Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis

New pleuromutilin-like compounds were synthesized in approximately 11 steps from 3-allylcyclopent-2-enone by a strategy featuring sequential carbonyl addition reactions. Several analogs possessing the C14 tiamulin ester side chain displayed activity in a Mycobacterium tuberculosis mc²7000 assay. The results described herein provide a basis for further efforts to expand the structural and stereochemical diversity of the pleuromutilin class of bacterial protein synthesis inhibitors through advances in chemical synthesis.