Bioinspired total synthesis of (+)-pleuromutilin

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Natural Products Synthesis

Background:

• (+)-Pleuromutilin is a natural antibiotic with a complex tricyclic structure.
• Its antibacterial activity and unique framework make it a target for total synthesis.
• Existing synthetic routes may be limited in scope or efficiency.

Purpose of the Study:

• To develop an efficient total synthesis of (+)-pleuromutilin.
• To establish a practical route to (+)-12-epi-mutilin.
• To expand the synthetic toolbox for complex natural products.

Main Methods:

• Total synthesis inspired by the natural biosynthetic pathway.
• Key reactions include t-BuOK-catalyzed Michael addition, LiDBB-promoted reductive coupling, and Zn-mediated Barbier reaction.
• Synthesis initiated from (+)-pulegone.

Main Results:

• Achieved total synthesis of (+)-pleuromutilin in 18 steps.
• Achieved total synthesis of (+)-12-epi-mutilin in 16 steps.
• Successfully constructed the 5/6/8 tricyclic skeleton and key quaternary center.

Conclusions:

• The developed synthetic strategy is efficient and practical.
• Provides a valuable new entry to (+)-pleuromutilin and (+)-12-epi-mutilin.
• Demonstrates the utility of bioinspired approaches in complex molecule synthesis.