Open Access Dissertation
Date of Award
Professor Carl R. Johnson
Novel methodology for the synthesis of 3'-deoxy- and 2' ,3'-dideoxy-4' -C-alkyl nucleosides has been developed. The target nucleosides are of interest as potential antiviral agents. Crucial features addressed by the methodology are: the ability to synthesize nucleosides analogs with a variety on 4'-C-alkyl substituents; exceptional stereocontrol over the C4' stereogenic center; and a semi-convergent synthesis, allowing the late stage N-glycosylation of heterocyclic bases. Both 4'-C-alkyl substituent variety and control of the C4' stereocenter are addressed by introducing the alkyl substituents and establishing the stereogenic center in a cyclopentene precursor. These alkyl substituted cyclopentenes are prepared by carbonyl alkylation of a biocatalitically derived enantiopure cyclopentenone. Employing the appropriate alkyl nucleophile in the alkylation of the cyclopentenone allows the introduction of a variety of alkyl substituents with exceptional stereocontrol. The five carbons of the alkyl substituted cyclopentene are then exposed as the five continuous carbons of a 4 -alkyl ribose analog by oxidative olefin cleavage. The 4-alkyl ribose analogs prepared in the fashion described above were then used to glycosylate a variety of heterocyclic bases by a Vorbrüggen type coupling. Providing complete β-selectivity in the formation of the N-glycoside. Adjustment of the C5' oxidation level then gives the 3'-deoxy-4'-C-alkyl nucleoside analogs. Deoxygenation at C2' by the method of Robins gave the 2' ,3' -dideoxy-4'-C-alkyl nucleoside analogs. Examples of target molecules prepared in this study include: 3'-deoxy- and 2' ,3' -dideoxy-4'-C-methyl analogs of uracil, 5-methyluracil, 5-fluorouracil, cytidine, 5-fluorocytidine, adenine and inosine; as well as, 3'-deoxy- and 2' ,3'-dideoxy-5-methyl-4' -C-phenyluridine.
Wells, Gregory William, "Synthesis of 3'-deoxy- and 2',3'-dideoxy-4'-C-alkyl-D-nucleosides: potential antiviral agents" (1998). Wayne State University Dissertations. 1220.