The general hypothesis of this proposal is that cycloadducts from Diels-Alder reactions of dienes with transient acyl nitroso moieties, generated by oxidation of hydroxamic acids, can serve as versatile building blocks for syntheses of a number of important and often novel bioactive molecules. The specific aims include (1) methodology development and enhancement, and (2) applications to the syntheses and study of focused targets. Methodology enhancement will include hydroxamate, 1, and diene, 3, variation, alternative asymmetric methods, and determination of the scope and limitations of a new pi-allyl polarity reversal process that will significantly increase synthetic versatility. Applications will include both nucleophilic and electrophilic C-O bond cleavage of 4 with N-O bond retention, in both intermolecular and intramolecular processes; N-O bond cleavage to give substituted carbocycles 5; and C=C bond reactions to give 6 and other intermediates. Products from these reactions will be used to prepare focused sets of targets, including: novel 5-lipoxygenase inhibitors, neuraminidase inhibitors, benzodiazepines, diazepines, carbocyclic nucleosides and analogs (aristeromycin, carbavir, abacavir, stavudine, carbocyclic oxanosine, and their nor analogs, carbocyclic forms of polyoxins, sinefungin, nucleoside Q, puromycin and analogs), novel phosphodiesterase inhibitors, streptazolin, novel oxazolidinone antibiotics, diketopiperazines (tryprostatin analogs), novel amino acids and peptides related to bacterial diaminopimelic acids (DAP) as well as new amino acids and peptides that represent the first of a novel class of antibiotics. That this tremendous variety of targets can be accessed from the same set of precursors attests to the tremendous potential of readily available acylnitroso cycloaddition products for the design, synthesis and study of bioactive compounds, many of which will be novel.