A Platform for the Production of Pleuromutilin and Core-Modified Derivatives

Abstract The structural complexity of pleuromutilin antibiotics has limited efforts to define aspects of the natural scaffold that are required for antibacterial activity. Here, we present a scalable synthetic platform that provides access to novel core-modified bicyclic pleuromutilins (BPs) and the natural tricyclic pleuromutilin skeleton from a common β-ketoester precursor. Structurally, BPs lack the cyclopentanone ring, C10, and C11 substituents, while retaining the 6/8 boat–chair framework, C22 extension, and C12 diversification vector. This approach proceeds through an advanced bis(sulfonate) intermediate, which can be prepared in 10 steps on a multigram scale. Diversification through a single-flask, 2-fold substitution then furnished >30 analogs. Among the analogs prepared, C12 carbamate derivatives possessed the most potent antibacterial activity, with selected analogs showing Gram-positive activity comparable to tiamulin and measurable activity against the Gram-negative pathogen Acinetobacter baumannii. Additionally, one analog had promising activity against cfr+Staphylococcus aureus, a clinically relevant pathogen that is resistant to ribosome-targeting antibiotics, including pleuromutilin itself. Additional derivatives showed activity against mycobacteria Mycobacterium avium and M. bovis. The route was further developed to enable new syntheses of (+)-mutilin and (+)-pleuromutilin. This platform enables synthesis-driven exploration of both minimal and fully elaborated pleuromutilin architectures.