Scalable and Divergent Total Synthesis of (+)-Colletoic Acid, a Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

An efficient and divergent total synthesis of (+)-colletoic acid, a selective 11-β hydroxysteroid dehydrogenase 1 (11-βHSD1) inhibitor, is presented along with its biological activity at the whole-cell level. A scalable, asymmetric synthetic strategy was designed featuring a diversity-oriented synthesis utilizing a diastereoselective intramolecular 5-exo-Heck reaction as the key step to provide the quaternary spirocenter intermediate 9 in multigram scale, thus establishing a platform for further structure–activity relationship studies and providing access to other acorane family members.