The Synthesis of Mycobactin Analogs and Heterocyclic Scaffolds From Acylnitroso Hetero-Diels-Alder Cycloadducts

The focus for this dissertation involved two main projects that complement the known chemistry of acylnitroso hetero-Diels-Alder (HDA) reactions. The first project involved the synthesis of novel mycobactin analogs from nitroso HDA cycloadducts, and also included the discovery and study of a new synthesis of imidazoles. The second main project involved developing new ways to use acylnitroso HDA cycloadducts to synthesize biologically useful heterocyclic molecules.

In chapter 2, the rationale behind the synthesis of mycobactin analogs was described. In chapter 3, the synthesis of mycobactin analog fragments is described from amino acids and acylnitroso HDA cycloadducts. Chapter 4 described the assembly of mycobactin analog fragments into fully elaborated and deprotected 1,2-diol-containing mycobactin analogs. General strategies toward the synthesis of α-hydroxy carboxylate-containing mycobactin analogs were also presented as well as interesting results from biological assays on final molecules and intermediates.

In chapter 5, the discovery of a new method for synthesizing imidazole analogs of mycobactin fragments from azides and 2-amidoacrylates was described. The initial reaction, optimization of reaction conditions, and a limited study of reaction scope was presented as well as the results of biological assays performed on selected intermediates. This discovery provided a new method for synthesizing imidazole-containing mycobactin analogs as well as a general method for preparing 1-substituted- and 1,2-disubstituted-imidazole-4-carboxylates in three steps from serine, carboxylic acids, and azides.

Chapter 6 described the development of the addition of azides to acylnitroso HDA cycloadducts and the effect of alkene strain on reactivity. The scope of the reaction was investigated as well as conversion of the triazoline products to aziridines. The significance of this research as it related to the synthesis of aziridine- and triazoline-containing 5'-norcarbocyclic nucleosides and bioconjugation chemistry was also described.

In chapter 7, other ways of utilizing the acylnitroso HDA reaction were investigated. Preliminary results on addition of diazoalkanes to cycloadducts, Brønsted acid-catalyzed opening of cycloadducts, acylnitroso [2+2+2] homo-Diels-Alder reactions, and acylnitroso cycloadditions to indole ortho-quinodimethanes were presented. A discussion of their significance toward the synthesis of biologically useful molecules was also included.