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Dissertation/Thesis Abstract

Thio-arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation of Chemical Glycosylations
by Li, Xiaoning, M.S., The University of Toledo, 2007, 132; 10835934
Abstract (Summary)

Oligosaccharides are usually found as protein or lipid conjugates in cellular systems. They play crucial roles in many biological processes. Among many approaches, organic synthesis is a very important way to obtain the desired oligosaccharides for biological studies. To date, no general synthetic procedures are available for oligosaccharide synthesis. Laborious synthetic transformations are generally required in order to obtain the desired regio- and/or stereo-selective control in oligosaccharide synthesis, due to their diverse and complex structures and many chemical equivalent hydroxyl functional groups. To achieve a rapid synthetic routine with high yields, a key step - glycosylation in oligosaccharide synthesis needs to be well understood. Thus an insight into the mechanism of glycosylation will provide valuable information potentially leading to the development of generalized glycosylation method.

In this work, kinetic properties of glycosylation were evaluated by model reactions between three different series of glycosyl donors and three different glycosyl acceptors. The glycosylation mechanism was analyzed in the context of a linear-free energy relationship. In order to do that, three series of glycosyl donors and one glycosyl acceptor were synthesized and the Relative Reactivity Values (RRVs) of these donors were then determined by HPLC competitive assay. Hammett plots were plotted using obtained RRVs. A linear correlation was found that allows an accurate prediction of glycosylation reactivities. The negative slopes of the Hammett plots (ρ-values) show that electron donating substituents increase the rate of the reactions and the magnitudes of slopes can be rationalized by neighboring group participation and electronic properties of the glycon protective groups. RRVmethanol values (using methanol as acceptor under standardized reaction conditions) have been employed as a quantitative measure to guide the design of building blocks with requisite anomeric reactivities for reactivity based chemoselective glycosylation. We extensively studied glycosylation reactivity by varying the reaction conditions such as by using different carbohydrate acceptors, glycosylation promoters, solvent or by quenching reaction at different time. Our results indicate that the reactivity differential was found to be dependent upon the identity of the acceptor with the less reactive carbohydrate acceptors resulting in lower reactivity differential. This result points out that the rate determining step of glycosylation reaction should involve the nucleophilic attack of the acceptor onto oxacarbenium ions or similar reactive intermediates as deduced from Hammett plots. The solvent could also play a role in varying the relative reactivity between two glycosyl donors. However, the RRVs were consistent under different promoter activation or by quenching at different reaction time. The electron density of sulphur atom on glycosyl donor and the bonding energy between glycosyl donor and promoter were found as qualitative indicators for RRVs. The knowledge gained from our results can provide valuable insights into further improvement of the powerful chemoselective armed-disarmed glycosylation methodology and understanding of chemical glycosylation in general.

Indexing (document details)
Advisor: Huang, Xuefei
School: The University of Toledo
Department: Chemistry
School Location: United States -- Ohio
Source: MAI 57/05M(E), Masters Abstracts International
Subjects: Chemistry
Keywords: Glycosylation, Hammett plot, Hplc competitive assay, Oligosaccharide, Rate determining step, Relative reactivity value
Publication Number: 10835934
ISBN: 978-0-355-97074-6
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