Boron-Catalyzed Regio- and Stereoselective Glycosylation via Fluoride Migration

Abstract

Carbohydrates play a crucial role in a variety of biological activities, such as molecular recognition, signal transduction, and intercellular adhesion. As one of the most omnipresent forms of post-translational modifications, glycosylation modulates a plethora of functions in physiological and pathophysiological states. Advances in glycosciences help to obtain a more profound understanding of disease and improve human health. However, the structural complexity arising from regioselectivity and anomeric stereochemistry poses a bottleneck for assembling complex oligosaccharides. Current limitations also include the use of stochiometric or superstochiometric amounts of activators and the requirement of drying agents. There is still a need in the field to develop new methodologies for constructing glycosidic linkages in a regio- and stereoselective manner.

In an effort to overcome the current limitations in the field of glycosylation, a boron-catalyzed glycosylation approach has been developed to construct glycosidic bonds using glycosyl fluorides as electrophiles and silyl ethers as nucleophiles. This approach is operationally simple and rapid, with a low catalyst loading of only 5 mol %. The reaction can be performed at room temperature and tolerate trace amounts of water. This work well covers a wide range of glycosyl donors and acceptors, such as glucose, mannose, galactose, and rhamnose. All possible stereochemical relationships of C1-C2 can be achieved by utilizing inter- or intramolecular strategies. Using neighboring group participation strategy, 1,2-trans glycosides can be obtained, while intramolecular aglycone delivery strategy, can be used to assemble 1,2-cis glycosides. Regioselectivity can be achieved by differentiating the size of the silyl protecting groups in the glycosyl acceptors. Taking advantage of this feature, one-pot iterative glycosylations were performed to assemble linear and branched trisaccharides. Furthermore, a complex hexasaccharide was synthesized in a total of four pots using this approach.

Among bioactive molecules containing carbohydrates, amino sugars are an important component, particularly 2-aminoaldohexoses and their corresponding N-acetyl forms. However, during the construction of the oligosaccharides, the formation of 2-methyl-2-oxazoline during the activation of N-acetyl glycosyl donors prevents efficient glycosylation of 2-acetamido-2-deoxy sugars. The 2-methyl-2-oxazoline moiety is highly stable even under harsh Lewis acid catalysis, requiring approaches utilizing 2-acetamido-2-deoxy glycosyl donors to use large amounts of activators and prolonged reaction time. To overcome this challenge, progress has been made by employing various other nitrogen protecting groups. However, the use of azido and phthalimdo protecting groups in glycosyl fluorides with the previously developed reaction condition promoted the reactions at the cost of stereocontrol. Then, 2,2,2-trichloroethoxycarbonyl (Troc) group has been employed in glycosyl fluorides to promote 1,2-trans glycosidic linkages with silyl ethers and B(C6F5)3 catalyst. Similarly, the relative reactivity of hydroxyl groups in glycosyl acceptors is governed by the silane structure rather than inherent reactivity. One-pot glycosylations were conducted to synthesize precursors of core structures of mucin-type O-glycans and human milk oligosaccharides.