Bioinspired total synthesis of (+)-pleuromutilin.

(+)-Pleuromutilin, a natural antibiotic, possesses an intriguing and complex 5/6/8 tricyclic skeleton with densely packed functional groups. It attracts extensive attention in the field of total synthesis due to its promising antibacterial activity and distinctive structural framework. Here we report the total synthesis of (+)-pleuromutilin inspired by its biosynthetic pathway, which expands the available toolbox, particularly by providing a practical and efficient entry to (+)-12-epi-mutilin. The key steps of the synthesis include a t-BuOK-catalyzed Michael addition to establish the C9 quaternary center, a LiDBB-promoted reductive coupling to construct the five-membered ring, and a bioinspired Zn-mediated Barbier reaction to connect C11 and C12, ultimately enabling the construction of the eight‑membered ring. Starting from (+)-pulegone, we accomplish the total synthesis of (+)-pleuromutilin in 18 steps and (+)-12-epi-mutilin in 16 steps, respectively.