Date of Award

1-1-1987

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

In order to facilitate the transport of a nucleotide across an artificial lipid bilayer, different amines were conjugated to the phosphate group of adenosine 5$\sp\prime$-phosphate. The effect of the amine conjugation was to enhance the lipophilicity of the consequent adenosine 5$\sp\prime$-phosphoramidate derivative.The synthesis of various nucleoside 5$\sp\prime$-phosphoramidate analogs have been investigated, using different methodologies. Adenosine 5$\sp\prime$-phosphoromorpholidate, 5$\sp\prime$-phosphor(adamantyl)amidate, (n-decyl)amidate, (n-stearyl)amidate, and (1,4,7,10,13-pentaoxo-16-azacyclooctadecyl)amidate were synthesized by adopting Moffatt and Khorana's procedures. Among these phosphoramidate analogs, the adamantyl, aza-18-crown-6, and stearyl derivates have never been reported before. These amine-nucleotides were prepared by refluxing a reaction mixture of the corresponding amine (4 fold excess), adenosine 5$\sp\prime$-phosphate, and N,N-dicyclohexyl-carbodiimide (DCC; 4 fold excess) in 50% aqueous t-butyl alcohol.Morpholine was the only amine that gave a complete conversion of the starting material to the desired product. Anion exchange chromatography involving DEAE Sephadex resins was used to purify the final phosphoramidate analog. The crown ether amine, 1,4,7,10,13-pentaoxo-16-azacyclooctadecane, was prepared via ditosylation of tetra-ethylene glycol, nucleophilic attack of the consequent ditosylate by N-benzyldiethanolic dianion, and subsequent debenzylation of the monoaza-18-crown-6 derivative.$\epsilon$-adenosine and $\epsilon$-adenosine 5$\sp\prime$-phosphate have been prepared by treatment of either adenosine or adenosine 5$\sp\prime$-phosphate with aqueous chloroacetaldehyde at pH 4.30, which could be obtained from acid hydrolysis of chloroacetaldehyde dimethylacetal. In addition, $\epsilon$-adenosine 5$\sp\prime$-phosphoromorpholidate was synthesized via Mukaiyama's oxidation-reduction condensation scheme.Other synthetic investigations included preparation of 5-chlorotubercidin and silacrown compounds. Analogous to 5-bromotubercidin, 5-chlorotubercidin was synthesized by direct chlorination of tubercidin with N-chlorosuccinimide in N,N-dimethylforamide solvent. The synthesis of 3-aminopropylmethylsila-14-crown-5 was accomplished via transetherification of 3-aminopropylmethyldiethoxysilane and tetraethylene glycol.The synthesized adenosine 5$\sp\prime$-phosphoramidate analogs are being used in ongoing transport studies. The results of the transport investigation will be reported by another researcher in the near future.

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