Synthetic Studies on Carbocyclic Nucleosides

The focus of this dissertation research was to develop efficient synthetic approaches to carbocyclic furanose nucleosides, which play an important role in the discovery for new anti-cancer, anti HIV and anti tuberculosis drugs. Chapter one provides a brief review of biologically interesting carbocyclic nucleosides classified by the ring size of the corresponding carbocycles and the strategies that were widely applied in the synthesis of carbocyclic furanose nucleosides. In Chapter two, four synthetic strategies to carbocyclic nucleosides were explored. They all started with cyclopentadiene and take full advantages of hetero Diels-Alder reactions or epoxidation and palladium catalyzed allylic substitution reactions. An aldehyde-cyclopentadiene strategy led to successful syntheses of carbocyclic analogs nucleosides A 500359s and an efficient synthesis of racemic aristeromycin as well as some derivatives of carbocyclic uridine. Nitroso-cyclopentadiene chemistry was utilized to synthesize unnatural amino acids and carbocyclic analogs of the nucleoside moiety in norascamycin. Norcarbovir and norabacavir were efficiently synthesized based on the cyclopentadiene-epoxide strategy, and their anti-cancer and anti-HIV activities were studied. The next chapter presents all of the asymmetric approaches involved in this project. Efforts toward developing a catalytic enantioselective acylnitroso Diels-Alder reaction and asymmetric palladium-catalyzed allylic substitution on mono epoxide of cyclopentadiene are discussed. Asymmetric aza Diels-Alder reactions were performed and the application of auxiliary chiral sulfinyl groups in this reaction was explored. Enzymatic resolution with Candida antarctica lipase B gave access to both enantiomers of a highly functionalized lactone for use in asymmetric syntheses of carbocyclic nucleosides in excellent optical purity.