Stereo- and Regioselective Glycosylation

Abstract

Whereas highly practical chemical methods for the synthesis of polypeptides and polynucleotides are well established and in common use, glycan synthesis remains a challenging endeavor largely reserved for specialists in sugar chemistry. Glycosylation reactions are fundamentally challenging relative to peptide and nucleotide couplings, which involve non-stereogenic linkages that are not strongly affected by the identity of the specific reacting partners. Sugar couplings engage highly variable, stereochemically complex, and densely functionalized reacting partners, while generating a new stereocenter in the glycosidic linkage. Glycosylation methods that can be applied easily and broadly would be greatly enabling to research in the role of sugars in biological chemistry and medicine. The dissertation presented herein describes the development of bis-hydrogen bond donor catalysts that perform stereo- and regioselective glycosylation reactions under mild conditions across a broad range of coupling partners. In Chapter 1, we review the emerging field of catalyst-controlled glycosylation, which seeks to develop simple, mild, and general strategies for regio- and stereoselective glycosidic bond construction. This chapter focuses on seminal examples in the literature where catalyst structure has a demonstrated effect on anomeric and/or regioselectivity of glycosylation. In Chapter 2, we report that a bis-thiourea catalyst promotes β-selective glycosylation reactions of phosphate donors under mild, neutral conditions. The catalytic method enables glycosylation of peptides, complex natural products, and pharmaceutical agents bearing a variety of reactive functionality, thereby representing an important step toward enabling convenient access to glycosylated chemical matter. This reactivity capitalizes on a proposed dual-activation mechanism whereby the catalyst activates both the electrophile and nucleophile simultaneously through general base-general acid interactions. In Chapter 3, the unique reactivity of bis-thioureas to catalyze glycosylation reactions between phosphate donors and protic acceptors is used to generate cis-1,2-β-linkages. While no reported method can access these linkages across multiple donor-acceptor pairs, our mild and catalytic approach robustly generates β-mannosides, and β-rhamnosides from easily prepared starting materials. In Chapter 4, we describe the design of bis-thiourea catalysts to control both the stereo- and regioselectivity of a glycosylation reaction. On the basis of the mechanistic hypothesis in Chapter 2, we modulate the putative general base of the catalyst through steric and electronic tuning to control both the regio- and stereoselectivity of several glycosylation reactions. Notably, increasing the electron richness of a key catalyst aromatic group improves regioselectivity in glycosylation reactions, consistent with a CH-π interaction being important in recognition and selectivity.