An Overview of Syntheses of Salvinorin A and its Analogues

Salvinorin A is a powerful hallucinogen in humans and a selective, high-efficacy agonist of the kappa-opioid receptor. It is the first plant-derived ligand with high selectivity for this receptor, and its structure is unrelated to other opioid receptor ligands, lacking any nitrogen. Its synthetic access is challenging due to a highly sensitive epimerizable center at carbon 8. Only nine completed syntheses have been achieved to date. This review summarizes the key strategies used in these syntheses, from Evans in 2007 to Barriault in 2023.

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Abstract

AbstractSalvinorin A is a powerful hallucinogen in humans, and a selective, high efficacy agonist of the kappa‐opioid receptor (κ‐OR). Salvinorin A is the first plant‐derived ligand with high selectivity for κ‐OR over other receptors, its structure is unrelated to any known opioid receptor ligands, even lacking any nitrogenous moieties. Mechanistically and pharmacologically, salvinorin A is distinct from other known hallucinogens in humans, making it the only selective κ‐OR ligand to gain wide‐spread interest outside of research. Structurally, salvinorin A bares a highly functionalized trans‐decalin core, containing two quaternary centers, and is fused to a δ‐lactone baring a furan moiety. Synthetic access of salvinorin A has been elusive due to a highly sensitive epimerizable center at carbon 8 (C8). All these features make salvinorin A a highly challenging synthetic target. With multiple synthetic efforts from around the world, only nine completed syntheses have been achieved to date. This review is intended to provide a look at the key strategies used to achieve the syntheses reported to date. We will summarize the efforts towards the syntheses of salvinorin A starting from Evans in 2007 to Barriault in 2023.