A route to potent, selective and biased salvinorin chemical space

Salvinorins are natural compounds that serve as templates for new analgesics, antipruritics, and dissociative hallucinogens by selectively activating the kappa-opioid receptor. Unlike most opioids, they lack basic amines and have complex structures that have hindered chemical modification. This work describes a short asymmetric synthesis using a sterically confined organocatalyst to enable a Robinson annulation of an unactivated nucleophile and unstable electrophile. Combined with a cobalt-catalyzed cycloaddition, the route provides access to a library of salvinorin analogs. The authors appraise the synthesis by generating multiple analogs that exceed the potency, selectivity, stability, and functional bias of salvinorin A itself.

Study at a glance

Abstract

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.