Computational and experimental studies of reactive intermediates in glycosylation reactions

Remmerswaal, W.A.

Carbohydrates, or sugars, are the most diverse and most abundant biomolecules known. However, the isolation of carbohydrate samples in sufficient amounts and purity is often impractical or even impossible, so the chemical synthesis of glycosides becomes relevant. The glycosylation reaction, in which a glycosidic linkage is constructed from two glycosyl building blocks to form more complex (oligo)saccharides, is a central reaction in this endeavor. The most common approach to chemically create glycosidic bonds is a nucleophilic substitution reaction between a glycosyl acceptor containing a nucleophilic alcohol, and a glycosyl electrophile (donor) carrying an anomeric leaving group. When this anomeric leaving group is activated by a promotor, this leads to an equilibrium of reactive intermediates. The stability and reactivity of these species strongly determine which intermediate acts as the dominant reactive intermediate. Covalent reactive intermediates provide more SN2-like...Show moreCarbohydrates, or sugars, are the most diverse and most abundant biomolecules known. However, the isolation of carbohydrate samples in sufficient amounts and purity is often impractical or even impossible, so the chemical synthesis of glycosides becomes relevant. The glycosylation reaction, in which a glycosidic linkage is constructed from two glycosyl building blocks to form more complex (oligo)saccharides, is a central reaction in this endeavor. The most common approach to chemically create glycosidic bonds is a nucleophilic substitution reaction between a glycosyl acceptor containing a nucleophilic alcohol, and a glycosyl electrophile (donor) carrying an anomeric leaving group. When this anomeric leaving group is activated by a promotor, this leads to an equilibrium of reactive intermediates. The stability and reactivity of these species strongly determine which intermediate acts as the dominant reactive intermediate. Covalent reactive intermediates provide more SN2-like reactions, while more dissociated intermediates give rise to SN1-like reactions. Although both SN2- and SN1-like reactions can give rise to both the α and β anomer, the stereoselectivity of these reactions is greatly determined by the nature of the reactive intermediates and the incoming nucleophile. The research described in this thesis aims to characterize reactive intermediates that dictate the stereoselectivity of glycosylation reactions.
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Computational and experimental studies of reactive intermediates in glycosylation reactions

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