Neoclerodane plant metabolite salvinorin A potently and selectively agonizes the <i>kappa</i> opioid receptor (KOR), which causes profound but short-lived dissociative hallucination in humans. This activity has recently attracted attention for treatment of resistant depression (TRD) and post-traumatic stress disorder (PTSD). Here we disclose an asymmetric synthesis of stabilized salvinorin A analogs via a short sequence from bulk materials. The synthesis reaches a diversifiable enone intermediate within nine steps and allows unprecedented exploration of salvinorin A chemical space, specifically aryl analogues at C12 and ketone derived analogues at C17. Highlights of the synthesis include a cobalt-catalyzed Diels-Alder cycloaddition followed by an asymmetric Shi epoxidation to form the A ring, an intramolecular Robinson annulation to form the B and C rings, and a Hayashi conjugate addition to diversify at the aryl ring. Chiral-at-P ligands were necessary to overcome the native Fürst-Plattner-like selectivity of the 1,4-conjugate addition. From the targeted enone, several analogues were generated and are being assayed for KOR potency and selectivity.

Asymmetric synthesis and diversification of a stabilized salvinorin A scaffold

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