Stereoselective Glycosylation: Mechanistic Insights and Applications

Nature employs carbohydrates as an integral source of structural biodiversity across all organisms. It is understood that the biological properties of these natural products can be fine-tuned via alteration of glycosidic patterns, particularly with respect to stereochemistry. Paradoxically, robust strategies for the stereoselective synthesis of carbohydrates are limited in the literature. This Thesis is concerned with methodology development for the stereoselective preparation of synthetically challenging 1,2-cis-glycosides. Herein, a highly α-selective methodology for galactosidation is reported, employing an orthogonal para-nitro-substituted benzoate protecting group at position 4 of the galactosyl donor substrate. The success of this 4-O-ester-mediated strategy using an electron-deficient substituent was contradictory to prevailing literature hypotheses, such as reaction via a stereodetermining dioxolenium cationic intermediate. Comprehensive mechanistic investigation, through experimental and computational means, revealed a H-bonded beta-glycosyl triflate transition state that was responsible for stereoinduction. Galactosyl α-1,2-, -1,3-, -1,4- and -1,6-linkages bearing a range of orthogonal functionalities were prepared in up to exclusive α-selectivity and 84% isolated yield, including one gram-scale example. The utility of this methodology was exemplified in the α-selective syntheses of a trisaccharide as well as a target mucin-derivative. This 4-O-(para-nitrobenzoate)-mediated strategy was then applied to the preparation of biologically relevant α-fucosides. Exclusive α-selectivities were maintained across the synthesis of orthogonally protected fucosyl α-1,3-, -1,4- and -1,6-linkages in up to 72% yield. This methodology was employed for the α-selective synthesis of a fucosyl trisaccharide, and progress was made towards the preparation of a target Lewis antigen derivative. Preliminary mechanistic studies revealed that a H-bonded β-glycosyl triflate transition state, analogous to that observed for α-galactosylation, was likely not operative in the corresponding α-fucosylation. An organocatalytic strategy for the stereoselective synthesis of 1,2-cis-glucosides was then investigated, using inexpensive 2-thiouracil as the catalyst (Scheme 3). 2-Thiouracil was found to activate a glucosyl trichloroacetimidate donor in 20% conversion and alpha/beta = 76:24 in a preliminary study. It was posited that this glycosylation occurred via a Brønsted acid mode of activation.