New Synthetic Applications of Nitroso Diels-Alder and Ene Chemistry

The focus for this dissertation involved the development of new synthetic applications of nitroso Diels-Alder (NDA) reactions and nitroso ene reactions. Three projects have evolved from this main research theme. In chapter 3, the stabilized iminonitroso Diels-Alder reaction, particularly the pyridinylnitroso Diels-Alder reaction, is demonstrated to be a remarkably efficient method for derivatization and functionalization of diene-containing natural products. Three structurally and biologically unique diene-containing natural products, including ergosterol, leucomycin A7, and colchicine were found to react with pyridinylnitroso agents in a highly efficient, and regio- and stereo-selective fashion. Further chemical derivatizations of the nitroso cycloadducts were investigated. Broad biological evaluations of novel analogs were also performed, suggesting that the nitroso heterocycles changed the biological activity profile of the parent natural products. The syntheses of streptazolin analogs as lipophilic antibiotics, were also attempted. In chapter 4, Lewis acid-mediated ring-opening reactions of nitroso cycloadducts are described. Indium triflate was demonstrated to be an efficient Lewis acid in promoting ring-opening reactions of various nitroso cycloadducts. Hydroxylamine containing cycloalkenes were selectively generated through the C-O bond cleavage when iminonitroso or acylnitroso cycloadducts were treated with indium triflate in the presence of alcohols. In direct contrast, indium triflate-mediated ring-opening reactions of nitrosobenzene-derived cycloadducts gave exclusive aromatic alkoxylated syn-1,4 aminocycloalkenol products through a nucleophilic aromatic substitution pathway. In chapter 5, an unprecedented ene reaction using iminonitroso agents is presented. The allyl hydroxylamine ene products were obtained in various yields and with high regioselectivity. A solid phase supported iminonitroso ene reaction as well as asymmetric nitroso ene reactions were also investigated. Three amino acid-derived hydroxamic acids were synthesized, and their use in diastereoselective acylnitroso ene reactions was also investigated. In chapter 6, 2-(N-hydroxy amino)-pyridine containing compounds, obtained from nucleophilic ring-opening reactions of nitroso cycloadducts as well as iminonitroso ene reactions, are shown to be a novel chemical scaffold, selectively active against Gram-positive Micrococcus luteus. Preliminary structure-activity relationship studies were also conducted. Several lead compounds with low micromolar levels of activity were identified.