Date of Award

2-2-1989

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

In Project 1 as part of an overall effort to synthesize modified nucleosides via organotransition metal chemistry, the nickel-catalyzed cross-coupling reactions between alkyl- and aryl-Grignard reagents and 6-chloropurine were investigated. A series of 6-substituted purine nucleosides have been made which may exhibit a considerable range of biological activity.Project 2 concerned the synthesis of nucleotide-insertanes as probes for transport; Part A specifically was related to macrocyclic ethers. Crown ethers were designed which, in addition to their intrinsic structural interest, were anticipated to be useful as synthetic intermediates, and as carriers for the transport of nucleotides through cell membranes. It was sought to synthesize derivatives which differed only in the atom(s) linking the side-arm crown ether (e.g., hydroxymethyl-15-crown-5) to the nucleotide phosphorus and to study the relative labilities of the bond between P and the heteroatom.Part B of the second project concerned nucleotide coupling reactions. Currently, 5$\sp\prime$-monophosphates are transported into cells with great difficulty. The goal was to create molecular structures that would facilitate transport of biologically significant molecules across cell membranes; specifically, modified or fluorescent nucleotides which had been linked to a series of moieties that would be rapidly incorporated into cellular lipid bilayers or membrane systems. A general contribution to the topic of biological transport was made.In Project 3, the reactions of cyanogen bromide with nucleosides and model compounds were dealt with. It was found that protected inosine reacts with BrCN to give N$\sp1$-cyano-2$\sp\prime$,3$\sp\prime$5$\sp\prime$-tri-O-(t-butyl-dimethylsilyl)inosine. Exploratory work was conducted because the product may either be synthetically useful for subsequent ring expansion reactions or be biologically active itself. N-Cyano-succinimide is labile to attack at the carbonyl by base or nucleophile, e.g., dimethyloxosulfonium methylide. Work was done to determine if this is a general new method for ring expansion of heterocycles and another route to the antibiotic coformycin.

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