Chemical syntheses of the salvinorin chemotype of KOR agonist†
Covering: 2000 to 2020
The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future.