Stereo- and Site-Selective Glycosylation Catalyzed by Bis-Thioureas

Abstract

Carbohydrates play numerous important roles in biological systems such as energy storage, structural support, and cellular recognition and signaling. Glycosylation of small molecules, peptides, and protein pharmaceuticals has shown significant potential for enhancing biodistribution by affecting molecular structure, hydrophilicity, stability, and bioavailability. With the goal of understanding the biological function of oligosaccharides, chemical glycosylation strategies have been developed to control the stereochemical outcome of sugar couplings. Glycosylation involves coupling partners that are stereochemically complex and densely functionalized, and the reactivity and stereoselectivity of glycosylation strongly depend on the identity of sugar coupling partners. Therefore, the development of a unified strategy for stereo- and site-control in the construction of glycosidic linkages presents a fundamental challenge. The dissertation presented herein describes the development of bis-thiourea-catalyzed stereo- and site-selective glycosylation of carbohydrates and complex pharmaceuticals under mild conditions.

In Chapter 1, we describe the current methods for the construction of β-1,2-cis glycosidic linkages and their limitations. Although high stereoselectivity can be achieved with current strategies, they employ coupling partners that require multi-step syntheses and highly Lewis acidic activation conditions. We also review the state-of-the-art strategies for catalyst-controlled site-selective glycosylation. Although cis-diols can be easily distinguished by current methods and undergo stereoselective glycosylation with excellent site-control, site-selective glycosylation of trans-diols still presents a fundamental challenge.

In Chapter 2, we describe the development of highly β-selective, bis-thiourea-catalyzed 1,2-cis-O-pyranosylations employing easily accessible acetonide-protected donors to address the limitations of current methodologies. A wide variety of alcohol nucleophiles, including complex natural products, glycosides, and amino acids were β-mannosylated and rhamnosylated successfully using an operationally simple protocol under mild and neutral conditions. Less nucleophilic acceptors such as phenols were also glycosylated efficiently in excellent yields and with high β-selectivities. Computational analysis supports our proposal that the enhancement in β-selectivity observed with acetonide protection is achieved by the acceleration of a stereospecific SN2-type pathway promoted by the bis-thiourea catalyst.

In Chapter 3, we describe catalyst-controlled, highly stereo- and site-selective glycosylations for the construction of β-1,2-trans and β-1,2-cis glycosidic linkages. The development of catalysts that effectively engage in CH/π interactions with glycosidic nucleophiles was critical for controlling site-selectivity. Kinetic and computational studies provided evidence that catalyst-controlled site-selectivity is achieved by stabilizing the rate-limiting transition state through attractive noncovalent interactions.