Here we present a platform for the total synthesis of pleuromutilins that provides access to diverse derivatives bearing alterations at previously inaccessible skeletal and peripheral positions. Pleuromutilins (antibiotics based on the fungal metabolite pleuromutilin) have remained resistant to this approach, in large part due to the difficulties encountered in the de novo construction of the decahydro-3a,9-propanocyclopentaannulene skeleton. Tetracyclines, macrolides, streptogramins and lincosamides are now accessible through flexible and general synthetic routes. The emergence of drug-resistant bacterial pathogens has placed renewed emphasis on the total chemical synthesis of novel antibacterials.