receptor, has been assigned. Limited, variable supply of GB alkaloids has im-peded their biological exploration and clinical development. Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to the challenging tetrahedral attached-ring motif re-quired 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 and lay the foundation to navigate and understand the biological activity of Galbulimima metabolites.

Content

Thumbnail image of GB18 ChemRxiv.pdf

Supplementary material

Thumbnail image of GB18 Supporting Information.pdf
Supporting Information
Full experimental section and notes, calculations, python code, biological data (raw and processed), spectra, x-ray crystallographic data