A route to potent, selective and biased salvinorin chemical space

28 April 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The salvinorins serve as templates for next generation analgesics, antipruritics and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically-confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile / unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability and functional bias of salvinorin A itself.


chiral phosphoric acid
total synthesis

Supplementary materials

Supporting Information
Experimental procedures, copies of NMR spectra, X-ray structure reports, full outlines of prior syntheses and all pharmacological protocols.


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