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-, and tetraketones. IV. Towards the total synthesis of salicifoline

by 1978- Hartung, Ryan E.

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 ii taxol, where DMAP and phosgene were added to a ?,?'-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 ?,?'-dihydroxycycloheptanone and ?,?'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 ?,?'dihydroxyketone and that the two alcohols must be trans, otherwise a sterically unfavorable cis epoxide or carbonate must be formed. The third project was happened upon as a side reaction during the synthesis of the ?,?'-dihydroxycyclooctanone. It was discovered that when a diketone was reacted with diazomethane, a ketoepoxide could be generated. Although this reaction was present in the literature, there was relatively little research on the subject and the reactions presented did not attempt to cover the scope or limitations of the process. This project dealt with the reaction of a wide variety of di-, tri-, and tetraketones with diazomethane. In almost all the examples studied, a reaction occurred and interestingly, when the diketone was part of a strained ring system, ring expansion was seen to immediately follow carbon insertion. The last project I have attempted is the synthesis of the natural product salicifoline. Salicifoline was isolated from Euphorbia saliciforia in 2000. Herein is detailed the partial synthesis of intermediates A and B, where A is realized from a zirconium-mediated ring contraction of a synthetically modified sugar. iii