A route to potent, selective and biased salvinorin chemical space
Sarah Hill, Nathan Dao, Vuong Dang et al.
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.