(+)-Pleuromutilin is a fungal natural product that binds to the peptidyl transferase center of bacterial ribosomes, inhibiting protein synthesis as its mechanism of action. This tricyclic diterpene has been successfully modified through semi-synthesis to access more potent analogs such as the recently FDA-approved lefamulin, which is used for treating adults with community –acquired bacterial pneumonia. However, semi-synthesis provides an inherently restricted approach to incorporating variations in the structure of chemical matter. Thus, pleuromutilins remain limited in their spectrum of activity and susceptible to modifications in the ribosomal binding site that confer resistance. Previous studies have provided evidence that modifications of the core are well-tolerated in that fully synthetic analogs may retain biological activity. Here, we will describe our efforts in developing an efficient synthesis of pleuromutilin that may not strictly follow its natural substitution pattern, but will allow for the construction of a diverse library of simplified pleuromutilin analogs.In Chapter 1, we report a synthetic route towards simplified pleuromutilin antibiotic candidates that uses a key photochemical reaction to access the six-, eight-membered bridged ring system. We describe our efforts in optimizing steps in this route, including the conditions necessary for the [2+2] cycloaddition in the de Mayo-type reaction sequence. In Chapter 2, we report the synthesis of antibody-drug conjugates for the targeted degradation of cell surface proteins.