Synthesis of Optically Active Nucleosides, Nucleotides and Oligonucleatide Analogues
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The main goal of this project was to synthesize various kinds of polynucleotide analogues that contained either 1,3-dioxane or 1,4-dioxane sugar moiety and several optically active nucleoside analogues that containing 1,3-dioxalane or 1,4-dioxane sugar moiety. In Chapter 1, a general introduction of nucleic acids and synthetic polynucleotide analogues, oligonucleotide analogues as well as nucleoside analogues is summarized. In Chaper 2, a short summary of the objective of the research is described. Chapter 3 presents the results of synthesis of polynucleotide analogues containing a polyvinyl alcohol backbone. Water soluble homo-base polynucleotide analogues were synthesized in which polyvinyl alcohol and partially phosphonated polyvinyl alcohol constituted the backbones. Nucleic bases uracil and adenine were grafted onto the polymer backbone via 1,3-dioxane spacers. The temperature versus UV-absorbance of these polynucleotide analogues were investigated and discussed. Chapter 4 shows the synthesis of uracil nucleoside analogue 5-U containing a 1,3-dioxolane sugar analogue and attempts of synthesis of the corresponding adenine nucleoside analogue 5-A. Uracil was reacted with 2-bromo-1,1-diethoxyethane to afford 1-(2’,2’-diethoxyethyl)uracil 2, which coupled with diethyl L-tartrate to provide uracil nucleoside analogue 7 containning the 1,3-dioxolane dicarboxylate. Dicarboxylate uracil nucleoside analogue7 was further reduced to give the desired uracil nucleoside analogue 5-U. Following the similar procedure, adenine nucleoside analogue 8 containning a 1,3-dioxolane dicarboxylate was synthesized. However, the reduction of 8 with sodium borohydride failed to give the desired nucleoside analogue 5-A. Chapter 5 presents the results of preparation of oligonucleotide analogues containing 1,4-dioxane ring with amide links. Starting from monoallylation of (2R,3R)-(+)-dimethyl tartrate, then ozonolysis, the sugar analogue 14 containing a 1,4-dioxane ring was prepared. Using the Vorbruggen coupling procedure, silylated uracil coupled with acetates 15, derivatives of 14, to provide uracil nucleotide analogues 16. Correspondingly, adenine nucleotide analogues 17 were synthesized by coupling silylated adenine with 20, the bromides of 15. Nucleotide analogues 16 and 17 condensed with ethylene diamine to provide corresponding water soluble oligonucleotides 22 and 23, respectively. In addition oligonucleotides 25 with an alternating sequence of the uracil and adenine nucleotide analogues were also synthesized via condensation of diamine 24a with the adenine diester monomer 17. Chapter 6 demostrates the synthesis of optically active nucleoside analogues that consist of a 1,4-dioxane ring, substituted with uracil or benzoyladenine and a 1,2-dihydroxyethyl substituent. Starting from allyl ether 11, after reduction, protection of vicinal diol, ozonolysis, the sugar analogues 28 were obtained. Using the Vorbruggen coupling procedure, silylated uracil was reacted with acetates 29, derivatives of 28, to afford uracil nucleoside analogues 30, which were further deprotected to give the desired nucleoside analogues 31. Correspondingly, compounds 40, triacetate derivatives of 28, were coupled with silylated N6-benzoyladenine to offer nucleoside analogues 41, which were further deacylated to give the desired N6-benzoyladenine nucleoside analogues 39. The corresponding dinucleotides 36 and 44 were further synthesized following the standard phosphorimidite procedure. Chapter 7 presents the results of formation of novel C-glycosidic nucleoside analogues containing a 1,4-dioxane sugar moiety. An intermediate 27, prepared from allyl ether 11, was iodocyclized to give a diastereomeric mixture of iodides 45, which were separated by flash chromatography to give trans- 45a and cis- 45b. Iodides 45a and 45b were reacted with uracil to afford the corresponding uracil nucleoside analogues 46a amd 46b, respectively. Correspondingly, adenine nucleoside analogues 52a amd 52b were also prepared. The acetal functions in compounds 46 and 52 were then removed using Amberlyst 15 in methanol providing the desired nucleoside analogues 48 and 53, respectively. Chapter 8 describes the synthesis of novel 1,3,5-triazine nucleosides containing 1,4-dioxane sugar moiety. Iodides 45a and 45b were reacted with sodium azide to give azides 58a and 58b, respectively. Subsequently hydrogenolysis of the azides provided the corresponding amines 57a and 57b, respectively. Amines 57 were reacted with 2- chloro-4,6-diamino-1,3,5-triazine, monosodium salt of 2-chloro-4,6-dihydroxy-1,3,5-triazine or 2,4-dichloro-6-amino-1,3,5-triazine to afford the various corresponding triazine nucleoside analogues. Chapter 9 presents all experiments and spectroscopic properties of novel compounds.