Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Herzon, Seth

Abstract

In this thesis, I describe how we built upon the foundation of our previous totalsynthesis of (+)-pleuromutilin (1) and its C12 epimer (125) in order to produce a new, scalable, and generalizable route to novel pleuromutilins. (+)-Pleuromutilin (1), the namesake of this antibiotic class, has been extensively developed by semisynthesis, and several semisynthetic derivatives are in clinical use for the treatment of Gram-positive infections. Pleuromutilins are associated with slow rates of resistance development, and limited cross-resistance with existing agents. Thus, they hold promise to combat the growing problem of antibiotic resistance. The utility of many semisynthetic pleuromutilins is hindered by their poor solubility and metabolic stability. Streamlined access to novel pleuromutilin skeletons that address these shortcomings has remained elusive due to their complex structure. Herein, I review the extensive semisynthetic and total synthetic studies ofpleuromutilins and describe how we developed a platform for the production of fully synthetic derivatives. I demonstrate the modularity of our approach by the production and evaluation of seventeen distinct analogs, many of which bear modifications that cannot be introduced by semisynthesis. The synthetic route was enabled by the discovery of a novel vinylogous Wolff rearrangement and the application of a robust and diastereoselective addition of propargylic nucleophiles to an a-quaternary aldehyde. The work advances our understanding of the structure–activity relationships of pleuromutilin and points to exciting new directions for further development.

Download
COinS