Selenium-Containing Glycosides and Glycosyl Phosphates as Precursors of Glycosyl Epoxides: New Approaches to the Synthesis of (5-Fluoro) and (5-Cyano) Glycosides.

Abstract

ABSTRACT Enzyme-catalyzed transformations of carbohydrates proceed through different transition states, which may be studied by altering the electron density at various positions of the carbohydrate ring. By placing fluorine near a developing partial charge of a donor substrate, the reaction may be inhibited due to destabilization of the transition state. The pKa of an acceptor alcohol is also lowered by fluorine, possibly affecting its nucleophilicity. Epoxide fluoridolysis has been previously used in our lab to synthesize (5-F) GlcNAc glycosides and glycosyl phosphates. This methodology involves a two-step process of oxidation of a phenylselenide to a selenoxide and thermal elimination with DHP. This thesis extends this fluoridolysis methodology to (5-F) isoLacNAc and (5-F) LacNAc glycosides and also investigates fluorination in the GalNAc series. Results from attempts at fluorination of the GalNAc glycosides have resulted in a premature epoxide opening hypothesis. This hypothesis was derived from differences in fluorination of glycosyl epoxides containing different neighboring protecting groups. In the pursuit of the (iso)LacNAc glycosides, selenium-containing monosaccharide acceptor substrates were unsuccessful in glycoside formation. In contrast, glycosylation of non-selenium containing monosaccharide acceptor substrates were successful in glycoside formation and were converted to selenium-containing disaccharides after glycosylation. The resulting selenium-containing disaccharides were then transformed into their corresponding epoxides and eventually into (5-F) isoLacNAc and (5-F) LacNAc glycosides. In addition to studying fluorinated glycosides, formation of a new stable C-C bond has been investigated. This new transformation would increase functionality on the carbohydrate ring by installing a CN group at C-5. The CN group was installed using a Lewis acid activator and TMS-CN in cyanosilylation of glycosyl epoxides. This new method allows for subsequent reduction of the CN functional group to an amine, which could then be transformed into a probe of carbohydrate metabolizing enzymes.