Scalable and modular synthesis enables pharmacological diversification of salvinorins

Salvinorin A is an atypical opioid characterized by a non-nitrogenous scaffold and potent, selective κ-opioid receptor (KOR) agonistic activity. Its distinctive pharmacology has motivated studies of pain and neuropsychiatric function, but structural complexity and limited synthetic access have constrained mechanistic investigation and pharmacological optimization. Here we report concise and scalable syntheses of EOM-salvinorin B and salvinorin A, together with modular access to 28 new analogs. Temporary skeletal rewiring generates a pyrone that enables photochemical construction of the congested C9 all-carbon quaternary center while directly furnishing a versatile intermediate for diversification at the underexplored C17 position. Notably, C17 substitution yielded potent, selective ligands with distinct signaling bias, binding kinetics and pharmacokinetic behavior. Replacing the C17 carbonyl with an aminomethyl group yielded an ultrapotent analogue with delayed onset and sustained antinociception, contrasting with the rapid, short-lived action of SalA and EOM-SalB, with no locomotor impairment detected under the tested conditions. This work establishes a modular synthetic platform that expands the accessible salvinorin chemical space, providing a foundation for further biological studies.