Development and Synthetic Applications of Anion Relay Chemistry Tactics — Design, Synthesis and Validation of Small-Molecule Mimics of the Immune Cell Receptor Cd4

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Doctor of Philosophy (PhD)
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Anion Relay Chemistry
Natural product
Organic Chemistry
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This thesis comprises two independent Parts. Part I describes the implementation of Anion Relay Chemistry (ARC) tactics in the synthesis of natural products and natural product precursor scaffolds. Chapter 1 discusses the design and execution of a unified strategy exploiting ARC Type I and Type II four- component fragment unions for the synthesis of natural products of the Cryptocarya family. The ARC tactics play here a pivotal role in generating, in a single flask, structurally elaborate synthetic intermediates from relatively simple, readily accessible starting materials, leading to increased efficiencies in the construction of the chosen synthetic targets compared to previous reports. Chapter 2, in turn, describes the validation of a Type II ARC protocol permitting the stereocontrolled introduction of a propionate unit in tricomponent adducts via a new aldehyde “linchpin,” followed by an application in the construction of a putative C16-C29 segment of natural product rhizopodin. Part II describes the synthesis and structure-based optimization of small-molecule mimics of CD4, a receptor that mediates infection of immune cells by Human v Immunodeficiency Virus (HIV). Chapter 1 describes the development of a synthetic route for the stereoselective, scalable preparation of compound JP-III-048, a small-molecule CD4 mimic that had exhibited promising activity in HIV entry inhibition assays. Structural modifications guided by crystallographic and computational data ultimately leading to both more potent and more broadly active analogues are discussed in Chapter 2. Extensive studies by our collaborators have led to the discovery that these small molecules have the capability of sensitizing both viral particles and infected cells to neutralization by the immune system. These findings are discussed in Chapter 3.

Amos B. Smith, III
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