Date of Award

Spring 1-1-2025

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 the first enantioselective synthesis of (–)-euonyminol (1), a heavily oxidized sesquiterpenoid. Structurally, (–)-euonyminol (1) features a tricyclic framework containing an all-carbon quaternary center and nine free hydroxyl groups. Following the initial failed attempts to achieve a semi-pinacol rearrangement of an allylic silyl ether, we developed a novel oxyalkylation reaction to establish the C10 quaternary center of 1. From this intermediate, we investigated three distinct strategies to construct the tricyclic framework of 1 employing a reductivecyclization, an aldol–dehydration sequence, and a radical cyclization reaction, respectively. Finally, a series of stereoselective transformations provided to (–)-euonyminol (1). Future development based on the route described may lead to the synthesis of other dihydro-β- agarofuran polyesters and macrocyclic terpenoid alkaloids, such as the cathedulins. In the second chapter, I present our investigation into the intramolecular alkene oxyalkylation reaction initially discovered during the synthesis of (–)-euonyminol (1). Our study showed that this reaction is general for a series of 6-oxa-bicyclo[3.2.1]-oct-3-ene derivatives and can proceed competitively with simple carbocyclic substrates. Mechanistic investigation suggested that the extent of charge separation in the transition state governs the product selectivity between cyclopropanation and oxyalkylation pathways. These findings can potentially lead to the development of a more general alkene oxyalkylation reaction. In the third chapter, I provide a comprehensive account of the isolation, structure elucidation, and biological evaluation of the lomaiviticins, a family of complex dimeric bacterial metabolites that contain diazofluorene and 2,6-dideoxy glycoside residues. I then detail MicroED, high-field NMR, and DFT studies that led to the structure revision of the lomaiviticins. In light of the structure revision, I reorganized previously published mechanism of action studies, integrating them with the revised structural assignment of lomaiviticin A (216). In the fourth chapter, I detail the development of a stereocontrolled synthesis of the fully glycosylated monomeric unit of (–)-lomaiviticin A (236). Key features of our synthesis include a decagram-scale synthesis of a naphthoquinone fragment, an alkylation–radical cyclization sequence to construct the tetracyclic framework of 236, and the stereocontrolled installation of the two 2,6-dideoxyglycoside residues employing a β-selective Koenigs–Knorr glycosylation and an α-selective Yu glycosylation, respectively. NMR studies of the synthetic 236 provided additional support for the structure revision. Biological evaluations revealed that 236 is not cytotoxic at concentrations below one micromolar. The route developed established a foundation for accessing other diazo-containing natural product, as well as the dimeric structure of (–)-lomaiviticin A (216). In the fifth chapter, I present our synthetic studies of (–)-lomaiviticin A (216), focusing on the strategies for constructing the bridging carbon–carbon bond. The discussion is organized around three key approaches: reductive dimerization, oxidative dimerization, and an “inside-out” strategy. Progress made, including the stereocontrolled synthesis of the dimeric structure 510, as well as obstacles encountered, are discussed in detail for each route. Finally, I will discuss how these findings can serve as a foundation for refining future synthetic efforts toward the total synthesis of (–)-lomaiviticin A (216), and briefly describe an ongoing synthetic effort.

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