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Synthesis and target annotation of the alkaloid GB18

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Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans1–4. 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.

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Correspondence to Ryan A. Shenvi.

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This file contains Experimental procedures, spectral data, biological assay data, chemical informatics data and code, references, crystallographic data.

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Woo, S., Shenvi, R.A. Synthesis and target annotation of the alkaloid GB18. Nature (2022).

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