Date of Award

Spring 1-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Herzon, Seth

Abstract

In the first chapter, I describe the development of a modular synthetic route that allows for the de novo synthesis of novel pleuromutilin analogs, including analogs with modified cores. (+)-Pleuromutilin (11) is a diterpene fungal metabolite that displays moderate antimicrobial activity against Gram-positive pathogens. Semisynthetic modifications of 11 resulted in derivatives with improved activity and pharmacological properties. However, the majority of derivatization studies have focused on modifying the periphery of the molecule. Studies on the impact of structural modifications to the tricyclic core have been limited as this type of diversification is inaccessible via semisynthesis. Herein, I outline our development of a new platform to access C12-normethyl pleuromutilin analogs. I demonstrate how we employed this sequence to access seventeen structurally diverse analogs including those possessing modified cores. Finally, I present our evaluation of the antimicrobial activity of the seventeen analogs accessed. This work delivers new insight into the structure–activity relationships of pleuromutilins and provides a platform for the further development of novel derivatives.In the second and third chapters, I present our work toward the total synthesis of (−)-lomaiviticin A (324). The lomaiviticins are a class of dimeric genotoxic metabolites containing a unique diazotetrahydro[b]benzofluorene core, whose structures were reassigned in 2021. Despite immense efforts, no member of the lomaiviticin family has been accessed synthetically. In the second chapter, I present our synthesis of the fully glycosylated monomeric unit of lomaiviticin A (325). Our route featured a site- and stereoselective α-alkylation–radical cyclization strategy to build the tetracyclic skeleton, the stereocontrolled introduction of both 2-deoxyglycosides and a direct diazo transfer to an electron-rich benzoindene. Additionally, I outline our biological evaluation of the monomer 325 in cell viability assays. In the third chapter, I report our synthetic efforts toward (−)-lomaiviticin A (324), along with the advantages and pitfalls of various dimerization strategies to install the sterically congested bridging carbon–carbon bond. Our work features an oxidative dimerization strategy toward 324, which provided a dimeric diazofluorene in a stereocontrolled manner, as well as the examination of a Giese-type radical dimerization and exploration toward a diazene-directed fragment assembly. The work in this thesis informs the current strategy toward 324 being explored in our laboratory.

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