The novel neoclerodane diterpene Salvinorin A is the most potent naturally occurring hallucinogen. It has been reported to be the first subtype selective opioid ligand. In a screening against an array of receptors, Salvinorin A inhibited only kappa-opioid receptors (KORs). The activation of KORs has been documented to induce a wide range of behavioral effects, including sedation and perceptual distortions. Given its high selectivity, Salvinorin A could be used to investigate the precise role of KORs in the modulation of human perception. This has promoted interest in the development of a concise chemical synthesis of Salvinorin A. The synthetic scheme proposed for Salvinorin A should construct the molecule in an efficient manner. The key step is an intramolecular double Michael reaction, which assembles the tricyclic core and five of the seven stereocenters. A chiral bis(oxazolinyl) copper(II)-catalyzed vinylogous aldol condensation and a chirl auxiliary-mediated aldol reaction will be used to install the remaining two stereogenic centers. A late stage intermediate is readily amenable toward the preparation of analogues for use in a structure-activity relationship study.
