Progress toward the Synthesis of Novel Bicyclic Analogs of Pleuromutilin Antibiotics

Abstract

The pleuromutilin antibiotics are intriguing compounds due to their novel mechanism of action against several drug-resistant strains of bacteria, including MRSA. While three pleuromutilin drugs have been licensed for human or veterinary use, their total synthesis is made difficult by the compounds’ unique tricyclic structure. Here, an attempt is made to simplify the synthesis of pleuromutilin-like molecules and expand the range of pleuromutilin derivatives screened for biological activity by preparing novel bicyclic analogs of the veterinary antibiotic tiamulin. Computational studies revealed that although removal of tiamulin’s eight-membered ring causes conformational changes in the active regions of the molecule, select nonpolar substitutions at C11 and C14 affect molecular geometry. Though efforts to synthesize a methylated bicyclic scaffold were unsuccessful, the corresponding demethylated compound was used to attempt to synthesize a series of bicyclic tiamulin analogs. Several routes utilizing carbonyl chemistry were probed to reach the targets. Ultimately, synthetic efforts produced a key precursor to a tiamulin-like bicyclic molecule. Recommendations for future work, including further diversification of the bicyclic tiamulin library from the identified intermediate, are made.