Methodology Development and Syntheses of Biologically Relevant Molecules from Acylnitroso Cycloadducts: Access to Benzodiazepines and Carbocyclic Nucleosides

New methodologies were developed and used to synthesize novel benzodiazepines with anti-cancer activity and carbocyclic nucleosides. Appropriatelyfunctionalized acylnitroso-derived hetero-Diels-Alder cycloadducts were subjected tointramolecular allylation chemistry to give benzodiazepines. Novel allyl alkyl malonatesystems, also derived from acylnitroso-derived hetero-Diels-Alder cycloadducts, weresynthesized and subjected to decarboxylative allylation reactions en route tohomocarbocyclic nuleosides.

In chapter one, palladium catalyzed allylic additions are introduced and the progression of the chemistry is summarized. Recent advances in the literature relating to allylic alkylations with in situ generated enolates are highlighted. In chapter two, the biological activity of several relevant carbocyclic nuleosides is explored and various synthetic strategies to the molecules and their analogs are discussed. Chapter three describes the intramolecular palladium(0)-mediated ring openings of acylnitroso-derived cycloadducts with emphasis on the syntheses of benzodiazepines. Progress towardsdiazepine analogs and pyrrole containing tricycles is also explored.

In chapter four, decarboxylative allylations of allyl 2,2,2-trifluoroethyl malonates is described. The reaction gives access to homoallylic esters in a single transformation. The homoallylic esters are used as key intermediates in the syntheses of several homocarbocyclic nuleosides, which are discussed in chapter five. The decarboxylativeallylations of allyl 2,2,2-trifluoroethyl malonates were the key steps en route to 5'-homocarbocyclic nucleoside core structures. Carbonucleosides 5'-homocarbovir, 5'-homoabacavir, epi-4'-homocarbovir, epi-4'-homoabacavir, and 5'-homoaristeromycinwere synthesized in order to further investigate their activity profiles in antiviral assays.

In chapter six, the use of in situ generated titanocene monochloride (Cp₂TiCl) as areducing agent for diverse N-O bonds is discussed. The method was applied tosynthesize a key benzodiazepine intermediate and as a key step in the synthesis of eachcarbocyclic nucleoside target molecule. Finally, a brief summary of synthetic accomplishments and an analysis of the biological activity of various molecules are given.