I. Synthesis of saturated, DNA, and RNA spirocyclic-4,4-nonane nucleosides. II. Studies toward epoxy carbonate formation and the synthesis of suitable precursors III. Methodological investigations involving the reactions of diazomethane with di-, tri-, an
Abstract (Summary)Nucleoside analogues, which can be incorporated into oligonucleotide chains, are of considerable current interest in the fight against cancer. When viral reverse transcriptase enzymes encounter the foreign nucleosides they are forced to shut down, therefore halting reproduction of the virus. Normal cellular enzymes, as they are often more complex, have the ability to “repair” the unnatural nucleosides and replication can continue. In this area of study we have designed a novel set of restricted nucleosides by spirocyclic annulation at C4' and insertion of a methylene unit in place of the furanoside oxygen. These two additions should generate enhanced duplex stability, increase lipophilicity relative to natual nucleosides, and augment resistance to cellular nucleases. These unnatural nucleosides also consist of an alcohol at position C5' of the added spirocycle, thus giving rise to two sets of diasteromers. The incorporation of all five free nucleoside bases into the spirocyclic framework at C1', which consisted of the DNA, RNA, and saturated skeletons, resulted in the synthesis of 30 novel unnatural nucleoside analogues. The second quarter of this thesis involves the synthesis of a relatively unknown functionality. This functionality consists of an epoxide and a carbonate, which share a central carbon. The epoxy carbonate was initially stumbled upon by accident en route to taxol, where DMAP and phosgene were added to a á,á'-dihydroxyketone in the hopes a carbonate would be generated. Since this new functionality had not yet been reported upon in the literature, it was the goal of this research project to determine the types of systems which could readily accommodate the strained moiety. These efforts included a novel synthetic strategy to form cis and trans á,á'-dihydroxycycloheptanone and á,á'-dihydroxycyclooctanone, which had also not been reported in the literature. The research led to the conclusion that epoxy carbonate formation relies upon the rigidity of the á,á'-dihydroxyketone and that the two alcohols must be trans, otherwise a sterically unfavorable cis epoxide or carbonate must be formed.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Date of Publication:01/01/2005